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Hemochromatosis: BEING AN “iron Man” carries risk!

Hemochromatosis: BEING AN “iron Man” carries risk!. Gina C. Guzman, MD, DBIM, FALU, FLMI 2nd VP & Medical Director. Hereditary Hemochromatosis (HH). All body cells need IRON. ENERGY PRODUCTION. OXYGEN TRANSPORT. CELLULAR GROWTH AND PROLIFERATION. Total Body Iron ~3.5 grams.

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Hemochromatosis: BEING AN “iron Man” carries risk!

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  1. Hemochromatosis:BEING AN “iron Man” carries risk! Gina C. Guzman, MD, DBIM, FALU, FLMI2nd VP & Medical Director

  2. Hereditary Hemochromatosis (HH)

  3. All body cells need IRON ENERGY PRODUCTION OXYGEN TRANSPORT CELLULAR GROWTH AND PROLIFERATION Total Body Iron ~3.5 grams

  4. Normal Iron Absorption and Metabolism 3-7mg Women – 2mg/day Menses Pregnancy Total Body Iron ~3.5 grams 2.5 gms 1 gm

  5. Pathophysiology of HH Persons with Hereditary Hemochromatosis continue to absorb ironeven when their body already has enough except BLOOD LOSS NORMAL PERSON Excessive Iron Deposition in Tissues (especially the liver, heart, pancreas, and pituitary)

  6. “Classic”19th Century Presentation

  7. 21st Century Presentation

  8. Why the switch?

  9. Prevalence of HH • 1 in 250 persons • Most common single-gene genetic disorder in the US • White Northern European descent (1 in 227) • Hispanic (1 in 3700) • Black (1 in 7000) • Asians (<0.001 per 1000) • Caucasian population (USA, Western Europe) • 10% carrier for the mutation • 0.5% homozygous state N Engl J Med 2005;352:1769-78.

  10. Iron Stores & Clinical Manifestations Dx here RARE ^ Diagnosis before Sx Adapted from Riely CA, Vera SR. Inherited liver disease. American Gastroenterological Association, 1993.

  11. Early Symptoms • No symptoms • A common early sign is asymptomatic elevation of LFT’s (75%) • Early, non-specific • Fatigue/Weakness (74%) • Joint pain (44%) • Weight loss • Abdominal pain • Palpitations Hepatology 1997;25:162-6.

  12. Late Symptoms – Where is Iron Deposited? Bronze Skin Impotence Early menopause Hypothyroidism Arthritis Hepatomegaly ^LFTs Cirrhosis Diabetes Cardiomyopathy Arrhythmia

  13. CASE FILE REVIEW

  14. 43 y/o NS male $5,000,000 term life No admitted medical history “Normal” physical last year AST 47 and ALT 72 Hep B & C - negative Case File Review

  15. Differential Diagnosis of ^LFTs Drugs and Alcohol

  16. Medications and Supplements Antibiotics Herbal therapy Lipid Lowering Drugs (Statins) Recreational drugs Seizure drugs

  17. Viral Hepatitis ( B and C) NAFLD Fatty liver/NASH Hemochromatosis Wilson’s disease Autoimmune Hepatitis Alpha-1-Antitrypsin deficiency Liver Disease

  18. Other Possibilities… • Muscle Disorders • Thyroid Disorders • Celiac Disease • Adrenal insufficiency

  19. Sample Evaluation of Mild ^LFTs

  20. Iron Studies

  21. Transferrin Saturation (TS) 95% accuracy in identifying iron overload

  22. Our case had iron studies… • Total Serum Fe = 221 (49-181 ug/dL) • TIBC = 261 (250-450 ug/dL) • Ferritin = 1277 (20-300 ng/mL) • Transferrin Sat = Serum iron/TIBC • 221/261 = 85% • ABNORMAL (>50% in women, 60% in men)

  23. Exogenous iron overload Chronic iron supplementation (in absence of blood loss) Transfusion Iron dextran injection Oral supplements (rare) Chronic liver diseases Viral hepatitis Alcoholic liver disease Nonalcoholic steatohepatitis Porphyriacutaneatarda Portacaval shunt Disorders Associated with Iron Overload • Hereditary hemochromatosis • Related to HFE gene • Not related to HFE gene • African (Bantu) hemochromatosis • Juvenile hemochromatosis • Neonatal hemochromatosis • Chronic anemias • Thalassemia major • Sideroblastic anemia • Congenital dyserythropoietic anemia • Congenital atransferrinemia

  24. Work-up for HH J Hepatol 2000;33:485-504.

  25. Ferritin • Iron storage protein – reflects the body’s stores of iron • Normal levels • 20-300 ng/mL (male), 20-150 ng/mL (female) • Acute Phase Reactant • Elevated in inflammation, infection, recent trauma, surgery, cancer • Less specific than the iron saturation (PPV 20% vs. 80%) for HH • Should NOT be used as a screening test • Ferritin > 600 needs work-up • Ferritin > 1000 despite normal TS, may need liver biopsy Clin Chim Acta 1996;245:139-200.

  26. GENETICS

  27. Basic Genetics • Human DNA • 46 Chromosomes (structures that hold our genes) • - organized in 23 pairs (one copy from each parent) • - 22 pairs of autosomes • - 1 pair of sex chromosomes (XX, XY) • ~30,000 pairs of Genes • Locus – point on the chromosome • where the gene is located • Alleles – 2 per locus

  28. Alleles HOMOZYGOTE HETEROZYGOTE Two copies of the same Two different

  29. More Genetics Definitions

  30. Genetic Testing for HH

  31. HFE gene defect

  32. HFE Mutation Combinations • Review: Chromosome 6 = 2 alleles • 3 possibilities for the HFE gene (C282Y, H63D, Normal version) • 6 possible combinations: • C282Y/C282Y • C282Y/H63D • H63D/H63D • C282Y/normal • H63D/normal • Normal/normal

  33. Transferrin Sat % and HFE Genotype (N Engl J Med 2005;352:1769-78)

  34. C282Y/C282Y (Homozygote) • 69-100% of clinically diagnosed HH (average 83%) • Very high prevalence in Caucasians in North America (1:227) • More severe than H63D • 72-99% likelihood of being free of signs/symptoms of HH at diagnosis • Variable penetrance (the proportion of individuals of a particular genotype that express its phenotypic effect) • Up to 50% may never develop clinically significant iron overload (population studies) • Females have lower penetrance over males Amer J of Epidemiology. Vol. 154, No 3, 2001 N Engl J Med 2005;352:1769-78 Lancet 2002;359:211-8.

  35. C282Y/C282Y with NL TS • Uncertain at the present time what percentage of these may eventually develop iron overload • Cost of follow-up is significant • Should be followed yearly (CPE, yearly iron studies) • Copenhagen Heart Study monitored 23 homozygotes over 25 years who never developed overt iron overload Blood 2004;103:2914-9.

  36. C282Y/H63D (Compound Heterozygote) • 3-5% of clinically diagnosed HH Comorbid factors (Steatosis, DM, Excess Alcohol) ^ risk of developing progressive clinical disease High prevalence of increased iron indices with reduced penetrance of <2% • Only 0.5 – 2 % will develop HH • Must have clinical correlation in order to make a diagnosis of HH • C282Y/H63D, normal iron studies, no comorbid factors => consider as only a carrier of HH gene with no additional mortality risk Blood Cells Mol Dis. 1997 Aug;23(2):314-20. ClinGastroenterolHepatol. 2006 Nov;4(11):1403-10.

  37. H63D/H63D (Homozygote) • 1% of diagnosed HH • Typically a mild course of disease with less iron accumulation • < 1% risk of developing HH • Most will NEVER develop any symptoms • 4-fold risk of amyotrophic lateral sclerosis (Hepatology. 2007 Sep 7:46(4):1071-1080.) • 2-3 fold risk of ischemic stroke (Neurology. 2007 Mar 27;68(13):1025-31.)

  38. C282Y/normal or H63D/normal (Heterozygotes) • 3-10% of clinical HH (presumed due to additional unknown mutations) • Many have mildly increased iron levels, but no clinical symptoms • Majority of these will be HEALTHY CARRIERS with NL iron levels (and no increased mortality risk) • 1 in 10 Caucasians in the USA Ann Intern Med. 1999 Jun 15;130(12):953-62.

  39. Caveat about HFE testing • HFE gene testing is only 85% accurate • Non-HFE related HH (false negatives) • 7-10% HH have mutations not commonly tested or not yet discovered • Familial cases of HH without detectable HFE mutation • N Engl J Med 2004;350:2383-97. • Semin Liver Dis 2005;25:450-60. • Amer J of Epidemiology. Vol. 154, No 3, 2001 • Variable penetrance (false positives)

  40. Newly, Identified Iron-Related Genes • Ferroportin • Hemojuvelin • Hepcidin • Ceruloplasmin • Transferrin Receptor 2 • Unrelated to HFE • Rare cases of iron overload • Complex genetic testing • Further research ongoing

  41. SCREENING for hh

  42. Screening for HH • American College of Physicians/ NIH/ CDC • (+) Family History and/or (+) symptoms • The College of American Pathologists • All adults over 18 • (+) Family History - Every 5 years • The American Hemochromatosis Society • Age 4 – routine iron testing • (+) Family History – Every 5 years • REMEMBER: BEST test for screening Transferrin Sat = Serum Fe / TIBC

  43. U.S. Preventive Services Task Force • Against routine genetic testing for HH in the asymptomatic general population • Genetic testing should NOT be used as a screening tool Ann Intern Med 2006 Aug 1;145(3):204-8

  44. USPSTF Grade D

  45. CASE FILE REVIEW

  46. Case summary • Elevated LFT’s in an asymptomatic male • Elevated iron and ferritin • Elevated transferrin saturation • Genetic Testing reveals: Heterozygote C282Y/H63D mutation • Do we have enough now to make the diagnosis of hereditary hemochromatosis?

  47. Minimum Criteria for Diagnosis • Increased iron stores • Elevated transferrin saturation • Serum iron/TIBC • (+) HFE Gene mutation • C282Y/C282Y or C282Y/H63D

  48. What about liver biopsy? • Liver biopsy is no longer essential for the diagnosis • Who needs one? • What information can be gained? • Liver is the major organ affected with HH • Easily accessible tissue • Prognostic rather than diagnostic

  49. Who should get a liver biopsy? • Age over 40 years old • Elevated LFT’s • Clinical evidence of liver disease • History of alcohol abuse • Coexisting diabetes, impotence • Ferritin level > 1000 ng/mL • ^ likelihood of fibrosis or cirrhosis Gastroenterology 1998;115:929-36. Hepatology 2002;36:673-8. Ann Int Med 2003;138:627-33

  50. Liver Biopsy Brown pigment = iron Trichrome stained tissue (blue) = fibrosis

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