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