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Genes and Metabolic Liver Disease: Hemochromatosis Bruce R. Bacon, M.D. James F. King M.D. Endowed Chair in Gastroenterology Professor of Internal Medicine.

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Presentation on theme: "Genes and Metabolic Liver Disease: Hemochromatosis Bruce R. Bacon, M.D. James F. King M.D. Endowed Chair in Gastroenterology Professor of Internal Medicine."— Presentation transcript:

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 – 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 HemochromatosisStudyFeder, et al. Beutler, et al Jouanolle, et al. Jazwinksa, Carella, Adams and ChakrabartiBacon, et al et al CountryUSA FranceAustraliaItalyCanadaUSA No. of Patients * Genotype n(%) C282Y 148 (83)121 (82)59 (91)112 (100)48 (64)122 (95)60 (91) C282Y** H63D8 (4)8 (5)3 (5)02 (2.27)2 (1.6)1 (1.5) C282Y Wild Type1 (0.5)2 (1)002 (2.27)2 (1.6)1 (1.5) H63D 1 (0.5)2 (1)1 (1.5)01 (1.3)00 H63D Wild type7 (4)4 (3)2 (3)03 (4)02 (3) Wild Type Wild type13 (7)10 (7)0016 (21)4 (3.1)1 (1.5) *All patients had a family history of iron overload ** Compound heterozygote

6 His63  Asp, H63D Cys282  Tyr, C282Y  Heavy Chain Ser65  Cys, S65C 11 22 NH2  2 -microglobulin Extracellular HOOC Plasma membrane Cytosol HOOC 33 Nature Genetics 13: , 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 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 % Weakness, lethargy, fatigue40-85 Apathy, lack of interest40-85 Abdominal pain30-60 Weight loss30-60 Arthralgias40-60 Loss of libido, impotence30-60 Amenorrhea20-60 Congestive heart failure symptoms 0-40

11 Common Physical Findings in HH % Hepatomegaly60-85 Cirrhosis50-95 Skin pigmentation40-80 Arthritis (second, third metacarpophalaneal joints) Clinical diabetes10-60 Splenomegaly10-40 Loss of body hair10-30 Testicular atrophy10-30 Dilated cardiomyopathy 0-30

12 Hereditary Hemochromatosis Symptoms and Physical Findings (%) No symptoms73 Lethargy, and/or weakness25 Loss of libido, impotence12 Arthralgias13 Diabetes 5 Skin pigmentation 5 Am J Gastroenterol 92: , 1997

13 FeaturesMilder et al Edwards et al Niederau et al Adams et al Bacon & Sadiq 1997 Number of subjects34†35*163*37‡40 Symptoms (#) Weakness, lethargy Abdominal pain Arthralgias Loss of libido, impotence Cardiac failure symptoms Physical and Diagnostic Findings (%) Cirrhosis (biopsy) Hepatomegaly Splenomegaly Loss of body hair Gynecomastia Testicular atrophy Skin pigmentation Clinical diabetes 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 NormalHH Serum iron (µg/dl) Transferrin (mg/dl) Transferrin saturation (%) Serum ferritin (ng/ml) Males ,000 Females ,000

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

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22 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

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

24 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

25 Hereditary Hemochromatosis Response to Therapy Edwards et al. Ann Int Med 93: , 1980

26 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.

27 Hereditary Hemochromatosis: Survival N Engl J Med 313: , 1985

28 Hereditary Hemochromatosis: Survival with Cirrhosis N Engl J Med 313: , 1985

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

30 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: , 1998

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

32 41,038 adults screened in San Diego Health appraisal unit CBC, transferrin saturation, ferritin level, HFE genotype Questionnaire Population Screening for Hemochromatosis Beutler et al., Lancet 359: , 2002

33 152 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: , 2002 Population Screening for Hemochromatosis

34 Beutler et al., Lancet 359: , 2002 Population Screening for Hemochromatosis

35 Population sample Countryn Prevalence of homozygotes C282Y homozygotes with a normal ferritin (%) Electoral rollNew Zealand1,0641 in Primary careUSA1,6531 in Epidemiological surveyAustralia3,0111 in Blood donorsCanada4,2111 in General publicUSA41,0381 in Primary careNorth America44,0821 in General publicAustralia29,6761 in Total124,6361 in Prevalence of C282Y Homozygotes Without Iron Overload in Screening Studies

36 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

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

38 Iron Overload Syndromes Ferroportin (SLC40A1) –2q32 –Autosomal dominant –RE cell distribution –African iron overload, Solomon Islanders –Pedigree described Pietrangelo et al., NEJM 341: , 1999 Montosi et al., JCI 108: , 2001 Gordeuk et al., Blood Cells Mol Dis 31: , 2003

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

40 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

41 Iron Overload Syndromes Hemojuvelin (HJV) –1q21 –Juvenile iron overload –Autosomal recessive –Parenchymal cell distribution –Pedigree described Fleming and Bacon, NEJM 352: , 2005

42 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

43 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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