Comparison of pathophysiology in subclinical hyperthyroidism with different etiologies.

Subclinical hyperthyroidism (SHyper) is defined as normal levels of free thyroxine (fT4) and free triiodothyronine (fT3) with suppressed levels of TSH. Previous studies have reported the individual pathophysiology of endogenous SHyper patients and athyreotic patients receiving TSH suppression therapy with levothyroxine; however, apparently no studies have compared the two conditions. Five-hundred-forty untreated endogenous SHyper patients and 1,024 patients receiving TSH suppression therapy who underwent total thyroidectomy for papillary thyroid carcinoma were sampled. Thyroid hormone profiles and peripheral indices related to thyrotoxicosis were investigated in endogenous SHyper patients, athyreotic patients receiving TSH suppression therapy, and healthy participants. Endogenous SHyper patients showed significantly higher thyroid hormone levels (fT4 [p < 0.001] and fT3 [p < 0.001]), and peripheral indices showed a significant tendency towards thyrotoxicosis (strong TSH suppression: alkaline phosphatase [ALP, p < 0.001], creatinine [Cre, p < 0.001], pulse rate [p < 0.05]; and mild TSH suppression: Cre [p < 0.05]) than healthy participants. In contrast, athyreotic patients receiving TSH suppression therapy showed a significant tendency towards thyrotoxicosis than healthy participants only when TSH was strongly suppressed (fT3 [p < 0.001] and Cre [p < 0.001]). Endogenous SHyper patients showed significantly higher fT3 levels (p < 0.001) than athyreotic patients receiving TSH suppression therapy; however, there was a significant tendency towards thyrotoxicosis only when TSH was strongly suppressed (ALP [p < 0.05] and pulse rate [p < 0.05]). The effects of endogenous SHyper and TSH suppression therapy on target organ function are different. Although the serum thyroid hormone profile is similar to that of the thyrotoxic state, athyreotic patients receiving TSH suppression therapy with mildly suppressed serum TSH levels are not thyrotoxic.

Pancreatic ß-cell glutaminase 2 maintains glucose homeostasis under the condition of hyperglycaemia.

Glutaminase 2 (GLS2), a master regulator of glutaminolysis that is induced by p53 and converts glutamine to glutamate, is abundant in the liver but also exists in pancreatic ß-cells. However, the roles of GLS2 in islets associated with glucose metabolism are unknown, presenting a critical issue. To investigate the roles of GLS2 in pancreatic ß-cells in vivo, we generated ß-cell-specific Gls2 conditional knockout mice (Gls2 CKO), examined their glucose homeostasis, and validated the findings using a human islet single-cell analysis database. GLS2 expression markedly increased along with p53 in ß-cells from control (RIP-Cre) mice fed a high-fat diet. Furthermore, Gls2 CKO exhibited significant diabetes mellitus with gluconeogenesis and insulin resistance when fed a high-fat diet. Despite marked hyperglycaemia, impaired insulin secretion and paradoxical glucagon elevation were observed in high-fat diet-fed Gls2 CKO mice. GLS2 silencing in the pancreatic ß-cell line MIN6 revealed downregulation of insulin secretion and intracellular ATP levels, which were closely related to glucose-stimulated insulin secretion. Additionally, analysis of single-cell RNA-sequencing data from human pancreatic islet cells also revealed that GLS2 expression was elevated in ß-cells from diabetic donors compared to nondiabetic donors. Consistent with the results of Gls2 CKO, downregulated GLS2 expression in human pancreatic ß-cells from diabetic donors was associated with significantly lower insulin gene expression as well as lower expression of members of the insulin secretion pathway, including ATPase and several molecules that signal to insulin secretory granules, in ß-cells but higher glucagon gene expression in α-cells. Although the exact mechanism by which ß-cell-specific GLS2 regulates insulin and glucagon requires further study, our data indicate that GLS2 in pancreatic ß-cells maintains glucose homeostasis under the condition of hyperglycaemia.

ICAM1-Negative Intravascular Large B-Cell Lymphoma of the Pituitary Gland: A Case Report and Literature Review.

OBJECTIVE: Intravascular large B-cell lymphoma (IVLBCL) is a rare and aggressive type of B-cell lymphoma with large cells growing within the lumen of blood vessels. Although previous reports revealed highly variable symptoms resulting from small-vessel occlusion by neoplastic cells in a variety of organs, there are few reports of IVLBCL with pituitary involvement. METHOD: We present a case of IVLBCL with pituitary infiltration from our institution together with a literature review of similar cases to better understand this rare case of IVLBCL involving the pituitary gland. RESULTS: Our case and the pertinent literature demonstrated that IVLBCL with pituitary involvement predominantly occurred in women at a mean age of 64 years, and most of them showed panhypopituitarism that was reversible after standard therapy of rituximab-containing chemotherapy with intrathecal methotrexate. Notably, the pituitary biopsy in our case revealed that atypical large B-cells found within blood vessels and the pituitary gland were negative for intercellular adhesion molecule 1. Intercellular adhesion molecule 1-negative lymphoid cells may have contributed to panhypopituitarism by extravasation into the pituitary tissues, which do not have a blood-brain barrier and receive abundant blood flow. CONCLUSION: IVLBCL of the pituitary gland is a rare lymphoma with nonspecific manifestations and a dismal prognosis. Recognition of the clinicopathological features is necessary for early clinical diagnosis and appropriate treatment.

Characteristics of benign adrenocortical adenomas with 18F-FDG PET accumulation.

INTRODUCTION: Although 18F-FDG PET was originally developed to evaluate benign and malignant tumors, the frequency of detection of benign adrenocortical adenomas showing FDG-PET accumulation has increased. However, the details of FDG-PET-accumulated benign adrenocortical adenomas have not been elucidated. METHODS: To elucidate the pathophysiology of FDG-PET-positive cortisol-producing adrenal tumors, we performed clinicopathological and genetic analyses of adrenocortical adenomas examing FDG-PET in 30 operated patients with unilateral cortisol-producing adrenal tumors (26 adrenal adenomas and 4 adrenal cancers). RESULTS: All adrenocortical carcinomas and 17/26 (65%) benign adrenocortical adenomas showed high FDG accumulation (SUVmax ≥ 3). In adrenocortical adenomas with high FDG accumulation (SUVmax ≥ 3), SUVmax showed a positive correlation with the CT Hounsfield units. A higher SUVmax showed a clear black adenoma appearance with predominantly compact cells, which exhibited high T1 and T2 signals, a lack of signal drop on out-of-phase imaging on MRI, and less accumulation on 131-I adsterol scintigraphy. Furthermore, RNA-sequencing analysis revealed significant increases in the lysosomal and autophagy pathways and metabolic pathways, including glycolysis through glucose transporter (GLUT) 1 and 3, in black adenomas with high-level FDG accumulation. DISCUSSION: A black adenoma is blackish due to lipofuscin, which accumulates as a result of damaged mitochondria or proteins that escape lysosomal degradation or autophagy. Since FDG in PET is taken up via GLUTs, alteration of the intracellular metabolic dynamics associated with mitochondrial damage in black adenomas may increase PET accumulation. CONCLUSION: Black adrenal adenomas should be considered with adrenal tumors showing PET accumulation and low lipid contents.

Two cases of symptomatic secondary hypophysitis due to Rathke's cleft cysts treated with glucocorticoids: long-term follow-up.

Rathke's cleft cyst (RCC) is a common incidental tumor in the hypothalamic-pituitary region. Some reports have shown that the clinical symptoms and endocrine functions of symptomatic RCCs are temporarily improved by glucocorticoid administration. However, it is still unknown whether glucocorticoid treatment is effective for symptomatic RCCs according to long-term observations. In this study, we describe the long-term clinical outcomes of two cases of glucocorticoid-treated biopsy-proven secondary hypophysitis caused by RCCs. We summarize the symptoms, imaging findings, and endocrine evaluations of two symptomatic RCC patients with concomitant hypophysitis before and after prednisolone treatment. In both evaluated cases, visual impairments and altered endocrine parameters were present due to chiasm and stalk compression; these outcomes improved after shrinkage of RCCs in response to prednisolone administration, and partial recovery of anterior pituitary hormone secretion was observed. However, in both cases, the deficits in anterior pituitary hormone secretion recurred, possibly due to persistent inflammatory infiltration in the RCCs and pituitary glands. After relapse of hypophysitis, anterior hormone secretion did not fully recover. In our cases of secondary hypophysitis caused by RCCs, prednisolone administration had an early effect of cyst shrinkage, followed by partial improvements in clinical symptoms and pituitary functions. However, long-term observation showed that prednisolone treatment did not contribute to complete improvement in anterior pituitary hormone dysfunction.