Undergoing Chelation Therapy Research Articles

Beta-Thalassemia Major and Myocardial Iron Overload: A Longitudinal Study with Magnetic Resonance Imaging.

Patients with β-thalassemia major depend on lifelong transfusion, resulting in tissue iron overload. This longitudinal retrospective observational study aims to assess myocardial and liver iron overload using magnetic resonance imaging (MRI) and investigate the lag between myocardial and liver iron unloading in β-thalassemia patients undergoing chelation therapy. Beta-thalassemia major patients with at least two MRI studies between 2016 and 2020 were enrolled. Myocardial and liver iron overload were defined as T2 ∗ less than 20 and 2.1, respectively. Outcomes included mortality, myocardial and liver T2 ∗ changes, and systolic dysfunction assessed by cardiac MRI. Fifty-five patients with a mean age of 24.62 ± 7.94 years, a mean follow-up duration of 24.3 ± 12.9 months, and a mean ferritin level of 1475.75 ± 771.12 ng/mL were enrolled. All of the abovementioned patients only took deferoxamine as the iron-chelating medication. Mortality occurred in three patients (5.5%) during follow-up. Liver T2 ∗ significantly increased (p value <0.05), while myocardial T2 ∗ showed a nonsignificant increase. Iron unloading of the myocardium was not significantly different from that of the liver and did not result in a significant lag (56% vs. 44%; p value = 0.419). Baseline myocardial T2 ∗ correlated with extramedullary hematopoiesis, weekly number of deferoxamine injections (p value <0.01), timing between the transfusions, and serum ferritin (p value <0.05). Liver T2 ∗ reduced during deferoxamine chelation therapy, while myocardial T2 ∗ remained unchanged. No significant lag was observed between myocardial and liver iron unloading. Further studies are required to elucidate these findings.

Optimizing the Management of Iron Overload in Patients with Hemoglobin Disorders in Centers with Limited Access to Magnetic Resonance Imaging

Background:Transfusion therapy for severe chronic anemias is a major cause of iron overload. Patients with hemoglobin disorders are often transfused, either chronically or occasionally, and if iron overload is suspected, it is currently recommended they are subjected to so-called “iron studies” and determination of liver iron content (LIC) and heart T2* by magnetic resonance imaging (MRI). It remains common practice to request both laboratory and imaging tests, even for patients already undergoing iron chelation, despite the unreliability of laboratory markers such as ferritin in the presence of concurrent inflammatory conditions, which do not affect results from MRI scans. Since MRI is not widely available in most underdeveloped and developing countries, we aimed to assess the contribution of laboratory tests to the management of patients with hemoglobin disorders with iron overload by analyzing a cohort of patients who managed to undergo MRI during a period of limited access to MRI scans in our center.Methods: In this single-center, retrospective analysis, data were collected from digital MRI, laboratory information system, and electronic chart databases, upon approval of the local ethics board. Since access to MRI was limited during the period of time studied, physicians used the following criteria to indicate MRI scans to define clinical suspicion of iron overload: patient already undergoing chelation therapy based on previous laboratory tests and clinical assessment, current or previous chronic transfusion therapy, or elevated ferritin with transferrin saturation (TSAT) above 45%.Results and Discussion: From April 2014 to September 2016, 27 patients (17 with sickle cell disease - SCD, 10 with beta thalassemia - BT), median age 35 years (15-62), 9 male (33%), were evaluated at 34 different occasions with MRI and conventional iron studies. Patients with BT had significantly higher levels of serum iron and TSAT than patients with SCD (BT median 266ug/dL, range 93-328 and 0.94, range 0.41-1.00; SCD median 157ug/dL, range 58-264, and 0.64, range 0.21-1.00, P=0.004 and P=0.0138), which reflects a higher percentage of BT patients on chronic transfusions (8/11 vs. 6/17) and the higher transfusion volume for BT in comparison to what is needed for exchange transfusions in SCD. Four patients had normal MRI scans: 1 with SCD not in transfusion, 1 with SCD that had been treated with iron chelation, and 2 BT major in chronic transfusion and optimal response to iron chelation (ferritin <500ng/mL). Only one SCD and one BT patient were diagnosed with cardiac iron overload, with a T2* of 7.5ms and 2.95ms, respectively, in patients with extreme hyperferritinemia (11,567 and 7,090ng/mL) and low compliance to iron chelation. MRI liver iron concentration correlated positively with serum ferritin and total iron binding capacity (TIBC) measurements (r=0.67, 95% CI 0.41-0.83, P <0.0001, and r=-0.49, 95% CI -0.72 to -0.17, P <0.004, respectively) but no serum biomarkers correlated with myocardial iron concentrations. Receiver operating characteristic (ROC) curve analysis showed that ferritin levels performed best in our population as predictor of any increase of LIC above 2mg/g (area under curve 0.9753, P=0.0003), with a cutoff value of 731.6ng/mL with a sensitivity of 96.3% and specificity of 100% to discriminate for the presence of any increase in hepatic iron. In addition, a ferritin cutoff value of 1649ng/mL yielded 76.2% sensitivity and 91.7% specificity to detect a LIC above 5mg/g, comprising 17 (50%) of the MRI scans. Only one patient in this group had less than moderate liver iron overload, but still with an abnormal LIC of 3.5mg/g.Conclusions: Our data suggest that conventional iron studies cannot predict cardiac siderosis, but earlier evaluation with MRI may be warranted in the presence of clinical risk factors such as history of chronic transfusion along with low compliance to iron chelation, independently from laboratory tests. In settings with limited access to MRI, ferritin levels may be useful in pre-screening for hepatic iron overload, so postponing probable negative scans for patients undergoing iron chelation with optimal response or probable positive scans for those with certain levels of hyperferritinemia (e.g.>1649mg/dL) could be appropriate criteria to manage referrals to MRI scans and help prioritize patients with undetermined indication of iron chelation. DisclosuresFertrin:Alexion Pharmaceuticals: Consultancy.

Cardiac iron overload evaluation in thalassaemic patients using T2* magnetic resonance imaging following chelation therapy: a multicentre cross-sectional study

IntroductionMagnetic resonance imaging (MRI) T2* technique is used to assess iron overload in the heart, liver and pancreas of thalassaemic patients. Optimal iron chelation and expected tissue iron response rates remain under investigation. The objective of this study was to analyse serum ferritin and the iron concentration in the heart, liver and pancreas measured by MRI T2*/R2* during regular chelation therapy in a real-world cohort of patients with thalassemia. MethodsWe evaluated thalassaemic patients ≥ 7 years old undergoing chelation/transfusion therapy by MRI and assessed serum ferritin at baseline and follow-up from 2004-2011. ResultsWe evaluated 136 patients, 92% major thalassaemic, with a median age of 18 years, and median baseline ferritin 2.033ng/ml (range: 59–14,123). Iron overload distribution was: liver (99%), pancreas (74%) and heart (36%). After a median of 1.2 years of follow-up, the iron overload in the myocardium reduced from 2,63 Fe mg/g to 2,05 (p 0.003). The optimal R2* pancreas cut-off was 148 Hertz, achieving 78% sensitivity and 73% specificity. However, when combining the R2* pancreas cut off ≤ 50 Hertz and a ferritin ≤ 1222 ng/ml, we could reach a negative predictive value (NPV) of 98% for cardiac siderosis. Only 28% were undergoing combined chelation at baseline assessment, which increased up to 50% on follow up evaluation. ConclusionsChelation therapy significantly reduced cardiac siderosis in thalassaemic patients. In patients with moderate/severe liver iron concentration undergoing chelation therapy, ferritin levels and myocardium iron improved earlier than the liver siderosis.

Spinal Anesthesia in Cesarean Section Surgery of the Pregnant Women with Wilson's Disease

Wilson's disease is an autosomal recessive inherited chronic disease that occurs as a result of the deposition of copper in organs and tissues with impaired biliary excretion. With this case report, we aimed to share our experience in cesarean anesthesia in a pregnant woman with Wilson disease who had irregular medical follow-up and underwent chelation therapy.

Estimation of serum ferritin and TSH levels in thalassemia patients undergoing iron chelation therapy

Objectives &amp; introduction: Thalassemia, heterogenous group of disorders of haemoglobin,characterised by reduced or absent production of one or more of globin chains.Regular redcell transfusion with chelation therapy for iron overload are cornerstones of therapy for ßthalassemia major. Serum ferritin assay is widely available, relatively inexpensive methodfor assessing body iron burden and monitoring response to chelation process which in turnalso improves TSH levels in thalassemic subjects .The objective of this study was to assessprechelation and postchelation levels of serum ferritin and TSH and correlating post chelationlevels of serum ferritin and TSH in thalassemic patients &gt;6yrs undergoing chelation therapy.&#x0D; Materials &amp; methods: Serum TSH measured by Enzyme linked fluorescent assay and serumferritin measured by enzyme linked immunosorbent assay.&#x0D; Results: Amongst 500 participants,47% were males &amp; 53% females. Mean age was 9.04 yrs ;prechelation ferritin and TSH levelswere 2995.78ng/ml with SD of 802.53 and 5.07 μU/ml with SD of 2.52. The postchelationferritin and TSH levels were 2168.80 ng/ml with SD of 1335.89 and 4.51μU/ml with SD of4.76. Paired t test with respect to pre and postchelation ferritin and TSH levels showed 2 tailed pas 0.000 and t&gt;3, both of which considered significant. While correlating post chelation ferritinwith TSH levels; they showed a linear correlation ( Pearson coefficient of .836).&#x0D; Conclusion:Serum ferritin and TSH estimation in prechelation and postchelation periods give an estimateof iron overload with effect of chelation on it. Both levels decrease post chelation presenting alinear correlation between the two.&#x0D; Bangladesh Journal of Medical Science Vol.20(1) 2021 p.130-135

Changes in inflammatory cytokines, antioxidants and liver stiffness after chelation therapy in individuals with chronic lead poisoning

BackgroundChronic exposure to lead causes lead to accumulate mainly in the liver. In vivo studies have shown that lead toxicity is related to alterations in the inflammatory response. We aimed to evaluate the association between lead poisoning and liver fibrosis as well as the change in the degree of liver fibrosis, levels of inflammatory mediators and glutathione (GSH) after chelation therapy.MethodsWorkers from a battery factory who were exposed to lead for > 12 months and had a blood lead level (BLL) > 70 μg/dL were enrolled (n = 86) in the study. Participants underwent chelation therapy with intravenous CaNa2EDTA for 2 days followed by treatment with oral D-penicillamine for 90 days. The primary outcome was the change in the degree of liver fibrosis, which was presented as liver stiffness (LS) measured by FibroScan®. Secondary outcomes were the changes in the levels of serum GSH and inflammatory mediators such as tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) after chelation therapy.ResultsAmong the 86 participants, there was a positive correlation between the duration of lead exposure and LS (r = 0.249, p = 0.021). To avoid the confounding effect of obesity-related steatosis, only 70 individuals who had controlled attenuation parameters < 296 dB/m, BMI < 25 kg/m2 and normal waist circumference were included in the interventional analysis. After chelation, the mean LS significantly decreased from 5.4 ± 0.9 to 4.8 ± 1.4 kPa (p = 0.001). Similarly, all of the inflammatory cytokines studied significantly decreased after chelation (p < 0.001); TNF-α decreased from 371.6 ± 211.3 to 215.8 ± 142.7; the levels of IL-1β decreased from 29.8 ± 1.7 to 25.9 ± 4.3; and the levels of IL-6 decreased from 46.8 ± 10.2 to 35.0 ± 11.9. On the other hand, the mean GSH level increased significantly from 3.3 ± 3.3 to 13.1 ± 3.7 (p < 0.001) after chelation therapy.ConclusionThe duration of lead exposure was significantly correlated with the degree of liver fibrosis. Chelation treatment was associated with increased levels of GSH and decreased levels of proinflammatory cytokines and could potentially reduce the degree of LS.Trial registrationThis study was retrospectively registered and approved by the Thai Clinical Trial Registry (TCTR) on 2019-11-07. The TCTR identification number is TCTR20191108001.

Ocular abnormalities in beta thalassemia patients: prevalence, impact, and management strategies.

Beta thalassemia (β-thalassemia) is a hereditary disease caused by defective globin synthesis and can be classified into three categories of minor (β-TMi), intermedia (β-TI), and major (β-TM) thalassemia. The aim of our study is to investigate the effects of β-thalassemia and its treatment methods on different parts of the eye and how early-diagnostic methods of ocular complications in this disorder would prevent further ocular complications in these patients by immediate treatment and diet change. We developed a search strategy using a combination of the words Beta thalassemia, Ocular abnormalities, Iron overload, chelation therapy to identify all articles from PubMed, Web of Science, Scopus, and Google Scholar up to December 2018. To find more articles and to ensure that databases were thoroughly searched, the reference lists of selected articles were also reviewed. Complications such as retinopathy, crystalline lens opacification, color vision deficiency, nyctalopia, depressed visual field, reduced visual acuity, reduced contrast sensitivity, amplitude reduction in a-wave and b-wave in Electroretinography (ERG), and decrease in the Arden ratio in Electrooculography (EOG) have all been reported in β-thalassemia patients undergoing chelation therapy. Ocular problems due to β-thalassemia may be a result of anemia, iron overload in the body tissue, side effects of iron chelators, and the complications of orbital bone marrow expansion.

Decreasing cardiac iron overload with Amlodipine and Spirulina in children with β-thalassemia

Background & aimIron overload in thalassemia major (TM) leads to excessive iron deposition in a wide variety of tissues especially the heart leading to iron-overload cardiomyopathy, which is the major determinant of survival in those patients. Our goal was to study effects of Amlodipine and Spirulina on iron loading when added to chelation therapy in patients with TM. MethodForty patients with TM undergoing chelation therapy were randomized into two groups (1:1); group 1 received Amlodipine 5 mg/day, and group 2 received Spirulina 250 mg/kg/day for 3 months. Patients were assessed for MRI examination (cardiac T2*) and laboratory data including ferritin, troponin I, and NT-proBNP levels at baseline and after 3 months. ResultsAfter 3 months, cardiac T2* increased significantly from 21.8 ± 7.7 ms to 22.94 ± 7.1 ms (p = 0.03) in Spirulina group, and from 21.9 ± 8.7 ms to 24.6 ± 9.4 ms (p = 0.007) in Amlodipine group. There was significant reduction in ferritin levels in Spirulina group (p = 0.007), but not in Amlodipine group (p = 0.09). In addition, NT-proBNP level decreased significantly in both groups. There was no statistically significant difference between both groups concerning cardiac T2*, serum ferritin, troponin I, and NT-proBNP levels at 3 months. ConclusionOur findings suggest that the use of Amlodipine or Spirulina as a complementary treatment with standard chelation therapy could reduce iron overload in patients with TM.This trial was registered at www.ClinicalTrials.gov as #NCT02671695.

Total body irradiation and iron chelation treatment are associated with pancreatic injury following pediatric hematopoietic stem cell transplantation.

Whereas many studies have addressed the risk of organ dysfunction following hematopoietic stem cell transplantation (HSCT), little is known about pancreatic susceptibility in this setting. We aimed to investigate the effect of iron overload (IO) and total body irradiation (TBI) on pancreatic function of children undergoing HSCT.We retrospectively evaluated children admitted between 2012-2016 fulfilling the following criteria: normal pancreatic iron concentration (PIC), regular pancreatic function before HSCT, availability of abdominal magnetic resonance imaging with gradient-recalled-echo sequences and a full set of biochemical markers of IO and pancreatic function performed before HSCT and at discharge. We divided the patients according to the use of TBI or myeloablative chemotherapy (MCHT) in the conditioning regimen. All patients with severe IO or moderate IO with a high risk of engraftment delay or transplantation-related complications underwent chelation therapy with deferoxamine (DFO) from the first day of conditioning to discharge.63 patients had a HSCT in the study period, 13 did not fulfill the inclusion criteria; 50 (25 in each group) are included in the analysis, and did not show differences at baseline evaluation. At follow up testing the TBI group showed a significantly higher PIC (107,8±100,3 μmol/g vs 28,4±37,9 in MCHT group, p<0,0001). In the TBI group the patients who had DFO treatment had higher PIC (223,2±48,8 μmol/g vs 55,7±10,5 without DFO treatment, p<0,0001), and all patients having PIC >100 μmol/g at follow up had DFO-based chelation therapy, versus 26% of those with lower PIC (p<0,0001). The number of patients presenting exocrine pancreatic dysfunctions one month after transplantation was significantly higher in the TBI group (48% vs 4%; p<0.0001). The mean pancreatic volume reduction was significantly greater in the TBI group (39,1% vs 0,9% in the MCHT group; p<0,05), and was significantly worse on those who received DFO therapy.Based on our data, we suggest that TBI is detrimental for pancreatic functions, and speculate that DFO may contribute to the rapid pancreatic IO observed in these patients.

A case of secondary diabetes mellitus associated with chronic arsenic toxicity

Chronic arsenic exposure leads to systemic illness involving multiple organ systems, and has been associated with the development of diabetes mellitus (DM). While the majority of the literature surrounding arsenic-induced DM is from areas where the arsenic content of drinking water is high, population-based studies in North America have shown a similar association. Here, we present a case of newly-diagnosed DM thought to be secondary to chronic arsenic exposure. The patient was a previously healthy 54-year-old female who presented with progressive fatigue, weight loss and anorexia, and eventually developed colitis, cachexia, skin eruptions, and alopecia. She was also diagnosed with DM, and treatment was complicated by episodes of severe hyper- and hypoglycemia. She was evaluated for autoimmune, rheumatologic, oncologic, and infectious etiologies of her symptoms, all of which were negative. Also negative was an extensive workup for secondary causes of DM. During her final hospitalization, she underwent a workup for heavy metal toxicity, which revealed elevated serum (11 mcg/L, reference range &lt; 5 mcg/L) and urine (233.5 mcg/gram creatinine, reference range &lt; 50 mcg/gram creatinine) arsenic levels. A diagnosis of arsenic toxicity was made, and the patient underwent chelation therapy with British anti-Lewisite (BAL). This is an interesting case of DM that was thought to be secondary to chronic arsenic exposure. While BAL was effective at lowering arsenic levels, we were unable to observe clinical improvement due to the patient’s death shortly after completion of therapy. In cases where other secondary causes of DM are ruled out, it may be prudent to evaluate for heavy metal toxicity to allow for early diagnosis and initiation of treatment. Further studies are needed to determine the efficacy of different treatment strategies for arsenic-induced DM, and whether resolution of arsenic toxicity will reverse the diabetogenic effects.

Hepatic Gadolinium Deposition and Reversibility after Contrast Agent–enhanced MR Imaging of Pediatric Hematopoietic Stem Cell Transplant Recipients

Purpose To determine if hepatic gadolinium deposition occurs in pediatric patients with iron overload but normal renal and hepatic function who undergo gadolinium-based contrast agent (GBCA)-enhanced magnetic resonance (MR) imaging. Materials and Methods Design and execution of this study was approved by the Ethical Committee of Institute for Research in Maternal and Child Health Burlo Garofolo of Trieste (reference no. 1105/2015). Because of the retrospective nature of the study, the requirement to obtain informed consent was waived. Twenty-one recipients of allogeneic hematopoietic stem cell transplants who underwent GBCA-enhanced MR imaging for suspected infection or relapse followed by liver biopsy comprised the study group. The number of GBCA-enhanced MR examinations and cumulative gadolinium dose for each patient was analyzed by comparing liver histologic analysis and iron and gadolinium liver concentration (GLC). Eight patients had siderosis and underwent chelation therapy. The study group was compared with four control patients who were never exposed to GBCA. Statistical analysis was performed with Spearman rank coefficient for correlation. Results All 21 patients had positive correlations between GLC and total GBCA dose (r = 0.4486; P < .05) and between GLC and liver iron concentration (r = 0.56; P < .05). Patients who underwent deferoxamine therapy had a significant reduction of GLC (from 0.64 μg/g ± 0.29 to 0.20 μg/g ± 0.17 [standard deviation]; P < .05). Conclusion In the presence of siderosis, a transmetallation mechanism may be set off between ferric ion and gadoterate meglumine. Deferoxamine appears capable of binding to gadolinium ion. Further studies of the safety of GBCAs in severe siderosis are needed. Chelation should be considered in patients with iron overload and a history of GBCA exposure. © RSNA, 2016.

Novel DFO-functionalized mesoporous silica for iron sensing. Part 2. Experimental detection of free iron concentration (pFe) in urine samples.

Successful in vivo chelation treatment of iron(iii) overload pathologies requires that a significant fraction of the administered drug actually chelates the toxic metal. Increased mobilization of the iron(iii) in experiments on animals or humans, most often evaluated from urinary output, is usually used as an assessment tool for chelation therapy. Alternatively, the efficiency of a drug is estimated by calculating the complexing ability of a chelating agent towards Fe(iii). The latter is calculated by the pFe value, defined as the negative logarithm of the concentration of the free metal ion in a solution containing 10 μM total ligand and 1 μM total metal at a physiological pH of 7.4. In theory, pFe has to be calculated taking into account all the complexation equilibria involving the metal and the possible ligands. Nevertheless, complexation reactions in complex systems such as serum and urine may hardly be accurately modelled by computer software. The experimental determination of the bioavailable fraction of iron(iii) in biological fluids would therefore be of the utmost relevance in the clinical practice. The efficiency of the therapy could be more easily estimated as well as the course of overload pathologies. In this context, the aim of the present work was the development of a sensor to assess the free iron directly in biological fluids (urine) of patients under treatment with chelating agents. In the proposed device (DFO-MS), the strong iron chelator deferoxamine (DFO) is immobilized on the MCM-41 mesoporous silica. The characterization of the iron(iii) sorption on DFO-MS was undertaken, firstly in 0.1 M KNO3, then directly in urine samples, in order to identify the sorption mechanism. The stoichiometry of the reaction in the solid phase was found to be: with an exchange constant (average value) of log βex = 40(1). The application of DFO-MS to assess pFe in SPU (Simulating Pathology Urine) samples was also considered. The results obtained were very promising for a future validation and subsequent application of the sensor in samples of patients undergoing chelation therapy.

Amlodipine Reduces Cardiac Iron Overload in Patients with Thalassemia Major: A Pilot Trial

BackgroundIron chelation therapy in patients with thalassemia major may not prevent iron overload in all organs, especially those in which iron enters cells through specific calcium channels. We designed a controlled pilot study to assess the potential of the calcium channel blocker amlodipine in strengthening the efficacy of iron chelation. MethodsFifteen patients with thalassemia major undergoing chelation therapy were randomized to receive amlodipine added to standard treatment in a 1:2 allocation for 12 months. T2* values for assessment of iron overload in the liver and heart using magnetic resonance imaging were obtained at baseline and at 6 and 12 months. ResultsIn the amlodipine-treated group, heart T2* increased significantly in comparison to baseline at 6 and 12 months (21.7 ± 7.2 ms to 28.2 ± 7.9 ms and 28.3 ± 8.0 ms, with P = .007 and .03, respectively), while no differences were observed in the control group (25.1 ± 8.8 ms to 24.7 ± 7.8 ms and 26.2 ± 11.4 ms; P = .99 and 0.95, respectively); significant differences between groups were observed at 6 months (28.2 ± 7.9 ms vs 24.7 ± 7.8 ms in the control group, P = .03). A significant reduction in ferritin levels also was observed in the treated group at 12 months. ConclusionsThe use of amlodipine in conjunction with standard chelation therapy may suggest a new strategy in preventing and treating iron overload in patients with thalassemia major, especially in organs where iron absorption depends on active uptake by calcium channels like the heart.

Acute Effects of Blood Transfusion on Spermatogenesis and Pituitary Gonadal axis in Eugonadal Males with Beta Thalassemia Major (pilot study)

AbstractAbstract 1027 Objective:To evaluate semen parameters and measure serum follicle stimulating hormone (FSH), luteinizing hormone (LH), testosterone (T) and insulin-like growth factor-I (IGF-I) concentrations before and 7 days after packed red cell transfusion (PCTx) in young adults with thalassemia major (TM). Design:Prospective study. Setting, Patients, Interventions:We studied the effect of blood transfusion on semen parameters, the endocrine functions in 10 young adults with TM, aged from 17 to 32 years, with full pubertal development (Tanner’s stage 5) (euogonadal),and capacity to ejaculate. They were regularly transfused since early childhood and underwent chelation therapy using desferrioxamine which was replaced by deferasirox for the last 4 –5 years. At the time of the study their serum ferritin levels ranged from 500 to 5922 ng/ml (mean2686 ng/ml). Basal serum concentrations of FSH, LH, T and IGF-I were evaluated before and 7 days after packed red cell transfusion (PCTx). Main Outcome Measures and Results:After PCTx significant increase of Hb from 8.7 +/− 0.86 g/dl to 11.1 +/− 0.82 g/dl was associated with increased testosterone (from 16.5 +/− 8 nmol/L to 20 +/− 8.8 nmol/L, IGF-I (from 173 +/− 46ng/ml to 214 +/− 61ng/ml) and gonadotropins’ concentrations. Total sperm count increased significantly from 57.8 +/− 38.3 million/ml to 166 +/− 132 million/ml and rapid progressive sperm motility progressive motility increased from 20.6+/− 16.6 % to 79.7 +/− 67.4 %. After PCTx, LH concentrations were correlated significantly with T concentrations (r = 0.434, p < 0.001) and sperm volume and count (r = 0.439 and r = 0.376 respectively, p: 0.01). The increase of IGF-I concentration was correlated significantly with Hb level after PCTx (r = 0.535, p < 0.001) and negatively with ferritin concentration (r = −0.458, p < 0.001). Significant correlation were found between serum T concentrations and semen parameters before and after PCTx including sperm count (r = 0.658 and r = 0.73 respectively, p < 0.001)rapid progressive motility (r = 0.675 and r = 0.758 respectively p < 0.001), and the number of sperms with normal morphology (r = 0.752 and r = 0.834 respectively, p < 0.001) IGF-I levels and seminal parameters. No correlations were found between serum FSH and IGF-I concentrations and seminal parameters. Conclusion:Our study suggests that in thalassemic males blood transfusion is associated with significant acute enhancement of sperm parameters and with an increased concentrations of serum testosterone, LH, FSH and IGF-I. These “acute” effects on spermiogenesis are reached with an unknown mechanism/s and suggest a number of pathways that need further human and/or experimental studies.Table 1Hormonal and sperm data before versus after blood transfusion in thalassemic malesBeforeAfterP valuen = 10n = 10Hb (g/dl)8.7 +/− 0.8611.1 +/− 0.82 *0.000046LH (IU/L)2.5 +/− 1.653.8 +/− 1.87*0.049FSH (IU/L)3.3 +/− 2.454.4 +/− 2.27*0.008Testosterone (umol/L)16.5 +/− 820 +/− 8.8*0.0018Basal GH (ng/ml)0.88 +/− 1.3NDPeak GH (ng/ml) after clonidine6.7 +/− 2.66NDIGF-I (ug/L)173 +/− 46214 +/− 61*0.003Seminal parametersVolume (ml)1.65 +/− 0.782.1 +/− 0.58*0.0406Total sperm count (mil/ml)57.8 +/− 38.3166 +/− 132*0.0059Rapid progressive motility (%)23.9 +/− 15.364.9 +/− 12.6*0.0026Normal forms (%)41.7 +/− 17.648.3 +/− 12.4*0.045ND= not done.Table 2Correlations (R values) between serum testosterone level and sperm parameters before (1) and after (2) blood transfusionTestosterone (1)Testosterone (2)Sperm count (million/ml)10.660.73Volume (ml)10.430.47total PM (%) 10.680.76RPM (%) 10.690.71Normal morphology (%) 10.750.73Sperm count (million/ml)20.680.75Volume (ml)20.460.51Total PM 20.660.74RPM (%) 20.680.73Normal morphology (%) 20.750.83Abbreviations: TPM = Total progressive motility (%); RPM= Rapid Progressive motility (%); 1= before blood transfusion; 2 = after blood transfusion. Disclosures:Yassin:Hamad medical corporation MRC: Employment, Research Funding. Soliman:Hamad medical corporation MRC: Employment, Research Funding. Elawa:Hamad medical corporation MRC: Employment, Research Funding.

Acute Effects of Blood Transfusion On Pituitary Gonadal Axis and Sperm Parameters in Young Males with Sickle Cell Disease (SCD) Pilot Study

AbstractAbstract ▪3209▪This icon denotes a clinically relevant abstract Objective:To evaluate semen parameters and measure serum follicle stimulating hormone (FSH), luteinizing hormone (LH), and testosterone (T) concentrations before and 7 days after packed red cell transfusion (PCTx) in young adults with sickle cell disease (SCD). Design:Prospective study. Setting, Patients:This study investigated 18 young adults with transfusion – dependent SCD, aged 20.7 +/− 2.88 years, with full pubertal development (Tanner’s stage 5) (euogonadal), and capacity to ejaculate. They were regularly transfused since early childhood and underwent chelation therapy using desferrioxamine which was replaced by deferasirox for the last 4–5 years. Ten were on top-up transfusion (TTx) and 8 were on exchange transfusion (ETx) regimen. At the time of the study their serum ferritin levels were 1488 +/− 557ng/ml. Basal serum concentrations of FSH, LH, T and IGF-I were evaluated before and 7 days after packed red cell transfusion (PCTx). Interventions:We studied the effect of PCTx on semen parameters and the endocrine functions in these 18 patients with SCD. Main Outcome Measures and Results:After Packed RBCs Transfusion(PCTx) significant increase of Hb from 8.5 +/− 1.17 g/dl to 10.5 +/− 0.4 g/dl was associated with increased testosterone (12.3 +/− 1.24 nmol/L to 14.23 +/− 1.22nmol/L and gonadotropins’ concentrations.Total sperm count increased significantly from 87.4 +/− 24.6 million/ml to 146.2 +/− 51.25 million/ml and total progressive sperm motility (TPM) from 40.8 +/− 11.1 million/ml to 93.4 +/− 38.3 million/ml, and rapid progressive sperm motility progressive motility (RPM) increased from 29.26 +/− 8.75 million/ml to 67.4 +/− 29 million/ml. After PCTx the total sperm count, TPM and RPM were significantly higher in the ETx group versus the TTx group.Before and after PCTx, Testosterone (T) concentrations were correlated significantly with sperm total count, volume, TPM and RPM (r = 0.53, 0.55, 0.42 and 0.38 respectively, p: 0.01). Before and after PCTx, hemoglobin (Hb) concentrations were correlated significantly with Sperm count, TPM, RPM and % of sperms with normal morphology (r= 0.60, 0.69, 0.66 and 0.86 respectively, p < 0.001). Conclusion:Our study suggests that in males with SCD blood transfusion is associated with significant acute enhancement of sperm parameters and with an increased concentration of serum testosterone, LH and FSH. Improvements of sperm parameters were significantly higher in the Exchange Transfusion group vs. the Top up Transfusion group. These “acute” effects on spermatogenesis are reached with an unknown mechanism/s and suggest a number of pathways that need further human and/or experimental studies.TableHormonal and sperm parameters in patients with SCD before and after transfusionSCD-ExchangeSCD-Top-upTSCD-Totaln = 8n = 10n = 18Age (y)20.33 +/− 2.1621 +/− 3.6720.7 +/− 2.88LH-13.83 +/− 0.754.8 +/− 0.974.4 +/− 0.94LH-25.5 +/− 0.555.9 +/− 1.175.7 +/− 0.85FSH-15.5 +/− 1.055.8 +/− 0.975.4 +/− 1.46FSH-26.67 +/− 1.757.11 +/− 0.936.6 +/− 1.8Testost-112.1 +/− 1.4512.48 +/− 1.4212.3 +/− 1.24Testost-214.2 +/− 1.1714.26 +/− 1.3214.23 +/− 1.22Hb-17.9 +/− 1.58.1 +/− 1.98.5 +/− 1.17Hb-210 +/− 1.210.9 +/− 0.210.5 +/− 0.4Ferritin2085 +/− 3751189 +/− 2251488 +/− 557Sperm Count-185.3 +/− 15.590.56 +/− 2284.4 +/− 24.6Sperm Count-2197 +/− 38.4122.7 +/− 23.5146.2 +/− 51.25Volume-1(ml)2.5 +/− 0.322.11 +/− 0.552.1 +/− 0.63Volume-2 (ml)2.83 +/− 0.42.22 +/− 0.52.35 +/− 0.7Total PM (M/ml)-144.7 +/− 7.341.8 +/− 7.740.8 +/− 11.1Total PM (M/ml)-2129.2 +/− 3775.3 +/− 19.1693.4 +/− 38.3RPM (M/ml)-132 +/− 10.127.44 +/− 7.729.26 +/− 8.75RPM (M/ml)-288.2 +/− 3153.56 +/− 18.567.4 +/− 29.1NPM(M/ml)-117.8 +/− 9.1525.3 +/− 10.821.6 +/− 10.25NPM(M/ml)-227.8 +/− 12.222.7 +/− 9.1528.5 +/− 12.7Immotile-122.8 +/− 6.723.44 +/− 9.223.2 +/− 8Immotile-240 +/− 15.924.67 +/− 7.2630.8 +/− 13.45Normal morphology-132.7 +/− 5.4331.44 +/− 5.4331.9 +/− 5.27Normal morphology-257.2 +/− 3.351.56 +/− 1.1353.8 +/− 3.57*p < 0.05 Exchange transfusion group (ETx) versus Top-up group (PCTx).#p < 0.05, after versus before PCTx.1 = before, 2 = after PCTx. Disclosures:Yassin:Hamad medical corporation MRC: Employment, Research Funding. Soliman:Hamad medical corporation MRC: Employment, Research Funding. Elawwa:Hamad medical corporation MRC: Consultancy, Research Funding.

Acute effects of blood transfusion on pituitary gonadal axis and sperm parameters in adolescents and young men with thalassemia major: a pilot study

To evaluate semen parameters and measure serum FSH, LH, T, and insulin-like growth factor (IGF) 1 concentrations before and 7 days after packed red cell transfusion (PCTx) in young adults with thalassemia major (TM). Prospective study. Tertiary care hospital. This study investigated 10 young adults with TM, aged 17-32 years, with full pubertal development (Tanner stage 5, eugonadal) and capacity to ejaculate. They had been regularly transfused since early childhood and underwent chelation therapy with the use of desferrioxamine replaced by deferasirox for the past 4-5 years. At the time of the study their serum ferritin levels ranged from 500 to 5,922 ng/mL (mean 2,686 ng/mL). Basal serum concentrations of FSH, LH, T, and IGF-1 were evaluated before and 7 days after PCTx. We studied the effect of PCTx on semen parameters and the endocrine functions in these 10 patients with TM. After PCTx, a significant increase of hemoglobin from 8.7±0.86 g/dL to 11.1±0.82 g/dL was associated with increased T (from 16.5±8 nmol/L to 20±8.8 nmol/L), IGF-1 (from 173±46 ng/mL to 214±61 ng/mL), and gonadotropin concentrations. Total sperm count increased significantly from 57.8±38.3 million/mL to 166±132 million/mL, and rapid progressive sperm motility progressive motility increased from 20.6±16.6% to 79.7±67.4%. After PCTx, LH concentrations were correlated significantly with T concentrations and sperm volume and count. The increase of IGF-1 concentration was correlated significantly with hemoglobin level after PCTx and negatively with ferritin concentration. Significant correlations were found before and after PCTx between serum T concentrations and semen parameters, including sperm count, rapid progressive motility, and the number of sperm with normal morphology, and between IGF-1 levels and seminal parameters. No correlations were found between serum FSH and IGF-1 concentrations and seminal parameters. This study suggests that in thalassemic men, blood transfusion is associated with significant acute enhancement of sperm parameters and increased concentrations of serum T, LH, FSH, and IGF-1. These "acute" effects on spermiogenesis are reached by an unknown mechanism and suggest a number of pathways that need further human and/or experimental studies.

Effects of deferasirox on renal function and renal epithelial cell death

Iron-chelating therapy results in a significant improvement in the life expectancy of patients with transfusional iron overload. However, alterations of renal function have been observed in some patients undergoing chelation therapy. In the present study we evaluated the effect of treatment with deferasirox iron chelator on the renal function in normal Wistar rats and in mouse and human cultured tubular cell lines. Results indicate that deferasirox given daily via intraperitoneal route for 7 days induced: (1) an increased urinary protein, albumin and glucose excretion, (2) tubular necrosis/apoptosis, (3) and increased tubular damage markers, in spite of normal glomerular function. Moreover, in vitro studies revealed that: (1) mouse MCT cultures resulted more susceptible to the antiproliferative/cytotoxic effect of deferasirox, mainly at 24 h after treatment, than human HK-2 cultures, (2) MCT cell content of damage molecules increased after 24 h of iron chelator treatment with slight changes in their excretion into the culture medium and (3) MCT cultures showed a significant evidence of apoptotic cell death through an increased expression and activation of caspase-3 and marked DNA fragmentation. In conclusion, this renal side effect of deferasirox-chelating therapy seems to be based on direct toxic effects of deferasirox on renal tubular cells.

Anorexia Nervosa and Mercury Toxicity

Back to table of contents Previous article Next article Letters to the EditorFull AccessAnorexia Nervosa and Mercury ToxicityDHALIWAL RAVNEET M.D.SERGIO PARADISO M.D., Ph.D.,DHALIWAL RAVNEET M.D.Search for more papers by this authorSERGIO PARADISO M.D., Ph.D.Search for more papers by this author,Published Online:1 Nov 2008https://doi.org/10.1176/appi.ajp.2008.08020233AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Neuropsychiatric symptoms as a result of mercury poisoning following the excessive consumption of large predatory fish (methyl mercury levels >1 ppm) are well documented but often misdiagnosed.Mercury toxicity secondary to the excessive consumption of tuna was observed in a 47-year-old woman with a 30-year history of anorexia nervosa. The patient’s prolonged abuse of laxatives resulted in a small bowel obstruction and rectal prolapse 7 years prior to the detection of mercury intoxication. The rectal prolapse was treated with total proctocolectomy and ileostomy. A low fiber diet was recommended thereafter, and the patient commenced a diet consisting of two cans of tuna and one muffin daily for the subsequent 7 years until she came to our unit for observation and treatment of anorexia nervosa.The patient presented with a 1-month history of depressive symptoms, refusal to eat, fatigue, weakness, anxiety, insomnia, irritability, and “confusion.” She weighed 73.7 lbs, which was approximately 53% of her ideal body weight, and was afraid that her bowels would stop working. She reported increased sensitivity to loud noise and ringing sounds in the absence of auditory stimuli. A neuropsychological assessment revealed less than normal scores for processing speed, working memory, and attention. Her premorbid IQ was estimated within the 61st percentile. Her current full-scale intelligence quotient score was within the 45th percentile, with a verbal intelligence quotient score within the 75th percentile and a performance IQ score within the 30th percentile. Her memory was stronger for verbal information (scoring in the 50th percentile) relative to nonverbal information (scoring in the 4th–10th percentile). Psychiatric examination revealed longstanding symptoms consistent with anorexia nervosa, but due to her most recent symptoms of irritability and weakness as well as her neuropsychological deficits, a mercury level evaluation was obtained.The patient’s plasma mercury levels were markedly elevated at 74 mcg/dl (normal=<10 mcg/dl) on two repeated measurements. A complete blood count, electrolytes, amylase, and lipase were all unremarkable, but liver enzymes showed slight elevation. The patient underwent chelation therapy, with succimer 10 mg/kg t.i.d. for 5 days and then 10 mg/kg b.i.d. for the following 14 days. The mercury toxicity motivated her to change her diet and broaden her food repertoire. Although her attitudes toward food with high residue did not change, the patient became afraid of eating any type of fish. More than 200 neuropsychiatric symptoms have been attributed to mercury poisoning in the medical literature (1 – 3) . Our patient’s symptoms, including low mood, irritability, insomnia, cognitive impairment, and fatigue, may have been primarily mood symptoms, a consequence of severe malnutrition, or are attributable to mercury poisoning. Interestingly, mercury poisoning as a result of dental amalgam fillings may cause an anorexic syndrome (anorexia hydrargyrum) (4) . To our knowledge, this is the first report of mercury intoxication secondary to anorexia nervosa. We are currently following our patient to monitor her psychiatric and neurological response to chelation. Longitudinal observation and treatment of malnutrition and depressive and anxiety symptoms may clarify the extent to which our patient’s symptoms were attributable to mercury intoxication. Iowa City, IowaThe authors report no competing interests.This letter (doi: 10.1176/appi.ajp.2008.08020233) was accepted for publication in March 2008.

Radiographic and MRI features of deferiprone-related arthropathy of the knees in patients with beta-thalassemia.

This study was undertaken to describe the radiographic and MRI appearances of arthropathy of the knees in 14 patients with beta-thalassemia major undergoing chelation therapy with deferiprone (L1). All available radiographs and MRI studies of the knees in 14 beta-thalassemia major patients (mean age, 16.3 years; age range, 7-33 years) undergoing chelation therapy with L1 were retrospectively assessed for changes in the synovium, cartilage, and bone. Imaging findings and signs of knee arthropathy were correlated with chelation therapy and average serum ferritin concentration. Nine (64%) of the 14 patients developed arthralgia of the knees during treatment with L1. Abnormal imaging findings were present in all symptomatic and two asymptomatic patients (12/14, 86%) and included joint effusion, subchondral bone irregularity, and patellar beaks. Additional MRI findings were thickening and enhancement of the synovium; hypointense bands in the synovium; irregularly thickened epiphyseal and articular cartilage overlying subchondral bone defects; and, on T2-weighted sequences, hyperintense articular cartilage lesions. The degree of knee symptoms at the time of imaging did not reflect the severity of cartilage and subchondral bone changes. Radiologic changes can be seen in L1-related arthropathy and should be recognized. MRI of the knees should be considered in symptomatic children and young adults with thalassemia undergoing L1 chelation therapy for iron overload.

A Review of Chronic Lead Intoxication: An Unrecognized Cause of Chronic Kidney Disease

Chronic lead nephropathy occurs as a result of years of lead exposure. This disease has been prevalent throughout human history. It is important that primary care providers and internists recognize this disorder because it can contribute to progressive loss of kidney function. Diagnosis is made by a thorough history in combination with physical examination. A history of lead intoxication often requires knowledge of the various sources of lead exposure. Laboratory tests, many previously known and some newly described, are available to further support this diagnosis. Therapy to reduce lead burden may be useful when employed early in the disease; new data sheds more light on which patients should be treated and when such patients should undergo chelation therapy. In particular, treatment with calcium EDTA chelation may benefit certain patients with chronic kidney disease by slowing the progression to end-stage renal disease.