Subacute Thyroiditis Developing Within 2 Days of Vaccination Against COVID-19 with BNT162b2 mRNA.

A 32-year-old woman presented to the outpatient clinic with persistent fever, anterior neck pain, and palpitations over the past week which developed 2 days after she had received the first dose of the Pfizer/BioNTech SARS-CoV-2 mRNA vaccine. On examination, the patient's heart rate was 140 beats per minute and the thyroid gland was tender on palpation. Laboratory studies showed a low serum TSH level with elevated free thyroxine. Thyroid ultrasound revealed low-echoic lesions compatible with the site of tenderness. The patient was diagnosed with subacute thyroiditis and treatment was initiated with acetaminophen and propranolol, which resulted in symptom resolution within 2 weeks. Clinicians should be aware that subacute thyroiditis may occur within a few days following COVID-19 vaccination, especially in patients with anterior cervical pain with no significant abnormal pharyngeal findings and/or severe palpitations, because differentiating them from early non-specific adverse reactions can be challenging. LEARNING POINTS: Cases of subacute thyroiditis after vaccination, including against COVID-19, have been increasingly reported.Subacute thyroiditis should be considered in patients with anterior cervical pain with no significant abnormal pharyngeal findings and/or severe palpitations after COVID-19 vaccination because these can be diagnostic clues.It is important to note that this condition can occur as early as a few days after vaccination, in order to avoid diagnostic pitfalls.

IgG4-related hypophysitis diagnosed by retroperitoneal mass biopsy in a patient presenting with abducens nerve palsy: A case report (CARE-compliant article).

RATIONALE: Immunoglobulin G4 (IgG4)-related hypophysitis is a rare disorder which often requires invasive pituitary gland biopsy to confirm its diagnosis. We present a case whereby peripheral organ lesion biopsy and imaging findings were sufficient for the diagnosis. PATIENT CONCERNS: A 77-year-old man with diplopia was referred to our department by an opthomologist who had diagnosed the patient with right abducens nerve palsy. DIAGNOSES: Head magnetic resonance imaging revealed enlargement of the pituitary gland and pituitary stalk, while hormonal analysis revealed panhypopituitarism, thereby indicating a diagnosis of hypophysitis. Abdominal computed tomography imaging revealed a solid mass that encompassed the left kidney ureter. Although the patient did not have an increase in serum IgG4, a biopsy of the periureteral mass revealed infiltrating plasma cells that were positive when stained for IgG4. INTERVENTIONS: The patient was given corticosteroid pulse therapy (methylprednisolone: 1 g × 3 days), followed by oral corticosteroids (prednisolone, 0.5 mg/kg/d). OUTCOMES: The right abducens nerve palsy improved and the pituitary lesion shrank after the initiation of corticosteroid treatment. CONCLUSION: Based on the diagnosis of IgG4-related disease in the retroperitoneal organ and response to corticosteroid treatment, this patient was diagnosed with IgG4-related hypophysitis. This hypophysitis caused enlargement of the pituitary gland with resulting nerve compression, causing abducens nerve palsy. When IgG4-related hypophysitis is suspected, a thorough examination of other organ lesions and biopsy should be considered.

In the overnight dexamethasone suppression test, 1.0 mg loading is superior to 0.5 mg loading for diagnosing subclinical adrenal Cushing's syndrome based on plasma dexamethasone levels determined using liquid chromatography-tandem mass spectrometry.

The low-dose dexamethasone suppression test (DST) is one of the commonly used initial tests for endogenous Cushing's syndrome (CS). However, there are two loading dose regimens (0.5-mg and 1-mg), which may cause some confusion in daily practice in Japan; furthermore, there are no reports regarding whether 0.5-mg DST is a better loading dose for detecting adrenal subclinical CS (SCS) based on the plasma dexamethasone (DEX) levels. Therefore, the aims of this study were (a) to develop a novel assay to measure DEX by using liquid chromatography tandem-mass spectrometry (LC-MS/MS) and (b) to compare between the 0.5-mg and 1-mg DST for SCS diagnosis based on the DEX levels. The study retrospectively analyzed 52 consecutive subjects hospitalized for diagnosis of adrenal incidentaloma but who did not exhibit an overt CS phenotype; eight (15.4%) patients were affected with adrenal SCS. Inter-individual variability of DEX levels after the DST was high, but intra-individual variability was low. DEX levels after 1-mg loading in each patient was around two times higher than those after 0.5-mg loading (ρ = 0.853 and p < 0.001). There were 45 (86.5%) and 17 (32.7%) subjects with DEX levels ≤2.2 ng/mL after the 0.5-mg and 1-mg DST, respectively (p < 0.001). Twenty-eight (93.3%) of 30 subjects and four (21.1%) of 19 subjects with detectable ACTH levels after the 0.5-mg and 1.0-mg DST, respectively, did not exhibit DEX levels >2.2 ng/mL. These results clearly indicate that the 1-mg DST is superior to 0.5-mg loading for the diagnosis of adrenal SCS.

Controlling Tumor Progression with Cyclophosphamide, Vincristine, and Dacarbazine Treatment Improves Survival in Patients with Metastatic and Unresectable Malignant Pheochromocytomas/Paragangliomas.

Evidence has not been established to support that combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine (CVD) improves survival in patients with malignant pheochromocytoma and paraganglioma (M-PPGL). To investigate the efficacy of CVD for this disease, we retrospectively analyzed data of 23 patients with metastatic and unresectable M-PPGL (mean age, 41.7 ± 15.4 years) who received at least 2 cycles of this regimen. The follow-up period after initiation of CVD ranged from 0.3 to 13.7 years, with a median of 3.3 years. CVD therapy achieved a complete tumor response (CR) in 1 patient (4%), a partial response (PR) in 5 (22%), stable disease (SD) in 5 (22%), and progressive disease (PD) in 13 (52%), respectively. All of the responders (CR and PR) but 6% of the non-responders (SD and PD) showed substantial biochemical improvement. The progression-free survival period in the responders was significantly longer than in the non-responders (p < 0.01). Although the overall survival and survival after the diagnosis of M-PPGL were longer in the responders than the non-responders, the difference was not statistically significant (p = 0.08). The progression-free and overall survival period were significantly longer in the non-progression group (CR, PR, and SD) than in the progression group (PD) (1.7 ± 3.3 vs. 0.3 ± 0.3 years, p < 0.01, and 4.6 ± 3.6 vs. 2.0 ± 3.7 years, p = 0.01, respectively). It is therefore suggested that CVD chemotherapy could be useful in controlling tumor progression and improving survival in patients with metastatic and progressive M-PPGL.

Contralateral adrenal suppression on adrenocortical scintigraphy provides good evidence showing subclinical cortisol overproduction from unilateral adenomas.

Unilateral and/or predominant uptake on adrenocortical scintigraphy (ACS) may be related to autonomous cortisol overproduction in patients with subclinical Cushing's syndrome (SCS). However, there is no information regarding whether increased tracer uptake on the tumor side or decreased uptake on the contralateral side on ACS is more greatly associated with inappropriate cortisol production. Therefore, we evaluated the relationship between quantitative 131I-6ß-iodomethyl-norcholesterol (131I-NP-59) uptake in both adrenal glands and parameters of autonomic cortisol secretion and attempted to set a cut off for SCS detection. The study included 90 patients with unilateral adrenal adenoma who fulfilled strict criteria. The diagnosis of SCS was based on serum cortisol ≥3.0 µg/dL after 1-mg dexamethasone suppression test (DST) with at least 1 other hypothalamus-pituitary-adrenal axis function abnormality. Twenty-two (27.7%) subjects were diagnosed with SCS. The uptake rate on the affected side in the SCS group was comparable to that in the non-functioning adenoma group. In contrast, the uptake rate on the contralateral side was lower and the laterality ratio significantly higher in the SCS group. The two ACS indices were correlated with serum cortisol levels after a 1-mg DST, but uptake on the tumor side was not. Tumor size was also important for the functional statuses of adrenal tumors and NP-59 imaging patterns. The best cut-off point for the laterality ratio to detect SCS was 3.07. These results clearly indicate that contralateral adrenal suppression in ACS is good evidence showing subclinical cortisol overproduction.

Immunohistochemical analysis of insulin-like growth factor 1 and its receptor in sporadic schwannoma/peripheral nerve sheath tumour.

OBJECTIVE: To investigate the immunohistochemical localization of insulin-like growth factor 1 (IGF-1) and IGF-1 receptor (IGF-1R) in archival specimens of sporadic schwannoma. METHOD: This study retrospectively analysed the immunolocalization of IGF-1 and IGF-1R in schwannoma specimens collected from all patients with sporadic schwannoma that were treated by two institutions in Japan. The study also evaluated the association between the extent of the IGF-1 and IGF-1R immunoreactivity and several clinicopathological characteristics (age, sex and maximum tumour dimension). RESULTS: The study examined a total of 29 sporadic schwannoma specimens. IGF-1 and IGF-1R immunoreactivity was detected in the majority of the specimens regardless of their anatomical location. IGF-1 and IGF-1R were not co-localized. There was no association between the extent of the IGF-1 and IGF-1R immunoreactivity and the clinicopathological characteristics of the patients. CONCLUSIONS: As IGF-1 and IGF-1R immunoreactivity was detected in the majority of sporadic schwannoma specimens regardless of their anatomical location, these findings suggest that an IGF-1/IGF-1R loop could play a role in the tumorigenesis and progression of schwannomas via an autocrine-paracrine mechanism.

Effect of sitagliptin on glycemic control and beta cell function in Japanese patients given basal-supported oral therapy for type 2 diabetes.

We evaluated the effect of sitagliptin on glycemic control, endogenous insulin secretion, and beta cell function in Japanese patients with type 2 diabetes mellitus (T2DM) receiving a combination of oral antidiabetics and basal insulin analog glargine (basal-supported oral therapy [BOT]). Twenty-one patients showing inadequate glycemic control with BOT were given dipeptidylpeptidase-4 inhibitor (DPP-4I) sitagliptin at 50 mg/day for 12 weeks. Clinical markers of glycemic control, HbA1c, glycated albumin (GA), and 1,5-anhydroglucitol (1,5-AG), were measured before and 4 and 12 weeks after the start of sitagliptin. A 2-hour morning meal test was performed upon enrollment and at 12 weeks, and plasma glucose (PG), serum C-peptide, and plasma intact proinsulin (PI) were measured. HbA1c, GA, and 1,5-AG at 4 and 12 weeks were significantly improved over enrollment levels. The area under the PG concentration curve (AUC-PG) during the meal test at 12 weeks was significantly reduced (from 350 ± 17 mg ï½¥ hr/dL before sitagliptin treatment to 338 ± 21 mg ï½¥ hr/dL [mean ± SE], P < 0.05,); the AUC-C-peptide was unchanged (from 3.4 ± 0.4 ng ï½¥ hr/mL to 3.6 ± 0.5 ng ï½¥ hr/mL). However, both fasting and 2-hour PI/C-peptide ratios at 12 weeks were significantly decreased (from 13.3 ± 2.3 to 11.1 ± 2.0 [P < 0 .05] and from 9.5 ± 1.6 to 5.3 ± 0.9 [P < 0.01], respectively). Adding sitagliptin to BOT in Japanese T2DM patients appears to improve glycemic control without increasing endogenous insulin secretion and to reduce fasting and 2-hour postprandial PI/C-peptide ratios.

In Silico Analysis Identification of a Novel Germ-Line VHL Mutation in a Patient of Malignant Pheochromocytoma.

OBJECTIVE: Von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited tumor syndrome caused by a VHL gene mutation. Here we report a novel mutation of VHL in a patient diagnosed with malignant pheochromocytoma at the age of 17. METHODS: A 17-year-old female was referred for paroxysmal supraventricular tachycardia and anemia. She was diagnosed with a left adrenal pheochromocytoma based on biochemical and imaging studies. A left adrenalectomy was performed. Six months after surgery, metastatic lesions were suspected in the lung. The histopathologic findings of thoracoscopic lung biopsy specimens confirmed metastasis of the malignant pheochromocytoma. RESULTS: Genetic analysis of VHL showed a novel missense mutation at codon 194 (V194G) in exon 3. This mutation was inherited from the paternal allele, and a loss of heterozygosity was noted in 3 of the patient's distinct tumors. Two independent in silico analyses suggested that this amino acid substitution was pathogenic. CONCLUSION: We identified a novel missense mutation of VHL in a young patient with malignant pheochromocytoma.

Effect of insulin glargine on endogenous insulin secretion and beta-cell function in Japanese type 2 diabetic patients using oral antidiabetic drugs.

The aim of the present study was to evaluate the effect of insulin glargine (Gla) (as part of basal-supported oral therapy) on endogenous insulin secretion and beta-cell function in type 2 diabetic patients. In 33 insulin-naive patients showing poor glycemic control on treatment with sulfonylurea (SU)-based OADs without DPP4 inhibitors, once-daily injection of Gla was added without changing OADs, and the dose of Gla was titrated to attain a fasting plasma glucose (FPG) <110 mg/dL over 24 weeks. Morning meal tests were done at baseline, 12 weeks and 24 weeks. FPG and 2-hour plasma glucose (2HPG) and serum C-peptide (FCPR and 2HCPR) were measured 3 times, while serum intact proinsulin (FPI and 2HPI) was measured at baseline and 24 weeks. Levels of FPG, FCPR, 2HPG, and HbA1c were significantly reduced from baseline at 24 weeks (176±52 to 117±27 mg/dL, p<0.01; 2.0±0.9 to 1.6±1.0 ng/mL, p<0.01; 257±53 to 202±27 mg/dL, p<0.01; and 8.4±0.9 to 7.3±0.6%, p<0.01, Mean±SD), but 2HCPR was unchanged. The patients were divided into two groups depending on whether FPG at 24 weeks was <110 mg/dL or not: attained group (n=15) and not attained group (n=18). The dose of Gla did not differ between the two groups, but the 2HPI/2HCPR ratio at 24 weeks showed a significant decrease from baseline in the attained group. Supplementation with Gla improved glycemic control and maintained intrinsic basal insulin secretion, without changing 2-hour postprandial secretion. Achieving good glycemic control with an FPG<110 mg/dL by adding Gla decreased the 2HPI/2HCPR ratio at 24 weeks.

Comparison of daily glucose excursion by continuous glucose monitoring between type 2 diabetic patients receiving preprandial insulin aspart or postprandial insulin glulisine.

Insulin glulisine (Glu) is a rapidly-acting insulin analog with a faster onset of action than the other insulin analogs of its class, which are insulin aspart (Asp) and insulin lispro (Lisp). While insulin Glu is usually injected just before meals, postprandial injection may help to avoid unexpected postprandial hypoglycemia or hyperglycemia by adjusting the insulin dosage according to food intake. However, the effect of postprandial insulin Glu on the glucose profile has not been evaluated. The aim of this study was to compare daily glucose excursion by continuous glucose monitoring (CGM) between multiple daily doses of preprandial insulin Asp or postprandial insulin Glu. In a randomized cross-over trial, we performed CGM to evaluate the 48-hour glucose profile during treatment with the same dosage of insulin Asp just before each meal in 12 hospitalized patients with type 2 diabetes. Patients also received the same dosage of long-acting insulin glargine at bedtime. The average glucose level, standard deviation of the glucose level, mean amplitude of glucose excursion, and daily glucose profile did not differ between preprandial Asp and postprandial Glu. The incidence of hypoglycemic episodes (glucose level<70 mg/dL with or without symptoms) and the area under the curve of glucose<70 mg/dL also did not differ between the two insulin regimens. Multiple daily injections of preprandial Asp and postprandial Glu achieved the same daily glucose excursion profile. Postprandial injection of Glu may provide greater flexibility for patients who require insulin therapy.

Intrahepatic lipid content is linked to insulin resistance in obese subjects.

BACKGROUND: Abdominal visceral fat (VAT) and intrahepatic lipid (IHL) are associated with insulin resistance in obese subjects, but VAT is usually measured on CT scans at the umbilical level or on MRI images of the partial abdomen. Thus, the association of the total abdominal visceral fat volume (VFV) with insulin resistance is unclear. In this study, we evaluated the correlations of obesity-related factors, including VFV and IHL, with clinical markers of insulin resistance (HOMA-R and the MATSUDA Index), and then assessed the effect of weight loss on these factors and markers. METHODS: The study population consisted of 30 obese Japanese subjects with a BMI > 25 kg/m(2) (13 men and 17 women) who underwent a 75-g oral glucose tolerance test to calculate HOMA-R and the MATSUDA Index, dual energy X-ray absorptiometry (DEXA) for measurement of body fat (%-Fat), proton magnetic resonance spectroscopy ((1)H MRS) to assess IHL, and whole abdominal CT scanning (from the top of the liver to the floor of the pelvic cavity = about 700 slices) to determine the total abdominal subcutaneous fat volume (SFV) and VFV. Seven subjects from the original population were placed on a diet and exercise program, and these indices were examined again after 5% reduction of body weight. RESULTS: Abdominal SFV, VFV, and IHL were mutually independent, but BMI and %-Fat were not independent of the other factors. According to multiple regression analysis, IHL (but not SFV or VFV) was significantly correlated with both HOMA-R and the MATSUDA Index in obese patients. Weight reduction by 5% led to improvement of the MATSUDA Index and decreased the number of subjects with metabolic syndrome, and the reduction of IHL was greater than that of SFV or VFV. These results suggest that IHL may be a superior marker of insulin resistance.

Evaluation of whole-abdominal fat volume by 700-slice CT scanning and comparison with the umbilical fat area anthropometric indices.

BACKGROUND: The fat area at the umbilical region on CT scans is widely used to identify visceral obesity. However, whether it precisely represents the abdominal visceral fat volume is uncertain, because of technical difficulty in evaluating whole-abdominal visceral fat volume. In this study, we compared the whole-abdominal visceral fat and subcutaneous fat volumes with the visceral fat area at the umbilical region and anthropometric indices. METHODS: The study population consisted of 131 Japanese diabetic and non-diabetic subjects (72 males and 59 females) who underwent anthropometric measurements (height, weight, waist circumference, and hip circumference) and CT scanning from the top of the liver to the pelvic floor (about 700 slices) to analyze the whole-abdominal and umbilical contents of visceral and subcutaneous fat. RESULTS: The visceral fat volume of the male group was 1.3-fold higher than that of the female group, while the subcutaneous fat volume of the female group was 1.3-fold higher than that of the male group. The visceral fat area at the umbilical region was strongly correlated with visceral fat volume (r = 0.921 in males and 0.931 in females). Both visceral and subcutaneous fat volumes were strongly correlated with the waist circumference (r = 0.768 and 0.809 in males and 0.744 and 0.803 in females), but not with the BMI or waist/hip ratio. CONCLUSION: The visceral fat area at the umbilical region is an optimal indicator for whole-abdominal visceral fat volume, and the waist circumference is the anthropometric index that reflects visceral obesity more closely than BMI or the waist/hip ratio.

No ghrelin response to oral glucose in diabetes mellitus with gastroparesis.

To investigate the role of ghrelin, an endogenous ligand of the growth hormone secretagogue receptor, in diabetic gastroparesis, we evaluated the plasma ghrelin profile during the oral glucose tolerance test in 55 patients with diabetes (men/women: 36/19, mean +/- SE of age: 55.1 +/- 1.7 years) with or without gastroparesis (diagnosed by the (13)C-acetate breath test). We also further examined cardiac autonomic neuropathy by assessing 24-hour variation of the R-R interval in randomly selected 32 patients with diabetes (men/women: 23/9, mean +/- SE of age: 54.2 +/- 2.5 years), and evaluated the influence of autonomic neuropathy on ghrelin. The fasting plasma ghrelin level was significantly lower in diabetes mellitus with gastroparesis than in healthy controls (7.9 +/- 0.7 fmol/ml versus 16.6 +/- 5.3 fmol/ml, p = 0.006). Patients with diabetes with gastroparesis showed no decrease of plasma ghrelin after glucose loading, unlike patients without gastroparesis or healthy controls. Diabetes mellitus with autonomic neuropathy, but not those without it, also showed no decrease of plasma ghrelin after glucose loading. Diabetic gastroparesis may be related to ghrelin-associated neurohormonal abnormalities, but the pathophysiological meaning of this abnormal ghrelin response needs further clarification.

Fulminant type 1 diabetes complicated by leukemoid reaction.

A 28-year-old woman with severe ketoacidosis was admitted to our hospital on day 11 after giving birth. However, her HbA(1C) level was normal (5.2%) and both GAD and anti-insulin autoantibody were negative, and the WBC count was extremely high (57,500/ml) with immature leucocytes in the peripheral blood. Her WBC count decreased along with control of ketoacidosis and reduction of the plasma glucose level, and was normalized on day 5 after admission. Bone marrow aspiration subsequently showed no malignant cells, so the final diagnosis was fulminant type 1 diabetes combined with a leukemoid reaction. This is the first report of a patient with both fulminant type 1 diabetes and a leukemoid reaction. The mechanism that triggered the leukemoid reaction could not be clarified, but severe ketoacidosis may have been involved.