Pathophysiological consequences and benefits of HFE mutations: 20 years of research

Abstract

Mutations in the HFE (hemochromatosis) gene cause hereditary hemochromatosis, an iron overload disorder that is hallmarked by excessive accumulation of iron in parenchymal organs. The HFE mutation p.Cys282Tyr is pathologically most relevant and occurs in the Caucasian population with a carrier frequency of up to 1 in 8 in specific European regions. Despite this high prevalence, the mutation causes a clinically relevant phenotype only in a minority of cases. In this review, we summarize historical facts and recent research findings about hereditary hemochromatosis, and outline the pathological consequences of the associated gene defects. In addition, we discuss potential advantages of HFE mutations in asymptomatic carriers.

Figure 1.

Hereditary hemochromatosis (HH). Three different HH classes (HFE-related HH, non-HFE-related HH, and ferroportin disease) are subcategorized into different subtypes (I, II A + B, III and IV) depending on mutations in iron-related genes (HFE, HJV, HAMP, TFR2, FPN/SLC40A1) and related pathophysiology. FD: ferroportin disease.

Figure 2.

The positive and negative effects of HFE mutations. Hereditary hemochromatosis (HH)-associated mutations affect the health of their carriers in various ways. Besides provoking classical HH disease symptoms (left), these mutations can provide benefits for affected individuals (right). Some of the benefits associated with HH have remained speculative to date and need further experimental validation (marked with a question mark).