1.
Iron and the liver.
Pietrangelo, A
Liver international : official journal of the International Association for the Study of the Liver. 2016;:116-23
Abstract
Humans have evolved to retain iron in the body and are exposed to a high risk of iron overload and iron-related toxicity. Excess iron in the blood, in the absence of increased erythropoietic needs, can saturate the buffering capacity of serum transferrin and result in non-transferrin-bound highly reactive forms of iron that can cause damage, as well as promote fibrogenesis and carcinogenesis in the parenchymatous organs. A number of hereditary or acquired diseases are associated with systemic or local iron deposition or iron misdistribution in organs or cells. Two of these, the HFE- and non-HFE hemochromatosis syndromes represent the paradigms of genetic iron overload. They share common clinical features and the same pathogenic basis, in particular, a lack of synthesis or activity of hepcidin, the iron hormone. Before hepcidin was discovered, the liver was simply regarded as the main site of iron storage and, as such, the main target of iron toxicity. Now, as the main source of hepcidin, it appears that the loss of the hepcidin-producing liver mass or genetic and acquired factors that repress hepcidin synthesis in the liver may also lead to iron overload. Usually, there is low-grade excess iron which, through oxidative stress, is sufficient to worsen the course of the underlying liver disease or other chronic diseases that are apparently unrelated to iron, such as chronic metabolic and cardiovascular diseases. In the future, modulation of hepcidin synthesis and activity or hepcidin hormone-replacing strategies may become therapeutic options to cure iron-related disorders.
2.
Hereditary hemochromatosis.
Fix, OK, Kowdley, KV
Minerva medica. 2008;(6):605-17
Abstract
Hereditary hemochromatosis (HH) refers to several inherited disorders of iron metabolism leading to tissue iron overload. Classical HH is associated with mutations in HFE (C282Y homozygotes or C282Y/H63D compound heterozygotes) and is almost exclusively found in populations of northern European descent. Non-HFE associated HH is caused by mutations in other recently identified genes involved in iron metabolism. Hepcidin is an iron regulatory hormone that inhibits ferroportin-mediated iron export from enterocytes and macrophages. Defective hepcidin gene expression or function may underlie most forms of HH. Target organs and tissues affected by HH include the liver, heart, pancreas, joints, and skin, with cirrhosis and diabetes mellitus representing late signs of disease in patients with markedly elevated liver iron concentration. Compound heterozygotes have milder disease than C282Y homozygotes and clinical signs of HH in these patients are usually associated with other factors such as alcoholism and the dysmetabolic syndrome. The most frequent causes of death in HH are liver cancer, cirrhosis, cardiomyopathy, and diabetes, but patients who undergo successful iron depletion before the development of cirrhosis or diabetes can have normal survival. Classical HH is characterized by incomplete penetrance and variable expressivity, and women are less affected than men by iron overload and iron overload-related disease. The diagnosis of HH is established by genetic testing in patients with elevated transferrin saturation values. Patients with an established diagnosis of HH and iron overload should be treated with phlebotomy to achieve body iron depletion followed by maintenance phlebotomy. Population screening for HH is controversial principally because of incomplete penetrance, but screening of selected, high risk populations and first-degree relatives of affected probands may be cost effective.
3.
[Hereditary haemochromatosis: novel genes, novel diseases and hepcidin].
Bergmans, JP, Kemna, EH, Janssen, MC, Jacobs, EM, Stalenhoef, AF, Marx, JJ, Swinkels, DW
Nederlands tijdschrift voor geneeskunde. 2007;(20):1121-7
Abstract
Since the discovery of the HFE gene of hereditary haemochromatosis in 1996 several new genetic defects have been identified, enabling explanation of the cause and variety of this disease. To date, at least 5 major types of hereditary haemochromatosis have been recognised. All these genes encode for proteins that are involved in metabolic pathways relevant to hepcidin synthesis in the liver. Hepcidin is a small protein that regulates the activity of the iron exporting protein ferroportin in the basolateral membrane of duodenal cells and the cell membrane of macrophages and thereby controls serum iron concentration. Plasma hepcidin concentration is elevated in body iron excess and by inflammatory stimuli, and is lowered in erythroid iron demand, hypoxia and most types of hereditary haemochromatosis. It is the clinician's task to diagnose hereditary haemochromatosis before irreversible tissue damage arises and at the same time to differentiate between ongoing iron accumulation and increasingly prevalent disorders with elevated serum ferritin such as the metabolic syndrome.
4.
Non-HFE hemochromatosis: genetics, pathogenesis, and clinical management.
Nelson, JE, Kowdley, KV
Current gastroenterology reports. 2005;(1):71-80
Abstract
Recent advances in our understanding of iron metabolism and the epidemiology of iron overload disorders have shown that hereditary forms of hemochromatosis can result from mutations in several iron metabolism genes other than HFE, including Hamp, HJV, TFR2, and SCL40A. These "non-HFE" forms of hemochromatosis are much rarer than HFE-related hemochromatosis but exhibit a similar phenotype, and with the exception of ferroportin disease, a similar pattern of inheritance and parenchymal iron accumulation. Therefore, these diseases can be thought of as variant forms of a primary hepatic iron overload syndrome; thus, a unified approach can be used for evaluation and diagnosis. Management generally consists of periodic phlebotomies until iron is depleted.