System at a Glance
The Gastrointestinal System at a Glance
The Gastrointestinal System
at a Glance
MBBCh (Wits), DPhil(Oxon), MRCP (UK)
Director, Centre for Gastroenterology
Royal Free and University College Medical School
University College London
Rowland Hill Street
London NW3 2PF
© 2004 by Blackwell Science Ltd
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First published 2004
Library of Congress Cataloging-in-Publication Data
The gastrointestinal system at a glance/Satish Keshav. — 1st ed.
p. ; cm.
1. Gastrointestinal system. 2. Gastrointestinal system — Diseases.
[DNLM: 1.–Digestive System. 2. Digestive System Diseases. WI 100
K42g 2003] I.–Title.
612.3¢2 — dc21
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
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Production Controller: Kate Charman
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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
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
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
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.
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
List of abbreviations
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
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
DMT divalent metal transporter
DNA deoxyribonucleic acid
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
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
IBD inﬂammatory bowel disease
IBS irritable bowel syndrome
IF intrinsic factor
IMMC interdigestive migrating motor complex
IPSID immunoproliferative small intestinal disease
K+ ionized potassium
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+ ionized sodium
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
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
10 Introduction and overview
Diseases and disorders
Digestion, absorption, nutrition
Hepatic portal vein
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.
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.
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
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
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
Floor of mouth
Soft palateOral cavity
Muscles of mastication
6 months to 3 years
2 incisors (cutting)
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
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.
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.
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
Side view of glands
fibres (VIIth, IXth nerves)
(via carotid plexus)
saliva (1–2 L/day)
• Ca2+, PO4–
• Lysozyme sIgA
Impermeable to H2O
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.
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
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
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.
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+,
-, 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.
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
Nucleus of the
Glossopharyngeal (IXth) and
vagus (Xth) nerves Motor
Hypoglossal (XIIth) nerve
(superior, middle and
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
Body of tongue
Gustatory nerve fibres travel via chorda
tympani branch of facial (VIIth cranial)
and glossopharyngeal (IXth cranial) nerves
(to nucleus of
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 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
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
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.
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
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
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
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
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 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
Motor and sensory ﬁbres mainly travel in the glossopharyngeal (IXth
cranial) and vagus (Xth cranial) nerves.
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
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
Striated muscleSmooth muscle
Axis of cardia
Axis of oesophagus
Lower oesophageal sphincter
Gastric veins drain into
hepatic portal system
Z-line gastro-oesophageal junction
Stratified non-cornified squamous epithelium
Submucosal nerve plexus
Myenetric nerve plexus
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
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
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.
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.
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
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
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
20 Structure and function
Reinforced circular muscle
Gastric gland Gastric pit
Few lamina propria
(G cell, produces
ECL cell (produces histamine)
Submucosal nerve plexus
Vagal nerve fibres
Gastric gland Canalicular
Basolateral receptors stimulating secretion
Blocked by H2
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.
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
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:
• longitudinal muscle layer;
• circular muscle layer;
• oblique muscle layer;
• 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,
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).
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).
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
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.
22 Structure and function
Acid + chyme
Goblet cellPaneth cell
Intestinal lumen Brush boarder
Lysozyme, phospholipase A2,
muscle Serosa or
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.
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
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
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.
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).
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).
24 Structure and function
Main pancreatic duct
Inferior mesenteric vein
Coeliac trunk and coeliac nerve plexus
Hepatic portal vein
Common bile duct
H2O, HCO3–, K+
Lipase and colipase
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.
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
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.
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:
• procarboxypeptidases A and B;
• phospholipase A;
• pancreatic lipase (and colipase);
• pancreatic amylase;
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).
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).
26 Structure and function
Right lobe Left lobe
(25% of flow)
(75% of flow)
Common bile duct
View from front
View of liver from inferior surface
Inferior vena cava
• 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
Hepatic artery branch
Portal vein branch
Hepatocytes Zone 1 of acinus
Portal vein blood carrying antigens, toxins, pathogens
Space of Disse
(loose connective tissue)
Mitochondria (energy, urea cycle) Fat droplet
Vesicles and lysosomes
Rough endoplasmic reticulum
Smooth endoplasmic reticulum
(detoxification, lipid metabolism)
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.
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
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
The walls of adjacent hepatocytes form bile canaliculi. Specialized
biliary epithelial cells line small bile ductules, larger ducts and the
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
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.
The liver’s complex functions have not yet been reproduced artiﬁcially.
• Regulating homeostasis of carbohydrate, lipid and amino acid
• 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
In addition, hepatocytes retain the capacity to proliferate, so that the
liver can regenerate dramatically after injury.
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
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).
28 Structure and function
1° bile salts
BAT = Bile acid transporter
MOAT = Multispecific organic
NTCP = Na+ Taurocholate
OAT = Organic acid transporter
2° bile acids
into portal vein
Left hepatic duct
Common bile duct
Ampulla of Vater
Sphincter of Oddi
2° bile salts
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.
Macroscopically, the intrahepatic bile ducts, common hepatic duct,
cystic duct, gallbladder and common bile duct constitute the biliary
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.
Each day, 600·mL of thick, mucoid, alkaline bile is produced. Its main
• primary bile acids: cholic and chenodeoxycholic acid;
• secondary bile acids: deoxycholic and lithocholic acid;
• conjugated drugs and endogenous waste products;
• electrolytes: Na+, Cl-, HCO3
– and trace metals, such as copper;
• secretory dimeric immunoglobulin A (sIgA) and other antibacterial
• 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
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
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
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
Inferior vena cava
Area of portosystemic anastomosis
and shunting (oesophageal varices)
and growth factors
Inferior mesenteric vein
Middle/inferior haemorrhoidal veins
Bacterial metabolism producing
amines, NH4–, false neuro-transmitters contributing to
Area of portosystemic
anastomosis and shunting
Leakage of fluid
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.
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.
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
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
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.
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
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
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
Hepatic portal system 31
32 Structure and function
Hepatic portal vein
2.5 m Meckel’s diverticulum
(May contain ectopic gastric mucosa
and develop peptic ulcer)
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.
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.
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).
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
Salmonella typhi, the cause of typhoid fever, gains entry into the
body through Peyer’s patches, which may become acutely inﬂamed and
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
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
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
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 Vermiform appendix
twists on normal
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
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
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.
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.
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
The thin-walled caecum is prone to perforation, for example, due to
intestinal obstruction or in severe colitis (toxic dilatation) (see Chapter
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
factors, e.g. trefoil
Goblet cellBasement membrane
The colon comprises most of the large intestine, is about 1.5 m long and
is not essential for life.
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:
• longitudinal muscle layer (taenia);
• circular muscle layer;
• muscularis mucosae;
• mucosal layer comprising the lamina propria and a simple columnar
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.
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
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
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
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
Constipation, diarrhoea and abdominal pain are frequently due to the
irritable bowel syndrome (IBS), without any evident organic pathol-ogy (see Chapter 29).
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
Reduced muscle bulk Old age and debility
Local nerve damage Following obstetric trauma,
Reduced rectal Colitis, proctitis, colorectal
reservoir function cancer, surgical removal
Levator ani and
Dentate line and
Axis of anusAxis of rectum
Sacral spinal motor neurons
Urge to defecate
Cause of incontinence
Internal anal sphincter
Sacral p a rasympathetic ef erent
Sacral spinal cord segment
Rectum dilates to
14 Rectum and anus
The rectum and anus comprise the most distal part of the gastrointestinal
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
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
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 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.
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.
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
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
Pain in the anus, without any discernable organic cause is proctalgia
fugax (see Chapter 29).
Rectum and anus 39
40 Integrated function
upper 3rd oesophagus
internal sphincterStriated external
moves rapidly circumferentially
Intestinal smooth muscle
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.
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.
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
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
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.
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’.
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.
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
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
Enteric motility 41
42 Integrated function
Vasoactive intestinal peptide (VIP)
Pancreatic polypeptide family
Peptide YY (PYY)
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
Duodenum and jejunum, released in response to fatty meal in
Ileum, proximal colon
ECL cells in proximal small intestine
Throughout intestine and pancreas
Small intestine, adipocytes
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
Æ carcinoid syndrome
Appetite control centres
in mid-brain and hypothalamus
Parietal cells Enterochromafin-like cells (ECL)
Mucosal blood vesselEnteric
b cells (insulin)
5HT carried in
tumour 5HT intact in
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.
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
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.
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
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
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
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.
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
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
ACh Acetylcholine (parasympathetic)
Substance P Pain sensation
CGRP Calcitonin gene-related peptide—
ending (sensory fibre)
Efferent and afferent
Sensory nerve ending
Vagus nerve (Xth)
Glossopharyngeal nerve (IXth)
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
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 control the lips, tongue, muscles of mastication, as well
as pelvic ﬂoor muscles and the external anal sphincter.
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.
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
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
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
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.
Many structures contribute to gastrointestinal defences. Innate defence
• The constant movement of intestinal contents, and their periodic
• 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
• 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
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
• 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.
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
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
Mucosal immune system 47
48 Integrated function
acidification and digestion
(Vitamin K, folic acid)
Bile acids, vitamin B12
Preferential uptake sites
Increased surface area
– plicae circulare (3x)
– villi (10x)
– microvilli (20x)
Total = 600x
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.
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.
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.
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
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
-, secreted in the bile and pancreatic juice.
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.
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.
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
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
Digestion and absorption 49
50 Integrated function
Na+Glucose Na+Na+ Na+
Free fatty acids
To regional lymphatics
and thoracic duct
(lymph channel)Lamina propria
To portal vein
Specific amino acid and peptide–
Dietary starch and glycogen
Dietary fat (lipids)
A, D, E, K
H2O; alkali; bile salts
Emulsion (fat droplets)
+ Bile salts
Carboxypeptidase A, B
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 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.
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
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
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.
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
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
Fe2+ + gastroferrin DMT expressionØ
Regulation of iron absorption
Folic acidVitamin B12 + IF
Stores vitamins A, K, B12
Increased expression of Ca2+-
binding protein, calbindin and
intestinal membrane calcium-
Ca2+ B12 + transcobalamin
Vitamin C Folic
A, D + essential
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.
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
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
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
Vitamin A (retinoic acid) is essential for many cellular functions and
is critically important for vision. Deﬁciency causes night-blindness and
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
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 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
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
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 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 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
• BMR (basal metabolic rate)
• Physical activity
• Special needs
e.g. deficiency state
• Weight, height, growth rate
• BMI, body density
• Mid-arm circumference
• Skin-fold thickness
• Waist–hip ratio
Basal metabolic rate
Genetic factors, weight,
fitness, stress, illness,
‘What we eat’ ‘What we are’ ‘What we do’
Nutrition and the gastro-intestinal system
Neuropeptide Y (NPY)
Inhibit fe ding
glycogenolysis, fat storage
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
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
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
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.
56 Integrated function
Food and drinks
1500 mL Intestinal juice
Reabsorbs 7000 mL
Lungs, sweat, kidneys
Obligatory losses 1000 mL
CFTR Cl– channel
Guanylin E. coli
Na+ K+ 2K+
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
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.
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
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
– 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
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).
– 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
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
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
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
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
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
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
II, VII, IX, X
Acute phase proteins,
Free fatty acids
source during fasting,
Pyruvate ´ Lactate
24 Hepatic metabolic and synthetic function
stores before a competition by eating a carbohydrate-rich meal
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.
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 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
CO2 + NH4+
(e.g. steroids, drugs and
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.
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
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.
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.
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 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, 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
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 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.
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
vomiting centre (VC)
Motion sickness, vertigo, diseases of
Intracranial pathology such as
meningitis, raised intracranial pressure,
Strong emotions, ‘disgusting’ sights,
Drugs and chemicals, e.g. opiates,
Drugs that irritate the intestinal tract,
e.g. chemotherapeutic agents for
Gastrointestinal infections, food
poisoning, appendicitis, cholecystitis
Intestinal obstruction, and distension
Systemic illness: diabetic ketoacidosis,
Bulimia, voluntary emesis
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
Vagal and autonomic inputs on
VC, some emetogenic toxins
directly stimulate VC
Vagal and autonomic inputs on
Hormonal changes including
secretion of human chorionic
Various pathways, including
vagal afferents stimulated via
the oropharynx (gag reflex)
• Drugs, metabolic
Vomiting centre efferents
and vagus nerves
Soft palate closes
Glottis seals off
larynx and trachea
Causes of vomiting
Neurotransmitters and drugs
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.
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
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
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
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
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.
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
Lactase deficiency, malabsorptionAutonomic neuropathy
Diarrhoea caused by
Rapid food transit
in lumen, e.g. lactose
increased stool volume
≠white cells and blood
eg VIP or serotonin
Bacterial toxin inducing secretion,
Cl– + H2O
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 &
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.
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.
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
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
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
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
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
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.
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).
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
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.
66 Disorders and diseases
Stool bulking agents
Fibre supplements (e.g. bran)
Ispaghula husk, sterculia,
(e.g. lactulose, lactitol)
Liquid paraffin, arachis
Senna, bisacodyl, dantron,
Specific receptor antagonists
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
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
3 x per day
1 x per 3 days
Normal stool volume
• Incomplete evacuation
• Reduced frequency or volume
Inhibition by cortical centres
(e.g. move to strange environment)
and food intake
(e.g. stress) Spinal
Enteric nerves and
smooth muscle dysfunction
e.g. idiopathic slow transit,
e.g. hernia, tumour, stricture
HaemorrhoidsLocal pain e.g. fissure, anal ulcer
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
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
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 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 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.
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
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
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.
Perceived and actual problems must be distinguished. A careful history
of dietary habits and any drugs that might cause constipation should be
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.
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
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.
68 Disorders and diseases
e.g. Globus, rumination
e.g. Functional dyspepsia
e.g. Gallbladder disorders
Sphincter of Oddi dysfunction
e.g. Proctalgia fugax
e.g. Irritable bowel syndrome
Functional abdominal bloating
enteric nerve function
Inhibitory descending fibres
• Diet alteration
• Correct fibre intake
• Correct fluid intake
e.g. low dose
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.
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.
Discrete syndromes, classiﬁed according to the part of the gastrointesti-nal system affected, have been formally deﬁned to assist diagnosis,
treatment and research.
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.
Here symptoms mimic peptic ulcer disease, gastritis and other serious
disorders, without any evident pathology. The commonest syndrome is
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
• passage of mucus;
• abdominal bloating.
The symptoms suggest biliary disease without any evidence of pathol-ogy. In some cases spasm of the sphincter of Oddi can be demonstrated.
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
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
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.
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.
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
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.
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.
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
of sphincter (loss of
angle, no diaphrag-matic contraction)
Axis of oesophagus
Lower oesophageal sphincter
Axis of gastro-oesophegeal junction
Abrupt Z-line transition
Acid in contact with
causes pain and
heartburn and possibly
Oesophageal squamous lining
(gastric or intestinal type)
lining lower oesophagus
Barrett’s oesophagusDiaphragmatic hiatus hernia
Sliding hiatus hernia Rolling hiatus
• increased abdominal pressure
• lying supine
• eating meals before bed
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
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
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.
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.
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
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).
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
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
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
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:
– gastric cancer
– gastric lymphoma
• Most remain well
Ulcer treatment in evolution
• Antacids – ineffective
• H2 receptor antagonists
• Proton pump inhibitors
+ 2 antibiotics
to eradicate H. pylori
31 Peptic ulcer and Helicobacter pylori
• 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
• 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
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
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
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
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.
• 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
• 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
Diarrhoea ± blood
Afferent nerve signals
Salmonella, E. coli
Live bacteria, viruses,
aureus and Bacillus
Preformed toxin in food
abruptly causes vomiting
Toxin preformed and
synthesized in the gut
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
Food poisoning, followed by
and haemorrhage, and
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.
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.
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
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.
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).
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
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.
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.
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).
Blood and leucocytes in stool distinguish inﬂammatory diarrhoea from
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 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
Use to treat infection, or selectively
Cytomegalovirus (CMV) colitis
>500 species, mainly anaerobes
(may resemble Crohn’s
‘Normal’ commensal bacteria
administered orally or rectally
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.
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.
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.
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.
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.
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.
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
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,
Genetic predisposition Disease
Ulcerative colitis extends
proximally for variable distance
Terminal ileal Crohn’s
(5% of UC)
Paneth cell metaplasia
* Inflammation confined to mucosa
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
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
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.
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’.
The mucosa is ulcerated and there is an inﬂammatory reaction in the
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
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
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
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
Longstanding UC predisposes to colon cancer and primary sclerosing
cholangitis (PSC) occurs in about 5% of patients with UC.
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.
• 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
Osteoporosis Weight loss
Q Q Q P P S Q Q
Wheat, rye, barley
Latent disease (+ve tTG
antibody, no pathology)
TNFa, interferon g
*Q = glutamine
cell, e.g. dendritic cell
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
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
The concentration of dietary gluten is highest proximally in the intes-tine and therefore coeliac disease affects the duodenum and proximal
jejunum most severely.
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
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
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.
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
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
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.
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
Truncal obesity General obesity
Surgical therapy for obesity
BMI, BMR, age, morbidity and mortality
Medical therapy for obesity
and weight maintenance
• Low-fat diet
• Calorie-restricted diet
• Regular exercise BMR≠
• Appetite suppressants:
5HT re-uptake inhibitors
• Hormone-based treatments
• Intestinal lipase inhibitor
• Reduced serum protein
• Muscle wasting
• Reduced immunity
• Listless, tired
• Weight loss
• ØSkin fold thickness
• ØMuscle strength
Gradual refeeding or
CO2 + H2O
(especially in children)
Morbidity and mortalityBasal metabolic rate (BMR)
Body mass index (BMI)
Age (years)BMI (kg/m2)
20 30 40
20 30 40
36 Obesity and malnutrition
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).
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.
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
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.
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
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
Obesity and malnutrition 83
84 Disorders and diseases
Multi-step cancer causation
Altered bowel habit,
Weight loss, anaemia
Dukes’ D <5% survival
Dukes’ A 85–100% survival
Dukes’ C 30–60% survival
Dukes’ B 50–80% survival
• high fat
• high meat
Prevention by NSAIDS,
high carbohydrate diet
Chronic colitis Inherited predisposition
Focus of high-grade dysplasia
Early invasion through
e.g. k-ras, p53
Invasion of lymphatics and blood vessels
e.g. APC in 80%
mutations in APC
or HNPCC genes
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.
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
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.
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.
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.
• 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
• 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
Colon and rectal cancer 85
86 Disorders and diseases
Cirrhosis, e.g. hepatitis B
Lymphoproliferation and lymphoma
Tail of pancreas
Lymphoproliferation Æ Lymphoma
Gastrin, insulin, glucagon, VIP, 5HT
Head of pancreas
5HT enters hepatic vein
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 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.
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
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.
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
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 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
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
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
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
Peri-anal abscess and fistula
Acute thrombosis in
superficial vein Æ External pile
1st degree internal
haemorrhoid 2nd and 3rd degree 4th degree
Occasional bright red
bleeding, leakage, pruritis
2° Spontaneous reduction
3° Manual reduction
Deep anal gland
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
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
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
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
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.
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).
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
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
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 is a stabbing pain in the rectum, often after defecation,
and usually has no discernable organic cause and is hard to treat (see
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.
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
or ascending cholangitis
Common bile duct stone
Causes of pancreatitis
• Abnormal pancreatic secretion,
e.g. cystic fibrosis
• Alcohol, drugs
Chronic damage to:Release of enzymes,
e.g. amylase, lipase,
Lung damage Tissue damage
Pa i n
+ Pancreatic insufficiency
Pancreatic islets Diabetes mellitus
Acute pancreatitis = severe multisystem failure
Common duct stone
Nidus, e.g. bacteria
= Cholesterol stone
Cystic duct stone causes
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.
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
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.
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
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.
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
Cholecystitis, cholangitis and pancreatitis are serious multisystem
inﬂammatory disorders. Treatment includes supportive care, analgesia
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).
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.
Abdominal pain, anorexia, vomiting and fever are the main symptoms.
Multisystem failure, with hypotension, hypoxia and widespread
intravascular haemorrhage, occurs in severe cases.
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.
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.
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
Severe liver failure Hepatitis
Abnormal blood tests
Pain, nausea, anorexia
Hypoalbuminaemia and coagulopathy
Oedema and ascities
Raised levels of liver enzymes
Hepatitis A, B, E viruses
e.g. Epstein–Barr virus
Causes Clinical effects
Swelling and stretching of capsule
Reduced bile excretion
Reduced protein production
acute liver damage
Whole organ Cellular
Drugs and toxins
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.
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
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).
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
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.
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
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
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 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
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.
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
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.
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
leakage of fluid
• Chronic viral hepatitis
(B & C)
• Wilson’s disease
Hepatic veinNormal cords of
Loss of body hair
Normal blood flow portal vein
and adequate number
Possible fatigue, lethargy, weight loss
Decompensation caused by
• Slow deterioration due to
• Electrolyte disturbance
• Variceal haemorrhage
• Development of hepatocellular
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
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
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.
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
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.
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
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
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).
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
g glutamyl transferase
Digital rectal examination
Stool microscopy and culture
• Rectal bleeding
• Altered bowel habit
• Normal = 18–25
• Overweight = 25–30
• Obese = 30–40
• Morbid obesity >40
• Underweight <18
Electron microscope = virus
+ Occult blood test
Liver size and texture
Pain or tenderness
Any abnormal masses
Urea and electrolytes
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
• 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
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
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
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.
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
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
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
• 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
Side-viewing endoscope for ERCP
Charge-coupled device camera
• Suction/biopsy channel
• Air/water insufflation channel
Controls for turning scope tip
To power source
Clear plastic barrel
Pill dissolving in stomach
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
Flexible upper gastrointestinal endoscopy
The oesophagus, stomach and proximal duodenum are routinely
visualized and the distal duodenum and jejunum may occasionally be
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.
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.
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.
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
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.
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
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.
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.
There is a small risk of colonic perforation, and of bleeding following
polypectomy. Sedation and analgesia may also cause respiratory
Endoscopic retrograde cholangiopancreatography and
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.
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
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.
100 Diagnosis and treatment
Transjugular liver biopsy
Barium meal and
Barium swallow Pharynx, oesophagus
Barium meal Stomach, duodenum
Barium meal and follow Duodenum, jejunum, ileum
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
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 (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.
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.
Radiological guidance with USS, CT or MRI, enables invasive proce-dures, such as a liver biopsy, to be performed more safely and with
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
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
pH monitoring, Bernstein test
24-hour pH monitor
I.M. loading dose
saturates body stores
Oral test dose (labelled)
Oral test dose + IF
= dietary deficiency
= IF deficiency
= terminal ileal
Vitamin B12 13C-urea
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.
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.
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
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.
This test investigates the various steps in the absorption of vitamin B12
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
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
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 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
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.
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.
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
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
e.g. botulinum toxin
Single effect/cell target,
One substance (5HT),
many receptor subtypes
HCl output reduced
e.g. alcohol, NSAIDS
Enzyme and food supplements
neuronSmooth muscle cell
Enema—local action or absorbed
Rectal absorption, e.g. diazepam
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.
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
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
Food as therapy
Intolerance to various food elements occurs, for example, in coeliac
disease, lactose intolerance, cow’s milk protein, peanut and other food
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, 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.
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
106 Diagnosis and treatment
Light source and air insufflator
Incision and drainage
48 Gastrointestinal surgery
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.
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.
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.
• 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.
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
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
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.
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
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
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
anorectal 88, 89
anus 38, 39
crypt 78, 79
intestinal 78, 79
liver 27, 35, 76, 77
peri-anal 76, 77
absorption 48, 49
tests 102, 103
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)
acrodermatitis enteropathica 53
actin 40, 41
acute phase response, hepatic 59
adenomatous polyposis (apc) gene 84, 85
cyclic adenosine monophosphate (cAMP) 56,
adenylyl cyclase 65
adhesins 74, 75, 77
air insufﬂation 101, 106
albumin 58, 59, 61
serum levels 96, 97
alcohol 27, 49, 61, 73
cirrhosis 94, 95
consumption 96, 97
hepatitis 92, 93
oesophageal squamous cell carcinoma
pancreatitis 90, 91
alcohol dehydrogenase 61
alkali tide 21
alkaline phosphatase 93, 96, 97
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
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
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
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
antacids 72, 73
antibiotics 72, 73, 75, 79
bacterial overgrowth 77
selective decontamination 104, 105
antibodies to Saccharomyces cerevisiae (ASCA)
anticholinergic drugs 67, 72, 73
antidiarrhoeals 65, 68, 69
antiendomysial antibody 81
antiepileptic drugs 61
antigen presentation 46, 47
antigen presenting cells 81
antimicrobial environment of duodenum 23
antimitochondrial antibodies 95
antineutrophil cytoplasmic antibodies (ANCA)
antrum 20, 21
anus 38, 39
abscess 38, 39
ﬁstula 38, 39
innervation 44, 45
obstruction 66, 67
apc gene 84, 85
apolipoprotein B genetic deﬁciency 51
apolipoproteins 50, 51, 58, 59
apoptosis 81, 92, 93
laparoscopic 106, 107
appendicitis 35, 45
appendix 34, 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
atrophic gastritis 53, 55
autoantibodies to liver antigens 93
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
B cells 46, 47
b cells, pancreatic 24, 25
Bacillus cereus 74, 75
commensal 35, 37, 47, 76, 77
vitamin K production 48, 49
diet interactions 69
overgrowth 33, 76, 77, 102, 103
toxins 57, 64, 65
enema 85, 101
meal and follow-through 79
plain X-ray with luminal contrast 100, 101
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
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
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
biliary syndromes 68, 69
biliary system 11, 28, 29
endoscopy 98, 99
bilirubin 26, 27, 60, 61, 94, 95
excretion 28, 29
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
neurological damage 66, 67
sensory motor cortex 44, 45
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,
C-urease breath test 102, 103
caecal volvulus 35
caecum 34, 35
calbindin 53, 53
calcitonin gene-related peptide 44, 45
calcium 53, 53
coeliac disease 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
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
ascending 76, 90, 91, 93
primary sclerosing 78, 79, 87
laparoscopic 106, 107
cholecystitis 29, 90, 91
cholecystokinin 23, 24, 25, 28, 29
gastrin inhibition 42, 43
intestinal motility 45
secretin test 103
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
cirrhosis 11, 27, 94–5
liver 31, 87, 92, 93
primary biliary 29, 53, 94
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
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
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
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
colorectal cancer 11, 35, 37, 84, 85, 87
carcinoma in situ 84, 85
colectomy 106, 107
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
colorectal cancer 84, 85
enteric and autonomic nerve dysfunction
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
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
small intestine 81
vitamin B12 deﬁciency 53
crypt abscesses 78, 79
Cryptosporidia 33, 75
colonic 36, 37
crypts of Lieberkühn 22, 23
cystic duct 28, 29
cystic ﬁbrosis 25
cystic ﬁbrosis transmembrane receptor (CFTR)
24, 25, 56, 57
pancreatitis 90, 91
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
dehydration 57, 96, 97
dendritic cells 26, 27, 46, 47
dental caries 13
dental hygiene 13
dentate line 38, 39
dentine 12, 13
herpetiformis 80, 81
diabetes mellitus 21, 25, 45
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
endemic 74, 75
enteric and autonomic nerve dysfunction 45
epidemic 74, 75
gastroenteritis 74, 75
inﬂammatory 64, 65
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
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
disaccharidases, brush-border 49
diseases/disorders of gastrointestinal system 10,
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
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
dysentery 37, 65, 74, 75
dysmotility 19, 41
non-ulcer 68, 69
dysphagia 19, 41
Ecchinococcus 76, 77
electrolyte balance 56, 57
embolization of vessels 101
emulsiﬁcation 48, 49
enamel 12, 13
bovine spongiform 47
hepatic 31, 61, 77
cirrhosis 94, 95
endocrine cells 10, 11
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
enterokinase 23, 51
enterotoxins 74, 75
colorectal cancer 84, 85
gastric cancer 86, 87
enzymes 24, 25
antibacterial 14, 15
digestive 48, 49
liver 60, 61
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
Escherichia coli 74, 75
heat stable toxin (STa) 56, 57
Eustachian tube 17
tests 102, 103
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)
fat cells see stellate cells, hepatic
fat droplets 26, 27
fats 50, 51
energy dense 55
see also steatorrhoea
fatty acids 55
essential 52, 53
fauces 12, 13
gastroenteritis 74, 75
ﬁbreoptic instruments 98
ﬁrst-pass metabolism 31
anal 38, 39
anorectal 88, 89
intestinal 78, 79, 107
ﬂuid balance 56, 57
ﬂuid intake 66, 67, 68, 69
ﬂuoride, drinking water 13
ﬂushing 42, 43
folic acid 33, 48, 49
coeliac disease 81
digestion 52, 53
allergies 47, 105
antigens 31, 47
intake 54, 55
solubilization 48, 49
as therapy 104, 105
food poisoning 74, 75
fructose 50, 51
functional bowel disorders 68, 69
functional tests 102, 103
fundus of stomach 20, 21
G cells 20, 21, 73
G-protein coupled receptors 16, 17
gallbladder 26, 27, 28, 29
gallstones 29, 90, 91
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
inhibition 42, 43
neuro-endocrine tumour production 86, 87
gastrinoma 25, 43
gastritis 21, 72, 73
atrophic 53, 55
gastro-oesophageal reﬂux 70–1
oesophageal cancer 87
gastrocolic reﬂex 41
gastroduodenal disorders 68, 69
gastroenteritis 51, 65, 74, 75
gastroferrin 20, 21, 52, 53
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
glucagon 24, 25, 58, 59
inhibition 42, 43
neuro-endocrine tumour production 86, 87
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 granules 26, 27
glycogenolysis 54, 55, 58, 59
glycosaminoglycans 36, 37
goblet cells 22, 23
colonic 36, 37
Golgi apparatus 24, 25
growth assessment 54, 55
growth charts 55
growth hormone 58, 59
cyclic guanosine monophosphate (cGMP) 56, 57
guanyl cyclase 56, 57
guanylin 56, 57
Guillain–Barré syndrome 75
gut–brain peptides 42, 43
haematemesis 19, 21, 23, 31
peptic ulcer 72, 73
haematochesia 31, 37, 39
haemochromatosis 48, 49, 94
haemolytic disorders 61
pigment stones 90, 91
haemolytic–uraemic syndrome 75
haemorrhoidal plexus 38, 39
haemorrhoids 38, 39, 88, 89
prolapsed 66, 67
haustrae 36, 37
-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
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
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)
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,
target speciﬁcity 104, 105
histamine H2 receptors 21
HMG CoA reductase 59
hookworms 33, 76, 77
5HT see serotonin
5HT receptor subtype targeting 104, 105
5HT1–5 receptors 41, 43, 45
ﬂuid regulation 56, 57
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,
gastro-oesophageal reﬂux 70, 71
5-hydroxyindoleacetic acid (5-HIAA) 43, 87
hypoglossal nerve 16, 17
hypoglycaemia 58, 59
hypokalaemia 43, 57, 63
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
ileum 32, 33
absorption 48, 49
terminal inﬂammation 78, 79
iliac fossa, right 35, 45
imaging 100, 101
immune regulation 35
mucosal 46, 47
immune tolerance 26, 27
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
incisors 12, 13
infections 11, 47, 76, 77
systemic 76, 77
inferior mesenteric artery 36, 37
inferior mesenteric vein 30, 31, 36, 37
diarrhoea 64, 65
inﬂammatory bowel disease 11, 37, 47, 78,
diarrhoea 64, 65
environmental triggers 77, 78, 79
surgery 106, 107
see also Crohn’s disease; ulcerative colitis
inﬂammatory cells, liver 92, 93
inﬂammatory markers 96, 97
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)
interferon a 93
interleukin 6 (IL-6) 59
intestinal abscesses 78, 79
intestinal dysmotility 65
intestinal failure 33
intestinal ﬁstulae 78, 79
intestinal function augmenting/inhibiting 104,
intestinal housekeeper 41
intestinal lining 56, 57
intestinal lymphoma 47, 81, 86, 87
anticholinergic drugs 67
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
intra-abdominal pressure 38, 39, 70, 71
intrinsic factor 20, 21, 48, 49
vitamin B12 binding 52, 53
intrinsic nerves 39
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
isotopes, gamma-ray emitting 101
itching 29, 91
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
jaw-wiring 82, 83, 107
jejuno-ileal bypass 82, 83
jejunum 32, 33
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
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
laparoscopy 106, 107
emergency 106, 107
large intestine 10, 11
see also anal entries; caecum; colon; rectal
larynx 17, 62, 63
laser treatment 99
laxatives 65, 66, 67, 68, 69
bowel purging 107
leptin 42, 43, 54, 55, 82, 83
levator ani muscles 38, 39
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
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
acute 92, 93
chronic 55, 87, 94–5
liver failure 27
liver tumours 86, 87
lymphocytes 26, 27, 92, 93
intraepithelial 80, 81
lamina propria 46, 47
lymphoid tissue, appendix 34, 35
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
magnetic resonance imaging (MRI) 101
major histocompatibility complex (MHC) class II
malabsorption 23, 25, 51, 55
bacterial overgrowth 77
coeliac disease 81
diarrhoea 64, 65
intestinal worms 33
pancreatic failure 49
Mallory bodies 93
Mallory–Weiss tear 19, 63
malnutrition 82, 83
children 82, 83
pancreatic failure 49
mandible 12, 13
manometry 102, 103
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
melaena 21, 23, 31
peptic ulcer 72, 73
memory disturbance 31
MeninI gene 43
metabolic acidosis/alkalosis 63
colorectal cancer 84, 85
liver cancer 27, 87, 92, 93
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
molar teeth 12, 13
monoclonal antibodies 101
motor cortex, sensory 44, 45
motor nerves, autonomic/voluntary 45
motor neuron disease 17
mouth 10, 11, 12, 13
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
multiple endocrine neoplasia I (MEN-I) 43
multiple sclerosis 66, 67
multispeciﬁc organic anion transporter (MOAT)
multisystem failure 90, 91
multisystem inﬂammatory disorders 91
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
exchanger 56, 57
ATPase pump 21, 50, 51, 56, 57
nasopharynx 17, 62, 63
nausea 45, 62, 63
gallstones 90, 91
hepatitis 92, 93
neuro-endocrine tumours 25, 86, 87
neuro-muscular coordination 48, 49
neuropeptide Y 44, 45
neurotransmitters 44, 45, 54, 55
neutrophils 46, 47, 92, 93
nitric oxide 41, 44, 45
nitrogen balance 55
NOD2 gene 33, 78, 79
non-steroidal anti-inﬂammatory drugs (NSAIDs)
noradrenaline 44, 45
Norwalk virus 74, 75
nutrition 10, 11, 54, 55
nutritional deﬁciency 23, 25, 29, 55
mouth disorders 13
small intestinal disorders 33
see also starvation
obesity 11, 82, 83
surgical management 107
octreotide 43, 87
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
oesophagectomy 71, 87
oesophagitis 19, 70, 71
oesophagus 10, 11, 18, 19
disorders 68, 69
muscles 18, 19
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
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
osmotic gradients 56, 57
coeliac disease 80, 81
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
hormones 42, 43
protease secretion 51
pancreatic adenocarcinoma 25, 86, 87
pancreatic duct 24, 25, 28, 29
pancreatic enzymes 48, 49
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
chronic 25, 45, 51, 90, 91
peptic ulcer 72, 73
Paneth cells 22, 23, 34, 35, 46, 47
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
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
intestinal motility 49
reverse 62, 63
peritonitis 35, 73
spontaneous bacterial 31, 77, 95
peroxisomes 26, 27
Peyer’s patches 46, 47
pH measurement 103
pharmacotherapy 104, 105
pharynx 16, 17, 18, 19
phosphate, saliva levels 14, 15
phospholipases 50, 51
phospholipids 50, 51
pigment stones 90, 91
plasma proteins 58, 59
plicae circulare 22, 23, 48, 49
pneumonia, aspiration 17, 19, 63
polypectomy 85, 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
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
probiotics 77, 79
proctalgia fugax 39, 68, 69, 89
proctitis 38, 39, 89
proctoscopy 39, 89
prostate gland 39
protease inhibitors 58, 59
protein–energy malnutrition 83
proteins 50, 51
carrier 58, 59
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
pylorus 20, 21
pyoderma gangrenosum 78, 79
pyruvate dehydrogenase 83
radioisotope scans 100, 101
radiology 11, 100, 101
interventional 100, 101
colorectal cancer 85
ranitidine 21, 71
re-esteriﬁcation 50, 51
rectal bleeding 99
colorectal cancer 85
haemorrhoids 88, 89
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
Reiter’s syndrome 75
retinoic acid 26, 27
rheumatic fever 17
rice-water stool 65
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
salivary nuclei 15
salivation 14, 15, 63
Salmonella 74, 75, 76, 77
Salmonella typhi 33
Schilling test 53, 102, 103
secretin 23, 24, 25, 42
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
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
surface area 48, 49
smell sense 17
colorectal cancer 84, 85
mouth squamous cell carcinoma 13
oesophageal carcinoma 19, 87
smooth muscle 40, 41
dysfunction 66, 67
sodium glucose cotransporter (SGLT-1) 50,
sodium ion channels 56, 57
somatostatin 21, 24, 25, 42, 43, 57
diarrhoea control 65
space of Disse 26, 27
sphincter of Oddi 28, 29
spasms 68, 69
sphincterotomy 88, 89, 91, 99
function regulation 44, 45
intestinal 40, 41
intestinal motility 49
see also anal sphincter; ileocaecal valve;
spider naevi 95
spinal cord, neurological damage 66, 67
splanchnic nerves 44, 45
splenic ﬂexure 36, 37
splenic vein 30, 31
splenomegaly 31, 94, 95
squamo-columnar junction 38, 39
anal 38, 39
mouth 12, 13, 49
oesophageal 18, 19
tongue 16, 17
Staphylococcus aureus 74, 75
starches 50, 51
starvation 11, 51, 82, 83
statin drugs 59
steatorrhoea 25, 29, 64, 65
coeliac disease 80, 81
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
bulk 66, 67
examination 96, 97
hard 88, 89
storage vacuoles 26, 27
straining, defecation 67, 89
Streptococcus 17, 77
stricture dilatation 101
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
difﬁculties 19, 41
neuro-muscular coordination 48, 49
oesophageal obstruction 19
sympathetic nerves 15, 44, 45
pancreas innervation 24, 25
syphilis 39, 89
gdT-cell receptors 47
T cells 46, 47
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
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
thoracic duct 33
thorax 18, 19
thymus and epithelial expressed chemokine
(TECK) 46, 47
tight junctions 22, 23, 26, 27
intestinal lining 56, 57
tissue transglutaminase (tTG) 81, 82
see also smoking
tongue 16, 17
tonsils 12, 13, 17
immune function 46, 47
total parenteral nutrition (TPN) 55
touch sensation 45
toxic megacolon 101
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
two-hit and multiple gene theory 85
typhoid fever 33, 75
ulcerative colitis 35, 37, 39, 78, 79
environmental triggers 77, 78, 79
ulcers, apthous 13, 78, 79
ultrasound imaging 99, 100, 101
undernutrition see nutritional deﬁciency
excretion 55, 61
urea cycle 60, 61
urease breath test 73
urine, urea excretion 61
selective 72, 73
vagus nerve 17, 18, 19, 20, 21
foregut/midgut innervation 44, 45
pancreas innervation 24, 25
peptic ulcer surgery 72, 73
valves of Houston 38, 39
varices 30, 31
see also oesophageal varices
vascular structure CT contrast imaging 101
vasoactive intestinal peptide (VIP) 42, 43, 57
neuro-endocrine tumour production 86,
vasoactive intestinal peptide (VIP)-secreting
tumours 43, 57, 64, 65
vermillion border of lips 12, 13
Verner–Morrison syndrome 87
very low density lipoprotein (VLDL) 58,
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
vitamin E 52, 53
vitamin K 49
coagulation 58, 59
digestion 52, 53
vomiting 19, 21, 62, 63
with diarrhoea 65
gastroenteritis 74, 75
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
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
Zollinger–Ellison syndrome 21, 25, 43, 87
zymogen granules 24, 25