Beta-globin mutations are associated with parenchymal siderosis and fibrosis in patients with non-alcoholic fatty liver disease

Valenti, Luca; Canavesi, Elena; Galmozzi, E.; Dongiovanni, Paola; Rametta, Raffaela; Maggioni, P; Maggioni, Marco; Fracanzani, Anna Ludovica

doi:10.1016/j.jhep.2010.05.023

Cited by 61 publications

(63 citation statements)

References 35 publications

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“…Genetics (mutations in the b-globin and a1-antitrypsin genes) (22) and dietary habits may explain some of the phenotypic variability. Different mechanisms have been hypothesized to answer the question, from alterations in diet or duodenal iron absorption to dysfunction of target molecules involved in iron metabolism ( Fig.…”

Section: Impact Of Iron On Insulin-sensitive Tissuesmentioning

confidence: 99%

Mechanisms Linking Glucose Homeostasis and Iron Metabolism Toward the Onset and Progression of Type 2 Diabetes

2015

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OBJECTIVEThe bidirectional relationship between iron metabolism and glucose homeostasis is increasingly recognized. Several pathways of iron metabolism are modified according to systemic glucose levels, whereas insulin action and secretion are influenced by changes in relative iron excess. We aimed to update the possible influence of iron on insulin action and secretion and vice versa. RESEARCH DESIGN AND METHODSThe mechanisms that link iron metabolism and glucose homeostasis in the main insulin-sensitive tissues and insulin-producing b-cells were revised according to their possible influence on the development of type 2 diabetes (T2D). RESULTSThe mechanisms leading to dysmetabolic hyperferritinemia and hepatic overload syndrome were diverse, including diet-induced alterations in iron absorption, modulation of gluconeogenesis, heme-mediated disruption of circadian glucose rhythm, impaired hepcidin secretion and action, and reduced copper availability. Glucose metabolism in adipose tissue seems to be affected by both iron deficiency and excess through interaction with adipocyte differentiation, tissue hyperplasia and hypertrophy, release of adipokines, lipid synthesis, and lipolysis. Reduced heme synthesis and dysregulated iron uptake or export could also be contributing factors affecting glucose metabolism in the senescent muscle, whereas exercise is known to affect iron and glucose status. Finally, iron also seems to modulate b-cells and insulin secretion, although this has been scarcely studied. CONCLUSIONSIron is increasingly recognized to influence glucose metabolism at multiple levels. Body iron stores should be considered as a potential target for therapy in subjects with T2D or those at risk for developing T2D. Further research is warranted.Iron levels help to modulate the clinical manifestations of numerous systemic diseases. The importance of adequate amounts of iron for health and well-being in humans is well known. Iron is involved in binding and transporting oxygen and regulating cell growth and differentiation, as well as electron transport, DNA synthesis, and many important metabolic processes (1).From a clinical standpoint, assessing serum ferritin concentrations is a useful measure of iron storage. Ferritin is also an acute-phase reactant and, as such, is

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Section: Impact Of Iron On Insulin-sensitive Tissuesmentioning

confidence: 99%

Mechanisms Linking Glucose Homeostasis and Iron Metabolism Toward the Onset and Progression of Type 2 Diabetes

2015

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“…This is a very common polymorphism in the general population, as 25-30% of the population carries the H63D variant, but its contribution to the pathogenesis of HH and iron overload syndromes is negligible, with the exception of compound heterozygosity with the C282Y. The penetrance of HH depends on age, gender, environmental factors, and on the role of the so-called modifier genes (Wood, Powell et al 2008): for example, iron overload and clinical phenotype are more serious in patients with beta-thalassemic trait (Piperno, Mariani et al 2000;Valenti, Canavesi et al 2010). Mutations of TFR-2 cause a rare recessive form of HH, clinically similar to HFE HH, which is consistent with the hypothesis that HFE and TFR-2 might be part of the same signaling pathway.…”

Section: Hfe Mutations and Iron Overloadmentioning

confidence: 99%

Modulation of Iron Metabolism and Hepcidin Release by HFE Mutations in Chronic Hemodialysis Patients: Pathophysiological and Therapeutic Implications

Canavesi¹,

Valenti²

2011

Hemodialysis - Different Aspects

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“…Additionally the betaglobin trait [73] , TMPRSS6 [74] , and the alpha1antitrypsin genotype [75] may modify the iron phenotype of NAFLD. It appears reasonable to conclude that the contribution of the genetic background may vary according to the geographic region.…”

Section: Nafldmentioning

confidence: 99%

Dysregulation of iron and copper homeostasis in nonalcoholic fatty liver

Aigner

Weiss

Datz

2014

WJH

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Elevated iron stores as indicated by hyperferritinemia with normal or mildly elevated transferrin saturation and mostly mild hepatic iron deposition are a characteristic finding in subjects with non-alcoholic fatty liver disease (NAFLD). Excess iron is observed in approximately one third of NAFLD patients and is commonly referred to as the "dysmetabolic iron overload syndrome". Clinical evidence suggests that elevated body iron stores aggravate the clinical course of NAFLD with regard to liver-related and extrahepatic disease complications which relates to the fact that excess iron catalyses the formation of toxic hydroxylradicals subsequently resulting in cellular damage. Iron removal improves insulin sensitivity, delays the onset of type 2 diabetes mellitus, improves pathologic liver function tests and likewise ameliorates NAFLD histology. Several mechanisms contribute to pathologic iron accumulation in NAFLD. These include impaired iron export from hepatocytes and mesenchymal Kupffer cells as a consequence of imbalances in the concentrations of iron regulatory factors, such as hepcidin, cytokines, copper or other dietary factors. This review summarizes the knowledge about iron homeostasis in NAFLD and the rationale for its therapeutic implications.

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Beta-globin mutations are associated with parenchymal siderosis and fibrosis in patients with non-alcoholic fatty liver disease

Cited by 61 publications

References 35 publications

Mechanisms Linking Glucose Homeostasis and Iron Metabolism Toward the Onset and Progression of Type 2 Diabetes

Mechanisms Linking Glucose Homeostasis and Iron Metabolism Toward the Onset and Progression of Type 2 Diabetes

Modulation of Iron Metabolism and Hepcidin Release by HFE Mutations in Chronic Hemodialysis Patients: Pathophysiological and Therapeutic Implications

Dysregulation of iron and copper homeostasis in nonalcoholic fatty liver

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