Episode 137. Haemochromatosis with Professor Darrell Crawford
We are dedicating this podcast to the memory of Professor Lawrie Powell, both a gentleman, mentor and giant in the field of hepatology and whose very significant contributions to our understanding of hemochromatosis laid down a firm foundation of knowledge and insight for everyone practicing internal medicine. It is upon his shoulders that much further research in the field of hemochromatosis and hepatology generally has prospered.
Haemochromatosis is the most common autosomal recessive disorder in Caucasians with an incidence of about 1 :260 and carriage of about 1: 10. Untreated the excess iron storage from hemochromatosis may lead to cirrhosis and hepatocellular carcinoma, diabetes, cardiomyopathy, hypogonadism, arthritis, bronzing of the skin and render some susceptibility to siderophilic bacteria including some vibrio and Yersinia species. The consequences of iron overload are exacerbated by preexisting condition such as NASH and alcohol associated liver disease.
A key breakthrough in the understanding of hemochromatosis came with the discovery of a negative regulatory protein coded for by the HAMP gene on chromosome 19 called Hepcidin. Hepcidin serves as a counterregulatory protein. As iron absorption and stores increase Hepcidin levels in healthy individuals also increase leading to decreased iron absorption and restoration of normal iron levels. Hepcidin appears to work by internalization and degradation of Ferroportin thereby inhibiting iron absorption across the basolateral membrane of enterocytes as serum iron levels climb.
A transferrin receptor on the surface of hepatocytes relays information concerning serum iron concentration as part of this elaborate feedback mechanism.
Mutations of the so-called High Iron -or Hemostatic Iron Regulator -HFE gene on the short arm of chromosome 6 modulate the expression of Hepcidin, effectively blocking the elaborate feedback mechanism that senses serum iron and leading to inappropriately lowered levels of Hepcidin production as iron levels climb. This defect underlies the problem of excess iron absorption in Hemochromatosis with the consequent adverse physiologic effects mentioned above.
The gene mutation responsible for Hemochromatosis is thought to have arisen some 6000 years ago within Viking or Celtic communities possibly protecting against iron deficiency states when resources were scarce.
Treatment by regular phlebotomy remains the preferred method of management and screening for HCC in cases of established cirrhosis is mandatory.
I was honored to further this conversation about hemochromatosis with Professor Darrell Crawford, one of my mentors from Queensland in a previous life. Darrell has both the reputation for being an excellent hepatologist as well as having significant international standing in the field of liver disease and has published widely. He has held leadership positions within the national and international professional societies relevant to his discipline including GESA and the University of Queensland including as the Acting Deputy Executive Dean and Head, School of Medicine where he has played a key role in reshaping the medical program and medical faculty at the University of Queensland. Please welcome Darrell to the podcast.
Treatment by regular phlebotomy remains the preferred method of management and screening for HCC in cases of established cirrhosis is mandatory.
References:
Professor Darrell Crawford-medicine.uq.edu.au,
Queensland Gastroenterology
Greenberger’s Current Diagnosis and Treatment, 4th Ed, Friedman et al, McGraw Hill Lange
Principles of Medical Biochemistry, 3Rd Ed, Meisenberg and Simmons, Elsevier Saunders