Mean Liver Iron Concentration Research Articles

Rusfertide for the treatment of iron overload in HFE-related haemochromatosis: an open-label, multicentre, proof-of-concept phase 2 trial

Hereditary haemochromatosis protein (HFE)-related haemochromatosis, an inherited iron overload disorder caused by insufficient hepcidin production, results in excessive iron absorption and tissue and organ injury, and is treated with first-line therapeutic phlebotomy. We aimed to investigate the efficacy and safety of rusfertide, a peptidic mimetic of hepcidin, in patients with HFE-related haemochromatosis. This open-label, multicentre, proof-of-concept phase 2 trial was done across nine academic and community centres in the USA and Canada. Adults (aged ≥18 years) with HFE-related haemochromatosis on a stable therapeutic phlebotomy regimen (maintenance phase) for at least 6 months before screening and who had a phlebotomy frequency of at least 0·25 per month (eg, at least three phlebotomies in 12 months or at least four phlebotomies in 15 months) and less than one phlebotomy per month, with serum ferritin of less than 300 ng/mL and haemoglobin of more than 11·5 g/dL, were eligible. Patients initiated 24 weeks of subcutaneous rusfertide treatment within 7 days of a scheduled phlebotomy at 10 mg once weekly. Rusfertide doses and dosing schedules could be adjusted to maintain serum transferrin iron saturation (TSAT) at less than 40%. During rusfertide treatment, investigators were to consider the need for phlebotomy when the serum ferritin and TSAT values exceeded the patient's individual pre-phlebotomy serum ferritin and TSAT values. No primary endpoint or testing hierarchy was prespecified. Prespecified efficacy endpoints included the change in the frequency of phlebotomies; the proportion of patients achieving phlebotomy independence; change in serum iron, TSAT, serum transferrin, serum ferritin, and liver iron concentration (LIC) as measured by MRI; and treatment-emergent adverse events (TEAEs). The key efficacy analyses for phlebotomy rate and LIC were conducted by use of paired t tests in the intention-to-treat population, defined as all patients who received any study drug and who had pretreatment and at least one post-dose measurement. We included all participants who received at least one dose of rusfertide in the safety analyses. This trial is closed and completed and is registered with ClinicalTrials.gov, NCT04202965. Between March 11, 2020, and April 23, 2021, 28 patients were screened and 16 (ten [63%] men and six [38%] women) were enrolled. 16 were included in analyses of phlebotomy endpoints and 14 for the LIC endpoint. 12 (75%) patients completed 24 weeks of treatment. The mean number of phlebotomies was significantly reduced during the 24-week rusfertide treatment (0·06 phlebotomies [95% CI -0·07 to 0·20]) compared with 24 weeks pre-study (2·31 phlebotomies [95% CI 1·77 to 2·85]; p<0·0001). 15 (94%) of 16 patients were phlebotomy-free during the treatment period. Mean LIC in the 14 patients in the intention-to-treat population was 1·4 mg iron per g dry liver weight (95% CI 1·0 to 1·8) at screening and 1·1 mg iron per g dry liver weight (95% CI 0·9 to 1·3) at the end of treatment (p=0·068). Mean TSAT was 45·3% (95% CI 33·2 to 57·3) at screening, 36·7% (24·2 to 49·2) after the pretreatment phlebotomy, 21·8% (15·8 to 27·9) 24 h after the first dose of rusfertide, 40·4% (27·1 to 53·8) at the end of treatment, and 32·6% (25·0 to 40·1) over the treatment duration. Mean serum iron was 24·6 μmol/L (95% CI 18·6 to 30·6), 20·1 μmol/L (14·8 to 25·3), 11·9 μmol/L (9·2 to 14·7), 22·5 μmol/L (15·9 to 29·1), and 19·0 μmol/L (15·3 to 22·6) at these same timepoints, respectively. Mean serum ferritin was 83·3 μg/L (52·2 to 114.4), 65·5 μg/L (32·1 to 98·9), 62·8 μg/L (33·8 to 91·9), 150·0 μg/L (86·6 to 213.3), and 94·3 μg/L (54·9 to 133.6) at these same timepoints, respectively. There were only minor changes in serum transferrin concentration. 12 (75%) patients had at least one TEAE, the most common of which was injection site pain (five [31%] patients). All TEAEs were mild or moderate in severity, except for a serious adverse event of pancreatic adenocarcinoma, which was considered severe and unrelated to treatment and was pre-existing and diagnosed 21 days after starting rusfertide treatment. Rusfertide prevents iron re-accumulation in the absence of phlebotomies and could be a viable therapeutic option for selected patients with haemochromatosis. Protagonist Therapeutics.

5613374 ASSOCIATION BETWEEN GENOTYPE AND DISEASE COMPLICATIONS IN EGYPTIAN PATIENTS WITH BETA THALASSEMIA

Background: In beta thalassemia, the degree of globin chain imbalance is determined by the nature of the mutation of the β-gene. β° refers to the complete absence of production of β-globin on the affected allele. β+ refers to alleles with some residual production of β-globin. The homozygous state results in severe anemia that necessitates regular blood transfusion. On the other hand, frequent blood transfusion can lead to iron overload resulting in progressive dysfunction of the heart, Liver as well as multiple endocrinopathies. Aim: We aimed to evaluate the impact of genotype on the development of disease complications in patients with β thalassemia. Methods: A Cross sectional study was carried on 73 patients with beta thalassemia. Genotyping was determined by DNA sequencing technique. Routine investigations as well as MRI liver and heart were performed to assess iron overload. Results: We found that β+β+ was the most common genotype in our patients followed by β°β° and β°β+. Mean Liver iron content (LIC) was significantly higher in β°β° compared to β°β+ and β+β+ genotypes and mean cardiac T2* was significantly lower in β°β° compared to β°β+ and β+β+ genotypes. Hepatic complications, hepatitis C, cardiac complications and some endocrinopathies were significantly higher in patients with β°β° genotype compared to other genotypes which explain the role of the underlying genetic defect in thalassemia patients in development of disease complications. Conclusion: Clinical severity of thalassemia and development of such complications can be influenced by the type of β-thalassemia mutation and genotype.

Relationship between pancreatic iron overload, glucose metabolism and cardiac complications in sickle cell disease: An Italian multicentre study

Evidence about the cross-talk between iron, glucose metabolism, and cardiac disease is increasing. We aimed to explore the link of pancreatic iron by Magnetic Resonance Imaging (MRI) with glucose metabolism and cardiac complications (CC) in sickle cell disease (SCD) patients. We considered 70 SCD patients consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia Network. Iron overload was quantified by R2* technique and biventricular function by cine images. Macroscopic myocardial fibrosis was evaluated by late gadolinium enhancement technique. Glucose metabolism was assessed by the oral glucose tolerance test. Patients with an altered glucose metabolism showed a significantly higher pancreas R2* than patients with normal glucose metabolism. Pancreatic siderosis emerged as a risk factor for the development of metabolic alterations (OddsRatio 8.25, 95%confidence intervals 1.51-45.1; p=.015). Global pancreas R2* values were directly correlated with mean serum ferritin levels and liver iron concentration. Global pancreas R2* was not significantly associated with global heart R2* and macroscopic myocardial fibrosis. Patients with history of CC showed a significantly higher global pancreas R2* than patients with no CC. Our findings support the evaluation of pancreatic R2* by MRI in SCD patients to prevent the development of metabolic and cardiac disorders.

Association of Habitual Dietary Intake with Liver Iron-A Population-Based Imaging Study.

Iron-related disorders of the liver can result in serious health conditions, such as liver cirrhosis. Evidence on the role of modifiable lifestyle factors like nutrition in liver iron storage is lacking. Thus, we aimed to assess the association of habitual diet with liver iron content (LIC). We investigated 303 participants from the population-based KORA-MRI study who underwent whole-body magnetic resonance imaging (MRI). Dietary habits were evaluated using repeated 24 h food lists and a food frequency questionnaire. Sex-stratified multiple linear regression models were applied to quantify the association between nutrition variables of interest and LIC, adjusting for liver fat content (LFC), energy intake, and age. Mean age of participants was 56.4 ± 9.0 years and 44.2% were female. Mean LIC was 1.23 ± 0.12 mg/g dry weight, with higher values in men than in women (1.26 ± 0.13 and 1.20 ± 0.10 mg/g, p < 0.001). Alcohol intake was positively associated with LIC (men: β = 1.94; women: β = 4.98, p-values < 0.03). Significant negative associations with LIC were found for fiber (β = −5.61, p < 0.001) and potassium (β = −0.058, p = 0.034) for female participants only. Furthermore, LIC was highly correlated with liver fat content in both sexes. Our findings suggests that there are sex-specific associations of habitual dietary intake and LIC. Alcohol, fiber, and potassium may play a considerable role in liver iron metabolism.

Ferritin Levels Do Not Reflect the Severity of Iron Overload in Diamond Blackfan Anemia

▪Introduction: Diamond Blackfan anemia (DBA) is an inherited bone marrow failure syndrome (IBMFS) characterized by hypoplastic anemia, congenital malformations and an increased risk to develop malignancies.Until now, treatment of DBA consists of red blood cell (RBC) transfusions, glucocorticoids (GC) and allogeneic hematopoietic stem cell transplantation in a selection of patients. Whereas RBC transfusions are the main cause of IO, elevated iron parameters have also been reported in non-transfusion-dependent DBA patients. Here we investigated the incidence and severity of IO in a well-described cohort of transfusion-dependent and non-transfusion-dependent DBA patients in order to gain more insight in the regulation of iron metabolism in DBA, and to provide clinical guiding to improve the diagnosis and management of IO in DBA.Methods: In this retrospective, observational study we have included twenty-nine pediatric and adult DBA patients for whom at least one serum ferritin level and/or MRI result was available. Ten patients (34%) were classified as transfusion-dependent (TD) (ten or more transfusions during the twelve months prior to evaluation). Non-transfusion-dependent (NTD) patients (66%) were treated with either GC, incidental transfusions or received no treatment. Transfusion burden (transfusion history) was assessed via medical records. Serum ferritin levels ≥250 ng/mL in males and ≥150 ng/mL in females were considered to be elevated. Results of MRI were expressed as liver iron content (LIC) and as cardiac T2* in milliseconds (ms). LIC ≥3 mg/g indicates significant hepatic IO, and LIC ≥7 mg/g is associated with clinical morbidity. Cardiac T2* ≤20 ms indicates significant cardiac IO.Results: In 15/29 (52%) MRI analysis of IO was performed. Hepatic IO (LIC >3 mg/g) was present in 9/29 (31%) of DBA patients, of which 8/9 (89%) had moderate to severe IO (LIC>7mg/g), despite the fact that all but one were treated with chelation therapy. Overall serum ferritin levels and LIC correlated significantly (r=0.7907, p<0.001), and all TD patients with LIC ≥7 mg/g had serum ferritin levels ³400 ng/mL, however, none of the patients had a serum ferritin >1000 ng/mL (Figure 1A). Interestingly, in the NTD group, hepatic IO was present in 2/7 patients (29%), who both only had mildly elevated serum ferritin levels (263 ng/mL and 277 ng/mL) and were not treated with iron chelation therapy. Based on total transfusion burden since birth, patients were classified in distinct groups: nine patients who received ³10 transfusions during life (9/10) were diagnosed with hepatic IO, whilst none of the patients who received <10 transfusions were diagnosed with hepatic IO. Both mean serum ferritin levels and mean LIC values were significantly higher in patients with ³10 transfusions compared to all with <10 transfusions (Figure 1B-C).Discussion: We demonstrate that IO is common in DBA yet can be easily overlooked in NTD patients that were treated with transfusions in the past. While serum ferritin levels significantly correlated with LIC values, this parameter cannot be used exclusively to screen for IO or titrate iron chelation therapy. We conclude that in clinical practice, biochemical parameters in combination with transfusion history justify a low-threshold to perform an MRI-based evaluation of IO, and to start adequate chelation therapy. [Display omitted] DisclosuresVan Beers: Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Novartis: Research Funding; RR Mechatronics: Research Funding. Wijk: Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Axcella health: Research Funding; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.

An Experimental Model for Iron Deficiency Anemia in Sows and Offspring Induced by Blood Removal during Gestation.

Simple SummaryAnemia is a common condition in sow herds especially during gestation. The condition occurs despite iron supplementation in feed and has been associated with increased stillbirth rate. We currently have limited knowledge about the consequences of anemia during gestation in sows. The aim of this study was to assess the effects of severe iron deficiency during gestation on sow and piglet health outcomes in an experimental model. For sows, hematologic parameters were monitored at regular intervals and farrowing results were recorded. After farrowing, tissue iron concentrations in sows and new born piglets were measured. Results of our study showed that sows and piglets were adversely affected by iron deficiency anemia (IDA) during gestation. Mild to severe IDA resulted in reduced tissue iron stores at farrowing in sows and piglets. Strategies to overcome the condition could therefore be beneficial to the pig industry.Anemia is a common condition in sow herds. We aimed to study the effects of severe iron deficiency during gestation on sow and piglet health outcomes with an experimental model for blood-removal-induced iron deficiency anemia. In total, 18 multiparous sows (8 in trial I and 10 in trial II) were allocated to either a blood removal group or a control group. Hematologic parameters were monitored at regular intervals and the tissue iron concentrations were measured for the sows and newborn piglets after farrowing. In trial I, the mean liver iron content was reduced to 46.7 µg/g in the blood removal sows compared to 252.6 µg/g in the controls (p < 0.001). In trial II, sows in the blood removal group had lower iron content in the liver (147.8 µg/g), kidney (46.3 µg/g) and spleen (326.5 µg/g) compared to the control sows (323.2 µg/g, 81.3 µg/g and 728.9 µg/g, respectively; p = 0.009, 0.016, 0.01, respectively). In trial I, piglets from sows in the blood removal group had significantly decreased hematocrit (Hct), red blood cells (RBC) and a tendency for reduced hemoglobin (Hb) compared to the control piglets. We established a blood removal model that resulted in mild- to severe degrees of sow anemia and reduced tissue iron stores at farrowing.

Correlation Between Serum Ferritin and Viral Hepatitis in Thalassemia Patients

Serum ferritin is an acute phase protein; importantly, its level is noticeably increased in response to iron overload and systemic inflammation. The iron overload status in thalassemia patients has been recognized as a potential way to measure liver iron concentration (LIC) levels using magnetic resonance imaging (MRI). The aim of this study was to investigate the effect of chronic viral hepatitis on the level of serum ferritin in patients with thalassemia. A cross-sectional study was conducted involving chronic viral hepatitis infection. Mean serum ferritin and LIC levels were recorded. The LIC values were used to divide the patients into two groups; a higher LIC group (>5 mg Fe/g) and a lower LIC group (<5 mg Fe/g). Mean serum ferritin levels were then compared between the two LIC groups. We identified 32 thalassemia patients comprising of 13 chronic viral hepatitis patients, seven patients with hepatitis B virus (HBV), and six patients with hepatitis C virus (HCV). With regard to the group with higher LIC values, the mean serum ferritin levels in the hepatitis group were significantly higher than for those in the non hepatitis group (1776 ± 488 vs. 967 ± 860 ng/mL, p = 0.03). Furthermore, the linear correlation between the mean serum ferritin levels and the viral load in the non transfusion-dependent thalassemia (NTDT) group were found to be significantly correlated (r = 0.7, p = 0.04). Chronic viral hepatitis was determined to be a possible casualty of disproportionately high ferritin levels in the NTDT group.

Efficacy and Safety of Combined Oral Chelation with Deferiprone and Deferasirox on Iron Overload in Transfusion Dependent Children with Thalassemia - A Prospective Observational Study.

To assess the efficacy and safety of dual oral iron chelation therapy (deferiprone and deferasirox) in decreasing iron overload status, using serum ferritin and liver and cardiac MRI as indicators, in transfusion dependent thalassemic children. This was a prospective observational study conducted in a tertiary care hospital for a period of one year. Children with thalassemia between 2 and 18 y of age with serum ferritin above 1500ng/ml were started on oral deferiprone and deferasirox. They were followed up for one year. Serum ferritin and MRI quantification of liver and cardiac iron concentration was done at enrolment and end of 12 mo. They were also monitored monthly for any adverse effects. Twenty one thalassemic children with mean age of 7.8 y (range 4-12 y) and a mean ferritin value of 3129 + 1231.5ng/ml were enrolled. Mean serum ferritin decreased by 1226.3ng/ml (p = 0.047, 95% CI =10.2, 1504.3) with 16.8% fall from baseline. The reduction in ferritin correlated significantly with the initial ferritin level (spearman's rho = 0.742, p = 0.001). Mean liver iron concentration and myocardial iron concentration did not change significantly. Red color urine, transient rise in creatinine and liver enzymes were noted during the study period. Combined oral chelation with deferiprone and deferasirox significantly decreases the serum ferritin level in children with severe iron overload. The drugs were tolerated well without any serious adverse effects.

Trends in Iron Overload over Past Two Decades: Results from the Natural History of Iron Burden Study with the SQUID Biosusceptometer

Established in 2002, the Iron Overload Program in Oakland relies on a biosusceptometer (Ferritometer®, model 5700, Tristan Technologies, San Diego, USA) utilizing low temperature SQUID technology to quantify liver iron concentration (LIC). The procedure is non-invasive and patients as young as 2 years can be been measured without sedation. The measurement and analysis are rapid (30 - 45 min) and the results have been validated against biopsy. Over 3500 measurements have been performed on 1055 patients at risk of iron overload. Longitudinal data were acquired under the natural history of iron burden by non-invasive measurement techniques study since November 2002. Patients were referred for liver iron assessment at intervals determined by their providers. Seventy-one patients had ≥10 measurements, 34 had ≥15 measurements, and 7 had ≥20 measurements. Over the course of the study, the average age at enrollment fell from 23 +/- 17 years (range 2 - 88 years) to 18 +/- 15 years (2 - 73 years). There was an increase in the proportion of patients with non-transfusion dependent thalassemia and those with iron overload from red cell transfusions associated with chemotherapy or stem cell transplantation. In comparison to the first five years (2003 - 2008) in the most recent five years (2014 - 2018) chelation has shifted from deferoxamine to deferasirox and there has been an increase in the simultaneous use of two chelators. We observed an overall decrease in mean LIC from 2400 to 1800 micrograms Fe/g liver wet weight (14.4 to 10.8 mg/g liver dry weight). Ferritin to LIC ratios were 0.46 in non-transfused thalassemia, 0.85 in intermittently transfused (&amp;lt; 7 mL/Kg/month), and 1.10 in transfusion-dependent (≥7 mL/Kg/month). A subgroup analysis of longitudinal data in transfusion-dependent thalassemia with multiple measurements was conducted. The mean (±s.d.) LIC decreased by 42% from 15.8 ± 10.2 at the first measurement to 9.2 ± 9.7 mg/g at the last visit. At the same time, mean ferritin decreased from 2629 to 2115 ng/mL, a change of 20%. In this group of patients ferritin levels now overestimate LIC by a significant amount (Figure). This reflects either a change in transfusion practices or the type of chelation. These results show a positive impact of oral chelators and combined chelation regimens leading to a significant improvement in iron overload in thalassemia. The development of organ complications from iron toxicity is expected to decrease, but there is a risk of over-chelation if ferritin is the sole measure of iron status. Liver biosusceptometry has been a valuable method to assess diverse conditions associated with iron overload and to monitor chelation treatment in patients across all ages. Figure Disclosures Lal: Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Terumo Corporation: Research Funding; Insight Magnetics: Research Funding; bluebird bio: Research Funding; Protagonist Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; La Jolla Pharmaceutical Company: Research Funding. Vichinsky:Pfizer: Research Funding; Global Blood Therapeutics: Consultancy; Agios: Research Funding.

Effects of Luspatercept on Iron Overload and Impact on Responders to Luspatercept: Results from the BELIEVE Trial

Effects of Luspatercept on Iron Overload and Impact on Responders to Luspatercept: Results from the BELIEVE Trial

Evaluating the Volumetric Liver Fat Fraction in Patients Referred for Investigation of Hyperferritinemia

Introduction Elevated serum ferritin (hyperferritinemia, HF) can result from increased iron load, increased inflammation or from liver damage. In the most common forms of hereditary hemochromatosis (HH), elevated ferritin is usually seen with elevated transferrin saturations, [1,2]. In patients with HF but without raised liver iron concentration (LIC, mg/g dry wt [dw]), increased liver fat (hepatic steatosis, HS), either in isolation or as part of a metabolic syndrome, needs to be considered. HS is important to identify as it may progress to chronic liver damage and is potentially reversible with lifestyle interventions. Hepatic fat can now be quantified with magnetic resonance imaging (Hepafat-Scan®)[3]. Here, we evaluate the usefulness of this method in the diagnosis and subsequent management of patients referred with HF. Methods A total of 132 patients (median age 48 years, range 21-86 ; female: male ratio 1:2.5) referred for investigation of HF and who underwent estimation of liver iron concentration (LIC) by R2-MRI (FerriScan®) over a four-year period (January 2015 - December 2018) are included in this analysis. Data on patient demographics, presenting serum ferritin (SF) and transferrin saturation were obtained. Genetic testing for C282Y and H63D was also performed. Genetic testing for rarer forms of haemochromatosis was confined to patients with unexplained raised LIC. Patients with iron overload secondary to chronic iron ingestion or blood transfusion were excluded from this analysis. Results Patients were subdivided by genetic diagnosis: C282Y homozygote (26, 19.7%), C282Y/H63D (18, 13.6%), H63D homozygote (10, 7.6%), C282Y heterozygote (8, 6.1%), H63D heterozygote (18, 13.6%), autosomal dominant ferroportin disease (4, 3%) and negative HFE gene testing (48, 36.4%). There was no statistical difference between mean presenting SF (p= 0.307) between the different groups. C282Y homozygotes, and those with autosomal ferroportin disease had a significantly higher LIC than others (p&amp;lt;0.001). C282Y homozygotes and compound heterozygotes had a significantly higher transferrin saturation than other groups (p&amp;lt;0.001). SF positively correlated with LIC (p&amp;lt;0.001). After genetic testing and LIC quantification, 32 patients underwent a HepaFat-Scan®. Median age was 63 years, range 23 - 74 years; female: male ratio 1:3.5. 54.5% had a volumetric liver fat fraction (VLFF) &amp;gt; 5%. 7.4% of patients, who did not undergo Hepafat-Scan®, had HS based on sonographic findings. Patients with definitive evidence of HS as defined by VLFF &amp;gt;5% had mean LIC of 1.36mg/g dw, and a higher mean presenting SF of 926 µg/L than those with HS &amp;lt;5% (NS, p= 0.47). Those with VLFF &amp;lt;5% had a mean presenting SF of 783 mg/ml and mean LIC of 2.2 mg/g dw. In patients with LIC ≤3mg/g dw (n= 91, mean 1.6), mean presenting SF was 728 mg/ml. 28 of these patients went onto have a Hepafat-Scan®, 16 of which (57.1%) had confirmed steatosis with VLFF &amp;gt;5%. In patients with LIC &amp;gt;3mg/g dw (n= 41, mean LIC 6.9), mean presenting SF was significantly higher at 1056 mg/ml (p=0.021). 4 patients with LIC &amp;gt;3mg/g dw also had a Hepafat-Scan®, with 1 patient having VLFF &amp;gt;5%. Patients with confirmed steatosis were referred for specialist hepatology consultation. Conclusion In patients referred for investigation of HF, demonstrable steatosis (VLFF &amp;gt;5%) by Hepafat-Scan® is remarkably high (13.3% of all referred patients and 54% of patients who received Hepafat-Scan®). The Hepafat-Scan® data show that HS is generally confined to patients with low LIC (≤3mg/g dw) (Figure 1) reflecting the selective decision pathway adopted of excluding hepatic siderosis before proceeding to Hepafat-Scan®. SF is significantly higher in non-iron overloaded patients with HS (VLFF &amp;gt;5%) than those without HS (Figure 1). Estimation of HS should be considered in the diagnostic pathway of patients referred for investigation of HF, particularly when LIC values are not found to be meaningfully increased.

The Effect of Chronic Viral Hepatitis on Serum Ferritin Level in Thalassemia Patients

Background: Serum ferritin is widely used as a marker of iron overload in thalassemia patients. However, the ferritin level is affected by active infections or inflammation. The association between viral hepatitis and serum ferritin level in thalassemia patients is still unclear. This study aimed to determine the effect of chronic viral hepatitis on serum ferritin level in thalassemia patients. Methods: This was a cross-sectional study in thalassemia patients aged ≥15 years-old at Chiang Mai University hospital. We expected that thalassemic patients in our clinic have a mean serum ferritin of 767 ng/mL with a standard deviation of 210 ng/mL. As a result, we have to enroll a total of 28 patients to demonstrate 30% difference of mean serum ferritin when the power was set at 80% with alpha level of 0.05. Information on chronic viral hepatitis, mean serum ferritin and liver iron concentration (LIC) as measured by T2* MRI were collected. Chronic viral hepatitis status was confirmed by either HBV DNA or HCV RNA testing. Patients were categorized to hepatitis and non-hepatitis group. Serum ferritin levels were compared between two groups. LIC measurement was used as a gold standard for iron overload. Subgroup analysis was performed according to iron overload and transfusion requirement status. Categorical and continuous variables were compared using the Chi-squared test and T-test, respectively. The correlation between viral loads and mean serum ferritin levels was analyzed by Pearson's correlation. Result: Of 32 thalassemia patients (25 non-transfusion dependent [NTDT] and 7 transfusion dependents [TDT]), 13 patients had chronic viral hepatitis (7 with hepatitis B and 6 with hepatitis C infections). The LIC between hepatitis and non-hepatitis groups were not significantly different (7.28 [SD 4.7] vs 9.08 [SD 5.2] mg Fe/g, p=0.19). In the higher LIC group (≥ 5 mg Fe/g), the mean serum ferritin level was higher in the hepatitis group than non-hepatitis group (1,776 [SD 488] vs 967 [SD 860] ng/mL, p=0.03). For the lower LIC group (&lt;5 mg Fe/g), the mean ferritin levels were not significantly different between the hepatitis and non-hepatitis groups (646 [SD 224] vs 459 [SD 205] ng/mL, p=0.22). The correlation between the viral load and mean ferritin level in NTDT group showed a significant linear correlation with R=0.7 (p=0.04). Conclusions: We observe a higher serum ferritin level among thalassemia patients who concurrently have chronic viral hepatitis. Chronic viral hepatitis is a possible cause of a falsely high ferritin level in these patient population. Furthermore, the viral load is positively correlated with serum ferritin level. Disclosures No relevant conflicts of interest to declare.

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.

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.

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.

PS1298 TISSUE IRON DISTRIBUTION IN PATIENTS WITH LOW‐RISK MDS

Background:Iron accumulation occurs in MDS patients by upregulated iron absorption due to ineffective erythropoiesis with decreased hepcidin levels (Santini et al, 2011) and by chronic blood transfusion therapy. Elevated liver iron concentration (LIC) is regularly found in transfusion dependent patients. Abnormal cardiac iron (50–1) was observed in few studies and severe cardiac iron overload was almost not present although cardiac death appeared in 8% of deceased patients (Nachtkamp et al, 2016). Little is known about corresponding pancreatic iron and iron accumulation in the bone marrow. The release of NTBI in the bone marrow may directly affect hematopoiesis by oxidative stress (Porter et al, 2016).Aims:To compare the relationship of iron concentration and fat content in different organs in low ‐ risk MDS patients.Methods:We studied the iron accumulation in bone marrow, liver, spleen, pancreas and septal heart muscle in 14 mainly low‐risk MDS patients (age 39–87 y), partly transfused and chelated. Tissue iron concentration and fat content were assessed by magnetic resonance imaging (MRI ‐ R2∗) with 3D data acquisition at 3 Tesla using chemical shift relaxometry (Pfeifer et al, 2015).Results:About 50% of patients showed iron overload in the spleen, pancreas and vertebral bone marrow (VBM). Mean LIC (±SD) was found as 1.709 ± 0.914 mg/gliver (10.3 ± 5.5 mg/gdry weight). Patients with iron overload in the pancreas showed as well abnormal pancreatic fat contents (11–32%) and fasting glucose values (101–186 mg/dL). As expected, septal cardiac iron was normal for all patients. Bone marrow (VBM) iron was elevated in 8/14 patients (R2∗ = 149–330 s−1) with the highest R2∗ in a non‐chelated patient.Summary/Conclusion:The feasibility of multi‐organ iron and fat measurements by MRI in heart, liver, spleen, pancreas and bone marrow was shown in a small group of elderly MDS patients within a reasonable scan time (30 min).The iron concentration and fat content in different organs will contribute further information about disease process in low ‐ risk MDS patients, as well as success of iron chelation therapy.

Cardiac and hepatic siderosis in myelodysplastic syndrome, thalassemia and diverse causes of transfusion-dependent anemia: the TIMES study.

The significant morbidity and mortality associated with iron overload can be reduced by effective iron chelation. Magnetic resonance imaging (MRI) provides accurate and reproducible iron load assessment. The aim of this epidemiological study was to assess the prevalence and severity of cardiac and hepatic siderosis by MRI and to evaluate the impact of MRI on clinical management in patients with transfusion-dependent anemia and non-transfusion-dependent thalassemia (NTDT). We enrolled 243 patients with myelodysplastic syndromes (MDS), thalassemia major (TM), NTDT or other chronic anemia. Overall, 10% and 48% had cardiac and hepatic siderosis, respectively. Mean liver iron concentration (LIC) was above target range in all groups; mean myocardial T2∗ was normal. Hepatic siderosis was more prevalent than myocardial siderosis in patients with MDS, occurring in 54.4% and 4.4% of patients, respectively. As also observed in patients with NTDT or other anemia, hepatic siderosis was present in a large proportion of MDS patients who were chelation naïve (57.7%), as well as in patients receiving iron chelation therapy (ICT) (52.4%), despite a lower transfusion load compared with TM. Correlation between LIC and serum ferritin was observed across diseases; however, not all patients requiring ICT could be identified with serum ferritin alone, as serum ferritin underestimated LIC in 4.4% and overestimated LIC in 7.5% of patients. Exploratory analyses showed serum ferritin thresholds for liver siderosis detected by MRI at approximately 300 ng/mL higher in MDS than in TM. Most patients reported low-medium adherence to ICT; MRI assessment led to change in ICT in 46% of evaluable patients, including 52% of MDS patients. Accurate organ iron monitoring by MRI facilitated appropriate initiation of chelation, dose optimization and clinical decision making. Trial registration: ClinicalTrials.gov: NCT01736540.

Measurement of liver iron by magnetic resonance imaging in the UK Biobank population.

The burden of liver disease continues to increase in the UK, with liver cirrhosis reported to be the third most common cause of premature death. Iron overload, a condition that impacts liver health, was traditionally associated with genetic disorders such as hereditary haemochromatosis, however, it is now increasingly associated with obesity, type-2 diabetes and non-alcoholic fatty liver disease. The aim of this study was to assess the prevalence of elevated levels of liver iron within the UK Biobank imaging study in a cohort of 9108 individuals. Magnetic resonance imaging (MRI) was undertaken at the UK Biobank imaging centre, acquiring a multi-echo spoiled gradient-echo single-breath-hold MRI sequence from the liver. All images were analysed for liver iron and fat (expressed as proton density fat fraction or PDFF) content using LiverMultiScan. Liver iron was measured in 97.3% of the cohort. The mean liver iron content was 1.32 ± 0.32 mg/g while the median was 1.25 mg/g (min: 0.85 max: 6.44 mg/g). Overall 4.82% of the population were defined as having elevated liver iron, above commonly accepted 1.8 mg/g threshold based on biochemical iron measurements in liver specimens obtained by biopsy. Further analysis using univariate models showed elevated liver iron to be related to male sex (p<10−16, r2 = 0.008), increasing age (p<10−16, r2 = 0.013), and red meat intake (p<10−16, r2 = 0.008). Elevated liver fat (>5.6% PDFF) was associated with a slight increase in prevalence of elevated liver iron (4.4% vs 6.3%, p = 0.0007). This study shows that population studies including measurement of liver iron concentration are feasible, which may in future be used to better inform patient stratification and treatment.

Association between genotype and disease complications in Egyptian patients with beta thalassemia: A Cross-sectional study

In beta thalassemia, the degree of globin chain imbalance is determined by the nature of the mutation of the β-gene. β° refers to the complete absence of production of β-globin on the affected allele. β+ refers to alleles with some residual production of β-globin. The homozygous state results in severe anemia that necessitates regular blood transfusion. On the other hand, frequent blood transfusion can lead to iron overload resulting in progressive dysfunction of the heart, Liver as well as multiple endocrinopathies. We studied the impact of genotype on the development of disease complications in patients with β thalassemia. A Cross sectional study was carried on 73 patients with beta thalassemia. Genotyping was determined by DNA sequencing technique. Routine investigations as well as MRI liver and heart were performed to assess iron overload. We found that β+β+ was the most common genotype in our patients followed by β°β° and β°β+. Mean Liver iron content (LIC) was significantly higher in β°β° compared to β°β+ and β+β+ genotypes and mean cardiac T2* was significantly lower in β°β° compared to β°β+ and β+β+ genotypes. Hepatic complications, hepatitis C, cardiac complications and some endocrinopathies were significantly higher in patients with β°β° genotype compared to other genotypes which explain the role of the underlying genetic defect in thalassemia patients in development of disease complications.

Impact of Genotype of Beta Globin Gene on Hepatic and Myocardial Iron Content in Egyptian Patients with Beta Thalassemia.

Iron overload causes most of the mortality and morbidity associated with thalassemia. Excess iron deposits primarily in the liver, but once a threshold level is reached, iron loading may occur in other tissues such as the heart. Magnetic resonance imaging is a well established technique to noninvasively quantify myocardial and liver iron content. More than 300 disease-causing mutations have been identified. We aimed to determine the impact of genotype on liver iron content in patients with beta thalassemia. Cross sectional study was carried on 73 patients with beta thalassemia. MRI liver and heart was performed to determine hepatic and myocardial iron overload. Genotyping was determined by DNA sequencing technique. The mean liver iron content was 17.4mg/g dw and mean cardiac T2* was 25.5ms in our patients. Patients with β0β0 were associated with significantly higher liver and myocardial iron content compared to those with β0β+ and β+β+ genotypes. There was a clear association between genotype and both hepatic and myocardial iron overload. Patients with β0β0 had significantly higher liver and heart iron content compared to those with β0β+ and β+β+ genotypes. Liver iron content was strongly correlated to serum ferritin levels and myocardial iron overload.