Conjugated Hyperbilirubinemia



Determining the cause of unconjugated hyper­bilirubinemia rarely poses difficulty. Usually, the major difficulty in evaluating jaundice is encoun­tered in differentiating an intrahepatic excretion defect from obstruction in a patient with predom­inantly conjugated hyperbilirubinemia. This clin­ical situation is often described as cholestatic jaundice, and the approach to its differential di­agnosis is discussed in detail below.

Cholestasis implies that, clinically and bio­chemically, there is impairment of bile formation or flow. Typically, a patient with cholestatic jaun­dice has predominantly conjugated hyperbiliru­binemia and an elevated alkaline phosphatase, usually to at least three to four times normal. When prolonged, cholestasis may lead to hyper­cholesterolemia, fat and fat-soluble vitamin mal­absorption, and retention of bile salts, which may lead to pruritus. Biochemical evidence of liver cell damage (elevated transaminases, prolonged prothrombin time uncorrected by administration of vitamin K) may be minimal or marked, de­pending upon the cause of the cholestasis. An im­portant corollary is that all the features of cho­lestasis may be present in some patients without jaundice.

Impaired Hepatic Excretion. This pathogenetic category of jaundice, also called intrahepatic cho­lestasis, is applied to all disorders in the transport of conjugated bilirubin from the hepatocyte up to the radiologically visible bile ducts. Thus it in­cludes a wide range of conditions from drug-in­duced cholestasis (impaired canalicular trans­port) to primary biliary cirrhosis (destruction of the small intrahepatic bile ductules). The follow­ing are some important causes of intrahepatic cho­lestasis.

Drug-induced Cholestasis. Typical cholestatic jaundice may be produced by phenothiazines, oral contraceptives, and methyltestosterone. Eosinophilia may accompany drug-induced jaun­dice.

Sepsis. Systemic sepsis, mainly due to gram-negative organisms, may produce a predomi­nantly conjugated hyperbilirubinemia, usually accompanied by mild elevation of serum alkaline phosphatase levels.

Post-operative Jaundice. This increasingly rec­ognized syndrome has an incidence of 15 per cent following heart surgery and 1 per cent following elective abdominal surgery. Occurring one to ten days postoperatively, the jaundice is multifacto­rial in origin but predominantly of the conjugated variety with increased alkaline phosphatase and minimally abnormal transaminases.
Hepatocellular Disease. Hepatocellular disease (i.e., hepatitis and cirrhosis) from a variety of causes (see Chapters 44 and 46) may result in a typical cholestatic jaundice. Evidence of hepato­cellular damage and dysfunction is usually prominent and includes marked elevation of transaminases, prolonged prothrombin time, hypoalbuminemia, and clinical features of he­patic dysfunction (see Chapter 45). In hepatocel­lular disease there is interference with all three steps of hepatic bilirubin metabolism. Excretion, the rate-limiting step, is usually the most’ pro­foundly disturbed, leading to a predominantly conjugated hyperbilirubinemia. Jaundice may be profound in acute hepatitis (see Chapter 44) with­out prognostic implications. On the contrary, in chronic liver disease, jaundice is a sign that usu­ally implies severe decompensation of hepatic function with a poor prognosis.

Extrahepatic Biliary Obstruction. Complete or partial obstruction of the extrahepatic bile ducts may result from a variety of causes, including im­paction of gallstones, carcinoma of the head of the pancreas, tumors of the bile ducts, bile duct stric­tures, and chronic pancreatitis with bile duct compression. In complete obstruction, conjugated hyperbilirubinemia is prominent and usually pla­teaus at 30 to 40 mg/dl in the absence of renal failure, hepatocellular damage, or infection within the bile ducts, all of which may antedate or develop during the course of mechanical ob­struction. Stools may become clay colored as a result of the failure of bile to enter the intestine. In partial obstruction, jaundice may be mild or even absent, becoming prominent when infection of the ducts complicates the obstruction.