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Hemochromatosis – Diagnosis and Management

Hemochromatosis – Diagnosis and Management. Pramod K. Mistry , MA, PhD, MD, FRCP Professor of Pediatrics and Medicine Chief, Pediatric Gastroenterology and Hepatology Indian Association for the Study of the Liver ‘Metabolic Liver Disease’ Mumbai. January 13, 2012.

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Hemochromatosis – Diagnosis and Management

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  1. Hemochromatosis – Diagnosis and Management Pramod K. Mistry, MA, PhD, MD, FRCP Professor of Pediatrics and Medicine Chief, Pediatric Gastroenterology and Hepatology Indian Association for the Study of the Liver ‘Metabolic Liver Disease’ Mumbai. January 13, 2012

  2. What is the diagnosis? Non-contrast CT 65 yr old male, ferritin 2660, AFP 6324 DDx GSD, thorotrast, amiodarone, cisplatin

  3. Inherited Causes of Cirrhosis Inherited Causes of Cirrhosis Hemochromatosis Familial intrahepatic cholestasis Wilson's CF Other a1 – antitrypsin deficiency Adults Newborn and infants

  4. Clinical Manifestations Hemochromatosis - Clinical Manifestations Pituitary Gonadotropin deficiency Skin bronzing Cardiomyopathy Conduction disorders Cirrhosis Hepatocellular carcinoma Diabetes mellitus Bacteremia Testicular atrophy Arthropathy Arthritis Pseudogout

  5. Clinical Manifestations of Hereditary Hemochromatosis

  6. Hemochromatosis - Iron Balance Values Serum Transferrin Quantitative iron TIBC saturation Ferritin hepatic iron (mg/dL) (mg/dL) (%) (mg/dL) (mg/g dry wt) 60-180 230-370 20-50 20-200 300-1500 >180 <300 >50 >300 >3000 Normal Hemochromatosis

  7. Classification of Iron Overload Syndromes

  8. Normal Iron Balance Normal 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. Iron Homeostasis in Health and Disease HH – sparing of Kuppfer cells Pietrangelo, A. N Engl J Med 2004;350:2383-2397

  10. Iron Transport and Storage Iron Transport and Storage Transport Transferrin - two iron atoms Intracellular storage Ferritin - thousands of iron atoms Total body iron - 4g RBCs Storage iron Other

  11. Hfe Mutation ‘Mild’ Hemochromatosis Normal

  12. HJV hemochromatosis Massive iron overload TfR2 hemochromatosis Mild iron overload Ferroportin hemochromatosis – Tissue iron overload with Relative circulatory iron deficiency HAMP hemochromatosis Dramatic iron overload

  13. HFE Protein Structure HFE Protein Structure H63D Mutation S65C mutation a Heavy chain a1 a2 NH2 NH2 b2 microglobulin a3 C282Y Mutation COOH COOH Bacon BR, et al. Gastroenterology 1999; 116: 193

  14. What about India?

  15. Global Prevalence of HFE Mutations Global Prevalence of HFE Mutations Frequency (%) C282Y H63D Population allelic allelic United Kingdom 6.4 12.8 Norway 6.4 11.2 Denmark 9.5 12.2 Finland 0 11.8 Former USSR 1.0 10.4 Germany 3.9 14.8 Italy 0.5 12.6 Spain 3.2 26.3 Greece 1.3 13.5 Saudi Arabia 0 8.5 Africa 0 2.6 Indian subcontinent 0.2 8.4 Asia 0 1.9 Australasia 0 0.2 Americas 0.7 2.6 Bacon, et al., Gastroenterology 1999; 116:193

  16. Andrews, N. C. et al. N Engl J Med 2005;353:189-198 Pietrangelo, A. N Engl J Med 2004;350:2383-2397

  17. Hemochromatosis Natural History Cirrhosis, organ failure 40 Tissue injury 30 Total body iron (g) 20 ­ Hepatic iron 10 ­ Serum iron Normal 0 10 40 20 30 50 Age (years)

  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. Prognosis Risk of HCC 119 x N Cirrhosis 10 xN Cardiomyopathy 306 x N Diabetes mellitus 10 x N Reduced survival in cirrhotic HH. Non-cirrhotic HH, normal survival (Niederau, Gastro 1996 250 patients followed for 14 +/- 7 yrs – 69 patients died)

  20. Iron Balance Values Serum Transferrin Quantitative iron TIBC saturation Ferritin hepatic iron (mg/dL) (mg/dL) (%) (mg/dL) (mg/g dry wt) 60-180 230-370 20-50 20-200 300-1500 >180 <300 >50 >300 >3000 Normal Hemochromatosis

  21. Diagnostic Testing ? Modified Diagnostic Algorithm for Use in India Family 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 Extrahepatic manifestations of iron overload; Positive FH Liver biopsy with iron stain and quantitative iron ­ stainable Fe Iron index >2 Therapeutic Phlebotomy, response confirms diagnosis Equivocal results

  22. Interpretation of Ferritin Levels ­ iron ¯ iron Interpretation of Ferritin Levels Hemochromatosis Acute liver injury ­ Ferritin and Acute phase reactant Normal ferritin and ¯ iron Chronic disease ¯ Ferritin and ¯ iron Iron deficiency

  23. Hepatic Iron Index Hepatic Iron Index Liver iron Age (mmol/g) (yr) 15 10 5 Cirrhotic 4 Index 3 2 Precirrhotic 1 0 Normals Alcoholic Hemochromatosis Heterozygotes Homozygotes

  24. Phlebotomy – Therapy for Iron Overload Phlebotomy Acute 1 unit (250 mg Fe) weekly or biweekly until mildly anemic Maintenance Once iron stores are depleted (ferritin <50ng/ml, transferrin sat <50%) continue with phlebotomy every 2-3 months. Monitor hemoglobin, ferritin and transferrin saturation

  25. Phlebotomy Improves Survival Phlebotomy Improves Survival Preventable: all clinical manifestations Reversible: cardiac dysfunction, glucose intolerance, hepatomegaly, skin pigmentation Irreversible: cirrhosis risk of hepatocellular carcinomaarthropathy, hypogonadism Niederau C, et al. N Engl J Med 1985; 313:1256

  26. Iron Depletion Improves Survival 100 80 Iron depleted after 18 months 60 Cumulative survival (%) Untreated after 18 months 40 20 0 5 20 10 15 25 0 Time (years) Iron Depletion Improves Survival Niederau C, et al. N Engl J Med 1985; 313:1256

  27. Response to Phlebotomy 100 2000 Transferrin saturation 80 1500 Serum ferritin 60 Transferrin % Ferritin ng/ml 1000 Hgb drops 40 500 20 Phlebotomy 0 0 4 8 12 16 20 24 28 32 Time (months) Response to Phlebotomy Edwards CQ, et al. Hospital Practice 1991; 26:30

  28. Quantitative Phlebotomy As A Diagnostic Test For HH • Indication • liver 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 produce • an iron deficiency anemia • In contrast, patients with significant iron loading usually • have at least 5 g (and often 20 g or more) of iron stores, requiring at least • 20 units of phlebotomy to induce iron deficiency

  29. Inherited Causes of Cirrhosis Genetic Diseases - Liver Inherited Causes of Cirrhosis Hemochromatosis Familial intrahepatic cholestasis Wilson's CF Other a1 – antitrypsin deficiency Adults Newborn and infants

  30. Neonatal Hemochromatosis • Late fetal or early neonatal loss • Renal hypoplasia • Often with oligohydramnios Features • Raised ferritin • Hepatocellular synthetic failure • Extensive cholestasis • Low or absent AST/ALT • AFP >200,000 • Systemic iron overload – Dx investigation: buccal biopsy

  31. Neonatal Hemochromatosis Andrews, N. C. et al. N Engl J Med 2005;353:189-198

  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 in hemolysis with giant cell hepatitis congentalnephrotic 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. NH – Treatments • IVIG (Whitington, Lancet, 2001) • Chelation/antioxidant cocktail • NAC • Transplant

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