• Clinical science

Hemochromatosis (Iron overload disease)

Abstract

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.

Epidemiology

  • The most frequent genetic disease in the white population

References:[1][2][3]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

Primary (hereditary) hemochromatosis

Secondary hemochromatosis

References:[4][2][5][6][7]

Pathophysiology

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

Clinical features

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

References:[9][2][6][10][11]

Diagnostics

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

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-yellowhemosiderin 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]

Treatment

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]