Jaundice and Evaluation of Liver Function

JAUNDICE

DEFINITION Yellow skin pigmentation caused by elevation in serum

bilirubin level (also termed icterus); often more easily discernible in sclerae.

Scleral icterus becomes clinically evident at a serum bilirubin level of _51

_mol/L (_3 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 54-1).

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. 54-1,Tables 54-2 and 54-

3). Essential clinical examination includes history (especially duration of jaundice,

pruritus,associated pain,risk factors for parenterally transmitted diseases,

medications,ethanol use, travel history,surgery,pregnancy, presence of any accompanying symptoms),physical examination (hepatomegaly, tenderness

over liver, palpable gallbladder,splenomegaly,gynecomastia,testicular atrophy,

other stigmata of chronic liver disease), blood liver tests (see below), and complete blood count.

Gilbert’s Syndrome Impaired conjugation of bilirubin due to reduced bilirubin

UDP glucuronosyltransferase activity. Results in mild unconjugated hyperbilirubinemia

almost always _103 _mol/L (_6 mg/dL). Affects 3–7% of

the population; males/females 2–7:1.

Causes of Isolated Hyperbilirubinemia

I. Indirect hyperbilirubinemia

A. Hemolytic disorders

1. Inherited

a. Spherocytosis,elliptocytosis

b. Glucose-6-phosphate dehydrogenase and pyruvate kinase

deficiencies

c. Sickle cell anemia

2. Acquired

a. Microangiopathic hemolytic anemias

b. Paroxysmal nocturnal hemoglobinuria

c. Immune hemolysis

B. Ineffective erythropoiesis

1. Cobalamin,folate, thalassemia, and severe iron deficiencies

C. Drugs

1. Rifampicin,probenecid, ribavirin

D. Inherited conditions

1. Crigler-Najjar types I and II

Gilbert’s syndrome

II. Direct hyperbilirubinemia

A. Inherited conditions

1. Dubin-Johnson syndrome

Rotor’s syndrome

HEPATOMEGALY

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.

BLOOD TESTS OF LIVER FUNCTION

Used to detect presence of liver disease,discriminate among different types of

liver disease (Table 54-4),gauge the extent of known liver damage, follow

response to treatment.

BILIRUBIN Provides indication of hepatic uptake,metabolic (conjugation)

and excretory functions; conjugated fraction (direct) distinguished from

unconjugated by chemical assay (Table 54-1).

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 fractionation or 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. -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. 66) 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.