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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
  • 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.

Epidemiology

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 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.

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.

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

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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