Excess bilirubin production results from accelerated red cell destruction. Occasionally, markedly ineffective erythropoiesis may be responsible. The excessive amounts of hemoglobin and resultant bilirubin released into the bloodstream overwhelm the normal hepatic capacity for uptake, and an unconjugated hyperbilirubinemia ensues. Total bilirubin rises as a result of the increased indirect fraction. The results of all tests of hepatocellular function are normal (as are urine and stool appearances). Symptoms, signs, and laboratory test findings point to hemolysis or ineffective erythropoiesis (see Chapter 79).

Decreased uptake and conjugation are other mechanisms of unconjugated hyperbilirubinemia. The only evidence of hepatocellular dysfunction is an increase in unconjugated bilirubin. Frequently, the cause is a concurrent acquired illness, such as an infection, cardiac disease, or cancer in a patient with a hereditary predisposition to decreased uptake and conjugation (Gilbert syndrome). This benign disorder produces recurrent, self-limited episodes of mild jaundice; typically, the unconjugated fraction rises to no more than 1.5 to 3.0 mg/100 mL. Fasting and minor illness can also precipitate mild jaundice.

Intrahepatic cholestasis may occur at a number of levels: intracellularly (e.g., hepatitis), at the canalicular level (when estrogen induced), at the ductule (phenothiazine exposure), at the septal
ducts (primary biliary cirrhosis), and at the intralobular ducts (cholangiocarcinoma). Regardless of site, there are similarities in presentation. Jaundice begins gradually; pruritus is common. The liver is large, smooth, and nontender; it may be firm but not rock hard. Splenomegaly is uncommon except in primary biliary cirrhosis. Stools are pale, and steatorrhea develops in severe cases. A hyperbilirubinemia is present, predominantly of the conjugated fraction, with marked alkaline phosphatase elevation, mild transaminase rise, and normal serum albumin. Urine is dark and tests positive for bilirubin. The prothrombin time may be prolonged because of malabsorption; the prolongation is reversible with vitamin K administration.

Extrahepatic obstruction occurs when stone, stricture, or tumor blocks the flow of bile within the extrahepatic biliary tree. A history of gallstones, biliary tract surgery, or prior malignancy may be elicited. The gallbladder is sometimes palpable, especially when cancer produces obstruction gradually, allowing time for painless dilation of the biliary tree. Sudden onset with pain results from passage of a stone that becomes wedged into the common duct; fever and sepsis may follow, indicating cholangitis. Weight loss is a nonspecific finding, but when it is marked and accompanied by jaundice, it suggests carcinoma of the head of the pancreas or metastatic disease obstructing the common duct. Extrahepatic obstruction and intrahepatic cholestasis may be identical in presentation. The liver is usually enlarged; tenderness is minimal unless cholangitis or rapid distention occurs. A rock-hard mass strongly points to malignancy. As in intrahepatic cholestasis, conjugated bilirubin exhibits the greatest rise in association with a high serum alkaline phosphatase level and a mild to moderate increase in the transaminase level. Any prolongation of the prothrombin time is at least partially reversible with parenteral vitamin K. Urine is dark because of the conjugated bilirubinuria. Stools may be pale from absence of bile.

Hepatocellular disease is typified by hepatitis, with prodromal symptoms of anorexia, nausea, abdominal pain, and malaise preceding jaundice (see Chapters 52 and 70). Hepatic tenderness and some hepatomegaly are common. Aminotransferases may reach dramatic levels, except in cases of hepatitis C and alcoholic hepatitis, in which the rise is no more than five times normal. The alkaline phosphatase rises modestly to two to four times above the baseline. Urine is dark, and stools are pale. There may be evidence of decreased protein synthesis. The prothrombin time is the first measure of synthetic function to become abnormal because the half-lives of the clotting factors made in the liver are less than 7 days. If synthetic function remains depressed beyond 2 weeks, the serum albumin begins to fall. Chronic hepatocellular disease may lead to fibrosis and cirrhosis with portal hypertension, peripheral edema, ascites, gynecomastia, testicular atrophy, bleeding, and encephalopathy (see Chapter 71).

The history and physical examination can help narrow the differential diagnosis by suggesting the underlying pathophysiology (e.g., differentiating hepatocellular injury from biliary obstruction). In a study of 61 cases of jaundice documented by liver biopsy, history and physical examination alone correctly identified 70% of viral hepatitis cases, 80% of cirrhosis cases, and 77% of those with obstructive jaundice. The working pathophysiologic hypothesis (or hypotheses) can be tested and confirmed by a few basic laboratory studies.

Key historical items found useful for discriminating among etiologies include the presence of abdominal pain (indicative of obstruction) and a history of alcoholism, exposure to hepatitis, and flulike onset (all suggestive of a hepatocellular etiology). History of weight loss, pruritus, nausea, vomiting, and distaste for tobacco are of little discriminant value. Dark urine and pale stools confirm a conjugated hyperbilirubinemia but do not distinguish between hepatic and obstructive disease. Absence of abdominal pain does not rule out obstruction, especially that which develops slowly from tumor growth or primary biliary cirrhosis. The history should also be reviewed for other hepatocellular disease risk factors (e.g., previous blood transfusion, travel to an area endemic for hepatitis, consumption of raw shellfish, intravenous drug abuse, high-risk sexual practices, and use of potentially hepatotoxic drugs, especially acetaminophen). A history of gallstones, previous biliary tract surgery, and high fever points to an obstructive cause. A family history of episodic jaundice in the setting of an intercurrent illness is consistent with Gilbert disease. Intrahepatic cholestasis is a consideration if the patient reports use of estrogens, phenothiazines, and other drugs that can cause cholestasis.