Chapter 15

Bilirubin and Urobilinogen

Zhang Lixia

Content Content

● BILIRUBIN AND UROBILINOGEN

* DISORDERS OF BILIRUBINMETABOLISM

● SUGGESTED READINGS

* important

BILIRUBIN

AND UROBILINOGEN

Bilirubin -1 Bilirubin -1

■ 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 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 Bilirubin - 3

■ 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) Bilirubin Metabolism (normal)

Urobilinogen -1 Urobilinogen -1

■ 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 Urobilinogen -2

■ The remainder of unconjugated bilirubin

is reduced to form d-urobilinogen,

mesobilirubinogen, and stercobilinogen

(collectively known as urobilinogen).

Urobilinogen -3Urobilinogen -3

■ Urine urobilinogen may be elevated

in conditions associated with increased

bilirubin production such as hemolytic

jaundice.

Laboratory AssaysLaboratory Assays

■ 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 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

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 -1Unconjugated 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 -2Unconjugated 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 jaundiceHemolytic jaundiceHemolytic jaundiceHemolytic 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 -1Conjugated 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 -2Conjugated 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 jaundiceHepatic jaundiceHepatic jaundiceHepatic jaundice

Obstructive jaundiceObstructive jaundiceObstructive jaundiceObstructive jaundice

Pattern of Jaundice in Conjugated Hyperbilirubinemia 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: RareClinical presentation: Severe jaundice, typically resulting in kernicterusLaboratory 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 normalDifferential diagnoses: Crigler-Najjar syndrome type 2

CRIGLER-NAJJAR SYNDROME TYPE Ⅱ

Epidemiology: RareClinical presentation: Mid-moderate jaundice, exacerbated under stressLaboratory 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 normalDifferential 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

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