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Haemochromatosis is a disease of the liver

Haemochromatosis is not, as has been previously assumed, a disease of the small intestine but a disease of the liver. Scientists at the University Hospital of Heidelberg and the European Molecular Biology Laboratory (EMBL) have shown in the animal model that the disease is caused by a mutated gene.

Haemochromatosis is one of the most frequent hereditary metabolic diseases in northern Europe; in Germany alone, approximately 100,000 people suffer from this disease. Iron is essential for the human body because it is a central component of red blood cells. The genetic defect leads to a reduction in hepcidin production, a hormone that normally inhibits the absorption of too much iron. The results, which may lead to new therapies, have been published in the current issue of the journal “Cell Metabolism”.

In patients suffering from haemochromatosis, the intestines absorb too much iron from their diet. As the body is unable to excrete surplus iron, it builds up over the course of many years in organs such as the liver, pancreas, heart and joints and damages their function. Eventually, the iron overload may become serious and lead to liver cancer, diabetes mellitus, cardiac insufficiency and joint diseases. The slowly progressive disease occurs in men between the ages of 20 and 40 and in women often after menopause, as they usually then require higher amounts of iron. The only therapy currently available is venesection.

Mutation has been known for a long time, not so the mechanism

Prof. Dr. Martina Muckenthaler (Photo: University Hospital Heidelberg)
The genetic cause of the disease is known: It is a gene called HFE that is located on chromosome 6. “We already knew that defective HFE genes lead to haemochromatosis,” explained Professor Dr. Martina Muckenthaler of the Department of Oncology, Haematology, Immunology and Pneumology at the Centre for Children’s and Youth Medicine in Heidelberg. “However, what we did not know is in which organ or tissue the gene acts to prevent iron overload.”

A group of researchers led by Professor Muckenthaler, Professor Dr. Wolfgang Stremmel (Medical Director of the Department of Gastroenterlogy, Hepatology, Infectious Diseases and Intoxications at the University of Heidelberg Hospital) and Professor Dr. Matthias Hentze, (Associate Director of EMBL) bred mice that are genetically engineered to have no HFE in different tissues.

It is not the small intestine but the liver that is the weak point

Prof. Dr. Matthias Hentze (Photo: EMBL)
The researchers found that mice that are genetically engineered to have no HFE in liver cells, show all the key features of the disease. “For a long time, scientists thought of haemochromatosis as a disease of the small intestine, because this is where iron uptake normally takes place,” said Matthias Hentze, Associate Director of EMBL. “Our research now reveals that the crucial point is actually the liver.”

HFE encodes a protein that is most likely involved in transmitting signals relating to the current iron content of the body to liver cells. In response to these signals, the liver cells produce a special iron hormone, hepcidin, which is released into the bloodstream and reduces the uptake of iron in the intestine. “HFA influences hepcidin expression through a series of intermediate molecules. But when the HFE gene is mutated, less hepcidin is produced. This means that iron uptake in the intestine cannot be limited as effectively, resulting in an iron overload,” said Martina Muckenthaler.

Successful cooperation in the ‘Molecular Medicine Partnership Unit’ (MMPU)

Prof. Dr. Wolfgang Stremmel (Photo: University Hospital Heidelberg)
The Heidelberg University Hospital and the European Molecular Biology Laboratory (EMBL) have been successfully working together since 2002 within the Molecular Medicine Partnership Unit (MMPU). The Unit is dedicated to combining basic molecular research with clinical medicine and to gaining deeper insights into the molecular mechanisms of a range of different diseases, of which disorders of the iron metabolism are a central focus.

Vujic Spasic M, Kiss J, Herrmann T, Galy B, Martinache S, Stolte J, Gröne HJ, Stremmel W, Hentze MW, Muckenthaler MU: Hfe acts in hepatocytes to prevent hemochromatosis. Cell Metab. 2008 Feb;7(2):173-8.

University Hospital Heidelberg - 12.02.2008 (EJ)
Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/haemochromatosis-is-a-disease-of-the-liver