Retrospective study on long-term effects of hormone replacement therapy (HRT) and iron chelation therapy on glucose homeostasis and insulin secretion in female ß- thalassemia major (ß-TM) patients with acquired hypogonadotropic- hypogonadism (AHH).

BACKGROUND AND AIM: Hypogonadism and abnormalities of glucose homeostasis, resulting from iron-induced pituitary and pancreatic ß-cell dysfunction respectively, are the most frequently reported endocrine abnormalities in patients with ß-thalassemia major (ß-TM), also identified as transfusion-dependent thalassemia (TDT). STUDY DESIGN AND PATIENTS: The aim of the present retrospective study was to evaluate the long-term effects of hormone replacement therapy (HRT) on glucose metabolism and insulin secretion/sensitivity during 3-h oral glucose tolerance test (OGTT) in adolescent and young ß-TM women with acquired hypogonadototropic -hypogonadism (AHH).Twelve hypogonadal ß-TM females with AHH on HRT were followed for 8.26 ± 1.49 years. RESULTS: At baseline, 10 patients (83.3%) had normal OGTT, 1 patient presented with impaired glucose tolerance (IGT) and 1 patient had an isolated PG level of 165 mg/dL at 1-h during OGTT (H-NGT). At last evaluation, 7 patients (58.4 %) had normal OGTT, while 5 patients (41.6%) had abnormal OGTT. Reduced insulin sensitivity and impaired first-phase insulin secretion were also documented. Three of 4 ß-TM patients on treatment with estradiol hemihydrate MX 50 patches plus oral medroxyprogesterone acetate (MPA), associated with a very effective iron chelation therapy, maintained normal glucose tolerance from baseline to last evaluation. Significant adverse events due to HRT or additional endocrine complications were not documented in any cases during the follow-up. CONCLUSION: Deterioration of glycemia (dysglycemia) occurred in 45.4% (5/11) of thalassemic females on long-term HRT. Additional studies are needed to elucidate the validity of our preliminary observations.

Assessment of glucose homeostasis in young adult female ß-thalassemia major patients (ß-TM) with acquired hypogonadotropic hypogonadism (AHH) never treated with sex steroids compared to eugonadal ß-TM patients with spontaneous menstrual cycles.

BACKGROUND: Acquired ypogonadotropic hypogonadism (AHH) is the most prevalent endocrine complication in thalassemia major (TM). STUDY DESIGN: Considering the detrimental effect of estrogen deficiency on glucose metabolism, the ICET-A Network promoted a retrospective study on the long-term effects of estrogen deficiency on glucose homeostasis in female ß-TM patients with HH without hormonal replacement therapy (HRT). PATIENTS AND METHODS: Seventeen ß-TM patients with AHH (4 had arrested puberty; Tanners' breast stage 2-3), never treated with sex steroids, and 11 eugonadal ß-TM patients with spontaneous menstrual cycles at the time of referral were studied. A standard 3-h OGTT was performed in the morning, after an overnight fast. Six-point plasma glucose and insulin level determinations, indices of insulin secretion and sensitivity, early-phase insulin insulinogenic index (IGI), HOMA-IR and ß-cell function (HOMA-ß), oral disposition index (oDI), glucose and insulin areas under the OGTT curves were evaluated. RESULTS: Abnormal glucose tolerance (AGT) or diabetes was observed in 15 (88.2%) of 17 patients with AHH and 6 (54.5%) of 11 patients with eumenorrhea. The difference between the two groups was statistically significant (P: 0.048). However, the group of eugonadal patients was younger compared to AHH patients (26.5 ± 4.8 years vs. 32.6 ± 6.2 years ; P: 0.010). Advanced age,  severity of iron overload, splenectomy, increased ALT levels and reduced IGF-1 levels were the main clinical and laboratory risk factors for glucose dysregulation observed in ß-TM with AHH compared to eugonadal ß-TM patients with spontaneous menstrual cycles. CONCLUSION: These data further support the indication for an annual assessment of OGTT in patients with ß-TM. We believe that a registry of subjects with hypogonadism is necessary for a better understanding of the long-term consequences of this condition and  refining treatment options.

Unilateral breast enlargement in males during adolescence (10-19 years): Review of current literature and personal experience.

Idiopathic unilateral breast enlargement (UBE) in males is a, commonly overlooked, diagnosis of exclusion that requires careful history, meticulous physical examination, and pertinent laboratory studies to exclude the possible pathologic causes. The aims of the present update are to review the current literature on UBE in subjects during adolescent age (10-19 years) in 18 cases, and to report the personal experience in 13 adolescents referred to our unit during the last four decades. In total, our survey and personal experience include 31 UBE cases, 10 of whom (32.2 %) being idiopathic or familial gynecomastia (GM). In 3/31 (9.6%) UBE was due to breast sarcoma/ carcinoma; one patient (11-years old) had a 5-year history of painless lump in the right breast, which increased gradually in size followed by bloody nipple discharge. In the personal cases of 13 adolescents, a moderate to marked UBE was secondary to: treatment with androgens (2 ß-thalassemic patients with hypogonadism), high estrogen/androgen ratio in 2 Klinefelter syndrome patients, peripheral aromatization of androgens in 1 patient with non-classical 21-hydroxylase deficiency (NC-21-OH-D). One patient had subareolar hematoma due to injury. In 2 patients (15,3%) marked UBE was due to cystic lymphangioma (histologically proved). Furthermore, 5 patients were characterized as idiopathic UBE In clinical practice, the persistence of UBE for long period before diagnosis necessitates attention and further evaluation. Underlying causes should be treated, when possible, while surgery can be offered to patients with persistent or atypical signs and/or symptoms of UBE. For the optimal management of this condition, better collaboration between primary care physician and specialists is mandatory.

Longitudinal study of ICET-A on glucose tolerance, insulin sensitivity and ß-cell secretion in eleven ß-thalassemia major patients with mild iron overload.

BACKGROUND: Iron chelation therapy (ICT) is the gold standard for treating patients with iron overload, though its long-term effects are still under evaluation. According to current recommendations regarding  transfusion-dependent  (TD)  ß-thalassemia major (ß-TM) patients, their serum ferritin (SF) levels should be maintained below 1,000 ng/mL and ICT should be discontinued when the levels are <500 ng/mL in two successive tests. Alternatively, the dose of chelator could be considerably reduced to maintain a balance between iron input and output of  frequent transfusions. STUDY DESIGN: Due to the paucity of information on long-term effects of ICT  in ß-TM with low SF levels on glucose homeostasis, the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescence Medicine (ICET-A) promoted a retrospective and an ongoing prospective observational study with the primary aim to address the long-term effects of ICT on glucose tolerance and metabolism (ß-cell function and peripheral insulin sensitivity) in adult ß-TM patients with persistent SF level below 800 ng/mL. PATIENTS AND METHODS: 11 ß-TM patients (mean age: 35.5 ± 5.5 years; SF range: 345-777 ng/mL) with normal glucose tolerance test (OGTT) or abnormal glucose tolerance (AGT) for a median of 5.3(1.1-8.3) years. RESULTS: Abnormal glucose tolerance (AGT) was observed in 7 patients (63.6%) at first observation and ) persisted in 6 patients (54.5%) at last observation. None of them developed diabetes mellitus. AGT was reversed in two patients. One patient with NGT developed early glucose intolerance (1-h PG ≥155 and 2-h PG <140 mg/dL). Three out of  5 patients with isolated impaired glucose tolerance presented a variation of  ATG. Stabilization of low indices for ß-cell function and insulin sensitivity/resistance was observed. One patient developed hypogonadotrophic hypogonadism. Three out of 6 patients with SF below 500 ng/dL had hypercalciuria. CONCLUSION: Despite low SF level, the burden of endocrine complications remains a challenge in ß-TM patients. The ability to keep iron at near "normal" level with acceptable risks of toxicity remains to be established.

A Concise Review on the Frequency, Major Risk Factors and Surveillance of Hepatocellular Carcinoma (HCC) in ß-Thalassemias: Past, Present and Future Perspectives and the ICET-A Experience.

Due to the recent alarming increase in the incidence of hepatocellular carcinoma (HCC) in thalassemias, the present report reviews briefly the frequency, the major risk factors, and the surveillance of HCC in ß-thalassemias. Over the past 33 years, 153 cases of HCC were reported in patients with thalassemia, mainly in Italy and Greece. Among HCV-infected patients, additional factors promoting the development of HCC included: advanced age, male sex, chronic hepatitis B (CHB) co-infection, and iron overload. For early diagnosis of HCC, sequential ultrasound screening is recommended especially for thalassemia patients with chronic hepatitis C (CHC), which coincides with (one or more) additional risk factors for HCC. Here we report also the preliminary data from thalassemic patients, above the age of 30 years, followed in 13 ICET-A centers. The total number of enrolled patients was 1,327 (males: 624 and 703 females). The prevalence of HCC in thalassemia major patients [characterized by transfusion-dependency (TDT)] and thalassemia intermedia [characterized by nontransfusion dependency (NTDT)] was 1.66 % and 1.96 %, respectively. The lowest age at diagnosis of HCC was 36 years for TDT and 47 years for NTDT patients. We hope that this review can be used to develop more refined and prospective analyses of HCC magnitude and risk in patients with thalassemia and to define specific international guidelines to support clinicians for early diagnosis and treatment of HCC in thalassemic patients.

Thyroid Disorders in Homozygous ß-Thalassemia: Current Knowledge, Emerging Issues and Open Problems.

Changes in thyroid function and thyroid function tests occur in patients with ß-thalassemia major (TM). The frequency of hypothyroidism in TM patients ranges from 4% to 29 % in different reports. The wide variation has been attributed to several factors such as patients' genotype, age, ethnic heterogeneity, treatment protocols of transfusions and chelation, and varying compliance to treatment. Hypothyroidism is the result of primary gland failure or insufficient thyroid gland stimulation by the hypothalamus or pituitary gland. The main laboratory parameters of thyroid function are the assessments of serum thyroid-stimulating hor-mone (TSH) and serum free thyroxine (FT4). It is of primary importance to interpret these measurements within the context of the laboratory-specific normative range for each test. An elevated serum TSH level with a standard range of serum FT4 level is consistent with subclinical hypothyroidism. A low serum FT4 level with a low, or inappropriately normal, serum TSH level is consistent with secondary hypothyroidism. Doctors caring for TM patients most commonly encounter subjects with subclinical primary hypothyroidism in the second decade of life. Several aspects remain to be elucidated as the frequency of thyroid cancer and the possible existence of a relationship between thyroid dysfunction, on one hand, cardiovascular diseases, components of metabolic syndrome (insulin resistance) and hypercoagulable state, on the other hand. Further studies are needed to explain these emerging issues. Following a brief description of thyroid hormone regulation, production and actions, this article is conceptually divided into two parts; the first reports the spectrum of thyroid disease occurring in patients with TM, and the second part focuses on the emerging issues and the open problems in TM patients with thyroid disorders.

Adverse events during testosterone replacement therapy in 95 young hypogonadal thalassemic men.

BACKGROUND: Hormonal treatment of hypogonadism in thalassaemia major (TM) is a complex issue due to the co-existence of other contributing factors such as severity of iron overload, associated chronic liver disease and other endocrine complications. OBJECTIVES: Data about adverse events (AEs) of testosterone replacement therapy (TRT) in hypogonadal males with TM is scarce.We report the adverse events registered during TRT in 95 young patients with TM. RESULTS: These AEs included gynecomastia, documented in 41/95 (43.1%) TM patients of mild to moderate severity (90%). Persistent pain in the injection site and local reactions to testosterone (T) skin patch occurred in a third of patients. Priapism was reported in 2 patients on treatment with intramuscular T enanthate. In both patients, substitution with T gel was successful, and no recurrence during the following 24 months was observed. CONCLUSIONS: Clinicians should exercise caution when considering TRT for hypogonadal men with TM. (www.actabiomedica.it).

An ICET-A survey on occult and emerging endocrine complications in patients with ß-thalassemia major: Conclusions and recommendations.

In adult thalassemia major (TM) patients, a number of occult and emerging endocrine complications, such as: central hypothyroidism (CH), thyroid cancer, latent hypocortisolism, and growth hormone deficiency (GHD) have emerged and been reported. As the early detection of these complications is essential for appropriate treatment and follow-up, the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine (ICET-A) promoted a survey on these complications in adult TM patients, among physicians (pediatricians, hematologists and endocrinologists) caring for TM patients in different countries. The data reported by 15 countries are presented.The commonest endocrine complications registered in 3.114 TM adults are CH and GHD (4.6 % and 3.0 %, respectively), followed by latent hypocortisolism (1.2%). In 13 patients (0.41%) a cytological papillary or follicular thyroid carcinoma was diagnosed in 11 and 2 patients, respectively, and a lobectomy or thyroidectomy was carried out. Of 202 TM patients below the age of 18 years, the  reported endocrine complications were: GHD in 4.5%, latent hypocortisolism in 4.4% and central hypothyrodisim in 0.5%. Transition phase was an area of interest for many clinicians, especially as patients with complex chronic health conditions are responding to new treatments extending their lifespan beyond imagination.. In conclusion, our survey provides a better understanding of  physicians' current clinical practices and beliefs in the detection, prevention and treatment of some endocrine complications prevailing in adult TM patients. Regular surveillance, early diagnosis, treatment and follow-up in a multi-disciplinary specialized setting are recommended.

Noninvasive assessment and risk factors of liver fibrosis in patients with thalassemia major using shear wave elastography.

OBJECTIVES: This study aimed to estimate the prevalence of liver fibrosis and assess the risk factors for developing significant liver fibrosis in patients with Thalassemia Major (TM). METHODS: All patients with TM over the age of 10 years were included in the study. RESULTS: A total of 94 eligible patients underwent 2-D SWE. The median age was 26.7 years. The median of the average 5-year serum ferritin (5yrSF) and liver iron concentration (LIC) assessed by MRI T2* were 1326 µg/L and 6.7 mg/g dw, respectively. Hepatitis C and hepatitis B core antibodies were positive in 38% and 1% of the patients respectively. The proportion of patients with significant fibrosis was 60%. Male gender increased the risk of significant fibrosis (Odds ratio of 0.4; p = .0373). Additionally, the 5yrSF (p = .00661), the LIC (p = .0225) and the lowest LIC of the previous 5 years (p = .0211) were significant. In the multivariable logistic regression model, only 5yrSF (p = .0035) and gender (p = .00984) remained significant. CONCLUSIONS: The risk of liver fibrosis is associated with iron overload and gender in patients with TM.

Correlation of iron overload and glomerular filtration rate estimated by cystatin C in patients with ß-thalassemia major.

Historically, renal involvement has not been a commonly recognized complication in patients with ß-thalassemia major (ß-TM). Herein, we studied the impact of iron overload on glomerular filtration rate (GFR) estimated by cystatin C based GFR (Cyst C eGFR). We enrolled 149 patients with ß-TM in a cross sectional study in a single center in Oman. We investigated the correlation between measurement of serum ferritin and Cyst C eGFR. We used univariable linear regression to study the impact of serum ferritin on Cyst C eGFR and backwards stepwise regression to adjust for potential confounders. We included 78 males and 71 females with a mean age of 17.3 ± 9 years (range 2.5-38.5). Seventeen patients had diabetes mellitus. Patients were taking deferiprone (DFP) and deferoxamine (DFO) (26 patients), DFP (58 patients), deferasirox (DFX) (62 patients) and one patient was taking only DFO. There was a very weak negative linear relationship between serum ferritin and Cyst C eGFR (correlation coefficient -0.25). In the univariable analyses, serum ferritin (p = 0.004), diabetes status (p < 0.001) and chelation therapy (p < 0.001) were statistically significant. In the multivariable model, age (p = 0.033), chelation with DFX (p = 0.05) and diabetes status (p < 0.001) were statistically significant. We found a very weak inverse linear correlation between serum ferritin and Cyst C eGFR. However, when concomitant use of chelation therapy was considered, serum ferritin did not associate with glomerular function. Prospective and larger studies are needed to confirm these findings.

Multicenter validation of spin-density projection-assisted R2-MRI for the noninvasive measurement of liver iron concentration.

PURPOSE: Magnetic resonance imaging (MRI)-based techniques for assessing liver iron concentration (LIC) have been limited by single scanner calibration against biopsy. Here, the calibration of spin-density projection-assisted (SDPA) R2-MRI (FerriScan®) in iron-overloaded ß-thalassemia patients treated with the iron chelator, deferasirox, for 12 months is validated. METHODS: SDPA R2-MRI measurements and percutaneous needle liver biopsy samples were obtained from a subgroup of patients (n = 233) from the ESCALATOR trial. Five different makes and models of scanner were used in the study. RESULTS: LIC, derived from mean of MRI- and biopsy-derived values, ranged from 0.7 to 50.1 mg Fe/g dry weight. Mean fractional differences between SDPA R2-MRI- and biopsy-measured LIC were not significantly different from zero. They were also not significantly different from zero when categorized for each of the Ishak stages of fibrosis and grades of necroinflammation, for subjects aged 3 to <8 versus ≥8 years, or for each scanner model. Upper and lower 95% limits of agreement between SDPA R2-MRI and biopsy LIC measurements were 74 and -71%. CONCLUSION: The calibration curve appears independent of scanner type, patient age, stage of liver fibrosis, grade of necroinflammation, and use of deferasirox chelation therapy, confirming the clinical usefulness of SDPA R2-MRI for monitoring iron overload.

Side effects of Deferasirox Iron Chelation in Patients with Beta Thalassemia Major or Intermedia.

OBJECTIVES: Chelating agents remain the mainstay in reducing the iron burden and extending patient survival in homozygous beta-thalassemia but adverse and toxic effects may increase with the institution and long term use of this essential therapy. This study aimed to estimate the incidence of deferasirox (DFX) side effects in patients with thalassemia major or intermedia. METHODS: A retrospective study of 72 patients (mean age: 20.3±0.9 yrs; 36 male, 36 female) with thalassemia major or intermedia treated at Sultan Qaboos University Hospital, Oman, was performed to assess the incidence of side effects related to deferasirox over a mean of 16.7 month follow-up period. RESULTS: Six patients experienced rashes and 6 had gastro-intestinal upset. DFX was discontinued in 18 patients for the following reasons: persistent progressive rise(s) in serum creatinine (7 patients; 40% mean serum creatinine rise from baseline), feeling unwell (2), severe diarrhea (1), pregnancy (1), death unrelated to chelator (2) and rise in serum transaminases (2). Three patients were reverted to desferoxamine and deferiprone combination therapy as DFX was no longer biochemically effective after 18 months of therapy. There was no correlation between baseline serum ferritin and serum creatinine or a rise in serum creatinine. Cardiac MRI T2* did not change with DFX therapy. However, there was an improvement in liver MRI T2* (p=0.013). CONCLUSION: Renal side effects related to deferasirox appear to be higher than those reported in published clinical trials. Further larger studies are required to confirm these findings.

T2* MRI in regularly transfused children with thalassemia intermedia: serum ferritin does not reflect liver iron stores.

Nontransfused patients with thalassemia intermedia (TI) accumulate iron due to increased gastrointestinal absorption of iron. Recent studies using T2* MRI revealed that serum ferritin does not reflect the severity of iron overload in nontransfused TI patients. We evaluated the iron overload status in TI children on monthly transfusion. Based on serum ferritin levels, 11 such patients (mean age 13.18 ± 4.09 years), were classified into two groups, group 1 (six patients) and group 2 (five patients) with serum ferritin levels below and above 1000 ng/mL, respectively. T2* MRI assessments were done for evaluation of hepatic and cardiac iron status. Group 1 and group 2 had mean serum ferritin levels of 817.300 ± 244.690 ng/mL and 1983.80 ± 662.862 ng/mL, respectively (P = .003). T2* MRI showed comparable moderate to severe hepatic iron overload status in both. None of the patients had myocardial iron deposition. We conclude that serum ferritin does not reflect the hepatic iron overload status in our patients with TI on regular transfusion.

Achieving treatment goals of reducing or maintaining body iron burden with deferasirox in patients with ß-thalassaemia: results from the ESCALATOR study.

This analysis evaluated the effects of deferasirox on liver iron concentration in moderate and heavily iron-overloaded patients with ß-thalassaemia from the ESCALATOR trial (n = 231). Mean liver iron concentrations (LIC) decreased significantly from 21.1 ± 8.2 to 14.2 ± 12.1 mg Fe/g dry weight (dw) at 2 yr (P < 0.001) in patients with LIC ≥ 7 mg Fe/g dw at baseline; patients with LIC < 7 mg Fe/g dw maintained these levels over the treatment period. The proportion of patients with LIC < 7 mg Fe/g dw increased from 9.4% at core baseline to 39.3% by the end of year 2. The results showed that deferasirox enabled therapeutic goals to be achieved, by maintaining LIC in patients with LIC < 7 mg Fe/g dw at a mean dose of 22.4 ± 5.2 mg/kg/d and significantly reducing LIC in patients with LIC ≥ 7 mg Fe/g dw at a mean dose of 25.7 ± 4.2 mg/kg/d, along with a manageable safety profile.

Improved treatment satisfaction and convenience with deferasirox in iron-overloaded patients with beta-Thalassemia: Results from the ESCALATOR Trial.

Patient-reported outcomes of once-daily oral deferasirox (Exjade) in iron-overloaded patients with beta-thalassemia not achieving successful chelation with prior deferoxamine and/or deferiprone were investigated in a prospective, open-label, 1-year, multicenter study in the Middle East (ESCALATOR). The initial dose of deferasirox was 20 mg/kg/day, with subsequent dose adjustments. At baseline and the end of study (EOS), patients (n = 237) completed a 5-point rating scale for treatment satisfaction and convenience, and recorded time lost to treatment. At EOS, 90.7% of patients were 'satisfied'/'very satisfied' with their iron chelation therapy (ICT) versus 23.2% at baseline. 92.8% (EOS) versus 21.5% (baseline) of patients considered their therapy to be 'convenient'/'very convenient'. Time lost to therapy for daily activities was substantially reduced (3.2 +/- 8.6 [mean +/- SD; EOS] vs. 30.1 +/- 44.2 [baseline] h/month). Patients reported greater satisfaction and convenience, and lower impact on daily activities, with deferasirox than with previous ICT. This may help improve adherence to lifelong ICT in iron-overloaded beta-thalassemia patients.

Rapid iron loading in heart and liver in a patient with transfusion dependent thalassaemia after brief poor compliance with iron chelation therapy.

Iron loading in patients with transfusion dependent thalassaemia is considered to occur primarily in the liver and, once the liver becomes saturated, other organs begin loading. We report here a splenectomised male patient who was treated for hepatitis C virus infection. Prior to starting antiviral therapy, his serum ferritin was maintained below 500 ng/ml with deferiprone monotherapy; cardiac T2* by magnetic resonance imaging was 48.8ms and hepatic T2* was 19.5ms. After twelve months of antiviral treatment during which time he was very poorly compliant with his deferoxamine chelation therapy, his ferritin had risen to 3820 ng/ml and cardiac and hepatic T2* findings were 12.7 ms and 14.5 ms respectively, indicating increased iron loading in both organs, but particularly in the heart. Fifteen months after recommencing combination chelation, his ferritin was 95 ng/ml and cardiac and hepatic T2* were 27.5 and 28.4ms respectively, indicating complete clearance of iron load in both organs. This case demonstrates that iron overload can develop rapidly and in some cases there is relatively rapid iron loading in the heart as compared to the liver.

Deferasirox (Exjade) significantly improves cardiac T2* in heavily iron-overloaded patients with beta-thalassemia major.

Noninvasive measurement of tissue iron levels can be assessed using T2* magnetic resonance imaging (MRI) to identify and monitor patients with iron overload. This study monitored cardiac siderosis using T2* MRI in a cohort of 19 heavily iron-overloaded patients with beta-thalassemia major receiving iron chelation therapy with deferasirox over an 18-month period. Overall, deferasirox therapy significantly improved mean + or - standard deviation cardiac T2* from a baseline of 17.2 + or - 10.8 to 21.5 + or - 12.8 ms (+25.0%; P = 0.02). A concomitant reduction in median serum ferritin from a baseline of 5,497 to 4,235 ng/mL (-23.0%; P = 0.001), and mean liver iron concentration from 24.2 + or - 9.0 to 17.6 + or - 12.9 mg Fe/g dry weight (-27.1%; P = 0.01) was also seen. Improvements were seen in patients with various degrees of cardiac siderosis, including those patients with a baseline cardiac T2* of <10 ms, indicative of high cardiac iron burden. These findings therefore support previous observations that deferasirox is effective in the removal of myocardial iron with concomitant reduction in total body iron.