Inborn Errors of Bilirubin Metabolism

&Wilson

Disease

Bilirubin Metabolism

Inherited Deficient Conjugation of Bilirubin (Familial Nonhemolytic

Unconjugated Hyperbilirubinemia)

• Bilirubin is metabolic end product of heme.

• Bfr excretion it is glucuronidated by UDP-glucuronyltransferase

• UDPGT activity is deficient or altered in 3 disorders CRIGLER-NAJJAR syndromes type 1 & 2 GILBERT syndrome• Produces congenital nonobstructive, nonhemolytic,

unconjugated hyperbilirubinemia

Gilbert syndrome• Autosomal dominant trait

• The cause of this hyperbilirubinemia is the reduced activity of the enzyme  glucuronyltransferase which conjugates bilirubin.

• Usually occurs after puberty

• Not associated with c/c liver ds

• No treatment required• Total S.bilirubin fluctuates from 1-6mg/dl

Crigler-Najjar type-1• Rare

• Autosomal recessive trait

• Severe deficiency of UDP glucuronyl transferase.

• Often fatal

Crigler-Najjar type-1• Clinical manifestations

Severe unconjugated hyperbilirubinemia develops in the 1st 3 days of life

Without trtmnt, S.unconjugated bilirubin concentrations of 25-35mg/dl are reached in 1st month.

Kernicterus – universal complication

Crigler-Najjar type-1 Stools – pale yellow Persistence of unconjugated

hyperbilirubinemia >20mg/dl after 1st week of life

In the absence of hemolysis

suggests CN type 1

Diagnosis • Early age of onset

• Extreme level of bilirubin elevation in the absence of hemolysis

• In the bile, bilirubin conc <10mg/dl (nly 50-100mg/dl)

• Definitive diagnosis- measuring hepatic glucuronyl transferase activity in liver specimen

• Identification of heterozygous state in parents also strongly suggests the diagnosis

Treatment • The S.unconjugated bilirubin conc. Should be kept to

<20 mg/dl for atleast 1st 2-4 wk of life

• This requires repeated exchange transfusions & phototherapy in the immediate neonatal period.

• Oral calcium phosphate supplementation renders phototherapy more effective as it forms complexes with bilirubin in the gut.

• Phenobarbital therapy thru CYP450 enzyme induction- determine responsiveness & differentiation btw type 1 & 2 [ CN type1- no response to phenobarbital Rx ]

Treatment • The risk of kernicterus persists into adult life; therefore

phototherapy is continued thru the early yrs of life

• Despite the administration of ↑sing intensities of light for longer periods, the S.bilirubin response to phototherapy ↓ses with age

• Adjuvant therapy using agents that bind photobilirubin products such as cholestyramine or agar can also be used

• Orthotopic liver transplantation cures d ds

Treatment • Inhibiting bilirubin production via heme oxygenase

inhibitors – metalloporphyrin therapy

• Prompt trtmnt of intercurrent infections, febrile episodes might help in preventing later development of kernicterus

Crigler-Najjar type-2

• autosomal recessive ds

• characterized by unconjugated hyperbilirubinemia due to reduced and inducible activity of hepatic bilirubin glucuronosyltransferase (GT)

• Milder form

• CNS2 can be differentiated from CNS1 by the marked decline in S.bilirubin level that occurs in type2 ds after Rx with phenobarbital

Clinical manifestations• Appears in neonatal period

• Unconjugated hyperbilirubinemia occurs in 1st 3 days of life

• Bilirubin level does not exceed 20mg/dl in type 2

• Development of kernicterus is unusual

• Stool color- normal

• Liver enzymes & synthetic function tests are normal

Diagnosis

• Respond readily to 5mg/kg/24 hr of oral phenobarbital, with a decrease in S.bilirubin conc. To 2-3mg/dl in 7-10 days

Treatment

• Long term reduction- continued administration of phenobarbital at 5mg/kg/24hr

• Good prognosis

Inherited Conjugated Hyperbilirubinemia

• Caused by a small no of rare autosomal recessive conditions

• Characterized by mild jaundice

• The transfer of bilirubin & other organic anions from the liver cell to bile is defective

• Usually detected during adolescence or early adulthood

• Routine liver function tests are normal

• Jaundice can be exacerbated by infection, pregnancy, OCP, alcohol consumption & surgery

• No morbidity & life expectancy is normal

Dubin-Johnson syndrome

• Autosomal recessive

• defective excretion of conjugated bilirubin due to defective ATP dependent organic anionic transport in bile canaliculi

• There is mutation in the MRP-2 protein ( multi drug-resistant protein2) which is responsible for transport of conjugated bilirubin into bile

Dubin-Johnson syndrome

• Clinical manifestations

1. Abdominal pain2. Fatigue3. Jaundice- fluctuates in intensity & is aggravated

by intercurrent ds4. Dark urine5. Slight enlargement of liver

Diagnosis conjugated hyperbilirubinemia

normal liver function findings

Total urinary coproporphyrin excretion is n/l, but coproporphyrin 1 excretion ↑ses to approximately 80% with a concomitant ↓se in coproporphyrin 3 excretion .[ Nly coproporphyrin 3 is >75% of the total]

Cholangiography fails to visualize biliary tract & xray gal bladder is also abnormal

Diagnosis• Liver histology demonstrates n/l architecture, but

hepatocytes contain black pigment similar to melanin

So referred as BLACK LIVER JAUNDICE

Rotor Syndrome• Autosomal recessive

• The SLCO1B1 and SLCO1B3 genes are involved in Rotor syndrome. Mutations in both genes are required for the condition to occur.

Diagnosis • conjugated hyperbilirubinemia

• Total urinary coproporphyrin excretion is elevated with a relative ↑se in the amt o the coproporphyrin 1 isomer

• There is no staining of the liver

• The gall bladder is normal by radiography

Wilson’s disease

Wilson’s disease (hepatolenticular

degeneration)Autosomal recessive

Incidence – 1 in 30,000- 1in 50,000 births worldwide

Abnormal gene- localized to the long arm of chromosome 13

The Wilson’s ds gene – ATP7B

Pathogenesis The Wilson ds gene encodes a copper transporting P-

type adenosine triphosphatase

Mainly expressed in hepatocytes & is critical for biliary copper excretion & for copper incoporation into ceruloplasmin

Absence/Malfunction of ATP7B → ↓sed biliary copper excretion & diffuse accumulation of copper in the cytosol of hepatocytes

↓ Liver cells become overloaded & Cu is redistributed to other tissues, including brain & kidneys.

Absorption & Metabolism

Dietary source - meat, liver, sea food, cereals, nuts & seeds

Approximately 40% of ingested Cu is absorbed in stomach & small intestine

↓ Transported to the liver bound to albumin ↓ Utilized by hepatocytes for synthesis of ceruloplasmin

[8 Cu atoms/ molecule; accounts for 95% of the ion in blood]

↓ Released into systemic circulation

Clinical Manifestations• HEPATIC

1. Asymptomatic hepatomegaly2. Subacute or chronic hepatitis3. Acute hepatic failure4. Portal hypertension5. Ascites6. Edema7. Variceal bleeding

The younger the pt, the more likely hepatic involvement will be the predominant feature

Clinical Manifestations• NEUROLOGICAL

1. Intention tremor2. Dysarthria3. Rigid dystonia4. Parkinsonism5. Choreiform movts6. Lack of motor coordination7. Deterioration in school performance8. Behavioral changesPSYCHIATRIC MANIFESTATIONS: depression, personality changes, anxiety, psychosis

Clinical Manifestations• Kayser-Fleischer Ring

KF ring are absent in young pts with hepatic Wilson’s ds up to50% of the time but are present in 95% of pts with neurologicsymptoms

Clinical Manifestations Coombs-negative hemolytic anaemia may be an

initial manifestation

Due to release of large amts of Cu from damaged hepatocytes

This form is usually fatal

During hemolytic episodes, urinary Cu excretion & serum copper levels are markedly elevated

Diagnosis • The clinical suspicion is confirmed by study of indices of

Cu metabolism

1. Decreased ceruloplasmin levels (<20mg/dl)[ Ceruloplasmin may be ↑sed in a/c inflammation, in states of elevated estrogen such as pregnancy, OCP & may be low in autoimmune hepatitis, familial aceruloplasminemia ]

2. Serum free copper elevated in early Wilson ds

3. Urinary Cu excretion (usually <40ựg/day)is ↑sed to >100ựg/day

Diagnosis 4. Demonsatration of KF ring

5. Liver biopsy- determine the extent & severity of liver ds & for measuring hepatic Cu content Hepatic Cu accumulation is the hallmark of Wilson ds & measurement of hepatic parenchymal Cu conc. is the method of choice for diagnosis >250ựg/g dry wt

Family mebers of pt require screening for pesymptomatic Wilson ds

Treatment 1. Restrict dietary Cu <1mg/day

2. Foods suchs as liver, shellfish, nuts & chocolates should be avoided

3. Symptomatic pts- CHELATION THERAPY: oral administration of D-penicillamine in a dose 1g/day in 2 doses bfr meals for adults & 20mg/kg/day for pediatric pts

or4. Triethylene tetramine dihydrochloride (Ttien,TETA, trientine) @ 0.5-2g/day for adults & 20mg/kg/day for children

Treatment • Penicillamine is an antimetabolite of vit B6, so vit

supplementation is necessary.

• Ammonium tetrathiomolybdate is another alternative chelating agent under investigation for pts with neurologic ds

5. ZINC – used as adjuvant therapy, maintenance therapy or primary therapy in presymptomatic pts. Zinc acetate is given in adults @ dose of 25-50mg elemenatl zinc 3 times a day & 25mg 3 times a day in children >5yrs

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