Hemochromatosis (Iron overload disease)

Hemochromatosis is a condition that leads to abnormal iron deposition in specific organs. There are two main types: primary (hereditary) and secondary (e.g., transfusion-related). The most common form is hereditary autosomal recessive hemochromatosis type 1, which is caused by an underlying genetic defect that results in partially uninhibited absorption of iron in the small intestine. Hemochromatosis is mostly asymptomatic but can become symptomatic, usually between the third and fifth decade of life, when poisonous levels of iron have had time to accumulate in the body. Symptoms include fatigue, hyperpigmentation, diabetes mellitus ("bronze diabetes"), and arthralgia. The deposits may lead to various organ diseases, the most typical being the development of liver cirrhosis, which is accompanied by an increased risk of hepatocellular carcinoma (HCC). Serum ferritin and transferrin saturation levels are typically elevated. Molecular genetic testing or a liver biopsy may be used to confirm the diagnosis. Treatment primarily consists of repeated phlebotomy to reduce iron levels. In addition, dietary changes and drug therapy (chelating agents such as deferoxamine) may be used to influence the amount of iron in the body.

• Prevalence: the most frequent genetic disease in the white population
• Age of onset: individuals > 40 years
  • Symptoms start to show when body iron levels reach > 20 g.
  • Before menopause, women lose iron via menstruation and pregnancy, which slows down iron accumulation within the body. As a result, symptom onset occurs later in women (typically postmenopausal) than in men.

References:^[1][2][3]

Epidemiological data refers to the US, unless otherwise specified.

Primary (hereditary) hemochromatosis

• Classical and most frequent form: adult hemochromatosis type I
  • Homozygous or heterozygous for the HFE gene defect
    • Located on chromosome 6
    • Most commonly affects C282Y and H63D
    • Associated with HLA-A3 genotype
  • Inheritance: autosomal recessive with incomplete penetrance
• Further forms: Hemochromatosis types II–IV are also hereditary, but significantly less frequent.

HLA A3 as in HA3mochromatosis!

Secondary hemochromatosis

• Caused by iron overload
  • Transfusion-related (e.g., in individuals with β-thalassemia major or other forms of chronic anemia requiring chronic transfusion)
  • Ineffective erythropoiesis
    • Thalassemia
    • Sickle-cell anemia
    • Sideroblastic anemia (e.g., hereditary sideroblastic anemia; anemia of chronic disease)
  • Excessive alcohol consumption

References:^[2][4]

Hemochromatosis type I

• The HFE gene regulates iron hemostasis (see “Iron” in the articles on trace elements).
• HFE gene defect (homozygous) → defective binding of transferrin to its receptor → ↓ hepcidin synthesis by the liver → unregulated ferroportin activity in enterocytes → ↑ intestinal iron absorption → iron accumulation throughout the body → damage to the affected organs

In hereditary hemochromatosis, decreased hepcidin leads to iron overload. In secondary hemochromatosis, iron overload leads to increased hepcidin (unless liver fibrosis or cirrhosis, which leads to decreased hepcidin synthesis, is present)

References:^[5][6]

• Asymptomatic: 75% of cases
• General symptoms: fatigue, lethargy
• Organ-specific symptoms
  • Liver
    • Abdominal pain
    • Hepatomegaly
    • Cirrhosis
    • Increased risk of hepatocellular carcinoma (common cause of death) ^[7]
  • Pancreas: signs of diabetes mellitus (polydipsia, polyuria)
  • Skin: hyperpigmentation, bronze skin
  • Pituitary gland: hypogonadism, erectile dysfunction, testicular atrophy, loss of libido, amenorrhea
  • Joints: arthralgia (typically symmetrical arthropathy of the MCP joints II and III); , chondrocalcinosis (accumulation of calcium pyrophosphate)
  • Heart
    • Cardiomyopathy
      • Restrictive cardiomyopathy
      • Dilated cardiomyopathy (reversible)
    • Cardiac arrhythmias: paroxysmal atrial fibrillation (most common), sinus node dysfunction, complete AV block, atrial and ventricular tachyarrythmias, and sudden cardiac death
    • Congestive heart failure

In combination with diabetes mellitus, bronze-colored skin pigmentation is also referred to as "bronze diabetes.”
References:^{[8][2][9][10]}

As a result of its subtle and primarily asymptomatic course, hemochromatosis is often an incidental diagnosis first detected during routine checks or diagnosed only once signs of advanced organ involvement become apparent.

Laboratory tests

• ↑ Serum iron
• ↑ Ferritin in serum (> 200 μg/L)
• ↓ Total iron-binding capacity (TIBC)
• ↑ Transferrin saturation (> 45%)
• ↑ Liver enzymes (AST, ALT)

Genetic tests

• Indications
  • First-degree relative with hemochromatosis
  • Confirmed iron overload
• Findings: homozygote C282Y, homozygote H63D, or heterozygote C282Y/H63D mutations of the HFE gene confirm the diagnosis.

Imaging

• MRI; : noninvasive way to estimate the iron concentration in the liver
• Chest x-ray and echocardiography: diagnose and monitor cardiac hemochromatosis

Liver biopsy

• Indications: elevated liver enzymes caused by hereditary hemochromatosis; increased serum ferritin levels (> 1000 μg/L)
• Histology
  • Color stain: Prussian blue
  • Pronounced siderosis in iron staining with iron deposits primarily observed in hepatocytes
  • Macrophages containing hemosiderin: cytoplasmic granules that stain golden-yellow (caused by chronic hemolysis)

References:^{[11][12][13][14]}

Primary hemochromatosis

• Dietary changes
  • Diet low in iron
  • Restriction of alcohol and vitamin C supplements
  • Consumption of tea
• Therapeutic phlebotomy (first-line treatment)
  • Initially 1–2 phlebotomy sessions per week; after reaching target ferritin and hemoglobin levels, phlebotomy should be performed every 2–4 months.
  • Target levels: serum ferritin 20–50 μg/L; hemoglobin > 12 g/dL (or 120 g/L)
  • Prognosis: initiation of therapy in the pre-cirrhotic phase → normal life expectancy and no organ damage
• Drug-induced iron chelation
  • Agents: deferoxamine, deferasirox, or deferiprone
  • Indication: particularly when phlebotomy is contraindicated, e.g., in cases of anemia, severe heart disease, or difficult venipuncture

Drugs that delete iron (Fe) in hemochromatosis: deFeroxamine, deFerasirox, deFeriprone.

Secondary hemochromatosis

• Depends on the underlying cause
• Consider iron chelation therapy
• Phlebotomy is often not advisable

References:^{[15][16][17][14]}