Haptoglobin polymorphism and serum ferritin concentration in ageing subjects Carter et al (2003) investigated the haptoglobin (Hp) poly- morphism and its inﬂuence on iron metabolism. They concluded that Hp type neither inﬂuences iron status in normal subjects nor predicts clinical presentation of hereditary haemochromatosis in South Wales, in contrast to our ﬁndings in Belgian populations (Langlois et al, 2000; Van Vlierberghe et al, 2001). In randomly selected control subjects, in blood donors homo- zygous for the HFE C282Y mutation, and in ﬁrst-time blood donors lacking the HFE mutations, Carter et al (2003) found no inﬂuence of Hp type on transferrin saturation and serum ferritin concentration. The authors provided no ready explanation for the discrepancy between their results and ours (Langlois et al, 2000). Because of the limited number of individuals, their study may have not had the statistical power needed to detect the inﬂuence of Hp type on these serum iron indices. Our group investigated and needed a large cohort to clearly demonstrate the higher serum iron indices in Hp 2-2 individuals. It is possible that the conﬂicting results may reﬂect geographical differences between study populations. It is of interest, in this regard, that no relationship between serum iron indices and Hp type could be found in reports from Africa (Kasvosve et al, 2002) and southern California (Beutler et al, 2002). More importantly, potential confounders such as blood dona- tion, intake of iron supplements, alcohol abuse and inﬂamma- tion were excluded in our study (Langlois et al, 2000). Moreover, we found that the inﬂuence of Hp type on serum iron status was exclusively present in males aged 18–50 years. Table I presents serum ferritin concentrations in 359 healthy Caucasians aged 51–89 years, from the region of Flanders (Belgium), selected according to previously described exclusion criteria (Langlois et al, 2000). In contrast to our data from younger males, we were unable to demonstrate an inﬂuence of Hp type on serum ferritin concentration. This discrepancy between age groups might be attributable to different underlying conditions that may additionally affect iron status in ageing men. Haptoglobin 2-2 complexed with haemoglobin exhibits a higher afﬁnity for the CD163 receptor than the other phenotypes (Kristiansen et al, 2001), which contributes to haem iron retention in monocyte macrophages as evidenced by a higher cytosolic l-ferritin content (Langlois et al, 2000). In the short term, the impact of the haptoglobin pathway is relatively small compared with major iron homeostasis pathways. In younger males, the Hp type-mediated variation of serum ferritin concentration occurred within the generally accepted reference ranges (Langlois et al, 2000). However, a long-term contribu- tion to iron accumulation may have clinical consequences, e.g. in the insidious evolution towards haemochromatosis. In patients presenting clinically with haemochromatosis, who were homozygous for C282Y, Carter et al (2003) found no inﬂuence of Hp polymorphism on transferrin saturation and serum ferritin. Unfortunately, no data were shown in a table to support this conclusion. Again, the size of their patient group is statistically underpowered compared with our hae- mochromatotic study population (Van Vlierberghe et al, 2001). In contrast to Carter et al (2003), we could clearly demonstrate that the Hp 2-2 type was overrepresented in haemochromatotic C282Y homozygotes and that male patients with the Hp 2-2 type showed higher serum ferritin concen- trations and a higher amount of iron removed by phlebotomy to achieve iron depletion. However, it seems unlikely that the Hp polymorphism (having only a minor contribution to iron accumulation) would solely explain the large variability of the clinical manifestation of haemochromatosis. In conclusion, the inﬂuence of Hp 2-2 type on serum ferritin concentrations cannot be observed in subjects aged >50 years. However, the literature data for males seem to conﬂict at a younger age. Michel R. Langlois 1 Marc L. De Buyzere 1 Hans Van Vlierberghe 2 Joris R. Delanghe 1 Departments of 1 Clinical Chemistry and 2 Gastroenterology, Ghent University Hospital, Ghent, Belgium. E-mail: michel.langlois@azbrugge.be Table I. Serum ferritin concentration according to haptoglobin (Hp) type in healthy subjects aged 51–89 years. Hp type n Ferritin (l g/l) Males 1-1 28 155 (110–282) 2-1 82 140 (91–290) 2-2 62 163 (108–277) Females 1-1 31 82 (41–143) 2-1 90 90 (50–137) 2-2 66 75 (55–154) Data are median (interquartile range). Serum ferritin was not signiﬁ- cantly different between Hp type groups (Kruskal–Wallis test). correspondence ª 2004 Blackwell Publishing Ltd, British Journal of Haematology, 124, 555–563 doi:10.1046/j.1365-2141.2003.04797.x