HLA investigation in ICI-induced T1D and isolated ACTH deficiency including meta-analysis.

OBJECTIVE: Widespread use of immune checkpoint inhibitors (ICIs) in cancer treatment has led to an increase in the number of reported cases of immunotherapy-related endocrinopathies. This study aimed to analyze and compare human leukocyte antigen (HLA) signatures associated with ICI-induced type 1 diabetes (ICI-T1D) and isolated adrenocorticotropic hormone deficiency (ICI-IAD) in patients with both conditions. METHODS: HLA signatures were examined for their frequencies of occurrence in 22 patients with ICI-T1D without concurrent IAD, including 16 patients from nationwide reports (ICI-T1D group) and 14 patients with ICI-IAD without concurrent T1D (ICI-IAD group). The HLA signatures were also compared for their respective frequencies in 11 patients with ICI-T1D and ICI-IAD, including eight from nationwide reports (ICI-T1D/IAD group). RESULTS: In the ICI-T1D group, HLA-DRB1*09:01-DQB1*03:03 and DQA1*03:02, which are in linkage disequilibrium with DRB1*09:01-DQB1*03:03 and DRB1*13:02-DQB1*06:04, were susceptible to ICI-T1D, whereas DRB1*15:02-DQB1*06:01 was protective against ICI-T1D. In the ICI-IAD group, DPB1*09:01, C*12:02-B*52:01, and DRB1*15:02-DRB1*06:01, which are in strong linkage disequilibrium, were associated with susceptibility to ICI-IAD. Moreover, DRB1*15:02-DRB1*06:01 was not detected in the ICI-T1D/IAD group. CONCLUSIONS: This study revealed specific HLA signatures associated with ICI-T1D and ICI-IAD. Moreover, HLA-DRB1*15:02-DRB1*06:01, an ICI-IAD-susceptible HLA haplotype, coincides with the ICI-T1D-protective HLA haplotype, suggesting that the presence of DRB1*15:02-DRB1*06:01 may protect against the co-occurrence of T1D in patients with ICI-IAD.

[Medical Therapies in Functioning Pituitary Neuroendocrine Tumors(PitNETs)].

Transsphenoidal surgery is the first-line treatment for most functioning pituitary neuroendocrine tumors(PitNETs). Medical therapies are usually chosen for patients with residual or refractory tumors after surgery or contraindications to surgery. Dopamine agonists(DA)are the first-line treatment for prolactinomas. Somatostatin analogs are the first line of therapy for GH- and TSH-producing PitNETs. In severe hypercortisolemia due to ACTH-producing PitNETs, adrenal enzyme inhibitors such as 11ß-hydroxylase inhibitors should be started immediately, as marked hypercortisolemia leads to serious opportunistic infections. Pasireotide and DA are usually administered to treat mild hypercortisolemia. Based on the histological pattern of secretory granules, somatotroph, lactotroph, and corticotroph tumors can be divided into two subtypes: densely granulated and sparsely granulated. Densely granulated lactotroph tumors tend to be resistant to DA. In contrast, densely granulated somatotroph and corticotroph tumors express high levels of somatostatin receptors and are more responsive to somatostatin analogs. Since ACTH-producing PitNETs express SSTR5 without SSTR2, the second-generation somatostatin analog, pasireotide, is effective against ACTH-producing PitNETs.

A case of pheochromocytoma associated with liver abscess and intestinal pseudo-obstruction.

Pheochromocytomas can present with various symptoms. Nonspecific manifestations of pheochromocytoma include intestinal pseudo-obstruction and weight loss. Here, we present a case of pheochromocytoma in which prolonged intestinal pseudo-obstruction due to excess catecholamines was one of the factors leading to the development of a liver abscess. An 18-year-old male patient with a history of status epilepticus and severe intellectual disability was transferred to our hospital for a thorough examination of fever and constipation that had lasted for 2 months. When admitted to our hospital, he had fever, and his body mass index was 9.5 kg/m2. Upon comprehensive examination of the patient's fever, the blood culture was found positive for Bacteroides. Computed tomography showed findings of intestinal pseudo-obstruction and a low density region in the liver that indicated a liver abscess. Imaging studies also revealed a right adrenal mass and endocrinological test showed elevated plasma norepinephrine and urine normetanephrine levels. In addition, the right adrenal mass showed uptake on 123I-metaiodobenzylguanidine scintigraphy. These findings led to a definite diagnosis of pheochromocytoma. The patient was eventually diagnosed with a pheochromocytoma coexisting with a liver abscess. After treating the liver abscess with antibiotics and ultrasound-guided drainage, an adrenalectomy was performed. The pathological findings were consistent with pheochromocytoma. Postoperatively, the catecholamine excess normalized and intestinal pseudo-obstruction and weight loss improved. We suspected that prolonged intestinal pseudo-obstruction resulted in bacterial translocation and development of a liver abscess. To the best of our knowledge, this is the first report of a pheochromocytoma associated with a liver abscess. Moreover, the clinical presentation of this patient was unusual for pheochromocytoma, as the patient did not have typical symptoms such as hypertension or tachycardia, but rather presented with constipation, intestinal pseudo-obstruction, and weight loss. This case provides valuable insight regarding the impact of catecholamine excess on the intestinal tract and body weight.

Perioperative glycemic status is linked to postoperative complications in non-intensive care unit patients with type-2 diabetes: a retrospective study.

Background: Perioperative hyperglycemia is a risk factor for postoperative complications in the general population. However, it has not been clarified whether perioperative hyperglycemia increases postoperative complications in patients with type-2 diabetes mellitus (T2D). Therefore, we aimed to analyze the relationship between perioperative glycemic status and postoperative complications in non-intensive care unit (non-ICU) hospitalized patients with T2D. Materials and Methods: Medical records of 1217 patients with T2D who were admitted to the non-ICU in our hospital were analyzed retrospectively. Relationships between clinical characteristics including perioperative glycemic status and postoperative complications were assessed using univariate and multivariate analyses. Perioperative glycemic status was evaluated by calculating the mean, standard deviation (SD), and coefficient of variation (CV) of blood glucose (BG) measurements in preoperative and postoperative periods for three contiguous days before and after surgery, respectively. Postoperative complications were defined as infections, delayed wound healing, postoperative bleeding, and/or thrombosis. Results: Postoperative complications occurred in 139 patients (11.4%). These patients showed a lower BG immediately before surgery (P = 0.04) and a higher mean postoperative BG (P = 0.009) than those without postoperative complications. There were no differences in the other perioperative BG parameters including BG variability and the frequency of hypoglycemia. The multivariate analysis showed that BG immediately before surgery (adjusted odds ratio (95% confidence interval [CI]), 0.91 (0.85-0.98), P = 0.01) and mean postoperative BG (1.11 (1.05-1.18), P < 0.001) were independently associated with postoperative complications. Conclusion: Perioperative glycemic status, that is, a low BG immediately before surgery and a high mean postoperative BG, are associated with the increased incidence of postoperative complications in non-ICU patients with T2D.

HLA analysis of immune checkpoint inhibitor-induced and idiopathic isolated ACTH deficiency.

PURPOSE: Isolated adrenocorticotropic hormone deficiency is a rare disease; however, since immune check point inhibitors (ICIs) have become widely used, many more cases have been reported. In this study, we compared the human leukocyte antigen (HLA) signatures between ICI-induced isolated adrenocorticotropic hormone deficiency (IAD) and idiopathic IAD (IIAD). DESIGN AND METHODS: Clinical features and HLA frequencies were compared among 13 patients with ICI-induced IAD, 8 patients with IIAD, and healthy controls. HLA frequencies of healthy controls were adopted from a HLA database of Japanese population. RESULTS: Age and body mass index were higher, while the rate of weight loss was lower, in patients with ICI-induced IAD than in those with IIAD. No HLA alleles had a significantly higher frequency in patients with ICI-induced IAD than in healthy controls, whereas the frequencies of HLA-DRB1*09:01, HLA-DQA1*03:02, and DQB1*03:03 were significantly higher in patients with IIAD than in healthy controls. CONCLUSIONS: ICI-induced IAD and IIAD were different in terms of HLA frequencies. There were no specific HLAs related to ICI-induced IAD, whereas several HLAs in strong linkage disequilibrium were associated with IIAD. This might suggest that the two diseases have different pathological mechanisms. HLAs unique to IIAD may be helpful in predicting its pathophysiology.

Efficacy and safety of semaglutide in glycemic control, body weight management, lipid profiles and other biomarkers among obese type 2 diabetes patients initiated or switched to semaglutide from other GLP-1 receptor agonists.

PURPOSE: Evidence of the efficacy and safety of semaglutide among patients with type 2 diabetes who were initiated on or were switched to semaglutide from other GLP-1 RAs remains limited. The objective of this study was to investigate the short-term effects of switching to semaglutide from other GLP-1 RAs. METHODS: This retrospective cohort study evaluated patients with type 2 diabetes who were initiated on or were switched to semaglutide due to poor diabetes control with other GLP-1 RAs or other medications, or obesity. HbA1c, body weight, serum creatinine, serum uric acid, parameters of lipid metabolism, and parameters of liver function were measured before and 6 months after administration of semaglutide. RESULTS: A total of 50 patients were registered in the study. After switching to semaglutide (n = 43), HbA1c and body weight significantly decreased (p < 0.01, p < 0.01), respectively. The same findings were observed in semaglutide-naïve patients (p = 0.04, p < 0.02) (n = 7). Serum uric acid, total cholesterol, triglycerides, and urinary albumin-creatinine ratio decreased significantly as well (p = 0.04, p = 0.04, p = 0.02, p = 0.04), whereas serum creatinine did not change significantly (p = 0.51). CONCLUSIONS: Semaglutide showed excellent efficacy, even in patients switched from other GLP-1 RAs. Semaglutide appears to be a promising agent for blood glucose and body weight control in obese type 2 diabetes mellitus patients and could be more potent in treating type 2 diabetes than existing GLP-1 RAs.

Painless destructive thyroiditis in a patient with resistance to thyroid hormone: a case report.

BACKGROUND: Resistance to thyroid hormone (RTH) usually features a syndrome of inappropriate secretion of thyroid-stimulating hormone (SITSH) without suppression of the typical high thyroid hormone levels. However, some patients with RTH show thyroid-stimulating hormone (TSH) suppression due to thyrotoxicosis. We report a case of painless thyroiditis in a patient with RTH that was misdiagnosed as Graves' disease because of TSH-suppressed thyrotoxicosis. CASE PRESENTATION: A sixteen-year-old boy consulted a local general physician for fatigue. He had a goiter, and biochemical analysis showed TSH < 0.1 µIU/mL, free triiodothyronine (FT3) of 2.70 pg/mL, and free thyroxine (FT4) of 3.6 ng/dL. He was diagnosed with Graves' disease and was treated with 20 mg thiamazole. One year later, he was referred to the department of endocrinology because of SITSH. He was finally diagnosed with RTH due to the finding of a heterozygous missense mutation (methionine 334 threonine) in the thyroid hormone receptor ß gene. Three years after cessation of thiamazole, his hyperthyroxinemia showed marked exacerbation with TSH suppression. We diagnosed him with painless destructive thyroiditis because of low technetium-99 m (Tc-99 m) uptake in the thyroid. Extreme hyperthyroxinemia was ameliorated, with a return to the usual SITSH levels, within 1 month without any treatment. CONCLUSION: The present case demonstrates that diagnosing RTH is difficult when patients show hyperthyroxinemia with complete suppression of TSH to undetectable levels, and the data lead to misdiagnosis of RTH as Graves' disease. The initial diagnosis is important, and Tc-99 m scintigraphy is useful for the differential diagnosis of thyrotoxicosis accompanying RTH.

Levels of glucose-regulatory hormones in patients with non-islet cell tumor hypoglycemia: including a review of the literature.

Non-islet cell tumor hypoglycemia (NICTH) is one of the causes of spontaneous hypoglycemia. The pathogenesis of NICTH is thought to be an excessive production by tumors of big insulin-like growth factor (IGF)-II. This study investigated the levels of glucose-regulatory hormones in patients with NICTH with high serum levels of big IGF-II (big IGF-II group) and compared these with profiles of patients with spontaneous hypoglycemia with normal IGF-II (normal IGF-II group). Circulating IRI, CPR, ACTH, cortisol, GH, and IGF-I levels measured during hypoglycemic episodes were examined retrospectively in 37 patients with big IGF-II producing NICTH and 6 hypoglycemic patients with normal IGF-II. The hormone profile data of 15 patients with NICTH from published case reports were reviewed and included in the analyses. Mean plasma glucose levels (36 vs. 29 mg/dL), serum IRI (0.53 vs. 0.37 µIU/mL), CPR (0.15 vs. 0.20 ng/mL), IGF-I SDS (-3.55 vs. -3.18 SD) and ACTH levels (27.3 vs. 33.8 pg/mL) were not significantly different between the big and normal IGF-II groups. However, mean serum GH (0.85 vs. 9.62 ng/mL) and plasma cortisol levels (16.2 vs. 34.5 µg/dL) were significantly lower in the big IGF-II group than in the normal IGF-II group (both p<0.05). In conclusion, although the magnitude of the decrease in insulin and IGF-I levels did not differ between spontaneous hypoglycemic patients caused by other etiologies, patients with NICTH tended to have low basal GH levels during hypoglycemic episodes. These differences in hormone profile may be helpful for selecting patients who require analysis of IGF-II.

ACTH stimulation test and computed tomography are useful for differentiating the subtype of primary aldosteronism.

The diagnostic steps for primary aldosteronism (PA) include case screening tests, confirmatory tests, and localization. The aim of this study was to identify useful confirmatory tests and their cut-off values for differentiating the subtype of primary aldosteronism, especially in unilateral PA, such as aldosterone-producing adenoma, and bilateral PA, such as idiopathic hyperaldosteronism. Seventy-six patients who underwent all four confirmatory tests, the captopril-challenge test (CCT), furosemide upright test (FUT), saline infusion test (SIT), and ACTH stimulation test (AST), and who were confirmed to have an aldosterone excess by adrenal venous sampling (AVS) were recruited. Subjects were diagnosed as having unilateral aldosterone excess (n=17) or bilateral aldosterone excess (n=59) by AVS. The SIT-positive rate was significantly higher in the unilateral group (94.1%) than in the bilateral group (57.6%). Multivariable logistic regression analysis showed that tumor on computed tomography (CT) and plasma aldosterone concentration (PAC)max/cortisol on the AST were useful for differentiating the subtype of PA. Receiver operating characteristic (ROC) curve analysis for distinguishing the subtype of PA showed that a cut-off value of 18.3 PACmax/cortisol on the AST had a sensitivity of 83% and a specificity of 88%. The area under the ROC curve was 0.918 (95% confidence interval 0.7916-0.9708). These data suggest that abdominal CT and AST are useful for differentiating the subtype of PA and the indication for AVS.

Preventive effect of ipragliflozin on nocturnal hypoglycemia in patients with type 2 diabetes treated with basal-bolus insulin therapy: An open-label, single-center, parallel, randomized control study.

The efficacy of the administration of sodium-glucose co-transporter 2 inhibitor or the co-administration of sodium-glucose co-transporter 2 inhibitor and dipeptidyl peptidase-4 inhibitor to insulin therapy is not well known. A total of 58 patients with type 2 diabetes, admitted for glycemic control, were randomized to basal-bolus insulin therapy (BBT) alone or BBT plus 50 mg ipragliflozin and/or 20 mg teneligliptin. Insulin doses were adjusted to maintain normal blood glucose levels. Plasma glucose profiles were estimated by continuous glucose monitoring before discharge. Required insulin doses were not significantly different among the treatment groups. The frequency of nocturnal hypoglycemia was significantly lower in the groups treated with ipragliflozin (6.5 ± 10.6%) and ipragliflozin plus teneligliptin (6.9 ± 14.3%) than in the group treated with BBT alone (42 ± 43.6%). The administration of sodium-glucose co-transporter 2 inhibitor with or without dipeptidyl peptidase-4 inhibitor prevented nocturnal hypoglycemia in type 2 diabetes patients with BBT.

Neonatal alloimmune thrombocytopenia caused by an antibody specific for a newly identified allele of human platelet antigen-7.

BACKGROUND: Neonatal alloimmune thrombocytopenia (NAIT) is a neonatal disorder characterized by maternal alloimmunization against fetal platelet (PLT) antigens inherited from the father. A healthy 30-year-old Japanese woman (Hit) gave birth to her second child after an uneventful pregnancy. Nine hours after birth, the infant presented with severe petechiae and a PLT count of 6 x 10(9)/L. STUDY DESIGN AND METHODS: To elucidate the maternal cause of NAIT in the infant, serologic and genetic studies, including PLT genotyping and sequence-based analysis, were conducted. Additionally, serologic screening for the new PLT antigen was performed. RESULTS: Serum from the NAIT infant's mother contained antibodies directed against a human PLT antigen (HPA) of the newborn. Using five-cell-lineage flow cytometry, we localized the antigen to a PLT glycoprotein (GP). Subsequent monoclonal antibody immobilization of PLT antigen assay and PLT immunofluorescence inhibition experiments localized the antigen to the GPIIIa subunit of the GPIIb/IIIa complex. GPIIIa localization was confirmed by sequence-based typing studies, which identified a 1297C>T (407proline>serine substitution) mutation on the ninth exon of the GPIIIa gene. This mutation identified the third allele of HPA-7. Anti-Hit(a) reacted with mutated GPIIIa-transfected cells but not with stable transfectants expressing wild-type GPIIIa. Serologic screening for Hit(a) in the Japanese population revealed a phenotypic frequency of approximately 0.0015. CONCLUSIONS: We identified a new third allele of HPA-7, which is characterized by a 1297C>T mutation in the GPIIIa gene. This 1297C>T allele was found in 0.15% of the Japanese population. An antibody against this antigen could be the cause of severe NAIT.