HEMOCHROMATOSIS: BEING AN IRON MAN CARRIES RISK! Gina C. Guzman, MD, DBIM, FALU, FLMI 2nd VP & Medical Director Hereditary Hemochromatosis (HH) 2 Genetic Disorder of Iron Metabolism Autosomal Recessive Excessive Iron Overload Symptoms Due to Iron Accumulation in Various Tissues Cause of Significant Morbidity and Mortality Nov 17, 2015 NHOLUA Total Body Iron ~3.5 grams Nov 17, 2015 NHOLUA 3 Normal Iron Absorption and Metabolism Nov 17, 2015 NHOLUA gms 1 gm Total Body Iron ~3.5 grams Women 2mg/day Menses Pregnancy Women 2mg/day Menses Pregnancy 3-7mg Pathophysiology of HH Nov 17, 2015 NHOLUA 5 Persons with Hereditary Hemochromatosis continue to absorb iron even when their body already has enough Excessive Iron Deposition in Tissues (especially the liver, heart, pancreas, and pituitary) except BLOOD LOSS NORMAL PERSON Classic19 th Century Presentation Middle-aged man Diabetes Mellitus Bronzed skin Hepatomegaly +/- cirrhosis Bronze diabetic with cirrhosis Advanced end- organ damage with poor mortality Considered rare 6 Nov 17, 2015 NHOLUA 21 st Century Presentation Younger person Asymptomatic Elevated liver function tests No end organ damage with good prognosis Common disease 7 Nov 17, 2015 NHOLUA Why the switch? Increased routine iron testing during routine physical exams Increased awareness of the diseaseIncreased diagnosis before symptoms developDevelopment of a genetic test in 1996 Nov 17, 2015 NHOLUA 8 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 (50% in women >60% in men Should be done fasting 21 Nov 17, 2015 NHOLUA 95% accuracy in identifying iron overload Our case had iron studies Total Serum Fe = 221 ( ug/dL) TIBC = 261 ( ug/dL) Ferritin = 1277 ( ng/mL) Transferrin Sat = Serum iron/TIBC 221/261 = 85% ABNORMAL (>50% in women, 60% in men) 22 Nov 17, 2015 NHOLUA 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 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 Porphyria cutanea tarda Portacaval shunt Nov 17, 2015 NHOLUA Work-up for HH Fasting Transferrin Saturation >50% in women >60% in men Ferritin CBC LFTs Genetic TestingLiver Biopsy 24 J Hepatol 2000;33: Nov 17, 2015 NHOLUA Ferritin Iron storage protein reflects the bodys stores of iron Normal levels ng/mL (male), 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 25 Clin Chim Acta 1996;245: Nov 17, 2015 NHOLUA GENETICS Nov 17, 2015 NHOLUA 26 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 27 Nov 17, 2015 NHOLUA Alleles 28 Two copies of the sameTwo different HOMOZYGOTE HETEROZYGOTE Nov 17, 2015 NHOLUA More Genetics Definitions Genotype the genetic makeup of an individual (AA, Aa, aa) Phenotype the observable appearance of an individual (Black, Brown, Blonde) Autosomal Dominant only a single abnormal gene from either parent can cause disease Autosomal Recessive two copies or an abnormal gene must be present for disease Nov 17, 2015 NHOLUA 29 Genetic Testing for HH Mutation in the HFE gene regulates Fe absorptionDiscovered in 1996Short arm of chromosome 6 (6p21.3) 40 allelic variants of the HFE gene have been described to date Only two are significantly correlated with HH 30 Nov 17, 2015 NHOLUA HFE gene defect Two mutations have been described in the majority of patients with HH C282Y Cysteine to Tyrosine at position 282 (C282Y) Strong association with the phenotypic changes of iron overload H63D Histidine to Aspartate at position 63 (H63D) Limited clinical effect 31 Nov 17, 2015 NHOLUA HFE Mutation Combinations Review: Chromosome 6 = 2 alleles 3 possibilities for the HFE gene (C282Y, H63D, Normal version) 6 possible combinations: 1.C282Y/C282Y 2.C282Y/H63D 3.H63D/H63D 4.C282Y/normal 5.H63D/normal 6.Normal/normal Nov 17, 2015 NHOLUA 32 Transferrin Sat % and HFE Genotype 33 (N Engl J Med 2005;352: ) Nov 17, 2015 NHOLUA C282Y/C282Y (Homozygote) % 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 34 Amer J of Epidemiology. Vol. 154, No 3, 2001 Lancet 2002;359: N Engl J Med 2005;352: Nov 17, 2015 NHOLUA 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 35 Blood 2004;103: Nov 17, 2015 NHOLUA 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 consider as only a carrier of HH gene with no additional mortality risk 36 Blood Cells Mol Dis Aug;23(2): Clin Gastroenterol Hepatol Nov;4(11): Nov 17, 2015 NHOLUA 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 Sep 7:46(4): ) 2-3 fold risk of ischemic stroke (Neurology Mar 27;68(13): ) 37 Nov 17, 2015 NHOLUA 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 38 Ann Intern Med Jun 15;130(12): Nov 17, 2015 NHOLUA 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: Semin Liver Dis 2005;25: Amer J of Epidemiology. Vol. 154, No 3, 2001 Variable penetrance (false positives) 39 Nov 17, 2015 NHOLUA 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 40 Nov 17, 2015 NHOLUA SCREENING FOR HH Nov 17, 2015 NHOLUA 41 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 42 Nov 17, 2015 NHOLUA 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 43 Ann Intern Med 2006 Aug 1;145(3):204-8 Nov 17, 2015 NHOLUA USPSTF Grade D 44 Nov 17, 2015 NHOLUA CASE FILE REVIEW Nov 17, 2015 NHOLUA 45 Case summary Elevated LFTs 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? 46 Nov 17, 2015 NHOLUA Minimum Criteria for Diagnosis Increased iron stores Elevated transferrin saturation Serum iron/TIBC (+) HFE Gene mutation C282Y/C282Y or C282Y/H63D 47 Nov 17, 2015 NHOLUA 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 48 Nov 17, 2015 NHOLUA Who should get a liver biopsy? Age over 40 years old Elevated LFTs Clinical evidence of liver disease History of alcohol abuse Coexisting diabetes, impotence Ferritin level > 1000 ng/mL ^ likelihood of fibrosis or cirrhosis 49 Gastroenterology 1998;115: Hepatology 2002;36: Ann Int Med 2003;138: Nov 17, 2015 NHOLUA Liver Biopsy 50 Brown pigment = iron Trichrome stained tissue (blue) = fibrosis Nov 17, 2015 NHOLUA Prognostic value of liver biopsy Document the degree of fibrosis, if any Liver cirrhosis/fibrosis => ^ risk HCC Normal biopsy => normal life expectancy with treatment Confirm the diagnosis with Hepatic Iron Index Negative genetic testing Compound Heterozygote mutation 51 Nov 17, 2015 NHOLUA Hepatic Iron Index (HI) Measurement of the iron concentration HI = Hepatic Iron Concentration (HIC)/patients age Normal HI < 1.0 HI > 1.9 is a strong marker for HH CAVEAT up to 15 % of homozygous HH will have a normal hepatic iron index despite clinical evidence of disease 52 Nov 17, 2015 NHOLUA Who may NOT get a liver biopsy? Age < 40 years old No clinical evidence of liver disease (e.g. normal LFTs, no hepatomegaly) Fasting serum ferritin level < 1000 ng/mL These people are unlikely to have significant hepatic injury Clinician may not recommend liver biopsy and proceed directly to treatment A LIVER BIOPSY IS NOT NECESSARY FOR THOSE < 40 Y/O WITH GENOTYPICALLY DEFINED HH (C282Y HOMOZYGOUS) WITH NL LFTS 53 Nov 17, 2015 NHOLUA Back to Our Case One Last Time Applicant has iron overload and probably has hemochromatosis Liver biopsy would be very helpful Age>40, elevated LFTs, ferritin>1000 Can help confirm diagnosis in a heterozygote Treatment is indicated 54 Nov 17, 2015 NHOLUA Treatment = Phlebotomy 55 Nov 17, 2015 NHOLUA Treatment Goals Initial treatment = de-ironing Removal of 1-2 units of whole blood/week (several months) 1 unit of whole blood = 1 pint = ~ 500 cc = mg of iron Goal Ferritin < 50 ng/mL, TS < 50% Hgb < 12 for men, Hgb < 11 for women Maintenance Every 2 to 4 months for life Maintain Ferritin < 100 ng/mL with normal hemoglobin 56 Nov 17, 2015 NHOLUA Iron Chelation Binds to iron allowing iron to be excreted in either urine or bile thereby reducing the body burden of iron Used in the rare case when phlebotomy contraindicated (e.g., HH with severe cardiac involvement unstable hemodynamic status) Deferoxamine Deferiprone Deferasirox Almost never necessary due to the ease/efficacy of phlebotomy Nov 17, 2015 NHOLUA 57 Dietary Management Avoid iron supplements Avoid excess Vitamin C, which promotes iron absorption Increased risk of cardiac arrhythmia due to acceleration of iron metabolism Avoid uncooked seafood / raw oysters Increases the risk of Vibrio vulnificus and Salmonella enteritidis infections These bacteria grow well in an iron-rich environment ^ iron may also impair WBCs fighting capability Limit EtOH consumption Mild/moderate EtOH consumption ^ prevalence of iron overload EtOH ^ severity of disease => > 2 drinks/day ^ risk of cirrhosis 58 Nov 17, 2015 NHOLUA Role of Alcohol in HH 59 Scotet V. Am J Epidemiol Jul 15;158(2): Nov 17, 2015 NHOLUA HH and Mortality 60 % of all deaths are related to complications of iron overload #1 LIVER (75% of above) Cirrhosis HCC #2 DIABETES #3 CARDIOMYOPATHY Survival is NORMAL in HH patients in whom treatment was initiated before the development of cirrhosis or diabetes 60 Gastroenterology 1996;110: Can J Gastroenterol 1993;7: Nov 17, 2015 NHOLUA Prognosis Early diagnosis => early effective treatment => GOOD prognosis with normal life expectancy BEST CASE Compliant with treatment, good follow-up Ferritin < 100 ng/mL, TS < 50% No end organ damage No symptoms Non-specific symptoms (weakness, fatigue) can resolve Liver function can return to normal Endocrine changes may improve (impotence can resolve, insulin requirements can decrease) Joint pain can resolve 61 Ann Intern Med 1998;129: Gastroenterology 1996;110: Nov 17, 2015 NHOLUA Prognosis Evidence of end organ damage e.g. cirrhosis or DM => WORSE/BAD prognosis Significant fibrosis in any organ is irreversible Cirrhosis increases risk for HCC 75% of HH-related deaths Screen with routine AFP testing Without treatment, eventual fatal iron overload 62 Gastroenterology 1996;110: Hepatology 1992;15: Nov 17, 2015 NHOLUA Conclusions 63 Nov 17, 2015 NHOLUA Most people with HH will have a normal life expectancyEarly diagnosis and effective treatment is the key Phlebotomy therapy, if initiated early, can prevent cirrhosis, cardiac complications, and diabetes Patients with evidence of iron overload, positive family history, or other risk factors should be screened The best screening test for iron overload is the TRANSFERRIN SATURATION (Serum Fe/TIBC) Thank you! 64