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1.  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.
doi:10.2119/2006-00057.Fujita
PMCID: PMC1869620  PMID: 17515961
2.  Decreased Serum Hepcidin Concentration Correlates with Brain Iron Deposition in Patients with HBV-Related Cirrhosis 
PLoS ONE  2013;8(6):e65551.
Purpose
Excessive brain iron accumulation contributes to cognitive impairments in hepatitis B virus (HBV)-related cirrhotic patients. The underlying mechanism remains unclear. Hepcidin, a liver-produced, 25-aminoacid peptide, is the major regulator of systemic iron metabolism. Abnormal hepcidin level is a key factor in some body iron accumulation or deficiency disorders, especially in those associated with liver diseases. Our study was aimed to explore the relationship between brain iron content in patients with HBV-related cirrhosis and serum hepcidin level.
Methods
Seventy HBV-related cirrhotic patients and forty age- sex-matched healthy controls were enrolled. Brain iron content was quantified by susceptibility weighted phase imaging technique. Serum hepcidin as well as serum iron, serum transferrin, ferritin, soluble transferrin receptor, total iron binding capacity, and transferrin saturation were tested in thirty cirrhotic patients and nineteen healthy controls. Pearson correlation analysis was performed to investigate correlation between brain iron concentrations and serum hepcidin, or other iron parameters.
Results
Cirrhotic patients had increased brain iron accumulation compared to controls in the left red nuclear, the bilateral substantia nigra, the bilateral thalamus, the right caudate, and the right putamen. Cirrhotic patients had significantly decreased serum hepcidin concentration, as well as lower serum transferring level, lower total iron binding capacity and higher transferrin saturation, compared to controls. Serum hepcidin level negatively correlated with the iron content in the right caudate, while serum ferritin level positively correlated with the iron content in the bilateral putamen in cirrhotic patients.
Conclusions
Decreased serum hepcidin level correlated with excessive iron accumulation in the basal ganglia in HBV-related cirrhotic patients. Our results indicated that systemic iron overload underlined regional brain iron repletion. Serum hepcidin may be a clinical biomarker for brain iron deposition in cirrhotic patients, which may have therapeutic potential.
doi:10.1371/journal.pone.0065551
PMCID: PMC3679136  PMID: 23776499
3.  Highly Elevated Serum Hepcidin in Patients with Acute Myeloid Leukemia prior to and after Allogeneic Hematopoietic Cell Transplantation: Does This Protect from Excessive Parenchymal Iron Loading? 
Advances in Hematology  2011;2011:491058.
Hepcidin is upregulated by inflammation and iron. Inherited (HFE genotype) and treatment-related factors (blood units (BU), Iron overload) affecting hepcidin (measured by C-ELISA) were studied in 42 consecutive patients with AML prior to and after allogeneic hematopoietic cell transplantation (HCT). Results. Elevated serum ferritin pre- and post-HCT was present in all patients. Median hepcidin pre- and post-HCT of 358 and 398 ng/mL, respectively, were elevated compared to controls (median 52 ng/mL) (P < .0001). Liver and renal function, prior chemotherapies, and conditioning had no impact on hepcidin. Despite higher total BU after HCT compared to pretransplantation (P < .0005), pre- and posttransplant ferritin and hepcidin were similar. BU influenced ferritin (P = .001) and hepcidin (P = .001). No correlation of pre- or posttransplant hepcidin with pretransplant ferritin was found. HFE genotype did not influence hepcidin. Conclusions. Hepcidin is elevated in AML patients pre- and post-HCT due to transfusional iron-loading suggesting that hepcidin synthesis remains intact despite chemotherapy and HCT.
doi:10.1155/2011/491058
PMCID: PMC3112503  PMID: 21687645
4.  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.
doi:10.1371/journal.pone.0135486
PMCID: PMC4535884  PMID: 26270641
5.  Hepcidin levels in diabetes mellitus and polycystic ovary syndrome 
Diabetic Medicine  2013;30(12):1495-1499.
Aim
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.
Methods
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).
Results
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).
Conclusion
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.
doi:10.1111/dme.12262
PMCID: PMC4232927  PMID: 23796160
6.  Treatment with anti-IL-6 receptor antibody prevented increase in serum hepcidin levels and improved anemia in mice inoculated with IL-6–producing lung carcinoma cells 
BMC Cancer  2016;16:270.
Background
Hepcidin, a key regulator of iron metabolism, is produced mainly by interleukin-6 (IL-6) during inflammation. A mechanism linking cancer-related anemia and IL-6 through hepcidin production is suggested. To clarify the hypothesis that overproduction of IL-6 elevates hepcidin levels and contributes to the development of cancer-related anemia, we evaluated anti-IL-6 receptor antibody treatment of cancer-related anemia in an IL-6–producing human lung cancer xenograft model.
Methods
Nude mice were subcutaneously inoculated with cells of the IL-6–producing human lung cancer cell line LC-06-JCK and assessed as a model of cancer-related anemia. Mice bearing LC-06-JCK were administered rat anti-mouse IL-6 receptor antibody MR16-1 and their serum hepcidin levels and hematological parameters were determined.
Results
LC-06-JCK–bearing mice developed anemia according to the production of human IL-6 from xenografts, with decreased values of hemoglobin, hematocrit, and mean corpuscular volume (MCV) compared to non–tumor-bearing (NTB) mice. LC-06-JCK–bearing mice showed decreased body weight and serum albumin with increased serum amyloid A. MR16-1 treatment showed significant inhibition of decreased body weight and serum albumin levels, and suppressed serum amyloid A level. There was no difference in tumor volume between MR16-1-treated mice and immunoglobulin G (IgG)-treated control mice. Decreased hemoglobin, hematocrit, and MCV in LC-06-JCK–bearing mice was significantly relieved by MR16-1 treatment. LC-06-JCK–bearing mice showed high red blood cell counts and erythropoietin levels as compared to NTB mice, whereas MR16-1 treatment did not affect their levels. Serum hepcidin and ferritin levels were statistically elevated in mice bearing LC-06-JCK. LC-06-JCK–bearing mice showed lower values of MCV, mean corpuscular hemoglobin (MCH), and serum iron as compared to NTB mice. Administration of MR16-1 to mice bearing LC-06-JCK significantly suppressed levels of both serum hepcidin and ferritin, with increased values of MCV and MCH.
Conclusions
Our results suggest that overproduction of hepcidin by IL-6 signaling might be a major factor that leads to functionally iron-deficient cancer-related anemia in the LC-06-JCK model. We demonstrated that inhibition of the IL-6 signaling pathway by MR16-1 treatment resulted in significant recovery of iron-deficiency anemia and alleviation of cancer-related symptoms. These results indicate that IL-6 signaling might be one possible target pathway to treat cancer-related anemia disorders.
doi:10.1186/s12885-016-2305-2
PMCID: PMC4828826  PMID: 27068103
Interleukin-6; Anemia; Hepcidin; Cancer; Iron metabolism
7.  New Insights on Iron Study in Myelodysplasia 
Turkish Journal of Hematology  2014;31(4):394-398.
Objective: Hepcidin plays a pivotal role in iron homeostasis. It is predominantly produced by hepatocytes and inhibits iron release from macrophages and iron uptake by intestinal epithelial cells. Competitive ELISA is the current method of choice for the quantification of serum hepcidin because of its lower detection limit, low costs, and high throughput. This study aims to discuss the role of hepcidin in the pathogenesis of iron overload in recently diagnosed myelodysplasia (MDS) cases.
Materials and Methods: The study included 21 recently diagnosed MDS patients and 13 healthy controls. Ferritin, hepcidin, and soluble transferrin receptor (sTFR) were measured in all subjects.
Results: There were 7 cases of hypocellular MDS, 8 cases of refractory cytopenia with multilineage dysplasia, and 6 cases of refractory anemia with excess blasts. No difference was observed among the 3 MDS subtypes in terms of hepcidin, sTFR, and ferritin levels (p>0.05). Mean hepcidin levels in the MDS and control groups were 55.8±21.5 ng/mL and 19.9±2.6 ng/mL, respectively. Mean sTFR was 45.7±8.8 nmol/L in MDS patients and 31.1±5.6 nmol/L in the controls. Mean ferritin levels were significantly higher in MDS patients than in controls (539.14±83.5 ng/mL vs. 104.6±42.9 ng/mL, p<0.005). There was a statistically significant correlation between hepcidin and sTFR (r=0.45, p=0.039). No difference in hepcidin levels between males and females was observed, although it was lower in males in comparison to females (47.9±27.6 vs. 66.7±35.7, p>0.05).
Conclusion: Hepcidin may not be the main cause of iron overload in MDS. Further studies are required to test failure of production or peripheral unresponsiveness to hepcidin in MDS cases.
doi:10.4274/tjh.2012.0154
PMCID: PMC4454055  PMID: 25541657
Hepcidin; Myelodysplasia; iron overload
8.  Understanding and exploiting hepcidin as an indicator of anemia due to chronic kidney disease 
Hepcidin, produced by the liver, is the master regulator of iron balance. Serum hepcidin is increased by high iron stores, blocks intestinal iron absorption, and impairs storage iron release. Conversely, iron deficiency lowers hepcidin levels and enhances intestinal iron absorption and the release of storage iron. As with ferritin, hepcidin is an acute phase reactant. Consequently, inflammation increases hepcidin and leads to impaired iron absorption, lowers serum iron and transferrin saturation, and contributes to the anemia of chronic kidney disease (CKD). We review the physiology of iron absorption, its relationship to hepcidin and the transmembrane iron transporter ferroportin, the role of hepcidin in CKD related anemia, and the possible diagnostic implications and limitations of using hepcidin as a marker of iron status.
doi:10.1016/j.krcp.2013.01.001
PMCID: PMC4716122  PMID: 26894030
Anemia; Chronic kidney disease; Hepcidin; Iron
9.  Hepcidin and iron status among pregnant women in Bangladesh 
Although hepcidin, a recently discovered peptide hormone, is considered a major regulator of iron metabolism and the anemia of chronic inflammation, its role in the anemia of pregnancy has not been characterized. Our objective was to characterize the role of hepcidin in the anemia of pregnancy. We examined the relationships between urinary hepcidin, iron status indicators, hemoglobin, erythropoietin, alpha-1 acid glycoprotein, and C-reactive protein in a cross-sectional study conducted among 149 pregnant rural Bangladeshi women in biospecimens obtained during home visits. Urinary hepcidin was measured using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. Urinary hepcidin, as log(intensity per mmol/L creatinine), was correlated with log ferritin (r = 0.33, p <0.001), the transferrin receptor index (r = −0.22, p = 0.007), and log alpha-1 acid glycoprotein (r = 0.20, p = 0.01), but not hemoglobin (r = 0.07, p= 0.40), log transferrin receptor (r = −0.07, p = 0.41), log erythropoietin (r = −0.01, p = 0.88) or log C-reactive protein (r = 0.06, p = 0.48). The strength of the relationship between hepcidin and ferritin was maintained in a multiple linear regression analyses after enhancing the sample with women selected for low iron stores (n = 41). Among pregnant women in a community-based study in rural Bangladesh, urinary hepcidin levels were related to iron status and AGP but not hemoglobin, erythropoietin, or C-reactive protein.
PMCID: PMC2789317  PMID: 18818166
anemia; hepcidin; inflammation; iron; pregnancy
10.  Hepcidin-25 in Diabetic Chronic Kidney Disease Is Predictive for Mortality and Progression to End Stage Renal Disease 
PLoS ONE  2015;10(4):e0123072.
Background
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1371/journal.pone.0123072
PMCID: PMC4404250  PMID: 25894587
11.  Reduced serum hepcidin levels in patients with chronic hepatitis C 
Journal of hepatology  2009;51(5):845-852.
Background/Aims
Patients with chronic hepatitis C (CHC) often have increased liver iron, a condition associated with reduced sustained response to antiviral therapy, more rapid progression to cirrhosis, and development of hepatocellular carcinoma. The hepatic hormone hepcidin is the major regulator of iron metabolism and inhibits iron absorption and recycling from erythrophagocytosis. Hepcidin decrease is a possible pathophysiological mechanism of iron overload in CHC, but studies in humans have been hampered so far by the lack of reliable quantitative assays for the 25-amino acid bioactive peptide in serum (s-hepcidin).
Methods
Using a recently validated immunoassay, we measured s-hepcidin levels in 81 untreated CHC patients and 57 controls with rigorous definition of normal iron status. All CHC patients underwent liver biopsy with histological iron score.
Results
S-hepcidin was significantly lower in CHC patients than in controls (geometric means with 95% confidence intervals: 33.7, 21.5–52.9 vs. 90.9, 76.1–108.4 ng/mL, respectively; p < 0.001). In CHC patients, s-hepcidin significantly correlated with serum ferritin and histological total iron score, but not with s-interleukin-6. After stratification for ferritin quartiles, s-hepcidin increased significantly across quartiles in both controls and CHC patients (chi for trend, p < 0.001). However, in CHC patients, s-hepcidin was significantly lower than in controls for each corresponding quartile (analysis of variance, p < 0.001).
Conclusions
These results, together with very recent studies in animal and cellular models, indicate that although hepcidin regulation by iron stores is maintained in CHC, the suppression of this hormone by hepatitis C virus is likely an important factor in liver iron accumulation in this condition.
doi:10.1016/j.jhep.2009.06.027
PMCID: PMC2761995  PMID: 19729219
Chronic hepatitis C; Hemochromatosis; Hepcidin; Iron overload; Ferritin
12.  Hepcidin: A Promising Therapeutic Target for Iron Disorders 
Medicine  2016;95(14):e3150.
Abstract
Iron is required for most forms of organisms, and it is the most essential element for the functions of many iron-containing proteins involved in oxygen transport, cellular respiration, DNA replication, and so on. Disorders of iron metabolism are associated with diverse diseases, including anemias (e.g., iron-deficiency anemia and anemia of chronic diseases) and iron overload diseases, such as hereditary hemochromatosis and β-thalassemia. Hepcidin (encoded by Hamp gene) is a peptide hormone synthesized by hepatocytes, and it plays an important role in regulating the systematic iron homeostasis. As the systemic iron regulator, hepcidin, not only controls dietary iron absorption and iron egress out of iron storage cells, but also induces iron redistribution in various organs. Deregulated hepcidin is often seen in a variety of iron-related diseases including anemias and iron overload disorders. In the case of iron overload disorders (e.g., hereditary hemochromatosis and β-thalassemia), hepatic hepcidin concentration is significantly reduced.
Since hepcidin deregulation is responsible for iron disorder-associated diseases, the purpose of this review is to summarize the recent findings on therapeutics targeting hepcidin.
Continuous efforts have been made to search for hepcidin mimics and chemical compounds that could be used to increase hepcidin level. Here, a literature search was conducted in PubMed, and research papers relevant to hepcidin regulation or hepcidin-centered therapeutic work were reviewed. On the basis of literature search, we recapitulated recent findings on therapeutic studies targeting hepcidin, including agonists and antagonists to modulate hepcidin expression or its downstream signaling. We also discussed the molecular mechanisms by which hepcidin level and iron metabolism are modulated.
Elevating hepcidin concentration is an optimal strategy to ameliorate iron overload diseases, and also to relieve β-thalassemia phenotypes by improving ineffective erythropoiesis. Relative to the current conventional therapies, such as phlebotomy and blood transfusion, therapeutics targeting hepcidin would open a new avenue for treatment of iron-related diseases.
doi:10.1097/MD.0000000000003150
PMCID: PMC4998755  PMID: 27057839
13.  An Insight into the Relationships between Hepcidin, Anemia, Infections and Inflammatory Cytokines in Pediatric Refugees: A Cross-Sectional Study 
PLoS ONE  2008;3(12):e4030.
Background
Hepcidin, a key regulator of iron homeostasis, is increased in response to inflammation and some infections, but the in vivo role of hepcidin, particularly in children with iron deficiency anemia (IDA) is unclear. We investigated the relationships between hepcidin, cytokines and iron status in a pediatric population with a high prevalence of both anemia and co-morbid infections.
Methodology/Principal Findings
African refugee children <16 years were consecutively recruited at the initial post-resettlement health check with 181 children meeting inclusion criteria. Data on hematological parameters, cytokine levels and co-morbid infections (Helicobacter pylori, helminth and malaria) were obtained and urinary hepcidin assays performed. The primary outcome measure was urinary hepcidin levels in children with and without iron deficiency (ID) and/or ID anaemia (IDA). The secondary outcome measures included were the relationship between co-morbid infections and (i) ID and IDA, (ii) urinary hepcidin levels and (iii) cytokine levels. IDA was present in 25/181 (13.8%). Children with IDA had significantly lower hepcidin levels (IDA median hepcidin 0.14 nmol/mmol Cr (interquartile range 0.05–0.061) versus non-IDA 2.96 nmol/mmol Cr, (IQR 0.95–6.72), p<0.001). Hemoglobin, log-ferritin, iron, mean cell volume (MCV) and transferrin saturation were positively associated with log-hepcidin levels (log-ferritin beta coefficient (β): 1.30, 95% CI 1.02 to 1.57) and transferrin was inversely associated (β: −0.12, 95% CI −0.15 to −0.08). Cytokine levels (including IL-6) and co-morbid infections were not associated with IDA or hepcidin levels.
Conclusions/Significance
This is the largest pediatric study of the in vivo associations between hepcidin, iron status and cytokines. Gastro-intestinal infections (H. pylori and helminths) did not elevate urinary hepcidin or IL-6 levels in refugee children, nor were they associated with IDA. Longitudinal and mechanistic studies of IDA will further elucidate the role of hepcidin in paediatric iron regulation.
doi:10.1371/journal.pone.0004030
PMCID: PMC2603326  PMID: 19107209
14.  Serum iron metabolism and erythropoiesis in patients with myelodysplastic syndrome not receiving RBC transfusions 
Leukemia research  2014;38(5):545-550.
Dysregulation of hepcidin, a key iron regulating hormone, is important in the pathogenesis of iron overload in patients with myelodysplatic syndrome (MDS). However, most studies of hepcidin levels are complicated by concomitant RBC transfusions. To evaluate the relationship between iron metabolism and erythropoiesis, we measured serum levels of hepcidin, growth-differentiation factor-15 (GDF15) and other markers of erythropoiesis in 107 subjects with MDS not receiving RBC transfusions. Patients with MDS had significantly higher levels of hepcidin than normals. However, their hepcidin–ferritin ratio was markedly decreased compared to normals (P < 0.001) and varied substantially between MDS subtypes (P = 0.011). GDF15 levels positively correlated with percent of bone marrow erythroblasts (P < 0.001), soluble transferrin receptor (sTfR) (P = 0.018), and also with transferrin saturation (ISAT) (P = 0.038). The hepcidin–ferritin ratio negatively correlated with serum erythropoietin (EPO) levels (P < 0.001), and also with GDF15 levels (P = 0.014). Colony forming cells (CFC) were evaluated in 70 subjects. Those with serum ferritin (SF) levels <500 ng/ml had significantly more BFU-E than subjects with SF≥ 500 ng/L (P = 0.007), but numbers of granulocyte/macrophage-colony-forming cells (CFU-GM) were similar (P = 0.190). Our data indicate serum hepcidin levels are inappropriately low in patients MDS not receiving RBC transfusions. GDF15 levels correlated with low hepcidin levels and may contribute to iron overload in this setting. Iron overload may in turn suppress erythropoiesis by imparing the proliferative capacity of the erythroid progenitor cells.
doi:10.1016/j.leukres.2014.01.016
PMCID: PMC4439195  PMID: 24598841
Myelodysplastic syndromes; Iron metabolism; Hematopoiesis
15.  Gender-related variations in iron metabolism and liver diseases 
World Journal of Hepatology  2010;2(8):302-310.
The regulation of iron metabolism involves multiple organs including the duodenum, liver and bone marrow. The recent discoveries of novel iron-regulatory proteins have brought the liver to the forefront of iron homeostasis. The iron overload disorder, genetic hemochromatosis, is one of the most prevalent genetic diseases in individuals of Caucasian origin. Furthermore, patients with non-hemochromatotic liver diseases, such as alcoholic liver disease, chronic hepatitis C or nonalcoholic steatohepatitis, often exhibit elevated serum iron indices (ferritin, transferrin saturation) and mild to moderate hepatic iron overload. Clinical data indicate significant differences between men and women regarding liver injury in patients with alcoholic liver disease, chronic hepatitis C or nonalcoholic steatohepatitis. The penetrance of genetic hemochromatosis also varies between men and women. Hepcidin has been suggested to act as a modifier gene in genetic hemochromatosis. Hepcidin is a circulatory antimicrobial peptide synthesized by the liver. It plays a pivotal role in the regulation of iron homeostasis. Hepcidin has been shown to be regulated by iron, inflammation, oxidative stress, hypoxia, alcohol, hepatitis C and obesity. Sex and genetic background have also been shown to modulate hepcidin expression in mice. The role of gender in the regulation of human hepcidin gene expression in the liver is unknown. However, hepcidin may play a role in gender-based differences in iron metabolism and liver diseases. Better understanding of the mechanisms associated with gender-related differences in iron metabolism and chronic liver diseases may enable the development of new treatment strategies.
doi:10.4254/wjh.v2.i8.302
PMCID: PMC2999297  PMID: 21161013
Alcohol; Hepcidin; Hepatitis C; Hemochromatosis; Non-alcoholic steatohepatitis
16.  Increased Serum Hepcidin Levels in Subjects with the Metabolic Syndrome: A Population Study 
PLoS ONE  2012;7(10):e48250.
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.
doi:10.1371/journal.pone.0048250
PMCID: PMC3483177  PMID: 23144745
17.  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.
Background
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.
Conclusions/Significance
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.
doi:10.1371/journal.pntd.0004029
PMCID: PMC4578949  PMID: 26394303
18.  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.
doi:10.1371/journal.pone.0039783
PMCID: PMC3396629  PMID: 22808058
19.  Is serum hepcidin causative in hemochromatosis? Novel analysis from a liver transplant with hemochromatosis 
BACKGROUND:
Hepcidin is a circulating hepatic hormone that regulates iron balance. It has been speculated that hepcidin insufficiency or dysregulation may be the primary defect in genetic hemochromatosis.
METHODS:
A 62-year-old woman underwent elective liver transplantation for chronic hepatitis C cirrhosis. Genetic testing for hemochromatosis was subsequently performed on the donor and recipient. Liver iron concentration was measured in the donated liver at the time of transplantation, and at day 2 and day 652 post-transplant. Serum hepcidin was measured at day 935 in the recipient and in three other liver transplant recipients.
RESULTS:
The donor was discovered to have significant iron overload without fibrosis, with a liver iron concentration of 326 μmol/g (normal is 0 μmol/g to 35 μmol/g). Genetic testing confirmed that the 89-year-old female donor was a typical C282Y homozygote for hemochromatosis. The recipient did not carry either the C282Y or the H63D mutation of the HFE gene for hemochromatosis. Liver biopsy was performed on the recipient on day 2 and day 652 post-transplant; the liver iron concentrations were 333 μmol/g and 253 μmol/g, respectively. Serum hepcidin in the recipient was elevated at 111 ng/mL compared with that of the three other ambulatory liver transplant recipients (66 ng/mL, 76 ng/mL and 81 ng/mL).
CONCLUSION:
The liver transplant recipient described in the present report demonstrated a slight decrease in liver iron concentration over a 1.8-year follow-up period without specific therapy. Hepcidin insufficiency as a primary cause of genetic hemochromatosis seems unlikely based on the clinical profile of the present patient and the hepcidin measurements.
PMCID: PMC2661307  PMID: 18925311
Hemochromatosis; HFE; Iron overload
20.  Hepcidin antagonists for potential treatments of disorders with hepcidin excess 
The discovery of hepcidin clarified the basic mechanism of the control of systemic iron homeostasis. Hepcidin is mainly produced by the liver as a propeptide and processed by furin into the mature active peptide. Hepcidin binds ferroportin, the only cellular iron exporter, causing the internalization and degradation of both. Thus hepcidin blocks iron export from the key cells for dietary iron absorption (enterocytes), recycling of hemoglobin iron (the macrophages) and the release of storage iron from hepatocytes, resulting in the reduction of systemic iron availability. The BMP/HJV/SMAD pathway is the major regulator of hepcidin expression that responds to iron status. Also inflammation stimulates hepcidin via the IL6/STAT3 pathway with a support of an active BMP/HJV/SMAD pathway. In some pathological conditions hepcidin level is inadequately elevated and reduces iron availability in the body, resulting in anemia. These conditions occur in the genetic iron refractory iron deficiency anemia and the common anemia of chronic disease (ACD) or anemia of inflammation. Currently, there is no definite treatment for ACD. Erythropoiesis-stimulating agents and intravenous iron have been proposed in some cases but they are scarcely effective and may have adverse effects. Alternative approaches aimed to a pharmacological control of hepcidin expression have been attempted, targeting different regulatory steps. They include hepcidin sequestering agents (antibodies, anticalins, and aptamers), inhibitors of BMP/SMAD or of IL6/STAT3 pathway or of hepcidin transduction (siRNA/shRNA) or ferroportin stabilizers. In this review we summarized the biochemical interactions of the proteins involved in the BMP/HJV/SMAD pathway and its natural inhibitors, the murine and rat models with high hepcidin levels currently available and finally the progresses in the development of hepcidin antagonists, with particular attention to the role of heparins and heparin sulfate proteoglycans in hepcidin expression and modulation of the BMP6/SMAD pathway.
doi:10.3389/fphar.2014.00086
PMCID: PMC4009444  PMID: 24808863
hepcidin; heparin; anemia of chronic diseases; inflammation; iron metabolism
21.  Hepcidin Expression in Iron Overload Diseases Is Variably Modulated by Circulating Factors 
PLoS ONE  2012;7(5):e36425.
Hepcidin is a regulatory hormone that plays a major role in controlling body iron homeostasis. Circulating factors (holotransferrin, cytokines, erythroid regulators) might variably contribute to hepcidin modulation in different pathological conditions. There are few studies analysing the relationship between hepcidin transcript and related protein expression profiles in humans. Our aims were: a. to measure hepcidin expression at either hepatic, serum and urinary level in three paradigmatic iron overload conditions (hemochromatosis, thalassemia and dysmetabolic iron overload syndrome) and in controls; b. to measure mRNA hepcidin expression in two different hepatic cell lines (HepG2 and Huh-7) exposed to patients and controls sera to assess whether circulating factors could influence hepcidin transcription in different pathological conditions. Our findings suggest that hepcidin assays reflect hepatic hepcidin production, but also indicate that correlation is not ideal, likely due to methodological limits and to several post-trascriptional events. In vitro study showed that THAL sera down-regulated, HFE-HH and C-NAFLD sera up-regulated hepcidin synthesis. HAMP mRNA expression in Huh-7 cells exposed to sera form C-Donors, HFE-HH and THAL reproduced, at lower level, the results observed in HepG2, suggesting the important but not critical role of HFE in hepcidin regulation.
doi:10.1371/journal.pone.0036425
PMCID: PMC3346721  PMID: 22586470
22.  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.
Introduction
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/ar4323
PMCID: PMC3978580  PMID: 24286116
23.  Evidence for a Lack of a Direct Transcriptional Suppression of the Iron Regulatory Peptide Hepcidin by Hypoxia-Inducible Factors 
PLoS ONE  2009;4(11):e7875.
Background
Hepcidin is a major regulator of iron metabolism and plays a key role in anemia of chronic disease, reducing intestinal iron uptake and release from body iron stores. Hypoxia and chemical stabilizers of the hypoxia-inducible transcription factor (HIF) have been shown to suppress hepcidin expression. We therefore investigated the role of HIF in hepcidin regulation.
Methodology/Principal Findings
Hepcidin mRNA was down-regulated in hepatoma cells by chemical HIF stabilizers and iron chelators, respectively. In contrast, the response to hypoxia was variable. The decrease in hepcidin mRNA was not reversed by HIF-1α or HIF-2α knock-down or by depletion of the HIF and iron regulatory protein (IRP) target transferrin receptor 1 (TfR1). However, the response of hepcidin to hypoxia and chemical HIF inducers paralleled the regulation of transferrin receptor 2 (TfR2), one of the genes critical to hepcidin expression. Hepcidin expression was also markedly and rapidly decreased by serum deprivation, independent of transferrin-bound iron, and by the phosphatidylinositol 3 (PI3) kinase inhibitor LY294002, indicating that growth factors are required for hepcidin expression in vitro. Hepcidin promoter constructs mirrored the response of mRNA levels to interleukin-6 and bone morphogenetic proteins, but not consistently to hypoxia or HIF stabilizers, and deletion of the putative HIF binding motifs did not alter the response to different hypoxic stimuli. In mice exposed to carbon monoxide, hypoxia or the chemical HIF inducer N-oxalylglycine, liver hepcidin 1 mRNA was elevated rather than decreased.
Conclusions/Significance
Taken together, these data indicate that hepcidin is neither a direct target of HIF, nor indirectly regulated by HIF through induction of TfR1 expression. Hepcidin mRNA expression in vitro is highly sensitive to the presence of serum factors and PI3 kinase inhibition and parallels TfR2 expression.
doi:10.1371/journal.pone.0007875
PMCID: PMC2773926  PMID: 19924283
24.  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.
doi:10.1371/journal.pone.0099781
PMCID: PMC4076189  PMID: 24978810
25.  Serum prohepcidin is associated with soluble transferrin receptor-1 but not ferritin in healthy post-menopausal women 
Blood cells, molecules & diseases  2008;41(3):265-269.
Hepcidin is a 25-amino-acid iron peptide hormone originated from its two precursors of prohepcidin (60-amino-acid) and preprohepcidin (84-amino-acid). Serum prohepcidin levels have been widely used to evaluate iron overload in clinical and preclinical studies. However, its usefulness is often questioned and its stepwise conversion mechanism remains largely unknown. Using New York University Women’s Health Study subjects, we measured serum levels of prohepcidin with ELISA and hepcidin with mass spectrometry as well as ferritin and soluble transferrin receptor 1 (sTfR1) in 45 normal healthy postmenopausal women over a 1-year period with 2 samples per subject. We found that serum prohepcidin levels are correlated with the serum sTfR1 levels (r=0.45, p<0.01) but not to ferritin levels (r=0.08, p=0.60), suggesting that serum prohepcidin is not a biomarker of iron overload that was originally thought and designed for. Interestingly, serum hepcidin levels are associated with serum ferritin levels (r=0.64, p<0.0001) but not with sTfR1 levels (r=0.04, p=0.69), indicating that hepcidin is a measure of iron overload. Although hepcidin is a downstream product of prohepcidin, the amounts of hepcidin and prohepcidin are not related to each other (r=−0.007, p=0.90) under normal physiological conditions. The interrelationships between sTfR1 and prohepcidin or between ferritin and hepcidin suggest that ferritin- and sTfR1-sensed hepcidin conversion system exists in human body and maybe regulated at the post-translational level.
doi:10.1016/j.bcmd.2008.06.009
PMCID: PMC2602946  PMID: 18694648
Iron; homeostasis; transferrin receptor; ferritin; hepcidin

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