Severe Liver Siderosis Research Articles

Relation of Liver Siderosis to Liver Fibrosis in Hemodialysis Patients With Severe Hyperferritinemia Secondary to High Doses of Intravenous Iron Supplementation

ObjectiveAggressive iron substitution in hemodialysis (HD) patients leads to iron overload. The association between liver siderosis and fibrosis is still debatable. We studied the association of liver siderosis with liver fibrosis in HD patients. Furthermore, we studied the performance of liver stiffness measurements (LSMs) in identifying advanced liver fibrosis. We investigated the performance of biochemical indicators of iron status in identifying advanced liver fibrosis. MethodsFifty-five HD patients (average HD duration 6 ± 2 years) with hyperferritinemia secondary to intravenous iron supplementation (weakly iron dose 252.7 ± 63 mg; median blood transfusions 3 [2-5]) were recruited. The liver fibrosis grade was determined with Fibroscan, aminotransferase-to-platelet ratio index (APRI), and Fib-4 index. Liver iron concentration (LIC) was estimated with magnetic resonance imaging (MRI). Iron parameters and liver function biochemical indicators were also assessed. ResultsThe median serum ferritin and transferrin saturation (TSAT) were 3531 μg/L and 77%, respectively. 34.5%, 20%, and 45.5% of the patients showed mild, moderate, or severe liver siderosis, respectively. All patients with severe liver siderosis showed advanced liver fibrosis. Patients with severe liver siderosis and advanced liver stiffness showed higher serum iron, TSAT, aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum bilirubin, APRI, and Fib-4 index scores than those with mild liver siderosis. Serum iron and TSAT showed good utility in identifying advanced liver fibrosis determined with Fibroscan, APRI, and Fib-4 index. Liver stiffness exhibited good utility in identifying advanced liver fibrosis diagnosed with APRI and Fib-4 index. ConclusionsHigh weekly intravenous iron dose associated with severe hyperferritinemia, high serum iron, and TSAT might lead to severe liver siderosis and concomitant liver fibrosis in HD patients. Serum iron, TSAT, Fibroscan, Fib-4, and APRI scores might offer noninvasive tools for identifying advanced liver fibrosis in those patients.

Prognosis and Overall Survival of Thalassemia Patients using Semi-Parametric Mixture Cure-Rate Model: a 30-Year Retrospective Cohort Study

Understanding the determinants of long-term overall survival (OS) of thalassemia patients (TPs) is the mainstay of care. As a retrospective survey, we assessed the data of 769 TPs who had regular follow-up and blood transfusion for at least 30 years from 1990 - 2019. We utilized semi-parametric proportional hazards mixture cure-rate regression to discover the factors with a significant effect on short- and long-term OS separately. The 25- and 30-year OS for the TPs were calculated to be 98.7% and 90.4%, respectively. Each five-year age escalation was associated with a 30% decrease in the probability of being short-term survivors (HR = 1.06, p = 0.047). Parental family relationship influenced both cured (OR = 3.00, p = 0.017) and uncured (HR = 0.50, p = 0.046) TPs. Moreover, the type of iron chelation drug, liver iron concentration, and normal EF results had a significant effect on long-term OS. Aging, parental consanguinity, liver and cardiac siderosis, higher ferritin levels, and low hemoglobin level were associated with poorer prognosis in TPs. However, deferoxamine followed by multiple drugs as iron chelation, severe liver siderosis, and abnormal EF declined the probability of long-term OS among TPs. This can be considered by health policy decision-makers to enforce the screening program more strictly.

Moderate to severe liver siderosis and raised AST are independent risk factors for vitamin D insufficiency in \u03b2-thalassemia patients

Numerous problematic disorders such as vitamin D (Vit-D) deficiency subsequent to large iron loading can be developed in patients with β-thalassemia. The study aimed to estimate Vit-D insufficiency and its risk factors in patients with β-thalassemia. In this multicenter and observational study, all β-thalassemia patients, who referred to 14 hospital-based thalassemia divisions or clinics in Mazandaran province, Iran were included in the study. The data belong to December 2015 until December 2019. The study population was made of transfusion dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT) patients. Serum levels of 25-OHD3 have been measured by high performance liquid chromatography (HPLC) method as ng/mL. Demographic and clinical information along with some biological tests, as well as the results of T2*-weighted magnetic resonance imaging were analyzed. Of 1959 registered patients, 487 (24.9%) patients had Vit-D-related data. The prevalence of Vit-D insufficiency (< 30 ng/mL) was 41.9, 95% CI 37.5–46.3. The adjusted risks of moderate to severe liver siderosis and raised AST (aspartate aminotransferase) for Vit-D insufficiency (< 30 ng/mL) were 2.31, 95% CI 1.38–3.89 and 2.62, 95% CI 1.43–4.79, respectively. The receiver operating characteristic (ROC) curve analysis showed that the predictive accuracy of ferritin for Vit-D insufficiency status was 0.61, 95% CI 0.54–0.68 with a cutoff point of 1,078 ng/mL (P = 0.03, sensitivity 67%, specificity 49%, positive predictive value [PPV] 47% and negative predictive value [NPV] 68%). In spite of the national programs for treating Vit-D deficiency and our previous efforts for giving supplements to all patients, Vit-D insufficiency/deficiency is still common in our patients. Also, moderate to severe liver siderosis and raised AST were the independent risk factors for the Vit-D insufficiency.

Reduction of Liver Iron Load in Adult Patients with β-Thalassemia Major Treated with Modern Chelation Modalities.

Management of beta-thalassemia major (TM) requires life-long hemotransfusions leading to iron overload. Iron elimination is enhanced by the use of modern chelators. To assess the effect of modern chelation therapy by dynamics of serum ferritin concentration and liver MRI T2*. Forty-six patients with TM (male to female ratio =1:1, mean age 33.2±10.9 years) were prospectively studied between 2011 and 2014. Twenty-one patients (45.7%) were treated with deferasirox, 17 (37%) - with deferiprone, and 8 (17.3%) - with deferiprone in combination with deferoxamine. Ferritin was measured by ELISA. MRI T2* was assessed by Siemens Magnetom Avanto 1.5T. The patients were allocated into 3 groups based on their initial ferritin level and liver MRI T2*. Statistical analysis was performed using SPSS v. 18 for Windows. Data were analysed by descriptive analysis, analysis of variance and correlative analysis, means were compared using t-test and one-way ANOVA. In 2011, 9 (19.5%) patients had normal liver MRI T2*; in 2014 they were 17 (37%). The patients with mild grade liver siderosis were 12 (26%) in 2011, and in 2014 they were 14 (30.4%). In 2011, the patients with moderate liver siderosis were 14 (30.4%), and in 2014 - 12 (26.0%). Eleven patients (23.9%) had severe liver siderosis in 2011 and only two patients (4.0%) were diagnosed with the condition in 2014. A reduction of iron overload was found in all studied groups. This positive effect is attributed to the use of modern chelators and the ease of access to accurate monitoring.

Longitudinal Serum Ferritin Cut-Off Level for Cardiac Iron Overload Prediction in Transfusion-Dependent Thalassemia in a Resource Limited Country

Longitudinal Serum Ferritin Cut-Off Level for Cardiac Iron Overload Prediction in Transfusion-Dependent Thalassemia in a Resource Limited Country

Assessment of Heart and Liver Iron Overload in Thalassemia Major Patients Using T2* Magnetic Resonance Imaging.

Accumulation of excess iron in heart can lead to cardiac dysfunction, which is the most common cause of death in thalassemia major patients. Biopsy is an invasive procedure and therefore not an ideal option to assess iron load. However, standard/usual non-invasive methods, such as ferritin measurement, have some limitations and the results show poor correlations with iron load. Magnetic Response Imaging (MRI-T2*), as a non-invasive and reliable method for iron load assessment in organs such as liver and heart, can be suggested as a favorable alternative. This cross-sectional study was implemented in Thalassemia and Hemophilia Clinic Center (Sarvar) affiliated with Mashhad University of Medical Sciences, Mashhad, Iran, from 2012 to 2013. After the approval of the research protocol by the local ethic committee, laboratory tests, including CBC and serum ferritin, were carried out, and echocardiography and heart and liver MRI-T2* were performed. All statistical analysis was done through SPSS software (version 11.5), using independent sample t test and Pearson's correlation coefficient test. A P value ≤0.05 was considered to be significant. 88 patients with the mean (±SD) age of 21.2 (±5.6) years, (range 11-37years) were observed. Iron load was assessed using MRI-T2* with the following results: Out of 88 patients, 48.9% had mild to severe cardiac siderosis, and 75.2% had mild to severe liver siderosis. We demonstrated a correlation between liver MRI-T2* and serum ferritin, and heart MRI-T2* and ejection fraction. However, no correlation between liver and heart MRI-T2* was observed. Heart and liver siderosis is a common and serious problem in thalassemia major patients, and MRI-T2* as a sensitive and non-invasive technique can be used for early/timely detection of siderosis and good therapeutic monitoring in these patients.

Tumor necrosis factor α promoter polymorphisms influence the phenotypic expression of hereditary hemochromatosis

Severe iron overload usually develops in patients with hereditary hemochromatosis (HHC), but variability in the phenotypic expression of the disease has been reported. This study assessed whether tumor necrosis factor alpha (TNF-alpha) plays a role in phenotypic expression of HHC. Sixty-four patients with HHC and 172 healthy volunteers (controls) were studied. Release of TNF-alpha from stimulated peripheral blood monocytes was measured by enzyme-linked immunosorbent assay, and 308 and 238 TNF-alpha polymorphisms were detected with polymerase chain reaction and restriction fragment-length polymorphism analysis. The relation between TNF-alpha polymorphisms and clinical expression of HHC was evaluated. Patients with HHC released less TNF-alpha than controls, but the difference was significant only in homozygotes for the C282Y mutation. The prevalence of the 308 TNF-alpha polymorphism was similar in patients and controls, whereas the prevalence of the 238 polymorphic allele was significantly lower in patients (3% versus 16%; P =.002). A lower prevalence of cirrhosis was observed in patients with TNF-alpha polymorphism than in those without it (4 of 15 [27%] versus 28 of 49 [57%]), but the difference was not significant (P =.07). In nonhomozygotes for the C282Y mutation, severe liver siderosis was less prevalent in patients with the 308 polymorphism than in those without it (P =.05). Alanine aminotransferase (ALT) values were significantly lower in patients with TNF-alpha polymorphism (P =.006), even when patients with other hepatotoxic factors were excluded. Multivariate analysis showed that TNF-alpha polymorphism was independently associated with ALT values (P =.0008 and P =.045, respectively, in homozygotes and nonhomozygotes for the C282Y mutation) and siderosis in nonhomozygotes (P =.047). Thus, TNF-alpha appears to play a role in HHC by modulating the severity of liver damage. (Blood. 2001;97:3707-3712)

Ethane exhalation and vitamin E/ubiquinol status as markers of lipid peroxidation in ferrocene iron—loaded rats

Organ damage caused by iron overload has been mostly attributed to iron-induced peroxidation of membrane lipids. Using the ferrocene iron-loaded rat model, we studied ethane exhalation as a direct marker of in vivo lipid peroxidation, as well as concentrations of alpha-tocopherol and ubiquinol 9/10 in liver and plasma as indirect markers of this process. The feeding of a diet enriched with 0.5% TMH-ferrocene up to 31 weeks resulted in a large increase in liver iron concentration to about 25 mg/g wet weight (w wt). At lower, predominantly hepatocellular liver siderosis, the breath ethane exhalation was dependent on dietary vitamin E (VitE) supplements (onset of ethane exhalation at liver-Fe > 2 mg/g w wt on vitE-restricted diet; > 5 mg Fe per gram on VitE-replete diet). At severe liver siderosis, breath ethane exhalation reached a maximum of approximately 8 nmol/kg/hr independent of VitE supplementation. Plasma as well as hepatic alpha-tocopherol decreased with progressive iron loading. In addition, a significant depletion in hepatic ubiquinol 9 and 10 was noted.

Ethane exhalation and vitamin e/ubiquinol status as markers of lipid peroxidation in ferrocene iron—loaded rats

Organ damage caused by iron overload has been mostly attributed to iron-induced peroxidation of membrane lipids. Using the ferrocene iron—loaded rat model, we studied ethane exhalation as a direct marker of in vivo lipid peroxidation, as well as concentrations of α-tocopherol and ubiquinol 9/10 in liver and plasma as indirect markers of this process. The feeding of a diet enriched with 0.5% TMH-ferrocene up to 31 weeks resulted in a large increase in liver iron concentration to about 25 mg/g wet weight (w wt). At lower, predominantly hepatocellular liver siderosis, the breath ethane exhalation was dependent on dietary vitamin E (VitE) supplements (onset of ethane exhalation at liver-Fe >2 mg/g w wt on vitE-restricted diet; >5 mg Fe per gram on VitE—replete diet). At severe liver siderosis, breath ethane exhalation reached a maximum of approximately 8 nmol/kg/hr independent of VitE supplementation. Plasma as well as hepatic α-tocopherol decreased with progressive iron loading. In addition, a significant depletion in hepatic ubiquinol 9 and 10 was noted.

Elevated interleukin-8 serum concentrations in beta-thalassemia and graft-versus-host disease

Neutrophil chemotactic and functional defects occur in beta-thalassemia and in patients after bone marrow transplantation (BMT). Interleukin-8 (IL-8) is a novel chemotactic and activating peptide for neutrophils and can be detected in the circulation. IL-8 serum concentrations were evaluated in 30 beta-thalassemic patients before and after BMT. Serial samples from 16 patients were also studied. Fourteen sera from healthy children, 43 patients with chronic viral hepatitis, 16 patients on chronic transfusion treatment for various hematologic disorders, and 28 healthy adults were studied as controls. IL-8 was evaluated by an enzyme-linked immunosorbent assay. Patients with beta-thalassemia had higher IL-8 concentrations than did normal controls, patients with liver disease, and patients on chronic transfusion. beta-Thalassemic patients with severe liver siderosis and fibrosis had the highest IL-8 concentrations. After BMT in patients with successful engraftment, IL-8 concentrations decreased significantly. In contrast, in patients with acute graft-versus-host disease (GVHD), IL-8 concentrations were not statistically different from the concentrations found before BMT and were higher than in patients with no complications and patients with graft rejection. IL-8 may play a part in the immune dysregulation that occurs in beta-thalassemia and may be involved in the immune mechanisms leading to GVHD.

Elevated Interleukin-8 Serum Concentrations in β-Thalassemia and Graft-Versus-Host Disease

Neutrophil chemotactic and functional defects occur in beta-thalassemia and in patients after bone marrow transplantation (BMT). Interleukin-8 (IL-8) is a novel chemotactic and activating peptide for neutrophils and can be detected in the circulation. IL-8 serum concentrations were evaluated in 30 beta-thalassemic patients before and after BMT. Serial samples from 16 patients were also studied. Fourteen sera from healthy children, 43 patients with chronic viral hepatitis, 16 patients on chronic transfusion treatment for various hematologic disorders, and 28 healthy adults were studied as controls. IL-8 was evaluated by an enzyme-linked immunosorbent assay. Patients with beta-thalassemia had higher IL-8 concentrations than did normal controls, patients with liver disease, and patients on chronic transfusion. beta-Thalassemic patients with severe liver siderosis and fibrosis had the highest IL-8 concentrations. After BMT in patients with successful engraftment, IL-8 concentrations decreased significantly. In contrast, in patients with acute graft-versus-host disease (GVHD), IL-8 concentrations were not statistically different from the concentrations found before BMT and were higher than in patients with no complications and patients with graft rejection. IL-8 may play a part in the immune dysregulation that occurs in beta-thalassemia and may be involved in the immune mechanisms leading to GVHD.