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.

Primary (hereditary) hemochromatosis

• Classical and most frequent form: adult hemochromatosis type 1
  • Homozygous or heterozygous for the HFE gene defect
    • Located on chromosome 6
    • Most commonly affects C282Y and H63
  • Inheritance: autosomal recessive with incomplete penetrance
• Further forms: Hemochromatosis types II–IV are also hereditary, but significantly less frequent.

Secondary hemochromatosis

• Caused by iron overload
  • Transfusion-related (e.g., for correcting chronic anemia)
  • Thalassemia
  • Sickle-cell anemia
  • Sideroblastic anemia
    • Pathogenesis: ineffective erythropoiesis with disturbances in the uptake of iron in heme or iron metabolism disorder → iron overload
    • Examples: hereditary sideroblastic anemia; anemia of chronic disease
  • Excessive alcohol consumption

References:^{[4][2][5][6][7]}

Hemochromatosis type I: HFE gene defect (homozygous) → defective binding of transferrin to its receptor → liver stops producing the acute phase reactant hepcidin → unregulated ferroportin causes ↑ iron reabsorption in duodenal enterocytes → 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!

References:^[8]

• Asymptomatic in 75% of cases
• The onset of symptoms: typically between the 3^rd and 5^th decade of life
• Abdominal pain, hepatomegaly → liver cirrhosis (+ hepatocellular carcinoma)
• Fatigue, lethargy
• Hyperpigmented, bronze skin
• Signs of diabetes mellitus (polydipsia, polyuria)
• Arthralgia , chondrocalcinosis
• Erectile dysfunction, testicular atrophy, loss of libido, amenorrhea
• Cardiomyopathy (restrictive or dilated) → congestive heart failure and/or cardiac conduction abnormalities (e.g., sick sinus syndrome)

In combination with diabetes mellitus, bronze-colored skin pigmentation is also referred to as "bronze diabetes.”

References:^{[9][2][6][10][11]}

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
• ↑ Transferrin saturation (> 45%)
• ↑ Liver enzymes (AST, ALT)

Genetic tests

• Indications
  • First-degree relative with hemochromatosis
  • Confirmed iron overload
• Findings: homozygote C282Y mutation of the HFE gene confirms the diagnosis.
  • Consider screening family members if confirmed

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 cytoplasmic granules which stain golden-yellow → hemosiderin from chronic hemolysis
• Determination of iron levels
  • The hepatic iron index is calculated by dividing the liver iron concentration by the age (in years) of the patient
    • Values > 1.9 indicate hemochromatosis.

References:^{[12][13][14][15]}

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.
  • One phlebotomy session of 500 mL blood → removal of 250 mg iron
  • 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
  • Agent: deferoxamine
  • Indication: particularly when phlebotomy is contraindicated, e.g., in cases of anemia, severe heart disease, or difficult venipuncture
  • In cases of intolerance: deferiprone

Secondary hemochromatosis

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

References:^{[16][17][18][15]}