Iron and the liver

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.

Clinical quantitative susceptibility mapping (QSM): Biometal imaging and its emerging roles in patient care

“…With increasing body iron, hepatocytes may eventually exhaust the capacity to safely store the excess iron. Consequent oxidative damage to hepatocytes causes paracrine induction of hepatic stellate cells and portal myofibroblasts, resulting in collagen deposition, fibrosis, micronodular cirrhosis and, finally, hepatocellular carcinoma (94)…”

Key Events Participating in the Pathogenesis of Alcoholic Liver Disease

“…However, it is not definitively known whether it is the effect of alcohol that is responsible for such overload [52]. Considering that hepcidin expression in the liver inhibits iron absorption from the diet and the release of iron from its storage, it is feasible that modulation of hepcidin synthesis and activity or hepcidin hormone-replacing strategies may become therapeutic options for patients with ALD in the future [53]. …”

The hemochromatosis protein HFE signals predominantly via the BMP type I receptor ALK3 in vivo

“…Upon binding, ferroportin is ubiquitinated and degraded, which results in the inhibition of iron absorption from the diet and of iron release from macrophages 1–3 . In hereditary hemochromatosis, the regulation of hepcidin expression is impaired, so that iron uptake is increased 4–7 . Iron overload occurs because vertebrates have no mechanisms to control iron efflux from their bodies.…”

“…So far, treatment has been limited to repeated phlebotomy or administration of iron chelators. However, given that symptoms of hereditary hemochromatosis are typically non-specific and iron accumulation gradual, the disease often remains undiagnosed for decades 4,5 .…”