March 1, 2007

ABSTRACT: In patients with jaundice and normal liver function, the cause of hyperbilirubinemia is an isolated disorder of bilirubin metabolism. In patients with hyperbilirubinemia who have abnormal liver enzyme levels, hepatocellular disease must be differentiated from cholestatic liver injury. In general, if the cause of jaundice is global hepatocellular dysfunction, the serum alanine aminotransferase and aspartate aminotransferase levels will be predominantly elevated. If the cause is cholestasis, the serum alkaline phosphatase and gγ-glutamyl peptidase levels will be elevated. In most patients, imaging studies will be needed. The initial workup should include abdominal ultrasonography, which can identify dilated intrahepatic and extrahepatic biliary ducts as well as findings that may suggest cirrhosis or signs of portal hypertension, including splenomegaly and ascites.

Because jaundice may indicate a serious underlying condition, timely diagnosis is critical. Rapid determination of the cause relies on proper history taking, physical examination, and interpretation of serum and biochemical tests. The liver biochemistry will indicate whether the jaundice is related to mechanical biliary obstruction or intrinsic liver disease. Ancillary laboratory tests and radiologic imaging can help pinpoint the diagnosis.

In this article, we offer a systematic approach to the evaluation of the patient who presents with jaundice.

A diagnostic approach is outlined in the Algorithm. Results of the physical examination (which should focus on the stigmata of liver disease), the presence of comorbid conditions, and the medication history may point to the cause of jaundice. For example, a history of abdominal pain, fever, and biliary surgery in elderly patients may suggest obstructive jaundice. Other risk factors include a history of anorexia, malaise, viral prodrome, exposure to hepatotoxins, injection drug use, and a family history of jaundice associated with liver disease.

The differential diagnosis of yellowish skin includes carotenoderma, which occurs in healthy persons who ingest excessive amounts of vegetables and fruits that contain beta-carotene. In patients with carotenoderma, the pigment is concentrated on the palms, soles, forehead, and nasolabial fold. Persons with this condition do not have scleral icterus or hyperbilirubinemia.

Jaundice, or icterus, is characterized by yellow discoloration of the skin, sclera, and mucous membranes, as a result of an elevation of serum bilirubin concentration (hyperbilirubinemia) and subsequent tissue deposition. About 70% to 80% of bilirubin produced each day is derived from the breakdown of hemoglobin from red blood cells. The remainder comes from prematurely destroyed erythroid cells in the bone marrow and from hemoproteins such as myoglobin and cytochrome. Elevated serum bilirubin levels result from an imbalance of bilirubin formation and clearance.

Circulating bilirubin is tightly bound to albumin. Elimination of bilirubin requires conversion to water-soluble conjugates by the hepatocytes through the action of uridine diphosphate (UDP)-glucuronyl transferase (glucuronidation) and secretion into the bile. Conjugated bilirubin, along with bile salts, is then excreted via the biliary system into the duodenum and deconjugated by bacterial enzymes in the terminal ileum and colon. Twenty percent of deconjugated bilirubin (urobilinogen) is reabsorbed and re- excreted in bile. Unconjugated bilirubin is mostly bound to albumin and is not filtered by the kidney; conjugated bilirubin, however, may be filtered and reabsorbed in the kidney, with a small fraction excreted in the urine. A significant amount of conjugated bilirubin in the urine suggests cholestasis and hepatobiliary dysfunction.

Bilirubin tests can be ordered as total bilirubin and the subfractions "direct" and "indirect" bilirubin. The direct fraction provides an approximate determination of the serum level of conjugated bilirubin. The indirect fraction, which is the arithmetical difference between the serum total bilirubin and the direct fraction, represents unconjugated bilirubin. Determine whether hyperbilirubinemia is predominantly conjugated or unconjugated (direct fraction, less than 15%). Up to 30% of total bilirubin is in conjugated form. Normal total serum bilirubin concentrations are between 0.2 and 0.9 mg/dL.

Elevations in other serum liver function values vary according to the cause of liver dysfunction. In general, if the cause of jaundice is cholestasis, the serum alkaline phosphatase (ALP) and γ-glutamyl peptidase (GGT) levels will be predominantly elevated. If the cause is global hepatocellular dysfunction, the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) will be predominantly elevated. Often, however, a mixed pattern is seen that has features of both cholestasis and hepatocellular dysfunction.

Other helpful tests for patients with abnormal liver enzyme levels include serum albumin and a coagulation screen (ie, international normalized ratio). Radiologic imaging will, in most cases, also be needed. The initial diagnostic imaging workup should include abdominal ultrasonography, which can identify dilated intrahepatic and extrahepatic biliary ducts as well as the echotexture of the liver (findings such as surface nodularity and increased echogenicity may suggest cirrhosis) and signs of portal hypertension, including splenomegaly and ascites. Later investigations may include CT, endoscopic retrograde cholangiopancreatography (ERCP), and liver biopsy.

In patients who have normal liver function test values, the cause of hyperbilirubinemia is not biliary obstruction or hepatocellular dysfunction but rather an isolated disorder of bilirubin metabolism that may result in unconjugated or conjugated hyperbilirubinemia.

Unconjugated hyperbilirubinemia. This condition results from increased production, impaired hepatic uptake, or decreased conjugation of bilirubin. Increased bilirubin production may be associated with hemolysis, ineffective erythropoiesis, or resorption of a hematoma. Hemolytic disorders are either inherited or acquired. Inherited disorders, such as spherocytosis or sickle cell anemia, may be suggested by other laboratory abnormalities, including peripheral blood smear, elevated levels of lactate dehydrogenase, and decreased levels of haptoglobin. In these settings, serum bilirubin levels rarely exceed 5 mg/dL.1

Impaired bilirubin conjugation is associated with 3 genetic conditions-Gilbert syndrome and Crigler-Najjar syndrome types I and II. Gilbert syndrome, the most common of the 3 conditions, is found in 3% to 7% of the American population.2 The conjugation process is impaired because of reduced bilirubin UDP glucuronosyltransferase activity. This syndrome is benign and rarely produces clinical jaundice. Serum bilirubin levels may rise 2- or 3-fold with fasting or dehydration, but are almost always less than 6 mg/dL.

Crigler-Najjar type I is an exceptionally rare condition caused by the absence of bilirubin UDP glucuronyltransferase (UGT-1) activity. This syndrome usually develops during the neonatal period and leads to infant death. Crigler-Najjar type II is more common than type I and less severe. The UGT-1 activity is usually markedly reduced; however, phenobarbital increases this activity and reduces jaundice. Patients with this disorder have a normal life expectancy.

Rarely, certain drugs may decrease bilirubin uptake. A prime example is rifampin, which may exacerbate unconjugated hyperbilirubinemia in those with Gilbert syndrome.3

Conjugated hyperbilirubinemia. This condition, caused by impaired biliary excretion, is associated with 2 rare inherited disorders-Dubin-Johnson syndrome and Rotor syndrome. Patients with these conditions present with asymptomatic jaundice. The syndromes can be distinguished biochemically and histologically; neither is associated with adverse clinical outcomes.

Conjugated hyperbilirubinemia is usually associated with abnormal liver function tests. In this setting, hepatocellular disease must be differentiated from cholestatic liver injury.

Hepatocellular disease. ALT and AST are normally present within hepatocytes and enter the systemic circulation after injury to these cells. The hepatocellular pattern is characterized by an elevation of AST and ALT levels disproportionate to ALP levels.

A variety of disorders can produce acute, subacute, or chronic hepatocellular injury. Acute liver injury may result from acute viral hepatitis (eg, hepatitis A or B, as well as Epstein-Barr virus and cytomegalovirus), alcoholic hepatitis and, rarely, acute metabolic derangement (such as Wilson disease). Acute liver injury may also be caused by hepatotoxins (such as medications, including over-the-counter agents, street drugs, and herbal preparations). The Table provides a partial listing of these agents.

 Table - Drug-induced liver disease by type of toxicity
Dose-dependent hepatotoxins Agents associated with idiosyncratic drug-induced liver disease*

Acetaminophen Isoniazid
Ethanol Ketoconazole
Carbon tetrachloride Amoxicillin/clavulanate, nitrofurantoin
Niacin (nicotinic acid) Dantrolene
Vitamin A Estrogen, corticosteroids
Methotrexate Diclofenac, sulindac
Metal: copper, iron, mercury Phenytoin
  Herbal preparations

*Drug-induced liver disease may be caused by any drug.

A focused history taking includes questions about recent medication use, travel, blood and body fluid exposure, alcohol consumption, and contaminated food. In acute viral or hepatotoxic injury, serum ALT and AST are usually markedly elevated and can approach or exceed 1000 U/L. Serum viral markers, including serologic tests for hepatitis A IgM, hepatitis B surface antigen, hepatitis B core IgM, and hepatitis C, should be evaluated routinely.

Alcoholic hepatitis is often suggested by the history. The serum AST/ALT ratio is often greater than 2:1, and the aminotransferase levels rarely exceed 300 U/L.

An acute presentation of Wilson disease, an inherited disorder of copper metabolism, is very rare. Patients with this condition demonstrate significant jaundice and modest elevations in AST, ALT, ALP, and GGT levels in conjunction with marked coagulopathy and other clinical features of significantly decompensated liver disease. Coombs test-negative hemolytic anemia is usually present to some degree, the serum ceruloplasmin is low, and Kayser-Fleischer corneal rings may be apparent by ophthalmic slit-lamp examination.

Autoimmune hepatitis, whether an acute episode or an acute relapse of chronic disease, may present with markedly elevated serum ALT and AST levels. An appropriate autoimmune screen includes antinuclear antibodies, anti-smooth muscle antibodies, and protein electrophoresis to look for elevated gamma globulin levels.

Cholestatic hepatobiliary disease. ALP and γ-glutamyltransferase are widely used as markers of cholestasis and are elevated disproportionately to the elevation of serum aminotransferases. The next step in the workup of patients with these results is abdominal ultrasonography to determine whether intrahepatic or extrahepatic biliary ducts are obstructed. The absence of biliary dilatation suggests intrahepatic cholestasis; the presence of biliary dilatation indicates extrahepatic cholestasis from mechanical obstruction.

Intrahepatic cholestasis. Causes of intrahepatic cholestasis can be categorized according to the pattern of bile duct injury and whether inflammation of the liver is acute or chronic. The diagnosis is often made by serologic markers in combination with liver biopsy.

Primary biliary cirrhosis (PBC), a rare progressive liver disease, is most frequently seen in middle-aged women. The most common presenting symptoms are fatigue and pruritus. It is characterized by liver inflammation and loss of small intrahepatic bile ducts and ductules. Antimitochondrial antibody testing is 95% sensitive and 98% specific for PBC. Marked hyperbilirubinemia indicates diminished chances of long-term survival.

Primary sclerosing cholangitis (PSC) is characterized by fibrosing inflammation in the intrahepatic and extrahepatic bile ducts. Most patients are asymptomatic at the time of diagnosis. Consider this diagnosis in patients with a history of inflammatory bowel disease who have abnormal liver function tests, especially elevated ALP levels. The diagnosis is made by ERCP or magnetic resonance cholangiopancreatography.

A number of drugs may cause intrahepatic cholestasis or a mixed pattern of cholestasis and hepatitis (see Table). Drugs commonly associated with cholestasis include acetaminophen, penicillins, and anabolic and estrogenic corticosteroids.4Cholestasis usually develops within 2 months of the initiation of therapy; it is generally reversible but may take many months to resolve. A biopsy may help establish a diagnosis of drug-induced intrahepatic cholestasis.

Infiltrative disease. The most common infiltrative liver diseases are granulomatous disorders, such as tuberculosis and sarcoidosis. Causes include Mycobacterium avium complex, fungal and parasitic infections, lymphoma, and toxins such as beryllium. Most of these conditions are accompanied by nonspecific systemic symptoms such as fever, night sweats, and weight loss. The presence of eosinophilia may suggest sarcoidosis, parasitic disease, or drug toxicity.

Mechanical biliary obstruction. Such obstruction may have a malignant or benign origin. Choledocholithiasis is found in about 15% of patients with gallbladder stones.5 The clinical presentation ranges from mild right upper quadrant pain with minimal elevation of liver enzymes to ascending cholangitis. Ultrasonography is as sensitive as CT for the detection of choledocholithiasis. ERCP is also highly accurate in the diagnosis of biliary obstruction, with a sensitivity of 89% to 98% and a specificity of 89% to 100%.6 ERCP can also be used for therapeutic interventions, including stone removal and endobiliary stent placement.

Biliary obstruction may also be caused by parasitic infections (as with Ascarislumbricoides); on endoscopy, the organisms can sometimes be seen protruding from the ampulla.

Malignant causes include carcinoma of the pancreas or gallbladder, ampullary carcinoma, and cholangiocarcinoma. ERCP facilitates procedures such as diagnostic brushings or biopsy in cholangiocarcinoma and ampullary cancer, as well as the placement of an endobiliary stent to temporarily relieve the obstruction. Jaundice in PSC is typically a result of end-stage liver disease; however, occasionally a dominant nonmalignant extrahepatic biliary stricture is the cause, and this condition is treatable with endobiliary stent placement.

End-stage liver disease. End-stage decompensated liver disease from any cause inevitably results in jaundice as the failing liver becomes unable to effectively excrete bilirubin. This condition may occur acutely in patients without previous liver disease, as in acute liver failure from drug toxicity or viral hepatitis. More commonly, it is seen in end-stage cirrhosis. Other indicators of decompensation are invariably present in end-stage disease; these include hepatic encephalopathy, ascites, renal impairment (such as hepatorenal syndrome), and variceal hemorrhage. Laboratory findings include coagulopathy and, in chronic cirrhosis, hypoalbuminemia. The prognosis for end-stage decompensated disease is usually poor and warrants consideration of liver transplantation.


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