An Autopsy Case of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis Induced by Propylthiouracil.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a complication caused by antithyroid drugs, particularly propylthiouracil (PTU). Most patients experience organ failure due to the affects of the treatment regimen. We herein report the case of an 89-year-old woman whose severe AAV induced by PTU resulted in various instances of organ failure that eventually led to death after 9 years of PTU therapy. During autopsy, we identified five types of organ failure. As AAV is a potentially fatal disease, the development of various vasculitis symptoms during PTU therapy should therefore be carefully monitored.

Clinical features of anti-pituitary-specific transcription factor-1 (PIT-1) hypophysitis: a new aspect of paraneoplastic autoimmune condition.

The pathogenesis of anti-pituitary-specific transcription factor-1 (PIT-1) hypophysitis was gradually revealed as cases emerged. Our comprehensive analysis, including all reported cases, identified a new instance of anti-PIT-1 hypophysitis postimmune checkpoint inhibitor therapy. All 9 patients exhibited extremely low growth hormone (GH), prolactin (PRL), and thyroid-stimulating hormone (TSH) levels; 2 had a slightly atrophic pituitary gland; 4 had thymoma, and 5 had malignant neoplasms of diffuse large B-cell lymphoma (DLBCL) and other origins. Patients with thymoma showed multiple autoimmune diseases. HLA-A*24:02 and/or A*02:06 were present in six and DR53 in 5 cases analyzed. High anti-PIT-1 antibody titers and ectopic PIT-1 expression in the cytosol and nucleus of the tumor tissues were observed in patients with thymoma or DLBCL, whereas it was exclusively observed in the nuclei of a bladder cancer patient. These findings provide new insights into the pathophysiology of paraneoplastic autoimmune hypophysitis.

Cellular immunity reflects the persistent symptoms among COVID-19 recovered patients in Japan.

Coronavirus disease (COVID-19) often causes persistent symptoms long after infection, referred to as "long COVID" or post-acute COVID-19 syndrome (PACS). This phenomenon has been studied primarily concerning B-cell immunity, while the involvement of T-cell immunity is still unclear. This retrospective study aimed to examine the relationship among the number of symptoms, cytokine levels, and the Enzyme-linked immunosorbent spot (ELISPOT) assay data in patients with COVID-19. To examine inflammatory conditions, plasma interleukin (IL)-6, IL-10, IL-18, chemokine ligand 9 (CXCL9), chemokine ligand 3 (CCL3), and vascular endothelial growth factor (VEGF) levels were analyzed using plasma obtained from COVID-19 recovery patients and healthy controls (HC). These levels were significantly higher in the COVID-19 group than those in the HC group. ELISPOT assays were performed to investigate the correlation between COVID-19 persistent symptoms and T-cell immunity. Cluster analysis of ELISPOT categorized COVID-19 recovery patients in the ELISPOT-high and -low groups, based on the values of S1, S2, and N. The number of persistent symptoms was significantly higher in the ELISPOT-low group than those in the ELISPOT-high group. Thus, T cell immunity is critical for the rapid elimination of COVID-19 persistent symptoms, and its measurement immediately after COVID-19 recovery might predict long-term COVID-19 or PACS.

Coexistence of growth hormone, adrenocorticotropic hormone, and testosterone deficiency associated with coronavirus disease 2019: a case followed up for 15 months.

Coronavirus disease 2019 (COVID-19) is associated with endocrine disorders, but their long-term clinical course remains unclear. We here report the 15-month clinical course for an individual with multiple endocrine disorders of the pituitary gland and testis likely triggered by COVID-19. A 65-year-old man with no history of endocrinopathy was admitted for acute COVID-19 pneumonia. Although his respiratory condition improved after administration of antiviral drugs, his blood pressure dropped suddenly to a preshock level and was refractory to vasopressors. The circulating adrenocorticotropic hormone (ACTH) and cortisol concentrations were low, and secondary adrenal insufficiency was suspected. Administration of hydrocortisone rapidly ameliorated the hypotension, and the patient was discharged taking 15 mg of hydrocortisone daily. An insulin tolerance test performed 3 months later revealed impaired ACTH, cortisol, and growth hormone (GH) responses, indicative of combined hypopituitarism. The patient also manifested symptoms of hypogonadism, and a hormonal workup suggested primary hypogonadism. At 12 months after discharge, GH and ACTH responses had recovered completely and partially, respectively. After another 3 months, basal ACTH and cortisol levels had been restored to the normal range and the patient discontinued hydrocortisone replacement without exacerbation of symptoms, although his hypogonadism persisted. The patient thus developed transient GH and ACTH deficiency that lasted for more than a year as well as persistent primary hypogonadism during intensive care for COVID-19. Certain prolonged symptoms of COVID-19 might be accounted for by such hormonal disturbance.

Diagnostic reference value of antibody levels measured using enzyme immunoassay for subacute sclerosing panencephalitis.

High measles-specific antibody titers in the cerebrospinal fluid (CSF) have important diagnostic significance for subacute sclerosing panencephalitis (SSPE), a progressive neurological disorder caused by measles virus variants. However, the diagnostic reference value of antibody levels and the usefulness of the CSF/serum ratio measured using enzyme immunoassays (EIAs) for SSPE diagnosis remain unclear. To facilitate SSPE diagnosis using EIAs, measles immunoglobulin G (IgG) titers in the CSF and serum of patients with and without SSPE were measured and their CSF/serum antibody ratios evaluated. Serum and CSF antibody levels were compared among three patients with SSPE (59 paired samples), 37 non-SSPE patients, and 2618 patients of unknown backgrounds. Of the 59 paired samples from three patients with SSPE, 56 paired samples (94.9%) showed CSF measles IgG levels ≥0.5 IU/mL and a CSF/serum ratio ≥0.05, whereas non-SSPE cases showed CSF measles IgG levels <0.1 IU/mL and a CSF/serum ratio <0.03. Of the 2618 CSF samples with unknown backgrounds, 951 showed measurable IgG levels with EIA, with a CSF/serum ratio peak of 0.005-0.02, with a 90th percentile of 0.05. Assuming the SSPE criteria as CSF measles IgG ≥0.5 IU/mL and a CSF/serum ratio ≥0.05, only 20 samples (0.8%) with unknown backgrounds were categorized as having SSPE. Conversely, assuming the non-SSPE criteria as CSF measles IgG <0.1 IU/mL and a CSF/serum ratio <0.03, 2403 samples (92%) with unknown backgrounds were categorized as not having SSPE. In conclusion, high CSF/serum ratios (≥0.05) and high measles CSF IgG levels (≥0.5 IU/mL) may be useful for diagnosing SSPE.

Analysis of thyroid function in Japanese patients with coronavirus disease 2019.

Thyroid dysfunction that is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is becoming increasingly recognized. However, only a few reports in Japan have addressed this issue to date. In this study, we sought to clarify whether infection with SARS-CoV-2 affected thyroid hormone levels and whether these hormones could be better predictors of prognosis in patients with coronavirus disease 2019 (COVID-19). Accordingly, we retrospectively examined 147 cases wherein thyroid hormones were measured at the time of admission among 848 Japanese patients with COVID-19 admitted to the Hyogo Prefectural Kakogawa Medical Center. All patients underwent thyroid function testing upon hospital admission. More than half (59.1%) of the patients were euthyroid. Twenty-four percent of patients had serum thyroid-stimulating hormone (TSH) levels lower than the reference range with normal serum free thyroxine (fT4) levels, and 3.4% of the patients had low TSH with high fT4 levels. Over 70% of the patients with moderate and severe COVID-19 had low serum free triiodothyronine (fT3) levels. Serum TSH and fT3 levels were inversely correlated with disease severity. The mortality rate in patients with low serum fT3 levels was significantly higher than that in those with normal serum fT3 levels.

Clinical Heterogeneity of Acquired Idiopathic Isolated Adrenocorticotropic Hormone Deficiency.

Objective: Heterogeneous clinical characteristics are observed in acquired isolated adrenocorticotropic hormone (ACTH) deficiency (IAD); however, its classification remains to be established because of its largely unknown pathophysiology. In IAD, anti-pituitary antibodies have been detected in some patients, although their significance remains unclear. Therefore, this study aimed to classify patients with IAD and to clarify the significance of anti-pituitary antibodies. Design and Methods: We analyzed 46 consecutive patients with IAD. Serum anti-pituitary antibodies were analyzed via immunofluorescence staining using a mouse pituitary tissue. Principal component and cluster analyses were performed to classify IAD patients based on clinical characteristics and autoantibodies. Results: Immunofluorescence analysis using the sera revealed that 58% of patients showed anti-corticotroph antibodies and 6% of patients showed anti-follicular stellate cell (FSC) antibodies. Principal component analysis demonstrated that three parameters could explain 70% of the patients. Hierarchical cluster analysis showed three clusters: Groups A and B comprised patients who were positive for anti-corticotroph antibodies, and plasma ACTH levels were extremely low. Groups A and B comprised middle-aged or elderly men and middle-aged women, respectively. Group C comprised patients who were positive for the anti-FSC antibody and elderly men; plasma ACTH levels were relatively high. Conclusions: Patients with IAD were classified into three groups based on clinical characteristics and autoantibodies. The presence of anti-corticotroph antibody suggested severe injury to corticotrophs. This new classification clearly demonstrated the heterogeneity in the pathogenesis of IAD.

Effects of Insulin Degludec and Insulin Glargine U300 on Day-to-Day Fasting Plasma Glucose Variability in Individuals with Type 1 Diabetes: A Multicenter, Randomized, Crossover Study (Kobe Best Basal Insulin Study 2).

INTRODUCTION: Administered basal insulin markedly influences the fasting plasma glucose (FPG) level of individuals with type 1 diabetes. Insulin degludec (IDeg) and insulin glargine U300 (IGlar U300) are now available as ultra-long-acting insulin formulations, but whether or how their glucose-stabilizing effects differ remains unclear. We will compare the effects of these basal insulins on parameters related to blood glucose control, with a focus on day-to-day glycemic variability, in individuals with type 1 diabetes treated with multiple daily injections. METHODS: A multicenter, randomized, open-label, crossover, comparative study (Kobe Best Basal Insulin Study 2) will be performed at 13 participating institutions in Japan. A total of 46 C-peptide-negative adult outpatients with type 1 diabetes will be randomly assigned 1:1 by a centralized allocation process to IGlar U300 (first period)/IDeg (second period) or IDeg (first period)/IGlar U300 (second period) groups, in which subjects will be treated with the corresponding basal insulin for consecutive 4-week periods. The basal insulin will be titrated to achieve an FPG of less than 130 mg/dL initially and then less than 110 mg/dL if feasible. In the last week of each period, plasma glucose will be determined seven times a day by self-monitoring of blood glucose (SMBG) and intraday and day-to-day glucose excursions will be determined by flash glucose monitoring (FGM). The primary end point is comparison of day-to-day glycemic variability as evaluated by the standard deviation (SD) of FPG during the last week of each treatment period. Secondary end points include the coefficient of variance of FPG, the frequency of severe hypoglycemia as evaluated by SMBG, the duration of hypoglycemia as evaluated by FGM, intraday glycemic variability calculated from both SMBG and FGM data, and the administered insulin dose. PLANNED OUTCOMES: The results of the study will be submitted for publication in a peer-reviewed journal to report differences in the effects of two ultra-long-acting basal insulins, IDeg and IGlar U300. CONCLUSION: This head-to-head comparison will be the first study to compare the effects of IDeg and IGlar U300 on day-to-day FPG variability in C-peptide-negative individuals with type 1 diabetes. TRIAL REGISTRATION: Registered in University Hospital Medical Information Network (UMIN) Clinical Trials Registry as 000029630 on 20 June 2017. FUNDING: Novo Nordisk Pharma Ltd.

Effects of insulin degludec and insulin glargine on day-to-day fasting plasma glucose variability in individuals with type 1 diabetes: a multicentre, randomised, crossover study.

AIMS/HYPOTHESIS: We compared the effects of insulin degludec (IDeg; Des(B30)LysB29(γ-Glu Nε-hexadecandioyl) human insulin) and insulin glargine (IGlar; A21Gly,B31Arg,B32Arg human insulin) on the day-to-day variability of fasting plasma glucose (FPG) levels in individuals with type 1 diabetes treated with basal-bolus insulin injections. METHODS: The effects of basal-bolus insulin therapy for 4 weeks with either IDeg or IGlar as the basal insulin in adult C-peptide-negative outpatients with type 1 diabetes were investigated in an open-label, multicentre, randomised, crossover trial. Randomisation was conducted using a centralised allocation process. The primary endpoints were the SD and CV of FPG during the final week of each treatment period. Secondary endpoints included serum glycoalbumin level, daily dose of insulin, intraday glycaemic variability and frequency of severe hypoglycaemia. RESULTS: Thirty-six randomised participants (17 in the IDeg/IGlar and 19 in the IGlar/IDeg groups) were recruited, and data for 32 participants who completed the trial were analysed. The mean (7.74 ± 1.76 vs 8.56 ± 2.06 mmol/l; p = 0.04) and SD (2.60 ± 0.97 vs 3.19 ± 1.36 mmol/l; p = 0.03) of FPG were lower during IDeg treatment than during IGlar treatment, whereas the CV did not differ between the two treatments. The dose of IDeg was smaller than that of IGlar (11.0 ± 5.2 vs 11.8 ± 5.6 U/day; p < 0.01), but other secondary endpoints did not differ between the treatments. CONCLUSIONS/INTERPRETATION: IDeg yielded a lower FPG level and smaller day-to-day variability of FPG at a lower daily dose compared with IGlar in participants with type 1 diabetes. IDeg serves as a good option for basal insulin in the treatment of type 1 diabetes. TRIAL REGISTRATION: University Hospital Medical Information Network 000009965. FUNDING: This research recieved no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

A PROP1-binding factor, AES cloned by yeast two-hybrid assay represses PROP1-induced Pit-1 gene expression.

PROP1 mutation causes combined pituitary hormone deficiency (CPHD). Several mutations are located in a transactivation domain (TAD) of Prop1, and the loss of TAD binding to cofactors is likely the cause of CPHD. PROP1 cofactors have not yet been identified. In the present study, we aimed to identify the PROP1-interacting proteins from the human brain cDNA library. Using a yeast two-hybrid assay, we cloned nine candidate proteins that may bind to PROP1. Of those nine candidates, amino-terminal enhancer of split (AES) was the most abundant, and we analyzed the AES function. AES dose-dependently decreased the PROP1-induced Pit-1 reporter gene expression. An immunoprecipitation assay revealed the relationship between AES and PROP1. In a mammalian two-hybrid assay, a leucine zipper-like motif of the AES Q domain was identified as a region that interacted with TAD. These results indicated that AES was a corepressor of PROP1.

Branched-chain amino acids reduce hindlimb suspension-induced muscle atrophy and protein levels of atrogin-1 and MuRF1 in rats.

Atrogin-1 and MuRF1, muscle-specific ubiquitin ligases, and autophagy play a role in protein degradation in muscles. We hypothesized that branched-chain amino acids (BCAAs) may decrease atrogin-1, MuRF1, and autophagy, and may have a protective effect on disuse muscle atrophy. To test this hypothesis, we selected hindlimb suspension (HS)-induced muscle atrophy as a model of disuse muscle atrophy because it is an established model to investigate the effects of decreased muscle activity. Sprague-Dawley male rats were assigned to 4 groups: control, HS (14 days), oral BCAA administration (600 mg/[kg day], 22.9% L-isoleucine, 45.8% L-leucine, and 27.6% L-valine), and HS and BCAA administration. After 14 days of the treatment, muscle weights and protein concentrations, cross-sectional area (CSA) of the muscle fibers, atrogin-1 and MuRF1 proteins, and microtubule-associated protein 1 light chain 3 II/I (ratio of LC3 II/I) were measured. Hindlimb suspension significantly reduced soleus muscle weight and CSA of the muscle fibers. Branched-chain amino acid administration partly but significantly reversed the HS-induced decrease in CSA. Hindlimb suspension increased atrogin-1 and MuRF1 proteins, which play a pivotal role in various muscle atrophies. Branched-chain amino acid attenuated the increase in atrogin-1 and MuRF1 in soleus muscles. Hindlimb suspension significantly increased the ratio of LC3 II/I, an indicator of autophagy, whereas BCAA did not attenuate the increase in the ratio of LC3 II/I. These results indicate the possibility that BCAA inhibits HS-induced muscle atrophy, at least in part, via the inhibition of the ubiquitin-proteasome pathway. Oral BCAA administration appears to have the potential to prevent disuse muscle atrophy.

Crosstalk of humoral and cell-cell contact-mediated signals in postnatal body growth.

The growth hormone (GH)-insulin-like growth factor 1 (IGF1) axis mediates postnatal body growth. The GH receptor has been regarded as the sole receptor that mediates the Janus kinase 2 (JAK2)/signal transducers and activators of the transcription 5B (STAT5B) signal toward IGF1 synthesis. Here, we report a signaling pathway that regulates postnatal body growth through EphA4, a member of the Eph family of receptor tyrosine kinases and a mediator of the cell-cell contact-mediated signaling. EphA4 forms a complex with the GH receptor, JAK2, and STAT5B and enhances Igf1 expression predominantly via the JAK2-dependent pathway, with some direct effect on STAT5B. Mice with a defective Epha4 gene have a gene dose-dependent short stature and low plasma IGF1 levels. Igf1 messenger RNA (mRNA) in the liver and many other tissues was also significantly reduced in Epha4-knockout mice, whereas pituitary Gh mRNA and plasma GH levels were not. These findings suggest that the local cell-cell contact-mediated ephrin/EphA4 signal is as important as the humoral GH signal in IGF1 synthesis and body size determination.

Silent intravascular lymphoma initially manifesting as a unilateral adrenal incidentaloma.

Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of malignant lymphoma. Although the involvement of adrenal glands in IVLBCL is often observed, primary adrenal IVLBCL is rare. Most reported cases of adrenal IVLBCL showed bilateral lesions resulting in rapidly progressive adrenal failure and poor prognosis. Here, we report a case of slowly progressive primary adrenal IVLBCL manifesting initially with unilateral adrenal incidentaloma. This case is a silent IVLBCL and shows that the enlargement of both adrenal glands can be followed.

A case of myxedema coma caused by isolated thyrotropin stimulating hormone deficiency and Hashimoto's thyroiditis.

Myxedema coma (MC) is a rare, but often fatal endocrine emergency. The majority of cases that occur in elderly women with long-standing primary hypothyroidism are caused by particular triggers. Conversely, MC of central origin is extremely rare. Here, we report a case of MC with both central and primary origins. A 56-year-old woman was transferred to our hospital due to loss of consciousness; a chest x-ray demonstrated severe cardiomegaly. Low body temperature, bradycardia, and pericardial effusion suggested the presence of hypothyroidism. Endocrinological examination revealed undetectable levels of serum free thyroxine (T(4)) and free triiodothyronine (T(3)), whereas serum thyroid-stimulating hormone (TSH) levels were not elevated. The woman's serum anti-thyroid peroxidase antibody and anti-thyroglobulin antibody tests were positive, indicating that she had Hashimoto's thyroiditis. Provocative tests to the anterior pituitary revealed that she had TSH and growth hormone (GH) deficiency; however, GH levels were restored after supplementation with levothyroxine for 5 months. This was not only a rare case of MC with TSH deficiency and Hashimoto's thyroiditis; the patient also developed severe osteoporosis and possessed transient elevated levels of serum carcinoembryonic antigen (CEA). This atypical case may suggest the role of anterior pituitary hormone deficiencies, as well as hypothyroidism, in the regulation of bone metabolism.

Adult combined GH, prolactin, and TSH deficiency associated with circulating PIT-1 antibody in humans.

The pituitary-specific transcriptional factor-1 (PIT-1, also known as POU1F1), is an essential factor for multiple hormone-secreting cell types. A genetic defect in the PIT-1 gene results in congenital growth hormone (GH), prolactin (PRL), and thyroid-stimulating hormone (TSH) deficiency. Here, we investigated 3 cases of adult-onset combined GH, PRL, and TSH deficiencies and found that the endocrinological phenotype in each was linked to autoimmunity directed against the PIT-1 protein. We detected anti-PIT-1 antibody along with various autoantibodies in the patients' sera. An ELISA-based screening revealed that this antibody was highly specific to the disease and absent in control subjects. Immunohistochemical analysis revealed that PIT-1-, GH-, PRL-, and TSH-positive cells were absent in the pituitary of patient 2, who also had a range of autoimmune endocrinopathies. These clinical manifestations were compatible with the definition of autoimmune polyendocrine syndrome (APS). However, the main manifestations of APS-I--hypoparathyroidism and Candida infection--were not observed and the pituitary abnormalities were obviously different from the hypophysitis associated with APS. These data suggest that these patients define a unique "anti-PIT-1 antibody syndrome," related to APS.

Glucose-responsive insulinoma in a patient with postprandial hypoglycemia in the morning.

We report the case of an obese 79-year-old woman who experienced postprandial hypoglycemia in the morning. The serum immunoreactive insulin (IRI) and C-peptide levels responded in parallel with her serum glucose level during a 75-g oral glucose tolerance test. A prolonged fast test lowered her serum glucose level to 30 mg/dL, but serum IRI was not fully suppressed. Abdominal computed tomography revealed a tumor in the uncinate process of the pancreas. The tumor was histologically diagnosed as benign insulinoma after surgery. Therefore, glucose-responsive insulinoma as well as reactive hypoglycemia should be considered in patients who exhibit postprandial hypoglycemia.