Male Gender Increases the Risk of Liver Fibrosis in Patients with Thalassemia Major Independent of Iron Overload

Abstract Introduction and Objectives: Iron overload in patients with Thalassemia Major (TM) leads to various complications including liver fibrosis. The independent impact of gender on this risk has been previously investigated but not yet confirmed. We, therefore, planned to assess the independent impact of gender in patients with TM on the risk of liver fibrosis. Methods: We included 96 patients with TM followed and transfused in one academic tertiary hospital. Patients underwent assessment of liver fibrosis using ultrasound elastography (FibroScan device) with a cut off value of 7.8 kPa. The mean ferritin in the 5 years prior to elastography assessment was used to represent iron overload. Association was tested using Chi-squared and the independent impact of gender was confirmed in the multivariable logistic regression with a model that included mean ferritin and gender. Results: The median age of the 96 included patients was 26 years (Interquartile range [IQR]: 22-30). Males constituted 45% of patients and 33% of patients were splenectomised. The median alanine transaminase, aspartate transaminase, albumin and total bilirubin were 30 U/L (IQR: 18-64), 30 U/L (IQR: 18-46), 46 g/L (IQR: 44-48) and 21 µmol/L (IQR: 14-32) respectively. The median ferritin and liver iron concentration assessed by MRI T2* were 1293 µg/L (IQR: 753-2715) and 6.7 mg/gdw (IQR: 3.5-16.1) respectively. Thirty seven percent of patients had positive serology for HCV while 1% of patients had positive serology for HBV. The proportion of patients with fibrosis as assessed by elastography was 59%. The proportion of male patients with fibrosis was 70% compared to 51% in female patients with a trend towards statistical significance (odds ratio [OR] of 2.2 with a p value of 0.094). In the multivariable logistic regression model, both gender (OR of 3.0, P value of 0.0188) and ferritin (OR of 1.0004, p value of 0.0036) were statistically significant independent predictors of liver fibrosis. Conclusion: Male gender increases the risk of liver fibrosis independent from iron overload. Our study confirms the previously suspected but unproven association. Follow up and therapy may be tailored to include gender as a decision factor. Larger studies are needed to further confirm these results. Disclosures No relevant conflicts of interest to declare.

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Genotype in Patients with Thalassemia Major Has No Impact on Risk of Liver Fibrosis

Blood ◽

10.1182/blood.v128.22.4835.4835 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4835-4835

Author(s):

Murtadha K. Al-Khabori ◽

Shahina Daar ◽

Shoaib Al-Zedjali ◽

Al Ghaliya Al Omairi ◽

Moez Hassan ◽

...

Keyword(s):

Logistic Regression ◽

Liver Fibrosis ◽

Iron Overload ◽

Conflicts Of Interest ◽

Iron Concentration ◽

Thalassemia Major ◽

Ultrasound Elastography ◽

Positive Serology ◽

Multivariable Logistic Regression ◽

The Impact

Abstract Introduction and Objectives: Patients with Thalassemia Major (TM) develop various complications related to iron overload and transfusion associated infections. It is unknown as yet if the specific genotype leading to TM has further impact on the development of liver fibrosis. Therefore, we planned to assess the impact of genotypes in patients with TM on the risk of liver fibrosis. Methods: We included 88 patients with TM with available genotyping data in this study. These patients were followed and transfused in a single tertiary academic center. All those patients had their liver fibrosis assessed by ultrasound elastography (FibroScan device) with a cut off value of 7.8 kPa. The genotyping was done using Amplification Refractory Mutation System (ARMS)-hot start-polymerase chain reaction (PCR) technique. Iron overload was assessed using the average serum ferritin in the 5 years prior to the liver fibrosis assessment. Association was assessed using Chi-squared test and adjustment using multivariable logistic regression. Results: A total of 88 patients were included with a median age of 27 years (Interquartile range [IQR]: 23-31). Females constituted 54% of patients and 34% of patients were splenectomised. The median alanine transaminase, aspartate transaminase, albumin and total bilirubin were 31 U/L (IQR: 20-58), 30 U/L (IQR: 18-46), 46 g/L (IQR: 43-48) and 23 µmol/L (IQR: 15-34) respectively. The median ferritin and liver iron concentration assessed by MRI T2* were 1472 µg/L (IQR: 741-2760) and 7.0 mg/gdw (IQR: 3.5-15.9) respectively. Thirty seven percent of patients had positive serology for HCV while 1% of patients had positive serology for HBV. The genotypes seen in this study included homozygous IVS-I, 5 (G-C) in 39 patients, homozygous codon 44 (-C) in 19 patients, double heterozygous IVS-I, 5 (G-C)/25 bp deletion in 5 patients and others (≤ 3 patients each) in 25 patients. The proportion of patients with fibrosis was 55%. The proportion of patients with fibrosis in the homozygous IVS-I, 5 (G-C) group was 58% compared to 52% in all other genotypes and the difference was not statistically significant (odds ratio of 1.3 with a p value of 0.6652). The impact of the genotype remained non-significant after adjustment of iron overload in the multivariable logistic regression model. The only statistically significant factor was the iron overload (p values: iron overload 0.006, genotype 0.966). Conclusion: The risk of liver fibrosis is associated with the iron overload in patients with TM. There is no additional independent impact of the genotype. Further studies with larger sample size to study the impact of various genotypes are required to confirm these results. Disclosures No relevant conflicts of interest to declare.

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Long-Term Iron Chelation Therapy with Deferiprone in Patients with Thalassemia Major and Low Iron Load

Blood ◽

10.1182/blood.v128.22.3626.3626 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3626-3626 ◽

Cited By ~ 1

Author(s):

Shahina Daar ◽

Murtadha K. Al-Khabori ◽

Khalil Al Farsi ◽

Bader Abdulla Al-Rawahi ◽

Arwa Z. Al-Riyami

Keyword(s):

Iron Overload ◽

Safety Profile ◽

Chelation Therapy ◽

Conflicts Of Interest ◽

Serum Magnesium ◽

Iron Concentration ◽

Thalassemia Major ◽

P Value ◽

Patient Reported

Abstract Introduction and Objectives: Iron chelators are effective in reducing iron burden and in improving clinical outcomes in patients with transfusional iron overload. However, limited data are available on their efficacy and safety in transfusion-dependent patients with low iron overload, due mainly to concerns of chelation toxicity observed with deferoxamine (DFO) in patients with serum ferritin (SF) < 1500ug/L. Deferiprone (DFP) has markedly lower affinity for iron (pFe3+ log stability constant = 19.9) than that of deferoxamine (26.6), and may provide a better safety profile in patients with low iron overload. The objective of this study is to evaluate the safety and efficacy of DFP in patients with thalassemia major (TM) and SF <500 ug/L. Methods: A total of 32 patients with TM (15 males) who had achieved SF <500 ug/L while on chelation with combined DFO and DFP (n=30) or on deferasirox (DFX) (n=2) had their chelation switched to DFP monotherapy (75-100mg/kg/day). All patients received 50 mg of oral zinc sulfate once a week for the duration of the study. Iron overload was assessed using SF and MRI T2* of liver and heart within 3 months of switch and then 6-12 monthly thereafter. Renal and liver function tests were performed monthly and trace elements (serum magnesium, copper, zinc and selenium) were also assessed. Results: Patients were followed for a median of 4.5 years (Range: 1-11 years). The median age at time of switch was 22.7 years (Range 11-28). The mean packed red blood cell volume transfused during the study was 197 mL/kg/year (Range: 157-282 mL). There was no significant increase in the SF (Baseline 392 ug/L; Last assessment 418 ug/L; p value 0.55) or the liver iron concentration (Baseline 3.44 mg/g dw; Last assessment 3.1 mg/g dw; p value 0.54) during the follow up. On the contrary, there was a statistically significant improvement in the cardiac T2* (Baseline 30 ms; Last assessment 38 ms; p <0.001). DFP was discontinued in 28% of patients (Ineffective in 3; Agranulocytosis in 1; Pregnancy in 1; Bone marrow transplantation in 2; Deaths in 2). The two deaths were unrelated to the chelation therapy (Decompensated HCV related liver cirrhosis and severe hypoglycaemia in a patient with diabetes mellitus). Two patients had mild asymptomatic hypocalcemia, and one had low copper levels. All three patients normalized their results with no treatment and without stopping DFP. No patient reported gastrointestinal disturbances or arthralgia, and none had elevation of liver enzymes or serum creatinine. Conclusion: Long-term DFP therapy in patients with TM and low iron overload was effective in stabilizing SF and LIC and was associated with improvement in the myocardial iron. The safety profile was consistent with those observed during therapy in patients with more severe iron burden and there were no increase in the unexpected adverse drug reactions. Disclosures No relevant conflicts of interest to declare.

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Efficacy and Safety of Amlodipine in Preventing Myocardial Iron Overload in Patients with Transfusion-Dependent Thalassemia Major : A Systematic Review and Meta-Analysis

Blood ◽

10.1182/blood-2020-137713 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 48-49

Author(s):

Richi Kashyap ◽

Muhammad Ashar Ali ◽

Saad Ullah Malik ◽

Farhan Khalid ◽

Ali Jaan ◽

...

Keyword(s):

Adverse Effects ◽

Iron Overload ◽

Meta Analysis ◽

Iron Concentration ◽

Iron Chelation ◽

Thalassemia Major ◽

Iron Toxicity ◽

Control Group ◽

P Value ◽

Myocardial Iron

Background: Patients diagnosed with thalassemia major who are transfusion dependant, have iron accumulation leading to iron toxicity and severe impairment in organs like heart, liver and endocrine organs which are highly sensitive to iron toxicity. This makes iron chelation therapy imperative for these patients. Half of the deaths resulting from iron toxicity related complications are attributed to cardiac complications. Iron chelation therapies have not been completely successful to prevent iron toxicity related complications like arrhythmia, cardiomyopathy and heart failure. Higher doses of iron chelation therapies have been associated with various side effects. Studies have shown L-type calcium channel blocker might be able to reduce iron uptake by myocardium. The aim of this meta-analysis is to assess the efficacy and safety of amlodipine to reduce myocardial iron concentration (MIC). Methods: We used PICO framework to do a systematic literature search using four database PubMed, Cochrane, Embase, and Web of Science using keywords, "Thalassemia" AND "Amlodipine" from the inception till July 2020. The initial search showed 90 articles out of which, six randomized clinical trials (RCT) (N= 226) were selected after exclusion of case reports, case series, preclinical trials, review articles, meta-analysis, and trials not providing any information about preventing iron overload in patients with transfusion dependent thalassemia. We extracted the data for myocardial iron concentration (MIC), myocardial T2, ferritin, hepatic iron/liver iron concentration (LIC), liver T2, left ventricular ejection fraction, response rate and adverse effects. DerSimonian-Laird random effects model was used to derive mean differences along with their 95% confidence interval (CI) using comprehensive meta-analysis version 3.0. Results: In six RCT, 96 patients were tested in experimental group and 97 in control group. In five RCT total number of male participants were 45 in experimental group and 54 in control group. 33 patients had splenectomy in experimental group and 41 in control group. The age range was 8 years to 31 years. The myocardial T2 score increased in amlodipine group compared to standard chelation group with significant mean difference estimated to be -0.62 (95% CI: -0.95-0.29, p-value: <0.001) in favor of amlodipine in meta-analysis of the four trials (Fig 1.). Statistically significant reduction in myocardial iron was seen in two trials on adding amlodipine to standard chelation therapy (N=55) (Table 1.) (Khaled et al and Fernandes et al). Significant difference was reported in liver T2 score and LIC at the end of six months between amlodipine and control group by Khaled et al. But, there was no statistically significant mean difference in serum ferritin and in liver MRI T2 between amlodipine group and control group with mean difference of -1143 (95% CI: -2410 to 124, p-value = 0.07) and -0.06 (95% CI: -0.463 to 0.338, p-value = 0.76) in meta-analysis of four and two trials respectively (Fig 2. And Fig 3.). El-Haggar et al compared amlodipine with spirulina and statistically significant improvement in myocardial T2 and NT-proBNP level was seen in both groups. Spirulina group also showed significant reduction in serum ferritin, which showed spirulina could also help reduce iron overload. Only mild adverse effects were reported by trials (Table 2.). No cases of severe hypotension, palpitation or any other serious adverse effects were seen in the amlodipine group. Conclusion: This systematic review and meta-analysis suggests that addition of amlodipine 2.5-5 mg/day to standard chelation therapy with monitoring for potential adverse effects, could benefit patients with thalassemia major by reducing cardiac iron overload and thus improve survival and quality of life. Future studies are required to study the role of amlodipine in reducing iron overload in endocrine organs that also absorb iron through voltage-gated channels, particularly considering the close association of cardiac siderosis with endocrine complications and the correlation of pancreas and MICs. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

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Characteristics and Outcomes of COVID-19 Patients with Mature B-Cell Non-Hodgkin Lymphomas (mB-Cell NHL): A US Nationwide Electronic Health Record (EHR) Database Study

Blood ◽

10.1182/blood-2021-145042 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2418-2418

Author(s):

Xiaomeng Yue ◽

David Hallett ◽

Yangyang Liu ◽

Reethi Iyengar ◽

Elisa Basa ◽

...

Keyword(s):

Risk Factors ◽

Logistic Regression ◽

B Cell ◽

Clinical Characteristics ◽

Index Date ◽

B Cell Lymphoma ◽

Male Gender ◽

Older Age ◽

Multivariable Logistic Regression ◽

The Impact

Abstract Introduction COVID-19 poses a serious concern for mB-cell NHL patients given their advanced age, high burden of comorbidities, and immune dysfunction. Limited by smaller sample sizes during the early period of the COVID-19 pandemic, previous studies were unable to thoroughly evaluate the impact of COVID-19 on patients with mB-cell NHL 1,2. We aim to describe demographics and clinical characteristics, outcomes, and risk factors associated with death and other severe outcomes among COVID-19 patients with mB-cell NHL in a large US nationwide database. Methods This retrospective cohort study was conducted using the Optum EHR database, comprising data from an integrated network of ambulatory and hospital care providers across the US. Patients with COVID-19 (diagnosis code of U07.1, U07.2, or a positive result of SARS-Cov-2 virus PCR or antigen tests) between Feb. 1, 2020 and Jan 7, 2021 (index date) and mB-cell NHL diagnosis prior to the COVID-19 diagnosis were included. Patients were excluded if they were under 18 years of age, had missing age or sex, or had <1year continuous eligibility prior to their index date (pre-index period). All baseline characteristics, including demographics and comorbidities, were determined during the one-year pre-index period. Severe outcomes, including death, hospitalization, ICU admission, and acute respiratory insufficiency (ARI), were evaluated within 30 days post-index date. Multivariable logistic regression was conducted to identify variables independently associated with severe outcomes. Results Among 2,767 patients with mB-cell NHL who were infected with SARS-CoV-2 between Feb. 1, 2020 and Jan. 7, 2021 (mean age±SD: 67.9 years±14.7, 53.9% male), majority were white (73.9%), followed by African American (10.9%), Hispanic (6.9%), and Asian (1.2%). The most common subtypes of mB-cell NHL were chronic lymphocytic leukemia/small lymphocytic lymphoma (26.9%), multiple myeloma (22.4%), diffuse large B-cell lymphoma (13.2%), and follicular lymphoma (7.3%). Of these patients, 93.4% have at least one comorbidity. The most common comorbidities were hypertension (58.5%), neurological disease (49.4%), diabetes (28.2%), ischemic heart disease (25.5%), cardiac arrhythmia/conduction disorders (24.4%), chronic kidney disease (CKD, 19.2%), heart failure/cardiomyopathy (18.1%), and COPD (12.3%). Overall, 960 patients (34.7%) developed severe outcomes, among which, 847 patients (30.6%) were hospitalized, 214 patients (7.7%) were admitted to the ICU, 201 patients (7.3%) experienced ARI, and 220 patients (8.0%) died. Multivariable logistic regression showed that increased odds of severe outcomes were independently associated with older age (85+ years vs. <65 years; adjusted odds ratio [OR], 2.0; 95% CI, 1.4-2.7), male gender (OR, 1.4; 95% CI, 1.1-1.6), insurance coverage with Medicaid (OR, 1.8; 95% CI, 1.1-2.9) and/or Medicare (vs. commercial only; OR, 1.9; 95% CI, 1.5-2.5), infected during the first quarter (OR, 5.6; 95% CI, 3.4-9.4) or second quarter of 2020 (vs. fourth quarter of 2020; OR, 1.7; 95% CI, 1.4-2.1), having CKD (OR, 1.3; 95% CI, 1.0-1.6), COPD (OR, 1.4; 95% CI, 1.0-1.8), diabetes (OR, 1.3; 95% CI, 1.1-1.6), and receiving active treatment for NHL (OR, 1.4; 95% CI, 1.0-2.0) within 30 days prior to COVID-19 diagnosis (Figure). Conclusions This study demonstrated key demographic and clinical characteristics associated with severe outcomes among COVID-19 patients with mB-cell NHL using one of the largest nationwide databases. Risk factors for severe outcomes identified in the general population, such as older age, male gender, and having certain underlying medical conditions were also identified in this study. In addition, COVID-19 infection occurring earlier in the pandemic and receiving active NHL treatments were associated with severe outcomes. These latter two observations might reflect the improvement in patient management during the latter period of the pandemic and that active mB-cell NHL disease and treatment rendered an increased risk of severe outcomes in COVID-19 patients with mB-cell NHL. These insights highlight the importance of utilizing demographic, clinical and treatment information to estimate the risk for severe outcomes, whereas prospective studies focusing on optimal COVID-19 management are required to identify specific actions that can be taken to improve outcomes of COVID-19 in patients with mB-cell NHL. Figure 1 Figure 1. Disclosures Yue: Joule: Current Employment. Hallett: AbbVie: Current Employment. Liu: AbbVie: Current Employment. Iyengar: AbbVie: Current Employment. Basa: AbbVie: Current Employment. Yang: AbbVie: Current Employment.

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Effects of iron overload and hepatitis C virus positivity in determining progression of liver fibrosis in thalassemia following bone marrow transplantation

Blood ◽

10.1182/blood.v100.1.17 ◽

2002 ◽

Vol 100 (1) ◽

pp. 17-21 ◽

Cited By ~ 193

Author(s):

Emanuele Angelucci ◽

Pietro Muretto ◽

Antonio Nicolucci ◽

Donatella Baronciani ◽

Buket Erer ◽

...

Keyword(s):

Liver Fibrosis ◽

Iron Overload ◽

Iron Content ◽

Hazard Rate ◽

Iron Concentration ◽

Dry Weight ◽

Interquartile Range ◽

Hepatic Iron ◽

Fibrosis Progression

Abstract To identify the role of iron overload in the natural history of liver fibrosis, we reviewed serial hepatic biopsy specimens taken annually from patients cured of thalassemia major by bone marrow transplantation. The patients underwent transplantation between 1983 and 1989 and did not receive any chelation or antiviral therapy. Two hundred eleven patients (mean age, 8.7 ± 4 years) were evaluated for a median follow-up of 64 months (interquartile range, 43-98 months) by a median number of 5 (interquartile range, 3-6) biopsy samples per patient. Hepatic iron concentration was stratified by tertiles (lower, 0.5-5.6 mg/g; medium, 5.7-12.7 mg/g; upper, 12.8-40.6 mg/g dry weight). Forty-six (22%) patients showed signs of liver fibrosis progression; the median time to progression was 51 months (interquartile range, 36-83 months). In a multivariate Cox proportional hazard model, the risk for fibrosis progression correlated to medium hepatic iron content (hazard rate, 1.9; 95% confidence interval [CI], 0.74-5.0), high hepatic iron content (hazard rate, 8.7; 95% CI, 3.6-21.0) and hepatitis C virus (HCV) infection (hazard rate, 3.1; 95% CI, 1.5-6.5). A striking increase in the risk for progression was found in the presence of both risk factors. None of the HCV-negative patients with hepatic iron content lower than 16 mg/g dry weight showed fibrosis progression, whereas all the HCV-positive patients with hepatic iron concentration greater than 22 mg/g dry weight had fibrosis progression in a minimum follow-up of 4 years. Thus, iron overload and HCV infection are independent risk factors for liver fibrosis progression, and their concomitant presence results in a striking increase in risk.

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Consequences and management of iron overload in sickle cell disease

Hematology ◽

10.1182/asheducation-2013.1.447 ◽

2013 ◽

Vol 2013 (1) ◽

pp. 447-456 ◽

Cited By ~ 57

Author(s):

John Porter ◽

Maciej Garbowski

Keyword(s):

Sickle Cell Disease ◽

Blood Transfusion ◽

Iron Overload ◽

Sickle Cell ◽

Iron Concentration ◽

Thalassemia Major ◽

Iron Loading ◽

Cell Disease ◽

Liver Iron Concentration ◽

Liver Iron

Abstract The aims of this review are to highlight the mechanisms and consequences of iron distribution that are most relevant to transfused sickle cell disease (SCD) patients and to address the particular challenges in the monitoring and treatment of iron overload. In contrast to many inherited anemias, in SCD, iron overload does not occur without blood transfusion. The rate of iron loading in SCD depends on the blood transfusion regime: with simple hypertransfusion regimes, rates approximate to thalassemia major, but iron loading can be minimal with automated erythrocyte apheresis. The consequences of transfusional iron overload largely reflect the distribution of storage iron. In SCD, a lower proportion of transfused iron distributes extrahepatically and occurs later than in thalassemia major, so complications of iron overload to the heart and endocrine system are less common. We discuss the mechanisms by which these differences may be mediated. Treatment with iron chelation and monitoring of transfusional iron overload in SCD aim principally at controlling liver iron, thereby reducing the risk of cirrhosis and hepatocellular carcinoma. Monitoring of liver iron concentration pretreatment and in response to chelation can be estimated using serum ferritin, but noninvasive measurement of liver iron concentration using validated and widely available MRI techniques reduces the risk of under- or overtreatment. The optimal use of chelation regimes to achieve these goals is described.

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Safety and Efficacy of High Dose Intravenous Desferoxamine for Reduction of Iron Overload Due to Chronic Transfusion in Sickle Cell Patients.

Blood ◽

10.1182/blood.v112.11.1430.1430 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1430-1430

Author(s):

Ram Kalpatthi ◽

Brittany Peters ◽

David Holloman ◽

Elizabeth Rackoffe ◽

Deborah Disco ◽

...

Keyword(s):

Serum Creatinine ◽

Iron Overload ◽

Sickle Cell ◽

Serum Ferritin ◽

Liver Tissue ◽

Iron Concentration ◽

P Value ◽

High Dose ◽

Liver Iron ◽

Iron Storage

Abstract Background: Patients with sickle cell disease (SCD) receiving chronic blood transfusions are at risk of developing iron overload and organ toxicity. Chelation therapy with either subcutaneous (SQ) desferoxamine (DFO) or oral deferasirox is effective in preventing and reducing iron overload but poses significant challenges with patient compliance. Intravenous (IV) infusions of high dose DFO (HDD) have been utilized in non compliant patients with heavy iron overload in small case series. We review our experience of high dose IV DFO in a large cohort of SCD patients with significant iron overload who are non compliant with SQ DFO. Methods: The medical records of SCD patients who received HDD in our center between 1993 and 2004 were reviewed. All of them were on chronic transfusion, had significant iron overload defined by serum ferritin > 1500 and/or liver iron concentration (LIC) more than 10 μg/g of liver tissue and were non-compliant with SQ DFO. All patients underwent annual ophthalmologic, hearing, pulmonary and cardiac evaluation. Demographic data, treatment details, serum ferritin levels, liver iron concentration (LIC), liver enzymes, renal function tests, audiogram and other relevant clinical data were collected. Results: There were 27 patients (19 males, 8 females), 19 patients were on transfusion for history of cerebrovascular accident, 5 for abnormal transcranial Doppler flow velocity, 2 for transient ischemic attack and one for recurrent pain crises. All continued to receive packed red blood cell transfusions aimed to keep HbS levels below 30 or 50% during this time. They were treated in-hospital with DFO 15 mg/kg/hr IV for 48 hrs every 2 weeks (20 patients), 3 weeks (4 patients) and 4 weeks (3 patients). The mean age at start of high dose regimen was 14.6 years (range 9–27 years). The mean duration of HDD treatment was 8.9 months (range 3–49 months). Fourteen patients had LIC determined by liver biopsy. Significant reductions in LIC were observed after HD (table I). This was more pronounced in patients who had higher LIC and received at least 6 months of HDD. Histological examination of liver biopsies revealed a decrease in the grade of liver iron storage. Four patients had portal triaditis initially which resolved after starting HDD therapy. Also there was significant improvement in liver enzymes (ALT, AST) after HDD. There was a trend in decreasing ferritin levels after HDD but this did not achieve statistical significance. All patients tolerated HDD without any major reactions. No audiologic or ophthalmologic toxicity or acute or chronic pulmonary complications were observed. Blood urea nitrogen remained normal in all patients after HDD but there was mild increase in serum creatinine. One patient had high serum creatinine (1.2 mg/dL) after two doses HDD. This patient had focal segmental glomeurosclerosis which was most probably the cause for the rise in creatinine. There was no significant increase in serum creatinine in our series when this patient was excluded. Conclusions: In our cohort of SCD patients we observed a significant decrease in liver iron burden with high dose IV DFO. Our patients tolerated the therapy well without any major toxicity. This regimen is safe and may be an option for poorly compliant patients with significant iron overload. In addition, combination of this regimen with oral iron chelators may be of benefit to patients with significant iron overload and organ dysfunction. Table 1: Laboratory characteristics of sickle cell patients before and after high dose IV DFO Parameter No. of Patients Mean (SD) prior to HDD Mean (SD)after HDD p Value* * Changes in mean levels analyzed using two-tailed Paired T Test with significant p value ≤ 0.05. SD – Standard deviation + See text Liver iron (μg/g of liver tissue ) 14 16864 (10903) 12681 (8298) 0.04 Liver iron min of 6 months of HDD (μg/g of liver tissue ) 8 18677 (8319) 9362 (4521) 0.01 Liver iron >10 mg & minimum 6 months of HDD (μg/g of liver tissue) 7 21181 (7054) 10092 (4443) 0.01 Grade of liver iron storage 14 3.57 (0.9) 3.07 (1) 0.05 Serum Ferritin (ng/mL) 27 3842 (2619) 3238 (1780) 0.06 Serum AST (IU/L) 27 54.1 (27.2) 44.6 (17.6) 0.04 Serum ALT (IU/L) 27 39.2 (36) 27.5 (14.2) 0.01 Blood urea nitrogen (mg/dL) 27 8.9 (2.9) 9.5 (4.3) 0.20 Serum Creatinine (mg/dL)+ 26 0.50 (0.1) 0.55 (0.2) 0.07

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Safety of Deferasirox (Exjade®) in Patients with Transfusion-Dependent Anemias and Iron Overload Who Achieve Serum Ferritin Levels <1000 Ng/Ml during Long-Term Treatment

Blood ◽

10.1182/blood.v112.11.5423.5423 ◽

2008 ◽

Vol 112 (11) ◽

pp. 5423-5423 ◽

Cited By ~ 3

Author(s):

John B Porter ◽

Antonio Piga ◽

Alan Cohen ◽

John M Ford ◽

Janet Bodner ◽

...

Keyword(s):

Clinical Trials ◽

Abdominal Pain ◽

Iron Overload ◽

Serum Ferritin ◽

Safety Profile ◽

Iron Concentration ◽

Thalassemia Major ◽

Liver Iron ◽

Long Term Treatment ◽

Baseline Characteristics

Abstract Background: Maintaining serum ferritin (SF) levels below 1000 ng/mL has been reported to predict longer survival and a reduced risk of complications (eg heart failure) in patients with thalassemia major. Experience with deferoxamine (Desferal®, DFO) has indicated that the toxicity of DFO may increase as SF levels decrease. A target SF value in the deferasirox clinical trials was not specified per protocol, but was determined by the individual investigators. This analysis evaluates the safety of deferasirox (Exjade®) in a cohort of adult and pediatric patients with transfusion-dependent anemias and iron overload from two large clinical trials (107 and 108) who were chelated to SF levels <1000 ng/mL. Methods: In core studies 107 and 108, frequently-transfused patients with chronic anemias ≥2 years old received deferasirox 5–30 mg/kg/day for 1 year. Eligible patients were then enrolled in 4-year extension trials, where initial dosing was based on the end of core study liver iron concentration; dose adjustments were based on SF levels. Patients eligible for this analysis had an initial SF ≥1000 ng/mL. Patients who achieved a SF level <1000 ng/mL on ≥2 consecutive visits, any time after starting deferasirox, were identified. The number of days when SF was <1000 ng/mL was calculated for each patient. AEs in these patients were calculated for the entire period on deferasirox, and for the period following the first SF measurement of <1000 ng/mL, irrespective of future SF levels. Results: 474 patients were included in this analysis: underlying anemias were β-thalassemia (n=379), myelodysplastic syndromes (n=43), Diamond-Blackfan anemia (n=30) and other anemias (n=22). Overall, 13.5% patients achieved SF<1000 ng/mL in year 1, 18.6% in year 2, 25.7% in year 3, 32.5% in year 4 and 36.7% by the time of this analysis. Therefore, overall 174 patients (36.7%) reached a SF level <1000 ng/mL on ≥2 consecutive visits, while in 300 patients SF levels remained ≥1000 ng/mL. The median period for a SF value <1000 ng/mL was 149 days [range 18–1726]. Patient demographics, baseline characteristics and safety profiles of the two groups throughout deferasirox treatment are shown in Table 1. At month 54, median SF levels in the <1000 and >1000 ng/mL groups were 872 and 2118 ng/mL, respectively. The incidence of drug-related AEs (gastrointestinal, renal and liver) did not appear to increase during the periods after SF levels first decreased below 1000 ng/mL (data not shown). Table 1. Demographics, baseline characteristics and safety profile of patients who achieved SF levels <1000 ng/mL and patients who did not Patients who achieved SF <1000 ng/mL Patients who did not achieve SF <1000 ng/mL *Investigator-assessed; SCr, serum creatinine; ULN, upper limit of normal; ALT, alanine aminotransferase n 174 300 Male:female 85:89 145:155 Mean age ± SD, years 23.8 ± 16.7 23.5 ± 18.2 <16, n (%) 65 (37.4) 123 (41.0) ≥16, n (%) 109 (62.6) 177 (59.0) Enrolled from study 107:108 120:54 175:125 Median exposure to deferasirox, months 56.3 45.2 Mean actual deferasirox dose, mg/kg/day 20.3 22.9 Median baseline SF, ng/mL 1791 2883 Drug-related AEs* (≥5% in either group), n (%) Nausea 26 (14.9) 38 (12.7) Diarrhea 17 (9.8) 42 (14.0) Vomiting 14 (8.0) 25 (8.3) Abdominal pain 12 (6.9) 32 (10.7) Upper abdominal pain 6 (3.4) 20 (6.7) Rash 9 (5.2) 16 (5.3) Audiological abnormalities 7 (4.0) 4 (1.3) Ophthalmological abnormalities 4 (2.3) 5 (1.7) Two consecutive SCr increases >33% above baseline and above ULN 26 (14.9) 36 (12.0) Increase in ALT >10×ULN on at least 1 visit 12 (6.9) 20 (6.7) Baseline levels elevated 6 (3.4) 16 (5.3) Conclusions: Over the core and extension phases of these clinical studies, the safety profile of patients achieving SF levels <1000 ng/mL was similar to that observed in patients who did not achieve SF levels <1000 ng/mL. There was also no apparent increase in AEs associated with a decrease in SF levels <1000 ng/mL. In particular, no increase in the proportion of patients with creatinine increases >33% above baseline and ULN or with ALTs >10×ULN were observed in these patients. These findings suggest that ironoverloaded patients can be safely chelated with deferasirox to low SF levels.

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Liver Transient Elastography (FibroScan) Correlates with Liver Iron Concentration and Reflects Liver Fibrosis In Patients with Sickle Cell Disease

Blood ◽

10.1182/blood.v116.21.1646.1646 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1646-1646 ◽

Cited By ~ 3

Author(s):

Ersi Voskaridou ◽

Maria Schina ◽

Eleni Plata ◽

Dimitrios Christoulas ◽

Maria Tsalkani ◽

...

Keyword(s):

Liver Fibrosis ◽

Iron Overload ◽

Hepatic Fibrosis ◽

Sickle Cell ◽

Serum Ferritin ◽

Transient Elastography ◽

Iron Concentration ◽

Liver Stiffness ◽

Cell Disease ◽

Liver Iron

Abstract Abstract 1646 Liver transient elastography (FibroScan) is an interesting new technology that allows estimation of hepatic fibrosis through measurement of liver stiffness. The technique is based on changes in tissue elasticity induced by hepatic fibrosis and is considered as a noninvasive, reproducible and reliable method to assess hepatic fibrosis as well as to diagnose liver cirrhosis. Hepatic iron overload is a severe complication of chronic transfusion therapy in patients with hemoglobinopathies and plays an important role in the development of hepatic fibrosis and cirrhosis. Iron overload is present in several cases of sickle cell disease (SCD) including sickle cell anemia (HbS/HbS) and double heterozygous sickle-cell/beta-thalassemia (HbS/beta-thal). The aim of the study was to evaluate liver fibrosis by measuring the liver rigidity (Liver Stiffness Measurement, LSM, kPascals) using transient elastography (FibroScan, Echosens, Paris, France) in patients with SCD and explore possible correlations with clinical and laboratory characteristics of the patients, including iron overload. We studied 110 consecutive patients with SCD who are followed-up in the Thalassemia Center of Laikon General Hospital in Athens, Greece. Forty-four patients were males and 66 females; their median age was 44 years (range: 21–73 years). Twenty-two patients had HbS/HbS and 88 patients had HbS/beta-thal. On the day of Fibroscan, all patients had a thorough hematology and biochemical evaluation, including hemoglobin, reticulocyte counts, serum ferritin, liver biochemistry, bilirubin, lactate dehydrogenase (LDH) and serology for viral hepatitis. Liver iron concentration was evaluated by magnetic resonance imaging (MRI) T2* in all patients. The median LSM of all patients was 6.1 kPascals (range: 3.4–48.8 kPascals) with no differences between HbS/HbS (6.1 kPascals, 3.5–17.3 kPascals) and HbS/beta-thal (6.1 kPascals, 3.4–48.8 kPascals) patients (p=0.835). LSM values strongly correlated with liver MRI T2* values (r=0.337, p<0.001), serum ferritin (r=0.328, p=0.001), number of transfusions (r=0.332, p=0.001), bilirubin (r=0.299, p=0.003), LDH (r=0.287, p=0.004), Hb (r=-0.275, p=0.006) and reticulocyte counts (r=0.244, p=0.015). LSM values showed also strong positive correlations with biochemical indicators of liver function: gamma-glutamyl transpeptidase (r=0.522, p<0.0001), glutamic oxaloacetic transaminase (r=0.484, p<0.0001), glutamic pyruvic transaminase (r=0.422, p<0.0001), alkaline phosphatase (r=0.334, p=0.001), gamma-globulin (r=0.296, p=0.005) and weak correlation with PT-International Normalized Ratio (r=0.184, p=0.094). The above correlations were similar in patients with HbS/HbS and in patients with HbS/beta-thal. However, in HbS/HbS patients the correlation between LSM and liver T2* values was very strong (r=0.770, p=0.001). Patients who were regularly transfused had higher values of LSM (median: 6.7 kPascals, range: 2.3–48.8 kPascals) compared with patients who were sporadically transfused or were not transfused (4.4 kPascals, 3.6–17.5 kPascals, p=0.003). Patients who were under iron chelation therapy had lower values of LSM (6.3 kPascals, 3.4–15 kPascals) compared with those who did not receive iron chelators (13.9 kPascals, 8.5–17.3 kPascals, p=0.013). We found no correlations between the presence of HBV or HCV positivity and the levels of LSM. In conclusion, FibroScan may constitute a reliable and easy to apply noninvasive method to assess liver fibrosis in patients with SCD; the strong correlations between LSM values with MRI T2* values and serum ferritin supports this observation. Furthermore, FibroScan seems also to reflect the presence of chronic hepatic injury in these patients. If our results are confirmed by other studies, FibroScan may be regularly used in the management of SCD patients in whom liver is the main target organ of the disease. Disclosures: No relevant conflicts of interest to declare.

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Exome Sequencing Identifies Genes and Variant Alleles Associated With Severity Of Iron Overload In Hemochromatosis HFE C282Y Homozygotes

Blood ◽

10.1182/blood.v122.21.179.179 ◽

2013 ◽

Vol 122 (21) ◽

pp. 179-179

Author(s):

Christine E. McLaren ◽

Mary J. Emond ◽

Pradyumna D. Phatak ◽

Paul C. Adams ◽

V. Nathan Subramaniam ◽

...

Keyword(s):

Iron Overload ◽

Serum Ferritin ◽

Iron Concentration ◽

Missense Variant ◽

Dry Weight ◽

P Value ◽

Hepatic Iron ◽

Common Variants ◽

Iron Stores ◽

Hepatic Iron Concentration

Abstract Variability in the severity of iron overload among homozygotes for the HFE C282Y polymorphism is one of the major problems extant in our understanding of hereditary hemochromatosis (HH). We conducted exome sequencing of DNA from C282Y homozygotes with markedly increased iron stores (cases) and C282Y homozygotes with normal or mildly increased iron stores (controls) to identify rare and common causal variants associated with variability of disease expression in HH. Criteria for cases included serum ferritin >1000 µg/L at diagnosis, and (a) mobilized body iron >10 g by quantitative phlebotomy, and/or (b) hepatic iron concentration >236 µmol/g dry weight. Criteria for controls included (a) serum ferritin <300 µg/L, or (b) age ≥50 y with ≤3.0 g iron removed by phlebotomy or age ≥40 y with ≤2.5 g iron removed by phlebotomy to achieve serum ferritin <50 µg/L. Deep sequencing of the full exome was performed in 33 cases and 14 controls. After quality control filtering, the dataset included 82,068 SNPs and 1,403 insertions/deletions (indels). Our initial analysis tested for differences in the distribution of variants between groups for each gene separately using the Sequence Kernel Association Test (SKAT) that includes rare and common variants but downweights the contribution of common variants to the test statistic. Only non-synonymous variants were included in the by-gene tests. Principal components were constructed from the exome variants to adjust for possible confounding by ancestry and to confirm no ancestral outliers. All study participants were male, and all clustered closely together within a larger group of Europeans in a principal components analysis of ancestry. Mean (SD) ages at presentation were 54 (11.0) y and 56 (9.4) y for cases and controls, respectively. Median serum ferritin was 2788 µg/L in those with increased iron stores and 309 μg/L in those with normal or mildly increased iron stores. The median transferrin saturation (94%) was greater in cases than in the comparison group (70%). In a preliminary analysis, we found 9 genes associated with case-control status. To separate effects of alcohol use and/or alcohol addiction variants, an analysis was conducted to compare the 13 controls and 22 cases who reported never using alcohol or only very light use. The two most significant genes identified in this comparison were GNPAT (p=7.4x10-6) and CDHR2 (p=2.8x10-4). A quantile-quantile (QQ) plot is shown in the Figure, comparing the observed distribution of –(log10p-values) from 10,337 genes to the expected uniform distribution if there were no variants modifying severity of expression, and gives evidence of the effect of the GNPAT gene.Figure 1Figure 1. Inspection of the two variants contributing to the GNPAT by-gene p-value revealed one missense variant (rs11558492) for which 0/13 controls had a polymorphism, while 16/22 cases had at least one missense variant, and one case was homozygous for this missense variant. The latter case presented at the early age of 26 with a serum ferritin of 1762 µg/L, 4+ hepatocellular iron and hepatic iron concentration of 284.4 µmol/g dry weight. GNPAT (aka DHAPAT) mutations/deletions have been found in peroxisomal disease, a class of diseases in which increased hepatic iron is observed (Biochim Biophys Acta 1801:272-280, 2010). GNPAT rs11558492 is common among people of European descent but might interact with aberrant HFE to increase risk of hepatic iron overload. Three rare variants in CDHR2 accounted for its low p-value, having a cumulative frequency of 4/13 among controls and 0/22 among cases: rs115050587, rs752138, rs143224505 with minor allele frequencies, MAF = 1.4%, 4.7% and 0.06%, respectively. The first two polymorphisms are predicted to be highly damaging by PolyPhen2 and the third probably damaging. Expression levels of CDHR2 recently have been associated with increased hepatocyte iron and elevated serum ferritin in liver allograft patients (J Clin Invest 122:368-382, 2012). These data indicate associations between iron status in HFE C282Y homozygotes and genes with previous links to iron overload that may modify severity of disease expression. Of note, the data suggest that more than one modifier gene may be involved in determining severity of disease in HFE C282Y homozygotes. Our results identify candidate genes for expanded studies that would examine their functional significance for iron absorption and metabolism. Disclosures: No relevant conflicts of interest to declare.

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