Liver Iron Concentration Research Articles

Sensing of Liver Iron Content Requires Cell-Cell Communication between Hepatocytes and Liver Sinusoidal Endothelial Cells

The liver stores iron and senses systemic and tissue iron availability. Hepatocytes control iron homeostasis by producing the peptide hormone hepcidin that controls dietary iron absorption and iron release from intracellular stores. Recent data challenged the exclusive role of hepatocytes in controlling iron levels. Indeed, liver sinusoidal endothelial cells (LSECs) increase BMP2 and BMP6 levels in response to iron, which control hepcidin expression in a paracrine manner. However the molecular mechanism(s) of how BMPs respond to iron levels remain unknown. We established primary murine LSEC cultures and exposed these to iron sources. Unexpectedly, BMP2 mRNA expression is strongly reduced by iron treatment, while BMP6 levels are only mildly increased. This finding suggests that intracellular iron content cannot directly activate BMP2 transcription and only slightly contribute to BMP6 upregulation in LSEC cultures. However, if LSECs are co-cultured with iron-loaded primary hepatocytes the expression of BMP2 and BMP6 is increased and the fold induction of BMP6 is greater compared to LSECs cultured alone, suggesting that the iron status of hepatocytes instructs the LSEC BMP response. These data are supported by findings in a genetic mouse model of iron overload (Slc40a1C326S/C326S). Hepatocytes isolated from Slc40a1C326S/C326S mice display an iron-loaded molecular signature and the expected low mRNA expression of Transferrin Receptor 1 (Tfr1). By contrast, LSECs show high expression of Tfr1, indicating intracellular iron deficiency. Despite this, hepatic BMP levels are increased, suggesting that BMP2 and BMP6 expression are directly related to the intracellular iron content of hepatocytes but not LSECs. RNA-sequencing of isolated hepatic cell populations is ongoing to identify putative hepatocyte regulators involved in the iron-mediated BMP2 and BMP6 regulation. Disclosures Muckenthaler: Silence Therapeutics: Consultancy; Novartis: Research Funding.

Glucose dysregulation in patients with iron overload: is there a relationship with quantitative pancreas and liver iron and fat content measured by MRI?

The aim was to investigate the relationship between pancreatic and hepatic iron and fat to glucose metabolism in patients with iron overload and address conflicting results in literature as regards the relationship between pancreas iron and glucose dysregulation. We retrospectively evaluated pancreatic and hepatic R2*, fat fraction (FF), liver iron concentration (LIC), and glucose metabolism in 105 patients with iron overload obtained with a multi-echo gradient echo R2* technique and assessed the correlation between pancreatic R2* and FF to glucose dysregulation. There were no significant differences in pancreatic R2*, liver R2*, and FF in patients with iron overload and glucose dysregulation compared to those with normoglycemia (p = 0.435, p = 0.674, and p = 0.976), whereas pancreatic FF was significantly higher, 23.5% vs 16.7% respectively (p = 0.011). Pancreatic FF and R2* demonstrated an area under the curve of 0.666 and 0.571 for discriminating glucose dysregulation. Pancreatic FF of 26.2% yielded specificity and sensitivity of 80% and 45% for prediction of glucose dysregulation. Pancreatic R2* weakly correlated with pancreatic FF, r = 0.388 (p < 0.001), and liver R2*, r = 0.201 (p = 0.033), and showed no correlation with hepatic FF r = -0.013 (p = 0.892) or LIC categories (p = 0.493). Pancreatic FF but not pancreatic R2* was associated with glucose dysregulation in patients with iron overload. Prior studies reporting correlation of pancreatic R2* to glucose dysregulation likely relate from inadequate MRI technique or analysis employed, which unlike our study did not perform simultaneous measurements of fat and iron essential to avoid their confounding effects during quantitative analysis. • Pancreatic fat fraction, unlike iron, is associated with glucose dysregulation in iron overload. • Simultaneous measurement of pancreatic iron and fat content with MRI is essential to avoid confounding effects of one another during quantitative analysis. • Pancreatic fat fraction could be utilized to predict glucose dysregulation in iron overload states.

Macrophage iron accumulation promotes the development of atherosclerosis in Apolipoprotein E knockout mice

Objective To investigate the effect of iron accumulation in macrophage on atherosclerosis. Methods Generating ApoE-/-Fpn1Lysm/Lysm mice by breeding Fpn1Lysm/Lysm mice with ApoE-/- mice. ApoE-/-Fpn1Lysm/Lysm mice and ApoE-/- mice (8 weeks old) were fed with Western diet for 8 weeks. Blood routine tests were performed to detect whether there was anemia. Immunohistochemical staining of ferroportin was performed in liver and spleen to see the expression of ferroportin. Perls’ Prussian Blue stain in liver, spleen and aortic sinus were performed to evaluate the iron content. Western blotting was performed to determine the protein level of ferritin in liver and spleen. Ferrozines were performed to detect the total iron content of liver and spleen. Hematoxylin and eosin (HE) stains of aortic sinus were performed to display the morphology of plaques. Oil Red O staining was performed to evaluate area and sizes of the plaques. Immunohistochemical staining of CD68 and α-smooth muscle actin (α-SMA) and Masson’s trichrome staining were performed to evaluate the composition of atherosclerotic plaque. Hepcidin and interleukin (IL)-6 in serum were detected through enzyme linked immunosorbent assay (ELISA). Results Iron in the plaques of ApoE-/-Fpn1Lysm/Lysm mice was significantly increased [(2.42±0.51)% vs. (11.93±1.62)%, t=17.707, P<0.01] and plaques tends to be unstable [α-SMA: (9.88±2.20)% vs. (2.63±1.02)%, t=9.454, P<0.01; Masson: (87.33±10.40)% vs. (55.28±11.20)%, t=6.631, P<0.01]. Conclusion Iron accumulates in macrophages of ApoE-/-Fpn1Lysm/Lysm mice and atherosclerosis of ApoE-/-Fpn1Lysm/Lysm mice is significantly increased. Key words: Atherosclerosis; Macrophages; Iron metabolism disorders; Ferroportin

GSTM1 and Liver Iron Content in Children with Sickle Cell Anemia and Iron Overload.

Chronic blood transfusions in patients with sickle cell anemia (SCA) cause iron overload, which occurs with a degree of interpatient variability in serum ferritin and liver iron content (LIC). Reasons for this variability are unclear and may be influenced by genes that regulate iron metabolism. We evaluated the association of the copy number of the glutathione S-transferase M1 (GSTM1) gene and degree of iron overload among patients with SCA. We compared LIC in 38 children with SCA and ≥12 lifetime erythrocyte transfusions stratified by GSTM1 genotype. Baseline LIC was measured using magnetic resonance imaging (MRI), R2*MRI within 3 months prior to, and again after, starting iron unloading therapy. After controlling for weight-corrected transfusion burden (mL/kg) and splenectomy, mean pre-chelation LIC (mg/g dry liver dry weight) was similar in all groups: GSTM1 wild-type (WT) (11.45, SD±6.8), heterozygous (8.2, SD±4.52), and homozygous GSTM1 deletion (GSTM1-null; 7.8, SD±6.9, p = 0.09). However, after >12 months of chelation, GSTM1-null genotype subjects had the least decrease in LIC compared to non-null genotype subjects (mean LIC change for GSTM1-null = 0.1 (SD±3.3); versus −0.3 (SD±3.0) and −1.9 (SD±4.9) mg/g liver dry weight for heterozygous and WT, respectively, p = 0.047). GSTM1 homozygous deletion may prevent effective chelation in children with SCA and iron overload.

Effects of dietary iron on growth, haematology, oxidative stress and hepatic ascorbic acid concentration of stinging catfish Heteropneustes fossilis

This study was aimed to evaluate the effects of dietary iron on growth, haematology oxidative stress and determine the optimum dietary iron level for Heteropneustes fossilis by feeding graded levels of iron (6.9, 25.5, 47.0, 66.7, 86.6, 107.1, 126.8 and 146.9 mg kg−1) achieved by supplementing ferrous sulfate (0, 99.4, 198.8, 298.2, 397.6, 497.0, 596.4 and 695.4 mg kg−1). Increase in dietary iron levels from 6.9 to 86.6 mg kg−1 significantly improved (P < 0.05) the growth performance and conversion efficiencies in terms of absolute weight gain (AWG; 50.4 g fish−1), feed conversion ratio (FCR; 1.6), specific growth rate (SGR; 2.5% day−1) and protein retention efficiency (PRE; 28.2%) beyond which no significant change was observed. The concentration of iron in liver also increased up to 86.6 mg kg−1 while whole body iron increased up to the level of 107.1 mg kg−1 and then stabilized. Red blood cells (RBC) counts, haemoglobin (Hb), haematocrit (Hct), mean cell haemoglobin (MCH) and mean corpuscular volume (MCV) also improved up to 86.6 mg kg−1 and then stabilized. Activities of hepatic superoxide dismutase (SOD) and catalase (CAT) were found to increase while malondialdehyde (MDA) content decreased with increasing levels of dietary iron up to 86.6 mg kg−1. Hepatic ascorbic acid concentration was found to decrease up to 86.6 mg kg−1. Based on broken-line regression analysis of AWG, PRE, Hct and serum iron concentration against increasing levels of dietary iron, optimum level of dietary iron for H. fossilis was found to range between 82.51 and 86.05 mg kg−1 of dry diet.

The Course of Hepatitis C Infection and Response to Anti-viral Therapy in Patients with Thalassemia major and Hepatitis C Infection: A Longitudinal, Prospective Study.

BackgroundThe course of hepatitis C infection (HCV) in patients with thalassemia has not been adequately studied, and management has not been optimized. The current prospective longitudinal study assessed the clinical course, outcome, progression, and management of recently acquired HCV in patients with transfusion-dependent thalassemia major versus acute HCV without thalassemia.MethodsA well-characterized cohort of patients with thalassemia and recent HCV infection or recent HCV without thalassemia were enrolled and prospectively followed. The blood transfusion needs and chelating agents were determined. Liver functions tests, HCV-RNA, iron, and ferritin levels were measured. Patients with chronic HCV evolution received treatment for HCV. The fibrosis progression rate was determined in chronic HCV patients with or without thalassemia by paired liver biopsies or serial transient elastography (TE), or serum markers of liver fibrosis. Liver iron content (LIC) was assessed by R2 MRI.ResultsSelf-limited acute HCV was observed in 17% of patients with acute HCV and thalassemia versus 35% of patients without thalassemia (P=0.031). The fibrosis progression rates were significantly higher in patients with chronic HCV and thalassemia compared to those with chronic HCV alone (1.14±0.48) and (0.35±0.14) (P<0.0001), respectively. A direct linear correlation was observed between the fibrosis progression rate and each of LIC (R=+0.67; P=0.01) and ferritin (R=0.77; P<0.01). In patients with chronic HCV and thalassemia, the sustained virologic response (SVR) to pegylated interferon-based therapy and direct antiviral agents (DAAS) were 33% and 82% respectively (P<0.0001), while in chronic HCV patients without thalassemia, the SVR rates to PEG-IFN/RBV and DAAs were 51% and 92% respectively. Five patients with concomitant HCV and thalassemia died during the study due to cardiac causes (n=3) and liver cancer (n=2).ConclusionsPatients with acute HCV and thalassemia have low rates of spontaneous resolution of HCV infection, and the majority develop chronic HCV. Direct-acting antiviral combinations are associated with high SVR rates and low adverse event in treatment naïve and experienced patients with chronic HCV and thalassemia. Liver fibrosis is accelerated in thalassemia patients with chronic HCV; therefore, early diagnosis, treatment with DAAs, adequate iron chelation, and non-invasive monitoring liver status are recommended to prevent cirrhosis and hepatocellular carcinoma.

1553. Human-Simulated Pharmacokinetic Profiles of Cefiderocol and Meropenem Are Conserved in Murine Models of Thigh Infection With or Without Iron Overload

BackgroundA translational murine model of thigh infection with comorbid iron overload was previously developed to study the efficacy of iron-dependent siderophore-antibiotic conjugates under conditions where the hypoferremic response of innate immunity may be compromised. Given the potential for functional organ damage from excessive tissue iron, which could alter the pharmacokinetic (PK) profiles of antibiotics being compared for efficacy using this model, the effects of iron overload on a siderophore-β-lactam conjugate, cefiderocol (CFDC), and a non-siderophore β-lactam, meropenem (MEM), were studied.MethodsFemale CD-1 mice received iron dextran (Fe-D) 100 mg/kg intraperitoneally for 14 days as previously shown to produce vastly supranormal iron concentrations in serum, liver, and spleen (ASM Microbe 2019 abstract HMB-373). Age-matched control mice were not dosed with Fe-D. Mice were rendered neutropenic. On day 15, both thighs of iron-overloaded and control mice were inoculated intramuscularly with Acinetobacter baumannii suspensions of 107 CFU/mL. Two hours after inoculation, mice in each model were dosed with previously developed human-simulated regimens (HSR) of CFDC or MEM simulating human PK profiles after doses of 2g q8h (3 hours infusion) for both drugs. At 4 time points per regimen, 6 mice per model were sacrificed for blood collection. Plasma total MEM and CFDC concentrations were measured with HPLC and LC-MS-MS, respectively. Free concentrations were calculated with murine protein binding. At each time point, mean free concentrations in both models were compared using Student’s t-test.ResultsObserved murine-free plasma concentrations ± 95% CI of CFDC and MEM are overlaid with simulated human and murine profiles in the figure. In both models, these regimens approximated human exposures after clinical doses. For all time points and both drugs, concentrations were not significantly different (P > 0.05) between models with or without iron overload.ConclusionIron overload did not significantly alter PK profiles of a siderophore-β-lactam conjugate, CFDC, or a non-siderophore β-lactam, MEM. These data support the use of CFDC and MEM HSR for pharmacodynamic studies utilizing both iron-overloaded and standard murine thigh infection models. Disclosures All authors: No reported disclosures.

Association between Different Animal Protein Sources and Liver Status in Obese Subjects with Non-Alcoholic Fatty Liver Disease: Fatty Liver in Obesity (FLiO) Study.

Non-alcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of metabolic syndrome. Obesity and unhealthy dietary habits are described as risk factors for NAFLD. The aim of this study was to investigate the association between the consumption of different animal protein sources and hepatic status in NAFLD adults. A total of 112 overweight/obese participants with NAFLD from Fatty Liver in Obesity (FLiO) study were evaluated at baseline. Diet, body composition, and biochemical variables were evaluated. Hepatic status was also assessed by Magnetic Resonance Imaging, ultrasonography, and elastography. Red meat consumption showed a positive relationship with liver iron content (r = 0.224; p = 0.021) and ferritin concentration (r = 0.196; p = 0.037). Processed meat consumption exhibited a positive association with liver iron content (r = 0.308; p = 0.001), which was also found in the quantile regression (β = 0.079; p = 0.028). Fish consumption was related with lower concentration of ferritin (r = −0.200; p = 0.034). This association was further evidenced in the regression model (β = −0.720; p = 0.033). These findings suggest that the consumption of different animal protein sources differentially impact on liver status in obese subjects with NAFLD, showing fish consumption as a healthier alternative for towards NAFLD features.

PP-110 - Relationship between liver iron concentration determined by liver MRI (SIR method) serum ferritin and liver enzymes in patients with thalassemia major

PP-110 - Relationship between liver iron concentration determined by liver MRI (SIR method) serum ferritin and liver enzymes in patients with thalassemia major

Liver iron concentration in dysmetabolic hyperferritinemia: Results from a prospective cohort of 276 patients

Introduction and objectivesWe aimed to study the liver iron concentration in patients referred for hyperferritinemia to six hospitals in the Basque Country and to determine if there were differences between patients with or without metabolic syndrome. Patients and methodsMetabolic syndrome was defined by accepted criteria. Liver iron concentration was determined by magnetic resonance imaging. ResultsWe obtained the data needed to diagnose metabolic syndrome in 276 patients; a total of 135 patients (49%), 115/240 men (48%), and 20/36 women (55.6%) presented metabolic syndrome. In all 276 patients, an MRI for the determination of liver iron concentration (mean±SD) was performed. The mean liver iron concentration was 30.83±19.38 for women with metabolic syndrome, 38.84±25.50 for men with metabolic syndrome, and 37.66±24.79 (CI 95%; 33.44–41.88) for the whole metabolic syndrome group. In 141 patients (51%), metabolic syndrome was not diagnosed: 125/240 were men (52%) and 16/36 were women (44.4%). The mean liver iron concentration was 34.88±16.18 for women without metabolic syndrome, 44.48±38.16 for men without metabolic syndrome, and 43.39±36.43 (CI 95%, 37.32–49.46) for the whole non-metabolic syndrome group. Comparison of the mean liver iron concentration from both groups (metabolic syndrome vs non-metabolic syndrome) revealed no significant differences (p=0.12). ConclusionsPatients with hyperferritinemia and metabolic syndrome presented a mildly increased mean liver iron concentration that was not significantly different to that of patients with hyperferritinemia and non-metabolic syndrome.

T2 ∗ Relaxation Time Obtained from Magnetic Resonance Imaging of the Liver Is a Useful Parameter for Use in the Construction of a Murine Model of Iron Overload.

Aim Iron overload is a life-threatening disorder that can increase the risks of cancer, cardiovascular disease, and liver cirrhosis. There is also a risk of iron overload in patients with chronic kidney disease. In patients with renal failure, iron storage is increased due to inadequate iron utilization associated with decreased erythropoiesis and also to the inflammatory status. To evade the risk of iron overload, an accurate and versatile indicator of body iron storage in patients with iron overload is needed. In this study, we aimed to find useful iron-related parameters that could accurately reflect body iron storage in mice in order to construct a murine model of iron overload. Methods To select an appropriate indicator of body iron status, a variety of parameters involved in iron metabolism were evaluated. Noninvasively measured parameters were R1, R2, and R2∗ derived from magnetic resonance imaging (MRI). Invasively measured parameters included serum hepcidin levels, serum ferritin levels, and liver iron contents. Histopathological analysis was also conducted. Results/Conclusion Among the several parameters evaluated, the MRI T2∗ relaxation time was able to detect iron storage in the liver as sensitively as serum ferritin levels. Moreover, it is expected that using an MRI parameter will allow accurate evaluation of body iron storage in mice over time.

From the Editor’s Desk: September 2019

From the Editor’s Desk: September 2019

Long-term effects of chromium on morphological and immunological parameters of Wistar rats

Hexavalent chromium raises high concern because of its wide industrial applications and reported toxicity. Long-term (135 days) oral exposure of Wistar rats to chromium in the form of K2Cr2O7 (exposed group~20 mg/kg/day) led to a decrease in thymus mass and thymocytes' number and caused structural and functional changes in the lymph nodes and spleen, namely lymphoreticular hyperplasia and plasmocytic macrophage transformation. Programmed cell death was increased in both thymocytes and splenocytes and decreased in lymphocytes in the T-zones of spleen and lymph nodes. Moreover, Cr (VI) administration decreased myeloid cells' and neutrophils' number, while it increased lymphoid and erythroid cells' number in bone marrow. Cr (VI) immune system effects seem to be related to oxidative stress induction, as depicted by the increased levels of diene conjugates and malondialdehyde in the spleen and liver and by the decreased activity of catalase and superoxide dismutase in rats’ erythrocytes. In addition, exposure to Cr (VI) decreased copper, nickel and iron concentrations in blood and liver, while Cr levels in blood, spleen and liver were increased, as expected. The observed changes in the series of immunological parameters studied contribute to the development of new approaches for the prevention of low level Cr exposure toxicity.

Effective method of evaluating myocardial iron concentration in pediatric patients with thalassemia major.

BackgroundThe use of T2* magnetic resonance imaging (MRI) has been promoted by recent studies as a noninvasive method for the detection of iron overload in thalassemia major patients. This study aims to estimate the iron load in the heart and liver of thalassemia major patients using T2* MRI and to determine its correlation with the left ventricle ejection fraction and serum ferritin level.MethodsForty β-Thalassemia major patients were included in the study. We evaluated the serum ferritin level, echocardiography, cardiac T2*, myocardial iron concentration (MIC), liver iron concentration (LIC) and hepatic T2* in all patients. CMR T2* findings were categorized as normal cardiac T2* (T2* >20 ms) or abnormal cardiac T2* (T2* <20 ms).ResultsThe study found that 85% of patients had a normal cardiac T2* value. The median serum ferritin level was 2189. A significant inverse correlation was found between the serum ferritin level and the cardiac T2* (r=−0.381, =0.015); however, the correlations between serum ferritin and the hepatic T2* and liver iron concentration were statistically non-significant (P=0.539 and P=0.637, respectively). Additionally, the LVEF correlation was statistically non-significant with SF, hepatic T2* and cardiac T2*.ConclusionRegardless of the serum ferritin level or left ventricle function, a cardiac T2* MRI should be done for all patients with β-Thalassemia major in order to estimate the myocardial iron concentration.

A randomized controlled trial evaluating the effects of amlodipine on myocardial iron deposition in pediatric patients with thalassemia major.

BackgroundMortality rates increase due to iron deposition in the cardiac muscles of thalassemia major (TM) patients. Iron overload cardiomyopathy could be treated with a combination therapy of an iron chelator and an L-type calcium channel blocker. We designed a randomized controlled study to assess the potential of amlodipine, alongside chelation, in reducing myocardial iron concentration in TM patients compared with a placebo.ObjectivesThis study aims to estimate the change in myocardial iron concentration (MIC) determined by magnetic resonance imaging after 6 months of treatment with amlodipine, as well as measuring the changes in the secondary outcomes (liver iron concentration (LIC), serum ferritin level (SF), and left ventricle ejection fraction (LVEF)) of study participants.MethodsA single, randomized, placebo-controlled trial was performed in 40 β-Thalassemia major patients aged between 6 and 20 years old, who received either oral amlodipine 2.5–5 mg/day or a placebo, in addition to a Deferasirox chelation regimen in a 1:1 allocation ratio.ResultsAfter 6 months, a significant reduction was noted in the MIC of patients receiving amlodipine (n=20), compared with the patients receiving the placebo (n=20). At baseline, the mean was 0.76±0.11 mg/g dry weight, while at 6 months, the mean was 0.51±0.07 mg/g dry weight (p<0.001). Also, there was a significant change in the myocardial T2* after 6 months; the amlodipine increased the myocardial T2* from 40.63±5.45 ms at baseline to 43.25±5.35 ms (p<0.001). However, amlodipine did not significantly affect the secondary outcomes by the end of the study.ConclusionThe addition of amlodipine to the standard chelation therapy in transfusion-dependent thalassemia major patients improves myocardial iron overload without increasing the adverse effects.

Copper, Iron, Manganese, Zinc, Cobalt, Arsenic, Cadmium, Chrome, and Lead Concentrations in Liver and Muscle in Iranian Camel (Camelus dromedarius).

Camel meat as healthy food has received much attention for human consumption. In the present study, liver and muscle from 60 camels (Camelus dromedarius) including 26 males and 34 females were sampled to determine the concentration of As, Cd, Pb, Cr, Cu, Fe, Mn, Zn, and Co using the inductively coupled plasma-optical emission spectrometry (ICP-OES). Based on the obtained results, the average content of essential or toxic elements in the liver and muscle was as follows: 111.2 ± 26.51, 38.57 ± 7.97 (Zn), 3.28 ± 0.79, 2.12 ± 0.49 (Cu), 76.98 ± 14.20, 59.34 ± 11.81 (Fe), 0.87 ± 0.22, 0.48 ± 0.12 (Mn), 0.52 ± 0.27, 0.03 ± 0.01 (Co), ND ± 0.008, 0.012 ± 0.008 (Cd), 7.06 ± 1.58, 3.90 ± 0.86 (Cr), 0.85 ± 0.043, and 0.18 ± 0.02, and 1.12 ± 0.21 (As) mg kg-1. Pb concentration was lower than the detection limit (ND). The results showed that the liver concentrations of Cu, Zn, Fe, Mn, Co, and Cr were significantly higher than those in the muscle. The association of sex, age, region, and sampling period, with a concentration of these elements, revealed that concentration of zinc in the liver and cobalt in the muscle were significantly higher in the male. Also, significantly higher cobalt and zinc concentrations in muscle were seen in the first 6 months of the year. Age-related differences in muscle concentrations were observed for cobalt. The concentration of trace elements and heavy metals in the liver and muscle samples were not correlated. Comparison of heavy metals concentration in both tissues with European Commission regulation showed that except Cd, the other heavy metals had a higher level than the EU standard. The results of this study showed that camel meat can be contaminated with heavy metals, but more investigations are needed.

Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration

Excess liver iron content is common and is linked to the risk of hepatic and extrahepatic diseases. We aimed to identify genetic variants influencing liver iron content and use genetics to understand its link to other traits and diseases. First, we performed a genome-wide association study (GWAS) in 8,289 individuals from UK Biobank, whose liver iron level had been quantified by magnetic resonance imaging, before validating our findings in an independent cohort (n = 1,513 from IMI DIRECT). Second, we used Mendelian randomisation to test the causal effects of 25 predominantly metabolic traits on liver iron content. Third, we tested phenome-wide associations between liver iron variants and 770 traits and disease outcomes. We identified 3 independent genetic variants (rs1800562 [C282Y] and rs1799945 [H63D] in HFE and rs855791 [V736A] in TMPRSS6) associated with liver iron content that reached the GWAS significance threshold (p <5 × 10-8). The 2 HFE variants account for ∼85% of all cases of hereditary haemochromatosis. Mendelian randomisation analysis provided evidence that higher central obesity plays a causal role in increased liver iron content. Phenome-wide association analysis demonstrated shared aetiopathogenic mechanisms for elevated liver iron, high blood pressure, cirrhosis, malignancies, neuropsychiatric and rheumatological conditions, while also highlighting inverse associations with anaemias, lipidaemias and ischaemic heart disease. Our study provides genetic evidence that mechanisms underlying higher liver iron content are likely systemic rather than organ specific, that higher central obesity is causally associated with higher liver iron, and that liver iron shares common aetiology with multiple metabolic and non-metabolic diseases. Excess liver iron content is common and is associated with liver diseases and metabolic diseases including diabetes, high blood pressure, and heart disease. We identified 3 genetic variants that are linked to an increased risk of developing higher liver iron content. We show that the same genetic variants are linked to higher risk of many diseases, but they may also be associated with some health advantages. Finally, we use genetic variants associated with waist-to-hip ratio as a tool to show that central obesity is causally associated with increased liver iron content.

Liver iron concentration is not raised in patients with dysmetabolic hyperferritinemia

Background & aims. Hyperferritinemia (HF) is frequently present in patients with metabolic syndrome (MS). MS associated with HF is named dysmetabolic hyperferritinemia (DH). There are some publications that propose that DH is associated with a raised liver iron concentration (LIC). We studied the LIC in patients referred for HF to a secondary hospital to determine if there are differences between patients with or without MS.Material and methods. We conducted a prospective study of 132 consecutive patients with HF from January to December 2010. The MS was defined by the International Diabetes Federation criteria (2005). LIC was determined by Magnetic resonance imaging (MRI).Results. The number of patients for which there was enough data to determine MS was 97, out of which 54 had MS and 43 had no MS (NMS). In 54/97 patients, MRI for LIC determination was performed. From the MS group, 44 were men (27 underwent MRI) and 10 women (9 MRI). The mean LIC was 27.83 ± 20.90 μmol/g for the MS group. In the NMS group, 36 were men (13 MRI), and 7 women (5 MRI). In 18 patients from the NMS group, LIC was determined by MRI. The mean LIC was 33.16 ± 19.61 μmol/g in the NMS group. We compared the mean values of LIC from both groups (MS vs. NMS) and no significant differences were found (p = 0.067).Conclusion. Patients with DH present a mean LIC within normal values and their values do not differ from those of patients with HF but without MS.

Chronic alcohol abuse may lead to high skin iron content, but not to hepatic siderosis

IntroductionIn forensic cases, ante mortem chronic alcohol abuse can be of central importance in clarifying circumstances of death. However, reliable markers of alcohol consumption, which are still available postmortem, are needed. In addition to medical history data which may not be always authentic, the determination of ethyl glucuronide (EtG) in hair as a promising parameter is of no value in cases of missing or cosmetically treated hair. On the other hand, there exist reports that iron ions accumulate in liver tissue (siderosis) during chronic, excessive alcohol consumption, which, therefore, may be useful to serve as alcohol abuse correlate. However, the influence of ethanol on iron stored in the liver has not been adequately investigated and the study situation appears to be inconsistent. AimsThe aim of the present study was to assess the suitability of assaying iron concentrations in liver and other tissues as postmortem alcoholism marker. MethodsThe iron concentration in tissue samples (liver, brain, skin, pancreas, spleen), vitreous fluid and blood taken during autopsy was analyzed by atomic absorption spectroscopy. The analytical method has been validated before. Cases were divided into two groups: chronic alcohol abusers and non-chronic alcohol consumers including total abstainers using ethyl glucuronide levels in hair as well as anamnestic data as criteria. ResultsNo elevated iron concentrations in the liver of chronic alcohol abusers were detected. Surprisingly, the iron concentration in skin tissue was found to be significantly higher in cases of chronic alcohol abuse, independent on whether fatty liver or liver cirrhosis was present (as diagnosedduring autopsy).In 18.5% of the cases, chronic alcohol abuse was not confirmed by the EtG concentration in hair. Thus, anamnestic data should not be overestimated. ConclusionThe general assumption that chronic alcohol abuse induces hepatic siderosis, i.e. high iron concentrations in liver tissue, has not been supported by results of the present study. However, there seems to exist a correlation between chronic alcohol abuse and high iron concentrations in the skin.

Dietary gelatin enhances non-heme iron absorption possibly via regulation of systemic iron homeostasis in rats

Gelatin-based traditional Chinese medicines have long been used to treat anemia. Here, rats on the gelatin-based AIN-93G diet showed higher hemoglobin regeneration efficiencies and liver iron concentrations than those fed the diets based on several other animal proteins from muscle sarcoplasm and fibrils, egg white, whey and casein. However, among these animal proteins, gelatin had the lowest digestibility under simulated gastric-proximal intestinal digestion, and its hydrolysate showed the lowest capacity to aid iron absorption in Caco-2 monolayers via templating ferric oxyhydroxide nanoparticles. In another rat hemoglobin regeneration assay, dietary supplementations with gelatin and its two major degradation products, glycine and prolyl-hydroxyproline, revealed that gelatin boosted iron absorption not through glycine, but rather via prolyl-hydroxyproline, which had inhibitory and stimulatory effects on the plasma levels of hepcidin and erythropoietin, respectively. Dietary gelatin thus seems to enhance non-heme iron absorption via regulating systemic iron homeostasis rather than via solubilizing luminal ferric iron.