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Hemochromatosis is a disease defined by iron overload. Hereditary hemochromatosis is an autosomal recessive disease with a prevalence of 2 per 1,000 in those of European ancestry. It most commonly presents with liver disease but can also affect many other organ systems [1].

Gastrointestinal symptoms often include [1]:

  • Abdominal pain

  • Symptoms related to complications of cirrhosis and portal hypertension

  • Hepatomegaly

  • Cirrhosis/end-stage liver disease with portal hypertension

    • Ascites/fluid retention

    • Esophageal/rectal varices

    • Portal hypertensive gastropathy

    • Hemorrhagic diathesis

    • Hepatic encephalopathy

  • Diabetes mellitus/“bronze diabetes”

  • Cardiomyopathy

  • Impotence from hypogonadotropic hypogonadism due to pituitary involvement

  • Development of hepatocellular carcinoma

  • Elevated aminotransferase levels

The pathogenesis is based on genetic mutations that affect transport of iron. The most common involve HFE, a regulator of hepcidin, the major serum signaling protein [2–4]

  • Autosomal recessive

  • Mutation of HFE gene

    • Homozygous at C282Y (80% of cases have mutations at this locus)

    • Compound heterozygote mutation of C282Y and H63D plus another risk factor for iron overload

    • Homozygous H63D not clinically significant for development of iron overload

    • Leads to inappropriately high levels of iron absorption and deposition in the liver and other organs

The pathology of iron overload of the liver can show [1]:

  • Liver biopsy (see Fig. 71.1)

    • Two to 4+ or more hepatocellular iron stores on staining with higher density in the periportal area

    • Severe iron storage shows 4+ staining with fibrosis

    • Hepatic iron index of 1.9 μmol/g/year

    • Hepatic iron concentration of >71 μmol/g/dry weight

Fig. 71.1
figure 00711

A photomicrograph of a liver biopsy specimen stained with Prussian Blue showing iron overload liver parenchymal (hepatocytes) (arrows) typical of hemochromatosis. In addition, because of heavy overload, there is also iron present in epithelium of bile educts, Kupffer cells, and stroma of portal areas (High-power magnification)

Full size image

The diagnosis is made with [1]:

  • Transferrin saturation >45%

  • Elevated ferritin

  • C282Y and H63D mutation genetic testing

  • Abnormal liver enzymes

  • Hepatomegaly

  • Liver biopsy

  • Hepatic magnetic resonance imaging

The differential diagnosis of hemochromatosis should include [1]:

  • Secondary iron overload

    • Sideroblastic anemia

    • Thalassemia major

    • Sickle cell anemia

    • Excess alcohol consumption

    • Parenteral iron overload from transfusions

  • Nonalcoholic steatohepatitis

The treatment involves removal of iron and reduction of iron body stores [1]:

  • Phlebotomy to remove excess iron stores performed weekly until

    • Ferritin is <50 ng/mL

    • Transferrin iron saturation <50%

  • Chelation with deferoxamine, deferasirox, or deferiprone, if anemia and iron overload are present concomitantly

  • Avoidance of vitamin C, which enhances iron toxicity

  • Liver transplant; screen for hepatocellular carcinoma if cirrhosis is present