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Matt McCollough, M.D. GI Grand Rounds March 20, 2008 Case y 77 year‐old white female y Referred to Hepatology Clinic for asymptomatic elevation of transferrin saturation level Case y Past Medical Hx: y HLD y HTN y OA y Schatzki’s ring s/p dilt for dysphagia y Bilateral Breast CA s/p bil mastectomy y s/p complete hysterectomy y cataracts Case y Medications: y Lipitor 10mg daily y Avalide 150/125mg daily y Calcium + D daily y Glucosamine/Chondroitin daily y Ibuprofen 400‐800mg daily y Allergies ‐ PCN Case y Social Hx: y Retired secretary y Widowed y Three 12 oz cans of beer daily y Denies tobacco, IVDU, tattoos y Family Hx: y M ‐ Cerebral hemorrhage, deceased 67 y F‐ CVA, deceased 72 y B ‐Oat cell lung Ca, deceased 52 Case y ROS: y Positives: moderate knee pain bilaterally y Denies: jaundice, diabetes, darkening of skin, dyspnea, orthopnea, swelling, abdominal pain Case y Physical Exam: y BP 173/86, P 77, R, 19, T 97.5, Ht 5’6”, Wgt 178 y ++Crepitis in knees bilaterally y Normal heart and lungs y No icterus, jaundice, spiders, hepatomegaly, splenomegaly or skin discoloration Case y Laboratories: y WBC 5.9 y BUN 12 y Hgb 13.8 y Cr 0.7 y MCV 97 y Glu 98 y Plt 203 y TG 77 y AlkP 120 y AST 27 y IBC 226 y ALT 33 y Fe 187 y TB 0.7 y % sat 83 y DB 0.17 y Ferritin 380 y TP 6.9 y Alb 4.4 Case y A diagnostic test was performed… Objectives y Review the pathophysiology of iron overload and hemochromatosis y Identify non‐HFE iron overload mutations and causes of secondary iron overload y Review AASLD Guidelines for Diagnosis and Management of Hereditary Hemochromatosis (HH) What is normal anyway? y Normal total body iron content is 3‐4 grams y Hemoglobin 2.5 g y Ferritin and hemosiderin 1 g (men) y Proteins (myoglobin, cytochromes, catalase) 400 mg y Transferrin bound 3‐7 mg Pluses and Minuses y Absorption y Dietary absorption is regulated so that it matches daily iron loss (Increased absorption in deficient states) y Mostly through the duodenum y Western diet 10‐20mg/day y About 10% absorbed y Losses y Sweat, shed skin cells, ?gi (1mg/day) y Premenopausal adult women (0.5 – 1.0mg/day) Pathophysiology of Hemochromatosis y Mechanisms y Alterations in HFE protein function y Increased intestinal absorption of dietary iron y Iron induced tissue injury and fibrosis HFE protein y Structure is similar to major histocompatibility complex (MHC) class I molecules but does not present antigen y The HFE protein forms a complex with the transferrin receptor (TfR1) which effects cellular Fe uptake y It may also participate with transferrin receptor (TfF2) to regulate hepcidin which acts to reduce dietary iron absorption and inhibit iron release by macrophages Hepcidin y Produced in the liver y Possible iron storage regulator y Inhibits iron absorption in the small intestine and prevents release of iron from macrophages y Levels are low in HH y Is an acute phase reactant and plays a central role in anemia of chronic disease (levels are high) Duodenal absorption Feldman: Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 8th ed Duodenal iron absorption y Regulated by: y Demands of erythropoesis independent of iron stores y Storage regulator (i.e. hepcidin) that prevents iron overload when needs are met Iron Toxicity y Increased iron causes saturation of circulating transferrin which leads to more “non‐transferrin‐ bond” iron y Iron tends to deposit in cells with high levels of transferrin receptors (i.e. heart, liver, thyroid, gonads, pancreatic islets) y Reactive oxygen species attack lipids, proteins, RNA and DNA causing tissue damage and fibrosis HH Stages of iron Years Parenchymal iron overload storage (grams) Insignificant 0-20 0-5 Iron overload 20-40 10-20 without disease Iron overload with >40 >20 organ damage Causes of Iron Overload y There is NO mechanism for increasing iron excretion, therefore, overload will ensue if there is excess absorption y Genetic (Increased iron absorption with normal intake) y Chronic liver diseases y Iatrogenic (Surely, it wasn’t my fault?) Secondary Iron overload (Acquired) Iron‐loading anemias Parenteral Iron overload y Thalassemia major y RBC transfusion y Sideroblastic anemia y IV iron y Chronic hemolytic anemia y Long‐term hemodialysis y Aplastic anemia y Pyruvate kinase deficiency y Pyridoxine‐responsive anemia Secondary Iron overload (Acquired) Chronic liver disease Other y HCV y Dietary iron overload y HBV y Dysmetabolic iron overload y Alcoholic liver disease syndrome y NASH y Porphyria cutanea tarda y Portacaval shunt Clinical Presentation y Symptomatic iron overload usually occurs after the 5th decade y Expression is influenced by age, sex, dietary iron, blood loss and unknown factors y Women express the disease less frequently than men y Alcohol and Hepatitis C may accelerate the disease expression Symptoms Occurrence, % Weakness, lethargy, fatigue 40–85 Apathy, lack of interest 40–85 Abdominal pain 30–60 Weight loss 30–60 Arthralgias 40–60 Loss of libido, impotence 30–60 Amenorrhea 20–60 Congestive heart failure 0–40 symptoms Bacon BR, Powell LW, Adams PC, et al. Molecular medicine and hemochromatosis: at the crossroads. Gastroenterology. 1999. 116:193-207. Edwards CQ, Cartwright GE, Skolnick MH, et al. Homozygosity for hemochromatosis: Clinical manifestations. Ann Intern Med. 1980. 93:511-525. Hereditary Hemochromatosis (HH) y “Several inherited disorders of iron homeostasis characterized by increased intestinal iron absorption resulting in tissue iron deposition” Feldman: Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 8th ed. HH y HFE‐related y C282Y homozygosity y C282Y/H63D compound heterozygosity y Other HFE mutations y Non‐HFE‐related y Hemojuvelin (HJV) mutations y Hepcidin (HAMP) mutations y Transferrin receptor 2 (TfR2) mutations y Ferroportin 1 (SLC40A1) mutations HH (alternate nomenclature) y Type 1 (HFE) y Type 2 (Hemojuvelin/Hepcidin) y Type 3 (Transferrin Receptor 2) y Type 4 (Ferroportin) HFE‐related HH y The most common genetic disorder in the Caucasian population, especially northern European (Nordic, Celtic) y Autosomal recessive y Prevalence for homozygotic mutation in U.S. whites is 1:200‐250 y 1:10 are heterozygous carriers HFE Gene y The clinically significant gene mutations are C282Y and H63D y C282Y y Described in 1996 y G to A missense mutation y Substitutes tyrosine for cysteine y 60‐93% of patients with iron overload are C282Y homozygous HFE Gene y Prevalence of compound heterozygotes (C282Y/H63D) is 1‐2 % y Only a small percentage of compound heterozygotes will develop iron overload y A negative HFE gene test does not exclude iron overload HFE‐Gene y All C282Y homozygotes had elevated transferrin saturation (100% positive predictive accuracy) y C282Y homozygotes –full expression with progressive tissue iron overload in 58% y The rate of iron accumulation is variable Olynyk JK, et al. A population based study of the clinical expression of the hemochromatosis gene. N Engl J Med 1999;341:718-724. Hemojuvelin and Hepcidin y Hemojuvelin (HJV/1q) Mutation y Hepcidin Antimicrobial Peptide (HAMP/19q13.1) Mutation y “Juvenile Hemochromatosis” y Autosomal recessive y HJV is a regulator of hepcidin y Very low hepcidin causes massive Fe influx. y High ferritin and transferrin saturation in 1st decade. y Hypogonadism before end of 2nd decade, cardiac disease & abdominal pain y Cirrhosis occurs later y Death during 3rd decade from heart failure Transferrin Receptor 2 (TfR2) y Located on hepatocytes y Autosomal recessive mutation y TfR2 is regulator of hepcidin ‐> Low hepcidin ‐>causes increased Fe influx. y High transferrin saturation in 2nd to 3rd decades y HHC may develop from 2nd to 4th decades y Mild to severe Fe overload in periportal hepatocytes y Hypochromic anemia Ferroportin y Missense mutation of ferroportin 1 gene y Iron exporter located in enterocytes, macrophages, and hepatocytes y Rare autosomal dominant mutations Ferroportin y Worldwide distribution y Decreased Fe efflux y High ferritin in 1st decade y Fe deposit in RES with very high ferritin but low or normal transferrin saturation; high saturation late in life. y Mild hypochromic anemia. y Mild liver injury with sinusoidal fibrosis y May cause cirrhosis y Treatment: Phlebotomy q 2‐3 weeks (not weekly) African Iron Overload y Sub‐Saharan Africa y Non‐HFE related genetic trait (? Ferroportin 1) exacerbated by dietary iron loading (maize beverage) y Iron loaded Kupffer cells y This contrasts HFE‐related HH were Kupffer cells are spared Aceruloplasminemia y Autosomal recessive y Decreased Fe efflux y Lack of ceruloplasmin, which has ferroxidase activity needed to release Fe from cells y Causes deposit in the: y basal ganglia, dentate nucleus (ataxia and dementia) y Pancreas (diabetes mellitus) y RES (hypochromic microcytic anemia) y Liver disease is mild y Treatment: Chelation, Exjade® (deferasirox) & desferoxamine Other y Atransferrinemia/Hypotransferrinemia y Autosomal recessive y Increased Fe influx y Severe anemia y Onset in 1st & 2nd decade y H‐Ferritin associated hereditary Fe‐Overload y Autosomal dominant y Increased Fe influx y Liver Fe overload in 4th‐5th decade Diagnosis and Management of Hereditary Hemochromatosis 2001 Management Objectives for HH y Early diagnosis to prevent organ damage and dysfunction due to tissue iron toxicity y Screening and early detection of asymptomatic HH cases to reduce mortality y Recognition and diagnosis of symptomatic cases of HH, to minimize progression and complications of the disease y Adequate treatment of HH to promote rapid, safe, and effective removal of iron y Vigilant follow‐up and maintenance treatment of all cases of HH Tavill, A. Diagnosis and Management of Hemochromatosis. Hep May 2001. Who gets screened? y Symptomatic patients y Unexplained liver disease or known liver disease with abnormal serum iron studies y Type 2 DM especially with hepatomegaly, abnormal lft’s, atypical cardiac disease, and/or early onset sexual dysfunction y Early‐onset atypical arthropathy, cardiac disease, male sexual dysfunction Tavill, A.
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