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1.
Dysmetabolic Iron Overload in Metabolic Syndrome.
Sachinidis, A, Doumas, M, Imprialos, K, Stavropoulos, K, Katsimardou, A, Athyros, VG
Current pharmaceutical design. 2020;(10):1019-1024
Abstract
BACKGROUND We sought to determine the association of dysmetabolic iron overload syndrome (DIOS) with metabolic syndrome (MetS). METHODS Several studies have shown that DIOS is associated with Mets, mainly through the pathogenesis of its components: type 2 diabetes mellitus (T2DM), essential hypertension, non-alcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (POS). RESULTS Serum ferritin levels increase proportionally according to the degree of insulin resistance (IR) and the number of components of Mets. Moreover, DIOS predicts the onset of T2DM and NAFLD. Dysregulation of iron metabolism in DIOS is due to a multifactorial and dynamic process triggered by an unhealthy diet, facilitated by environmental and genetic cofactors, and resulting in a bidirectional relation between the liver and visceral adipose tissue (VAT). Iron removal combined with a healthy diet improved both insulin sensitivity and beta-cell function, but had no significant effect on blood glucose; however, phlebotomy therapy might be considered with conflicting results. CONCLUSION Iron overload is closely associated with metabolic syndrome and its components; however, it remains under-appreciated in everyday clinical practice. Diet and lifestyle modification offer some clinical benefit; however, it is not adequate for successful management of the disease. The results of phlebotomy remain controversial, underlying the necessity of further efforts in this field.
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Dysmetabolic Hyperferritinemia and Dysmetabolic Iron Overload Syndrome (DIOS): Two Related Conditions or Different Entities?
Rametta, R, Fracanzani, AL, Fargion, S, Dongiovanni, P
Current pharmaceutical design. 2020;(10):1025-1035
Abstract
Hyperferritinemia is observed in one-third of patients with non-alcoholic fatty liver disease (NAFLD) and Metabolic Syndrome (MetS). The condition characterized by increased body iron stores associated with components of MetS has been defined as Dysmetabolic Iron Overload Syndrome (DIOS). DIOS represents the most frequent iron overload condition, since it is observed in 15% of patients with MetS and in half of those with NAFLD and its clinical presentation overlaps almost completely with that of dysmetabolic hyperferritinemia (DH). The pathogenetic mechanisms linking insulin resistance (IR), NAFLD and DIOS to iron overload are still debated. Hepcidin seems to play a role in iron accumulation in DIOS and NAFLD patients who show elevated serum hepcidin levels. The iron challenge does not restrain iron absorption despite adequate hepcidin production, suggesting that an impaired hepcidin activity rather than a deficit of hormone production underlies DIOS pathogenesis. Acquired and genetic factors are recognized to contribute to iron accumulation in NAFLD whereas additional studies are required to clearly demonstrate whether the same or different genetic factors lead to iron overload in DIOS. Finally, iron depletion by phlebotomy, together with the modification of diet and life-style habits, represents the therapeutic approach to decrease metabolic alterations and liver enzymes in NAFLD and DIOS patients. In this review, we summarized the current knowledge on the dysregulation of iron homeostasis in NAFLD and DIOS in the attempt to clarify whether they are different or more likely strictly related conditions, sharing the same pathogenic cause i.e. the MetS.
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3.
[Myelodysplastic syndromes and iron metabolism].
Kawabata, H
[Rinsho ketsueki] The Japanese journal of clinical hematology. 2018;(10):2042-2049
Abstract
Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by ineffective hematopoiesis in bone marrow and cytopenias in peripheral blood. In patients with MDS, iron overload is frequent due to red blood cell transfusions and ineffective erythropoiesis. Dysplastic erythroblasts in MDS secrete humoral factors such as erythroferrone, which suppress hepatic expression of hepcidin. Hepcidin is the key regulator of systemic iron homeostasis, and suppression of hepcidin expression leads to an increase in iron absorption from the intestines, exacerbating systemic iron overload. Patients with MDS with ring sideroblasts (MDS-RS) are prone to iron overload, with most harboring splicing factor 3B subunit 1 (SF3B1) mutations in hematopoietic cells. SF3B1 mutations may induce ring sideroblasts by downregulating ATP binding cassette subfamily B member 7, which exports iron-sulfur clusters from the mitochondria to the cytoplasm. Iron overload in MDS causes hepatic dysfunction, diabetes, cardiac failure, and atherosclerosis, whereas excess iron may suppress normal hematopoiesis. Though randomized control studies are lacking, results from retrospective and cohort studies indicate that iron chelation therapy is appropriate for lower-risk MSD patients with transfusion-related iron overload, although it is not recommended for higher-risk MSD patients with short life expectancy.
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4.
Iron overload across the spectrum of non-transfusion-dependent thalassaemias: role of erythropoiesis, splenectomy and transfusions.
Porter, JB, Cappellini, MD, Kattamis, A, Viprakasit, V, Musallam, KM, Zhu, Z, Taher, AT
British journal of haematology. 2017;(2):288-299
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Abstract
Non-transfusion-dependent thalassaemias (NTDT) encompass a spectrum of anaemias rarely requiring blood transfusions. Increased iron absorption, driven by hepcidin suppression secondary to erythron expansion, initially causes intrahepatic iron overload. We examined iron metabolism biomarkers in 166 NTDT patients with β thalassaemia intermedia (n = 95), haemoglobin (Hb) E/β thalassaemia (n = 49) and Hb H syndromes (n = 22). Liver iron concentration (LIC), serum ferritin (SF), transferrin saturation (TfSat) and non-transferrin-bound iron (NTBI) were elevated and correlated across diagnostic subgroups. NTBI correlated with soluble transferrin receptor (sTfR), labile plasma iron (LPI) and nucleated red blood cells (NRBCs), with elevations generally confined to previously transfused patients. Splenectomised patients had higher NTBI, TfSat, NRBCs and SF relative to LIC, than non-splenectomised patients. LPI elevations were confined to patients with saturated transferrin. Erythron expansion biomarkers (sTfR, growth differentiation factor-15, NRBCs) correlated with each other and with iron overload biomarkers, particularly in Hb H patients. Plasma hepcidin was similar across subgroups, increased with >20 prior transfusions, and correlated inversely with TfSat, NTBI, LPI and NRBCs. Hepcidin/SF ratios were low, consistent with hepcidin suppression relative to iron overload. Increased NTBI and, by implication, risk of extra-hepatic iron distribution are more likely in previously transfused, splenectomised and iron-overloaded NTDT patients with TfSat >70%.
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A case report of deferasirox-induced kidney injury and Fanconi syndrome.
Murphy, N, Elramah, M, Vats, H, Zhong, W, Chan, MR
WMJ : official publication of the State Medical Society of Wisconsin. 2013;(4):177-80
Abstract
Cases of kidney injury associated with the use of deferasirox chelation therapy during the course of treatment for iron overload have been reported infrequently. We present the case of a patient treated with deferasirox who had biopsy-proven tubular injury in the setting of clinical Fanconi syndrome. The patient required hospitalization for metabolic acidosis, electrolyte abnormalities, and associated symptoms. With supportive care and cessation of chelation therapy he improved, but has yet to fully recover. This is the first known case reporting biopsy-proven tubular damage in the setting of deferasirox use.
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Iron homeostasis in the metabolic syndrome.
Datz, C, Felder, TK, Niederseer, D, Aigner, E
European journal of clinical investigation. 2013;(2):215-24
Abstract
The metabolic syndrome (MetS) affects iron homeostasis in a many-faceted fashion. On the one side, hyperferritinaemia with normal or mildly elevated transferrin saturation is observed in approximately one-third of patients with non-alcoholic fatty liver disease (NAFLD) or the MetS. This constellation has been named the 'dysmetabolic iron overload syndrome (DIOS)'. Current evidence suggests that elevated body iron stores exert a detrimental effect on the clinical course of obesity-related conditions and that iron removal improves insulin sensitivity and delays the onset of T2DM. On the other side, iron deficiency is a frequent finding in more progressed stages of obesity. The mechanisms underlying the DIOS and obesity-related iron deficiency appear strikingly similar as elevated hepcidin concentrations, low expression of duodenal ferroportin (FPN) and impaired iron absorption are found in both conditions. This review summarizes the current knowledge about the dysregulation of iron homeostasis in the MetS and particularly in its hepatic manifestation NAFLD.
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The role of iron in type 2 diabetes in humans.
Rajpathak, SN, Crandall, JP, Wylie-Rosett, J, Kabat, GC, Rohan, TE, Hu, FB
Biochimica et biophysica acta. 2009;(7):671-81
Abstract
The role of micronutrients in the etiology of type 2 diabetes is not well established. Several lines of evidence suggest that iron play may a role in the pathogenesis of type 2 diabetes. Iron is a strong pro-oxidant and high body iron levels are associated with increased level of oxidative stress that may elevate the risk of type 2 diabetes. Several epidemiological studies have reported a positive association between high body iron stores, as measured by circulating ferritin level, and the risk of type 2 diabetes and of other insulin resistant states such as the metabolic syndrome, gestational diabetes and polycystic ovarian syndrome. In addition, increased dietary intake of iron, especially that of heme iron, is associated with risk of type 2 diabetes in apparently healthy populations. Results from studies that have evaluated the association between genetic mutations related to iron metabolism have been inconsistent. Further, several clinical trials have suggested that phlebotomy induced reduction in body iron levels may improve insulin sensitivity in humans. However, no interventional studies have yet directly evaluated the effect of reducing iron intake or body iron levels on the risk of developing type 2 diabetes. Such studies are required to prove the causal relationship between moderate iron overload and diabetes risk.
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Prevalence of body iron excess in the metabolic syndrome.
Bozzini, C, Girelli, D, Olivieri, O, Martinelli, N, Bassi, A, De Matteis, G, Tenuti, I, Lotto, V, Friso, S, Pizzolo, F, et al
Diabetes care. 2005;(8):2061-3
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[Genetics of hereditary iron overload].
Le Gall, JY, Jouanolle, AM, Fergelot, P, Mosser, J, David, V
Bulletin de l'Academie nationale de medecine. 2004;(2):247-62; discussion 262-3
Abstract
The classification of hereditary abnormalities of iron metabolism was recently expanded and diversified. Genetic hemochromatosis now corresponds to six diseases, namely classical hemochromatosis HFE 1; juvenile hemochromatosis HFE 2 due to mutations in an unidentified gene on chromosome 1; hemochromatosis HFE 3 due to mutations in the transferrin receptor 2 (TfR2); hemochromatosis HFE 4 caused by a mutation in the H subunit of ferritin; and hemochromatosis HFE 6 whose gene is hepcidine (HAMP). Systemic iron overload is also associated with aceruloplasminemia, atransferrinemia and the "Gracile" syndrome caused by mutations in BCS1L. The genes responsible for neonatal and African forms of iron overload are unknown. Other genetic diseases are due to localized iron overload: Friedreich's ataxia results from the expansion of triple nucleotide repeats within the frataxin (FRDA) gene; two forms of X-linked sideroblastic anemia are due to mutations within the delta aminolevulinate synthetase (ALAS 2) or ABC-7 genes; Hallervorden-Spatz syndrome is caused by a pantothenate kinase 2 gene (PANK-2) defect; neuroferritinopathies; and hyperferritinemia--cataract syndrome due to a mutation within the L-ferritin gene. In addition to this wide range of genetic abnormalities, two other features characterize these iron disorders: 1) most are transmitted by an autosomal recessive mechanism, but some, including hemochromatosis type 4, have dominant transmission; and 2) most correspond to cytosolic iron accumulation while some, like Friedreich's ataxia, are disorders of mitochondrial metabolism.
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[Correction of insulin resistance syndrome does not cause normalisation of hyperferritinaemia].
Roblin, X, Phelip, JM, Hilleret, MN, Heluwaert, F, Bonaz, B, Zarski, JP
Gastroenterologie clinique et biologique. 2003;(12):1079-83
Abstract
UNLABELLED The consequences of iron overload from dysmetabolic hyper-ferritinaemia are a strong motivation for an active medical care program. Venesection therapy is known to be effective in controlling iron overload parameters although no study has evaluated the impact of the normalization of metabolic dysfunction on iron overload. AIMS To evaluate the impact of normalization of metabolic dysfunction on iron overload. METHODS Sixty consecutive patients with dysmetabolic hepatosiderosis were included in a prospective study. Patients with hyper-ferritinaemia above 1000 microg/l were excluded. Multidisciplinary care was offered to all patients to normalize metabolic disorders (body mass index, arterial hypertension, fasting and postprandial hyperglycemia, hyperuricemia, hypercholesterolemia and hypertriglyceridemia) every three months. All patients were followed for one year. At clinical examinations, ferritinaemia concentrations were measured and all dysmetabolic parameters evaluated. MRI was performed at the beginning of the study and at the one year follow-up, to measure hepatic iron load. RESULTS Despite efficient medical care of insulin resistance syndrome, ferritinaemia remained stable. In two thirds of the study population, hyper-ferritinaemia reached at least one and a half times the baseline value, although the dysmetabolic disorders of 40% of the patients were strictly normalized. In this group of 44 patients with strict normalization of metabolic functions, 24 (54%) had hyper-ferritinaemia at one year follow-up whereas 16 other (36%) normalized this parameter. Only 4 patients who had a ferritinaemia below 450 microg/l at baseline, normalized this value at one year. Intra-hepatic iron overload, evaluated by MRI imaging remained stable except for 2 patients who normalized ferritinaemia. CONCLUSION Although efficient handling of dysmetabolic disorders is essential, it is not sufficient to normalize dysmetabolic hyper-ferritinaemia. Only patients with a ferritinaemia value below a baseline of 450 microg/l had normalization of iron overload. Therefore venesection must be offered to all patients with a hyper-ferritinaemia above this value.