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The Gastrointestinal System

The Gastrointestinal
System at a Glance
SATISH KESHAV
The Gastrointestinal System at a Glance

The Gastrointestinal System
at a Glance
SATISH KESHAV
MBBCh (Wits), DPhil(Oxon), MRCP (UK)
Consultant Gastroenterologist
Director, Centre for Gastroenterology
Royal Free and University College Medical School
University College London
Rowland Hill Street
London NW3 2PF
Blackwell
Science
© 2004 by Blackwell Science Ltd
A Blackwell Publishing company
Blackwell Science, Inc., 350 Main Street, Malden, Massachusetts 02148-5020, USA
Blackwell Publishing Ltd, 9600 Garsington Road, Oxford OX4 2DQ, UK
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The right of the Author to be identified as the Author of this Work has been asserted in accordance with
the Copyright, Designs and Patents Act 1988.
All rights reserved. No part of this publication may be reproduced, stored in a retrieval system,
or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or
otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the
prior permission of the publisher.
First published 2004
Library of Congress Cataloging-in-Publication Data
Keshav, Satish.
The gastrointestinal system at a glance/Satish Keshav. — 1st ed.
p. ; cm.
Includes index.
ISBN 0-632-05472-7
1. Gastrointestinal system. 2. Gastrointestinal system — Diseases.
[DNLM: 1.–Digestive System. 2. Digestive System Diseases. WI 100
K42g 2003] I.–Title.
QP145.K447 2003
612.3¢2 — dc21
2003004942
ISBN 0-632-05472-7
A catalogue record for this title is available from the British Library
Set in 9/11.5 Times by SNP Best-set Typesetter Ltd., Hong Kong
Printed and bound in the United Kingdom by Ashford Colour Press, Gosport
Commissioning Editor: Fiona Goodgame
Managing Editor: Geraldine Jeffers
Production Editor: Fiona Pattison
Production Controller: Kate Charman
For further information on Blackwell Publishing, visit our website:
http://www.blackwellpublishing.com
Contents
Preface 7
Acknowledgements 8
List of abbreviations 9
Introduction and overview 10
Part 1 Structure and function
1 Mouth and teeth 12
2 Salivary glands 14
3Tongue and pharynx 16
4 Oesophagus 18
5 Stomach 20
6Duodenum 22
7 Pancreas 24
8 Liver 26
9 Biliary system 28
10 Hepatic portal system 30
11 Jejunum and ileum 32
12 Caecum and appendix 34
13 Colon 36
14 Rectum and anus 38
Part 2 Integrated function
15 Enteric motility 40
16 Enteric endocrine system 42
17 Enteric and autonomic nerves 44
18 Mucosal immune system 46
19 Digestion and absorption 48
20 Digestion of carbohydrates, proteins and fats 50
21 Digestion of vitamins and minerals 52
22 Nutrition 54
23 Fluid and electrolyte balance 56
24 Hepatic metabolic and synthetic function 58
25 Hepatic detoxification and excretion 60
Part 3 Disorders and diseases
26 Nausea and vomiting 62
27 Diarrhoea 64
28 Constipation 66
29 Functional disorders and irritable bowel syndrome 68
30 Gastro-oesophageal reflux and hiatus hernia 70
31 Peptic ulcer and Helicobacter pylori 72
32 Gastroenteritis and food poisoning 74
33 Gastrointestinal system infections 76
34 Ulcerative colitis and Crohn’s disease 78
35 Coeliac disease 80
36 Obesity and malnutrition 82
37 Colon and rectal cancer 84
38 Gastrointestinal, pancreatic and liver tumours 86
39 Haemorrhoids and anorectal disease 88
40 Gallstones and pancreatitis 90
41 Hepatitis and acute liver disease 92
42 Cirrhosis and chronic liver disease 94
Part 4 Diagnosis and treatment
43 Clinical assessment and blood tests 96
44 Endoscopy 98
45 Radiology and imaging 100
46 Functional tests 102
47 Pharmacotherapy 104
48 Gastrointestinal surgery 106
Index 109
5

7
Preface
How to use this book
This book presents a graphic scaffold for further detailed study and is an
aid to revision. Therefore, it will be useful for students approaching a
subject for the first time, particularly as part of an integrated systems-based medical curriculum. The diagrams will make abstract concepts
more memorable and help the student to recall details that might other-wise be lost in plain text. The student may further annotate the diagrams
with additional details from lectures, tutorials and self-directed study, to
help with later revision.
Organization of the book
The book is organized in four parts, starting with a structural and func-tional overview of the main components of the gastrointestinal system,
followed by consideration of integrated gastrointestinal function,
which requires some preceding basic knowledge. Clinical examples
are included throughout these early chapters highlighting the practical
importance of each subject.
The third and fourth sections are more clinical, and cover the most
important gastrointestinal and hepatobiliary diseases and the main
aspects of diagnosis and treatment. Fundamental pathophysiological
mechanisms are emphasized.
Anatomical and clinical detail
The anatomical diagrams are functional representations, and not exact
reproductions, and they are used to illustrate how structure supports
function.
Similarly, specific diseases are discussed to demonstrate pathogenic
mechanisms and general principles, rather than to provide exhaustive
detail. This book should be used to understand the normal physiology,
how it goes wrong in disease, and the principles underlying modern
clinical practice in gastroenterology and heptology.
Satish Keshav
8
Acknowledgements
I thank all the staff at Blackwell Publishing, particularly Geraldine
Jeffers and Fiona Goodgame who were endlessly patient, enthusiastic
and supportive. My students and colleagues provided inspiration,
pertinent questions and useful comments. I also thank Michael Stein,
who suggested this book, and Camilla and Vijay, who helped me to
complete it.
List of abbreviations
ACh acetylcholine
AFP a-fetoprotein
AIDS acquired immune deficiency syndrome
ALP alkaline phosphatase
ALT alanine transaminase
ANCA antineutrophil cytoplasmic antibodies
5ASA 5-aminosalicylic acid
ASCA antibodies to Saccharomyces cerevisiae
AST aspartate transaminase
ATP adenosine triphosphate
ATPase adenosine triphosphatase
BAT bile acid transporter
BEE basal energy expenditure
BMI body mass index
BMR basal metabolic rate
BSE bovine spongiform encephalopathy
Ca2+ ionized calcium
cAMP cyclic adenosine 3¢,5¢-cyclic monophosphate
CCK cholecystokinin
CD Crohn’s disease
CEA carcino-embryonic antigen
CFTR cystic fibrosis transmembrane regulator
cGMP cyclic guanosine monophosphate
CGRP calcitonin gene-related peptide
Cl- chloride ion
CO2 carbon dioxide
CoA coenzyme A
CRC colorectal cancer
CRP C-reactive protein
CT computerized tomography
CTZ chemoreceptor trigger zone
DA dopamine
DMT divalent metal transporter
DNA deoxyribonucleic acid
ECL entero-chromaffin-like
EHEC enterohaemorrhagic Escherichia coli
EPEC enteropathogenic Escherichia coli
ERCP endoscopic retrograde cholangiopancreatography
ESR erythrocyte sedimentation rate
ETEC enterotoxigenic Escherichia coli
FAP familial adenomatous polyposis
Fe2+ ferrous iron
Fe3+ ferric iron
GABA g-amino butyric acid
g GT g-glutamyl transferase
H+ ionized hydrogen
H2O water
H2R histamine receptor type 2
HCG human chorionic gonadotrophin
HCl hydrochloric acid
HDL high-density lipoproteins
5-HIAA 5-hydroxyindole acetic acid
HIV human immunodeficiency virus
HNPCC hereditary non-polyposis colon cancer
5HT 5-hydroxytryptamine
IBD inflammatory bowel disease
IBS irritable bowel syndrome
IF intrinsic factor
Ig immunoglobulin
IL interleukin
IMMC interdigestive migrating motor complex
IPSID immunoproliferative small intestinal disease
K+ ionized potassium
LPS lipopolysaccharide
MAD-CAM mucosal addressin-cell adhesion molecule
MEN multiple endocrine neoplasia
Mg2+ ionized magnesium
MHC major histocompatibility complex
MOAT multispecific organic anion transporter
MRA magnetic resonance angiography
MRCP magnetic resonance cholangiopancreatography
MRI magnetic resonance imaging
NA noradrenaline
Na+ ionized sodium
NAPQI N-acetyl-p-benzoquinone-imine
NO nitric oxide
NSAIDs non-steroidal anti-inflammatory drugs
OAT organic acid transport
PBC primary biliary cirrhosis
PET positron emission tomography
pIgA polymeric immunoglobulin A
POMC pro-opiomelanocortin
PSC primary sclerosing cholangitis
PT prothrombin time
PY peptide Y
RNA ribonucleic acid
SBP spontaneous bacterial peritonitis
SC secretory component
SGLT sodium–glucose co-transporter
sIgA secretory dimeric immunoglobulin A
STa heat-stable enterotoxin
TECK thymus and epithelial expressed chemokine
TGFb transforming growth factor b
TIPSS transjugular intrahepatic portosystemic shunt
TNFa tumour necrosis factor a
TPN total parenteral nutrition
tTG tissue transglutaminase
UC ulcerative colitis
USS ultrasound scanning
VC vomiting centre
VIP vasoactive intestinal peptide
VLDL very low-density lipoproteins
WHO World Health Organization
9
10 Introduction and overview
Functional anatomy
Diseases and disorders
Endocrine system
Blood
vessels
Mouth
Oesophagus
Peripheral
nerves
Central nervous
system
Digestion, absorption, nutrition
Stomach
Liver
Gallbladder
Hepatic portal vein
Pancreas
Small intestineColon
Rectum
Anus
Mucosa
Submucosa
Muscularis
Enteric
endocrine
cells
Epithelium
Immune
cells
Intrinsic
nerves
Extrinsic
nerves
Introduction and overview
10 Introduction and overview
Structure and function
The gastrointestinal system comprises the hollow organs from mouth to
anus that form the gastrointestinal tract, the pancreas, which mainly
secretes digestive juices into the small intestine, and the liver and biliary
system, which perform vital metabolic functions in addition to their con-tribution to digestion and absorption of nutrients.
The intestinal tract
A hollow tubular structure into which nutrient-rich food is coerced, and
from which wastes are expelled, is found in the most primitive multicel-lular organisms, from the hydra onwards. In humans, the tract is highly
specialized throughout, both structurally and functionally. The mouth
and teeth are the first structures in this tract and are connected by a pow-erful muscular tube, the oesophagus, to the stomach. The stomach stores
food after meals and is the site where major digestive processes com-mence. The small intestine is the main digestive and absorptive surface.
The large intestine acts mainly as a reservoir for food waste and allows
reabsorption of water from the mainly liquid material leaving the small
intestine. It is not essential for life and, paradoxically, is affected by a
number of common, serious diseases, such as inflammatory bowel dis-ease and colorectal cancer.
The pancreas
Digestive enzymes are produced in many parts of the gastrointestinal
tract, including the mouth (salivary glands) and small intestine (entero-cytes), although the exocrine pancreas is the most prodigious producer
of digestive enzymes. Pancreatic failure causes malabsorption, which
can be reversed by artificial enzyme supplements.
The liver and biliary system
Without the liver, survival is measured in hours, and no artificial system
has yet been devised to substitute for hepatic function. The liver is the
largest solid organ in the body and its essential functions include regula-tion of protein, fat and carbohydrate metabolism, synthesis of plasma
proteins, ketones and lipoproteins, and detoxification and excretion. Via
the hepatic portal circulation it receives and filters the entire venous
drainage of the spleen, gastrointestinal tract and pancreas. Through the
production of bile, it is also essential for digestion and absorption, par-ticularly of dietary fats and fat-soluble vitamins.
Integrated function
The gastrointestinal system is controlled by both intrinsic and extrinsic
neuronal and endocrine mechanisms. Enteric nerves and endocrine
cells are particularly important in coordinating motility, digestion and
absorption, and in regulating feeding and overall nutrition, including the
control of body weight.
The gastrointestinal system presents a huge surface area that has to be
protected against injury, particularly from microbial pathogens that are
ingested with food and from the large population of commensal bacteria
that populate the intestine. The mucosal immune system is critically
important in regulating how the intestine responds to these challenges,
providing protection and not reacting inappropriately to normal compo-nents of the diet.
Diseases and disorders
Nausea, vomiting, diarrhoea and constipation are common symptoms
and their basic pathophysiology illustrates important aspects of gas-trointestinal function.
Gastrointestinal symptoms are frequently not associated with any
discernible pathological abnormality. These medically unexplained
symptoms are often labelled functional disorders and, as our under-standing of gastrointestinal physiology becomes more sophisticated,
we may discover new explanations and treatments that are more
effective.
Gastrointestinal system infections are common and are associated
with significant morbidity and mortality worldwide. They range from
self-limiting food poisoning to life-threatening local and systemic infec-tions. Even peptic ulceration is most frequently caused by infection, with
the Helicobacter pylori bacterium.
For some major diseases, such as inflammatory bowel disease, the
aetiological agent has not been identified, despite rapidly advancing
genetic and molecular research. Conversely, coeliac disease, another
serious and common gastrointestinal inflammatory disease, is caused by
a well-characterized immune response to wheat-derived proteins.
Colon cancer is a major cause of cancer-related death and our molecu-lar and cellular understanding of its pathogenesis, and the pathophysiol-ogy of other gastrointestinal, pancreatic and liver tumours, is rapidly
increasing.
Liver damage is often caused by infections or drugs and may be acute
or chronic. Acute liver disease can rapidly progress to liver failure, or can
resolve, either spontaneously or with appropriate treatment. Chronic
liver disease may cause cirrhosis, which is characterized by a variety of
signs and symptoms and changes throughout the body, including the
effects of hepatic portal venous hypertension.
The gastrointestinal system is essential to nutrition, and disordered
nutrition is a major issue worldwide – both through undernutrition and
starvation and through overnutrition, which causes obesity, possibly the
single most important modern health problem in the affluent world.
Diagnosis and treatment
Clinical assessment, including a focused history and examination, is the
foundation of diagnosis. In addition, the gastrointestinal system can be
investigated by endoscopy, radiology and specific functional tests.
Endoscopy and radiology may also be used therapeutically, and phar-macotherapy and surgery for gastrointestinal disorders exploit many
unique features of the structure and function of the system.
Introduction and overview 11
12 Structure and function
Vermillion border
Soft palate
and uvula
Fauces
Tonsils
Floor of mouth
Tongue
Lips

Teeth
Nasopharynx
Oropharynx
Hypopharynx
Hard palate
Soft palateOral cavity
Mandible
Nasal cavity
Orbicularis ori
Trigeminal
(Vth) nerve
Temporalis
Masseter
Facial
(VIIth) nerve
Pterygoid muscles
Buccinator
Mandible
Maxilla
Zygomatic arch
Permanent teeth
Muscles of mastication
Crown
Milk teeth
6 months to 3 years
2 incisors (cutting)
1 canine
(gripping)
3 molars
Root
Erosion of
enamel
Dental plaque
Gingival
retraction
Enamel
Dentine
Pulp
Squamous
epithelium
of mouth
Gingival
tissue
(gum)
Alveolar bone
Periodontal
membrane
(joint)
Nerves
(trigeminal)
Blood
vessels

Tooth structure
Tongue
2 premolars
(grinding)
1 Mouth and teeth
The mouth and teeth admit food into the gastrointestinal tract. They cut
and break large pieces, chop, grind and moisten what can be chewed,
and prepare a smooth, round bolus that can be swallowed and passed on
to the rest of the system. Of course, the lips and mouth also serve other
functions.
Structure
The sensitive, flexible, muscular lips that form the anterior border of the
mouth can assess food by palpation, and their flexibility enables them
to seal off the oral cavity and form variously a funnel, suction tube or
shallow ladle to ingest fluids and food of varying consistency. The main
muscles of the lips are orbicularis ori.
The maxilla and mandible support the roof and floor of the mouth,
respectively. The arch of the mandible supports a sling of muscles that
forms the floor, including the tongue. The maxilla is continuous with the
rest of the skull and forms the roof of the mouth anteriorly and, simulta-neously, the floor of the nasal cavity and paranasal maxillary sinus.
Posteriorly, the roof is formed by the soft palate, composed of cartilage
and connective tissue.
The sides of the mouth comprise the cheek muscles, chiefly
buccinator, and supporting connective tissue. Posteriorly, the oral
cavity opens into the oropharynx and the tonsils are situated between
the fauces laterally, marking the posterior limit of the oral cavity.
The entire mouth, including the  gingivae  or gums, is lined with a
tough, non-cornified stratified squamous epithelium, which changes
to skin (cornified stratified squamous epithelium) at the  vermillion
border of the lips.
Teeth arise in the alveolar bone of the mandible and maxilla. Infants
are born without external teeth and with precursors within the jaw. A
transient set of 20 ‘milk’ teeth erupts through the surface of the bone
between 6 months and 2 years of age. They are shed between 6 and 13
years of age and permanent teeth take their place. There are 32 perma-nent teeth and the posterior molars, also known as wisdom teeth, may
only erupt in young adulthood.
Teeth are living structures with a vascular and nerve supply (derived
from the trigeminal, or IIIrd cranial, nerve) in the centre of each tooth,
which is termed the pulp. Surrounding the pulp is a bony layer called
dentine and surrounding this is an extremely hard, calcified layer called
enamel. Teeth lie in sockets within the alveolar bone and the joint is
filled with a layer of tough fibrous tissue (the periodontal membrane)
allowing a small amount of flexibility. The margins of the tooth joint are
surrounded by gingivae, which are a continuation of the mucosal lining
of the mouth.
Function
The lips, cheeks and tongue help to keep food moving and place it in the
optimal position for effective chewing. The main muscles of chewing or
mastication are the masseter and temporalis, which powerfully bring
the lower jaw up against the upper jaw, and the pterygoids, which open
the jaws, keep them aligned, and moves them sideways, and backwards,
and forwards for grinding. The trigeminal (Vth cranial) nerve controls
the muscles of mastication.
Teeth are specialized for different tasks as follows:
• Incisors have flat, sharp edges for cutting tough foods, such as meat
and hard fruits.
• Canines have pointed, sharp ends for gripping food, particularly
meat, and tearing away pieces.
• Premolars and molars have flattened, complex surfaces that capture
tiny bits of food, such as grains, and allow them to be crushed between
the surfaces of two opposed teeth. As people get older, the grinding sur-faces of the molars are gradually worn down.
Certain drugs can be absorbed across the oral mucosa and may be pre-scribed sublingually (under the tongue). In this way, the need to swallow
is avoided and the absorbed drug bypasses the liver and avoids hepatic
first-pass metabolism. Glyceryl trinitrate is one of the most common
drugs administered in this way.
Common disorders
Herpes simplex infection of the mouth is very common, causing cold
sores, which often erupt on the lips when people have other illnesses.
Serious oral infections, usually caused by a mixture of anaerobic bacte-ria, are less common.
The corners of the mouth may be ulcerated or fissured in patients who
cannot take care of their mouths, for example after a stroke, so careful
oral hygiene is important in these cases. Nutritional deficiency, particu-larly of B complex vitamins and iron, is also associated with fissures at
the edge of the mouth, known as angular stomatitis.
Shallow ‘apthous’ ulcers in the mouth are common and are usually
not associated with a more serious condition. Rarely squamous cell car-cinoma can develop. Risk factors include smoking and chewing tobacco
or betel nut, which is particularly common on the Indian subcontinent.
Dental caries is the commonest disorder of teeth, resulting in tooth
loss with advancing age. It is caused by chronic bacterial infection of the
gums and periodontal membrane, encouraged by carbohydrate and
sugar-rich food residues left in the mouth. Bacteria grow in the gap
between the tooth enamel and gums, forming a hard, impenetrable layer
called plaque, within which they multiply. Their metabolic products,
including  organic acids, damage tooth enamel. Gradual erosion of
enamel and retraction of the gingivae weakens the tooth joint. Infection
can penetrate the pulp causing an abscess, and chronic infection can
destroy and devitalize the pulp.
Dental hygiene, including brushing and flossing and having fluoride
in drinking water, which strengthens tooth enamel, reduces the
incidence of caries.
Mouth and teeth 13
14 Structure and function
Front view of glands
Microscopic structure
Side view of glands
Frenulm
Maxilla
Tongue
Mandible
Glossopharyngeal
(IXth) nerve
Submandibular
gland
Sublingual gland
Carotid artery
Sympathetic
plexus
Smaller salivary
glands
Parotid duct
Parotid gland
Maxilla
Parotid
gland
Parotid
duct
Mandible
Submandibular
gland
Sublingual
gland
Facial
(VIIth) nerve
Secretomotor parasympathetic
fibres (VIIth, IXth nerves)
Sympathetic nerves
(via carotid plexus)
Hypotonic, alkaline
saliva (1–2 L/day)
• H2O
• Mucus
• Ca2+, PO4–
• Lysozyme sIgA
• Amylase

Mucus-secreting cells
Impermeable to H2O
Basement membrane
Serous demilune
Mucus
Capillary network
Acinus
Serous-secreting cellCa2+
Na+ Cl–
HCO3– K+
Larger
(striated) ducts
Amylase
Lysozyme
2 Salivary glands
Saliva lubricates the mouth and teeth, provides antibacterial and diges-tive enzymes, and maintains the chemical balance of tooth enamel. Sali-vary glands are structurally similar to exocrine glands throughout the
gastrointestinal tract and are also regulated in a typical way.
Structure
The three main pairs of salivary glands are the parotid, submandibular
and sublingual glands and there are many smaller, unnamed glands lin-ing the mouth. The larger glands have main ducts that transport the saliva
to the oral cavity.
The parotid gland is the largest, situated on the side of the face, in front
of the ears and below the zygomatic arch. The facial nerve courses
through the parotid gland. The parotid duct enters the mouth opposite the
second molar teeth.
The submandibular gland is situated medial to the body of the
mandible and the sublingual glands lie medial to the submandibular
glands. The duct of the submandibular gland opens onto the mouth at the
side of the base of the tongue.
Microscopically, salivary glands typify the structure of  exocrine
glands throughout the body. They are lobulated, with fibrous septae or
partitions between lobules. The functional unit is the spherical acinus,
which comprises a single layer of secretory epithelial cells around the
central lumen.
The secretory cells are pyramidal shaped, with the base resting on the
basement membrane and the tip towards the lumen. The cell’s synthetic
machinery, comprising of endoplasmic reticulum and ribosomes, is
located near the base and the protein-exporting machinery, comprising
of golgi apparatus and secretory vesicles, is located in the apical portion.
Nuclei are located centrally. Serous cells tend to have small dense apical
granules, while mucus-secreting cells tend to be more columnar and
have larger, pale-staining apical granules.
The secretory epithelium merges with the epithelial lining of duc-tules, which coalesce to form progressively larger ducts that convey
saliva to the surface.
Most secretory cells in salivary gland acini are seromucoid, secreting
a thick mucoid fluid that also contains proteins. Some cells secrete a
watery, serous fluid, while others secrete predominantly mucoid
material. Acini with mainly mucus-secreting cells also have  serous
demilunes lying just outside the main acinus and within the basement
membrane. The parotid gland secretes the most watery saliva and most
acini in this gland are composed entirely of serous cells, while
the submandibular and sublingual glands secrete a more viscid mucus
saliva.
The facial  (VIIth cranial) and glossopharyngeal  (IXth cranial)
nerves supply secretomotor parasympathetic fibres from the salivary
nuclei in the brainstem, and sympathetic nerves are derived from the
cervical sympathetic chain.
Function
One to two litres of saliva are secreted each day and almost all is swal-lowed and reabsorbed. Secretion is under autonomic control. Food in
the mouth stimulates nerve fibres that end in the nucleus of the tractus
solitarius and, in turn, stimulate salivary nuclei in the mid-brain. Saliva-tion is also stimulated by sight, smell and anticipation of food through
impulses from the cortex acting on brainstem salivary nuclei. Intense
sympathetic activity inhibits saliva production, which is why nervous
anxiety causes a dry mouth. Similarly, drugs that inhibit parasympa-thetic nerve activity, such as some antidepressants, tranquillizers and
opiate analgesics, can cause dry mouth (xerostomia).
Saliva, composed of water and mucins, forms a gel-like coating over
the oral mucosa and lubricates food. Lubrication is essential for chew-ing and the formation of a bolus of food that can be easily swallowed.
Saliva also dissolves chemicals in food and allows them to interact more
efficiently with taste buds. Taste is an important sense as it allows us to
choose nutritious foods and to avoid unpleasant tasting foods that may be
harmful, or to which we have developed an aversion as a result of previ-ous experience.
Saliva also contains a-amylase, which begins the process of carbohy-drate digestion, although its overall contribution is probably minor.
Saliva contains  antibacterial enzymes, such as lysozyme, and
immunoglobulins that may help to prevent serious infection, and main-tain control of the resident bacterial flora of the mouth.
Salivary duct cells are relatively impermeable to water and secrete K+,
HCO3
-, Ca2+, Mg2+, phosphate ions and water, so that the final product
of salivary gland secretion is a hypotonic, alkaline fluid that is rich in
calcium and phosphate. This composition is important to prevent
demineralization of tooth enamel.
Common disorders
Anticholinergic drugs are the most common cause of decreased saliva
production and dry mouth, also known as xerostomia. Less common
causes include autoimmune damage to salivary glands in  Sjogren’s
syndrome and sarcoidosis. Xerostomia is a serious condition, because
chewing and swallowing rely on adequate saliva, as does maintaining
teeth in good condition.
Occasionally stones can form in the salivary glands, causing obstruc-tion, pain and swelling in the proximal part of the gland.
The mumps virus, for unknown reasons, preferentially attacks the
salivary glands, pancreas, ovaries and testicles, and parotid inflamma-tion causes the typical swollen cheeks appearance of mumps.
Salivary glands 15
16 Structure and function
Hard
palate
Soft
palate
Muscle
fibres
of tongue
Mandible
Hyoid bone
Larynx
Oesophagus
Chorda
typani
Sensory
(gustatory)
Nucleus of the
tractus solitarius
Glossopharyngeal (IXth) and
vagus (Xth) nerves Motor
Hypoglossal (XIIth) nerve
Pharyngeal muscles
(superior, middle and
inferior constrictors)
Oral phase
Bolus formed by tongue
Chewing pushes bolus to rear of mouth
Upper oesophageal sphincter closed
Soft palate seals off nasopharynx
Bolus in pharynx
Upper oesophageal sphincter closed

Superior and middle constrictors contract
Upper oesophageal sphincter relaxes
Epiglottis covers laryngeal opening
Glottis sealed

Body of tongue
Base of
tongue
Papillae
Epiglottis
Sulcus
Squamous epithelium
Taste buds
Gustatory nerve fibres travel via chorda
tympani branch of facial (VIIth cranial)
and glossopharyngeal (IXth cranial) nerves

Support cells
Tongue epithelium
Nerve fibre
(to nucleus of
tractus solitarius)
Nerve endings
Sensory cells
Taste modalities
• Sweet
• Salt
• Sour
• Bitter
• ‘Umami’
Also:
• Cold
• Heat
• Pain
Taste bud
Papilla Swallowing
Food
Pharyngeal phase
Oesphageal phase
3 Tongue and pharynx
The tongue and taste buds are an essential part of the mouth, involved in
taste, chewing, talking and many other functions.
The tongue
The tongue is a powerful, mobile, muscular organ attached to the
mandible and hyoid bone. The body is a flat, oblong surface with a longi-tudinal ridge along the top. It lies on the floor of the mouth and a thin
membranous  frenulum runs along the under surface in the mid-line
anteriorly. Posteriorly, the root is formed from muscle fibres passing
downward towards the pharynx and the epiglottis forms its posterior
border.
The tongue is covered with a tough non-cornified stratified squamous
epithelium continuous with the rest of the oral mucosa. On its upper
surface it is thrown up into numerous  ridges and papillae, creating
a roughened surface to rasp and lick food. Papillae around the lateral
and posterior edges contain numerous  taste buds. These contain
specialized sensory cells that communicate directly with nerve endings
from sensory nerve dendrites. The sensory cells are surrounded and sup-ported by adjacent epithelial cells. They express receptors for chemicals
dissolved in  saliva and each taste bud is sensitive to a single major
modality.
The hypoglossal (XIIth cranial) nerve innervates the tongue muscle.
Sensory fibres travel in the glossopharyngeal (IXth cranial) nerve and
in the chorda tympani branch of the facial (VIIth cranial) nerve. Taste
fibres terminate in the nucleus of the tractus solitarius in the mid-brain.
The tongue also has a large representation in the somatic motor and
sensory cortex of the brain.
Function
The tongue moves in all planes and reaches throughout the mouth. It
directs food between the teeth, retrieves pieces stuck between the teeth
and clears away obstructions. It propels food and drink posteriorly to
initiate the pharyngeal phase of swallowing. The tongue is also crucial to
speech, varying its shape and selectively closing off and opening air
channels.
The major modalities of taste are sweet, sour, salt and bitter, and a
fifth modality, called  umami, typified by monosodium glutamate, is
now also recognized. Taste receptors include G-protein-coupled recep-tors, ion channels and cold, heat and pain receptors. The flavour of food
is a combination of taste and smell, which is sensed by a large family of
G-protein-coupled olfactory receptors that bind to a myriad of different
chemicals.
Common disorders
The tongue may be paralyzed by damage to the hypoglossal nerve or
a stroke affecting its central connections. In  motor neuron disease,
spontaneous fasciculations are readily seen in the denervated tongue
muscle.
The tongue may be affected by squamous cell carcinoma and herpes
simplex infection (see Chapter 1). Occasionally the tongue may be
pigmented, which is not pathological. Glossitis, manifest by a smooth,
red, swollen, painful tongue occurs; for example, with B-vitamin
deficiencies.
Dry mouth, or  xerostomia, affects taste profoundly, as chemicals
must be dissolved for the taste buds to function. Systemic diseases, such
as uraemia, and drugs, such as metronidazole, may alter taste by inter-fering with the function of taste buds.
The pharynx
The pharynx is an air-filled cavity at the back of the nose and mouth,
above the openings of the larynx and oesophagus. The walls of the
oropharynx are lined by the same non-cornified stratified  squamous
epithelium that lines the oral cavity.
Superiorly, the floor of the sphenoidal air sinus and the skull base
bound the nasopharynx. The soft palate can be drawn up, closing the
connection between the nasopharynx and oropharynx.
The  oropharynx is bounded posteriorly by tissues overlying the
bodies of the upper cervical vertebrae and laterally by the tonsils and
the openings of the  Eustachian tubes, which connect the pharynx
with the middle ear. Inferiorly it narrows into the hypopharynx.
Three straps of voluntary muscle surround the pharynx, overlapping
each other and forming the superior, middle and inferior constrictors.
The circular muscle of the upper oesophagus is continuous with the
inferior constrictor.
Motor and sensory fibres mainly travel in the glossopharyngeal (IXth
cranial) and vagus (Xth cranial) nerves.
Function
The pharynx is a conduit for air, food and drink, and swallowing requires
coordinated action of the tongue, pharyngeal, laryngeal and oesophageal
muscles, and is controlled by the brainstem, via the glossopharyngeal
and trigeminal nerves.
The tongue forces a bolus of food backwards into the oropharynx,
initiating a reflex that raises the soft palate, sealing off the nasopharynx,
and inhibits respiration.
The superior and middle pharyngeal constrictors force the bolus down
into the hypopharynx, and the glottis closes. The epiglottis is forced
backwards and downwards, forming a chute over the larynx, opening
onto the upper oesophageal sphincter.
The sphincter relaxes, allowing the bolus to enter the oesophagus.
It is then conveyed downwards by peristalsis. The glottis reopens and
respiration recommences.
Common disorders
The pharynx is critically important in ensuring that the upper airway is
protected from aspiration of food, saliva and drink during swallowing
and vomiting. Thus neurological disorders, including  stroke,  motor
neuron disease, myasthenia gravis or reduced conscious level associ-ated with intoxication, anaesthesia or coma can cause aspiration into
the lungs, and pneumonia.
Upper respiratory tract infections often cause pharyngitis and may
cause tonsillitis. Common pathogens include viruses, such as influenza
and the Epstein–Barr virus, and bacteria, such as streptococci. Group A
b-haemolytic streptococci may also cause rheumatic fever, a systemic
autoimmune disorder that can affect the skin, heart and brain. Diphthe-ria is a serious cause of pharyngitis that is preventable by immunization.
Tongue and pharynx 17
18 Structure and function
Longitudinal
muscle

Peristalsis
Direction of
movement
Food
bolus
Food
bolus
Wave of
contraction
Wave of
relaxation
Wave of
contraction
Wave of
relaxation
Tongue
Pharyngeal
muscle
Striated muscleSmooth muscle
Epiglottis
Larynx
Vagus nerve
Oesophagus
Oesophageal
veins drain
into systemic
circulation
Diaphragm
Diaphragm Cardia
Columnar
epithelium
Axis of cardia
Axis of oesophagus
Diaphragmatic hiatus
Gastro-oesophageal angle
Lower oesophageal sphincter
Gastric veins drain into
hepatic portal system
Z-line gastro-oesophageal junction
Lumen
Stratified non-cornified squamous epithelium
Muscularis
mucosae
Submucosal nerve plexus
Submucosal glands
Myenetric nerve plexus
Vagus
Circular
muscle
4 Oesophagus
The oesophagus carries food and liquid from the mouth to the stomach
and the rest of the intestinal tract and is an important site of common
gastrointestinal disorders.
Structure
The oesophagus is a muscular tube, beginning at the pharynx and end-ing at the stomach. It traverses the neck and thorax, where it lies close to
the trachea, the great vessels and the left atrium of the heart. The upper
opening of the oesophagus lies behind the opening of the larynx and
is separated from it by the arytenoid folds. The epiglottis, attached to
the back of the tongue, can flap over the larynx, protecting it during
swallowing and funnelling food towards the oesophagus. Just above
the gastro-oesophageal junction, the oesophagus traverses a natural
hiatus or gap in the diaphragm, to enter the abdomen.
The walls of the oesophagus reflect the general organization of the
intestinal wall. The walls are formed from outside to inside by:
• adventitia or serosa;
• longitudinal muscle layer;
• circular muscle layer;
• submucosal layer;
• muscularis mucosae;
• mucosa and epithelium.
The muscle in the upper third is striated muscle and in the lower
two-thirds,  smooth muscle similar to the rest of the gut. The lower
oesophageal muscle remains in tonic contraction and forms part of the
lower oesophageal sphincter. The angulation of the oesophagus as it
enters the stomach and the diaphragmatic muscle help to keep the lower
oesophagus closed.
The  vagus nerve runs alongside the oesophagus and innervates
oesophageal muscle directly and via intrinsic nerves in the myenteric
nerve plexus located between the longitudinal and circular muscle
layers, and the submucosal plexus.
The submucosa contains lobulated  glands that secrete lubricating
material through small ducts that penetrate the epithelial surface.
The oesophageal epithelium is a tough, non-cornified stratified squa-mous epithelium, which changes abruptly to a non-stratified columnar
epithelium at the gastro-oesophageal junction, known as the Z-line.
Importantly, venous drainage of the oesophagus forms a submucosal
venous plexus that drains directly into the systemic venous circulation,
avoiding the hepatic portal vein and liver. This plexus anastomoses with
veins in the stomach that drain into the hepatic portal system. In portal
hypertension, collateral veins divert gastric blood to the oesophageal
veins, which enlarge and form varices.
Function
The oesophagus conveys food, drink and saliva from the pharynx to the
stomach, by  peristalsis. Peristalsis comprises a coordinated wave of
contraction behind the bolus of food, with relaxation ahead of it, pro-pelling the food bolus forward. It is involuntary, resulting from intrinsic
neuromuscular reflexes in the intestinal wall, independent of extrinsic
innervation. However, external stimuli modify the frequency and
strength of peristaltic activity throughout the intestine. Very strong peri-staltic contractions can cause pain.
In  vomiting, peristaltic waves travel in the reverse direction, pro-pelling food upward towards the mouth.
Common disorders
Dysphagia is difficulty in swallowing and  odynophagia is painful
swallowing. Sensations arising from the oesophagus are usually felt
retrosternally in the lower part of the centre of the chest. Heartburn
describes a burning, unpleasant retrosternal sensation that may be
caused by acid reflux from the stomach into the oesophagus.
Obstruction to flow down the oesophagus causes dysphagia and may
be complete, halting swallowing altogether, so that the patient cannot
even swallow saliva and drools continually. Chronic obstruction may
lead to aspiration of food into the larynx, causing pneumonia. Refluxed
stomach acid reaching the larynx can cause inflammation, causing
cough and a hoarse voice.
Cancer of the oesophagus or trauma, caused, for example, by a fish-bone, can create a fistula from the oesophagus to the trachea, which lies
immediately anteriorly. This can lead to recurrent infection caused by
bacteria in the oesophageal fluid (aspiration pneumonia).
The lower oesophageal sphincter is relatively weak; therefore,
acid reflux is common even in health, but can be excessive, when it may
cause oesophagitis. Chronic acid reflux can induce the epithelium to
change from the normal squamous lining to a gastric or intestine-like
columnar lining. This epithelial metaplasia is called Barrett’s oesoph-agus and it increases the risk of developing adenocarcinoma of the
oesophagus.
The diaphragmatic hiatus through which the oesophagus passes from
the thorax to the abdomen widens with age and it may allow the upper
part of the stomach to herniate into the thorax. This is known as a sliding
hiatus hernia, which increases the risk of reflux oesophagitis. The slid-ing is aggravated by obesity and lying flat in bed (see Chapter 30).
Very powerful muscular contraction and peristalsis (dysmotility) can
cause discomfort or pain. Progressive failure of peristalsis and a chroni-cally hypertonic lower oesophageal sphincter, leading to a dilated, non-functioning oesophagus, is called achalasia.
Forceful retching or vomiting can cause a Mallory–Weiss tear in the
oesophageal mucosa, which may bleed, causing (usually) self-limiting
haematemesis. By contrast, oesophageal  varices formed in portal
hypertension can bleed catastrophically (see Chapter 10).
Infections of the oesophagus are rare. The most common is candidia-sis, occurring in immunocompromised patients and those with diabetes
mellitus.
Squamous carcinoma of the oesophagus is particularly common in
southern Africa and may relate to diet, smoking and carcinogens in the
soil, as well to genetic factors. Adenocarcinoma, arising from Barrett’s
oesophagus, is becoming more common in the Western world (see
Chapter 38).
Oesophagus 19
20 Structure and function
Greater curve
Pylorus
Blocked by
vagotomy

Muscularis mucosae

Longitudinal
muscle
Circular muscle
Oblique
muscle
Serosa
Submucosa Mucosa
Lamina propria
Mucus
Lumen
Reinforced circular muscle
Oesophagus
Cardia
Fundus
Vagus nerve
Sensory fibres
Secretomotor
fibres
Rugae
Body (corpus)
Incisura (angulus)
Lesser
curve
Antrum
Duo-denum
Gastric lumen
Mucus
Gastric gland Gastric pit
IsthmusNeckBase
Intrinsic
factor
HCl
Gastroferrin
Pepsinogen
HCl
Mucus
layer
Mucus storage
vesicles
Mucous cells
Precursor cells
Few lamina propria
inflammatory cells
Chief cell
Endocrine cell
(G cell, produces
gastrin)
ECL cell (produces histamine)
Submucosal nerve plexus
Vagal nerve fibres
Gastric gland Canalicular
secretion
Parietal cell
Intrinsic
factor
Apical
surface
Nucleus
Mitochondria
M2 H2
Acetylcholine Histamine
Basolateral receptors stimulating secretion
Gastrin
Blocked by
proton pump
inhibitors
Blocked by H2
receptor
antagonists
Canaliculus
Gastroferrin
Canaliculus
Mitochondrion
Cytoplasm
Proton pump
Basolateral
surface
Acid
H+
K+
Cl–
Cl– Cl–
Cl–
HCO3–
CO2CO2
+
H2O
H+
+
HCO3–
Basolateral surface
5 Stomach
The stomach is the first wholly intra-abdominal intestinal organ. It is
adapted for mechanical churning, storage and digestion of food and con-tributes to neuro-endocrine coordination of intestinal function. The
basic rhythm of the intestine, the gastric slow wave, originates here.
Structure
The stomach is ‘J’-shaped, with lesser and greater curvatures, facing to
the right. The spleen lies to the left and the pancreas lies inferiorly and
posteriorly. The liver lies to the right. The stomach lies behind the left
hypochondrial region on the surface of the abdomen.
The stomach comprises five distinct regions:
1 the cardia immediately adjoining the oesophagus;
2 the dome-shaped fundus extending to the left of the cardia;
3 the body or corpus;
4 the antrum;
5 the  pylorus, in which the circular muscle layer is reinforced,
and which forms a tight sphincter separating the stomach from the
duodenum.
The structure of the gastric wall reflects the general organization of
hollow intestinal organs, with an additional oblique muscle layer that
supports its mechanical churning function and allows it to expand. From
outside to inside the walls are formed from:
• serosa;
• longitudinal muscle layer;
• circular muscle layer;
• oblique muscle layer;
• submucosa;
• muscularis mucosae;
• mucosa comprising the lamina propria and columnar gastric epithe-lium with its pits and glands.
The coeliac artery supplies arterial blood to the stomach and venous
blood drains into the  hepatic portal vein. The stomach receives
parasympathetic nerves via the vagus (Xth cranial) nerve and sympa-thetic fibres from the splanchnic nerves.
Most of the gastric mucosa is thrown up in coarse folds called rugae,
while the antral mucosa is much smoother. A thick mucus layer protects
against mechanical trauma, HCl and proteolytic enzymes.
Gastric pits are narrow invaginations of the epithelium into the lam-ina propria. Two or three gastric glands are connected to each pit via a
narrow isthmus, leading to the neck region of each gland. Gastric glands
are tubular structures with specialized cells for the production of
HCl (parietal or oxyntic cells) and  pepsin (chief cells), as well as
mucus-producing  goblet cells, undifferentiated epithelial cells,
entero-endocrine cells and stem cells.
Parietal cells are found in glands throughout the fundus, corpus and
antrum. They secrete HCl, the glycoproteins intrinsic factor and gas-troferrin, which facilitate the absorption of vitamin B12 and iron,
respectively.
Chief cells are found predominantly in the corpus. They secrete
pepsinogen and have an extensive rough endoplasmic reticulum and
prominent apical secretory granules.
The main entero-endocrine cells of the stomach are G cells, producing
gastrin, D cells, producing somatostatin, and entero-chromaffin-like
(ECL) cells, producing histamine (see Chapter 16).
Function
Food is  mixed thoroughly by the churning action of gastric muscle
against a closed pyloric sphincter. The pylorus opens only to allow semi-liquid material (chyme) through into the duodenum, preventing the pas-sage of large food particles. Mechanical dysruption increases the surface
area for more efficient digestion and prevents damage to the delicate
intestinal mucosa from large, hard, irregular food particles.
Rhythmic electric activity in the stomach produces regular peristaltic
waves three times a minute, known as the gastric slow wave.
Gastric secretion is stimulated by the anticipation of food, the so-called cephalic phase, and by food reaching the stomach, the gastric
phase. Acetylcholine and histamine, acting through M2 muscarinic
and H2 receptors stimulate the secretion of HCl.
Parietal cells have an extensive intracellular  canalicular system,
numerous mitochondria to generate energy, and a highly active K+/H+
adenosine triphosphatase (ATPase) pump (proton pump) that secretes
H+ into the lumen. An apical chloride channel transports Cl- into the
lumen, to form HCl.
At the basolateral surface, HCO3
-, formed intracellularly from CO2
and H2O, is exchanged for Cl-, so that circulating HCO3
– levels rise
when the stomach secretes acid (‘alkali tide’). The basolateral Na+/K+
ATPase pump also replenishes intracellular K+ levels.
Differentiation and secretion of parietal cells is also stimulated by
gastrin. Acid secretion is increased by excess gastrin, for example, in the
Zollinger–Ellison syndrome (see Chapter 16), and is inhibited by vago-tomy, which removes cholinergic stimulation, by H2 receptor antago-nists, such as  ranitidine, and by proton pump inhibitors, such as
omeprazole, which irreversibly bind to the K+/H+ ATPase.
HCl activates pepsinogen, to produce pepsin, initiating protein diges-tion. Intrinsic factor binds to vitamin B12, allowing it to escape degra-dation in the stomach and intestine and to be safely transported to the
terminal ileum, where it is absorbed. Gastroferrin binds to Fe2+, facilitat-ing absorption in the duodenum (see Chapter 21).
Common disorders
Symptoms relating to the stomach are extremely common, but are
frequently not caused by discernable organic disease (see Chapter 29).
Typical symptoms include  nausea,  epigastric pain and  bloating.
Collectively these symptoms are termed dyspepsia and patients may
refer to them as indigestion. With serious conditions of the stomach,
there may also be  vomiting,  haematemesis,  melaena and  loss of
weight.
The main serious gastric conditions are peptic ulcer and gastritis,
which are most frequently associated with Helicobacter pylori infection
and the use of non-steroidal anti-inflammatory drugs (NSAIDs), and
gastric carcinoma (see Chapter 31).
Hiatus hernia occurs when part of the stomach herniates through
the diaphragmatic hiatus through which the oesophagus passes (see
Chapters 30 & 38). Gastric outlet obstruction may occur in young male
infants, due to a congenitally hypertrophied sphincter, causing projectile
vomiting. In adults, a more common cause is autonomic neuropathy,
caused, for example, by diabetes mellitus.
Stomach 21
22 Structure and function

Liver
Bile
Bulb
1st part
Acid + chyme
Pylorus
2nd
part
Alkali
Common
bile duct
Pancreatic duct
Pancreatic juice
Pancreas
Ampulla
of Vater
Digestion
Fe2+
Ca2+
3rd part
4th part
Microvilli
Villi
Absorptive enterocyte
Goblet cellPaneth cell
Entero-endocrine cell
Stem cell
(undifferentiated)
Glycoproteins
Enzymes
Intestinal lumen Brush boarder
(apical surface)
Tight junction
Basolateral surface
Basement membrane
Basolateral
surface
Secretory
vesicles
Lysozyme, phospholipase A2,
defensins
Secretary vesicles
with antibacterial
proteins
Rough endoplasmic
reticulum
Villus
Crypt
Plicae
circulare
Submucosa
Muscularis
mucosae
Brunner’s
glands
Circular muscle
Longitudinal
muscle Serosa or
adventitia
Bile duct
Chylomicrons
FatsSugars
Amino
acids
Arteriole
Venule
Fe2+
Ca2+
Capillary
plexus
Lacteal
(lymphatic)
Afferent arteriole
Efferent
venule
To portal
circulation
To lymphatics
Mucin-filled
vesicles
VillusCrypt
6 Duodenum
The duodenum is the first major digestive and absorptive region of the
intestine, receiving chyme from the stomach and mixing it with bile,
pancreatic juice and enteric secretions.
Structure
The duodenum extends from the pylorus, to the jejunum at the ligament
of Treitz. It is approximately 30·cm long and ‘C’-shaped, facing the left,
and is mostly retroperitoneal. The first part of the duodenum is called
the  bulb. The second part receives bile and pancreatic juice via
the ampulla of Vater and lies adjacent to the pancreas on the left. The
coeliac artery supplies the duodenum and venous drainage is via the
superior mesenteric vein into the hepatic portal vein.
The walls of the duodenum reflect the general organization of
the intestinal wall. They comprise from the outside to the inside:
• adventitia or serosa;
• longitudinal muscle layer;
• circular muscle layer;
• submucosa containing Brunner’s glands;
• muscularis mucosae;
• mucosal layer comprising the lamina propria and epithelial lining.
The epithelium rests on a basement membrane, on the loose connec-tive tissue of the lamina propria, which is thrown up into finger-like
villi and is indented into long, thin crypts (of Lieberkühn) from which
new epithelial cells emerge. A thin layer of smooth muscle, the muscu-laris mucosa, separates the mucosa from the  submucosa, which is
thrown up in transverse folds known as  plicae circulare. Branched
tubular glands, called Brunner’s glands, are located in the submucosa
and are connected to the lumen by narrow ducts. The lamina propria con-tains numerous fibroblasts, macrophages, lymphocytes, neutrophils,
mast cells, vascular endothelial cells and other cells.
An arteriole, venule and a lymphatic channel called a lacteal supply
each villus. The arteriole and venule form a countercurrent circulation
enhancing intestinal absorption. Intrinsic enteric nerves ramify through
the layers of the intestine, controlling motor and secretory function (see
Chapter 17).
The small intestinal epithelium contains a number of distinct cell
types, all of which differentiate from stem cells located in the crypt.
Enterocytes constitute most of the intestinal lining. They are colum-nar, with a round or oblong nucleus located centrally. On the luminal sur-face,  microvilli, supported by an extensive network of cytoskeletal
proteins, increase the surface area available for digestion and absorption.
The surface of the microvilli are covered by glycoproteins and attached
enzymes and mucins, forming a prominent brush border. Tight junc-tions link adjacent enterocytes, so that the apical surface of the cell, and
consequently the luminal surface of the intestine, is isolated from the
basal surface. Thus, gradients of nutrients and electrolytes can be main-tained and pathogens can be excluded. Enterocytes synthesize digestive
enzymes and secrete them to the apical brush border.
Goblet cells are specialized secretory cells that produce mucin. Cyto-plasmic stores of mucin are not stained by conventional histochemistry
and create the typical ‘empty goblet’ appearance.
Paneth cells are found at the base of the small intestinal crypts. They
are specialized for protein synthesis and secretion and contain antibac-terial proteins such as lysozyme, phospholipase A2 and defensins. They
may also have other, undefined, roles in intestinal health and disease (see
Chapter 18).
Entero-endocrine cells are found predominantly near the crypt bases
and produce many different enteric hormones (see Chapter 16).
Stem cells are located just above the Paneth cell zone. They retain the
capacity to replenish the entire epithelium, by dividing to produce one
daughter stem cell and one daughter cell that proliferates, differentiates
and migrates up the crypt.
Function
Alkaline bile and pancreatic juices neutralize stomach acid. Powerful
enzymes from the  pancreas, which are activated in the lumen by
autocatalysis and by the action of enterokinase released from duodenal
enterocytes, support rapid and efficient digestion. The final stages of
digestion occur in the brush border of enterocytes under the action of
disaccharidases and peptidases. Bile salts emulsify fatty foods, allowing
digestive enzymes to act more efficiently. Transport proteins in the
apical membrane actively absorb sugars, amino acids and electrolytes
into the enterocyte. Fatty acids and cholesterol enter by direct diffusion
across the lipid membrane, are re-esterified intracellularly, complexed
with apolipoproteins to form chylomicrons and released at the basolat-eral surface. The jejunum and ileum constitute the major digestive
surfaces of the intestine, but iron and calcium in particular are preferen-tially absorbed in the duodenum (see Chapters 19–21).
The small intestine is relatively free from resident bacteria and an
antimicrobial environment is maintained by the action of gastric acid
and antibacterial substances produced by Brunner’s glands and Paneth
cells. Biliary epithelial cells and enterocytes transport secretory dimeric
immunoglobulin A (sIgA) into the lumen, which may also contribute to
antimicrobial defence in the small intestine (see Chapter 18).
Entero-endocrine cells in the duodenum secrete cholecystokinin and
secretin in response to food, stimulating gallbladder contraction and
pancreatic secretion, and inhibiting gastric motility. Thus, the duode-num participates in neuro-endocrine coordination of gastrointestinal
function (see Chapter 16).
Common disorders
Duodenal disorders may cause epigastric pain, diarrhoea, malabsorp-tion, loss of weight and nutritional deficiencies. Bleeding ulcers may
cause anaemia, haematemesis and melaena, the characteristic black
tarry appearance of stool caused by partially digested blood.
Cancer of the duodenum is extremely rare, while peptic ulcer and
coeliac disease are common (see Chapters 31 & 35).
Giardia lamblia is a protozoal pathogen that causes traveller’s diar-rhoea, by adhering to and damaging the duodenal and jejunal epithelium,
resulting in flatulence, diarrhoea and malabsorption (see Chapter 32).
Duodenum 23
24 Structure and function
Efferent venule
Spleen
Splenic vein
Neck Body
Tail
Main pancreatic duct
Inferior mesenteric vein
Coeliac trunk and coeliac nerve plexus
Hepatic portal vein
Sympathetic nerves
Common bile duct
Cholecystokynin
Secretin
Food
+
+
Duodenum
Accessory
duct
Ampulla
of Vater
Sphincter
of Oddi
2 L/day
Head
Pancreatic
sphincter
Uncinate
process
Superior
mesenteric
vein
Exocrine acinus
Pancreatic islet
Duct cells
H2O, HCO3–, K+
CFTR
Centroacinar cells
Secretory
vesicles
Rough
endoplasmic
reticulum
Acinar cell
Golgi
Proteases
-Trypsinogen
-Cholecystokinin
-Pro-elastase
-Procarboxypeptidases
Amylase
Lipase and colipase
Phospholipase A2
Ribonucleases
Deoxyribonucleases
Afferent
arteriole
(> 106/pancreas)
a cell
(glucagons)
b cell
(insulin)
D cell
(somatostatin)
7 Pancreas
The pancreas is critically important for intestinal digestion. It is a large
exocrine gland, synthesizing and secreting the great majority of diges-tive enzymes into the intestine. It also contains important endocrine tis-sue producing insulin and glucagons, thus also regulating nutrition and
gastrointestinal function globally.
Structure
The pancreas lies transversely on the posterior abdominal wall and is
covered by peritoneum. The head lies to the right, adjacent to the duo-denum, and the body and tail extend across the epigastrium to the spleen.
The splenic vein runs along the superior border of the pancreas and loops
of intestine are related to it anteriorly.
Branches of the coeliac and superior mesenteric arteries supply the
gland and venous blood drains into the hepatic portal vein, supplying
the liver with hormone- and growth factor-laden blood from the
pancreas.
The vagus nerve and splanchnic sympathetic nerves innervate the
pancreas. Sensory nerves are routed through the coeliac ganglion and
pancreatic pain may be relieved by its surgical removal or destruction.
The main pancreatic duct extends along the length of the gland and a
smaller accessory duct drains the superior part of the head and may open
separately into the duodenum. The main duct joins the common bile
duct before opening into the duodenum through the ampulla of Vater.
Smaller pancreatic ducts drain into the main duct, forming a ‘fishbone’
pattern. Exocrine pancreatic tissue is arranged in lobules composed of
the functional units, acini, which secrete pancreatic enzymes and fluid
into the ducts.
Microscopically, pancreatic cells are arranged in spherical acini,
with their secretory or apical surface towards the centre and the basolat-eral surface resting on a basement membrane. Ductules drain each aci-nus and coalesce to form larger ducts that eventually drain into the main
pancreatic duct, carrying digestive juices to the duodenum. Pancreatic
acinar cells are highly specialized for protein synthesis and secretion.
They have a pyramidal cross-section, with prominent basal rough
endoplasmic reticulum, where protein synthesis occurs, extensive
golgi apparatus and apical secretory (zymogen) granules.
Over 106 endocrine pancreatic islets are scattered throughout the pan-creas and are supplied with a rich capillary network of blood vessels.
They are not connected by ducts to the exocrine pancreas, but secrete
directly into the bloodstream. The principle cells in these islets are b
cells, which secrete insulin, a cells, that secrete glucagon, and D cells,
which synthesize somatostatin.
Function
The pancreas is a powerful producer of digestive enzymes. These are
synthesized and stored as inactive precursors or pro-enzymes, to avoid
autodigestion of the enzyme-producing cells and the pancreatic ducts.
Pancreatic enzymes include:
• trypsinogen;
• chymotrypsinogen;
• procarboxypeptidases A and B;
• pro-elastase;
• phospholipase A;
• pancreatic lipase (and colipase);
• pancreatic amylase;
• ribonucleases;
• deoxyribonucleases.
Pancreatic secretion is stimulated by hormonal signals, particularly
cholecystokinin, which is released when food enters the duodenum.
Secretin enhances the effect of cholecystokinin.
The pancreas secretes about 2L/day of a bicarbonate-rich alkaline
fluid that helps to neutralize stomach acid and provides optimal condi-tions for digestion by pancreatic enzymes. Centroacinar and duct cells
secrete most of the fluid and alkali, by exchanging HCO3
– for Cl- ions,
using the cystic fibrosis transmembrane regulator (CFTR) protein.
Pancreatic insufficiency therefore occurs in cystic fibrosis, where an
abnormal CFTR gene is inherited.
Pancreatic islets are the only source of insulin and glucagon, which
are produced by pancreatic b and a cells, respectively. Insulin secretion
is stimulated mainly by increased blood glucose, while glucagon secre-tion is stimulated by hypoglycaemia. Hormones, such as adrenaline,
have additional modulatory effects on pancreatic islet secretion and
islets also produce hormones, such as  somatostatin, which modifies
entero-endocrine function locally and throughout the gastrointestinal
tract (see Chapter 16).
Common disorders
Pancreatic diseases may remain entirely asymptomatic until they are far
advanced. They may cause abdominal pain, felt in the epigastrium and
radiating to the back. Damage to the common pancreatic and bile ducts
may cause jaundice and pancreatic exocrine insufficiency may result in
malabsorption of food, causing  diarrhoea,  steatorrhoea (fat-rich
stools),  weight loss and  nutritional deficiencies. Islet damage can
cause diabetes mellitus.
Acute pancreatitis is a serious, potentially life-threatening illness.
The most common causes are excess alcohol ingestion and passage of
gallstones through the ampulla of Vater (see Chapter 40). Less frequent
causes include various drugs, abdominal trauma and viral infection. The
inflamed pancreas releases enzymes into the circulation and acute pan-creatitis is a systemic illness, affecting the whole body. Pancreatic
lipases release fatty acids that interact with calcium to form insoluble
calcium-fatty acyl salts, potentially lowering the concentration of cal-cium in the circulation to dangerous levels. A dramatic rise in the serum
lipase or amylase level helps to diagnose acute pancreatitis.
Chronic pancreatitis may follow repeated bouts of acute pancreati-tis. The main symptoms are abdominal pain and malabsorption due to
failure of the exocrine pancreas. Patients may also develop endocrine
pancreatic insufficiency (see Chapter 40).
Pancreatic  adenocarcinoma is a leading cause of cancer-related
death and often becomes symptomatic only at an advanced stage, when
the tumour has become inoperable. Neuro-endocrine tumours, which
arise from enteric endocrine cells, are often located in the pancreas,
although they may also arise from other parts of the gastrointestinal tract.
They are generally less aggressive than adenocarcinoma, but may cause
symptoms due to their secretion of gut hormones. Gastrin-producing
tumours (gastrinomas) cause excess gastric acid secretion and peptic
ulceration (Zollinger–Ellison syndrome). Tumours may also secrete
insulin, glucagon and other hormones (see Chapters 16 & 38).
Pancreas 25
26 Structure and function
Diaphragm
Right lobe Left lobe
Ribs
1.5 kg
Front
Back
Hepatic artery
(25% of flow)
Portal vein
(75% of flow)
Common bile duct
Gallbladder
View from front
View of liver from inferior surface
Functions
Inferior vena cava

Gallbladder
Hepatic vein
Hilum
• Carbohydrate, lipid, protein metabolism
• Storage of fat, glycogen, vitamins B12, A, K
• Plasma proteins, lipoproteins synthesis
• Bile salts synthesis
• Bilirubin metabolism, detoxification
• Portal vein clearance, tolerance

Bile ductule
Hepatic artery branch
Portal vein branch
Portal triad
Central
hepatic vein
Hepatocytes Zone 1 of acinus
Zone 2
Zone 3
Portal vein blood carrying antigens, toxins, pathogens
Nutrients, hormones
Kupffer
cell
Sinusoid
Endothelial cell
Lymphocyte
Red cell
Fenestrae
Space of Disse
(loose connective tissue)
Droplets of
retinoic acid
Stellate cell
Mitochondria (energy, urea cycle) Fat droplet
Vesicles and lysosomes
Peroxisome
Golgi
Rough endoplasmic reticulum
(protein synthesis)
Glycogen
Tight junctions
Cytoplasm
Nucleolus
Nucleus
Smooth endoplasmic reticulum
(detoxification, lipid metabolism)
Canalicular
membrane
Microvilli
Bile canaliculus
Tight junctions
Imaginary outline
of lobule
8 Liver
The liver is the largest solid organ in the body, weighing 1.5 kg in a 70-kg
adult. It develops from the embryonic foregut endoderm and is an inte-gral part of the gastrointestinal system. It performs vital metabolic, syn-thetic, secretory and excretory roles, and life cannot be sustained for
more than a few hours without the liver.
Structure
The liver lies in the right upper quadrant of the abdomen, directly
under the right hemidiaphragm, protected by the lower ribs. It crosses the
mid-line, where the falciform ligament traverses it, separating the left
lobe from the right. The liver can be divided into nine  functional
segments that can be identified surgically, based on vascular supply and
biliary drainage.
On the inferior surface, in the mid-line, the portal vein and hepatic
artery enter and common bile duct and lymphatic channels leave the
hilum of the liver. These structures divide into major right and left
branches within the liver. The inferior vena cava traverses the liver pos-teriorly, where the main hepatic vein joins it.
The gallbladder lies under the liver to the right of the mid-line and is
connected to the common bile duct by the cystic duct. The hepatic flex-ure of the colon lies to the right of the gallbladder. The liver parenchyma
is enclosed in a tough fibrous capsule, which is mostly covered by peri-toneum, apart from the bare area under the dome of the diaphragm.
The hepatic artery, arising from the coeliac trunk delivers arterial
blood to the liver, although 75% of the hepatic blood flow arrives via the
portal vein, which drains the spleen, pancreas and intestines. Venous
drainage is via the hepatic vein.
Microscopically the liver parenchyma is homogeneous, with repeti-tion of the same basic organization throughout.  Hepatocytes form
three-dimensional cords and plates in the liver. These are separated by
sinusoids through which blood flows slowly. There are two main ways
of conceptualizing the microscopic arrangement. In the lobular model,
the hepatic venule is at the centre, with portal vein branches at three cor-ners of a six-sided lobule. In the  acinar model, the portal vein and
hepatic artery branches and bile ductules are at the centre in the portal
triads, with three zones (1, 2 and 3) defined by their distance from the
centre.
The walls of adjacent hepatocytes form bile canaliculi. Specialized
biliary epithelial cells line small bile ductules, larger ducts and the
gallbladder.
Hepatic stellate cells, also known as Ito cells or fat cells because they
contain prominent droplets of fat and retinoic acid (a vitamin A deriva-tive), are situated deep to the sinusoidal endothelium. They elaborate the
connective tissue matrix of the liver and respond to injury by causing
fibrosis.
Endothelial cells line the sinusoids. They rest on a loose connective
tissue matrix, known as the space of Disse, and are discontinuous. They
also contain gaps or fenestrae, which may allow molecules, particles
and even cells to easily penetrate the parenchyma from the sinusoids.
Within sinusoids, resident macrophages called Kupffer cells interact
with particles and cells. Numerous lymphoid cells are present, including
special subsets of lymphocytes and dendritic cells. Their function is
unknown, although they probably contribute to special immunological
properties of the liver (see Chapter 18).
Hepatocytes are large, cuboidal cells with a central nucleus that is
occasionally tetraploid. They are functionally  polarized, with  sinu-soidal and canalicular poles. Tight junctions and desmosomes seal off
the canalicular membranes, across which hepatocytes secrete the con-stituents of bile. Microvilli help to increase the cell surface area.
Hepatocytes are extremely metabolically active and contain many
intracellular organelles. There is extensive  smooth endoplasmic
reticulum for lipid and cholesterol synthesis and rough endoplasmic
reticulum for protein synthesis. There are many mitochondria in which
metabolic reactions, such as the Krebs cycle, occur and where chemical
energy is generated. There are lysosomes, peroxisomes and endocytic
vesicles supporting digestive functions, and storage vacuoles, glyco-gen granules and fat droplets.
Function
The liver’s complex functions have not yet been reproduced artificially.
They include:
• Regulating  homeostasis of carbohydrate, lipid and amino acid
metabolism.
• Storing nutrients such as glycogen, fats and vitamins B12, A and K.
• Producing and secreting plasma proteins and lipoproteins, including
clotting factors and acute phase proteins.
• Synthesizing and secreting bile salts for lipid digestion.
• Detoxifying and excreting bilirubin, other endogenous waste prod-ucts and exogenous metal ions, drugs and toxins (xenobiotics).
• Clearing toxins and infective agents from the portal venous blood
whilst maintaining systemic immune tolerance to antigens in the portal
circulation.
In addition, hepatocytes retain the capacity to proliferate, so that the
liver can regenerate dramatically after injury.
Common disorders
Liver disorders can cause many symptoms and signs, ranging from
vague malaise to fulminant liver failure, with disordered coagulation
and coma. Typical features include jaundice, fatigue, loss of appetite
and pain in the right upper quadrant of the abdomen. Because of the
great reserve capacity of the liver, extensive damage may remain
asymptomatic.
Viral hepatitis is common throughout the world. Liver abscesses,
caused by amoebae, bacteria and parasites, are common in some parts of
the world. Drugs and toxins, including medications, also commonly
affect the liver and the most important of these is alcohol. Chronic dam-age may cause scarring and lead to cirrhosis. Overwhelming liver dam-age, either acutely or chronically, causes liver failure. Although primary
liver cancer is rare, metastatic cancers are common (see Chapters 33,
38, 41 & 42).
Liver 27
28 Structure and function
225 mL/day
Paracellular
water and
electrolytes
Cholesterol
Tight junction
1°  bile salts
Lithocholic acid
Deoxycholic acid
BAT  = Bile acid transporter
MOAT =  Multispecific organic
acid transporter
NTCP =  Na+ Taurocholate
transport protein
OAT  = Organic acid transporter
Conjugation
(UDP, taurine,
glycine)
2° bile acids
Bile acids
Na+
Na+
Entero-hepatic circulationRe-absorption
into portal vein
Terminal ileum
Organic
anions
MOAT
Organic
cations
BAT
Bile acids
Ca2+
Cholesterol
Bilirubin-conjugated
phospholipids
Bilirubin
Organic
anions
Organic
anions
K+
NTCP OAT
cAMP
ATP
Secretin
Sinusoid
450 mL/day
canalicular secretion
Left hepatic duct
CFTR
Duct epithelium
Cl–
Liver
Right
hepatic
duct
HCO3–
150 mL/day
600 mL/day
Cystic duct
Cholecystokinin
Contraction
H2O/Cl–
Biliary epithelium
60 ml
Gallbladder
Common bile duct
Pancreas
Duodenum
Ampulla of Vater
Sphincter of Oddi
Pancreatic duct
HCO3–
Bile
salts
2° bile salts
Deconjugation and
oxidation by bacteria
9 Biliary system
Bile is formed by hepatocytes and modified by the specialized biliary
epithelium. It is an exocrine secretion necessary for digestion, an excre-tion product for removal of toxins and metabolic waste and a part of the
host defence system.
Structure
Macroscopically, the intrahepatic  bile ducts, common hepatic duct,
cystic duct, gallbladder and common bile duct constitute the biliary
system.
The gallbladder is a pouch-like structure with a thin fibromuscular
wall located under the anterior edge of the liver. Its epithelium is thrown
up in complex fronds, increasing the surface area. The neck of the gall-bladder leads to the cystic duct, which joins the common hepatic duct,
formed from the union of the right and left intrahepatic ducts, to form the
common bile duct, which leaves the liver at the hilum. The common bile
duct lies adjacent to the hepatic artery and portal vein and joins the main
pancreatic duct before entering the duodenum through the ampulla of
Vater, which is kept closed by the sphincter of Oddi.
The biliary epithelium lining the major ducts and the gallbladder is
composed of a single layer of columnar or cuboidal cells resting on a
basement membrane. It can secrete Cl- and water and in the gallbladder
the same cells absorb water, to concentrate bile.
The biliary canaliculus is the primary site of bile production. It is a
channel formed from apposed surfaces of adjacent hepatocytes. Tight
junctions separate the canalicular membrane from the basolateral sur-face of the hepatocyte, allowing transport proteins to create and maintain
concentration gradients. As biliary canaliculi converge and enlarge, spe-cialized biliary epithelial cells replace hepatocytes.
Function
Each day, 600·mL of thick, mucoid, alkaline bile is produced. Its main
constituents are:
• primary bile acids: cholic and chenodeoxycholic acid;
• secondary bile acids: deoxycholic and lithocholic acid;
• phospholipids;
• cholesterol;
• bilirubin;
• conjugated drugs and endogenous waste products;
• electrolytes: Na+, Cl-, HCO3
– and trace metals, such as copper;
• secretory dimeric immunoglobulin A (sIgA) and other antibacterial
proteins;
• mucin glycoproteins.
Transporter proteins on the basolateral surface of the hepatocyte,
such as the organic acid transport (OAT) protein, facilitate uptake of
substances such as bilirubin and bile salts from the circulation. Trans-porters in the canalicular membrane then secrete compounds from the
hepatocyte into bile. Important canalicular transporters include the bile
acid transporter (BAT) and the multispecific organic anion transporter
(MOAT). Specific transporters help to excrete potential toxins; for
example, excess copper is excreted by an adenosine triphosphate (ATP)
-dependent copper transporter that is defective in  Wilson’s disease,
causing accumulation of copper in the brain and liver.
Active secretion of bile acids, electrolytes and organic compounds
draws water with it and bile flow is encouraged by coordinated contrac-tion of cytoskeletal proteins adjacent to the canalicular membrane. The
canaliculi secrete 450·mL/day and bile ducts add 150·mL/day.
About 60·mL of bile is stored in the gallbladder. Cholesterol is a major
insoluble constituent of bile and it is stabilized by incorporation into
mixed micelles, formed by bile salts and phospholipids.
Abnormal bile may be formed if hepatocytes are overloaded with one
or other component; for example, haemolysis results in overproduction
of bilirubin, which may crystallize to form gallstones.
Cholecystokinin is released from the duodenum when food arrives in
it, stimulating contraction of the gallbladder and relaxation of the
sphincter of Oddi, thus delivering bile to the duodenum just when it is
needed.
Bile promotes the digestion and absorption of fats and fat-soluble
vitamins in several ways. The alkaline bile promotes emulsification of
fats, which allows greater access to digestive enzymes, and bile acids,
cholesterol and phospholipids form mixed micelles, into which digested
fatty acids and other lipids are incorporated. The alkaline pH is also
optimal for pancreatic lipases.
Primary bile acids are synthesized in the liver from cholesterol and
95% of the secreted bile acids are reabsorbed in the terminal ileum and
carried into the portal venous circulation. These secondary bile acids,
which have been metabolized by bacteria in the intestine, are taken up by
hepatocytes and resecreted into the bile. This constitutes the entero-hepatic circulation (see Chapter 24).
Bile is the main pathway for excretion of hydrophobic wastes such as
bilirubin.
Common disorders
Jaundice, caused by accumulation of bilirubin, is the classic symptom
of biliary disease. Interrupting bile flow to the intestine causes pale stool
and dark urine as bilirubin is excreted via the urine. Itching is caused by
accumulation of pruritogenic substances that are normally excreted in
bile. Longstanding obstruction interferes with fat absorption and may
cause steatorrhoea, weight loss and nutritional deficiency. Obstruc-tion and inflammation of the biliary tract can cause  pain,  fever and
malaise (see Chapters 33 & 40).
Damage to hepatocytes, for example by viral hepatitis, may inhibit
bile secretion, by decreasing ATP levels, interfering with transporter
function and damaging cytoskeletal proteins. This causes intrahepatic
cholestasis, with no macroscopic blockage to the biliary system. Certain
drugs can produce a similar effect (see Chapter 41).
Autoimmune damage to intrahepatic bile ducts, in primary biliary
cirrhosis (PBC), causes progressive jaundice and liver damage.
Gallstones are very common and may remain asymptomatic. They
form when constituents, such as cholesterol or bile pigments, that are
partially soluble, reach supersaturated concentrations and crystallize
around a nidus, such as a stray bacterial cell. They can cause cholecysti-tis in the gallbladder and cholangitis or pancreatitis when they lodge
in the bile ducts, causing obstruction and superadded infection (see
Chapter 40).
Biliary system 29
30 Structure and function
Transjugular approach to the liver for TIPSS*
TIPSS* between hepatic vein and portal vein
*TIPSS = Transjugular intrahepatic porto-systemic shunt
Hepatic vein
Right atrium
Inferior vena cava
Oesophagus
Area of portosystemic anastomosis
and shunting (oesophageal varices)
Surgical shunt
Gastro-epiploic veins
Splenic vein
Renal vein
Spleen
KidneyPancreas
Duodenum
Caecum
Ileum
Hepatic artery
Portal vein
Bile duct
Colon
Superior
mesenteric vein
Nutrients, antigens
and growth factors
Inferior mesenteric vein
Middle/inferior haemorrhoidal veins
Iliac veins
Colon
Rectum
Bacterial metabolism producing
amines, NH4–, false neuro-transmitters contributing to
hepatic encephalopathy
Area of portosystemic
anastomosis and shunting
(rectal varices)
Portal hypertension
Back pressure
Serosal
covering
of intestine
Leakage of fluid
(transudation)
Ascites
10 Hepatic portal system
The liver receives 25% of the cardiac output, of which 75% arrives via
the portal vein, which drains the spleen, pancreas and gastrointestinal
tract from stomach to colon. Thus, all the blood from these organs nor-mally traverses the liver before it enters the systemic circulation. This
arrangement serves many important functions.
Structure
The portal vein is formed from the confluence of the splenic vein, which
drains the stomach, pancreas and spleen, and the superior mesenteric
vein, which drains the entire small intestine and most of the large intes-tine. The inferior mesenteric vein, which drains the rest of the large
intestine, joins the splenic vein. The portal vein enters the liver at the
hilum, alongside the hepatic artery and common bile duct.
Within the liver the portal vein divides, first into left and right main
branches and then further, so that small branches supply each acinus or
lobule. These small branches lie in portal triads, with branches of the
hepatic artery and bile ducts, surrounded by a small amount of connec-tive tissue. Portal venous blood flows slowly through the hepatic sinu-soids and exits the liver through terminal hepatic venules, which join to
form the hepatic veins, rejoining the systemic circulation at the inferior
vena cava (see Chapter 8).
Importantly, the venous drainage of the oesophagus and lower rec-tum goes directly into the systemic circulation, bypassing the portal
venous system and the liver. When portal venous flow is obstructed, col-laterals develop in these (and other) areas, joining portal and systemic
circulations, causing portosystemic shunting. Increased flow causes
the collateral veins to dilate and enlarge, forming varices, which can
bleed. Furthermore, when blood is diverted away from the portal circu-lation, it enters the systemic circulation directly, without first being
detoxified by the liver.
Function
Nutrients and hormones from the pancreas and intestine are carried by
the portal vein to the liver, enabling it to regulate nutrition and metabo-lism. Hepatocytes cannot survive without the portal circulation, even if
total blood flow is maintained from the systemic arterial circulation. This
is probably due its need for growth factors, including insulin, derived
from the intestines and pancreas.
The liver removes toxins that are ingested with food and produced by
bacterial metabolism  in the intestine. Toxic products of bacterial
metabolism include amino acids that mimic neurotransmitters, such
as glutamine and  g-amino butyric acid (GABA), and ammonia,
which interfere with mental function, contributing to  hepatic
encephalopathy.
Medicines absorbed from the intestine first encounter the liver, where
they can be efficiently metabolized. This ‘first-pass metabolism’ is so
efficient for some drugs that the oral dose has to be increased or an alter-native route of administration, for example, sublingual or parenteral,
substituted. Some drugs are designed for clearance by the liver, preserv-ing the local therapeutic effect in the intestine, while the first-pass
metabolism removes the drug from the systemic circulation, reducing
side-effects. The synthetic glucocorticoid budesonide, which is used to
treat inflammatory bowel disease, is an example.
Microorganisms inevitably cross the intestinal epithelium and enter
the bloodstream (bacterial translocation). Kupffer cells in the hepatic
sinusoids normally clear them effectively. Patients with chronic liver
disease and portal hypertension are therefore at increased risk of
bacterial infection.
The body recognizes that food antigens are usually harmless, and
they generally do not elicit an immune response, a phenomenon called
oral tolerance. The liver contributes to this, and antigens injected into
the portal vein also induce tolerance.
Portal hypertension
Liver cirrhosis is the commonest cause of portal hypertension but it
may also occur when the liver is congested in chronic heart failure or
with portal vein thrombosis, for example following trauma or infec-tion. Portal hypertension causes splenomegaly and ascites. Portosys-temic shunting causes varices to form and, particularly if there is severe
underlying liver disease, it causes hepatic encephalopathy.
Splenomegaly may cause hypersplenism and thrombocytopenia as
platelets are trapped in the enlarged spleen.
Ascites is the accumulation of fluid in the peritoneal space. Portal
hypertension increases hydrostatic pressure in intestinal and mesenteric
capillaries, causing fluid leakage. The protein concentration of this
ascitic fluid is low (transudate) and it lacks antibacterial factors, such as
complement, so that it is prone to becoming infected, resulting in spon-taneous bacterial peritonitis.
Varices may form in the oesophagus and gastric fundus, around the
splenic hilum, at the umbilicus, in the rectum and in scar tissue and adhe-sions created by abdominal surgery. They are prone to damage and may
rupture, causing massive, life-threatening gastrointestinal haemor-rhage. This usually causes haematemesis, melaena or haematochesia
(rectal bleeding).
Encephalopathy causes disturbances of  memory, a characteristic
flapping tremor of the hands (asterixis), clumsiness and an inability to
draw simple shapes (constructional apraxia), and drowsiness, which
can progress to coma. Encephalopathy is caused by shunting of toxins
to the systemic circulation and is worse when the capacity of the liver to
inactivate toxins is reduced. It is also aggravated by gastrointestinal
haemorrhage, as blood protein is digested, releasing excess amino
acids that are broken down to release ammonia, which contributes to the
encephalopathy.
Portal pressure can be reduced by creating an artificial portosystemic
shunt or with drugs such as b-blockers. Surgical shunts can connect
the portal vein to the inferior vena cava, or a flexible metal stent
can be placed within the liver, via the jugular vein, under radiological
guidance. This is called a transjugular intrahepatic portosystemic shunt
(TIPSS). Shunts can reduce varices and ascites, and aggravate
encephalopathy.
Hepatic portal system 31
32 Structure and function
Lacteal
Hepatic portal vein
Superior
mesenteric vein
Jejunum
Chyme
Colon
Ileo-caecal
valve
Peyer’s
patches
Caecum
Appendix
Vitamin B12
Bile salts
Folic
acid
Sugars
Amino
acids
Ileum
Mesentery
Plicae circulare
3.5 m
Duodenum
2.5 m Meckel’s diverticulum
(May contain ectopic gastric mucosa
and develop peptic ulcer)

Crypts
Crypt
Villus
Sugars
Amino
acidsTriglycerides
Vitamins
Chylomicrons
Lacteal
Sugars,
amino
acids
Arteriole
Venule
Muscularis mucosae
Crypt
Antigens, viruses,
bacteria
Muscularis mucosae
Short villus
Dome epithelium
Paneth cells
Peyer’s patch
Vitamin B12
Other nutrients
Bile salts
Venule
Arteriole
H2O
11 Jejunum and ileum
The jejunum and ileum are the main absorptive surfaces of the gastroin-testinal tract. They are essential for life and intestinal failure occurs when
surgery or disease leaves less than a metre of functional small intestine.
Structure
The jejunum begins at the junction with the duodenum at the ligament of
Treitz and measures about 3.5·m. The ileum comprises the most distal
2.5·m of small intestine, terminating in the caecum. A loose, redundant
fold of mucosa protrudes into the caecum, forming a flap, the ileocaecal
valve, which prevents reflux of caecal contents into the terminal ileum.
The jejunum and ileum are attached to the posterior abdominal wall by
a long mesentery that allows free movement and rotation, so that the
position of loops of small intestine is highly variable.
The blood supply is derived from the superior mesenteric artery.
Venous drainage is via the superior mesenteric vein into the portal vein
and lymphatics drain into the thoracic duct via mesenteric lymph nodes
and ascending lymphoid channels.
The microscopic structure of the jejunum and ileum is similar to
that of the duodenum, except that Brunner’s glands are absent (see
Chapter 6). Jejunal villi are long, broad and leaf-shaped, while ileal villi
are shorter, rounder and more blunted. Jejunal crypts are deeper than
ileal crypts and contain fewer Paneth cells. Plicae circulare, which are
submucosal folds, increase surface area and are most prominent in the
jejunum. The size of the lumen gradually reduces distally.  Peyer’s
patches are most prominent in the distal ileum.
Function
Mucosal enzymes, particularly disaccharidases and peptidases com-plete the digestive processes initiated by pancreatic enzymes in the
lumen (see Chapter 20).
In addition, jejunal epithelial cells express specialized enzymatic
pathways to process and absorb dietary folic acid. The terminal ileal
epithelium is specialized for the digestion of vitamin B12, which is dis-associated from intrinsic factor in the terminal ileum (see Chapter 21).
Bile salts are released from mixed micelles as fats are digested and
absorbed proximally and are reabsorbed in the terminal ileum through
specific transport proteins. The liver then recycles bile salts through the
entero-hepatic circulation. Specialized ileal function is therefore
essential for healthy nutrition (see Chapter 24).
Approximately  1·m of functioning small intestine must remain to
allow adequate absorption of nutrients. Surgery or disease that leaves
less than this causes short-bowel syndrome and intestinal failure.
There is more lymphoid tissue in the distal ileum than the jejunum and
proximal intestine. This reflects a higher bacterial load and, as the
terminal ileum is also particularly prone to Crohn’s disease, intestinal
tuberculosis and Yersinia infection, it may serve a more fundamental
immunological function (see Chapters 18, 33 & 34).
Common disorders
Abdominal  pain,  diarrhoea,  flatulence,  weight loss and nutritional
deficiencies are the main symptoms of small intestinal disorders.
Obstruction of the small intestine may be caused by disease within the
intestine, or by external compression, or twisting, as in a strangulated
hernia. Typical symptoms are pain, anorexia and vomiting.
Chronic infection with  Giardia lamblia, and with various round-worms, hookworms and tapeworms, is a common cause of malabsorp-tion in endemic areas. Microsporidia and cryptosporidia are particularly
troublesome in immunocompromised individuals, causing intractable
diarrhoea.
Salmonella typhi, the cause of  typhoid fever, gains entry into the
body through Peyer’s patches, which may become acutely inflamed and
can perforate.
Commensal bacteria that are normally found only in the large intestine
may overgrow and accumulate in the small intestine in patients with
anatomical abnormalities, such as congenital pouches and diverticulae,
or surgically created blind loops, or with motility disorders.  Bac-terial overgrowth causes flatulence, abdominal pain, diarrhoea and
malabsorption.
Tropical sprue is associated with chronic bacterial infection of the
intestine, particularly in visitors to tropical regions, and causes malab-sorption due to damage to the small intestinal mucosa. Its incidence has
declined dramatically.
Neoplasia is rare and the most frequent tumours are benign or
maligant neuro-endocrine tumours, lymphomas and smooth muscle
tumours. In areas of high endemic gastrointestinal infection, such as the
Far East, a form of small intestinal lymphoma known as immunoprolif-erative small intestinal disease (IPSID) is relatively frequent.
Meckel’s diverticulum in the small intestine, at the site of attachment
to the embryonic yolk sac, may contain ectopic, acid-secreting gastric
mucosa that can develop peptic ulceration, causing pain and bleeding.
It is the most common malformation of the small intestine, but is rarely
symptomatic.
Crohn’s disease can affect any part of the intestine, but in about
60% of cases it preferentially affects the terminal ileum, causing
mucosal ulceration and transmural granulomatous inflammation.
An inflammatory mass and fistulae between the small intestine and
adjacent structures, such as the bladder, may occur. Crohn’s disease
of the terminal ileum has been shown to be associated with mutations in
the NOD2 gene, which may determine how monocytes and Paneth cells
interact with enteric bacteria (see Chapter 34). Ileocaecal tuberculosis
and Yersinia enterocolitica infection can appear clinically identical to
ileal Crohn’s disease.
Loops of small intestine are extremely mobile and may be caught in
hernial sacs or in adhesions. This can cause intestinal obstruction,
which may need to be relieved surgically.
Jejunum and ileum 33
34 Structure and function
Blood supply and
lumen occluded

Ascending colon
Ileocaecal valve
Superior
mesenteric vein
Terminal ileum
AppendixAppendiceal orifice
Taeniae
Taeniae
Caecum
Triradiate fold
ÆGeneralized peritonitis

Faecalith blocks
appendiceal orifice
Faecalith
Local
inflammation
Acute appendicitis
Perforated appendix
Lumen Vermiform appendix
Caecal volvulus
Appendicitis
Mucus layer
Colonocytes
Scattered
Paneth cells
Muscularis
mucosae
Serosa
Longitudinal muscle
(taeniae)
Goblet cells
Circular
muscle
Epithelium
Lymphoid
follicles
Entero-endocrine
cells
Serosa
Longitudinal
muscle
Circular
muscle
Lumen
Rotates and
twists on normal
mesentery position
Displaced,
dilated
caecum
12 Caecum and appendix
The caecum is the most proximal part of the large intestine, into which
the ileum opens. The appendix is a blind-ended tube protruding from the
caecum.
Structure
The caecum and appendix lie in the right iliac fossa. The  ileocaecal
valve, protruding into the lumen of the large intestine, marks the upper
border of the caecum, which extends down to form a bowl-shaped cavity.
The appendix lies in the distal portion of the caecum and is connected to
it by a slit-like opening.
The blood supply is derived from branches of the superior mesen-teric artery and drains via the superior mesenteric vein into the portal
vein. Lymphatics drain into the thoracic duct via mesenteric lymph
nodes and ascending lymphoid channels.
The caecum and appendix are connected to the posterior abdominal
wall on a variable length of mesentery, which generally fixes the cae-cum to the posterior abdominal wall and leaves the appendix more freely
mobile.
The caecal walls are relatively thin and the longitudinal muscle layer
is gathered into three cords, or taeniae, which meet at the apex of the cae-cum, forming a triradiate fold that can be seen during colonoscopy.
The microscopic structure of the caecum is typical of the large intes-tinal epithelium, with no villi and deep crypts (see Chapter 13). The
epithelial cells are mainly mature enterocytes and goblet cells with scat-tered entero-endocrine and Paneth cells.
The epithelium of the appendix may be disrupted and ulcerated,
exposing the extensive lymphoid tissue in the mucosa and submucosa.
Entero-endocrine cells are scattered through the epithelium.
Function
The caecum and appendix apparently have no special function in
humans, although in other species they are well developed, containing
commensal bacteria that metabolize complex plant carbohydrates, par-ticularly cellulose, that cannot be digested by mammalian enzymes.
Lymphoid tissue in the appendix may somehow contribute to
immune regulation; for example, the incidence of ulcerative colitis is
reduced in people who have had an appendicectomy.
Common disorders
Appendicitis results from obstruction of the appendiceal lumen, caus-ing infection and inflammation. An obstructing faecalith is often seen
when surgery is performed for appendicitis. Initially, appendicitis
causes peri-umbilical pain, nausea and vomiting. This is because vis-ceral nerves from mid-gut structures refer pain to the peri-umbilical
area and stimulate the vomiting centre. As inflammation progresses,
reaching the outside of the appendix, from the parietal peritoneum nerve
fibres carry precise spatial information to the  somatosensory cortex
and pain is localized to the  right iliac fossa, overlying the inflamed
appendix. Untreated, appendicitis may progress to form an appendiceal
abscess or rupture into the peritoneal cavity, causing peritonitis.
Bacterial translocation into the veins draining the appendix may
travel in the portal vein to the liver, where they may cause liver abscess
(see Chapter 33).
Carcinoid tumours occur frequently in the appendix, where they may
remain asymptomatic.
The thin-walled caecum is prone to perforation, for example, due to
intestinal obstruction or in severe colitis (toxic dilatation) (see Chapter
34).
Caecal volvulus occurs when the caecum twists on its own mesen-tery, obstructing the lumen and the blood supply, ultimately causing
necrosis and perforation.
Tuberculosis and Crohn’s disease can affect the caecum, as can colo-rectal cancer. Unfortunately, caecal tumours can remain asymptomatic
for a long time and so may only be detected at a late stage.
Caecum and appendix 35
36 Structure and function
H2O
H2O
H2O
H2OH2O
H2OH2OH2O
H2O
H2O
Transverse mesocolon
Transverse colonTaenia
Haustrae
Ascending colon
Caecal
mesentery
Caecum
Appendix
Superior
mesenteric
Greater
omentum
Ileum
Rectum
Sigmoid mesocolon
Sigmoid colon
Inferior
mesenteric
Descending colon
Mucus layer
Goblet cells
Muscularis mucosae
Circular muscle
Serosa
Taenia
Mucosal protective
factors,  e.g. trefoil
peptidesHydrated
glycosaminoglycan
Tight
junctions
Trefoil peptides
Goblet cellBasement membrane
Luminal
pressure
Luminal
pressure
Thin-walled
diverticulm
Epithelium
Penetrating
artery
Muscularis
(circular
layer only)
Diverticulum formation
13 Colon
The colon comprises most of the large intestine, is about 1.5 m long and
is not essential for life.
Structure
The colon is divided into four parts. The ascending colon begins at the
top of the caecum and ascends in the right flank to the inferior surface of
the liver, where it turns sharply to the left — the hepatic flexure. This is
the start of the transverse colon, which forms a lax arch of variable
length from right to left. It ends at the spleen, turning sharply downwards
and backwards, forming the splenic flexure and joining the descending
colon, which descends along the left flank to the pelvic rim. Here it joins
the sigmoid colon, which is fixed at its upper end, and at its lower end
where it joins the rectum. In between, it curves over the pelvic brim, sus-pended on a length of mesentery.
The ascending and descending colon are largely  retroperitoneal,
while the transverse colon is suspended on a short mesentery attached to
the posterior abdominal wall.
The greater omentum is a sheet of mesentery covered with peritoneal
epithelium and filled with fatty, loose connective tissue. It is suspended
from the lower border of the transverse colon, forming an intra-abdominal apron-like structure and is a site of fat storage, accounting
for some of the abdominal girth of obese middle-aged people.
The superior mesenteric artery supplies the ascending colon and the
proximal transverse colon, and the inferior mesenteric artery supplies
the remainder of the colon. Venous drainage is via the  superior and
inferior mesenteric veins into the hepatic portal vein.
The wall of the colon reflects the general organization of the intestinal
tract, although the external longitudinal muscle is discontinuous. The
layers are, from the outside in:
• serosa;
• longitudinal muscle layer (taenia);
• circular muscle layer;
• submucosa;
• muscularis mucosae;
• mucosal layer comprising the lamina propria and a simple columnar
epithelial lining.
The longitudinal muscle layer is collected into three bands or taeniae.
These are in constant tonic contraction, shortening the colon and pro-ducing characteristic saccular bulges (haustrae).
The lamina propria contains fibroblasts, lymphocytes and other leu-cocytes, entero-chromaffin cells, nerve cell processes and blood vessels,
but lacks lymphatic vessels, which is why lymphatic invasion occurs rel-atively late in colon cancer.
The colonic epithelium lacks villi and has numerous crypts that open
onto the surface. It is lined by a single layer of columnar epithelial cells
(colonocytes), goblet cells and scattered entero-endocrine cells. Stem
cells reside at the crypt bases. There are a few Paneth cells in the ascend-ing colon, even in healthy individuals, and numbers are increased in
inflammatory bowel disease (IBD).
Goblet cells produce copious amounts of mucus that coats the epithe-lium in a tough, hydrated layer, protecting it from mechanical trauma and
bacterial invasion. The main constituents of mucus are polypeptide
chains held together by disulphide bonds, which are heavily glycosy-lated (glycosaminoglycans). The extensive carbohydrate side chains
attract water and become hydrated, forming a slippery gel. Goblet cells
also produce  trefoil peptides, which contribute to host defence by
stimulating epithelial healing.
Blood vessels supplying the colon penetrate the circular muscle layer,
creating a gap and a potential mechanical weakness. In the sigmoid
colon particularly, these gaps can allow herniation of the mucosa and,
with time, allow pouches or diverticulae to form.
Function
The major function of the colon is to reabsorb water from the liquid
intestinal contents remaining after digestion and absorption in the
jejunum and ileum. This converts the faecal stream into a semisolid mass
that is then excreted. Muscular action in the colon mixes and squeezes
faecal matter and propels it toward the rectum. Total colectomy is well
tolerated, apart from potential fluid and electrolyte depletion that can be
avoided by ingesting extra salt and water.
The colon contains 1012 bacteria/g of its content, which are normal
commensals. There are about 500 different species of bacteria, includ-ing lactobacilli, bifidobacteriae, bacteroides and enterobacteriacae.
Most colonic bacteria are anaerobes. Some are potential pathogens,
such as the clostridial species and Escherichia coli, which can acquire
virulence factors via plasmids and bacteriophages. The balance of
species in the commensal flora probably helps to maintain health and,
conversely, alterations in this balance may contribute to illness (see
Chapters 32–34).
Common disorders
Abdominal pain, altered bowel habit (constipation or diarrhoea) and
flatulence are common symptoms arising from colonic disorders.
Bleeding may cause anaemia or may be detected as visible blood in the
stool (haematochesia), or by special testing for faecal occult blood (see
Chapter 43).
Colon and rectal cancer (colorectal cancer) is the second most com-mon cause of cancer-related death in the Western world, where the life-time risk of dying from this disease is 1·:·50 (see Chapter 37).
Bacterial and amoebic dysentery affect the colon and are particularly
common in travellers to endemic areas.
Ulcerative colitis only affects the colon and rectum, while Crohn’s
disease can also cause ileitis and peri-anal inflammation (see
Chapter 34).
Colonic diverticulae may become impacted with faeces, and
inflamed, causing pain; this is a condition known as  diverticulitis.
Blood vessels in diverticulae may be eroded, causing torrential haemor-rhage. The pain of diverticulitis is usually felt in the left lower quadrant
of the abdomen.
Polyps, cancer and vascular abnormalities (angiodysplasia) may
cause anaemia.
Constipation, diarrhoea and abdominal pain are frequently due to the
irritable bowel syndrome (IBS), without any evident organic pathol-ogy (see Chapter 29).
Colon 37
38 Structure and function
Traumatic or surgical   Following obstetric trauma,
damage to sphincter   surgery for haemorrhoids
Peri-anal seepage or  Prolapsed haemorrhoids,
leakage   peri-anal abscess and
fistula formation,
particularly in
Crohn’s disease
Reduced muscle bulk  Old age and debility
and function
Local nerve damage  Following obstetric trauma,
radiation damage
Reduced rectal   Colitis, proctitis, colorectal
reservoir function  cancer, surgical removal
of rectum
Sacrum
Sigmoid
colon
Pubic
symphysis
Puborectalis
Levator ani and
pelvic diaphragm
Dentate line and
sqamocolumnar
junction
Axis of anusAxis of rectum
Anorectal
angle
Squamous
epithelium
Rectal
columns
Deep anal
glands
Haemorrhoidal
cushion
Valves of
Houston
Rectum
Cortical
efferents
Cortical
afferents
Sacral spinal motor neurons
External
anal sphincter
Urge to defecate
Defecation
Defecation
Cause of incontinence
No defecation
Internal anal sphincter
Sacral p a rasympathetic ef erent
Myenteric
plexus
External
sphincter
relaxes
Sensory
para-sympathetic
nerves
Sacral spinal cord segment
Intra-abdominal
pressure
Intra-abdominal
pressure
Contraction
Anorectal
angle
straightens
Anorectal
angle more
acuteInternal
sphincter
closes
Rectum dilates to
accommodate
increased volume
or
14 Rectum and anus
The rectum and anus comprise the most distal part of the gastrointestinal
tract.
Structure
The rectum is 12·cm long and extends from the sigmoid colon to the
anus. It lies in front of the sacrum and is retroperitoneal, except proxi-mally and anteriorly. It lies behind the  prostate gland and seminal
vesicles in men and behind the pouch of Douglas, uterus and vagina in
women.
The wall of the rectum is similar to the colon, except that the longitu-dinal muscle layer is continuous. The mucosa is thrown into three semi-lunar transverse folds, known as the  valves of Houston, which sep-arate flatus from faeces and prevents them entering the distal rectum
spontaneously.
Distally, the mucosa forms longitudinal ridges, called  rectal
columns, and the intervening furrows terminate in small folds at the
anorectal junction, termed anal valves. The line through the anal valves
is also the  squamocolumnar junction between the rectal and anal
mucosae and is termed the dentate line.
Three cushions of loose connective tissue are arranged circumferen-tially above the dentate line. They contain a venous plexus (haemor-rhoidal plexus) and contribute to anal sphincter function. The veins
enlarge with time, forming piles or haemorrhoids.
The anus is  2.5–4.0·cm long and its lumen is directed posteriorly,
forming a 70∞ angle with the rectal lumen. This angulation assists anal
sphincter function. The circular smooth muscle layer, which is continu-ous with the rectal muscular layer, forms the powerful internal anal
sphincter. An external layer of voluntary (striated) muscle constitutes
the external anal sphincter. Muscle fibres of the levator ani and pubo-rectalis muscles, which form part of the pelvic floor, encircle the anus;
the levator ani lift the anus while the puborectalis pulls it forward and
upward, making the anorectal angle more acute, further strengthening
the sphincter.
The anus is lined by a non-cornified stratified squamous epithe-lium that is continuous with the peri-anal skin. Submucosal anal glands
situated deep to the sphincter communicate with the surface through
narrow ducts and their secretions lubricate and protect the anal canal.
Autonomic and  somatic nerves from the sacral segments of the
spinal cord innervate the rectum and anus. Internal anal sphincter tone is
maintained by parasympathetic signals and the external anal sphincter
is controlled by  sacral motor neurons. The anus is innervated by
somatic sensory nerve endings and is, therefore, as sensitive as the skin
to pain and touch.
Function
The rectum acts as a reservoir for faeces and the anus is a powerful
sphincter controlling defecation. The rectum is wider than the rest of the
large intestine and can be further distended.
Defecation is initiated by distension of the rectum, causing increased
pressure, which stimulates  intrinsic nerves to increase  peristalsis
proximally in the sigmoid colon and to relax the internal anal sphinc-ter. Parasympathetic nerves from the sacral plexus amplify this intrin-sic neural reflex. The external anal sphincter is under voluntary control
and if it relaxes when the internal anal sphincter relaxes, defecation com-mences.  Puborectalis and  levator ani relax, allowing the  anorectal
angle to straighten, and abdominal muscles contract, to increase intra-abdominal pressure and help expel faeces. Conversely, if the external
anal sphincter does not relax, the urge to defecate passes.
Although the rectum does not normally absorb nutrients, medications
can be administered by a suppository or an enema and are absorbed into
the systemic circulation. This is particularly useful in babies and patients
who cannot swallow.
Common disorders
Anorectal disorders typically cause  pain, itching (pruritis ani) and
bleeding (haematochesia). Pain can inhibit defecation, resulting in
hardening of the stool and a self-perpetuating cycle of constipation.
Inflammation causes  diarrhoea and the passage of  mucus. Chronic
inflammation can reduce the ability of the rectum to dilate, causing
urgency of defecation. Tenesmus is the sense of incomplete defecation.
Incontinence is a distressing symptom, which may result from local dis-ease, severe diarrhoea or neuromuscular disorders.
Bright red rectal bleeding occurring at the end of defecation is usually
caused by haemorrhoids. Blood mixed with stool indicates bleeding
from a more proximal source.
The anus can be examined externally to reveal prolapsed haem-orrhoids, skin tags and anal fissure. To complete clinical examination
of the anorectum, a gloved finger is inserted into the anus (digital
rectal examination) and this can be followed by a proctoscopy or a
sigmoidoscopy (see Chapters 43 & 44).
Cancer and  inflammation affect the rectum as frequently as the
remainder of the large intestine. In ulcerative colitis, proctitis (inflam-mation of the rectum) is almost invariably present. Crohn’s disease does
not always affect the rectum; however, anorectal Crohn’s disease caus-ing abscesses and fistulae occurs in 30% of cases (see Chapters 34 & 37).
Haemorrhoids are caused by engorgement of veins in the soft con-nective tissue cushions around the anorectal junction. First degree
haemorrhoids remain within the rectum, second degree haemorrhoids
reversibly prolapse out of the anus, and third degree haemorrhoids are
permanently prolapsed.
Passage of hard stool against a tight anal sphincter can tear the anal
skin, causing an anal fissure.
Abscesses and fistulae in the soft tissue around the anus are caused by
infection of the peri-anal glands. They are treated with antibiotics and
surgical incision and drainage.
Sexually transmitted diseases, including peri-anal warts caused by
the human papilloma virus, genital herpes and syphilis may affect the
anorectum.
Pain in the anus, without any discernable organic cause is proctalgia
fugax (see Chapter 29).
Rectum and anus 39
40 Integrated function
Smooth
muscle cell
Striated muscles
(cricopharyngeus) and
upper 3rd oesophagus
Longitudinal
muscle
Muscularis
mucosae
Epitheium
Circular muscle
Lumen
Oblique muscle
Circular
muscle
Longitudinal
muscle layers
Myosin
Taeniae
(longitudinal)
Circular layer
Smooth muscle
internal sphincterStriated external
sphincter
Anal
sphincter
Wave of
relaxation
Wave of
contraction
Migrating
motor
complex
Phase II
Colonic mass
movement
Gastric churningPyloric
sphincter
Sphincter
of Oddi
Lower oesophageal
sphincter
Diaphragm
Pacemaker
potential
moves rapidly circumferentially
Moves slowly
longitudinally
Ion channels
K+
Ca2+
Ca2+
Pacemaker
cell
Gap
junction
Actin
Junctional
complex
Intestinal smooth muscle
Peristalsis
Pacemaker
Segmentation
15 Enteric motility
Smooth muscle in the intestinal tract powers the disruption, mixing and
propulsion of food from mouth to anus. It also discharges glandular con-tents and allows sphincters to separate intestinal compartments.
Structure
Apart from the mouth, tongue, pharynx and external anal sphincter,
which have striated muscle under voluntary control, the gastrointestinal
system contains non-striated smooth muscle under enteric and auto-nomic nervous control. Unusually, the upper oesophagus has striated
muscle that is not under voluntary control.
The main muscle bulk is arranged in an outer longitudinal layer and
an inner circular layer, allowing shortening and constriction of the hol-low tube. In the caecum and colon, the longitudinal layer is bundled in
three separate cords or taenia. An inner oblique layer augments these
layers in the stomach and the circular layer is thickened around sphinc-ters, increasing the constrictive force. The main sphincters are the lower
oesophageal sphincter, the pylorus, the sphincter of Oddi, the ileocaecal
valve and the anal sphincter.
A thin layer of muscle, the muscularis mucosae, separates the lamina
propria from the submucosa.
Smooth muscle cells are spindle-shaped and lack striations created
by organized bundles of actin and myosin.
Function
Contraction is mediated by  cross-linking of actin and myosin, as
in striated muscle. Contraction is initiated by increased intracel-lular Ca2+ concentration, which is regulated by hormonal and neural
signals.
Intrinsic electric  pacemaker cells are interspersed among the
muscle cells and these provide a characteristic, low frequency wave of
electrical depolarization and repolarization, known as the slow wave,
that travels down the intestine. Pacemaker cells communicate via gap
junctions, with the signal travelling faster circumferentially than
transversely, so that a  synchronous wave is propagated along the
intestine. Distinct pacemaker frequencies characterize each organ; for
example, the  gastric slow wave frequency is three contractions per
minute, which can be measured through electrodes on the abdominal
wall (electrogastrography).
Tonic contractions
These are mainly  sustained, low-pressure contractions that occur in
organs with a major storage function, such as the gallbladder and rec-tum. High-pressure tonic activity characterizes sphincters.
Phasic contractions
These short-lived, rhythmic contractions predominate in the intestine.
They are controlled by intrinsic pacemakers, autonomic nerves and
coordinated reflex enteric nerve activity, and include:
• Peristalsis: which is a complex movement whereby a wave of muscu-lar relaxation, followed by a wave of contraction, passes down the intes-tinal tract proximally to distally. The wave forces intestinal contents
before it and is most prominent in the oesophagus, stomach and small
intestine. In vomiting, peristaltic contractions move retrogradely
(distally to proximally).
• Gastric churning: which is the result of tonic contraction of the
pylorus and vigorous peristalsis in the stomach, repeatedly squeezing
and mixing solid food, turning it into a  semi-liquid chyme that is
released into the duodenum.
• Segmenting movements: which are randomly spaced,  non-propagating circular muscle contractions that mix intestinal contents.
• Colonic mass movement: which is a powerful, sweeping contraction
that occurs a few times a day, forcing faeces into the rectum and stimu-lating defecation.
• Interdigestive migrating motor complex  (IMMC): which com-prises three stages lasting about an hour each, occurring between meals.
In stage I, movement is absent. Stage II, comprising of random segment-ing movements, is followed by stage III, which comprises a forceful
wave of contraction that migrates from lower oesophagus to terminal
ileum. This wave, sweeping the stomach and intestine clean of food
debris, is termed the ‘intestinal housekeeper’.
Regulation
Peristalsis is intrinsic to the intestine, occurring even in surgically iso-lated segments, and is mediated by reflex enteric nerve activity. Nitric
oxide (NO) is the main mediator of relaxation in the advancing front of a
peristaltic wave, while acetylcholine (ACh) and other neurotransmit-ters mediate contraction.
Entero-endocrine and neural pathways mediate  reflex motility
involving spatially separated parts of the gastrointestinal system, such as
the cholecystokinin-induced contraction of the gallbladder in response
to food in the duodenum, the gastrocolic reflex (urge to defecate after
eating) and the ileal brake (reduced ileal peristalsis when food reaches
the distal small intestine).
Serotonin (5-hydroxytryptamine,  5HT), released by entero-endocrine cells, is a critical regulator of intestinal motility through its
effects on enteric neurons. 5HT3 receptors mediate increased intestinal
motility, while 5HT4 receptors mediate the opposite effect, and selective
inhibitors could prove to be useful therapeutically.
Common disorders
Dysmotility may manifest as pain, discomfort, early satiety, vomiting,
diarrhoea or constipation. It is associated with some rare but serious
conditions and some more common conditions.
Oesophageal dysmotility can cause pain (odynophagia) and difficulty
in swallowing (dysphagia). Powerful, uncoordinated spasms (nut-cracker oesophagus) can cause severe pain. In achalasia, tonic hyper-activity of the lower oesophageal sphincter, and absent peristalsis
proximally, causes dysphagia and dilatation of the distal oesophagus.
Infants may develop gastric outlet obstruction with persistent projec-tile vomiting due to congenital hypertrophy of the pyloric sphincter.
Following surgery or severe illness, generalized paralysis of the intes-tine, known as  paralytic ileus, may develop. This is aggravated by
hypokalaemia, hypocalcaemia and the use of opiates, which inhibit
intestinal motility. It usually resolves spontaneously, although the intes-tine may dilate to such an extent that the wall becomes ischaemic and
emergency surgery is necessary.
Less well-defined abnormalities of motility may contribute to slow-transit constipation, functional bowel disorders and irritable bowel
syndrome (IBS).
Muscular spasm may be treated medically with relaxants such as
mebeverine and hyoscine. Sphincter spasm may be mechanically
dilated or botulinum toxin injections may induce temporary paralysis.
Both techniques are used to treat achalasia.
Metoclopramide may stimulate foregut motility, as may erythromy-cin, acting on motilin receptors, and neostigmine, acting on muscarinic
acetylcholine receptors.
Enteric motility 41
42 Integrated function
Peptide hormone
Secretin-VIP family
Secretin
Vasoactive intestinal peptide (VIP)
Glucagon
Enteroglucagon
Gastrin-cholecystokinin family
Gastrin
Cholecystokinin (CCK)
Pancreatic polypeptide family
Peptide YY (PYY)
Motilin
Miscellaneous
Somatostatin
Leptin
Ghrelin
Main source
Duodenum, jejunum, released in response to acid in duodenum
Nerve endings throughout intestine
Pancreatic a cells
Ileum, released in response to luminal food
Gastric G cells, in response food in stomach, pancreas, small
intestine
Duodenum and jejunum, released in response to fatty meal in
duodenum
Ileum, proximal colon
ECL cells in proximal small intestine
Throughout intestine and pancreas
Small intestine, adipocytes
Intestine
Function
Stimulates  pancreatic secretion, inhibits acid production, reduces motility
Stimulates secretion of fluid and chloride by enterocytes
Counteracts effects of insulin
Trophic to the small intestine: promotes intestinal cell proliferation
Stimulates gastric acid production, growth factors
Stimulates gallbladder contraction, pancreatic secretion, slows gastric
emptying, signals satiety to brain

Slows peristalsis in response to food in ileum and colon (ileal brake)
Stimulates migrating motor complex (see Chapter 15)
Inhibits secretion by most entero-endocrine cells, reduces splanchnic blood flow
Signals satiety centrally and stimulates energy expenditure
Signals satiety
Flushing wheezing
Æ carcinoid syndrome
Appetite control centres
in mid-brain and hypothalamus
Gastric
gland
Parietal cells Enterochromafin-like cells (ECL)
Mast cells
Histamine
Paracrine
effect
Gastrin
G cells
Gastrin
Endocrine
effect
Mucosal blood vesselEnteric
nerve cellVagus
nerve
Acetyl
choline
Somatostatin
D cell
Pancreatic
acini
HCl
HCl
HCl
HCl
D cells
(somatostatin)
b cells (insulin)
a cells
(glucagon)
Pancreatic islet
Capillary
Villus
ECL cells
CryptEntero-endocrine
cells
Small
intestine
Pancreas
Stomach
Leptin
Ghrelin
Appendiceal
carcinoid tumour
5HT
Large
intestine
Goblet
cells
Epithelial
entero-endocrine cell
5HT carried in
portal circulation
Portal vein
5HT metabolized
by hepatocytes
Metastic
carcinoid
tumour 5HT intact in
systemic
circulation
ECL
cells
16 Enteric endocrine system
The first hormone ever discovered was the enteric hormone secretin.
Subsequently, over 30 enteric (or gut) hormones have been described, all
secreted by specialized entero-endocrine (also called neuro-endocrine)
cells distributed throughout the gastrointestinal system. They mainly
control gastrointestinal motility and secretion, and they mediate
communication from one part of the intestine to another and outside the
intestine, for example, to the central nervous system.
Structure
Entero-endocrine cells
The entero-endocrine system is  diffusely distributed. Most entero-endocrine cells are found in the epithelium of the intestine. They vary
in shape, although most are pyramidal with the base of the pyramid on
the basement membrane, where prominent  secretory granules are
located. Some cells span the epithelium, with the apex in contact with the
lumen, while others do not. Entero-chromaffin-like cells (ECL) are
similar in structure but are located in the submucosa or in the pancreatic
islets.
Many entero-endocrine cells contain more than one hormone, and
hormones are preferentially distributed in cells in different parts of the
system. Enteric hormones are also found in neurons in the enteric and
central nervous systems and are, therefore, often called  gut-brain
peptides. Endocrine and neuro-endocrine effects in the gastrointestinal
system therefore often overlap.
Enteric hormones
Almost all entero-endocrine cells contain serotonin (5-hydroxytrypta-mine,  5HT), in addition to peptide hormones, while ECL cells
contain histamine. Most enteric hormones are short peptides that are
synthesized as larger prepropeptides and modified by, for example,
cleavage, amidation and sulphation. They fall into structural families
and tissue distribution and function vary widely (see  table in figure
opposite).
Function
Enteric hormones perform a great range of functions and work in differ-ent ways. Some are relatively well understood and others are only now
beginning to be understood. The functions of some peptide hormones are
shown in the table opposite.
Enteric hormones may act locally (paracrine action) in the im-mediate vicinity of where they are secreted; for example, somatostatin
produced by D cells in pancreatic islets inhibit insulin and glucagon
secretion. They may also first enter the circulation and then be trans-ported to targets in other parts of the intestine (endocrine action). An
example is cholecystokinin (CCK) released by cells in the duodenum
and then inhibiting gastric gastrin production and stimulating gallblad-der contraction. They may also be transported to other organs and, in par-ticular, to the central nervous system. Leptin and ghrelin are recently
discovered examples, which signal satiety, and are involved in the
control of nutrition.
Individual hormones may also have different effects on different tar-gets, sometimes mediated by separate receptors. Examples include gas-trin, which binds to CCK-Aand CCK-B receptors, and 5HT, which has at
least five different receptors (5HT1–5 receptors), sometimes mediating
opposite effects.
Some enteric hormones and their receptors have very specific effects
that have been successfully targeted therapeutically.  Histamine re-ceptor type 2 (H2R) antagonists, such as cimetidine and ranitidine, that
reduce gastric acid secretion, are among the most successful agents of
this type.
Similarly, octreotide, a modified octapeptide (8 amino acid) homo-logue of somatostatin, is widely used to inhibit the secretion of other
enteric hormones, inhibit intestinal exocrine secretion and reduce
splanchnic blood flow.
There are now also new agents aimed at inhibiting different 5HT
receptors, to treat aspects of the irritable bowel syndrome (IBS).
Attempts to use leptin to decrease appetite and induce weight loss
have been generally unsuccessful; however, now that the role of enteric
hormones in regulating body mass has been appreciated, this is a chal-lenging and promising area of clinical research.
Common disorders
Subtle entero-endocrine dysfunction may be responsible for very
common conditions such as the irritable bowel syndrome and obesity;
however, this is hard to prove and remains speculative.
Most serious entero-endocrine diseases are rare, although clinically
silent carcinoid tumours are frequently noted at autopsy.
Symptoms caused by disorders of the entero-endocrine system are
protean, reflecting the many effects of enteric hormones. To diagnose
entero-endocrine dysfunction, circulating enteric hormone levels may
be measured (in the fasting state, as feeding alters the levels of most
hormones) and excess 5HT secretion may be determined by measuring
urinary excretion of 5-hydroxyindole acetic acid (5-HIAA).
Carcinoid tumours arise from entero-endocrine cells, and are rela-tively common. They may secrete a variety of hormones and growth fac-tors and 5HT secretion is usually prominent. Carcinoids usually arise in
the appendix, but may occur in other parts of the intestine. The portal cir-culation delivers 5HT from intestinal carcinoids to the liver, which effi-ciently clears it, so that patients remain asymptomatic. However, when
the tumours metastasize to the liver and deliver their hormones directly
into the systemic circulation, they give rise to the carcinoid syndrome,
characterized by episodes of  flushing caused by release of 5HT and
fibrosis of the heart and peripheral tissues, caused by growth factors,
such as transforming growth factor b (TGFb) released by the tumour.
G-cell tumours (gastrinomas) secrete excess gastrin, causing the
Zollinger–Ellison syndrome, which is characterized by severe gastric
hyperacidity, recurrent peptic ulceration and malabsorption due to the
reduced efficiency of digestive enzymes in an acid milieu. Gastrinomas
may occur sporadically, or in association with other endocrine tumours
in a syndrome known as multiple endocrine neoplasia I, or MEN-I.
The syndrome is caused by an inherited abnormality in the tumour sup-pressor gene MEN1.
There are many other rare entero-endocrine tumour syndromes, such
as  glucagonomas and vasoactive intestinal peptide (VIP)-secreting
tumours that cause the syndrome of watery diarrhoea and hypokalaemia
(Werner–Morrison syndrome) (see Chapter 38).
Enteric endocrine system 43
44 Integrated function
5HT5HT
5HT
ACh
VIP
5HT
NO
Submucosal
plexus
(Meissner)
Sensory
motor
cortex
Hypothalamus
Nodose ganglion
Medulla oblongata
S2
S3
S4
Generally
≠secretion
≠motility
Generally
Øsecretion
Ømotility
asphincter tone
Sacral
parasympathetic
nerves
Pelvic plexus
Hypogastric plexus
Inferior
mesenteric
plexus
Coeliac plexus
Superior
mesenteric
plexus
T1
Colon
Gall-bladder
Via carotid
artery plexus
Superior
cervical ganglion
Splanchnic nerves
Sympathetic chain
S2
S3
Selected neurotransmitters

5HT  Serotonin (entero-endocrine cells
+ enteric nerves)
NA Noradrenaline (sympathetic)
DA Dopamine (sympathetic)
NPY Neuropeptide Y (sympathetic)
NO  Nitric oxide (enteric nerves)
VIP  Vasoactive intestinal peptide
(enteric nerves)
ACh Acetylcholine (parasympathetic)
Substance P  Pain sensation
CGRP  Calcitonin gene-related peptide—
pain sensation
Enteric nerves
Autonomic nerves
Sympathetic Parasympathetic
Epithelium
Myenteric
plexus
(Auerbach)
Sympathetic
nerves
Efferent and
afferent
Bare nerve
ending (sensory fibre)
Entero-endocrine cells
Blood vessel
Longitudinal muscle
Circular muscle
Substance P
Parasympathetic nerve
Efferent and afferent
ECL
CGRP
Sensory nerve ending
Vagus nerve (Xth)
Facial nerve
(VIIth)
Submandibular
ganglion
Otic ganglion
Glossopharyngeal nerve (IXth)
Salivary
gland
17 Enteric and autonomic nerves
Neural as well as hormonal signals coordinate gastrointestinal func-tion, including motility, and the gastrointestinal system has its own
intrinsic enteric nervous system, as well as being innervated by the
sympathetic and parasympathetic divisions of the autonomic nervous
system.
Structure
Enteric nervous system
There are between 107 and 108 nerve cells in the enteric nervous system,
which almost matches the number in the spinal cord. Most are small,
with  short processes that terminate locally, and they are generally
arranged in two layers: the  myenteric (Auerbach’s) plexus that lies
between the circular and longitudinal muscle layers and the submucosal
(Meissner’s) plexus that lies in the submucosa. The submucosal plexus
mainly responds to and regulates epithelial cell and submucosal blood
vessel function, while the myenteric plexus mainly regulates intestinal
motility and sphincter function.
Enteric nerves typically use more than one neurotransmitter, includ-ing a variety of amino acid derivatives, peptides, acetylcholine (ACh),
and nitric oxide (NO). There may also be multiple receptor types for
any one neurotransmitter; for example, there are at least five different
subtypes of serotonin (5-hydroxytryptamine, 5HT) receptors. Enteric
nerves respond to stimuli from other enteric nerves, from autonomic
nerves, and from epithelial cells, including entero-endocrine cells.
Extrinsic motor (efferent) nerves
Voluntary nerves
Voluntary nerves control the lips, tongue, muscles of mastication, as well
as pelvic floor muscles and the external anal sphincter.
Autonomic nerves
Sympathetic nerves originating from the cervical sympathetic chain
and travelling in the splanchnic nerves, via the coeliac and other gan-glia, innervate the entire gastrointestinal system.
Parasympathetic innervation is provided mainly via the glossopha-ryngeal (IXth) and vagus (Xth) cranial nerves to foregut and mid-gut
structures. The salivary glands also receive parasympathetic fibres via
the facial (VIIth) cranial nerve. The sacral parasympathetic plexus
provides parasympathetic innervation distally beyond the hepatic
flexure of the colon.
Extrinsic sensory (afferent) nerves
Touch, pain and temperature sensation in the mouth and tongue are
similar to those in the skin and are represented on the sensory cortex in
the same way. In fact the tongue has a relatively large cortical represen-tation. Similarly, somatic sensory nerves innervate the  anus.  Taste
sensation is carried by fibres that synapse in the nucleus of the tractus
solitarius in the mid-brain.
Sensory information from the rest of the gastrointestinal system trav-els to the central nervous system via the sympathetic and parasympa-thetic nerves. Most enteric vagal fibres are afferent; nonetheless, the
density of sensory nerves in the internal organs is much lower than, for
example, the skin. Visceral afferents send signals to the hypothalamus,
where some pain sensation is processed and also to centres controlling
swallowing, vomiting, blood pressure, heart rate and other autonomic
functions. Afferent nerves use substance P and calcitonin gene-related
peptide (CGRP) as transmitters.
Function
Complex motor functions, such as peristalsis, remain intact in isolated
intestinal segments lacking external innervation, confirming the com-plexity and completeness of the enteric nervous system. Enteric nerves
also control other important functions, including secretion and regula-tion of blood flow under the changing conditions imposed by intermit-tent feeding. Their function is, however, modified by autonomic
innervation. Sympathetic nerves, using  noradrenaline (NA),
dopamine (DA) and  neuropeptide Y (PY) as transmitters, tend to
decrease intestinal motility and secretion and increase sphincter tone.
Parasympathetic nerves mainly use acetylcholine (ACh) and cholecys-tokinin (CCK) as neurotransmitters and tend to increase secretion and
motility.
Although there is some spatial coding of visceral sensory input in the
central nervous system, visceral sensation is spatially and temporally
much less precise than somatic sensation. Many factors contribute to
this, including the relative low density of sensory nerves in the intestine
and other internal organs, and the fact that visceral afferent nerves use
non-specific  naked nerve endings rather than specialized sensory
organs, such as the touch, temperature and pain receptors found in the
skin, so that they cannot differentiate widely divergent stimuli. Further-more, visceral afferent fibres are  unmyelinated and relatively slow-conducting, so temporal resolution is reduced.
The poor resolution and specificity of visceral sensation contributes to
difficulty in localizing visceral pain and is partly responsible for the phe-nomenon of referred pain. This is illustrated by the classic symptom
pattern in evolving acute appendicitis. The earliest symptoms include
peri-umbilical abdominal pain, anorexia and nausea, which are medi-ated by visceral nerves serving the entire mid-gut. As inflammation pro-gresses and the visceral and parietal peritoneum are involved, somatic
nerves innervating the parietal peritoneum are stimulated and pain is
localized to the right iliac fossa, overlying the inflamed organ. Finally,
muscles overlying the region become tense, causing guarding, a protec-tive reflex mediated by motor nerves to voluntary muscle (see Chapter
12).
Common disorders
Abnormalities of enteric and autonomic nerve function can contribute
to many typical gastrointestinal symptoms, including nausea, vomit-ing,  diarrhoea,  constipation and abdominal  pain. Dysfunction of
the enteric nervous system, causing increased visceral sensitivity and
abnormal motility and secretion, may contribute to functional bowel
disorders and the irritable bowel syndrome (IBS), although there is no
definitive proof of this.
Diabetes mellitus and other systemic illnesses can damage peripheral
nerves in the intestine causing autonomic neuropathy.
Hirschsprung’s syndrome is a rare disorder caused by the congenital
absence of myenteric nerves in a segment of the colon, causing chronic,
severe constipation. Patients may develop a massively dilated, faeces-filled colon (megacolon) proximal to the affected segment and surgical
removal of the affected segment is curative.
Visceral pain may sometimes be treated by ablation of the sympa-thetic autonomic nerves to the affected part; for example, in chronic pan-creatitis, the coeliac ganglion may be removed or destroyed in situ.
Enteric and autonomic nerves 45
46 Integrated function
H2O
H2OH2O
H2O
S
H2OH2O
H2OH2O
H2O
H2O
S
Liver-associated
lymphocytes
Salivary pH,
mucins,
proteins
Tonsils
Mucus
layer
Acid
Constant
movement
Jejunum
Ileum
Regional lymph
nodes
Alkali
Portal vein
Commensal
bacteria
Hepatocytes Lumen
Villus
Crypt
Dendritic
cell
Stem
cell
Lysozyme
defensins
PLA2
H+
OH–
Mast
cell
Macrophage
Eosinophil
Neutrophil
Lymphocytes
Glycocalyx
Intra-epithelial
lymphocyte
(IEL)
Paneth cells
M cell
Peyer’s patches
sIgA secretion
Mucin
Goblet cell
Lamina
propria
Enterocyte
VirusLumen
Bacteria
ProteinPrion
Lamina propria
Lymphocyte
Dendritic cell
Macrophage
M cell
Lumen
Dome epithelium
Follicle Chemokines
(e.g. TECK)
Endothelium
Madcam
b7 integrin
Gut-homing lymphocyte
Cortex
sIgA
Lumen
Enterocyte
Secretory
component
Transcytosis
Dimeric
IgA
Plasma cell
Kupffer
cell
Mucus layer
18 Mucosal immune system
The gastrointestinal system presents a large exposed surface area that
must be maintained and defended. Furthermore, prions, viruses, bacte-ria, parasites, inert particles and toxins are constantly ingested and there
is a large resident microbial flora, particularly in the large intestine. The
mucosal immune system regulates how the body responds to these chal-lenges.
Structure
Many structures contribute to gastrointestinal defences. Innate defence
mechanisms include:
• The constant  movement of intestinal contents, and their periodic
expulsion.
• The pH and chemical composition of intestinal secretions; for exam-ple, corrosive stomach acid and detergent bile salts.
• Antibacterial enzymes and peptides, such as lysozyme in saliva and
other exocrine secretions.
• Mucins form a tough, slippery mucous gel, protecting epithelial cells
from mechanical damage.
• Intrinsic cellular defences in epithelial cells, which can resist and
limit invasion by pathogens.
• Specialized intestinal epithelial cells, such as  Paneth cells, which
secrete many antibacterial enzymes and peptides, such as defensins.
• Mast cells, eosinophils, neutrophils, macrophages and dendritic
cells in the lamina propria constitute a first line of defence against
pathogens that breach the epithelial layer and also process and present
antigens to cells of the adaptive immune system.
Adaptive immunedefences include:
• Lamina propria lymphocytes: these B and T cells are distinct from
those found in the blood and are specifically targeted to the intestine.
• Intra-epithelial lymphocytes: T lymphocytes are found between
epithelial cells, particularly in the small intestine. They are not migrating
through, but are resident in this position. Many of these cells express gd
T-cell receptors, with a restricted repertoire, rather than the regular ab
T-cell receptors found elsewhere. They react to lipid antigens presented
on CD1 cell surface molecules rather than peptides presented on classic
major histocompatibility complex (MHC) class I or II molecules, and
may have a special role responding to proteolipid antigens in bacterial
cell membranes.
• Peyer’s patches: these are distinctive structures with a specialized
epithelial lining, containing B and T lymphocytes and antigen presenting
cells. They are most numerous in the terminal ileum. The specialized
dome epithelium lacks villi and crypts and the glycocalyx formed by
microvilli and membrane glycoproteins is deficient. It contains special-ized epithelial cells called microfold or M cells, which lack microvilli
and contain membranous folds enclosing lymphocytes, macrophages
and dendritic cells. They trap antigens and transport them across the
epithelium, to interact with immune cells.
Under the dome epithelium, lymphocytes, macrophages and dendritic
cells form a loose T-cell-rich cortical region and compact B-cell-rich
follicles, resembling the organization of lymph nodes.
•Tonsils are lymphoid aggregates surrounding the opening of the
hypopharynx, with a broadly similar structure and function to Peyer’s
patches, and in the stomach, colon and appendix, Peyer’s patches may
be substituted by less well-defined lymphoid aggregates in the lamina
propria.
Function
While host defences must prevent infection and damage to the absorp-tive epithelium of the gastrointestinal tract, the commensal flora of the
intestine is essential for health and the system must distinguish between
beneficial and harmful bacteria. Furthermore, while the intestine must
mount immune responses to pathogens, it must also prevent reactivity to
food antigens to avoid  allergies and  hypersensitivity. The mucosal
immune system fulfils these functions in ways that are still poorly under-stood. Thus while pathogens are generally repelled,  oral tolerance
develops towards to harmless intestinal contents.
• M cells. These transport intact peptides, viruses and bacteria across
the epithelium and pass them on to antigen processing and presenting
cells. The surface molecules involved in this transport are presently
unknown.
• Mucosal homing. Antigens taken orally are transported to regional
lymph nodes where they cause proliferation of lymphocytes. These spe-cific T lymphocytes and antibody-producing B lymphocytes leave the
lymph nodes and return to mucosal surfaces.
Homing to the mucosa is mediated by cell surface molecules that
interact with receptors on blood vessels in the gastrointestinal tract
(addressins). Lymphocytes homing to the intestine express the a4b7
integrin molecule that interacts with the mucosal addressin-cell adhe-sion molecule (MAD-CAM). Specific cytokines (chemokines) also
attract subsets of lymphocytes to different parts of the intestine; for
example, thymus and epithelial expressed chemokine (TECK) attracts
cells to the small intestine.
• Secretory dimeric immunoglobulin A (sIgA). Most B cells at
mucosal surfaces produce IgA, which is the most abundant
immunoglobulin in bronchial, reproductive tract and intestinal secre-tions. Two IgA molecules, joined together to form polymeric IgA
(pIgA), bind to a receptor called  secretory component  (SC) on the
basolateral surfaces of epithelia. The complex is transported across
the cell cytoplasm (transcytosed) and sIgA is released at the luminal
surface, by proteolytic cleavage of SC.
Common disorders
The intestinal epithelium is not impervious to proteins, viruses and
bacteria, as was previously assumed. Prions, such as the bovine
spongiform encephalopathy (BSE) agent, viruses, such as human
immunodeficiency virus (HIV), and pathogenic bacteria, such as
Shigella, are taken up by M cells, allowing systemic spread and
infection.
Selective IgA deficiency affects about 1·:·500 people, without much
effect on enteric immunity.
Chronic immune stimulation, for example, by Helicobacter pylori or
by coeliac disease, can lead to excess proliferation of immune cells, neo-plastic change and intestinal lymphoma.
True food allergies are rare, although they may be becoming more
frequent; particularly those caused by nut antigens.
Dysregulated immune responses are implicated in coeliac disease,
where there is hypersensitivity to peptides derived from wheat and
other cereals and in  inflammatory bowel disease  (IBD). Inflam-mation may normally be actively prevented by subsets of T lympho-cytes, which might have regulatory functions that are defective in
IBD.
Mucosal immune system 47
48 Integrated function
Neural signalling
and coordination
Salivary lubrication
and digestion
Gastric maceration,
acidification and digestion
Gastric
intrinsic
factor
Pancreatic alkalinization
and digestion
Oral mastication
and lubrication
Mixed micelle
Villi
Hydrophobic
core
Fatty
acid
Phospholipids
Bile
salts
Bacterial production
(Vitamin K, folic acid)
Bile acids, vitamin B12
Preferential uptake sites
Folic acid
Iron
Water and
electrolytes
Plicae
circulare
Vitamin
B12
Antral
churning
and liquefaction
Enteroendocrine signalling
and coordination
Intestinal
digestion
and absorption
Vagus nerve
Bilary alkalinization
and emulsification
Increased surface area
– plicae circulare (3x)
– villi (10x)
– microvilli (20x)
Total =  600x
Microvilli
19 Digestion and absorption
The main function of the intestine is to digest and absorb nutrients, and it
is variously adapted for this. Taste provides a guide to the nutritional
value or potential toxicity of food, and while the colon is not essential for
nutrition it helps to conserve water and salts. Details of digestion and
absorption are considered in Chapters 20 and 21 and here general
principles are emphasized.
Coordination
Hunting, gathering and supermarket shopping all require exquisite
neuromuscular coordination, as do biting, chewing and swallowing.
Thus, patients who are weak or who have neurological disease, such as a
stroke, can rapidly become malnourished. Once food passes from the
mouth to the oesophagus, the involuntary enteric and autonomic nerv-ous systems and hormones produced by the entero-endocrine system
coordinate digestion and absorption.
Motility
Food moves progressively through the intestine aided by peristalsis,
which is modified by neuronal and endocrine signals. Antegrade move-ment is complemented by churning in the stomach, which mixes and
pulverizes food into chyme, and the action of sphincters, which sepa-rate food into appropriate compartments. For example, the pyloric
sphincter keeps food in the stomach until it is the correct consistency for
digestion in the duodenum.
Mechanical disruption
Many foods are hard and irregular and could damage the delicate intes-tinal lining. The tough oral epithelium and teeth break and grind food
into small pieces, while saliva moistens and lubricates it. Particle sizes
are further reduced in the stomach, where powerful muscular churning
converts food into a thick suspension called chyme. Reducing the size of
food particles increases the surface area to volume ratio, enhancing the
action of digestive enzymes. Chyme remains liquid until it reaches the
large intestine, where waste is converted into semi-solid faeces by water
reabsorption.
Solubilization
Food must be dissolved in an aqueous medium for digestive enzymes to
act and while some fluid is ingested, most of the liquid in the intestinal
lumen is actively secreted by the intestine and exocrine glands. It is sub-sequently reabsorbed, to maintain fluid balance.
Emulsification and micelle formation
Most dietary fat is too hydrophobic to dissolve in water, so mixing in
the  alkaline intestinal lumen emulsifies it, creating tiny particles
and increasing the surface area available for lipid-digesting enzymes.
Amphiphilic bile salts, phospholipids and cholesterol esters secreted in
bile form micelles, which are microscopic particles with a hydrophobic
core and the hydrophilic parts of the molecules on the outside. Digested
lipids, such as fatty acids, partition into the hydrophobic core and can be
absorbed from the intestinal lumen.
Acidification and alkalization
Optimal digestion in the stomach requires an acid environment, created
by HCl, secreted by gastric parietal cells. Conversely, optimal digestion
by pancreatic enzymes requires an alkaline medium, provided by
HCO3
-, secreted in the bile and pancreatic juice.
Enzymes
Enzymes are the most critical element of digestion, enabling chemically
complex, polymeric foods to be processed to absorbable monomers at
physiological temperatures and in a reasonable timescale.
Enzymatic digestion starts in the mouth with  salivary amylase,
which breaks down starch to form sugars. Stomach acid inhibits amylase
activity and activates gastric pepsinogen to form pepsin, thus initiating
protein digestion. Most enzymatic digestion takes place in the duo-denum and jejunum, where pancreatic and small intestinal enzymes
act in an alkaline milieu. The pancreas produces a prodigious amount
and variety of digestive enzymes, including  proteinases,  amylases,
lipases and nucleases, and pancreatic failure invariably causes malab-sorption and malnutrition.
Enzymes can potentially digest components of the cells that produce
them (autodigestion); therefore, many are synthesized as inactive pro-enzymes. Other enzymes activate them by proteolytic cleavage; for
example, pancreatic trypsinogen (pro-enzyme) is cleaved to trypsin by
enterokinase secreted by duodenal enterocytes.
Enterocytes contribute a critical final stage of enzyme digestion,
whereby  brush-border disaccharidases and  peptidases attached to
their apical surfaces break down partially digested sugars and peptides to
absorbable monomers and oligomers.
Within enterocytes, enzymes continue the digestive process; for
example, fatty acids are reconstituted into triglycerides and assembled
into chylomicrons before export at the basolateral membrane and trans-port to the circulation via lymphatic channels.
Special factors
Intrinsic factor is a glycoprotein produced by the stomach, which binds
vitamin B12, protecting it from breakdown in the proximal intestine. In
the terminal ileum, vitamin B12 is released and absorbed. Similar sys-tems operate for other essential minerals and vitamins. Some nutrients,
for example, vitamin K, may be synthesized in the intestine by com-mensal bacteria.
Surface area
Absorption of digested food depends critically on a well-adapted and
ample surface area. The small intestine is the main absorptive surface,
although some substances can be absorbed through the oral mucosa and
others in the stomach (e.g. alcohol, which notoriously ‘goes straight to
the head’).
Plicae circulare are transverse folds, which increase the surface area
threefold, and  villi are finger-like projections into the lumen, which
increase intestinal surface area 10-fold. Microvilli, which are micro-scopic, finger-like projections on the apical surface of enterocytes,
increase the absorptive surface area 20-fold, so that overall the surface
area is increased 600¥ over that of a simple hollow tube.
Specialized absorptive surfaces
Enterocytes are exquisitely adapted for absorption by expressing the
appropriate cell membrane transporters and channels. In addition, sec-tions of the intestine are specialized for absorbing particular nutrients;
for example, folic acid is mostly absorbed in the jejunum and vitamin
B12 and bile acids are mostly absorbed in the terminal ileum.
Enterocytes can regulate the extent of absorption; for example, iron
transport is inhibited when there are sufficient body stores and, in genetic
haemochromatosis, regulation malfunctions and patients accumulate
iron.
Digestion and absorption 49
50 Integrated function
Na+
2K+
3Na+
Na+Glucose Na+Na+ Na+
β apolipoprotein
Lipid-rich
micelles
Fat
digestion
Fat re-esterification
Chylomicron
synthesis
Chylomicron
secretion
Free fatty acids
Membrane-bound
chylomicron precursor
Membrane-bound
chylomicron
Glycerol
To regional lymphatics
and thoracic duct
Chylomicron
Lacteal
(lymph channel)Lamina propria
Glucose, monosaccharides
Amino acids
Metabolism
Basolateral
transporters
and channels
To portal vein
Golgi
Capillary
Basement membrane
Na+/K+
pump
Specific amino acid and peptide–
Na+ co-transporters
Fructose,
glucose,
galactose
Basolateral
surface
Limited
paracellular
transport
Tight
junction
Apical
surface
Sodium–glucose
co-transporters
Dietary starch and glycogen
(glucose polymers)
Dietary sugar
(disaccharides)
Dietary protein
(linear polypeptides)
Dietary fat (lipids)
Cholesterol
esters
Vitamins
A, D, E, K
+Triglycerides
Phospholipids
H2O; alkali;  bile salts
Mixing, churning
Emulsion (fat droplets)
+ Bile salts
Mixed micelles
Cholesterol
Fatty acids
Monoglycerides
Lysophosphatidic
acidOligopeptidases
Amino acids
Dipeptides
Tripeptides
Oligopeptides
Endopeptidases
and
Exopeptidases
Pepsin (ogen)
Trypsin (ogen)
Chymotrypsin (ogen)
Elastase
Exopeptidases
Carboxypeptidase A, B
Lipase. Co-lipase
Cholesterol esterase
Phospholipase A2
Monosaccharides
Maltose
Glucose
Maltotriose
Maltase
Sucrase
Lactase
(Disaccharidases)
α amylases
Lactose Sucrose
P P
P
P P
P
P
20 Digestion of carbohydrates, proteins and fats
Carbohydrates, proteins and lipids form the major part of the diet and are
known as macronutrients, in contrast to micronutrients, such as vita-mins, which are only needed in milligram or microgram quantities.
Macronutrients provide all the dietary energy and most of the structural
materials needed for body tissues. Robust mechanisms efficiently
extract and absorb macronutrients from the diet.
Carbohydrates
Carbohydrates are ingested as starches and sugars, which are longer or
shorter polymers of monosaccharides. Plant starch is a complex,
branched polysaccharide of glucose linked by a1–4 and a1–6 glycosidic
linkages, while cane sugar (sucrose) is a disaccharide composed of
glucose and fructose. Lactose, the major sugar in milk, is composed of
glucose and galactose. Humans cannot digest b1–4 glycosidic linkages
in cellulose, the major polysaccharide in plant cell walls, which is also
known as dietary fibre or roughage.
Polysaccharides are digested by amylases. Although some amylase is
produced by salivary glands, most digestion is performed by pancre-atic amylase. Amylases produce monosaccharides (glucose), disaccha-rides (maltose) and maltotriose, and limit dextrins with short branches;
however, enterocytes can only absorb monosaccharides. Oligosaccha-ridases, such as sucrase, maltase and lactase, produced by enterocytes
are present in the  brush border and perform the final digestion of
dissaccharides and trisaccharides to monosaccharides.
Specific transporters, such as the sodium–glucose co-transporter
(SGLT- 1), in the apical surface of enterocytes, transport monosaccha-rides into the cytoplasm. The enterocyte cytoplasm is constantly
depleted of sodium by the basolaterally situated Na+/K+ pump that
pumps two K+ ions into the cell in exchange for three Na+ ions, using
energy derived from the hydrolysis of adenosine triphosphate (ATP).
This adenosine triphosphatase (ATPase) also maintains a small negative
electric potential within the cell. The electrogenic and osmotic Na+
gradient generated by the Na+/K+ ATPase is used to transport monosac-charides, amino acids and bile salts into the cytoplasm using different
Na+-coupled transporters. This co-transport of Na+ ions and sugars is
used clinically in the composition of oral rehydration solution, which
combines glucose and salt, so that Na+, which is depleted by, for
example, gastroenteritis, is replaced when enterocytes absorb Na+
together with glucose.
Absorbed monosaccharides leave the enterocyte by facilitated diffu-sion, through selective channels in the basolateral surface. They then
enter the circulation via the rich capillary network in the villus.
Proteins
Protein digestion begins in the stomach with the action of  pepsin,
although the  pancreas secretes the bulk of important  proteases.
Trypsinogen, chymotrypsinogen and proelastase are endopeptidases
that cleave at specific residues in the peptide chain, while the  car-boxypeptidases A and B are  exopeptidases that remove single
amino acids from the carboxyl terminal, leaving short oligopeptides.
Enterokinase is an enterocyte-derived endopeptidase that activates
trypsinogen. Trypsin then can activate other molecules of trypsinogen
(autocatalysis).
Enterocyte-derived  peptidases in the  brush border complete the
digestion of peptides, producing single amino acids and di- and tri-peptides that are absorbed. Amino acids enter enterocytes along with
Na+ ions, using  five different  co-transporters that are  selective for
neutral, aromatic, imino, positively charged and negatively charged
amino acids. From the cytoplasm, amino acids enter the circulation via
selective channels in the basolateral membrane, and are carried to the
circulation.
Lipids
Unlike carbohydrates and proteins, which are water soluble and there-fore easily accessible to digestive enzymes and membrane transporters,
lipids require partition into a hydrophobic or  amphipathic environ-ment. Churning and mixing and the  alkaline pH of intestinal fluid
promotes the formation of an emulsion.
Furthermore, bile salts, phospholipids and cholesterol esters, which
are amphipathic, help to form mixed micelles with emulsified dietary
lipids. These macromolecular complexes, in which amphipathic compo-nents create a hydrophobic core and a more hydrophilic, charged
surface, carry digested lipids to the enterocyte surface.
The main dietary lipids are triglycerides, comprising three fatty acyl
chains covalently linked to a glycerol backbone,  phospholipids, in
which one fatty acyl chain is replaced by a hydrophilic molecule,
and  cholesterol esters.  Lipases,  phospholipases and  cholesterol
esterases, the most important of which are synthesized by the pancreas,
break down dietary lipids to fatty acids, monoacyl glycerol, lysophos-pholipids and cholesterol.
These digested lipids are absorbed across the cell membrane into the
enterocyte cytoplasm where they are re-esterified and complexed with
proteins called apolipoproteins to form lipid-rich lipoprotein particles
known as chylomicrons.
Chylomicrons are actively secreted into the basolateral space and
carried via lymphatic channels in the core of each villus, called lacteals,
which carry them to the circulation via the thoracic duct. After a fatty
meal, lacteals are filled with a milky, chylomicron-rich suspension.
Common disorders
The inability to digest and absorb macronutrients rapidly leads to wast-ing of muscle and fat. Eventually essential tissues such as skin, heart
and epithelia cannot be maintained and patients die from multiorgan
failure. These changes are also seen in  starvation; however, if the
cause is not reduced intake, but incomplete digestion and malabsorption,
diarrhoea,  bloating and  steatorrhoea (passing fat-laden stool) also
occur.
The commonest serious causes of macronutrient malabsorption are
coeliac disease, which damages the intestinal mucosa, and  chronic
pancreatitis, which leads to pancreatic enzyme deficiency.
Other abnormalities of macronutrient absorption are relatively rare,
except for selective lactase deficiency, which is genetically determined
and very frequent in some ethnic groups, and may transiently may
develop following a bout of infectious gastroenteritis. Genetic abnor-malities of specific transporters cause deficiencies of specific amino
acids. Genetic deficiency of apolipoprotein B, which is an essential
component of chylomicrons, causes lipid deficiency and accumulation
in enterocytes, which in turn causes general malabsorption.
Digestion of carbohydrates, proteins and fats 51
52 Integrated function
B12 + Transcobalamin
Haem
iron
Vit C
Fe3+
Fe2+
Fe3+
H+
Fe2+ + gastroferrin DMT expressionØ
= DMT
Transferrin
Hepcidin
(from liver)
Maturation
of cells
[HFE]≠
[Fe2+]≠
Duodenum
Regulation of iron absorption
Vitamin B12
Ca2+
Folic acidVitamin B12 + IF
Ileum
Liver
Stores vitamins A, K, B12
Bile
Cu2+
Bound
B12
Free B12
+ Intrinsic
factor
B12–IF
Gastroferrin
Dietary pteroylglutamate
pteroylpolyglutamate Bacteria
Folic
acid
Polyglutamate hydrolase
Jejunum
Jejunum,
ileum,
duodenum
Vitamin D
Increased
calcium
absorption
Increased expression of Ca2+-
binding protein, calbindin and
intestinal membrane calcium-
binding protein
Ca2+ B12 + transcobalamin
IF-receptor
IF-receptor
B12–IF
Vitamin C Folic
acid
Ca2+
Fat-soluble vitamins
A, D + essential
fatty acids
B-complex vitamins
Water-soluble vitamins
Hepcidin
21 Digestion of vitamins and minerals
Vitamins and minerals are essential dietary elements that are required in
relatively small quantities and are known as micronutrients. Some are
scarce and special adaptations help to garner the maximum amount from
the diet. Some are potentially toxic and special mechanisms regulate
their absorption, accumulation and excretion.
Water-soluble vitamins
The main water-soluble vitamins are vitamin C (ascorbic acid) and the
B-complex vitamins. Ascorbic acid, thiamine (vitamin B1), riboflavin,
niacin, pyridoxine, biotin, pantothenic acid, inositol and choline are
absorbed by passive diffusion or Na+-dependent active transport in the
small intestine. Vitamin C deficiency interferes with collagen synthesis
and causes scurvy. B-complex vitamins are mainly involved in energy
metabolism and deficiencies cause widespread abnormalities in epithe-lial, neuronal and cardiac function.
Vitamin B12 (hydroxocobalamin)
Dietary vitamin B12 is complexed with proteins that are degraded in the
stomach. Vitamin B12 then binds to intrinsic factor (IF), a glycoprotein
synthesized by gastric epithelial parietal cells. Intrinsic factor protects
vitamin B12 from degradation in the intestine and binds to a receptor
expressed on ileal enterocytes, which allows the complex to dissociate,
so that the vitamin can be absorbed. In the circulation, absorbed vitamin
B12 is transported bound to another protein, transcobalamin.
At least 3 months reserve of vitamin B12 is usually stored in the liver.
Vitamin B12 is mainly derived from meat, eggs and milk, with little in
vegetarian foods. Vegans are therefore particularly at risk of deficiency.
Vitamin B12 deficiency may also be caused by gastric pathology, such as
atrophic gastritis, where IF is not synthesized, or terminal ileal disease,
such as Crohn’s disease, where the absorptive surface is damaged. The
Schilling test can distinguish between these causes (see Chapter 46).
Folic acid (pteroylmonoglutamate)
Folic acid is mainly derived from green leafy plants but may also be syn-thesized by intestinal bacteria. Folic acid and pteroylpolyglutamates are
absorbed in the jejunum, where enterocytes cleave the polyglutamates to
monoglutamates.
Folic acid and vitamin B12 are required for methylation reactions
and deficiency has widespread effects, although the first observed
clinical effect is usually  anaemia, with enlarged,  megaloblastic red
cells.
Fat-soluble vitamins and essential fatty acids
Absorption of the  fat-soluble vitamins A, D, E and K depends on
adequate bile salt secretion and an intact small intestinal mucosa. Defi-ciencies therefore occur in  liver disease, obstructive  jaundice and
pancreatic insufficiency, and with small intestinal pathology, such as
coeliac disease.
Vitamin A (retinoic acid) is essential for many cellular functions and
is critically important for vision. Deficiency causes night-blindness and
dermatitis.
Vitamin D is essential for calcium homeostasis and healthy bone for-mation. Deficiency causes osteomalacia and rickets.
Vitamin E is an antioxidant and its exact role is being investigated.
Vitamin K is required for the post-translational modification (g-carb-oxylation) of clotting factors. Deficiency causes coagulopathy.
Vitamin A is stored in Ito cells in the liver and vitamin D and K are
stored in hepatocytes. They are not efficiently excreted, so they can
accumulate in toxic quantities and supplements should be prescribed
cautiously.
Linoleic, g-linoleic, linolenic and arachidonic acid are all essential
polyunsaturated fatty acids that cannot be synthesized in the body and
are required for the synthesis of myelin in nerve tissue and prostaglandin
synthesis (arachidonic acid).
Iron
Iron is an essential component of haemoglobin and other haem-containing proteins.  Iron deficiency is a worldwide health problem
causing  anaemia, particularly in women of childbearing age. Con-versely, excess iron is harmful and sophisticated mechanisms control its
absorption.
Iron in haem (mainly derived from eating meat) is rapidly absorbed in
the duodenum and is the most bio-available form.
Free dietary iron is usually present as ferrous (Fe2+) or ferric (Fe3+)
iron. Ferric iron is not absorbed. Stomach acid and reducing agents, such
as vitamin C, promote the conversion of Fe3+ to Fe2+ iron and absorption
is therefore maximal in the acidic environment of the proximal duode-num.  Gastroferrin, a glycoprotein secreted by gastric parietal cells,
binds Fe2+, preventing its binding to anions and maintaining its avail-ability for absorption.
Iron is absorbed via the divalent metal transporter (DMT) protein in
enterocytes. Absorbed iron leaves the basolateral membrane where it
binds to circulating transferrin.
Excess body iron stores reduce iron absorption partly through
decreased DMT expression. The HFE protein, expressed in immature
intestinal cells, may act as an iron sensor, reducing DMT expression, and
a circulating liver-derived peptide, hepcidin, also reduces intestinal iron
absorption.  HFE mutations in  hereditory haemochromatosis cause
uncontrolled iron absorption, which accumulates in the liver, pancreas,
heart and other tissues and can cause liver cirrhosis, diabetes mellitus
and cardiomyopathy.
Calcium
Calcium absorption occurs throughout the small intestine and is regu-lated by vitamin D, which stimulates the synthesis of calcium binding
and transporting proteins in enterocytes, including the intestinal mem-brane calcium-binding protein and intracellular calbindin. Vitamin D
deficiency therefore causes calcium deficiency, resulting in osteomala-cia and rickets.
Copper
Copper is an essential cofactor for many oxidative enzymes. It is stored
in the liver, bound to copper-binding proteins, and excess is excreted in
the bile by an adenosine triphosphate (ATP)-dependent transporter,
which is mutated in Wilson’s disease, causing hepatic and neurological
damage due to copper accumulation. Excess copper may also accumu-late in biliary diseases such as primary biliary cirrhosis (PBC).
Zinc
Zinc is an essential cofactor in many enzymes and transcription factors
and supplementation improves childhood resistance to gastroenteritis,
suggesting that it plays a role in immunity. Zinc deficiency causes skin
and intestinal abnormalities, including inclusions in Paneth cells, in a
syndrome called acrodermatitis enteropathica.
Digestion of vitamins and minerals 53
54 Integrated function
Ascending and descending nerves
Needs
•  BMR (basal metabolic rate)
• Age
• Growth
• Pregnancy
• Illness
• Physical activity
• Special needs
e.g. deficiency state

Intake
• Quantity:
Calories
Vitamins
Minerals
Fluid
• Quality:
Macronutrient balance
Micronutrients

Nutritional state
•  Weight, height, growth rate
•  BMI, body density
• Mid-arm circumference
• Skin-fold thickness
• Waist–hip ratio

Intake OutputMetabolism
Digestion
and
absorbtion
Basal metabolic rate
Work
Waste
Socio-economic,
cultural, genetic,
psychological factors
Genetic factors, weight,
fitness, stress, illness,
metabolic deficiencies
Socio-economic,
cultural, psychological,
genetic factors
‘What we eat’ ‘What we are’ ‘What we do’
Nutrition and the gastro-intestinal system
Nutritional assessment
Appetite,
eating behaviour,
nausea and
vomiting
Chewing,
smell, taste
Swallowing
Digestion,
storage
Digestion,
absorption,
control of
bowel flora
Cortex
Neuropeptide Y (NPY)
Pro-opiomelanocortin
(POMC)
Nor-adrenalin
Feeding centre
Satiety centre
Inhibit fe ding
Adipocytes
Ghrelin
Leptin
Insulin
Leptin
Gluconeogenesis glycogenesis/
glycogenolysis, fat storage
and synthesis
Vitamins
Colonic
fermentation,
and
reabsorption
of water
and
electrolytes
22 Nutrition
Assimilating nutrients is the central function of the gastrointestinal sys-tem, which also regulates their distribution, storage and disposal. Conse-quently, gastrointestinal dysfunction causes disordered nutrition and
disordered nutrition has profound effects on the gastrointestinal system.
The slogan: ‘what we eat, what we are and what we do’ encapsulates
nutrition. An adequate supply of nutrients must be available, the recipi-ent must be in a state to metabolize nutrients to build and repair tissues
and utilize chemical energy, and what ultimate use is made of nutrients is
determined by what the recipient does.
Thus, a sedentary office worker uses food differently to an Olympic
athlete or a critically ill patient on a mechanical ventilator. In each case
what they do is potentially enhanced or limited by nutrition.
Basic nutritional concepts
The main foods, protein, carbohydrate and fat, are  macronutrients,
required in relatively large quantities to provide energy and organic
building materials. Micronutrients are required in milligram or micro-gram quantities for special biochemical functions; these are mainly vita-mins, minerals and essential fatty acids. Non-digestible plant material,
called fibre or roughage, is needed for optimal intestinal function.
Energy intake must at least equal output. Even in a state of total rest,
energy is required for metabolism — the  basal energy expenditure
(BEE). Basal energy expenditure varies with age and sex and most
people must consume 1.3–1.5·¥·their BEE to remain in equilibrium,
although this may increase to 2·¥·BEE with severe metabolic stress.
Metabolic energy is stored in the chemical bonds in organic com-pounds, with fats being the most energy dense, with the highest number
of calories per gram weight, followed by carbohydrates and then
proteins.
Glucose is essential for energy supply to the brain and red blood cells.
It is usually derived from ingested polysaccharides, and the liver can
maintain blood glucose levels from stored glycogen (glycogenolysis)
and by converting amino acids to glucose (gluconeogenesis).
Although fats cannot be converted into glucose, metabolic adaptation
in starvation means that the brain can use fatty acids and ketones for
some of its energy requirements.
Amino acids are required to produce proteins, which are constantly
renewed and replaced, even in adulthood when growth has ceased.
Amino acid flux is measured in terms of nitrogen balance, as dietary
nitrogen is almost entirely contained in amino acids and nitrogen excre-tion, via urea, is mainly due to amino acid breakdown. The dietary pro-tein requirement to remain in nitrogen balance varies with age, sex and
metabolic state.
Assessing nutrition
In children, growth charts help to detect potential nutritional problems.
Other simple clinical measures include the  body mass index (BMI)
(weight/height2), measured in kilograms and metres, giving a global
measure, mid-arm circumference, reflecting muscle mass, and skin-fold thickness, reflecting body fat.
Simple blood tests can identify deficiencies in iron, calcium, zinc,
copper, vitamins A, D, K, B12 and folate, and nitrogen balance can be
estimated by measuring urinary urea excretion.
Control of body mass
Maintaining healthy body weight and proportion through life is a com-plex feat of neural and endocrine control, the details of which are only
now being discovered.
Food and calorie  intake is regulated  behaviourally and neuronal
control involves the cortex and centres in the hypothalamus and
brainstem. Many neurotransmitters, including peptide Y (PY), pro-opiomelanocortin (POMC), noradrenaline (NA) and serotonin (5-hydroxytryptamine, 5HT), are involved in the control of appetite.
POMC- and PY-containing hypothalamic neurons integrate signals and
communicate with the brainstem, which in turns signals to the hypothal-amus using NA.
Leptin is a critically important peptide hormone released by
adipocytes and  intestinal cells to signal that adequate calories have
been consumed and stored as fat. Ghrelin, released from the intestine,
mediates long-term control of eating and body mass.
Body mass can also be controlled by regulating energy expenditure.
In rodents, the basal metabolic rate (BMR) is increased by adaptive
thermogenesis, whereby energy expenditure is increased in brown fat,
generating heat. Humans have little brown fat, although BMR rises with
regular exercise, which may explain how regular exercise improves
weight control. However, BMR falls as body weight decreases, counter-acting slimmers’ efforts to lose weight.
Gastrointestinal disease and nutrition
Gastrointestinal disease inevitably interferes with nutrition. Reduced
intake may be due to nausea and vomiting, poor dentition, or dysphagia
secondary to oesophageal disease. Pancreatic, biliary and intestinal
diseases cause malabsorption. Coeliac disease and Crohn’s disease in
particular are associated with multiple deficiencies, including calcium
and vitamin D deficiency leading to osteoporosis.
Chronic liver disease is characterized by nutritional abnormalities
and wasting of muscle and fat, while cholestatic liver disease reduces
absorption of fats and fat-soluble vitamins.
Gastrointestinal diseases can also cause specific nutrient deficiencies,
such as atrophic gastritis causing vitamin B12 deficiency.
Metabolic derangement caused by systemic disease is aggravated
when the intestine, liver or pancreas is involved, as the patient’s ability to
assimilate nutrients is compromised.
Enteral and parenteral nutrition
High calorie liquid diets that can be administered by intravenous infu-sion have made total parenteral nutrition (TPN) possible. Total par-enteral nutrition is used when patients cannot be fed enterally, for
example, because of intestinal failure, or surgery.
With TPN, homeostatic mechanisms regulating digestion and absorp-tion are bypassed; therefore, nutrient levels must be carefully monitored
and the feed modified accordingly. This, and the risk of infection asso-ciated with infusing nutrient-rich solutions, make TPN demanding and
potentially dangerous.
Furthermore, the lack of  enteral feeding atrophies the intestinal
epithelium and may increase bacterial translocation and the risk of
sepsis. Thus, enteral or partial enteral nutrition is preferred.
Nutrition 55
56 Integrated function
Saliva
1400 mL
1200 mL
enters
colon
+
++


+
Food and drinks
1200 mL
Gastric juice
2500 mL
Pancreatic juice
1500 mL Intestinal juice
1000 mL
Reabsorbs 7000 mL
200 mL
stool volume
Reabsorbs
1000 mL
(maximum
capacity
5000 mL)
Bile
600 mL
Lungs, sweat, kidneys
Obligatory losses 1000 mL
High [Na+]
Low [Na+]
Paracellular
transport HCO3–
H2O
H2O
Ca2+
H2O
Cl–
HCO3–/Cl–
exchanger
Na+
coupled
co-transporters
Na+
CFTR Cl– channel
Cholera
toxincAMP
cGMP
Adenyl
cyclase
Guanyl cyclase
Guanylin E. coli
heat-stable toxin
5HT4
receptor
5HT3
receptor
Na+
Na+ K+ 2K+
2Cl–
Na+/K+
ATPase
3Na+
Na+/H+
exchange
CO2
+
H2O
Na+
H2O
HCO3–
+
H+
H+
VIP
receptor
Intracellular
2nd messengers
Carbonic
anhydrase
Sugars,
amino acids
Tight
junctionSmall
electrochemical
gradient
Intake     Secretion into lumen  Absorption    Loss

Food    Saliva   1400  Small     Stool  200
and         Gastric   2500  intestine  7000  Urine,
drink  1200  Bile   600  Colon   1000  sweat,
Pancreas   1500      lungs  1000
Intestine   1000
1200   7000    8000    1200
Typical fluxes (mL)
23 Fluid and electrolyte balance
Body fluids and electrolytes must be replenished daily to make up for
obligatory losses in sweat, urine, faeces and through the lungs. These
amount to at least 1000·mL of water per day and are replaced by absorp-tion in the intestine. Actual fluid fluxes are much larger, as exocrine
glands secrete digestive juices that are reabsorbed distally.
Fluid flux
Typical fluid movements in the intact intestine are shown in the Figure.
The small intestine has a great capacity to secrete and absorb fluid
under the regulation of enteric endocrine and neural signals and modi-fied by bacterial and viral toxins, and drugs.
The  colon can absorb up to 5000·mL of water per day, although
inflammation, toxins and drugs can reduce this capacity. Small increases
in fluid volumes reaching the colon can be compensated for by increased
absorption; however, watery diarrhoea occurs when the amount of fluid
leaving the terminal ileum exceeds colonic reabsorptive capacity.
Osmotically active substances in the small or large intestine,
such as non-digestible or non-absorbable sugars, can overwhelm
the ability of the small or large intestine to reabsorb water, causing
diarrhoea.
Mechanisms
The intestinal lining comprises a single layer of polarized epithelial
cells joined by tight junctions, effectively separating the luminal sur-face from the basolateral surface. Most fluid and electrolytes must there-fore cross the epithelial cells, which maintain gradients and regulate
fluxes through specialized  pores,  channels and  ion pumps in their
basolateral and apical membranes. There is also some  paracellular
movement of fluid and electrolytes, as tight junctions are not totally
impermeable and their permeability can be altered by disease.
Water passively follows osmotic gradients generated by the secre-tion and absorption of ions and other osmotically active molecules.
Apart from diet-derived small molecules, the main osmotic substances
are Na+, Cl- and HCO3
– ions. Also, K+ is secreted along with Cl- and
HCO3
– and, because body stores are relatively small, they can be
severely depleted through intestinal losses.
The basolaterally situated 3·:·2 Na+/K+ ATPase pump plays a major
role in maintaining electrochemical gradients in enterocytes. It pumps
two K+ ions into the cell in exchange for three Na+ ions out and thus
depletes the enterocyte of Na+ and maintains a small negative electric
potential within the cell. Luminal Na+ can then be transported into the
enterocyte through selective pores and channels, along with, for exam-ple, monosaccharides and amino acids. Water passively follows these
osmotically active ions.
In the ileum, caecum and distal large intestine, Na+ channels allow
Na+ absorption independent of any co-transport, enabling further water
reabsorption.
Cl- secretion is mainly driven by a basolateral 2Cl-/Na+/K+ trans-porter that imports Cl- into the cell. Regulated apical Cl- channels,
including the  cystic fibrosis transmembrane regulator (CFTR),
enable Cl- efflux from the enterocyte along its electrochemical gradient.
Intracellular cyclic adenosine 3¢,5¢-cyclic monophosphate (cAMP) lev-els regulate the opening of CFTR, while other Cl- channels are regulated
by cyclic guanosine monophosphate (cGMP).
HCO3
– secretion is important for maintaining alkaline pH of secre-tions in the salivary glands, small intestine, pancreas and biliary
canaliculus. In the stomach, HCO3
– secretion into the mucus layer
buffers secreted HCl, protecting surface epithelial cells. HCO3
– secre-tion is achieved by a combination of a basolateral Na+/H+ exchanger
that transports H+ out of the enterocyte, cytoplasmic carbonic anhy-drase, which generates HCO3
– and H+ from CO2 and H2O, and an apical
HCO3
-/Cl- exchanger.
Regulation
Dehydration is poorly tolerated and losing more than a few percent of
body water results in fatigue, weakness, hypotension and circulatory
failure. Hypothalamic centres that sense blood pressure and plasma
osmolality, and use vasopressin as a neurotransmitter, control thirst and
drinking.
A dry mouth also contributes to the sense of thirst; however, drinking
rapidly satisfies subjective thirst, even if total body water is not re-plenished. Hydration should therefore be carefully evaluated and
maintained in people who cannot eat and drink freely, such as critically
ill patients.
Secretion is modified by many stimuli, including enteric hormones,
inflammatory cytokines, bacterial and viral toxins and drugs.
Prostaglandins, including synthetic misoprostol, used to counteract the
ulcerogenic effects of non-steroidal anti-inflammatory drugs (NSAIDs)
cause increased intestinal secretion.  Vasoactive intestinal peptide
(VIP) also enhances secretion, and VIP-secreting tumours cause the syn-drome of watery diarrhoea and hypokalaemia. Serotonin (5-hydrox-ytryptamine,  5HT) can increase or decrease secretion, depending on
whether it acts on  5HT3 or 5HT4 receptors.  Somatostatin inhibits
intestinal secretion, partly by inhibiting the secretion of other enteric
hormones. Opioids inhibit intestinal secretion and may promote reab-sorption by reducing intestinal motility, which contribute to their
antidiarrhoeal effect.
The main intracellular regulators of secretion and absorption are
cAMP, cGMP and Ca2+, which stimulates protein kinase C and its asso-ciated intracellular signalling pathways.
Certain bacterial toxins have well-characterized effects that illus-trate how intestinal secretion is regulated. Cholera toxin B binds to cell
surface receptors (GM1 ganglioside) facilitating the intracellular entry
of cholera toxin A. Toxin A then irreversibly activates adenyl cyclase,
generating excess cAMP. This stimulates Cl- secretion through CFTR,
which is followed by K+ and Na+ to maintain electroneutrality, and water
along the osmotic gradient. The result is profound secretory diarrhoea
that can cause life-threatening dehydration within hours.
The  heat-stable enterotoxin (STa) of  Escherichia coli  stimulates
receptors on the enterocyte surface that have guanyl cyclase activity and
intracellular cGMP levels rise as a result. This stimulates Cl- secretion,
causing secretory diarrhoea similar to that caused by cholera toxin. The
physiological role of guanylin, which is the natural, endogenous ligand
for the receptor used by E. coli (STa), is still unknown.
Fluid and electrolyte balance 57
The liver is the metabolic powerhouse of the body, processing and con-trolling the daily inflow of nutrients from the digestive tract to maintain
homeostasis. Biochemical pathways in the liver are internally inte-grated and externally controlled by hormones, growth factors and
cytokines. The complexity of hepatic metabolic function is such that so
far no totally artificial liver support device to replace the failing liver has
been created.
Carbohydrates
Blood glucose levels are maintained within tight limits. Glucose is
essential for neuronal function and, if levels fall too low,  hypogly-caemia causes neuroglycopenia, which can cause coma and death. On
the other hand, sustained high blood glucose levels cause widespread
damage to the body, particularly to blood vessels, as in diabetes
mellitus.
The liver plays a critical role in maintaining normal blood glucose
levels. It is a major store of glucose, in the form of glycogen, which is
synthesized when there is excess substrate. The liver can store enough
glycogen to be broken down by glycogenolysis, to maintain normogly-caemia for about 18·h. Athletes sometimes maximize liver glycogen
58 Integrated function
Glucose
Transporter
Insulin
Hormone
and cytokine
receptors
Growth hormone
Catecholamines
Steroids
Thyroxine
Glucagon
Amino acids
Transporters
Receptor
Interleukin-6
Inflammation
Albumin, plasma
proteins, complement
components
Clotting factors
II, VII, IX, X
Hepcidin
(regulates Fe2+
absorption)
Acute phase proteins,
e.g. CRP
Vitamin K
(g-carboxylation)
post-transcriptional
modification
Protein
synthesis
Amino
acids
Free fatty acids
Circulating energy
source during fasting,
starvation
Lipoprotein
receptors
Lipoprotein
uptake
(chylomicrons,
LDL)
Exported lipoproteins
(VLDL, HDL)
Entero-hepatic bile
salt reabsorption
Glycogen
Glycogen synthesis
Glycogenolysis
Glucose 6-phosphate
Glycolysis
Pyruvate ´ Lactate
Acetyl-CoAKrebs
cycle
Gluconeogenesis
Transamination
Rough
endoplasmic
reticulum
Transporters
Bile
2nd
messengers
2nd messengers
+

+

Gene regulation
Bile salts
APO- lipoproteins
Lipoproteins
Conjugation
with glycine
or taurine
Phospholipids
Energy
Oxidase
chain
RNA
Transcription
Deamination
NH4+
Fatty acid
synthesis
Acetyl-CoA
Storage
b-oxidation
Fatty
acids
Ketones
HMG-CoA
reductase
HMG-CoA
Cholesterol
24 Hepatic metabolic and synthetic function
stores before a competition by eating a carbohydrate-rich meal
(carbo-loading).
The liver also produces glucose from amino acids by gluconeogene-sis, whereby transaminases remove the amine group and feed the prod-ucts into the  Krebs cycle. Fatty acid metabolism also produces the
two-carbon-containing acetyl coenzyme A (acetyl-CoA) molecule that
feeds into the Krebs cycle; however, new six-carbon sugars, such as glu-cose, cannot be synthesized from fatty acids via the Krebs cycle. Thus
sugar can be laid down as fat, but fat cannot be converted to sugar.
Hormones such as insulin, glucagons, growth hormone, cortico-steroids and catecholamines, acting via cell-surface and intracellular
receptors in the hepatocyte, determine the balance of glycogen synthe-sis, glycogenolysis and gluconeogenesis.
Lipids
Dietary lipids carried, for example, in chylomicrons, are taken up from
the circulation by the liver and broken down into component parts
including fatty acids, phospholipids and cholesterol.
The liver then repackages these lipids as lipoproteins, for export to
the rest of the body via the bloodstream. Lipoproteins are macromo-lecular complexes formed from lipids and specific proteins called
apolipoproteins. They allow hydrophobic lipids to be transported in the
blood, and specific receptors that bind to different apolipoproteins allow
targeting to the different tissues that express the necessary receptors. The
main lipoproteins exported from the hepatocyte are very low-density
lipoproteins (VLDL) and high-density lipoproteins (HDL).
The liver also takes up and recycles lipoproteins and free fatty acids
from the circulation, further regulating the distribution of lipids around
the body.
The liver is the major site of cholesterol synthesis and most circulat-ing cholesterol is derived from hepatic synthesis rather than directly
from the diet. The statin drugs, which are the most effective treatment
for hypercholesterolaemia, act primarily on the liver, by inhibiting the
rate-limiting enzyme in cholesterol synthesis, HMG-CoA reductase.
Cholesterol is used to synthesis bile salts, which are then conjugated
with taurine and glycine (amino acids) and secreted in bile.
Ketones are synthesized from acetyl-CoA, derived from the oxida-tion of fatty acids and provide a source of circulating metabolic fuel dur-ing fasting and starvation. Cells such as neurons, which normally require
glucose, can adapt their metabolism to use ketones.
Amino acids and proteins
Essential amino acids cannot be synthesized in sufficient amounts from
precursors and must be derived from the diet. The liver produces a full
complement of amino acids by transamination and other modifications
of dietary amino acids and exports these for use in protein synthesis
throughout the body.
Excess amino acids are metabolized by removal of the amino groups,
releasing ammonia, which is potentially toxic and is converted into urea
in the liver, via the urea cycle, and excreted in the urine. The carbon
skeletons are used for energy production or converted into glucose for
storage or export. Thus, during fasting, starvation or severe illness, the
liver can convert muscle protein and other tissues into essential energy.
The liver synthesizes many proteins, including enzymes for its own
metabolic processes, and plasma proteins for export. The liver pro-duces albumin, which constitutes 50% of plasma protein, coagulation
factors (including II, VII, IX and X, which are post-translationally mod-ified by vitamin K-dependent g-carboxylation) complement proteins,
circulating protease inhibitors, apolipoproteins and carrier proteins
that bind hormones and other small molecules in the circulation.
Inflammation causes the release of circulating peptide mediators
called cytokines, of which interleukin 6 (IL-6), is particularly important
in stimulating the hepatic  acute phase response, whereby the liver
rapidly increases its synthesis of host defence proteins and reduces
albumin synthesis. Acute phase proteins include C-reactive protein
(CRP), serum amyloid A, secretory phospholipase A2 and coagulation
and complement proteins.
Metabolic and synthetic failure
All hepatocytes can perform basic metabolic and synthetic functions,
so there is a vast reserve capacity. Disrupted carbohydrate, protein and
lipid metabolism results in  fatigue,  wasting of body muscle and fat
reserves, and biochemical abnormalities including  hypoglycaemia,
hypoalbuminaemia and reduced coagulation factors.
Hypoalbuminaemia can cause  oedema, due to reduced plasma
oncotic pressure allowing extravasation of fluid from capillaries into tis-sues. Reduced clotting factors cause a coagulopathy, with a prolonged
prothrombin time (PT).
Coagulation factors have a half-life of few hours in the circulation and
rapidly disappear when the liver fails suddenly. Albumin has a half-life
of about 21 days, so it takes longer for levels to fall. Thus, the PT is the
most sensitive clinical test of rapidly deteriorating liver function.
Hepatic metabolic and synthetic function 59
60 Integrated function
Bilirubin
Myoglobin and
tissue cytochromes
Haemolysis
Deamination of
amino acids
Amino acid
breakdown
and dietary
NH4+
CO2 + NH4+
Urea
Urinary excretion
Drugs, toxins
Bilirubin–albumin
complex
Ethanol
Acetaldehyde
dehydrogenase
Alcohol
dehydrogenase Microsomal
compartment
(smooth endoplasmic
reticulum)
Cytochrome
P450 enzymes
Oxidized
drug/toxin
Metabolizing
enzymes
Urinary
excretion
AcetylationSulphation
Synthesis
Glucuronidation
Transporters
Bile
ATPase
Cu2+
Fatty
acids
Acetyl-CoA
Acetaldehyde
Regulated by
substrate,  hormones
(e.g. steroids, drugs and
barbiturates)
Bilirubin monoglucuronide
Bilirubin
diglucuronide
Urinary
excretion
UDP-glucronide
UDP
UDP
UDP–glucuronide
Glucuronyl
transferase
Glucuronyl
transferase
Urea
cycle
Macrophage
Red cell
turnover Heme
Biliverdin
Bilirubin
Mitochondrial
fatty acid
synthetesis
25 Hepatic detoxification and excretion
The liver has an immense capacity to metabolize biomolecules, inacti-vating them in most cases, and preparing them for excretion in bile
or urine. Bilirubin metabolism typifies this and jaundice caused by
impaired bilirubin excretion is a time-honoured marker of liver or biliary
disease. The liver metabolizes many drugs and they should be cautiously
prescribed to patients with impaired liver function.
Conjugation
Conjugating enzymes and their cofactors in the hepatocyte covalently
link drugs, toxins and waste products with water-soluble moieties,
such as  glucuronate,  sulphate and  alkyl groups. The conjugated
products are generally more water-soluble and are excreted either in
the bile, via specific and general transporters, or in the urine, via the
bloodstream.
Oxidases and cytochrome P450
The smooth endoplasmic reticulum, or microsomal compartment of
the hepatocyte contains a large family of oxidizing enzymes linked to
the cytochrome P450 proteins. These inactivate compounds by sequen-tial oxidation, often rendering intermediates more water-soluble as well.
Paradoxically, oxidation can increase the toxicity of a molecule, or may
be required to activate the beneficial effect of a drug. Oxidized products
are excreted in the bile or urine, or further conjugated.
Canalicular secretion
Conjugated molecules and certain essential micronutrients, which are
potentially toxic, are excreted by hepatocytes into the bile. For example,
copper is excreted by an adenosine triphosphate (ATP)-dependent
transporter that is mutated in Wilson’s disease, causing copper accumu-lation in the liver and in the central nervous system.
Urea cycle
Ammonia, generated by the metabolism of amino acids, is conjugated
with CO2 in a series of enzymatic reactions known as the urea cycle, gen-erating urea, which is efficiently excreted in the urine.
Rare inherited defects in urea cycle enzymes cause hyperammon-aemia and neurological dysfunction. Urea cycle activity is also reduced
in severe liver disease and, when this occurs rapidly, as in fulminant
liver failure, hyperammonaemia can cause acute hepatic encephalo-pathy, resulting in severe neurological damage, with incoordination,
drowsiness, coma, and death due to cerebral oedema.
In chronic liver disease other factors, including toxins absorbed from
the intestine, contribute to chronic hepatic encephalopathy.
The laxative lactulose, which is widely used to treat encephalopathy,
acidifies the stool and limits ammonia absorption by ionizing it to non-absorbable ammonium ions.
Bilirubin
Bilirubin is a yellow-green  pigment derived from the breakdown of
haem, which is the oxygen-binding component of haemoglobin, myo-globin and  cytochromes. Senescent red blood cells are ingested by
macrophages, primarily in the spleen, and released haem is oxidized to
biliverdin and then to bilirubin. Bilirubin is transported in the blood-stream bound to albumin and taken up by hepatocytes, where it binds to
cytoplasmic proteins including glutathione S-transferase.
Bilirubin is conjugated with glucuronic acid by glucuronyl trans-ferase, first forming bilirubin monoglucuronide, and then  diglu-curonide, which are more water-soluble. Some conjugated bilirubin
diffuses into the bloodstream and is excreted in the urine. Thus, there is
normally some conjugated, and a much smaller amount of unconju-gated, circulating bilirubin. Most conjugated bilirubin in hepatocytes is
excreted into bile by canalicular secretion.
Unconjugated hyperbilirubinaemia may be caused by increased
bilirubin production, as in  haemolytic disorders (prehepatic
jaundice). Liver disease seldom causes unconjugated hyperbilirubi-naemia as there is a large reserve capacity of conjugating enzymes. How-ever, a common inherited defect in the glucuronyl transferase enzyme
can cause mild, fluctuating jaundice (Gilbert’s syndrome) and no other
abnormalities. In contrast, Criggler–Najjar syndrome, which is caused
by a structural defect in the same gene, causes severe neonatal jaundice
and neurological damage.
Conjugated hyperbilirubinaemia may be caused by biliary obstruc-tion (post-hepatic jaundice). It may also be caused by liver disease
affecting hepatocyte function, such as hepatitis, which interferes with
transport protein function. This is called  intrahepatic cholestasis
(hepatic jaundice), as there is no macroscopic obstruction in the extra-hepatic biliary system. Typically both conjugated and unconjugated
bilirubin concentrations are increased.
Rarely, inherited defects in transport proteins cause conjugated
hyperbilirubinaemia, as in the Dubin–Johnson and Rotor syndromes.
Alcohol (ethanol)
Alcohol, the most widely used psychoactive drug, is primarily metabo-lized in the liver. It diffuses freely into hepatocytes and is oxidized to
acetaldehyde by the alcohol dehydrogenase enzyme. Acetaldehyde is
extremely reactive, causing brain, liver and heart damage. It is inacti-vated by the enzyme aldehyde dehydrogenase, generating acetyl coen-zyme A (acetyl-CoA), which can be converted into energy or stored
as fat.
Inhibitors of aldehyde dehydrogenase, such as disulfiram, produce
violent symptoms of intoxication if taken concurrently with ethanol and
can be used to help people give up alcohol. Aldehyde dehydrogenase
activity may be congenitally deficient, for example, in many Japanese
people, who therefore are particularly sensitive to alcohol.
Paracetamol (acetaminophen)
Paracetamol is a potent cause of fulminant liver failure when taken in
accidental or deliberate  overdose. Paracetamol is normally mainly
detoxified by conjugation with glucuronide. A small proportion is also
oxidized by  microsomal oxidases, forming a toxic metabolite,  N-acetyl-p-benzoquinone-imine (NAPQI), which is then inactivated by
conjugation with sulphate, derived from  glutathione. However, in
overdose, conjugation is saturated and a large amount of NAPQI is
generated, which exhausts the liver’s capacity for sulphation. NAPQI
damages hepatocytes, further reducing the ability to neutralize the toxin.
If administered soon enough, an antidote,  N-acetylcysteine, which
replenishes hepatic glutathione stores by donating sulphate groups, may
prevent liver failure.
Regulation
Levels of detoxifying enzymes are regulated and, in some cases, for
example with alcohol, regularly providing more  substrate induces
increased synthesis of the corresponding enzymes.  Drugs, such as
steroid hormones, barbiturates and certain antiepileptics, also induce
the synthesis of hepatic enzymes. This is one mechanism by which drugs
may interact, enhancing or diminishing each other’s actions.
Hepatic detoxification and excretion 61
62 Disorders and diseases
Drug
Hyoscine
Cyclizine
Metoclopramide,
prochlorperazine
Ondansetron
Neurotrasmitter
receptor
Acetylcholine
(ACh)
Histamine H1
Dopamine D2
Serotonin
(5HT3)
Target
Vestibulocochlear nuclei,
vomiting centre (VC)
Vestibulocochlear nuclei
Chemoreceptor trigger
zone (CTZ)
CTZ, gastrointestinal
tract afferents

Cause
Motion sickness, vertigo, diseases of
the ear
Intracranial pathology such as
meningitis, raised intracranial pressure,
migraine
Strong emotions, ‘disgusting’ sights,
pain
Drugs and chemicals, e.g. opiates,
alcohol
Drugs that irritate the intestinal tract,
e.g. chemotherapeutic agents for
cancer
Gastrointestinal infections, food
poisoning, appendicitis, cholecystitis
Intestinal obstruction, and distension
Systemic illness: diabetic ketoacidosis,
ureamia, etc.
Pregnancy
Bulimia, voluntary emesis
Mechanism
Vestibulocochlear inputs on
vomiting centre (VC)
Cortical and subcortical centre
inputs on VC
Cortical inputs on VC
Chemoreceptor trigger zone
(CTZ) inputs on VC
Vagal and autonomic inputs
on VC
Vagal and autonomic inputs on
VC, some emetogenic toxins
directly stimulate VC
Vagal and autonomic inputs on
VC
CTZ
Hormonal changes including
secretion of human chorionic
gonadotrophin (bHCG)
Various pathways, including
vagal afferents stimulated via
the oropharynx (gag reflex)
ACh
Higher cortical
centres
Thalamic
and
hypo-thalamic
centres
Vestibulo-cochlear
afferents
ACh
5HT
Vomiting
centre
Chemoreceptor
trigger zone
Chemical stimuli
• Drugs,  metabolic
waste products,
toxins, acidosis
Visceral
afferents
Distension
inflammation
Somatic afferentsPain
Cold
Vomiting centre efferents
via glossopharyngeal
and vagus nerves
Soft palate closes
off nasopharynx
Glottis seals off
larynx and trachea
Reverse peristalsis
Gastro-oesophageal
sphincter relaxes
Contraction of
diaphragm
and
abdominal muscles
Causes of vomiting
Neurotransmitters and drugs
H1
D2, 5HT3
26 Nausea and vomiting
Forcefully expelling luminal contents from the stomach and intestine is
an important defence against noxious agents that could be swallowed
with food, and the process is tightly controlled. Vomiting is coordinated
by signals from the intestine, body and brain, reaching nerve centres in
the brainstem, which control voluntary and involuntary muscles in the
abdomen, chest and gastrointestinal and respiratory tracts.
Nausea is the dysphoric desire to vomit, often accompanied by dis-taste for food and loss of appetite (anorexia). Although nausea usually
precedes vomiting, either may occur in isolation.
Retching is the rhythmic reverse peristaltic activity of the stomach
and oesophagus, accompanied by contraction of abdominal muscles and
deep, sighing respiratory movements that often precede actual vomiting.
Retching is ‘dry’, i.e. while it feels as though one is about to vomit, there
is no efflux of vomitus. During retching, the oesophagus dilates and may
accumulate vomitus that is subsequently expelled.
Vomiting is the forceful expulsion of food out of the mouth, usually
accompanied by increased  salivation,  sweating and  tachycardia.
Vomiting is different from passive regurgitation, where acid stomach
contents and partly digested food reflux into the mouth.
Muscular coordination
Intrinsic muscles of the stomach and oesophagus relax the gastro-oesophageal sphincter and force gastric contents out of the stomach and
oesophagus by  reverse peristalsis. Vomitus rarely contains material
from beyond the ileocaecal valve, although reverse peristalsis can con-vey intestinal contents all the way from the ileum.
Abdominal muscles, including the diaphragm, contract, greatly
increasing intra-abdominal and intrathoracic pressure, thus helping to
empty the upper gastrointestinal tract.
Simultaneously, the  epiglottis shuts off the  larynx, which is
drawn forward and upwards by muscles in the jaw and neck. The
soft palate is drawn upwards, closing off the  nasopharynx. These
coordinated muscular movements protect the  airway as vomitus is
expelled. In unconscious or inebriated individuals these protective
mechanisms are disrupted and vomitus may be aspirated into the
airway.
Neural control
The vomiting centre (VC), in the dorsal part of the reticular formation of
the medulla oblongata, is the main site of neural control of vomiting.
The VC is essential for vomiting, whatever the primary stimulus, as it
receives and coordinates signals from a number of other centres and
coordinates the output.
The chemoreceptor trigger zone (CTZ) in the floor of the fourth
ventricle lies outside the  blood–brain barrier and therefore senses
blood-borne chemical stimuli that induce vomiting, such as drugs like
morphine and digoxin. The CTZ in turn stimulates the VC to induce
vomiting.
Motion sickness and diseases of the inner ear cause vomiting by send-ing nerve signals from the nucleus of the  vestibulocochlear (VIIIth
cranial) nerve to the VC, possibly via the CTZ.
Other areas of the brain, such as the cortex, thalamus and hypothal-amus, also signal to the VC, mediating vomiting associated with, for
example, pain, emotional upset, fever and serious physical illness. Vari-ability in the way that these stimuli are processed may account for why
some people vomit more readily than others.
Sensory inputs from the gastrointestinal tract and other viscera, car-ried by the vagal and splanchnic autonomic nerves, also stimulate the
VC, so that gastrointestinal distension, infection and inflammation can
all induce vomiting.
The autonomic centres regulating sweating, lacrimation, salivation
and heart rate all lie close to the VC and these autonomic phenomena
are all stimulated in the surge of neuronal activity that accompanies
vomiting.
Common causes
Common causes are detailed in the figure.  Neurogenic or  psychic
stimuli,  chemicals and  mechanical or chemical irritation of the
intestinal tract itself may stimulate vomiting. In many instances the
exact pathway remains unknown.
Effects and consequences
Physiologically, vomiting expels noxious material from the gastroin-testinal tract. Normally, neuromuscular reflexes protect the respiratory
tract, but in inebriated or unconscious individuals protective mecha-nisms may fail, allowing  aspiration of vomitus, which can cause
asphyxiation or chemical inflammation and bacterial infection of the
lungs (pneumonia).
The strong propulsive forces generated during retching and vomiting
can cause a tear in the oesophageal mucosa (Mallory–Weiss tear). This
typically causes haematemesis (vomiting blood). Generally the tear is
superficial and heals rapidly.
Chronic vomiting, as in bulimia, can cause acid damage to the teeth
and gums. Furthermore, prolonged or profuse vomiting can  deplete
fluid and electrolytes, leading to dehydration and altered blood chem-istry. Vomiting of gastric contents typically causes  hypokalaemia,
hyponatraemia and metabolic alkalosis, while loss of HCO3
– in intes-tinal contents can cause metabolic acidosis.
Treatment
Vomiting should generally be viewed as a protective mechanism and
attention should be focused on treating the underlying cause, while sup-portive measures for the patient should aim to replace fluid and elec-trolyte losses.
In other cases, however, nausea and vomiting are stimulated by minor
events, or by an essential treatment, such as chemotherapy for cancer,
and must be treated even while the inducing agent is present. Fortu-nately, powerful drugs that interrupt vomiting in different ways are
available. These include acetylcholine (ACh) receptor antagonists and
histamine H1 receptor antagonists, which are particularly useful for
motion sickness and vestibulocochlear dysfunction;  dopamine D2
receptor antagonists, such as phenothiazines and metoclopramide, that
block stimuli from the CTZ; serotonin (5-hydroxytryptamine, 5HT)
5HT3 receptor antagonists, such as ondansetron, that block the VC and
afferents from the gastrointestinal tract; and  cannabinoids, whose
mechanism of action is still unknown.
Nausea and vomiting 63
64 Disorders and diseases
Secretory diarrhoea
Inflammatory
diarrhoea
Increased
nerve and
smooth
muscle
activity
Dysentery, IBD
Cholera, hormone-secreting
tumours
Lactase deficiency, malabsorptionAutonomic neuropathy
Diarrhoea caused by
hypermotility
Rapid food transit
Unabsorbable
osmolar substance
in lumen, e.g. lactose
H2O
H2O
H2O
Osmotic diarrhoea
Extruded
pus cells
Extruded
fluid, protein
Ulceration
Lamina propria
inflammation
Stimulation
of secretion
Diarrhoea =
increased stool volume
(>200–300 mL/day)
Also:
≠liquidity,
≠frequency,
≠fat (steatorrhoea),
≠white cells and blood
(inflammation)
Tumour producing
secretagogue,
eg VIP or serotonin
Bacterial toxin inducing secretion,
e.g. cholera
Cl– + H2O
H2O
27 Diarrhoea
Infectious diarrhoea is not only a nuisance to travellers — it also causes
major morbidity and mortality in parts of the world where sanitation,
clean drinking water and nutrition are inadequate. Diarrhoea can also be
symptomatic of serious underlying gastrointestinal diseases, such as
inflammatory bowel disease (IBD) and colorectal cancer.
By definition, diarrhoea implies that an excess volume of stool is
passed, and this is usually accompanied by  increased frequency of
defecation and increased liquidity of the stool. Normal stool volume
varies between individuals and is about 200–300·mL/day.
Diarrhoea may be accompanied by abdominal and rectal  pain,
urgency to defecate and  incontinence of faeces. When diarrhoea is
caused by food poisoning, there may be concurrent vomiting.
Diarrhoeal stool is usually more liquid. It may also contain more fat
when caused by malabsorption (steatorrhoea) and it may contain pus
and blood when caused by intestinal inflammation (see Chapters 34 &
35).
Diarrhoea is usually acute; that is, sudden in onset and short-lived,
although it can be chronic. The causes, mechanisms and treatment are
generally different in acute and chronic diarrhoea.
Mechanisms
Although the mechanisms are considered separately, for any one cause
of diarrhoea multiple mechanisms may operate. For example, ulcerative
colitis causes inflammation and also increased secretion and motility
secondary to the stimulation of enteric neuro-endocrine pathways.
Secretory diarrhoea
When increased secretion into the intestine exceeds the capacity of the
small and large intestine to reabsorb fluid, stool volume increases.
Increased secretion by enterocytes is often aggravated by a concurrent
absorptive defect.
Cholera is a common, serious and well-characterized example,
where hypersecretion is mediated by the bacterial exotoxin of Vibrio
cholerae. Cholera toxin A irreversibly activates adenyl cyclase to pro-duce cyclic adenosine  3¢,5¢-cyclic monophosphate (cAMP), which
stimulates sustained chloride secretion into the intestinal lumen by the
cystic fibrosis transmembrane regulator (CFTR). Na+ and water are
secreted with Cl-, maintaining electroneutrality and osmotic balance.
Cholera can kill in a few hours by causing profound dehydration. The
stool may be virtually clear electrolyte-rich fluid, known as ‘rice-water
stool’ (see Chapter 23).
Cholera is spread via the faecal–oral route, so diarrhoea enhances
infectivity and aids the organism’s survival. Conversely, diarrhoea
clears bacteria from the intestine and is part of the body’s defence
system.
Other bacterial toxins, hormones elaborated by hormone-producing
tumours, particularly carcinoids  and vasoactive intestinal peptide
(VIP)-omas, and  tubulovillous colonic adenomas that secrete fluid
and mucus from the abnormal epithelium can also cause secretory
diarrhoea. Excess bile salts that are not reabsorbed in the terminal ileum,
as a result of terminal ileal disease or resection, can induce colonic
hypersecretion.
Osmotic diarrhoea
A non-absorbable osmotic load in the intestine can overload the intes-tine’s capacity for reabsorbing water against the osmotic gradient. Thus
more fluid remains in the intestinal lumen and is excreted, causing
diarrhoea. An example is inherited or acquired  lactase deficiency.
Lactase is the enzyme that normally splits lactose, the predominant
disaccharide in milk, into the absorbable monosaccharides glucose and
galactose. Without lactase, ingested lactose remains in the intestine, cre-ating an osmotic load. Hereditary lactase deficiency is more frequent in
populations where milk is a minor part of the traditional diet, and can also
be acquired as a result of damage to the intestinal epithelium, caused by,
for example, gastroenteritis.
Other causes of osmotic diarrhoea include the use of non-absorbable
food sweeteners, such as sorbitol, and laxatives, such as lactulose and
magnesium sulphate.
Malabsorption of other dietary components can also cause diarrhoea,
although generalized malabsorption, such as in pancreatic failure,
predominantly causes  steatorrhoea, which is increased  faecal fat
content, causing large, pale stools that float on water and have an
unpleasant odour, partly due to metabolism of fatty acids by colonic
bacteria.
Inflammation
Damage to the intestinal lining, caused by bacterial or viral infection, or
immune-mediated processes, causes infiltration of fluid and inflamma-tory cells into the intestinal wall and extrusion of this inflammatory exu-date into the intestinal lumen. Excess mucus may also be secreted by the
damaged epithelium. Inflammation also increases fluid secretion and
inhibits reabsorption (see Chapters 32 & 34).
Pain and urgency often accompany inflammatory diarrhoea and leu-cocytes and blood are found mixed in with the stool.
Common causes include bacterial and amoebic dysentery and IBD.
Dysmotility
Increased motility can increase the frequency of defecation, and when it
is severe there may be insufficient time for normal reabsorption of fluid
from the stool, resulting in increased stool volumes. Dysmotility may
occur with autonomic neuropathy, for example, in diabetes mellitus.
Other causes include  thyrotoxicosis and motility-stimulating  drugs,
such as acetylcholinesterase inhibitors used to treat myasthenia gravis
(see Chapters 15 & 17).
Treatment
Most acute diarrhoea is caused by short-lived and self-limiting bacter-ial or viral infection and, as the diarrhoea is a  defence mechanism
against infection, antidiarrhoeals should be used with caution. Treat-ment should be mainly supportive, to prevent dehydration and elec-trolyte depletion.
Hydration can be maintained using a slightly hypotonic and alkaline
oral rehydration solution containing glucose and sodium in the correct
ratio to exploit active absorption via the apical Na+–glucose co-transporter on enterocytes, which draws water into the cells along the
osmotic gradient (see Chapter 23). The WHO rehydration formulation is
3.5 g NaCl, 1.5 g KCl, 2.9 g Na citrate and 20 g glucose per litre. This
provides 90 mM Na+, 20 mM K+, 80 mM Cl-, 10 mM citrate and 111 mM
glucose. In more severely ill patients intravenous hydration may be
required.
Specific causes can also be treated, for example, antibiotics for bac-terial or amoebic dysentery and steroids and 5-aminosalicylates for
IBD. Malabsorption caused by pancreatic insufficiency can be treated
with oral pancreatic enzyme supplements, while secretory diarrhoea
caused by hormone-secreting tumours can be controlled using somato-statin, which reduces hormone secretion.
The most frequently used antidiarrhoeals are the opiates codeine
and loperamide, which inhibit intestinal motility and increase the time
available for intestinal fluid reabsorption.
Diarrhoea 65
66 Disorders and diseases
Stool bulking agents
Fibre supplements (e.g. bran)
Ispaghula husk, sterculia,
methylcellulose

Osmotic laxatives
Non-absorbed sugars
(e.g. lactulose, lactitol)
Polyethylene glycol
Magnesium and
phosphate salts
Stool softeners
Liquid paraffin, arachis
oil

Stimulant laxatives
Senna, bisacodyl, dantron,
sodium docusate

Specific receptor antagonists
5HT4 antagonists,
e.g. Tergaserod

Increase stool bulk by drawing water
around their fibres—require
adequate fluid intake
Draw water into the intestinal lumen
and may cause dehydration and
electrolyte abnormalities in some
people. Phosphate salts can be given
rectally

Retained in the stool. Ease passage
of stools, defecation particularly with
haemorrhoids and anal fissure

Probably act by stimulating mucosal
entero-endocrine cells, which in turn
stimulate motility and fluid secretion
Stimulate motility, and may be
particularly useful for constipation
associated with abdominal pain in
the irritable bowel syndrome
Normal frequency of
defecation
3 x per day
1 x per 3 days
Normal stool volume
200–300 mL/day
200–300 g/day
Constipation
• Straining
• Pain
• Incomplete evacuation
•  Reduced frequency or volume
Inhibition by cortical centres
(e.g. move to strange environment)
Reduced fluid
and food intake
(especially fibre)
Motility≠
Sympathetic
overactivity
(e.g. stress) Spinal
damage
e.g. Multiple
sclerosis
H2O
H2O
5HT
5HT
5HT
H2O
Pelvic nerve
damage
e.g. autonomic
neuropathy
Enteric nerves and
smooth muscle dysfunction
e.g. idiopathic slow transit,
ileus, hypokalaemia,
hypocalcaemia, drugs

Mechanical obstruction
e.g. hernia, tumour, stricture
Absence of
enteric nerves
(Hirschsprung
disease)
HaemorrhoidsLocal pain e.g. fissure, anal ulcer
Stimulants
Stool bulk
formers
Osmotic
laxatives
Stool
softeners
Laxatives
28 Constipation
Constipation is one of the commonest gastrointestinal complaints. In
addition, people often attribute symptoms such as tiredness, lethargy,
nausea and headache to what they perceive as constipation. Often no
medical explanation is found and there is no proven link between infre-quent defecation and general ill health.
Causes and mechanisms
Irregular bowel habit can exacerbate constipation, as the colon and
rectum continue to remove water from stool, hardening it and making
passage more difficult. Thus, constipation can be  self-perpetuating.
In severe chronic constipation, particularly in the elderly, faeces may
become so hard, dry and immovable (faecal impaction) that they cannot
be passed without medical or surgical assistance, leading to intestinal
obstruction.
Reduced motility
Reduced colonic motility may be congenital as in Hirschsprung’s dis-ease, where myenteric nerves are absent from the distal colon, causing
chronic obstruction and a massively dilated, faeces-filled proximal
colon (megacolon).
Paralytic ileus occurs after abdominal surgery, or with electrolyte
abnormalities, such as hypokalaemia. Intestinal motility may be
reduced acutely by stress, due to sympathetic autonomic nerve activity,
and people who are severely injured or otherwise unwell may become
constipated for several days.
Neuromuscular dysfunction caused by  hypercalcaemia directly
reduces intestinal motility.
Reduced colonic motility may also be constitutive, i.e. normal for
that person (slow transit constipation).
Drugs
Drugs such as opiates, antidepressants and others with anticholinergic
effects reduce intestinal motility. Similar effects are seen with oral iron
supplements and aluminium-containing antacids.
Excessive, chronic use of stimulant laxatives, such as senna, can
reduce motility, presumably by damaging or depleting enteric neurons,
causing colonic atonia.
5HT3 receptor antagonists that have been used to treat diarrhoea in
irritable bowel syndrome (IBS) can also cause severe constipation.
Stool bulk
Stool volume and the frequency of defecation vary with diet, fluid intake
and intestinal secretion. Dietary fibre, which mainly comprises non-digestible plant polysaccharides, draws water around itself, increasing
stool volume. Thus, chronic constipation is often caused by lack of
dietary fibre and/or  inadequate fluid intake, which is required to
hydrate dietary fibre and to soften the stool.
With fasting, the frequency of defecation declines, partly because of
reduced reflex colonic activity and also because of reduced stool vol-ume, although a large proportion of the solid material in stool actually
comprises enteric bacteria rather than food residue.
Neuro-psychological dysfunction
Defecation is imbued with  social and psychosexual  constraints
that influence bowel habit, and it can be inhibited voluntarily via the
external anal sphincter and by cortical signals acting on autonomic
nerves.
Neurological damage to the  brain and spinal cord, for example,
in multiple sclerosis and peripheral neuropathy can lead to chronic
constipation as well as incontinence.
Local causes and obstruction
Local obstruction, for example, by a tumour, may cause pain and diffi-culty in defecation. Painful local lesions, such as prolapsed haemor-rhoids and anal fissure, inhibit the urge to defecate. Constipation and
straining at stool contributes to the development of haemorrhoids and
fissure.
Clinical features
The normal frequency of defecation (bowel movement, bowel open-ing) varies in the population from around three times a day to once every
3 days, although many people lie outside this range.
Alteration of previously regular bowel habit is more likely to indicate
disease, although some causes of constipation are congenital.
True constipation implies reduced defecation frequency or stool vol-ume, although patients also complain of straining during defecation,
pain on defecation and hard, dark stool. The sense of incomplete evacu-ation is called tenesmus.
Paradoxically, chronic constipation and faecal impaction, particu-larly in the elderly, may cause incontinence and passage of fluid per rec-tum, so-called overflow incontinence.
Diagnosis
Perceived and actual problems must be distinguished. A careful history
of dietary habits and any drugs that might cause constipation should be
taken.
Faecal impaction and local lesions, including anal and rectal cancer,
can be detected by digital rectal examination. Faecal loading of the
colon may be seen on plain abdominal X-ray. Timing the passage of
radio-opaque markers through the intestine (shape test) is used to diag-nose slow transit constipation.
Treatment
Stopping drugs that cause constipation and ensuring that sufficient
fibre and fluid are ingested are essential. Increasing dietary fibre forms
the basis of laxatives that rely on increasing stool bulk, although excess
fibre can exacerbate constipation.
Where psychological or social factors are implicated, it is important
that they are identified.
Correcting electrolyte abnormalities and allowing the bowel time to
recover usually resolves paralytic ileus.
Mechanical obstruction and Hirschsprung’s disease are treated surgi-cally. Painful or obstructive peri-anal and rectal conditions may also
require surgery.
Where constipation does not respond to simple dietary or lifestyle
measures, and is not caused by identifiable pathology, laxatives may be
used. They work in a number of different ways, including increasing
stool bulk, increasing osmotic fluid secretion, softening stool, stimu-lating secretion and motility via enteric neuro-endocrine pathways and
directly stimulating neuro-endocrine responses by receptor-targeting.
These are detailed in the table within the figure opposite.
Constipation 67
68 Disorders and diseases
Gall-
bladder
Sphincter
of Oddi
Pancreas
Small intestineColon
Oesophageal disorders
e.g. Globus, rumination
Functional dysphagia
Functional heartburn
Gastroduodenal disorders
e.g. Functional dyspepsia
Aerophagia
Functional
abdominal
pain
Biliary disorders
e.g. Gallbladder disorders
Sphincter of Oddi dysfunction

Anorectal disorders
e.g. Proctalgia fugax
Bowel disorders
e.g. Irritable bowel syndrome
Functional abdominal bloating
Functional diarrhoea
Functional constipation
Autonomic and
enteric nerve function
Cortical centres
Somato-sensory
cortex
Limbic system
Thalamus
Midbrain
Inhibitory descending fibres
Dorsal root
ganglion
Lateral
spinathalamic
tract
Spinal cord
Autonomic
ganglion
Visceral
ganglion
Viseral
sensory
fibres
Sigmoid colon
Rectum
Anus
Diet
Motility
Sensitivity
to distension
Colonic
flora
Psychological factors
• Behavioural
• Psychological
• Diet alteration
• Correct fibre intake
(avoid excess)
• Correct fluid intake
• Antispasmodics
e.g. Mebeverine
• Analgesics
e.g. low dose
Amitriyptyline
• Antidiarrhoeals
• Laxatives
• Reassurance
Classification
Treatment options
29 Functional disorders and irritable bowel syndrome
Gastrointestinal symptoms without discernable organic pathology are
common, occurring in a quarter of the population and accounting for
half of all consultations with gastroenterologists. Although many people
have symptoms that are consistent with a clinical diagnosis of a func-tional bowel disorder, only a minority seek medical attention.
Although the symptoms can be distressing, these disorders do not pre-dispose to more serious illness, so patients can be reassured once serious
pathology has been excluded.
The pathogenesis of functional bowel disorders is unknown and their
treatment remains unsatisfactory, but in some patients at least, symp-toms can be partially relieved.
Definition
The basic feature of these disorders is pain or discomfort referred to the
gastrointestinal tract, with some altered bowel function, such as diar-rhoea or constipation. The diagnosis is  clinical, based on patients in
the right demographic group presenting with typical symptoms in the
absence of any evident pathology. Symptoms are more likely to be due
to functional bowel disorders in younger people and due to more serious
disorders, such as cancer, in older people.
Classification
Discrete syndromes, classified according to the part of the gastrointesti-nal system affected, have been formally defined to assist diagnosis,
treatment and research.
Oesophageal disorders
These include common conditions, such as heartburn without signifi-cant acid regurgitation, and rare syndromes, such as globus hystericus,
where patients sense a lump in the throat.
Gastroduodenal disorders
Here symptoms mimic peptic ulcer disease, gastritis and other serious
disorders, without any evident pathology. The commonest syndrome is
non-ulcer dyspepsia.
Abdominal pain syndromes
Chronic abdominal pain can be very troublesome and when no obvious
pathology accounts for the symptoms, the pain is classified as functional.
Irritable bowel syndrome
Many patients fall into this diagnostic group, with abdominal pain,
bloating and altered intestinal function. Diarrhoea or constipation may
predominate and both symptoms can occur in the same patient.
Formal diagnostic criteria are still being evolved and the original for-mal criteria established in the 1980s gives a sense of what irritable bowel
syndrome (IBS) comprises of:
• At least 6 months of abdominal pain or discomfort, typically relieved
by defecation, and two or more of the following:
• altered stool frequency;
• altered stool consistency;
• altered stool passage (e.g. urgency, straining, incomplete
evacuation);
• passage of mucus;
• abdominal bloating.
Biliary syndromes
The symptoms suggest biliary disease without any evidence of pathol-ogy. In some cases spasm of the sphincter of Oddi can be demonstrated.
Anorectal syndromes
Patients may complain of difficulty passing stool, or pain associated
with defecation. Recurrent pain in the anal canal with no demonstrable
organic pathology is known as  proctalgia fugax. Excessive anal
sphincter tension and sweating may lead to peri-anal itching (pruritis
ani).
Pathophysiology
Numerous physiological alterations have been described that could
account for some of the functional bowel disorder syndromes. Often,
however, so-called abnormalities simply reflect extremes of normal
function.
Increased visceral sensitivity
Experiments show, for instance, that patients with IBS experience pain
on rectal distension more readily than do control subjects.
Cultural and psychological factors affect pain perception, partly
through spinal gating of painful stimuli, whereby inhibitory neurons
from cortical centres release endogenous opiates onto spinal interneu-rons that convey pain signals to the brain, and thus reduce the central
transmission of pain.
Altered motility
Diarrhoea and constipation could result from altered intestinal transit
time, but physiological studies of intestinal motility are still incon-clusive. Altered function of smooth muscle in extra-intestinal organs,
such as the lungs and urinary bladder has been demonstrated in IBS.
Altered autonomic and enteric nervous system function
Vagal and sympathetic dysfunction has been demonstrated in small
numbers of patients. Increased activity of intrinsic enteric neurons,
particularly those using serotonin (5-hydroxytryptamine, 5HT), may
account for altered motility and visceral hypersensitivity.
Diet, infection and altered bowel flora
Many patients report increased sensitivity to particular foods. Interac-tions between diet and the resident intestinal bacteria probably have
significant effects on bowel function, but systematic studies and experi-mental data to support this are still lacking.
Psychological factors
Patients with functional bowel disorders generally score higher on anx-iety and depression questionnaires, although cause, effect and simple
association are hard to separate. Even if psychological factors do
not cause symptoms, they may predispose people to seek medical
attention.
Diagnosis
While avoiding excessive investigation, which increases the patient’s
anxiety that ‘something must be wrong and the doctors still can’t find it’,
some simple tests are usually performed to exclude serious underlying
pathology. These include a blood count, serum electrolyte deter-mination, serological tests for coeliac disease, gastro-oesophageal
endoscopy, sigmoidoscopy or colonoscopy, and stool culture.
There are no specific tests for functional bowel disorders, although
visceral sensitivity, intestinal motility and alterations in bowel flora are
all being investigated experimentally.
Treatment
Establishing a firm diagnosis, excluding serious organic pathology and
reassuring patients are the mainstay of treatment so far.
Dietary and lifestyle changes often help, especially avoiding excess
alcohol and foods that precipitate symptoms, and regulating  dietary
fibre and fluid intake. Excess fibre can aggravate abdominal pain and
bloating, while too little can contribute to chronic constipation.
Behavioural therapy including relaxation, hypnosis and biofeedback
helps some patients, as does psychotherapy.
Symptomatic pharmacological treatment is appropriate. Thus diar-rhoea may be treated with antidiarrhoeals, constipation with laxatives
and pain with low doses of tricyclic antidepressants that reduce pain per-ception. Smooth muscle relaxants, or antispasmodics such as mebever-ine and peppermint oil may relieve the pain associated with spasm and
bloating. 5HT3 and 5HT4 receptor antagonists are being developed to
target diarrhoea and constipation specifically.
Functional disorders and irritable bowel syndrome 69
Symptoms indicating possible gastro-oesophageal reflux are common in
the general population. They vary greatly in severity and the actual
underlying damage is also variable, so that careful and thorough diag-nostic evaluation is needed to guide treatment.
Pathogenesis
Tonic contraction of thickened intrinsic  circular smooth muscle
closes off the gastro-oesophageal junction, separating the gastric
and oesophageal lumens. Diaphragmatic muscle fibres reinforce this
70 Disorders and diseases
Clinical features
Reduced efficacy
of sphincter (loss of
angle, no diaphrag-matic contraction)

Reflux
of acid
Hoarseness
and cough
Heartburn and
epigastric pain
Axis of oesophagus
Angulation of
gastro-oesophagel junction
Diaphragm
contributes
to sphincter
function
Cardia
H+ Cl–
H+
H+
H+
H+
Lower oesophageal sphincter
Axis of gastro-oesophegeal junction
Abrupt Z-line transition
Acid in contact with
squamous epithelium
causes pain and
heartburn and possibly
damage (oesophagitis)
Oesophageal squamous lining
Gastric
columnar
lining
Columnar epithelium
(gastric or intestinal type)
lining lower oesophagus
May cause
Barrett’s oesophagusDiaphragmatic hiatus hernia
Sliding hiatus hernia Rolling hiatus
hernia (rare)
Adenocarcinoma
Pressure Relief
Worsened by:
• increased abdominal pressure
• obesity
• lying supine
• eating meals before bed
Raised
intra-abdominal
pressure
Herniated
stomach
Low intrathoracic
pressure
Diaphramatic
hiatus
Diaphragm
30 Gastro-oesophageal reflux and hiatus hernia
sphincter function and the oesophagus enters the gastric fundus at an
angle, which also tends to seal the junction. Furthermore, while the
lower oesophagus and gastro-oesophageal junction remain in the
abdominal cavity, any increase in  intra-abdominal pressure, which
tends to squeeze gastric contents out of the stomach, also impinges on the
junction and counteracts this effect.
Stomach contents do regularly reflux through the gastro-oesophageal
sphincter, even in normal individuals, when the lower oesophageal
sphincter relaxes to allow food, drink and swallowed saliva to enter the
stomach. This physiological reflux is probably not harmful.
However, when oesophageal and diaphragmatic muscle tone declines
and intra-abdominal pressure is chronically increased, for example, by
obesity, particularly in older individuals, reflux may become more fre-quent and severe.
Reflux of gastric contents stimulates  nerve endings in the lower
oesophagus, which can cause pain and discomfort. Chronic stimulation
may also increase the sensitivity of nerve endings, causing pain even
in the absence of concurrent reflux. Severe and prolonged reflux can
damage and erode the lower oesophageal epithelium and provoke
inflammation (oesophagitis).
Chronic reflux can also induce metaplastic change in the epithelial
lining of the lower oesophagus, which is normally a non-cornified
stratified squamous epithelium, and can change to a simple columnar
epithelium, with gastric or small intestinal features. This  gastric or
intestinal metaplasia is known as Barrett’s oesophagus, which may
undergo dysplasia and can go on to develop into adenocarcinoma (see
Chapters 4 & 38).
The most likely cause of damage due to reflux is gastric hydrochloric
acid (HCl), although other gastric contents, such as enzymes, and bile
acids from the duodenum, may also contribute. Bile acids, chemically
altered by acid, may be particularly important in inducing metaplasia,
dysplasia and cancer.
Helicobacter pylori infection tends to reduce gastric acid secretion,
particularly when it causes chronic gastritis, so that, theoretically, eradi-cation of H. pylori infection, which reduces the risk of gastritis, peptic
ulcer and gastric cancer, may actually exacerbate acid reflux (see
Chapter 31).
Reflux can be further aggravated by the development of a hiatus her-nia, which forms when part of the stomach herniates through the hiatus
(or gap) in the diaphragm through which the oesophagus enters the
abdomen. As a result, the herniated portion of the stomach comes to lie in
the thorax. Usually the gastro-oesophageal junction and gastric cardia
slide upwards, creating a sliding hiatus hernia, which compromises
sphincter function by straightening out the angle of the gastro-oesophageal junction and removing the diaphragmatic contribution
to sphincter function. Furthermore, as the junction now lies within the
thorax, which has a low pressure, increased intra-abdominal pressure,
transmitted through the stomach, tends to force gastric contents
through the sphincter.
Asliding hiatus hernia can spontaneously reduce, for example, when
lying flat, and by reducing intra-abdominal pressure, which encourages
the stomach to return to the abdomen.
Less frequently, a fold of gastric cardia may herniate through the
diaphragmatic hiatus alongside the oesophagus, creating a  rolling
hiatus hernia, which can become strangulated.
Clinical features
Heartburn is described by patients as an acid, burning sensation in the
epigastrium or lower chest, often localized to just behind the sternum
(retrosternally). It is the typical symptom of gastro-oesophageal reflux.
Patients may also complain of epigastric pain and dyspepsia aggra-vated by meals, alcohol and lying flat in bed.
Stomach contents may reflux into the mouth and occasionally be
aspirated into the larynx, causing cough and hoarseness. Reflux may
also be completely asymptomatic and, paradoxically, the development
of Barrett’s oesophagus, which is relatively resistant to acid damage,
may improve symptoms.
Diagnosis
Upper gastrointestinal endoscopy is the main diagnostic test. Biopsies
are taken to distinguish oesophagitis and Barrett’s oesophagus histolog-ically. A barium swallow can demonstrate hiatus hernia and reflux of
stomach contents into the oesophagus, as well as severe degrees of
oesophagitis.
Oesophageal and gastric pH can be measured directly via a nasogas-trically placed sensor. Episodes of reduce pH can then be correlated with
symptoms and in the  Bernstein test, acid is infused into the lower
oesophagus, in an attempt to reproduce the symptoms and confirm the
diagnosis (see Chapter 46).
Oesophageal manometry helps to distinguish dysmotility from reflux
(see Chapter 46).
Treatment
Lifestyle changes such as having smaller meals, giving up smoking,
reducing alcohol intake, losing weight and sleeping with the head of the
bed raised can effectively reduce symptoms. Simple antacids are also
effective, although selective histamine H2 receptor antagonists, such
as ranitidine, and the proton pump inhibitors, such as omeprazole,
which irreversibly block acid production by parietal cells, are the most
effective treatment.
Hiatus hernia usually does not require specific treatment, such as
surgery, although it can be repaired by fundoplication, whereby the
gastric fundus is partially wrapped around the lower oesophagus,
strengthening the sphincter and preventing migration through the
diaphragmatic hiatus. Fundoplication can also be used to treat
intractable reflux in the absence of a hiatus hernia.
Barrett’s oesophagus is  premalignant and, therefore, regular
endoscopic  surveillance with biopsies to detect dysplasia is
advocated. If dysplasia is detected, the patient may undergo
oesophagectomy.
Gastro-oesophageal reflux and hiatus hernia 71
Peptic ulcers are common, affecting 15% of individuals in the Western
world. In many cases they cause only mild symptoms and little damage,
but in others they can be life threatening. The treatment of peptic ulcer
has dramatically changed following our improved understanding of
its pathogenesis, representing a triumph of the power of scientific
medicine.
Pathology
The surface epithelium of the stomach or duodenum is damaged and
ulcerates, and the resulting inflammation extends into the underlying
mucosa and submucosa. Gastric acid and digestive enzymes penetrate
into the tissues, causing further damage, for example, to blood vessels
and adjacent tissues.
72 Disorders and diseases
•  Up to 80% of population infected
•  15% get peptic ulcer
•  Others may develop:
– gastritis
– gastric cancer
– gastric lymphoma
•  Most remain well
Helicobacter pylori
Ulcer treatment in evolution
Clinical features
Anorexia
Nausea
Vomiting
Haematemesis
Epigastric
pain
Anaemia
Melaena Alcohol
NSAIDs
ØProstglandins
CO2
NH4+
H+pH≠
Urea
Urease
Acid
neutralized
Helicobacter
pylori
Virulence
factors
Gastritis, ulcer,
cancer

Host response
Secretomotor fibres
Vagus nerve
Gastric ulcer
?Malignant
Promotility fibres
Smoking reduces
blood flow
Coeliac artery
Ulcer erodes
artery
Ulcer
perforates
Pentrating
ulcer
Pancreatitis
Scarring &
fibrosis
causes
obstruction
• Gastrectomy
• Vagotomy
• Antacids – ineffective
• H2 receptor antagonists
•  Proton pump inhibitors
+ 2 antibiotics
(combined therapy)
to eradicate H. pylori

Obsolete
Effective
Cure
31 Peptic ulcer and Helicobacter pylori
Pathogenesis
• Acid. Gastric acid (HCl) production is stimulated by gastrin secreted
by G cells in the antrum, acetylcholine released by the vagus nerve and
histamine released by entero-chromaffin-like (ECL) cells, all of which
stimulate receptors on acid-producing parietal cells.
Duodenal ulcers are exceedingly rare in people who do not produce
gastric acid and multiple, recurrent ulcers occur when acid production
is greatly increased, for example, by gastrin-secreting tumours (see
Chapters 16 & 38). However, gastric acid production is usually low in
people with gastric ulcers and this may be the result of chronic gastritis.
• Prostaglandins. The risk of peptic ulcer is increased in patients who
use non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin,
which inhibit prostaglandin production by epithelial cells. Furthermore
the risk of peptic ulcer is reduced by an artificial prostaglandin E2 ago-nist, misoprostil.
• Smoking, alcohol, genetics and stress. Other risk factors include
smoking tobacco and drinking alcohol, although the mechanisms by
which these act are unknown. In addition, there is a small genetic predis-position. There is little evidence that stress or lifestyle factors play any
role.
• Helicobacter pylori. Spiral bacteria in the stomach had been noted for
over a hundred years, yet their significance only became apparent in
1982 when Warren and Marshall cultured H. pylori from 11 patients with
gastritis and Dr Marshall then demonstrated that it caused gastritis by
ingesting a test dose himself. He was subsequently cured by antibiotic
treatment.
H. pylori infection is present in the majority of patients with peptic
ulcer, although only about 15% of infected people develop ulcers.
Eradicating H. pylori infection permanently cures peptic ulcer in the
majority of cases.
H. pylori infection of the gastric antrum, which stimulates gastrin
production, causes the greatest hyperacidity and duodenal ulceration,
while infection of the gastric corpus, where most parietal cells are pres-ent, tends to reduce stomach acid production and is associated with gas-tritis, gastric ulcer, gastric cancer and gastric lymphoma.
Strains of H. pylori vary in pathogenicity and virulence, determined
by various bacterial gene clusters. Thus both host factors and the bacter-ial strain determine the outcome of infection.
Peptic ulceration results from an imbalance between gastroprotec-tive factors, such as the mucus layer and prostaglandins, and aggressive
factors, such as stomach acid and the effects of smoking, alcohol
and NSAIDs. H. pylori infection dramatically tips the balance against
protection.
Clinical features
Epigastric pain, often aggravated by hunger or by meals and relieved
by antacids, suggests peptic ulceration or gastritis. There may be
nausea, vomiting and anorexia. Anaemia may develop from chronic
haemorrhage.
Peptic ulcer may cause major acute bleeding, leading to haemateme-sis and/or melaena, which is a medical emergency. Similarly, peptic
ulcers may perforate the stomach or duodenum, causing  peritonitis.
Peptic ulcer may penetrate into the pancreas and cause pancreatitis.
Scarring of the duodenum by chronic ulceration may cause intestinal
obstruction.
Diagnosis
Upper gastrointestinal endoscopy is the best diagnostic test. Ulcers can
also be detected by barium contrast X-rays.
H. pylori infection can be diagnosed serologically, or by the urease
breath test, in which 13C-labelled urea is taken orally and the resulting
13CO2 released by the urease enzyme is measured on the breath (see
Chapter 46). H. pylori organisms can be demonstrated histologically
and the urease enzyme can be detected using a simple colorimetric test
(CLO test, for Campylobacter-like organism) in mucosal biopsies taken
during endoscopy (see Chapter 46).
Gastric ulcers may be caused by carcinoma or lymphoma, so they
must always be biopsied to check that they are not malignant. Duodenal
ulcers are very rarely malignant.
Treatment
• Surgery. Except for emergencies, surgical treatment is now obsolete.
Partial gastrectomy to remove part of the gastrin-producing, G-cell-rich antrum was once routinely performed. Another approach was to
selectively section branches of the vagus nerve (selective vagotomy)
that stimulated acid secretion, sparing fibres that controlled the pyloric
sphincter.
• Simple antacids and anticholinergics are relatively ineffective, have
to be taken frequently and produce side-effects.
• The first effective medical treatment for peptic ulcer emerged when
selective histamine H2 receptor antagonists were developed. For some
time drugs such as cimetidine and ranitidine were the most widely pre-scribed medications worldwide.
• Proton pump inhibitors, which irreversibly block acid production
by parietal cells, have overtaken the H2 receptor antagonists, and
omeprazole, the first proton pump inhibitor, accounts for the greatest
worldwide expenditure on a single drug.
• Helicobacter pylori eradication provides a permanent cure for most
cases of peptic ulcer. Successful eradication requires combined ther-apy with an acid suppressor and two or three antibiotics. Most standard
regimes are successful in up to 90% of cases, although antibiotic resist-ance is emerging.
• Emergency treatment. Bleeding or perforation may require emer-gency surgical or endoscopic therapy, such as injection of adrenaline
around an exposed vessel, to arrest haemorrhage.
Peptic ulcer and Helicobacter pylori 73
74 Disorders and diseases
Clinical features
Low blood
pressure
Conjunctivitis
Uveitis
Fever
Renal
failure
Vomiting
Abdominal pain
Diarrhoea ± blood
and leucocytes
Urethritis
Arthritis
Vomiting
centre
CTZ
Afferent nerve signals
Vagus
Toxins via
bloodstream
Staphylococcus aureus
Bacillus cereus
Campylobacter, Shigella,
Salmonella, E. coli
Atypical
mycobacteria
Cytomegalo-virus
Clostridium
difficile
Entamoeba
histolytica
Vibrio
cholera
Microsporidia,
cryptosporidia
Rotavirus,
Norwalk
agent
Giardia
lamblia
5HT
Spores Preformed
toxins
Live bacteria, viruses,
parasites
Food poisoning
Organism

Staphylococcus
aureus and Bacillus
cereus
Clostridium
perfringens
Vibrio
parahaemolyticus
Vibrio cholera

Escherichia coli,
Campylobacter jejuni,
Shigella species,
Salmonella species
Enterohaemorrhagic
E. coli
(EHEC) 0157:H7

1–8
8–16
6–96
24–72
24–72
24–72

Features

Preformed toxin in food
abruptly causes vomiting
and diarrhoea
Toxin preformed and
synthesized in the gut
causes diarrhoea
Bacteria in seafood causes
diarrhoea and vomiting
Bacteria in food and water
causes severe diarrhoea,
often in epidemics
Bacteria in food causes
diarrhoea, often with blood
and leucocytes in stool.
Typical causes of traveller’s
diarrhoea
Food poisoning, followed by
widespread coagulation
and haemorrhage, and
renal dysfunction
(haemolytic-uraemic
syndrome)
Incubation
period
(hours)
32 Gastroenteritis and food poisoning
Gastroenteritis is common, causing illness ranging from self-limited
episodes of food poisoning, experienced occasionally by most people, to
devastating epidemics that cause many deaths worldwide. In addition,
many systemic infections enter the body through the intestine. Viruses,
bacteria, fungi, protozoa and multicellular parasites are all implicated.
Pathogenic mechanisms
Microorganisms cause gastroenteritis in a number of ways:
• Enterotoxins. These are usually secreted proteins that act on the
intestinal epithelium, or are absorbed into the bloodstream and have sys-temic effects. For example, vibrios and enterotoxigenic Escherichia coli
(ETEC) secrete heat-sensitive or heat-stable enterotoxins that drive
excessive intestinal secretion.  Staphylococcus aureus and  Bacillus
cereus produce emetogenic toxins that are absorbed systemically and
stimulate the vomiting centre. Some toxins cause intestinal inflamma-tion; for example, the cytotoxin secreted by Clostridium difficile.
• Adhesion and persistence in the intestine. The flow of luminal con-tents through the intestine limits harmful microbial effects and some
organisms overcome this defence mechanism by producing adhesive
structures (adhesins) that interact with proteins on the host cell surface.
Multicellular parasites, such as worms, may use mechanical hooks and
suckers to resist being swept away.
• Invasion of epithelial cells and mucosal damage. Enteropathogenic
E. coli (EPEC), Campylobacter jejuni, Salmonella and Shigella species,
Vibrio parahaemolyticus, viruses such as cytomegalovirus, and amoe-bae (Entamoeba histolytica), invade the epithelium, causing ulceration
and inflammation. In bacterial, viral and amoebic dysentery, the stools
contain blood and leucocytes and there is a systemic inflammatory
response, resembling inflammatory bowel disease.
• Invasion through the intestine. The dysentery-causing bacteria, E.
histolytica and Salmonella typhi, the cause of typhoid fever, may cross
the epithelium and cause local and distant disease. S. typhi initially mul-tiplies in intestinal lymphoid tissue; however, the most serious effects of
typhoid result from systemic bacteraemia. Invasion is an essential step in
the lifecycle of some parasites and worms.
Clinical features
Typically infection rapidly follows ingestion of contaminated food or
drink and is short-lived and self-limiting.
Vomiting may be induced directly by emetogenic enterotoxins and
is also mediated by efferent nerves stimulated by intestinal distension
and mucosal damage. Serotonin (5-hydroxytryptamine, 5HT) released
from neuro-endocrine cells may stimulate the chemoreceptor trigger
zone (CTZ) (see Chapter 26).
Diarrhoea is caused by numerous factors: toxins stimulating secre-tion;  neuro-endocrine reflexes stimulating motility and secretion;
inflammation causing exudation of fluid and cells into the intestine;
and a reduced digestive and absorptive capacity for sugars (particularly
lactose), creating an osmotic load (see Chapter 27).
Abdominal pain  is caused by  distension of the intestine, muscle
spasms resulting from hypermotility, and inflammatory damage to the
mucosa.
Fever and other systemic symptoms are unusual with simple gas-troenteritis or food poisoning, although they are frequent in bacterial or
amoebic dysentery. They suggest invasive infection.
Dehydration may cause hypotension and renal failure.
Heamolytic–uraemic syndrome  is a life-threatening syndrome
caused by enterohaemorrhagic  E. coli (EHEC) serotype 0157·:·H7,
which is endemic among cattle. Outbreaks have often been traced to
inadequately cooked ground beef. Vomiting and diarrhoea are followed
by high fever and damage to blood vessels, and the kidneys may be dam-aged by the EHEC cytotoxin. Antibiotics may aggravate the syndrome.
Reiter’s syndrome and other reactive arthritis syndromes, character-ized by combinations of arthritis, urethritis, conjunctivits, uveitis and
various mucocutaneous lesions may follow bacterial dysentery.
Guillain–Barré syndrome, caused by immune-mediated demyeli-nation of peripheral nerves, may follow Campylobacter infection.
Gastroenteritis can also cause prolonged  lactose intolerance and
post-infectious irritable bowel syndrome.
Food poisoning
This is the common syndrome of gastroenteritis caused by contaminated
food. Usually  spores or  organisms that multiply in the intestine are
ingested. In cases where  preformed toxins are ingested, symptoms
occur sooner, within hours (see table within the figure).
Traveller’s diarrhoea
Travellers to areas where gastrointestinal infection is common, typically
Africa, the Far East and Latin America, are at risk. Bacteria like Campy-lobacter,  Shigella,  Salmonella and  E. coli are the commonest cause,
followed by  viruses and  protozoa (Giardia lamblia and  Entamoeba
histolytica).
Endemic and epidemic diarrhoea
Outbreaks of gastroenteritis occur in nurseries, schools, camps and hos-pitals where overcrowding and communal facilities allow rapid spread.
Viruses such as the rotavirus and the Norwalk agent are the commonest
cause. Wars, floods and earthquakes can create conditions for outbreaks
of  cholera and  typhoid. These outbreaks, aggravated by scarcity of
clean drinking water and basic medical care, can cause great suffering.
Immunocompromised patients
Diarrhoea is common and often chronic in patients with acquired
immune deficiency syndrome (AIDS) and in those who are immunosup-pressed. Organisms that are normally non-pathogenic, such as Cryp-tosporidia and microsporidia, can cause opportunistic disease.
Antibiotic-associated diarrhoea
Antibiotics alter the normal balance of enteric commensal bacteria
and may cause diarrhoea. This is frequently caused by overgrowth of
toxin-producing Clostridium difficile, which can cause severe inflam-mation (pseudomembranous colitis).
Diagnosis
Blood and leucocytes in stool distinguish inflammatory diarrhoea from
other causes.
Microbiological diagnosis may be necessary for public health rea-sons, or to diagnose the cause of persistent diarrhoea. Rotavirus is
detected in the stool by  electron microscopy and amoebae can be
detected by light microscopy. Bacterial pathogens require stool culture,
while giardiasis requires jejunal aspiration and microscopy to make
the diagnosis.
Treatment
The mainstay of treatment is to maintain hydration, either with  oral
rehydration solutions or intravenous fluids (see Chapters 23 & 27).
Antibiotics like ciprofloxacin can reduce the duration and severity of
bacterial gastroenteritis but are usually unnecessary. Giardiasis and
amoebiasis are effectively treated with metronidazole.
Because diarrhoea is a host defence mechanism against infection,
antidiarrhoeals like loperamide should generally be avoided.
Gastroenteritis and food poisoning 75
76 Disorders and diseases
Clinical features
Jaundice,
pallor
Fever
Night sweats
Right upper
quadrant pain
Diarrhoea
Steatorrhoea
Weight loss
Use to treat infection, or selectively
decontaminate intestine

Odynophagia,
dysphagia
Abdominal
pain
Candida
Herpes simplex
Cytomegalovirus
103 bacteria/mL
Tapeworm
Cytomegalovirus (CMV) colitis
Commensals
1012 bacteria/g
>500 species, mainly anaerobes
Escherichia coli
Bacteroides
Bifidobacteria
Lactobacillus
Peri-anal abscess
Tropical sprue
Roundworm
Hookworm
Salmonella
typhi bacteraemia
Portal vein
bacteraemia
Whipple’s
disease
Ascending
cholangitis
Gall-bladder
Yersinia infection
Intestinal tuberculosis
(may resemble Crohn’s
disease)
Appendicitis
Hydatid cyst
Pancreas
Bacterial or
amoebic liver
abscess
Normal
intestinal flow
‘Blind-loop’
colonized
by bacteria
Bacterial overgrowth
Non-absorbable antibiotics
‘Normal’ commensal bacteria
administered orally or rectally

Probiotics
Surgical
anastamosis
Gas
production H2
CH4
33 Gastrointestinal system infections
In addition to gastroenteritis and food poisoning, microorganisms cause
various other gastrointestinal system-related illness. Furthermore, there
is a large resident or commensal population of bacteria, whose role in
health and disease remains unknown.
Commensal flora
Bacteria colonize the entire intestinal tract, with the greatest number,
1012/g, in the large intestine. They apparently cause no harm and poten-tially benefit the host, possibly by excluding pathogenic species. There
are over 500 different species and the dominant species and genera are
Escherichia coli, Bifidobacteria and Lactobacillus.
E. coli, Enterococcus, Streptococcus, Clostridia and others retain the
ability to cause disease, either by acquiring virulence factors, which are
usually plasmid or phage DNA-encoding toxins, adhesins, etc., or by
exploiting reduced host defence.  Clostridium difficile, for example,
causes diarrhoea when antibiotic treatment upsets the normal microbial
population, allowing it to produce its cytotoxin.
Bacterial overgrowth
The small intestine normally contains very few bacteria because of the
constant movement of food and the effect of antimicrobial proteins pro-duced by Paneth cells, for example. Bacteria overgrow, however, when
the normal anatomy is disrupted, for example surgically, or where dis-eases like systemic sclerosis cause dysmotility and stasis.
The bacteria metabolize nutrients, thus depriving the patient, and pro-duce excess intestinal gas, damage the mucosa and cause malabsorp-tion. Symptoms include abdominal pain and flatulence. Breath tests can
be used to establish the diagnosis. Antibiotics and corrective surgery
may be necessary.
Worms and parasites
Multicellular worms and parasites commonly infest the intestine,
particularly where sanitation is poor.  Hookworms, tapeworms  and
roundworms can remain in the intestine for many years, causing
chronic diarrhoea, malabsorption and anaemia. Roundworms invade
the intestine and migrate through the lungs as part of their life cycle,
causing systemic disease. The pork tape-worm, Taenia solium, leaves
encysted eggs throughout the body, causing cysticercosis. Treatment
requires helminthicides such as albendazole.
Candidiasis
Candida albicans, the only major fungal pathogen of the intestinal tract,
is a commensal in most people. Reduced immunity, as in neutropenia,
diabetes mellitus, steroid use or acquired immune deficiency syn-drome (AIDS) allows Candida to invade the superficial epithelial layers
of the tongue, mouth, pharynx and oesophagus, causing inflammation
and pain. Diagnosis is confirmed by detecting fungal hyphae in cytolog-ical specimens, or by culture. Topical or systemic antifungals such as
nystatin or fluconazole are effective therapy.
Whipple’s disease
This rare, chronic, intestinal infection caused by Tropheryma whippelii
typically affects middle-aged Caucasian males, resulting in diarrhoea,
malabsorption and fever. Duodenal biopsy shows macrophages contain-ing many bacteria and the treatment is a prolonged course of antibiotics.
Tropical sprue
Chronic diarrhoea and malabsorption, associated with enteric infection,
which used to be common in long-term residents of the tropics is now
disappearing. Duodenal biopsy demonstrates blunt villi and hyperplas-tic crypts, resembling coeliac disease, and antibiotics are curative.
Systemic infection, abscesses and masses
Intestinal bacteria can migrate into the  portal vein and form  liver
abscesses, while some enteric organisms, especially streptococci from
the mouth and gut, can cause infective endocarditis. Therefore, people
with valvular heart disease have prophylactic antibiotics before dental
and some endoscopic procedures.  Salmonella typhi causes systemic
infection and in immunocompromised patients, less virulent, non-typhi
Salmonella species can also cause osteomyelitis, brain abscess, endo-carditis, etc.
Entamoeba histolytica causes  liver abscess and abdominal wall
masses (ameoboma) as well as acute dysentery.
Echinococcus species (hydatid worm), acquired from sheep and
dogs, invade the intestinal wall, spread systemically and form large, egg-filled cysts in the liver, lungs and other organs.
Liver abscesses typically cause abdominal pain, fever and abnormal
blood tests, although they may be asymptomatic. Ultrasound and com-puterized tomography (CT) scanning are used to make the diagnosis and
antibiotics, with or without surgical drainage, are used to treat bacterial
and amoebic abscesses. Hydatid disease requires surgical treatment.
Peri-anal abscesses, arising from anaerobic infection of the deep
anal glands, are relatively common and are treated by incision and
drainage and antibiotics. Recurrent peri-anal sepsis may indicate
anorectal Crohn’s disease.
Inflammatory bowel disease
IBD is not caused by a discrete intestinal infection, although both ulcer-ative colitis (UC) and Crohn’s are triggered by environmental factors
that are almost certainly enteric microbes or their products. Antibiotics
are generally ineffective in UC, but do improve some forms of Crohn’s
disease, and administering probiotics, which are live commensal bacte-ria, ameliorates some forms of IBD.
Intestinal infection with Mycobacterium tuberculosis and Yersinia
species can strikingly resemble ileocaecal Crohn’s disease. Similarly,
bacterial and amoebic dysentery, cytomegalovirus and herpes simplex
virus infection can cause bloody diarrhoea, abdominal pain and intes-tinal ulceration that can be confused with UC.
Clinical presentation and diagnosis
Chronic intestinal infections can cause abdominal pain, diarrhoea, flatu-lence, weight loss, malabsorption and/or anaemia.
Stool culture can detect bacterial pathogens and microscopy can
detect ova, cysts and parasites. Radiological imaging, endoscopy with
biopsy and culture, blood culture and serological tests detect deep-seated abscesses and distant infection.
Treatment
The potential role of enteric commensals in health and disease is
a reminder that  antibiotics should be used cautiously. Conversely,
live bacteria or  probiotics may be used therapeutically in certain
circumstances.
Selective enteric decontamination, with non-absorbed antibiotics,
such as neomycin and norfloxacin, can be used before  intestinal
surgery and in chronic liver disease, to treat hepatic encephalopathy
and to prevent spontaneous bacterial peritonitis. The intestine is not
sterilized but the balance of species is altered.
Gastrointestinal system infections 77
78 Disorders and diseases
Clinical features Anaemia, uveitis, fevers,
sweats, jaundice
Diarrhoea, blood,
mucus
Right iliac
fossa mass/pain
Abdominal
pain
Primary sclerosing
cholangitis
Skin rash
(pyoderma,
erythema
nodosum)
Weight loss
Apthous
ulcers
Arthritis
arthralgia
Environmental
trigger
?Bacterial
Genetic predisposition Disease
Ulcerative colitis extends
proximally for variable distance
Proctitis
Deep anal
gland
Abscess
Fistula
Peri-anal Crohn’s
Ulcerative colitis
Terminal ileal Crohn’s
Primary
sclerosing
cholangitis
(5% of UC)
NOD2
gene
Bacterial products
Crohn’s
colitis can
be segmental
Skip lesions
Granuloma
Bacteria
Paneth cells
Ulcer
Crypt
Paneth cell metaplasia
Crypt
abscess
Branched
crypts
Bacteria
ulcer
Mucus depletion
* Inflammation confined to mucosa
Mucosa *
Transmural inflamation
Bile duct
Fibrosed, scarred
duct
34 Ulcerative colitis and Crohn’s disease
Two diseases constitute idiopathic inflammatory bowel disease (IBD):
ulcerative colitis (UC) and Crohn’s disease (CD). They are distinct but
similar, and both are chronic, relapsing and remitting conditions.
Together they affect about 150/100·000 of the population in Western
countries.
Aetiology
The intestine is constantly in contact with the harsh digestive environ-ment and may be regarded as being in a state of chronic low-grade
inflammation. Challenges to the intestine include  pH extremes,
mechanical trauma, ingested bacterial and viral pathogens and toxins,
and the microorganisms that comprise the  resident commensal
microflora of the bowel.  Immunological reactivity may, therefore,
develop to components of the diet or the microflora.
The aetiology of IBD remains unknown and it probably results from
one or more environmental triggers acting against a background of
inherited genetic predisposition.
Recently, CD of the terminal ileum has been genetically linked to
mutations in the NOD2 gene, which is probably an intracellular receptor
for bacterial cell wall components, expressed in monocytes and Paneth
cells.
Furthermore, experimentally disrupting the immune system in
laboratory animals often leads to intestinal inflammation, which only
develops when enteric bacteria are present.
Ulcerative colitis and CD may have a number of different primary
causes, all resulting in similar clinical and pathological outcomes.
Macroscopic pathology
Ulcerative colitis only affects the large intestine and does not extend to
the small intestine. Furthermore, the rectum is almost invariably affected
and inflammation extends proximally to a variable extent.
Crohn’s disease can affect any part of the intestinal tract, although
three patterns predominate:  terminal ileal inflammation,  colitis and
anorectal inflammation. An individual patient could have one, two or
three of these areas affected, in any combination. Furthermore, while
inflammation in UC is contiguous, extending for a variable distance
from the rectum, in CD there may be normal areas interspersed between
inflamed segments: ‘skip lesions’.
Microscopic pathology
The mucosa is ulcerated and there is an inflammatory reaction in the
lamina propria.
In UC, there are reduced numbers of goblet cells (goblet cell deple-tion) and increased numbers of Paneth cells. Furthermore, while nor-mal colonic crypts are short and straight, in UC they are distorted and
branched. Another typical feature is a collection of neutrophils within
the crypt lumen, forming crypt abscesses.
Within the lamina propria there are increased numbers of inflamma-tory cells. The inflammatory reaction in UC does not extend deeper than
the lamina propria. In contrast, in CD, inflammation typically extends
transmurally through the wall of the intestine. In addition, there
are  granulomas in CD, consisting of activated lymphocytes and
macrophages.
Clinical features
Colitis (UC or Crohn’s colitis) causes diarrhoea, which usually con-tains blood and pus or mucus. In addition, there may be abdominal pain
and malaise due to the systemic response to inflammation.
In CD, terminal ileitis may cause diarrhoea or constipation, abdomi-nal pain and a palpable  inflammatory mass in the right iliac fossa.
Chronic terminal ileitis may interfere with absorption of  vitamin
B12 and  bile salts, causing  anaemia and predisposing to gallstones.
Inflammation may also cause strictures, resulting in intestinal
obstruction.
In CD, because the inflammation extends transmurally, intestinal fis-tulae and deep-seated abscesses occur.
The systemic inflammatory response characterized by fever, malaise
and  weight loss tends to be milder in UC and more pronounced in
CD.
Extra-intestinal features of IBD include skin rashes, such as
pyoderma gangrenosum and  erythema nodosum, arthralgia and
arthritis (in up to 15% of patients), and inflammation of the eyes
(iritis and  uveitis).  Apthous ulcers in the mouth are particularly
common.
Longstanding UC predisposes to colon cancer and primary sclerosing
cholangitis (PSC) occurs in about 5% of patients with UC.
Diagnosis
The mainstay of diagnosing colitis is to perform sigmoidoscopy and
colonoscopy, with mucosal biopsies to histologically confirm the diag-nosis. A barium meal and follow-through examination visualizes the
terminal ileum, demonstrating inflammation, fistulae and strictures.
There are no specific blood tests for UC or CD, but anaemia, vitamin B12
deficiency, and raised inflammatory markers, such as the  C-reactive
protein, are common. In a proportion of UC patients, antineutrophil
cytoplasmic antibodies (ANCA) are found, while in CD, antibodies to
Saccharomyces cerevisiae (ASCA) may be detected.
Treatment
• 5-Aminosalicylic acid (5ASA, mesalazine). This compound has a
local anti-inflammatory action, particularly in the colon, and can be
administered rectally or orally. Slow release formulations (pentasa or
asacol) dissolve in the colon, while conjugated forms of 5ASA (sul-phasalazine, olsalazine and balsalazide) are enzymatically released in
the colon by bacteria.
• Corticosteroids. Steroid treatment is usually effective at inducing
remission and is used particularly to treat acute exacerbations. It may be
administered parenterally, orally or rectally. Prolonged systemic steroid
treatment has many adverse effects, including worsening osteoporosis.
Budesonide is a synthetic steroid that is rapidly metabolized by the liver,
resulting in low systemic levels, and it may be particularly effective for
terminal ileal CD.
• Immunosuppressives. Drugs such as azathioprine, 6-mercapto-purine and methotrexate are used, particularly when frequent relapses
necessitate repeated steroid use. Antibodies to the cytokine tumour
necrosis factor a (TNFa) are dramatically effective in a proportion of
people with CD.
• Antibiotics. Metronidazole may induce remission in some cases of
CD but is not effective in UC.
• Probiotics. Live bacteria, to restore the normal balance of enteric
flora, are used with some success.
• Surgery. Panproctocolectomy (removal of the colon and rectum) is
curative for UC and is used as a last resort for severe disease or where
dysplasia develops. CD almost invariably recurs after surgery; therefore
the use of surgery is largely limited to, for example, relieving sympto-matic strictures or draining abscesses.
Ulcerative colitis and Crohn’s disease 79
80 Disorders and diseases
Clinical features
Neurological
symptoms
Positive tTG
antibody
Anaemia
Diarrhoea,
steatorrhoea
Osteoporosis Weight loss
Dermatitis
herpetiformis rash
Lethargy, fatigue
Abdominal
pain
O
OOO
Q Q Q P P S Q Q
O
O
Q
O
O
O
O
O
O
O
QQQQQ
Q
Q
OO
O
O
O O
O
Q
Q Q
Q
Q
Q
Q
Q
Q
Q
Activation
and proliferation
Tissue
damage
Wheat, rye, barley
Silent disease
Latent disease (+ve tTG
antibody, no pathology)
Coeliac
disease
Coeliac iceberg
Duodenum

Smooth-looking
mucosa (subtotal
villus atrophy)
Jejunum
Atrophied
villi
Crypt
depth
Villus
height
Deep
crypts
Damaged
epithelium
Healthy absorptive
epithelium
Lymphocyte
infiltration
Scattered
lymphocytes
TNFa, interferon g
Glutamine-rich
gliadin peptides
T cell
*Q = glutamine
Wheat protein
Antigen-presenting
cell, e.g. dendritic cell
Enterocyte
De-amidated peptides
Tissue transglutaminase
(tTG)
35 Coeliac disease
Coeliac disease is also known as  gluten enteropathy because it is
caused by immune reactivity triggered by glutamine- and proline-rich
gluten proteins, found mainly in wheat, rye, barley and oats. The illness
may become apparent at any age, from infancy to old age, may remain
asymptomatic, and may be detected incidentally.
Aetiology and pathogenesis
The healthy small intestinal epithelium is maintained by constant cell
turnover, and the balance between normal shedding of old epithelial
cells at the tips of villi and the formation of new cells from  stem
cells in the crypts maintains a  2·:·1 ratio between villus height and
crypt depth. The  lamina propria contains a small number of lym-phocytes, macrophages, fibroblasts, capillary endothelial cells and
other cells. The epithelium itself contains a population of resident
intraepithelial lymphocytes that maintain  surveillance against
potential pathogens.
In  genetically susceptible individuals, immunological reaction to
gluten-derived gliadin peptides develops upon dietary exposure. The
exact genes causing coeliac disease have not been identified but certain
major histocompatibility complex (MHC) class II gene alleles are
strongly associated with the condition. Early dietary exposure to gluten,
particularly after weaning from milk, may increase the risk of develop-ing the disease.
The ubiquitous cellular enzyme  tissue transglutaminase  (tTG),
which normally cross-links glutamine residues with lysine in connective
tissue proteins, plays an essential role in the pathogenesis, by converting
glutamine residues in native gliadin peptides to glutamate, creating more
immunogenic peptides. However no disease-associated polymorphisms
in the tTG gene have been identified.
Lymphocytes react with the modified gliadin peptides on the surface
of antigen-presenting cells and proliferate, increasing the number of
intraepithelial and lamina propria lymphocytes. Activated lymphocytes
secrete inflammatory mediators, including the cytokines, g-interferon
and tumour necrosis factor a (TNFa), recruiting and activating more
inflammatory cells, altering the proliferative rate of intestinal epithelial
stem cells, and increasing the rate of programmed cell death (apoptosis)
in mature enterocytes. This creates an oedematous, swollen intestinal
mucosa, with short, thick, blunt villi and deeper than normal crypts
(subtotal villus atrophy), and the reduced epithelial surface area
and compromised epithelial digestive and absorptive capacity leads to
malabsorption.
The concentration of dietary gluten is highest proximally in the intes-tine and therefore coeliac disease affects the duodenum and proximal
jejunum most severely.
Clinical features
Coeliac disease can become apparent at  any age, although most
cases are diagnosed in early childhood or in middle age. Coeliac
disease may remain clinically silent and people with circulating anti-bodies to tTG, but no overt pathology, may be considered to have latent
disease.
Malabsorption causes  diarrhoea and  weight loss. Inability to
absorb fats results in  steatorrhoea, with bulky, pale, foul-smelling
stools that float in water, because of their high fat content. Anaemia,
caused by iron deficiency is frequent. Malabsorption of calcium and
vitamin D increases the risk of developing osteoporosis.
Nutrients that are mainly absorbed in the proximal small intestine,
such as iron and calcium, are most affected by coeliac disease, while
nutrients predominantly absorbed in the jejunum and ileum, such as folic
acid, vitamin C and vitamin B12, are affected only in more advanced
disease.
Patients may complain of abdominal pain and tiredness and, for
unknown reasons, neurological complaints, ranging from mild periph-eral neuropathy to more severe central nervous system disturbance,
occur in up to 10% of patients.
A small number of people develop a blistering rash called dermatitis
herpetiformis, associated with antibodies to tTG reacting with a form of
this enzyme in dermal cells.
Possibly as the result of chronic inflammation, people with uncon-trolled coeliac disease are at increased risk of developing intestinal neo-plasms, particularly intestinal  lymphoma. This risk is substantially
reduced by strict adherence to a gliadin-free diet (see Chapter 38).
All these signs and symptoms disappear when gliadin is omitted from
the diet and reappear if it is reintroduced.
Diagnosis
Unexplained anaemia and vague abdominal and neurological symptoms
should prompt the physician to check for coeliac disease, as it is often
missed and is particularly common in some populations, such as people
originating from western Ireland. Conversely, it remains rare among
Africans.
Circulating antibodies to tTG offer an excellent serological marker
of coeliac disease, with sensitivity and specificity approaching 100%.
The test was first described as detecting an unknown antigen in the lining
of oesophageal smooth muscle (endomysium), hence the term  anti-endomysial antibody. This test replaces the antigliadin anti-body test
that has lower sensitivity and specificity. Serological tests rely on detect-ing immunoglobulin A (IgA) antibodies and are unreliable in the 1·:·500
individuals with selective IgA deficiency (see Chapter 18).
Upper gastrointestinal endoscopy and duodenal mucosal biopsy, to
confirm subtotal villus atrophy and lymphocytic infiltration, is per-formed before treatment, after initiating a gliadin-free diet, and again
after reintroduction of a gliadin challenge diet, and is the gold standard of
diagnosis. With the advent of reliable serological testing, it is now used
less frequently.
Rare forms of small intestinal disease, such as Whipple’s disease,
Crohn’s disease of the small intestine and tropical sprue may mimic
coeliac disease and here a duodenal or jejunal biopsy may be particularly
helpful in the diagnosis.
Treatment
The mainstay of treatment is for patients to follow a gluten-free diet.
Wheat, rye and barley proteins are present in many ready-made meals
and snacks, so the help of a professional dietician and a patients’ associ-ation, such as the Coeliac Society in the UK, should be enlisted to main-tain vigilance. In severe, uncontrolled coeliac disease, acute intestinal
inflammation can be treated with corticosteroids, but this is hazardous
and rarely indicated.
Coeliac disease 81
82 Disorders and diseases
Starvation and refeeding
Obesity related disease
Osteoarthritis
Truncal obesity General obesity
Hypertension
Stroke
Coronary
artery
disease
Diabetes
mellitus
Complicated
surgery
Fatty
liver
Surgical therapy for obesity
BMI, BMR, age, morbidity and mortality
Medical therapy for obesity
and weight maintenance
Gastroplication
• Low-fat diet
• Calorie-restricted diet
•  Regular exercise BMR≠
• Appetite suppressants:
Amphetamines
Amphetamine derivatives
5HT re-uptake inhibitors
(sibutramine)
• Hormone-based treatments
Leptin
Ghrelin
•  Intestinal lipase inhibitor
Orlistat

Liposuction
Jaw wiring
Adverse
effects
under
evaluation
Experimental
Normal
Jejunal bypass
DEATHInfection
Kwashiorkor
(protein/energy deficiency)
•  Reduced serum protein
• Muscle wasting
• Oedema
• Reduced immunity
Starvation
• BMRØ
• Listless, tired
• Weight loss
•  ØSkin fold thickness
•  ØMuscle strength

Fasting, illness,
old age,
anorexia
Metabolic
adaptation
Ketones
ØGlycoytic
enzymes
or thiamine
deficiency
e.g. alcoholics
Gradual refeeding or
thamine
supplements
Rapid refeeding
or thamine
deficiency
Glucose Glucose
Lactate
Acidosis
CO2 + H2O
+ Energy
(especially in children)
Morbidity and mortalityBasal metabolic rate (BMR)
BMI
Underweight
Normal
Overweight
Obesity
Morbid obesity
Body mass index (BMI)
=  wt/ht2
(kg/m2)
20 30
Age (years)BMI (kg/m2)
BMI (kg/m2)
40

20 30 40
20 30 40
36 Obesity and malnutrition
Obesity
Obesity is arguably the most prevalent health problem in the Western
world and its incidence is increasing worldwide. Body weight is tightly
regulated so that strategies to gain or lose weight must overcome strong
homeostatic mechanisms (see Chapter 22).
Measuring obesity
Obesity implies an abnormal ratio of adipose tissue to lean mass (mainly
bone and muscle). The body mass index (BMI) (weight in kg/(height in
m)2) is a practical guide to healthy body weight. The normal BMI is
between 18 and 25; over 25 is overweight, over 30 is obese and over 40 is
morbidly obese. Skin-fold thickness also measures body fat stores, as
does total body impedance to a low frequency electrical current, and
total body density, which can be determined in research settings.
Obesity is associated with excessive rates of illness, particularly
hypertension,  diabetes mellitus,  stroke, vascular  thrombosis and
heart disease. A simple measure of overweight that correlates with the
risk of cardiovascular disease is the waist·:·hip ratio, with the normal
ratio being less than one.
Treating obesity
Body weight tends to increase with age, and preventing obesity is as
important as reducing weight.
• Diet. Restricting calorie intake reduces body weight. Initial weight
loss tends to be followed by rebound weight gain after a few months.
Some diets restrict fluid intake and dehydration causes rapid but spuri-ous weight loss. To maintain weight control, diets must be sustainable
and nutritionally adequate and not lack essential vitamins, minerals or
macronutrients. Very low calorie diets, carry the risk of undernutrition
and should be supervised by a physician, while low calorie diets, for
example, those advocated by WeightWatchers™, are safer.
Large portions and a preponderance of calorie-dense foods, that is,
fats, tend to increase calorie intake. Ideally the proportion of calories
consumed as fat should be between 20 and 30% of the total.
• Exercise. Regular exercise helps to limit body weight, partly by con-suming calories to provide energy to muscle and also by suppressing
appetite and raising the basal metabolic rate (BMR) (see Chapter 22).
• Pharmacotherapy. The medical consequences of obesity are being
increasingly recognized and effective treatments actively sought, partly
stimulated by the discovery of leptin and other endogenous appetite-suppressants, and the results of research into neuro-endocrine control of
body weight.
The most effective appetite suppressants were the  amphetamine
derivatives dexfenfluramine and phenteramine, which unfortunately
caused major cardiac side-effects and were withdrawn from use. Sibu-tramine is another effective appetite suppressant acting through sero-toninergic pathways. Orlistat is a specific pancreatic lipase inhibitor
that causes fat malabsorption and weight loss. Side-effects, such as oily
stool and fat-soluble vitamin deficiencies, limit its use.
• Occasionally, obesity is caused by endocrine dysfunction, such as
hypothyroidism, and treating the underlying condition is effective.
• Surgery. Surgical removal of fat, for example, by liposuction and
gastrointestinal surgery to limit food intake and absorption are the main
options. Cosmetic surgery has only short-term benefits and risks
scarring and infection. Gastrointestinal surgery is reserved for treating
morbid obesity. Jejuno-ileal bypass is no longer performed, because it
caused severe liver disease (steatohepatitis). Jaw-wiring, which limits
food intake, and gastroplication, whereby a portion of the stomach is
stitched or enclosed with a rubber band, reducing the size of the gastric
reservoir, are the most frequent operations for obesity (see Chapter 48).
Starvation, malnutrition and anorexia
Malnutrition has many causes, of which economic deprivation is the
commonest. However, even in wealthy societies, ill health, gastroin-testinal diseases, such as oesophageal cancer, and anorexia nervosa, as
well as voluntary fasting, can all cause malnutrition and starvation.
Measuring malnutrition
The  BMI is abnormally low and other measures, such as  skin-fold
thickness and muscle strength and mass, are low.  Listlessness and
lethargy occur and with severe starvation, multiple organ failure may
occur. In women, menstruation ceases. There may also be signs of spe-cific vitamin and mineral deficiencies.
Effects of malnutrition
Malnutrition causes widespread abnormalities, including changes in
the gastrointestinal tract. Villi are shorter, less digestive enzymes are
synthesized and the intestinal barrier to the entry of pathogens is
reduced. This  atrophy occurs whenever the intestine is not used, so
patients who are fed parenterally are also at risk. Malnourished children
have stunted growth and, due to mucosal atrophy and a general reduction
in immune competence, are particularly susceptible to infections,
such as gastroenteritis, which aggravates the malnutrition and may be
fatal.
Metabolic adaptation, which reduces dependence on glucose and
lowers the BMR, allows the organism to survive for longer at a lower
energy intake. An important consequence is that rapid refeeding after a
period of starvation can induce serious metabolic abnormalities (refeed-ing syndrome).
Kwashiorkor, or protein-energy malnutrition, occurs when protein
deficiency is greater than overall calorie deficiency. Tissue and blood
proteins are inadequately renewed, causing skin, hair and serum protein
abnormalities and, characteristically, peripheral oedema. Marasmus,
in contrast, is global malnutrition, without oedema.
Specific micronutrient deficiencies also occur in malnutrition and,
paradoxically, global malnutrition may mask specific vitamin deficien-cies. For example, malnourished alcohol-dependent people, who
neglect nutrition in favour of alcohol, may be thiamine (vitamin B1)
deficient. The deficiency may not be clinically apparent while they con-sume a diet lacking carbohydrates. However, if they are admitted to hos-pital and given intravenous glucose or a good meal, acute thiamine
deficiency occurs, because thiamine is an essential cofactor for the pyru-vate dehydrogenase enzyme, which metabolizes glucose in cells. Acute
thiamine deficiency is a medical emergency and can cause permanent
neurological damage (Wernicke’s encephalopathy) if thiamine is not
administered immediately.
Obesity and malnutrition 83
84 Disorders and diseases
Clinical features
Dukes’ staging
Multi-step cancer causation
Altered bowel habit,
rectal bleeding
Weight loss, anaemia
Abdominal pain
Intestinal obstruction
Family history
Epithelium
Musclaris
mucosae
Circular
muscles
Region lymph
nodes
Liver Lungs
Dukes’ D <5% survival
Dukes’ A 85–100% survival
Dukes’ C 30–60% survival
Dukes’ B 50–80% survival
Diet
• high fat
• high meat
Prevention by NSAIDS,
high carbohydrate diet
Smoking
Chronic colitis Inherited predisposition
Focus of high-grade dysplasia
Late, critical
mutations
Carcinoma
in situ
Early
carcinoma
Early invasion through
basement membrane
Adenomatous polyp
High-grade
mutations,
e.g. k-ras, p53
Carcinoma
Metastatic cancer
Invasion of lymphatics and blood vessels
Further genetic
abnormalities
Aberrant focus
accumulating
early mutations,
e.g. APC in 80%
Normal epithelium
or heterozygous
for inherited
mutations in APC
or HNPCC genes
Environment and
food carcinogens

37 Colon and rectal cancer
Gastrointestinal cancers impose a major health burden: colon and rectal
cancer (colorectal cancer, CRC) is the second commonest cause of
cancer-related death in the Western world, while gastric, oesophageal,
pancreatic and liver cancer are also relatively frequent.
Pathology
The development of colorectal cancer follows a characteristic pattern in
most cases, with the earliest lesion being a microscopic focus of aber-rant epithelial cells. With time these form a small dysplastic polyp,
which enlarges, comprising epithelial cells with increasing numbers
of mutations in cancer-related genes and a progressively dysplastic
phenotype.
Some cells may become malignant, forming a focus of carcinoma in
situ, which is confined to the epithelium of the polyp. These malignant
cells may penetrate the basement membrane and invade first the intes-tinal wall and then lymphatics via which they are carried to regional
lymph nodes. Finally they may invade blood vessels and so metastasize
to distant organs such as the liver and lungs.
The Dukes staging is used to determine prognosis and optimal treat-ment (see figure).
Aetiology and pathogenesis
Environmental factors including diet influence the incidence of CRC.
Western diets that are high in fat and red meat and low in fibre predis-pose to CRC, while vegetables, vitamins, trace elements, such as sele-nium, and non-steroidal anti-inflammatory drugs (NSAIDs), such as
sulindac, seem to be protective. Smoking tobacco also increases the risk
of CRC. High-fat diets induce the production of  carcinogens, while
reduced dietary fibre causes constipation so that the carcinogens remain
in contact with the epithelium for longer.
Chronic intestinal inflammation, as in ulcerative colitis, also
increases the risk, possibly by increasing epithelial cell turnover, and
thus increasing the chance of genetic mutations.
There is a strong genetic element and the risk of CRC is increased in
people who have one or more affected first-degree relatives. The study of
familial forms of CRC, particularly autosomal dominant familial ade-nomatous polyposis (FAP) and hereditary non-polyposis colon can-cer (HNPCC), have helped to elucidate the molecular pathogenesis of
CRC, based on the ‘two-hit’ and multiple gene theory of how tumour
suppressor genes function.
Colonic epithelial cells undergo progressive change from normal,
through increasing dysplasia, to carcinoma. These cellular changes are
caused by genetic changes; some of which may be inherited and others
acquired through the effect of carcinogens. Mutation of a single allele
is usually insufficient to alter cellular function, so, for each gene, both
alleles must be mutated.
In genetic CRC syndromes, one mutant allele is inherited, so only a
single second mutation in that gene is required. To produce cancer,
numerous genes must be mutated; therefore, it takes many years to accu-mulate sufficient mutations. For example, FAP is caused by mutations in
the  adenomatous polyposis coli (APC) gene, which is frequently
mutated even in sporadic, non-familial CRC. Patients with FAP develop
many hundreds of polyps and then cancer in their early 20s in almost all
cases. This occurs because each colonocyte already carries one mutated
APC gene, so that environmental carcinogens only have to mutate and
inactivate the single remaining copy to produce a polyp, which can then
go on to develop into a cancer.
HNPCC does not involve a polyp-forming stage and is associated
with mutations in the genes responsible for ensuring that mistakes in
copying DNA during mitosis are repaired (mismatch repair genes).
Patients lose the ability to correct genetic mistakes and thus accumulate
mutations in neoplasia-inducing genes, including ACP, p53 and k-ras.
Clinical features
Except in familial syndromes, CRC is rare before the age of 50 years and
it increases in incidence thereafter. Early cancers and adenomas in the
colon may remain entirely asymptomatic. Larger adenomas and can-cers may bleed microscopically over time, causing  anaemia. Larger
tumours may cause overt rectal bleeding and altered bowel habit (con-stipation and/or diarrhoea). Intestinal obstruction, abdominal pain and
weight loss occur when the disease is further advanced.
Diagnosis
Barium enema and colonoscopy are the main diagnostic tests. Histol-ogy of colonic polyp biopsies can demonstrate dysplasia and neoplasia
(see Chapters 44 & 45).
Stool examination may demonstrate occult bleeding. Faecal occult
blood testing is based on the guiaic chemical reaction with haem, and
false positives may be caused by dietary haem, for example, from meat
(see Chapter 43).
Blood tests may show iron deficiency or anaemia. Increased circulat-ing levels of an embryonic protein, carcino-embryonic antigen (CEA),
are associated with CRC and can be used to monitor tumour recurrence
after surgery and chemotherapy.
Removal of adenomatous polyps before they become malignant dra-matically reduces the risk of developing CRC. Therefore, because CRC
is so common, some authorities advocate population screening, using
barium enema, colonoscopy or faecal occult blood testing for people
over the age of 50 years.
In FAP, the  panproctocolectomy (surgical removal of the whole
colon and rectum) in early adulthood prevents CRC.
Treatment
• Surgery: simple adenomas may be removed during colonoscopy by
snaring and excision (polypectomy), while CRC has to be removed sur-gically together with a margin of normal tissue to ensure total resection.
If CRC is detected early, particularly if it has not extended beyond the
intestinal wall, the operation may be curative. Metastatic CRC cannot be
cured, although surgery may palliate symptoms, such as bleeding,
obstruction and pain.
• Chemotherapy and radiotherapy: adjuvant chemotherapy may
increase survival after surgery and radiotherapy may be used to reduce
tumour bulk.
• Prevention: a diet that is low in fat and red meat and high in carbohy-drate and fibre is recommended, and the use of NSAIDs is being
investigated.
Colon and rectal cancer 85
86 Disorders and diseases
Clinical features
Jaundice,
pallor
Right upper
quadrant pain
Diarrhoea
Steatorrhoea
Weight loss
Dysphagia
Abdominal pain
Nausea, anorexia
Barrett’s oesophagus
Cirrhosis, e.g. hepatitis B
Lymphoproliferation and lymphoma
Flushing, other
hormonal effects
Smoking,
geographical
factors
Squamous
carcinoma
Oesophageal
adenocarcinoma
H. pylori
Gastric lymphoma,
adenocarcinoma
Tail of pancreas
Immune
stimulation
Bacteria
+ gluten
peptides
Lymphoproliferation Æ Lymphoma
1° carcinoid
5HT, growth
factors
Gastrin, insulin, glucagon, VIP, 5HT
Neuro-endocrine
tumour
Head of pancreas
tumour
Benign adenoma
(contraceptive pill)
2°, metastatic
carcinoid
5HT enters hepatic vein
Carcinoid
syndrome
Hepato-cellular
cancer
a feto-protein
Regenerating nodules
of hepatocyes
Fibrous
scar
38 Gastrointestinal, pancreatic and liver tumours
Tumours of the colon, oesophagus, stomach, pancreas and liver are com-mon worldwide. Colon cancer is the most common (see Chapter 37).
There is marked geographical and racial variation in the incidence of
gastric, oesophageal, pancreatic and liver cancer. In cirrhosis, primary
liver cancer is common and the liver is also a frequent site for metastasis
from many other cancers.
Gastric cancer
Gastric cancer is particularly prevalent in Japan, but the incidence is
decreasing worldwide. Environmental factors, such as smoked foods,
play a role and chronic gastritis, caused by autoimmune disease, or
more commonly by Helicobacter pylori infection, predisposes to both
adenocarcinoma and gastric lymphoma (see Chapter 31).
Symptoms include abdominal pain, dyspepsia, anaemia and occult or
overt intestinal bleeding. Advanced cancer may cause a palpable mass in
the epigastrium and lymphatic spread may create a palpable lymph node
in the neck — ‘Virchow’s node’.
Endoscopy may reveal a gastric ulcer. All gastric ulcers should be
biopsied and a second endoscopy performed after 2 months of treatment
to assess healing: non-healing gastric ulcers may be malignant.
Oesophageal cancer
Squamous cell carcinoma of the oesophagus is the commonest form
and is particularly prevalent in parts of southern Africa. In the Western
world, however, the incidence of oesophageal  adenocarcinoma is
increasing.
Squamous cell carcinoma is related to smoking and drinking alcohol,
while chronic gastro-oesophageal reflux and  Barrett’s oesophagus
predispose to adenocarcinoma. Chronic reflux can cause metaplasia
of the oesophageal epithelium, from stratified squamous to simple
columnar, intestinal-type epithelium. This change is termed Barrett’s
oesophagus, which carries a risk of dysplasia and subsequent malignant
transformation (see Chapters 4 & 30).
Dysphagia (food sticking) and odynophagia (pain on swallowing)
signify oesophageal disease and may be accompanied by weight loss.
Malignant tracheo-oesophageal fistulae may cause recurrent aspiration
pneumonia. Barium swallow, endoscopy, biopsy and brush cytology
confirm the diagnosis.
Very early disease may be cured by oesophagectomy but usually the
cancer is non-resectable and patients receive palliative treatment by
dilatation of strictures, placement of mechanical stents or laser treatment
to reduce tumour bulk.
Some authorities advocate regular endoscopic surveillance to detect
dysplasia in Barrett’s oesophagus so adenocarcinoma can be detected
and treated early.
Gastrointestinal lymphoma
Gastric and intestinal lymphomas are rare and are usually caused by
chronic inflammation and activation of the local immune system, as
with  H. pylori infection,  coeliac disease and immunoproliferative
small intestinal disease (IPSID), which occurs with chronic intestinal
infection (see Chapters 18, 31 & 35).
Symptoms include  weight loss, diarrhoea, malabsorption and
abdominal pain. Diagnosis is hampered by the difficulty in reaching
parts of the small intestine by endoscopy (see Chapter 44). Barium meal
and follow-through examination, computerized tomography (CT), mag-netic resonance imaging (MRI) scanning and exploratory laparotomy
with intestinal biopsy are often used to make the diagnosis (see Chapter
45).
Eradicating H. pylori infection, or prolonged antibiotic treatment of
IPSID, may cure early cases. In coeliac disease, strict adherence to a
gluten-free diet removes the antigenic stimulus to lymphocytes and
reduces the risk of lymphoma.
Pancreatic cancer
Pancreatic  adenocarcinomas may present with abdominal pain or,
when they occur in the head of the pancreas, may obstruct the common
bile duct, causing jaundice. Very early cancers may be treated by wide
excision of the pancreas, duodenum and related structures (Whipple’s
operation).
Neuro-endocrine tumours and carcinoids
Tumours arising from entero-endocrine tissue may be benign or malig-nant, and may occur sporadically or as part of inherited multiple
endocrine neoplasia (MEN) syndromes. They may be asymptomatic for
many years, or may produce symptoms by virtue of aberrant hormone
secretion, even while the tumour itself is extremely small and physically
inapparent; for example, tumours of G-cell origin produce gastrin,
resulting in excess stomach acid production and peptic ulceration
(Zollinger–Ellison syndrome). Other tumours may produce insulin,
glucagon or vasoactive intestinal peptide (VIP), causing diarrhoea and
hypokalaemia (Verner–Morrison syndrome) (see Chapter 16).
Carcinoids are typically slow-growing tumours that produce an
excess of serotonin (5-hydroxytryptamine, 5HT) and peptide growth
factors. They usually remain asymptomatic, as the liver rapidly meta-bolizes 5HT. However, when carcinoids metastasize to the liver,
5HT is released directly into the systemic circulation, causing symptoms
such as  flushing and  diarrhoea, which constitute the  carcinoid
syndrome.
Hormonal effects are often the first sign of neuro-endocrine tumours.
Anatomical localization can be difficult and relies on CT and MRI imag-ing and radionuclide-based scans to localize tumour cells expressing
surface somatostatin receptors, which are present on most neuro-endocrine tumours (octreotide scan). Excess urinary excretion of 5-hydroxy-indole acetic acid (5-HIAA), a metabolite of 5HT, can be used
to diagnose carcinoid syndrome.
Octreotide or somatostatin injections may alleviate symptoms by sup-pressing hormone secretion, and surgery is potentially curative.
Liver cancer and masses
Primary liver cancer (hepatoma) is rare, except in chronic liver disease
and cirrhosis, particularly when the liver disease is caused by hepatitis B
virus infection. People with primary sclerosing cholangitis (PSC) are
particularly prone to develop cancer of the biliary epithelium, cholan-giocarcinoma. Non-malignant hepatic adenoma is associated with the
use of the oral contraceptive pill. The most commonly occurring can-cers in the liver are metastatic deposits from cancer of the stomach,
colon, pancreas and breast.
Typical symptoms include right upper quadrant  pain and, if the
tumour obstructs bile flow, jaundice. Serum levels of liver enzymes
and bilirubin may be raised. In hepatoma, elevated circulating
levels of the embryonic protein,  a-fetoprotein (AFP) may be
detected.
Ultrasound, CT and MRI scans and a liver biopsy may be needed
to confirm the diagnosis and to distinguish cancer from benign cysts,
haemangiomas, abscesses and benign tumours (see Chapters 33 & 45).
Treatment remains unsatisfactory.
Gastrointestinal, pancreatic and liver tumours 87
88 Disorders and diseases
Fistula track
Clinical features
Anal fissure
Pain
Bleeding
Swelling
Discharge
Embarrassment
Anal canal
Constipation
Haemorrhoids
Peri-anal abscess and fistula
External pile
Hard faeces
External anal
sphincter
Rectum
Sacrum
Internal sphincter
Tight anal
sphincter
Acute mucosal
tear
Sentinal skin
tag
Painful fissure
Acute thrombosis in
superficial vein Æ External pile

1st degree internal
haemorrhoid 2nd and 3rd degree 4th degree
Engorged
vein
Swollen
mucosal
cushion
Occasional bright red
bleeding, leakage, pruritis
Prolapsed
2°  Spontaneous reduction
3°  Manual reduction
Non-reducible, ulcerated,
bleeding, painful
Abscess
External sphincter
Internal sphincter
Anus
Abscess
Peri-anal
swelling
Deep anal gland
Fever
39 Haemorrhoids and anorectal disease
The peri-anal region is a frequent source of pain, discomfort and distress.
Fortunately, many conditions affecting this region are benign and
treatable.
Haemorrhoids
Heamorrhoids are commonly known as piles. They may cause rectal
pain and bleeding and may interfere with defecation.
External piles are actually dilated superficial veins in the peri-anal
skin, which become thrombosed and exquisitely painful. Occasionally,
the thrombosed pile may bleed. When they heal, an external skin tag may
remain.
Internal haemorrhoids arise from superficial veins in the mucosa of
the lower rectum, which become engorged through chronically raised
intra-abdominal pressure and straining during defecation. The veins are
supported by cushions of soft connective tissue, which hypertrophy and
contribute to the swelling (see Chapter 14). Chronic straining is the
commonest cause of haemorrhoidal vein enlargement and contributing
factors include pregnancy, obesity and weight lifting.
First-degree internal haemorrhoids comprise hypertrophied cush-ions, with enlarged veins that may bleed but do not protrude out of the
rectum into the anus.
Second-degree haemorrhoids prolapse through the anus, but reduce
spontaneously.
Third-degree haemorrhoids require manual reduction of the pro-lapse and fourth-degree haemorrhoids cannot be reduced manually.
Internal haemorrhoids generally do not cause pain unless they pro-lapse and ulcerate. They may cause a sense of rectal fullness, discomfort
and incomplete evacuation (tenesmus). The most common symptoms
include bleeding, typically at the end of defecation, and the effects of
prolapse, which include chronic leakage of mucus and subsequent peri-anal itching (pruritis ani) and excoriation.
The diagnosis is confirmed by careful examination of the peri-anal
region and anal canal using a  proctoscope. Barium enema and
colonoscopy may be needed to exclude other causes of rectal bleeding.
Medical treatment includes altering  diet to avoid constipation,
using stool softeners and changing behaviour to avoid straining during
defecation.
Surgically, haemorrhoids can be treated by elastic band ligation, scle-rotherapy or excision. External piles do not usually require treatment,
apart from incision and evacuation of an acutely painful thrombus.
Anal fissure
A split in the skin of the anal canal causes acute tearing pain, particu-larly on defecation. There may also be some bleeding. The cause is con-stipation and hard stool.
On examination, there is a linear tear in the skin. Ninety percent of
tears are posterior and 10% anterior. There may be a skin tag, called a
sentinel pile, at the edge of a chronic tear.
Stool softeners and alleviating constipation are the main treatments
and, in the acute state, local application of glyceryl trinitrate ointment,
which relaxes the anal sphincter, may allow the fissure to heal. In chronic
cases, surgical division of the internal anal sphincter (sphincterotomy)
may be performed.
Anorectal abscess and fistula
The deep anal glands, which secrete mucus into the anal canal, extend
between the internal and external sphincters and may become
obstructed and infected. This causes deep-seated peri-anal abscesses
that manifest with anal pain, fever and usually a palpable peri-anal
mass. When the abscess ruptures onto the surface, a tract or  fistula
may persist and can become chronically infected, discharging mucus
and pus. Anorectal fistulae may also occur after surgical incision and
drainage of abscesses.
Abscesses and fistulae may be deeper than clinically apparent and
computerized tomography (CT) and magnetic resonance imaging
(MRI) scanning of the pelvis may be helpful before surgical treatment.
Surgical  incision and drainage are usually required and broad-spectrum antibiotics, including metronidazole to treat anaerobic infec-tion, are used.
Chronic and recurrent anorectal sepsis may be caused by anorectal
Crohn’s disease, in which case additional anti-inflammatory treatment
is also required (see Chapter 34).
Proctitis
Superficial inflammation of the rectal mucosa, causing bleeding, diar-rhoea, urgency of defecation and mucus discharge, may be caused by
ulcerative colitis or Crohn’s disease. In many cases, inflammation
remains confined to the rectum and never extends proximally. Rectal
steroids and 5-aminosalicylic acid (5ASA, mesalazine) are usually
effective and long-term treatment with oral 5ASA may be
initiated.
Radiation proctitis. Pelvic irradiation, for example, to treat cervical
cancer in women, or prostrate cancer in men, may cause chronic vascular
damage and mucosal fibrosis, with the formation of friable, abnormal
blood vessels that bleed spontaneously. The symptoms of diarrhoea,
rectal bleeding and discharge may develop years after the initial
radiotherapy.
Pruritis ani
Poor perineal hygeine may cause irritation of the peri-anal skin and, con-versely, overzealous cleaning with soaps may dry the skin, also causing
irritation. Infestation with pinworms (Enterobius vermicularis), which
crawl onto the peri-anal skin, may also cause pruritis, as might chronic
mucus discharge caused by haemorrhoids.
Proctalgia fugax
Proctalgia fugax is a stabbing pain in the rectum, often after defecation,
and usually has no discernable organic cause and is hard to treat (see
Chapter 29).
Anal warts and sexually transmitted infections
Infection with human papillomavirus may cause peri-anal warts that are
treated in the same way as genital warts. Syphilis may also cause wart-like papules, as well as peri-anal ulcers. Other sexually transmitted
diseases, such as herpes simplex virus infection and gonorrhoea, may
cause peri-anal inflammation and ulceration.
Peri-anal tumours
Squamous cell carcinoma is the most common anal tumour and may be
associated with infection by human papillomavirus 16 and 18. Chronic
hypertrophic ulcers with rolled edges are the typical manifestation and
they may cause bleeding, itching and pain.
Haemorrhoids and anorectal disease 89
90 Disorders and diseases
Clinical features
Jaundice
Right upper
quadrant pain
Dark urine
Pale stool
Steatorrhea
Abdominal pain
Vomiting
Fever
Anorexia, nausea
Sterile obstruction
or ascending cholangitis
Common bile duct stone
Causes of pancreatitis
•  Abnormal pancreatic secretion,
e.g. cystic fibrosis
• Gallstones
• Alcohol, drugs
• Trauma
• Mumps
Pancreatic acini
Chronic damage to:Release of enzymes,
e.g. amylase, lipase,
trypsin
Infection
Lung damage Tissue damage
Pancreatitis
Hypoxia Inflammation
Pa i n
+ Pancreatic insufficiency
Pancreatic islets Diabetes mellitus
Chronic pancreatitis
Acute pancreatitis = severe multisystem failure
Common duct stone
Cholangitis
+ pancreatitis
Bile
salts
Ileal disease
Reduced bile
salt recycling
Nidus,  e.g. bacteria
Supersaturated bile
+
= Cholesterol stone
Cystic duct stone causes
obstructed gallbladder
±  cholecystitis
Abnormal or
increased
bile secretion
Excess bile
pigments
Pigment
stones
40 Gallstones and pancreatitis
Gallstones affect up to 20% of the population in the Western world and
the incidence increases with age. They may remain asymptomatic or
they may cause serious illness.
Pancreatitis is often caused by passage of gallstones. It can be very
severe, may become chronic and can impair pancreatic function.
Gallstones
Formation
Bile is stored in the gallbladder, where it is concentrated by epithelial
cells reabsorbing water. This causes  supersaturation of bile con-stituents, particularly cholesterol, which form stable  mixed micelles
with phospholipids and bile salts. However, the supersaturated solution
is unstable and cholesterol may crystallize around a microscopic parti-cle or nidus, such as a bacterial cell. Initially crystals are very small,
forming sludge or biliary sand, but they grow by accretion over time.
Eighty-five percent of gallstones are cholesterol stones, formed in this
way.
Less frequently, bile with excessively high concentrations of bile pig-ments is secreted, for example, in haemolytic diseases, such as sickle
cell anaemia, causing the formation of pigment stones.
Ileal disease that interrupts the entero-hepatic circulation of bile
salts, increases the risk of gallstone formation.
Pathogenesis
Most gallstones remain in the gallbladder and are  asymptomatic,
although there is a slightly increased risk of gallbladder cancer, which
itself is very rare. Gallstones ejected from the gallbladder, however, may
obstruct the bile ducts and are the main cause of symptomatic gallstone
disease. A stone in the cystic duct can obstruct the gallbladder, which
may then become infected, causing cholecystitis. Impacted stones in
the common bile duct cause intrahepatic and extrahepatic biliary
obstruction and, if the obstructed bile ducts become infected, ascending
cholangitis results. Stones in the common bile duct or the ampulla of
Vater may cause pancreatic obstruction, resulting in pancreatitis as well
as cholangitis.
Clinical presentation
Biliary disease often causes nausea and anorexia. Symptoms may be
aggravated by  fatty meals, which stimulate cholecystokinin release,
which in turn stimulates gallbladder contraction. Abdominal pain, local-ized to the right upper quadrant, is caused by distension of the gall-bladder and bile ducts, and a tender, inflamed gallbladder may be
palpable. The pain is typically colicky, or episodic, aggravated by waves
of ineffective peristalsis. Pancreatitis and bacterial infection cause
severe, persistent pain, which may be accompanied by fever and rigors.
Biliary obstruction causes jaundice, pale stools, due to absent bile
pigments in the intestine, and dark urine, due to urinary excretion of
conjugated bilirubin. Inadequate excretion of pruritogenic substances,
which have not been well characterized, causes itching. Persistent
biliary obstruction results in  malabsorption of fats and fat-soluble
vitamins due to the lack of bile salts in the intestine.
Symptoms may be transient, as stones can be spontaneously ejected
through the sphincter of Oddi.
Diagnosis
Blood tests show raised biliary enzymes, conjugated bilirubin and
inflammatory markers, such as C-reactive protein (see Chapter 43).
Ultrasound scanning of the abdomen sensitively detects gallstones
and also shows if they are causing obstruction. Computerized tomogra-phy (CT) and magnetic resonance imaging (MRI) scanning may also be
used (see Chapter 45).
Endoscopic retrograde cholangiopancreatography (ERCP) provides
contrast-enhanced images of the biliary tract, demonstrating obstruction
and stones in clear detail. In addition, stones can be removed endoscopi-cally, or the sphincter of Oddi cut (sphincterotomy), allowing stones to
pass spontaneously.
Treatment
Cholecystitis, cholangitis and pancreatitis are serious  multisystem
inflammatory disorders. Treatment includes supportive care, analgesia
and antibiotics.
Gallstones are only removed when they cause clinical problems. Dur-ing an episode of acute obstruction, infection or pancreatitis, they may
be removed urgently by ERCP or surgery. More usually, the gallbladder
and stones are removed surgically (cholecystectomy), when the acute
episode has settled (see Chapter 48).
Pancreatitis
Pathogenesis
Obstruction and damage to pancreatic ducts by  stones, tumours or
trauma releases pancreatic enzymes that auto-digest duct tissue, initi-ating a self-perpetuating cycle of tissue damage and enzyme release that
can rapidly destroy large parts of the pancreas. Bacterial infection and
leakage of enzymes into the bloodstream often accompany this tissue
damage, causing severe tissue damage at distant sites, particularly the
lungs. Thus acute pancreatitis is a severe multisystem disorder that can
be rapidly fatal.
The same mechanisms can be initiated by chemical damage to the
pancreas caused by drugs, particularly excess alcohol, which is the sec-ond commonest cause of acute pancreatitis. Pancreatitis may also be
caused by trauma, for example following ERCP, and by infection, for
example with the mumps virus.
Clinical presentation
Abdominal pain, anorexia, vomiting and fever are the main symptoms.
Multisystem failure, with hypotension, hypoxia and widespread
intravascular haemorrhage, occurs in severe cases.
Diagnosis
Blood tests show greatly elevated circulating levels of pancreatic
enzymes, particularly amylase and lipase. Inflammatory markers such
as C-reactive protein are raised. Hypoxia and hypocalcaemia indicate
severe pancreatitis. Abdominal ultrasound and CT or MRI scanning
may demonstrate an enlarged, oedematous pancreas.
Treatment
To minimize pancreatic enzyme production, the patient is kept nil-by-mouth and the stomach is emptied by nasogastric suction. Antibiotics
for presumed infection and supportive measures are the mainstay of
treatment. Specific inhibitors of pancreatic secretion, and of pancreatic
enzymes, have not yet proved clinically useful.
Chronic pancreatitis
Repeated passage of stones and chronic alcohol excess may cause recur-rent pancreatitis. Inherited abnormalities in the  cystic fibrosis gene
(CFTR), which regulates Cl- secretion in duct cells, also predisposes to
chronic pancreatitis. Repeated damage affects exocrine and endocrine
pancreatic function, causing malabsorption due to pancreatic enzyme
deficiency and diabetes mellitus due to insulin deficiency. In addition,
damage to sensory nerves and scarring and obstruction of the pancreatic
duct cause abdominal pain, which can be extreme.
The scarred pancreas may develop calcified areas that are visible on
plain abdominal X-ray.
Treatment involves replacing pancreatic enzymes with oral supple-ments, treating diabetes with  insulin injections and  relieving pain,
which may be difficult.
Gallstones and pancreatitis 91
92 Disorders and diseases
Clinical features
Deep jaundice
Severe liver failure Hepatitis
Right upper
quadrant pain
Dark urine
Pale stool
Myalgia
Anorexia, nausea
Ascites
Bruising
Arthralgia
Fever
Abnormal blood tests
Low glucose
Low albumin
Encephalopathy Fatigue
Malaise
Pain, nausea, anorexia
Jaundice
Hypoalbuminaemia and coagulopathy
Oedema and ascities
Hypoglycaemia
Encephalopathy
Raised levels of liver enzymes
Toxins
Ethanol
Paracetamol
Other drugs
Viruses
Hepatitis A, B, E viruses
other viruses
e.g. Epstein–Barr virus
Vascular damage
Severe hypotension,
Budd–Chiari syndrome
Autoimmune hepatitis
Tumour infiltration
e.g. lymphoma
Ascending cholangitis
Causes Clinical effects
Swelling and stretching of capsule
Reduced bile excretion
Reduced protein production
Reduced gluconegensis
Reduced detoxification
Mechanisms of
acute liver damage
Stone
Cytokines
Lymphocyte
Cytotoxicity
Antibodies
Proteins
Bile secretion
Mitochondrion
Microsome
Whole organ Cellular
Immune damage
Drugs and toxins
Viral infection
Infiltration
Vascular obstruction
Biliary obstruction
41 Hepatitis and acute liver disease
Hepatitis (inflammation of the liver) can occur as a result of infection,
toxins, drugs and autoimmune, vascular or biliary disease. Rapidly pro-gressive damage causes acute liver disease, while more insidious dam-age leads to chronic liver disease. Life-threatening  liver failure can
occur in both cases.
Viral hepatitis
Many viruses infect the liver as well as other organs, but the hepatitis
viruses A, B, C, D, E and G primarily target the liver.
Hepatitis A virus is the commonest cause of viral hepatitis and, like
the hepatitis E virus, is transmitted via the faecal–oral route through
contaminated food or water. Infection is short-lived (about 6 weeks) and
never becomes chronic, although it can be severe and even fatal. Infec-tion induces immunity and a vaccine is available.
Hepatitis B and C viruses are transmitted by blood and sexual con-tact, or from mother to child. They can cause acute hepatitis, as well as
chronic hepatitis that may progress to cirrhosis. In the acute phase of
hepatitis B infection, patients may develop liver failure. However most
develop immunity and recover, with about 10% remaining chronically
infected. Acute hepatitis C infection is rarely severe, but results in
chronic infection in the majority of infected individuals.
Hepatitis D virus only infects individuals with hepatitis B virus infec-tion, which it suppresses. Hepatitis G virus infection is probably harmless.
The vaccine for hepatitis B is highly effective and there are major
efforts to develop a vaccine against hepatitis C.
Drugs and toxins
The liver metabolizes drugs and toxins and is, therefore, particularly
sensitive to these.
The most common liver-damaging toxin is  alcohol, which causes
metabolic damage to hepatocytes, partly by interfering with energy
metabolism, resulting in fatty liver, and also by inducing inflammation,
when it can cause alcoholic hepatitis. Sustained excess drinking can
cause cirrhosis.
Some drugs and toxins (e.g. isoniazid, used to treat tuberculosis) may
cause an illness resembling viral hepatitis and, in other cases, the bile
ducts are targeted with little hepatocyte damage (e.g. chlorpromazine,
used to treat psychosis).
Paracetamol (acetaminophen), the widely used over-the-counter
analgesic, can cause massive hepatic necrosis when taken in overdose.
Metabolism of paracetamol by microsomal oxidases generates a toxic,
reactive metabolite,  N-acetyl-p-benzoquinone-imine (NAPQI) that
inactivates hepatocyte proteins. NAPQI is normally inactivated using
glutathione, and hepatic stores are depleted in paracetamol overdose.
N-acetylcysteine  replenishes hepatic glutathione and therefore
counteracts paracetamol toxicity (see Chapter 25).
Miscellaneous causes
Autoimmune hepatitis, characterized by reactivity against the liver,
may develop in susceptible individuals, typically young women. High
circulating levels of  antibodies, some of which are directed against
hepatic antigens, are typical.
Ascending cholangitis, with bacterial infection of the biliary tree and
liver, may occur with biliary obstruction, caused, for example, by
impacted gallstones (see Chapter 33).
Budd–Chiari syndrome is caused by obstruction of the hepatic veins,
resulting in hepatic congestion and disrupted function. It is usually asso-ciated with inherited or acquired thrombophilia.
Infiltration of the liver by tumours can cause acute liver dysfunction
and failure.
Pathogenesis
Hepatocyte damage causes accumulation of  fatty vacuoles, and  cell
death  by necrosis  and apoptosis. Alcohol-induced damage causes
typical Mallory bodies formed from precipitated intracellular proteins.
In viral hepatitis, there is direct viral damage to hepatocytes, as well as
immune-mediated damage to virally infected cells.
Inflammatory cells infiltrate the parenchyma and portal tracts.
Typically, in alcoholic hepatitis,  neutrophils predominate; while in
viral hepatitis and autoimmune disease,  lymphocytes predominate.
Eosinophil-rich infiltrates characterize drug-induced liver disease. Bile
duct damage causes proliferating bile ducts and accumulation of bile.
Clinical features
In viral hepatitis, there may be a preceding prodromal flu-like episode,
with fever, malaise, arthralgia and myalgia. Later, nausea, anorexia,
jaundice, itching and abdominal pain caused by stretching of the liver
capsule develop.
Patients may develop signs of liver failure, including deep jaundice,
hepatic encephalopathy, ascites, bruising due to decreased circulating
coagulation factors, and hypoglycaemia due to the reduced hepatic glu-coneogenesis. Liver failure is a medical emergency requiring urgent
treatment.
Diagnosis
Liver cell damage causes increased serum levels of  transaminase
enzymes (alanine transaminase, ALT, and aspartate transaminase, AST)
and damage to biliary epithelium raises alkaline phosphatase (ALP)
and g-glutamyl transferase (g GT) levels (see Chapter 43).
Deteriorating liver function increases the serum bilirubin, lowers
the serum  albumin and prolongs the  prothrombin time, reflecting
declining excretory and protein synthetic capacity (see Chapter 43).
The cause of acute liver damage must be determined. Antibodies to
viruses, and circulating viral DNAor RNA can be measured. Circulating
paracetamol levels can be measured and, in autoimmune hepatitis, cir-culating autoantibodies to liver antigens can be detected.
Ultrasound scan helps to determine whether the liver is chronically
scarred (cirrhotic), if vascular flow is normal or obstructed, and if gall-stones or biliary obstruction are present (see Chapter 45).
Treatment
Treatment is  supportive, including nutrition, intravenous fluids and
symptomatic relief of nausea and pruritis. Liver function can deteriorate
rapidly and must be closely monitored.
Antiviral treatment. No specific treatment is available for hepatitis
A or E. Hepatitis B and C infection may be treated, with partial
success, using  interferon  a and antivirals such as  lamivudine and
ribavirin.
Autoimmune hepatitis may be treated with corticosteroids. Alcohol-related acute liver disease is improved by  abstinence and alcoholic
hepatitis may also require steroid treatment.
The specific antidote, N-acetylcysteine, should be administered early
in paracetamol poisoning, before massive liver damage occurs.
Where supportive measures fail, emergency liver transplantation is
an option. Liver function is difficult to replicate artificially and a reliable
liver support device is not yet available.
Hepatitis and acute liver disease 93
Longstanding damage to the liver eventually causes scarring and cirrho-sis. Many forms of liver injury produce cirrhosis and the exact cause
needs to be determined in each case to guide further treatment.
Causes
The most common causes in the Western world are excessive alcohol
consumption, chronic viral hepatitis and autoimmune liver disease,
particularly primary biliary cirrhosis (PBC), which affects women more
frequently than men. There are many other causes, including inherited
diseases such as genetic haemochromatosis and Wilson’s disease (see
figure above).
Multiple causes of cirrhosis can coexist and probably accelerate the
rate of liver damage, for example, in people with chronic viral hepatitis
or haemochromatosis who also drink alcohol.
Pathophysiology
The main effects of chronic liver damage are reduced numbers of hepa-tocytes and disruption of the normal sinusoidal architecture, which
94 Disorders and diseases
Compensated cirrhosis
Decompensated cirrhosis
Ascites
Disrupted flow
Varices
Portosystemic
shunting
Platelets
sequestered in
enlarged spleen
Po rtal
hypertension
Fibrous
scar tissue
Hepatocytes in
regenerating nodules
Conjested
mesentery and
intestines Æ
leakage of fluid
Æ ascites
Common causes
• Chronic viral hepatitis
(B & C)
• Alcohol
• Autoimmune
disease, e.g.
PBC, PSC
• Haemochromatosis
• Wilson’s disease
• Idiopathic
Stomach
Spleen
Oesophagus
Hepatic veinNormal cords of
hepatocytes
Portal tract
Mesenteric veins
Intestines
Easy bruising
Muscle wasting
Variceal bleeding
Loss of body hair
Encephalopathy
Normal blood flow portal vein
Portal vein
Normally arranged
and adequate number
of hepatocytes
Possible fatigue, lethargy, weight loss
Subclinical encephalopathy
Decompensation caused by
•  Slow deterioration due to
ongoing damage
• Infection
• Dehydration
• Electrolyte disturbance
• Surgery
• Variceal haemorrhage
•  Development of hepatocellular
carcinoma
Susceptible to
infection(spontaneous
bacterial peritonitis)
Jaundice
Hypoalbuminaemia
42 Cirrhosis and chronic liver disease
alters blood flow through the liver and increases pressure in the portal
vein (portal hypertension). Haphazard regeneration of hepatocytes in
nodules and formation of fibrous scar tissue by Ito (stellate) cells disrupt
sinusoidal architecture (see Chapters 8 & 10). Altered blood flow further
compromises liver function.
Reduced hepatic function results in the accumulation of bilirubin and
other toxins, causing jaundice and itching (see Chapter 25).
As the liver is the main regulator of carbohydrate, lipid and
protein metabolism, chronic liver disease results in widespread meta-bolic dysregulation, with steady weight loss and wasting (see Chapter
24).
The liver is the main source of circulating plasma proteins, including
critical clotting factors, so that patients develop a tendency to bleeding
(coagulopathy) and have reduced circulating  albumin (see Chapter
24).
As a result of portal hypertension, portosystemic shunting of blood
occurs where the portal and systemic venous systems meet, allowing
toxin-laden blood from the intestine to bypass the liver. This contributes
to chronic  hepatic encephalopathy (also known as  portosystemic
encephalopathy), because toxic metabolites from the intestine, particu-larly bacterial amines, interfere with cerebral function. Shunting also
promotes the development of varices, which can rupture and bleed cata-strophically (see Chapter 10).
In addition, portal hypertension and splenic vein congestion result in
splenomegaly, which leads to pooling of platelets in the spleen and
thrombocytopenia. Congestion of the mesenteric veins, combined with
hypoalbuminaemia can lead to transudation of fluid into the peritoneal
cavity, causing ascites.
Clinical features
The liver has a large  functional reserve capacity, so there may be
extensive damage that remains clinically undetected, and people with
cirrhosis may be totally asymptomatic or complain only of vague ill
health and tiredness.
Eventually, however, as liver damage continues, or when an addi-tional strain is placed on the liver, it fails to compensate and liver failure
becomes apparent.
The effects of chronic liver disease and portal hypertension include
weight loss, loss of body hair, loss of libido, testicular atrophy, jaun-dice, abnormal  coagulation,  fluid retention in the form of ankle
swelling and ascites, and chronic hepatic  encephalopathy. Hepatic
encephalopathy can cause mood and sleep disturbances, a characteristic
flapping tremor of the hands and reduced ability to perform simple
mechanical tasks, such as joining dots on a page (constructional
apraxia). Hormonal and vascular changes induce the formation of cuta-neous spider naevi, which are arteriolar vascular malformations.
Cirrhosis may be complicated by catastrophic events, such as
variceal haemorrhage, development of  hepatocellular carcinoma
and development of ascites and infection. Patients with ascites are at
risk of developing spontaneous bacterial peritonitis (SBP), caused by
translocation of gram-negative bacteria from the intestinal lumen into
the protein-rich ascitic fluid. This complication carries a high mortality
and occurs particularly when liver disease is far advanced.
Diagnosis
Ultrasound scanning of the abdomen can detect an abnormal texture to
the liver and splenomegaly resulting from portal hypertension. Com-puterized tomography (CT) and magnetic resonance imaging (MRI)
scanning is more sensitive and can also identify portosystemic vascular
shunts (see Chapter 45).
Blood tests often show abnormalities, such as raised hepatic enzyme
levels, raised bilirubin, lowered albumin and abnormal coagulation
tests, although all of these may be normal despite advanced cirrhosis (see
Chapter 43).
Liver biopsy, showing fibrosis and regenerative hepatocyte nodules,
confirms the diagnosis and may demonstrate the cause of cirrhosis, espe-cially when special histochemical and immunohistochemical stains are
used.
Blood tests can identify some causes of cirrhosis: for example auto-antibodies to mitochondrial pyruvate dehydrogenase (antimitochondr-ial antibodies) indicate PBC; genetic testing for haemochromatosis is
available and circulating hepatitis B DNA or hepatitis C RNA or antigen
can be measured (see Chapter 41).
Treatment
Because cirrhosis is mainly irreversible, treatment is aimed at palliating
symptoms, delaying or reducing complications, preventing further
damage and avoiding liver failure.
Symptoms such as itching, weight loss and encephalopathy can be
palliated. Itching can be treated with antihistamines and oral bile acid-binding resins, to reduce entero-hepatic recirculation.
Regular small meals with adequate calories may compensate for the
loss of hepatic storage capacity, and prevent weight loss. Adequate pro-tein intake is required to prevent muscle wasting. Chronic hepatic
encephalopathy is mainly caused by portosystemic shunting rather
than by hyperammonia resulting from amino acid catabolism (see
Chapter 25). Encephalopathy itself is treated by laxatives, to reduce
intestinal bacterial load.
Specific treatments may also be available once the cause of cirrhosis
is known. For example,  antiviral treatment may be effective for
hepatitis B or C,  steroids are effective in autoimmune hepatitis and
venesection is used to reduce body iron stores in haemochromatosis.
Alcohol should be avoided, to prevent further liver damage.
With advanced cirrhosis, where the risk of life-threatening complica-tions, such as variceal haemorrhage, is high, patients may be considered
for liver transplantation. Unfortunately, many diseases, particularly
viral hepatitis, tend to recur in the transplanted liver, often at an acceler-ated rate.
Cirrhosis and chronic liver disease 95
96 Diagnosis and treatment
Liver chemistry
Transaminases
Alkaline phosphatase
g glutamyl transferase
Bilirubin
Albumin
Clotting tests
Antimitochronorial
antibody

History
Blood tests
General examination
Digital rectal examination
Stool microscopy and culture
Abdominal examination
BMI
• Diet
• Weight
• Vomiting
• Rectal bleeding
• Altered bowel habit
• Pain
weight      (kg)
(height)2    (m2)
BMI =
• Normal = 18–25
• Overweight = 25–30
• Obese = 30–40
• Morbid obesity >40
• Underweight <18
Colour -Pallor?
-Jaundice?
Fever?
Hydration
Pulse
BP
Skin, joints,
general health
?Blood
?Palpable mass
Peri-anal abnormalities
Microscopy
• Leucocytes
• Parasites
-Ova
-CystsCulture bacteria
Electron microscope = virus
+ Occult blood test
Stool
Spleen size
Bowel sounds
Liver size and texture
Pain or tenderness
Any abnormal masses
Serology for
pathogens
Inflammatory markers
e.g. CRP
Anti-endomysial antibody
Urea and electrolytes
Amylase  lipase
Blood count
Haemoglobin
White cells
Fe2+ ferritin
Vitamin B12
Folic acid
43 Clinical assessment and blood tests
Gastrointestinal symptoms and disorders occur frequently in clinical
practice. Good clinical assessment allows one to determine how unwell
the patient is and what the underlying pathological processes may be.
This allows focused and effective use of endoscopy, imaging and other
specialized tests.
History
• Lifestyle, particularly details of  diet and  alcohol intake must be
noted, as must the use of medications, such as non-steroidal anti-inflammatory drugs (NSAIDs).
• Travel and potential exposure to infection is relevant.
• Pain or discomfort must be characterized and localized, and aggravat-ing or relieving factors ascertained.
• Altered bowel habit, particularly of recent onset, is significant, as is
recent nausea, vomiting or anorexia (loss of appetite).
Ask the patient to describe any vomitus and their stool. Does it con-tain blood (haematemesis or haematochezia), or is the stool black and
tarry with altered blood (melaena), indicating bleeding in the upper gas-trointestinal tract. Obstructive jaundice makes the stool pale and excess
bile pigments darken the urine.
Any change in body weight should be noted, particularly weight loss,
which may indicate malabsorption, chronic inflammation or cancer.
Liver, gallbladder, pancreas, stomach, small intestine and colon disor-ders cause vague, poorly localized symptoms. By contrast, dysphagia
(difficulty in swallowing) usually indicates oesophageal disease.
A focused family history may reveal genetic predisposition to, for
example, coeliac disease, inflammatory bowel disease or colorectal
cancer.
Examination
Thorough general examination is mandatory, including height and
weight determination and calculation of the body mass index (BMI).
Examining the mucosae, jugular venous pressure and skin turgor helps
detect dehydration.
The skin and sclerae should be examined for pallor, jaundice and any
rash.  Lymphadenopathy may indicate gastrointestinal disease; for
example, Virchow’s node, in the root of the neck, may indicate gastric
cancer.
The abdomen should be examined with the patient lying comfortably
on their back, with their arms by the side and neck and knees slightly
flexed allowing the anterior abdominal wall muscles to relax. The patient
should point to any area of discomfort or tenderness and this should be
avoided initially during palpation.
Inspection may reveal prominent veins, herniae, visible peristalsis,
protuberances or scars.
Palpation should define the position, size, texture and any tenderness
of the liver, gallbladder and spleen, and any masses or lymphadenopathy.
Percussion is used to define the size and position of the liver, spleen
and any masses, and to detect free fluid in the peritoneum (ascites),
which shifts when the patient’s position is altered (shifting dullness).
Ausculation is used to assess bowel sounds. In paralytic ileus they are
absent, while in intestinal obstruction they may be increased.
Genitalia and digital rectal examination: inspect the external geni-talia, inguinal hernial orifices and peri-anal region. For the digital rectal
examination, the patient lies on their left-hand side, with their knees
drawn up. The peri-anal skin should be inspected and palpated, and a
gloved, lubricated finger inserted gently into the anus, assessing anal
tone and feeling for any abnormal masses or swellings. The withdrawn
gloved finger should be inspected to detect bleeding.
Stool examination
Volume, consistency, colour and the presence of fat globules, indicating
malabsorption, should be noted. True diarrhoea implies an increased
stool volume, above 200–300·mL/day.
Microscopy is used to detect parasites, ova or cysts and leucocytes or
pus cells, which occur in dysentery or intestinal inflammation. Electron
microscopy can be used to detect viral infection and stool culture to
identify bacterial pathogens. Toxins can be detected by special tests.
Chemical testing can be used to detect small amounts of blood that are
macroscopically invisible (faecal occult blood). This may indicate
intestinal bleeding, although dietary haem and enzymes can cause false
positive reactions.
Basic blood tests
• Blood count. Anaemia may indicate many serious gastrointestinal
diseases, such as peptic ulcer, malabsorption and intestinal cancer. The
platelet count, white cell count and red cell indices, as well as levels of
iron, ferritin, vitamin B12 and folic acid, may be abnormal in malabsorp-tion, inflammatory bowel disease and liver disease.
• Clotting tests. A prolonged prothrombin time (PT) may indicate
synthetic liver failure or vitamin K deficiency, for example, caused by
malabsorption of fat-soluble vitamins.
• Urea and electrolytes. Intestinal bleeding causes increased amino
acid absorption and, therefore, increases the amount of urea produced by
the liver. Urea and electrolyte levels may also indicate dehydration, or
renal damage. Calcium levels may be reduced in malabsorption.
• Liver chemistry. The serum albumin level is reduced in liver failure,
as part of the acute phase response caused by inflammation, and in
malnutrition.
Alanine and aspartate transaminase (ALT and AST) levels are raised
by liver cell damage and the  alkaline phosphatase (ALP) and  g-glutamyl transferase (g GT) levels are increased in biliary tract
disease. g GT levels are also raised by excess alcohol consumption.
Bilirubin levels are increased in liver and biliary disease. Jaundice
is clinically readily apparent when bilirubin levels are raised two- to
threefold.
• Inflammatory markers. Increased levels of C-reactive protein
(CRP) and a raised erythrocyte sedimentation rate (ESR) may indicate
inflammatory bowel disease (IBD), acute pancreatitis or infection.
• Amylase and lipase levels. Acute pancreatitis causes massively
raised amylase or lipase levels and more modestly increased levels are
seen in conditions such as peptic ulcer.
• Serological tests. Exquisitely sensitive and specific serological tests
can be used to diagnose coeliac disease (antibodies to tissue transglut-aminase) and primary biliary cirrhosis (antimitochondrial antibody).
Circulating autoantibodies are also found in atrophic gastritis and
autoimmune hepatitis. Serological tests for hepatitis viruses and gas-trointestinal infections, such as amoebiasis, are also available.
Clinical assessment and blood tests 97
Direct visualization of the interior of the hollow gastrointestinal organs
is one of the most powerful diagnostic and therapeutic modalities in
modern medicine. The earliest endoscopes were rigid instruments,
allowing visualization along a straight line.  Fibreoptic instruments,
which transmit light around curves, extended the range of endoscopy.
Modern video endoscopes use a  charge-coupled device, or an elec-tronic camera, to capture and transmit images electronically, so there is
no optical limit to their movement. Most instruments have channels for
insufflation and suction and to introduce instruments, such as forceps,
for taking biopsies.
98 Diagnosis and treatment
ERCP
Ileoscopy
Gastroscopy
Oesophagoscopy
Colonoscopy
Viewing port
Side-viewing endoscope for ERCP
Rugae
Z-line
Charge-coupled device camera
• Light
• Suction/biopsy channel
•  Air/water insufflation channel
Videosignal cable
Controls for turning scope tip
Biopsy port
Flexible shaft
To power source
Clear plastic barrel
Pill dissolving in stomach
Plicae
Haustrae
44 Endoscopy
Rigid instruments
These are stainless steel or plastic tubes with a light source and a single
channel for observation and instrumentation.
The rigid sigmoidoscope can be inserted up to 20·cm into the rectum
and proximal sigmoid colon, and is routinely used to diagnose proctitis
and rectal tumours. The shorter and wider proctoscope allows examina-tion of the anal canal and rectum. Haemorrhoids can be treated by scle-rotherapy or elastic band ligation through a proctoscope.
Rigid  oesophagogastroscopes are now mainly used to treat
oesophageal obstruction caused by foreign bodies, such as food boluses,
because the wide channel allows rapid removal or displacement of the
obstruction.
Flexible upper gastrointestinal endoscopy
The oesophagus, stomach and proximal duodenum are routinely
visualized and the distal duodenum and jejunum may occasionally be
seen.
Diagnostic uses
Investigation of heartburn, dyspepsia and occult blood loss are the com-monest indications.  Biopsies can be taken to diagnose  Helicobacter
pylori infection, inflammation or neoplasia. Plastic  brushes can be
rubbed along lesions, capturing superficial cells or pathogens to diag-nose cancer and infection. Jejunal fluid can be aspirated and examined
for pathogens such as Giardia lamblia.
Therapeutic uses
The commonest lesions treated endoscopically are  bleeding peptic
ulcers, which can be injected with epinephrine (adrenaline) to cause
vasospasm, and ruptured oesophageal varices, which can be injected
with sclerosant or ligated with rubber bands to halt bleeding and cause
fibrosis and subsequent obliteration. Other bleeding lesions may be
treated using lasers or electrocautery.
Obstruction caused either by gastro-oesophageal tumours or by
benign strictures can be relieved by dilatation using balloon or rigid
dilators, and plastic or metal stents can then be introduced to maintain
patency of the lumen. Pneumatic dilatation or endoscopic injection of
botulinum toxin into the lower oesophageal sphincter may relieve
obstruction caused by achalasia.
Complications
Upper endoscopy itself is relatively safe and can be performed with or
without light sedation of the patient. Therapy such as dilatation may
cause rupture of the oesophagus.
Enteroscopy
Long, thin instruments with a rigid outer casing that straightens the shaft
proximally can be introduced into the jejunum and ileum. The tip of a
Sonde enteroscope is propelled by peristalsis and can reach the distal
small intestine. Unfortunately, the distance either instrument has pro-gressed cannot be reliably ascertained and biopsies cannot be taken with
Sonde enteroscopes.
Colonoscopy and flexible sigmoidoscopy
Fibreoptic and video colonoscopes allow examination of the entire large
intestine and the terminal ileum. The patient must be adequately pre-pared beforehand with powerful laxatives to remove solid material from
the colon. During the examination, light sedation and analgesia are usu-ally necessary. In flexible sigmoidoscopy the instrument is only inserted
into the left side of the colon.
Diagnostic uses
The commonest indications include investigation of  altered bowel
habit, rectal bleeding, suspected colorectal cancer and inflammatory
bowel disease. Colonoscopic screening for colon cancer is advocated
for patients at high risk, for example, those with a strong family history
of the disease, and there is a debate about introducing population-wide
screening.
The normal colonic mucosa is smooth and shiny with a regular vascu-lar pattern. Pouches or  diverticulae can be easily detected, as can
inflamed, ulcerated or bleeding areas, polyps and malignant tumours.
Biopsies for histology can safely be taken and polyps and small tumours
removed by snaring and electrocautery.
Ileoscopy: the tip of the colonoscope can be manoeuvred through the
ileocaecal valve into the terminal ileum.
Therapeutic uses
Bleeding lesions can be treated by electrocautery or heat coagulation
and small polyps removed (polypectomy). Large tumours causing
bleeding or obstruction can be treated with lasers, and stents introduced
to maintain a patent lumen.
Complications
There is a small risk of colonic perforation, and of bleeding following
polypectomy. Sedation and analgesia may also cause  respiratory
depression.
Endoscopic retrograde cholangiopancreatography and
biliary endoscopy
A duodenoscope with a sideways-facing tip allows visualization and
cannulation of the ampulla of Vater. Contrast material can then be
injected into the pancreatic and biliary ducts and X-ray images taken.
Close-up  ultrasound images can be obtained by inserting compact
ultrasound probes into the duct. Cannulae and instruments can be
introduced to obtain  brushings or  biopsies, remove  gallstones, and
dilate strictures. The sphincter of Oddi may be cut (sphincterotomy),
allowing gallstones to pass spontaneously.
Endoscopic retrograde cholangiopancreatography (ERCP) is usually
performed to investigate and treat obstructive jaundice. Larger bile ducts
can also be viewed with very fine flexible endoscopes inserted percuta-neously into the liver. Injecting contrast material into the pancreatic duct
can provoke pancreatitis.
Future directions
Advanced instruments are making endoscopy safer and more versatile.
Ingeniously designed instruments that can be inserted alongside the
endoscope or through the biopsy channel are expanding the range of
therapeutic interventions to include  cutting and  suturing, enabling
endoscopic surgery.
Wireless capsule endoscopy: tiny encapsulated electronic cameras
can be swallowed, allowing visual data be collected remotely, by radio
transmission. Images are thus obtained from areas that cannot be
reached by conventional endoscopic instruments, although biopsies
cannot yet be taken.
Endoscopy 99
100 Diagnosis and treatment
Plain X-ray
Barium meal
Transjugular liver biopsy
Barium meal and
follow through
Ultrasound
Barium enema
Test Structure
Barium swallow  Pharynx, oesophagus
Barium meal  Stomach, duodenum
Barium meal and follow  Duodenum, jejunum, ileum
through
Barium enema  Large intestine, terminal ileum
ERCP  Gallbladder, bile ducts, pancreas
Scan name  Principle and uses
Gastric emptying scan  The rate of passage of a labelled meal measures gastric motility
Meckel’s scan  Labelled pertechnate taken up by parietal cells localizes ectopic gastric tissue
Red cell scan  Labelled red cells reinjected into the patient localize rapidly bleeding lesions
White cell scan  Labelled white cells reinjected into the patient accumulate at sites of inflammation
HIDA(hydroxyliminodi-  Labelled HIDA is excreted in the bile, and scanning delineates the biliary tract
acetic acid) scan
Octreotide scan  Labelled octreotide binds to somatostatin receptors, localizing neuroendocrine
tumours that strongly express these receptors
45 Radiology and imaging
X-rays, ultrasound scanning, magnetic resonance imaging (MRI) and
isotope scanning are powerful techniques for investigating structure
and function in the gastrointestinal system and can also be used
therapeutically.
Plain X-rays
There is little intrinsic difference in radio-opacity, or contrast, between
most intra-abdominal structures, which makes plain abdominal X-rays
challenging to interpret. Nonetheless, they can be rapidly and cheaply
performed and help to diagnose a number of common conditions. For
example, excess gas and fluid accumulate in intestinal obstruction, cre-ating multiple air–fluid levels, and in severe colitis, colonic dilatation
may create an enlarged gas-filled colon (toxic megacolon) that is readily
visualized. Free air in the peritoneum is detected in intestinal perfora-tion and pancreatic calcification is visible in  chronic pancreatitis.
Colonic transit time can be simply determined by sequentially ingest-ing radio-opaque shapes and performing plain X-rays at intervals there-after (shape test).
Plain X-rays with luminal contrast
X-ray contrast material can be administered orally, instilled rectally or
injected endoscopically to delineate the interior of the intestinal tract and
demonstrate  ulcers, strictures, diverticulae, fistulae  and tumours.
Fluoroscopic real-time views of the passage of contrast allow peri-stalsis and functional abnormalities of, for example, swallowing,
oesophageal and gastric emptying, and defecation to be investigated.
The most frequently used contrast agents are barium, and gastrograf-fin, which is more water-soluble. Striking double-contrast images of the
mucosal surface are obtained by instilling air with the liquid contrast.
Common specific tests are shown in the table in the figure.
Computerized tomography scan
Cross-sectional images produced by computerized tomography (CT)
scanning effectively image the liver, gallbladder and pancreas. It is
less useful for imaging the hollow organs, although new techniques,
using increased computing power, allow three-dimensional reconstruc-tion of the colon, providing high-resolution virtual colonoscopy with
contrast provided by luminal insufflation of air or CO2.
CT scanning can also be enhanced by oral or rectal contrast, delineat-ing the bowel lumen or by intravenous contrast, which increases the
definition of vascular structures in the liver, pancreas and bowel wall.
Magnetic resonance imaging
The resolution of magnetic resonance imaging (MRI) scans is generally
greater than that of CT scans and intravenous gadolinium, which is a
magnetic contrast agent, further enhances the definition of vascular
structures. With powerful computer algorithms that analyze the effect of
blood or bile flow on the image, magnetic resonance angiography
(MRA) and magnetic resonance cholangiopancreatography (MRCP)
allow reconstruction of the vascular and biliary anatomy, and may
replace conventional vascular angiography and endoscopic retrograde
cholangiopancreatography (ERCP) in some cases. Thus MRI scanning,
which does not involve harmful radiation, is rapidly becoming a major
imaging modality in gastroenterology.
Ultrasound scanning
Ultrasound scanning (USS) is particularly useful for examining the liver
and gallbladder. USS detects 90% of  gallstones (compared to 10%
detected by X-rays) and can also be used to evaluate the texture of the
liver, the thickness of the gallbladder wall and the calibre of bile ducts.
USS can also image the pancreas although overlying bowel gas makes
this unreliable. Free fluid in the peritoneum, or ascites, is also readily
demonstrated by USS. It is less helpful for examining air-filled struc-tures, such as the intestinal tract.
Using Doppler measurements, the rate and direction of blood flow in
the portal and hepatic veins can be determined, which is useful in portal
hypertension and the Budd–Chiari syndrome.
An ultrasound probe inserted into the anal canal (endoanal USS) can
provide high-resolution images of the sphincter muscles and surround-ing tissues, helping to evaluate the depth of anorectal inflammation or
neoplasia. Endoscopic USS probes in the oeosphagus, stomach, duode-num and ampulla of Vater to produce similarly close-up images of the
walls of these structures.
Radioisotope scans
Gamma-ray emitting isotopes can be attached to various molecules
that localize to different body compartments and their distribution
detected with a gamma ray detector. For example, isotopes can be
attached to monoclonal antibodies with exquisite specificity for their
target proteins, allowing localization of rare tumours and cells. This can
also be used to target high-dose local radiotherapy. Thus, the technique
is versatile, although it provides relatively low anatomical resolution.
Various radioisotope scans are listed in the table in the figure.
Positron emission tomography (PET) detects the abnormal accu-mulation of labelled compounds, such as glucose in metabolically active
cells, and can localize tumours and inflammation with greater sensitivity
and spatial resolution than conventional radioisotope scanning.
Interventional radiology
Radiological guidance with USS, CT or MRI, enables invasive proce-dures, such as a liver biopsy, to be performed more safely and with
greater precision.
X-ray fluoroscopy can guide dilatation of strictures and placement of
stents in, for example, the oesophagus, and allows vascular manipula-tions, such as embolization of bleeding vessels in the intestinal tract.
Similarly, liver tumours can be treated by X-ray guided embolization of
the arterial supply, as the portal vein continues to supply blood to the sur-rounding liver.
Liver biopsies can be taken by passing forceps transjugularly into
the hepatic vein under fluoroscopic guidance, avoiding the bleeding risk
associated with percutaneous biopsy. Similarly, a shunt between the
hepatic vein and portal vein can be created transjugularly, under fluoro-scopic guidance, to relieve portal hypertension and associated bleeding
varices. This is known as a transjugular intrahepatic portosystemic shunt
(TIPSS).
Insufflating air and barium into the colon during a barium enema
may suffice to reduce and treat volvulus of the sigmoid colon. Similarly,
increased luminal pressure created by a barium enema can reduce intus-suception, where a proximal part of the intestine is drawn into the distal
lumen by peristalsis.
Radiology and imaging 101
102 Diagnosis and treatment
Urease breath test
NH4+
pH≠Indicator
dye colour
CLO test
13C urea
Urea
H. pylori
Urease
Small intestinal
bacterial
fermentation Organic
acids
H2
Colonic bacterial
fermentation Organic
acids
H2
pH
0
Oesophageal manometry
pH monitoring, Bernstein test

24-hour pH monitor
Reflux
and pain
Reflux
and pain
Time
Schilling test
Kidney
B12 deficiency
I.M. loading dose
saturates body stores
Oral test dose (labelled)
Oral test dose + IF
Normal excretion
= dietary deficiency
ØExcretion
= malabsorption
Normal excretion
= IF deficiency
(pernicious anaemia)
ØExcretion
= terminal ileal
disease
Lactulose Lactose
CO2H2
Vitamin B12 13C-urea
Xylose rhamnose
13CO2
Lactulose
Lactose
Anorectal manometry
B12
Xylose
46 Functional tests
Functional tests measure aspects of gastrointestinal pathophysiology
and complement endoscopy, radiological imaging and blood tests. There
are many specific tests available and some of the underlying principles
are discussed here.
Breath tests
The principle underlying these tests is that gases such as CO2 and H2 that
can be generated in the intestine are rapidly absorbed into the circulation
and excreted through the lungs.
13
C-urease breath test
This test detects the presence of the urease enzyme of  Helicobacter
pylori in the stomach. A drink containing 13C-labelled urea is adminis-tered and, after a short interval, a sample of expiratory breath is taken to
detect the presence of 13C-labelled CO2, produced by the breakdown
of  13C- urea, principally by the urease enzyme of  H. pylori.  13C is a
non-radioactive isotope and it is measured by mass spectrometry;
similar tests use  14C-labelled urea, which emits beta particles that
are detected by scintigraphy.
Lactose breath test
A test meal containing lactose is administered and the amount of H2
excreted on the breath is measured over the subsequent few hours. Nor-mally lactose is digested in the intestine by the enzyme lactase and
absorbed, resulting in no excess production of H2. However, in lactase
deficiency, either congenital, or acquired, for example after a bout of
gastroenteritis, lactose passes undigested into the large intestine, where
bacteria metabolize it, releasing H2. The excess H2 is absorbed into the
bloodstream and excreted via the lungs.
Lactulose breath test
Lactulose is a disaccharide that is not absorbed or metabolized in the
small intestine and passes to the colon, where bacteria digest it, releasing
H2. H2 is produced after a delay necessitated by the passage of lactulose
through the small intestine. However, where there is bacterial over-growth in the small intestine, lactulose metabolism occurs in the
small intestine and is accelerated, resulting in excessive and early H2
production.
Absorption and excretion tests
The principle underlying these tests is that tracer compounds absorbed
from the intestine can be readily detected in the bloodstream or in the
urine when they are excreted. The chosen tracer compounds are easily
detected, either by measuring radioactivity, or by a simple chemical test.
Schilling test
This test investigates the various steps in the absorption of vitamin B12
(hydroxocobalamin).
Firstly, a large dose of vitamin B12 is administered by intramuscular
injection, to saturate body stores and ensure that any additional vita-min B12 that is absorbed will be excreted in the urine rather than
stored.
Next an oral dose of radiolabelled vitamin B12 is administered and the
urinary excretion measured. Providing that intestinal absorption is nor-mal, most of the labelled vitamin will be detected in the urine, suggesting
that any previous deficiency was due to dietary insufficiency.
If, however, excretion cannot be detected, implying that there is inad-equate intestinal absorption, a further oral dose of radiolabelled vitamin
B12 is administered, this time together with intrinsic factor (IF). If exoge-nous IF restores normal absorption and excretion, the interpretation is
that the patient has pernicious anaemia, or IF deficiency caused by
atrophic gastritis.
If, however, exogenous IF fails to restore normal absorption and
excretion, the likely cause of vitamin B12 deficiency is disease of, or
damage to, the terminal ileum.
Bromsulpthalein excretion test
Bromsulpthalein administered orally is almost entirely taken up by the
liver and excreted in the bile. If there is reduced hepatic function, or
altered biliary excretion, an increased proportion of bromsulpthalein is
excreted in the urine.
Xylose excretion
Xylose is a non-metabolized sugar that is absorbed in the small intestine.
Once absorbed into the bloodstream, it is excreted unchanged in the
urine. Thus urinary excretion allows intestinal absorption and perme-ability to be measured. The xylose excretion test is mainly used as a
research tool.
Stimulation tests
In these tests a hormone or other physiological stimulus is administered
and the response noted. In most cases this involves measuring the secre-tion of another hormone or chemical into the circulation.
Secretin test
This test is used to assess the extent of functional pancreatic tissue. The
duodenum is intubated and secretin infused intravenously. The amount
of pancreatic juice secreted and the HCO3
– concentration and content
is measured. These are directly correlated with the amount of functional
pancreatic tissue and low levels indicate  pancreatic insufficiency
caused, for example, by chronic pancreatitis.
The test can be augmented by also infusing  cholecystokinin and
measuring pancreatic enzyme secretion.
Manometry
Pressure transducers introduced into parts of the intestinal tract allow the
function of sphincters to be studied. The most commonly performed
measurements are of the lower oesophageal and anal sphincters and the
sphincter of Oddi.
Oesophageal manometry is used to diagnose various dysmotility dis-orders, including diffuse oesophageal spasm and achalasia of the cardia,
while anal manometry helps in the diagnosis of the causes of faecal
incontinence.
pH measurement
pH electrodes introduced into the oesophagus and stomach through the
nose or mouth allow the frequency and severity of gastro-oesophageal
acid reflux to be evaluated. Episodes of low pH in the distal oesophagus
are correlated with symptoms, to ensure that reflux symptoms are actu-ally caused by acid reflux. The test can be used to document the effects of
medical and surgical treatment.
In the  Bernstein test, dilute HCl may be infused into the lower
oesophagus, to determine if this reproduces heartburn for the patient.
Oesophageal pH measurement can be performed in ambulatory
patients, over a 24-h period, allowing documentation of the effects of
meals, posture and sleeping.
Functional tests 103
104 Diagnosis and treatment
De creased mot ility
Buccal or oral absorption,
e.g. GTN, buccastem
Endoscopic injection,
e.g. botulinum toxin
Single effect/cell target,
many receptors
One substance (5HT),
many receptor subtypes
Proton pump
inhibitor
Somatostatin
HCl output reduced
Anticholinergic
H2 receptor
antagonist
Gastric absorption,
e.g. alcohol, NSAIDS
Budesonide
Hepatic
first pass
metabolism
Probiotics
(e.g. Lactobacillus)
Non-absorbed
antibiotics
(e.g. neomycin)

Enteric
coated
5-ASA
5-ASA
5ASA
Enzyme and food supplements
Bacterial metabolism
Entero-endocrine
cells
Increased motility
5HT3
receptor5HT4
receptor
Enteric
neuronSmooth muscle cell
Suppository
Enema—local action or absorbed
Rectal absorption, e.g. diazepam
active
Sulpha
5-ASA
released
47 Pharmacotherapy
Pharmacological treatment of gastrointestinal disorders is a mature and
well-advanced field, and new treatments are constantly emerging. The
largest selling drugs recently have been gastrointestinal acid suppres-sants, reflecting the high incidence of dyspepsia and peptic ulceration
and the exquisite specificity of the medications with the resulting low
incidence of adverse effects.
Special considerations
Target specificity
Many drugs bind to cellular receptors or proteins selectively. By mim-icking the structure of the naturally occurring chemical, its effect is
either replicated (agonist) or blocked (antagonist). An example is the
group of histamine H2 receptor antagonists that block acid secretion by
parietal cells. With advancing scientific knowledge, greater specificity
can be achieved: for example different serotonin (5-hydroxytryptamine,
5HT) receptor subtypes are now being selectively targeted.
Selective release and topical treatment
Another way of achieving selective effects is to only apply the medica-tion where it can reach the target tissue. In the gastrointestinal system,
this can be achieved by oral administration of non-absorbed drugs that
then act locally. The 5-aminosalicylic acid (5ASA, mesalazine) drugs
used to treat inflammatory bowel disease (IBD) are delivered this way,
either as slow-release preparations that dissolve in the distal intestine or
as pro-drugs that are activated by bacterial metabolism in the colon.
Some drugs are significantly absorbed through the rectal mucosa,
such as diazepam, used to treat active epileptic fitting, while others, such
as rectal 5ASA compounds, act locally.
Hepatic first pass effect
Enterically administered drugs that are rapidly and completely metabo-lized by the liver are said to have high hepatic first pass metabolism. This
allows high doses to be delivered to the intestine, with fewer systemic
side-effects. An example is the synthetic corticosteroid, budesonide,
used to treat IBD.
Augmenting or inhibiting intestinal function
Pancreatic enzyme supplements and lactase can be taken by mouth to
correct the effects of pancreatic failure and intestinal hypolactasia,
respectively. The enzyme supplements act locally in the intestine.
Orlistat, which is designed to reduce fat absorption, acts by inhibiting
pancreatic lipase in the intestine.
Oral tolerance, immunotherapy and vaccination
Orally administered antigens stimulate a strong secretory immune
response with immunoglobulin A (IgA) and IgM antibodies, while the
systemic immune response is inhibited. Thus the live polio vaccine
and vaccines against salmonellae and Vibrio cholera are administered
orally. Orally administered autoantigens may induce selective immuno-logical tolerance and could be used to treat autoimmune diseases, such as
multiple sclerosis, although results of clinical trials have so far been
discouraging.
Antibiotics and probiotics
Some intestinal symptoms may be due to a proliferation of abnormal
intestinal bacteria or reduced normal commensals, and oral or rectal
administration of live commensal bacteria is currently being investi-gated, particularly in the treatment of IBD. This is a counterpart to the
administration of antibiotics to selectively decontaminate the intes-tinal lumen, for example, before abdominal surgery or in chronic liver
disease.
Food as therapy
Intolerance to various food elements occurs, for example, in coeliac
disease, lactose intolerance, cow’s milk protein, peanut and other food
allergies.
A totally bland, antigen-free diet comprising monomers or short
oligomers of carbohydrate, fat and protein is apparently effective in
treating Crohn’s disease, although the mechanism of action is unknown.
Enteral feeding
Enteral, as opposed to parenteral, feeding, even in severely ill patients
is critically important, as the food-free intestine atrophies, increasing the
risk of bacterial translocation and systemic sepsis.
Pharmacotherapy 105
Incision of the abdominal wall to gain access to the peritoneal cavity is
termed  laparotomy.  Minimally invasive laparoscopic surgery has
transformed many abdominal operations from major, hazardous under-takings, to routine day-case procedures. However, gastrointestinal sur-gery is frequently performed as an  emergency and remains highly
demanding for the patient and surgeon.
In addition, many gastrointestinal disorders are treated jointly by
physicians and surgeons, who collaborate to determine the best
combined therapeutic approach for individual patients, particularly
when managing inflammatory bowel disease (IBD) and hepatobiliary
conditions.
106 Diagnosis and treatment
Cholecystectomy
Cholecystectomy
Liver
transplant
Laparotomy
Appendicectomy
Instrument
channel
Ileostomy
bag

Light source and air insufflator
Nissen fundoplication
Emergency
ulcer surgery
Colectomy
for bowel
cancer
Hernia repair
Haemorrhoidectomy
Incision and drainage
of abscess
Appendicectomy
Gastric bypass
48 Gastrointestinal surgery
Basic considerations
As for any surgery performed under general anaesthetic, patients fast
beforehand and, for intestinal surgery, the bowel is also purged with lax-atives, and prophylactic antibiotics are administered peri-operatively.
Manipulating the intestine temporarily halts peristalsis, causing
paralytic ileus; therefore, patients cannot eat or drink immediately
after abdominal surgery.
Stomas
Parts of the intestinal tract are commonly brought out onto the surface of
the abdomen, creating an artificial opening or stoma. This may be per-manent or temporary, allowing time for the distal part of the bowel to
heal, or to defunction the distal intestine prior to further surgery.
Stomas release intestinal or colonic contents onto the skin, which is
not adapted for constant exposure to their pH, salt and enzymatic com-position; therefore, stomas require special care, involving equipment
such as adhesive dressings and bags.
In addition, small intestinal stomas lose large volumes of intestinal
juice that can no longer be reabsorbed by the colon and patients risk salt
and water depletion unless they compensate by increasing intake.
Laparoscopic surgery
Operations such as a  cholecystectomy are now usually performed
laparoscopically whereby instead of a large incision of the anterior
abdominal wall, a small ‘keyhole’incision is made through which a nar-row laparoscope is inserted. This allows visualization of the internal
organs and instruments are introduced through the same or additional
incisions to perform the surgery. The technique requires skill and prac-tice and is much less traumatic for the patient.
Common operations
• Cholecystectomy: usually to remove symptomatic gallstones caus-ing cholangitis or pancreatitis.
• Hernia repair: such as inguinal hernias, particularly in men.
• Appendicectomy: usually for acute appendicitis.
Gastrointestinal bleeding
Fifty per cent of gastrointestinal bleeding is caused by peptic ulcers and,
although many cases can be treated medically or endoscopically, uncon-trollable bleeding, especially where the bleeding source cannot be iden-tified, necessitates emergency laparotomy.
Gastrointestinal bleeding caused by portal hypertension may require
surgically constructed vascular shunts (portocaval shunts) to reduce
portal pressure and prevent variceal haemorrhage.
Inflammatory bowel disease
Inflammatory bowel disease, particularly Crohn’s disease, can cause
intestinal strictures and fistulae that require surgical correction. How-ever, as Crohn’s disease typically recurs after surgery, surgery is used
sparingly.
Medically uncontrolled colitis may necessitate emergency colectomy
as a life-saving measure. Furthermore, in ulcerative colitis, colectomy is
curative and is sometimes also performed because of the high risk of
colorectal cancer.
Cancer
Cancers of the intestinal tract, pancreas, liver or gallbladder may be
treated surgically, particularly if they are detected at an early, potentially
curable stage. However, most operations are palliative, aiming to reduce
tumour bulk before chemotherapy or radiotherapy, or to relieve intes-tinal obstruction or bleeding.
Obesity
Surgical treatment of obesity is still evolving. The earliest operations,
in which the jejunum and varying lengths of ileum were  bypassed,
achieved weight loss but were complicated by steatohepatitis causing
severe liver damage, and are no longer performed.
Wiring the jaws closed, so that the patient cannot eat solid food
and must subsist on liquids is effective. Gastroplication reduces the
effective size of the gastric reservoir, forcing patients to eat smaller
meals.
Transplantation
Transplant surgery may be performed to replace the liver, pancreas or
pancreatic islet tissue, or small intestine. Orthotopic liver transplantion,
whereby the original liver is removed and replaced with a donor organ is
the most successful, and 85% of liver transplant recipients survive for at
least 5 years post-operatively. Pancreatic and small intestinal transplan-tation are less successful, although when the small intestine and liver are
transplanted together, the outcome improves, possibly because liver
transplantation induces donor-specific immune tolerance in the host,
reducing the risk of rejection.
Gastrointestinal surgery 107

Index 109
Note: page numbers in italics refer to figures
a cells, pancreatic 24, 25
a fetoprotein (AFP) 87
abdomen examination 96, 97
abdominal pain 45
coeliac disease 80, 81
colitis 78, 79
gallstones 90, 91
gastroenteritis 74, 75
hepatitis 92, 93
pancreatitis 90, 91
syndromes 68, 69
treatment 68, 69
abdominal surgery 67
abscess
anorectal 88, 89
anus 38, 39
appendiceal 35
brain 77
crypt 78, 79
intestinal 78, 79
liver 27, 35, 76, 77
peri-anal 76, 77
tooth 13
absorption 48, 49
tests 102, 103
acetaldehyde 61
acetaminophen see paracetamol
acetylcholine 21, 41, 44, 45, 72, 73
acetylcholine receptor antagonists 62, 63
acetylcholinesterase inhibitors 65
N-acetylcysteine 61, 93
achalasia 19, 41
acid reflux 19
acini 14, 15, 24, 25, 42
acquired immune deficiency syndrome (AIDS)
75, 77
acrodermatitis enteropathica 53
actin 40, 41
acute phase response, hepatic 59
addressins 47
adenomatous polyposis (apc) gene 84, 85
cyclic adenosine monophosphate (cAMP) 56,
57, 65
adenylyl cyclase 65
adhesins 74, 75, 77
adipocytes 55
air insufflation 101, 106
albumin 58, 59, 61
cirrhosis 95
hepatitis 93
serum levels 96, 97
alcohol 27, 49, 61, 73
cirrhosis 94, 95
consumption 96, 97
dependence 83
hepatitis 92, 93
oesophageal squamous cell carcinoma
87
pancreatitis 90, 91
alcohol dehydrogenase 61
alkali tide 21
alkaline phosphatase 93, 96, 97
allergies 47
alveolar bone 12, 13
amino acids 55, 58, 59
essential 58, 59
metabolism 60, 61
transamination 58, 59
5-aminosalicylic acid 79
ammonia 31, 58, 59
urea cycle 60, 61
amoeboma 77
amphetamines 82, 83
ampulla of Vater 22, 23, 24, 25, 28, 29
endoscopy 98, 99
amylase 14, 15, 25, 49, 50, 51
levels 96, 97
pancreatitis 90, 91
anaemia 23, 37
coeliac disease 80, 81
colorectal cancer 85
folic acid deficiency 53
iron deficiency 53
parasitic worms 77
peptic ulcer 72, 73
terminal ileitis 78, 79
anaesthesia 17
anal fissure 39, 66, 67, 88, 89
anal glands, submucosal 38, 39
anal sphincter 40, 41
external/internal 38, 39
manometry 102, 103
anal valves 38, 39
angiodysplasia 37
angular stomatitis 13
anorectal abscess 88, 89
anorectal angle 38, 39
anorectal disease 88, 89
anorectal fistula 88, 89
anorectal inflammation 78, 79
anorectal syndromes 68, 69
see also rectal conditions
anorexia 82, 83
gallstones 90, 91
hepatitis 92, 93
pancreatitis 91
antacids 72, 73
antibiotics 72, 73, 75, 79
bacterial overgrowth 77
prophylactic 107
selective decontamination 104, 105
antibodies to Saccharomyces cerevisiae (ASCA)
79
anticholinergic drugs 67, 72, 73
antidiarrhoeals 65, 68, 69
antiendomysial antibody 81
antiepileptic drugs 61
antifungals 77
antigen presentation 46, 47
antigen presenting cells 81
antimicrobial environment of duodenum 23
antimitochondrial antibodies 95
antineutrophil cytoplasmic antibodies (ANCA)
79
antispasmodics 69
antrum 20, 21
anus 38, 39
abscess 38, 39
fistula 38, 39
innervation 44, 45
obstruction 66, 67
anxiety 69
apc gene 84, 85
apolipoprotein B genetic deficiency 51
apolipoproteins 50, 51, 58, 59
apoptosis 81, 92, 93
appendicectomy 35
laparoscopic 106, 107
appendicitis 35, 45
appendix 34, 35
abscess 35
carcinoid tumours 35
immune function 47
appetite control 54, 55
suppression 82, 83
apraxia, constructional 31, 95
apthous ulcers 13, 78, 79
arthritis 78, 79
ascites 31, 94, 95
aspiration 19
protection 17
vomit 63
asterixis 31
atrophic gastritis 53, 55
autoantibodies to liver antigens 93
autocatalysis 51
autodigestion 49, 91
autoimmune disease 87
hepatitis 92, 93
autonomic nerves 44, 45
dysfunction 68, 69
autonomic nervous system 48, 49
autonomic neuropathy 21, 45
constipation 66, 67
diarrhoea 65
b-blockers 31
B cells 46, 47
b cells, pancreatic 24, 25
Bacillus cereus 74, 75
bacteria
commensal 35, 37, 47, 76, 77
vitamin K production 48, 49
diet interactions 69
overgrowth 33, 76, 77, 102, 103
pathogenic 37
plaque 13
Index
110 Index
bacteria (cont.)
toxins 57, 64, 65
translocation 31
barbiturates 61
barium examinations
enema 85, 101
meal and follow-through 79
plain X-ray with luminal contrast 100, 101
swallow 71
Barrett’s oesophagus 19, 70, 71
endoscopic surveillance 87
oesophageal cancer 86, 87
basal energy expenditure (BEE) 54, 55
basal metabolic rate (BMR) 55, 82, 83
Bernstein test 71, 103
betel nut chewing 13
bicarbonate ions 20, 21, 49
electrolyte balance 56, 57
pancreatic juices 103
vomiting 63
bile 23, 27, 28, 29
pancreatic enzymes 49
bile acid transporter (BAT) 28, 29
bile acids 28, 29
absorption 48, 49
gastro-oesophageal reflux 70, 71
bile canaliculi 26, 27, 28, 29
bile ducts 28, 29
common 24, 25, 28, 29
obstruction 29, 61, 93
ultrasound imaging 101
bile salts 26, 27, 33, 47
amphiphilic 48, 49
excess 65
gallstones 90, 91
mixed micelle formation 50, 51
synthesis 58, 59
terminal ileitis 79
biliary cirrhosis, primary 29, 53, 94
biliary epithelial cells 26, 27
hepatitis 93
biliary syndromes 68, 69
biliary system 11, 28, 29
endoscopy 98, 99
bilirubin 26, 27, 60, 61, 94, 95
excretion 28, 29
hepatitis 93
levels 96, 97
biopsy 98, 99
biting 48, 49
blood count 97
blood pressure control 45
blood tests 96, 97
body mass control 54, 55
body mass index 54, 55, 82, 83
calculation 96, 97
bone formation 53
botulinum toxin 41, 99
bovine spongiform encephalopathy (BSE) 47
bowel disorders, functional 45
bowel habit 67
altered 96, 97, 99
colorectal cancer 85
brain
abscess 77
neurological damage 66, 67
sensory motor cortex 44, 45
starvation 55
see also vomiting centre
brainstem, swallowing control 17
breath tests 77, 102, 103
bromsulphthalein excretion test 103
Brunner’s glands 22, 23
brush border 22, 23
peptidases 50, 51
buccinator muscles 12, 13
Budd–Chiari syndrome 92, 93
Doppler ultrasound 101
budesonide 31, 79, 105
bulb of duodenum 22, 23
C-reactive protein (CRP) 58, 59, 79, 91, 96,
97
13
C-urease breath test 102, 103
caecal volvulus 35
caecum 34, 35
calbindin 53, 53
calcitonin gene-related peptide 44, 45
calcium 53, 53
absorption 23
coeliac disease 81
deficiency 55
malabsorption 81
saliva 14, 15
calorie intake 54, 55
restriction 82, 83
Campylobacter jejuni 74, 75
cancer surgery 106, 107
candidiasis 19, 76, 77
canine teeth 12, 13
cannabinoids 63
carbo-loading 59
carbohydrates 50, 51
hepatic metabolic function 58–9
carbonic anhydrase 56, 57
carboxypeptidases 50, 51
carcinoembryonic antigen (CEA) 85
carcinogens, colorectal cancer 84, 85
carcinoid syndrome 42, 43, 86, 87
carcinoid tumours 35, 42, 43, 86, 87
diarrhoea 64, 65
cardia 20, 21
carrier proteins 58, 59
catecholamines 58, 59
central nervous system 42, 43
cervical sympathetic chain 44, 45
chemoreceptor trigger zone (CTZ) 62, 63
chemotherapy in colorectal cancer 85
chewing 48, 49
chief cells 20, 21
children, malnutrition 82, 83
cholangiocarcinoma 87
cholangitis 29
ascending 76, 90, 91, 93
primary sclerosing 78, 79, 87
cholecystectomy 91
laparoscopic 106, 107
cholecystitis 29, 90, 91
cholecystokinin 23, 24, 25, 28, 29
gastrin inhibition 42, 43
intestinal motility 45
secretin test 103
cholera 75
cholera toxin A 57, 64, 65
cholestasis, intrahepatic 29, 61
cholesterol 28, 29
gallstones 90, 91
synthesis 58, 59
cholesterol esterases 50, 51
cholesterol esters 50, 51
chylomicrons 49, 50, 51
chyme 21, 41, 49
chymotrypsinogen 50, 51
ciprofloxacin 75
cirrhosis 11, 27, 94–5
liver 31, 87, 92, 93
primary biliary 29, 53, 94
Cl
-/Na
+
/K
+
transporter 56, 57
clinical assessment 96, 97
CLO test 73
Clostridium difficile 74, 75, 77
Clostridium perfringens 74
clotting tests 97
coagulation factors 58, 59
coagulopathy 53, 59
cirrhosis 95
coeliac artery 21, 23, 24, 25
coeliac disease 11, 23, 47, 80, 81
food intolerance 105
gastrointestinal lymphoma 86, 87
malabsorption 51, 55
coeliac ganglion 25, 45
coeliac trunk 26, 27
cold sores 13
colectomy 106, 107
colitis 78, 79
diagnosis 101
pseudomembranous 75
see also Crohn’s disease; inflammatory bowel
disease; ulcerative colitis
colon 36, 37
fluid flux 56, 57
reduced motility 66, 67
sigmoid 36, 37, 38, 39
volvulus 101
colonic adenoma, tubulovillous 65
colonic diverticulae 36, 37, 99
colonic mass movement 40, 41
colonic transit time 101
colonocytes 36, 37
colonoscopy 79, 85, 99
virtual 101
colorectal cancer 11, 35, 37, 84, 85, 87
carcinoma in situ 84, 85
colectomy 106, 107
diagnosis 99
diarrhoea 64, 65
Dukes staging 84, 85
genetic element 84, 85
coma 17, 31
common bile duct 24, 25, 28, 29
complement 31, 58, 59
computed tomography (CT) scan 101
constipation 37, 39, 66, 67
anal fissure 88, 89
Index 111
colorectal cancer 84, 85
dysmotility 41
enteric and autonomic nerve dysfunction
45
neuro-psychological dysfunction 66, 67
slow-transit 41, 67
treatment 68, 69
contractions, phasic/tonic 41
copper 53, 53
excretion 29, 61
cortex 17, 62, 63
constipation control 66, 67
corticosteroids 58, 59, 79
autoimmune hepatitis 93, 95
candidiasis 77
Crigler–Najjar syndrome 61
Crohn’s disease 33, 35, 37, 78, 79
anorectal 38, 39, 76, 77, 88, 89
diet 104, 105
environmental triggers 77, 78, 79
malabsorption 55
proctitis 89
small intestine 81
treatment 79
vitamin B12 deficiency 53
crypt abscesses 78, 79
Cryptosporidia 33, 75
crypts
caecal 35
colonic 36, 37
crypts of Lieberkühn 22, 23
cystic duct 28, 29
cystic fibrosis 25
cystic fibrosis transmembrane receptor (CFTR)
24, 25, 56, 57
cholera 65
pancreatitis 90, 91
cysticercosis 77
cytochrome P450–61
cytochromes 60, 61
cytokines 58, 59
cytomegalovirus (CMV) 74, 75, 76, 77
D cells 21, 24, 25, 42, 43
defecation 38, 39
neuro-psychological dysfunction 66, 67
normal frequency 67
straining 67, 89
defensins 47
dehydration 57, 96, 97
gastroenteritis 75
prevention 65
dendritic cells 26, 27, 46, 47
dental caries 13
dental hygiene 13
dentate line 38, 39
dentine 12, 13
depression 69
dermatitis 53
herpetiformis 80, 81
diabetes mellitus 21, 25, 45
candidiasis 77
pancreatitis 90, 91
peripheral neuropathy 66, 67
diaphragm, hiatus 18, 19
diarrhoea 23, 25, 33, 37, 39
antibiotic-associated 74, 75
coeliac disease 81
colitis 78, 79
definition 65
dysmotility 41
endemic 74, 75
enteric and autonomic nerve dysfunction 45
epidemic 74, 75
gastroenteritis 74, 75
inflammatory 64, 65
malabsorption 51
mechanisms 64, 65
osmotic 64, 65
osmotically active substances 57
secretory 57, 64, 65
traveller’s 74, 75
treatment 65, 68, 69
watery 43, 57
diet 69, 96, 97
colorectal cancer 84, 85
Crohn’s disease 104, 105
food as therapy 104, 105
gliadin-free 81
haemorrhoids 89
obesity treatment 82, 83
dietary fibre 66, 67, 68, 69
colorectal cancer 84, 85
digestion 23, 29, 48, 49
minerals/vitamins 52, 53
see also enzymes
diphtheria 17
disaccharidases, brush-border 49
diseases/disorders of gastrointestinal system 10,
11
disulfiram 61
divalent metal transporter (DMT) protein 52, 53
diverticulitis 36, 37
dome epithelium 46, 47
dopamine 44, 45
dopamine D2 receptor antagonists 62, 63
Doppler ultrasound 101
drooling 19
drugs
anticholinergic 15
hepatitis 92, 93
liver damage 27
selective release 104, 105
sublingual administration 12, 13
target specificity 104, 105
taste alteration 17
topical treatment 105
Dubin–Johnson syndrome 61
duodenum 22, 23
cancer 23
ulceration 73
dysentery 37, 65, 74, 75
amoebic 77
dysmotility 19, 41
dyspepsia 21
non-ulcer 68, 69
dysphagia 19, 41
Ecchinococcus 76, 77
electrocautery 99
electrograstrography 41
electrolyte(s)
abnormalities 67
depletion 65
levels 97
electrolyte balance 56, 57
abnormalities 67
vomiting 63
embolization of vessels 101
emulsification 48, 49
enamel 12, 13
demineralization 15
encephalopathy 31
bovine spongiform 47
hepatic 31, 61, 77
cirrhosis 94, 95
Wernicke’s 83
endocarditis 77
endocrine cells 10, 11
endocrine system
dysfunction 82, 83
enteric 42, 43
endopeptidases 50, 51
endoplasmic reticulum 24, 25, 26, 27
smooth 60, 61
endoscopic retrograde cholangiopancreatography
(ERCP) 91, 98, 99
endoscopic surgery 99
endoscopy 11, 71, 81, 98–9
biliary 98, 99
flexible upper gastrointestinal 98, 99
wireless capsule 99
endothelial cells, liver sinusoid 26, 27
enemas 38, 39
energy expenditure regulation 54, 55
energy metabolism 53, 54, 55
basal energy expenditure 54, 55
basal metabolic rate 55, 82, 83
Entameoba histolytica 74, 75, 77
enteral nutrition 55, 105
enteric decontamination, selective 77
enteric motility 40, 41
enteric nerves 10, 11, 22, 23
dysfunction 66, 67
enteric nervous system 44, 45, 48, 49
dysfunction 68, 69
entero-chromaffin-like cells (ECL) 20, 21, 42, 43
entero-endocrine cells 20, 21, 22, 23, 42, 43
large intestine 35
entero-endocrine system 42, 43, 48, 49
entero-hepatic circulation 28, 29, 32, 33
ileal disease 90, 91
Enterobius vermicularis 89
enterocytes 22, 23, 49
enteroglucagon 42
enterokinase 23, 51
enteroscopy 99
enterotoxins 74, 75
environmental factors
colorectal cancer 84, 85
gastric cancer 86, 87
enzymes 24, 25
antibacterial 14, 15
digestive 48, 49
liver 60, 61
112 Index
enzymes (cont.)
polysaccharide digestion 50, 51
see also pancreatic enzymes
eosinophils 46, 47
epigastric pain 70, 71, 72, 73
epiglottis 17, 18, 19
vomiting 62, 63
Epstein–Barr virus (EBV) 17
erythema nodosum 78, 79
erythrocyte sedimentation ratio (ESR) 97
erythromycin 41
Escherichia coli 74, 75
heat stable toxin (STa) 56, 57
Eustachian tube 17
excretion
bile 29
tests 102, 103
exercise 55
obesity management 82, 83
exocrine glands 14, 15
exopeptidases 50, 51
eye inflammation 79
facial nerve 14, 15, 44, 45
chorda tympani branch 16, 17
faecal impaction 67
faecal occult blood 37, 85, 96, 97
familial adenomatous polyposis (FAP)
85
fasting 67
fat cells see stellate cells, hepatic
fat droplets 26, 27
fats 50, 51
energy dense 55
storage 37
see also steatorrhoea
fatty acids 55
essential 52, 53
fauces 12, 13
fecoliths 35
fever
gastroenteritis 74, 75
pancreatitis 91
fibreoptic instruments 98
first-pass metabolism 31
fistula
anal 38, 39
anorectal 88, 89
intestinal 78, 79, 107
oesphageal–tracheal 19
fluid balance 56, 57
vomiting 63
fluid intake 66, 67, 68, 69
fluoride, drinking water 13
flushing 42, 43
folic acid 33, 48, 49
coeliac disease 81
digestion 52, 53
food
allergies 47, 105
antigens 31, 47
intake 54, 55
intolerance 105
smoked 87
solubilization 48, 49
sweeteners 65
as therapy 104, 105
food poisoning 74, 75
frenulum 17
fructose 50, 51
functional bowel disorders 68, 69
functional tests 102, 103
fundoplication 71
fundus of stomach 20, 21
G cells 20, 21, 73
G-protein coupled receptors 16, 17
gallbladder 26, 27, 28, 29
contraction 43
imaging 101
gallstones 29, 90, 91
impacted 93
removal 99
ultrasound imaging 101
gap junctions 40, 41
gastrectomy, partial 72, 73
gastric cancer 86, 87
adenocarcinoma 86, 87
carcinoma 21, 72, 73
lymphoma 72, 73, 86, 87
gastric churning 40, 41, 48, 49
gastric glands 20, 21
see also stomach
gastric motility 23
gastric mucosa 20, 21
gastric outlet obstruction 21
gastric pits 20, 21
gastric secretion 20, 21
gastric slow wave 21, 40, 41
gastric ulcers 72, 73, 87
gastrin 73
inhibition 42, 43
neuro-endocrine tumour production 86, 87
gastrinoma 25, 43
gastritis 21, 72, 73
atrophic 53, 55
chronic 87
gastro-oesophageal reflux 70–1
oesophageal cancer 87
gastrocolic reflex 41
gastroduodenal disorders 68, 69
gastroenteritis 51, 65, 74, 75
malnutrition 83
gastroferrin 20, 21, 52, 53
gastrograffin 101
gastrointestinal disease 55
gastrointestinal haemorrhage 31
emergency surgery 106, 107
gastrointestinal surgery 106–7
gastrointestinal tumours 86, 87
gastroplication 82, 83, 107
ghrelin 42, 43
body mass control 55
Giardia lamblia 23, 33, 74, 75
Gilbert’s syndrome 61
gingivae 12, 13
gliadin enteropathy 80, 81
globus hystericus 68, 69
glossopharyngeal nerve 14, 15, 17, 44, 45
glottis 17
glucagon 24, 25, 58, 59
inhibition 42, 43
neuro-endocrine tumour production 86, 87
glucagonoma 43
gluconeogenesis 54, 55, 58, 59
glucose 50, 51, 55, 65
blood levels 58
glucuronyl transferase 61
g-glutamyl transferase 96, 97
glutathione 61, 93
glyceryl trinitrate 12, 13, 88, 89
glycogen 58
glycogen granules 26, 27
glycogenolysis 54, 55, 58, 59
glycosaminoglycans 36, 37
goblet cells 22, 23
colonic 36, 37
depletion 79
Golgi apparatus 24, 25
gonorrhoea 89
growth assessment 54, 55
growth charts 55
growth hormone 58, 59
cyclic guanosine monophosphate (cGMP) 56, 57
guanyl cyclase 56, 57
guanylin 56, 57
guarding 45
Guillain–Barré syndrome 75
gut–brain peptides 42, 43
haem 61
haematemesis 19, 21, 23, 31
peptic ulcer 72, 73
haematochesia 31, 37, 39
haemochromatosis 48, 49, 94
hereditary 53
venesection 95
haemoglobin 61
haemolysis 29
haemolytic disorders 61
pigment stones 90, 91
haemolytic–uraemic syndrome 75
haemorrhoidal plexus 38, 39
haemorrhoidectomy 106
haemorrhoids 38, 39, 88, 89
prolapsed 66, 67
haustrae 36, 37
HCO3
-/Cl
-exchanger 56, 57
see also bicarbonate ions
heart rate control 45
heartburn 19, 70, 71
Helicobacter pylori 11, 21, 47, 72, 73
acid reflux 71
diagnosis 102, 103
eradication 72, 73
gastric cancer 86, 87
gastrointestinal lymphoma 86, 87
helminthicides 77
hepatic adenoma 86, 87
see also liver
hepatic artery 26, 27
hepatic encephalopathy 31, 61, 77
cirrhosis 94, 95
hepatic first pass test 104, 105
hepatic flexure 36, 37
Index 113
hepatic portal circulation 10, 11, 19
hepatic portal system 30, 31
hepatic portal vein 21, 23, 24, 25, 36, 37
hepatic sinusoids 30, 31
hepatic vein 26, 27, 30, 31
hepatitis 92, 93
drug-induced 92, 93
viral 27, 29, 92, 93, 94
hepatocellular carcinoma 95
hepatocytes 26, 27, 28, 29
canalicular secretion 61
hepatic metabolism 58, 59
reduction in cirrhosis 94
reserve capacity 59
vitamins D and K storage 53
hepatoma 86, 87
hepcidin 52, 53
hereditary haemochromatosis 53
hereditary non-polyposis colon cancer (HNPCC)
85
hernia repair 107
herpes, genital 39
herpes simplex virus (HSV) 13, 17, 89
HFE protein 52, 53
hiatus hernia 19, 21, 70–1
high density lipoprotein (HDL) 58, 59
Hirschsprung’s syndrome 45, 66, 67
histamine 20, 21
gastric acid secretion 72, 73
histamine H1 receptor antagonists 62, 63
histamine H2 receptor antagonists 43, 71, 72,
73
target specificity 104, 105
histamine H2 receptors 21
HMG CoA reductase 59
homeostasis 58
hookworms 33, 76, 77
5HT see serotonin
5HT receptor subtype targeting 104, 105
5HT1–5 receptors 41, 43, 45
fluid regulation 56, 57
5HT3
receptor antagonists 62, 63, 67
human immunodeficiency virus (HIV) 47
human papilloma virus (HPV) 39, 89
hydatid cyst 76, 77
hydration, intravenous 65, 75
hydrochloric acid (HCl) 20, 21, 42, 49, 72,
73
gastro-oesophageal reflux 70, 71
5-hydroxyindoleacetic acid (5-HIAA) 43, 87
hyperammonaemia 61
hyperbilirubinaemia 61
hypercalcaemia 67
hypercholesterolaemia 59
hypersensitivity 47
hypoalbuminaemia 59
hypoglossal nerve 16, 17
hypoglycaemia 58, 59
hypokalaemia 43, 57, 63
constipation 67
hyponatraemia 63
hypopharynx 17
hypothalamus 44, 45
fluid regulation 57
vomiting centre stimulus 62, 63
ileal brake 41
ileal disease 90, 91
ileitis, terminal 78, 79
ileocaecal valve 32, 33, 34, 35, 40, 41
ileoscopy 99
ileum 32, 33
absorption 48, 49
bypass 107
terminal inflammation 78, 79
vomiting 63
iliac fossa, right 35, 45
imaging 100, 101
immune regulation 35
immune system
mucosal 46, 47
zinc 53
immune tolerance 26, 27
donor-specific 107
immunocompromised patients 75
immunoglobulin(s) 14, 15
immunoglobulin A (IgA) 23, 105
secretory dimeric 46, 47
immunoglobulin M (IgM) 105
immunoproliferative small intestinal disease
(IPSID) 33, 87
immunosuppressive drugs 79
immunotherapy 105
incisors 12, 13
incontinence 39
faecal 65
overflow 67
indigestion 21
infections 11, 47, 76, 77
cirrhosis 95
diarrhoea 65
systemic 76, 77
inferior mesenteric artery 36, 37
inferior mesenteric vein 30, 31, 36, 37
inflammation 59
diarrhoea 64, 65
eyes 79
systemic 55
inflammatory bowel disease 11, 37, 47, 78,
79
diagnosis 99
diarrhoea 64, 65
environmental triggers 77, 78, 79
management 106
surgery 106, 107
see also Crohn’s disease; ulcerative colitis
inflammatory cells, liver 92, 93
inflammatory markers 96, 97
influenza 17
insulin 24, 25, 31
diabetes mellitus 91
inhibition 42, 43
liver function 58, 59
neuro-endocrine tumour production 86, 87
a4b7 integrin 46, 47
interdigestive migrating motor complex (IMMC)
40, 41
interferon a 93
interleukin 6 (IL-6) 59
intestinal abscesses 78, 79
intestinal dysmotility 65
intestinal failure 33
intestinal fistulae 78, 79
surgery 107
intestinal function augmenting/inhibiting 104,
105
intestinal housekeeper 41
intestinal lining 56, 57
intestinal lymphoma 47, 81, 86, 87
intestinal motility
altered 69
anticholinergic drugs 67
diarrhoea 65
reduction 57
regulation 44, 45, 48, 49
intestinal obstruction 72, 73
plain X-rays 100, 101
intestinal perforation 101
intestinal strictures 107
intestinal tract 10, 11
selective decontamination 104, 105
smooth muscle 40, 41
intoxication 17
intra-abdominal pressure 38, 39, 70, 71
intrinsic factor 20, 21, 48, 49
vitamin B12 binding 52, 53
intrinsic nerves 39
intussusception 101
investigations 11
iron
absorption 23
coeliac disease 80, 81
deficiency 13, 53, 81
digestion 52, 53
transport 48, 49
irritable bowel syndrome 37, 41, 45, 68, 69
5HT receptor inhibitors 43
post-infectious 75
isotopes, gamma-ray emitting 101
itching 29, 91
cirrhosis 95
hepatitis 92, 93
Ito cells see stellate cells, hepatic
jaundice 27, 96, 97
bilirubin accumulation 29
cirrhosis 94, 95
gallstones 90, 91
hepatitis 92, 93
pancreatic adenocarcinoma 86, 87
pancreatic disorders 25
pre-/post-hepatic 61
jaw-wiring 82, 83, 107
jejuno-ileal bypass 82, 83
jejunum 32, 33
aspiration 75
folic acid absorption 48, 49
k-ras oncogene 85
ketones 55, 58, 59
Krebs cycle 58, 59
Kupffer cells 26, 27, 31
kwashiorkor 82, 83
lactase 50, 51
deficiency 64, 65, 103
114 Index
lactase (cont.)
oral administration 105
selective deficiency 51
lacteals 22, 23
lactose 50, 51
breath test 102, 103
intolerance 75, 105
lactulose 61, 65
breath test 102, 103
lamina propria 22, 23
coeliac disease 81
lymphocytes 46, 47
lamivudine 93
laparoscopy 106, 107
laparotomy 106
emergency 106, 107
large intestine 10, 11
see also anal entries; caecum; colon; rectal
entries; rectum
larynx 17, 62, 63
laser treatment 99
laxatives 65, 66, 67, 68, 69
bowel purging 107
stimulant 67
leptin 42, 43, 54, 55, 82, 83
levator ani muscles 38, 39
lifestyle
change 68, 69, 71
history 96, 97
ligament of Treitz 23
lipase 25, 49, 50, 51
levels 96, 97
pancreatitis 90, 91
lipid antigens 47
lipids 50, 51
hepatic function 58, 59
lipopolysaccharide, bacterial 78, 79
lipoproteins 58, 59
liposuction 82, 83
lips 12, 13
liver 10, 11, 21, 26, 27
abscess 27, 35, 76, 77
architecture disruption 94–5
chemistry 96, 97
cirrhosis 11, 27, 31
conjugation 60, 61
CT scan 101
damage 11
detoxification 60, 61
enzymes 60, 61
excretion 60, 61
fatty 92, 93
function deterioration 93
hydatid cyst 76, 77
metabolic function 58–9
synthetic function 58–9
toxin removal 31
transjugular biopsy 100, 101
transplantation 93, 95, 107
see also hepatic entries
liver cancer 86, 87
metastatic 27, 87, 92, 93
liver disease
acute 92, 93
chronic 55, 87, 94–5
liver failure 27
fulminant 61
liver tumours 86, 87
loperamide 75
lymphadenopathy 97
lymphocytes 26, 27, 92, 93
intraepithelial 80, 81
lamina propria 46, 47
lymphoid tissue, appendix 34, 35
lymphoma
gastric 72, 73, 86, 87
intestinal 47, 81, 86, 87
lysosomes 26, 27
lysozyme 14, 15, 47
M-cells 46, 47
M2 muscarinic receptors 21
macronutrients 51, 54, 55
macrophages 46, 47
magnetic resonance angiography (MRA) 101
magnetic resonance cholangiopancreatography
(MRCP) 101
magnetic resonance imaging (MRI) 101
major histocompatibility complex (MHC) class II
81
malabsorption 23, 25, 51, 55
bacterial overgrowth 77
coeliac disease 81
diarrhoea 64, 65
gallstones 91
intestinal worms 33
pancreatic failure 49
pancreatitis 91
Mallory bodies 93
Mallory–Weiss tear 19, 63
malnutrition 82, 83
children 82, 83
pancreatic failure 49
mandible 12, 13
manometry 102, 103
marasmus 83
masseter muscle 12, 13
mast cells 46, 47
maxilla 12, 13
maxillary sinus 13
Meckel’s diverticulum 33
medulla oblongata 62, 63
megacolon 45, 67
toxic 101
melaena 21, 23, 31
peptic ulcer 72, 73
memory disturbance 31
MeninI gene 43
mesalazine 79
mesentery 35
metabolic acidosis/alkalosis 63
metaplasia 19
metastases
colorectal cancer 84, 85
liver cancer 27, 87, 92, 93
metoclopramide 41
metronidazole 17, 75, 77
micelle formation 48, 49
micronutrients 51, 54, 55, 61
microsomal oxidases 61
microsporidia 33, 75
microvilli 22, 23, 26, 27
absorption 48, 49
mid-arm circumference 54, 55
minerals, digestion 52, 53
mismatch repair genes 85
mitochondria 26, 27
mixed micelles 29, 33, 50, 51
gallstones 91
molar teeth 12, 13
monoclonal antibodies 101
motilin 42
motor cortex, sensory 44, 45
motor nerves, autonomic/voluntary 45
motor neuron disease 17
mouth 10, 11, 12, 13
epithelium 49
squamous cell carcinoma 13
see also oral entries
mucins 22, 23, 46, 47
mucosal addressin-cell adhesion molecule
(MAD-CAM) 46, 47
mucosal biopsy 81
mucosal homing 46, 47
mucosal immune system 11
mucus, anal passage 39
mucus layer, colonic 36, 37
multiorgan failure 51, 83
multiple endocrine neoplasia (MEN) syndromes
87
multiple endocrine neoplasia I (MEN-I) 43
multiple sclerosis 66, 67
multispecific organic anion transporter (MOAT)
28, 29
multisystem failure 90, 91
multisystem inflammatory disorders 91
mumps 15
muscularis mucosa 22, 23, 41
myasthenia gravis 17
mycobacterial infection 75, 77
see also tuberculosis
Mycobacterium tuberculosis 77
myenteric enteric nerve plexus 18, 19, 44, 45
myenteric nerves, congenital absence 45
myoglobin 60, 61
myosin 40, 41
Na
+
/H
+
exchanger 56, 57
Na
+
/K
+
ATPase pump 21, 50, 51, 56, 57
nasopharynx 17, 62, 63
nausea 45, 62, 63
gallstones 90, 91
hepatitis 92, 93
neostigmine 41
neuro-endocrine tumours 25, 86, 87
neuro-muscular coordination 48, 49
neuroglycopenia 58
neuropeptide Y 44, 45
neurotransmitters 44, 45, 54, 55
neutropenia 77
neutrophils 46, 47, 92, 93
night-blindness 53
nitric oxide 41, 44, 45
nitrogen balance 55
NOD2 gene 33, 78, 79
Index 115
non-steroidal anti-inflammatory drugs (NSAIDs)
21, 73
noradrenaline 44, 45
Norwalk virus 74, 75
nucleases 49
nutrition 10, 11, 54, 55
nutritional deficiency 23, 25, 29, 55
mouth disorders 13
small intestinal disorders 33
undernutrition 11
see also starvation
obesity 11, 82, 83
surgical management 107
octreotide 43, 87
odynophagia 19
oesophageal cancer 19
adenocarcinoma 19, 70, 71, 86, 87
squamous cell carcinoma 19, 87
oesophageal sphincter, lower 18, 19, 40, 41
manometry 102, 103
vomiting 62, 63
oesophageal varices 19
ruptured 99
oesophagectomy 71, 87
oesophagitis 19, 70, 71
oesophagogastroscopes 99
oesophagus 10, 11, 18, 19
disorders 68, 69
muscles 18, 19
nutcracker 41
obstruction 19, 99
venous drainage 30, 31
see also Mallory–Weiss tear
oligopeptides 50, 51
oligosaccharidases 50, 51
omentum, greater 36, 37
omeprazole 21, 71, 72, 73
opiates 65
opioids 57
oral contraceptive pill 86, 87
oral hygiene 13
see also mouth
oral mucosa 49
oral rehydration solution 51, 65, 75
oral tolerance 31, 47, 105
orbicularis muscle 12, 13
organic acid transport (OAT) protein 28, 29
organic acids 13
orlistat 82, 83, 105
oropharynx 17
osmotic gradients 56, 57
osteomalacia 53
osteomyelitis 77
osteoporosis 55
coeliac disease 80, 81
overnutrition 11
oxidizing enzymes 60, 61
oxyntic cells 20, 21
p53 tumour suppressor genes 85
pacemaker cells 40, 41
pain 96, 97
rectal with haemorrhoids 88, 89
sensation 44, 45
see also abdominal pain
palate, soft 12, 13
pan-proctocolectomy 79, 85
pancreas 10, 11, 21, 22, 23, 24, 25
CT scan 101
failure 49
hormones 42, 43
protease secretion 51
transplantation 107
pancreatic adenocarcinoma 25, 86, 87
pancreatic duct 24, 25, 28, 29
pancreatic enzymes 48, 49
autodigestion 91
measurement 103
supplements 65, 104, 105
pancreatic insufficiency 65, 103
pancreatic islets 24, 25
pancreatic juices 23, 49, 103
pancreatic lipase inhibitor 82, 83
pancreatic tumours 86, 87
pancreatitis 29, 90, 91
acute 25
chronic 25, 45, 51, 90, 91
diagnosis 101
peptic ulcer 72, 73
Paneth cells 22, 23, 34, 35, 46, 47
colonic 37
inclusions 53
ulcerative colitis 79
papillae, tongue 16, 17
paracetamol 61, 92, 93
paralytic ileus 41, 67
parasites 76, 77
parasympathetic nerves 38, 39, 44, 45
parenteral nutrition 55
parietal cells 20, 21
intrinsic factor synthesis 52, 53
receptors 73
parotid gland 14, 15
pepsin 49, 50, 51
pepsinogen 21, 50, 51
peptic ulceration 11, 21, 23, 72, 73
bleeding 99, 106, 107
treatment 72, 73
peptidases 49, 50, 51
peptide YY 42
peri-anal abscess 76, 77
peri-anal tumours 89
peri-anal warts 39, 89
periodontal membrane 12, 13
peripheral neuropathy 66, 67
peristalsis 18, 19, 40, 41
control 44, 45
defecation 38, 39
fluoroscopic real-time views 101
gastric 21
intestinal motility 49
reverse 62, 63
peritoneum 25
peritonitis 35, 73
spontaneous bacterial 31, 77, 95
peroxisomes 26, 27
Peyer’s patches 46, 47
pH measurement 103
pharmacotherapy 104, 105
pharyngitis 17
pharynx 16, 17, 18, 19
phosphate, saliva levels 14, 15
phospholipases 50, 51
phospholipids 50, 51
gallstones 91
pigment stones 90, 91
pinworm 89
plaque 13
plasma proteins 58, 59
plicae circulare 22, 23, 48, 49
pneumonia, aspiration 17, 19, 63
polypectomy 85, 99
polyps 99
dysplastic 84, 85
portal hypertension 19, 94, 95
Doppler ultrasound 101
portal triads 26, 27, 30, 31
portal vein 26, 27, 33
bacteraemia 76, 77
thrombosis 31
portosystemic shunting 30, 31, 94, 95
positron emission tomography (PET) 101
pouch of Douglas 39
premolar teeth 12, 13
prions 46, 47
pro-drugs 104, 105
pro-enzymes 49
probiotics 77, 79
proctalgia fugax 39, 68, 69, 89
proctitis 38, 39, 89
proctoscopy 39, 89
proelastase 51
prostaglandins 73
prostate gland 39
protease inhibitors 58, 59
proteinases 49
protein–energy malnutrition 83
proteins 50, 51
carrier 58, 59
plasma 95
trefoil 36, 37
prothrombin time 59, 93, 97
proton pump 20, 21
proton pump inhibitors 71, 72, 73
pruritis ani 39, 69, 89
pseudomembranous colitis 75
puborectalis muscles 38, 39
pulp 12, 13
pyloric sphincter 20, 21, 40, 41
hypertrophy 41
pylorus 20, 21
pyoderma gangrenosum 78, 79
pyruvate dehydrogenase 83
radioisotope scans 100, 101
radiology 11, 100, 101
interventional 100, 101
radiotherapy 101
colorectal cancer 85
ranitidine 21, 71
re-esterification 50, 51
rectal bleeding 99
colorectal cancer 85
haemorrhoids 88, 89
116 Index
rectal cancer 38, 39
rectal columns 38, 39
rectal examination, digital 39, 67, 96, 97
rectal inflammation 39
rectal pain, haemorrhoids 88, 89
rectum 36, 37, 38, 39
venous drainage 30, 31
red cells, megaloblastic 53
refeeding syndrome 82, 83
reflex motility 41
rehydration 65
Reiter’s syndrome 75
retching 63
retinoic acid 26, 27
rheumatic fever 17
ribavirin 93
rice-water stool 65
rickets 53
rotavirus 74, 75
Rotor syndrome 61
roundworms 33, 76, 77
sacral motor neurons 38, 39
sacral parasympathetic plexus 44, 45
saliva 14, 15, 17, 49
salivary glands 14, 15
stones 15
salivary nuclei 15
salivation 14, 15, 63
Salmonella 74, 75, 76, 77
Salmonella typhi 33
sarcoidosis 15
Schilling test 53, 102, 103
scurvy 53
secretin 23, 24, 25, 42
test 103
secretory component 46, 47
secretory granules 42, 43
sentinel pile (skin tag) 88, 89
serological tests 96, 97
serotonin 41, 42, 43
carcinoid tumour production 87
functional disorders 69
sexually transmitted diseases 39, 89
shape test 101
Shigella 47, 74, 75
short bowel syndrome 33
shunts, surgical 30, 31
sibutramine 82, 83
sigmoidoscopy 39, 79
flexible/rigid 99
sinusoids 26, 27
Sjögren’s syndrome 15
skin examination 96, 97
skin-fold thickness 54, 55, 83
skip lesions 78, 79
small intestine 10, 11
enzymes 48, 49
fluid flux 56, 57
neoplasia 33
obstruction 33
surface area 48, 49
transplantation 107
smell sense 17
smoking 73
colorectal cancer 84, 85
mouth squamous cell carcinoma 13
oesophageal carcinoma 19, 87
smooth muscle 40, 41
dysfunction 66, 67
relaxants 69
sodium 65
sodium glucose cotransporter (SGLT-1) 50,
51
sodium ion channels 56, 57
somatostatin 21, 24, 25, 42, 43, 57
diarrhoea control 65
injections 87
space of Disse 26, 27
sphincter of Oddi 28, 29
cutting 99
gallstones 91
manometry 103
spasms 68, 69
sphincterotomy 88, 89, 91, 99
sphincters
function regulation 44, 45
intestinal 40, 41
intestinal motility 49
spasm 41
see also anal sphincter; ileocaecal valve;
pyloric sphincter
spider naevi 95
spinal cord, neurological damage 66, 67
splanchnic nerves 44, 45
spleen 21
splenic flexure 36, 37
splenic vein 30, 31
splenomegaly 31, 94, 95
squamo-columnar junction 38, 39
squamous epithelium
anal 38, 39
mouth 12, 13, 49
oesophageal 18, 19
pharynx 17
tongue 16, 17
Staphylococcus aureus 74, 75
starches 50, 51
starvation 11, 51, 82, 83
statin drugs 59
steatohepatitis 83
steatorrhoea 25, 29, 64, 65
coeliac disease 80, 81
malabsorption 51
stellate cells, hepatic 26, 27
vitamin A storage 53
stem cells 22, 23, 81
stents 99, 101
steroid hormones 61
see also corticosteroids
stimulation tests 102, 103
stoma 106, 107
stomach 10, 11, 18, 19, 20, 21
absorption 48, 49
curvatures 20, 21
digestion 48, 49
see also gastric entries
stool softeners 89
stools
bulk 66, 67
examination 96, 97
hard 88, 89
storage vacuoles 26, 27
straining, defecation 67, 89
Streptococcus 17, 77
stricture dilatation 101
stroke 17
sublingual gland 14, 15
submandibular gland 14, 15
submucosal plexus 18, 19, 44, 45
substance P 44, 45
sucrase 50, 51
sucrose 50, 51
sugars 50, 51
superior mesenteric artery 25, 33, 35, 36, 37
superior mesenteric vein 23, 30, 31, 34, 35
suppositories 38, 39
swallowing 16, 17
control 45
difficulties 19, 41
neuro-muscular coordination 48, 49
oesophageal obstruction 19
sweating 63
sweeteners 65
sympathetic nerves 15, 44, 45
dysfunction 69
pancreas innervation 24, 25
syphilis 39, 89
gdT-cell receptors 47
T cells 46, 47
tachycardia 63
taeniae 36, 37, 40, 41
tapeworms 33, 76, 77
taste buds 16, 17
taste receptors 16, 17
taste sensation 44, 45
teeth 11, 12, 13, 49
acid damage with vomiting 63
decay 13
milk 12, 13
nerve supply 12, 13
permanent 12, 13
vascular supply 12, 13
temperature sensation 45
temporalis muscle 12, 13
tenesmus 39, 67, 89
thalamus 62, 63
thermogenesis, adaptive 55
thiamine deficiency 82, 83
thirst 57
thoracic duct 33
thorax 18, 19
thrombocytopenia 95
thymus and epithelial expressed chemokine
(TECK) 46, 47
thyrotoxicosis 65
tight junctions 22, 23, 26, 27
intestinal lining 56, 57
tissue transglutaminase (tTG) 81, 82
tobacco
chewing 13
see also smoking
tongue 16, 17
tonsillitis 17
Index 117
tonsils 12, 13, 17
immune function 46, 47
total parenteral nutrition (TPN) 55
touch sensation 45
toxic megacolon 101
toxins 77
shunting 31
tractus solitarius 16, 17, 45
transaminases 58, 59, 93, 96, 97
transcobalamin 52, 53
transcytosis 46, 47
transferrin 52, 53
transforming growth factor b (TGFb)43
transjugular intrahepatic portosystemic shunt
(TIPSS) 30, 31, 100, 101
transplant surgery 107
liver 93, 95, 107
transporter proteins 28, 29
genetic abnormalities 51
trefoil proteins 36, 37
tremor, flapping 95
tri-radiate fold 34, 35
tricyclic antidepressants 69
trigeminal nerve 12, 13, 17
triglycerides 49, 50, 51
Tropheryma whippelii 77
tropical sprue 33, 76, 77, 81
trypsin 50, 51
trypsinogen 50, 51
tuberculosis 35, 75, 77
ileocaecal 33
two-hit and multiple gene theory 85
typhoid fever 33, 75
ulcerative colitis 35, 37, 39, 78, 79
environmental triggers 77, 78, 79
proctitis 89
treatment 79
ulcers, apthous 13, 78, 79
ultrasound imaging 99, 100, 101
undernutrition see nutritional deficiency
uraemia 17
urea
excretion 55, 61
levels 97
urea cycle 60, 61
urease breath test 73
urine, urea excretion 61
vaccination 105
vagotomy 21
selective 72, 73
vagus nerve 17, 18, 19, 20, 21
dysfunction 69
foregut/midgut innervation 44, 45
pancreas innervation 24, 25
peptic ulcer surgery 72, 73
valves of Houston 38, 39
varices 30, 31
cirrhosis 95
see also oesophageal varices
vascular structure CT contrast imaging 101
vasoactive intestinal peptide (VIP) 42, 43, 57
neuro-endocrine tumour production 86,
87
vasoactive intestinal peptide (VIP)-secreting
tumours 43, 57, 64, 65
vasopressin 57
vegans 53
venesection 95
vermillion border of lips 12, 13
Verner–Morrison syndrome 87
very low density lipoprotein (VLDL) 58,
59
vestibulocochlear nerve 62, 63
Vibrio 74, 75
villi 22, 23, 48, 49
subtotal atrophy 81
VIPomas 43, 57, 64, 65
Virchow’s node 87
viruses 46, 47
visceral sensation 45
vitamin(s) 52, 53
vitamin A 52, 53
vitamin B-complex 52, 53
vitamin B deficiencies 13, 17
vitamin B12 33, 49
absorption 48, 49, 102, 103
coeliac disease 81
deficiency 53, 55
digestion 52, 53
terminal ileitis 79
vitamin C 52, 53
coeliac disease 81
vitamin D 52, 53
deficiency 55
malabsorption 81
vitamin E 52, 53
vitamin K 49
coagulation 58, 59
digestion 52, 53
volvulus 101
vomiting 19, 21, 62, 63
control 45
with diarrhoea 65
dysmotility 41
gastroenteritis 74, 75
pancreatitis 91
small intestine obstruction 33
treatment 62, 63
vomiting centre 35, 62, 63
warts, peri-anal 39, 89
wasting in cirrhosis 94, 95
water reabsorption 36, 37
weight control 55
weight loss 21, 23, 25, 29
cirrhosis 95
coeliac disease 81
small intestinal disorders 33
Werner Morrison syndrome 43
Wernicke’s encephalopathy 83
Whipple’s disease 76, 77, 81
Whipple’s operation 87
Wilson’s disease 29, 53, 61, 94
worms, intestinal 33, 76, 77
X-rays, plain 100, 101
xerostomia 15, 17
xylose excretion test 102, 103
Yersinia enterocolitica 33
Yersinia infection 76, 77
Z-line 18, 19
zinc 53
Zollinger–Ellison syndrome 21, 25, 43, 87
zymogen granules 24, 25

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