Haptoglobin polymorphism and serum ferritin concentration in ageing subjects

Abstract

Carter et al (2003) investigated the haptoglobin (Hp) poly-morphism and its influence on iron metabolism. Theyconcluded that Hp type neither influences iron status innormal subjects nor predicts clinical presentation of hereditaryhaemochromatosis in South Wales, in contrast to our findingsin Belgian populations (Langlois et al, 2000; Van Vlierbergheet al, 2001).In randomly selected control subjects, in blood donors homo-zygous for the HFE C282Y mutation, and in first-time blooddonors lacking the HFE mutations, Carter et al (2003) found noinfluenceofHp typeontransferrinsaturationandserumferritinconcentration. The authors provided no ready explanation forthe discrepancy between their results and ours (Langlois et al,2000). Because of the limited number of individuals, their studymay have not had the statistical power needed to detect theinfluence of Hp type on these serum iron indices. Our groupinvestigatedandneededalargecohorttoclearlydemonstratethehigher serum iron indices in Hp 2-2 individuals.It is possible that the conflicting results may reflect geographicaldifferences between study populations. It is of interest, in thisregard, that no relationship between serum iron indices andHp 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-tionwereexcludedinourstudy(Langloiset al,2000).Moreover,we found that the influence of Hp type on serum iron status wasexclusively present in males aged 18–50 years.Table I presents serum ferritin concentrations in 359 healthyCaucasians aged 51–89 years, from the region of Flanders(Belgium), selected according to previously described exclusioncriteria (Langlois et al, 2000). In contrast to our data fromyounger males, we were unable to demonstrate an influence ofHp type on serum ferritin concentration. This discrepancybetweenagegroupsmightbeattributable todifferent underlyingconditionsthatmayadditionallyaffectironstatusinageingmen.Haptoglobin 2-2 complexed with haemoglobin exhibits ahigheraffinityfortheCD163receptorthantheotherphenotypes(Kristiansen et al, 2001), which contributes to haem ironretention in monocyte macrophages as evidenced by a highercytosolic l-ferritin content (Langlois et al, 2000). In the shortterm, the impact of the haptoglobin pathway is relatively smallcompared with major iron homeostasis pathways. In youngermales, the Hp type-mediated variation of serum ferritinconcentration occurred within the generally accepted referenceranges (Langlois et al, 2000). However, a long-term contribu-tiontoironaccumulationmayhaveclinicalconsequences,e.g.inthe insidious evolution towards haemochromatosis.In patients presenting clinically with haemochromatosis,who were homozygous for C282Y, Carter et al (2003) foundno influence of Hp polymorphism on transferrin saturationand serum ferritin. Unfortunately, no data were shown in atable to support this conclusion. Again, the size of their patientgroup is statistically underpowered compared with our hae-mochromatotic study population (Van Vlierberghe et al,2001). In contrast to Carter et al (2003), we could clearlydemonstrate that the Hp 2-2 type was overrepresented inhaemochromatotic C282Y homozygotes and that male patientswith the Hp 2-2 type showed higher serum ferritin concen-trations and a higher amount of iron removed by phlebotomyto achieve iron depletion. However, it seems unlikely that theHp polymorphism (having only a minor contribution to ironaccumulation) would solely explain the large variability of theclinical manifestation of haemochromatosis.In conclusion, the influence of Hp 2-2 type on serumferritin concentrations cannot be observed in subjects aged>50 years. However, the literature data for males seem toconflict at a younger age.Michel R. Langlois