Shaping the bone through iron and iron-related proteins.

20 years of Hepcidin: How far we have come.

Hereditary hemochromatosis (HH) is a disease associated with iron overload caused by mutations in genes regulating the hepcidin/ferroportin regulatory axis. Toxic iron accumulation in tissues is responsible for multiple pathologies. HH is associated with skeletal complications and an increased fracture risk. Skeletal complications in HH may be the result of direct effects of iron on bone; effects of mutated iron regulatory genes expressed in bones; or effects secondary to HH-associated endocrinopathies, including hypogonadism and diabetes. HH therapy aims to reduce iron accumulation. Bone health should be considered and monitored. Hereditary hemochromatosis (HH) is a genetic disorder in which mutations affect systemic iron homeostasis. Most subtypes of HH result in low hepcidin levels and iron overload. Accumulation of iron in various tissues can lead to widespread organ damage and to various complications, including liver cirrhosis, arthritis, and diabetes. Osteoporosis is another frequent complication of HH, and the underlying mechanisms are poorly understood. Currently, it is unknown whether iron overload in HH directly damages bone or whether complications associated with HH, such as liver cirrhosis or hypogonadism, affect bone secondarily. This review summarizes current knowledge of bone metabolism in HH and highlights possible implications of metabolic dysfunction in HH-driven bone loss. We further discuss therapeutic considerations managing osteoporosis in HH. Hereditary hemochromatosis (HH) is a genetic disorder in which mutations affect systemic iron homeostasis. Most subtypes of HH result in low hepcidin levels and iron overload. Accumulation of iron in various tissues can lead to widespread organ damage and to various complications, including liver cirrhosis, arthritis, and diabetes. Osteoporosis is another frequent complication of HH, and the underlying mechanisms are poorly understood. Currently, it is unknown whether iron overload in HH directly damages bone or whether complications associated with HH, such as liver cirrhosis or hypogonadism, affect bone secondarily. This review summarizes current knowledge of bone metabolism in HH and highlights possible implications of metabolic dysfunction in HH-driven bone loss. We further discuss therapeutic considerations managing osteoporosis in HH. 

Iron effects versus metabolic alterations in hereditary hemochromatosis driven bone loss

Currently, non-alcoholic fatty liver disease is one of the most common chronic liver diseases. In recent years, this condition has been considered as a hepatic manifestation of the metabolic syndrome, which is associated with overweight and impaired glucose and fat metabolism. Despite the obvious role of lifestyle in the development of this disease, it is increasingly being suggested that disorders in the metabolism of fats and carbohydrates have a genetic basis, which determines the tendency to develop NAFLD. Mutant polymorphisms of the HSD17B13, GCKR, HFE, and CP genes have been shown to affect the course of NAFLD, but these effects require further study. Therefore, the aim of this work was to analyze and systematize the available data from foreign articles over the past 10 years. In this study, 573 articles were analyzed, the most important 64 original research works were used here. Mutations in  the HSD17B13  gene are associated with a  milder course of  NAFLD, while GCKR gene polymorphisms, on the contrary, are associated with more severe histological manifestations of this disease, such as steatosis and fibrosis. The HFE and CP genes, although not directly related to macronutrient metabolism, nevertheless contribute to the development of more severe forms of NAFLD, which may be associated with the development of inflammation and oxidative stress caused by excessive accumulation of iron in hepatocytes.

/pdf/polymorphisms-of-hsd17b13-gckr-hfe-and-cp-as-factors-of-the-3pev3imn.pdf

Polymorphisms of HSD17B13, GCKR, HFE, and CP as factors of the development of non-alcoholic fatty liver disease and comorbid diseases

Hemochromatosis (HC) is a systemic iron overload disease of genetic origin. Its commonest form, HFE-related HC, is one the most prevalent genetic diseases in the Caucasian population, but with variable penetrance and expression. In the context of documented high transferrin saturation, serum ferritin (SF), and body iron excess, genetic testing revealing homozygosity for the p.Cys282YTyr mutation confirms the diagnosis in the individual patient and provides the foundation for a family study. In case of very low penetrant genotypes (e.g., compound heterozygosity for p.Cys282Tyr/p.His63Asp and p.His63Asp homozygosity), assessment of coexistent disorders that can increase SF and/or favor iron overload is needed. Quantitation of liver iron by magnetic resonance imaging is useful to definitely assess iron overload and adequate therapy. If there is only heterozygosity for p.Cys282Tyr, specializing centers should perform HFE sequencing to search for rare compound heterozygosity. In case of non-at-risk HFE genotypes, the patient might have a rare non-HFE-related HC. Some of these non-HFE-related forms share the HFE-HC phenotype due to hepcidin insufficiency (biallelic mutations in HJV, HAMP, and TFR2) or ferroportin resistance to hepcidin (gain-of-function mutations of SLC40A1) with similar or more severe expression (juvenile HC). In rare HFE and non-HFE-HC, molecular testing performed by specialty laboratories is critical, not only for diagnosis of the individual patient, but also for family screening. Next-generation sequencing is radically changing the technological face of molecular diagnosis of HC, bringing obvious benefits, but also raising important medical and ethical issues. 

Molecular testing in hemochromatosis

HFE and ALK3 act in the same signaling pathway

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HFE and ALK3 act in the same signaling pathway