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- The disease, hemochromatosis, a disorder of iron metabolism, occurs as a result of excess iron
accumulation in tissues and organs.
- Early detection of iron overload and hemochromatosis treatment can
delay or prevent irreversible complications and prolong life.
- The diagnosis of hemochromatosis is often missed, especially when the
disease is in its early stages.
- Early non-specific symptoms of hemochromatosis (i.e., fatigue,
arthralgias, weakness, weight loss, abdominal pain) resemble various other
disease processes.
- Health care professionals therefore need to maintain a high index of
suspicion for patients who have early non-specific hemochromatosis
symptoms.
- Phlebotomy, the treatment of choice, is relatively easy, safe, and
inexpensive.
Iron Overload
- Iron overload is the accumulation of excess iron in body tissues.
- Once iron is absorbed, there is no physiologic mechanism for
excretion of excess iron from the body other than blood loss i.e.,
pregnancy, menstruation or other bleeding.
- Iron is bound and transported in the body via transferrin and stored
in ferritin molecules.
- The liver and heart are especially vulnerable.
Hemochromatosis
- Hemochromatosis is a disease that occurs as a result of significant
iron overload. It can have genetic (majority of cases) or non-genetic
causes.
- Men thus tend to become symptomatic in middle age (40s) and women who
stop menstruating develop symptoms about 15 years later.
HFE Gene Mutations
- HFE gene mutations can lead to iron overloading.
Hereditary Hemochromatosis
- Hereditary hemochromatosis is the genetic disease that results from
significant iron overload.
- The majority of hereditary hemochromatosis (also known as Type 1
Hemochromatosis) is associated with homozygous mutations in the HFE
gene.
- People with HFE mutations absorb a few extra milligrams of iron per
day. Over decades, this leads to iron overloading that can lead to
disease.
Prevalence
- Reported U.S. population prevalence estimates of iron overloading
(based on random non-fasting elevated TS values) range from 1% to 6%.
- A lower percentage of people who initially have a random elevated TS
also have persistently elevated TS: estimates range from 35% to 50%.
- An even lower percentage of people with persistently elevated TS
measures also have elevated serum ferritin values.
- Thus, the proportion of people who will develop clinical signs and
symptoms of hemochromatosis is even lower than the proportion of people
with elevated SF values.
HFE Gene Mutations
- Two HFE gene mutations, C282Y and H63D, account for the majority of
hereditary hemochromatosis cases; C282Y is most common.
- Hereditary hemochromatosis is inherited in an autosomal recessive
pattern.
HFE Genotype Frequencies
- The population prevalence of HFE mutations depends on race and
ethnicity but is most prevalent among persons of European origin and
descent.
Penetrance
- Of people with HFE gene mutations, only a subset will develop
an elevated TS. Of those with an elevated TS, only a subset will develop
an elevated SF. Of those with an elevated SF, only a subset will develop
hemochromatosis symptoms. Of those with symptoms, only a subset will
develop clinical signs consistent with hemochromatosis.
- Most clinicians reserve the hemochromatosis diagnosis for patients
whose signs and symptoms are clearly referable to documented iron overload
as reflected by serum iron testing measurements.
- Iron status testing is more clinically relevant than genetic testing
for identifying those who have hemochromatosis.
Population Screening
- At this time, CDC does not recommend population screening for
HFE
gene mutations because of the uncertainty about what proportion of people
with HFE gene mutations will develop hemochromatosis.
Clinical Expression
- The iron accumulation rate and the frequency and severity of clinical
symptoms vary widely and may be dependent on factors such as age, gender,
and diet.
Early Stages
- The most commonly associated early hemochromatosis symptoms are
non-specific and may include
- Fatigue.
- Weakness.
- Weight loss.
- Abdominal pain.
- Arthralgia.
- As iron accumulation progresses, patients may also experience
- Arthritis.
- Symptoms of gonadal failure.
- For example, amenorrhea, early menopause, loss of libido, impotence.
- Shortness of breath/dyspnea.
- Maintain a high index of suspicion of hemochromatosis for patients with
early signs or symptoms of this disease.
Advanced Stages
- Iron accumulates in the parenchymal cells of several organs; the liver is
a major site followed by the heart and pancreas.
- The liver is usually the first organ to be affected, but signs of organ
damage occur in the later stages of the disease.
Primary Disorders Associated with Advanced Hemochromatosis
- Most advanced hemochromatosis complications are also common primary
disorders.
- A hemochromatosis diagnosis can be missed even in advanced stages unless
looked for specifically.
Biochemical Testing
- Biochemical testing for iron status is recommended for patients with
- Symptoms or signs suggestive of hemochromatosis.
- Porphyria, hepatitis or other liver diseases.
- Abnormal blood tests consistent with hemochromatosis.
- Evaluation for other causes of these medical problems should also be
performed.
- Testing is also recommended for family members of diagnosed patients.
- Recommended laboratory iron tests for the workup of a patient you
suspect may have hemochromatosis are
- Fasting transferrin saturation test (TS).
- Serum ferritin test (SF).
Testing Protocol
- Transferrin saturation (TS).
- Fasting values >45% should be followed by a serum ferritin test and
additional workup.
- Serum ferritin (SF).
- Values >200 ng/mL for premenopausal females OR >300 ng/mL for
postmenopausal females and males indicate iron overload; phlebotomy
treatment is warranted in the absence of other causes.
- SF values can be elevated with liver disease, inflammation, and
neoplasm.
- Confirmation of iron overload is typically required
- Most health care providers consider quantitative phlebotomy the
confirmatory test of choice.
- Genotyping for HFE mutations can provide additional confirmatory
evidence that a patient has hereditary hemochromatosis.
- Many authorities once considered liver biopsy an essential
diagnostic test, but it is now used more often as a prognostic, rather
than a diagnostic, test.
Phlebotomy Treatment
- Therapeutic phlebotomy is the preferred treatment for reducing iron
stores in hemochromatosis patients.
- For a patient who has no evident tissue or organ damage, proper
disease management may result in normal long-term outcome and life
expectancy.
Phleblotomy Regimen
- Clinicians must design phlebotomy treatment regimens that are
individualized to each patient and account for age, gender, weight,
health, and likelihood of compliance.
Monitoring Treatment
- Serum ferritin levels should be measured after each additional one or
two phlebotomy treatments once the value is less than or equal to 100 ng/mL.
- Careful monitoring of each patient throughout treatment is imperative.
If treatment is too aggressive, anemia may result.
Lifetime Maintenance
- Continued lifetime monitoring is key to appropriate management.
- Phlebotomy should be performed throughout a patient’s life to keep the
ferritin level between 25 and 50 ng/mL.
Patient Compliance
Patients and Their Families
- A hemochromatosis diagnosis identifies a patient who needs treatment
and a family potentially at risk.
- Encouraging hemochromatosis patients to urge family members to have
biochemical tests for iron overload, (fasting transferring saturation and
serum ferritin), is an important disease prevention opportunity.
- Download and print on your letterhead information for patients and
their families:
Genetic Testing Genetic testing in families with HFE-associated hemochromatosis
can be particularly useful for determining:
- Who is NOT at increased risk: A family member who has no HFE
mutations has the same risk of developing hemochromatosis as the general
population.
- If iron overloading is genetic: In a person with hemochromatosis,
finding two HFE mutations confirms that iron overloading is
genetic.
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