CONCORDANCE OF IRON STORAGE IN SIBLINGS WITH GENETIC HEMOCHROMATOSIS - EVIDENCE FOR A PREDOMINANTLY GENETIC EFFECT ON IRON STORAGE

Phenotypic concordance between siblings has been demonstrated in some inherited conditions, and such data provide strong evidence that the severity of disease is affected by genetic factors. We assessed the concordance of liver iron stores between siblings in 22 sibling pairs (15 same-sex pairs and 7 opposite-sex pairs) with genetic hemochromatosis. In this study population a wide range was found in the hepatic iron concentration and the hepatic iron index (32 to 833 mumol/gm dry wt and 1.65 to 14.4, respectively), which could not be accounted for by differing exposure to the environmental factors that influence iron stores. Despite the large variation of hepatic iron concentration within the group, siblings of identical sex had accumulated similar amounts of liver iron. A highly significant correlation for hepatic iron concentration (r = 0.81) and hepatic iron index (r = 0.70) was found between siblings of the same sex. The hepatic iron concentration and the hepatic iron index of one sibling was less than 50% of the other in only three same-sex sibling pairs. In each instance, reasons existed (blood donation, age at diagnosis and human leukocyte antigen nonidentity) for this discordance. In six of the seven opposite-sex pairs, the woman had lower hepatic iron stores than her male sibling, consistent with previous studies on the extent of iron overload in women and its modification by physiological blood loss. The correlation coefficients for hepatic iron concentration and hepatic iron index between the male and female siblings within families were 0.73 and 0.63, respectively, suggesting that female hemochromatotic siblings of affected men with high levels of liver iron also have high liver iron stores relative to other affected women. These findings provide strong evidence that genetic factors are the principal determinants of the amount of iron that accumulates in patients with genetic hemochromatosis and that only major environmental factors, such as significant blood donation or blood loss, will modify hepatic iron stores.