Inborn errors of bilirubin metabolism & wilson disease

Inborn errors of bilirubin metabolism & wilson disease

1. Inborn Errors of Bilirubin Metabolism & Wilson Disease

2. Bilirubin Metabolism

3. 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

4. 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

5. Crigler-Najjar type-1 Rare Autosomal recessive trait Severe deficiency of UDP glucuronyl transferase . Often fatal

6. Crigler-Najjar type-1 Clinical manifestations Severe unconjugated hyperbilirubinemia develops in the 1 st 3 days of life Without trtmnt , S.unconjugated bilirubin concentrations of 25-35mg/dl are reached in 1 st month. Kernicterus – universal complication

7. Crigler-Najjar type-1 Stools – pale yellow Persistence of unconjugated hyperbilirubinemia >20mg/dl after 1 st week of life In the absence of hemolysis suggests CN type 1

8. 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

9. Treatment The S.unconjugated bilirubin conc. Should be kept to <20 mg/dl for atleast 1 st 2-4 wk of life This requires repeated exchange transfusions & phototherapy i n 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 r esponse to phenobarbital Rx ]

10. 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

11. 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

12. 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

13. Clinical manifestations Appears in neonatal period Unconjugated hyperbilirubinemia occurs in 1 st 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

14. 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

15. Treatment Long term reduction- continued administration of phenobarbital at 5mg/kg/24hr Good prognosis

16. 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

17. Routine liver function tests are normal Jaundice can be exacerbated by infection, pregnancy, OCP, alcohol consumption & surgery No morbidity & life expectancy is normal

18. 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

19. Dubin -Johnson syndrome Clinical manifestations Abdominal pain Fatigue Jaundice- fluctuates in intensity & is aggravated by intercurrent ds Dark urine Slight enlargement of liver

20. 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

21. Diagnosis Liver histology demonstrates n/l architecture, but hepatocytes contain black pigment similar to melanin So referred as BLACK LIVER JAUNDICE

22. 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 .

23. 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 radiogra p hy

24. Wilson’s disease

25. 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

26. 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

27. 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 .

28. 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

29. Clinical Manifestations HEPATIC Asymptomatic hepatomegaly Subacute or chronic hepatitis Acute hepatic failure Portal hypertension Ascites Edema Variceal bleeding The younger the pt , the more likely hepatic involvement will be the predominant feature

30. Clinical Manifestations NEUROLOGICAL Intention tremor Dysarthria Rigid dystonia Parkinsonism Choreiform movts Lack of motor coordination Deterioration in school performance Behavioral changes PSYCHIATRIC MANIFESTATIONS : depression, personality changes, anxiety, psychosis

31. Clinical Manifestations Kayser -Fleischer Ring KF ring are absent in young pts with hepatic W ilson’s ds up to 50% of the time but are present in 95% of pts with neurologic symptoms

32. 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

33. Diagnosis The clinical suspicion is confirmed by study of indices of Cu metabolism 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 W ilson ds Urinary Cu excretion (usually <40 ự g/day)is ↑ sed to >100 ựg/day

34. 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 >250 ự g/g dry wt Family mebers of pt require screening for pesymptomatic Wilson ds

35. Treatment Restrict dietary Cu <1mg/day Foods suchs as liver, shellfish, nuts & chocolates should be avoided 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 or Triethylene tetramine dihydrochloride ( Ttien,TETA , trientine ) @ 0.5-2g/day for adults & 20mg/kg/day for children

36. 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 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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