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Inborn errors of bilirubin metabolism & wilson disease

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Inborn errors of bilirubin metabolism & wilson disease

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Inborn errors of bilirubin metabolism & wilson disease

  1. 1. Bilirubin Metabolism
  2. 2. 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
  3. 3. 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
  4. 4. Crigler-Najjar type-1 • Rare • Autosomal recessive trait • Severe deficiency of UDP glucuronyl transferase. • Often fatal
  5. 5. 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
  6. 6. 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
  7. 7. 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
  8. 8. 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 ]
  9. 9. 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
  10. 10. 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
  11. 11. 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
  12. 12. 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
  13. 13. 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
  14. 14. Treatment • Long term reduction- continued administration of phenobarbital at 5mg/kg/24hr • Good prognosis
  15. 15. 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
  16. 16. • Routine liver function tests are normal • Jaundice can be exacerbated by infection, pregnancy, OCP, alcohol consumption & surgery • No morbidity & life expectancy is normal
  17. 17. 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
  18. 18. Dubin-Johnson syndrome • Clinical manifestations 1. Abdominal pain 2. Fatigue 3. Jaundice- fluctuates in intensity & is aggravated by intercurrent ds 1. Dark urine 2. Slight enlargement of liver
  19. 19. 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
  20. 20. Diagnosis • Liver histology demonstrates n/l architecture, but hepatocytes contain black pigment similar to melanin So referred as BLACK LIVER JAUNDICE
  21. 21. 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.
  22. 22. 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
  23. 23. Wilson’s disease
  24. 24. 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
  25. 25. 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
  26. 26.  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.
  27. 27. 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
  28. 28. Clinical Manifestations • HEPATIC 1. Asymptomatic hepatomegaly 2. Subacute or chronic hepatitis 3. Acute hepatic failure 4. Portal hypertension 5. Ascites 6. Edema 7. Variceal bleeding  The younger the pt, the more likely hepatic involvement will be the predominant feature
  29. 29. Clinical Manifestations • NEUROLOGICAL 1. Intention tremor 2. Dysarthria 3. Rigid dystonia 4. Parkinsonism 5. Choreiform movts 6. Lack of motor coordination 7. Deterioration in school performance 8. Behavioral changes PSYCHIATRIC MANIFESTATIONS: depression, personality changes, anxiety, psychosis
  30. 30. Clinical Manifestations • Kayser-Fleischer Ring KF ring are absent in young pts with hepatic Wilson’s ds up to 50% of the time but are present in 95% of pts with neurologic symptoms
  31. 31. 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
  32. 32. 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
  33. 33. 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
  34. 34. 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 or 4. Triethylene tetramine dihydrochloride (Ttien,TETA, trientine) @ 0.5-2g/day for adults & 20mg/kg/day for children
  35. 35. 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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