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Jaundice - epidemiology, pathophysiology, diagnosis, treatment
From American Family Physician, 3/1/92 by Jerry T. McKnight

Jaundice (icterus) is yellow pigmentation of tissues and body fluids due to elevated serum bilirubin. Bilirubin is formed from breakdown of the heme ring of hemoglobin molecules and hemoproteins, primarily the cytochromes. (1) The average daily production of total bilirubin in adults is 250 to 350 Mg.2

Bilirubin occurs in unconjugated and conjugated forms. Unconjugated bilirubin, the direct breakdown product of heme, is water-insoluble at physiologic pH and is measured as indirect bilirubin. Conjugated bilirubin is produced in hepatocytes by esterification of unconjugated bilirubin with glucuronic acid. This process is catalyzed by microsomal uridine diphosphate glucuronyl transferase (UDP-glucuronyl transferase).(3) Conjugation of bilirubin confers water solubility and is measured as direct bilirubin. Normally, total serum bilirubin ranges from 0.3 to 1.2 mg per dL (6 to 20 (micro)mol per L), with conjugated bilirubin accounting for less than 15 percent.2 The relative proportions of conjugated and unconjugated bilirubin are important in establishing the etiology of jaundice.


The prevalence of jaundice varies with age and sex; newborns and older adults are most often affected. Figure 1 shows the age and sex distribution of jaundice in family practice, based on a study of more than 526,000 diagnoses among 88,000 patients.(4)

The causes of jaundice also vary with age. (The most common causes are listed in Table 1.) Approximately 20 percent of term newborns develop jaundice in the first week of life, primarily because of immaturity of the hepatic conjugation process.(5) Congenital abnormalities, hemolytic or bilirubin uptake disorders, and conjugation defects are also responsible for jaundice in infancy or childhood. Viral hepatitis A is the most frequent cause of jaundice among school-age children. Common duct stones, alcoholic liver disease and neoplastic jaundice occur in middle-aged and older patients.(6)

Jaundice in men is most likely to be due to cirrhosis, chronic hepatitis B, hepatoma, pancreatic cancer or sclerosing cholangitis. In contrast, women tend to have higher rates of common duct stones, primary biliary cirrhosis and carcinoma of the gallbladder.


The mechanisms responsible for jaundice include excess production, decreased hepatic uptake or impaired conjugation of bilirubin, intrahepatic cholestasis, hepatocellular injury and extrahepatic obstruction. Jaundice becomes noticeable when the serum bilirubin level reaches approximately 3.0 mg per dL (52 (micro)mol per L).(7) UNCONJUGATED HYPERBILIRUBINEMIA

Unconjugated hyperbilirubinemia may result from excessive production of unconjugated bilirubin or from decreased ability to conjugate bilirubin. Thus, the causes are hemolytic (excess production) or hepatic (decreased conjugation). Hemolysis may be due to intrinsic defects in blood cells, such as hemoglobinopathies, enzyme abnormalities or cell structure defects (Figure 2). Extrinsic factors, including drug toxicity, infectious agents, immunologic abnormalities, malignancy and trauma, can also result in hemolysis.

Other causes of unconjugated hyperbilirubinemia are disorders involving defective uptake and impaired conjugation of bilirubin. Gilbert's syndrome is a relatively common inherited condition in which decreased (UDP-glucuronyl transferase activity causes mild increases in unconjugated bilirubin.(2) Physiologic jaundice of the newborn represents defective uptake due to immaturity of hepatic cells. Breastmilk jaundice results from competitive inhibition of UDP-glucuronyl transferase by the maternal hormone pregnanediol.(8)

Type 1 and type 2 nonhemolytic jaundice are manifestations of inherited defects that cause moderate or severe increases in unconjugated bilirubin. Type 1 nonhemolytic jaundice (formerly known as Crigler-Najjar syndrome) represents total absence of UDP-glucuronyl transferase and is usually fatal in infancy. Type 2 is characterized by a marked decrease in the enzyme.(9) CONJUGATED HYPERBILIRUBINEMIA

Conjugated hyperbilirubinemia occurs when bilirubin is returned to the bloodstream after conjugation in the liver, instead of draining into the bile ducts. The most common causes are hepatocellular disease, intrahepatic cholestasis and extrahepatic obstruction. Hepatocellular dysfunction may be due to hepatitis, cirrhosis, tumor invasion or toxic injury (Table 2). Intrahepatic cholestatic syndromes may occur in hepatitis, in pregnancy and with certain medications, such as phenothiazines and estrogens.(10-12) Table 3 lists medications that can cause jaundice. The mechanism of drug-induced jaundice may be intrahepatic cholestasis or direct hepatocellular injury. Primary biliary cirrhosis and cholangiocarcinoma also can induce cholestasis.(13) Dubin-Johnson and Rotor syndromes are rare inherited disorders that may cause jaundice due to impaired excretion of conjugated bilirubin.(2)

Extrahepatic obstruction occurs when stone, stricture or tumor blocks the flow of bile within the extrahepatic biliary tree.(14)

Other causes of cholestasis are listed in Table 4.



The history and physical examination, together with routine laboratory tests, will suggest the diagnosis in approximately 80 percent of patients with jaundice.(15-17) Physical and laboratory findings in selected jaundice syndromes are given in Table 5.

The history may disclose pruritus, abdominal pain, exposure to infectious hepatitis, alcoholism, exposure to medications or toxins, illicit drug use, homosexuality, raw shellfish ingestion, travel or family history of jaundice. A history of gallstones or biliary tract exploration, as well as a history of malignancy, should be noted. Other important historical features are fever, easy bruising, pale stools, dark urine or mental status changes.

Notable physical findings include stigmata of cirrhosis, palpable gallbladder or right upper quadrant tenderness, hepatomegaly, abdominal mass, evidence of cachexia, fever, lymphadenopathy, enlarged spleen, ascites, skin coloration and Kayser-fleischer rings (corneal copper deposits seen in Wilson's disease).


The laboratory investigation initially includes a complete blood count, urinalysis and automated serum profile. Leukocytosis, bilirubin in the urine, the degree of serum bilirubin elevation, and aminotransferase (transaminase) and alkaline phosphatase activity are important laboratory features. Increased alkaline phosphatase activity occurs with normal bone growth, bone disease and pregnancy, but in the absence of these conditions, elevation of alkaline phosphatase usually suggests impaired biliary tract function. Alkaline phosphatase levels may be elevated to twice the normal value in hepatitis and cirrhosis, but marked elevation (more than three times normal) is usually associated with extrahepatic biliary obstruction (e.g., choledocholithiasis) and intrahepatic cholestasis (e.g., drug-induced and biliary cirrhosis).(12,18 )

Aspartate aminotransferase (AST; formerly SGOT) and alanine aminotransferase ALT; formerly SGPT) are two serum enzymes that provide evidence of hepatocellular damage. ALT is found primarily in the liver, whereas AST is also found abundantly in other organs, such as the heart, kidney, skeletal muscle and brain. Thus, AST is less specific for liver function. Elevations of AST and ALT usually parallel each other, except in alcoholic hepatitis, in which the AST-TO-ALT ratio is usually greater than 2.(20) Uremia may lead to falsely low aminotransferase levels.

The serum enzyme gamma-glutamyl transpeptidase (GGTP) is found throughout the hepatobiliary system, as well as in other tissues such as the pancreas, heart, kidneys and lungs. The GGTP level correlates with the alkaline phosphatase level and may be the most sensitive indicator of biliary tract disease.(20)

Elevation of 5'-nucleotidase, a serum enzyme with widespread tissue distribution, is associated with hepatobiliary disease. The principal value of determining 5-nucleotidase activity is to confirm the hepatic origin of an elevated alkaline phosphatase level. 20 This is particularly helpful in children, pregnant women and patients who may have bone disease. The lactic dehydrogenase (LDH) level is usually of little value in the evaluation of liver disease.

Decreased serum albumin is associated with severe chronic liver injury. A prolonged prothrombin time is an important prognostic indicator in patients with acute hepatitis. In chronic liver disease, failure of the prothrombin time to respond to vitamin K is indicative of more severe hepatocellular injury. Coombs'test results may be positive in drug-induced hemolysis.(21)

Division of the bilirubin into direct and indirect fractions is useful in distinguishing conditions primarily associated with conjugated bilirubin from those involving unconjugated bilirubin (Table 6). Bilirubin in the urine is conjugated and thus will give similar information. Immunologic profiles for infectious hepatitis, including hepatitis A, hepatitis B and hepatitis C (formerly non-A, non-B hepatitis), are helpful in diagnosing and staging hepatitis syndromes.(22) Cytomegalovirus, rubella virus, herpes simplex virus and Epstein-Barr virus can also cause hepatitis with jaundice, and tests for these agents should be considered in clinically appropriate situations.(23)


Useful radiologic studies in patients presenting with jaundice include plain abdominal radiographs, ultrasound examination of the liver and gallbladder, hepatic nuclear scan (HIDA, PIPIDA, DISIDA) and computed tomographic (CT) scan. 24 Plain abdominal radiographs may show evidence of hepatic and splenic enlargement or calcifications in the biliary system.

Ultrasound is the most effective initial imaging technique. It is useful in imaging the pancreas as well as the liver, gallbladder and bile ducts. The presence of ductal dilatation is a reliable indicator of extrahepatic obstruction. Ultrasound is more than 90 percent effective in identifying cholelithiasis.(24) It does, however, have a relatively high rate of false-negative results in early choledocholithiasis. Tumors of the liver and head of the pancreas are usually well visualized, although overlying bowel gas may obscure distal bile duct and pancreatic findings. Ultrasound is especially helpful in distinguishing solid liver tumors from cystic structures.

CT scanning is superior to ultrasound in detecting pancreatic tumors as well as other intra-abdominal tumors, because bowel gas causes no interference.(25) CT scanning can help differentiate fluid-containing structures, since fluid density can be determined.

The HIDA scan employs technetium99m-labeled N-substituted iminodiacetic acids, injected intravenously. The technique is an accurate method of diagnosing acute cholecystitis or cystic duct obstruction, 24,26 because the gallbladder cannot be visualized with these agents in cholecystitis or cystic duct obstruction. Unfortunately, cholescintigraphy has limited use in the differential diagnosis of jaundice.(25,27)

The liver-spleen scan uses 99m-Tc-sulfur colloid, which is taken up by Kupffer cells in the liver.(20,24) Colloidal scans are commonly used to assess hepatic parenchyma. A tumor, a hepatoma or an abscess is seen as a filling defect ("cold spot") on the scan. Cirrhosis is demonstrated by patchy uptake of the colloid.

Other diagnostic procedures include endoscopic retrograde cholangiopancreatography (ERCP), percutaneous needle biopsy of the liver, transhepatic cholangiography and angiography. ERCP is performed with the fiberoptic duodenoscope. The ampulla of Vater is cannulated under direct vision, and contrast material is injected into the pancreatic and biliary ducts.(28) ERCP provides a means for obtaining cytologic material from tumors of the ampulla and pancreatic head. ERCP may also be used for placement of an internal stent, allowing drainage of infected bile. Papillotomy using ERCP may permit passage of a common duct stone, obviating the need for emergency surgery.

Percutaneous needle biopsy is quite helpful in diagnosing parenchymal hepatic disorders. Conditions in which needle biopsy is useful include cirrhosis, chronic hepatitis, granulomatous hepatitis, tumors, undiagnosed hepatomegaly, cholestasis of unknown cause, infiltrative processes and miliary tuberculosis. (30) Bleeding and peritonitis are major risks, but these problems are relatively uncommon with experienced operators and proper patient selection.

Percutaneous transhepatic cholangiography is valuable when intrahepatic ductal dilatation is present. This procedure can be used to determine the location of biliary tract obstruction.(24)

The average costs for a number of the diagnostic imaging tests used in the evaluation of jaundice are given in Table 7. Treatment

Treatment of jaundice depends on the underlying cause. In general, obstructive extrahepatic jaundice is treated surgically, whereas medical therapy is used for obstructive intrahepatic or nonobstructive jaundice. Figure 3 illustrates a diagnostic and therapeutic approach to obstructive jaundice.(10,17,24) Obstructive extrahepatic jaundice secondary to choledocholithiasis requires either open surgical treatment or papillotomy using ERCP. Stent placement using ERCP may be needed for common bile duct obstruction secondary to a tumor. This is a palliative procedure, but it allows drainage of bile and may obviate the need for major surgery and general anesthesia.(31)

Obstructive or nonobstructive intrahepatic jaundice usually allows a nonsurgical approach. When a drug is thought to be a causative factor, withdrawal of the medication is appropriate. Education about ethanol use is indicated if jaundice is secondary to alcoholic liver disease. Type 2 nonhemolytic jaundice responds to phenobarbital.(9)

Interferon has been approved for use in chronic hepatitis B and chronic hepatitis C.(32-34) Wilson's disease and hemochromatosis can be effectively treated with penicillamine and phlebotomy, respectively. (19,35) Phototherapy is a safe and effective treatment for neonatal jaundice. Corticosteroids are useful in treating chronic hepatitis of autoimmune origin.

Final Comment

For the family physician, the challenge of jaundice lies in differentiating its numerous causes, which range from relatively benign to life-threatening. Anatomically, jaundice can be prehepatic, hepatic or posthepatic. Physiologically, it may result either from increased production, decreased conjugation or decreased excretion of bilirubin or from obstruction of biliary outflow. Diagnosis requires skilled use of laboratory and imaging procedures, possibly coupled with invasive diagnostic techniques. Treatment may consist of expectant management, newer endoscopic techniques or surgical intervention. The authors thank Bobby Selwyn for technical assistance in the preparation of this manuscript. REFERENCES

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