Professor Crawford, Dr Stuart and Dr St John, authors of the article, comment:
We thank Dr Lee for his interesting comments and important observations. He has raised a number of issues that are worthy of further consideration. Whilst non-HFE related iron overload is uncommon, some cases have been described in Asian patients.
Our research team has methodology to sequence many genes involved in iron metabolism, and we would be happy to assist Dr Lee (and other clinicians) to define the exact nature of the genetic defect in his Asian patients who do not carry conventional mutations in the HFE gene.
However, as Dr Lee infers, the cause of the elevated serum ferritin concentration in the majority of his Asian patients is hepatic necroinflammation, often due to non-alcoholic fatty liver disease. The growing frequency of this problem probably reflects increased exposure of his patients to a Western diet rich in carbohydrates and saturated fats. Dr Lee infers that his patients benefit from venesection, and there is some evidence to support an improvement in insulin resistance associated with such therapy. There is also recent evidence of a strong association between altered iron metabolism and lipid metabolism. However, the benefit of venesection in patients with non-alcoholic fatty liver disease, elevated serum ferritin concentration and heterozygosity for HFE mutations in relation to lipid profiles, cardiovascular mortality and liver histology is controversial and awaits definitive study.