Osilodrostat treatment in patients with Cushing's disease of Asian or non-Asian origin: a pooled analysis of two Phase III randomized trials (LINC 3 and LINC 4).

Cushing's disease is associated with increased morbidity and mortality. Osilodrostat, a potent oral 11ß-hydroxylase inhibitor, provided rapid, sustained mean urinary free cortisol (mUFC) normalization in Cushing's disease patients in two Phase III studies (LINC 3, NCT02180217; LINC 4, NCT02697734). Here, we evaluate the efficacy and safety of osilodrostat in Cushing's disease in patients of Asian origin compared with patients of non-Asian origin. Pooled data from LINC 3 and LINC 4 were analyzed. Outcomes were evaluated separately for Asian and non-Asian patients. For the analysis, 210 patients were included; 56 (27%) were of Asian origin. Median (minimum-maximum) osilodrostat dose was 3.8 (1-25) and 7.3 (1-47) mg/day in Asian and non-Asian patients, respectively. mUFC control was achieved at weeks 48 and 72 in 64.3% and 68.1% of Asian and 68.2% and 75.8% of non-Asian patients. Improvements in cardiovascular and metabolic-related parameters, physical manifestations of hypercortisolism, and quality of life were similar in both groups. Most common adverse events (AEs) were adrenal insufficiency (44.6%) in Asian and nausea (45.5%) in non-Asian patients. AEs related to hypocortisolism and pituitary tumor enlargement occurred in more Asian (58.9% and 21.4%) than non-Asian patients (40.3% and 9.1%). Of Asian and non-Asian patients, 23.2% and 13.6%, respectively, discontinued because of AEs. Asian patients with Cushing's disease generally required numerically lower osilodrostat doses than non-Asian patients to achieve beneficial effects. Hypocortisolism-related AEs were reported in more Asian than non-Asian patients. Together, these findings suggest that Asian patients are more sensitive to osilodrostat than non-Asian patients.

A giant invasive macroprolactinoma with recurrent nasal bleeding as the first clinical presentation: case report and review of literature.

BACKGROUND: Giant prolactinoma (> 4 cm in dimension) is a rare disorder. Invasive macroprolactinoma has the potential to cause base of skull erosion and extend into the nasal cavity or even the sphenoid sinus. Nasal bleeding caused by intranasal tumor extension is a rare complication associated with invasive giant prolactinoma. We report a case of giant invasive macroprolactinoma with repeated nasal bleeding as the initial symptom. CASE PRESENTATION: A 24-year-old man with an invasive giant prolactinoma in the nasal cavity and sellar region who presented with nasal bleeding as the initial symptom, misdiagnosed as olfactory neuroblastoma. However, markedly elevated serum prolactin levels (4700 ng/mL), and a 7.8-cm invasive sellar mass confirmed the diagnosis of invasive giant prolactinoma. He was treated with oral bromocriptine. Serum prolactin was reduced to near normal after 6 months of treatment. Follow-up magnetic resonance imaging showed that the sellar lesion had disappeared completely and the skull base lesions were reduced. CONCLUSION: This case is notable in demonstrating the aggressive nature of untreated invasive giant prolactinomas which can cause a diagnostic difficulty with potential serious consequences. Early detection of hormonal levels can avoid unnecessary nasal biopsy. Early identification of pituitary adenoma with nasal bleeding as the first symptom is particularly important.

Acromegaly and non-parathyroid hormone-dependent hypercalcemia: a case report and literature review.

BACKGROUND: Hypercalcemia associated with acromegaly is mostly parathyroid hormone (PTH)-dependent, being caused by parathyroid hyperplasia or adenoma, which are common in individuals with multiple endocrine adenomatosis-1 (MEN-1). The rare occurrence of non-PTH-dependent hypercalcemia associated with acromegaly is attributable to complex factors involving increased intestinal calcium absorption, enhanced bone calcium release, and reduced urinary calcium elimination. Although patients with acromegaly often have mild hyperphosphatemia and hypercalciuria, clinically significant hypercalcemia is extremely rare. CASE PRESENTATION: Here we present a case of non-PTH-dependent hypercalcemia associated with a growth hormone- (GH) and prolactin- (PRL) co-secreting pituitary macroadenoma. A 37-year-old Chinese man presented with a 6-year history of increasing ring and shoe sizes and was referred to the West China Hospital of Sichuan University for treatment of acromegaly. Pituitary magnetic resonance imaging (MRI) showed a 2.0 × 1.7 × 1.9 cm macroadenoma. Laboratory examinations revealed high serum concentrations of GH and PRL with mild hypercalcemia, hyperphosphatemia, hypercalciuria, inhibited PTH concentration, and increased bone turnover markers. Administration of cabergoline together with somatostatin resulted in sharp decreases in his GH, PRL, and serum and urinary calcium concentrations. These values were further reduced 5 months later and his PTH and bone turnover markers gradually returned to within the normal range. CONCLUSIONS: Mild hyperphosphatemia and hypercalciuria are common in individuals with acromegaly and deserve attention because they may contribute to osteoporosis and urolithiasis. However, overt hypercalcemia is rare in such individuals. It is usually attributable to a coexisting parathyroid hyperplasia or adenoma, rarely being non-PTH-dependent. In such cases, the hypercalcemia is attributable to excessive PRL and hypogonadism and reverses with remission of acromegaly.

Managing pasireotide-associated hyperglycemia: a randomized, open-label, Phase IV study.

PURPOSE: Pasireotide is an effective treatment for acromegaly and Cushing's disease, although treatment-emergent hyperglycemia can occur. The objective of this study was to assess incretin-based therapy versus insulin for managing pasireotide-associated hyperglycemia uncontrolled by metformin/other permitted oral antidiabetic drugs. METHODS: Multicenter, randomized, open-label, Phase IV study comprising a core phase (≤ 16-week pre-randomization period followed by 16-week randomized treatment period) and optional extension (ClinicalTrials.gov ID: NCT02060383). Adults with acromegaly (n = 190) or Cushing's disease (n = 59) received long-acting (starting 40 mg IM/28 days) or subcutaneous pasireotide (starting 600 µg bid), respectively. Patients with increased fasting plasma glucose (≥ 126 mg/dL on three consecutive days) during the 16-week pre-randomization period despite metformin/other oral antidiabetic drugs were randomized 1:1 to open-label incretin-based therapy (sitagliptin followed by liraglutide) or insulin for another 16 weeks. The primary objective was to evaluate the difference in mean change in HbA1c from randomization to end of core phase between incretin-based therapy and insulin treatment arms. RESULTS: Eighty-one (32.5%) patients were randomized to incretin-based therapy (n = 38 received sitagliptin, n = 28 subsequently switched to liraglutide; n = 12 received insulin as rescue therapy) or insulin (n = 43). Adjusted mean change in HbA1c between treatment arms was - 0.28% (95% CI - 0.63, 0.08) in favor of incretin-based therapy. The most common AE other than hyperglycemia was diarrhea (incretin-based therapy, 28.9%; insulin, 30.2%). Forty-six (18.5%) patients were managed on metformin (n = 43)/other OAD (n = 3), 103 (41.4%) patients did not require any oral antidiabetic drugs and 19 patients (7.6%) were receiving insulin at baseline and were not randomized. CONCLUSION: Many patients receiving pasireotide do not develop hyperglycemia requiring oral antidiabetic drugs. Metformin is an effective initial treatment, followed by incretin-based therapy if needed. ClinicalTrials.gov ID: NCT02060383.

Computed tomography combined with confirmatory tests for the diagnosis of aldosterone-producing adenoma.

Primary aldosteronism (PA) is the most common cause of secondary hypertension, and a simpler non-invasive method for identification of aldosterone-producing adenoma (APA) is required to improve the standard of medical treatment for PA patients. We retrospectively analyzed the clinical data of hypertensive patients with an aldosterone/renin ratio (ARR) ≥30 (ng/dL)/(ng/mL/h), and surgical and/or adrenal venous sampling (AVS) results served as the gold standard for APA diagnosis. The study aimed to determine whether positive CCT and SIT results plus a unilateral adrenal nodule found by CT allow unambiguous identification of an APA with high diagnostic specificity. Clinical data from 71 APA and 47 non-APA patients were collected, and logistic regression analysis was performed to construct models. Receiver operating characteristic (ROC) curves were used to analyze the efficacy of diagnostic tests. The areas under the ROC curves (AUCs) were similar between the post-SIT plasma aldosterone concentration (PAC) and post-CCT PAC (p > 0.05). The optimal post-SIT and post-CCT PAC cutoff values were 17.2 and 21.2 ng/dL, respectively. Positive CT findings combined with a post-SIT PAC >17.2 ng/dL or post-CCT PAC >21.2 ng/dL provided specificities of 97.8% and 95.7% for predicting APA, respectively. Logistic diagnostic models 1 (M1, CT finding + post-SIT PAC) and 2 (M2, CT finding + post-CCT PAC) were built, which showed equivalent diagnostic value (AUC = 0.959 and 0.932, respectively) (p > 0.05). The models combining CT findings with post-SIT PACs or post-CCT PACs represent an easier method to distinguish APA patients from other hypertensive patients with positive upright ARR results, especially in primary care where AVS may be unavailable.

The usefulness of the combined high-dose dexamethasone suppression test and desmopressin stimulation test in establishing the source of ACTH secretion in ACTH-dependent Cushing's syndrome.

Bilateral inferior petrosal sinus sampling (BIPSS) is the current gold standard test for differentially diagnosing ACTH-dependent Cushing's syndrome (CS). However, BIPSS is an invasive procedure, and its availability is limited. We retrospectively analysed the 24-hour urinary free cortisol (UFC) level during the high-dose dexamethasone suppression test (HDDST) and plasma ACTH/cortisol levels after the desmopressin stimulation test (DDAVP test) in subjects with confirmed Cushing's disease (CD) (n = 92) and ectopic ACTH-dependent CS (EAS) (n = 16), and evaluated the positive predictive value (PPV) of the two combined-tests in the aetiological diagnosis of ACTH-dependent CS. The percent changes in UFC levels after the HDDST and in ACTH/cortisol levels after DDAVP administration relative to the corresponding basal levels and the area under the receiver operating characteristic (ROC) curve (AUC) were analysed. UFC suppression below 62.7% suggested a pituitary origin with a sensitivity (SE) of 80% (95% CI: 70-88) and a specificity (SP) of 80% (95% CI: 52-96). A threshold increase in the ACTH level after DDAVP stimulation of 44.6% identified CD with an SE of 91% (95% CI: 83-97) and an SP of 75% (95% CI: 48-93). The combination of both tests yielded an SE of 95.5% and PPV of 98.4% for CD, and significantly improved the efficiency of the differential diagnosis between CD and EAS. These dual non-invasive endocrine tests may substantially reduce the need for BIPSS in the etiological investigation of ACTH-dependent CS.

[The Diagnostic Value of Captopril Challenge Test for Primary Aldosteronism].

OBJECTIVE: To investigate the diagnostic value of different captopril challenge test (CCT) diagnostic criteria for diagnosing primary aldosteronism (PA). METHODS: We collected the clinical data of 184 patients with hypertension retrospectively in West China Hospital of Sichuan University. Receiver operating characteristic (ROC) curves were used to analyze the post-CCT efficacy of aldosterone renin activity ratio (ARR), plasma aldosterone concentration (PAC), plasma renin activity (PRA) and PAC suppression rate for PA diagnosis. RESULTS: This study included 125 cases of primary aldehyde (PA group) and 59 cases of essential hypertension (EH group), and there were 38 normal renin primary hypertension (NREH group) and 21 low renin primary hypertension (LREH group) in EH group. The post-CCT PAC suppression rate (median (P 25, P 75)) of EH and PA group were 0.190 (0.083, 0.351) and 0.125 (0.024, 0.237), respectively. Compared with the NREH group, the basic and post-CCT PRA of LREH group were lower ( P<0.001), and there were no significant differences compared with the PA group ( P>0.05). We found significant overlap of post-CCT PRA and ARR between PA group and LREH group, while the overlap of post-CCT PAC between the two groups was small. In differential diagnosis of PA and EH, the areas under ROC curve of the post-CCT ARR, PAC, PRA and PAC suppression rate were 0.860 (95% confidence interval ( CI): 0.800-0.907), 0.881 (95% CI: 0.825-0.924), 0.771 (95% CI: 0.703-0.831) and 0.632 (95% CI: 0.558-0.701), respectively. There was no significant difference between the first two indexes ( Z=0.443, P=0.658), and both of them were higher than the latter two ( P<0.05). The optimal post-CCT cut-off values for ARR and PAC in differential diagnosis of PA and EH were 19.24 ng·dL -1 with a sensitivity of 78.4% and a specificity of 88.1%, and 32.47 (ng·dL -1)/(ng·mL -1·h -1) with a sensitivity of 84.17% and a specificity of 72.41%. CONCLUSION: Both ARR and PAC have higher diagnostic value than the post-CCT PAC suppression rate, post-CCT PAC is especially suitable as a confirmatory testing criterion of PA.

Unusual ectopic ACTH syndrome in a patient with orbital neuroendocrine tumor, resulted false-positive outcome of BIPSS:a case report.

BACKGROUND: Cushing's syndrome has been described as a complex endocrine disorder characterized with high cortisol concentration. Correct and early diagnosis of Cushing's syndrome is challenging. According to the latest guideline, bilateral inferior petrosal sinus sampling (BIPSS) is considered to be the gold standard for the differential diagnosis. However, in some unusual cases, this method may be false positive. Here, we presented a rare case of orbital neuroendocrine tumor secreting adrenocorticotrophic hormone with false positive inferior petrosal sinus sampling. CASE PRESENTATION: A 48-year-old woman was admitted to West China Hospital of Sichuan University, presenting with fatigue, whole body edema for 1 year, alopecia and skin pigmentation for 5 months. Hormonal profiles including plasma cortisol and adrenocorticotrophic hormone (ACTH) measurements and low-dose dexamethasone inhibition test suggested that the patient had Cushing's syndrome. However, during tumor location phase, the results of high-dose dexamethasone inhibition test (HDDST) contradicted desmopressin (DDAVP) stimulation test. Thus, BIPSS was employed, and its results indicated a pituitary origin. Interestingly, MRI of sellar region showed an innocent pituitary but caught a serendipitous lesion in the lateral rectus muscle of left eye, which was later proved to be an orbital neuroendocrine tumor secreting ACTH by pathological and immunohistochemical results. ACTH level of the patients was < 0.1 ng/L and cortisol level was 51.61 nmol/L 1 week after surgery. At 24 months follow-up, the patient appeared stable with no complaints nor any symptoms of Cushing's syndrome, including moon face, purple striate and central obesity. The patient's life quality also improved significantly. CONCLUSION: We reported a rare case of endogenous Cushing's syndrome due to ectopic ACTH secreting from an orbital neuroendocrine tumor. This unique case of orbital EAS suggests that orbital venous blood backflow, owning to abnormal anatomic structures, may possibly lead to false positive BIPSS results.

THERAPEUTIC EFFECTS OF COMBINATION REGIMENS INCLUDING METHIMAZOLE ON GRAVES HYPERTHYROIDISM: A NETWORK META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS.

Objective: To analyze the effects of methimazole (MMI)-containing combination regimens on the thyroid status and relapse rates in patients with Graves hyperthyroidism (GH) using a network meta-analysis to provide guidance for clinical application. Methods: We conducted a literature review, which identified 21 trials for inclusion. The major outcomes were serum free triiodothyronine (FT3) and free thyroxine (FT4) concentrations. The secondary outcome was relapse rate. A network meta-analysis was used to compare multiple regimens to identify the most advantageous regimen. Results: The types of combined drugs included anti-oxidant complexes, selenium, vitamin D3, cholestyramine, risedronate, iodine, potassium bromide, immunosuppressants, and ß-adrenergic antagonists. Regarding the FT3 results, the rank probability of the best result showed that potassium bromide (0.897) and vitamin D3 (0.833) had relative advantages in reducing FT3 at the 1-month time point. According to the time trend analysis, compared with the control treatment, cholestyramine and iodine showed advantages in reducing FT3 during the early stage (0 to 3 months). The immunosuppressants showed advantages in reducing FT3 during the late stage (>9 months) but not the early stage. Regarding the FT4 results, potassium bromide had the highest P-score (.965) at the 1-month time point. Iodine and cholestyramine had advantages in reducing FT4 during the early stage. The immunosuppressants had advantages during both the early and late stages. Conclusion: MMI combined with cholestyramine or iodine was shown to regulate serum FT3 and FT4 during the early stage of GH. MMI combined with immunosuppressants had a long-term advantage in FT3/FT4 regulation and reduced the relapse rate. Abbreviations: ATD = antithyroid drug; CI = confidence interval; FT3 = free triiodothyronine; FT4 = free thyroxine; GH = Graves hyperthyroidism; MMI = methimazole; OR = odds ratio; RCT = randomized controlled trial; SMD = standard mean difference; TCM = traditional Chinese medicine.

[The Value of Postural Stimulation Test Combined with Adrenal CT in the Diagnosis of Aldosterone-producing Adenoma].

OBJECTIVE: Adrenal vein sampling (AVS) and pathological report were selected as gold standard to assess the value of adrenal CT scan combined with postural stimulation test in diagnosing aldosterone-producing adenoma. METHODS: The clinical data of primary aldosteronism (PA) patients including aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA) were retrospectively collected in the West China Hospital of Sichuan University. The sensitivity and specificity of adrenal CT scan combined with postural stimulation test in diagnosing APA were studied. RESULTS: A total of 83 APA patients and 42 IHA patients were enrolled in this study. ROC curve was plotted with increase percentage of serum aldosterone in upright position compared with recumbent position. The optimal cutoff point for APA diagnosis by postural stimulation test was 11%, and the percentage less than 11% was taken as a positive result. The patients were diagnosed by postural stimulation test, with 60 cases positive and 23 cases negative in APA patients and 12 cases positive and 30 cases negative in IHA patients. When AVS and pathological report were selected as the gold standard, the sensitivity and specificity of postural stimulation test in diagnosing APA were 72.3% and 71.4% respectively. Among the 83 APA patients, 65 patients with unilateral nodules and 18 patients with bilateral nodules were diagnosed by CT scan. The coincidence rate in APA diagnosis between CT scan and AVS or pathological report was 78.3% (65/83). Among the 60 patients with positive result in postural stimulation test, who were diagnosed bilateral nodules by CT scan, 51 patients were diagnosed as APA by AVS or pathological report (51/60). CONCLUSION: Adrenal CT combined with postural test can increase the diagnostic accuracy of APA patients.

[The Pharmacokinetics, Pharmacodynamics and Bioequivalence of Insulin Aspart Produced by the United Laboratories Evaluated by Euglycemic Clamp Study].

OBJECTIVE: To investigate the pharmacokinetics (PK) and pharmacodynamics (PD) of a rapid-acting insulin analog-insulin aspart (the tested formulation) which was manufactured by The United Laboratories and to evaluate the bioequiavailability to the reference formulation (NovoRapid ®) produced by Novo Nordisk in Chinese healthy volunteers. METHODS: A total of 24 male healthy volunteers were recruited from February to April 2016 to participant in this before-after, single dose, and randomized crossover study. And the experimental observation was conducted on 2 test days respectively with a between-period from 7 to10 d. According to a random number table, the volunteers were divided into group A or B, group A was administrated with tested insulin aspart (IAsp) for the first time and reference NovoRapid ® for the second time and group B had the revered order differed from group A. The PK/PD of these insulin analogs were estimated by euglycemic clamp study. RESULTS: The relative biological effectiveness (reflecting gloucose-lowing effect) and bioavailability on behalf of plasma-drug concentration were 98.3±18.8% and 97.3%±8.3% respectively. For PK parameters, the 90% confidence interval ( CI) of peak plasma insulin concentration ( C max) and area under the curve of insulin aspart concentration from 0 to 10 hours ( AUC IAsp, 0-10 h) of IAsp were 88.8%-106% (equivalent range 70%-143%) and 94.0%-100% (equivalent range 80%-125%) respectively; for PD parameters, the 90% CI of the maximum glucose infusion rate ( GIR max) and AUC GIR, 0-10 h were 95.5%-113% (equivalent range 70%-143%) and 89.9%-104% (equivalent range 80%-125%) respectively, which indicated that IAsp and NovoRapid® was bioequivalent. One of the subjects discovered hyperuricemia without clinical symptoms and the rest had no clinically significant abnormalities in the safety indexes before and after the tests. No hypoglycemic events, allergic reactions, or local injection adverse reaction occurred in this trial. CONCLUSION: The tested IAsp has comparable relative bioavailability to the reference NovoRapid ®.

Hypercortisolism and primary aldosteronism caused by bilateral adrenocortical adenomas: a case report.

BACKGROUND: Co-existing Cushing's syndrome and primary aldosteronism caused by bilateral adrenocortical adenomas, secreting cortisol and aldosterone, respectively, have rarely been reported. Precise diagnosis and management of this disorder constitute a challenge to clinicians due to its atypical clinical manifestations and laboratory findings. CASE PRESENTATION: We here report a Chinese male patient with co-existing Cushing's syndrome and primary aldosteronism caused by bilateral adrenocortical adenomas, who complained of intermittent muscle weakness for over 3 years. Computed tomography scans revealed bilateral adrenal masses. Undetectable ACTH and unsuppressed cortisol levels by dexamethasone suggested ACTH-independent Cushing's syndrome. Elevated aldosterone to renin ratio and unsuppressed plasma aldosterone concentration after saline infusion test suggested primary aldosteronism. Adrenal venous sampling adjusted by plasma epinephrine revealed hypersecretion of cortisol from the left adrenal mass and of aldosterone from the right one. A sequential bilateral laparoscopic adrenalectomy was performed. The cortisol level was normalized after partial left adrenalectomy and the aldosterone level was normalized after subsequent partial right adrenalectomy. Histopathological evaluation of the resected surgical specimens, including immunohistochemical staining for steroidogenic enzymes, revealed a left cortisol-producing adenoma and a right aldosterone-producing adenoma. The patient's symptoms and laboratory findings resolved after sequential adrenalectomy without any pharmacological treatment. CONCLUSIONS: Adrenal venous sampling is essential in diagnosing bilateral functional adrenocortical adenomas prior to surgery. Proper interpretation of the laboratory findings is particularly important in these patients. Immunohistochemistry may be a valuable tool to identify aldosterone/cortisol-producing lesions and to validate the clinical diagnosis.

[The Functional Analysis of Glucocorticoid Receptor in Peripheral Blood of Endogenous Cushing's Syndrome Patients].

OBJECTIVE: To evaluate the expression level and binding affinity glucocorticoid receptor (GR) in endogenous Cushing's syndrome patients. METHODS: The patients of endogenous Cushing's syndrome were enrolled in the department of endocrinology in West China Hospital of Sichuan University, and age- and sex-matched healthy volunteers were studied as control group. The expression level and binding affinity of GR in peripheral blood mononuclear cells (PBMCs) were examined by flow cytometry. The differences between the two groups were compared, and the correlations of GR level and affinity to serum cortisol concentration or 24 h urine free cortisol were also analyzed. RESULTS: There were 17 Cushing's syndrome patients and 17 healthy volunteers. The expression level and binding affinity of GR in Cushing's syndrome patients were 11.9±3.1 and 6.6±2.6, while the values of normal controls were 20.6±3.3 and 9.9±3.2. A significant decrease in GR expression and binding affinity in the patients with Cushing's syndrome was found. No correlation was observed between plasma cortisol concentration or 24 h urinary free cortisol and GR expression or binding affinity in Cushing's syndrome patients. CONCLUSION: The expression level and binding affinity of GR are obviously decreased in Cushing's syndrome patients, which suggests 1.6 times of physiological dose of glucocorticoid for the patients with hypocortisolism after surgery, in order to overcome glucocorticoid resistance and maintain physiological function of glucocorticoid.

[Risk Factors Associated with Thyroid Nodules in Patients with Acromegaly].

OBJECTIVE: To identify risk factors associated with thyroid nodular lesions in patients with acromegaly. METHODS: Clinical and thyroid ultrasonography data of patients with acromegaly diagnosed in the West China Hospital of Sichuan University from May 2009 to January 2018 were reviewed and analyzed. Multivariate linear regression models were established to identify factors associated with thyroid volumes and size of thyroid nodules. Multivariate binary logistic regression models were established to determine risk factors associated with thyroid nodules in patients with acromegaly. RESULTS: Of the 240 acromegaly patients, 70 received thyroid ultrasonography and 56 had thyroid nodules (56/70, 80%). The patients with thyroid nodules had a longer median duration of acromegaly than 14 patients who without thyroid nodules (8.0 years vs. 3.0 years, P＜0.05), but had a similar mean age and female to male ratio with the latter. The risk of thyroid nodules increased with the duration of acromegaly (odds ratio=1.306, 95% confidence interval (1.010, 1.688), P=0.042). The level of random growth hormone was linearly correlated with thyroid volumes. Gender, age, and serum growth hormone were not predictors of thyroid nodules in patients with acromegaly. CONCLUSION: Duration of acromegaly is an independent predictor of thyroid nodules.

[Quality Assessment of Euglycemic Glucose Clamp Test].

OBJECTIVE: To explorethe quality of euglycemic glucose clamptest performed in the West China Hospital from 2014 to 2017 and to evaluate whether the quality control indexes are suitable for the quality assessment of the clamp test. METHODS: The data collected from 80 euglycemic glucose clamp tests performed between 2014 and2017 were divided into 4 groups according to the coefficient of variation of the blood glucose concentrations (CVBG): group A (CVBG≤4.5%), group B (4.5% < CVBG≤5.0%), group C (5.0% < CVBG≤5.5%) and group D(CVBG > 5.5%).The differences in percentage of glucose excursion from target range (GEFTR), the duration of GEFTR, the area under curve (AUC) of GEFTR, the mean value of excursion from target glucose (GEFT) and the AUC of GEFT were calculated and compared. RESULTS: In group A, the mean value of CVBG was 3.75%. In group B, the mean value of CVBG was 4.76%. In group C, the mean value of CVBG was 5.28%. The median value of CVBG in group D was 6.07%. The percentage of GEFTR, the duration of GEFTR, the AUC of GEFTR, the mean value of GEFT and the AUC of GEFT in group A were all less than those of other groups (P < 0.05).For the same indexes, there were no significant differences between group B and C, while they were higher in group D compared with the other three groups. CVBG was positively correlated with other quality control indexes (correlation coefficient r was 0.770-0.805). Based on the cut-off point 5% of CVBG, the cut-off points of the percentage of GEFTR, the duration of GEFTR, the AUC of GEFTR, the mean value of GEFT and the AUC of GEFT were 5.8%, 14.6 min, 22.82 mg/dL×min, 3.23 mg/dL, 216.25 mg/dL×min/h respectively, with the sensitivity range from 79.3% to 100% and the specificity range from 74.5% to 89.7%.Combined with these indexes, 8.11% of euglycemic clamps were found to havepoor quality in group A, while 66.67% of euglycemic clamps showed acceptable quality in group C. CONCLUSIONS: The investigators should provide an estimation of the quality of the clamps when reporting the results of the insulin analogues' PK/PD characteristics using euglycemic clamps. CVBG less than 4.5% indicates a good quality, and the above-mentioned quality control indexes especially the AUC of GEFT(cut-off point: 216.25 mg·/dL×min/h) should be evaluated when CVBG is more than 4.5%.False high quality and false low quality euglycemic clamps will be detected and a more precise estimation of quality assessment should be made by the combination of these indexes.

ACTH-independent Cushing's syndrome with bilateral cortisol-secreting adrenal adenomas: a case report and review of literatures.

BACKGROUND: Adrenocorticotropic hormone (ACTH)-independent Cushing's syndrome (CS) with bilateral cortisol-secreting adenomas has been rarely reported in the literatures. Precise recognition and management of this disorder constitute a challenge to clinicians due to the difficulty of exact location of the functional lesions. CASE PRESENTATION: We herein report a new case of a Chinese female patient with a complaint of exertional dyspnea for over 10 years. ACTH-independent CS was diagnosed based on undetectable ACTH and unsuppressed cortisol levels by dexamethasone. Computed tomography (CT) scan indicated bilateral adrenal masses, and adrenal venous sampling (AVS) adjusted by plasma aldosterone revealed hypersecretion of cortisol from both adrenal glands. Bilateral cortisol-secreting adrenal adenomas were suspected and confirmed by the postoperative pathology in subsequent two-step bilateral laparoscopic adrenalectomy. The symptoms and signs of CS relieved after surgery with continuous glucocorticoid replacement. CONCLUSIONS: AVS adjusted by plasma aldosterone could be a useful technique in diagnosing ACTH-independent CS with bilateral adrenal adenomas prior to surgery. And the aldosterone ratio could be used to confirm the success of adrenal vein cannulation in this situation.

Free fatty acid can induce cardiac dysfunction and alter insulin signaling pathways in the heart.

BACKGROUND: Insulin resistance has been independently related to heart failure. However, the specific mechanisms of high FFA levels in the pathophysiology of heart failure in insulin-resistant states are remain largely unclear. This study investigated whether elevated circulating free fatty acids (FFA) levels result in impaired cardiac structure and function in vivo via insulin-related signaling pathways in myocardium. METHODS: Male Wistar rats were randomly divided into the intralipid group (20% intralipid plus heparin infusion) and the control group (glycerol infusion). Blood samples were collected before and after 6-, 12-, and 24-h infusions. Cardiac structure and function were measured using echocardiography. Maximum velocity of myocardial contraction (+dP/dt max) and diastole (-dP/dt max) were measured using a physiological polygraph in vivo. Heart tissues were collected for western blotting. RESULTS: Compared with the control group, plasma FFA, plasma glucose, and serum insulin levels increased significantly in the intralipid group. With increasing infusion time, cardiac function in the intralipid group decreased gradually compared with the control group. After a 24-h infusion, early (E', cm/s) diastolic peak velocities and (-dP/dt max) decreased significantly. Protein expression of phosphatidylinositol 3-kinase (PI3K), the serine/threonine kinase Akt, and phosphorylated Akt in myocardium increased after a 6-h infusion and decreased significantly after a 24-h infusion in the intralipid group. Protein expression of glucose transporter type 4 (GLUT4), Adenosine 5'-monophosphate -activated protein kinase (AMPK), phosphorylated AMPK(p-AMPK), and endothelial nitric oxide synthase (eNOS) in myocardium gradually decreased in the intralipid group. CONCLUSIONS: Elevated FFA levels may impair cardiac function and cardiac dysfunction might result from myocardial insulin resistance with significant changes to PI3K-Akt-GLUT4 and AMPK-eNOS signaling pathways with increasing FFA levels.

A novel uromodulin mutation in autosomal dominant tubulointerstitial kidney disease: a pedigree-based study and literature review.

Autosomal dominant tubulointerstitial kidney disease caused by mutations in uromodulin gene (ADTKD-UMOD) is a spectrum of hereditary renal disorders, characterized by early-onset hyperuricemia, gout and progressive nephropathy. This study presented a novel UMOD mutation in an ADTKD pedigree and reviewed studies in Chinese population. The index patient is a 16-year-old girl with hypertension, hyperuricemia and normal serum creatinine level. Four affected and six unaffected members were available for genetic screen. The mutation analysis was performed by next-generation sequencing and direct sequencing. A literature research was conducted to review Chinese ADTKD-UMOD cases. MEDLINE and Chinese Biomedicine Databases were searched with 'uromodulin', 'juvenile gout' and their related terms. Genetic sequencing revealed a de novo mutation within exon 3 (Cys223Gly), which was co-segregating with phenotype in this pedigree. In the review, four studies and our study involving a total of 67 ADTKD patients from 11 families were identified. Of these patients, 27 were confirmed to carry UMOD mutations. Mutations occurred in exon 3 were commonly observed, while mutations within exon 4, 5 and 9 occurred less frequently in Chinese ADTKD-UMOD cases. Among these cases, median age of symptom onset was 26.5 years, median age of end-stage renal diseases (ESRD) or death by ESRD was 41.9 years without renal replacement treatment. Phenotype caused by mutations in D8C domain seemed to be severe than those in GPI domain. Compared with patients of other race, Chinese ADTKD-UMOD patients advanced more aggressively to ESRD.

[Pancreatic ß-cell Dysfunction and Apoptosis Induced by Elevated Free Fatty Acids Synergize with Hyperglycemia].

OBJECTIVES: To analysis the effects of glucoxicity and lipotoxicity on the function and apoptosis of pancreatic ß-cells. METHODS: The levels of circulating glucose and free fat acids (FFAs) were elevated by infusion dextrose and fat emulsion in high-fat obese rats. The insulin resistance model obese rats were divided into four gourp: obese group with saline infusion (OB-NS group, n=7), obese group with glucose infusion (OB-GS group, n=9), obese group with Lipid emulsion infusion (OB-FFA group, n=8), obese group with glucose and lipid emulsion infusion (OB-FG group, n=9). Five rats fed with general diet were taken as normal group (NC group).Plasma FFAs and ß-hydroxybutyric acid (ß-HBA) concentrations were determined by an enzymatic colorimetric method. An intravenous glucose tolerance test (IVGTT) was performed to examine the glucose-stimulated insulin secretion in vivo and immunohistochemical staining to detect the storage volume of insulin. FFA and ß-HBA concentrations were measured at baseline and post-infusion. The apoptosis of pancreatic ß-cell was detected byin situ end labeling technique (TUNEL). RESULTS: Glucose infusion rate (GIR) of obese rats was significantly lower than that in NC group [(10.82±1.8) mg/(kg·min) vs. (25.21±1.7) mg/(kg·min), P<0.05], confirming insulin resistance rat model successfully established. The insulin secretion peak load time of OB-FG group rats delayed, and the serum insulin level was significantly lower than that of NC group and OB-NS group during IVGTT. The differences were statistically significant ( P<0.05). Compared with OB-NS and NC groups, storage volume of insulin of OB-GS group reduced, and ß cell apoptosis rate elevated significantly. CONCLUSIONS: Glucolipotoxicity could induce ketone overproduction, insulin resistance and defective insulin secretion.

Free fatty acids, not triglycerides, are associated with non-alcoholic liver injury progression in high fat diet induced obese rats.

BACKGROUND: The incidence of non-alcoholic fatty liver disease (NAFLD), commonly associated with obesity and metabolic syndrome, is increasing worldwide. However, the specific mechanisms that mediate the progression from simple steatosis to non-alcoholic steatohepatitis remain largely unclear. This study aimed to investigate the time dependent changes of triglyceride (TG) and free fatty acid (FFA) levels in the blood and liver over 24 weeks in high-fat diet-induced obese rats with NAFLD and to clarify the role of high FFA levels in the progression of liver injury. METHODS: Male Wistar rats were randomly divided into three groups (n = 30 per group): the Control group, fed standard chow; the High-fat diet (HFD) group, fed high-fat chow; and the Acipimox group, fed an HFD plus acipimox (100 mg/kg/d, ig) for 8, 16 and 24 weeks. After treatment, blood and liver samples were collected for biochemical analyses, western blotting analysis and a histopathological study. RESULTS: The visceral fat/weight and liver/body weight ratios were higher in both the HFD and Acipimox groups than in the Control group. The TG and FFA concentrations in blood and liver were increased in the HFD group and associated with elevated serum alanine aminotransferase (ALT) and liver malondialdehyde (MDA) levels and macro/microvesicular steatosis on hepatic fragments. Although the TG levels in the liver were similar between the HFD and Acipimox groups (p > 0.05), the FFA concentrations in the blood and liver were much lower in the latter group (p < 0.05). The Acipimox group showed normal ALT and MDA levels as well as less severe hepatic histological changes than did the HFD group (NAFLD activity score: 2.14 ± 0.14, 2.43 ± 0.20 and 2.63 ± 0.26 at 8, 16 and 24 weeks, respectively; p < 0.05 versus the HFD group at 24 weeks). The diacylglycerol acyltransferase 2 (DGAT2) protein levels were similar between the HFD and Acipimox groups (p > 0.05), but the protein expression level of carnitine palmitoyltransferase 1a (CPT-1a) was higher in the Acipimox group. CONCLUSIONS: Liver TG accumulation does not cause cellular injury in the liver; rather, FFAs or their metabolites are responsible for liver injury via increased oxidative stress. It is suggested that the therapeutic efforts to prevent non-alcoholic liver injury progression should be focused on reducing the burden of fatty acids transported to the liver or those being synthesized in the liver.