Pituitary Iron Deposition Research Articles

MRI changes of the pituitary gland and brain in Thalassemia major: A comprehensive review of clinical implications

Introduction: Thalassemia major is a genetic disorder characterized by chronic anemia requiring frequent blood transfusions, leading to iron overload in various organs, including the pituitary gland and brain. MRI is a pivotal tool in assessing the extent of iron deposition and its clinical consequences in these patients. Objective: To summarize the MRI findings related to pituitary and brain changes in thalassemia major and to elucidate their clinical implications based on existing literature. Methods: A comprehensive review of the literature was conducted, focusing on studies that employed MRI to investigate pituitary and brain changes in patients with thalassemia major. Data extracted from these studies included the number of patients, MRI findings, and associated clinical outcomes. Results: The review included studies published between 1998 and 2022. Key findings are as follows: Pituitary Gland Changes: Multiple studies reported reduced pituitary gland volume and signal intensity, correlating with hypogonadotropic hypogonadism (HH) and delayed puberty. Specific MRI metrics such as pituitary-to-fat signal intensity ratios (SIRs) and pituitary-R2 values were elevated in patients with HH, indicating significant iron overload. Brain Changes: Increased brain T2* values indicative of iron overload was observed. Clinical Associations: The MRI findings were consistently associated with various endocrinal abnormalities, including hypogonadism, short stature, delayed puberty, and growth hormone deficiency. Severe pituitary iron deposition and volume loss were predictive of hypogonadism. Specific studies highlighted the independent progression of iron overload in different organs, emphasizing the importance of organ-specific MRI evaluation. Additional Findings: Notably, iron chelation therapy showed potential benefits in reversing some of the endocrinal and cardiac complications associated with iron overload. Discussion and Conclusions: MRI is a valuable diagnostic tool for detecting iron overload in the pituitary gland and brain in thalassemia major patients. The findings from various studies highlight significant clinical implications, including hypogonadotropic hypogonadism, delayed puberty, and growth hormone deficiency. Regular MRI assessments, along with appropriate chelation therapy, are crucial in managing and mitigating these complications. Further research is needed to establish standardized MRI protocols and improve early diagnosis and treatment outcomes in thalassemia major.

Delayed growth and puberty due to pituitary iron deposition from beta-thalassaemia major

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Assisted Reproductive Technology Required to Achieve High Conception Rates, Despite a Low Incidence of Hypogonadotrophic Hypogonadism in Thalassemia and Sickle Cell Disease Patients

BackgroundEarly and effective iron chelation has improved life expectancy and decreased disease complications for people with transfusion dependent thalassemia (TDT) and Sickle Cell Disease (SCD). Fertility challenges and pregnancy complications have historically limited reproductive options in this group, however improved disease management has made subfertility a chronic disease complication requiring attention. Despite this, there are very few reports on rates of conception and pregnancy outcomes in this population.MethodsA 20 year retrospective analysis (1997 - 2017) was performed to evaluate fertility outcomes in women with TDT and SCD at an Australian referral centre. Patients with TDT and SCD who tried to conceive during the study period were included. Use of assisted reproductive technologies (ART), as well as pregnancy outcomes and neonatal and maternal complications were assessed.ResultsEleven women with TDT and 3 with SCD tried to conceive during the study period. Median age at conception was 28 years (range 21-35). A total of 28 pregnancies and 25 live births were reported, including 2 spontaneous early pregnancy losses, a termination for anencephaly and a reduction of triplets. There was 1 multiple gestation in the cohort. At least 1 live birth occurred in 13 of the 14 women (93%). Spontaneous conception was reported in 9 women, of whom 8 had at least one resulting live birth, with a total of 15 live births from spontaneous conception. Of 5 women who were unable to conceive spontaneously, four had a diagnosis of hypogonadotrophic hypogonadism (HH) - two conceived following ovarian stimulation (OS), one required in vitro fertilization (IVF), and one did not pursue IVF following unsuccessful OS. The cause of subfertility was unknown in one patient, who conceived with IVF following failed OS. Three women who had an initial spontaneous conception required assisted reproductive technology (ART) for subsequent pregnancies, with no cause for subfertility identified.Mean ferritin at conception was 2911 mmol/L (range 164 to 8697mmol/L), and there was no association between ferritin at conception and need for ART. A trend was observed between increasing age and use of ART. Nine of the thirteen (69%) women who achieved pregnancy underwent Cesarean section for their first delivery. Prematurity (birth prior to 37 weeks' gestation) occurred in 5 (20%) of live births. Intrauterine growth restriction (IUGR) evidenced by birth weight <10 th centile for gestational age at birth was observed in 7 of 25 births (28%). This included one very low birth weight neonate delivered following induction for suspected IUGR. Respiratory distress syndrome occurred in two neonates in the setting of prematurity (delivered at 31 and 33 weeks gestation), both from women with TDT. Post partum hemorrhage (PPH) occurred after four deliveries in three women with TDT. There were no neonatal or maternal deaths.ConclusionsOur data is the first analysis of fertility and pregnancy outcomes in Australian patients with TDT or SCD. Publications in this area are limited, and primarily report on pregnancy outcomes without capturing failure to conceive. Our findings are encouraging, with high conception rates achieved, with the use of ART where needed. Ferritin level did not predict difficulty with spontaneous conception and few of the women (29%) had HH, despite many having significant hyperferritinemia. Overall, 48% of live births resulted from ART, despite 58% of these patients not having a diagnosis of HH. This indicates that pituitary iron deposition with resultant HH alone does not adequately explain subfertility in this population. Our data also highlight the importance of affordable ART access for this patient population despite the clinical gains achieved with effective chelation therapy.Pregnancies were largely uncomplicated with excellent maternal and foetal outcomes. A high rate of IUGR was observed, supporting classification of pregnancy in this population as high risk. Rates of Cesarean section for first delivery were more than double the Australian average, likely in part due to high IUGR rates. Neonatal complications and PPH occurred at general population rates. Guidelines around pregnancy management in this population abound, however large prospective studies are needed to identify those at risk of sub- and infertility, even in the era of effective chelation. DisclosuresNo relevant conflicts of interest to declare.

Is Normal Growth and Development Achieved By Current Management Approaches to Thalassemia Major in the New Era?

Introduction: Growth retardation (GR) and pubertal disturbances are the earliest consequences of iron toxicity resulting from the pituitary iron deposition in children and adolescents with thalassemia major (TM). It is suggested that adequate transfusion regimens together with appropriate management of iron chelation with timely initiation and dose tailoring by close monitoring using surrogate markers of the iron load may achieve a normal pattern of complication-free survival in TM. Objectives: The purpose of this study was to evaluate the fact that the current approach to the management of the disease has provided a normal growth progression and sexual development in patients (pts) with TM. Methods: We recruited male (M) and female (F) TM pts born after 2000 and followed-up (FU) in Ege University Thalassemia Center. The pts. with an acute or chronic illness that may interfere with growth and development or stem cell transplantation recipients were excluded. The Committee of Clinical Investigation at Ege University Hospital (19.02.2020, 20-2.1T/2) approved this study. Height (H) and weight (W) assessments were performed by using the Harpenden stadiometer and puberty was evaluated by Tanner staging at 3 monthly intervals. H-standard deviation scores (h-SDS) were calculated. Target-H based on mid-parental-H for M &amp; F pts was estimated. All pts. were evaluated annually for bone mineral density (BMD) using dual-energy X-ray absorptiometry (Hologic QDR-4500W, USA) after 8 years (y) of age. The mean SDS of the lumbar spine (L1-4) BMD between -1 and -2.5 was defined as osteopenia and &amp;lt;-2.5 as osteoporosis. Growth hormone (GH) secretion was evaluated by L-dopa and insulin tests in pts. with standing-H below the -2 SD. Pts whose GH response to both stimulation tests were less than 5 ng/ml with the monoclonal assay were considered as GH deficient. Transfused pRBC units (U) and average pre-transfusion hemoglobin (Hb) per year were recorded. Serum ferritin (SF) was monitored at monthly intervals. Myocardial (T2*) and liver (R2) iron were assessed by a 1.5 Tesla magnetic resonance imaging (MRI) machine (Siemens, Symphony Vision 16034 scanner) after 8 y. Annual median SF, prescribed chelator(s), mean chelator doses were recorded by reviewing pts' records. Transfusional iron intake (TII) was estimated as the total amount of pure RBCs (each U, 250 ml with 57% Hct) transfused in a y (ml) x 1.08. Daily TII was expressed as annual TII (mg)/ mean kg b.w./days of the y. Results: We recruited 30 TM (28 β/β, 1 β/δβ, and 1 non-deletional HbH) pts (13 F and 17 M). Demographics for the population are summarized in Table1. All pts maintained annual mean pre-transfusion Hb&amp;gt; 9 g/dl. Twenty-two of 24 pts maintained Deferasirox (DFX) chelation during 9 ± 3.6 y (median 9, range 2-13 y) and achieved optimum SF levels at all times (Figure a). The dose tailoring of DFX found parallel to the changes in TII during FU (Figure b). Liver iron concentration (LIC) and myocardial T2* (mT2*) in 22 pts on DFX chelation were between 0.9-5.4 (2.1 ± 1.3 SD) mg Fe/g d.w. and 19.4-43.5 (28 ± 6.7 SD) ms, respectively, in all assessments. The only pt with mT2* of 19.4 ms revealed mT2* of &amp;gt;20 ms on FU scans. The puberty initiated at 12.8 ± 1.1 y in M (n=12) &amp; 11.2 ± 1.3 y in F (n=12) and progressed without hormone replacement in all, regardless of the chelator. Overall, growth reduced compared to the non-thalassemic population after 8 y with clear evidence of growth catch-up by the introduction of puberty. h-SDS detected &amp;lt;-2 in 6 pts in whom one had a familial GR and 5 found GH deficient and received GH therapy. All pts but one developed h-SDS&amp;lt; -2 at 10-12 y-old when they had S1/2 puberty. The pt no 4 who was entirely unresponsive to GH stimulation tests, developed GR at 1 y-old. He remained unresponsive to GH therapy (Table 2). The 14 (%58) and 5 (21%) of 24 pts demonstrated osteopenia and osteoporosis, respectively. Improvement in BMD-SDS was observed following pubertal spurt. Conclusions: Puberty was the main determinant of growth and bone maturation in TM. Despite, puberty has achieved within physiological limits in M &amp; F pts, a slight delay was observed compared to the non-thalassemic population. The relative delay in pubertal spurt may lead to overdiagnosis of growth and bone-maturation failure and unnecessary intervention in adolescent TM pts. This hypothesis as well as the appropriateness of current management guidelines remains to be elucidated. Disclosures No relevant conflicts of interest to declare.

Pituitary Iron Deposition and Endocrine Complications in Patients with β-Thalassemia: From Childhood to Adulthood

The endocrinological complications are a great concern in transfusion-dependent β-thalassemia (β-thal) patients. The pituitary iron deposition is regarded as the main cause of hormonal changes in thalassemic patients. In this study, our aim was to explore the association between endocrinological complications and pituitary iron overload by magnetic resonance imaging (MRI). Fifty transfusion-dependent thalassemia (TDT) patients were recruited for the study. Pituitary MRIs of patients were taken using a 1.5 Tesla Philips MRI machine. There was at least one clinical endocrine complication in two of three patients. The iron accumulation was moderate in the liver (60.0%) and was mild in hypophysis (16.0%) and in heart (8.0%). The hypogonadism and diabetes mellitus (DM) were not seen with a significantly increased pituitary iron burden. The hypogonadism was related to cardiac iron deposition (p = 0.04). The short stature was associated with a hepatic iron overload (p = 0.05). The conventional follow-up of patients with TDT might be inadequate and screening of patients with MRI of hypophysis along with heart and liver leads to better results.

Insulin-like Growth Factor-1 (IGF-1): Demographic, Clinical and Laboratory Data in 120 Consecutive Adult Patients with Thalassaemia Major.

IntroductionIGF-1 deficiency in TM patients in children and adolescents has been attributed to chronic anemia and hypoxia, chronic liver disease, iron overload and other associated endocrinopathies, e.g. growth hormone deficiency (GHD). Few data are available in the literature regarding adult TM patients and growth disorders. The aim of this study was to measure IGF-1 values and other clinical data in a large number of adult patients with TM to evaluate the possible relationships between them.Patients and MethodsA cohort of 120 adult patients with TM was studied for plasma levels of IGF-1. Plasma total IGF-1 was determined by chemiluminescent immunometric assay (CLIA) method. In eleven patients (3 females) the GH response during glucagon stimulation test (GST) was also evaluated.ResultsFifty percent of patients (33 males and 27 females) had IGF-1 levels <- 2 SDs below normative values for healthy subjects matched for age and sex. In these patients endocrine complications and elevations of aminotransferases (ALT) were more common compared to TM patients with IGF1 > -2SDs. In multivariate regression analyses, height, weight, BMI, serum ferritin, ALT, HCV serology and left ventricular ejection fraction (LVEF) were not significantly related to IGF-1, but a significant correlation was found in females between HCV-RNA positivity and IGF-1, ALT and serum ferritin. AGHD was diagnosed in 6 (4 males) out of 11 patients (54.5%) who had glucagon stimulation tests and in 5 out of 8 (62.5%) with IGF-1 <-2SD. The mean age of patients with GHD was 39.3 years (range: 25–49 years, median: 39 years) versus 35.8 years (range: 27–45 years, median: 37.5 years) in non-GHD patients. A positive correlation between GH peak after GST and IGF-1 level was found (r: 0.6409; p: < 0.05).ConclusionsIn 50% of TM patients the IGF-1 levels were 2SDs below average values for healthy individuals. IGF-1 deficiency was more common in TM patients with associated endocrine complications, and a significant correlation was found in HCV-RNA positive females among IGF-1, ALT, and serum ferritin. Further data in a larger group of patients are needed to confirm whether IGF-1 level <-2 SDs may be a potential criterion for additional studies in TM patients. This datum could avoid performing GH stimulation tests in the majority of them.

Changes in Pituitary Iron, Volume, and Function Over Two Years in Pediatric Patients Treated with Deferasirox

AbstractAbstract 3206 Introduction:Pituitary iron toxicity remains a critical problem in thalassemia and other transfusional iron overload syndromes because gonadotropic iron deposition occurs early and remains clinically silent until puberty. While MRI screening of heart and liver iron have improved overall survival in these disorders, the heart develops iron overload only after prolonged, unprotected exposure to transfusional iron. We previously demonstrated that overt, clinical hypogonadism is common (83%) in patients having detectable cardiac iron, and is independently associated with pituitary iron deposition and gland shrinkage. The US29T study was an investigator-initiated, industry-sponsored prospective observational trial examining trends in pituitary iron (by MRI R2) and pituitary volume over two years in children and young adults receiving deferasirox monotherapy for iron overload. We hypothesized that deferasiroxtherapy would prevent pituitary iron accumulation and gland shrinkage over the study interval. Methods:31 chronically-transfused subjects with thalassemia major (N=28) and Blackfan-Diamond (N=3) syndrome, ages 2–25 years participated in this study. MRI assessment of pituitary R2 and volume was performed at baseline, 1 year, and 2 years; technical details are in (1) and (2).Iron chelation was prescribed by the patient's referring hematologist based upon the patients LIC, cardiac R2*, and pancreas R2* according to local clinical practice; prescribing physicians were screened to the pituitary results. Hypogonadismwas defined clinically based upon inadequate progression of secondary sex characteristics during puberty, primary or secondary amenorrhea in women, or low testosterone in men.All MRI measurements were transformed to Z-scores using age and sex matched norms from 100 nonthalassemic subjects (1). Analysis of variance was used with DunnettÕspost hoc correction. Results:26 patients completed two years. Reasons for discontinuation were a change to combination deferoxamine/deferasirox therapy (N=2), bone-marrow transplantation (N=1), loss to follow up (N=1), and inability to complete the baseline MRI examination. In the remaining patients, 10 were prepubertal, 12 had achieved normal puberty, and 4 were hypogonadalat baseline.Figure 1 summarizes the change in pituitary R2 Z-score and volumes over the study interval. Pituitary R2 Z-score was elevated at baseline (2.9 ±0.6) but remained stable over two years. Changes in pituitary R2 correlated with mean cardiac and pancreatic R2* but not LIC.Anterior and total pituitary volume were decreased at baseline (mean Z-score −1.1 and −1.4, respectively) but normalized over time; both Year 1 and Year 2 volumes were significantly improved (p<0.03) from baseline. Changes were most strongly correlated with average LIC; 24 out of 26 subjects increased their volume Z-scores over two years. [Display omitted] The single patient whose anterior pituitary shrank significantly (DZ = −0.8) during the study interval was openly noncompliant. Her liver iron rose from 10.4 mg/g to 21.4 mg/g, her cardiac R2* increased from 81 to 142 and her pituitary R2 Z-score climbed from 5.4 to 10.3 over two years. Although she had normal initiation of puberty at study entry, she developed pubertal arrest and has not begun her periods by the age of 16. The endocrine status of all of the other subjects in the study was clinically stable. Discussion:The most striking finding was the systematic restoration of pituitary volume toward the normal range, despite no net change in pituitary R2. We postulate that suppression of oxidative stress from labile plasma iron may represent the mechanism of improvement. Stabilization of pituitary R2 is also encouraging. Based upon the baseline cross-sectional relationship of R2 and age, one would have predicted a 0.4 increase in the average R2 Z-score over two years instead of the 0.1 decline observed. Deferasirox monotherapy, in clinical practice, appears to protect the pituitary gland for iron accumulation, shrinkage and dysfunction. Disclosures:Wood:Ferrokin Biosciences: Consultancy; Shire: Consultancy; Apotex: Consultancy, Honoraria; Novartis: Honoraria, Research Funding. Paley:Novartis Pharmaceuticals: Employment. Berdoukas:Apopharma: Consultancy. Coates:Novartis: Speakers Bureau; Apopharma: Consultancy.

Iron Trafficking and Distribution in Transfusional Overload: Insights From Comparing Diamond Blackfan Anemia with Sickle Cell Disease and Thalassemia

AbstractAbstract 995 Background:β-thalassemia major (TM) is the paradigm for chronic transfusional iron overload, in which the extra-hepatic organ failure is best described. In Sickle Cell Disease (SCD), these consequences appear later and at a lower frequency. In chronically transfused Diamond Blackfan Anemia (DBA), extra-hepatic iron overload, although less well documented, appears to occur early and at high frequency. A Multicenter Study of Iron Overload (MCSIO) aims to explore how key candidate factors affect iron distribution; including inflammation, ineffective erythropoiesis, level of iron overload, and hepcidin synthesis. Plasma non-transferrin bound iron (NTBI) could be a key mechanism by which iron is delivered to tissues and may determine the propensity for extra-hepatic iron distribution. Here we focus on how markers of ineffective erythropoiesis (IE) and erythron expansion impact iron distribution, with particular reference to NTBI and iron distribution determined by MRI. Methods:Iron-overloaded patients (5 TM, 5 SCD, and 5 DBA) with ferritin > 1500 g/dl or LIC > 7 mg/g dry wt, age ≥16, age 0 to 9 at initiation of transfusion and 10 to 20 years of transfusion exposure were enrolled from 3 sites in the US and Europe. 5 non-transfused healthy controls were also enrolled. A detailed medical, transfusion and chelation history were obtained with standardized MRI evaluations for hepatic, cardiac, and pituitary iron deposition. Fasting, early morning blood samples were obtained one day prior to transfusion. Chelation was held for 72 hours prior to each sample.Pre-transfusion Median ValuesTM (n=5)SCD (n=5)DBA (n=5)ControlHB (g/dl)10.909.409.2013.5Ferritin (μg/L)3,25112,0002,15032NTBI (μM)1.861.919.39−1.83EPO (mIU/ml)41.028.02,0047.0GDF15 (pgm/ml)5,504538789279solubleTfr (nmol/l)11.658.40<0.053.2CRP (mg/l)0.92.21.80.24LIC [mg/gd.w.] from R2*18.329.66.1<2.2Cardiac R2* (s-1)28.625.231.3<50Pituitary R2 (s-1)15.614.911.6<13 Results:Results are shown in the table as median values. DBA patients had the highest NTBI prior to transfusion despite having the lowest ferritin and LIC levels. GDF15 levels were highest in TM, with similar levels in SCD and DBA. EPO levels were nearly two orders of magnitude higher in DBA than TM or SCD. DBA patients also had the highest median cardiac R2*; two patients showing values above the control range. Whereas the median pituitary R2 in DBA was not above control, two of the patients had the highest R2 values, suggesting heavy iron deposition. EPO values in DBA are nearly two orders of magnitude higher that in SCD or TM despite similar pre-transfusion Hb values. GDF15 values are approximately three times controls, while soluble transferrin receptors (sTfR) values are almost undetectable. With SCD, no patients had increased cardiac iron loading, despite median SF and LIC being the highest in this group. Surprisingly all SCD patients had pituitary R2 values above the upper limit of normal. 1 TM patient had increased cardiac R2* whereas three had increased pituitary iron. In TM, NTBI was strongly correlated with GDF15 (Pearson's Rho=0.93) but in DBA, GDF15 was inversely correlated with NTBI (-.95). Conclusions:High GDF15 levels have been reported in conditions associated with IE, such as TM, but not in DBA. GDF15 reputedly suppresses hepcidin synthesis, thereby increasing iron absorption and potentially NTBI levels. The increased GDF15 in DBA, while sTfr remain less than controls, suggests that erythropoietic precursors do not reach the stage where sTfr are expressed and that this occurs at a later differentiation stage than GDF15. Increasing NTBI in TM with increasing GDF15 is consistent with IE contributing to NTBI formation, but the lack of this relationship in DBA suggest another mechanism for high NTBI. As the erythron is destroyed at a pre-hemoglobinised stage in DBA, IE would not contribute directly to NTBI formation. However, the extremely high EPO levels in DBA may inhibit hepcidin synthesis, as in other conditions, thereby increasing NTBI. This in turn may account for the extra-hepatic iron distribution demonstrated by MRI in DBA. The increased pituitary iron without cardiac loading in the heavily loaded SCD patients suggests that with prolonged exposure to heavy iron overload, the pituitary iron loading may be the first indicator of extra-hepatic deposition. Disclosures:Porter:Novartis: Consultancy, Research Funding. Walter:Novartis: Research Funding. Harmatz:Novartis: Research Funding; Ferrokin: Research Funding. Wood:Ferrokin Biosciences: Consultancy; Shire: Consultancy; Apotex: Consultancy, Honoraria; Novartis: Honoraria, Research Funding. Vichinsky:Novartis: Consultancy, Research Funding; ApoPharma: Consultancy, Research Funding; ARUP Research lab: Research Funding.

Pituitary iron and volume predict hypogonadism in transfusional iron overload

Hypogonadism is the most common morbidity in patients with transfusion-dependent anemias such as thalassemia major. We used magnetic resonance imaging (MRI) to measure pituitary R2 (iron) and volume to determine at what age these patients develop pituitary iron overload and volume loss. We recruited 56 patients (47 with thalassemia major, five with chronically transfused thalassemia intermedia and four with Blackfan-Diamond syndrome) to have pituitary MRIs to measure pituitary R2 and volume. Hypogonadism was defined clinically based on the timing of secondary sexual characteristics or the need for sex hormone replacement therapy. Patients with transfusional iron overload begin to develop pituitary iron overload in the first decade of life; however, clinically significant volume loss was not observed until the second decade of life. Severe pituitary iron deposition (Z > 5) and volume loss (Z < -2.5) were independently predictive of hypogonadism. Pituitary R2 correlated significantly with serum ferritin as well as liver, pancreatic, and cardiac iron deposition by MRI. Log pancreas R2* was the best single predictor for pituitary iron, with an area under the receiving operator characteristic curve of 0.88, but log cardiac R2* and ferritin were retained on multivariate regression with a combined r(2) of 0.71. Pituitary iron overload and volume loss were independently predictive of hypogonadism. Many patients with moderate-to-severe pituitary iron overload retained normal gland volume and function, representing a potential therapeutic window. The subset of hypogonadal patients having preserved gland volumes may also explain improvements in pituitary function observed following intensive chelation therapy.

Pituitary Iron and Volume Predicts Hypogonadal Hypogonadism in Transfusional Iron Overload

Abstract 1094 Introduction:Hypogonadotropic Hypogonadism (HH) is one of the most common morbidities in patients with transfusion-dependent anemias such as thalassemia major. Unfortunately, pituitary dysfunction is difficult to detect prior to puberty because of immaturity of the hypothalamic-pituitary-gonadal axis. We used MRI to measure pituitary R2 and volume to determine at what age these patients develop pituitary iron overload and volume loss. Additionally, we aimed to stratify the risk of clinical HH based on pituitary R2 and pituitary volume, and determine predictors of pituitary iron deposition and volume loss. Methods:We recruited 56 patients (52 with thalassemia major and 4 with Blackfan-Diamond syndrome) to have pituitary MRIs to measure pituitary R2 and volume. Diagnosis of HH was determined by either lack of secondary pubertal characteristics by age 13 for females or age 14 for males, by primary or secondary amenorrhea in females ages 16 or older, or by the need for testosterone administration in males. Patients also had pancreas R2*, heart R2*, and liver iron concentration measured by MRI. Normative pituitary R2 and volume trends were determined by a cohort of 100 control patients. Results:Patients were 20.4 ± 12.1 years old and well distributed by sex (31 males, 25 females). All subjects received blood transfusions every 2–4 weeks and were on appropriate chelation therapy as indicated by their physician. Mean pituitary R2 Z-score was 4.5 and mean anterior pituitary volume Z-score was −0.9. Figure 1 shows pituitary R2 values as a function of age, superimposed on normal trends from the control population. Patients with transfusional iron overload began to develop pituitary iron overload in the first decade of life; however, significant iron deposition were observed beginning in the second decade. Heavy pituitary iron deposition (Z-score > 5) and volume loss (Z-score < −2.5) were predictive of HH (Figure 2). Volume loss was highly specific (87%) but identified only half of HH cases. The remaining HH patients had heavy pituitary iron (Z-score > 5), but preserved pituitary volume. Pituitary R2 correlated significantly with serum ferritin as well as liver iron concentration, pancreatic R2*, and cardiac R2* by MRI. [Display omitted] [Display omitted] Discussion:Pituitary iron loading begins as early as the first decade of life in chronically transfused patients, meriting a pituitary MRI in children under 10 years old. Severe pituitary iron loading as well as volume loss throughout the second decade of life, and are predictive of HH, warranting more intensive screening in this age group. However, many patients with moderate-to-severe pituitary iron overload retained normal gland volume and function, representing a potential therapeutic window. This may also be explained by improvements in gland function observed following intensive chelation therapy. Serial tracking of pituitary iron and volume trends on age-appropriate nomograms should improve diagnostic accuracy and toxicity prophylaxis. Disclosures:Wood:Novartis: Research Funding; Ferrokin Biosciences: Consultancy; Cooleys Anemia Foundation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Changes In Pituitary Iron and Volume with Deferasirox In Transfusional Iron Overload

AbstractAbstract 5161 Introduction:The relationship between organ iron overload and clinical toxicity in chronically transfused patients is not completely understood. Given that hypogonadotropic hypogonadism (HH) is the most common endocrine problem in chronically transfused patients, it is important to qualify the effects of pituitary iron overload. MRI can image preclinical pituitary iron deposition, similar to its use in the heart, liver and pancreas. Increased pituitary R2, a surrogate for iron, and decreased pituitary volume predict clinical and biochemical HH in iron overloaded adults 1,2. However, data regarding pituitary iron deposition and its effect on pituitary growth in the pediatric population is lacking. In addition, the effect of chelation therapy on pituitary iron and volume over time is unknown. We present first year results from a two year observational trial of changes in pituitary R2 and volume in response to deferasirox therapy in patients with transfusional siderosis. Methods:We report 16 chronically-transfused patients with Thalassemia Major and one patient with Diamond Blackfan Anemia studied over a one year period. All patients were on deferasirox for at least 6 months prior to start of study; drug dosing was determined by the patient's physician and was independent of the research study. The average age at the final exam was 14.1 ± 5.2 years (range: 5.1–24.6 years). All studies were performed on a 1.5 T Philips Achieva. Anterior pituitary R2 was assessed in the sagittal and coronal planes using multiple spin echoes from 15 to 120 ms. Pituitary volume was assessed using a 3D spoiled gradient echo sequence with 1 mm3 isotropic voxels. Pituitary R2 was calculated by pixelwise monoexponential fit, with median values used to represent the overall gland R2; boundaries were confirmed by a board-certified neuroradiologist. Normative data for pituitary iron and volume was drawn from another study in 100 normal volunteers. Patient height, pituitary R2, and pituitary volume were all expressed as age corrected Z-scores. MRI estimates of hepatic iron concentration (HIC), cardiac iron (T2*), and pancreatic iron (R2*) were obtained as clinical standard of care. All statistics were performed using JMP5.1 (SAS, Cary, NC). Results:Patients were mild to moderately iron overloaded with HIC of 6.7 ± 6.9 mg/g dry weight, cardiac T2* of 31.3 ± 7.8 ms, and pancreas R2* of 117.2 ± 128.7 Hz at the beginning of the study. These results were not yet available for the one year follow up. Ferritin values were available for 16/17 of the patients at both baseline (1346.9 ± 1479.5 ng/mL) and year one visits (1102.2 ± 1074.0 ng/mL, p=0.24). Change in ferritin did not correlate with change in pituitary R2. Median sagittal measurements of pituitary R2 were 13.7 ± 1.9 Hz (baseline) and 13.4 ± 1.7 Hz (year one). An improvement was seen in average Z-score for patient height and in average Z-score for anterior pituitary volume. There was no correlation between the change in Z-score for height and the change in Z-score for pituitary volume. Figure 1 summarizes the average Z-scores for height, pituitary volume, and pituitary R2 at baseline and at year one; p-values reflect paired statistics. Discussion:The present data suggest that deferasirox monotherapy stabilizes pituitary iron levels and facilitates normal pituitary and somatic growth in children and young adults. Although reductions in pituitary R2 Z-score did not reach statistical significance, the favorable glandular and somatic growth responses suggest that deferasirox is successfully detoxifying glandular iron. Although encouraging, these data are limited by small sample size and short follow-up; two-year data will provide more robust estimates of treatment efficacy and predictors of response.

Predicting pituitary iron and endocrine dysfunction

Patients with thalassemia major (TM) require lifelong transfusion therapy to survive, leading to toxic iron overload in the endocrine glands and heart. The pituitary gland is one of the most vulnerable targets, leading to irreversible hypogonadotropic hypogonadism in approximately half of patients. Improvements in magnetic resonance imaging (MRI) technology and understanding have allowed earlier recognition of preclinical iron deposition in the heart, pancreas, and liver; prior work also supports a similar role for the pituitary. The purpose of this study is threefold, (1) to develop age-specific nomograms for pituitary iron and volume metrics; (2) to determine the prevalence, severity, and age of onset of pituitary iron deposition and volume loss in TM patients, and (3) to determine whether deferasirox monotherapy can modify the trajectory of pituitary iron accumulation and damage over a two-year period. This article outlines relevant background studies and methodological details as well as providing preliminary results from our first two aims.

Pituitary Iron and Volume in Transfusional Iron Overload.

Abstract 2017Poster Board I-1039 Introduction:Hypogonadotropic hypogonadism (HH) is the most common endocrine problem in chronically transfused patients. Unfortunately, gonadotrophe iron toxicity is not readily detectable until puberty and stimulation tests can be difficult to interpret in adolescents. MRI can image preclinical pituitary iron deposition, similar to its use in the heart, liver and pancreas. Increased pituitary R2, a surrogate for iron, and decreased pituitary volume have both been shown to predict clinical and biochemical HH in iron overloaded adults 1,2. However, data regarding pituitary iron deposition and toxicity is lacking in younger patients with iron overload. We present baseline results from a two year observational trial of changes in pituitary R2 and volume in response to deferasirox therapy in patients with transfusional siderosis. Methods:We studied 22 chronically-transfused patients with Thalassemia Major and 2 patients with Diamond Blackfan Anemia. The average age was 13.1 ± 5.2 years (range: 3.7-23.6 years). All studies were performed on a 1.5 T Philips Achieva. Anterior pituitary R2 was assessed in the sagittal and coronal planes using multiple spin echoes from 15 to 120 ms. Pituitary volume was assessed using a 3D spoiled gradient echo sequence with 1 mm3 isotropic voxels. Pituitary R2 was calculated by pixelwise monoexponential fit, with median values used to represent the overall gland R2; boundaries were confirmed by a board-certified neuroradiologist. Normative data for pituitary iron and volume was drawn from another study in 49 normal volunteers. MRI estimates of hepatic iron concentration (HIC), cardiac iron (T2*), and pancreatic iron (R2*) were obtained as clinical standard of care. All statistics were performed using JMP5.1 (SAS, Cary, NC). Results:Patients were mild to moderately iron loaded, with a HIC of 10.2 ± 12.0 mg/g dry wt (median 4.5 mg/g, nl < 1.5 mg/g), cardiac T2* of 29.4 ± 9.2 ms (median 31.5 ms, nl > 20ms), and pancreas R2* of 136 ± 156 Hz (median 73 Hz, nl < 27 Hz). Fourteen patients were below the 10th percentile for height including 7 below the 5th percentile. One patient had been diagnosed with delayed puberty and was on estrogen replacement.Pituitary R2 was elevated in 13/24 patients, beginning in the first decade of life and worsening in patients older than 13 years of age (Figure 1, left). Mean Z-score was 3.2 ± 3.7 (median 2.5, range -0.5 to12.8). Pituitary R2 was correlated with HIC (r2=0.68) and pancreatic R2* (r2=0.40), but not cardiac R2*. Area under the receiver operator characteristic curve was 0.76 for both HIC and pancreatic iron for the prediction of pituitary iron loading. Anterior pituitary volumes were low-normal in the first decade of life but were below the 1st percentile in 4/16 patients older than 13 years of age (Figure 1, right); all 4 patients with severe pituitary shrinkage had significant pituitary iron loading (Z-scores ranging from 2.8 to 12.8). The patient having documented HH had an iron Z-score of 12.8 and a volume Z-score of –5.0. Discussion:HH remains one of the most difficult endocrinopathies to recognize and prevent in transfusional siderosis. The present data demonstrate that iron accumulation occurs early in these patients and worsens dramatically in the second decade of life. Pituitary R2 was closely correlated with liver and pancreatic iron suggesting more rapid iron transport kinetics than for the heart. The low-normal pituitary volumes in childhood may reflect ethnic mismatches between the control and study populations, early iron toxicity, or hypothalamic dysfunction from increased erythropoiesis and metabolic demand. However, severe pituitary volume loss was limited to the second decade of life and associated with markedly increased pituitary iron (R2). Thus, there appears to be a broad, preclinical window to reduce pituitary toxicity. MRI screening of pituitary size and iron concentration needs to be expanded, clinically, to explore this hypothesis and hopefully prevent the significant physiological and psychological sequelae associated with hypogonadism. [Display omitted] [Display omitted] Disclosures:Coates:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Wood:Novartis: Research Funding.

Pituitary Iron and Volume in Transfusional Iron Overload: Normative Data.

Abstract 4073Poster Board III-1008 IntroductionDespite continuing advances in iron chelation therapy, endocrine dysfunction is common in chronically transfused patients with iron overload. In thalassemia major, hypogonadotropic hypogonadism (HH), impaired glucose tolerance, delayed growth, and hypothyroidism are common, but gonadotrophic function is the most vulnerable and least reversible. Unfortunately, clinical effects of gonadotrophe iron toxicity are not detectable until puberty. Provocative GnRH stimulation can be used to detect preclinical HH, but it can be difficult to interpret in adolescents. Thus, surrogates for preclinical pituitary iron deposition and damage are imperative. MRI can be used to measure pituitary iron (R2) and volume, analogous to its use for the heart, liver, and pancreas. Increased pituitary R2 and decreased pituitary volume predict clinical and biochemical HH in adults with thalassemia major 1,2. However, to apply these techniques to prepubertal patients with iron overload, it is imperative to develop age-appropriate normative data for pituitary iron and volumes. The goal of this study was to determine trends/limits of pituitary R2 and volume in normal subjects between the ages of 2 and 25 years. MethodsWe studied 49 normal volunteers between the ages of 2 and 25 years old; informed consent was obtained in all examinations. Patients as young as four years of age were studied without anesthesia by using video goggles and appropriate coaching. Seven patients were studied under general anesthesia by adding the research MRI (< 10” duration) on to a clinically indicated sedated head MRI. All studies were performed on a 1.5 T Philips Achieva. Anterior pituitary R2 was assessed in the sagittal and coronal planes using a multi-echo spin echo sequence using eight echoes from 15 to 120 ms, five mm thick slices, 1 mm2 inplane resolution, and repetition time (TR) of 500 ms. Pituitary volume was assessed using a 3D spoiled gradient echo sequence with 1 mm3 isotropic voxels, TR 7.2 ms, echo time 3.3 ms, and flip angle of eight degrees.Pituitary R2 was calculated by pixelwise fitting to a monoexponential without a background offset. Regions of interest incorporating the anterior pituitary were manually traced, with mean and median values were used to represent the overall gland R2. All contours were confirmed by a board certified neuroradiologist. Piecewise linear regression was used to describe anterior pituitary volume, while R2 values were well described by simple linear regression. All statistics were performed using JMP5.1 (SAS, Cary, NC). ResultsAnterior pituitary volume increased linearly with age (Figure 1, left) and plateaued at 18 years of age. Normalization with respect to age produced lower variability than normalization with respect to height, weight, and body surface area. No gender differences were observed. Posterior pituitary volume also increased with age but appeared larger in mid puberty than in adulthood (not shown). Sagittal and coronary pituitary R2 increased linearly (r2 = 0.10 and 0.38, p = 0.03 and < 0.001) with age throughout the study interval (Figure 1, right). Mean and median R2 values were unbiased and highly correlated (r2 = 0.93) with one another but median values were more robust to outliers. Pituitary R2 estimates in the sagittal and coronal planes were not statistically equivalent. Sagittal R2 values exhibited a bias of -3% that increased with R2 value. Limits of agreement were ± 20%. With respect to age-normalization, coronal R2 values exhibited 31% lower variability than sagittal images. DiscussionPituitary R2 values and pituitary volumes are age-dependent. Coronal R2 estimates were slightly higher and had lower variability than values calculated in the sagittal plane. This likely reflects the larger and more homogeneous sampling area in coronal pituitary views. Nomograms from these data will improve recognition of preclinical pituitary iron loading and volume-loss in iron overloaded patients. Additional subjects will be necessary to resolve peripubertal changes in posterior pituitary volume, trends in early adulthood, and gender or ethnicity differences. [Display omitted] [Display omitted] Disclosures:Coates:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Wood:Novartis: Research Funding.

Delayed Epiphyseal Closure in a Patient With β-Thalassemia Major Complicated by Hypogonadotrophic Hypogonadism

Abstract: A 25-year-old man was referred for a bone scan to assess sacral pain on a background of β-thalassemia major complicated by severe anemia. He required repeated blood transfusions resulting in iron overload, which was treated with long-term iron chelation therapy. This case illustrates the potential skeletal manifestations of thalassemia and its treatment as demonstrated on bone scintigraphy, which include alterations in skeletal development and maturation, particularly delayed epiphyseal closure as well as complications of severe osteoporosis. Although the causes are multifactorial, pituitary iron deposition complicated by hypogonadotrophic hypogonadism should be considered as these patients may benefit from hormone replacement.

T2 Relaxation Time of the Pituitary Gland in Patients with Beta-Thalassemia and its Relation to Iron Overload and Somatic and Sexual Development

Chelation therapy with deferoxamine mesylate [DFO] has revolutionized management of transfusion-dependent β-thalassaemia, but monitoring of tissue iron deposition, particularly in the endocrine glands, is still largely empirical. Clinical, haematological, and endocrinal evaluation of 54 transfusion-dependent β-thalassaemic patients and 25 age- and sex-matched controls was done. Pituitary T2 relaxation time was studied in them by Magentic Resonance Imaging [MRI] to evaluate pituitary iron overload. Thalassaemic patients had significantly lower mean stature, growth velocity, and more delayed pubertal stage. Sixty per cent of thalassaemic females had amenorrhoea, either 1ry or 2ry. Serum insulin-like growth factor 1 [IGF-1] and luteniing hormone [LH] were significant lower in thalassaemic patients compared with controls. Serum growth hormone [GH] and follicule stimulating hormone [FSH] were also lower, but the difference was not statistically significant. Pituitary T2 relaxation rate was significantly higher in patients compared with controls. Serum ferritin in thalassaemic patients showed a statistically significant positive correlation with pituitary T2 relaxation time, and a statistically significant negative correlation with serum IGF-1. It was concluded that monthly follow up of hemoglobin level and serum ferritin are vital to guide a satisfactory transfusion/chelation regimen in thalassaemic patients. However, once a diviation arises in physical/sexual development, measurement of GH, IGF1, FSH, and LH is warranted. Patients with clinical and/or laboratory evidence of pituitary dysfunction will benefit from an MRI study to assess pituitary iron deposition and provide a better guide for the intensity of chelation therapy

MRI of the liver and the pituitary gland in patients with beta-thalassemia major: does hepatic siderosis predict pituitary iron deposition?

Our objective was to study, in thalassemic patients, if hepatic siderosis evaluated by MRI could predict the pituitary iron overload. In 36 thalassemic patients (age range 6-44 years, mean age 21.7 years) the liver/fat ratio (L/F), the pituitary/fat ratio (P/F), the liver and pituitary T2 relaxation times were evaluated, by using a multiecho spin-echo sequence. Serum ferritin levels were measured and an extensive endocrine evaluation was performed. The L/F, the P/F and pituitary T2 showed a good correlation with serum ferritin ( r=-0.55, r=-0.55 and r=-0.53, respectively; p<0.01). Liver T2 did not show significant correlation with serum ferritin. The variability of L/F explained only the 10.8% of the variability of pituitary T2 and of the P/F. When ferritin was added to the model it predicted only the 26.85% and the 30.8% of the variability of pituitary T2 and of the P/F, respectively. The P/F and pituitary T2 were lower in patients with hypogonadotropic hypogonadism (group 1) compared with those without pituitary dysfunction (group 2). No significant differences of L/F were found between the two groups. Hepatic iron overload evaluated by MR is a poor predictor of pituitary siderosis. The MR studies of the pituitary gland might be necessary to evaluate the pituitary iron overload.

MRI in haemochromatosis: pituitary versus testicular iron deposition in five patients with hypogonadism

MRI in haemochromatosis: pituitary versus testicular iron deposition in five patients with hypogonadism