Transcript Hemochromatosis - Being an Iron Man Carries Risk

HEMOCHROMATOSIS:
BEING AN “IRON MAN” CARRIES RISK!
Gina C. Guzman, MD, DBIM, FALU, FLMI
2nd VP & Medical Director
Hereditary Hemochromatosis (HH)
Genetic Disorder
of Iron
Metabolism
Excessive Iron
Overload
Autosomal
Recessive
Symptoms Due
to Iron
Accumulation in
Various Tissues
Cause of
Significant
Morbidity and
Mortality
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All body cells need
ENERGY
OXYGEN
GROWTH AND
PROLIFERATION
Total Body Iron
~3.5 grams
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Normal Iron Absorption and Metabolism
3-7mg
Women – 2mg/day
Menses
Pregnancy
Total Body Iron
~3.5 grams
2.5 gms
1 gm
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Pathophysiology of HH
Persons with Hereditary
Hemochromatosis continue to absorb
iron even when their body already has
enough
except
BLOOD LOSS
NORMAL PERSON
Excessive Iron Deposition in
Tissues (especially the liver,
heart, pancreas, and pituitary)
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“Classic”19th Century Presentation
Middle-aged
man
Hepatomegaly
+/- cirrhosis
Diabetes
Mellitus
Bronze diabetic
with cirrhosis
Considered
“rare”
Bronzed skin
Advanced endorgan damage
with poor
mortality
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21st Century Presentation
Younger
person
Asymptomatic
Common
disease
Elevated liver
function tests
No end organ
damage with
good prognosis
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Why the switch?
Increased routine iron testing during routine
physical exams
Increased awareness of the disease
Increased diagnosis before symptoms develop
Development of a genetic test in 1996
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Prevalence of HH
1 in 250 persons
Most common single-gene genetic disorder in the US
 White Northern European descent (1 in 227)
 Hispanic (1 in 3700)
 Black (1 in 7000)
 Asians (<0.001 per 1000)
Caucasian population (USA, Western Europe)
 10% carrier for the mutation
 0.5% homozygous state
N Engl J Med 2005;352:1769-78.
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Iron Stores & Clinical Manifestations
Dx here RARE
^ Diagnosis before Sx
Adapted from Riely CA, Vera SR. Inherited liver disease. American
Gastroenterological Association, 1993.
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Early Symptoms
No symptoms
 A common early sign is asymptomatic elevation of LFT’s (75%)
Early, non-specific
 Fatigue/Weakness (74%)
 Joint pain (44%)
 Weight loss
 Abdominal pain
 Palpitations
Hepatology 1997;25:162-6.
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Late Symptoms – Where is Iron Deposited?
Bronze Skin
Impotence
Early menopause
Hypothyroidism
Arthritis
Hepatomegaly
^LFTs
Cirrhosis
Cardiomyopathy
Arrhythmia
Diabetes
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CASE FILE REVIEW
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Case File Review
 43 y/o NS male
 $5,000,000 term life
 No admitted medical history
 “Normal” physical last year
 AST 47 and ALT 72
 Hep B & C - negative
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Differential Diagnosis of ^LFTs
Drugs and Alcohol
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Medications and Supplements
Antibiotics
Lipid Lowering Drugs
(Statins)
Herbal therapy
Recreational drugs
Seizure drugs
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Liver Disease
Viral Hepatitis ( B and C)
NAFLD
Fatty liver/NASH
Hemochromatosis
Wilson’s disease
Autoimmune Hepatitis
Alpha-1-Antitrypsin deficiency
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Other Possibilities…
 Muscle Disorders
 Thyroid Disorders
 Celiac Disease
 Adrenal insufficiency
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Sample Evaluation of Mild ^LFTs
HepBsAg
Hep C Ab
Iron studies
Abdominal
ultrasound of the
liver
Serum
ceruloplasmin (decreased in
Wilson’s)
ANA, anti-smooth
muscle Ab (ASMA)
(+ in autoimmune
hepatitis)
Serum alpha-1antitrypsin –
(decreased in
deficiency)
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Iron Studies
Serum Fe
Total Iron
Binding
Capacity (TIBC)
Transferrin
Saturation
Ferritin
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Transferrin Saturation (TS)
95% accuracy in identifying iron overload
How much iron
is bound to the
carrier protein
BEST TEST for
detecting iron
overload
Earliest lab
abnormality in
iron overload
Serum Fe/TIBC
Abnormal
>50% in women
>60% in men
Should be done
fasting
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Our case had iron studies…
Total Serum Fe = 221 (49-181 ug/dL)
TIBC = 261 (250-450 ug/dL)
Ferritin = 1277 (20-300 ng/mL)
Transferrin Sat = Serum iron/TIBC
221/261 = 85%
ABNORMAL (>50% in women, 60% in men)
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Disorders Associated with Iron Overload
Hereditary hemochromatosis
Exogenous iron overload
Related to HFE gene
 Chronic iron supplementation
(in absence of blood loss)
Not related to HFE gene
 African (Bantu) hemochromatosis
 Transfusion
 Juvenile hemochromatosis
 Iron dextran injection
 Neonatal hemochromatosis
 Oral supplements (rare)
Chronic anemias
Chronic liver diseases
Thalassemia major
 Viral hepatitis
Sideroblastic anemia
 Alcoholic liver disease
Congenital dyserythropoietic anemia
 Nonalcoholic steatohepatitis
Congenital atransferrinemia
 Porphyria cutanea tarda
 Portacaval shunt
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Work-up for HH
Fasting Transferrin
Saturation
>50% in women
>60% in men
Ferritin
CBC
LFT’s
Genetic Testing
J Hepatol 2000;33:485-504.
Liver Biopsy
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Ferritin
Iron storage protein – reflects the body’s stores of iron
Normal levels
 20-300 ng/mL (male), 20-150 ng/mL (female)
Acute Phase Reactant
 Elevated in inflammation, infection, recent trauma, surgery, cancer
 Less specific than the iron saturation (PPV 20% vs. 80%) for HH
 Should NOT be used as a screening test
Ferritin > 600 needs work-up
Ferritin > 1000 despite normal TS, may need liver biopsy
Clin Chim Acta 1996;245:139-200.
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GENETICS
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Basic Genetics
Human DNA
46 Chromosomes (structures that hold our genes)
- organized in 23 pairs (one copy from each parent)
- 22 pairs of autosomes
- 1 pair of sex chromosomes (XX, XY)
~30,000 pairs of Genes
Locus – point on the chromosome
where the gene is located
Alleles – 2 per locus
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Alleles
HOMOZYGOTE
Two copies of the same
HETEROZYGOTE
Two different
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More Genetics Definitions
Genotype – the genetic makeup of an individual
(AA, Aa, aa)
Phenotype – the observable appearance of an
individual (Black, Brown, Blonde)
Autosomal Dominant – only a single abnormal
gene from either parent can cause disease
Autosomal Recessive – two copies or an
abnormal gene must be present for disease
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Genetic Testing for HH
Mutation in the HFE gene – regulates Fe absorption
Discovered in 1996
Short arm of chromosome 6 (6p21.3)
40 allelic variants of the HFE gene have been described to
date
Only two are significantly correlated with HH
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HFE gene defect
Two mutations have
been described in
the majority of
patients with HH
C282Y
H63D
Cysteine to
Tyrosine
at position 282
(C282Y)
Histidine to
Aspartate
at position 63
(H63D)
Strong association
with the phenotypic
changes of iron
overload
Limited clinical
effect
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HFE Mutation Combinations
Review: Chromosome 6 = 2 alleles
3 possibilities for the HFE gene (C282Y, H63D, Normal version)
6 possible combinations:
1. C282Y/C282Y
2. C282Y/H63D
3. H63D/H63D
4. C282Y/normal
5. H63D/normal
6. Normal/normal
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Transferrin Sat % and HFE Genotype
(N Engl J Med 2005;352:1769-78)
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C282Y/C282Y (Homozygote)
69-100% of clinically diagnosed HH (average 83%)
Very high prevalence in Caucasians in North America (1:227)
More severe than H63D
72-99% likelihood of being free of signs/symptoms of HH at diagnosis
Variable penetrance (the proportion of individuals of a particular genotype that
express its phenotypic effect)
 Up to 50% may never develop clinically significant iron overload (population
studies)
 Females have lower penetrance over males
Amer J of Epidemiology. Vol. 154, No 3,
2001 N Engl J Med 2005;352:1769-78
Lancet 2002;359:211-8.
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C282Y/C282Y with NL TS
Uncertain at the present time what percentage of these may eventually develop iron
overload
Cost of follow-up is significant
Should be followed yearly (CPE, yearly iron studies)
Copenhagen Heart Study monitored 23 homozygotes over 25 years who never
developed overt iron overload
Blood 2004;103:2914-9.
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C282Y/H63D (Compound Heterozygote)
3-5% of clinically diagnosed HH
Comorbid factors (Steatosis, DM, Excess Alcohol) ^ risk of developing progressive
clinical disease
High prevalence of increased iron indices with reduced penetrance of <2%
 Only 0.5 – 2 % will develop HH
Must have clinical correlation in order to make a diagnosis of HH
C282Y/H63D, normal iron studies, no comorbid factors => consider as only a carrier
of HH gene with no additional mortality risk
Blood Cells Mol Dis. 1997 Aug;23(2):314-20.
Clin Gastroenterol Hepatol. 2006 Nov;4(11):1403-10.
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H63D/H63D (Homozygote)
1% of diagnosed HH
• Typically a mild course of disease with less iron accumulation
< 1% risk of developing HH
Most will NEVER develop any symptoms
4-fold risk of amyotrophic lateral sclerosis
(Hepatology. 2007 Sep 7:46(4):1071-1080.)
2-3 fold risk of ischemic stroke
(Neurology. 2007 Mar 27;68(13):1025-31.)
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C282Y/normal or H63D/normal
(Heterozygotes)
3-10% of clinical HH (presumed due to additional unknown mutations)
Many have mildly increased iron levels, but no clinical symptoms
Majority of these will be HEALTHY CARRIERS with NL iron levels (and no increased
mortality risk)
1 in 10 Caucasians in the USA
Ann Intern Med. 1999 Jun 15;130(12):953-62.
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Caveat about HFE testing
HFE gene testing is only 85% accurate
Non-HFE related HH (false negatives)
 7-10% HH have mutations not commonly tested or not yet discovered
 Familial cases of HH without detectable HFE mutation

N Engl J Med 2004;350:2383-97.

Semin Liver Dis 2005;25:450-60.

Amer J of Epidemiology. Vol. 154, No 3, 2001
Variable penetrance (false positives)
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Newly, Identified Iron-Related Genes
Ferroportin
Hemojuvelin
Hepcidin
Ceruloplasmin
Transferrin Receptor 2
Unrelated to HFE
Rare cases of iron overload
Complex genetic testing
Further research ongoing
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SCREENING FOR HH
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Screening for HH
American College of Physicians/ NIH/ CDC
 (+) Family History and/or (+) symptoms
The College of American Pathologists
 All adults over 18
 (+) Family History - Every 5 years
The American Hemochromatosis Society
 Age 4 – routine iron testing
 (+) Family History – Every 5 years
REMEMBER: BEST test for screening Transferrin Sat = Serum Fe / TIBC
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U.S. Preventive Services Task Force
• Against routine genetic testing for HH in the
asymptomatic general population
• Genetic testing should NOT be used as a
screening tool
Ann Intern Med 2006 Aug 1;145(3):204-8
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USPSTF Grade D
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CASE FILE REVIEW
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Case summary
Elevated LFT’s in an asymptomatic male
Elevated iron and ferritin
Elevated transferrin saturation
Genetic Testing reveals: Heterozygote C282Y/H63D mutation
Do we have enough now to make the diagnosis of hereditary
hemochromatosis?
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Minimum Criteria for Diagnosis
Increased iron stores
 Elevated transferrin saturation
 Serum iron/TIBC
(+) HFE Gene mutation
 C282Y/C282Y or C282Y/H63D
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What about liver biopsy?
Liver biopsy is no longer essential for the diagnosis
Who needs one?
What information can be gained?
Liver is the major organ affected with HH
Easily accessible tissue
Prognostic rather than diagnostic
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Who should get a liver biopsy?
Age over 40 years old
Elevated LFT’s
Clinical evidence of liver disease
History of alcohol abuse
Coexisting diabetes, impotence
Ferritin level > 1000 ng/mL
 ^ likelihood of fibrosis or cirrhosis
Gastroenterology 1998;115:929-36.
Hepatology 2002;36:673-8.
Ann Int Med 2003;138:627-33
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Liver Biopsy
Brown pigment = iron
Trichrome stained tissue (blue) = fibrosis
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Prognostic value of liver biopsy
Document the degree of fibrosis, if any
 Liver cirrhosis/fibrosis => ^ risk HCC
 Normal biopsy => normal life expectancy with treatment
Confirm the diagnosis with Hepatic Iron Index
 Negative genetic testing
 Compound Heterozygote mutation
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Hepatic Iron Index (HI)
Measurement of the iron concentration
HI = Hepatic Iron Concentration (HIC)/patient’s age
 Normal HI < 1.0
 HI > 1.9 is a strong marker for HH
CAVEAT – up to 15 % of homozygous HH will have a normal hepatic iron
index despite clinical evidence of disease
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Who may NOT get a liver biopsy?
Age < 40 years old
No clinical evidence of liver disease (e.g. normal LFT’s, no hepatomegaly)
Fasting serum ferritin level < 1000 ng/mL
These people are unlikely to have significant hepatic injury
Clinician may not recommend liver biopsy and proceed directly to treatment
A LIVER BIOPSY IS NOT NECESSARY FOR THOSE < 40 Y/O WITH
GENOTYPICALLY DEFINED HH (C282Y HOMOZYGOUS) WITH NL LFTS
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Back to Our Case One Last Time
Applicant has iron overload and probably has hemochromatosis
Liver biopsy would be very helpful
 Age>40, elevated LFTs, ferritin>1000
 Can help confirm diagnosis in a heterozygote
Treatment is indicated
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Treatment = Phlebotomy
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Treatment Goals
Initial treatment = “de-ironing”
 Removal of 1-2 units of whole blood/week (several months)
 1 unit of whole blood = 1 pint = ~ 500 cc = 200-250 mg of iron
 Goal Ferritin < 50 ng/mL, TS < 50%
 Hgb < 12 for men , Hgb < 11 for women
Maintenance
 Every 2 to 4 months for life
 Maintain Ferritin < 100 ng/mL with normal hemoglobin
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Iron Chelation
 Binds to iron allowing iron to be excreted in either urine or bile thereby reducing
the body burden of iron
 Used in the rare case when phlebotomy contraindicated (e.g., HH with severe
cardiac involvement – unstable hemodynamic status)
 Deferoxamine
 Deferiprone
 Deferasirox
 Almost never necessary due to the ease/efficacy of phlebotomy
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Dietary Management
Avoid iron supplements
Avoid excess Vitamin C, which promotes iron absorption
 Increased risk of cardiac arrhythmia due to acceleration of iron metabolism
Avoid uncooked seafood / raw oysters
 Increases the risk of Vibrio vulnificus and Salmonella enteritidis infections
 These bacteria grow well in an iron-rich environment
 ^ iron may also impair WBC’s fighting capability
Limit EtOH consumption
 Mild/moderate EtOH consumption ^ prevalence of iron overload
 EtOH ^ severity of disease => > 2 drinks/day ^ risk of cirrhosis
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Role of Alcohol in HH
Scotet V. Am J Epidemiol. 2003 Jul 15;158(2):129-34.
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HH and Mortality
60 % of all deaths are related to complications of iron overload
#1 LIVER (75% of above)
 Cirrhosis
 HCC
#2 DIABETES
#3 CARDIOMYOPATHY
Survival is NORMAL in HH patients in whom treatment was initiated before the
development of cirrhosis or diabetes
Gastroenterology 1996;110:1107-19.
Can J Gastroenterol 1993;7:37-41.
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Prognosis
Early diagnosis => early effective treatment => GOOD prognosis with normal life
expectancy
 BEST CASE
 Compliant with treatment, good follow-up
 Ferritin < 100 ng/mL, TS < 50%
 No end organ damage
 No symptoms
 Non-specific symptoms (weakness, fatigue) can resolve
 Liver function can return to normal
 Endocrine changes may improve (impotence can resolve, insulin requirements
can decrease)
 Joint pain can resolve
Ann Intern Med 1998;129:932-9.
Gastroenterology 1996;110:1107-19.
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Prognosis
Evidence of end organ damage e.g. cirrhosis or DM => WORSE/BAD prognosis
 Significant fibrosis in any organ is irreversible
 Cirrhosis increases risk for HCC
 75% of HH-related deaths
 Screen with routine AFP testing
 Without treatment, eventual fatal iron overload
Gastroenterology 1996;110:1107-19.
Hepatology 1992;15:655-9.
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Conclusions
Most people with HH will have a normal life expectancy
Early diagnosis and effective treatment is the key
Phlebotomy therapy, if initiated early, can prevent cirrhosis,
cardiac complications, and diabetes
Patients with evidence of iron overload, positive family
history, or other risk factors should be screened
The best screening test for iron overload is the
TRANSFERRIN SATURATION (Serum Fe/TIBC)
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Thank you!
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