Yoshihisa Sugimura

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2, and various complications have been reported. Furthermore, there have been increasing reports of endocrinopathy related to COVID-19 following the pandemic. We report a 49-year-old healthy woman who developed rapid onset of polydipsia and polyuria three weeks after COVID-19. Laboratory tests indicated low urine osmolarity and increased serum osmolarity, and antidiuretic hormone (ADH) was undetectable. Urine osmolality remained low with water deprivation. Similarly, plasma ADH responses to hypertonic-saline infusion were blunted and urine osmolality increased in response to desmopressin. There was no clear evidence of anterior pituitary dysfunction. T1-weighted magnetic resonance imaging (MRI) showed pituitary stalk thickening and absence of posterior pituitary bright signal spots, suggesting the presence of hypophysitis. Based on these results, we made a probable diagnosis of lymphocytic infundibulo-neurohypophysitis (LINH) which have caused central diabetes insipidus. Positive findings for serum anti-rabphilin-3A antibodies, reported as a potential diagnostic marker for LINH, were also noted. Following oral desmopressin administration, polydipsia and polyuria were quickly improved, though treatment with desmopressin was still required over four months. This is the first report of a patient with a probable diagnosis of LINH after COVID-19 who tested positive for anti-rabphilin-3A antibodies. Positive findings for those antibodies suggest that pituitary dysfunction associated with COVID-19 is hypophysitis involving an abnormal immune mechanism. The presence of anti-rabphilin-3A antibodies may be useful as a non-invasive diagnostic marker of LINH and potentially serve as a valuable diagnostic aid in cases of LINH associated with COVID-19.

Hyponatremia is the most common clinical electrolyte disorder. Chronic hyponatremia has been recently reported to be associated with falls, fracture, osteoporosis, neurocognitive impairment, and mental manifestations. In the treatment of chronic hyponatremia, overly rapid correction of hyponatremia can cause osmotic demyelination syndrome (ODS), a central demyelinating disease that is also associated with neurological morbidity and mortality. Using a rat model, we have previously shown that microglia play a critical role in the pathogenesis of ODS. However, the direct effect of rapid correction of hyponatremia on microglia is unknown. Furthermore, the effect of chronic hyponatremia on microglia remains elusive. Using microglial cell lines BV-2 and 6-3, we show here that low extracellular sodium concentrations (36 mmol/L decrease; LS) suppress Nos2 mRNA expression and nitric oxide (NO) production of microglia. On rapid correction of low sodium concentrations, NO production was significantly increased in both cells, suggesting that acute correction of hyponatremia partly directly contributes to increased Nos2 mRNA expression and NO release in ODS pathophysiology. LS also suppressed expression and nuclear translocation of nuclear factor of activated T cells-5 (NFAT5), a transcription factor that regulates the expression of genes involved in osmotic stress. Furthermore, overexpression of NFAT5 significantly increased Nos2 mRNA expression and NO production in BV-2 cells. Expressions of Nos2 and Nfat5 mRNA were also modulated in microglia isolated from cerebral cortex in chronic hyponatremia model mice. These data indicate that LS modulates microglial NO production dependent on NFAT5 and suggest that microglia contribute to hyponatremia-induced neuronal dysfunctions.

BACKGROUND: Arginine vasopressin deficiency (AVP-D) can occur due to various conditions, so clarifying its cause is important for deciding treatment strategy. Although several cases of AVP-D following coronavirus disease 2019(COVID-19) infection or COVID-19 vaccination have been reported, the diagnosis of the underlying disease has not been reported in most cases. CASE PRESENTATION: A 75-year-old woman who presented with polydipsia and polyuria 9 weeks after contracting COVID-19 and 5 weeks after receiving the SARS-CoV-2 vaccination, leading to the final diagnosis of AVP-D 8 months after the first appearance of symptoms. Interestingly, pituitary magnetic resonance imaging (MRI) still revealed stalk enlargement frequently observed in patients with SARS-CoV-2 vaccination-induced AVP-D. Although this finding could not rule out any malignancies, we additionally measured anti-rabphilin-3A antibodies, a known marker for lymphocytic infundibulo-neurohypophysitis (LINH), and found that the results were positive, strongly suggesting LINH as the cause of this disease. Thus, we avoided pituitary biopsy. At the follow-up MRI conducted 12 months after the initial consultation, enlargement of the pituitary stalk was still observed. CONCLUSION: We experienced a case with LINH probably induced by SARS-CoV-2 vaccination. In SARS-CoV-2 vaccination-related LINH, unlike typical LINH, there is a possibility of persistent pituitary stalk enlargement on MRI images for an extended period, posing challenges in differential diagnosis from other conditions. Pituitary stalk enlargement and positive anti-rabphilin-3A antibodies may help in the diagnosis of AVP-D induced by SARS-CoV-2 vaccination.

(1) Background: Proglucagon-derived peptides (PDGPs) including glucagon (Gcg), GLP-1, and GLP-2 regulate lipid metabolism in the liver, adipocytes, and intestine. However, the mechanism by which PGDPs participate in alterations in lipid metabolism induced by high-fat diet (HFD) feeding has not been elucidated. (2) Methods: Mice deficient in PGDP (GCGKO) and control mice were fed HFD for 7 days and analyzed, and differences in lipid metabolism in the liver, adipose tissue, and duodenum were investigated. (3) Results: GCGKO mice under HFD showed lower expression levels of the genes involved in free fatty acid (FFA) oxidation such as Hsl, Atgl, Cpt1a, Acox1 (p < 0.05), and Pparα (p = 0.05) mRNA in the liver than in control mice, and both FFA and triglycerides content in liver and adipose tissue weight were lower in the GCGKO mice. On the other hand, phosphorylation of hormone-sensitive lipase (HSL) in white adipose tissue did not differ between the two groups. GCGKO mice under HFD exhibited lower expression levels of Pparα and Cd36 mRNA in the duodenum as well as increased fecal cholesterol contents compared to HFD-controls. (4) Conclusions: GCGKO mice fed HFD exhibit a lesser increase in hepatic FFA and triglyceride contents and adipose tissue weight, despite reduced β-oxidation in the liver, than in control mice. Thus, the absence of PGDP prevents dietary-induced fatty liver development due to decreased lipid uptake in the intestinal tract.

Orthostatic hypotension (OH) is a common condition. Many potential etiologies of OH have been identified, but in clinical practice the underlying cause of OH is often unknown. In the present study, we identified a novel and extraordinary etiology of OH. We describe a first case of acquired severe OH with syncope, and the female patient had extremely low levels of catecholamines and serotonin in plasma, urine and cerebrospinal fluid (CSF). Her clinical and biochemical evidence showed a deficiency of the enzyme aromatic l-amino acid decarboxylase (AADC), which converts l-DOPA to dopamine, and 5-hydroxytryptophan to serotonin, respectively. The consequence of pharmacologic stimulation of catecholaminergic nerves and radionuclide examination revealed her catecholaminergic nerves denervation. Moreover, we found that the patient's serum showed presence of autoantibodies against AADC, and that isolated peripheral blood mononuclear cells (PBMCs) from the patient showed cytokine-induced toxicity against AADC. These observations suggest that her autoimmunity against AADC is highly likely to cause toxicity to adrenal medulla and catecholaminergic nerves which contain AADC, resulting in hypocatecholaminemia and severe OH. Administration of vitamin B6, an essential cofactor of AADC, enhanced her residual AADC activity and drastically improved her symptoms. Our data thus provide a new insight into pathogenesis and pathophysiology of OH.