Hemochromatosis

Thomas W. Faust, M.D., M.B.E.Professor of Clinical MedicineDivision of Gastroenterology

The University of Pennsylvania

Hemochromatosis

• Introduction• Classification of

iron overload syndromes

• Pathogenesis

• Clinical manifestations

• Diagnosis• Treatment• Screening

Hereditary HemochromatosisIntroduction

• Inherited disorder of inappropriate dietary iron absorption

• Prevalent in 1/250 individuals• Most patients are asymptomatic• Hepatic and extrahepatic manifestations• HFE (autosomal recessive) mutations account for

majority of cases• Non-HFE mutations are rare causes of iron overload• Secondary iron overload states

Phatak P et al., Ann Intern Med 2008;149:270-272

HemochromatosisHereditary Causes

• HFE hemochromatosis• C282Y/C282Y (95%)• C282Y/H63D (4%)• H63D/H63D or C282Y/S65C (1%)

• Non HFE hemochromatosis (rare)• Hemojuvelin • Hepcidin• Ferroportin• Transferrin receptor 2• DMT-1

Beutler E. et al, Lancet 2002;359:211-218

HemochromatosisNon-Hereditary Causes

• Secondary iron overload• Thalassemia major• Sideroblastic anemias• Liver disease (ETOH, HCV, HBV, PCT, NAFLD)• Excessive iron ingestion

• Parenteral iron overload• RBC transfusions• Iron-dextran infusions• Long-term dialysis

Duodenal Iron Absorption

• Crypt cells• HFE-transferrin receptor complex senses body iron

stores• Upregulation or downregulation of DMT-1 based

upon body iron stores• Villous cells• Dietary iron absorption occurs via DMT-1 and

ferroportin• Transporter expression based upon body iron stores

sensed by crypt cells

Bacon B et al, Gastroenterology. 1999;116:193-207.

Regulation of Iron AbsorptionCrypt Cell Model

• HFE-transferrin receptor acts as sensor of iron stores in Crypt

• DMT-1 synthesized based upon iron stores

• Iron absorbed at villus tip

Zoller H. et al, Lancet. 1999;353:2120-2123.

Regulation of Iron StoresInfluence of Hepcidin

• Regulation of ferroportin-mediated iron export from enterocyte

• Regulation of ferroportin-mediated iron export from macrophages

Ganz T. Cell Metab 2008;7:288-290

Regulation of Iron StoresNormal

• Hepcidin regulates ferroportin-mediated iron export from duodenum, macrophages, and liver

• BMP, HJV, HFE, and TFR2 sense body iron stores and regulates release of hepcidin

Nemeth E. et al, Science 2004;306:2090–2093

HemochromatosisNon-Ferroportin Mutations

• Mutations of BMP, HJV, HFE, and TFR2 alter ability of liver to sense body iron stores

• Inappropriately low level of hepcidin

• Excess ferroportin-mediated export of iron from duodenum, macrophages, and liver

Nemeth E. et al, Science 2004;306:2090–2093

HemochromatosisFerroportin Mutations

• Loss of function • Limited ability to export

iron• Accumulation of iron in

macrophages• Hepcidin increased

• Gain of function• Resistant to inhibitory

effects of hepcidin• Phenotypically similar to

classic hemochromatosis• Hepcidin increased

Letocart E. et al, Br J Haematol. 2009;147(3):379

HemochromatosisOverview of Clinical Manifestations

• Asymptomatic state (majority)• Abnormal iron studies and liver function tests

• Non-specific systemic symptoms• Weakness, fatigue, lethargy, apathy, weight loss,

abdominal pain• Organ-related disease• Hepatic manifestations• Extrahepatic manifestations

HemochromatosisHepatic Manifestations

• Hepatosplenomegaly• Micronodular cirrhosis• Portal hypertensive

bleeding• Ascites/SBP/HRS• Encephalopathy

• Hepatocellular carcinoma

www.gfmer.ch/genetic_diseases_v2/gendis_detail_list.php?cat3=821

HemochromatosisPhysical Examination

• Physical findings in patients with progressive liver disease

• Findings not specific to hemochromatosis

HemochromatosisHepatocellular Carcinoma

• Patients with cirrhosis at risk for HCC.

• All patients with cirrhosis should be screened per AASLD guidelines

• OLT considered for cirrhotic patients with HCC

Netter’s Gastroenterology, 2nd ed., Elsevier Inc., 2010, all rights reserved

HemochromatosisExtrahepatic Manifestations

• Cardiac• Restrictive/dilated

cardiomyopathy• Arrhythmias

• Rheumatologic• Arthalgias/arthritis • Chondrocalcinosis• Osteoporosis

• Dermatologic• Hyperpigmentation• Porphyria cutanea tarda

• Endocrinologic• Diabetes• Loss of libido/impotence• Amenorrhea• Hypothyroidism

• Infectious• Yersinia, pasteurella,

vibrio vulnificus, listeria

HemochromatosisSystemic Disorder

• Multiple organs involved with progressive iron overload

• Therapeutic phlebotomy may correct some of the clinical manifestations

Netter’s Gastroenterology, 2nd ed., Elsevier Inc., 2010, all rights reserved

HemochromatosisExtrahepatic Manifestations

Diagnosis of HemochromatosisIron Studies

Transferrin Saturation• Value ≥ 45% most

common early phenotypic marker

• Sensitivity > 90%• Fasting value preferable• F/U with genetic testing

Ferritin• Rises with progressive

iron overload• F/U with genetic testing• Other diseases• ETOH, NAFLD, viral

hepatitis, inflammatory disorders, neoplasms

• Predicts fibrosis

Beutler E. et al, Lancet 2002;359:211-218

Diagnosis of HemochromatosisGenetic Testing

• C282Y/C282Y• For all patients with TS ≥

45%• For all patients with

elevated ferritin• Liver biopsy for ferritin ≥

1000 μg/L or elevated AST/ALT

• C282Y/H63D or other• For all patients with TS ≥

45%• For all patients with

elevated ferritin• Exclude other liver or

hematologic diseases• Testing for non-HFE

mutations not widely available

• Consider liver biopsy

Guyader D. et al, Gastroenterology 1998;115:929-936

Liver BiopsyDiagnosis of Hemochromatosis or Fibrosis• Not required• C282Y/C282Y• Ferritin < 1000 μg/L• Normal AST/ALT

• Required or suggested• C282Y/C282Y, ferritin ≥ 1000 μg/L, elevated AST/ALT• Consider for C282Y/H63D or other• Routine histopathology• Qualitative and quantitative iron assessment

Adams P et al, J Lab Clin Med 1997;130:509-514

HemochromatosisLiver Histopathology

• Hepatocytes• Progressive iron accumulation from periportal

(zone 1) to pericentral (zone 3) regions• Routine H&E and Prussian blue stains

• Kupffer and biliary epithelial cells• Iron accumulation with progressive iron loading

• Fibrosis and cirrhosis• Trichrome stain• Associated with advanced iron overload• Hepatocellular carcinoma

Hepatic Iron OverloadOther Diseases

• ETOH, NAFLD, viral hepatitis, PCT, parenteral• Panlobular and patchy iron distribution• Iron accumulation in hepatocytes and Kupffer

cells• Iron accumulation is usually mild• Ferroportin disease associated with iron

overload in macrophages and reticuloendothelial cells

HemochromatosisPathology

Progressive hepatic iron overload Myocardial iron overload

Cirrhosis: H&E Cirrhosis: Prussian Blue

www.gfmer.ch/genetic_diseases_v2/gendis_detail_list.php?cat3=821

HemochromatosisImaging

CT MR

Taouli B et al, AJR 2009;193:14-27Jensen P, Br J Haematol 2004 Mar;124(6):697-711

HemochromatosisTreatment

• Weekly or twice weekly phlebotomy• Removal of 2-3 units per week or 0.5 units every other week• Check Hgb/HCT prior to each phlebotomy• Follow TS and ferritin every 3 mo.• Endpoints: TS < 50%, ferritin < 50 μg/L• Maintenance phlebotomy: 1 unit every 3 mo.• Avoid iron deficiency• Imaging and AFP every 6 mo. to screen for HCC in cirrhotic

patients• OLT for hepatic decompensation or HCC

Bacon B. Gastroenterology 2001;120:718-725

HemochromatosisResponse to Phlebotomy

• Improvement• Tissue iron stores• Survival in absence of cirrhosis and DM• Liver-associated enzymes• Cardiac function, DM, skin pigmentation, fibrosis

• No improvement• Established cirrhosis• Arthropathy• Testicular atrophy

HemochromatosisScreening

Family Screening• HFE (C282Y, H63D) and iron

testing for first degree relatives• C282Y/C282Y and C282Y/H63Y

relatives with iron overload undergo phlebotomy

• C282Y/wt, H63D/H63D, H63D/wt not at risk for iron overload

• C282Y/C282Y or C282Y/H63D children undergo yearly ferritin assessment

Population Screening• Role for population screening

with genetic testing unclear• Incomplete penetrance raises

questions about clinical utility, cost effectiveness, and genetic discrimination

• Non HFE hemochromatosis is rare and genetic testing only available in research labs

Tavil A. Hepatology 2001;33:1321-1328

Symptomatic

Transferrin saturation/ferri

tin

TS < 45% and normal ferritin

No further evaluation

TS ≥ 45% and/or

elevated ferritin

HFE genotype

Asymptomatic

Transferrin saturation/ferri

tin

TS < 45% and normal ferritin

No further evaluation

TS ≥ 45% and/or

elevated ferritin

HFE Genotype

Adult 1st degree relative

of HH

HFE genotypeTransferrin

saturation/ferritin

TS < 45% and normal ferritin

No further evaluation

TS ≥ 45% and/or

elevated ferritin

HFE genotype

Hemochromatosis Algorithm

Bacon B et al, Hepatology,2011;54:328-343

HFE genotype

C282Y/H63D, C282Y

heterozygote, non-C282Y

Exclude other liver or hematologic diseases. ± liver biopsy

Therapeutic phlebotomy

C282Y/C282Y

Ferritin < 1000 μg/L and normal liver

enzymes

Therapeutic phlebotomy

Ferritin ≥ 1000 μg/L or elevated liver

enzymes

Liver biopsy for HIC and

histopathology

Therapeutic phlebotomy

Hemochromatosis Algorithm

+

±

Bacon B et al, Hepatology,2011;54:328-343

HemochromatosisTake Home Points

• HFE (C282Y/C282Y) mutations account for most cases of hereditary hemochromatosis.

• Be aware of other non-HFE inherited and secondary causes of iron overload.

• Interrelationship between duodenal iron absorption and hepcidin is important.

• Patients can present with a variety of hepatic and extrahepatic manifestations.

• Diagnosis based upon iron studies, genetic testing, and liver biopsy.• Phlebotomy is mainstay of therapy• Genetic testing recommended for family members of patients with

hereditary hemochromatosis.

HemochromatosisQuestion 1

• A 55 yr old man presents with mildly elevated transaminases. His serum ferritin is 3000 mcg/L, with transferrin saturation exceeding 90%. He is homozygous for C282Y. Liver ultrasound is normal and liver biopsy shows bridging fibrosis and markedly elevated hepatocellular iron. Weekly phlebotomy is started. The patient’s wife is heterozygous for C282Y and one normal allele. The patient has 2 sons ages 26 and 18. The older son’s ferritin is 2500 mcg/L, whereas the younger son’s ferritin is 180 mcg/L. At this time you make all of the following recommendations except:

DDSEP 6, AGA Press, 2011.

HemochromatosisQuestion 1

• A. The older son should be tested for C282Y mutation of HFE gene

• B. For the older son, liver biopsy may be justified to R/O cirrhosis

• C. The younger son should be tested for C282Y mutation

• D. For the younger son, liver biopsy may be justified to R/O cirrhosis

• E. The older son should have liver ultrasoundDDSEP 6, AGA Press, 2011.

HemochromatosisQuestion 2

• A baby born to parents of Irish descent (father homozygous for C282Y, mother genetic status unknown) is found to be homozygous for C282Y. What is the lifetime risk of hepatic decompensation and/or hepatocellular carcinoma if the child is carefully followed and undergoes phlebotomy over his/her lifetime?• A. Zero• B. 5%• C. 20%• D. 50%• E. 80%

DDSEP 6, AGA Press, 2011.

HemochromatosisQuestion 3

• An autosomal dominant form of hemochromatosis accompanied by high levels of hepcidin production is associated with mutations of the gene coding for which of the following?• A. HFE protein• B. Transferrin receptor type 2• C. Hemojuvelin• D. Hepcidin• E. Ferroportin

DDSEP 6, AGA Press, 2011.

HemochromatosisQuestion 4

• Which one of the following statements about liver biopsy in patients with HFE (C282Y homozygous) hemochromatosis is correct?• A. Liver biopsy should be performed in all patients after genetic

testing.• B. Kupffer cells take up iron before hepatocytes in patients with

HFE (C282Y homozygous) hemochromatosis.• C. Panlobular patchy iron accumulation in hepatocytes and

Kupffer cells is classic for C282Y homozygous disease.• D. In patients with C282Y disease, iron is taken up by periportal

(zone 1) hepatocytes prior to pericentral (zone 3) hepatocytes.• E. Bridging fibrosis is seen in early disease

HemochromatosisQuestion 5

• A 65 yr old male is recently diagnosed with C282Y hemochromatosis and cirrhosis. His transferrin saturation is 95% and his ferritin is 5284 mcg/L. Which one of the following statements is incorrect?

• A. He will not require surveillance for hepatocellular carcinoma once iron stores have been removed from the liver by phlebotomy.

• B. Phlebotomy should be initiated to achieve endpoints of T. Sat of < 50% and ferritin < 50 μg/L.

• C. Phlebotomy may improve cardiac function and glucose intolerance.

• D. Arthropathy does not usually improve with phlebotomy• E. At the beginning of treatment, weekly or twice weekly

phlebotomy is necessary to reach desired endpoints.

HemochromatosisQuestion 6

• Which one of the following statements about HFE hemochromatosis is correct?• A. C282Y/H63D disease is the most common genetic

abnormality.• B. H63D/H63D commonly results in iron overload.• C. Population-based screening for genetic

hemochromatosis is recommended.• D. CT and MR of the liver are sensitive tests for

diagnosing disease.• E. Hepcidin regulates ferroportin-mediated iron export

from duodenal enterocytes.

HemochromatosisAnswers to Questions

• 1. D• 2. A• 3. E• 4. D• 5. A• 6. E