Glucose intolerance in acromegaly is driven by low insulin secretion; results from an intravenous glucose tolerance test.

PURPOSE: Insulin sensitivity (Si) and its role in glucose intolerance of acromegaly has been extensively evaluated. However, data on insulin secretion is limited. We aimed to assess stimulated insulin secretion using an intravenous glucose tolerance test (IVGTT) in active acromegaly. METHODS: We performed an IVGTT in 25 patients with active acromegaly (13 normal glucose tolerance [NGT], 6 impaired glucose tolerance [IGT] and 6 diabetes mellitus [DM]) and 23 controls (8 lean NGT, 8 obese NGT and 7 obese IGT). Serum glucose and insulin were measured at 20 time points along the test to calculate Si and acute insulin response (AIRg). Medical treatment for acromegaly or diabetes was not allowed. RESULTS: In acromegaly, patients with NGT had significantly (p for trend < 0.001) higher AIRg (3383 ± 1082 pmol*min/L) than IGT (1215 ± 1069) and DM (506 ± 600). AIRg was higher in NGT (4764 ± 1180 pmol*min/L) and IGT (3183 ± 3261) controls with obesity than NGT (p = 0.01) or IGT (p = 0.17) acromegaly. Si was not significantly lower in IGT (0.68 [0.37, 0.88] 106*L/pmol*min) and DM (0.60 [0.42, 0.84]) than in NGT (0.81 [0.58, 1.55]) patients with acromegaly. NGT (0.33 [0.30, 0.47] 106*L/pmol*min) and IGT (0.37 [0.21, 0.66]) controls with obesity had lower Si than NGT (p = 0.001) and IGT (p = 0.43) acromegaly. CONCLUSION: We demonstrated that low insulin secretion is the main driver behind glucose intolerance in acromegaly. Compared to NGT and IGT controls with obesity, patients with NGT or IGT acromegaly had higher Si. Together, these findings suggest that impaired insulin secretion might be a specific mechanism for glucose intolerance in acromegaly.

Trabecular bone score and bone mineral density in acromegalic osteopathy assessment: a cross-sectional study.

PURPOSE: The evaluation of acromegalic osteopathy is a subject of current interest as there is a lack of evidence concerning proper evaluation techniques and clear diagnostic criteria. The aim of this study was to evaluate lumbar spine trabecular bone score (TBS) and bone mineral density (BMD) in acromegaly patients compared to healthy controls. METHODS: We conducted a cross-sectional study on 43 acromegaly patients recruited between 2018 and 2020 and a healthy control group matched 1:1 for age, gender, and body mass index (BMI). All subjects underwent DXA, lumbar spine TBS, and bone turnover markers measurement. RESULTS: Acromegaly patients showed significantly decreased lumbar spine TBS (1.244 ± 0.117 vs. 1.343 ± 0.124, p < 0.001) and no difference regarding BMD compared to control patients. In the subgroup analysis, TBS was significantly lower in both males and females (1.282 ± 0.075 vs. 1.366 ± 0.113, p = 0.01 and 1.222 ± 0.132 vs. 1.329 ± 0.130, p = 0.005) and, also, in hypogonadal and eugonadal acromegaly subjects compared to their healthy controls (1.231 ± 0.130 vs. 1.306 ± 0.125, p = 0.04 and 1.280 ± 0.065 vs. 1.381 ± 0.113, p = 0.008). Femoral neck BMD was higher in acromegalic hypogonadal patients [1.027 (IQR: 0.939-1.135) vs. 0.876 (IQR: 0.737-1.014), p = 0.004]. CONCLUSION: Our study indicates that TBS, but not BMD, is significantly decreased in acromegaly patients, regardless of gender and gonadal status. This data suggests that TBS could be a valuable tool in the assessment of acromegalic osteopathy.

Clinicopathological Features of Growth Hormone-producing Pituitary Adenomas and Correlation With Preoperative Laboratory Findings.

BACKGROUND/AIM: The histopathological variability of each type of pituitary adenoma (PA) that causes growth hormone (GH) excess influences the phenotype, radiological characteristics and therapy response of acromegaly patients. We correlated the immunohistochemical (IHC) features of GH-secreting PAs with their clinical, laboratory and imaging data. PATIENTS AND METHODS: We included 32 patients with documented acromegaly; tumour specimens were histologically and IHC examined: anterior pituitary hormones, pituitary-specific transcription factor-1 (PIT-1), Ki-67 labelling index were evaluated. RESULTS: Macroadenomas represented 93.75%. Post-surgery disease control negatively correlated with the maximum initial tumour diameter (p=0.04). Ki-67 did not predict remission. No correlation was found between GH serum levels and IHC expression (p=0.45). PIT-1 was positive in all specimens, two had a weak expression. Four were considered PIT-1 positive plurihormonal adenomas and several had unusual IHC combinations. CONCLUSION: PIT-1 accurately classifies GH-secreting PAs. The IHC classification as well as radiological dimensions and extent influence disease control, probably being the best prognosis factors.

Utility of Trabecular Bone Score (TBS) in Bone Quality and Fracture Risk Assessment in Patients on Maintenance Dialysis.

Maintenance dialysis is associated with almost universal changes in bone metabolism collectively known as chronic kidney disease-mineral and bone disorder (CKD-MBD). These are accompanied in various proportions by bone loss and altered bone quality that led to an increased risk of fracture. Osteoporosis, age-related or postmenopausal, a condition that often coexists with CKD, is also a leading cause of fracture. Dual-energy X-ray densitometry (DXA) is the main tool for assessing the bone quantity and bone loss and the associated fracture risk. It has been validated in both CKD-MBD and osteoporosis. Trabecular bone score (TBS) is a DXA-derived algorithm for the evaluation of bone microarchitecture, and its clinical value has been repeatedly demonstrated in large cohorts of osteoporotic patients. However, its utility in patients on maintenance dialysis has not been conclusively shown. Published studies showed a lower TBS score and implicitly an altered bone microarchitecture in patients on maintenance dialysis, even after adjusting for various variables. Moreover, FRAX-based fracture risk is higher after adjusting for TBS, showing promise on an algorithm better estimating the clinical fracture risk in dialysis patients. However, TBS has not been demonstrated to independently predict clinical fractures in prospective studies on dialysis patients. Also, aortic calcifications and altered fluid balance could significantly affect TBS score and could hamper the widespread clinical use in patients on maintenance dialysis. In this mini-review, we focus on the benefits and pitfalls of TBS in the management of CKD-MBD and fracture risk assessment in patients on maintenance dialysis.

Seasonal periodicity of serum parathyroid hormone and its relation with vitamin D in Romania.

We measured serum parathyroid hormone in 8409 Romanian subjects and found a mild seasonal variation with highest levels in March and lowest levels in September. PTH was dependent on serum vitamin D, particularly below 12.82 ng/mL. Together, these suggest that vitamin D supplementation is warranted only in at-risk groups. PURPOSE: Seasonal variation of parathyroid hormone (PTH) and its dependency on serum 25-hydroxy vitamin D (25(OH)D) levels are well-described. However, there are few studies from Europe, and genetic, nutritional, and cultural differences are important. We describe the seasonal variation of serum PTH and its relation with serum 25(OH)D levels in Romania. METHODS: We retrieved from our endocrinology center database all PTH measurements between 2011 and 2019 together with age, sex, diagnosis, and date of blood sampling. Simultaneous serum 25(OH)D levels were partially available. Intact PTH was measured using the same electrochemiluminescence assay. RESULTS: There were 8409 subjects (median age 49 (36, 60) years; 20.5% men) without a diagnosis of hyperparathyroidism (primary or secondary to chronic kidney disease), hypoparathyroidism, or low bone mass. Serum PTH showed a mild seasonal variation with highest levels at the end of March (47.61 pg/mL) and lowest levels at the end of September (43.15 pg/mL). All sex and age subgroups showed highest levels in the spring and lowest levels in the fall. Males had significantly lower PTH levels than females irrespective of season. PTH correlated inversely with serum 25(OH)D with a breakpoint of 12.82 ng/mL in 2800 subjects who had a simultaneous measurement of 25(OH)D. Increasing age was associated with increasing PTH levels independently of serum 25(OH)D. CONCLUSIONS: We showed a mild seasonal variation of serum PTH in Romania, at an inverse sinusoidal pattern than serum 25(OH)D. The breakpoint on the PTH-25(OH)D correlation suggests that vitamin D supplementation is warranted only in at-risk groups.

Improvement of acromegaly control with multimodal therapy in Romania.

INTRODUCTION: In Romania, there is no acromegaly national register and there are no nationwide data available. However, some studies have reported the control rates in the country's main referral centres. Our aim was to assess the overall control rate in our tertiary referral centre. Also, we assessed the control rate in the last three years, and we compared the results with our previous reports. MATERIAL AND METHODS: We reviewed the charts of 186 patients with acromegaly assessed in our department between January 1st, 2012 and May 31st, 2019. We also compared the control rates for patients treated between April 1st, 2016 and May 31st, 2019 with historical controls (assessed between January 1st, 2012 and March 31st, 2016). RESULTS: Primary analysis: There were 19 untreated and 167 treated patients, mean age 52.46 years, surgery being the most commonly used treatment. The surgical cure rate was 14.8%, and disease control with medical treatment was 35.3%. Secondary analysis: In the first group there were 45 patients, surgery also being the most commonly used treatment. The surgical cure rate was 26.9%, and disease control was 30.4%. In the second group (historical controls) there were 42 patients, surgery being the most commonly used treatment. The surgical cure rate was 9.7%, and disease control with medical treatment was 15.4%. Random GH and IGF-1 after surgery were lower in the first group (p < 0.05) CONCLUSIONS: Changes in the Romanian protocol and highly specialised pituitary centres has improved the cure rate and disease control in patients with acromegaly.

Bone turnover correlates with bone quantity but not bone microarchitecture in chronic hemodialysis.

INTRODUCTION: In chronic hemodialysis, high-turnover bone disease was associated with decreased bone mineral density (BMD), poor bone quality (chemical and structural), and increased fracture risk. Our aim was to correlate bone turnover markers (BTMs) with bone microarchitecture measured by trabecular bone score (TBS) before and after correction for BMD. MATERIALS AND METHODS: We measured lumbar spine (LS), femoral neck, and 1/3 radius BMD and LS TBS by dual X-ray absorptiometry in 81 patients on permanent hemodialysis. Bone turnover was assessed using serum parathyroid hormone, osteocalcin, C-terminal crosslaps of type 1 collagen, procollagen 1 N-terminal propeptide (P1NP), and alkaline phosphatase (ALP). No patient had any partial or total parathyroidectomy and no previous or current treatment with anti-osteoporotic drugs. RESULTS: All BTMs correlated significantly with each other. Univariate regressions showed significant negative correlations between BTMs and BMD (best r = - 0.53, between P1NP and 1/3 radius Z-score) or BTMs and TBS (best r = - 0.27, p < 0.05 between ALP and TBS T-score). TBS correlated significantly with BMD at all three sites (best r = 0.5, between LS BMD and TBS T-score). Multivariate regression showed that TBS, crude or adjusted, correlated with LS BMD. No model retained any of the BTMs as independent variables due to the better prediction of BMD and multicollinearity. CONCLUSION: We showed a progressively impaired bone microarchitecture with increasing bone turnover in chronic hemodialysis. However, this correlation is no longer present when controlling for bone mass. This suggests that impaired bone microarchitecture and increased fracture risk are dependent upon factors other than high bone turnover.

Disposition Index in Active Acromegaly.

Background: The relative contribution of reduced insulin sensitivity (Si) or insulin secretion to impaired fasting glucose (IFG) or diabetes mellitus (DM) has not been clarified in active acromegaly. An intravenous glucose tolerance test (IVGTT) was never used for the calculation of Si, acute insulin response (AIRg), and disposition index (DI) in this population. Our aim was to assess Si, AIRg and DI using an IVGTT in acromegaly with normal (NGT) and abnormal glucose tolerance. Methods: We performed an IVGTT in 13 patients (8 NGT, 2 IFG, and 3 DM; 5 males, age 47.9 ± 11 years, body mass index 29.7 ± 4.1 kg/m2) with active acromegaly (insulin-like growth factor-1 4.1 ± 1.3 × upper limit of normal, basal GH 29.1 ± 25 ng/mL) and 3 healthy controls (2 males, age 39 ± 3 years, body mass index 23 ± 5 kg/m2). No patient had any growth hormone- or glucose-lowering medication. Results: NGT patients had significantly lower Si than healthy controls but higher AIRg. Hyperglycemic and normoglycemic patients had similar Si. DM patients had severely diminished AIRg (5-260 pmol × min/L) while IFG patients maintained their insulin secretion (3,862 and 912 pmol × min/L). Patients with abnormal glucose tolerance (IFG + DM) had a significantly lower DI (353 ± 350) than both NGT patients (3,685 ± 2,544) and healthy controls (5,837 ± 1,894; p < 0.01 for ANOVA). Conclusions: Disposition index suggests that although reduced insulin sensitivity is characteristic of active acromegaly it is the impaired insulin secretion that mainly drives glucose intolerance. The clinical utility of DI in predicting DM in acromegaly must be further investigated.

Cystic appearance - a new feature of solid fibrous tumours in the lacrimal gland: a case report with literature review.

BACKGROUND: Solitary fibrous tumours (SFTs) rarely occur in the orbit, especially in the lacrimal area. These tumours are mostly solid. Cystic changes have been documented, but they remain very rare. Only three cases of primary orbital solitary fibrous tumours with cystic changes have been reported in the literature, but no cases have been reported to occur in the lacrimal gland. Solitary fibrous tumours generally follow a benign course and are treated definitively with surgical excision. Data from the literature suggest that the cystic nature of SFT presents a risk of recurrence and could be a harbinger of malignancy. CASE PRESENTATION: A 42-year-old woman was admitted to the endocrinology department for right unilateral exophthalmia and epiphora in the last 8 months. An ophthalmological evaluation showed exophthalmia only in the right eye (22 mm) and normal visual acuity, visual field and extraocular movements. Investigations revealed normal thyroid function. Orbital magnetic resonance imaging detected a 4 × 2,2 × 2,7 cm septate pseudocystic mass in the right lacrimal gland. Given her lacrimal gland tumour diagnosis, the patient was submitted for neurosurgical intervention with total ablation of the tumoural mass and complete right dacryoadenectomy. Although the intraoperative extemporaneous examination results were suggestive of a haemangiopericytoma, histological and immunocytochemical examination showed an extrapleural SFT. The postoperative clinical evolution was favourable, with remission of the exophthalmia. Fifteen months after surgery, no signs of recurrence were noticed. CONCLUSIONS: We report the first case of an SFT with cystic changes in the lacrimal gland. Although the presence of cavitary lesions alone does not necessarily indicate aggressive behaviour, cystic changes pose a risk of recurrence and may suggest malignant transformation over time. As a result, our case requires long-term follow-up due to recurrence and malignant potential.

Chronic hemodialysis is associated with lower trabecular bone score, independent of bone mineral density: a case-control study.

We measured trabecular bone score (TBS) in 98 patients on permanent hemodialysis (HD) and 98 subjects with similar bone mineral density and normal kidney function. TBS was significantly lower in HD patients, indicating deteriorated bone microarchitecture, independent of bone mass. This might partially explain the increased fracture risk in HD. PURPOSE: In the general population, trabecular bone score (TBS) was shown to predict fracture independent of bone mineral density (BMD). In end-stage renal disease patients on hemodialysis (HD), the value of TBS is beyond that of BMD in currently unclear. Our aim was to assess lumbar spine (LS) TBS in HD patients compared with subjects with normal kidney function matched for age, sex, and LS BMD. METHODS: We assessed TBS and LS and femoral neck (FN) BMD in 98 patient on permanent HD (42.8% males; mean age 57.5 ± 11.3 years; dialysis vintage 5.5 ± 3.8 years) and 98 control subjects (glomerular filtration rate > 60 mL/min) using DXA. We simultaneously controlled for sex, age (± 3 years), and LS BMD (± 0.03 g/cm2). RESULTS: HD patients had significantly lower LS TBS (0.07 [95% CI 0.03-0.1]; p = 0.0004), TBS T-score (0.83 SD [95% CI 0.42-1.24]; p = 0.0001)) and TBS Z-score (0.81 SD [95% CI 0.41-1.20]; p = 0.0001) than matched controls. TBS significantly correlated with LS BMD in both HD patients (r = 0.382; p = 0.001) and controls (r = 0.36; p = 0.002). The two regression lines had similar slopes (0.3 vs. 0.28; p = 0.84) with different intercepts (0.88 vs. 0.98). TBS adjustment significantly increased the 10-year fracture risk from 3.7 to 5.3 for major osteoporotic fracture and from 0.9 to 1.5 for hip fracture. CONCLUSIONS: HD patients have lower TBS than controls matched for LS BMD, indicating altered bone microarchitecture. Also, the magnitude of TBS reduction in HD patients is constant at any LS BMD. Adjustment for TBS partially corrects the absolute 10-year fracture risk.

Seasonal variation of serum vitamin D levels in Romania.

We measured serum vitamin D in 8024 Romanian subjects and found a marked seasonal variation with highest levels in September and lowest levels in March. The seasonal variation (early autumn vs. early spring) persisted in all age and sex groups. The prevalence of vitamin D deficiency was very high. PURPOSE: Romania is located in Eastern Europe, roughly between 44°N and 48°N latitude. Seasonal variation of serum vitamin D in Romanian subjects is unknown. We assessed the seasonal variation of 25-hydroxy vitamin D [25(OH)D] in Romanian population. METHODS: We retrieved from our endocrinology center database all 25(OH)D measurements between 2012 and 2016. We also evaluated age, sex, diagnosis, and date of blood sampling. The 25(OH)D was measured by two different chemiluminescence or electrochemiluminescence assays. RESULTS: There were 8024 subjects (median age 50 (37, 62); 1429 men (17.8%)) without a diagnosis of low bone mass (osteopenia or osteoporosis). The median serum 25(OH)D was 18.6 (12.7, 25.4) ng/mL. Of the subjects, 0.73, 14.4, 55.6, and 86.1% had a serum 25(OH)D level below 4, 10, 20, and 30 ng/mL, respectively. Serum 25(OH)D showed a marked seasonal variation with highest levels in September (24.1 [18.3, 30.3] ng/mL) and lowest levels in March (13.5 [9.4, 19.6] ng/mL) (p < 0.001). The seasonal variation (early autumn vs. early spring) persisted in all age and sex groups and was maximal for 21-40 years of age (26.5 (20.8, 33.1) vs. 12.9 (9.7, 17.9) ng/mL) and minimal for >65 years of age (18.6 (13.0, 27.2) vs. 12.7 (7.8, 19.7) ng/mL). Men and women showed similar amplitude of serum 25(OH)D variation. CONCLUSION: The prevalence of vitamin D deficiency is high, particularly in the elderly. The data show a strong seasonal variation of serum 25(OH)D in all subgroups of our Romanian population with highest levels in September and lowest levels in March.

SERIAL CHANGES OF LIVER FUNCTION TESTS BEFORE AND DURING METHIMAZOLE TREATMENT IN THYROTOXIC PATIENTS.

OBJECTIVE: Overt hyperthyroidism and methimazole (MMI) treatment are frequently associated with abnormal liver function tests (LFTs). We describe the serial changes of LFTs in MMI-treated hyperthyroid patients. METHODS: We retrospectively analyzed all 77 patients presenting with newly diagnosed overt hyperthyroidism (59 Graves diseases, 11 toxic nodular goiters, 4 toxic adenomas, 3 amiodarone-induced thyrotoxicosis) between 2012 and 2014. All patients started MMI at 10 to 60 mg/day that was gradually tapered. We measured thyroid-stimulating hormone, free thyroxine, alanine aminotransferase (ALT) and aspartate aminotrasnferase (AST) at baseline and at 6 weeks, 4.5 months and 10 months after starting the MMI treatment. The concomitant medication was stable during MMI treatment. RESULTS: At baseline, 25 patients (32.5%) had abnormal LFT, of which 5 had ALT or AST levels >2× the upper limit of normal (ULN). In most patients with baseline abnormal LFT, MMI treatment resulted in a normalization of serum ALT and AST. Thirteen patients with normal baseline LFT had <2× the ULN elevations of LFT sometime during treatment. There was a case of significant hepatotoxicity. During treatment, there were no significant differences in LFT levels between patients with initially normal or abnormal LFT. In a Cox proportional hazard regression model, abnormal LFT at baseline, abnormal thyroid function at the last evaluation, and MMI dose were not predictors of abnormal LFT at the final evaluation. CONCLUSION: MMI treatment can induce insignificant LFT elevation, <2× the ULN. MMI can be safely administered in hyperthyroid patients with abnormal LFT, and normalization of increased AST and ALT levels should be anticipated. ABBREVIATIONS: ALT = alanine aminotransferase AST = aspartate aminotransferase fT4 = free thyroxine HCV = hepatitis C virus LFT = liver function test LOCF = last observation carried forward MMI = methimazole PTU = propylthiouracil TSH = thyroid-stimulating hormone ULN = upper limit of normal.