Studies on anti-rabphilin-3A antibodies in 15 consecutive patients presenting with central diabetes insipidus at a single referral center.

Central diabetes insipidus (CDI) is a rare condition caused by various underlying diseases including inflammatory and autoimmune diseases, and neoplasms. Obtaining an accurate definitive diagnosis of the underlying cause of CDI is difficult. Recently, anti-rabphilin-3A antibodies were demonstrated to be a highly sensitive and specific marker of lymphocytic infundibuloneurohypophysitis (LINH). Here, we report a detailed case series, and evaluated the significance of anti-rabphilin-3A antibodies in differentiating the etiologies of CDI. A prospective analysis was conducted in 15 consecutive patients with CDI from 2013 to 2020 at a single referral center. Anti-rabphilin-3A antibodies were measured and the relationship between antibody positivity and the clinical/histopathological diagnoses was evaluated. Among 15 CDI patients, the positive anti-rabphilin-3A antibodies were found in 4 of 5 LINH cases, 3 of 4 lymphocytic panhypophysitis (LPH) cases, one of 2 sarcoidosis cases, and one intracranial germinoma case, respectively. Two Rathke cleft cyst cases and one craniopharyngioma case were negative. This is the first report of anti-rabphilin-3A antibodies positivity in CDI patients with biopsy-proven LPH. Measurement of anti-rabphilin-3A antibodies may be valuable for differentiating CDI etiologies.

Type 1 diabetes mellitus following COVID-19 RNA-based vaccine.

The epidemic of coronavirus disease-2019 (COVID-19) is the major public health issue in the world. COVID-19 vaccines are one of the most effective strategies against COVID-19. Here we report a 36-year-old female patient who had thirst, polydipsia, polyuria, palpitations, loss of appetite, and fatigue 3 days after the first dose of COVID-19 RNA-based vaccines without a prior history of diabetes. Ten days after vaccination, she visited our hospital with diabetic ketoacidosis and was diagnosed with type 1 diabetes. Hyperglycemia (501 mg/dL), anion gap metabolic acidosis and ketonuria were observed. The glycated hemoglobin level was 7.0%. Islet-related autoantibodies were all negative. The glucagon tolerance test revealed attenuated secretion of insulin. Human leukocyte antigen was haplotype DRB1*0405-DQB1*0401, which was associated with type 1 diabetes in Japan. The present case suggests that COVID-19 RNA-based vaccines might trigger the onset of type 1 diabetes, even in subjects without prior histories of diabetes.

Fulminant Type 1 Diabetes Mellitus Developed about Half a Year after Discontinuation of Immune Checkpoint Inhibitor Combination Therapy with Nivolumab and Ipilimumab: A Case Report.

The cytotoxic T-lymphocyte antigen-4 and programmed cell death 1 pathways are novel therapeutic targets in immune checkpoint inhibitor (ICI) therapy for cancer. However, they may cause endocrine-related adverse events, including hypophysitis, autoimmune thyroiditis and type 1 diabetes mellitus (DM). Moreover, delayed immune-related adverse events (irAEs) after discontinuation of ICI therapy have been reported. Here we report a 60-year-old female patient with advanced renal cell carcinoma with brain metastasis who was treated with nivolumab, ipilimumab and prednisolone. At the 3rd course of combination therapy, the administration was discontinued due to the onset of colitis and the dosage of prednisolone was increased. About half a year after discontinuation, she was admitted to the hospital with general malaise, hyperglycemia (330 mg/dL) and diabetic ketoacidosis. Glycated hemoglobin level was 6.5%. Islet-related autoantibodies were negative. The glucagon tolerance test showed complete depletion of insulin. Therefore, we diagnosed fulminant type 1 DM and treated with multiple daily injections of insulin. The onset of type 1 DM was rapid in many cases treated with combination therapy of ICIs. The present case is a rare case in which fulminant type 1 DM developed about half a year after discontinuation of nivolumab and ipilimumab. The literature shows two cases of type 1 DM occurring 4 months after discontinuation of ICI therapy by nivolumab or atezolizumab. The present case indicates that regular monitoring is mandatory for fulminant type 1 DM and other delayed irAEs after discontinuation of ICI therapy even under the low-dose prednisolone treatment.

Sight-Threatening Graves' Ophthalmopathy during the Third Trimester of Pregnancy: A Case Report.

Dysthyroid optic neuropathy is a severe manifestation of Graves' ophthalmopathy that can result in permanent vision loss. We report a 37-year-old pregnant woman with Graves' ophthalmopathy which was deteriorated to dysthyroid optic neuropathy in the third trimester of pregnancy. Diplopia, bilateral eye lid retraction, lid edema and proptosis were observed in the 29th week of gestation. Thyroid-stimulating hormone (TSH) level was decreased with a normal level of free triiodothyronine (FT3) and an upper normal level of free thyroxine (FT4). Anti-TSH receptor antibodies (16.2 IU/L, reference range < 2.0 IU/L) and thyroid stimulating antibody (4,443%, reference range < 120%) were positive. Magnetic resonance imaging (MRI) demonstrated a significant enlargement of the extraocular muscles with a high signal intensity on T2-weighted image. She was diagnosed as Graves' ophthalmopathy and subclinical hyperthyroidism, and followed without treatment. In the 34th week of gestation, the symptom of color vision abnormality appeared, suggesting dysthyroid optic neuropathy. She delivered a female infant during the 36th week of gestation. Four days after delivery, she had a spontaneous orbital pain. MRI showed that the extraocular muscles were more enlarged than the findings in the 29th week of gestation. FT3 and FT4 levels were mildly elevated. Dysthyroid optic neuropathy was diagnosed. She was treated with methylprednisolone pulse therapy and retrobulbar injections of betamethasone valerate, and the ocular symptoms improved. The present case shows that the glucocorticoid therapy performed one week after delivery is effective against Graves' ophthalmopathy which was deteriorated to dysthyroid optic neuropathy during the third trimester of pregnancy.

Painless Thyroiditis and Fulminant Type 1 Diabetes Mellitus in a Patient Treated with an Immune Checkpoint Inhibitor, Nivolumab.

The programmed cell death-1 (PD-1) pathway is a novel therapeutic target in immune checkpoint therapy for cancer. Nivolumab, an anti-PD-1 monoclonal antibody, blocks PD-1 and can restore anti-cancer immune responses by disrupting the signal that inhibits T-cell activation. Nivolumab may induce endocrine-related adverse events, including hypophysitis, autoimmune thyroiditis, and type 1 diabetes mellitus. Here we report a 68-year-old female patient with advanced renal cell carcinoma who was treated with nivolumab. She had positive anti-thyroglobulin antibodies and anti-thyroid peroxidase antibodies with slightly elevated thyroid-stimulating hormone (9.048 µU/mL), and was diagnosed as chronic thyroiditis with subclinical hypothyroidism before nivolumab therapy. She developed painless thyroiditis after the first cycle of the therapy (Day 14). At the 7th cycle of nivolumab therapy (Day 98), hyperglycemia (473 mg/dL) was noted, whereas glycated hemoglobin level was 6.9%. Islet-related autoantibodies were all negative. The glucagon tolerance test showed complete depletion of insulin. Human leukocyte antigen typing showed haplotype DRB1*09:01-DQB1*03:03, which was reported to be closely associated with type 1 diabetes mellitus in Japan. Fulminant type 1 diabetes mellitus was diagnosed, and she was immediately treated with multiple daily injections of insulin. Fulminant type 1 diabetes mellitus is characterized by rapid-onset diabetic ketoacidosis, and negative islet-related autoantibodies, and was proposed as a novel subtype of non-autoimmune diabetes. Preceding painless thyroiditis with positive thyroid autoantibodies observed in the present case, however, raises the possibility that autoimmune mechanisms are involved in the pathogenesis of nivolumab-induced fulminant type 1 diabetes mellitus.

Bromocriptine, a dopamine agonist, increases growth hormone secretion in a patient with acromegaly.

Bromocriptine, a potent D2-dopamine agonist, suppresses growth hormone (GH) secretion in most patients with acromegaly and has been approved for the treatment of acromegaly. Here we report a patient with acromegaly who showed increased GH secretion after administration of bromocriptine. A 70-year-old man with acromegalic manifestation was admitted to our hospital because of a pituitary tumor invading to the right cavernous sinus detected by brain magnetic resonance imaging. Serum GH and insulin-like growth factor-I (IGF-I) levels were elevated in several occasions (GH: 15.0-51.7 ng/mL, reference range: <2.47 ng/mL; and IGF-I: 776-856 ng/mL, reference range: 57-175 ng/mL). Effect of bromocriptine on serum GH levels was then studied because pre-operative treatment with a D2-dopamine agonist was planned in order to reduce the tumor size and serum GH levels before surgery. After oral administration of 2.5 mg of bromocriptine, serum GH levels were unexpectedly increased from 30.7 ng/mL to 189 ng/mL, despite the fact that the levels of prolactin (PRL) were decreased from 4.2 ng/mL to 0.6 ng/mL. By contrast, serum GH levels were decreased by a somatostatin analogue, octreotide. Transsphenoidal surgery of the pituitary tumor was performed after treatment of octreotide. Histological analysis and immunohistochemistry revealed a GH-producing pituitary adenoma positive for D2-dopamine receptor. This case of acromegaly suggests that the preliminary test with a single administration of a short-acting D2-dopamine agonist, bromocriptine, is mandatory before the long-term therapy with a D2-dopamine agonist in patients with GH-secreting pituitary tumors.