Hemochromatosis Diagnosis and Management Pramod K Mistry MA

Hemochromatosis – Diagnosis and Management Pramod K. Mistry, MA, Ph. D, 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 SLIDE 1

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

Inherited Causes of Cirrhosis Hemochromatosis Familial intrahepatic cholestasis Wilson's CF Other a 1 – antitrypsin deficiency Newborn and infants Adults

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

Clinical Manifestations of Hereditary Hemochromatosis

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

Classification of Iron Overload Syndromes

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

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

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

Normal Hfe Mutation ‘Mild’ Hemochromatosis

Tf. R 2 hemochromatosis Mild iron overload HAMP hemochromatosis Dramatic iron overload HJV hemochromatosis Massive iron overload Ferroportin hemochromatosis – Tissue iron overload with Relative circulatory iron deficiency

HFE Protein Structure a Heavy chain H 63 D Mutation S 65 C mutation a 1 a 2 NH 2 b 2 microglobulin COOH Bacon BR, et al. Gastroenterology 1999; 116: 193 NH 2 a 3 C 282 Y Mutation

What about India?

Global Prevalence of HFE Mutations Frequency (%) Population United Kingdom Norway Denmark Finland Former USSR Germany Italy Spain Greece Saudi Arabia Africa Indian subcontinent Asia Australasia Americas Bacon, et al. , Gastroenterology 1999; 116: 193 C 282 Y allelic 6. 4 9. 5 0 1. 0 3. 9 0. 5 3. 2 1. 3 0 0 0. 2 0 0 0. 7 H 63 D allelic 12. 8 11. 2 12. 2 11. 8 10. 4 14. 8 12. 6 26. 3 13. 5 8. 5 2. 6 8. 4 1. 9 0. 2 2. 6

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

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

Phenotype Expression · Men > women · Increases with age · Correlates with amount of iron in the diet · Chronic hemolysis, alcoholism, steatohepatitis, hepatitis C

Prognosis Risk of HCC 119 x N Cirrhosis 10 x. N 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)

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

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 Equivocal results Therapeutic Phlebotomy, response confirms diagnosis

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

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

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 <50 ng/ml, transferrin sat <50%) continue with phlebotomy every 2 -3 months. Monitor hemoglobin, ferritin and transferrin saturation

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

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

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

Quantitative Phlebotomy As A Diagnostic Test For HH • Indication liver biopsy cannot be performed but suspected iron overload • Determine the number of weekly 500 m. L 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

Inherited Causes of Cirrhosis Genetic Diseases - Liver Inherited Causes of Cirrhosis Hemochromatosis Familial intrahepatic cholestasis Wilson's CF Other a 1 – antitrypsin deficiency Newborn and infants Adults

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

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

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 congental nephrotic syndrome, arthrogryphosis multiplex, allo-immune mediated maternal diseases • Ig. G from NH affected mother into pregnant mouse dams leads to liver failure in the newborn

NH – Treatments • • IVIG (Whitington, Lancet, 2001) Chelation/antioxidant cocktail NAC Transplant