Hereditary hemochromatosis (HH) is a clinically heterogeneous disease. Among other factors, the individual immunological profile of CD8+ T-lymphocytes has been described to influence the severity of iron overload, with low numbers being negatively correlated with the total amount of body iron stored. With the objective of testing the modifier effect of the individual CD8+ T-lymphocyte profile on the levels of iron stores with age in HH, we reviewed the clinical and immunological data from a group of well-characterized C282Y homozygous HH subjects, regularly followed-up for a period of 20 years. A total of 70 subjects were analyzed. Sixty-four were adults (> or = 18 years): 42 males (mean age 47 +/- 14; range 22-75 years) and 22 females (mean age 46 +/- 14; range 19-65 years). Six were younger than 18 years, 5 males (mean age 9 +/- 4; range 5-14 years) and 1 female (15 years). The characterization of subjects included measurements, at diagnosis, of the iron parameters, transferrin saturation (TfSat) and serum ferritin, quantification of total body iron stores (TBIS) removed by phlebotomies, presence of associated clinical manifestations, and the T-cell immunophenotype (CD4+ and CD8+ T-lymphocytes) determined by flow cytometry. In general, statistically significant lower values of TfSat (67 +/- 17% vs. 89 +/- 14%, P = 0.0006) and ferritin levels (58 +/- 9 vs. 949 +/- 233 ng/ml, P = 0.02) were found in the young subjects in comparison to adults. After the age of 18, however, no further effect of age was significantly found on the biochemical iron parameters either in males or females. A modifier effect of the individual CD8+ T-lymphocyte profile on the association between iron stores and age was demonstrated by multiple regression analysis, where a significant correlation between TBIS and age was found only in males with low (< or = 0.41 x 10(6)/ml) CD8+ T-cell numbers (R2 = 0.43, P < 0.0001). In conclusion, in the present population of C282Y homozygous subjects, the CD8+ T-lymphocyte profile could be considered a modifier of the iron overload with increasing age in males, with low numbers predicting a severe outcome.