Elevated Serum Hepcidin Levels Research Articles

Dry immersion rapidly disturbs iron metabolism in men and women: results from the VIVALDI studies

Iron is essential for cell respiration, muscle metabolism, and oxygen transport. Recent research has shown that simulated microgravity rapidly affects iron metabolism in men. However, its impact on women remains unclear. This study aims to compare iron metabolism alterations in both sexes exposed to 5 days of dry immersion. Our findings demonstrate that women, similarly to men, experience increased systemic iron availability and elevated serum hepcidin levels, indicative of iron misdistribution after short-term exposure to simulated microgravity.

AB0487 HEPSIDINE LEVEL IN PATIENTS WITH ANKYLOSING SPONDYLITIS, RELATIONSHIP WITH HEMOPOESIS AND FERROKINETICS

Background:Hypoferimia, as a manifestation of systemic inflammation, is quite common in patients with ankylosing spondylitis (AS). Anemic syndrome can be represented by anemia of chronic disease (ACD), iron deficiency anemia (IDA) and their combination. Its frequency of occurrences ranges from 18.5 to 45.8 %. The discovery of the hormone hepcidin in 2001 changed the perception of iron metabolism disorders and demonstrated its association with the inflammatory component. Over the last decade, scientific databases have accumulated a lot of information about hepcidin and its role in the development of anemia and the response to inflammation. However, in the context of the AS, such data are contradictory and therefore need further study.Objectives:To determine the level of hepcidin in patients with ankylosing spondylitis and to assess its relationship with hematopoiesis and ferrokinetics.Methods:The hepcidin levels of 76 patients with ankylosing spondylitis (13 women and 63 men with a mean age of 43.67±0.97 years). The diagnosis of AS was made according to the New York modified criteria of 1984. All patients were divided into three groups: without anemia (n=47), with anemia (n=29) and the control group, representative by age and sex (n=26). According to the percentile analysis, all patients were divided into a group with an optimal <25 ng/ml, extremely high - 25-35 ng/ml and a high level of hepcidin > 35 ng/ml. In addition to hepcidin, hematopoiesis and ferrokinetic parameters were measured in each patient: hemoglobin (Hb), erythrocyte, MCV, serum iron, total serum iron-binding capacity (TIBC), serum ferritin, transferrin saturation (TS). Statistical processing of the obtained results was performed with the use of statistical software package “Microsoft Office Excel 2007”.Results:When conducting a percentile comparison in 95 % of people in the control group, the level of hepcidin was in the range of 17.97-38.8 ng/ml (P5 - P95), and in patients with AS in 95 % - 14.62-87.38 ng/ml. At P95, the level of hepcidin in patients with AS was 2.3 times higher than in P95 control group. Comparing the mean values of hepcidin, a significant difference was found between the group of patients without anemia, where it was 36.08±2.57 ng/ml and the group of patients with anemia, where the level of hepcidin was 51.77±4.62 ng/ml. The lowest level of hepcidin was in patients with IDA (35.8 ±7.50 ng/ml), and the highest (62.78±5.94 ng/ml) - among patients with ACD. The group of patients with ACD and iron deficiency, according to the levels of hepcidin (48.53±9.50 ng/ml) took an intermediate place.In terms of hematopoiesis and ferrokinetics, the level of hemoglobin and erythrocytes did not differ significantly between the groups of optimal, extremely high and high levels of hepcidin. According to the levels of serum iron, TS and ferritin in the group of patients with anemia, a significant association with hepcidin was established (with increasing levels of hepcidin, the values of serum iron, TS and ferritin also increased). In contrast,sTfR levels were the highest in the group with optimal hepcidin levels (6.02±0.71 mg/l) and decreased to 4.88±0.64 mg/l in the group with high hepcidin levels. Such changes in hematopoiesis and ferrokinetics were explained by the accumulation of mostly people with symptoms of ACD in the group with high levels of hepcidin, and the group with optimal levels of hepcidin consisted mainly of patients with IDA.Conclusion:Patients with AS have elevated serum hepcidin levels, it is higher in individuals with anemic syndrome than in patients without anemia and is associated with serum iron, TS and ferritin levels.Disclosure of Interests:None declared.

A Phase 1/2 Study of INCB000928 As Monotherapy or in Combination with Ruxolitinib in Patients with Anemia Due to Myelofibrosis (INCB 00928-104)

A Phase 1/2 Study of INCB000928 As Monotherapy or in Combination with Ruxolitinib in Patients with Anemia Due to Myelofibrosis (INCB 00928-104)

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

Hyperferritinemia is observed in one-third of patients with non-alcoholic fatty liver disease (NAFLD) and Metabolic Syndrome (MetS). The condition characterized by increased body iron stores associated with components of MetS has been defined as Dysmetabolic Iron Overload Syndrome (DIOS). DIOS represents the most frequent iron overload condition, since it is observed in 15% of patients with MetS and in half of those with NAFLD and its clinical presentation overlaps almost completely with that of dysmetabolic hyperferritinemia (DH). The pathogenetic mechanisms linking insulin resistance (IR), NAFLD and DIOS to iron overload are still debated. Hepcidin seems to play a role in iron accumulation in DIOS and NAFLD patients who show elevated serum hepcidin levels. The iron challenge does not restrain iron absorption despite adequate hepcidin production, suggesting that an impaired hepcidin activity rather than a deficit of hormone production underlies DIOS pathogenesis. Acquired and genetic factors are recognized to contribute to iron accumulation in NAFLD whereas additional studies are required to clearly demonstrate whether the same or different genetic factors lead to iron overload in DIOS. Finally, iron depletion by phlebotomy, together with the modification of diet and life-style habits, represents the therapeutic approach to decrease metabolic alterations and liver enzymes in NAFLD and DIOS patients. In this review, we summarized the current knowledge on the dysregulation of iron homeostasis in NAFLD and DIOS in the attempt to clarify whether they are different or more likely strictly related conditions, sharing the same pathogenic cause i.e. the MetS.

Anemia of Inflammation with An Emphasis on Chronic Kidney Disease.

Iron is vital for a vast variety of cellular processes and its homeostasis is strictly controlled and regulated. Nevertheless, disorders of iron metabolism are diverse and can be caused by insufficiency, overload or iron mal-distribution in tissues. Iron deficiency (ID) progresses to iron-deficiency anemia (IDA) after iron stores are depleted. Inflammation is of diverse etiology in anemia of chronic disease (ACD). It results in serum hypoferremia and tissue hyperferritinemia, which are caused by elevated serum hepcidin levels, and this underlies the onset of functional iron-deficiency anemia. Inflammation is also inhibitory to erythropoietin function and may directly increase hepcidin level, which influences iron metabolism. Consequently, immune responses orchestrate iron metabolism, aggravate iron sequestration and, ultimately, impair the processes of erythropoiesis. Hence, functional iron-deficiency anemia is a risk factor for several ailments, disorders and diseases. Therefore, therapeutic strategies depend on the symptoms, severity, comorbidities and the associated risk factors of anemia. Oral iron supplements can be employed to treat ID and mild anemia particularly, when gastrointestinal intolerance is minimal. Intravenous (IV) iron is the option in moderate and severe anemic conditions, for patients with compromised intestinal integrity, or when oral iron is refractory. Erythropoietin (EPO) is used to treat functional iron deficiency, and blood transfusion is restricted to refractory patients or in life-threatening emergency situations. Despite these interventions, many patients remain anemic and do not respond to conventional treatment approaches. However, various novel therapies are being developed to treat persistent anemia in patients.

Elevated Serum Hepcidin Levels during an Intensified Training Period in Well-Trained Female Long-Distance Runners

Iron is essential for providing oxygen to working muscles during exercise, and iron deficiency leads to decreased exercise capacity during endurance events. However, the mechanism of iron deficiency among endurance athletes remains unclear. In this study, we compared iron status between two periods involving different training regimens. Sixteen female long-distance runners participated. Over a seven-month period, fasting blood samples were collected during their regular training period (LOW; middle of February) and during an intensified training period (INT; late of August) to determine blood hematological, iron, and inflammatory parameters. Three-day food diaries were also assessed. Body weight and lean body mass did not differ significantly between LOW and INT, while body fat and body fat percentage were significantly lower in INT (p < 0.05). Blood hemoglobin, serum ferritin, total protein, and iron levels, total iron-binding capacity, and transferrin saturation did not differ significantly between the two periods. Serum hepcidin levels were significantly higher during INT than LOW (p < 0.05). Carbohydrate and iron intakes from the daily diet were significantly higher during INT than LOW (p < 0.05). In conclusion, an elevated hepcidin level was observed during an intensified training period in long-distance runners, despite an apparently adequate daily intake of iron.

Risk factors for anemia in the early stages of chronic kidney disease

To identify the early markers of anemia in chronic kidney disease (CKD) in patients with chronic glomerulonephritis (CGN) and glomerulonephritis (GN) in systemic diseases. Seventy-nine patients with some male preponderance who were aged 21 to 65 years (45.3±11.1 years) and had CKD (CGN and GN) in systemic diseases (systemic lupus erythematosus and Wegener's granulomatosis) in the early stages (Stages I-II) of CKD were examined. GN was diagnosed by a lifetime renal biopsy. Systemic diseases were diagnosed according to the criteria for each nosological entity. The stages of CKD were defined according to the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) criteria; the glomerular filtration rate (GFR) was calculated using the CKD EPI equation (2012). According to the presence or absence of anemia, all the patients included in the study were divided into 2 groups: 1) 43 (54.4%) anemic patients; 2) 36 (45.6%) non-anemic patients (a control group). In addition to general clinical examination adopted for a nephrology department, special studies, such as determination of the serum levels of hepcidin, interferon-γ (IFN-γ), soluble Klotho protein (s-Klotho), as well as iron, ferritin, and transferrin saturation (TSAT) ratio, were performed to solve the set tasks. Forty-three anemic patients who had a hemoglobin level of 110 (100; 119) g/l and 36 control patients who had the similar values were noted to have statistically significantly (p<0.001) higher levels of IFN-γ (11 (10; 14) and 0.2 (0.09; 0.6) ng/ml), hepcidin (26 (25; 27) and 5.1 (3.8; 5.9) ng/ml) and C-reactive protein (1.5 (1.1; 2.1) and 0.3 (0.2; 0.6) mg/dl), and lower levels of s-Klotho protein (12 (10; 18) pg/ml) and TSAT (18 (14; 19)%. Forty-three patients with anemia were also found to have a statistically significantly (p<0.01) lower GFR (65 (62; 87) and 80.5 (62; 90) ml/min) and higher systolic blood pressure (145 (125; 160) and 120 (115; 16) mm Hg) as compared with those in 36 control patients. At the same time, the compared groups displayed no statistically significant differences in serum ferritin levels (123 (110; 150) and 115 (100; 140) µg/l). Among 43 CKD patients with anemia, its detection rate in the presence of systemic diseases was 3.2 times higher than that in CGN patients (41.7 and 12.7%). ROC analysis revealed that in the CKD patients with CGN and GN, the serum hepcidin level ≥ 25 ng/ml, with the sensitivity and specificity being of 89.7% and 74%, respectively (p > 0.001), was associated with the development of anemia. Moreover, the hemoglobin level of<120 g/ l was found to have an independent impact on the risk of reducing serum s-Klotho production. In Stage I-II CKD patients with CGN and GN in the presence of systemic diseases, elevated serum hepcidin levels should be regarded as a predictor for anemia of chronic disease (ACD). Herewith, the decrease in hemoglobin levels <120 g/l is associated with the reduced production of the nephroprotective factor s-Klotho. The treatment of ACD for Stages I-II CKD should encompass intravenous administration of iron in order to increase its content and availability for erythropoiesis.

Evaluation of Hepcidin and Atherosclerosis in Dialysis Patients.

Chronic kidney disease (CKD) is a condition that involves 10% - 15% of population worldwide, which increases the risk of cardio-vascular diseases (CVD). Chronic kidney disease is one of the main reasons for illness and mortality in the world. Chronic kidney disease is a serious health problem caused by involvement of a large number of patients with kidney injury, especially in industrial countries. Among the main reasons for this are population living longer and the number of diseases in elderly persons, such as diabetes mellitus type 2, hypertension, and cardio-vascular diseases. We evaluated 63 patients on chronic dialysis at the Dialysis Centre at University "Aleksandrovska" Hospital; the average age was 49.9 ± 7.8. Their results were compared to 63 age matched controls. Blood samplings were taken before dialysis procedure. In the included groups, we measured CBC, serum iron (by Ferrozine method), ferritin, soluble transferrin receptors and hsCRP (by nephelometric method), hepcidin (by ELISA method), and homocysteine (by CLIA method). IMT was measured by using electronic calipers and evaluated by automated software programs. We established elevated serum hepcidin levels in CKD patients (205.1 ± 29.9 µg/L) compared to the control group (20.8 ± 3.1 µg/L), p < 0.001. Serum homocysteine and hsCRP concentrations were elevated in CKD cases (48.7 ± 6.8 µmol/L; 29.7 ± 4.1 mg/L) compared to controls (7.9 ± 1.8 µmol/L; 1.1 ± 0.4 mg/L), p < 0.005. In patients with CKD we found a strong positive correlation between serum hepcidin and homocysteine concentrations, r = 0.879, p < 0.001. In patients with impaired kidney function soluble transferrin receptors correlated negatively to hepcidin: r = -0.799, p < 0.001. In dialysis, the transferrin concentration correlated highly positive to hepcidin: r = 0.691, p < 0.001. IMT in CKD patients correlated positively to hepcidin and homocysteine levels: r = 0.788 and r = 0.841, respectively, p < 0.005. Chronic kidney disease is connected to cardio-vascular disease risk factors. CKD might be an independent CVD risk factor. In early kidney injury stages, increased morbidity is found from CVD. The risk of fatal and non-fatal cardio-vascular incidents is connected to kidney injury. For clinical practice, early evaluation of hepcidin and atherosclerosis in chronic kidney disease patients is very important.

Serum Hepcidin Levels in Multiple Myeloma.

Multiple myeloma (MM) is a malignant disease with a 10% frequency among all haematology neoplasms. It is characterized by clone proliferation of plasmatic cells in bone marrow, monoclonal gammopathy, and anemia, hypercalcemia, and kidney failure and bone lesions. IL-6 is an inflammatory cytokine, potential growth factor for myeloma cells, as elevated serum levels are connected with poor disease prognosis. IL-6 modulates many gene transcriptions, encoding synthesis of acute phase proteins, including C-reactive protein (CRP) and hepcidin. We evaluated 21 patients newly diagnosed with multiple myeloma at the Department of Haematology at "Aleksandrovska" Hospital; average age 51 ± 5.2. Their results were compared to 21 age matched controls. Included patients were enrolled before treatment onset. In the included groups, we measured CBC, serum iron and total iron binding capacity, ferritin, soluble transferrin receptors, IL-6, and hepcidin. We established elevated serum hepcidin levels in MM patients compared to the control group: 99.4 ± 10.5 µg/L to 19.9 ± 2.8 µg/L (p < 0.001). Serum IL-6 and CRP concentrations were elevated in MM cases compared to controls (p < 0.005). In patients with MM we found strong negative correlation between serum hepcidin and inflammation markers, IL-6 and CRP. IL-6 shows r = -0.894, and CRP - r = -0.916; p < 0.001. Soluble transferrin receptors correlate negatively to hepcidin: r = -0.831, p < 0.001. Transferrin concentration correlated highly positive to hepcidin: r = 0.580; p < 0.001. Our results show an important role of hepcidin in the evaluation of iron homeostasis disorders. Quantification of the peptide's concentration shows increased concentration in multiple myeloma patients. Treatment of anemia associated with multiple myeloma is still a serious challenge for clinicians.

The Jak1/Jak2 Inhibitor Momelotinib Inhibits Alk2, Decreases Hepcidin Production and Ameliorates Anemia of Chronic Disease (ACD) in Rodents

▪Many patients with myelofibrosis (MF) develop anemia and are, or become, dependent on frequent red blood cell transfusions [1]. Results from the phase 2 studies for the treatment of myelofibrosis (MF) with the Jak1/2 inhibitor momelotinib (MMB) demonstrated that MMB treatment provided an anemia benefit, in addition to providing a durable spleen response and improvement in constitutional symptoms in MF patients [2]. MMB's anemia benefit was an unexpected outcome as erythropoietin (EPO)-mediated JAK2 signaling is essential for erythropoiesis [3, 4]. Systemic iron homeostasis is controlled by the peptide hormone hepcidin produced by the liver. Hepcidin reduces iron export from duodenal enterocytes and splenic and hepatic macrophages by binding to and down-regulating the iron exporter ferroportin [5-7]. In chronic disease, there is a significant increase in hepcidin levels which can result in severe anemia; this pathologic condition is termed anemia of chronic disease (ACD). Recently, MF patients have been shown to have elevated serum hepcidin levels and this increase is associated with inferior overall survival in these patients [8].This study aimed to determine whether MMB's clinical anemia benefit is driven by direct activity of MMB on the hepcidin pathway. We assayed MMB inhibitory activity on the BMP-receptor kinase pathway (the central driver of hepcidin transcription in hepatocytes) and assessed the activity of MMB in a rodent model of anemia of chronic disease (ACD). We demonstrate that MMB inhibits BMP6-induced in vitro production of hepcidin in cultured hepatocytes (HepG2 cells) with an EC50 = 651 +/- 203 nM (n=3). This inhibitory activity is mediated by direct suppresion of the BMP-receptor kinase Alk2 as MMB inhibits Alk2 enzymatic activity with an IC50 = 8.4 +/- 1.5 nM (n=3). Ruxolitinib has no activity on either Alk2 or the BMP-receptor kinase pathway. To understand whether MMB could modulate hepcidin levels in vivo and ameliorate anemia in vivo we assessed the effect of MMB in a peptidoglycan-polysaccharide fragment (PG-APS)-induced rat ACD model. Treatment with clinically relevant exposure levels of MMB for 3 days resulted in a dose dependent reduction in both liver RNA and serum protein hepcidin levels and caused an increase in serum iron. Furthermore, long-term treatment with MMB for 21 days increased the numbers and percent of reticulocytes and mature red blood cells in the bone marrow and increased Hgb and hematocrit to normal levels in the blood.Our data suggest that MMB's clinical anemia benefit results from inhibition of ALK2-mediated expression of hepcidin in the liver, which results in increased release of iron from sequestered cellular stores and enhanced erythropoiesis. A phase 2 translational study in anemic subjects with MPNs is scheduled to confirm this mechanism. The Alk2-mediated activity on iron metabolism through hepcidin could prove beneficial in a number of additional indications, and facilitate the combination of MMB with myelosuppressive agents.1. Tefferi, A., et al., One thousand patients with primary myelofibrosis: the mayo clinic experience. Mayo Clin Proc, 2012. 87 (1): p. 25-33.2. Pardanani, A., et al., Update On The Long-Term Efficacy and Safety Of Momelotinib, a JAK1 and JAK2 Inhibitor, For The Treatment Of Myelofibrosis. Vol. 122. 2013. 108-108.3. Verstovsek, S., et al., Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med, 2010. 363 (12): p. 1117-27.4. Verstovsek, S., et al., A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med, 2012. 366 (9): p. 799-807.5. Nemeth, E., et al., Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science, 2004. 306 (5704): p. 2090-3.6. Theurl, I., et al., Dysregulated monocyte iron homeostasis and erythropoietin formation in patients with anemia of chronic disease. Blood, 2006. 107 (10): p. 4142-8.7. Theurl, I., et al., Autocrine formation of hepcidin induces iron retention in human monocytes. Blood, 2008. 111 (4): p. 2392-9.8. Pardanani, A., et al., Associations and prognostic interactions between circulating levels of hepcidin, ferritin and inflammatory cytokines in primary myelofibrosis. Am J Hematol, 2013. 88 (4): p. 312-6. DisclosuresWarr:Gilead Science: Employment. Maciejewski:Gilead Science: Employment. Fowles:Gilead Science: Employment. Whitney:Gilead Sciences: Employment. Theurl:Gilead Science: Research Funding.

B-cell translocation gene 2 promotes hepatic hepcidin production via induction of Yin Yang 1

Hepcidin is a peptide hormone secreted in the liver and plays a key role in maintaining iron homeostasis. Here, we demonstrate that B-cell translocation gene 2 (BTG2) is a key player in hepatic hepcidin regulation via induction of Yin Yang 1 (YY1). Hepatic hepcidin gene expression significantly enhanced by fasting states and glucagon exposure led to induction of gluconeogenic gene expression, and elevated serum hepcidin production in mice. Notably, overexpression of BTG2 using adenoviral system (Ad-BTG2) significantly elevated serum hepcidin levels via a significant induction of YY1 gene transcription. Immunoprecipitation studies demonstrated that BTG2 physically interacted with YY1 and recruited on the hepcidin gene promoter. Finally, ablation of hepatic BTG2 gene by gene silencing markedly attenuated the elevation of serum hepcidin production along with YY1 and hepcidin mRNA expression in fasting state. Likewise, forskolin (FSK)-stimulated hepcidin promoter activity was dramatically disrupted by endogenous BTG2 knockdown. Overall, our current study provides a novel molecular mechanism of BTG2-mediated induction of hepcidin gene expression, thereby contributing to a better understanding of the hepatic hepcidin production involved in iron homeostasis.

Is There a Link Between Changes in Levels of Hepcidin and Stroke?

Iron is an essential element for the living body. It is well known that iron homeostasis disorders are important in two ways--its deficiency and its overload lead to several pathologies. We measured 17 patients with iron deficiency anemia (IDA); 19 with anemia of chronic diseases (ACD); 15 with ischemic stroke (IS). The results were compared to a previously selected control group. For evaluation of iron metabolism status, we measured serum iron levels, ferritin, and soluble transferrin receptors. For inflammation, serum interleukin-6 and hsCRP were measured. Serum hepcidin quantification was performed using a previously validated immunosorbent method. Ferritin was measured by an ECLIA method; serum iron on AAS; hsCRP using a nephelometric analysis. We found statistically significant elevated serum hepcidin levels in patients with ACD and IS compared to the control group (p < 0.001). Patients with IDA had statistically significant lower hepcidin levels compared to the control group (p < 0.001). Serum ferritin levels in the IS group was higher compared to the control and other groups (p < 0.001). The lowest ferritin concentrations were established in the IDA group compared to the control (p < 0.001). We found a strong correlation between serum hepcidin and ferritin levels in the IS group (r = 0.583; p < 0.001). Quantification of serum hepcidin levels might be used as a link for prediction of acute ischemic stroke and future therapeutic influences.

Do the first, second and third trimester maternal serum hepcidin concentrations clarify obstetric complications?

Objective: To evaluate whether first, second, and third-trimester maternal serum hepcidin levels are different in pregnancies with and without adverse pregnancy outcomes (APO).Methods: A 165 nullipar pregnant women were included in this prospective cohort study. Serum hepcidin, ferritin, IL-6, C-reactive protein (CRP) and Hb values were measured at 11–14, 24–28, and 30–34 weeks of gestation. The relation between these parameters and APO and neonatal outcomes were investigated. Preterm delivery, intrauterine growth restriction, pre-eclampsia, gestational hypertension and placental abruption were determined as adverse pregnancy outcomes.Results: The risk of APO was three times higher in women with high IL-6 levels in the second trimester. High hepcidin levels in the second trimester were associated with a 1.6 times increased risk of APO. Newborns of women with high IL-6 levels in the third trimester had a 1.6-fold increased risk of neonatal complications. High ferritin levels in the third trimester were associated with minimally increased risk of neonatal complications.Conclusions: Mean serum hepcidin levels were similar in all pregnant women, however, elevated second trimester serum hepcidin and IL-6 levels were associated with a higher risk of APO and high third trimester hepcidin, ferritin and IL-6 levels were associated with higher risk of neonatal complications.

Inverse Relationship of Serum Hepcidin Levels with CD4 Cell Counts in HIV-Infected Patients Selected from an Indonesian Prospective Cohort Study

BackgroundDistortion of iron homeostasis may contribute to the pathogenesis of human immunodeficiency virus (HIV) infection and tuberculosis (TB). We studied the association of the central iron-regulatory hormone hepcidin with the severity of HIV and the association between hepcidin and other markers of iron homeostasis with development of TB.MethodsThree groups of patients were selected from a prospective cohort of HIV-infected subjects in Bandung, Indonesia. The first group consisted of HIV-infected patients who started TB treatment more than 30 days after cohort enrollment (cases). The second group consisted of HIV-infected patients who were matched for age, gender and CD4 cell count to the cases group (matched controls). The third group consisted of HIV-infected patients with CD4 cell counts above 200 cells/mm3 (unmatched controls). Iron parameters including hepcidin were compared using samples collected at cohort enrollment, and compared with recently published reference values for serum hepcidin.ResultsA total of 127 HIV-infected patients were included, 42 cases together with 42 matched controls and 43 unmatched controls. Patients with advanced HIV infection had elevated serum hepcidin and ferritin levels. Hepcidin levels correlated inversely with CD4 cells and hemoglobin. Cases had significantly higher hepcidin and ferritin concentrations at cohort enrollment compared to matched controls, but these differences were fully accounted for by the cases who started TB treatment between day 31 and 60 after enrollment. Hepcidin levels were not different in those with or without hepatitis C infection.ConclusionIron metabolism is distorted in advanced HIV infection with CD4 cell counts correlating inversely with serum hepcidin levels. High serum hepcidin levels and hyperferritinemia were found in patients starting TB treatment shortly after cohort enrollment, suggesting that these parameters have a predictive value for development of manifest TB in HIV-infected patients.

Hepcidin is a Potential Regulator of Iron Status in Chronic Kidney Disease

Hepcidin is a small defensin-like peptide produced primarily by hepatocytes, but also by other cells, including macrophages. In addition to hepcidin's antimicrobial properties, it is the main regulator of iron metabolism and controls both the amount of dietary iron absorbed in the duodenum and the iron release by reticuloendothelial cells. Hepcidin expression is upregulated by a variety of stimuli, including inflammation and iron overload, and downregulated by anemia, hypoxia, and iron deficiency. Chronic kidney disease (CKD) is associated with increased serum hepcidin levels, and the increased levels may contribute to the development and severity of anemia and to resistance to erythropoiesis-stimulating agents (ESAs). Elevated serum hepcidin levels contribute to the dysregulation of iron homeostasis in CKD patients. Although parenteral iron supplementation can bypass some of the iron-blocking effects of hepcidin in CKD patients with anemia, and free iron and iron stores increase as a result, the anemia is only partially corrected, and the ESA dose requirements remain significantly higher than needed for physiological replacement. Treatment with agents that lower serum hepcidin levels or inhibit its actions may be an effective strategy for restoring normal iron homeostasis and improving anemia in CKD patients. The aim of this article was to review the regulation of hepcidin levels and the role of hepcidin in CKD-related anemia, and to discuss hepcidin's potential as a clinical biomarker and several investigational treatments designed to lower serum hepcidin levels.

Identification and characterization of the first SLC11A2 isoform 1a mutation causing a defect in splicing process and an hypomorphic allele expression of the SLC11A2 gene

Identification and characterization of the first <scp>SLC</scp>11<scp>A</scp>2 isoform 1a mutation causing a defect in splicing process and an hypomorphic allele expression of the <i><scp>SLC</scp>11<scp>A</scp>2</i> gene

Chronic IL‐22Fc administration induces liver hepcidin expression and relative iron deficiency anemia.

Interleukin‐22 (IL‐22), a member of the IL‐10 cytokine family, is produced by activated TH17 and NK cells and binds to a specific heterodimeric receptor expressed on epithelium of the skin, respiratory and digestive tracts and hepatocytes. In vitro, IL‐22 stimulates hepatoma cell lines to express α1‐antichymotrypsin, haptoglobin, serum amyloid A, and in vivo administration stimulates LPS binding protein expression by the liver. Treatment of C57BL/6 mice with IL‐22Fc for either 9 days (200 μg I.P. SID) or 4 weeks (150 μg I.P., 3 times per week) induced hypochromic anemia associated with a decreased serum iron concentration, suggesting relative iron deficiency. Given that IL‐22 is also known as “hepatocyte stimulating factor” and iron balance is partially controlled by hepatic expression of the protein hepcidin, we measured serum hepcidin levels by mass spectrometer analysis. Animals treated with IL‐22 had elevated serum hepcidin levels as compared to controls. Previously reported to be elevated in chronically inflamed tissues, IL‐22 may participate in the anemia of chronic inflammatory disease through hepcidin‐induced alterations of iron metabolism.

PP-010 Serum hepcidin: a predictor of early graft dysfunction following orthotopic liver transplantation?

<h3>Introduction</h3> The hepatic peptide hepcidin is a critical regulator of iron metabolism. Serum levels of hepcidin correlate with liver function in humans and rodent studies have shown that liver injury modulate hepcidin expression. This is the first study of hepcidin levels in patients undergoing liver transplantation. We show that post-transplant serum hepcidin levels identify patients with severe preservation/reperfusion injury and hence predict graft dysfunction following liver transplantation. <h3>Methods</h3> Serial serum hepcidin levels were measured by SELDI-TOF mass spectrometry in 11 patients undergoing liver transplantation. Liver biopsies (T0) were taken during transplantation in 9/11 patients. Clinicopathological, biochemical and haematological data were compared. <h3>Results</h3> 5/11 patients had poor graft function after transplantation (determined by graft cholestasis, elevated PT and AST levels). Patients with poor graft function were more likely to have evidence of moderate/severe preservation injury at T0 biopsy than patients with normal graft function and were more likely to have received a liver from a non-heart beating (NHB) than a heart-beating donor (3/5 vs 1/7, respectively). While there was no difference in hepcidin levels between the two groups at the time of transplantation (90 vs 76 ng/ml p=0.68), the five patients with poor graft function had significantly higher hepcidin levels on day 3 post-transplantation compared to the six patients with mild preservation injury (Mean 135 (91–179) vs 39 (17–61) ng/ml, respectively, p&lt; 0.01 ANOVA). Mean serum hepcidin values rose by 393% between day 1 and day 3 post transplant in the group with poor graft function whereas there was a 49% drop in serum hepcidin level in the group with normal function. The rise in hepcidin values at day 3 anticipated the onset of graft cholestasis in all of the patients with severe preservation injury. <h3>Conclusion</h3> This is the first study of serum hepcidin levels in patients undergoing liver transplantation. We show that hepcidin values rapidly fall in patients with normal graft function following transplantation, but remain elevated in patients with early graft dysfunction. Elevated serum hepcidin levels accurately predicted the onset of preservation injury and anticipated graft dysfunction. Moreover we show that hepcidin levels are a better determinant of future graft dysfunction than AST or CRP. Early identification of graft dysfunction is important as it allows for modification of immunosuppression. We show that day 3 hepcidin levels correlate well with the severity of graft injury and can be used as a predictor of early graft dysfunction.