Jaundice - epidemiology, pathophysiology, diagnosis, treatment

Author: Jerry T. McKnight, Jerry E. Jones
Date: March, 1992

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.

Epidemiology

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.

Pathophysiology

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.

Diagnosis

HISTORY AND PHYSICAL EXAMINATION

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).

LABORATORY INVESTIGATION

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)

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Med Clin North TABULAR DATA OMITTED

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