Jaundice

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CHAPTER 20 Jaundice

Jaundice (icterus), is a condition characterized by yellow discoloration of the skin, conjunctivae, and mucous membranes as a result of widespread tissue deposition of the pigmented metabolite bilirubin. Although jaundice is generally associated with liver and biliary tract disease, it has many causes. It is thus not surprising that the diagnosis and management of jaundice have challenged clinicians for centuries.

Attempts to classify icteric syndromes appeared as early as the treatises of Hippocrates. By the time of Osler, distinctions were already made between biliary tract obstruction and nonobstructive causes of jaundice. In the latter part of the twentieth century, elucidation of the molecular mechanisms that underlie bilirubin metabolism, as well as the development of more sophisticated biochemical and imaging techniques, made it possible to pinpoint the cause of jaundice in most cases. Despite the impressive array of tools available today, it should be emphasized that to minimize risk to the patient, an effective approach to jaundice requires selection of diagnostic and therapeutic modalities on the basis of a careful assessment of the likelihood of possible underlying diseases.

This chapter covers four major areas: (1) bilirubin metabolism; (2) differential diagnosis of jaundice; (3) role of the history, physical examination, and routine biochemical tests in narrowing the differential diagnosis and the usefulness of selected laboratory and hepatobiliary imaging studies; and (4) therapeutic approaches to the management of jaundice.

BILIRUBIN METABOLISM AND MEASUREMENT

METABOLISM

Bilirubin, a hydrophobic and potentially toxic compound, is a tetrapyrrole that is an end product of heme degradation. Bilirubin metabolism has been reviewed in depth elsewhere1,2 and is summarized briefly in Figure 20-1. Each day, a healthy adult produces approximately 4 mg/kg of bilirubin (i.e., almost 0.5 mmol in a 70-kg person). Most bilirubin (70% to 80%) is derived from degradation of hemoglobin from senescent erythrocytes, and a minor component arises from premature destruction of newly formed erythrocytes in the bone marrow or circulation (i.e., ineffective erythropoiesis). Most of the remaining 20% to 30% is formed from breakdown of hemoproteins, such as catalase and cytochrome (CYP family) oxidases, in hepatocytes. Although nonhemoglobin heme-containing proteins are also present in extrahepatic tissues, their mass is so small or their turnover rate so slow (as for myoglobin) that their overall contribution to bilirubin production is minimal.

The breakdown of heme to bilirubin occurs by a two-step process. First, heme is converted to biliverdin by heme oxygenase, which functions predominantly as an integral membrane protein of the smooth endoplasmic reticulum. Second, biliverdin is converted rapidly to bilirubin by the cytosolic protein biliverdin reductase. Catabolism of erythrocyte-derived hemoglobin to bilirubin takes place primarily in reticuloendothelial cells in the spleen, liver, and bone marrow. By contrast, free hemoglobin, haptoglobin-bound hemoglobin, and methemalbumin are catabolized to bilirubin predominantly in hepatocytes.

Bilirubin circulates in plasma tightly, but noncovalently, bound to albumin. Excretion of bilirubin requires conversion to water-soluble conjugates by hepatocytes and subsequent secretion into bile. Bilirubin metabolism and elimination is a multistep process for which several inherited disorders have been identified (see later). Bilirubin is taken up across the sinusoidal (basolateral) membrane of hepatocytes by a carrier-mediated mechanism. The uptake of bilirubin is inhibited competitively by certain organic anions such as sulfobromophthalein (BSP) and indocyanine. Bilirubin uptake has been suggested to be mediated by a liver-specific sinusoidal organic anion transport protein, (OATP1B1, SLC21A6), but this is not entirely certain.3,4 After uptake, bilirubin is directed by cytosolic binding proteins (e.g., glutathione S-transferase B, fatty acid binding protein) to the endoplasmic reticulum, where it is conjugated with uridine diphosphate (UDP)–glucuronic acid by the enzyme bilirubin UDP–glucuronyl transferase (B-UGT). Conjugation converts hydrophobic bilirubin into a water-soluble form suitable for excretion. Conjugated bilirubin is then directed primarily toward the canalicular (apical) membrane, where it is transported into the bile canaliculus by an adenosine triphosphate (ATP)-dependent export pump. The responsible protein, multidrug resistance–associated protein-2 (MRP2, ABCC2), appears to function as a multispecific transporter of various organic anions (including BSP, glutathione, and conjugated bile salts).5 Small amounts of bilirubin glucuronides are secreted across the sinusoidal membrane via a pathway postulated to be mediated by a distinct multispecific organic ion export pump, MRP3 (ABCC3)6; conjugated bilirubin in plasma undergoes renal elimination (see Fig. 20-1). This pathway may be up-regulated in disorders characterized by cholestasis (impaired bile flow). With prolonged cholestasis (or a metabolic disorder of conjugated hyperbilirubinemia; see later), an increasing proportion of conjugated bilirubin in plasma becomes covalently bound to albumin, and this covalently bound bilirubin cannot be excreted into urine.

Approximately 80% of bilirubin in human bile is in the form of diglucuronides. Almost all the rest is in the form of monoglucuronides, and only trace amounts are unconjugated. Resorption of conjugated bilirubin by the gallbladder and intestine is negligible; however, bilirubin can be deconjugated by bacterial enzymes in the terminal ileum and colon and converted to colorless tetrapyrroles called urobilinogens. Up to 20% of urobilinogens are resorbed and ultimately excreted in bile and urine.

MEASUREMENT

The normal bilirubin concentration in the serum of adults is lower than 1 to 1.5 mg/dL. In general, jaundice is not evident until the serum bilirubin concentration exceeds 3 mg/dL. In healthy persons, most bilirubin circulates in its unconjugated form; less than 5% of circulating bilirubin is present in conjugated form. In cholestatic conditions, the proportion of unconjugated bilirubin may increase as a consequence of upregulated MRP3 expression. The importance of accurate measurement of bilirubin is underscored by its incorporation as a critical variable in scoring systems such as the Model for End-stage Liver Disease (MELD), which provide estimates of survival in various acute and chronic liver disorders.7

Serum bilirubin is detected conventionally by the diazo van den Bergh reaction. With this colorimetric method, bilirubin is cleaved by compounds such as diazotized sulfanilic acid to form an azodipyrrole that can be assayed by spectrophotometry. Conjugated bilirubin is cleaved rapidly (directly) by diazo reagents. By contrast, unconjugated bilirubin reacts slowly with diazo reagents because the site of chemical cleavage is rendered inaccessible by internal hydrogen bonding. Therefore, reliable measurement of total bilirubin concentration requires the addition of an accelerator compound, such as ethanol or urea, which disrupts this hydrogen bonding and facilitates the cleavage of unconjugated bilirubin by the diazo reagent. The concentration of the indirect bilirubin fraction is calculated by subtracting the direct bilirubin concentration (measured in the absence of the accelerator compound) from that of the total bilirubin concentration (measured in the presence of the accelerator compound).

Although the direct bilirubin concentration is influenced by changes in conjugated bilirubin levels, the two are not equivalent. Similarly, indirect bilirubin is not equivalent to unconjugated bilirubin. In particular, reliance on direct and indirect bilirubin measurements can lead to errors in the diagnosis of isolated disorders of bilirubin metabolism (e.g., suspected Gilbert’s syndrome; see later). Many clinical laboratories have abandoned measurements of direct and indirect bilirubin and instead use automated reflectance spectroscopic assays that provide more accurate estimates of conjugated and unconjugated bilirubin. These assays are useful clinically in the management of physiologic jaundice of the newborn (see later), in which neurotoxicity may result from the passage of unconjugated bilirubin across the blood-brain barrier (kernicterus). In disorders characterized by prolonged cholestasis, however, such assays may underestimate the conjugated bilirubin concentration, because they do not accurately detect albumin-bound conjugated bilirubin (so-called delta bilirubin). Indeed, if an isolated disorder of bilirubin metabolism is suspected, the diagnosis may require more sophisticated chromatographic techniques that precisely measure the concentrations of unconjugated, monoglucuronidated, and diglucuronidated bilirubin, as well as conjugated bilirubin-albumin complexes.2 In practice, these techniques are not widely used. Even with such accurate methods, measurements of conjugated and unconjugated bilirubin will not distinguish hepatic disorders from biliary obstruction. Therefore, in most cases, these tests are of limited use.

DIFFERENTIAL DIAGNOSIS

Jaundice can result from an increase in the formation of bilirubin or a decrease in the hepatobiliary clearance of bilirubin. From a practical standpoint, conditions that produce jaundice can be classified under the broad categories of isolated disorders of bilirubin metabolism, liver disease, and obstruction of the bile ducts (Table 20-1).

Table 20-1 Differential Diagnosis of Jaundice and Hyperbilirubinemia

Isolated Disorders of Bilirubin Metabolism
Unconjugated Hyperbilirubinemia

Conjugated or Mixed Hyperbilirubinemia Liver Disease Hepatocellular Dysfunction Hepatic Disorders with Prominent Cholestasis Obstruction of the Bile Ducts Choledocholithiasis Diseases of the Bile Ducts Extrinsic Compression

AIDS, acquired immunodeficiency syndrome.

ISOLATED DISORDERS OF BILIRUBIN METABOLISM

Unconjugated Hyperbilirubinemia

Three basic mechanisms can lead to isolated unconjugated hyperbilirubinemia: (1) increased bilirubin production; (2) decreased hepatocellular uptake of unconjugated bilirubin; and (3) decreased bilirubin conjugation. In each of the resulting conditions, liver function is otherwise normal, and the results of standard biochemical liver tests other than the serum bilirubin concentration are normal.

Increased Bilirubin Production

Processes that can generate excessive bilirubin production include hemolysis, ineffective erythropoiesis, and resorption of a hematoma.2 Jaundice may thus complicate the clinical course of patients with hemolytic anemias, megaloblastic anemia from folate or vitamin B12 deficiency, iron deficiency anemia, sideroblastic anemia, and polycythemia vera. With these disorders, bilirubin concentration does not generally exceed 4 to 5 mg/dL. Jaundice can follow massive blood transfusions, because the foreshortened lifespan of transfused erythrocytes leads to excessive hemoglobin release. Hyperbilirubinemia resulting from resorption of hematomas and blood transfusions also may develop in patients who have experienced major trauma.8

Decreased Bilirubin Conjugation

Three autosomally inherited disorders of unconjugated hyperbilirubinemia are attributable to impaired bilirubin conjugation (Table 20-2). The most common of these disorders is Gilbert’s syndrome, which has a prevalence of approximately 10% in white populations. The disorder is entirely benign and rarely produces clinical jaundice. Serum bilirubin levels may rise two- to threefold with fasting or dehydration but are generally below 4 mg/dL. Patients with Gilbert’s syndrome typically present during or after adolescence, when isolated hyperbilirubinemia is detected as an incidental finding on routine multiphasic biochemical screening. The molecular basis of Gilbert’s syndrome has been linked to a reduction in transcription of the B-UGT gene UGT1A1 as a result of mutations in the promoter region and, less commonly, in the coding region.1

Mutations in the coding region of UGT1A1 appear to be responsible for Crigler-Najjar syndrome.12 In type I Crigler-Najjar syndrome, B-UGT activity is absent, and many patients die of kernicterus in the neonatal period (see Table 20-2). Phototherapy (see later) is required to prevent kernicterus, and liver transplantation can be lifesaving. Persons with type II Crigler-Najjar syndrome have markedly reduced B-UGT activity, with serum bilirubin levels between those of patients with Gilbert’s syndrome and those with type I Crigler-Najjar syndrome (see Table 20-2). In contrast to patients with type I Crigler-Najjar syndrome, those with type II Crigler-Najjar syndrome are not ill during the neonatal period and may not be diagnosed until early childhood. Although the degree of jaundice can wax and wane, most patients with type II Crigler-Najjar syndrome experience a fall in serum bilirubin levels to 2 to 5 mg/dL with phenobarbital, an agonist for the constitutive androstane receptor CAR, which increases expression of UGT1A1 and thus increases B-UGT activity.13 Such patients have normal life expectancies and do not manifest neurologic impairment.

A related disorder of bilirubin metabolism is physiologic jaundice of the newborn. This syndrome, which is believed to result from delayed developmental expression of B-UGT, is characterized by transient jaundice that generally resolves rapidly in the neonatal period. A brief course of phototherapy may be required to prevent kernicterus. B-UGT is inhibited competitively by the viral protease inhibitors indinavir and atazanavir, which produce hyperbilirubinemia in more than 25% of patients who receive these agents.14,15

Conjugated or Mixed Hyperbilirubinemia

A selective decrease in bilirubin secretion into the bile canaliculus may produce conjugated or mixed hyperbilirubinemia (i.e., an increase in conjugated and unconjugated bilirubin concentrations). Such a defect underlies two autosomally inherited disorders, Dubin-Johnson syndrome and Rotor’s syndrome. Each of these disorders is associated with a benign clinical course. In Dubin-Johnson syndrome, the molecular defect has been linked to an absence of expression of or impaired canalicular membrane targeting of the multispecific organic anion transporter MRP2.5 Interestingly, in Dubin-Johnson syndrome and in selected cholestatic disorders (e.g., primary biliary cirrhosis), compensatory up-regulation of the sinusoidal export protein MRP3 has been reported.16 Up-regulation of MRP3 may prevent hepatocellular overload by potentially toxic organic anions that are normally secreted by MRP2. The molecular basis of Rotor’s syndrome is unknown and does not appear to involve mutations in MRP2.17 In both Dubin-Johnson and Rotor’s syndromes, global hepatic function is preserved. Serum bilirubin levels are elevated, but serum levels of other commonly measured liver biochemical tests are normal.

Dubin-Johnson and Rotor’s syndromes can be distinguished biochemically and histologically (see Table 20-2). In Dubin-Johnson syndrome, hepatocytes contain a characteristic black pigment that is not seen in Rotor’s syndrome. This pigment is believed to result from lysosomal deposition of aromatic amino acid metabolites that are putative substrates for MRP2.5 Liver biopsy is generally unnecessary in the diagnostic evaluation of patients suspected to have Dubin-Johnson or Rotor’s syndrome, however, because neither disorder is associated with an adverse clinical outcome.

LIVER DISEASE

Jaundice is a common feature of generalized hepatic dysfunction. In contrast to isolated disorders of bilirubin metabolism, icteric liver disease is characterized by an increase in serum bilirubin concentration that generally occurs in association with abnormalities in other standard biochemical liver test results. The extensive differential diagnosis of icteric liver disease is outlined briefly here. In the discussion that follows, disorders in which hyperbilirubinemia and jaundice are simply manifestations of global hepatocellular dysfunction will be distinguished from those for which cholestasis is a major or predominant manifestation. The latter are often difficult to distinguish clinically from obstruction of the bile ducts.

Acute Hepatocellular Dysfunction

Generalized impairment of hepatocellular function can result from acute or chronic liver injury. A clue to such disorders is the presence of elevated serum activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (see later and Chapter 73). Among conditions that produce acute or subacute hepatocellular injury are viral hepatitis, exposure to hepatotoxins, hepatic ischemia, and certain metabolic derangements. Acute viral hepatitis often is heralded by anorexia, malaise, myalgias, or discomfort in the epigastrium or right upper abdominal quadrant before jaundice develops (see Chapters 77 to 81). Five major hepatitis viruses have been isolated. Hepatitis A and E viruses are transmitted enterally. Each typically produces a self-limited illness that does not progress to chronic liver disease. By contrast, hepatitis B, C, and D viruses are transmitted parenterally, and illness produced by these agents can be prolonged and may lead to chronic disease. Major risk factors for hepatitis B, C, and D include injection drug use, exposure to blood products, and unprotected sexual exposures. The diagnosis of each of these disorders is aided by serologic testing (see later).

Many drugs and toxins produce hepatocellular injury (see Chapters 86 and 87). In particular, ingestion of acetaminophen (in large quantities) or of the mushroom Amanita phalloides may lead to hepatocellular necrosis and jaundice within several days after exposure. Toxic liver injury can have a fulminant course associated with a high mortality rate (see Chapter 93). In patients who survive, jaundice generally resolves and hepatic function recovers completely in those without preexisting liver disease. Certain drugs can produce idiosyncratic hepatocellular injury and jaundice, and these are discussed extensively elsewhere in this text (see Chapter 86). Alcoholic hepatitis should be a diagnostic consideration in the jaundiced patient with ethanol dependency, particularly when hepatomegaly and fever are present (see Chapter 84). Laboratory studies may help distinguish this entity from most other acute liver diseases (see later).

Jaundice related to hepatic ischemia may result from hypotension, hypoxia, hyperthermia, or hepatic venous outflow obstruction (see Chapter 83). Thrombosis of the hepatic vein (Budd-Chiari syndrome) or sinusoidal obstruction syndrome (hepatic veno-occlusive disease) should be suspected in a patient who presents with the rapid onset of ascites and hepatomegaly; the latter syndrome is more commonly associated with jaundice and is a complication of certain cytotoxic agents, particularly in the setting of hematopoietic cell transplantation (see also Chapter 34).

Wilson disease, an inherited disorder of hepatobiliary copper secretion, may manifest de novo with clinical features indistinguishable from those of acute viral hepatitis (see Chapter 75). The disease should be a diagnostic consideration in patients younger than 40 years, particularly when neurologic abnormalities are present or Kayser-Fleischer rings are seen on slit-lamp examination of the eye. Hemolytic anemia is a part of the spectrum of Wilson disease and contributes to the disproportionate hyperbilirubinemia often present in these patients. The diagnosis of Wilson disease is confirmed by biochemical testing and liver copper analysis (see later). Reye’s syndrome, a disorder of fatty infiltration of the liver associated with impaired mitochondrial metabolism of fatty acids, may produce jaundice as a manifestation of acute liver failure (see Chapter 86 and 93). It usually follows a viral illness in children, has been associated with the ingestion of aspirin, and is heralded by nausea and vomiting; its incidence has declined markedly as a result of public health campaigns advocating the avoidance of aspirin in children.

Chronic Hepatocellular Dysfunction

In contrast with acute liver disease, jaundice does not typically develop in chronic conditions associated with hepatocellular injury unless cirrhosis is present. A major cause of cirrhosis is chronic viral hepatitis, which should be a diagnostic consideration in patients with risk factors for parenteral exposure to causative agents. Diagnosis is aided by serologic testing (see later). Cirrhosis is part of the spectrum of nonalcoholic fatty liver disease, which is emerging as the most common cause of chronic hepatocellular injury in industrialized nations; major risk factors are obesity and diabetes mellitus (see Chapter 85). A similar histologic picture of steatohepatitis and sinusoidal fibrosis is found in the setting of alcoholic liver disease (see Chapter 84). Toxic injury by other compounds is less likely to produce cirrhosis, although cirrhosis has been described as a manifestation of industrial exposure to vinyl chloride and as a consequence of chronic ingestion of large quantities of vitamin A (see Chapter 87). Certain hereditary metabolic liver diseases may progress to cirrhosis. Hemochromatosis, a disorder characterized by excessive intestinal iron absorption with resulting hepatocellular iron accumulation and injury, is the most common of these (see Chapter 74). Although most affected persons are asymptomatic, the presence of diabetes mellitus, arthritis, or deep pigmentation in a jaundiced person should heighten suspicion for the disorder. The diagnosis is confirmed by detection of mutations in the HFE gene or by hepatic iron analysis. Hepatocellular copper overload and injury in Wilson disease also may progress to cirrhosis (see Chapter 75). As noted, the diagnosis should be suspected in younger persons, and the disease confirmed by biochemical testing and liver copper analysis. In a jaundiced patient with chronic obstructive pulmonary disease, α1-antitrypsin deficiency should be suspected (see Chapter 76). In this disorder, mutant α1-antitrypsin is misfolded and accumulates in the endoplasmic reticulum of hepatocytes, proteasomal degradation is impaired, and liver injury results. The diagnosis can be confirmed by laboratory testing and liver biopsy (see later). Autoimmune hepatitis, a disease that may be associated with systemic complaints such as malaise, fever, and arthralgias, is more common in women than in men (see Chapter 88). The diagnosis is aided by serologic testing and liver biopsy (see later). Celiac disease (see Chapter 104) may manifest as otherwise unexplained chronic liver disease—although rarely, if ever, with jaundice.