Hemochromatosis
Thomas W. Faust, M.D., M.B.E.
Professor of Clinical Medicine
Division of Gastroenterology
The University of Pennsylvania
Hemochromatosis
• Introduction
• Classification of
iron overload
syndromes
• Pathogenesis
• Clinical
manifestations
• Diagnosis
• Treatment
• Screening
Hereditary Hemochromatosis
Introduction
• 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
Hemochromatosis
Hereditary 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
Hemochromatosis
Non-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 Absorption
Crypt 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 Stores
Influence 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 Stores
Normal
• 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
Hemochromatosis
Non-Ferroportin Mutations
• Mutations of BMP, HJV,
HFE, and TFR2 alter
ability of liver to sense
body iron stores
• Inappropriately low
level of hepcidin
• Excess ferroportinmediated export of iron
from duodenum,
macrophages, and liver
Nemeth E. et al, Science 2004;306:2090–2093
Hemochromatosis
Ferroportin 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
Hemochromatosis
Overview 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
Hemochromatosis
Hepatic 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
Hemochromatosis
Physical Examination
• Physical findings in
patients with
progressive liver disease
• Findings not specific to
hemochromatosis
Hemochromatosis
Hepatocellular 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
Hemochromatosis
Extrahepatic 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
Hemochromatosis
Systemic 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
Hemochromatosis
Extrahepatic Manifestations
Diagnosis of Hemochromatosis
Iron Studies
Transferrin Saturation
Ferritin
• Value ≥ 45% most
common early
phenotypic marker
• Sensitivity > 90%
• Fasting value preferable
• F/U with genetic testing
• 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 Hemochromatosis
Genetic Testing
• C282Y/C282Y
• C282Y/H63D or other
• For all patients with TS ≥
45%
• For all patients with
elevated ferritin
• Liver biopsy for ferritin ≥
1000 μg/L or elevated
AST/ALT
Guyader D. et al, Gastroenterology 1998;115:929-936
• 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
Liver Biopsy
Diagnosis 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
Hemochromatosis
Liver 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 Overload
Other 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
Hemochromatosis
Pathology
www.gfmer.ch/genetic_diseases_v2/gendis_detail_list.php?cat3=821
Hemochromatosis
Imaging
CT
Taouli B et al, AJR 2009;193:14-27
Jensen P, Br J Haematol 2004 Mar;124(6):697-711
MR
Hemochromatosis
Treatment
• 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
Hemochromatosis
Response 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
Hemochromatosis
Screening
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
Tavil A. Hepatology 2001;33:1321-1328
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
Hemochromatosis Algorithm
Symptomatic
Asymptomatic
Transferrin
saturation/ferritin
Transferrin
saturation/ferritin
Adult 1st degree
relative of HH
HFE genotype
Transferrin
saturation/ferritin
TS < 45% and
normal ferritin
TS ≥ 45% and/or
elevated ferritin
TS < 45% and
normal ferritin
TS ≥ 45% and/or
elevated ferritin
TS < 45% and
normal ferritin
TS ≥ 45% and/or
elevated ferritin
No further
evaluation
HFE genotype
No further
evaluation
HFE Genotype
No further
evaluation
HFE genotype
Bacon B et al, Hepatology,2011;54:328-343
Hemochromatosis Algorithm
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
Ferritin ≥ 1000 μg/L
or elevated liver
enzymes
Therapeutic
phlebotomy
Liver biopsy for
HIC and
histopathology
+
Therapeutic
phlebotomy
Bacon B et al, Hepatology,2011;54:328-343
Hemochromatosis
Take 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.
Hemochromatosis
Question 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.
Hemochromatosis
Question 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 ultrasound
DDSEP 6, AGA Press, 2011.
Hemochromatosis
Question 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.
Hemochromatosis
Question 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.
Hemochromatosis
Question 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
Hemochromatosis
Question 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.
Hemochromatosis
Question 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.
Hemochromatosis
Answers to Questions
•
•
•
•
•
•
1. D
2. A
3. E
4. D
5. A
6. E
