HemochromatosisE83.1

Autosomal-recessive inherited metabolic disorder with increased iron absorption and consecutive hemosiderin deposition and tissue damage in various organs. The total iron content of the organism is increased from normally 3-5 g to 20-80 g.

Classification of the different Hemochromatosis types:

• Type 1 (classical hemochromatosis): Autosomal recessive mutations of the HFE 1 gene (Hereditary familial hemochromatosis gene 1; gene locus: 6p21.3). Prevalence of clinically manifest hemochromatosis in Europe 1:1,000; m:w=10:1 (cause: iron loss via menstruation).
• Type 2 (juvenile haemochromatosis): rare, autosomal recessive mutations of the HFE 2 gene (hereditary familial haemochromatosis gene 2; gene locus: 1q21). Other forms of type 2 are caused by mutations of the hepcidin antimicrobial peptide gene (HAMP gene; gene locus: 19q13). Iron overload before the age of 30. Often heart failure and hypogonadism.
• Type 3: Autosomal recessive mutations of the transferrin receptor-2 gene (TFR 2 gene; gene locus: 7q22).
• Type 4: Autosomal-dominantly inherited mutations of the SLC11A3 gene (solute carrier family 11 A gene; gene locus: 2q32) with consecutive defect of ferroportin.

Iron overlay of <10g usually progresses clinically without tangible symptoms (latent stage). Higher tissue iron concentrations (>10g) initially lead to discrete changes and later to manifest hemosiderosis. Clinical manifestations of manifest hemochromatosis related to their percentage frequency:

• liver cirrhosis (94%)
• Skin lesions: (82%):
  • smoky-gray, blue-brown or bronze-like, patchy or extensive skin discolorations, especially pronounced on the face, armpits, genital region, also on the lower extremities (see Fig.) as well as on light-exposed areas and on scars
  • others: diffuse effluvium
• hepatomegaly (76%)
• weakness, fatigue (73%)
• Potency- libido reduction (56%)
• Diabetes mellitus (53%)
• Upper abdominal pain (50%)
• testicular atrophy (50%)
• arthralgias (47%)
• Cardiomyopathy (35%): There is an increasing deposition of iron in the sarcoplasm of the cardiac myocytes and consequent ventricular dysfunction. Dilatation of the ventricles with signs of heart failure is possible.

Histology of the skin: Melanin proliferation in the basal stratum and haemosiderin deposits, especially in the deep corium.

History + Clinic; Laboratory: plasma ferritin ↑ (w=200ug/l; m=>300ug/l); transferrin saturation ↑ (w>45%; m>50%) - Remark: a normal trasferritin saturation largely excludes hemochromatosis. HFE genetic diagnosis (genetic findings can only be assessed in connection with clinical symptoms). Liver biopsy with iron detection (Berlin blue reaction)

Internist:

• Iron overlays in hemolytic anemia, e.g. in myelodysplastic syndrome.
• Alcoholic siderosis.
• Siderosis in the context of chronic liver diseases

Dermatological (DD clinical macro aspect)

• Haemosiderosis cutis (storage of haemosiderin in the skin)
• Porphyria cutanea tarda
• M. Addison
• Ochronosis
• hepatolenticular degeneration (Wilson's disease)

Internally: Low iron diet (avoid white beans, peas, lentils, leeks, soybeans, egg yolks, liver, heart, brewer's yeast).

Bloodletting 1 time per week (with 500 ml of blood an average of 250 mg iron is removed).

Iron chelators:

• If necessary administration of deferoxamine (e.g. Desferal®), 100 mg deferoxamine binds 8 mg iron.
• Alternative: Deferasirox

1. Hanot VC, Chauffard AME (1882) Cirrhosis hypertrophique pigmentaire dans le diabète sucré. Rev Médecine (Paris) 2: 385-403
2. Niederau C (2003) Hereditary hemochromatosis. Internist 44: 191-205
3. Rihl M et al (2004) Arthropathy of hereditary hemochromatosis. Z Rheumatol 63: 22-29
4. Troisier CE (1871) Diabète sucré.Bull Soc Anatomique (Paris) 16: 231
5. From Recklinghausen FD (1889) About hemochromatosis. Berliner klin weekday 26: 92