Dysmetabolic Hyperferritinemia Research Articles

Dysmetabolic Hyperferritinemia and Dysmetabolic Iron Overload Syndrome (DIOS): Two Related Conditions or Different Entities?

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.

Liver iron concentration in dysmetabolic hyperferritinemia: Results from a prospective cohort of 276 patients

Introduction and objectivesWe aimed to study the liver iron concentration in patients referred for hyperferritinemia to six hospitals in the Basque Country and to determine if there were differences between patients with or without metabolic syndrome. Patients and methodsMetabolic syndrome was defined by accepted criteria. Liver iron concentration was determined by magnetic resonance imaging. ResultsWe obtained the data needed to diagnose metabolic syndrome in 276 patients; a total of 135 patients (49%), 115/240 men (48%), and 20/36 women (55.6%) presented metabolic syndrome. In all 276 patients, an MRI for the determination of liver iron concentration (mean±SD) was performed. The mean liver iron concentration was 30.83±19.38 for women with metabolic syndrome, 38.84±25.50 for men with metabolic syndrome, and 37.66±24.79 (CI 95%; 33.44–41.88) for the whole metabolic syndrome group. In 141 patients (51%), metabolic syndrome was not diagnosed: 125/240 were men (52%) and 16/36 were women (44.4%). The mean liver iron concentration was 34.88±16.18 for women without metabolic syndrome, 44.48±38.16 for men without metabolic syndrome, and 43.39±36.43 (CI 95%, 37.32–49.46) for the whole non-metabolic syndrome group. Comparison of the mean liver iron concentration from both groups (metabolic syndrome vs non-metabolic syndrome) revealed no significant differences (p=0.12). ConclusionsPatients with hyperferritinemia and metabolic syndrome presented a mildly increased mean liver iron concentration that was not significantly different to that of patients with hyperferritinemia and non-metabolic syndrome.

Liver iron concentration is not raised in patients with dysmetabolic hyperferritinemia

Background & aims. Hyperferritinemia (HF) is frequently present in patients with metabolic syndrome (MS). MS associated with HF is named dysmetabolic hyperferritinemia (DH). There are some publications that propose that DH is associated with a raised liver iron concentration (LIC). We studied the LIC in patients referred for HF to a secondary hospital to determine if there are differences between patients with or without MS.Material and methods. We conducted a prospective study of 132 consecutive patients with HF from January to December 2010. The MS was defined by the International Diabetes Federation criteria (2005). LIC was determined by Magnetic resonance imaging (MRI).Results. The number of patients for which there was enough data to determine MS was 97, out of which 54 had MS and 43 had no MS (NMS). In 54/97 patients, MRI for LIC determination was performed. From the MS group, 44 were men (27 underwent MRI) and 10 women (9 MRI). The mean LIC was 27.83 ± 20.90 μmol/g for the MS group. In the NMS group, 36 were men (13 MRI), and 7 women (5 MRI). In 18 patients from the NMS group, LIC was determined by MRI. The mean LIC was 33.16 ± 19.61 μmol/g in the NMS group. We compared the mean values of LIC from both groups (MS vs. NMS) and no significant differences were found (p = 0.067).Conclusion. Patients with DH present a mean LIC within normal values and their values do not differ from those of patients with HF but without MS.

P179Absence of cardiac siderosis at cardiac magnetic resonance in patients with dysmetabolic hyperferritinemia

P179Absence of cardiac siderosis at cardiac magnetic resonance in patients with dysmetabolic hyperferritinemia

Possible dysmetabolic hyperferritinemia in hyperinsulinemic horses.

Background:Hyperinsulinemia associated with equine metabolic syndrome and pituitary pars intermedia dysfunction is a risk factor for laminitis. Research in other species has shown elevated body iron levels as both a predictor and consequence of insulin resistance. In humans, this is known as dysmetabolic hyperferritinemia. Aim:To explore the relationship between equine hyperinsulinemia and body iron levels.Methods:We reviewed case histories and laboratory results from an open access database maintained by the Equine Cushing’s and Insulin Resistance Group Inc. (ECIR). We identified 33 horses with confirmed hyperinsulinemia and laboratory results for serum iron, total iron binding capacity, and ferritin. Pearson correlation was used to test the relationship between insulin and iron indices. Additionally, we performed a secondary analysis of a previously reported controlled trial that was originally designed to test the correlation between iron status and the insulin response in horses. Here, we used a t-test to compare the mean values of insulin and ferritin between horses we categorized as normal or hyperinsulinemic based on their response to an oral challenge.Results:Serum ferritin exceeded published reference range in 100% of the horses identified from the ECIR database. There were no statistically significant associations between insulin indices (RISQI, log insulin) and iron indices (log serum iron, log TSI%, log ferritin). There were trends for a negative association between RISQI and log iron [r(31) = −0.33, p = 0.058] and a positive association between age and ferritin [r(30) = 0.34, p = 0.054]. From the secondary data analysis of published data, we found significantly elevated ferritin (p = 0.05) in horses considered hyperinsulinemic by dynamic insulin testing compared to horses with a normal response.Conclusion:These results suggest the potential for iron overload in hyperinsulinemic horses, a feature documented in other species and should stimulate further study into the relationship between insulin and iron dysregulation in the horse.

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

The 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. The mechanisms that link iron metabolism and glucose homeostasis in the main insulin-sensitive tissues and insulin-producing β-cells were revised according to their possible influence on the development of type 2 diabetes (T2D). The 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 β-cells and insulin secretion, although this has been scarcely studied. Iron 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.

P1006 : Liver iron concentration in the metabolic syndrome with hyperferritinemia (dysmetabolic hyperferritinemia). Results from a cohort of patients studied by MRI

P1006 : Liver iron concentration in the metabolic syndrome with hyperferritinemia (dysmetabolic hyperferritinemia). Results from a cohort of patients studied by MRI

Generalized pruritus in dysmetabolic hyperferritinemia treated by phlebotomy

This paper describes a case of pruritus caused by dysmetabolic hyperferritinemia treated by multiple phlebotomies. A 63-year-old man was followed for generalized pruritus, which was resistant to the usual treatments. He presented with metabolic syndrome. Physical examination showed only excoriations and lichenification on the skin. The serum ferritin was high at 1043 ng/ml, with transferrin saturation at 67%. The other biological investigations and genetic tests for hemochromatosis were negative. In spite of the dietary measures, the ferritin level was still high (853 ng/ml). Magnetic resonance imaging confirmed hepatic iron overload.The association of hyperferritinemia, hepatic iron overload, and metabolic syndrome led to the diagnosis of dysmetabolic hyperferritinemia. Phlebotomies are an unusual treatment, but because the pruritus and hyperferritinemia were still present, phlebotomy was initiated. After 19 months, the patient reported improvement of his pruritus and normalization of ferritin levels.

Increased Serum Hepcidin Levels in Subjects with the Metabolic Syndrome: A Population Study

The recent discovery of hepcidin, the key iron regulatory hormone, has changed our view of iron metabolism, which in turn is long known to be linked with insulin resistant states, including type 2 diabetes mellitus and the Metabolic Syndrome (MetS). Serum ferritin levels are often elevated in MetS (Dysmetabolic hyperferritinemia - DHF), and are sometimes associated with a true mild-to-moderate hepatic iron overload (dysmetabolic iron overload syndrome - DIOS). However, the pathophysiological link between iron and MetS remains unclear. This study was aimed to investigate, for the first time, the relationship between MetS and hepcidin at population level. We measured serum hepcidin levels by Mass Spectrometry in 1,391 subjects from the Val Borbera population, and evaluated their relationship with classical MetS features. Hepcidin levels increased significantly and linearly with increasing number of MetS features, paralleling the trend of serum ferritin. In multivariate models adjusted for relevant variables including age, C-Reactive Protein, and the HFE C282Y mutation, ferritin was the only significant independent predictor of hepcidin in males, while in females MetS was also independently associated with hepcidin. Overall, these data indicate that the fundamental iron regulatory feedback is preserved in MetS, i.e. that hepcidin tends to progressively increase in response to the increase of iron stores. Due to recently discovered pleiotropic effects of hepcidin, this may worsen insulin resistance and contribute to the cardiovascular complications of MetS.

Serum Hepcidin Levels Correlate with Phenotypes of the Metabolic Syndrome At Population Level

Abstract 348 Background and Aims:Hepcidin is a 25 amino acid hormone mainly produced by the liver in response to increased plasma or tissue iron to homeostatically down-regulate absorption and recycling of the metal from duodenum and macrophages, respectively. Hepcidin expression is also upregulated by inflammation. Dysmetabolic hyperferritinemia is among the commonest causes of increased serum ferritin levels encountered in clinical practice, but its pathophysiology remains unclear. Indeed, the Metabolic Syndrome (MS) that affects near 20–25% of western adults, is characterized by subclinical inflammation, which hampers the interpretation of serum ferritin as a marker of body iron stores. We recently measured serum hepcidin levels in the large Val Borbera (VB) population to evaluate their genetic determinants (Traglia et al. J Med Genet 2011). Taking advantage of this survey, we investigated for the first time the relationships between hepcidin, ferritin, C-Reactive Protein (CRP) and MS phenotypes at population level. Subjects and Methods:Serum hepcidin-25 levels measured by Mass Spectrometry were analyzed in 941 subjects for whom complete data allowing classification of MS according to NLHBI criteria (fasting glucose ≥100 mg/dl or antidiabetes medication; blood pressure ≥135/85 mmHg or antihypertensive medication; triglycerides ≥150 mg/dl; HDL cholesterol <40 mg/dl in men and < 50 mg/dl in women; and obesity) and CRP levels were available. MS was defined by having ≥3 of the above criteria. Due to the known important gender differences in hepcidin levels (Traglia M et al. J Med Genet 2011), multivariate analyses were done separately in males (n=400, 21.8% with MS) and females (n=541, 18.5% with MS). Main Results:Serum hepcidin-25 levels increased linearly with the increasing number of MS traits in males (ANOVA: F=6.8, P=0.009) and, even more strongly, in females (ANOVA: F=35.2, P<0.001). This trends paralleled those of serum ferritin levels in both genders. In multivariate analyses adjusted for age and SNP rs1800562 (C282Y mutation in the HFE gene), the inclusion of ferritin in males abolished but in females only reduced the association of hepcidin with MS. On the contrary, CRP did not influence the same association in both genders. Regarding the single MS criteria, the strongest association of hepcidin were observed with body mass index, triglycerides, and fasting blood glucose (P<0.001 for all three) in females. Conclusions:Hepcidin levels are strongly associated with MS features at population level, independently of subclinical inflammation. This association appears to reflect a response to increasing iron stores in males, while in females some MS traits may directly influence hepcidin levels. Disclosures:No relevant conflicts of interest to declare.

Dysmetabolic hyperferritinemia is associated with normal transferrin saturation, mild hepatic iron overload, and elevated hepcidin

Hyperferritinemia is common in individuals with the metabolic syndrome (dysmetabolic hyperferritinemia), but its pathophysiology and the degree to which it reflects tissue iron overload remains unclear. We conducted a cross-sectional study evaluating ten cases with dysmetabolic hyperferritinemia for liver iron overload and compared their serum iron indices and urine hepcidin levels to healthy controls. Seven out of ten cases had mild hepatic iron overload by magnetic resonance imaging (MRI) (median, 75 micromol/g dry weight). Cases had higher serum ferritin than controls (median, 672 microg/L vs. 105 microg/L, p < 0.001), but the median transferrin saturation was not significantly different (38% vs. 36%, p = 0.5). Urinary hepcidin was elevated in dysmetabolic hyperferritinemia (median; 1,584 g/mg of creatinine vs. 799 ng/mg of creatinine, p = 0.05). Dysmetabolic hyperferritinemia is characterized by hyperferritinemia with normal transferrin saturation, elevated hepcidin levels, and mild liver iron overload in a subset of patients.

Altered Hepcidin Regulation in Hereditary Hemochromatosis and Dysmetabolic Hyperferritinemia.

Hepcidin, the key iron-regulatory hormone synthesized by the liver, blocks iron absorption in duodenum and iron recycling from macrophages. Hepcidin dysregulation is implicated in the pathogenesis of several iron disorders. Hepcidin deficiency was observed in most types of hereditary hemochromatosis, including the HFE-related hemochromatosis, where decreased levels of hepcidin mRNA were found in patients with HFE mutations and in mice lacking HFE. However, levels of the bioactive hepcidin peptide in this disease have not been evaluated. We analyzed urinary hepcidin concentrations in a large cohort of patients with hepatic diseases associated with iron dysregulation, including untreated and treated HFE hemochromatosis (HH), dysmetabolic hyperferritinemia (DYSH) and alcoholic cirrhosis (AC). In untreated HH patients (n=33), hepcidin levels were marginally increased in comparison to controls (n=71). However, the hepcidin/ferritin ratio, an index of appropriateness of hepcidin response to iron load, was decreased in untreated HH group compared to controls, suggesting that hepcidin levels were inappropriately low for the degree of iron loading.In treated HH patients (n=41), hepcidin levels were decreased when compared to either controls or untreated HH group, but the hepcidin/ferritin ratio was not statistically different from the control group ratio. Since hemoglobin levels in the iron-depleted HH group remained unchanged, hepcidin decrease is likely not related to hypoxia, but rather demonstrates partial responsiveness to changes in iron stores.In alcoholic cirrhosis (n=43), hepcidin levels were decreased when compared to controls which may be due to decreased hemoglobin levels observed in these patients and to the replacement of hepcidin-producing hepatocytes by scar tissue. Patients with DYSH (n=40) had increased hepcidin levels in comparison to the controls. Although the underlying cause is yet unclear, the increased hepcidin levels in DYSH could be a contributing factor for the characteristic iron accumulation in both macrophages and parenchymal cells, similar to anemia of chronic diseases.Our study suggests that dysregulation of hepcidin is a likely cause of iron metabolism abnormalities in HH and in DYSH.

Dépistage de l'hémochromatose chez 120 sujets consultant pour une asthénie chronique

Aim. – Chronic fatigue is the more frequent symptom identified in the course of hereditary haemochromatosis. A screening for this disorder was carried out in 120 primary care patients consulting for unexplained chronic fatigue. Subjects and methods. – Transferrin saturation and serum ferritin were determined in all patients. If transferrin saturation was ≥ 45% and serum ferritin ≥ 300 μg/l, HFE1 genotyping for mutations C282Y and H63D was completed. Results. – One hundred and twenty patients were recruited, 19–86 years old, including 62 males and 58 females. 45 patients (38%) presented with serum ferritin ≥ 300 μg/l. Thirty two patients (27%) presented with transferrin saturation ≥ 45%. Twenty two patients (18%) presented with these two pathological values. Four C282Y/H63D compound heterozygous, one H63D/H63D homozygous, and eight simplex heterozygous (6 H63D and 2 C282Y) genotypes were found. Patients with serum ferritin ≥ 300 μg/l were predominantly male (89%), older (57 year) and plethoric (BMI: 26.4) corresponding mainly to dysmetabolic hyperferritinemia. Conclusion. – None of these 120 patients consulting for unexplained chronic fatigue was found with hereditary haemochromatosis. Therefore observed prevalence is 0, with upper limit of 95% confidence interval at 2.5%. But the high prevalence (38%) of serum ferritin ≥ 300 μg/l must be emphasized, corresponding usually to dysmetabolic hyperferritinemia.