Clinical
Practice Guideline
for
HEMOCHROMATOSIS
Developed for the
Aerospace Medical Association
by their
constituent organization
American Society of Aerospace Medicine Specialists
Overview: Hemochromatosis is an iron overload syndrome. The hereditary nature was recognized in the
1930’s. In 1996 the autosomal recessive
form, known as hereditary hemochromatosis, was linked to amino acid
substitutions on the short arm of chromosome 6 encoding HLA-A*3. This “hemochromatosis gene,” is listed as
HFE. Since the discovery of the HFE
gene, other genes related to the control of iron metabolism have been
identified. The Online Mendelian
Inheritance in Man (OMIM) database has four types of hereditary hemochromatosis
listed.4
The first
of the four types is classic hereditary hemochromatosis, a HFE-related
hemochromatosis. The most common HFE
mutation is a single substitution of tyrosine for cysteine at position 282
(C282Y); the other is a single substitution of aspartic acid for histidine at
position 63 (H63D). The second type,
juvenile hereditary hemochromatosis (HjV), is
associated with onset in early life and is much more fulminant. It is also an autosomal recessive trait
associated with the long arm of either chromosome 1 or 19. The third type, like the first two, is
autosomal recessive but is associated with the altered functioning of the
transferring receptor 2 (TfR2)
encoded by the long arm of chromosome 7.
The TfR2 is possibly
responsible for hepatocyte iron uptake.
The final type is an autosomal dominant alteration in the long arm of
chromosome 2 and alters ferroportin functioning. Ferroportin is responsible for export of iron
out of enterocytes, macrophages, placental cells and hepatocytes.
The
predominant hereditary form, C282Y mutation, has a heterozygous frequency of
about 10% in Caucasian populations in the
Early
presentation of symptomatic organ disease in the second or third decade of
life, and fulminant course are the hallmark features of HjV
that distinguish it from the other forms of hemochromatosis. Symptoms in classic HFE hemochromatosis,
and types 3 and 4 usually appear between the 4th and 5th
decade of life. Early non-specific
symptoms may manifest as lethargy, fatigue, weakness, apathy, and weight
loss. The clinical manifestations of
iron accumulation include liver disease, abdominal pain, skin pigmentation,
diabetes mellitus, arthropathy, impotence in males and cardiac enlargement with
or without heart failure or conduction defects.
The classic triad of cirrhosis, bronzed skin, and diabetes mellitus
reflects severe end-organ damage, when total body iron content has reached as
much as 20 grams (greater than five times normal). This is fortunately an uncommon presentation
due to increased awareness of the disease and improved diagnostic tests. When hepatic dysfunction is present, over 50%
will have diabetes mellitus. Hepatic
fibrosis is unusual in patients younger than 35 unless it is the HjV form or the individual is a heavy drinker. Hemochromatosis is characterized by excess
iron deposition in pituitary cells, leading to reduced serum levels of a number
of trophic hormones. Hypogonadism will
occur in 25% of male patients and primary hypoaldosteronism in 10%. Hypothyroidism or hyperthyroidism occurs in
about 8% of hemochromatosis homozygotes.
Up to 50% of patients over 40-years-old have EKG irregularities and 43%
of autopsied hearts from patients with hemochromatosis show iron deposits in
the AV node and conduction system.
Arthropathy is present in 30-50% and is commonly present in the proximal
interphalangeal and metacarpophalangeal joint.
Ten per cent of the patients have destructive arthropathy of the hip and
knee joints.
Phlebotomy
is the mainstay of treatment of hereditary hemochromatosis. These patients often have body stores of 25
to 50 grams of iron. A one-unit
phlebotomy (500 ml of whole blood) will remove approximately 250 mg of
iron. This is continued weekly until the
serum ferritin is less than 50 ng/ml
and the transferrin-saturation drops to a value below 50%. This is followed by maintenance phlebotomy of
one unit of blood removed usually every 2-4 months with the intent to maintain
the serum ferritin below 50 ng/ml,
and the transferrin-saturation value below 50%.
This treatment will reduce the incidence of complications other than
established cirrhosis, arthropathy and testicular atrophy. Patients with hemochromatosis diagnosed in
the precirrhotic stage and treated by venesection
have a normal life expectancy, whereas cirrhotic patients have a shortened life
expectancy and a high risk of liver cancer even when complete iron depletion
has been achieved.
All
first-degree relatives should be offered testing once an
hereditary hemochromatosis proband is diagnosed. If an adult relative of a C28Y homozygote is
identified, and is either a C282Y homozygote or a compound heterozygote
(C28Y/H63D) and if blood iron studies are abnormal then a presumptive diagnosis
can be made and therapeutic phlebotomy can be initiated. Early treatment can prevent complications.
Dietary
supplements containing iron should be avoided.
It may be reasonable to recommend avoidance of vitamin C supplements due
to its possible enhancement of free iron and the generation of reactive oxygen
species. Patients with hereditary
hemochromatosis should be advised to avoid consumption of uncooked seafood
because bacteria found in them can thrive on increased plasma iron
concentrations.
Aeromedical Concerns: Hemochromatosis has the potential to affect numerous organ systems of the body through the deposit of iron in the tissue. Some of the major aeromedical concerns include: 1) cardiac arrhythmias or cardiomyopathy, 2) cirrhosis of the liver and hepatocellular carcinoma, and 3) diabetes mellitus. Arthropathy could become severe enough to interfere with controlling the aircraft. Symptoms of hypogonadism and hypothyroidism would be of gradual onset and not likely to be suddenly incapacitating and treatment compatible with flying is available.
Medical Work-up: Prior
to consideration for a
waiver of hemochromatosis, the aeromedical summary should include the following
information:
A. Complete history of symptoms including
pertinent negatives, complete physical and treatment plan
B. Genetic testing
C. Serum iron, serum ferritin, serum
transferrin, and transferrin saturation
D. CBC
E. Liver function tests: ALT, AST, bilirubin, alk
phos
F. Thyroid function tests
G. Fasting electrolytes and glucose
H.
EKG, echocardiogram and Holter (reports, representative tracings and
echo tape should be sent to ACS (ECG Library) for FC II)
I. Liver
biopsy if liver function tests abnormal or ferritin levels greater than 1000 ng/mL.
I. Endoscopy for varices if evidence of liver
involvement
J. Copy of consults
Individuals
once on maintenance phlebotomy should be followed with yearly serum transferrin
saturation and ferritin. These values
should be included in the renewal aeromedical summary. Further studies are dependent on symptoms.
Aeromedical Disposition (military): Hemochromatosis is disqualifying for all flying classes. It is not waiverable in initial flying training. It is potentially waiverable in trained aircrew if the individual has no aeromedically significant complications from the hemochromatosis and is on maintenance phlebotomy. Maintenance phlebotomy to maintain control of iron stores will require a 72-hour grounding after each venesection.
Aeromedical Disposition (civilian): Hemochromatosis in an airman that has already progressed to
organ system involvement would be disqualifying. The FAA does permit medical
certification for all classes those cases that are heterozygous and are
controlled with phlebotomies. Those
airmen are required to provide a yearly follow up report from their treating
physician and a current complete blood count, serum transferrin saturation and
ferritin level.
Waiver Experience (military): Review of a military waiver database showed six cases of hemochromatosis; five were granted waivers and one was disqualified (an initial flying training candidate). The recommendation of the waiver is primarily contingent on the stage of the disease, the degree of complication(s) present, and treatment required. Deferoxamine therapy is not compatible with granting of waiver.
Waiver Experience (civilian): Due to its current pathology coding system the FAA groups
Hemochromatosis with other blood dsycrasias and thus an accurate count of those
airmen who have been granted medical certification is not possible.
References:
1. Adams, PC.
Hemochromatosis. In
2. Alexander J, Kowdley
KV. Hereditary Hemochromatosis: Genetics, Pathogenesis, and Clinical
Management. Ann Hepatology
2005; 4:240-7.
3.
4. Niederau C, Fischer
R, Sonnenberg A, Stremmel
W, Trampisch HJ, Strohmeyer G. Survival and causes of death in cirrhotic and
in noncirrhotic patients with primary
hemochromatosis. N Engl
J Med 1985; 313:1256-62.
5. Pietrangelo A. Hereditary Hemochromatosis – A New Look at
and Old Disease. N Engl
J Med 2004; 350:2383-97.
6. Robson K, Merryweather-Clarke
A, et.al.
Recent advances in understanding haemochromatosis: a transition state. J Med Genet 2004; 41:721-30.
7. Schmitt B, Golub R,
Green R. Screening
Primary Care Patients for Hereditary Hemochromatosis with Transferrin
Saturation and Serum Ferritin Level:
Systematic Review for the
8. Schrier SL., Bacon
9. Schrier SL., Bacon
10. Smith LH.
Overview of Hemochromatosis. West
2/15/08