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.

Symptoms

Patients may be asymptomatic at presentation or have nonspecific symptoms such as pruritus, malaise, or nausea. There are a few symptom complexes that can help narrow the differential diagnosis. Jaundice with abdominal pain suggests biliary obstruction or significant hepatic inflammation. New-onset painless jaundice is the classic presentation for a neoplasm involving the head of the pancreas. Patients may complain of ill-fitting clothing because of weight loss or increasing abdominal girth related to ascites. The patient or caregiver may note subtle personality changes or frank confusion, suggestive of hepatic encephalopathy.

Signs

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.

Laboratory Tests

Figure 28-2 lists the laboratory tests that are helpful in the evaluation of a patient with jaundice. Serum γ-glutamyl transpeptidase (GGT) rises in parallel with alkaline phosphatase (AP) in the setting of liver disease.¹ Although AP also can be elevated in diseases affecting bone or placenta, the concomitant increase in serum GGT or 5′-nucleotidase confirms a hepatic source. A reticulocyte count and evaluation of the peripheral blood smear may identify hemolysis. In cases of unexplained hepatocellular injury, a quantitative acetaminophen level may be helpful. Bedside stool guaiac testing assesses for the presence of gastrointestinal bleeding. Both glucose and ammonia metabolism can be altered in the presence of hepatocellular injury, and patients with altered mental status should have glucose and ammonia levels determined. The degree of elevation in serum ammonia does not correlate directly with the level of hepatic encephalopathy. Ascitic fluid should be analyzed in patients with new-onset ascites and in those with established ascites but new complaints of fever, abdominal pain, gastrointestinal bleeding, hepatic encephalopathy, hypotension, or renal failure. Cell count and differential, albumin, and total protein concentration are sufficient initial screening tests. In the setting of suspected bacterial peritonitis, fluid culture is also necessary; Gram stain is rarely helpful. Two sets of blood cultures should be performed for patients with fever and jaundice. If there is evidence of gastrointestinal bleeding with hemodynamic instability or severe anemia, a type and crossmatch should be performed by the laboratory.