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1.
BMC Nephrol ; 24(1): 20, 2023 01 25.
Article in English | MEDLINE | ID: mdl-36698076

ABSTRACT

BACKGROUND: Hepcidin is considered to play a central role in the pathophysiology of renal anemia. Recent studies in healthy individuals have demonstrated a suppressive effect of vitamin D (VD) on the expression of hepcidin. In this post-hoc analysis based on a randomized controlled study, we evaluated the effect of supplementing chronic kidney disease (CKD) patients (stage G3-G4) with a high daily dose of native VD on serum levels of hepcidin-25, the hepcidin/ferritin ratio, as well as on markers of erythropoiesis. METHODS: Patients with CKD stage G3-G4 included in a double blind, randomized, placebo (PBO) controlled study with available hepcidin measurements were analyzed. Study subjects received either 8000 international units (IU) of cholecalciferol daily or PBO for 12 weeks. We evaluated the change in markers of hepcidin expression, erythropoiesis, and iron status from baseline to week 12 and compared the change between the groups. RESULTS: Eighty five patients completed the study. Calcitriol, but not 25-hydroxyvitamin D (25(OH) D), was inversely correlated with serum levels of hepcidin-25 (rho = -0,38; p = < 0, 01 and rho = -0,02; p = 0, 89, respectively) at baseline. Supplementation with VD significantly raised the serum concentration of serum 25(OH)D in the treatment group (from 54 (39-71) to 156 (120-190) nmol/L; p = < 0, 01)) but had no effect on any of the markers of hepcidin, erythropoiesis, or iron status in the entire cohort. However, we did observe an increase in hemoglobin (HB) levels and transferrin saturation (TSAT) as compared to the PBO group in a subgroup of patients with low baseline 25(OH)D levels (< 56 nmol/L). In contrast, in patients with high baseline 25(OH)D values (≥ 56 nmol/L), VD supplementation associated with a decrease in HB levels and TSAT (p = 0,056) within the VD group in addition to a decrease in hepcidin levels as compared to the PBO group. CONCLUSION: High-dose VD supplementation had no discernible effect on markers of hepcidin or erythropoiesis in the entire study cohort. However, in patients with low baseline 25(OH)D levels, high-dose VD supplementation associated with beneficial effects on erythropoiesis and iron availability. In contrast, in patients with elevated baseline 25(OH)D levels, high-dose VD supplementation resulted in a decrease in hepcidin levels, most likely due to a deterioration in iron status.


Subject(s)
Renal Insufficiency, Chronic , Vitamin D Deficiency , Humans , Hepcidins , Erythropoiesis , Vitamins/therapeutic use , Vitamin D/therapeutic use , Iron , Cholecalciferol/therapeutic use , Dietary Supplements
2.
BMC Gastroenterol ; 18(1): 78, 2018 Jun 05.
Article in English | MEDLINE | ID: mdl-29871592

ABSTRACT

BACKGROUND: One-third of patients with non-alcoholic fatty liver disease (NAFLD) develop dysmetabolic iron overload syndrome (DIOS), the pathogenesis of which is unknown. Altered production of the iron-regulatory peptide hepcidin has been reported in NAFLD, but it is unclear if this is related to iron accumulation, lipid status or steatohepatitis. METHODS: Eighty-four patients with liver disease, 54 of which had iron overload, underwent liver biopsy (n = 66) and/or magnetic resonance imaging (n = 35) for liver iron content determination. Thirty-eight of the patients had NAFLD, 29 had chronic liver disease other than NAFLD, and 17 had untreated genetic hemochromatosis. Serum hepcidin was measured with ELISA in all patients and in 34 controls. Hepcidin antimicrobial peptide (HAMP) mRNA in liver tissue was determined with real-time-quantitative PCR in 36 patients. RESULTS: Serum hepcidin was increased similarly in NAFLD with DIOS as in the other chronic liver diseases with iron overload, except for genetic hemochromatosis. HAMP mRNA in liver tissue, and serum hepcidin, both correlated to liver iron content in NAFLD patients (r2 = 0.45, p < 0.05 and r2 = 0.27, p < 0.05 respectively) but not to body mass index, NAFLD activity score or serum lipids. There was a good correlation between HAMP mRNA in liver tissue and serum hepcidin (r2 = 0.39, p < 0.01). CONCLUSIONS: In NAFLD with or without dysmetabolic iron overload, serum hepcidin and HAMP mRNA in liver correlate to body iron content but not to the degree of steatohepatitis or lipid status. Thus, the dysmetabolic iron overload syndrome seen in NAFLD is not caused by an altered hepcidin synthesis.


Subject(s)
Hepcidins/blood , Iron/metabolism , Liver/metabolism , Non-alcoholic Fatty Liver Disease/metabolism , Adult , Aged , Biopsy , Body Mass Index , Chronic Disease , Female , Ferritins/blood , Gene Expression , Hemochromatosis/metabolism , Hepcidins/genetics , Hepcidins/metabolism , Humans , Iron Overload/metabolism , Lipids/blood , Liver/diagnostic imaging , Liver/pathology , Liver Diseases/metabolism , Magnetic Resonance Imaging , Male , Middle Aged , Non-alcoholic Fatty Liver Disease/genetics , RNA, Messenger/metabolism , Transferrin/metabolism
3.
Blood Cells Mol Dis ; 68: 35-42, 2018 02.
Article in English | MEDLINE | ID: mdl-27816428

ABSTRACT

BACKGROUND: The storage of glucosylceramide in macrophages produces an inflammatory response in Gaucher disease type 1 (GD1) resulting in iron metabolism dysregulation and cytokine release. PATIENTS AND METHODS: The study included 16 adults with GD1 aged 20-86years. All but one patient carried at least one allele with the c.1226A>G (N370S) mutation in the GBA1 gene. Ferritinemia, iron metabolism profiles including hepcidin, and inflammatory cytokine concentrations were assessed in GD1 patients in Sweden. RESULTS: Hyperferritinemia was present in 81% of patients. There was no correlation between hyperferritinemia and patient's gender, spleen status, or clinical status. Hepcidin was discrepantly low in relation to ferritin levels. TNF-α was moderately increased in 5 of 11 patients; 2 patients with the highest TNF-α concentrations showed mildly elevated IL-6 levels. The concentrations of IL-1ß, IL-8, and IL-10 were normal in all patients. Upon treatment, ferritinemia ameliorated but S-ferritin levels did not normalize. The increased TNF-α level however, normalized in all treated patients, reaching the lowest values after 2years of therapy and continued to be stable during the remaining 2years of follow-up. CONCLUSIONS: Hyperferritinemia is a frequent finding in GD1 in Sweden. The relatively low hepcidin levels reveal a distorted relationship between hepcidin and ferritin in GD1. Therapy has the potential to not only ameliorate hyperferritinemia but to also normalize the serum TNF-α concentration in GD1.


Subject(s)
Cytokines/blood , Ferritins/blood , Gaucher Disease/blood , Gaucher Disease/complications , Iron Overload/blood , Iron Overload/complications , Adult , Aged , Aged, 80 and over , Female , Gaucher Disease/epidemiology , Hepcidins/blood , Humans , Iron Overload/epidemiology , Male , Middle Aged , Sweden/epidemiology , Tumor Necrosis Factor-alpha/blood , Young Adult
4.
Scand J Clin Lab Invest ; 75(8): 652-8, 2015.
Article in English | MEDLINE | ID: mdl-26264426

ABSTRACT

BACKGROUND: Hepcidin-25 is a potential marker for iron disorders with a demand for accessible assays. This study aimed to evaluate a commercial competitive enzyme-linked immunosorbent assay (cELISA) for hepcidin quantitation. METHODS: Serum samples; 95 healthy subjects (HS), six patients with iron deficiency (ID), 84 patients with liver disorders (LD) and 220 hemodialysis patients (HD), were analyzed. Controls were used for imprecision, while accuracy was evaluated by quantitating hepcidin-25 with LC-MS/MS in 149 samples. Cross-reactivity for hepcidin-20 and hepcidin-22 was tested. Hepcidin-mRNA expression in 37 liver biopsies was measured. RESULTS: S-hepcidin ranged from 8-76 and 2-31 µg/L in healthy men and women. Levels in ID, LD and HD significantly differed from HS. Total coefficients of variation (CV) for controls were 24% and 22%. Within-sample CV was 10%. Despite a good correlation with LC-MS/MS (r = 0.89), the cELISA showed higher values and detected hepcidin-20 and hepcidin-22. Hepcidin-mRNA correlated well with S-hepcidin using cELISA and LC-MS/MS (r = 0.69 and 0.64). CONCLUSIONS: The correlation with LC-MS/MS is good and the examined kit can differentiate between patient groups although it is not specific for hepcidin-25. Considering ELISA's capacity to readily be set up, the investigated kit can be applied. Specific reference ranges are required.


Subject(s)
Hepcidins/blood , Adult , Aged , Blood Chemical Analysis , Case-Control Studies , Enzyme-Linked Immunosorbent Assay , Female , Hepcidins/genetics , Humans , Kidney Failure, Chronic/blood , Limit of Detection , Liver/metabolism , Liver Diseases/blood , Male , Middle Aged , RNA, Messenger/metabolism , Tandem Mass Spectrometry , Young Adult
5.
Hum Mutat ; 35(1): 15-26, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24115288

ABSTRACT

Congenital erythrocytosis (CE), or congenital polycythemia, represents a rare and heterogeneous clinical entity. It is caused by deregulated red blood cell production where erythrocyte overproduction results in elevated hemoglobin and hematocrit levels. Primary congenital familial erythrocytosis is associated with low erythropoietin (Epo) levels and results from mutations in the Epo receptor gene (EPOR). Secondary CE arises from conditions causing tissue hypoxia and results in increased Epo production. These include hemoglobin variants with increased affinity for oxygen (HBB, HBA mutations), decreased production of 2,3-bisphosphoglycerate due to BPGM mutations, or mutations in the genes involved in the hypoxia sensing pathway (VHL, EPAS1, and EGLN1). Depending on the affected gene, CE can be inherited either in an autosomal dominant or recessive mode, with sporadic cases arising de novo. Despite recent important discoveries in the molecular pathogenesis of CE, the molecular causes remain to be identified in about 70% of the patients. With the objective of collecting all the published and unpublished cases of CE the COST action MPN&MPNr-Euronet developed a comprehensive Internet-based database focusing on the registration of clinical history, hematological, biochemical, and molecular data (http://www.erythrocytosis.org/). In addition, unreported mutations are also curated in the corresponding Leiden Open Variation Database.


Subject(s)
Databases, Genetic , Genetic Predisposition to Disease , Mutation , Polycythemia/congenital , Receptors, Erythropoietin/genetics , Cell Hypoxia/genetics , Erythropoietin/metabolism , Humans , Internet , Polycythemia/genetics , Polycythemia/metabolism , Signal Transduction/genetics
6.
Clin Kidney J ; 7(3): 275-81, 2014 Jun.
Article in English | MEDLINE | ID: mdl-25852889

ABSTRACT

BACKGROUND: Inflammation impairs erythropoiesis, iron availability and is associated with a higher mortality risk in patients with end-stage renal disease. We studied the associations between Delta-He [the difference between the reticulocyte haemoglobin content (Ret-He) and erythrocyte haemoglobin content], a suggested marker of iron availability, and markers of inflammation, iron status, response to erythropoiesis-stimulating agents (ESAs) and mortality in prevalent peritoneal dialysis (PD) patients. METHODS: Eighty-two PD patients were followed weekly for 12 weeks with an additional follow-up of 36 months. Delta-He, Ret-He and high-sensitivity C-reactive protein (hs-CRP) were measured weekly and interleukin-6 (IL-6) and iron markers every fourth week. Mortality risk was assessed by Cox proportional hazards model adjusting for potential confounding factors. The relationships between ESA response, inflammatory markers, iron markers and Delta-He were evaluated in the PD patients. The relationship between Delta-He and iron markers was analysed in 87 healthy subjects. RESULTS: Delta-He correlated with IL-6 (rho = 0.48, P < 0.001), hs-CRP (rho = 0.36, P < 0.001) and ESA hyporesponsivess index (EHRI; rho = -0.44, P < 0.001) in the PD patients. Delta-He did not correlate with iron markers in PD patients nor in healthy subjects. The mean Delta-He levels were significantly different between the tertiles of EHRI (P < 0.01). Delta-He was associated with all-cause mortality risk in PD patients after adjusting for age, gender, hs-CRP, comorbidity and nutritional status [OR 0.70 (0.51-0.96), P < 0.05]. CONCLUSIONS: Delta-He independently predicts all-cause mortality in PD patients after adjusting for potential confounders and is a predictor of ESA response in PD patients.

8.
Hemoglobin ; 33(2): 137-42, 2009.
Article in English | MEDLINE | ID: mdl-19373590

ABSTRACT

A new beta-hemoglobin (Hb) variant, Hb Stockholm [beta7(A4)GluAsp], is described. The variant was characterized by mass spectrometry and DNA sequencing. The new variant is clinically silent but interferes with Hb A(1c) quantification using ion exchange chromatography, causing a falsely low Hb A(1c) level when using the Bio-Rad VARIANT II System.


Subject(s)
Hemoglobin A/analysis , Hemoglobins, Abnormal/genetics , beta-Globins/analysis , beta-Globins/genetics , Hemoglobins, Abnormal/analysis , Humans , Mutation , Spectrometry, Mass, Electrospray Ionization
9.
J Nephrol ; 17(4): 525-30, 2004.
Article in English | MEDLINE | ID: mdl-15372414

ABSTRACT

BACKGROUND: The optimal subcutaneous (SC) epoetin alfa strategy is unestablished. The individual variability in dose requirements needs consideration. In this study, prolonged intervals were assessed in relation to varying dose requirements. METHODS: The study included 153 hemodialysis (HD) patients on stable SC epoetin alfa. Based on dose requirements, the patients received either 4,000 U (group I, n=51) or 10,000 U (group II, n=102) as whole 1 mL vials at prolonged intervals. The study comprised three 8-week periods: an initial period maintaining the basal regimens, an adjustment period where the intervals were prolonged, and a maintenance period. Alterations in hemoglobin (Hb), weekly doses and intervals in each group were compared. RESULTS: One hundred and thirty-seven patients completed the study (48 in group I and 89 in group II). In group I, the mean interval was prolonged from 5.4 +/- 1.9 to 7.8 +/- 3.1 days (p=0,01) with stable Hb and EPO doses. In group II, prolonged intervals were associated with a reduction in mean Hb below target level and a significant increase in EPO doses (p=0,002). Iron deficiency and inflammation could explain the poor response in approximately one-third of the patients. CONCLUSIONS: In HD patients, the optimal injection frequency should be individually adjusted. Prolonged intervals can be applied to patients with low-dose requirements. Observing iron status and inflammation is necessary for optimal response.


Subject(s)
Anemia, Hypochromic/drug therapy , Erythropoietin/administration & dosage , Kidney Failure, Chronic/therapy , Renal Dialysis/adverse effects , Aged , Anemia, Hypochromic/etiology , Dose-Response Relationship, Drug , Drug Administration Schedule , Epoetin Alfa , Female , Follow-Up Studies , Hemoglobins/drug effects , Humans , Injections, Subcutaneous , Kidney Failure, Chronic/diagnosis , Male , Middle Aged , Prospective Studies , Recombinant Proteins , Renal Dialysis/methods , Risk Assessment , Sweden , Treatment Outcome
11.
Br J Haematol ; 120(5): 853-9, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12614222

ABSTRACT

Parenteral iron-polysaccharide complexes are increasingly applied. The pharmacokinetics of iron sucrose have been assessed by our group using positron emission tomography (PET). A single intravenous injection of 100 mg iron as iron (III) hydroxide-polymaltose complex, labelled with a tracer in the form of 52Fe/59Fe, was similarly assessed in six patients using PET for about 8 h. Red cell utilization was followed for 4 weeks. Iron polymaltose was similarly distributed to the liver, spleen and bone marrow. However, a larger proportion of this complex was rapidly distributed to the bone marrow. The shorter equilibration phase for the liver, about 25 min, indicates the minimal role of the liver for direct distribution. Splenic uptake also reflected the reticuloendothelial handling of this complex. Red cell utilization ranged from 61% to 99%. Despite the relatively higher uptake by the bone marrow, there was no saturation of marrow transport systems at this dose level. In conclusion, high red cell utilization of iron polymaltose occurred in anaemic patients. The major portion of the injected dose was rapidly distributed to the bone marrow. In addition, the reticuloendothelial uptake of this complex may reflect the safety of polysaccharide complexes. Non-saturation of transport systems to the bone marrow indicated the presence of a large interstitial transport pool, which might possibly be transferrin.


Subject(s)
Anemia/metabolism , Erythrocytes/metabolism , Ferric Compounds/pharmacokinetics , Adult , Aged , Female , Ferric Oxide, Saccharated , Follow-Up Studies , Glucaric Acid , Hemoglobins/analysis , Humans , Iron Radioisotopes , Liver/metabolism , Male , Middle Aged , Reticulocyte Count , Spleen/metabolism , Tomography, Emission-Computed
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