Clinical Studies in HFE haemochromatosis

Abstract

© 2018 Sim Yee OngHFE haemochromatosis is the most common iron overload disease. Since the discovery of the HFE gene is 1996, it is readily diagnosed using a genetic test rather than using liver biopsies. It is an autosomal recessive disease and the most common form of HFE haemochromatosis is homozygosity for p.C282Y. Homozygosity for this substitution accounts for more than 90% of haemochromatosis in Australia. Excessive iron accumulates due to malfunction of the HFE protein that leads to excess iron absorption. As a result, excess iron builds up in various organs including liver, joints, heart, pancreas, pituitary gland and skin, that may cause end-organ damage including liver cirrhosis, cardiac failure, diabetes mellitus, hypopituitarism and skin pigmentation. Symptomatically, fatigue and arthralgia are the major complaints reported by patients with haemochromatosis. This disease is easily treatable, as the blood contains a significant proportion of the body’s iron, so excess iron can be removed via the blood through phlebotomy. Multiple studies have found that individuals with high total body iron, defined by serum ferritin of more than 1000ug/L, have the highest risk of developing complications including liver cirrhosis. In the last decade, some have suggested that patients with elevated body iron but with serum ferritin less than 1000ug/L, here defined as moderate iron overload, might not need treatment, as they might not have symptomatic manifestations of the disease. However, there have been no randomised controlled trials to examine the treatment benefits for individuals with moderately elevated iron. To answer this question, a randomised controlled trial (Mi-Iron) was conducted which was the major aim of my PhD to examine if removing excess iron would have an impact on patient-reported outcomes, particularly fatigue, as well as liver fibrosis and oxidative stress. This demonstrated that with treatment, there was an improvement in fatigue and its cognitive subcomponent, and the affect component of the arthritis score. There was also an improvement in the liver fibrosis marker, Hepascore, and oxidative stress marker plasma F2-isoprostane, by removing excess iron in this cohort when compared to the control group who did not have iron reduction. These results, therefore, support current guidelines that all patients with haemochromatosis with elevated serum ferritin should have phlebotomy to return body iron levels to normal levels. In the second clinical study, the relationship of serum ferritin with non-invasive markers of liver fibrosis including transient elastography, Hepascore, aspartate aminotransaminase (AST) to platelet ratio index (APRI) and Fibrosis-4 (FIB-4) to assess for liver fibrosis and cirrhosis in HFE p.C282Y homozygotes was examined. This study was conceived due to the shift from using liver biopsy to the increasing use of non-invasive techniques to assess liver fibrosis and cirrhosis. This showed that there was a linear relationship of serum ferritin with Hepascore, indicating that higher body iron is associated with more advanced liver fibrosis and cirrhosis. This relationship was also found for APRI and FIB-4 scores. These findings are important as they provide extra information in utilising these scores to assess liver fibrosis and cirrhosis in haemochromatosis. In the third study, the hand joint arthritis in people with haemochromatosis was examined. Arthralgia is one of the major complaints of individuals with haemochromatosis and is often one of the earliest symptoms of haemochromatosis. It is often difficult to differentiate between haemochromatosis arthropathy and osteoarthritis in the hands. The second and third metacarpophalangeal joints are described to be more commonly affected in individuals with haemochromatosis. By examining the data from HealthIron, a haemochromatosis cohort extracted from a population study that assessed the burden of disease due to iron overload, I found that there was an increase in first metacarpophalangeal joint abnormalities in those with HFE p.C282Y homozygosity, comparable to the frequency of involvement of second and third metacarpophalangeal joints