A case of Empty Sella syndrome with adrenal insufficiency masked by prednisolone after administration of immune checkpoint inhibitors.

INTRODUCTION: The use of immune checkpoint inhibitors (ICIs) is gradually increasing; ICIs produce a variety of immune-related adverse events (irAEs), especially ICI-induced hypoadrenocorticism, which can be a lethal complication if treatment is delayed. PATIENT CONCERNS: A 63-year-old man received chemotherapy with pembrolizumab for nonsmall cell lung cancer. He developed drug-induced interstitial pneumonia 366 days after receiving pembrolizumab and was treated with prednisolone. Five hundred thirty-seven days later, he developed drug-induced eosinophilic enteritis, and pembrolizumab was discontinued and prednisolone was continued. After discontinuation of prednisolone, general malaise and edema of the lower extremities appeared, and adrenal insufficiency was suspected. DIAGNOSIS: In blood tests on admission adrenocorticotropic hormone (ACTH) was 2.2 pg/mL and cortisol was 15 µg/dL, with no apparent cortisol deficiency. However, the cortisol circadian rhythm disappeared and remained low throughout the day; a corticotropin-releasing hormone stimulation test showed decreased reactive secretion of ACTH. Pituitary magnetic resonance imaging showed pituitary emptying, suggesting Empty Sella syndrome. INTERVENTIONS AND OUTCOMES: We started hydrocortisone and his symptoms were improved. CONCLUSIONS: The administration of high-dose steroids after ICI administration may mask the symptoms of hypoadrenocorticism as irAEs. Therefore, we should bear in mind the possibility of hypoadrenocorticism when we stop steroid therapy in patients who are treated with steroids after ICI administration.

Clinical findings of acute necrotizing esophagitis complicated by diabetic ketoacidosis.

Acute necrotizing esophagitis (ANE) is a rare and potentially life-threatening complication of diabetic ketoacidosis (DKA). While its association with DKA is established, specific clinical characteristics that predict ANE in DKA patients remain less understood. This study aimed to identify these characteristics by analyzing data from 30 DKA patients admitted from January 2018 to September 2022. Seven patients in this study presented with ANE, forming the ANE group. The remaining 23 constituted the non-ANE group. We compared the clinical parameters and computed tomography (CT) between the groups. The mean age of participants was 57.7 ± 20.4 years, and their mean HbA1c was 11.1 ± 3.3%. Notably, ethanol intake was significantly higher in the ANE group (44.4 ± 25.4 g/day) compared to the non-ANE group (6.8 ± 14.0 g/day; p = 0.013). Additionally, sodium-glucose transport protein 2 inhibitor use was significantly more prevalent in the ANE group (p = 0.013). Gastrointestinal symptoms were also significantly more pronounced in the ANE group, with vomiting occurring in 85.7% of patients compared to only 13.0% in the non-ANE group. Admission CT scans revealed further distinguishing features, with the ANE group showing significantly higher rates of esophageal wall thickening, intra-esophageal effusion, and calcification of the celiac artery origin (p < 0.0001, 0.0038, 0.0038, respectively). In conclusion, our study suggests that heavy alcohol consumption and strong gastrointestinal symptoms in DKA patients warrant a heightened suspicion of ANE. Early consideration of CT or upper gastrointestinal endoscopy is recommended in such cases.

Structural and functional differences in auto-antibody positive compared to auto-antibody negative hypothyroid patients with chronic thyroiditis.

Most primary hypothyroidism in adults is caused by chronic thyroiditis. Autoantibodies such as anti-thyroglobulin antibody (TgAb) and anti-thyroid peroxidase antibody (TPOAb) are involved in the pathogenesis of chronic thyroiditis. On the other hand, the clinical features of antibody-negative hypothyroidism are not clear. In this study, we aimed to determine the prevalence of thyroid-related autoantibodies in patients with primary hypothyroidism and to evaluate the differences in thyroid structure between antibody-positive and antibody-negative hypothyroidism. Among 804 patients who attended Kawasaki Medical School Hospital for thyroid hormone abnormalities or thyroid gland enlargement between January 1, 2010 and December 31, 2021, 237 patients with primary hypothyroidism who underwent thyroid antibody measurement and thyroid ultrasound examination were included. Participants were divided into groups according to antibody positivity/negativity, and differences in antibody positivity and thyroid structure were evaluated. In this study, 34.6% of patients had antibody-negative hypothyroidism. The positive rate of each antibody was 62.0% for TgAb and 49.4% for TPOAb. The participants with antibody-positive hypothyroidism had significantly larger thyroid gland on thyroid ultrasound examination (p < 0.05). Thyroid-stimulating hormone was significantly higher in participants with antibody-positive compared to antibody-negative hypothyroidism. The present study reveals a positive rate of thyroid-related autoantibodies in patients with hypothyroidism and the differences in thyroid structure between patients with and without antibodies. This study clearly show that the prevalence of antibody-negative chronic thyroiditis is quite high among hypothyroid patients, although this point needs confirmation by further investigations. The data in this study would be useful for the treatment of antibody-negative hypothyroid patients.

Immune checkpoint inhibitor-induced hypothyroidism predicts treatment response in Japanese subjects.

Background: Immune checkpoint inhibitors (ICIs) cause a variety of immune-related adverse events (irAEs). Among them, thyroid dysfunction is most frequently observed. Patients with irAEs have higher survival rates than those without irAEs, but there is no certainty as to whether the degree of thyroid dysfunction is associated with treatment response or survival with ICIs. Method: This is a single-center, retrospective, observational study. The study included 466 patients who received ICI at Kawasaki Medical School Hospital from September 1, 2014, to May 31, 2022 and evaluated the degree of abnormal thyroid function and survival and remission rates after treatment with ICIs. Primary hypothyroidism of less than 10 µIU/mL TSH was classified as grade 1, and primary hypothyroidism requiring more than 10 µIU/mL TSH or levothyroxine as grade 2-4. Result: The mean age of the study participants was 68.2 ± 10.3 years, and the percentage of male participants was 72.6%. The frequency of ICI-induced thyroid dysfunction in the study participants was 28.2%. TSH levels were significantly higher in Grade 1 and Grades 2-4 when treated with ICI compared to NTF (p<0.0001). The survival rate at 1 year after ICI administration was significantly higher with 64.9% for grade 1 and 88.9% for grades 2-4 compared to 52.1% for NTF (p<0.0001). Cancer stage at the time of ICI administration did not differ among the groups (p=0.68). Nevertheless, the remission rate assessed by RECIST criteria was significantly higher in grades 2-4 compared to NTF (p<0.0001). Conclusion: ICI-induced thyroid dysfunction was significantly correlated with survival, mean observation time, and treatment remission rate. It is important to monitor thyroid hormone levels regularly in patients receiving ICIs.

Simple standing test without furosemide is useful in the diagnosis of primary aldosteronism.

Primary aldosteronism (PA) is a well-known cause of secondary hypertension. We have long performed the simple standing test in patients with PA. On the other hand, there are few reports on the usefulness of the simple standing test in PA. This study is a single-center, retrospective, observational study. A total of 173 patients with hypertension or adrenal tumor admitted to Kawasaki Medical School were included. Eighty patients who met the exclusion criteria were excluded, and 31 patients without PA (non-PA), 26 patients with unilateral PA, and 36 patients with bilateral PA were included in the study. The simple standing test was performed after 120 min of standing or sitting followed, and the aldosterone/renin ratio (ARR) and percentage of increase plasma aldosterone concentration (%increase of PAC) was calculated. The mean ARR in the simple standing test in unilateral PA (1143 (528-2200)) and bilateral PA subjects (521 (374-765)) were significantly higher compared to non-PA subjects (152 (102-240)) (p < 0.0001, p = 0.0013, respectively). The percentage increase of PAC after standing loading was significantly lower in unilateral PA subjects (110 (96-140)) compared to non-PA subjects (187 (155-244)) (p = 0.0003), with no difference between non-PA and bilateral PA subjects (p = 0.99). The cutoff value of the ARR in the simple standing test for diagnosis of PA in this study was 364 (AUC = 0.948, sensitivity = 83.8%, specificity = 93.5%, false positive rate = 3.7%, false negative rate = 25.6%, p < 0.001), which was not inferior to the diagnostic performance of the captopril loading test. The diagnostic performance of the simple standing test for PA was not inferior to that of the captopril loading test. The percentage increase of PAC in unilateral PA subjects was significantly lower compared to bilateral PA subjects. These results demonstrate the usefulness of the simple standing test, which can be performed simultaneously with general screening tests of PA.

Efficacy and safety of pemafibrate in patients with hypertriglyceridemia in clinical settings: A retrospective study.

BACKGROUND AND AIMS: Recently, pemafibrate, a selective PPARα modulator, has been developed as a treatment for hypertriglyceridemia and has attracted much attention. The aims of this study were to evaluate the efficacy and safety of pemafibrate in hypertriglyceridemia patients under clinical settings. METHODS AND RESULTS: We evaluated changes in lipid profiles and various parameters before and after 24-week pemafibrate administration in patients with hypertriglyceridemia who had not previously taken fibrate medications. There were 79 cases included in the analysis. 24 weeks after the treatment with pemafibrate, TG was significantly reduced from 312 ± 226 to 167 ± 94 mg/dL. In addition, lipoprotein fractionation tests using PAGE method showed a significant decrease in the ratio of VLDL and remnant fractionations, which are TG-rich lipoproteins. After pemafibrate administration, body weight, HbA1c, eGFR, and CK levels were not changed, but liver injury indices such as ALT, AST, and γ-GTP were significantly improved. CONCLUSION: In this study, pemafibrate improved the metabolism of atherosclerosis-induced lipoproteins in hypertriglyceridemia patients. In addition, it showed no off-target effects such as hepatic and renal damage or rhabdomyolysis.

Correlation of Baba's diabetic neuropathy classification with various diabetes-related complications.

It is known that Baba's diabetic neuropathy classification (BDC) is useful in quantitative evaluation of Diabetic polyneuropathy (DPN). In this study, we aimed to investigate the possible association between BDC and various diabetic microvascular and macrovascular complications in patients whose neuropathy was evaluated with BDC. As the results, BDC was significantly correlated with the severity of diabetic retinopathy and nephropathy. BDC was also significantly correlated with history of myocardial infarction or cerebral infarction, carotid IMT, and ABI. These data suggest that BDC may be useful in predicting the presence of various diabetic microvascular and macrovascular complications. The data also support the idea that we should perform further investigation of other diabetes-related complications in patients with severe DPN.

Addison's disease triggered by infection with mycobacterium abscessus, but not by adrenal tuberculosis or MAC pulmonary disease, in a subject with type 2 diabetes mellitus: case report.

BACKGROUND: Addison's disease is primary adrenal dysfunction and is characterized by decrease of cortisol level and increase of adrenocorticotropic hormone (ACTH) level. It is known that infection is one of main causes of Addison's disease. Among various infections, tuberculous infection accounts for the majority of them. Recently the number of subjects with non-tuberculous mycobacterial infection has been increased, and the infection can also bring about Addison's disease. Mycobacterium avium complex (MAC) pulmonary disease accounts for the majority of non-tuberculous mycobacterial infection. CASE PRESENTATION: An 83-year-old female was suspected of having adrenal failure in our outpatient care and hospitalized in our institution. There was pigmentation in her face, hands and legs, especially in auricle and nail beds in her hands and legs. In rapid ACTH load test (0.25 mg of 1-24 ACTH), cortisol level was not increased at all. An abdominal computed tomography (CT) showed swelling of both adrenal glands accompanied by calcification. QuantiFERON test was negative and mycobacterium tuberculosis complex was negative in PCR test using bronchial lung lavage fluid. These data ruled out the possibility of adrenal tuberculosis. It is known that MAC pulmonary disease accounts for the majority of non-tuberculous mycobacterial infection. In this subject, however, anti-MAC antibody was negative and MAC-related bacteria were not detected in PCR test using bronchial lung lavage fluid. These data ruled out the possibility of MAC pulmonary disease. Mycobacterium abscessus (Mab) was positive in bronchial lung lavage fluid culture. Based on these data, we diagnosed this subject with Addison's disease triggered by infection with mycobacterium abscessus, but not by adrenal tuberculous or MAC pulmonary disease. Decreased sodium level and increased eosinophil number were normalized and appetite loss was markedly mitigated after starting hydrocortisone therapy. A chest CT which was taken about 6 months later showed drastic reduction of consolidation in the upper lobe of the left lung although calcification in the adrenal gland was still observed. CONCLUSIONS: We should bear in mind the possibility of Addison's disease triggered by another type of infection rather than adrenal tuberculosis or MAC pulmonary disease.

Usefulness of cortisol/ACTH ratio (CAR) for diagnosis of cushing's syndrome: comparison of CAR with findings in dexamethasone suppression test.

Cushing's syndrome and subclinical Cushing's syndrome (SCS) are conditions of increased cortisol secretion from the adrenal glands. Cushing's syndrome includes adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome (Cushing's disease) and ACTH-independent Cushing's syndrome (AICS). The purpose of this study was to investigate the diagnostic potential of the cortisol / adrenocorticotropic hormone (ACTH) ratio (CAR) for diagnosis of Cushing's syndrome or SCS in adult subjects. This was a single-center, retrospective, observational study. This study enrolled 44 subjects with SCS, 14 AICS, 10 CD, and 248 non-Cushing's syndrome subjects who had undergone a 1 mg dexamethasone suppression test (1 mg DST). Definition of SCS was as follows: no physical signs characteristic of Cushing syndrome and cortisol was ≥ 83 nmol/L in 1 mg DST. The diagnostic potential of CAR for diagnosis of Cushing's syndrome was evaluated by comparing the correlation between CAR and after-load cortisol level in 1 mg DST. As the results, there was a strong positive correlation between CAR and after-load cortisol level in subjects with AICS (r = 0.800, p < 0.005). CAR was 10,040 ± 4170 nmol/pmol in subjects with NCS, 17,535 ± 10,246 nmol/pmol in SCS, 101,221 ± 18,009 nmol/pmol in AICS, and 4324 ± 2051 nmol/pmol in CD, all of which were significantly higher compared to those with AICS (p < 0.0005). The cutoff values of CAR for screening at our institution were 11,849.6 nmol/pmol for AICS (AUC 0.935, p < 0.005, sensitivity 92.3%, specificity 83.5%) and 7006.1 nmol/pmol for CD (AUC 0.714, p < 0.05, sensitivity 100.0%, specificity 46.8%). There was a positive correlation between CAR and adrenal adenoma diameter in subjects with AICS (r = 0.508, p < 0.05), but there was no correlation between tumor diameter and CAR in subjects with SCS and CD. In conclusion, high CAR indicates increased cortisol secretion from the adrenal glands. Since CAR is a simple indicator that can be easily evaluated by general practitioners as well as endocrinologists, we think CAR would be useful for the early detection of Cushing's syndrome.