Hereditary hemochromatosis (HH), an autosomal recessive disease, causes 1 in 7,000 hospital deaths and 1 in 20,000 annual hospital admissions (628). When the disease presents in adults, the patients are usually homozygous for a missense mutation (C282Y) in the HFE gene (629). Rare patients with mutations in the gene encoding the transferrin receptor 2 (TfR2) also present with a clinical phenotype that is similar to that seen in patients with HFE mutations. The disease in adults tends to be milder than that seen in children. Most juvenile cases have been mapped to chromosome 1q where the gene hemojuvelin (HJV), previously called HFE2, is located. Some children with HH may have mutations in the HAMP gene, which encodes hepcidin, a peptide that plays a key role in iron absorption (630).

Because there is no efficient pathway for iron excretion from the body, it is generally accepted that the main underlying pathophysiology of hereditary hemochromatosis is the excessive absorption of dietary iron in the face of adequate raised body iron stores. However, the mechanism underlying the enhanced iron uptake in HH remains poorly defined and complex, with many biochemical defects being present as summarized in reference 630.

Iron deposits in many organs including the gut (Fig. 6.222), resulting in structural and functional abnormalities. Histologically, one sees mucosal iron deposits throughout the lamina propria in the macrophages, in the epithelium (Fig. 6.222), and in a perivascular distribution.

Hemosiderosis usually follows oral or parenteral iron administration or multiple transfusions. The lamina propria of the villi contains macrophages filled with hemosiderin (Fig. 6.223). The epithelial cells lack iron, contrasting with primary hemochromatosis.

The presence of spotty brownish or blackish pigmentation in the duodenal mucosa seen at the time of endoscopy is termed duodenal melanosis or pseudomelanosis (631). Pigmentation is usually maximal in the second part of the duodenum and the duodenal bulb is affected to a lesser extent. The lesion affects AIDS patients and individuals on maintenance hemodialysis. Most patients receive oral iron supplementation. Patients may present with upper abdominal discomfort and anemia, which is the usual reason for the endoscopy. Mucosal pigmentation probably does not cause the symptoms. The macrophages acquire melanin, pseudomelanin, and iron. It is postulated that duodenal pseudomelanosis begins with mucosal iron deposition (631). However, sulfur becomes incorporated into the granules, altering their staining characteristics so that they
react positively with both iron stains and the Fontana-Masson stain. These pigments include iron, sulfur, and other metallic substances.