Hepcidin and Infection
Hepcidin was discovered first as a small antimicrobial peptide and was later linked to iron regulation. However, these two functions are not mutually exclusive. Cells utilize iron in response to infection in two ways; one as a cellular oxidant, two, it controls the pathogenic bacterias access to iron as it is a vital nutrient. Hepcidin is induced during infection and by inflammatory responses (Drakesmith 2012). While hepcidin is mainly produced in the liver, small amounts are also produced by leukocytes. It would be valuable to ascertain whether the function of hepatic hepcidin and leukocytic hepcidin differ. The interaction and proteins bound by the different hepcidin’s within their own cellular context may indicate a link to different functions. Additionally, utilizing known pathogens that are susceptible to hepcidin deficiency such as in salmonella may be used to isolate the effects of each cells role through the use of cellular knockouts.
Penetrance of HFE C282Y and testosterone
One of the main questions remain regarding hereditary hemochromatosis is the penetrance of the disease. Why do some people who are genetically homozygous for the HFE C282Y mutation never develop iron overload or disease phenotype and why do others develop severe overload? Environmental factors such as diet or alcohol use have been investigated, but no widespread conclusions could be drawn (Beutler 2003). Results of experiments attempting to link other mutations to the pathogenesis of the mutation have not yielded any conclusive results (McLaren 2009). One link to be explored further is the higher prevalence of iron overload phenotypes in males versus females. It is postulated that this is due to females periodic iron loss due to menstruation (Beutler 2003). However, it may be more complicated than this. Testosterone has been shown to increase iron acquisition by cells by promoting association of the androgen receptor to smad1/4 and BMP thereby reducing its binding to hepcidin and reducing its transcription (Guo 2013). A comprehensive study of the testosterone levels in both males and females with C282Y homozygous mutations and their iron status may indicate that there is a correlation between expression of testosterone and penetrance of the hemochromatosis phenotype. Additionally, one could look at the amount of iron deposition and plasma iron levels in hemochromatosis patients while going through puberty as this is a time in which levels of testosterone are increased.
Lastly, more studies need to be conducted on the therapeutic benefits of orally available chelators. Preliminary evidence has shown benefit, however, side effects need to be mitigated by lower dosages. A longitudinal analysis of patients outcomes after 5, 10 and 20 years after completing iron depletion therapy through chelation should be compared to those receiving iron depletion therapy by traditionally phlebotomy. Measures that should be record are ferritin levels, transferrin levels, hemoglobin/hemocrit. Additionally, iron overload symptoms such as deposition in the liver, cirrhosis, hepatomegaly and cardiac problems should also be documented. Subjective relief of symptoms in regards to fatigue and arthritic pain are also valuable as well as patients satisfaction with the treatment. By comparing the overall long term outcomes of patients physicians will be better able to understand the benefits of different types of treatments.