23 JAUNDICE AND EVALUATION OF LIVER FUNCTION
Harrison’s Manual of Medicine
JAUNDICE AND EVALUATION OF LIVER FUNCTION
Blood Tests of Liver Function
Hepatobiliary Imaging Procedures
DEFINITION Yellow skin pigmentation caused by elevation in serum bilirubin level (also termed icterus); often more easily discernible in sclerae. Scleral icterus become clinically evident at a serum bilirubin level of ³51 µmol/ L (³3 mg/dL); yellow skin discoloration also occurs with elevated serum carotene levels but without pigmentation of the sclerae.
BILIRUBIN METABOLISM Bilirubin is the major breakdown product of hemoglobin released from senescent erythrocytes. Initially it is bound to albumin, transported into the liver, conjugated to a water-soluble form (glucuronide) by glucuronosyl transferase, excreted into the bile, and converted to urobilinogen in the colon. Urobilinogen is mostly excreted in the stool; a small portion is reabsorbed and excreted by the kidney. Bilirubin can be filtered by the kidney only in its conjugated form (measured as the “direct” fraction); thus increased direct serum bilirubin level is associated with bilirubinuria. Increased bilirubin production and excretion (even without hyperbilirubinemia, as in hemolysis) produce elevated urinary urobilinogen levels.
ETIOLOGY Hyperbilirubinemia occurs as a result of (1) overproduction; (2) impaired uptake, conjugation, or excretion of bilirubin; (3) regurgitation of unconjugated or conjugated bilirubin from damaged hepatocytes or bile ducts (Table 23-1).
Table 23-1 Causes of Hyperbilirubinemia
EVALUATION The initial steps in evaluating the pt with jaundice are to determine whether (1) hyperbilirubinemia is conjugated or unconjugated, and (2) other biochemical liver tests are abnormal (Fig. 23-1). Essential clinical examination includes history (especially duration of jaundice, pruritus, associated pain, fever, weight loss, risk factors for parenterally transmitted diseases, medications, ethanol use, travel history, surgery, pregnancy), physical examination (hepatomegaly, tenderness over liver, palpable gallbladder, splenomegaly, gynecomastia, testicular atrophy), blood liver tests (see below), and complete blood count.
FIGURE 23-1. Evaluation of the patient with jaundice. ERCP, endoscopic retrograde cholangiopancreatography; CT, computed tomography; ALT, alanine aminotransferase; AST, aspartate aminotransferase; SMA, smooth muscle antibody; AMA, antimitochondrial antibody; LKM; liver-kidney microsomal antibody; SPEP, serum protein electrophoresis; CMV, cytomegalovirus; EBV, Epstein-Barr virus.
Gilbert’s Syndrome Impaired conjugation of bilirubin due to reduced bilirubin UDP glucoronosyltransferase activity. Results in mild unconjugated hyperbilirubinemia almost always <103 µmol/L (<6 mg/dL). Affects 3–7% of the population; males/females 2–7:1.
DEFINITION Generally a span of >12 cm in the right midclavicular line or a palpable left lobe in the epigastrium. It is important to exclude low-lying liver (e.g., with chronic obstructive pulmonary disease and lung hyperinflation) and other RUQ masses (e.g., enlarged gallbladder or bowel or kidney tumor). Independent assessment of size best obtained from ultrasound (US) or CT examination. Contour and texture are important: Focal enlargement or rocklike consistency suggests tumor; tenderness suggests inflammation (e.g., hepatitis) or rapid enlargement (e.g., right-sided heart failure, Budd-Chiari syndrome, fatty infiltration). Cirrhotic livers are usually firm and nodular, often enlarged until late in course. Pulsations frequently connote tricuspid regurgitation. Arterial bruit or hepatic rub suggests tumor. Portal hypertension is occasionally associated with continuous venous hum (Table 23-2).
Table 23-2 Important Causes of Hepatomegaly
BLOOD TESTS OF LIVER FUNCTION
Used to evaluate functional status of liver and to discriminate among different types of liver disease (inflammatory, infiltrative, metabolic, vascular, hepatobiliary; Table 23-3).
Table 23-3 Patterns of Liver Test Abnormalities
BILIRUBIN Provides indication of hepatic uptake, metabolic (conjugation) and excretory functions; conjugated fraction (direct) distinguished from unconjugated by chemical assay (Table 23-1).
AMINOTRANSFERASES (TRANSAMINASES) Aspartate aminotransferase (AST; SGOT) and alanine aminotransferase (ALT; SGPT); sensitive indicators of liver cell injury; greatest elevations seen in hepatocellular necrosis (e.g., viral hepatitis, toxic or ischemic liver injury, acute hepatic vein obstruction), occasionally with sudden, complete biliary obstruction (e.g., from gallstone); milder abnormalities in cholestatic, cirrhotic, and infiltrative disease; poor correlation between degree of liver cell damage and level of aminotransferases; ALT more specific measure of liver injury, since AST also found in striated muscle and other organs; ethanol-induced liver injury usually produces modest increases with more prominent elevation of AST than ALT.
ALKALINE PHOSPHATASE Sensitive indicator of cholestasis, biliary obstruction (enzyme increases more quickly than serum bilirubin), and liver infiltration; mild elevations in other forms of liver disease; limited specificity because of wide tissue distribution; elevations also seen in childhood, pregnancy, and bone diseases; tissue-specific isoenzymes can be distinguished by differences in heat stability (liver enzyme activity stable under conditions that destroy bone enzyme activity).
5′-NUCLEOTIDASE (5′-NT) Pattern of elevation in hepatobiliary disease similar to alkaline phosphatase; has greater specificity for liver disorders; used to determine whether liver is source of elevation in serum alkaline phosphatase, esp. in children, pregnant women, pts with possible concomitant bone disease.
g-GLUTAMYLTRANSPEPTIDASE (GGT) Correlates with serum alkaline phosphatase activity. Elevation is less specific for cholestasis than alkaline phosphatase or 5′-NT.
PROTHROMBIN TIME (PT) (See also Chap. 60) Measure of clotting factor activity; prolongation results from clotting-factor deficiency or inactivity; all clotting factors except factor VIII are synthesized in the liver, and deficiency can occur rapidly from widespread liver disease as in hepatitis, toxic injury, or cirrhosis; single best acute measure of hepatic synthetic function; helpful in Dx and prognosis of acute liver disease. Clotting factors II, VII, IX, X function only in the presence of the fat-soluble vitamin K; PT prolongation from fat malabsorption distinguished from hepatic disease by rapid and complete response to vitamin K replacement.
ALBUMIN Decreased serum levels result from decreased hepatic synthesis (chronic liver disease or prolonged malnutrition) or excessive losses in urine or stool; insensitive indicator of acute hepatic dysfunction, since serum half-life is 2 to 3 weeks; in pts with chronic liver disease, degree of hypoalbuminemia correlates with severity of liver dysfunction.
GLOBULIN Mild polyclonal hyperglobulinemia often seen in chronic liver diseases; marked elevation frequently seen in autoimmune chronic active hepatitis.
AMMONIA Elevated blood levels result from deficiency of hepatic detoxification pathways and portal-systemic shunting, as in fulminant hepatitis, hepatotoxin exposure, and severe portal hypertension (e.g., from cirrhosis); elevation of blood ammonia does not correlate well with hepatic function or the presence or degree of acute encephalopathy.
HEPATOBILIARY IMAGING PROCEDURES
ULTRASONOGRAPHY Rapid, noninvasive examination of abdominal structures; no radiation exposure; relatively low cost, equipment portable; images and interpretation strongly dependent on expertise of examiner; particularly valuable for detecting biliary duct dilatation and gallbladder stones (>95%); much less sensitive for intraductal stones (~60%); most sensitive means of detecting ascites; moderately sensitive for detecting hepatic masses but excellent for discriminating solid from cystic structures; useful in directing percutaneous needle biopsies of suspicious lesions; Doppler US useful to determine patency and flow in portal, hepatic veins and portal-systemic shunts; imaging improved by presence of ascites but severely hindered by bowel gas; endoscopic US less affected by bowel gas and is sensitive for determination of depth of tumor invasion through bowel wall.
CT Particularly useful for detecting, differentiating, and directing percutaneous needle biopsy of abdominal masses, cysts, and lymphadenopathy; imaging enhanced by intestinal or intravenous contrast dye and unaffected by intestinal gas; somewhat less sensitive than US for detecting stones in gallbladder but more sensitive for choledocholithiasis; may be useful in distinguishing certain forms of diffuse hepatic disease (e.g., fatty infiltration, iron overload).
MRI Most sensitive detection of hepatic masses and cysts; allows easy differentiation of hemangiomas from other hepatic tumors; most accurate noninvasive means of assessing hepatic and portal vein patency, vascular invasion by tumor; useful for monitoring iron, copper deposition in liver (e.g., in hemochromatosis, Wilson’s disease).
RADIONUCLIDE SCANNING Using various radiolabeled compounds, different scanning methods allow sensitive assessment of biliary excretion (HIDA, PIPIDA, DISIDA scans), parenchymal changes (technetium sulfur colloid liver/spleen scan), and selected inflammatory and neoplastic processes (gallium scan); HIDA and related scans particularly useful for assessing biliary patency and excluding acute cholecystitis in situations where US is not diagnostic; CT, MRI, and colloid scans have similar sensitivity for detecting liver tumors and metastases; CT and combination of colloidal liver and lung scans sensitive for detecting right subphrenic (suprahepatic) abscesses.
CHOLANGIOGRAPHY Most sensitive means of detecting biliary ductal calculi, biliary tumors, sclerosing cholangitis, choledochal cysts, fistulas, and bile duct leaks; may be performed via endoscopic (transampullary) or percutaneous (transhepatic) route; allows sampling of bile and ductal epithelium for cytologic analysis and culture; allows placement of biliary drainage catheter, and stricture dilatation; endoscopic route (ERCP) permits manometric evaluation of sphincter of Oddi, sphincterotomy, and stone extraction.
ANGIOGRAPHY Most accurate means of determining portal pressures and assessing patency and direction of flow in portal and hepatic veins; highly sensitive for detecting small vascular lesions and hepatic tumors (esp. primary hepatocellular carcinoma); “gold standard” for differentiating hemangiomas from solid tumors; most accurate means of studying vascular anatomy in preparation for complicated hepatobiliary surgery (e.g., portal-systemic shunting, biliary reconstruction) and determining resectability of hepatobiliary and pancreatic tumors. Similar anatomic information (but not intravascular pressures) can often be obtained noninvasively by CT- and MR-based techniques.
PERCUTANEOUS LIVER BIOPSY Most accurate in disorders causing diffuse changes throughout the liver; subject to sampling error in focal infiltrative disorders such as metastasis; should not be the initial procedure in the Dx of cholestasis.
For a more detailed discussion, see Pratt DS, Kaplan MM: Jaundice, Chap. 45, p. 255; and Pratt DS, Kaplan MM: Evaluation of Liver Function, Chap. 293, p. 1711, in HPIM-15.