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1.  Lower serum prohepcidin levels associated with lower iron and erythropoietin requirements in hemodialysis patients with chronic hepatitis C 
BMC Nephrology  2012;13:56.
Patients with chronic HCV infection have increased liver iron. Recently identified protein hepcidin synthesized in the liver, is thought to be a key regulator for iron homeostasis and is induced by infection and inflammation. Lower erythropoietin and iron supplementation requirements were previously reported in HD patients with HCV infection. We investigated the association of prohepcidin with inflammation and iron parameters in HD patients with and without chronic HCV infection.
Sixty patients (27 male, 33 female, mean age 50 ±15 years) on chronic HD were included. Parameters related to iron metabolism (ferritin, serum iron and total iron binding capacity (TIBC)), inflammation (hs-CRP, TNF-α and IL-6) and prohepcidin levels were measured. The response to treatment (erythropoiesis-stimulating agent (ESA) resistance index) was assessed from the ratio of the weekly erythropoietin (rhuEPO) dose to hemoglobin (Hb) per unit weight.
Serum prohepcidin levels of HCV positive patients (135 ± 25 ng/mL) were significantly lower than HCV negative patients [148 ± 18 ng/mL, (p = 0.025)]. Serum IL-6 levels of HCV positive patients were also significantly lower than HCV negative patients (p = 0.016). Serum prohepcidin levels were positively correlated with ferritin (r = 0.405, p = 0.001) and IL-6 (r = 0.271, p = 0.050) levels in HD patients. In the HCV positive group, serum prohepcidin levels significantly correlated with ferritin levels (r = 0.514 p = 0.004). In the HCV negative group, serum prohepcidin levels significantly correlated with serum IL-6 levels (r = 0.418, p = 0.027). In multiple regression analysis performed to predict prohepcidin in HCV positive patients, serum ferritin was found to be an independent variable (r = 0.28, p = 0.008).
HCV positive HD patients have low levels of serum prohepcidin and IL-6 which might account for iron accumulation together with lower iron and rhuEPO requirements in these patients.
PMCID: PMC3496582  PMID: 22768976
Hemodialysis; Hepcidin; Iron metabolism; Inflammation; Hepatitis C; Ferritin
2.  Serum Prohepcidin Levels Are Lower in Patients with Atrophic Gastritis 
Background/Aim. Hepcidin, an iron regulatory hormone, is increased in response to inflammation and some infections. We investigated the relationships among serum prohepcidin, iron status, Helicobacter pylori infection status, and the presence of gastric mucosal atrophy. Methods. Seventy subjects undergoing esophagogastroduodenoscopy underwent multiple gastric biopsies, and the possibility of H. pylori infection and the degree of endoscopic and histologic gastritis were investigated. In all subjects, serum prohepcidin and iron parameters were evaluated. Results. No correlations were observed between serum prohepcidin levels and the other markers of anemia, such as hemoglobin, serum iron, ferritin, and total iron binding capacity. Serum prohepcidin levels were not significantly different between the H. pylori-positive group and the H. pylori-negative group. Serum prohepcidin levels in atrophic gastritis patients were significantly lower than those in subjects without atrophic gastritis irrespective of H. pylori infection. Conclusion. Serum prohepcidin levels were not altered by H. pylori infection. Serum prohepcidin levels decrease in patients with atrophic gastritis, irrespective of H. pylori infection. It suggests that hepcidin may decrease due to gastric atrophy, a condition that causes a loss of hepcidin-producing parietal cells. Further investigations with a larger number of patients are necessary to substantiate this point.
PMCID: PMC3603588  PMID: 23533385
3.  Serum prohepcidin levels in chronic hepatitis C, alcoholic liver disease, and nonalcoholic fatty liver disease 
The Korean Journal of Hepatology  2010;16(3):288-294.
Patients with various chronic liver diseases frequently have increased body iron stores. Prohepcidin is an easily measurable precursor of hepcidin, which is a key regulator of iron homeostasis. This study investigated the serum prohepcidin levels in patients with various chronic liver diseases with various etiologies.
Serum prohepcidin levels were measured in patients with chronic hepatitis C (CH-C) (n=28), nonalcoholic fatty liver disease (NAFLD) (n=24), and alcoholic liver disease (ALD) (n=22), and in healthy controls (n=25) using commercial ELISA. Serum interleukin 6 (IL-6) levels and blood iron indices were also measured.
The serum levels of both prohepcidin and IL-6 were significantly higher in CH-C patients than in healthy controls, and there was a positive correlation between the IL-6 and prohepcidin levels (r=0.505, p=0.020). The prohepcidin levels in ALD patients did not differ from those in controls, despite their significantly elevated IL-6 levels. There was a tendency for a negative correlation between serum prohepcidin levels and transferrin saturation in ALD patients (r=-0.420, p=0.051). Neither prohepcidin nor IL-6 was significantly elevated in the NAFLD group, despite the presence of elevated serum iron and ferritin levels.
The role of prohepcidin may differ in different human liver diseases. In the setting of CH-C, both the serum prohepcidin and IL-6 levels were significantly elevated and were positively correlated with each other.
PMCID: PMC3304592  PMID: 20924211
Prohepcidin; Hepatitis C; Fatty liver; Alcohol; IL-6
4.  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.
PMCID: PMC2602946  PMID: 18694648
Iron; homeostasis; transferrin receptor; ferritin; hepcidin
5.  Serum prohepcidin levels are potential prognostic markers in patients with multiple myeloma 
Prohepcidin is the prohormone of hepcidin. Anemia is one of the main clinical features in patients with multiple myeloma (MM) and hepcidin may be associated with iron homeostasis in these patients. However, the clinical significance of prohepcidin is not fully understood. In this retrospective study, we measured serum prohepcidin levels using an immunoassay technique to study its clinical significance in 39 MM patients. Serum prohepcidin levels in patients with MM were weakly correlated with alkaline phosphatase (ALP) levels (r=0.32, P=0.048), calculated by Spearman’s rank correlation, but not with other clinical data, including hemoglobin, serum iron or ferritin. In addition, patients with severe renal insufficiency [creatinine clearance (CCr) <50 ml/min] had significantly higher prohepcidin levels compared with patients with mild or no renal insufficiency (CCr ≥50 ml/min, P=0.047). In contrast, low serum prohepcidin levels less than 110 ng/ml were an independent predictor of poor overall survival [hazard ratio (HR), 5.29; 95% confidence interval (CI), 1.65–17.03] in addition to serum creatinine levels of at least 2 mg/dl (HR, 5.32; CI, 1.10–25.64), serum calcium (HR, 3.53; CI, 1.01–12.33) and ECOG performance status grade 4 (HR, 4.15; CI, 1.32–13.09) in the multivariate analysis using Cox proportional hazards model. In the subset of 31 MM patients with CCr ≥50 ml/min, low serum prohepcidin (HR, 5.65; CI, 1.60–19.95) was an indicator of poor prognosis in multivariate analysis. These results indicate that serum prohepcidin levels may be associated with ALP and renal function but not iron homeostasis, in MM patients. In addition, lower serum prohepcidin levels are potential independent indicators of poor overall survival in MM patients regardless of renal function.
PMCID: PMC3501378  PMID: 23170109
hepcidin; prohepcidin; multiple myeloma; prognostic factor
6.  Serum Prohepcidin Levels in Helicobacter Pylori Infected Patients with Iron Deficiency Anemia 
Helicobacter pylori (H. pylori) infection appears to subvert the human iron regulatory mechanism and thus upregulates hepcidin, resulting in unexplained iron-deficiency anemia (IDA). We evaluated serum prohepcidin levels before and after eradication of H. pylori in IDA patients to assess whether it plays a role in IDA related to H. pylori infection.
Subjects diagnosed with unexplained IDA underwent upper gastrointestinal endoscopy and colonoscopy to confirm H. pylori infection and to exclude gastrointestinal bleeding. Blood was sampled before treatment to eradicate H. pylori and again 1 month later. Serum prohepcidin levels were measured using a commercial enzyme-linked immunosorbent assay kit.
Serum prohepcidin levels decreased significantly after oral iron replacement combined with H. pylori eradication (p = 0.011). The reduction ratio of serum prohepcidin levels after the treatment did not differ among the combined oral iron replacement and H. pylori eradication groups, the H. pylori eradication only group, and the iron replacement only group (p = 0.894).
Serum prohepcidin levels decrease after both H. pylori eradication and oral iron administration, with improvement in IDA. Serum concentration of prohepcidin is related to the anemia status, rather than to the current status of H. pylori infection, in IDA patients.
PMCID: PMC2880694  PMID: 20526394
Prohepcidin; Anemia, iron-deficiency; Helicobacter pylori
7.  Relationship between Serum Levels of Body Iron Parameters and Insulin Resistance and Metabolic Syndrome in Korean Children 
An increase in serum ferritin and levels of the cleaved soluble form of transferrin receptor (sTfR) are related to several metabolic conditions. We evaluated the relationship between body iron status indicators, including ferritin and sTfR, and insulin resistance and metabolic syndrome (MetS) in Korean children.
A cross-sectional study was conducted on 1350 children in Korea. Anthropometrical parameters; lipid profiles; levels of glucose, insulin, and leptin; and iron status indicators, including sTfR, serum ferritin, serum iron, total iron-binding capacity (TIBC), and transferrin saturation (TS), were analyzed.
Although serum sTfR levels were significantly higher in boys than in girls (2.20 vs. 2.06 mg/L, p < 0.0001), serum iron and TS were higher in girls than in boys (101.38 vs. 95.77 mg/L, p = 0.027 and 30.15 vs. 28.91%, p = 0.04, respectively). Waist circumference (WC) and leptin were most significantly associated with body iron indicators when adjusted for age and sex. After adjusting for age, sex, and WC, sTfR levels showed the strongest positive association with leptin levels (p = 0.0001). Children in the highest tertile for homeostasis model assessment-insulin resistance (HOMA-IR) had higher TIBC (p = 0.0005) and lower serum iron (p = 0.0341), and the lowest TS (p < 0.0001) after adjustment for confounders. Children with higher sTfR were most significantly associated with risk of MetS compared with those lower sTfR (p = 0.0077).
The associations of serum levels of iron metabolism markers with leptin levels, HOMA-IR, and MetS suggest that iron-related factors may involve insulin resistance and MetS.
PMCID: PMC4214999  PMID: 25379371
body iron store; HOMA-IR; metabolic syndrome; sTfR; TS
8.  Iron status, inflammation and hepcidin in ESRD patients: The confounding role of intravenous iron therapy 
Indian Journal of Nephrology  2010;20(3):125-131.
Uremia is a state of heightened inflammatory activation. This might have an impact on several parameters including anemia management. Inflammation interferes with iron utilization in chronic kidney disease through hepcidin. We studied the body iron stores, degree of inflammatory activation, and pro-hepcidin levels in newly diagnosed patients with end-stage renal disease (ESRD), and compared them with normal population. In addition to clinical examination and anthropometry, the levels of iron, ferritin, C-reactive protein, tumor necrosis factor alfa, interleukin-6, and prohepcidin were estimated. A total of 74 ESRD patients and 52 healthy controls were studied. The ESRD patients had a significantly lower estimated body fat percentage, muscle mass, and albumin; and higher transferrin saturation (TSAT) and raised serum ferritin. Inflammatory activation was evident in the ESRD group as shown by the significantly higher CRP, IL-6, and TNF-α levels. The pro-hepcidin levels were also increased in this group. Half of the ESRD patients had received parenteral iron before referral. Patients who had received intravenous iron showed higher iron, ferritin, and TSAT levels. These patients also showed more marked inflammatory activation, as shown by the significantly higher CRP, TNF-α, and IL-6 levels. We conclude that our ESRD patients showed marked inflammatory activation, which was more pronounced in patients who had received IV iron. High hepcidin levels could explain the functional iron deficiency. The cause of the relatively greater degree of inflammatory activation as well as the relationship with IV iron administration needs further studies.
PMCID: PMC2966977  PMID: 21072151
Anemia; end-stage renal disease; hepcidin; inflammation; intravenous iron
9.  Successful antiviral therapy is associated with a decrease of serum prohepcidin in chronic hepatitis C 
AIM: To assess serum concentrations of prohepcidin in chronic hepatitis C individuals and evaluate their associations with disease activity and efficacy of pegylated interferon (PEG-IFN)/ribavirin (RBV) therapy.
METHODS: Prohepcidin was measured in sera of 53 chronic hepatitis C patients. Concentrations of prohepcidin and other iron metabolism markers were analyzed at 9 time points before, during and after the end of antiviral therapy.
RESULTS: In hepatitis C virus (HCV) genotype 1-infected individuals, a gradual decrease of prohepcidin during antiviral therapy was observed in responders (88.8 ± 14.7 ng/mL before therapy vs 60.6 ± 0.3 ng/mL in the 48th wk, P = 0.04). In contrast, no decrease was observed in non-responders. A similar association was observed in HCV genotype 3a individuals, with a statistically significant decline in serum prohepcidin only in the responder group (99.5 ± 5.2 ng/mL at baseline vs 72.7 ± 6.1 ng/mL in the 24th wk, P = 0.01). Moreover, HCV-RNA at week 12 of therapy was positively correlated with baseline (R = 0.63, P < 0.005) and week 12 (R = 0.60, P = 0.01) serum prohepcidin concentrations in HCV genotype 1 infection.
CONCLUSION: Successful PEG-IFN/RBV therapy results in a decline of serum prohepcidin concentration in chronic hepatitis C, which may suggest a direct effect of HCV on iron metabolism at the prohormonal level of hepcidin.
PMCID: PMC2852823  PMID: 20380007
Iron metabolism; Hepcidin; Hepatitis C virus; Interferon; Sustained viral response
10.  Decreased Serum Hepcidin Concentration Correlates with Brain Iron Deposition in Patients with HBV-Related Cirrhosis 
PLoS ONE  2013;8(6):e65551.
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.
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.
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.
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.
PMCID: PMC3679136  PMID: 23776499
11.  Serum hepcidin levels and iron parameters in children with iron deficiency 
The Korean Journal of Hematology  2012;47(4):286-292.
Iron deficiency (ID) and iron deficiency anemia (IDA) are common nutritional disorders in children. Hepcidin, a peptide hormone produced in the liver, is a central regulator of systemic iron metabolism. We evaluated whether serum hepcidin levels can diagnose ID in children.
Sera from 59 children (23 males and 36 females; 5 months to 17 years) were analyzed for hepcidin-25 by ELISA. Patients were classified according to hemoglobin level and iron parameters as: IDA, (N=17), ID (N=18), and control (N=24).
Serum hepcidin, ferritin, soluble transferrin receptor (sTfR), transferrin saturation, and hemoglobin levels differed significantly between groups (P<0.0001). Serum hepcidin and ferritin levels (mean±SD) were 2.01±2.30 and 7.00±7.86, 7.72±8.03 and 29.35±24.01, 16.71±14.74 and 46.40±43.57 ng/mL in the IDA, ID, and control groups, respectively. The area under the receiver operating characteristic curve for serum hepcidin as a predictor of ID was 0.852 (95% CI, 0.755-0.950). Hepcidin ≤6.895 ng/mL had a sensitivity of 79.2% and specificity of 82.8% for the diagnosis of ID. Serum hepcidin levels were significantly correlated with ferritin, transferrin saturation, and hemoglobin levels and significantly negatively correlated with sTfR level and total iron binding capacity (P<0.0001).
Serum hepcidin levels are significantly associated with iron status and can be a useful indicator of ID. Further studies are necessary to validate these findings and determine a reliable cutoff value in children.
PMCID: PMC3538801  PMID: 23320008
Serum hepcidin; Iron deficiency; Children
12.  Coinfection with HIV-1 Alleviates Iron Accumulation in Patients with Chronic Hepatitis C Virus Infection 
PLoS ONE  2014;9(6):e98039.
Most chronically-infected hepatitis C virus (HCV) patients have increased levels of iron in the liver. Iron overload reduces sustained responses to antiviral therapy, leading to more rapid progression to liver cirrhosis and the development of hepatocellular carcinoma. However, it is still unclear how HIV-1 infection affects iron status in patients chronically infected with HCV. The present study recruited 227 patients from a village in central China. These patients were either monoinfected with HCV (n = 129) or coinfected with HCV/HIV-1 (n = 98). Healthy controls (n = 84) were also recruited from the same village. Indicators of iron status, such as serum levels of iron, ferritin, and transferrin, total iron-binding capacity (TIBC), transferrin saturation (Tfs), and hepcidin, were analyzed and compared across the three groups. The results showed that serum levels of iron (p = 0.001) and ferritin (p = 0.009) and the Tfs (p = 0.002) were significantly higher in HCV-monoinfected patients than in the healthy controls; however, there were no differences in iron levels and Tfs between HCV/HIV-1 coinfected patients and healthy controls. Additionally, although serum hepcidin levels in HCV-monoinfected and HCV/HIV-1-coinfected patients were lower (p<0.001) than those in health controls, the levels in coinfected patients were higher (p = 0.025) than those in HCV-monoinfected patients. Serum iron and ferritin levels in HCV-monoinfected patients were positively correlated with serum ALT/AST. Serum transferrin levels were negatively correlated with ALT/AST levels. The levels of iron in the serum of coinfected patients with a CD4+T-cell count <500/µl were lower than those in patients with a CD4+T-cell count ≥500/µl, whereas serum hepcidin levels showed the opposite trend. Taken together, these results suggest that coinfection with HIV-1 alleviates iron accumulation caused by chronic HCV infection. Our study indicated that determining the status of serum iron and other iron-associated parameters will be helpful to understand the complexity of alternations in iron distribution in HCV/HIV-1-coinfected patients.
PMCID: PMC4057081  PMID: 24927015
13.  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
14.  Serum heavy metals and hemoglobin related compounds in Saudi Arabia firefighters 
Firefighters are frequently exposed to significant concentrations of hazardous materials including heavy metals, aldehydes, hydrogen chloride, dichlorofluoromethane and some particulates. Many of these materials have been implicated in the triggering of several diseases. The aim of the present study is to investigate the effect of fire smoke exposure on serum heavy metals and possible affection on iron functions compounds (total iron binding capacity, transferrin saturation percent, ferritin, unsaturated iron-binding capacity blood hemoglobin and carboxyhemoglobin,).
Subjects and methods
Two groups of male firefighter volunteers were included; the first included 28 firefighters from Jeddah city, while the second included 21 firefighters from Yanbu city with an overall age rang of 20–48 years. An additional group of 23 male non-firefighters volunteered from both cities as normal control subjects. Blood samples were collected from all volunteer subjects and investigated for relevant parameters.
The results obtained showed that there were no statistically significant changes in the levels of serum heavy metals in firefighters as compared to normal control subjects. Blood carboxyhemoglobin and serum ferritin were statistically increased in Jeddah firefighters, (p < 0.05 and p < 0.05 respectively) and Yanbu firefighters, (p < 0.005 and p < 0.001 respectively) as compared to normal control group while serum TIBC and UIBC were statistically decreased in Yanbu firefighters as compared to Jeddah firefighters, (p < 0.005 and p < 0.005 respectively) and normal control group, (p < 0.005 and p < 0.01 respectively). On the other hand, serum transferrin saturation percent was elevated in only Yanbu firefighters, (p < 0.05) as compared to Jeddah firefighters. Besides, there was no statistically significant change in blood hemoglobin and serum iron on comparison between all studied groups.
Such results might point to the need for more health protective and prophylactic measures to avoid such hazardous health effects (elevated Blood carboxyhemoglobin and serum ferritin and decreased serum TIBC and UIBC) that might endanger firefighters working under dangerous conditions. Firefighters must be under regular medical follow-up through standard timetabled medical laboratory investigations to allow for early detection of any serum biochemical or blood hematological changes.
PMCID: PMC2713944  PMID: 19583874
15.  A 3-Marker Index Improves the Identification of Iron Disorders in CKD Anaemia 
PLoS ONE  2014;9(2):e84144.
Iron disorders are common and complex in chronic kidney disease (CKD). We sought to determine whether a 3-marker index would improve the classification of iron disorders in CKD anaemia.
We studied the association between Hb level and iron indexes combining 2 or 3 of the following markers: serum ferritin (<40 ng/mL), transferrin saturation (TSAT<20%) and total iron binding capacity (TIBC<50 µmol/L) in 1011 outpatients with non-dialysis CKD participating in the Nephrotest study. All had glomerular filtration rates measured (mGFR) by 51Cr-EDTA renal clearance; 199 also had hepcidin measures.
The TSAT-TIBC-ferritin index explained Hb variation better than indexes combining TSAT-TIBC or ferritin-TSAT. It showed hypotransferrinaemia and non-inflammatory functional iron deficiency (ID) to be more common than either absolute or inflammatory ID: 20%, 19%, 6%, and 2%, respectively. Hb was lower in all abnormal, compared with normal, iron profiles, and decreased more when mGFR was below 30 mL/min/1.73 m2 (interaction p<0.0001). In patients with mGFR<30 mL/min/1.73 m2, the Hb decreases associated with hypotransferrinaemia, non-inflammatory functional ID, and absolute ID were 0.83±0.16 g/dL, 0.51±0.18 and 0.89±0.29, respectively. Compared with normal iron profiles, hepcidin was severely depressed in absolute ID but higher in hypotransferrinaemia.
The combined TSAT-TIBC-ferritin index identifies hypotransferrinaemia and non-inflammatory functional ID as the major mechanisms of iron disorders in CKD anaemia. Both disorders were associated with a greater decrease in Hb when mGFR was <30 mL/min/1.73 m2. Taking these iron profiles into account may be useful in stratifying patients in clinical trials of CKD anaemia and might improve the management of iron therapy.
PMCID: PMC3929276  PMID: 24586229
16.  Iron homeostasis and distal colorectal adenoma risk in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial 
Red meat consumption has been positively associated with colorectal cancer; however, the biologic mechanism underlying this relationship is not understood. Red meat is a major source of iron, which may play a role in colorectal carcinogenesis via increased crypt cell proliferation, cytotoxicity, and endogenous N-nitrosation. In a nested case-control study within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, we prospectively evaluated multiple iron exposure parameters, including dietary intake and serum measures of iron, ferritin, transferrin, total iron binding capacity (TIBC), and unsaturated iron binding capacity (UIBC) in relation to incident colorectal adenoma in 356 cases and 396 matched, polyp-free controls. We also investigated variation in eight key genes involved in iron homeostasis in relation to colorectal adenoma in an additional series totaling 1,126 cases and 1,173 matched controls. We observed a positive association between red meat intake and colorectal adenoma (odds ratio comparing extreme quartiles [ORq4-q1] = 1.59, 95% confidence interval [CI]: 1.02-2.49, P-trend = 0.03). Serum TIBC and UIBC were inversely associated with colorectal adenoma (ORq4-q1 = 0.57, 95% CI: 0.37-0.88, P-trend = 0.03; and ORq4-q1 = 0.62, 95% CI: 0.40-0.95, P-trend = 0.04, respectively). Colorectal adenoma was not associated with serum ferritin, iron, or transferrin saturation, or with polymorphisms in genes involved in iron homeostasis. Serum TIBC and UIBC, parameters which have a reciprocal relationship with overall iron load, were inversely related to colorectal adenoma, suggesting that individuals with lower iron status have a reduced risk of colorectal adenoma.
PMCID: PMC3168068  PMID: 21685236
Diet; meat; iron; colorectal; adenoma; cancer
17.  Association of Serum Total Iron-Binding Capacity and Its Changes Over Time with Nutritional and Clinical Outcomes in Hemodialysis Patients 
American Journal of Nephrology  2009;29(6):571-581.
Serum transferrin, estimated by total iron-binding capacity (TIBC), may be a marker of protein-energy wasting (PEW) in maintenance hemodialysis (MHD) patients. We hypothesized that low TIBC or its fall over time is associated with poor clinical outcomes. In 807 MHD patients in a prospective 5-year cohort, associations of TIBC and its changes over time with outcomes were examined after adjustment for case-mix and markers of iron stores and malnutrition-inflammation including serum interleukin-6, iron and ferritin. Patients with serum TIBC ≥250 mg/dl had higher body mass index, triceps and biceps skinfolds and mid-arm muscle circumference and higher serum levels of iron but lower ferritin and inflammatory markers. Some SF-36 quality of life (QoL) components were worse in the lowest and/or highest TIBC groups. Mortality was incrementally higher in lower TIBC levels (p-trend <0.001). Adjusted death hazard ratio was 1.75 (95% CI: 1.00–3.05, p = 0.05) for TIBC <150 compared to TIBC of 200–250 mg/dl. A fall in TIBC >20 mg/dl over 6 months was associated with a death hazard ratio of 1.57 (95% CI: 1.04–2.36, p = 0.03) compared to the stable TIBC group. Hence, low baseline serum TIBC is associated with iron deficiency, PEW, inflammation, poor QoL and mortality, and its decline over time is independently associated with increased death risk.
PMCID: PMC2818472  PMID: 19136818
Transferrin; Total iron-binding capacity; Chronic kidney disease; Hemodialysis; Protein-energy wasting
18.  Serum transferrin receptors in rheumatoid arthritis. 
Annals of the Rheumatic Diseases  1994;53(10):699-701.
OBJECTIVE--Serum transferrin receptors (sTfR) were determined in patients affected by rheumatoid arthritis (RA) to verify a possible relationship with the degree of anaemia and with the severity of the inflammatory disease. METHODS--sTfR, IL1-b, TNF-a and common parameters of iron metabolism were studied in 72 patients with active RA. Anaemia (Hb < 12 g/dl) was present in 51 patients. Twenty normal healthy subjects and 40 iron-deficient anaemic patients without chronic inflammatory, infective or malignant diseases were studied as controls. RESULTS--In patients with RA sTfR levels were significantly higher than in the normal group but lower than in iron-deficient anaemic patients and correlated positively with ESR and IL1-b and negatively with Hb. Anaemic patients with RA were divided into two groups. Group A (56%) showed a possible iron deficiency (TSI < 16 and ferritin < 50 ng/ml); group B did not show iron deficiency (TSI > 16 and ferritin > 50 ng/ml). No significant difference in sTfR was observed in the two groups. CONCLUSION--sTfR appear to be elevated and related to the degree of anaemia and to the inflammatory process in RA. Reduced sTfR levels in patients with RA compared with patients with iron-deficiency anaemia may indicate a reduced erythropoietic activity in RA.
PMCID: PMC1005440  PMID: 7979586
19.  Treatment of chronic periodontitis decreases serum prohepcidin levels in patients with chronic kidney disease 
Clinics  2011;66(4):657-662.
To determine the impact of periodontal treatment on serum levels of prohepcidin (the prohormone of hepcidin) and systemic inflammation markers, as well as correlations among these markers, in patients with chronic periodontitis and chronic kidney disease who were not undergoing dialysis.
We included 56 chronic periodontitis patients, 36 with chronic kidney disease and 20 without systemic diseases and with normal renal function (control group). Chronic kidney disease was defined as suggested by the clinical practice guidelines in the National Kidney Foundation. Chronic periodontitis was defined through clinical attachment level and by probing pocket depth, according to the American Association of Periodontology. The inflammatory markers ultrasensitive C-reactive protein, interleukin-6, and prohepcidin were evaluated before and 3 months after periodontal treatment.
The efficacy of periodontal treatment was confirmed by the improvement in clinical parameters of chronic periodontitis in the control and chronic kidney disease groups. Periodontal treatment resulted in significant reductions in ultrasensitive C-reactive protein, interleukin-6 and serum prohepcidin levels in both groups. Moreover, in multivariate linear regression, the reduction in prohepcidin after periodontal treatment was significantly and independently associated with interleukin-6 levels in the control group.
By inducing a decline in the systemic inflammatory response and a decrease in serum prohepcidin, successful periodontal treatment may represent an important means of ameliorating the inflammatory burden seen in patients with chronic kidney disease. Trial registration: ISRCTN59866656.
PMCID: PMC3093797  PMID: 21655762
Prohepcidin; hronic periodontitis; hronic kidney disease; inflammatory markers; periodontal treatment
20.  Obesity modulate serum hepcidin and treatment outcome of iron deficiency anemia in children: A case control study 
Recently, hepcidin expression in adipose tissue has been described and shown to be increased in patients with severe obesity. We tried to assess the effect of obesity on hepcidin serum levels and treatment outcome of iron deficiency anemia in children.
This was a case control study included 70 children with iron deficiency anemia "IDA" (35 obese and 35 non-obese) and 30 healthy non-obese children with comparable age and sex(control group). Parameters of iron status (Serum iron, ferritin, transferrin, total iron binding capacity and transferrin saturation) and serum hepcidin levels were assessed initially and after 3 months of oral iron therapy for IDA.
Compared to the control group, serum hepcidin was significantly lower in non-obese children with IDA(p < 0.01) and significantly higher in obese children with IDA (p < 0.01). Hepcidin increased significantly in non-obese children with IDA after 3 months of iron therapy (P < 0.01). On the other hand, obese children showed non-significant change in hepcidin level after iron therapy (p > 0.05). Although hepcidin showed significant positive correlations with Hb, serum iron and transferrin saturation in non-obese children with IDA, it showed significant negative correlations with Hb, serum iron and transferrin saturation in obese children with IDA (P < 0.05).
Obesity increased hepcidin levels and was associated with diminished response to oral iron therapy in childhood iron deficiency anemia.
PMCID: PMC3154149  PMID: 21771327
Obesity; Hepcidin; Iron deficiency; Children
21.  Iron in Relation to Gastric Cancer in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study 
Iron is an essential micronutrient that can have carcinogenic effects when at high or low concentrations. Previous studies of iron in relation to gastric cancer have not assessed subtype-specific relationships. We used the prospective ATBC Cancer Prevention Study to assess whether iron metrics were associated with gastric cardia cancer (GCC) and gastric noncardia cancer (GNCC).
We selected 341 incident gastric cancer cases (86 cardia, 172 noncardia, and 83 non-specified), accrued during 22 years of follow-up, and 341 individually matched controls. We measured prediagnostic serum iron, ferritin, unsaturated iron binding capacity (UIBC), and C-reactive protein. Total iron binding capacity (TIBC) and transferrin saturation were estimated from these metrics. Dietary iron exposures were estimated from a food frequency questionnaire. Multivariable logistic regression was used for analysis.
Serum iron metrics were not associated with GCC, except for a potential ‘n’-shaped relationship with TIBC (global p=0.038). GNCC was inversely associated with serum ferritin (global p=0.024), serum iron (global p=0.060) and, possibly, transferrin saturation. TIBC appeared to share a ‘u’shaped relationship with GNCC (global p=0.033). Dietary iron exposures were not associated with either subsite. Adjustment for Helicobacter pylori and gastric atrophy had little effect on observed associations.
We found little evidence for the involvement of iron exposure in the pathogenesis of GCC. GNCC was associated with an iron profile similar to that of iron deficiency.
PMCID: PMC3493744  PMID: 23001240
Helicobacter pylori; Iron; Nested Case-Control Studies; Prospective Studies; Stomach Neoplasms
22.  Iron status of Hindu brahmin, Jain and Muslim communities in Surat, Gujarat 
Aim of the Study
To determine iron status of healthy, unrelated Brahmin, Jain and Muslim participants having different dietary habits.
Control participants other than above three communities, consumed vegetarian or non-vegetarian diet. Brahmin and Jain were strictly vegetarian but Jain did not consume roots or tubers. Muslims consumed non-vegetarian food. Standard techniques were used to measure hematological parameters, serum iron, total iron bindings capacity (TIBC), serum ferritin, transferrin and transferrin saturation. For statistical evaluation mean, standard deviation, pair t test, χ2 and ANOVA (F test) were employed.
Study includes 565 male and 198 female children and adults. Among them 205 were children and remaining adults. All four categories i.e. control, Brahmin, Jain and Muslims showed higher incidence of anemia and iron deficiency in females compared to males. Mean values of hematological parameters did not vary significantly in four groups. Serum iron, TIBC, transferrin and ferritin levels indicated iron deficiency anemia more frequently in Jains and less frequently in Muslims (p<0.05). Iron status of Brahmin was comparable with controls (p<0.01). Majority of the participants had serum ferritin concentration >15 ng/mL. Except one male Jain child none of the participants had serum ferritin concentration <12 ng/mL. Jain subjects more frequently had serum iron concentration <60 μg/dL.
Jain participants had higher incidence of iron deficiency anemia. Vegetarian diet consumed by Gujarati Hindu Brahmin community provided them with a sufficient iron to maintain their iron profile like Muslims consuming non-vegetarian diet.
PMCID: PMC3453124  PMID: 23100921
Anemia; Iron deficiency; Vegetarian; Non-vegetarian; Hindu; Muslim; Jain
23.  Markers of iron metabolism in retired racing Greyhounds with and without osteosarcoma 
Greyhounds have well-described clinicopathologic idiosyncrasies, including a high prevalence of osteosarcoma (OSA). Hematocrit, HGB, and HGB oxygen affinity are higher than in other dogs, while haptoglobin concentration is lower, so we hypothesized that Greyhounds have a different iron metabolism. To our knowledge, there are no reports on serum iron profiles in Greyhounds.
To elucidate iron metabolism in Greyhounds, we wanted to compare serum iron concentration, total iron-binding capacity (TIBC), and percent transferrin saturation (%SAT) in healthy retired racing Greyhounds (RRGs) with OSA (RRGs – OSA), and also with non-Greyhounds (NGs), without and with OSA (NGs – OSA).
Serum iron concentration and unsaturated iron-binding capacity (UIBC) were measured by standard methods, and TIBC and %SAT were calculated in RRGs (n = 25), RRGs – OSA (n = 28), NGs (n = 30), and NGs – OSA (n = 32).
TIBC was lower in RRGs than in NGs (P < .0001), and in RRGs – OSA than in NGs – OSA (P < .0001). NGs – OSA had lower TIBC than healthy NGs (P = .003). Percent SAT was higher in RRGs than in NGs (P < .0001) and in RRGs – OSA (P = .008), and %SAT was also lower in NGs than in NGs – OSA (P = .004). Percent SAT was also higher in RRGs – OSA than in NGs – OSA (P = .001). Both RRGs – OSA (P = .02) and NGs – OSA (P < .0001) had lower serum iron concentrations than their healthy counterparts.
Lower TIBC and higher %SAT may constitute another Greyhound idiosyncrasy compared with other dogs. In this study, all dogs with OSA had higher serum iron concentrations and %SAT than healthy dogs.
PMCID: PMC4120296  PMID: 24033801
Dihydroartemisinin; iron sequestration; percent transferrin saturation; serum iron concentration; total iron-binding capacity
24.  Profile of altered brain iron acquisition in restless legs syndrome 
Brain  2011;134(4):959-968.
Restless legs syndrome is a neurological disorder characterized by an urgency to move the legs during periods of rest. Data from a variety of sources provide a compelling argument that the amount of iron in the brain is lower in individuals with restless legs syndrome compared with neurologically normal individuals. Moreover, a significant percentage of patients with restless legs syndrome are responsive to intravenous iron therapy. The mechanism underlying the decreased iron concentrations in restless legs syndrome brains is unknown. We hypothesize that the source of the brain iron deficit is at the blood–brain interface. Thus we analysed the expression of iron management proteins in the epithelial cells of the choroid plexus and the brain microvasculature in post-mortem tissues. The choroid plexus, obtained at autopsy, from 18 neurologically normal controls and 14 individuals who had primary restless legs syndrome was subjected to histochemical staining for iron and immunostaining for iron management proteins. Iron and heavy chain ferritin staining was reduced in the epithelial cells of choroid plexus in restless legs syndrome. Divalent metal transporter, ferroportin, transferrin and its receptor were upregulated in the choroid plexus in restless legs syndrome. Microvessels were isolated from the motor cortex of 11 restless legs syndrome and 14 control brains obtained at autopsy and quantitative immunoblot analyses was performed. Expression of heavy chain ferritin, transferrin and its receptor in the microvessels from restless legs syndrome was significantly decreased compared with the controls but divalent metal protein 1, ferroportin, prohepcidin, mitochondrial ferritin and light-chain ferritin remained unchanged. The presence of an iron regulatory protein was demonstrated in the brain microvasculature and the activity of this protein is decreased in restless legs syndrome; a finding similar to our earlier report in neuromelanin cells from the substantia nigra of restless legs syndrome brains. This study reveals that there are alterations in the iron management protein profile in restless legs syndrome compared with controls at the site of blood–brain interface suggesting fundamental differences in brain iron acquisition in individuals with restless legs syndrome. Furthermore, the decrease in transferrin receptor expression in the microvasculature in the presence of relative brain iron deficiency reported in restless legs syndrome brains may underlie the problems associated with brain iron acquisition in restless legs syndrome. The consistent finding of loss of iron regulatory protein activity in restless legs syndrome brain tissue further implicates this protein as a factor in the underlying cause of the iron deficiency in the restless legs syndrome brain. The data herein provide evidence for regulation of iron uptake and storage within brain microvessels that challenge the existing paradigm that the blood–brain barrier is merely a transport system.
PMCID: PMC3069701  PMID: 21398376
iron deficiency; movement disorders; sleep disorders; blood–brain barrier; choroid plexus
25.  Blood iron, glutathione, and micronutrient levels and the risk of oral cancer and premalignancy 
Nutrition and cancer  2008;60(4):474-482.
The relationship between serological levels of iron, vitamins A, B2, C, E, zinc, thiamin, and glutathione (GSH) and the risk of oral cavity cancer was examined in a hospital-based case-control study. The case group included 65 patients with incident histologically-confirmed oral cancer and 13 patients with oral premalignancies, and the control group included 85 sex- and age-matched subjects without cancer attending the hospital dental clinic. Compared to the lowest tertiles, significant decreased risks were observed for the highest tertile of free iron (odds ratio [OR] = 0.3, 95% CI: 0.1,0.6) and transferrin saturation (iron/total iron binding capacity (TIBC) × 100) (OR= 0.4, 95% CI: 0.2,0.9). The OR for TIBC, which measures the concentration of the iron delivery protein transferrin and is increased in iron-deficiency, was 3.2 (95% CI: 1.3,8.1). These associations were stronger in never-smokers than in ever smokers. While the levels of the iron storage protein ferritin was higher in cases, this may be attributed to disease-related inflammation or comorbidity. Significant associations of the endogenous antioxidant GSH (OR = 0.4, 95% CI: 0.1,0.9) and GSH reductase activity coefficient (indicative of riboflavin deficiency) OR = 1.6, 95% CI: 1.3,3.7) with oral cancer risk were also observed. In premalignant cases, serum iron levels were 16% higher in controls (P<0.05). These findings suggest that mild iron deficiency, as indicated by low levels free iron and transferrin and high levels of TIBC, as well as low levels of the major cellular antioxidant GSH are associated with increased risk of oral cancer.
PMCID: PMC3520062  PMID: 18584481
oral cancer; micronutrients; iron; glutathione; antioxidants

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