Severe iron overload usually develops in patients with hereditary hemochromatosis (HHC), but variability in the phenotypic expression of the disease has been reported. This study assessed whether tumor necrosis factor α (TNF-α) plays a role in phenotypic expression of HHC. Sixty-four patients with HHC and 172 healthy volunteers (controls) were studied. Release of TNF-α from stimulated peripheral blood monocytes was measured by enzyme-linked immunosorbent assay, and 308 and 238 TNF-α polymorphisms were detected with polymerase chain reaction and restriction fragmentlength polymorphism analysis. The relation between TNF-α polymorphisms and clinical expression of HHC was evaluated. Patients with HHC released less TNF-α than controls, but the difference was significant only in homozygotes for the C282Y mutation. The prevalence of the 308 TNF-α polymorphism was similar in patients and controls, whereas the prevalence of the 238 polymorphic allele was significantly lower in patients (3% versus 16%; P=.002). A lower prevalence of cirrhosis was observed in patients with TNF-α polymorphism than in those without it (4 of 15 [27%] versus 28 of 49 [57%]), but the difference was not significant (P = .07). In nonhomozygotes for the C282Y mutation, severe liver siderosis was less prevalent in patients with the 308 polymorphism than in those without it (P = .05). Alanine aminotransferase (ALT) values were significantly lower in patients with TNF-α polymorphism (P = .006), even when patients with other hepatotoxic factors were excluded. Multivariate analysis showed that TNF-α polymorphism was independently associated with ALT values (P = .0008 and P = .045, respectively, in homozygotes and nonhomozygotes for the C282Y mutation) and siderosis in nonhomozygotes (P = .047). Thus, TNF-α appears to play a role in HHC by modulating the severity of liver damage.
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