Hepatic Iron Research Articles

Iron capture through CD71 drives perinatal and tumor-associated Treg expansion.

Besides suppressing immune responses, regulatory T cells (Tregs) maintain tissue homeostasis and control systemic metabolism. Whether iron is involved in Treg-mediated tolerance is completely unknown. Here, we showed that the transferrin receptor CD71 was upregulated on activated Tregs infiltrating human liver cancer. Mice with a Treg-restricted CD71 deficiency spontaneously developed a scurfy-like disease, caused by impaired perinatal Treg expansion. CD71-null Tregs displayed decreased proliferation and tissue-Treg signature loss. In perinatal life, CD71 deficiency in Tregs triggered hepatic iron overload response, characterized by increased hepcidin transcription and iron accumulation in macrophages. Lower bacterial diversity, and reduction of beneficial species, were detected in the fecal microbiota of CD71 conditional knockout neonates. Our findings indicate that CD71-mediated iron absorption is required for Treg perinatal expansion and is related to systemic iron homeostasis and bacterial gut colonization. Therefore, we hypothesize that Tregs establish nutritional tolerance through competition for iron during bacterial colonization after birth.

Correlation between plasma biochemical parameters and cardio-hepatic iron deposition in thalassemia major patients

Introduction Major Thalassemia patients suffer from iron overload and organ damage, especially heart and liver damage. Early diagnosis and treatment with a chelator can reduce the complications and mortality of iron overload. Therefore, we aimed to investigate the biochemical and hematological predictors as an alternative and indirect indicator of iron deposition in heart and liver cells in comparison with the MRI T2* method as the gold standard. Material and method MRI T2* was evaluated in the heart and liver tissues of 62 major beta-thalassemia patients undergoing regular transfusion and chelator therapy. Biochemical and hematological factors were also measured, including serum ferritin, serum electrolytes, liver enzymes, hemoglobin, blood glucose, and serum magnesium. The correlation between these factors was assessed using statistical evaluations. Result Serum ferritin had a positive and significant correlation with liver siderosis based on MRI T2* (p-value = .015), and no significant association was observed with cardiac siderosis (p-value = .79). However, there was a significant positive correlation between cardiac iron deposition and fasting blood sugar level (p-value = −.049), and plasma level of liver enzymes (alanine aminotransferase (ALT) (p-value = .001), aspartate aminotransferase (AST ((p-value = .01)). Moreover, there was a significant negative correlation between cardiac iron overload and plasma magnesium level (p-value = .014). According to MRI T2*, there was no significant correlation between cardiac and hepatic iron overload (p value = .36). Conclusion An increase in blood sugar or liver enzymes and a decrease in serum magnesium was associated with an increase in cardiac iron overload based on MRI T2*. Liver iron overload based on MRI T2* had a significant correlation with serum ferritin.

FRI-197 Implication of recent international consensus criteria for metabolic hyperferritinemia diagnosis and grade in a large cohort of patient with hepatic iron content assessed by magnetic resonance imaging

FRI-197 Implication of recent international consensus criteria for metabolic hyperferritinemia diagnosis and grade in a large cohort of patient with hepatic iron content assessed by magnetic resonance imaging

Effect of high-dose intravenous iron injection on hepatic function in a rat model of cirrhosis.

To investigate the hepatic effects of high-dose intravenous (IV) iron, including those on liver function and the degree of fibrosis, in a rat model of cirrhosis. We evenly allocated 25 Sprague-Dawley rats into five groups: normal rats (control group), cirrhotic rats receiving IV normal saline (liver cirrhosis [LC] group), and cirrhotic rats receiving 20, 40, or 80 mg/kg IV ferric carboxymaltose (LC-iron20, LC-iron40, and LC-iron80 group, respectively). Biochemical parameters were compared at 0, 7, 14, 21, and 28 days. The degrees of hepatic fibrosis and iron deposition were evaluated. Inflammatory and oxidative stress markers were also compared. There were no significant differences in the 28-day serum alanine aminotransferase levels among the LC-iron20, LC-iron40, and LC-iron80 groups (69 ± 7, 1003 ± 127, 1064 ± 309, 919 ± 346, and 820 ± 195 IU/L in the control, LC, LC-iron20, LC-iron40, and LC-iron80 groups, respectively). Hepatic iron accumulation increased in a dose-dependent manner, but the degree of hepatic fibrosis was comparable among the groups. The inflammatory and oxidative stress marker levels did not differ significantly according to the IV iron dose. Administration of IV iron at various high doses appears safe in our rat model of cirrhosis.

Genetic Determined Iron Starvation Signature in Friedreich's Ataxia.

Early studies in cellular models suggested an iron accumulation in Friedreich's ataxia (FA), yet findings from patients are lacking. The objective is to characterize systemic iron metabolism, body iron storages, and intracellular iron regulation in FA patients. In FA patients and matched healthy controls, we assessed serum iron parameters, regulatory hormones as well as the expression of regulatory proteins and iron distribution in peripheral blood mononuclear cells (PBMCs). We applied magnetic resonance imaging with R2*-relaxometry to quantify iron storages in the liver, spleen, and pancreas. Across all evaluations, we assessed the influence of the genetic severity as expressed by the length of the shorter GAA-expansion (GAA1). We recruited 40 FA patients (19 women). Compared to controls, FA patients displayed lower serum iron and transferrin saturation. Serum ferritin, hepcidin, mean corpuscular hemoglobin and mean corpuscular volume in FA inversely correlated with the GAA1-repeat length, indicating iron deficiency and restricted availability for erythropoiesis with increasing genetic severity. R2*-relaxometry revealed a reduction of splenic and hepatic iron stores in FA. Liver and spleen R2* values inversely correlated with the GAA1-repeat length. FA PBMCs displayed downregulation of ferritin and upregulation of transferrin receptor and divalent metal transporter-1 mRNA, particularly in patients with >500 GAA1-repeats. In FA PBMCs, intracellular iron was not increased, but shifted toward mitochondria. We provide evidence for a previously unrecognized iron starvation signature at systemic and cellular levels in FA patients, which is related to the underlying genetic severity. These findings challenge the use of systemic iron lowering therapies in FA. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Liver steatosis in patients with transfusion-dependent thalassaemia.

We evaluated the prevalence and the clinical associations of liver steatosis (LS) in patients with transfusion-dependent thalassaemia (TDT). We considered 301 TDT patients (177 females, median age = 40.61 years) enrolled in the Extension-Myocardial Iron Overload in Thalassaemia Network, and 25 healthy subjects. Magnetic resonance imaging was used to quantify iron overload and hepatic fat fraction (FF) by T2* technique and cardiac function by cine images. The glucose metabolism was assessed by the oral glucose tolerance test (OGTT). Hepatic FF was significantly higher in TDT patients than in healthy subjects (median value: 1.48% vs. 0.55%; p = 0.013). In TDT, hepatic FF was not associated with age, gender, serum ferritin levels or liver function parameters, but showed a weak inverse correlation with high-density lipoprotein cholesterol. The 36.4% of TDT patients showed LS (FF >3.7%). Active hepatitis C virus (HCV) infection, increased body mass index and hepatic iron were independent determinants of LS. A hepatic FF >3.53% predicted the presence of an abnormal OGTT. Hepatic FF was not correlated with cardiac iron, biventricular volumes or ejection fractions, but was correlated with left ventricular mass index. In TDT, LS is a frequent finding, associated with iron overload, increased weight and HCV, and conveying an increased risk for the alterations of glucose metabolism.

Hemoglobin scavenger receptor CD163 as a potential biomarker of hemolysis-induced hepatobiliary injury in sickle cell disease.

Sickle cell disease (SCD)-associated chronic hemolysis promotes oxidative stress, inflammation, and thrombosis leading to organ damage, including liver damage. Hemoglobin scavenger receptor CD163 plays a protective role in SCD by scavenging both hemoglobin-haptoglobin complexes and cell-free hemoglobin. A limited number of studies in the past have shown a positive correlation of CD163 expression with poor disease outcomes in patients with SCD. However, the role and regulation of CD163 in SCD-related hepatobiliary injury have not been fully elucidated yet. Here we show that chronic liver injury in SCD patients is associated with elevated levels of hepatic membrane-bound CD163. Hemolysis and increase in hepatic heme, hemoglobin, and iron levels elevate CD163 expression in the SCD mouse liver. Mechanistically we show that heme oxygenase-1 (HO-1) positively regulates membrane-bound CD163 expression independent of nuclear factor erythroid 2-related factor 2 (NRF2) signaling in SCD liver. We further demonstrate that the interaction between CD163 and HO-1 is not dependent on CD163-hemoglobin binding. These findings indicate that CD163 is a potential biomarker of SCD-associated hepatobiliary injury. Understanding the role of HO-1 in membrane-bound CD163 regulation may help identify novel therapeutic targets for hemolysis-induced chronic liver injury.

Repeated Injection of Very Small Superparamagnetic Iron Oxide Particles (VSOPs) in Murine Atherosclerosis: A Safety Study.

Citrate-coated electrostatically stabilized very small superparamagnetic iron oxide particles (VSOPs) have been successfully tested as magnetic resonance angiography (MRA) contrast agents and are promising tools for molecular imaging of atherosclerosis. Their repeated use in the background of pre-existing hyperlipidemia and atherosclerosis has not yet been studied. This study aimed to investigate the effect of multiple intravenous injections of VSOPs in atherosclerotic mice. Taurine-formulated VSOPs (VSOP-T) were repeatedly intravenously injected at 100 µmol Fe/kg in apolipoprotein E-deficient (ApoE KO) mice with diet-induced atherosclerosis. Angiographic imaging was carried out by in vivo MRI. Magnetic particle spectrometry was used to detect tissue VSOP content, and tissue iron content was quantified photometrically. Pathological changes in organs, atherosclerotic plaque development, and expression of hepatic iron-related proteins were evaluated. VSOP-T enabled the angiographic imaging of heart and blood vessels with a blood half-life of one hour. Repeated intravenous injection led to VSOP deposition and iron accumulation in the liver and spleen without affecting liver and spleen pathology, expression of hepatic iron metabolism proteins, serum lipids, or atherosclerotic lesion formation. Repeated injections of VSOP-T doses sufficient for MRA analyses had no significant effects on plaque burden, steatohepatitis, and iron homeostasis in atherosclerotic mice. These findings underscore the safety of VSOP-T and support its further development as a contrast agent and molecular imaging tool.

The Interplay of Iron and Lipid Homeostasis in Non-Alcoholic Fatty Liver Disease

The liver is essential for numerous metabolic functions and is the primary site of iron storage and regulation in addition to maintaining critical functions in lipid metabolism. Both iron deficiency and overload have been demonstrated as being involved with metabolic dysfunction; hence, tight regulation of iron absorption is essential to maintain health. Approximately one-third of individuals suffering from non-alcoholic fatty liver disease have elevated hepatic iron concentrations, with increased iron associated with increased disease severity, suggesting a convergence in dysregulation between lipid and iron metabolism. Increasingly, the literature is demonstrating, using a myriad of model organisms and iron-loading methods, that iron loading induces dysregulation in multiple aspects of hepatic lipid metabolism. However, the molecular mechanisms involved, and their subsequent effects on human diseases, are unclear. As iron is a fundamental component of many enzymes and proteins involved in lipid metabolism and is involved in the production of free radicals and oxidative stress, the mechanisms are numerous. In this review, we examine and summarise the dysregulation that iron loading elicits on hepatic lipid availability, de novo synthesis, catabolism, and export. We propose that understanding the interplay between iron and lipid metabolism holds the key to unlocking the complexities of disease development and progression, ultimately leading to improved therapeutic avenues.

Hemojuvelin-mediated hepcidin induction requires both bone morphogenetic protein type I receptors ALK2 and ALK3

AbstractHemojuvelin (HJV) is a glycosylphosphatidylinositol-anchored protein of the repulsive guidance molecule family acting as a bone morphogenetic protein (BMP) coreceptor to induce the hepatic iron regulatory protein hepcidin. Hepcidin causes ubiquitination and degradation of the sole known iron exporter ferroportin, thereby limiting iron availability. The detailed signaling mechanism of HJV in vivo has yet to be investigated. In the current manuscript, we used an established model of adeno-associated virus (AAV)-mediated liver-specific overexpression of HJV in murine models of hepatocyte-specific deficiency of the BMP type I receptors Alk2 or Alk3. In control mice, HJV overexpression increased hepatic Hamp messenger RNA (mRNA) levels, soluble HJV (sHJV), splenic iron content (SIC), as well as phosphorylated small mothers against decapentaplegic protein (pSMAD1/5/8) levels. In contrast, in Alk2fl/fl;Alb-Cre and Alk3fl/fl;Alb-Cre mice, which present with moderate and severe iron overload, respectively, the administration of AAV-HJV induced HJV and sHJV. However, it did not rescue the iron overload phenotypes of those mice. Serum iron levels were induced in Alk2fl/fl;Alb-Cre mice after HJV overexpression. In phosphate-buffered saline–injected Alk3fl/fl;Alb-Cre mice, serum iron levels and the expression of duodenal ferroportin remained high, whereas Hamp mRNA levels were decreased to 1% to 5% of the levels detected in controls. This was reduced even further by AAV-HJV overexpression. SIC remained low in mice with hepatocyte-specific Alk2 or Alk3 deficiency, reflecting disturbed iron homeostasis with high serum iron levels and transferrin saturation and an inability to induce hepcidin by HJV overexpression. The data indicate that ALK2 and ALK3 are both required in vivo for the HJV-mediated induction of hepcidin.

Impact of genotype on multi-organ iron and complications in patients with non-transfusion-dependent β-thalassemia intermedia.

We evaluated the impact of the genotype on clinical and hematochemical features, hepatic and cardiac iron levels, and endocrine, hepatic, and cardiovascular complications in non-transfusion-dependent (NTD) β-thalassemia intermedia (TI) patients. Sixty patients (39.09 ± 11.11years, 29 females) consecutively enrolled in the Myocardial Iron Overload in Thalassemia project underwent Magnetic Resonance Imaging to quantify iron overload, biventricular function parameters, and atrial areas and to detect replacement myocardial fibrosis. Three groups of patients were identified: homozygous β+ (N = 18), heterozygous β0β+ (N = 22), and homozygous β0 (N = 20). The groups were homogeneous for sex, age, splenectomy, hematochemical parameters, chelation therapy, and iron levels. The homozygous β° genotype was associated with significantly higher biventricular end-diastolic and end-systolic volume indexes and bi-atrial area indexes. No difference was detected in biventricular ejection fractions or myocardial fibrosis. Extramedullary hematopoiesis and leg ulcers were significantly more frequent in the homozygous β° group compared to the homozygous β+ group. No association was detected between genotype and liver cirrhosis, hypogonadism, hypothyroidism, osteoporosis, heart failure, arrhythmias, and pulmonary hypertension. Heart remodelling related to a high cardiac output state cardiomyopathy, extramedullary hematopoiesis, and leg ulcers were more pronounced in patients with the homozygous β° genotype compared to the other genotypes analyzed. The knowledge of the genotype can assist in the clinical management of NTD β-TI patients.

Difference in the Mechanism of Iron Overload-Enhanced Acute Hepatotoxicity Induced by Thioacetamide and Carbon Tetrachloride in Rats.

Iron overload has been recognized as a risk factor for liver disease; however, little is known about its pathological role in the modification of liver injury. The purpose of this study is to investigate the influence of iron overload on liver injury induced by two hepatotoxicants with different pathogenesis in rats. Rats were fed a control (Cont), 0.8% high-iron (0.8% Fe), or 1% high-iron diet (1% Fe) for 4 weeks and were then administered with saline, thioacetamide (TAA), or carbon tetrachloride (CCl4). Hepatic and systemic iron overload were seen in the 0.8% and 1% Fe groups. Twenty-four hours after administration, hepatocellular necrosis induced by TAA and hepatocellular necrosis, degeneration, and vacuolation induced by CCl4, as well as serum transaminase values, were exacerbated in the 0.8% and 1% Fe groups compared to the Cont group. On the other hand, microvesicular vacuolation induced by CCl4 was decreased in 0.8% and 1% Fe groups. Hepatocellular DNA damage was increased by iron overload in both models, whereas a synergistic effect of oxidative stress by excess iron and hepatotoxicant was only present in the CCl4 model. The data showed that dietary iron overload exacerbates TAA- and CCl4-induced acute liver injury with different mechanisms.

Iron Fortification and Inulin Supplementation in Early Infancy: Evaluating the Impact on Iron Metabolism and Trace Mineral Status in a Piglet Model

BackgroundInfant formula in the United States contains abundant iron, raising health concerns about excess iron intake in early infancy. ObjectivesUsing a piglet model, we explored the impact of high iron fortification and prebiotic or synbiotic supplementation on iron homeostasis and trace mineral bioavailability. MethodsTwenty-four piglets were stratified and randomly assigned to treatments on postnatal day 2. Piglets were individually housed and received an iron-adequate milk diet (AI), a high-iron milk diet (HI), HI supplemented with 5% inulin (HI with a prebiotic [HIP]), or HIP with an oral gavage of Ligilactobacillus agilis YZ050, an inulin-fermenting strain, every third day (HI with synbiotic [HIS]). Milk was provided in 14 meals daily, mimicking formula feeding in infants. Fecal consistency score and body weight were recorded daily or every other day. Blood and feces were sampled weekly, and tissues collected on postnatal day 29. Data were analyzed using mixed model analysis of variance with repeated measures whenever necessary. ResultsDiet did not affect growth. HI increased hemoglobin, hematocrit, and serum iron compared to AI. Despite marginal adequacy, AI upregulated iron transporter genes and maintained satisfactory iron status in most pigs. HI upregulated hepcidin gene expression in liver, caused pronounced tissue iron deposition, and markedly increased colonic and fecal iron. Inulin supplementation, regardless of L. agilis YZ050, not only attenuated hepatic iron overload but also decreased colonic and fecal iron without altering pH or the expression of iron regulatory genes. HI lowered zinc (Zn) and copper (Cu) in the duodenum and liver compared to AI, whereas HIP and HIS further decreased Zn and Cu in the liver and diminished colonic and fecal trace minerals. ConclusionsEarly-infancy excessive iron fortification causes iron overload and compromises Zn and Cu absorption. Inulin decreases trace mineral absorption likely by enhancing gut peristalsis and stool frequency.

Dietary Iron Overload Triggers Hepatic Metabolic Disorders and Inflammation in Laying Hen.

Iron, an essential trace element, is involved in various physiological processes; however, consumption of excessive iron possesses detrimental effects. In practical feed production, the iron content added to feeds often far exceeds the actual demand, resulting in an excess of iron in the body. The liver as a central regulator of iron homeostasis is susceptible to damage caused by disorders in iron metabolism. A model of hepatic iron overload in laying hens was developed in this study by incorporating iron into their diet, and the specific mechanisms underlying iron overload-induced hepatic injury were investigated. Firstly, this study revealed that a high-iron diet resulted in hepatic iron overload, accompanied by impaired liver function. Next, assessment of oxidative stress markers indicated a decrease in activities of T-SOD and CAT, coupled with an increase in MDA content, pointing to the iron-overloaded liver oxidative stress. Thirdly, the impact of iron overload on hepatic glycolipid and bile acid metabolism-related gene expressions were explored, including PPAR-α, GLUT2, and CYP7A1, highlighting disruptions in hepatic metabolism. Subsequently, analyses of inflammation-related genes such as iNOS and IL-1β at both protein and mRNA levels demonstrated the presence of inflammation in the liver under conditions of dietary iron overload. Overall, this study provided comprehensive evidence that dietary iron overload contributed to disorders in glycolipid and bile acid metabolism, accompanied by inflammatory responses in laying hens. Further detailing the specific pathways involved and the implications of these findings could offer valuable insights for future research and practical applications in poultry nutrition.

Application of the magnetic resonance 3D multiecho Dixon sequence for quantifying hepatic iron overload and steatosis in patients with thalassemia

ObjectiveTo investigate the feasibility and diagnostic efficacy of a 3D multiecho Dixon (qDixon) research application for simultaneously quantifying the liver iron concentration (LIC) and steatosis in thalassemia patients. Materials and methodsThis prospective study enrolled participants with thalassemia who underwent 3 T MRI of the liver for the evaluation of hepatic iron overload. The imaging protocol including qDixon and conventional T2* mapping based on 2D multiecho gradient echo (ME GRE) sequences respectively. Regions of interest (ROIs) were drawn in the liver on the qDixon maps to obtain R2* and proton density fat fraction (PDFF). The reference R2* value was measured and calculated on conventional T2* mapping using the CMRtools software. Correlation analysis, Linear regression analysis, and Bland–Altman analysis were performed. Results84 patients were finally included in this study. The median R2*-ME-GRE was 366.97 (1/s), range [206.68 (1/s), 522.20 (1/s)]. 8 patients had normal hepatic iron deposition, 16 had Insignificant, 42 had mild, 18 had moderate. The median of R2*-qDixon was 376.88 (1/s) [219.33 (1/s), 491.75 (1/s)]. A strong correlation was found between the liver R2*-qDixon and the R2*-ME-GRE (r = 0.959, P < 0.001). The median value of PDFF was 1.76% (1.10%, 2.95%). 8 patients had mild fatty liver, and 1 had severe fatty liver. ConclusionMR qDixon research sequence can rapidly and accurately quantify liver iron overload, that highly consistent with the measured via conventional GRE sequence, and it can also simultaneously detect hepatic steatosis, this has great potential for clinical evaluation of thalassemia patients.

Chronic dietary iron overload affects hepatic iron metabolism and cognitive behavior in Wistar rats

BackgroundIron accumulation in organs affects iron metabolism, leading to deleterious effects on the body. Previously, it was studied that high dietary iron in various forms and concentrations influences iron metabolism, resulting in iron accumulation in the liver and spleen and cognitive impairment. However, the actual mechanism and impact of long-term exposure to high dietary iron remain unknown. As a result, we postulated that iron overload caused by chronic exposure to excessive dietary iron supplementation would play a role in iron dyshomeostasis and inflammation in the liver and brain of Wistar rats. MethodsAnimals were segregated into control, low iron (FAC-Ferric Ammonium Citrate 5000 ppm), and high iron dose group (FAC 20,000 ppm). The outcome of dietary iron overload on Wistar rats was evaluated in terms of body weight, biochemical markers, histological examination of liver and brain tissue, and cognitive-behavioral studies. Also, gene expression of rat brain tissue involving iron transporters Dmt1, TfR1, iron storage protein Fpn1, inflammatory markers Nf-kB, Tnf-α, Il-6, and hepcidin was performed. ResultsOur data indicate that excess iron supplementation for 30 weeks leads to decreased body weight, increased serum iron levels, and decreased RBC levels in iron fed Wistar rats. Morris water maze (MWM) studies after 30 weeks showed increased escape latency in the high iron dose group compared with the control group. Histological studies of the high iron dose group showed an iron accumulation in the liver and brain loss of cellular architecture, and cellular degeneration was observed. Excess iron treatment showed upregulation of the Dmt1 gene in iron metabolism and a remarkable increase in the Nf-kB gene in rat brain tissue. ConclusionThe results show chronic excess iron supplementation leads to iron accumulation in the liver, leading to inflammation in Wistar rats.

Is iron overload associated with worse outcomes in patients with chronic liver disease undergoing liver transplantation?

Iron overload is frequent in patients with chronic liver disease, associated with shorter survival after liver transplantation in patients with hereditary hemochromatosis. Its effect on patients without hereditary hemochromatosis is unclear. The aim of the study was to study the clinical impact of iron overload in patients who underwent liver transplantation at an academic tertiary referral center. We performed a retrospective cohort study including all patients without hereditary hemochromatosis who underwent liver transplantation from 2015 to 2017 at an academic tertiary referral center in Mexico City. Explant liver biopsies were reprocessed to obtain the histochemical hepatic iron index, considering a score ≥ 0.15 as iron overload. Baseline characteristics were compared between patients with and without iron overload. Survival was estimated using the Kaplan-Meier method, compared with the log-rank test and the Cox proportional hazards model. Of 105 patients included, 45% had iron overload. Viral and metabolic etiologies, alcohol consumption, and obesity were more frequent in patients with iron overload than in those without iron overload (43% vs. 21%, 32% vs. 22%, p = 0.011; 34% vs. 9%, p = 0.001; and 32% vs. 12%, p = 0.013, respectively). Eight patients died within 90 days after liver transplantation (one with iron overload). Complication rate was higher in patients with iron overload versus those without iron overload (223 vs. 93 events/100 personmonths; median time to any complication of 2 vs. 3 days, p = 0.043), without differences in complication type. Fatality rate was lower in patients with iron overload versus those without iron overload (0.7 vs. 4.5 deaths/100 person-months, p = 0.055). Detecting iron overload might identify patients at risk of early complications after liver transplantation. Further studies are required to understand the role of iron overload in survival.

Hemochromatosis: Ferroptosis, ROS, Gut Microbiome, and Clinical Challenges with Alcohol as Confounding Variable.

Hemochromatosis represents clinically one of the most important genetic storage diseases of the liver caused by iron overload, which is to be differentiated from hepatic iron overload due to excessive iron release from erythrocytes in patients with genetic hemolytic disorders. This disorder is under recent mechanistic discussion regarding ferroptosis, reactive oxygen species (ROS), the gut microbiome, and alcohol abuse as a risk factor, which are all topics of this review article. Triggered by released intracellular free iron from ferritin via the autophagic process of ferritinophagy, ferroptosis is involved in hemochromatosis as a specific form of iron-dependent regulated cell death. This develops in the course of mitochondrial injury associated with additional iron accumulation, followed by excessive production of ROS and lipid peroxidation. A low fecal iron content during therapeutic iron depletion reduces colonic inflammation and oxidative stress. In clinical terms, iron is an essential trace element required for human health. Humans cannot synthesize iron and must take it up from iron-containing foods and beverages. Under physiological conditions, healthy individuals allow for iron homeostasis by restricting the extent of intestinal iron depending on realistic demand, avoiding uptake of iron in excess. For this condition, the human body has no chance to adequately compensate through removal. In patients with hemochromatosis, the molecular finetuning of intestinal iron uptake is set off due to mutations in the high-FE2+ (HFE) genes that lead to a lack of hepcidin or resistance on the part of ferroportin to hepcidin binding. This is the major mechanism for the increased iron stores in the body. Hepcidin is a liver-derived peptide, which impairs the release of iron from enterocytes and macrophages by interacting with ferroportin. As a result, iron accumulates in various organs including the liver, which is severely injured and causes the clinically important hemochromatosis. This diagnosis is difficult to establish due to uncharacteristic features. Among these are asthenia, joint pain, arthritis, chondrocalcinosis, diabetes mellitus, hypopituitarism, hypogonadotropic hypogonadism, and cardiopathy. Diagnosis is initially suspected by increased serum levels of ferritin, a non-specific parameter also elevated in inflammatory diseases that must be excluded to be on the safer diagnostic side. Diagnosis is facilitated if ferritin is combined with elevated fasting transferrin saturation, genetic testing, and family screening. Various diagnostic attempts were published as algorithms. However, none of these were based on evidence or quantitative results derived from scored key features as opposed to other known complex diseases. Among these are autoimmune hepatitis (AIH) or drug-induced liver injury (DILI). For both diseases, the scored diagnostic algorithms are used in line with artificial intelligence (AI) principles to ascertain the diagnosis. The first-line therapy of hemochromatosis involves regular and life-long phlebotomy to remove iron from the blood, which improves the prognosis and may prevent the development of end-stage liver disease such as cirrhosis and hepatocellular carcinoma. Liver transplantation is rarely performed, confined to acute liver failure. In conclusion, ferroptosis, ROS, the gut microbiome, and concomitant alcohol abuse play a major contributing role in the development and clinical course of genetic hemochromatosis, which requires early diagnosis and therapy initiation through phlebotomy as a first-line treatment.

Indoleamine 2,3-dioxygenase 1-mediated iron metabolism in macrophages contributes to lipid deposition in nonalcoholic steatohepatitis.

Non-alcoholic steatohepatitis (NASH) is a rapidly progressing chronic liver disease of global significance. However, the underlying mechanisms responsible for NASH remain unknown. Indoleamine 2,3-dioxygenase 1 (IDO1) has been recognized as essential factor in immune response and metabolic regulation. Here we aimed to investigate the functions and mechanisms of the IDO1 in macrophages on hepatic lipid deposition and iron metabolism in NASH. The effect of IDO1 in NASH was evaluated by WT and IDO1-/- mice model fed with methionine/choline-deficient (MCD) diet in vivo. Macrophages scavenger clodronate liposomes (CL) and overexpressing of IDO1 in macrophages by virus were employed as well. Lipid deposition was assessed through pathological examination and lipid droplet staining, while iron levels were measured using an iron assay kit and western blotting. Primary hepatocytes and bone marrow-derived macrophages were treated with oleic acid/palmitic acid (OA/PA) to assess IDO1 expression via Oil Red O staining and immunofluorescence staining in vitro. Pathological images demonstrated that the increase of IDO1 exacerbated lipid accumulation in the livers of mice with MCD diet, while reduction of iron accumulation was observed in the liver and the serum of MCD-fed mice. Scavenging of macrophages effectively mitigated both lipid and iron accumulation. In addition, the deficiency of IDO1 in macrophages significantly mitigated lipid accumulation and iron overload in hepatic parenchymal cells. Finally, lentivirus-mediated overexpression of IDO1 in liver macrophages exacerbated hepatic steatosis and iron deposition in NASH. Our results demonstrated that effective inhibition of IDO1 expression in macrophages in NASH alleviated hepatic parenchymal cell lipid accumulation and iron deposition, which provided new insights for the future treatment of NASH.

Impact of litter size on the hematological and iron status of gilts, sows and newborn piglets: a comparative study of domestic pigs and wild boars

BackgroundThe critically low hepatic iron stores of newborn piglets are considered to be a major cause of neonatal iron deficiency in modern breeds of domestic pig (Sus domestica). The main factor believed to contribute to this phenomenon is large litter size, which has been an objective of selective breeding of pigs for decades. As consequence, iron transferred from the pregnant sow has to be distributed among a greater number of fetuses.ResultsHere, we investigated whether litter size influences red blood cell (RBC) indices and iron parameters in Polish Large White (PLW) piglets and gilts. Small and large litters were produced by the transfer of different numbers of embryos, derived from the same superovulated donor females, to recipient gilts. Piglets from large litters obtained following routine artificial insemination were also examined. Our results clearly demonstrated that varying the number of piglets in a litter did not affect the RBC and iron status of 1-day-old piglets, with all showing iron deficiency anemia. In contrast, gilts with small litters displayed higher RBC and iron parameters compared to mothers with large litters. A comparative analysis of the RBC status of wild boars (having less than half as many piglets per litter as domestic pigs) and PLW pigs, demonstrated higher RBC count, hemoglobin level and hematocrit value of both wild boar sows and piglets, even compared to small-litter PLW animals.ConclusionsThese findings provide evidence that RBC and iron status in newborn PLW piglets are not primarily determined by litter size, and indicate the need to study the efficiency of iron transport across the placenta in domestic pig and wild boar females.