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Chapter 28




Normal Bilirubin Metabolism

Bilirubin is generated from heme products, primarily senescent red blood cells. A small portion is derived from myoglobin and maturing erythroid cells. Within the reticuloendothelial system, heme is oxidized to biliverdin, which is then converted to bilirubin. Bilirubin forms a tight but reversible bond with albumin in circulation. It is passively taken into the hepatocytes, where it undergoes glucuronidation. This conjugated fraction is secreted into the biliary system and emptied into the gut. Colonic bacteria metabolize the majority of the bilirubin to urobilinogen and stercobilin. Stercobilin is excreted in the stool, and urobilinogen is reabsorbed and excreted in the urine. The remaining conjugated bilirubin is deconjugated and reenters the portal circulation to be taken up again by the hepatocytes (enterohepatic circulation). In the laboratory, conjugated bilirubin and unconjugated bilirubin are reported as direct and indirect fractions, respectively.

Abnormalities in Bilirubin Metabolism

Clinical jaundice is usually not evident until the total serum bilirubin concentration rises above 2.5 mg/dL. It is observed in tissues with high albumin concentrations, for example, the skin and eyes. It is absent in albumin-poor fluids, such as tears or saliva. The physiology of bile metabolism may be altered in three principal areas: overproduction of heme products (hemolysis); failure of the hepatocyte to take up, conjugate, and excrete bilirubin (hepatocellular dysfunction); or obstruction of biliary excretion into the intestine. Unconjugated bilirubin that is not bound to albumin can cross the blood-brain barrier, causing adverse neurologic effects ranging from subtle developmental abnormalities to encephalopathy and death. Conditions that favor the unbound fraction of unconjugated bilirubin, including hemolysis, hypoalbuminemia, acidemia, and drugs that bind competitively to albumin, increase the risk of neurotoxicity. Conjugated bilirubins are not neurotoxic, although they may indicate serious disease.

Diagnostic Approach

Pivotal Findings

The pivotal findings related to history, physical examination, and ancillary testing are listed in Figure 28-2.


Pertinent physical examination findings are summarized in Figure 28-2. Examination of the skin and the abdomen is particularly helpful in narrowing the differential diagnosis.

Skin findings can point to acute or chronic liver disease. Jaundice is first apparent sublingually, in the conjunctiva and on the hard palate. From there, it spreads caudally; however, the extent of cephalocaudal progression does not accurately reflect the serum bilirubin concentration. Adequate lighting is necessary to detect the initial presentation of jaundice. Cutaneous findings of chronic liver disease include angiomas, excoriations from pruritus, and caput medusa.

The abdominal examination should begin with a thorough visual inspection. A distended or protuberant abdomen can indicate the presence of ascites. On palpation, an enlarged, tender liver suggests hepatic inflammation or engorgement caused by biliary obstruction. An enlarged nontender liver is concerning for malignant infiltration. A nonpalpable liver can indicate fibrosis caused by cirrhosis. A palpable gallbladder, a rare finding, suggests chronic cholestasis or malignancy. The presence of splenomegaly suggests hemolysis, malignancy, or portal hypertension.

Neurologic examination of the jaundiced patient may show depressed mental status, indicating hepatic encephalopathy or cerebral dysfunction caused by sepsis. Asterixis is a specific finding of hepatic encephalopathy. Table 28-1 addresses the clinical stages of hepatic encephalopathy.

Table 28-1

Clinical Stages of Hepatic Encephalopathy

Subclinical Normal examination findings, but work or driving may be impaired Subtle changes in psychometric testing
Stage 1 Impaired attention, irritability, depression, or personality changes Tremor, incoordination, apraxia
Stage 2 Drowsiness, behavioral changes, poor memory, disturbed sleep Asterixis, slowed or slurred speech, ataxia
Stage 3 Confusion, disorientation, somnolence, amnesia Hypoactive reflexes, nystagmus, clonus, muscular rigidity
Stage 4 Stupor and coma Dilated pupils and decerebrate posturing; oculocephalic reflex

From Fitz G: Systemic complications of liver disease. In Feldman M, Sleisenger M, eds: Gastrointestinal and Liver Disease, Philadelphia: WB Saunders; 1998.

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