HemeOnc
Hemochromatosis
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Hemochromatosis
, Bronze diabetes
Epidemiology
Hereditary Hemochromatosis
Clinically important hereditary Hemochromatosis is rare
Only 10% of C282Y
Homozygote
s manifest disease (remainder are asymptomatic)
Cirrhosis
develops in 1-2% of C282Y
Homozygote
s
Manifestations are twice as common and more severe in men
Homozygous
C282Y
Prevalence
varies across ethnicity
White: 4.4 per 1000
Hispanic: 0.27 per 1000
Black: 0.14 per 1000
Asian American: <0.001 per 1000
References
Whitlock (2006) Ann Intern Med 145:209-23 [PubMed]
Etiologies
Hereditary Hemochromatosis
Gene
ral
Autosomal Recessive
disease (HFE
Gene
)
Homozygous
HFE
Incidence
: 1 in 250-300 caucasians
Disrupted iron regulation results in toxic iron accumulation and tissue iron deposition
HFE protein regulates hepcidin (iron regulatory protein)
Hepatocytes secrete hepcidin in response to excess iron
Hepcidin decreases intestinal iron absorption and
Macrophage
iron release
Hepcidin expression is decreased in hereditary Hemochromatosis, resulting in excess iron levels
Chromosome
6 mutations responsible
C282Y Mutation (90% of cases)
Homozygous
in 0.64% of white patients (
Heterozygous
in 10%)
Missense mutation with Tyrosine for cysteine at 282 on
Chromosome
6
H63D Mutation (10% of cases)
Combination of C282Y/H63D occurs in 2% of white patients
S65C Mutation
Secondary iron overload
Chronic
Anemia
(e.g.
Thalassemia
major)
Chronic Liver Disease
(e.g.
Viral Hepatitis
)
Iron Supplementation
(rare with oral iron)
Multiple transfusions
Parenteral Iron
Dextran
Pathophysiology
Hereditary Hemochromatosis
Inappropriately high intestinal iron absorption
Only a few extra iron milligrams absorbed each day
Iron
slowly accumulates over decades
Results in excess body iron stores
Normal body iron stores: 4 grams
Exceeded by age 10 in hereditary Hemochromatosis
Tissue injury occurs when body iron 25 grams (age 30)
Cirrhosis
when body iron 30-40 grams (age 40)
Factors that provoke expression of disease
Male gender (women may be protected due to
Menses
)
Hepatitis C
Alcohol Abuse
Cirrhosis
risk increases 9 fold for daily
Alcohol
intake of more than 60g or 4 drinks
Manifestations
Organ iron deposition
Iron
deposits in heart, liver and
Pancreas
, bones and joints
Results in
Cardiomyopathy
,
Cirrhosis
,
Diabetes Mellitus
and
Arthritis
Increased oxidative DNA and free radical activity
Hepatocellular Carcinoma
risk (20 fold increase risk when
Cirrhosis
present)
Breast Cancer
risk (variable evidence)
Findings
Presentations
Classic Presentation - Bronze diabetes (late stage, rare)
Hyperpigmented skin
Diabetes Mellitus
Cirrhosis
Typical presentations
Weakness, lethargy and
Arthralgia
s
Erectile Dysfunction
Liver Function Test
abnormalities
Symptoms (asymptomatic in most cases)
Common symptoms
Fatigue
, Lassitude, or weakness
Arthralgia
s
Impotence
Other symptoms
Weight loss
Abdominal Pain
Hyperpigmented skin
Signs
Brown skin pigmentation
Hepatomegaly
Loss of body hair
Edema
Ascites
Peripheral neuritis
Testicular atrophy
Synovitis at second and third metacarpophalangeal joints
Complications
Cirrhosis
Associated 20 fold increased lifetime risk of
Hepatocellular Carcinoma
(4% annual
Incidence
)
Diabetes Mellitus
Arthritis
(MCP joints) or
Pseudogout
Hypogonadism
Hypothyroidism
Restrictive Cardiomyopathy
(reversible if treated before
Heart Failure
develops)
Diastolic Dysfunction
Atrioventricular Block
Dysrhythmia
s
Skin
Hyperpigmentation
(bronze or gray color)
Infection
Vibrio vulnificus
Listeria monocytogenes
Pasteurella
pseudotuberculosis
Labs
Screening
Indications for screening
Gene
ralized weakness
Arthralgia
s (especially involving hand joints, MCP joints 2 and 3)
Hepatomegaly
Aspartate Aminotransferase
(AST) elevation
Hypogonadism
(
Impotence
or
Infertility
)
Skin
Hyperpigmentation
Cardiomyopathy
or
Cardiac Arrhythmia
Diabetes Mellitus
Family History
of Hemochromatosis
Risk if sibling with Hemochromatosis: 25%
Risk if parent with Hemochromatosis: 5%
Iron Saturation
(
Serum Transferrin Saturation
)
Earliest lab change in hereditary Hemochromatosis
Previously guidelines recommended
Fastin
g iron tests (or confirmation with
Fastin
g test)
Fastin
g is no longer required as non-
Fastin
g values are accurate
Serum Iron
was thought to be impacted by oral intake and presumed most accurate when
Fastin
g
Test Sensitivity
approaches 94% in C282Y
Homozygote
Abnormal levels suggesting Hemochromatosis
Men >45-50%
Women >45%
Serum Ferritin
Obtain with
Iron Saturation
High
Test Sensitivity
but poor
Specificity
False Positive
s as an acute phase reactant
Positive Predictive Value
is <18%
Offers prognostic value
Cirrhosis
is unlikely when
Ferritin
<1000 ng/ml
Abnormal levels suggesting Hemochromatosis
Men >250-300 ng/ml
Women > 200 ng/ml
Labs
Genetic Test
ing
Test for C282Y Mutation (
Homozygous
)
Indications for testing
First degree relative of C282Y
Homozygote
Abnormal
Serum Ferritin
Abnormal
Transferrin Saturation
Diagnosis
Liver
biopsy
Indications
Non-hereditary Hemochromatosis
Late presentation
Aspartate Aminotransferase
(AST) >40 U/L
Ferritin
>1000 ng/ml
Findings
Hepatic tissue iron index>2 (tissue iron umoles/age)
Excessive Hemosiderin deposits
Site of iron deposition varies per cause
Hereditary Hemochromatosis: Hepatocytes
Secondary iron overload: Kupffer cells
Evaluation (If Hemochromatosis screening positive)
Rule-out secondary cause of iron overload (see above)
Alcoholic Liver Disease
Hepatitis C
and other
Viral Hepatitis
Exogenous iron intake
Thalassemia
major and other chronic
Anemia
s
Obtain HFE gene test (consider via
Consultation
)
Homozygous
for HFE C282Y mutation
Phlebotomy if liver biopsy indications not met
Liver
biopsy indications
Increased
Aspartate Aminotransferase
(AST)
Serum Ferritin
>1000 ng/ml
Hepatomegaly
Findings not consistent with hereditary form
Obtain
Liver
biopsy (see above) or abdominal MRI
Phlebotomy for Hemochromatosis liver findings
Management
Test ALL first degree relatives
Phlebotomy
May be performed at some blood donation centers (requires waiver)
Remove 500 ml blood weekly (one unit of blood or 200-250 ml
pRBC
)
Removes 200-250 mg iron
Reduces
Serum Ferritin
by 30 ng/ml
Goals:
Iron
depletion (reached in 6 to 24 months)
Hemoglobin
: 12.5 to 13 g/dl (check before each phlebotomy)
Serum Ferritin
: 50 to 150 ng/ml
Transferrin Saturation
<50%
Expected effects of phlebotomy
Removes excess iron and normalizes tissue iron stores
Prevents progression and complications
Fatigue
and lethargy resolve
Skin bronzing improves
Cardiac Function
and
Restrictive Cardiomyopathy
improve
Hepatomegaly
and
Liver Function Test
abnormalities improve (hepatic fibrosis improves in 30% of cases)
However,
Diabetes Mellitus
control may be unaffected
Complications
Iron
avidity
Results from overcorrection of iron overload
Presents with iron craving and normal
Serum Ferritin
with increased
Iron Saturation
Dietary recommendations
Avoid
Hepatotoxin
s including
Alcohol
Avoid exogenous iron sources
Avoid iron supplements
Avoid
Multivitamin
s with iron
Avoid
Vitamin C
Supplementation
Limit red meat intake
However unlikely to have significant impact at typically <4 mg
Dietary Iron
per day
Avoid exposure to
Vibrio vulnificus
Avoid raw seafood intake
Do not handle raw seafood
Management
Cirrhosis
Predictors of
Cirrhosis
development (each factor increases risk in succession up to risk >80%)
Increased
Serum Ferritin
over 1000 ng/ml
Increased hepatic transaminases (ALT or AST)
Decreased
Platelet Count
<200k
Excessive alchol use (>60 grams per day or 4 drinks per day)
Refer to gastroenterology for signs of
Cirrhosis
Surveillance for
Hepatocellular Carcinoma
Consideration for liver
Transplantation
Surveillance for
Hepatocellular Carcinoma
Obtain
RUQ Ultrasound
No
Liver Lesion
RUQ Ultrasound
every 6-12 months
Liver Lesion
<1 cm
RUQ Ultrasound
every 3-6 months
Gastroenterology consult
Liver Lesion
>1 cm
Evaluate for
Hepatocellular Carcinoma
Gastroenterology consult
Prognosis
Conditions increasing mortality
Cirrhosis
(5 year survival reduced 50%)
Diabetes Mellitus
Restrictive Cardiomyopathy
with
Heart Failure
Resources
Iron
Disorders Institute
http://www.irondisorders.org
Iron
Overload Diseases Association
http://www.ironoverload.org
References
Brandhagen (2002) Am Fam Physician 65(5):853-66 [PubMed]
Crownover (2013) Am Fam Physician 87(3): 183-90 [PubMed]
Felitti (1999) Am J Med Sci 318(4):257-68 [PubMed]
Harrison (2002) Can Fam Physician 48:1326-33 [PubMed]
Powell (1998) Ann Intern Med 129(11):925-31 [PubMed]
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