ALBERT

Description: Introduction: Hepatic iron concentration (HIC) is used as a surrogate for total iron balance to guide chelation therapy in transfusion-dependent and independent patients. Unfortunately, liver biopsy is invasive and provides only indirect information regarding other organ systems. FerriScanprovides an accurate validated measurement of liver iron concentration (LIC) through a non-invasive, using patented R2-MRI imaging technology. Aim: To determine the iron status of 11 patients with non-transfusion dependent (NT) patients with sickle cell disease (SCD). Patients and methods: FerriScan (a quick, easy and painless, with an MRI scan time of only two minutes) is used to determine LIC in eleven adults with NT-SCD. Serum ferritin, iron concentrations and hepatic enzymes (ALT and AST) concentrations and total iron binding capacity (TIBC) were measured. Results: 11 adults with NT-SCD were studied. Three had serum ferritin 〉 500 umol/L , 2 out of the three (ferritin level 1138 and 531 ug/L) had high liver iron measured by ferriScan (〉 30 mmol/kg dry tissue). One patient had high liver iron content despite a concomitant serum ferritin concentration = 237 ug/L. On the other hand a patient had serum ferritin = 1117 ug/L while his liver iron was still (27 mmol/kg dry tissue) in the normal range. Serum ferritin concentrations were correlated significantly with liver iron content measured by ferriScan (r = 0.47, p = 0.05). (fig) Three patients had elevated liver enzymes (ALT and AST). Neither serum ferritin, nor LIC was correlated significantly with hepatic function. Discussion: In this study significant number of patients with ND-SCD had high LIC and high serum ferritin and hepatic enzymes (ALT and AST). Elevated levels of LIC and ferritin impose high risk for hepatic disease and cardiac toxicity in these patients. Evidence suggests that patients with high LIC have higher risk of liver fibrosis and cirrhosis as a result of iron overload. In addition, Liver iron concentration (LIC) over 15.0 mg Fe/g dry weight is associated with increased risk of cardiac diseases. Moreover, the liver is considered the early warning system against later endocrine complications, due to iron overload. For NT-SCD, with increased LIC, effective management of liver iron concentration is critical to ensure risk of morbidity due to iron overload is minimized Summary: This is the first study that document increased iron overload in NT-SCD patients. Therefore, we recommend measuring serum ferritin and LIC in NT-SCD patients. Those with increased LIC and/or ferritin should be chelated to prevent long term complications of iron overload.Table.Ageserum FeTIBCFerritinliver ironALTASTyrumol/Lumol/Lug/Lmmol/kgU/LU/L32.323.755.7361.731.024.236.114.217.78.4405.717.716.422.3 Disclosures Nashwan: HMC MRC: Research Funding. Moustafa:HMC MRC: Research Funding. Elomry:HMC MRC: Research Funding.

Description: Abstract 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. 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.

Description: Introduction Iron deficiency is one of the most common disorders affecting humans, and iron-deficiency anemia (IDA) continues to represent a major public health problem worldwide. There are an estimated 3.5 billion iron deficient people worldwide; the vast majority in developing countries Anemia imposes a significant hypoxic environment in different organs and tissues including the testes. Men and adult male animals produce a great amount of sperm every day, indicating that spermatogenesis in the seminiferous tubules of the testis occurs under a high proliferation rate, which demands considerable oxygen consumption. However, blood vessels are located exclusively between the tubules, and oxygen reaches the lumen of the seminiferous tubules only by diffusion. The seminiferous epithelium was speculated to operate on the verge of hypoxia because the testicular PO2 is relatively low, oxygen extraction is highly related to the metabolic demands of spermatogenesis, oxygen diffusion distance is comparatively long and the testis has little capacity to increase total blood flow Aim of the study To evaluate semen parameters and to assess serum FSH, LH, Testosterone (T) concentrations before and 6-7 weeks after intravenous iron therapy (800-1200 mg elemental iron therapy - IVI) in adults with iron deficiency anemia (IDA). Patients and methods We studied 11 eugonadal adults with IDA , aged 40+/- 5 years, due to defective intake of iron. Anemia was diagnosed when haemoglobin (Hb) was equal or below 10g/dl. Serum iron, total iron binding capacity (TIBC) and ferritin concentrations confirmed the diagnosis of IDA. Basal serum concentrations of FSH, LH and T were measured.Semen parameters were evaluated before and 6-7 weeks after IVI therapy Results After IVI therapy and correction of anemia, a significant increase of Hb from 8.1 ± 1.17 g/dL to 13.1 ± 0.7 g/dL was observed and was associated with an increase of T (from 12.22 ± 1.4 nmol/L to 15.9 ± 0.96 nmol/L; p 〈 0.001), FSH (from 2.82 +/- 0.87 to 3.82 +/- 1.08 IU/L; p = 0.007) and LH (from 2.27 +/- 0.9 to 3.82 +/- 1.5 IU/L; p =0.0002). Total sperm count (TSC) increased significantly from 72 +/- 17.5 million/ml to 158 ± 49 million/mL (p 〈 0.001), sperm volume increased from 2.3 +/- 0.6 ml to 2.6 +/- 0.7 ml (p = 0.045), rapid progressive sperm motility (RPM) increased from 22+/- 9.4 to 69 ± 30 million/ml (p 〈 0.001), and sperms with normal morphology (NM) increased from 33 +/- 5 to 56 +/- 7 million/ml (p 〈 0.001). Increment in Hb concentration was correlated significantly with LH, FSH concentrations after IVI (r = 0.69 and r= 0.44 , r = 0.22 , respectively ; p〈 0.01) and T concentrations (r = 0.75, p

Description: Bone disease and short stature are frequent clinical features of patients with beta-thalassaemia major. Dysfunction of the GH-IGF-1 axis has been described in many thalassaemic children and adolescents with short stature and reduced growth velocity. Assessment of the GH-IGF-1 axis in short adults with TM after attainment of final height may be required to select those who are candidates for replacement therapy and to prevent the development of bone disease. The aim of our study was to investigate GH secretion in adult thalassaemic patients in relation to their bone mineral density (BMD) and serum ferritin concentrations. Patients and methods We performed clonidine stimulation test in 30 thalassaemic patients (18 males, 12 females) with a mean age of 31.5 +/- 7.2 years. The cut-off level for GH response was set at 7 microg/l, according to the literature. Serum ferritin, IGF-1, liver enzymes, alkaline phosphatase (ALP) and and type1 Collagen CarboxyTelopeptide (CCT1) were also determined. Results We diagnosed GH deficiency (GHD) in 12 patients (40 %) and IGF-I deficiency (IGF-I SDS 〈 -2) was diagnosed in 20 patients (67 %). Adult patients with TM had significantly decreased IGF-I concentrations and bone mineral density (BMD) at the femur neck and lumbar spine compared to normal controls. Thalassemic patients with GHD and IGF-I deficiency had significantly lower BMD T score at the lumbar spine compared to patients with normal GH and IGF-I levels. Thalassemic patients had higher serum CCT1 concentrations compared to normal controls. Peak GH levels were correlated significantly with IGF- I concentrations and IGF-I levels were correlated significantly with the height SDS (HtSDS) of thalassemic patients. Neither GH peak nor IGF-I concentrations were correlated to serum ferritin concentrations. Conclusions We conclude that GH status should be tested in adult thalassaemic patients especially those with short stature and/or decreased BMD. If the diagnosis of adult GHD is established, GH treatment may be considered for possible improvement of bone mineral density and heart function in thalassaemic patients. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 1688 Objective: The introduction of several classes of targeted therapeutics for the treatment of chronic myelogenous leukemia (CML) raises the question of whether male fertility is affected and the degree of this affection, if any, among the different generations of tyrosine kinase inhibitors. When two drugs are equally effective, the drug with less toxic effect on fertility is favorable. Our aims were to evaluate semen parameters and pituitary gonadal function before and 4 months after starting tyrosine kinase inhibitors (TKI) namely, Dasatinib, Nilotinib, and Imatinib in patients with CML. Design: Prospective study. Setting, Patients, Interventions: We studied the effect of TKIs' first generation (Imatinib) and second generation ( Dasatinib and nilotinib) on semen parameters, endocrine functions in 20 euogonadal male patients with CML, and capacity to ejaculate, aged from 35 to 51 years. They were receiving either Imatinib, Dasatinib or Nilotinib as upfront therapy. We studied gonadotrophins (LH and FSH) and testosterone (T) secretion and evaluated sperm parameters before and after four months of using these TKIs. Main Outcome Measures and Results: Four months after starting TKIs there were significant decreases in serum testosterone, LH, FSH concentrations. The total sperm count, total and rapid progressive sperm motility, and % sperms with normal morphology decreased significantly versus before treatment. (table 1). After 4 months of therapy, Dasatinib effects on sperm count (SC), volume(SV), all sperm motilities and % of sperms with normal morphology(%NM) were significantly less harmful compared to Imatinib and Nilotinib. (Table 2). Significant correlations were found between serum T concentrations and semen parameters before and after TKIs therapy including SC ( 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 % NM(r = 0.752 and r = 0.834 respectively, p 〈 0.001). After TKIs therapy, LH were correlated significantly with T concentrations ( r = 0.434, p 〈 0.001) and SV and SC (r = 0.439 and r = 0.376 respectively, p: 0.01). Conclusion: Our study suggests that in patients with CML TKIs are associated with significant decrease of sperm parameters and decreased concentrations of serum T, LH, FSH. These potentially toxic effects on spermatogenesis are less prominent in patients treated with Dasatinib compared to Imatinib and Nilotinib. The mechanisms and pathways for these effects need further human and/or experimental studies. 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.

Description: Hereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by excessive intestinal absorption of dietary iron, causing iron overload in different organs, especially the liver. Hemochromatosis may not be recognized until later in life. Patients are usually asymptomatic but may present with a variety of signs and symptoms. These include: hyper-pigmented skin, hepatomegaly, arthralgia, diabetes mellitusand/or heart failure/arrhythmia. The risk of HH related morbidity in HFE compound homozygotes patients (H63D /H63D) is considered rare, we report a male patient with H63D mutation who developed impaired glucose tolerance, and high hepatic enzymes due to significant iron accumulation in the liver as well as Parkinsonian-like syndrome due to iron deposition in the basal ganglia. A 40 year old Qatari male was referred for evaluation of a rise in hemoglobin and hematocrit values with normal MCV, total leucocyte and platelet counts. The patient was asymptomatic with normal vital signs, no depigmentation or hepato-splenomegaly. Hematologic findings included a hemoglobin concentration of Hb 16.5 g/dL, hematocrit 53%, mean corpuscular volume (MCV) 93 fL/red cell, leucocyte count of 7200/ μL and a platelet count of 199000/μL. His serum ferritin was 359 μg/l ( normal values: 〈 336 μg/l), serum iron: 37 μmol/l ( normal values

Description: Abstract 2121 Introduction: Osteoporosis is defined as a metabolic bone disease characterized by low bone mass and microarchitectural deterioration of bony tissue leading to enhanced bone fragility and a consequent increase in fracture risk. It represents the second most common cause of endocrinopathy in patients with Beta thalassmia major (BTM). Some of the drugs proved effective to reduce vertebral and non-vertebral fracture risk. Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor-κB ligand (RANKL), a member of the tumor necrosis factor receptor superfamily essential for osteoclastogenesis. However the efficacy and safety of Denosumab in BTM-induced osteoporosis has not been tested. This is the first study addressing this issue. Objective: To evaluate the efficacy and safety of anti RANK ligands on the biochemical and radiological parameters of bone mineralization in patients with BTM-induced osteoporosis. Radiological evaluation was done by DEXA scan (as per WHO criteria) and biochemical evaluation of bone turnover markers included bone specific alkaline phosphatase and type 1 collagen carboxy telopetide (T1CCT). Design: prospective study. Patients and methods: We studied 30 patients with BTM-induced osteoporosis as per WHO criteria (T score of less than −1.0 being defined as osteopenic and a T score of less than −2.5 being referred as osteoporotic). 19 males and 11 females aged between 17 and 32 years, with full pubertal development (Tanner's stage 5) at the time of the study were studied. Their serum ferritin levels ranged from 500 to 5922 ng/ml (mean= 2686 ng/ml). Every patients underwent DEXA scan as baseline and after 12 months of Denosumab therpy. All patients were evaluated biochemically by checking their serum calcium, phosphorus, bone specific alkaline phosphatase and T1CCT with the use of enzyme-linked immunosorbent assay (ELISA) (Nordic Bioscience Diagnostics A/S) at baseline 1860+/− 430 and 12 months after starting Denosumab. Fasting serum samples were collected before the injection,1 month and 6 months after the injection. Follicle stimulating hormone(FSH) 4.4+/−2.27IU/L, Luteinizing hormone (LH) 3.8+/−1.87IU/L and testosterone (T) 20+/−8.8μmol/l in males were measured at baseline and repeated every 3months. Baseline urea and electrolytes were measured at baseline including calcium and phosphorus two months. Circulating parathyroid hormone (PTH) levels were checked at baseline and then every 3months. Patients with renal impairment, hypocalcaemia or hyperparathyroidism were excluded from the study. Denosumab was administered as 60 mg subcutaneously twice yearly for a year. The mean bone mineral density T scores were −2.7 at the lumbar spine, −1.8 at the total hip, and −2.1 at the femoral neck. Main Outcome Measures and Results: Denosumab therapy for a year was associated with a significant increase in bone mineral density of 9.2% (95% CI, 8.2 to 10.1) at the lumbar spine and 6.0% (95% CI, 5.2 to 6.7) at the total hip. Denosumab treatment decreased serum TICCT levels by 56% at 1 month and normalized them in all patients at 1 year. Significant correlation were found between bone mineral density T score before and 1year after Denosumab in vertebral (r = 0.752,p 〈 0.001) and both hips (r = 0.758 respectively p 〈 0.001). The most common side effects were pain in the extremities (12%) and nausea (10%) of patients. Hypocalcemia was not reported in any patient. Conclusion: Denosumab therapy for BTM induced osteoporosis significantly decrease bone resorption and increased bone mineral density through inhibition of RANKL and is associated with a rapid and sustained reduction in bone turnover markers, a continuous marked increase in bone mineral density at vertebral and hips of patients with BTM. However further studies are required to confirm long-term effects of this therapy. Disclosures: Yassin: Hamad medical corporation: Employment, Research Funding. Off Label Use: the study about effects of denosumab antirank ligands in patients with Beta thalassemia major induced osteoporosis which is off label indication. Soliman:Hamad medical corporation: Employment, Research Funding. Osman:Hamad Medical Corporation: Employment. Elawwa:Hamad medical corporation: Employment, Research Funding.

Description: Abstract 3209 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. 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.

Description: Background; Transfusion-dependent β-thalassemia (TDT) is a severe form of congenital anemia. Regular blood transfusion and continual administration of iron-chelators are conventional therapeutic strategies in TDT. Despite progressive advancements in developing various iron scavenging drugs, iron overload is still considered a challenging conundrum in these patients. Multiple organ dysfunctions result from the toxic effect of excess iron deposition in parenchymal tissues that cause high morbidity and mortality among TDT patients. The greatest affected tissues include endocrine glands, liver, heart, and kidneys. Aim of the study: To investigate pulmonary function of patients with TDT in relation to their iron overload. Patients and Methods: Pulmonary function tests were done for 10 Patient with TDT (table 1) in a well-equipped lung function unit in a tertiary care hospital by experienced respiratory technicians. An ideal test session was taken up following ATS/ERS recommendations. A proper grading system including acceptability and repeatability criteria was applied. Measurement of DLCO is done with a technique of single breath carbon monoxide (CO) uptake in the lung and lung volume is measured with gas dilution and body plethysmography. Chest x ray (CXR) was obtained in all patients. Pulmonary function test was classified according to the following categories based on ATS/ERS criteria and American medical association criteria (AMA); Normal: FEV1/FVC more than 70% FEV1, FVC, TLC, RV and DLCO normal (at least 80% predicted)Obstructive: FEV1/FVC less than 70% FEV1 and FVC (less than 80% predicted). TLC and RV either normal or elevated (at least 120% predicted). DLCO normal (at least 80% predicted)Restrictive: FEV1/FVC ratio (more than 70%) (1) FEV1, FVC, and TLC decreased (no more than 80% predicted) and a decrease in DLCO (no more than 80% predicted) or (2) TLC and RV decreased (no more than 80% predicted) with normal DLCO, FEV1, FVC, and FEV1/FVC, suggestive of low lung volumes, or (3) reduced TLC and DLCO.Mixed obstructive and restrictive: FEV1/FVC ratio reduced, suggestive of obstructive disease. TLC and RV reduced, suggestive of restrictive disease. DLCO normalIsolated low DLCO: DLCO decreased with normal FEV1, FVC, FEV1/FVC, TLC, and RV (As per AMA DLCO less than 75% were considered abnormal) Results: In our 10 TDT patients 9 had normal CXR. One patient had minimal patchy ground glass opacity. Six patients (60%) had abnormally low DLCO indicating some impairment at the level of alveolar capillary membrane. None of them had obstructive pattern. However 2 patients had some air trapping. DLCO, DLCO/Hb, DLCO/VA and RV were correlated negatively with LIC (fig 1) . PFTs (DLCO, RV, and TLC) were correlated negatively with the LIC. In addition, FEV1 and FVC were correlated negatively with ferritin level (r = -0.7 and -0.77 respectively, p

Description: Patients with thalassemia major(TM ), especially those with inadequate iron chelation, have high prevalence of endocrinopathies. Several studies reported a significant prevalence of subclinical “biochemical” adrenal insufficiency, ranging from 18–45%, in patients with thalassemia. This variability may be due to the different severity of TM, iron overload status, the test used for assessing adrenal function, and the cutoff value used to define subnormal cortisol response. The low dose (LD) 1-microg (ug) ACTH test follows the insulin tolerance test (ITT) has been shown to be more closely and more sensitive than the standard ACTH test in detecting more subtle insufficiency of the hypothalamic-pituitary-adrenal axis. Therefore the 1 ug ACTH test may be more appropriate for screening for secondary AI in TM patients. Measurements of serum dehydroepiandrosterone sulfate (DHEA-S) levels during LD simulation provide additional valuable information that improves the diagnostic accuracy of LDC in patients suspected to have central adrenal insufficiency (AI). The aim of this study was to compare cortisol and DHEA-S responses to LD and SD ACTH tests in patients with TM. Patients and Methods This cross-sectional controlled study was conducted at the Departments of Pediatrics and Hematology, Hamad Medical Center (HMC). 10 children and 13 adolescents (age 8 to 26 years ) were randomly recruited. They had been receiving blood transfusion at a regular basis every 4 wk. Iron chelation therapy was suboptimal in most of them. Patients were excluded if they had any other endocrine or systemic disease or drugs known to affect adrenal functions. 13 healthy children and adolescents with normal variant short stature served as controls. Serum cortisol and DHEA-S concentrations were determined in each subject before blood transfusion both in basal condition and after low dose (LD) (1 microgram) followed by standard dose (SD) (250 micrograms) respectively) with synthetic corticotrophin beta 1-24 ACTH (Synacthen Ciba). Normal controls were a group of 13 age and sex matched normal subjects. Results Using a peak total cortisol cutoff level of 550 nmol/L and increments of 200 ug above basal cortisol, AI was demonstrated in 8 patients after the LD ACTH and in 2 patients after SD ACTH test and in none of the controls. Using a peak total cortisol cutoff level of 420 nmol/L and increments of 200 ug above basal cortisol, AI was demonstrated in 5 patients after the LD ACTH and in 2 patients after SD ACTH test but none of controls. All patients with biochemical AI were asymptomatic with normal serum Na and K concentrations and no history suggestive of adrenal pathology. The peak cortisol concentrations in thalassemic patients with impaired adrenal function both after 1ug and 250 ug cosyntropin, ( 294 +/- 51 nmol/L and 307 +/- 58.6) were significantly lower than those with patients with normal ( 454 +/- 79.7 nmol/L and 546.1 +/- 92.2 nmol/L respectively) and controls (460.2 +/- 133.4 nmol/L and 554.3 +/- 165.8 nmol/L respectively). Adolescents but not children with TM had significantly lower peak cortisol concentration after SD cosyntropin test versus controls. Peak cortisol response to LD cosyntropin test was correlated significantly with peak cortisol response to SD in all patients (r = 0.83, p 〈 0.0001). In adolescents with thalassemia DHEA-S levels before and after LD ACTH stimulation were significantly lower and the cortisol/DHEA-S ratios significantly higher than controls. In conclusion, the use of LD ACTH test diagnoses more adrenal abnormalities versus SD ACTH in thalassemic patients. The relatively high prevalence of AI in thalassemic adolescents necessitates that these patients have to be investigated for AI before major surgery and those with impaired cortisol secretion should receive stress doses of corticosteroids during the stressful event. Disclosures: No relevant conflicts of interest to declare.