Search tips
Search criteria

Results 1-25 (1776582)

Clipboard (0)

Related Articles

1.  Comparative evaluation of the effects of treatment with tocilizumab and TNF-α inhibitors on serum hepcidin, anemia response and disease activity in rheumatoid arthritis patients 
Arthritis Research & Therapy  2013;15(5):R141.
Anemia of inflammation (AI) is a common complication of rheumatoid arthritis (RA) and has a negative impact on RA symptoms and quality of life. Upregulation of hepcidin by inflammatory cytokines has been implicated in AI. In this study, we evaluated and compared the effects of IL-6 and TNF-α blocking therapies on anemia, disease activity, and iron-related parameters including serum hepcidin in RA patients.
Patients (n = 93) were treated with an anti-IL-6 receptor antibody (tocilizumab) or TNF-α inhibitors for 16 weeks. Major disease activity indicators and iron-related parameters including serum hepcidin-25 were monitored before and 2, 4, 8, and 16 weeks after the initiation of treatment. Effects of tocilizumab and infliximab (anti-TNF-α antibody) on cytokine-induced hepcidin expression in hepatoma cells were analyzed by quantitative real-time PCR.
Anemia at base line was present in 66% of patients. Baseline serum hepcidin-25 levels were correlated positively with serum ferritin, C-reactive protein (CRP), vascular endothelial growth factor (VEGF) levels and Disease Activity Score 28 (DAS28). Significant improvements in anemia and disease activity, and reductions in serum hepcidin-25 levels were observed within 2 weeks in both groups, and these effects were more pronounced in the tocilizumab group than in the TNF-α inhibitors group. Serum hepcidin-25 reduction by the TNF-α inhibitor therapy was accompanied by a decrease in serum IL-6, suggesting that the effect of TNF-α on the induction of hepcidin-25 was indirect. In in vitro experiments, stimulation with the cytokine combination of IL-6+TNF-α induced weaker hepcidin expression than did with IL-6 alone, and this induction was completely suppressed by tocilizumab but not by infliximab.
Hepcidin-mediated iron metabolism may contribute to the pathogenesis of RA-related anemia. In our cohort, tocilizumab was more effective than TNF-α inhibitors for improving anemia and normalizing iron metabolism in RA patients by inhibiting hepcidin production.
PMCID: PMC3978580  PMID: 24286116
2.  Rapidly Escalating Hepcidin and Associated Serum Iron Starvation Are Features of the Acute Response to Typhoid Infection in Humans 
PLoS Neglected Tropical Diseases  2015;9(9):e0004029.
Iron is a key pathogenic determinant of many infectious diseases. Hepcidin, the hormone responsible for governing systemic iron homeostasis, is widely hypothesized to represent a key component of nutritional immunity through regulating the accessibility of iron to invading microorganisms during infection. However, the deployment of hepcidin in human bacterial infections remains poorly characterized. Typhoid fever is a globally significant, human-restricted bacterial infection, but understanding of its pathogenesis, especially during the critical early phases, likewise is poorly understood. Here, we investigate alterations in hepcidin and iron/inflammatory indices following experimental human typhoid challenge.
Methodology/Principal Findings
Fifty study participants were challenged with Salmonella enterica serovar Typhi and monitored for evidence of typhoid fever. Serum hepcidin, ferritin, serum iron parameters, C-reactive protein (CRP), and plasma IL-6 and TNF-alpha concentrations were measured during the 14 days following challenge. We found that hepcidin concentrations were markedly higher during acute typhoid infection than at baseline. Hepcidin elevations mirrored the kinetics of fever, and were accompanied by profound hypoferremia, increased CRP and ferritin, despite only modest elevations in IL-6 and TNF-alpha in some individuals. During inflammation, the extent of hepcidin upregulation associated with the degree of hypoferremia.
We demonstrate that strong hepcidin upregulation and hypoferremia, coincident with fever and systemic inflammation, are hallmarks of the early innate response to acute typhoid infection. We hypothesize that hepcidin-mediated iron redistribution into macrophages may contribute to S. Typhi pathogenesis by increasing iron availability for macrophage-tropic bacteria, and that targeting macrophage iron retention may represent a strategy for limiting infections with macrophage-tropic pathogens such as S. Typhi.
Author Summary
An adequate supply of iron is essential for both human hosts and their infecting pathogens. Hepcidin is the human hormone that controls the quantity and distribution of iron throughout the body. During infections, hepcidin activity may redistribute iron away from serum and into macrophages, potentially affecting pathogen replication, depending on the niche of the invading microbe. However, the involvement of hepcidin in human bacterial infections remains poorly investigated. Similarly, the pathogenesis of typhoid fever, caused by infection with Salmonella Typhi is also poorly understood. We therefore investigated the behaviour of hepcidin and other iron/inflammation-related parameters during the course of typhoid fever in human volunteers challenged experimentally with Salmonella Typhi. Hepcidin concentrations rose rapidly during acute typhoid infection, in parallel with fever. Hepcidin induction was accompanied by a rapid decline in serum iron concentrations, likely reflecting iron sequestration in macrophages (a preferred replication site of Salmonella Typhi). The extent of hepcidin upregulation associated with the extent of serum iron starvation. We hypothesize that hepcidin activity during acute typhoid infection in humans may elevate iron levels in the niche used by the pathogen for replication. Targeting macrophage iron retention should be evaluated as a potential strategy for limiting typhoid fever.
PMCID: PMC4578949  PMID: 26394303
3.  Hepcidin-25 in Chronic Hemodialysis Patients Is Related to Residual Kidney Function and Not to Treatment with Erythropoiesis Stimulating Agents 
PLoS ONE  2012;7(7):e39783.
Hepcidin-25, the bioactive form of hepcidin, is a key regulator of iron homeostasis as it induces internalization and degradation of ferroportin, a cellular iron exporter on enterocytes, macrophages and hepatocytes. Hepcidin levels are increased in chronic hemodialysis (HD) patients, but as of yet, limited information on factors associated with hepcidin-25 in these patients is available. In the current cross-sectional study, potential patient-, laboratory- and treatment-related determinants of serum hepcidin-20 and -25, were assessed in a large cohort of stable, prevalent HD patients. Baseline data from 405 patients (62% male; age 63.7±13.9 [mean SD]) enrolled in the CONvective TRAnsport STudy (CONTRAST; NCT00205556) were studied. Predialysis hepcidin concentrations were measured centrally with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Patient-, laboratory- and treatment related characteristics were entered in a backward multivariable linear regression model. Hepcidin-25 levels were independently and positively associated with ferritin (p<0.001), hsCRP (p<0.001) and the presence of diabetes (p = 0.02) and inversely with the estimated glomerular filtration rate (p = 0.01), absolute reticulocyte count (p = 0.02) and soluble transferrin receptor (p<0.001). Men had lower hepcidin-25 levels as compared to women (p = 0.03). Hepcidin-25 was not associated with the maintenance dose of erythropoiesis stimulating agents (ESA) or iron therapy. In conclusion, in the currently studied cohort of chronic HD patients, hepcidin-25 was a marker for iron stores and erythropoiesis and was associated with inflammation. Furthermore, hepcidin-25 levels were influenced by residual kidney function. Hepcidin-25 did not reflect ESA or iron dose in chronic stable HD patients on maintenance therapy. These results suggest that hepcidin is involved in the pathophysiological pathway of renal anemia and iron availability in these patients, but challenges its function as a clinical parameter for ESA resistance.
PMCID: PMC3396629  PMID: 22808058
4.  Tubular reabsorption and local production of urine hepcidin-25 
BMC Nephrology  2013;14:70.
Hepcidin is a central regulator of iron metabolism. Serum hepcidin levels are increased in patients with renal insufficiency, which may contribute to anemia. Urine hepcidin was found to be increased in some patients after cardiac surgery, and these patients were less likely to develop acute kidney injury. It has been suggested that urine hepcidin may protect by attenuating heme-mediated injury, but processes involved in urine hepcidin excretion are unknown.
To assess the role of tubular reabsorption we compared fractional excretion (FE) of hepcidin-25 with FE of β2-microglobulin (β2m) in 30 patients with various degrees of tubular impairment due to chronic renal disease. To prove that hepcidin is reabsorbed by the tubules in a megalin-dependent manner, we measured urine hepcidin-1 in wild-type and kidney specific megalin-deficient mice. Lastly, we evaluated FE of hepcidin-25 and β2m in 19 patients who underwent cardiopulmonary bypass surgery. Hepcidin was measured by a mass spectrometry assay (MS), whereas β2m was measured by ELISA.
In patients with chronic renal disease, FE of hepcidin-25 was strongly correlated with FE of β2m (r = 0.93, P <0.01). In megalin-deficient mice, urine hepcidin-1 was 7-fold increased compared to wild-type mice (p < 0.01) indicating that proximal tubular reabsorption occurs in a megalin- dependent manner. Following cardiac surgery, FE of hepcidin-25 increased despite a decline in FE of β2m, potentially indicating local production at 12–24 hours.
Hepcidin-25 is reabsorbed by the renal tubules and increased urine hepcidin-25 levels may reflect a reduction in tubular uptake. Uncoupling of FE of hepcidin-25 and β2m in cardiac surgery patients suggests local production.
PMCID: PMC3623618  PMID: 23531037
AKI; β2-microglobulin; Hepcidin; Megalin; Kidney tubules
5.  Hepcidin-25 in Diabetic Chronic Kidney Disease Is Predictive for Mortality and Progression to End Stage Renal Disease 
PLoS ONE  2015;10(4):e0123072.
Anemia is common and is associated with impaired clinical outcomes in diabetic chronic kidney disease (CKD). It may be explained by reduced erythropoietin (EPO) synthesis, but recent data suggest that EPO-resistance and diminished iron availability due to inflammation contribute significantly. In this cohort study, we evaluated the impact of hepcidin-25—the key hormone of iron-metabolism—on clinical outcomes in diabetic patients with CKD along with endogenous EPO levels.
249 diabetic patients with CKD of any stage, excluding end-stage renal disease (ESRD), were enrolled (2003–2005), if they were not on EPO-stimulating agent and iron therapy. Hepcidin-25 levels were measured by radioimmunoassay. The association of hepcidin-25 at baseline with clinical variables was investigated using linear regression models. All-cause mortality and a composite endpoint of CKD progression (ESRD or doubling of serum creatinine) were analyzed by Cox proportional hazards models.
Patients (age 67 yrs, 53% male, GFR 51 ml/min, hemoglobin 131 g/L, EPO 13.5 U/L, hepcidin-25 62.0 ng/ml) were followed for a median time of 4.2 yrs. Forty-nine patients died (19.7%) and forty (16.1%) patients reached the composite endpoint. Elevated hepcidin levels were independently associated with higher ferritin-levels, lower EPO-levels and impaired kidney function (all p<0.05). Hepcidin was related to mortality, along with its interaction with EPO, older age, greater proteinuria and elevated CRP (all p<0.05). Hepcidin was also predictive for progression of CKD, aside from baseline GFR, proteinuria, low albumin- and hemoglobin-levels and a history of CVD (all p<0.05).
We found hepcidin-25 to be associated with EPO and impaired kidney function in diabetic CKD. Elevated hepcidin-25 and EPO-levels were independent predictors of mortality, while hepcidin-25 was also predictive for progression of CKD. Both hepcidin-25 and EPO may represent important prognostic factors of clinical outcome and have the potential to further define “high risk” populations in CKD.
PMCID: PMC4404250  PMID: 25894587
6.  Serum Hepcidin Predicts Uremic Accelerated Atherosclerosis in Chronic Hemodialysis Patients with Diabetic Nephropathy 
Chinese Medical Journal  2015;128(10):1351-1357.
Hepcidin, as a regulator of body iron stores, has been recently discovered to play a critical role in the pathogenesis of anemia of chronic disease. Atherosclerotic cardiovascular disease is the most common complication and the leading cause of death in chronic hemodialysis (CHD) patients. In the current study, we aimed to explore the relationship between serum hepcidin and uremic accelerated atherosclerosis (UAAS) in CHD patients with diabetic nephropathy (CHD/DN).
A total of 78 CHD/DN and 86 chronic hemodialyzed nondiabetic patients with chronic glomerulonephritis (CHD/non-DN) were recruited in this study. The level of serum hepcidin-25 was specifically measured by liquid chromatography-tandem mass spectrometry. Serum levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were measured by enzyme-linked immunosorbent assay.
High serum level of hepcidin-25 was seen in CHD patients. Serum hepcidin-25 in CHD/DN was significantly higher than that in CHD/non-DN patients. Serum hepcidin-25 was positively correlated with ferritin, high-sensitivity C-reactive protein (hs-CRP), TNF-α, and IL-6 in CHD/DN patients. CHD/DN patients exhibited higher common carotid artery intima media thickness (CCA-IMT), hs-CRP, and hepcidin-25 levels than that in CHD/non-DN patients. Moreover, in CHD/DN patients, CCA-IMT was positively correlated with serum hepcidin, hs-CRP, and low-density lipoprotein-cholesterol. On multiple regression analysis, serum hepcidin and hs-CRP level exhibited independent association with IMT in CHD/DN patients.
These findings suggest possible linkage between iron metabolism and hepcidin modulation abnormalities that may contribute to the development of UAAS in CHD/DN patients.
PMCID: PMC4830316  PMID: 25963357
Atherosclerosis; Hemodialysis; Hepcidin; Iron Status
7.  The Relation of Hepcidin to Iron Disorders, Inflammation and Hemoglobin in Chronic Kidney Disease 
PLoS ONE  2014;9(6):e99781.
The metabolism of hepcidin is profoundly modified in chronic kidney disease (CKD). We investigated its relation to iron disorders, inflammation and hemoglobin (Hb) level in 199 non-dialyzed, non-transplanted patients with CKD stages 1–5. All had their glomerular filtration rate measured by 51Cr-EDTA renal clearance (mGFR), as well as measurements of iron markers including hepcidin and of erythropoietin (EPO). Hepcidin varied from 0.2 to 193 ng/mL. The median increased from 23.3 ng/mL [8.8–28.7] to 36.1 ng/mL [14.1–92.3] when mGFR decreased from ≥60 to <15 mL/min/1.73 m2 (p = 0.02). Patients with absolute iron deficiency (transferrin saturation (TSAT) <20% and ferritin <40 ng/mL) had the lowest hepcidin levels (5.0 ng/mL [0.7–11.7]), and those with a normal iron profile (TSAT ≥20% and ferritin ≥40), the highest (34.5 ng/mL [23.7–51.6]). In multivariate analysis, absolute iron deficiency was associated with lower hepcidin values, and inflammation combined with a normal or functional iron profile with higher values, independent of other determinants of hepcidin concentration, including EPO, mGFR, and albuminemia. The hepcidin level, although it rose overall when mGFR declined, collapsed in patients with absolute iron deficiency. There was a significant interaction with iron status in the association between Hb and hepcidin. Except in absolute iron deficiency, hepcidin’s negative association with Hb level indicates that it is not down-regulated in CKD anemia.
PMCID: PMC4076189  PMID: 24978810
8.  Serum Hepcidin Levels and Reticulocyte Hemoglobin Concentrations as Indicators of the Iron Status of Peritoneal Dialysis Patients 
Hepcidin is the key mediator of renal anemia, and reliable measurement of serum hepcidin levels has been made possible by the ProteinChip system. We therefore investigated the iron status and serum hepcidin levels of peritoneal dialysis (PD) patients who had not received frequent doses of an erythrocytosis-stimulating agent (ESA) and had not received iron therapy. In addition to the usual iron parameters, the iron status of erythrocytes can be determined by measuring reticulocyte hemoglobin (RET-He). The mean serum hepcidin level of the PD patients (n = 52) was 80.7 ng/mL. Their serum hepcidin levels were significantly positively correlated with their serum ferritin levels and transferrin saturation (TSAT) levels, but no correlations were found between their serum hepcidin levels and RET-He levels, thereby suggesting that hepcidin has no effect on the iron dynamics of reticulocytes. Since low serum levels of CRP and IL-6, biomarkers of inflammation, were not correlated with the serum hepcidin levels, there is likely to be a threshold for induction of hepcidin expression by inflammation.
PMCID: PMC3501962  PMID: 23193472
9.  The role of vitamin D in regulating the iron-hepcidin-ferroportin axis in monocytes 
Chronic kidney disease affects 40% of adults aged 65 and older. Anemia of CKD is present in 30% of patients with CKD and is associated with increased cardiovascular risk, decreased quality of life, and increased mortality. Hepcidin-25 (hepcidin), the key iron regulating hormone, prevents iron egress from macrophages and thus prevents normal recycling of the iron needed to support erythropoiesis. Hepcidin levels are increased in adults and children with CKD. Vitamin D insufficiency is highly prevalent in CKD and is associated with erythropoietin hyporesponsiveness. Recently, hepcidin levels were found to be inversely correlated with vitamin D status in CKD. The aim of this study was to investigate the role of vitamin D in the regulation of hepcidin expression in vitro and in vivo. This study reports that 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the hormonally active form of vitamin D, is associated with decreased hepcidin and increased ferroportin expression in lipopolysaccharide (LPS) stimulated THP-1 cells. 1,25(OH)2D3 also resulted in a dose-dependent decrease in pro-hepcidin cytokines, IL-6 and IL-1β, release in vitro. Further, we show that high-dose vitamin D therapy impacts systemic hepcidin levels in subjects with early stage CKD. These data suggest that improvement in vitamin D status is associated with lower systemic concentrations of hepcidin in subjects with CKD. In conclusion, vitamin D regulates the hepcidin-ferroportin axis in macrophages which may facilitate iron egress. Improvement in vitamin D status in patients with CKD may reduce systemic hepcidin levels and may ameliorate anemia of CKD.
PMCID: PMC4119757  PMID: 25097830
Vitamin D; Hepcidin; Ferroportin; NRAMP1; IL-6; IL-1β; Macrophage; Chronic kidney disease; Anemia of inflammation
10.  Hepcidin-25, Mean Corpuscular Volume, and Ferritin as Predictors of Response to Oral Iron Supplementation in Hemodialysis Patients 
Nutrients  2014;7(1):103-118.
The benefit of oral iron therapy (OIT) and factors predictive of OIT response are not established in hemodialysis (HD) patients with iron deficiency anemia (IDA). We examined the values of hepcidin-25, mean corpuscular volume (MCV), and ferritin as predictors of OIT response. Oral ferrous fumarate (50 mg/day, 8 weeks) was given to 51 HD patients with IDA (hemoglobin (Hb) < 12 g/dL, ferritin < 100 ng/mL) treated with an erythropoietin activator. Sixteen patients were responders (improvement of Hb (ΔHb) ≥ 2 g/dL) and 35 were non-responders (ΔHb < 2g/dL). Baseline Hb, MCV, serum hepcidin-25, ferritin, iron parameters, and C-reactive protein (CRP) before and ΔHb after OIT were compared between groups. Hepcidin-25, MCV, ferritin, and transferrin saturation were lower in the responders than in the non-responders. Hepcidin-25 positively correlated with ferritin. Hepcidin-25, MCV, and ferritin positively correlated with baseline Hb and negatively correlated with ΔHb. Despite normal CRP levels in all patients, CRP correlated positively with hepcidin-25 and ferritin. Stepwise multiple linear regression analysis and receiver operating characteristics curve analysis revealed that hepcidin-25, MCV, and ferritin could predict OIT response. We conclude that hepcidin-25, MCV, and ferritin could be useful markers of iron storage status and may help predict OIT response in HD patients.
PMCID: PMC4303829  PMID: 25551249
anemia; ferritin; hemodialysis; hepcidin; iron; mean corpuscular volume
11.  Hepcidin Response to Iron Therapy in Patients with Non-Dialysis Dependent CKD: An Analysis of the FIND-CKD Trial 
PLoS ONE  2016;11(6):e0157063.
Hepcidin is the key regulator of iron homeostasis but data are limited regarding its temporal response to iron therapy, and response to intravenous versus oral iron. In the 56-week, open-label, multicenter, prospective, randomized FIND-CKD study, 626 anemic patients with non-dialysis dependent chronic kidney disease (ND-CKD) and iron deficiency not receiving an erythropoiesis stimulating agent were randomized (1:1:2) to intravenous ferric carboxymaltose (FCM), targeting higher (400–600μg/L) or lower (100–200μg/L) ferritin, or to oral iron. Serum hepcidin levels were measured centrally in a subset of 61 patients. Mean (SD) baseline hepcidin level was 4.0(3.5), 7.3(6.4) and 6.5(5.6) ng/mL in the high ferritin FCM (n = 17), low ferritin FCM (n = 16) and oral iron group (n = 28). The mean (SD) endpoint value (i.e. the last post-baseline value) was 26.0(9.1),15.7(7.7) and 16.3(11.0) ng/mL, respectively. The increase in hepcidin from baseline was significantly smaller with low ferritin FCM or oral iron vs high ferritin FCM at all time points up to week 52. Significant correlations were found between absolute hepcidin and ferritin values (r = 0.65, p<0.001) and between final post-baseline increases in both parameters (r = 0.70, p<0.001). The increase in hepcidin levels over the 12-month study generally mirrored the cumulative iron dose in each group. Hepcidin and transferrin saturation (TSAT) absolute values showed no correlation, although there was an association between final post-baseline increases (r = 0.42, p<0.001). Absolute values (r = 0.36, p = 0.004) and final post-baseline increases of hepcidin and hemoglobin (p = 0.30, p = 0.030) correlated weakly. Baseline hepcidin levels were not predictive of a hematopoietic response to iron therapy. In conclusion, hepcidin levels rose in response to either intravenous or oral iron therapy, but the speed and extent of the rise was greatest with intravenous iron targeting a higher ferritin level. However neither the baseline level nor the change in hepcidin was able to predict response to therapy in this cohort.
PMCID: PMC4898697  PMID: 27276035
12.  Effect of tocilizumab on haematological markers implicates interleukin-6 signalling in the anaemia of rheumatoid arthritis 
Arthritis Research & Therapy  2013;15(6):R204.
Our objective was to determine the interrelationships of interleukin (IL)-6 receptor inhibition with haemoglobin, acute-phase reactants and iron metabolism markers (including hepcidin) in patients with rheumatoid arthritis (RA).
Data of patients receiving tocilizumab or placebo in the MEASURE study were analysed. We investigated associations at baseline and during tocilizumab treatment among haemoglobin, parameters of haemoglobin and iron homeostasis [ferritin, total iron-binding capacity (TIBC), hepcidin, haptoglobin], IL-6 and acute-phase reactants [C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)] to identify statistical correlates of rise in haemoglobin level.
At baseline, CRP and haptoglobin were inversely correlated (modestly) with haemoglobin levels. After treatment with tocilizumab, CRP, hepcidin, ferritin and haptoglobin levels fell alongside increases in TIBC and haemoglobin. The falls in CRP, hepcidin and haptoglobin levels in the first 2 weeks correlated with a week 12 rise in TIBC and haemoglobin.
Inflammatory anaemia improves in patients with RA treated with tocilizumab. This improvement correlates with the degree of suppression of systemic inflammation, reduction in hepcidin and haptoglobin and increase in iron-binding capacity. These clinical data provide evidence of a role for IL-6 signalling in the inflammatory anaemia of RA.
PMCID: PMC3978585  PMID: 24295403
13.  Serum Hepcidin Levels in Childhood-Onset Ischemic Stroke 
Medicine  2016;95(9):e2921.
Recently, hepcidin, an antimicrobial-like peptide hormone, has evolved as the master regulator of iron homeostasis. Despite the growing evidence of iron imbalance in childhood-onset ischemic stroke, serum hepcidin level in those patients has not yet been researched.
In this study, we aimed to estimate serum (hepcidin) level in acute ischemic stroke (AIS) patients and to investigate whether subcutaneous enoxaparin sodium, which is a low-molecular-weight heparin (LMWH) derivative, could modulate serum hepcidin level in those patients.
This was a case–control study included 60 (AIS) cases, and 100 healthy children with comparable age and gender as control group. For all subjects’ serum hepcidin, interleukin-6 (IL-6), and soluble transferrin receptor [sTfR]) levels were assessed by (enzyme-linked immunosorbent assay [ELISA] method). Iron parameters including (serum iron, ferritin, transferrin, and total iron binding capacity [TIBC]) were also measured. The patients were subdivided according to treatment with an LMWH derivative into 2 groups and serum hepcidin levels were assessed initially and 1 week after stroke onset for all cases.
We found that AIS cases had higher serum iron, ferritin, and IL6 levels compared to the control group (all P < 0.01). Serum hepcidin was significantly higher in AIS cases (median, 36[15–73]ng/mL) compared to the control group (median, 24[10–41]ng/mL; P < 0.01). On the 1st day of AIS diagnosis, serum hepcidin levels were similar in both stroke subgroups (P > 0.05). However, on the 7th day of diagnosis serum hepcidin level decreased significantly in AIS cases treated with LMWH (group 1) (median, 36 vs 21 ng/mL; P < 0.01, respectively). Meanwhile, no significant change was observed in serum hepcidin level in AIS cases not treated with LMWH (group 2) (P > 0.05). Serum hepcidin showed significant positive correlations with serum iron, transferrin saturation, ferritin, and IL6 (r = 0.375, P < 0.05; r = 0.453, P < 0.05; r = 0.687, P < 0.01; r = 0.515, P < 0.01; respectively).
Our data brought a novel observation of elevated serum hepcidin level in pediatric AIS patients and pointed out that treatment with LMWH could modulate hepcidin level in those patients.
PMCID: PMC4782878  PMID: 26945394
14.  Hepcidin levels in diabetes mellitus and polycystic ovary syndrome 
Diabetic Medicine  2013;30(12):1495-1499.
Increased body iron is associated with insulin resistance. Hepcidin is the key hormone that negatively regulates iron homeostasis. We hypothesized that individuals with insulin resistance have inadequate hepcidin levels for their iron load.
Serum concentrations of the active form of hepcidin (hepcidin-25) and hepcidin:ferritin ratio were evaluated in participants with Type 2 diabetes (n = 33, control subjects matched for age, gender and BMI,n = 33) and participants with polycystic ovary syndrome (n = 27, control subjects matched for age and BMI,n = 16). To investigate whether any changes observed were associated with insulin resistance rather than insulin deficiency or hyperglycaemia per se, the same measurements were made in participants with Type 1 diabetes (n = 28, control subjects matched for age, gender and BMI,n = 30). Finally, the relationship between homeostasis model assessment of insulin resistance and serum hepcidin:ferritin ratio was explored in overweight or obese participants without diabetes (n = 16).
Participants with Type 2 diabetes had significantly lower hepcidin and hepcidin:ferritin ratio than control subjects (P < 0.05 and P < 0.01, respectively). Participants with polycystic ovary syndrome had a significantly lower hepcidin:ferritin ratio than control subjects (P < 0.05). There was no significant difference in hepcidin or hepcidin:ferritin ratio between participants with Type 1 diabetes and control subjects (P = 0.88 and P = 0.94). Serum hepcidin:ferritin ratio inversely correlated with homeostasis model assessment of insulin resistance (r = –0.59, P < 0.05).
Insulin resistance, but not insulin deficiency or hyperglycaemia per se, is associated with inadequate hepcidin levels. Reduced hepcidin concentrations may cause increased body iron stores in insulin-resistant states.
PMCID: PMC4232927  PMID: 23796160
15.  Hepcidin Expression in the Liver: Relatively Low Level in Patients with Chronic Hepatitis C 
Molecular Medicine  2007;13(1-2):97-104.
Patients with chronic hepatitis C frequently have serum and hepatic iron overload, but the mechanism is unknown. Recently identified hepcidin, exclusively synthesized in the liver, is thought to be a key regulator for iron homeostasis and is induced by infection and inflammation. This study was conducted to determine the hepatic hepcidin expression levels in patients with various liver diseases. We investigated hepcidin mRNA levels of liver samples by real-time detection-polymerase chain reaction; 56 were hepatitis C virus (HCV) positive, 34 were hepatitis B virus (HBV) positive, and 42 were negative for HCV and HBV (3 cases of auto-immune hepatitis, 7 alcoholic liver disease, 13 primary biliary cirrhosis, 9 nonalcoholic fatty liver disease, and 10 normal liver). We analyzed the relation of hepcidin to clinical, hematological, histological, and etiological findings. Hepcidin expression levels were strongly correlated with serum ferritin (P < 0.0001) and the degree of iron deposit in liver tissues (P < 0.0001). Hepcidin was also correlated with hematological parameters (vs. hemoglobin, P = 0.0073; vs. serum iron, P = 0.0012; vs. transferrin saturation, P < 0.0001) and transaminase levels (P = 0.0013). The hepcidin-to-ferritin ratio was significantly lower in HCV+ patients than in HBV+ patients (P = 0.0129) or control subjects (P = 0.0080). In conclusion, hepcidin expression levels in chronic liver diseases were strongly correlated with either the serum ferritin concentration or degree of iron deposits in the liver. When adjusted by either serum ferritin values or hepatic iron scores, hepcidin indices were significantly lower in HCV+ patients than in HBV+ patients, suggesting that hepcidin may play a pivotal role in the pathogenesis of iron overload in patients with chronic hepatitis C.
PMCID: PMC1869620  PMID: 17515961
16.  Study of Serum Hepcidin as a Potential Mediator of the Disrupted Iron Metabolism in Obese Adolescents 
Background & Aims
The prevalence of obesity continues to rise in both developed and developing nations. An association between iron status and obesity has been described in children and adults. We aimed to study the relation between serum hepcidin level and both iron as well as high sensitive CRP status in obese adolescents.
Materials & Methods
This work was conducted on 80 adolescents aging 12–14 years old, divided into two equal groups; obese and non-obese. Anthropometric measurements, determination of haemoglobin, serum iron, total iron binding capacity (TIBC), transferrin saturation, serum ferritin, soluble serum transferrin receptor (sTfR), high sensitive CRP (hs –CRP) and serum hepcidin were performed.
Obese adolescents showed significantly lower levels of haemoglobin, serum iron, serum ferritin and transferrin saturation. Significant higher diastolic blood pressure, higher mean TIBC, sTfR, serum hepcidin and hs –CRP were also found. Serum hepcidin level correlated positively with BMI and hs- CRP, but negatively with iron level in obese group.
These data suggest that hepcidin is an important modulator of anemia in obese patients. Obesity can be considered as a low grade inflammatory state, that stimulates the production of inflammatory markers such as CRP which can up-regulate hepcidin synthesis.
PMCID: PMC4538894  PMID: 26309436
Obesity; Hepcidin; Iron deficiency; Children
17.  Inflammation-induced hepcidin-25 is associated with the development of anemia in septic patients: an observational study 
Critical Care  2011;15(1):R9.
Anemia is a frequently encountered problem during inflammation. Hepcidin is an interleukin-6 (IL-6)-induced key modulator of inflammation-associated anemia. Human sepsis is a prototypical inflammatory syndrome, often complicated by the development of anemia. However, the association between inflammation, hepcidin release and anemia has not been demonstrated in this group of patients. Therefore, we explored the association between hepcidin and sepsis-associated anemia.
92 consecutive patients were enrolled after presentation on the emergency ward of a university hospital with sepsis, indicated by the presence of a proven or suspected infection and ≥ 2 extended systemic inflammatory response syndrome (SIRS) criteria. Blood was drawn at day 1, 2 and 3 after admission for the measurement of IL-6 and hepcidin-25. IL-6 levels were correlated with hepcidin concentrations. Hemoglobin levels and data of blood transfusions during 14 days after hospitalisation were retrieved and the rate of hemoglobin decrease was correlated to hepcidin levels.
53 men and 39 women with a mean age of 53.3 ± 1.8 yrs were included. Hepcidin levels were highest at admission (median[IQR]): 17.9[10.1 to 28.4]nmol/l and decreased to normal levels in most patients within 3 days (9.5[3.4 to 17.9]nmol/l). Hepcidin levels increased with the number of extended SIRS criteria (P = 0.0005). Highest IL-6 levels were measured at admission (125.0[46.3 to 330.0]pg/ml) and log-transformed IL-6 levels significantly correlated with hepcidin levels at admission (r = 0.28, P = 0.015), day 2 (r = 0.51, P < 0.0001) and day 3 (r = 0.46, P < 0.0001). Twelve patients received one or more blood transfusions during the first 2 weeks of admission, not related to active bleeding. These patients had borderline significant higher hepcidin level at admission compared to non-transfused patients (26.9[17.2 to 53.9] vs 17.9[9.9 to 28.8]nmol/l, P = 0.052). IL-6 concentrations did not differ between both groups. Correlation analyses showed significant associations between hepcidin levels on day 2 and 3 and the rate of decrease in hemoglobin (Spearman's r ranging from -0.32, P = 0.03 to -0.37, P = 0.016, respectively).
These data suggest that hepcidin-25 may be an important modulator of anemia in septic patients with systemic inflammation.
PMCID: PMC3222038  PMID: 21219610
18.  Relationship Between Serum Hepcidin and Ferritin Levels in Patients With Thalassemia Major and Intermedia in Southern Iran 
Hepcidin is a key regulator of iron absorption in humans. It is mainly affected by hypoxia and iron stores.
The current study aimed to determine the correlation between serum hepcidin and ferritin levels in patients with Thalassemia Major (TM) and Thalassemia Intermedia (TI).
Patients and Methods:
The current cross-sectional study investigated 88 randomly selected patients with Thalassemia, 48 TM and 40 TI, registered at the Thalassemia Clinic of Shiraz University of Medical Sciences, a referral center for Thalassemia in Southern Iran in 2013. All patients with TI were receiving Hydroxyurea (HU) 10 - 15 mg/kg/day for at least 10 years. The serum hepcidin, ferritin levels, hemoglobin (Hb) and nucleated Red Blood Cell (RBC) of the two groups were measured.
No statistically significant correlation was observed between serum hepcidin and ferritin levels in any of the two groups of patients with TM (rs = 0.02, P = 0.892) or TI (rs = 0.055, P = 0.734). The median Interquartile Range (IQR) for serum hepcidin and ferritin levels were significantly higher in TM compared to TI group, (hepcidin: 87.6 (43.9) vs. 51.8 (23.4), P < 0.001; ferritin: 2208 (3761) vs. 465 (632), P < 0.001).
There was insignificant correlation between serum hepcidin and ferritin levels in the two groups of patients with TM and TI. It seems that regulation of hepcidin in patients with Thalassemia is more affected by erythropoeitic activity than iron stores. Also, hepcidin levels were significantly higher in patients with TM than TI, possibly due to higher erythropoeitic activity in TI. In TI, it seems that low dose HU increases Hb levels and leads to transfusion-independence, but it is not high enough to suppress bone marrow activity and ineffective erythropoiesis. Consequently, serum hepcidin level decreases.
PMCID: PMC4583770  PMID: 26421179
Hepcidin; Hydroxyurea; Ferritin; Thalassemia Intermedia; Thalassemia Major
19.  Is hemojuvelin a possible new player in iron metabolism in hemodialysis patients? 
International Urology and Nephrology  2011;44(6):1805-1811.
Hemojuvelin (HJV) is highly expressed in the liver, skeletal muscles, and heart, seems to play a role in iron absorption and release from cells, and has anti-inflammatory properties. Moreover, HJV plays an essential role in the regulation of hepcidin expression, specifically in the iron-sensing pathway. Hepcidin has emerged as a key regulator of iron homeostasis. In this study we tested for the first time the hypothesis that HJV is related to iron metabolism in hemodialysis (HD) patients.
Iron status, complete blood count, and serum creatinine, albumin, and lipids were assessed, using standard laboratory methods. Serum levels of soluble transferrin receptor (sTFR), high-sensitivity CRP, IL-6, hepcidin, and HJV were measured using commercially available kits.
Serum HJV, hepcidin, ferritin, IL-6, hsCRP, and serum creatinine were significantly higher (all P < 0.001), whereas serum iron, sTFR, transferrin, hemoglobin, and erythrocyte count were significantly lower in HD patients, compared to healthy volunteers (all P < 0.001). In univariate analysis, HJV was strongly correlated (P < 0.001) with ferritin, transferrin saturation, and TIBC, as well as with hsCRP, hepcidin, Kt/V (P < 0.01) and residual renal function, the presence of diabetes, APKD, and coronary heart disease. Predictors of HJV level in multiple regression analysis were ferritin (beta value was 0.50, P = 0.00004) and transferrin saturation (beta value was 0.47, P = 0.0002), explaining 81% of the HJV variations.
Serum HJV is elevated in HD patients and related predominantly to kidney function and iron metabolism. However, HJV is probably not correlated to inflammation. HJV appears to be a new player in iron metabolism in these patients.
PMCID: PMC3510395  PMID: 22130959
Iron metabolism; Hemodialysis; Inflammation; Hepcidin; Hemojuvelin
20.  Plasma Concentrations of Hepcidin in Anemic Zimbabwean Infants 
PLoS ONE  2015;10(8):e0135227.
Anemia in infancy is a global public health problem. We evaluated the relative contributions of iron deficiency and inflammation to infant anemia.
We measured plasma hepcidin, ferritin, soluble transferrin receptor (sTfR), alpha-1-acid glycoprotein and C-reactive protein (CRP) by ELISA on archived plasma from 289 HIV-unexposed anemic or non-anemic Zimbabwean infants at ages 3mo, 6mo and 12mo. Among anemic infants, we determined the proportion with iron-deficiency anemia (IDA) and anemia of inflammation (AI). We undertook regression analyses of plasma hepcidin and anemia status, adjusting for sex, age and birthweight.
Anemic infants at 3mo were more stunted and had higher CRP (median 0.45 vs 0.21mg/L; P = 0.037) and hepcidin (median 14.7 vs 9.7ng/mL; P = 0.022) than non-anemic infants, but similar levels of ferritin and sTfR; 11% infants had IDA and 15% had AI. Anemic infants at 6mo had higher hepcidin (median 7.9 vs 4.5ng/mL; P = 0.016) and CRP (median 2.33 vs 0.32mg/L; P<0.001), but lower ferritin (median 13.2 vs 25.1μg/L; P<0.001) than non-anemic infants; 56% infants had IDA and 12% had AI. Anemic infants at 12mo had lower ferritin (median 3.2 vs 22.2μg/L; P<0.001) and hepcidin (median 0.9 vs 1.9ng/mL; P = 0.019), but similar CRP levels; 48% infants had IDA and 8% had AI. Comparing anemic with non-anemic infants, plasma hepcidin was 568% higher, 405% higher and 64% lower at 3mo, 6mo and 12mo, respectively, after adjusting for sex and birthweight (all p<0.01). Plasma hepcidin declined significantly with age among anemic but not non-anemic infants. Girls had 61% higher hepcidin than boys, after adjusting for age, anemia and birthweight (p<0.001).
Anemia is driven partly by inflammation early in infancy, and by iron deficiency later in infancy, with plasma hepcidin concentrations reflecting the relative contribution of each. However, there is need to better characterize the drivers of hepcidin during infancy in developing countries.
PMCID: PMC4529326  PMID: 26252205
21.  Hepcidin and Risk for Anemia in CKD: A Cross-sectional and Longitudinal Analysis in the CKiD Cohort 
Hepcidin, a key iron regulatory protein, is elevated in patients with chronic kidney disease (CKD). Its role in the development and progression of the anemia of CKD in children remains poorly defined.
Cross-sectional and longitudinal study in children aged 1–16 years with stage 2–4 CKD in the Chronic Kidney Disease in Children (CKiD) cohort (n=133) with hepcidin measured at baseline and hemoglobin (HGB) measured annually in follow-up. Anemia was defined as HGB < 5th percentile for age/sex OR treatment with an erythropoiesis stimulating agent (ESA).
Hepcidin levels correlated negatively with glomerular filtration rate (GFR) (r=−0.22, p=0.01) and positively with ferritin (r=0.67, p<0.001). At the lower end of the GFR spectrum at baseline (10th percentile, 27.5 ml/min/1.73m2), higher hepcidin was associated with a 0.87 g/dL decrease in HGB during follow-up (95% CI −1.69, −0.05 g/dL, p=0.038). At higher GFR percentiles there was no significant association between baseline hepcidin and HGB during follow-up. Among 90 non-anemic subjects at baseline, 23.3% developed incident anemia. In subjects with GFR ≤ the median, a higher hepcidin level was associated with an increased risk for incident anemia (at 10th %ile GFR, HR 3.471, 95% CI 1.228, 9.810, p=0.019; at 25th %ile GFR HR 2.641, 95% CI 1.213, 5.750, p=0.014; at 50th %ile GFR, HR 1.953, 95% CI 1.011, 3.772, p=0.046). Among subjects with GFR in the 75th percentile or above, incrementally higher baseline hepcidin was not associated with increased anemia risk.
Higher hepcidin levels are associated with a decreased HGB and an increased risk for incident anemia, and this association is most significant among subjects with lower GFR.
PMCID: PMC4336204  PMID: 25380788
Chronic kidney disease (CKD); children; anemia; hepcidin
22.  Hepcidin-Induced Iron Deficiency Is Related to Transient Anemia and Hypoferremia in Kawasaki Disease Patients 
Kawasaki disease (KD) is a type of systemic vasculitis that primarily affects children under the age of five years old. For sufferers of KD, intravenous immunoglobulin (IVIG) has been found to successfully diminish the occurrence of coronary artery lesions. Anemia is commonly found in KD patients, and we have shown that in appropriately elevated hepcidin levels are related to decreased hemoglobin levels in these patients. In this study, we investigated the time period of anemia and iron metabolism during different stages of KD. A total of 100 patients with KD and 20 control subjects were enrolled in this study for red blood cell and hemoglobin analysis. Furthermore, plasma, urine hepcidin, and plasma IL-6 levels were evaluated using enzyme-linked immunosorbent assay in 20 KD patients and controls. Changes in hemoglobin, plasma iron levels, and total iron binding capacity (TIBC) were also measured in patients with KD. Hemoglobin, iron levels, and TIBC were lower (p < 0.001, p = 0.009, and p < 0.001, respectively) while plasma IL-6 and hepcidin levels (both p < 0.001) were higher in patients with KD than in the controls prior to IVIG administration. Moreover, plasma hepcidin levels were positively and significantly correlated with urine hepcidin levels (p < 0.001) prior to IVIG administration. After IVIG treatment, plasma hepcidin and hemoglobin levels significantly decreased (both p < 0.001). Of particular note was a subsequent gradual increase in hemoglobin levels during the three weeks after IVIG treatment; nevertheless, the hemoglobin levels stayed lower in KD patients than in the controls (p = 0.045). These findings provide a longitudinal study of hemoglobin changes and among the first evidence that hepcidin induces transient anemia and hypoferremia during KD’s acute inflammatory phase.
PMCID: PMC4881537  PMID: 27187366
anemia; hepcidin; iron; Kawasaki disease
23.  Association of Hepcidin mRNA Expression With Hepatocyte Iron Accumulation and Effects of Antiviral Therapy in Chronic Hepatitis C Infection 
Hepatitis Monthly  2014;14(11):e21184.
Iron overload is frequently observed in patients with chronic hepatitis C (CHC) and is associated with the increased risk of liver fibrosis and carcinogenesis. Hepcidin is a regulator of iron homeostasis and a component of innate immunity. Based on experimental studies, iron overload might be a result of low hepcidin synthesis in CHC.
The aim of this case-control study was to assess hepcidin mRNA expression in liver tissue of patients with CHC in terms of iron metabolism parameters, hemochromatosis (HFE) gene mutations, disease activity, and efficacy of antiviral treatment with pegylated interferon and ribavirin.
Patients and Methods:
A total of 31 patients with CHC, who were qualified for antiviral therapy, were compared with 19 patients with chronic hepatitis B (CHB). In both groups, liver function tests and serum iron parameters were assayed and hepcidin mRNA expression was measured in liver specimens using real time PCR with normalization to reference genes mRNA of stable expression.
Patients with CHC had lower hepcidin mRNA expression and more frequently iron deposits in hepatocytes than subjects with CHB did. In CHC group, hepcidin mRNA expression was positively correlated with alanine aminotransferase activity and serum iron concentration. Low expression of hepcidin had no correlation with tissue iron overload in those with CHC. In univariate analysis, HCV viral load and efficacy of antiviral treatment were not significantly associated with hepcidin mRNA expression.
Further studies on the role of hepcidin in pathogenesis of CHC are needed to assess the potency of its use in antiviral treatment.
PMCID: PMC4286710  PMID: 25598789
Hepatitis C; Hepcidin; Iron Overload; Liver; Interferon-alpha
24.  Low Serum Hepcidin in Patients with Autoimmune Liver Diseases 
PLoS ONE  2015;10(8):e0135486.
Hepcidin, a liver hormone, is important for both innate immunity and iron metabolism regulation. As dysfunction of the hepcidin pathway may contribute to liver pathology, we analysed liver hepcidin mRNA and serum hepcidin in patients with chronic liver diseases. Hepcidin mRNA levels were determined in liver biopsies obtained from 126 patients with HCV (n = 21), HBV (n = 23), autoimmune cholestatic disease (primary biliary cirrhosis and primary sclerosing cholangitis; PBC/PSC; n = 34), autoimmune hepatitis (AIH; n = 16) and non-alcoholic fatty liver disease (NAFLD; n = 32). Sera sampled on the biopsy day from the same patients were investigated for serum hepcidin levels. Hepatic hepcidin mRNA levels correlated positively with ferritin and negatively with serum γ-GT levels. However, no correlation was found between serum hepcidin and either ferritin or liver hepcidin mRNA. Both serum hepcidin and the serum hepcidin/ferritin ratio were significantly lower in AIH and PBC/PSC patients’ sera compared to HBV, HCV or NAFLD (P<0.001 for each comparison) and correlated negatively with serum ALP levels. PBC/PSC and AIH patients maintained low serum hepcidin during the course of their two-year long treatment. In summary, parallel determination of liver hepcidin mRNA and serum hepcidin in patients with chronic liver diseases shows that circulating hepcidin and its respective ratio to ferritin are significantly diminished in patients with autoimmune liver diseases. These novel findings, once confirmed by follow-up studies involving bigger size and better-matched disease subgroups, should be taken into consideration during diagnosis and treatment of autoimmune liver diseases.
PMCID: PMC4535884  PMID: 26270641
25.  Deranged iron status in psoriasis: the impact of low body mass 
Iron deficiency (ID) frequently complicates inflammatory-mediated chronic disorders, irrespective of anaemia. Psoriasis is a chronic, immune-mediated skin disease with systemic pro-inflammatory activation; thus, these patients may be prone to develop ID. ID adversely affects immune cells function, which can further contribute to disease progression. This study investigates iron status in psoriasis.
Serum concentrations of ferritin, transferrin saturation (Tsat), soluble transferrin receptor (sTfR), and hepcidin were assessed as the biomarkers of iron status in 39 patients with psoriasis (17 men, age: 47 ± 10 years) and 44 healthy subjects (30 men, age: 53 ± 6 years).
Compared with healthy controls, patients with psoriasis demonstrated similar haematologic status but deranged iron status as evidenced by decreased Tsat and elevated sTfR (negative tissue iron balance) and low levels of hepcidin (depleted iron stores) (all P < 0.05 vs. controls). In patients, the levels of interleukin-6 (level of pro-inflammatory activation) significantly correlated with hepcidin (R = 0.54), but not with ferritin, Tsat, and sTfR. Biomarkers reflecting ID were not associated with the severity of the disease (assessed with the Psoriasis Area and Severity Index) but significantly correlated low body mass index (BMI). Patients with BMI < 24 kg/m2 compared with those with BMI ≥ 24 kg/m2 demonstrated lower levels of ferritin (40 ± 30 vs. 186 ± 128 ng/mL, P < 0.001) and hepcidin (4.9 ± 2.3 vs. 10.7 ± 6.7 ng/mL, P = 0.03).
Psoriasis is associated with deranged iron status characterized by depleted iron stores with concomitant unmet cellular iron requirements. The magnitude of these abnormalities is particularly strong in patients with low body mass index. Whether iron deficiency may become a therapeutic target in psoriasis needs to be investigated.
PMCID: PMC4670745  PMID: 26673741
Psoriasis; Iron deficiency; Hepcidin; Inflammation; Lean patients

Results 1-25 (1776582)