Genetic Diseases Hemochromatosis Normal Iron Balance Ingested 10

Genetic Diseases – Hemochromatosis 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 Andrews NC, New Engl J Med 1999; 341: 1986

Iron overload states Classification Hereditary hemochromatosis • HH: HFE related ØC 282 Y homozygosity ØC 282 Y/H 63 D compound heterozygosity ØOther mutations of HFE • HH: non-HFE related; other gene mutations ØJuvenile hemochromatosis ØAutosomal dominant hemochromatosis (Solomon Islands)

Iron overload states Classification Secondary iron overload § Iron-loading anemias ± transfusion ØThalassemia major ØSideroblastic anemia ØChronic hemolytic anemias § Dietary iron overload § Chronic liver diseases ØHepatitis C and B ØAlcohol-induced liver disease ØPorphyria cutanea tarda ØFatty liver disease

Target populations for screening for HH Target Populations for Hemochromatosis Evaluation Symptomatic patients Unexplained manifestations of liver disease or a presumably known cause of liver disease with abnormality of one or more indirect serum iron markers. Type 2 diabetes mellitus, particularly with hepatomegaly, elevated liver enzymes, atypical cardiac disease or early-onset sexual dysfunction. Early-onset atypical arthropathy, cardiac disease, and male sexual dysfunction.

Target populations for screening for HH Target Populations for Hemochromatosis Evaluation Asymptomatic patients Priority groups First-degree relatives of a confirmed case of hemochromatosis. Individuals with abnormal serum discovered during routine testing. iron markers Individuals with unexplained elevation of liver enzymes or asymptomatic hepatomegaly or radiologic detection of enhanced computed tomography attenuation of the liver, Bronzed skin.

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

Diagnosis § Indirect serologic markers of iron stores: 1. Transferrin saturation (TS): serum iron divided by TIBC, multiplied by 100 • > 50 % for women or > 60 % for men has a sensitivity of 0. 92, specificity of 0. 93, and PPV of 86 % • Saturation cutoff of 45 % used in screening recommendations

Diagnosis • Liver Biopsy: – Definitive diagnostic test of iron overload – Allows histochemical assessment of iron stores, measurement of hepatic iron concentration (HIC), detection of cirrhosis, and determination of disease stage – Qualitative hepatic iron determination with Perl’s staining – Quantitative confirmation of iron stores with HIC measurement

Hemochromatosis Serum Iron TIBC Ferritin ( µg /dl ) Transferrin Saturation ( µg /dl ) ( % ) Normal 50 -150 230 -370 20 -50 30 -270 150 -1850 Hemochro matosis >175 <300 >5600 >50 ( µg /L ) Quantitative Hepatic Iron ( µg /g dry weight)

Target population Symptomatic Step 1 Asymptomatic Fasting transferrin saturation & serum ferritin TS < 45 percent & normal ferritin Step 2 Adult 1 st degree Relative of HH No further iron evaluation TS ≥ 45 percent & ferritin elevated Genotype

Target population TS<45 percent & normal ferritin TS<45 percent & ferritin elevated No further iron evaluation Genotype Step 2 Compound heterozygote C 282 Y/H 63 D Heterozygote C 282 Y OR non-C 282 Y/C 282 Y Age<40 years Ferritin<1000 AND normal ALT/AST Age>40 years and/or Ferritin>1000 Or elevated ALT/AST

Target population Compound heterozygote C 282 Y/H 63 D Age<40 years Ferritin<1000 AND normal ALT/AST Heterozygote C 282 Y OR non-C 282 Y Step 3 Exclude other liver or hematologic diseases. ±Liver biopsy ± Therapeutic phlebotomy Age>40 years and/or Ferritin>1000 Or elevated ALT/AST + Liver biopsy for HIC and histopathology

RJ: Liver Biopsy Quantitative liver iron= 300 mmole/g dry weight Iron index = 300 divided by 60 years of age =5

Criteria for initiating therapeutic phlebotomy Patient Serum ferritin, ng/m. L Persons <18 years of age ≥ 200 Women Reproductive years, not ≥ 200 pregnant Reproductive years, pregnant ≥ 500 Postreproductive years ≥ 200 Men ≥ 300

Results of therapeutic phlebotomy in patients with hemochromatosis Complications of Iron Overload Expected Treatment Outcome None Prevention of complications of iron overload; normal life expectancy Weakness, fatigue, lethargy Resolution or marked improvement Elevated serum concentrations of hepatic enzymes Resolution or marked improvement Hepatomegaly Resolution often occurs Hepatic cirrosis No change Increased risk for primary liver cancer No change Right upper quadrant pain Resolution or marked improvement Arthropathy Improvement in arthralgias sometimes occurs; change in joint deformity is rare; progression is sometimes seen

Results of therapeutic phlebotomy in patients with hemochromatosis Complications of Iron Overload Expected Treatment Outcome Hypogonadotrophic hypogonadism Resolution is rare Diabetes mellitus Occasional improvement, often temporary Hypothyroidism, hypogonadism Resolution is rare Cardiomyopathy Resolution sometimes occurs Hyperpigmentation Resolution usually occurs Hyperferritinemia Resolution Excess absorption and storage of nonferrous metals Infection with Vibrio vulnificus or other bacteria Little or no change

Treatment of iron overload Treatment of Hemochromatosis Hereditary hemochromatosis One phlebotomy (removal of 500 m. L of blood) weekly or biweekly Check hematocrit prior to each phlebotomy; allow hematocrit to fall by no more than 20 percent of prior level Check serum ferritin level every 10 to 12 phlebotomies Stop frequent phlebotomy when serum ferritin falls below 50 ng/m. L Continue phlebotomy at intervals to keep serum ferritin to between 25 and 50 ng/m. L Avoid vitamin C supplements

Treatment of iron overload Treatment of Hemochromatosis Secondary ironoverload dueto dyserythropoiesis Deferoxamine (Desferal) at a dose of 20 to 40 mg/kg body weight per day Consider follow-up liver biopsy to ascertain adequacy of iron removal Avoid vitamin C supplements

The First case of HH from Iran