Anurag Lila

Clinical and genetic characterization of pituitary gigantism: an international collaborative study in 208 patients

Despite being a classical growth disorder, pituitary gigantism has not been studied previously in a standardized way. We performed a retrospective, multicenter, international study to characterize a large series of pituitary gigantism patients. We included 208 patients (163 males; 78.4%) with growth hormone excess and a current/previous abnormal growth velocity for age or final height >2 s.d. above country normal means. The median onset of rapid growth was 13 years and occurred significantly earlier in females than in males; pituitary adenomas were diagnosed earlier in females than males (15.8 vs 21.5 years respectively). Adenomas were ≥10 mm (i.e., macroadenomas) in 84%, of which extrasellar extension occurred in 77% and invasion in 54%. GH/IGF1 control was achieved in 39% during long-term follow-up. Final height was greater in younger onset patients, with larger tumors and higher GH levels. Later disease control was associated with a greater difference from mid-parental height (r=0.23, P=0.02). AIP mutations occurred in 29%; microduplication at Xq26.3 - X-linked acrogigantism (X-LAG) - occurred in two familial isolated pituitary adenoma kindreds and in ten sporadic patients. Tumor size was not different in X-LAG, AIP mutated and genetically negative patient groups. AIP-mutated and X-LAG patients were significantly younger at onset and diagnosis, but disease control was worse in genetically negative cases. Pituitary gigantism patients are characterized by male predominance and large tumors that are difficult to control. Treatment delay increases final height and symptom burden. AIP mutations and X-LAG explain many cases, but no genetic etiology is seen in >50% of cases.

Efficacy of cabergoline in uncured (persistent or recurrent) Cushing disease after pituitary surgical treatment with or without radiotherapy.

OBJECTIVE To evaluate the efficacy of cabergoline therapy in patients with Cushing disease who remained uncured (had persistent or recurrent disease) after a pituitary surgical procedure with or without radiotherapy. METHODS We undertook a prospective, open-label, single-arm study, with short-term (5 months) and longterm (1 year) evaluations. In 20 patients with uncured Cushing disease, treatment was initiated with cabergoline at a dosage of 1 mg/wk, with a monthly increment of 1 mg, until midnight serum cortisol (MNSC) or low-dose dexamethasone suppression serum cortisol (LDSC) (or both) normalized or a maximal dosage of 5 mg/wk was reached. RESULTS Overall, 5 of 18 patients (28%) responded in terms of LDSC or MNSC (or both) at a mean dosage of 3.6 mg/wk (range, 2 to 5). When the response was defined with use of either LDSC or MNSC level as an isolated criterion, it was achieved in 4 of 16 patients (25%) and 3 of 18 patients (17%), respectively. Four patients were treated for 1 year, and the response was persistent in 2 and 3 patients on the basis of MNSC and LDSC levels, respectively. Lower baseline serum cortisol (basal, MNSC, and LDSC) values were predictive of a therapeutic response. CONCLUSION Cabergoline was an effective therapy in 28%, 25%, and 17% of patients with uncured Cushing disease in terms of LDSC or MNSC (or both), LDSC alone, and MNSC alone, respectively. Further studies are needed to address the persistence of the drug response and the effects on the dynamics of the hypothalamic-pituitary-adrenal axis.

Tumor-induced osteomalacia: a single center experience.

OBJECTIVE To describe the clinical presentation, localization modalities, and management of patients with tumor-induced osteomalacia (TIO). METHODS We performed a retrospective analysis of case records of patients diagnosed with TIO between January 1996 and March 2010 at our institution in Mumbai, India. RESULTS Nine patients (6 female and 3 male) with a mean age of 37.5 ± 17.5 years with biochemical and imaging evidence of TIO were included in the study. Overall, patients presented with proximal muscle weakness and pain. Three patients had neurofibromatosis 1, one had isolated schwannoma, and one had epidermal nevus syndrome. The mean delay in diagnosis was 7.67 years. Biochemical studies revealed normal serum calcium (mean, 9.2 ± 0.8 mg/dL), low serum phosphorus (mean, 1.36 ± 0.54 mg/dL), and low maximal tubular reabsorption of phosphorus factored for glomerular filtration rate (mean, 0.94 ± 0.49 mg/dL). Fibroblast growth factor-23 was increased in 3 of the patients without neurofibromatosis but was normal or near-normal in all the patients with neurofibromas. A fludeoxyglucose F 18 positron emission tomography (FDG PET) scan helped to localize the tumors in 4 of the 5 patients with diagnoses other than neurofibromatosis. Three patients underwent surgical excision and were cured. One patient underwent biopsy and partial excision. Histopathologic findings were suggestive of phosphaturic mesenchymal tumor, benign fibrous histiocytoma, nonossifying fibroma, and sciatic nerve schwannoma. CONCLUSION There is a well-known delay in the diagnosis of TIO. FDG PET is a useful modality for localization of tumors. Preoperative localization increases the odds for cure after surgical excision.

Functional imaging in primary tumour-induced osteomalacia: relative performance of FDG PET/CT vs somatostatin receptor-based functional scans: a series of nine patients.

Localization of phosphatonin‐producing mesenchymal tumours in patients with primary tumour‐induced osteomalacia (pTIO) is challenging. Functional imaging plays an important role in the localization of these tumours.

Volume interpolated 3D‐spoiled gradient echo sequence is better than dynamic contrast spin echo sequence for MRI detection of corticotropin secreting pituitary microadenomas

Various techniques have been attempted to increase the yield of magnetic resonance imaging (MRI) for localization of pituitary microadenomas in corticotropin (ACTH)‐dependent Cushings syndrome (CS).

Clinical, biochemical and imaging characteristics of Cushing's macroadenomas and their long-term treatment outcome.

Cushings macroadenoma as a cause of Cushings disease is less common than microadenoma. The data on nature and behaviour of Cushings macroadenoma are limited to a few case series. We studied clinical, biochemical and imaging characteristics of macroadenoma and their long‐term treatment outcomes.

Peak Bone Mineral Density and Its Determinants in an Asian Indian Population

Data on peak bone mineral density (BMD) and its determinants in Asian Indians are limited. We studied the peak BMD and its determinants in Asian Indians. A total of 1137 young (age: 25--35yr) healthy volunteers of either sex (558 men and 579 women) were recruited for dietary evaluation, analyses of serum calcium, inorganic phosphorus, alkaline phosphatase, 25-hydroxyvitamin D [25(OH)D], and intact parathyroid hormone (iPTH) levels, and measurement of BMD with dual-energy X-ray absorptiometry. In men and women, peak bone mass (PBM) at the femoral neck, femoral trochanter, total femur, and lumbar spine was achieved between 25 and 30yr of age, whereas PBM at the femoral intertrochanter occurred between 30 and 35yr of age. Peak BMD was lower than that of Caucasians by 15.2--21.1% in men and 14.4--20.6% in women. On stepwise multiple regression, height and weight were the most consistent predictors of BMD at all sites in both groups. In men, 25(OH)D positively predicted BMD at the hip, whereas in women, serum iPTH negatively predicted BMD at the femoral trochanter and total femur. The study concluded that Asian Indians have significantly lower peak BMD than Caucasians and that weight and height are the most consistent predictors of BMD at all sites in both men and women.

Cushing disease in children and adolescents: twenty years' experience in a tertiary care center in India.

OBJECTIVE To analyze the clinical presentation, diagnostic evaluation, treatment modalities, and follow-up of pediatric patients with Cushing disease. METHODS In this retrospective analysis, we reviewed records of children (younger than 20 years) with Cushing disease who had undergone transsphenoidal adenomectomy in a tertiary health care center in India during the period of 1988 to 2008. Endogenous hypercortisolism was identified by a serum cortisol value ≥1.8 μg/dL during a low-dose dexamethasone suppression test (LDDST) with or without elevated midnight serum cortisol (≥3.2 μg/dL). Corticotropin dependence was defined by a basal plasma corticotropin concentration ≥5 pg/mL. Patients with normal pituitary imaging underwent bilateral inferior petrosal sinus sampling (BIPSS). Those with persistent or recurrent disease after surgery were treated with second-line interventions on a case-by-case basis. RESULTS Twenty-nine boys and 19 girls were included. Mean age was 14.85 (±2.5) years. Weight gain (98%), round facies (98%), and growth arrest (83%) were the most common manifestations. LDDST and midnight cortisol had 100% sensitivity for detecting endogenous hypercortisolism, while midnight corticotropin measurement had 100% sensitivity for defining corticotropin dependence. Magnetic resonance imaging and unstimulated BIPSS had 71% and 89% sensitivity, respectively, for diagnosing Cushing disease. Twenty-seven patients (56%) achieved remission after the first transsphenoidal operation with higher remission rates in those with microadenoma (75%). Basal serum cortisol <5 mg/dL on the fifth postoperative day predicted cure. Eight patients received postoperative radiotherapy, with 4 achieving remission. CONCLUSIONS Clinical presentation and diagnostic yield with various tests were similar to those previously reported in the literature. Remission rates were poor after first transsphenoidal operation in patients with macroadenoma and outcome was dismal with a second transsphenoidal operation. Serum cortisol concentration <5 mg/dL on the fifth postoperative day predicted cure.

The Performance and Reproducibility of Late-Night Salivary Cortisol Estimation by Enzyme Immunoassay for Screening Cushing Disease

OBJECTIVE Our study aimed to establish a local reference range for late-night salivary cortisol (LNSC) using enzyme immunoassay (EIA) and to study the intra-individual reproducibility of LNSC. METHODS Prospective study involving 30 healthy subjects (HS) with body mass index (BMI) <25 kg/m2, 37 obese/overweight subjects (OS) with BMI >25 kg/m2 and 28 patients with Cushing disease (CD). Salivary sampling was performed on 2 consecutive nights and assayed by EIA. The reference range was established using LNSC values of HS, and receiver operating characteristic (ROC) curves were used to determine diagnostic cutoffs. RESULTS The mean LNSC level of CD was significantly higher than HS and OS (CD: 16.96 ± 9.11 nmol/L, HS: 1.30 ± 0.95 nmol/L, and OS 1.21 ± 0.78 nmol/L). A cutoff of 2.92 nmol/L differentiated CD from HS with 100% sensitivity and 96.7 % specificity, and a cutoff of 5.04 nmol/L yielded a specificity of 100% with a sensitivity of 96.4% to distinguish CD from OS. There was more intra-individual variability in HS (55%) than in CD (49%) and OS (22%). There was no difference in the sensitivity and specificity derived from the ROCs using day 1 values or the higher of the 2 LNSCs. CONCLUSIONS In our cohort, we found that LNSC assayed by EIA showed good sensitivity and specificity to screen patients suspected to have CD. Although intra-individual variability was significant, it did not hamper the diagnostic performance of the test.

Ectopic ACTH-secreting syndrome: a single-center experience.

OBJECTIVE Ectopic adrenocorticotropic hormone (ACTH)-secreting syndrome (EAS) is a rare cause of ACTH-dependent endogenous hypercortisolism. The objective of this study was to analyze clinical, biochemical, and imaging characteristics; management strategies; and outcomes of EAS patients. METHOD We screened the records (1993-2012) of ACTH-dependent endogenous hypercortisolism cases managed at a tertiary care center. RESULTS Of the 218 patients, 17 were diagnosed with EAS. The median 8:00 AM serum cortisol was 36 μg/dL (11.4-82.7 μg/dL), and the median basal plasma ACTH was 156 pg/mL (53.5-468 pg/mL). Notably, ACTH levels below 100 pg/mL were found in 4 patients. Suspicious microadenoma was found on magnetic resonance imaging (MRI) of the pituitary in 5 patients, and all of them underwent transsphenoidal surgery (TSS). Inferior petrosal sinus sampling (IPSS) was performed in 8 patients, and the results were suggestive of a peripheral source in all 8. Computed tomography (CT) localized the lesion in 15/17 patients. In 2 patients with negative CTs, gallium DOTATATE positron emission tomography (PET) scans localized the lesion. Despite difficulties localizing bronchial carcinoids, the cure rate was high (72%). In contrast, thymic carcinoids were easily localized but had poor outcomes. CONCLUSION EAS cannot be ruled out on the basis of marginally elevated ACTH. In cases with an equivocal MRI pituitary finding, prior IPSS can help avoid unnecessary TSS. CT is a useful modality for localization of an ectopic source. Functional imaging may help in cases where anatomical imaging fails.