Iron Accumulation In Patients Research Articles

A Hemoglobin Bionics-Based System for Combating Antibiotic Resistance in Chronic Diabetic Wounds via Iron Homeostasis Regulation.

Owing to the increased tissue iron accumulation in patients with diabetes, microorganisms may activate high expression of iron-involved metabolic pathways, leading to the exacerbation of bacterial infections and disruption of systemic glucose metabolism. Therefore, an on-demand transdermal dosing approach that utilizes iron homeostasis regulation to combat antimicrobial resistance is a promising strategy to address the challenges associated with low administration bioavailability and high antibiotic resistance in treating infected diabetic wounds. Here, it is aimed to propose an effective therapy based on hemoglobin bionics to induce disturbances in bacterial iron homeostasis. The preferred "iron cargo" is synthesized by protoporphyrin IX chelated with dopamine and gallium (PDGa), and is delivered via a glucose/pH-responsive microneedle bandage (PDGa@GMB). The PDGa@GMB downregulates the expression levels of the iron uptake regulator (Fur) and the peroxide response regulator (perR) in Staphylococcus aureus, leading to iron nutrient starvation and oxidative stress, ultimately suppressing iron-dependent bacterial activities. Consequently, PDGa@GMB demonstrates insusceptibility to genetic resistance while maintaining sustainable antimicrobial effects (>90%) against resistant strains of both S. aureus and E. coli, and accelerates tissue recovery (<20 d). Overall, PDGa@GMB not only counteracts antibiotic resistance but also holds tremendous potential in mediating microbial-host crosstalk, synergistically attenuating pathogen virulence and pathogenicity.

A c.726C>G (p.Tyr242Ter) nonsense mutation-associated with splicing alteration (NASA) of WDR45 gene underlies β-propeller protein-associated neurodegeneration (BPAN)

Neurodegeneration with brain iron accumulation (NBIA) is a clinically and genetically heterogeneous disease characterized by increased iron deposition in the basal ganglia and progressive degeneration of the nervous system in adulthood. However, in early childhood, there were no characteristic features to perform early diagnosis. In our study, a female child exhibited global developmental delay, intellectual disability, and febrile seizure without other distinct clinical phenotypes. Through whole exome sequencing (WES), a de novo nonsense mutation (c.726C > G, p. Tyr242Ter) of WDR45 gene was identified in this child. She was finally diagnosed as β‐propeller protein-associated neurodegeneration (BPAN), one of the recently identified subtypes of NBIA. This mutation could act as a premature stop codon (PSC) which rendered the mutated transcripts to be degraded by nonsense-mediated mRNA decay (NMD), leading to decreased levels of PSC-containing mRNAs. Additionally, through mini-gene splicing assays, this mutation could result in an unprecedented novel transcript with the exon 9 of WDR45 excluded by nonsense-associated splicing alteration (NASA). Transcriptome sequencing (RNA-seq) on total RNAs from PBMCs of the trio revealed three types of alternative splicing events in the patient. Further research implied that downregulation of iron transport genes (TFRC, TFR2, SCARA5) might be the underlying mechanism for the iron accumulation in patients with deficient WDR45. This is the first report about NASA happening in WDR45. It implies that nonsense mutations approximal to splicing sites could affect the disease pathogenesis through more than one molecular mechanism and should be taken into consideration when conducting genetic counseling.

The association of pro-oxidant/antioxidant balance and blood parameters in patients with beta-thalassemia major: a cross-sectional study.

Oxidative stress due to iron accumulation in patients with beta-thalassemia major (BTM) causes complications such as tissue damage and destruction. This study aimed to assess the association between the serum prooxidant/antioxidant balance (PAB) and blood parameters in patients with BTM. This cross-sectional study included 92 patients with BTM. In this study, PAB was measured using an enzyme-linked immunosorbent assay (ELISA). Serum ferritin, blood urea nitrogen (BUN), creatinine (Cr), alanine aminotransferase (ALT), aspartate aminotransferase (AST), thyroid-stimulating hormone (TSH), total cholesterol (TC), triglyceride (TG), complete blood cell count (CBC), and history of blood transfusion were recorded. The association of the blood parameters was assessed across the tertiles (T) of serum PAB (highest T vs. lowest T). The results showed that high serum ferritin was directly associated with serum PAB [odds ratio (OR), 12.80; 95% confidence interval (CI), 2.98‒54.91; T3 vs. T1]. Also, direct associations were found for high TC (OR, 4.97; 95% CI, 1.42‒17.32; T3 vs. T1), high ALT (OR, 4.95; 95% CI, 1.33‒18.46; T3 vs. T1) and high TSH (OR, 3.78; 95% CI, 1.10‒13.02; T3 vs. T1). The findings of the present study showed that serum PAB levels were directly associated with ferritin, ALT, TC, and TSH levels. This indicates that improvements in blood parameters, especially ferritin and TSH levels, occur by ameliorating oxidative stress in patients with BTM.

C19orf12 ablation causes ferroptosis in mitochondrial membrane protein-associated with neurodegeneration

Mitochondrial membrane protein-associated with neurodegeneration (MPAN) is a rare genetic disease characterized by aggressive neurodegeneration and massive iron accumulation in patients’ brains. Genetics studies identified defects in C19orf12 locus being associated with MPAN which likely caused loss of function although underlying pathogenic mechanism(s) remain elusive. In the present study, we investigated C19orf12 knockout (KO) M17 neuronal cells and primary skin fibroblasts from MPAN patients with C19orf12 homozygous G58S or heterozygous C19orf12 p99fs*102 mutations as cellular models of MPAN. C19orf12 KO cells and MPAN fibroblast cells demonstrated mitochondrial fragmentation and dysfunction, iron overload and increased oxidative damage. Antioxidant NAC and iron chelator DFO rescued both oxidative stress and mitochondrial deficits. Moreover, C19orf12 KO cells and MPAN fibroblast cells were susceptible to erastin- or RSL3-induced ferroptosis which could be almost completely prevented by pretreatment of iron chelator DFO. Importantly, we also found mitochondrial fragmentation and increased ferroptosis related oxidative damage in neurons in the biopsied cortical tissues from an MPAN patient. Collectively, these results supported the notion that iron overload and ferroptosis likely play an important role in the pathogenesis of MPAN.

Iron overload in inherited anaemias: why one size can't fit all.

Iron overload in inherited anaemias: why one size can't fit all.

Quantitative susceptibility mapping to evaluate brain iron deposition and its correlation with physiological parameters in hypertensive patients.

BackgroundRegional excessive iron overload is pernicious to motor functions and cognitive functioning of the brain. The aim of this research was to utilize quantitative susceptibility mapping (QSM) to inspect brain iron accumulation in patients with hypertension (HP), and to evaluate whether it is correlated with physiological parameters.MethodsThirty-one HP and 31 age- and sex-matched healthy controls (HC) were included. All participants underwent brain magnetic resonance imaging (MRI), and QSM data were obtained. Differences in brain iron deposition in deep gray matter nuclei of participants were compared between HP and HC. The correlations between iron deposition, body mass index (BMI), maximum systolic blood pressure (SBP), and diastolic blood pressure (DBP) were analyzed.ResultsThe HP group showed increased susceptibility values in the caudate nucleus (CA), putamen (PU), globus pallidus (GP), and dorsal thalamus (TH), compared with the HC group. There was a significant positive correlation between BMI and the susceptibility values in the dentate nucleus (DN); the maximum SBP and DBP were positively correlated with magnetic susceptibility of the CA, PU, GP, and TH, respectively.ConclusionsThese results are indicative of the role of overload brain iron in deep brain gray matter nuclei in HP and suggest that HP is associated with excess brain iron in certain deep gray matter regions.

WDR45 Mutation Impairs the Autophagic Degradation of Transferrin Receptor and Promotes Ferroptosis.

WDR45 is an autophagy-related protein that involves in the formation of autophagosome. Mutations in WDR45 lead to the impairment of autophagy which is associated with the human β-propeller protein-associated neurodegeneration (BPAN). However, the relationship between autophagy and brain iron accumulation in patients with BPAN remains unclear. Here, we demonstrated that transferrin receptor (TfRC) which is critical for the iron import of cells was degraded via autophagy. TfRC was accumulated after the inhibition of autophagy by treatment with autophagic inhibitor chloroquine or knockdown of ATG2A. The intracellular iron content was increased in cells overexpressing TfRC or mutant WDR45, however, ferritin H (FTH) chain was decreased. Increased TfRC and simultaneously decreased FTH consequently resulted in an elevated level of ferrous iron (Fe2+) which further promoted cell ferroptosis, demonstrated by the increased lipid peroxidation and reactive oxygen species (ROS) and the decreased glutathione peroxidase 4 (GPX4) and cell viability. Taken together, these findings provide a piece of important evidence that WDR45 deficiency impairs autophagic degradation of TfRC, therefore leading to iron accumulation, and the elevated iron promotes ferroptosis which may contribute to the progression of BPAN.

Iron deposition in Parkinsonisms: A Quantitative Susceptibility Mapping study in the deep grey matter

PurposeThe aim of the study is to quantify the susceptibility in deep grey nuclei that are affected by pathological processes related to iron accumulation in patients with Parkinson's disease and primary atypical parkinsonisms such as Progressive Supranuclear Palsy, Multiple System Atrophy and Cortico-Basal Degeneration, in order to assist the differential diagnosis among parkinsonian syndromes. MethodsWe enrolled 49 patients with Parkinson’s disease and 26 patients with primary atypical parkinsonisms. Automatic segmentation of putamen, globus pallidus, caudate nucleus and thalamus and manual segmentation of red nuclei and substantia nigra were performed, and region of interest-based Quantitative Susceptibility Mapping analysis were performed. Statistical comparisons of the mean susceptibility values in the segmented brain regions were performed among primary atypical parkinsonisms and Parkinson's disease. ResultsSusceptibility values in red nuclei were increased in Progressive Supranuclear Palsy patients compared to parkinsonian phenotype Multiple System Atrophy (p = 0.004), and Parkinson's disease patients (p = 0.006). Susceptibility in thalamus was decreased in Cortico-Basal Degeneration patients compared to Parkinson's disease (p = 0.006), Multiple System Atrophy with cerebellar phenotype (p = 0.031) and parkinsonian phenotype (p = 0.001) patients, and in Progressive Supranuclear Palsy patients compared to Multiple System Atrophy with parkinsonian phenotype patients (p = 0.012). ConclusionsQuantitative Susceptibility Mapping allows the depiction and quantification of different patterns of iron deposition in the deep gray nuclei occurring in primary atypical parkinsonisms and Parkinson's disease and it may help as a non-invasive tool in the differential diagnosis between parkinsonian syndromes.

Clinical Factors Associated with Hepatocellular Iron Deposition in End-stage Liver Disease.

Background and Aims: Hepatocellular iron accumulation in patients with chronic liver disease has been linked to adverse outcomes. The objective of this study was to identify clinical factors associated with hemosiderosis.Methods: A total of 103 consecutive liver transplant recipients were identified, in whom liver biopsy had been performed prior to transplantation. Laboratory and clinical data at biopsy and transplant were abstracted from the medical records and hepatocyte iron was graded in the biopsy and explant. The association of change in iron score from biopsy to transplant, with the time interval between these two events, was examined using linear mixed model analysis for repeated measures.Results: Most subjects had advanced fibrosis (F3-F4) at liver biopsy, which was performed on average about 2.5 years before transplant. Over 80% of patients had no or 1+ hepatocyte iron at biopsy; iron increased between biopsy and transplant in about 40%. The only demographic or clinical feature that correlated with increased iron was the presence of a transjugular intrahepatic portosystemic shunt. Increased iron at transplant was associated with higher serum iron and transferrin saturation at biopsy, and with lower hemoglobin level, greater mean corpuscular volume, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration, higher ferritin and model for end-stage liver disease score at transplant.Conclusions: The development of hemosiderosis in end-stage liver disease is associated with lower hemoglobin levels and alterations in red blood cell indices that are suggestive of hemolysis. These observations suggest that extravascular hemolysis may play a role in the development of secondary iron overload.

Motor cortex hypointensity on susceptibility-weighted imaging: a potential imaging marker of iron accumulation in patients with cognitive impairment.

To assess the prevalence and characteristics of motor cortex hypointensity on 3-T susceptibility-weighted imaging (SWI) in patients with cognitive impairment and examine its clinical significance. The institutional review board approved this retrospective study and waived the requirement for informed consent. A total of 127 patients with a clinical diagnosis of probable Alzheimer's disease (AD) (n = 32) or mild cognitive impairment (MCI) (n = 95) and 127 age- and sex-matched control subjects underwent 3-T brain magnetic resonance imaging. SWI was analyzed for both subjective visual scoring and the quantitative estimation of phase shift in the posterior bank of the motor cortex. A multivariate logistic regression analysis was performed to identify clinical and imaging variables associated with motor cortex hypointensity on SWI. Motor cortex hypointensity on SWI was observed in 94/127 cognitively impaired patients (74.0%) and 72/127 control subjects (56.7%) (p = 0.004). Age was the only variable that was significantly associated with motor cortex hypointensity in patients with cognitive impairment (odds ratio, 1.15; 95% confidence interval, 1.065-1.242; p < 0.001). The quantitative analysis confirmed a significant increase in phase shifting in the posterior bank of the motor cortex in patients with positive motor cortex hypointensity on SWI (p < 0.001). Motor cortex hypointensity on SWI was more frequently found in patients with cognitive impairment than in age-matched controls and was positively associated with age. Thus, it may be a potential imaging marker of iron accumulation in patients with MCI or AD.

Increased Duodenal Iron Absorption through Upregulation of Ferroportin 1 due to the Decrement in Serum Hepcidin in Patients with Chronic Hepatitis C.

Hepatic iron accumulation is generally increased in the chronic hepatitis C (CHC) liver; however, the precise mechanism of such accumulation remains unclear. We evaluated iron absorption from the gastrointestinal tract of patients with CHC and control participants. We measured the expression of a panel of molecules associated with duodenal iron absorption and serum hepcidin levels to determine the mechanism of iron accumulation in the CHC liver. We enrolled 24 patients with CHC and 9 patients with chronic gastritis without Helicobacter pylori infection or an iron metabolism disorder as control participants. An oral iron absorption test (OIAT) was administered which involved a dosage of 100 mg of sodium ferrous citrate. Serum level of hepcidin-25 was measured by liquid chromatography-tandem mass spectrometry. Ferroportin 1 (FPN) mRNA was measured by RT-PCR and FPN protein was analyzed by western blot. Samples were obtained from duodenum biopsy tissue from each CHC patient and control participant. Caco-2/TC7 cells were incubated in Costar transwells (0.4 μm pores). The OIAT showed significantly greater iron absorption in CHC patients than control participants. Serum hepcidin-25 in the CHC group was significantly lower than in the control group. Compared with control participants, duodenal FPN mRNA expression in CHC patients was significantly upregulated. The FPN mRNA levels and protein levels increased significantly in Caco-2/TC7 cell monolayers cultured in transwells with hepcidin. Lower serum hepcidin-25 levels might upregulate not only FPN protein expression but also mRNA expression in the duodenum and cause iron accumulation in patients with CHC.

Whole-body iron transport and metabolism: Mechanistic, multi-scale model to improve treatment of anemia in chronic kidney disease.

Iron plays vital roles in the human body including enzymatic processes, oxygen-transport via hemoglobin and immune response. Iron metabolism is characterized by ~95% recycling and minor replenishment through diet. Anemia of chronic kidney disease (CKD) is characterized by a lack of synthesis of erythropoietin leading to reduced red blood cell (RBC) formation and aberrant iron recycling. Treatment of CKD anemia aims to normalize RBC count and serum hemoglobin. Clinically, the various fluxes of iron transport and accumulation are not measured so that changes during disease (e.g., CKD) and treatment are unknown. Unwanted iron accumulation in patients is known to lead to adverse effects. Current whole-body models lack the mechanistic details of iron transport related to RBC maturation, transferrin (Tf and TfR) dynamics and assume passive iron efflux from macrophages. Hence, they are not predictive of whole-body iron dynamics and cannot be used to design individualized patient treatment. For prediction, we developed a mechanistic, multi-scale computational model of whole-body iron metabolism incorporating four compartments containing major pools of iron and RBC generation process. The model accounts for multiple forms of iron in vivo, mechanisms involved in iron uptake and release and their regulation. Furthermore, the model is interfaced with drug pharmacokinetics to allow simulation of treatment dynamics. We calibrated our model with experimental and clinical data from peer-reviewed literature to reliably simulate CKD anemia and the effects of current treatment involving combination of epoietin-alpha and iron dextran. This in silico whole-body model of iron metabolism predicts that a year of treatment can potentially lead to 90% downregulation of ferroportin (FPN) levels, 15-fold increase in iron stores with only a 20% increase in iron flux from the reticulo-endothelial system (RES). Model simulations quantified unmeasured iron fluxes, previously unknown effects of treatment on FPN-level and iron stores in the RES. This mechanistic whole-body model can be the basis for future studies that incorporate iron metabolism together with related clinical experiments. Such an approach could pave the way for development of effective personalized treatment of CKD anemia.

Association of freezing of gait with nigral iron accumulation in patients with Parkinson's disease

Background and purposeThe objective of this work was to investigate whether patients with and without freezing of gait (FOG) in Parkinson's disease (PD) have differences in iron accumulation in substantia nigra using R2* relaxometry. Materials and methodsThis study included seventeen PD patients with FOG [FOG (+)], equal number of age and gender matched patients without FOG [FOG (−)] and 34 healthy controls (HC). T2* images were obtained from a 3-Tesla MRI system using multi-echo sequence. R2* values were extracted from Substantia Nigra (SN) and red nucleus and were compared among the three groups and correlated with clinical findings. ResultsR2* values were increased in PD group as a whole compared to HC in rostral and caudal segments of Substantia Nigra pars compacta (SNc) and in Substantia Nigra pars reticulata (SNr) but not in red nucleus. Within PD subgroups, FOG (+) group had increased iron accumulation in SNc compared to FOG (−) and HC. FOG score positively correlated with R2* values in the caudal region of SNc in FOG (+) group. ConclusionsOur study reveals higher nigral iron content in FOG (+) compared to FOG (−) and HCs. In addition, we observed positive correlation of FOG score with iron accumulation in SNc. Results of this study emphasize possible role of higher nigral iron content in the pathogenesis of FOG in PD.

Serum Prohepcidin Levels in Children with Thalassemia Major and Intermedia

Objective: To determine the role of hepcidin hormone levels in iron accumulation in patients with thalassemia major (TM) and thalassemia intermedia (TI). Materials and Methods: Serum prohepcidin and ferritin levels were determined in 34 patient with TM, 10 patient with TI, who attended the Department of Pediatric Hematology Adnan Menderes University Medical Faculty and the Department of Pediatrics at Aydin Ataturk State Hospital between 1 September 2006 and 30 September 2007 and 40 control patients without infection/inflammation, hepatitis or liver failure. Serum prohepcidin levels were measured using a commercial enzyme-linked immunosorbent assay kit (DRG International, Inc. Marburg, Germany); ferritin was studied with chemiluminescence method (Immulite 2000 DPC). Results: Mean serum ferritin levels in TM, TI and control groups were 2347.97±1724.81 ng/mL (range: 144-8015 ng/mL), 1352.40±918.94 ng/mL (range: 311-3109 ng/mL), and 33.35±12.03 ng/mL (range: 20-69.1 ng/mL), respectively. Serum prohepcidin levels in the same groups were 221.78±74.38 ng/mL (range: 7l.14-446.57 ng/mL), 173.31±52.14 ng/mL (range: 100.83-267.69 ng/mL), and 218.20±50.37 ng/mL (range: 116.18-330.43 ng/mL), respectively. There was a statistically significant difference in prohepcidin levels between patients with TI and control group only (p=0.016). No correlation was found between prohepcidin and ferritin levels in all groups (r=-0.023, p=0.839). Conclusion: Low levels of prohepcidin in patients with TI may be related to increased erythropoietic activity. Prohepcidin can be an indicator of active erythropoiesis.

Upregulation of Renal Iron Metabolism in Sickle Cell Disease Mice

BACKGROUND: Hemolysis and frequent blood transfusions lead to the iron overload and organ iron accumulation in patients with red blood cells disorders. The pattern of iron accumulation within different organs is disease specific. Abnormalities of renal iron metabolism and cortical iron deposition is characteristic for sickle cell disease (SCD) but not for β-thalassemia. Renal iron deposition does not correlate with iron overload and blood transfusion. Iron is reabsorbed from primary urine in the renal proximal epithelial cells and released into the renal intersitium by ferroportin. Iron-regulating hormone, hepcidin controls ferroportin expression. Binding of hepcidin to the ferroportin induces ferroportin degradation and intracellular iron accumulation. Low concentrations of circulating hepcidin are common in SCD patients and do not explain paradoxical renal iron accumulation. SCD mice accumulate iron in the epithelial cells of proximal tubules and may be a suitable model to study iron metabolism in SCD.OBJECTIVES: To characterize proteins of the renal iron metabolism in SCD mouse model.METHODS: The SCD (Townes) mice do not express mouse α- or β-globin alleles, but carry two copies of a human α1-globin gene and two copies of a human Aγ-globin and βS-globin genes. These animals synthesize approximately 94% human sickle (HbS) and 6% human fetal hemoglobin (HbF), and no murine hemoglobin. Control animals carry two copies of the human α1-globin gene and two copies of the human hemoglobin gamma (Aγ) gene and the human wildtype hemoglobin beta (βA) gene. Kidneys were collected from 5 months old SCD and control mice. Renal cortex was used for RNA and protein isolation. Levels of renal hepcidin, ferroportin, transferrin receptor (TFR1), divalent cation receptor (DMT1), ferritin and hepheastin were determined by q-RT-PCR, WB and ELISA. Paraffin-embedded sections were used for immunostaining. Perl’s Prussian blue staining was used for detection of renal iron accumulation.RESULTS:We detected significant accumulation of iron in the epithelial cells of proximal tubules in SCD mice. Expression of renal hepcidin was increased in SCD mice compared to controls. Surprisingly mRNA levels of all other proteins involved in renal iron metabolism (ferroportin, TFR1, DMT1, ferritin and hephaestin) were decreased in SCD mice kidney. In contrast, we found increased protein levels of transferrin receptor (iron importer), ferritin (iron storage protein) and slightly increased level of ferroportin (iron exporter). We also observed significant renal macrophages infiltration in SCD mice.CONCLUSIONS: Increased levels of renal hepcidin expression in SCD mice may be associated with renal inflammation. Higher levels of locally expressed hepcidin may lead to the partial degradation of the iron exporter (ferroportin). Increased levels of iron importers (TFR1 and DMT1) and no significant change in ferroportin expression can cumulatively saturate iron storage in ferritin and lead to the accumulation of intracellular iron.ACKNOWLEDGMENTS: This work was supported by NIH Research Grants 1P50HL118006, 1R01HL125005 and 5G12MD007597. The content is solely the responsibility of the authors and does not necessarily represent the official view of NHLBI, NIMHD or NIH. DisclosuresQuezado:IONIS Pharmaceuticals: Research Funding.

Magnetic resonance imaging of reconstructed ferritin as an iron-induced pathological model system

Iron, an essential element of the human body, is a significant risk factor, particularly in the case of its concentration increasing above the specific limit. Therefore, iron is stored in the non-toxic form of the globular protein, ferritin, consisting of an apoferritin shell and iron core. Numerous studies confirmed the disruption of homeostasis and accumulation of iron in patients with various diseases (e.g. cancer, cardiovascular or neurological conditions), which is closely related to ferritin metabolism. Such iron imbalance enables the use of magnetic resonance imaging (MRI) as a sensitive technique for the detection of iron-based aggregates through changes in the relaxation times, followed by the change in the inherent image contrast. For our in vitrostudy, modified ferritins with different iron loadings were prepared by chemical reconstruction of the iron core in an apoferritin shell as pathological model systems. The magnetic properties of samples were studied using SQUID magnetometry, while the size distribution was detected via dynamic light scattering. We have shown that MRI could represent the most advantageous method for distinguishing native ferritin from reconstructed ferritin which, after future standardisation, could then be suitable for the diagnostics of diseases associated with iron accumulation.

Combination Chelation Therapy for Severe Iron Overload

Severe myocardial iron accumulation in patients with β-thalassemia major eventually results in heart failure and death. The iron content of the

Activity of cytochrome P450 1A2 in relation to hepatic iron accumulation in transfusion-dependent β-thalassaemia major patients.

Cytochrome P450 1A2 (CYP1A2) is a cytochrome enzyme with a pivotal role in hepatic drug metabolism. Data from CYP1A2((-/-)) mouse suggest that CYP1A2 plays a role in aspects of hepatic iron toxicity. The aim of this study was to assess the activity of CYP1A2 in relation to hepatic iron load in patients with transfusion-dependent β-thalassaemia major. The (13) C-methacetin continuous breath test was performed on 30 consecutive patients with transfusion-dependent β-thalassaemia major. CYP1A2 activity was measured by the rate at which the (13) C substrate is metabolized and exhaled expressed as percentage dose recovery (PDR) per hour. CYP1A2 activity was correlated with clinical and laboratory parameters and hepatic iron accumulation by T2* magnetic resonance imaging (T2*MRI). Cytochrome P450 1A2 activity in patients with transfusion-dependent β- thalassaemia major was positivity correlated with plasma ferritin levels. No correlation was found with age, duration and amount of red blood cell transfusion and type of iron chelation therapy. Low CYP1A2 activity was negatively associated with hepatic iron accumulation (T2*MRI ≤ 6.3 ms); adjusted odds ratio (OR; 95% CI) for hepatic iron accumulation in patients with low CYP1A2 activity was 0.047 (0.003-0.72; P = 0.021). Of the six patients with decreased activity of CYP1A2, five had no hepatic iron accumulation and one had mild hepatic iron accumulation by T2*MRI. Activity of CYP1A2 is associated with hepatic iron accumulation in patients with transfusion-depended β-thalassaemia major. Further studies are needed to assess the exact role of CYP1A2 in iron metabolism in human.

Coinfection with HIV-1 alleviates iron accumulation in patients with chronic hepatitis C virus infection.

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.

Low hepcidin triggers hepatic iron accumulation in patients with hepatitis C

Persistent hepatitis C virus (HCV) infection is a major cause of chronic liver disease including fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Chronic hepatitis C (CHC) is also a problem in patients with chronic kidney disease (CKD), particularly in those on haemodialysis. Excessive iron in the liver of CHC patients contributes to hepatic fibrosis, cirrhosis and finally HCC, while iron depletion is beneficial. In CHC patients without CKD, in HCV-infected experimental animals and in cell culture studies, serum hepcidin levels and/or cellular hepcidin expression are low and directly suppressed by HCV, radical oxygen species, growth factors and/or transcription factors. In contrast, antiviral therapy (e.g. with pegylated interferon-alpha combined with ribavirin) raises hepcidin levels and reduces iron overload in patients with CHC. Hepcidin directly inhibits HCV replication mediated by STAT3 activation. HCV circumvents hepatic innate antiviral defence by lowering hepcidin. If hepcidin is also low in CKD patients with CHC, iron supplementation should be avoided even in CKD patients with CHC treated with erythropoiesis-stimulating agents.