Chapter 15 Bilirubin and Urobilinogen Zhang Lixia

Content * DISORDERS OF BILIRUBINMETABOLISM ● SUGGESTED READINGS ● BILIRUBIN AND UROBILINOGEN * DISORDERS OF BILIRUBINMETABOLISM ● SUGGESTED READINGS * important

BILIRUBIN AND UROBILINOGEN

Bilirubin -1 normally turn over on any given day. ■ Roughly 1% of a person's red blood cells normally turn over on any given day. ■ This results in the production of 175 to 250 mg of bilirubin daily. Another 75 to 100 mg of bilirubin is derived from ineffective erythropoiesis and the turnover of other hemoproteins

Bilirubin -2 ■ Heme is degraded to biliverdin, and biliverdin is rapidly converted to bilirubin through a series of enzymes ■ Bilirubin readily binds to albumin, and this complex is transported through the circulation to the liver. Bilirubin is transferred to ligandins within the hepatocyte.

Bilirubin - 3 does not pass into the urine. ■ Conjugated bilirubin is secreted into the bile. ■ Unconjugated bilirubin is protein-bound and does not pass into the urine. ■ Urine bilirubin reflects the conjugated form and may be elevated in conjugated Hyperbilirubinemia.

Bilirubin Metabolism (normal)

Urobilinogen -1 β- glucuronidases in the terminal ileum and ■ Some bilirubin is deconjugated by bacterial β- glucuronidases in the terminal ileum and colon, and the unconjugated bilirubin is reabsorbed into the blood stream via the enterohepatic circulation.

Urobilinogen -2 is reduced to form d-urobilinogen, ■ The remainder of unconjugated bilirubin is reduced to form d-urobilinogen, mesobilirubinogen, and stercobilinogen (collectively known as urobilinogen).

■ Urine urobilinogen may be elevated in conditions associated with increased bilirubin production such as hemolytic jaundice.

Laboratory Assays bilirubin are 0.3 to 1.2 mg/dL (5 to 20μmol/L) ■ Typical reference ranges for total and direct bilirubin are 0.3 to 1.2 mg/dL (5 to 20μmol/L) and <0.3 mg/dL (<5μmol/L), respectively. ■ Normal levels of urobilinogen, up to 1 mg/dL(17μmol/L) of urine . ■ Urobilinogen is not measured routinely in serum.

DISORDERS OF BILIRUBIN METABOLISM

DISORDERS OF BILIRUBIN MRTABOLISM ■ Disorders of heme catabolism are, for all practical purposes, disorders of bilirubin metabolism. ■ When serum bilirubin levels exceed about 2 mg/dL (34μmol/L), a yellow discoloration of the skin (jaundice) or sclera (icterus) becomes evident.

DIFFEERENTIAL DIANNOSIS OF JAUNDICE Unconjugated hyperbilirubinemia Conjugated hyperbilirubinemia Increased heme catabolism Impaired hepatic excretion Hemolytic anemia Hepatocellular disease Hematoma Dubin-Johnson syndrome Impaired hepatic conjugation Rotor syndrome Neonatal jaudice Posthepatic obstruction Gilbert syndrome Crigler-najjar syndrome, types 1 and 2

Unconjugated Hyperbilirubinemia

Unconjugated Hyperbilirubinemia -1 ■ Unconjugated hyperbilirubinemia is diagnosed when total bilirubin is elevated and <20% is direct. ■ The amount of unconjugated bilirubin is especially large , the conjugation capacity of liver is relatively low, or both.

Unconjugated Hyperbilirubinemia -2 ■ The diagnosis of hemolysis may be aided by evaluation of the patient’s history, complete blood count, and measurement of the serum haptoglobin among other tests. ■ The most common form of unconjugated hyperbilirubinemia is neonatal jaundice

Hemolytic jaundice

NEONATAL HYPERBILIRUBINEMIA Epidemiology: Most, if not all infants Clinical presentation: Jaundice, usually more pronounced in upper body Laboratory findings: Increased total bilirubin, with undetectable direct bilirubin. Transaminase, ALP, albumin, PT and PTT normal Differential diagnoses: Hemolytic disease of the newborn

Conjugated Hyperbilirubinemia

Conjugated Hyperbilirubinemia -1 ■ Whenever there are defects with hepatic excretion or post-hepatic obstruction, conjugated bilirubin levels generally will rise before unconjugated levels. ■ If more than 50% of the total bilirubin is direct, the condition is termed conjugated hyperbilirubinemia.

Conjugated Hyperbilirubinemia -2 ■ Conjugated bilirubin is elevated, the urinary bilirubin also may be increased. ■ Hepatocellular diseases and cholestasis also may be accompanied by elevations of alanine and aspartate transaminases and alkaline phosphatase.

Hepatic jaundice

Obstructive jaundice

Pattern of Jaundice in Conjugated Hyperbilirubinemia Jaundice pattern elevated enzymes disease （1）hepatocellular pattern ALT, AST↑>ALP, 5’NT hepatitis （2）obstructive pattern ALP, 5’NT ↑ >ALT, AST cholelithiasis tumors （3） mixed pattern ALP, 5’NT with (2) Intrahepatic ALT, AST with (1) cholestasis

CRIGLER-NAJJAR SYNDROME TYPE І Epidemiology: Rare Clinical presentation: Severe jaundice, typically resulting in kernicterus Laboratory findings: Increased total bilirubin above 20mg/dl (340μmol/L ), with undetectable direct bilirubin. Total bilirubin unchanged after phenobarbital ingestion Transaminase, alkaline phosphatase, albumin, PT and PTT normal Differential diagnoses: Crigler-Najjar syndrome type 2

CRIGLER-NAJJAR SYNDROME TYPE Ⅱ Epidemiology: Rare Clinical presentation: Mid-moderate jaundice, exacerbated under stress Laboratory findings: Increased total bilirubin between 6 and 20mg/dl, with low to undetectable direct bilirubin. Total bilirubin diminishes after phenobarbital ingestion Transaminase, alkaline phosphatase, albumin, PT and PTT normal Differential diagnoses: Crigler-Najjar syndrome type 1, Gilbert’s syndrome complicated by hemolytic anemia

DUBIN- JOHNSON SYNDROME Epidemiology: Rare, except among Sephardic Jews Clinical presentation: Mid-moderate jaundice, red to brown urine Laboratory findings: Increased direct bilirubin ranging from 3-15mg/dl Total bilirubin unchanged after phenobarbital ingestion Urinary coproporphyrin 1 levels can distinguish heterozygotes from homozygotes Transaminase, alkaline phosphatase, albumin, PT and PTT normal Differential diagnoses: Rotor syndrome

Diagnosis and differential diagnosis of jaundice Jaundice pattern hemolytic cholestatic hepatocellular Bilirubin of blood <75mmol/L later STB - - CB UCB Bilirubin in urine negative Urobilinogen or negative or normal Enzymes pattern LDH ALP>3 times ALP later upper limit of reference range; AST, ALT, LDH, moderately

Thanks!