Immune Checkpoint Inhibitors and Endocrine Disorders: A Position Statement from the Korean Endocrine Society

Immune checkpoint inhibitors (ICIs) including an anti-cytotoxic T-lymphocyte-associated antigen 4 inhibitor, anti-programmed cell death protein 1 (PD-1) inhibitors, and anti-PD-ligand 1 inhibitors are representative therapeutics for various malignancies. In oncology, the application of ICIs is currently expanding to a wider range of malignancies due to their remarkable clinical outcomes. ICIs target immune checkpoints which suppress the activity of T-cells that are specific for tumor antigens, thereby allowing tumor cells to escape the immune response. However, immune checkpoints also play a crucial role in preventing autoimmune reactions. Therefore, ICIs targeting immune checkpoints can trigger various immune-related adverse events (irAEs), especially in endocrine organs. Considering the endocrine organs that are frequently involved, irAEs associated endocrinopathies are frequently life-threatening and have unfavorable clinical implications for patients. However, there are very limited data from large clinical trials that would inform the development of clinical guidelines for patients with irAEs associated endocrinopathies. Considering the current clinical situation, in which the scope and scale of the application of ICIs are increasing, position statements from clinical specialists play an essential role in providing the appropriate recommendations based on both medical evidence and clinical experience. As endocrinologists, we would like to present precautions and recommendations for the management of immune-related endocrine disorders, especially those involving the adrenal, thyroid, and pituitary glands caused by ICIs.

Whole-Exome Sequencing in Papillary Microcarcinoma: Potential Early Biomarkers of Lateral Lymph Node Metastasis

Background@#Early identification of patients with high-risk papillary thyroid microcarcinoma (PTMC) that is likely to progress has become a critical challenge. We aimed to identify somatic mutations associated with lateral neck lymph node (LN) metastasis (N1b) in patients with PTMC. @*Methods@#Whole-exome sequencing (WES) of 14 PTMCs with no LN metastasis (N0) and 13 N1b PTMCs was performed using primary tumors and matched normal thyroid tissues. @*Results@#The mutational burden was comparable in N0 and N1b tumors, as the median number of mutations was 23 (range, 12 to 46) in N0 and 24 (range, 12 to 50) in N1b PTMC (P=0.918). The most frequent mutations were detected in PGS1, SLC4A8, DAAM2, and HELZ in N1b PTMCs alone, and the K158Q mutation in PGS1 (four patients, Fisher’s exact test P=0.041) was significantly enriched in N1b PTMCs. Based on pathway analysis, somatic mutations belonging to the receptor tyrosine kinase-RAS and NOTCH pathways were most frequently affected in N1b PTMCs. We identified four mutations that are predicted to be pathogenic in four genes based on Clinvar and Combined Annotation-Dependent Depletion score: BRAF, USH2A, CFTR, and PHIP. A missense mutation in CFTR and a nonsense mutation in PHIP were detected in N1b PTMCs only, although in one case each. BRAF mutation was detected in both N0 and N1b PTMCs. @*Conclusion@#This first comprehensive WES analysis of the mutational landscape of N0 and N1b PTMCs identified pathogenic genes that affect biological functions associated with the aggressive phenotype of PTMC.

COVID-19 Vaccination for Endocrine Patients: A Position Statement from the Korean Endocrine Society

Since the first outbreak of coronavirus disease 2019 (COVID-19), ongoing efforts have been made to discover an efficacious vaccine against COVID-19 to combat the pandemic. In most countries, both mRNA and DNA vaccines have been administered, and their side effects have also been reported. The clinical course of COVID-19 and the effects of vaccination against COVID-19 are both influenced by patients’ health status and involve a systemic physiological response. In view of the systemic function of endocrine hormones, endocrine disorders themselves and the therapeutics used to treat them can influence the outcomes of vaccination for COVID-19. However, there are very limited data to support the development of clinical guidelines for patients with specific medical backgrounds based on large clinical trials. In the current severe circumstances of the COVID-19 pandemic, position statements made by clinical specialists are essential to provide appropriate recommendations based on both medical evidence and clinical experiences. As endocrinologists, we would like to present the medical background of COVID-19 vaccination, as well as precautions to prevent the side effects of COVID-19 vaccination in patients with specific endocrine disorders, including adrenal insufficiency, diabetes mellitus, osteoporosis, autoimmune thyroid disease, hypogonadism, and pituitary disorders.

COVID-19 Vaccination for Endocrine Patients: A Position Statement from the Korean Endocrine Society

Since the first outbreak of coronavirus disease 2019 (COVID-19), ongoing efforts have been made to discover an efficacious vaccine against COVID-19 to combat the pandemic. In most countries, both mRNA and DNA vaccines have been administered, and their side effects have also been reported. The clinical course of COVID-19 and the effects of vaccination against COVID-19 are both influenced by patients’ health status and involve a systemic physiological response. In view of the systemic function of endocrine hormones, endocrine disorders themselves and the therapeutics used to treat them can influence the outcomes of vaccination for COVID-19. However, there are very limited data to support the development of clinical guidelines for patients with specific medical backgrounds based on large clinical trials. In the current severe circumstances of the COVID-19 pandemic, position statements made by clinical specialists are essential to provide appropriate recommendations based on both medical evidence and clinical experiences. As endocrinologists, we would like to present the medical background of COVID-19 vaccination, as well as precautions to prevent the side effects of COVID-19 vaccination in patients with specific endocrine disorders, including adrenal insufficiency, diabetes mellitus, osteoporosis, autoimmune thyroid disease, hypogonadism, and pituitary disorders.

Association between Serum Free Thyroxine and Anemia in Euthyroid Adults: A Nationwide Study

BACKGROUND: Studies on the relationship between thyroid function and anemia in the euthyroid range are scarce. We aimed to evaluate the association between anemia and serum free thyroxine (fT4) and thyrotropin (TSH) in euthyroid adults.METHODS: Data on 5,352 participants aged ≥19 years were obtained from the Korea National Health and Nutrition Examination Survey VI (2013 to 2015). Anemia was defined as hemoglobin (Hb) <13 and <12 g/dL for men and women, respectively.RESULTS: Overall, 6.1% of participants had anemia, and more women (9.9%) had anemia than men (2.8%, P<0.001). In multivariate analysis, serum fT4 levels, but not TSH, were positively associated with serum Hb levels in both sexes (P<0.001, each). Serum Hb levels linearly reduced across decreasing serum fT4 quartile groups in both sexes (P<0.001, each). After adjusting for potential confounding factors, participants with low-normal fT4 had 4.4 (P=0.003) and 2.8 times (P<0.001) higher risk for anemia than those with high-normal fT4 among men and women, respectively. When participants were divided into two groups at 50 years of age, in younger participants, men and women with the first quartile were at higher risk of anemia than men with the second quartile (odds ratio [OR], 3.3; P=0.029) and women with the forth quartile (OR, 3.2; P<0.001), respectively. This association was not observed in older participants.CONCLUSION: These results suggest that a low-normal level of serum fT4 was associated with a lower serum Hb level and a higher risk of anemia in euthyroid adults, especially in younger participants.

Measurement and Interpretation of Dual-Energy X-ray Absorptiometry Bone Density Measurements / 대한내과학회지

Dual-energy X-ray absorptiometry (DXA) is a widely used technology used to diagnosis osteoporosis and monitor changes in bone mineral density (BMD). The present paper reviews the clinical application of DXA in evaluating osteoporosis, including indications for BMD testing, interpretation of DXA results, diagnosis of osteoporosis, and serial BMD follow up. As the clinical utility of DXA depends on the quality of the scan acquisition, the precision assessment of DXA is also discussed.

The Relationship between Thyroid Function and Different Obesity Phenotypes in Korean Euthyroid Adults

BACKGROUND: Thyroid disease and metabolic syndrome are both associated with cardiovascular disease. The aim of this study was to investigate the correlation between thyroid hormones and obesity sub-phenotypes using nationwide data from Korea, a country known to be iodine replete.METHODS: This study was based on data obtained from the sixth Korea National Health and Nutrition Examination Survey, administered from 2013 to 2015. A total of 13,873 participants aged ≥19 years were included, and classified into four groups: metabolically healthy non-obesity (MHNO), metabolically healthy obesity (MHO), metabolically unhealthy non-obesity (MUNO), and metabolically unhealthy obesity (MUO) by body fat on the basis of body mass index and metabolic health.RESULTS: At baseline, serum free thyroxine (fT4) values were significantly higher in the MHNO phenotype (MHNO, 1.27±0.01 ng/dL; MHO, 1.25±0.01 ng/dL; MUNO, 1.24±0.01 ng/dL; MUO, 1.24±0.01 ng/dL, P<0.001) in total study population. However, this significant association no longer remained after adjustment for age, urine iodine concentration, and smoking (P=0.085). After adjustment for confounders, statistically significant association was observed between lower thyroid stimulating hormone (TSH) and MHNO phenotype (P=0.044). In men participants (not women), higher fT4 values were significantly associated with MHNO phenotype (P<0.001). However, no significant association was observed between thyroid function (TSH or fT4) and obesity phenotypes in groups classified by age (cutoff age of 55 years).CONCLUSION: Although there was a difference by age and sex, we found that the decrease of TSH and the increase of fT4 values were associated with MHNO.

Measurement and Interpretation of Dual-Energy X-ray Absorptiometry Bone Density Measurements / 대한내과학회지

Dual-energy X-ray absorptiometry (DXA) is a widely used technology used to diagnosis osteoporosis and monitor changes in bone mineral density (BMD). The present paper reviews the clinical application of DXA in evaluating osteoporosis, including indications for BMD testing, interpretation of DXA results, diagnosis of osteoporosis, and serial BMD follow up. As the clinical utility of DXA depends on the quality of the scan acquisition, the precision assessment of DXA is also discussed.

Effects of Thyrotropin Suppression on Bone Health in Menopausal Women with Total Thyroidectomy

BACKGROUND: This study examined the change in the trabecular bone score (TBS), areal bone mineral density (aBMD), and osteoporosis in postmenopausal women who underwent thyrotropin (TSH)-suppressive therapy for treating papillary thyroid cancer after a total thyroidectomy procedure. METHODS: We evaluated 36 postmenopausal women who received a total thyroidectomy for papillary thyroid cancer and were undergoing TSH suppressive therapy with levothyroxine. Postmenopausal women (n=94) matched for age and body mass index were recruited as healthy controls. The aBMD and TBS of the lumbar spine were compared between dual energy X-ray absorptiometry (DXA) at baseline and at follow-up after an average of 4.92 years. RESULTS: There was no significant difference in the rate of diagnoses of osteoporosis, osteopenia, or normal bone status between the 2 groups during the baseline DXA evaluation. However, the TBS was significantly lower whereas aBMD did not show significant difference at the time of baseline DXA measurement (1st DXA, 1.343±0.098 vs. 1.372±0.06317, P < 0.001; 2nd DXA, 1.342±0.095 vs. 1.370±0.062, P < 0.001). The TBS and aBMD did not differ significantly between the initial and follow-up DXA images in both groups of TSH suppressive patients and controls. CONCLUSIONS: The average value of TBS and aBMD did not significantly change during the follow-up period. The TSH suppressive therapy was revealed as not a significant factor for the progressive deterioration of bone status during long term follow-up.

Prevalence of BRAF(V600E) Mutation in Follicular Variant of Papillary Thyroid Carcinoma and Non-Invasive Follicular Tumor with Papillary-Like Nuclear Features (NIFTP) in a BRAF(V600E) Prevalent Area

BACKGROUND: BRAF V600E mutation status and prevalence of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) has not yet been reported in Korea. The aim of this study was to investigate the significance of the BRAF V600E mutation in the follicular variant of papillary thyroid carcinoma (FVPTC) and to determine the prevalence of NIFTP in BRAF V600E mutation-prevalent Korean patients. METHODS: This study retrospectively analyzed 1,417 consecutive patients who underwent total thyroidectomy with routine prophylactic central lymph node dissection for papillary thyroid carcinoma (PTC). BRAF V600E mutation analysis was performed routinely using multiplex polymerase chain reaction by applying dual priming oligonucleotide. Clinicopathological characteristics and ultrasonographic findings were compared between BRAF V600E mutation-positive and -negative groups for FVPTC. Pathologists reviewed the pathology slides according to consensus diagnostic criteria for the encapsulated FVPTC and NIFTP. RESULTS: The prevalence of the BRAF V600E mutation in all subtypes of PTC was 61.0% (861/1,411). FVPTC presented a BRAF V600E mutation rate of 27.3%. The FVPTC patients with BRAF V600E mutation were older than those with no BRAF V600E mutation (P = 0.021). The prevalence of NIFTP was 0.18% among all PTC patients (2/1,411) and the proportion of NIFTP among FVPTC was 9.1% (2/22). CONCLUSION: The BRAF V600E mutation is prevalent in Korean patients with FVPTC in a region with high frequency of the BRAF V600E mutation and very low prevalence of NIFTP compared with that reported in western studies.

IgA nephropathy in a patient with ankylosing spondylitis well controlled with etanercept / 고신대학교의과대학학술지

Ankylosing spondylitis (AS) can involve the eye, gastrointestinal system, cardiopulmonary system, skin, kidneys, and spinal and peripheral joints. It is rarely accompanied by immunoglobulin A (IgA) nephropathy. Although IgA is involved in both AS and IgA nephropathy, the relationship between these diseases remains unclear. We detected hematuria and proteinuria in a 32-year-old male patient with ankylosing spondylitis that remained stable for 4 years through treatment with etanercept, a tumor necrosis factor-α (TNF-α) inhibitor, and diagnosed IgA nephropathy through a renal biopsy. IgA nephropathy seems to be less commonly associated with AS disease activity or specific treatment such as TNF-α inhibitor use.

The Effectiveness of Multidisciplinary Team-Based Education in the Management of Type 2 Diabetes / 임상당뇨병

BACKGROUND: Although clinicians, nurse specialists, pharmacists, and nutritionists expend significant time and resources in optimizing care for patients with diabetes, the effectiveness of integrated diabetes care team approach remains unclear. We assessed the effects of a multidisciplinary team care educational intervention on glycated hemoglobin (HbA1c) levels among diabetes patients. METHODS: We conducted a matched case-control study in Korean patients with type 2 diabetes, comparing the propensity scores pertaining to the effectiveness in reducing HbA1c levels between a group receiving an educational intervention and a control group. We included 40 pairs of patients hospitalized between June 2014 and September 2016. HbA1c values measured at baseline, 3 months, and 6 months were compared between the two groups. RESULTS: The educated group showed an improvement in HbA1c levels compared to the control group at 3 months (6.3 ± 2.3% vs. 9.5 ± 4.0%; P = 0.020) and at 6 months (7.5 ± 1.5% vs. 9.6 ± 3.0%; P = 0.106). There was a significant difference in the change in mean HbA1c from baseline to 3 months between the two groups (−35.7 ± 26.1% vs. −9.1 ± 20.5%; P = 0.013). CONCLUSION: A multidisciplinary team care education intervention was advantageous for improving glucose control in patients with type 2 diabetes, and may help to optimize glycemic control in clinical practice.

Changes in Urinary Angiotensinogen Associated with Deterioration of Kidney Function in Patients with Type 2 Diabetes Mellitus

Urinary angiotensinogen (AGT) is potentially a specific biomarker for the status of the intrarenal renin-angiotensin system (RAS) in patients with diabetes mellitus. We explored whether changes in urinary AGT excretion levels were associated with the deterioration of kidney function in type 2 diabetes patients with preserved kidney function. Urinary baseline AGT levels were measured in 118 type 2 diabetic patients who were not taking RAS blockers and who had estimated glomerular filtration rates (eGFRs) ≥ 60 mL/min/1.73 m². A total of 91 patients were followed-up for 52 months. Changes in urinary levels of AGT (ΔAGT) were calculated by subtracting urinary AGT/creatinine (Cr) at baseline from urinary AGT/Cr after 1 year. ΔAGT was significantly inversely correlated with annual eGFR change (β = −0.29, P = 0.006; β = −0.37, P = 0.001 after adjusting for clinical factors). RAS blockers were prescribed in 36.3% of patients (n = 33) during follow-up. The ΔAGT values were lower in the RAS blockers users than in the non-RAS blockers users, but the differences were not statistically significant (7.37 ± 75.88 vs. 22.55 ± 57.45 μg/g Cr, P = 0.081). The ΔAGT values remained significantly correlated with the annual rate of eGFR change (β = −0.41, P = 0.001) in the patients who did not use RAS blockers, but no such correlation was evident in the patients who did. ΔAGT is inversely correlated with annual changes in eGFR in type 2 diabetes patients with preserved kidney function, particularly in RAS blocker-naïve patients.

Disease-Specific Mortality of Differentiated Thyroid Cancer Patients in Korea: A Multicenter Cohort Study

BACKGROUND: Little is known regarding disease-specific mortality of differentiated thyroid cancer (DTC) patients and its risk factors in Korea. METHODS: We retrospectively reviewed a large multi-center cohort of thyroid cancer from six Korean hospitals and included 8,058 DTC patients who underwent initial surgery between 1996 and 2005. RESULTS: Mean age of patients at diagnosis was 46.2±12.3 years; 87% were females. Most patients had papillary thyroid cancer (PTC; 97%) and underwent total thyroidectomy (85%). Mean size of the primary tumor was 1.6±1.0 cm. Approximately 40% of patients had cervical lymph node (LN) metastases and 1.3% had synchronous distant metastases. During 11.3 years of follow-up, 150 disease-specific mortalities (1.9%) occurred; the 10-year disease-specific survival (DSS) rate was 98%. According to the year of diagnosis, the number of disease-specific mortality was not different. However, the rate of disease-specific mortality decreased during the study period (from 7.7% to 0.7%). Older age (≥45 years) at diagnosis, male, follicular thyroid cancer (FTC) versus PTC, larger tumor size (>2 cm), presence of extrathyroidal extension (ETE), lateral cervical LN metastasis, distant metastasis and tumor node metastasis (TNM) stage were independent risk factors of disease-specific mortality of DTC patients. CONCLUSION: The rate of disease-specific mortality of Korean DTC patients was 1.9%; the 10-year DSS rate was 98% during 1996 to 2005. Older age at diagnosis, male, FTC, larger tumor size, presence of ETE, lateral cervical LN metastasis, distant metastasis, and TNM stages were significant risk factors of disease-specific mortality of Korean DTC patients.

Discovery of Splenic Sarcoidosis Concurrent with the Diagnosis of Ovarian Cancer: A Case Report

Sarcoidosis is a multisystem inflammatory disease of unknown etiology characterized by noncaseating epithelioid granuloma formation. Although the relationship between sarcoidosis and malignancy has been noted in recent decades, there are few case reports describing the concurrent diagnosis of sarcoidosis and malignancy. Herein, we describe a case of biopsy-proven splenic sarcoidosis mimicking metastasis at the time of ovarian adenocarcinoma. Imaging studies including positron-emission tomography-computed tomography were not useful for differentiating sarcoidosis from malignancy. Thus, our case highlights the importance of histopathological examination to rule out nonmalignant conditions before the diagnosis of metastatic disease is made.

Cardiac Tamponade and Pericarditis in Type B Intramural Hematoma: a Case Report / 대한내과학회지

We report the case of a patient with cardiac tamponade and pericarditis in type B intramural hematoma. A 75-year-old woman was admitted to the emergency department presenting with general weakness and dizziness for several hours and hemodynamic collapse. Thoracic echocardiography and computed tomography (CT) showed a large pericardial effusion and aortic intramural hematoma but no evidence of aortic dissection. Therefore, we concluded that the intramural hematoma did not involve the ascending aorta and thus immediately performed pericardiocentesis. Follow-up CT showed no pericardial effusion or specific changes in the range or depth of the intramural hematoma, and she was discharged continuing colchicines and ibuprofen therapy for acute pericarditis. Cardiac tamponade in type B intramural hematoma is extremely rare. Prompt diagnosis and initial treatment resulted in a substantial improvement in clinical status.

Association of the Preoperative Neutrophil-to-ymphocyte Count Ratio and Platelet-to-Lymphocyte Count Ratio with Clinicopathological Characteristics in Patients with Papillary Thyroid Cancer

BACKGROUND: Several inflammatory biomarkers, especially a high preoperative neutrophil-to-lymphocyte count ratio (NLR) and platelet-to-lymphocyte count ratio (PLR), are known to be indicator of poor prognosis in several cancers. However, very few studies have evaluated the significance of the NLR and PLR in papillary thyroid cancer (PTC). We evaluated the association of the preoperative NLR and PLR with clinicopathological characteristics in patients with PTC. METHODS: This study included 1,066 female patients who underwent total thyroidectomy for PTC. Patients were stratified into 4 quartiles by preoperative NLR and PLR. And the combination of preoperative NLR and PLR was calculated on the basis of data obtained value of tertile as follows: patients with both an elevated PLR and an elevated NLR were allocated a score of 2, and patients showing one or neither were allocated a score of 1 or 0, respectively. RESULTS: The preoperative NLR and PLR were significantly lower in patients aged > or =45 years and in patients with Hashimoto's thyroiditis. The PLR was significantly higher in patients with tumor size >1 cm (P=0.021).When the patients were categorized into the aforementioned four groups, the group with the higher preoperative PLR was found to have a significantly increased incidence of lateral lymph node metastasis (LNM) (P=0.018). However, there are no significant association between the combination of preoperative NLR and PLR and prognostic factors in PTC patients. CONCLUSION: These results suggest that a preoperative high PLR were significant associated with lateral LNM in female patients with PTC.