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Training & Education - Course Summary

Overview of the Disease

  • 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.

PathophysiologyFamily Detection

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 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.

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  • 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.
  • 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.

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Clinical Features

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.

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Diagnostic Testing

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.

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Treatment & Management

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

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Family-based Detection

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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