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The Hyperbilirubinemias

Chapter 349 | Part 10: Disorders of the Gastrointestinal System · Part 10 – Gastrointestinal Disorders

Detailed clinical reference synthesised from Harrison's Principles of Internal Medicine, 22nd Edition

🔑 Key Clinical Points

  1. Gilbert syndrome is the most common cause of unconjugated hyperbilirubinemia, characterized by mild elevation (<4 mg/dL) and normal liver tests.
  2. Crigler-Najjar syndrome Type I presents with severe unconjugated hyperbilirubinemia (>20 mg/dL) and high risk of kernicterus; Type II has lower levels and responds to phenobarbital.
  3. Dubin-Johnson syndrome is characterized by conjugated hyperbilirubinemia and a black liver due to lipofuscin pigment accumulation.
  4. Rotor syndrome presents with conjugated hyperbilirubinemia but lacks the characteristic black liver pigmentation of Dubin-Johnson.
  5. Progressive Familial Intrahepatic Cholestasis (PFIC) types 1, 2, and 3 present with severe cholestasis in childhood; PFIC3 is associated with elevated GGT.
  6. Bilirubin metabolism involves four steps: uptake, intracellular binding, conjugation, and biliary excretion; defects in any step cause hyperbilirubinemia.
  7. Drug-induced hyperbilirubinemia (e.g., atazanavir, irinotecan) should be considered in patients with preexisting Gilbert syndrome.
  8. Neonatal jaundice is physiologic due to immature UGT1A1; levels >20 mg/dL require intervention to prevent kernicterus.
  9. In Dubin-Johnson syndrome, urinary coproporphyrin isomer I is elevated (>80% of total), distinguishing it from Rotor syndrome.
  10. Phenobarbital induces UGT1A1 activity, reducing bilirubin in Gilbert and Crigler-Najjar Type II syndromes.

📑 Table of Contents

📋 Figures in This Chapter

# Type Description
1 🔀 Flowchart The Hyperbilirubinemias Figure 348-1 is tinct but interrelated steps (Fig
1 🖼 Figure Structural organization of the human UGT1 gene complex

1. DEFINITION & OVERVIEW

The hyperbilirubinemias are disorders characterized by elevated serum bilirubin levels resulting from perturbations in bilirubin metabolism and transport. The causes of liver test abnormalities vary according to region; in developing nations, infectious diseases are more commonly the etiology of abnormal serum liver tests than in developed nations. The tests and principles presented are applicable worldwide.

1.1 Liver Test Patterns

Liver test patterns direct further evaluation. No single set of liver tests will necessarily provide a diagnosis; it is often necessary to repeat tests over days to weeks for a diagnostic pattern to emerge.

Table 1 — Table 348-1 Liver Test Patterns in Hepatobiliary Disorders

TYPE OF DISORDER BILIRUBIN AMINOTRANSFERASES ALKALINE PHOSPHATASE ALBUMIN PROTHROMBIN TIME
Hemolysis/Gilbert's syndrome Normal to 86 μmol/L (5 mg/dL)\n85% due to indirect fractions\nNo bilirubinuria Normal Normal Normal Normal
Acute hepatocellular necrosis (viral, ischemic, and drug- or toxin-induced hepatitis) Both fractions may be elevated\nPeak usually follows aminotransferases\nBilirubinuria Elevated, often >500 IU, ALT > AST\nPeak usually follows aminotransferases Normal to <3× normal elevation Normal to <3× normal elevation Normal\nUsually normal. If >5× corrected by parenteral vitamin K, suggests poor prognosis
Chronic hepatocellular disorders Both fractions may be elevated\nBilirubinuria Elevated, but usually <300 IU Normal to <3× normal elevation Often decreased Often prolonged\nFails to correct with parenteral vitamin K
Alcoholic hepatitis, cirrhosis Both fractions may be elevated\nBilirubinuria AST:ALT >2 suggests alcoholic hepatitis or cirrhosis Normal to <3× normal elevation Often decreased Often prolonged\nFails to correct with parenteral vitamin K
Intra- and extrahepatic cholestasis (obstructive jaundice) Both fractions may be elevated\nBilirubinuria\nRarely >500 IU Normal to moderate elevation Elevated, often >4× normal elevation\nNormal, unless chronic Normal, unless chronic Normal\nIf prolonged, will correct with parenteral vitamin K
Infiltrative diseases (tumor, granulomata) Usually normal Normal to slight elevation Elevated, often >4× normal elevation Normal Normal\nFractionate, or confirm liver origin with 5′-nucleotidase or γ-glutamyl transpeptidase

2. EPIDEMIOLOGY

Gilbert syndrome is common, with many series placing its prevalence as high as 8%. Males predominate over females by reported ratios ranging from 1.5:1 to >7:1. These ratios may have a large artifactual component since normal males have higher mean bilirubin levels than normal females, but the diagnosis of GS is often based on comparison to normal ranges established in men. The high prevalence of GS in the general population may explain the reported frequency of mild unconjugated hyperbilirubinemia in liver transplant recipients.

2.1 Regional Variation

The causes of liver test abnormalities vary according to region. In developing nations, infectious diseases are more commonly the etiology of abnormal serum liver tests than in developed nations.

3. ETIOLOGY & PATHOPHYSIOLOGY

The hyperbilirubinemias are best understood in terms of perturbations of specific aspects of bilirubin metabolism and transport. Bilirubin is the end product of heme degradation. Some 70–90% of bilirubin is derived from degradation of the hemoglobin of senescent red blood cells. Bilirubin produced in the periphery is transported to the liver within the plasma, where, due to its insolubility in aqueous solutions, it is tightly bound to albumin. Under normal circumstances, bilirubin is removed from the circulation rapidly and efficiently by hepatocytes. Transfer of bilirubin from blood to bile involves four distinct but interrelated steps.

3.1 Bilirubin Metabolism Steps

  1. Hepatocellular uptake: Uptake of bilirubin by the hepatocyte has carrier-mediated kinetics. Although a number of candidate bilirubin transporters have been proposed, the identity of the actual transporter remains elusive.\n2. Intracellular binding: Within the hepatocyte, bilirubin is kept in solution by binding as a nonsubstrate ligand to several of the glutathione-S-transferases, formerly called ligandins.\n3. Conjugation: Bilirubin is conjugated with one or two glucuronic acid moieties by a specific UDP-glucuronosyltransferase to form bilirubin mono- and diglucuronides, which are actively transported across the canalicular membrane into the bile. In addition to this direct excretion of bilirubin glucuronides, a portion are transported into the portal circulation by MRP3 and subjected to reuptake into the hepatocyte by OATP1B1 and OATP1B3.\n4. Biliary excretion: It has been thought until recently that bilirubin mono- and diglucuronides are excreted directly across the canalicular plasma membrane into the bile canaliculus by an ATP-dependent transport process mediated by a canalicular membrane protein called multidrug resistance–associated protein 2 (MRP2, ABCC2). Mutations of MRP2 result in the Dubin-Johnson syndrome. However, studies in patients with Rotor syndrome indicate that after formation, a portion of the glucuronides is transported into the portal circulation by a sinusoidal membrane protein called multidrug resistance–associated protein 3 (MRP3, ABCC3) and is subjected to reuptake into the hepatocyte by the sinusoidal membrane uptake transporters organic anion transport protein 1B1 (OATP1B1, SLCO1B1) and OATP1B3 (SLCO1B3).

3.2 Extrahepatic Aspects of Bilirubin Disposition

Bilirubin in the Gut: Following secretion into bile, conjugated bilirubin reaches the duodenum and passes down the gastrointestinal tract without reabsorption by the intestinal mucosa. An appreciable fraction is converted by bacterial metabolism in the gut to the water-soluble colorless compound urobilinogen. Urobilinogen undergoes enterohepatic circulation. Urobilinogen not taken up by the liver reaches the systemic circulation, from which some is cleared by the kidneys. Unconjugated bilirubin ordinarily does not reach the gut except in neonates or, by ill-defined alternative pathways, in the presence of severe unconjugated hyperbilirubinemia (e.g., Crigler-Najjar syndrome, type I). Unconjugated bilirubin that reaches the gut is partly reabsorbed, amplifying any underlying hyperbilirubinemia.\nRenal Excretion of Bilirubin Conjugates: Unconjugated bilirubin is not excreted in urine, as it is too tightly bound to albumin for effective glomerular filtration and there is no tubular mechanism for its renal secretion. In contrast, the bilirubin conjugates are readily filtered at the glomerulus and can appear in urine in disorders characterized by increased bilirubin conjugates in the circulation. It should be kept in mind that the kidney can serve as an "overflow valve" for conjugated bilirubin. Consequently, the level of jaundice in individuals with conjugated hyperbilirubinemia can be amplified in the presence of renal failure.

3.3 Disorders of Bilirubin Metabolism Leading to Unconjugated Hyperbilirubinemia

■ INCREASED BILIRUBIN PRODUCTION\nHemolysis: Increased destruction of erythrocytes leads to increased bilirubin turnover and unconjugated hyperbilirubinemia; the hyperbilirubinemia is usually modest in the presence of normal liver function. In particular, the bone marrow is only capable of a sustained eightfold increase in erythrocyte production in response to a hemolytic stress. Therefore, hemolysis alone cannot result in a sustained hyperbilirubinemia of more than ∼68 μmol/L (4 mg/dL). Higher values imply concomitant hepatic dysfunction. When hemolysis is the only abnormality in an otherwise healthy individual, the result is a purely unconjugated hyperbilirubinemia, with the direct-reacting fraction as measured in a typical clinical laboratory being ≤15% of the total serum bilirubin. In the presence of systemic disease, which may include a degree of hepatic dysfunction, hemolysis may produce a component of conjugated hyperbilirubinemia in addition to an elevated unconjugated bilirubin concentration. Prolonged hemolysis may lead to the precipitation of bilirubin salts within the gallbladder or biliary tree, resulting in the formation of gallstones in which bilirubin, rather than cholesterol, is the major component. Such pigment stones may lead to acute or chronic cholecystitis, biliary obstruction, or any other biliary tract consequence of calculous disease.\nIneffective Erythropoiesis: During erythroid maturation, small amounts of hemoglobin may be lost at the time of nuclear extrusion, and a fraction of developing erythroid cells is destroyed within the marrow. These processes normally account for a small proportion of bilirubin that is produced. In various disorders, including thalassemia major, megaloblastic anemias due to folate or vitamin B12 deficiency, congenital erythropoietic porphyria, lead poisoning, and various congenital and acquired dyserythropoietic anemias, the fraction of total bilirubin production derived from ineffective erythropoiesis is increased, reaching as much as 70% of the total. This may be sufficient to produce modest degrees of unconjugated hyperbilirubinemia.\nMiscellaneous: Degradation of the hemoglobin of extravascular collections of erythrocytes, such as those seen in massive tissue infarctions or large hematomas, may lead transiently to unconjugated hyperbilirubinemia.

Flowcharts & Algorithms

Reproduced from Harrison's 22nd Edition.

Flowchart 1

The Hyperbilirubinemias Figure 348-1 is tinct but interrelated steps (Fig

Caption: The Hyperbilirubinemias Figure 348-1 is tinct but interrelated steps (Fig. 349-1). liver tests. 1. Hepatocellular uptake: Uptake of bilirubin by the hepatocyte has carrier-mediated kinetics. Although a number of candidate bilirubin applicable world- transporters have been proposed, the identity of the actual trans- to region. In porter remains elusive. the etiol- 2. Intracellular binding: Within the hepatocyte, bilirubin is kept in nations. solution by binding as a nonsubstrate ligand to several of the gluta- thione-S-transferases, formerly called ligandins.

Figures & Illustrations

Reproduced from Harrison's 22nd Edition.

Figure 1

Structural organization of the human UGT1 gene complex

Caption: FIGURE 349-2 Structural organization of the human UGT1 gene complex. This large at least 13 substrate-specific first exons (A1, A2, etc.). Since four of these are differing substrate specificities are expressed. Each exon 1 has its own promoter and substrate-specific ∼286 amino acids of the various UGT1-encoded isoforms, and carboxyl-terminal amino acids common to all of the isoforms. mRNAs for specific particular first exon such as the bilirubin-specific exon A1 to exons 2 to 5. The resulting enzyme, in this particular case, bilirubin-UDP-glucuronosyltransferase (UGT1A1). single isoform. Those in exons 2–5 affect all enzymes encoded by the UGT1 complex. bilirubin mono- and diglucuronide, respectively. Conjugation dis- — Figure 349-2 Structural organization of the human UGT1 gene complex. This large complex on chromosome 2 contains at least 13 substrate-specific first exons (A1, A2, etc.). Since four of these are pseudogenes, nine UGT1 isoforms with differing substrate specificities are expressed. Each exon 1 has its own promoter and encodes the amino-terminal substrate-specific ∼286 amino acids of the various UGT1-encoded isoforms, and common exons 2–5 encode the 245 carboxyl-terminal amino acids common to all of the isoforms. mRNAs for specific isoforms are assembled by splicing a particular first exon such as the bilirubin-specific exon A1 to exons 2 to 5. The resulting message encodes a complete enzyme, in this particular case, bilirubin-UDP-glucuronosyltransferase (UGT1A1).

Generated from Harrison's Principles of Internal Medicine, 22nd Edition.