A case of isolated hypothalamitis with a literature review and a comparison with autoimmune hypophysitis.

Idiopathic hypothalamitis is a rare condition that can cause anterior pituitary dysfunction and central diabetes insipidus (CDI), occasionally accompanied by a disturbance of autonomic regulation known as hypothalamic syndrome. This condition has been described as a subtype of autoimmune (lymphocytic) hypophysitis; however, some cases of isolated hypothalamic involvement with no inflammatory lesions in either the pituitary gland or infundibulum have been reported. The detailed epidemiology and pathophysiology of isolated hypothalamitis have not been clarified. We herein report a case of a solitary hypothalamic lesion in a young woman who showed spontaneous development of CDI and panhypopituitarism accompanied by hyperphagia. The hypothalamic lesion increased from 11 × 7 to 17 × 7 mm over 16 months based on the sagittal slices of magnetic resonance imaging examinations. The negative results for anti-pituitary antibodies and anti-Rabphilin-3A antibodies suggested that upward extension of lymphocytic adenohypophysitis or infundibulo-neurohypophysitis was unlikely. Infectious disease, granulomatosis, Langerhans cell histiocytosis, vasculitis, and systemic neoplastic diseases were excluded by the findings of a laboratory investigation, cerebrospinal fluid examination, and imaging studies. To make a definitive diagnosis, we performed a ventriculoscopic biopsy of the hypothalamic lesion. Histology revealed an infiltration of nonspecific lymphoplasmacytes with no evidence of neoplasm, which was consistent with a diagnosis of idiopathic hypothalamitis. Subsequently, the patient was treated with methylprednisolone pulse therapy followed by oral prednisolone. The hypothalamic lesion improved and remained undetectable after withdrawal of the prednisolone, suggesting that the glucocorticoid treatment was effective for isolated hypothalamitis while the patient remains dependent on the replacement of multiple hormones.

Sudden onset of thyrotoxicosis induced by amiodarone mimicking low cardiac output syndrome in a patient with dilated cardiomyopathy.

Amiodarone-induced thyrotoxicosis (AIT) is a complication of amiodarone therapy that can be difficult to diagnose and manage, especially in patients with dilated cardiomyopathy (DCM). We describe a 47-year-old female patient with DCM who experienced the sudden onset of type II AIT with symptoms mimicking low cardiac output syndrome, namely, general malaise and nausea. Early type II AIT was diagnosed, and effectively treated with prednisolone. .

VISCERAL AND SUBCUTANEOUS FAT INCREASED AFTER TREATMENT OF GRAVES DISEASE.

Objective: Patients with Graves disease (GD) tend to gain weight after treatment, but it remains unknown if weight gain is associated with an increase in the visceral and/or subcutaneous fat areas (VFA, SFA). Methods: We enrolled 25 newly diagnosed GD patients (22 females, median age 33.0 years) and studied their clinical parameters, and VFA and SFA measured by a dual bioelectric impedance analysis. We divided them into 2 groups based on the rates of change in the VFA and SFA, and we compared clinical parameters at the baseline between the groups to evaluate factors that influence increases in the VFA and/or SFA with treatment. Results: The patients' body weight (BW), VFA, and SFA were significantly increased after a 6-month treatment (BW: from 54.3 ± 10.3 kg to 58.0 ± 11.2 kg; P<.001; VFA: from 47.1 ± 21.3 cm2 to 54.7 ± 23.4 cm2; P = .004; SFA: from 159.8 ± 85.9 cm2 to 182.2 ± 82.9 cm2; P = .008). The percent changes of BW correlated with the SFA (ρ = .591, P = .002), but not with the VFA. The patients with larger VFA increases had significantly less VFA at the baseline compared to those with smaller increases, expressed as median and interquartile range (33.9 cm2 [22.7 to 47.5 cm2] versus 54.5 cm2 [45.2 to 64.0], respectively; P = .011). A larger increase in the SFA was negatively associated with serum alkaline phosphatase. An increase in the SFA was associated with free triiodothyronine (T3) in a multivariate logistic analysis (odds ratio: 0.80 [0.59 to 0.97]; P = .013). Conclusion: The patients' BW, VFA, and SFA were increased after GD treatment. The increase in SFA seemed to contribute to weight gain and was associated with a low baseline level of free T3. Abbreviations: ALP = alkaline phosphatase; BMI = body mass index; BW = body weight; GD = Graves disease; SFA = subcutaneous fat area; T3 = triiodothyronine; T4 = thyroxine; TG = triglycerides; VFA = visceral fat areas.

Isolated left adrenal medullary hyperplasia.

A 44-year-old Japanese man was referred to our hospital for the evaluation of paroxysmal hypertension. 123I-metaiodobenzylguanidine (MIBG) single-photon emission computed tomography (SPECT) revealed specific uptake in the left adrenal gland in addition to high levels of serum and urinary catecholamines although computed tomography and magnetic resonance imaging were not able to detect a definite adrenal mass. Left adrenalectomy was performed and he was diagnosed with adrenal medullary hyperplasia (AMH). A diagnosis of unilateral AMH is important because AMH resection can effectively treat hypertension. .

Impaired early-phase suppression of glucagon secretion after glucose load is associated with insulin requirement during pregnancy in gestational diabetes.

AIMS/INTRODUCTION: The role of glucagon abnormality has recently been reported in type 2 diabetes; however, its role in gestational diabetes mellitus (GDM) is still unknown. The glucose intolerance in GDM is heterogeneous, and not all patients require insulin treatment during pregnancy. Here, we investigated whether glucagon abnormality is associated with the requirement for insulin treatment during pregnancy. MATERIALS AND METHODS: A total of 49 pregnant women diagnosed with GDM were enrolled. They underwent a 75-g oral glucose tolerance test during mid-gestation, and we measured their plasma glucagon levels (by a new sandwich enzyme-linked immunosorbent assay) at fasting (0 min), and at 30, 60 and 120 min after glucose load in addition to the levels of plasma glucose and serum insulin. All participants underwent another oral glucose tolerance test at postpartum. RESULTS: Of the 49 patients, 15 required insulin treatment (Insulin group) and 34 were treated with diet therapy alone until delivery (Diet group). The early-phase glucagon secretion after glucose load, as determined by the changes in glucagon from the baseline to 30 min, was paradoxically augmented during mid-gestation in the Insulin group, but not in the Diet group. The impaired glucagon suppression during mid-gestation in the Insulin group was not associated with insulin secretory/sensitivity indexes studied, and was ameliorated postpartum, although the plasma glucose levels remained higher in the Insulin group versus the Diet group. CONCLUSIONS: Impaired early-phase suppression of glucagon could be associated with the requirement for insulin treatment during pregnancy in patients with GDM.

RENAL FUNCTION AND PLASMA RENIN ACTIVITY AS POTENTIAL FACTORS CAUSING HYPERKALEMIA IN PATIENTS WITH THYROID CARCINOMA UNDERGOING THYROID HORMONE WITHDRAWAL FOR RADIOACTIVE IODINE THERAPY.

Objective: Hypothyroidism is not commonly considered a cause of hyperkalemia. We previously reported that hyperkalemia was observed mainly in elderly patients treated with renin-angiotensin-aldosterone system (RAS) inhibitors when levothyroxine treatment was withdrawn for the thyroidectomized patients with thyroid carcinoma to undergo radioactive iodine treatment. Here, we investigated whether acute hypothyroidism causes hyperkalemia in patients who were not treated with RAS inhibitors. We also investigated factors influencing potassium metabolism in hypothyroid patients. Methods: We conducted a single-center, prospective cohort study of 46 Japanese patients with thyroid carcinoma undergoing levothyroxine withdrawal prior to radioiodine therapy. All patients were normokalemic before levothyroxine withdrawal. Blood samples were analyzed 3 times: before, and at 3 and 4 weeks after levothyroxine withdrawal. We investigated factors that may be associated with the elevation of serum potassium levels from a euthyroid state to a hypothyroid state. Results: None of the patients developed symptomatic hyperkalemia. The mean serum potassium level was significantly higher at 4 weeks after levothyroxine withdrawal compared to baseline. The serum sodium levels, the estimated glomerular filtration rate (eGFR), and the plasma renin activity (PRA) decreased significantly as hypothyroidism advanced. In contrast, the plasma levels of adrenocorticotropic hormone, cortisol, aldosterone, and antidiuretic hormone were not changed, while serum thyroid hormone decreased. At 4 weeks after their levothyroxine withdrawal, the patients' serum potassium values were significantly correlated with the eGFR and the PRA. Conclusion: Acute hypothyroidism can cause a significant increase in the serum potassium level, which may be associated with a decreased eGFR and decreased circulating RAS. Abbreviations: ACTH = adrenocorticotropic hormone; ADH = antidiuretic hormone; ATPase = adenosine triphosphatase; eGFR = estimated glomerular filtration rate; HbA1c = glycated hemoglobin; K+ = potassium; Na+ = sodium; PRA = plasma renin activity; RAS = renin-angiotensin-aldosterone system; T4 = thyroxine; TSH = thyroid-stimulating hormone.

[A Case of Flexion Contracture Associated with Hypopituitarism].

A 72-year-old Japanese man developed progressive disturbance in ambulation with flexion contractures 5years before this admission. At 49 years of age, he was diagnosed with hypopituitarism after an operation for a Rathke's cleft. On admission, he could not fully extend his knees and hips because of painful muscle stiffness of the lower extremities. Initially, we suspected Stiff-person syndrome and initiated diazepam, which had no effect. Serum anti-glutamic acid decarboxylase antibody was negative. Next, we suspected flexion contractures associated with hypopituitarism. Endocrine evaluation revealed that ACTH, cortisol, and other hormone levels were lower than those reported in the previous evaluation. We treated the patient with hydrocortisone and his symptoms dramatically improved. It is rare for patients with hypopituitarism to have flexion contracture. This case suggests that we should consider hypopituitararism in the setting of flexion contractures. (Received October 18, 2018; Accepted March 26, 2019; Published June 1, 2019).

Cinacalcet corrects biased allosteric modulation of CaSR by AHH autoantibody.

Biased agonism is a paradigm that may explain the selective activation of a signaling pathway via a GPCR that activates multiple signals. The autoantibody-induced inactivation of the calcium-sensing receptor (CaSR) causes acquired hypocalciuric hypercalcemia (AHH). Here, we describe an instructive case of AHH in which severe hypercalcemia was accompanied by an increased CaSR antibody titer. These autoantibodies operated as biased allosteric modulators of CaSR by targeting its Venus flytrap domain near the Ca2+-binding site. A positive allosteric modulator of CaSR, cinacalcet, which targets its transmembrane domain, overcame this autoantibody effect and successfully corrected the hypercalcemia in this patient. Hence, this is the first study to our knowledge that identifies the interaction site of a disease-causing GPCR autoantibody working as its biased allosteric modulator and demonstrates that cinacalcet can correct the AHH autoantibody effects both in vitro and in our AHH patient. Our observations provide potentially new insights into how biased agonism works and how to design a biased allosteric modulator of a GPCR. Our observations also indicate that the diagnosis of AHH is important because the severity of hypercalcemia may become fatal if the autoantibody titer increases. Calcimimetics may serve as good treatment options for some patients with severe AHH.

Relation between change in treatment for central diabetes insipidus and body weight loss.

BACKGROUND: Patients with central diabetes insipidus (CDI) are known to lose weight because their polydipsia interferes with their nutritional intake. We retrospectively examined weight changes in CDI patients when they switched from nasal to oral desmopressin. METHODS: Twenty-three patients with CDI were included. Weight change was defined as an increase or decrease of more than 3 kg or 3% body weight. As factors contributing to the weight change, we studied the patients' clinical characteristics and quality of life (QOL) scores as determined by our original questionnaire. RESULTS: Five patients showed a weight loss of 5.9 kg (2.4-9.0 kg), and two patients showed weight gain, while 16 out of 23 patients were weight neutral. When the patients with weight gain and weight neutral were analyzed together, the mean weight change was +0.3 kg (-0.5 to +1.1 kg). All the patients who lost weight had a Body Mass Index ≥22 kg/m2 (38% vs. 0%, P=0.027) and higher frequencies of abnormally high serum levels of AST (40% vs. 0%, P=0.005). The sum of the QOL scores was similar between the two groups, but higher in patients who lost weight after switching to oral desmopressin (43.3±2.7) than in those who did not (38.2±5.0, P=0.01). CONCLUSIONS: Switching the treatment from nasal to oral desmopressin may cause weight loss in patients with CDI who seemed to have polydipsia-associated weight gain.

HYPOTHYROIDISM COULD BE A POTENTIAL FACTOR TO PROLONG SUBCUTANEOUS NODULES OF EXENATIDE ONCE WEEKLY: A CASE REPORT.

OBJECTIVE: Exenatide once weekly (ExeOW) is one of the long-acting glucagon-like peptide 1 receptor agonists. Embedding exenatide in poly(D,L-lactide-co-glycolide) microspheres enables the once-weekly subcutaneous injection of exenatide as a treatment for diabetes. We report a case of a patient with type 2 diabetes and hypothyroidism who developed long-standing subcutaneous nodules after treatment by ExeOW injection. METHODS: Case report and review of the literature. A 57-year-old Japanese man with type 2 diabetes treated with ExeOW and primary hypothyroidism. RESULTS: We observed multiple subcutaneous nodules remaining at the ExeOW injection site for >10 weeks. As the patient's thyroid hormone levels normalized, these nodules decreased and disappeared, and his hemoglobin A1c levels improved. CONCLUSION: The patient's clinical course suggests that the hydrolysis of ExeOW at the site of injection may be inhibited by concomitant hypothyroidism, in which glycosaminoglycans including hyaluronic acid are known to accumulate (including in the skin). This case may indicate that hypothyroidism prolongs the existence of subcutaneous nodules from ExeOW treatment.

Predictive factors of efficacy of combination therapy with basal insulin and liraglutide in type 2 diabetes when switched from longstanding basal-bolus insulin: Association between the responses of ß- and α-cells to GLP-1 stimulation and the glycaemic control at 6 months after switching therapy.

AIMS: To evaluate the glycaemic control of combination therapy with basal insulin and liraglutide, and to explore the factors predictive of efficacy in patients with type 2 diabetes when switched from longstanding basal-bolus insulin therapy. METHODS: We studied 41 patients who switched from basal-bolus insulin therapy of more than 3 years to basal insulin/liraglutide combination therapy. Glycaemic control was evaluated at 6 months after switching therapy and used to subdivide the patients into good-responders (HbA1c <7.0% or 1.0% decrease) and poor-responders (the rest of participants). To evaluate the glucose-dependent insulin/glucagon responses without/with liraglutide, a 75-g oral glucose tolerance test (OGTT) was performed twice, before (1st-OGTT) and 2-days after (2nd-OGTT) liraglutide administration. RESULTS: Twenty-eight patients (68.3%) were identified as good-responders. No differences were found in baseline characteristics including insulin/glucagon responses during 1st-OGTT between the groups. 2nd-OGTT revealed that paradoxical hyperglucagonemia were significantly improved in both groups, but significant increases in insulin secretory response were observed only in good-responders. Logistic regression analyses revealed that the improvement of the insulin-response during 2nd-OGTT compared to that during 1st-OGTT is associated with the good-responder. CONCLUSIONS: Enhancement of glucose-dependent insulin-response under liraglutide administration is a potential predictor of long-term glycaemic control after switching the therapies.

Type 1 Diabetes Mellitus Diagnosed during Follow-up of Gestational Diabetes Mellitus in the Early Postpartum Period.

A 27-year-old woman with a history of gestational diabetes mellitus (GDM) developed type 1 diabetes mellitus (T1D) in the early postpartum period. Women with a history of GDM are at an increased risk of developing T1D, which is rarer than type 2 diabetes mellitus. A postpartum follow-up 75-g oral glucose tolerance test and the measurement of glutamic acid decarboxylase autoantibodies aided in the early detection of T1D in this patient. Careful attention should be paid to women with a history of GDM who exhibit clinical features suggestive of future development of T1D.

Sex differences in insulin and glucagon responses for glucose homeostasis in young healthy Japanese adults.

It has been reported that glucose responses during the oral glucose tolerance test differ between healthy women and men. However, it remains unknown what factors contribute to these differences between the sexes. The present study analyzed the insulin and glucagon responses during the oral glucose tolerance test in 25 female and 38 male healthy young adults aged 22-30 years. The plasma glucose levels at 120 min were significantly higher in women than men. Insulin secretion was significantly greater at 30, 90 and 120 min from baseline in women than men. Glucagon suppression was greater at 30 and 120 min from baseline in men than women when determined by a sandwich enzyme-linked immunosorbent assay glucagon kit. These results suggest that the differences in glucose responses during the oral glucose tolerance test are mediated by the difference between the sexes in bi-hormonal responses in healthy individuals.

Late-onset Cerebrotendinous Xanthomatosis with a Novel Mutation in the CYP27A1 Gene.

Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive, inborn disruption in bile acid synthesis characterized by severe systemic xanthomas, cataracts and neurological injuries occurring before adolescence without elevation of the serum cholesterol or triglyceride levels. CTX is caused by a deficiency of the mitochondrial enzyme sterol 27-hydroxylase, which is encoded by the CYP27A1 gene. We herein report a 50-year-old Japanese woman with late-onset CTX who had no relevant symptoms before the development of bilateral Achilles tendon xanthomas in middle age. A genetic analysis revealed a compound heterozygous mutation in the CYP27A1 gene with a previously known missense mutation (NM_000784.3:c.1421 G>A) and a novel frame shift mutation of NM_000784.3:c.1342_1343insCACC.

Sporadic pediatric papillary thyroid carcinoma harboring the ETV6/NTRK3 fusion oncogene in a 7-year-old Japanese girl: a case report and review of literature.

BACKGROUND: There have been great concerns about pediatric thyroid cancers after the accident at the Fukushima Daiichi Nuclear Power Plant in 2011. CASE PRESENTATION: We report a case of a 7-year-old Japanese girl with sporadic papillary thyroid carcinoma (PTC) harboring an ETV6/NTRK3 rearrangement. The patient presented with tumors in both lobes and underwent thyroidectomy followed by radioactive iodine (RAI) ablation. Histopathology showed a classic type of PTC with cervical lymph node metastasis. CONCLUSIONS: Genetic evaluation showed ETV6/NTRK3 fusion but no BRAF mutations or RET/PTC rearrangements. RET/PTC rearrangement and BRAF mutations often contribute to the pathogenesis of PTC; however, rearrangements of NTRK genes are relatively rare in pediatric PTC. Although NTRK rearrangement has been shown to often present unique pathological types and infiltrative architectures in the western population, such findings were not observed in this patient. Thus, the present case of classic PTC with ETV6/NTRK3 rearrangement highlights the disparate collection of clinic-pathological features compared to the trend in the western population. We therefore emphasize the need to further accumulate clinical as well as genetic data in pediatric PTCs.

Increased sugar intake as a form of compensatory hyperphagia in patients with type 2 diabetes under dapagliflozin treatment.

AIMS: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) cause substantially less weight loss than would be expected based on their caloric deficits, probably due to enhanced appetite regulation known as "compensatory hyperphagia," which occurs to offset the negative energy balance caused by increased glycosuria. We examined whether any specific nutrients contributed to the compensatory hyperphagia in diabetic patients taking SGLT2i. METHODS: Sixteen patients with type 2 diabetes were newly administered dapagliflozin 5 mg daily as the experimental SGLT2i group. Sixteen age-, sex- and BMI-matched type 2 diabetes patients not receiving dapagliflozin served as controls. A brief-type self-administered diet history questionnaire (BDHQ) was undertaken just before and 3 months after study initiation to evaluate changes of energy and nutrient intakes in each group. RESULTS: At 3 months, daily intakes of total calories and the proportions of the three major nutrients were not significantly increased in either group. However, daily sucrose intake was significantly increased after treatment versus the baseline value in the SGLT2i group (p = .003), but not in controls. The calculated intakes of all other nutrients were not significantly changed in either group. CONCLUSIONS: Dapagliflozin treatment specifically increased sucrose intake, which might be an ideal target for nutritional approaches to attenuate compensatory hyperphagia.

Thyroid Dysfunction and Autoimmune Thyroid Diseases Among Atomic Bomb Survivors Exposed in Childhood.

Context: The risk of thyroid cancer increases and persists for decades among individuals exposed to ionizing radiation in childhood, although the long-term effects of childhood exposure to medium to low doses of radiation on thyroid dysfunction and autoimmune thyroid diseases have remained unclear. Objective: To evaluate radiation dose responses for the prevalence of thyroid dysfunction and autoimmune thyroid disease among atomic bomb survivors exposed in childhood. Design, Setting, and Participants: Hiroshima and Nagasaki atomic bomb survivors who were younger than 10 years old at exposure underwent thyroid examinations at the Radiation Effects Research Foundation between 2007 and 2011, which was 62 to 66 years after the bombing. Data from 2668 participants (mean age, 68.2 years; 1455 women) with known atomic bomb thyroid radiation doses (mean dose, 0.182 Gy; dose range, 0 to 4.040 Gy) were analyzed. Main Outcome and Measures: Dose-response relationships between atomic bomb radiation dose and the prevalence of hypothyroidism, hyperthyroidism (Graves' disease), and positive for antithyroid antibodies. Results: Prevalences were determined for hypothyroidism (129 cases, 7.8%), hyperthyroidism (32 cases of Graves' disease, 1.2%), and positive for antithyroid antibodies (573 cases, 21.5%). None of these was associated with thyroid radiation dose. Neither thyroid antibody-positive nor -negative hypothyroidism was associated with thyroid radiation dose. Additional analyses using alternative definitions of hypothyroidism and hyperthyroidism found that radiation dose responses were not significant. Conclusions: Radiation effects on thyroid dysfunction and autoimmune thyroid diseases were not observed among atomic bomb survivors exposed in childhood, at 62 to 66 years earlier. The cross-sectional design and survival bias were limitations of this study.

Thyroid Storm Precipitated by Diabetic Ketoacidosis and Influenza A: A Case Report and Literature Review.

A 46-year-old woman with a history of Graves' disease presented with the chief complaints of appetite loss, weight loss, fatigue, nausea, and sweating. She was diagnosed with diabetic ketoacidosis (DKA), thyroid storm, and influenza A. She was treated with an intravenous insulin drip, intravenous fluid therapy, intravenous hydrocortisone, oral potassium iodine, and oral methimazole. As methimazole-induced neutropenia was suspected, the patient underwent thyroidectomy. It is important to maintain awareness that thyroid storm and DKA can coexist. Furthermore, even patients who have relatively preserved insulin secretion can develop DKA if thyroid storm and infection develop simultaneously.

Low-carbohydrate diet combined with SGLT2 inhibitor for refractory hyperglycemia caused by insulin antibodies.

A low-carbohydrate diet is effective to improve hyperglycemia via insulin-independent actions. We report here that a low-carbohydrate diet combined with an SGLT2 inhibitor was effective and safe to treat refractory hyperglycemia in the perioperative period in a type 2 diabetes patient complicated with a high titer of insulin antibodies.