Hemochromatosis talk pramod mistry

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Hemochromatosis talk pramod mistry

  1. 1. Hemochromatosis – Diagnosis and ManagementPramod K. Mistry, MA, PhD, MD, FRCPProfessor of Pediatrics and MedicineChief, Pediatric Gastroenterology and HepatologyIndian Association for the Study of the Liver‘Metabolic Liver Disease’Mumbai. January 13, 2012 SLIDE 1
  2. 2. What is the diagnosis? Non-contrast CT65 yr old male, ferritin 2660, AFP 6324DDx GSD, thorotrast, amiodarone, cisplatin
  3. 3. Inherited Causes of Cirrhosis Inherited Causes of Cirrhosis Hemochromatosis Familial intrahepatic cholestasis Wilsons CF Other a1 – antitrypsin deficiencyNewborn and infants Adults
  4. 4. Clinical ManifestationsHemochromatosis - Clinical Manifestations Pituitary Gonadotropin deficiency Skin bronzing Cardiomyopathy Conduction disorders Cirrhosis Hepatocellular carcinoma Diabetes mellitus Bacteremia Testicular atrophy Arthropathy Arthritis Pseudogout
  5. 5. Clinical Manifestations of Hereditary Hemochromatosis
  6. 6. Hemochromatosis - Iron Balance Values Serum Transferrin Quantitative iron TIBC saturation Ferritin hepatic iron (mg/dL) (mg/dL) (%) (mg/dL) (mg/g dry wt) Normal 60-180 230-370 20-50 20-200 300-1500 Hemochromatosis >180 <300 >50 >300 >3000
  7. 7. Classification of Iron Overload Syndromes
  8. 8. Normal Iron BalanceNormal Iron Balance Ingested 10-20 mg/day Absorbed 1-2 mg/day Lost Gut, skin, urine - 1-2 mg/day Menses - 30 mg/month In HH daily absorption of iron is 2-4 mg despite systemic iron overload
  9. 9. Iron Homeostasis in Health and Disease HH – sparing of Kuppfer cellsPietrangelo, A. N Engl J Med 2004;350:2383-2397
  10. 10. Iron Transport and Storage Iron Transport and StorageTransport Transferrin - two iron atomsIntracellular storage Ferritin - thousands of iron atomsTotal body iron - 4g RBCs Storage Other iron
  11. 11. Hfe MutationNormal ‘Mild’ Hemochromatosis
  12. 12. TfR2 hemochromatosis HJV hemochromatosis Mild iron overload Massive iron overload Ferroportin hemochromatosis – Tissue iron overload with Relative circulatory ironHAMP hemochromatosis deficiency Dramatic iron overload
  13. 13. HFE Protein Structure HFE Protein Structure S65C H63D Mutation mutation a Heavy chain a1 a2 NH2 NH2 b2 a3 microglobulin COOH C282Y Mutation COOHBacon BR, et al. Gastroenterology 1999; 116: 193
  14. 14. What about India?
  15. 15. Global Prevalence of HFE Mutations Global Prevalence of HFE Mutations Frequency (%) C282Y H63DPopulation allelic allelicUnited Kingdom 6.4 12.8Norway 6.4 11.2Denmark 9.5 12.2Finland 0 11.8Former USSR 1.0 10.4Germany 3.9 14.8Italy 0.5 12.6Spain 3.2 26.3Greece 1.3 13.5Saudi Arabia 0 8.5Africa 0 2.6Indian subcontinent 0.2 8.4Asia 0 1.9Australasia 0 0.2Americas 0.7 2.6Bacon, et al., Gastroenterology 1999; 116:193
  16. 16. Andrews, N. C. et al. N Engl J Med 2005;353:189-198Pietrangelo, A. N Engl J Med 2004;350:2383-2397
  17. 17. HemochromatosisNatural History Cirrhosis, 40 organ failure 30 Tissue injury Total body iron 20 (g)  Hepatic 10  iron Serum iron Normal 0 10 20 30 40 50 Age (years)
  18. 18. Phenotype Expression Phenotype Expression Men > women Increases with age Correlates with amount of iron in the diet Chronic hemolysis, alcoholism, steatohepatitis, hepatitis C
  19. 19. PrognosisRisk of HCC 119 x NCirrhosis 10 xNCardiomyopathy 306 x NDiabetes mellitus 10 x NReduced survival in cirrhotic HH. Non-cirrhoticHH, normal survival(Niederau, Gastro 1996 250 patients followed for 14 +/- 7 yrs – 69patients died)
  20. 20. Iron Balance Values Serum Transferrin Quantitative iron TIBC saturation Ferritin hepatic iron (mg/dL) (mg/dL) (%) (mg/dL) (mg/g dry wt)Normal 60-180 230-370 20-50 20-200 300-1500Hemochromatosis >180 <300 >50 >300 >3000
  21. 21. Diagnostic Testing ? Modified Diagnostic Algorithm for Use in IndiaFamily history or suspicion of hemochromatosis Fe / TIBC -% saturation Ferritin % sat. >50% Ferritin >250 mg/L >300 mg/L Repeat iron panel high; Ferritin >1000 Elevated AST/ALT Liver biopsy with iron stain Extrahepatic manifestations of iron overload; and quantitative iron Positive FH stainable Fe Iron index >2 Therapeutic Phlebotomy, Equivocal results response confirms diagnosis
  22. 22. Interpretation of Ferritin LevelsInterpretation of Ferritin Levels Hemochromatosis ironFerritin Acute liver injuryand iron Acute phase reactantNormal ferritin and  Chronic diseaseiron Ferritin and  iron Iron deficiency
  23. 23. Hepatic Iron Index Hepatic Iron Index Liver iron Age (mmol/g) (yr) 15 10 5 Cirrhotic 4Index 3 2 Precirrhotic 1 0 Normals Alcoholic Hemochromatosis Heterozygotes Homozygotes
  24. 24. Phlebotomy – Therapy for Iron Overload PhlebotomyAcute 1 unit (250 mg Fe) weekly or biweekly until mildly anemicMaintenance Once iron stores are depleted (ferritin <50ng/ml, transferrin sat <50%)continue with phlebotomy every 2-3months. Monitor hemoglobin, ferritinand transferrin saturation
  25. 25. Phlebotomy Improves Survival Phlebotomy Improves Survival Preventable: all clinical manifestations Reversible: cardiac dysfunction, glucose intolerance, hepatomegaly, skin pigmentation Irreversible: cirrhosis risk of hepatocellular carcinoma arthropathy, hypogonadismNiederau C, et al. N Engl J Med 1985; 313:1256
  26. 26. Iron Depletion Improves Survival Iron Depletion Improves Survival 10 0 80 Iron depleted after 18 months 60Cumulative survival (%) Untreated after 40 18 months 20 0 0 5 10 15 20 25 Time (years)Niederau C, et al. N Engl J Med 1985; 313:1256
  27. 27. Response to Phlebotomy Response to Phlebotomy 100 Transferrin 2000 saturation 80 1500 SerumTransferri 60 ferritin Ferritin n Hgb 1000 ng/ml drop % 40 s 20 500 Phlebotomy 0 0 4 8 12 16 20 24 28 32 Time (months) Edwards CQ, et al. Hospital Practice 1991; 26:30
  28. 28. Quantitative Phlebotomy As A Diagnostic Test For HH• Indicationliver biopsy cannot be performed but suspected iron overload• Determine the number of weekly 500 mL phlebotomies,each of which removes 200 to 250 mg of elemental iron,which are required to produce iron deficient erythropoiesis.• Normal men have approximately 1 g of iron stores.• Therefore, 4-5 phlebotomies during 4-8 weeks will producean iron deficiency anemia• In contrast, patients with significant iron loading usuallyhave at least 5 g (and often 20 g or more) of iron stores, requiring at least20 units of phlebotomy to induce iron deficiency
  29. 29. Inherited Causes of CirrhosisGenetic Diseases - Liver Inherited Causes of Cirrhosis Hemochromatosis Familial intrahepatic cholestasis Wilsons CF Other a1 – antitrypsin deficiency Newborn and infants Adults
  30. 30. Neonatal Hemochromatosis• Late fetal or early neonatal loss• Renal hypoplasia• Often with oligohydramniosFeatures• Raised ferritin• Hepatocellular synthetic failure• Extensive cholestasis• Low or absent AST/ALT• AFP >200,000• Systemic iron overload – Dx investigation: buccal biopsy
  31. 31. Neonatal HemochromatosisAndrews, N. C. et al. N Engl J Med 2005;353:189-198
  32. 32. NH – pathogenetic mechanisms• Non-specific consequence of any type of liver injury• Genetic: Recurrence rate 80% in children born to same mothers*• Infectious disease• Immune mediated disease• Occurs inhemolysis with giant cell hepatitiscongental nephrotic syndrome,arthrogryphosis multiplex,all allo-immune mediated maternal diseases• IgG from NH affected mother into pregnant mouse dams leads to liver failure in the newborn
  33. 33. NH – Treatments• IVIG (Whitington, Lancet, 2001)• Chelation/antioxidant cocktail• NAC• Transplant

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