Hemochromatosis

Hereditary hemochromatosis is a disorder in which iron is significantly absorbed by the digestive tract and accumulates in body tissues, which progressively causes diabetes, joint disorders, cardiac arrhythmia then heart failure, hepatic cirrhosis, skin color change, and increased risk of cancer.

Adult Hemochromatosis; Hereditary Hemochromatosis; Idiopathic Hemochromatosis.

Genetic disorder of iron metabolism described in 1865 by Trousseau and named from the Greek words heme (“of the blood”) and chroma (“color”).

Fewer than 1:250,000 per year in the general population but approximately 1:200 people in the United States is believed to have a mutation necessary for iron overload.

Autosomal recessive. Males are affected more severely with an earlier onset. Two mutations in the HFE gene can cause hereditary hemochromatosis: H63D (less severe and later onset form) and C282Y. HLA-A3 is found in 78.4% of cases (27% of controls) and HLA-B14 in 25.5% of cases (3.4% of controls). Gene located on 6p21.3, close to HLA-A locus. (Table H-1)

The HFE protein is normally expressed in crypt enterocytes of the duodenum (and the placenta) where it has a predominantly intracellular localization and forms a stable association with the transferrin receptor. The HFE protein is believed to modulate the uptake of transferrin-bound iron from plasma by crypt enterocytes. Impairment of this function could result in a paradoxical signal in crypt enterocytes, which causes them to absorb more dietary iron when they mature into villus enterocytes.

Usually delayed until adulthood after onset of clinical symptoms, although screening of family members may lead to early, asymptomatic diagnosis. Orientation tests include serum ferritin, sideremia, and liver biopsy for iron staining, which are all consistent with iron accumulation. Diagnosis established by molecular biology on blood samples (presence of HFE mutation).

Symptomatology usually begins at middle age but may be detected earlier. Early symptoms are nonspecific: weakness, joint and digestive pains, palpitations, and loss of menstrual periods. Abnormal liver function tests can be detected earlier, in the absence of other symptoms. Left untreated, late symptoms appear: bronze skin pigmentation, liver cirrhosis, or hepatocellular carcinoma, diabetes mellitus, panhypopituitarism, dysrhythmias, and cardiac failure, joint disorders, chronic abdominal pain, extreme weakness, and tendency to recurrent infections.

Ascertain that ferritin is at the low end of normal values; if not, postpone surgery (if possible) until this is achieved. Check ECG for conduction abnormalities; rule out cardiomyopathy by clinical findings and/or echocardiogram. Evaluate liver function: liver function test, prothrombin time, partial thromboplastin time for signs of liver dysfunction. Prepare to treat the presence of coagulopathy.

Avoid myocardial depressants. Titrate hepatic metabolized drugs to effect in patients with liver dysfunction. Avoid regional anesthesia in presence of coagulopathy.

Avoid any iron and vitamin C supplementation. Avoid any medication or nutriment that can cause hepatic toxicity.

Juvenile Hemochromatosis: Not caused by an HFE defect; more severe with earlier clinical course but otherwise very similar.

Neonatal Hemochromatosis: Not caused by an HFE defect; lethal.

Porphyrias: Autosomal dominant disease of porphyrin-heme metabolism characterized by cutaneous photosensitivity, acute episodes of abdominal pain and vomiting, central nervous system (CNS) disorders, peripheral and autosomal neuropathy; caused by a defective protoporphyrinogen oxidase mapped to chromosome 14.

Ceruloplasmin Deficiency: Group of genetic disorders affecting expression of the ceruloplasmin gene leading to an iron storage disorder with hepatic failure and progressive dementia.