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Genes and Metabolic Liver Disease: Hemochromatosis

Genes and Metabolic Liver Disease: Hemochromatosis. Bruce R. Bacon, M.D. James F. King M.D. Endowed Chair in Gastroenterology Professor of Internal Medicine Division of Gastroenterology and Hepatology Saint Louis University Liver Center St. Louis, Missouri. History of Hemochromatosis .

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Genes and Metabolic Liver Disease: Hemochromatosis

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  1. Genes and Metabolic Liver Disease: Hemochromatosis Bruce R. Bacon, M.D. James F. King M.D. Endowed Chair in Gastroenterology Professor of Internal Medicine Division of Gastroenterology and Hepatology Saint Louis University Liver Center St. Louis, Missouri

  2. History of Hemochromatosis • 1865 – Trosier – first case • 1889 – von Recklinghausen – hemochromatosis • 1935 – Sheldon – inherited defect in iron metabolism • 1976 – Simon – HLA-A3, short arm chromosome 6 • 1996 – Mecator Genetics – HFE • 1997 – present • DMT-1 • Ferroportin • Transferrin receptor-2 • Hemojuvelin • Hepcidin

  3. Classification of Inherited Iron Overload Syndromes • Hereditary Hemochromatosis • HFE-related • C282Y/C282Y • C282Y/H63D • Other HFE mutations • Non-HFE-related • Hemojuvelin (HJV) • Transferrin receptor-2 (TfR-2) • Ferroportin (SLC40A1) • Hepcidin (HAMP) • African iron overload

  4. Classification of Iron Overload Syndromes - 2 • Secondary Iron Overload • Iron-loading anemias • Thalassemia major • Sideroblastic • Chronic hemolytic anemia • Aplastic anemia • Pyruvate kinase deficiency • Pyridoxine-responsive anemia • Parenteral iron overload • Red blood cell transfusions • Iron-dextran injections • Long-term hemodialysis • Chronic liver disease • Porphyria cutanea tarda • Hepatitis C • Hepatitis B • Alcoholic liver disease • Nonalcoholic steatohepatitis • Following portocaval shunt • Dysmetabolic iron overload syndrome • Miscellaneous • Neonatal iron overload • Aceruloplasminemia • Congenital atransferrinemia

  5. HFE Genotype in Patients with Hemochromatosis *All patients had a family history of iron overload ** Compound heterozygote

  6. Ser65  Cys, S65C His63  Asp, H63D  Heavy Chain 1 2 NH2 2-microglobulin NH2 3 Cys282  Tyr, C282Y Extracellular HOOC Plasma membrane Cytosol HOOC Nature Genetics 13: 309-408, 1996

  7. HFE Genotype in Patients with Hemochromatosis • Patients with hemochromatosis • 771 patients with phenotypic HH • 670 (86.9%) with C282Y/C282Y • 44 (5.7%) with C282Y/H63D • 24 (3.1%) with C282Y/wt

  8. Incidence of Hereditary Hemochromatosis • 1 in 200 - 250 individuals of Northern European descent • 11% heterozygotes • Estimated 600,000 to 1,000,000 afflicted Americans • Estimated 27 million heterozygotes

  9. Hereditary Hemochromatosis - Diagnosis Requirements of Diagnosis • Suspicion, serum iron studies • Liver biopsy • Use of HII • Differential diagnosis • Alcoholic liver disease • Chronic viral hepatitis • Nonalcoholic steatohepatitis • Genetic test

  10. Typical Symptoms in Patients with HH %

  11. Common Physical Findings in HH %

  12. Hereditary Hemochromatosis Symptoms and Physical Findings (%) Am J Gastroenterol92:784-789, 1997

  13. Principal Clinical Features in Hereditary Hemochromatosis * Patient selection occurred by both clinical features and family screening. † Only symptomatic index cases were studied.‡ Discovered by family studies. Zakim Boyer, 1996;1453.

  14. Evaluation of Iron Stores • Serum iron, TF saturation and ferritin • Liver biopsy for stainable iron, biochemical determination of iron • Noninvasive imaging modalities • Computed tomography • Magnetic resonance imaging • Magnetic susceptibility • Iron removed by phlebotomy (1 U=250 mg)

  15. Blood Iron Studies in HH

  16. Hemochromatosis – Role of Liver Biopsy • In the past – establish diagnosis • Determine degree of fibrosis, cirrhosis • Determine other abnormalities • Phenotypic variability • Recommended if: • Ferritin > 1000 ng/mL • ALT, AST elevated • Hepatomegaly • Age > 40 years

  17. Therapeutic Phlebotomy for HH • Clearly improves survival • Prepare patients for up to 6 – 12 months • Iron burden in men greater than in women despite initial HIC • Difficult to predict phlebotomy requirements • Each unit of blood – approximately 30 ng/mL ferritin

  18. Therapeutic Phlebotomy for HH • Weekly phlebotomy • Hct. > 35% before each one • Ferritin to 50 to 100 ng/mL • Transferrin saturation to < 50%

  19. Maintenance Phlebotomy for HH • Most patients – one unit Q 2-3 months • TS < 50%; ferritin < 100 ng/mL • One unit of whole blood = 250 mg iron • Most patients absorb 2 to 3 mg/day, more than needed • Some patients – no re-accumulation

  20. Hereditary Hemochromatosis Response to Therapy Edwards et al. Ann Int Med 93:519-525, 1980

  21. Results of Therapy • Reduction to normal tissue iron stores. • Improved survival if diagnosis and treatment before development of cirrhosis and diabetes. • Improved sense of well-being, energy level. • Improved cardiac function. • Improved control of diabetes. • Reduction in abdominal pain. • Reduction in skin pigmentation. • Normalization of elevated liver enzymes. • Reversal of hepatic fibrosis (approximately 30% of cases). • No reversal of established cirrhosis. • Reduction in portal hypertension in cirrhotics. • No (or minimal) improvement in arthropathy. • No reversal of testicular atrophy.

  22. Hereditary Hemochromatosis: Survival N Engl J Med 313:1256-1262, 1985

  23. Hereditary Hemochromatosis: Survival with Cirrhosis N Engl J Med 313:1256-1262, 1985

  24. HH – Family Screening • HFE mutation analysis has replaced HLA-typing • Practically – HFE mutation analysis, TS, and ferritin all at once

  25. HH – Family Screening • For analysis of risk in children – perform mutation analysis in spouse (or other parent) first • May be able to avoid testing in children Adams, Clin Genet 53:176-178, 1998

  26. General Population Studies in HH • Transferrin saturation, ferritin, CBC • HFE mutation analysis • Several studies from around the world

  27. Population Screening for Hemochromatosis • 41,038 adults screened in San Diego • Health appraisal unit • CBC, transferrin saturation, ferritin level, HFE genotype • Questionnaire Beutler et al., Lancet 359:211-218, 2002

  28. Population Screening for Hemochromatosis • 152 C282Y/C282Y • 616 C282Y/H63D • 67% of C282Y/C282Y had elevated ferritin • No difference in symptoms from controls • 1 of 152 with signs and symptoms of hemochromatosis Beutler et al., Lancet 359:211-218, 2002

  29. Population Screening for Hemochromatosis Beutler et al., Lancet 359:211-218, 2002

  30. Prevalence of C282Y Homozygotes Without Iron Overload in Screening Studies

  31. Hereditary Hemochromatosis • Patients with C282Y/C282Y mutation without iron overload • Environmental factors • Nutritional deficiency, malabsorption • Gastrointestinal blood loss • Menstrual blood loss • Pregnancy • Genetic factors • Hepcidin • DMT-1 • Ferroportin • TfR-2 • Hemojuvelin • Others

  32. Hereditary Hemochromatosis • Patients with iron overload • 10% to 15% are negative for C282Y/C282Y • Mutations in other genes • Ferroportin • TfR-2 • Hepcidin • Hemojuvelin • Others

  33. Iron Overload Syndromes • Ferroportin (SLC40A1) • 2q32 • Autosomal dominant • RE cell distribution • African iron overload, Solomon Islanders • Pedigree described Pietrangelo et al., NEJM 341:725-732, 1999 Montosi et al., JCI 108:619-623, 2001 Gordeuk et al., Blood Cells Mol Dis 31:299-304, 2003

  34. Iron Overload Syndromes • Transferrin receptor-2 (TfR-2) • 7q22 • Autosomal recessive • Parenchymal cell distribution • Pedigree described Hoffman et al., Blood 100:1099-1100, 2002

  35. Iron Overload Syndromes • Hepcidin (HAMP) • 19q13.1 • 25 amino-acid peptide • Juvenile iron overload (rarely) • Autosomal recessive • Parenchymal cell distribution • More importantly – principal “hormone” involved in iron regulation Roetto et al., Nat Genet 33:21-22, 2003

  36. Iron Overload Syndromes • Hemojuvelin (HJV) • 1q21 • Juvenile iron overload • Autosomal recessive • Parenchymal cell distribution • Pedigree described Fleming and Bacon, NEJM 352:1741-1744, 2005

  37. Hereditary Hemochromatosis • Genetic testing for non-HFE HH • InVitae, San Francisco Genetic Testing Company • HFE • HAMP – hepcidin • HFE-2 – hemojuvelin • SLC40A1 – ferroportin • TFR2 • $1500 per order, 2 weeks • 415-374-7782 • clinical@invitae.com

  38. Hereditary Hemochromatosis Summary • In 2013… • Most patients with hemochromatosis do not need a liver biopsy • Only about 60% of C282Y homozygous patients have phenotypic expression • About 25% of C282Y homozygous men have signs or symptoms of hemochromatosis • Detailed gene testing available

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