Kosuke Inoue

Clinical Utility of the Adrenocorticotropin Stimulation Test with/without Dexamethasone Suppression for Definitive and Subtype Diagnosis of Primary Aldosteronism

The adrenocorticotropin (ACTH) stimulation test (AST) has been reported to be useful for diagnosing primary aldosteronism (PA), particularly for differentiating PA subtypes under 1-mg dexamethasone suppression (DS). The aim of our study was to clarify the effect of 1-mg DS on AST results. A retrospective cohort study was conducted using data for 48 patients (PA: 30/48). We estimated the difference in plasma aldosterone concentration (PAC) responsiveness to ACTH stimulation with single (AST alone) and combined (AST under 1-mg DS) tests within the same patient. We compared the diagnostic accuracy of these two tests for PA and the laterality of hyperaldosteronism. We found no differences in PAC responsiveness to ACTH stimulation between single and combined tests, and observed a significant positive linear relationship (30 min, R2 = 0.75, p-value < 0.01). Both tests showed the highest diagnostic accuracy for PA following 30 min of ACTH stimulation. The ability to detect the laterality of hyperaldosteronism was inconsistent and differed according to the two definitions: lateralization ratio and the absolute aldosterone levels in adrenal venous sampling. PAC responsiveness to ACTH stimulation was similar for AST with and without 1-mg DS. AST can be performed under both conditions with similar accuracy to detect PA.

Evaluation of Cortisol Production in Aldosterone-Producing Adenoma

Aldosterone-producing adenoma (APA) is sometimes accompanied with subclinical hypercortisolism. We investigated the ability of cortisol production in APA, both clinically and pathologically. A retrospective cohort study was conducted at Yokohama Rosai Hospital from 2009 to 2016. Thirty patients with APA and serum cortisol levels during the 1 mg dexamethasone suppression test (F-DST)<3.0 μg/dl were included. We evaluated the 1) difference between pre-adrenalectomy F-DST (pre-F-DST) and post-adrenalectomy F-DST (ΔF-DST), 2) correlation between ∆F-DST and pre-F-DST, tumour size determined by CT, and type of adrenalectomy (total or partial), and 3) relationship between the ratio of F-DST divided by tumour size (ΔF-DST/pre-F-DST/mm) and immunoreactivity of CYP17A1, CYP11B1, and CYP11B2. The median [interquartile range] age was 48 [38-58] years. We found a significant decrease in F-DST after adrenalectomy [before: 1.4 (1.1-1.8); after: 0.9 (0.6-1.2); p<0.001]. Additionally, a significant correlation was found for ΔF-DST and both pre-F-DST (Spearman, ρ=-0.68, p<0.001) and tumour size (ρ=-0.51, p 0.005). No significant difference was found in ΔF-DST between total and partial adrenalectomy. CYP17A1 and CYP11B1 were positive in 21 (100%) and 17 (81%) adenomas, respectively. CYP17A1 immunoreactivity in the tumour was significantly related with ΔF-DST/pre-F-DST/mm (p 0.049). F-DST significantly decreased after adrenalectomy, and most of the adenomas were immunohistochemically positive for CYP17A1 and CYP11B1 as well as CYP11B2. We should consider the possibility of autonomous cortisol production as well as hyperaldosteronism in the evaluation and treatment of APA patients.

Syndrome of inappropriate antidiuretic hormone accompanied by bilateral hypothalamic and anterior thalamic lesions with serum antiaquaporin 4 antibody.

We described a rare case of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and severe unconsciousness accompanied by bilateral hypothalamic and anterior thalamic lesions with positive serum antiaquaporin 4 (AQP4) antibody. A 29-year-old man was admitted to our hospital due to the subacute progression of an unconscious state. He was observed to be hyponatraemic secondary to SIADH. Brain MRI showed bilateral hypothalamic and anterior thalamic lesions. Anti-AQP4 antibody was detected in his serum. After the administration of intravenous methylprednisolone pulse therapy, his symptoms improved with complete recovery from SIADH and regression of the hypothalamic and anterior thalamic lesions. The patient was transferred to another hospital for rehabilitation with 20 mg/day of oral prednisolone 127 days after admission. This case highlights the importance of testing for anti-AQP4 antibody in patients with unexplainable SIADH, subacute progressive unconsciousness and bilateral hypothalamic and anterior thalamic lesions.

Urinary Iodine Concentration and Mortality Among U.S. Adults

BACKGROUND Iodine deficiency has long been recognized as an important public health problem. Global approaches such as salt iodization that aim to overcome iodine deficiency have been successful. Meanwhile, they have led to excessive iodine consumption in some populations, thereby increasing the risks of iodine-induced thyroid dysfunction, as well as the comorbidities and mortality associated with hypothyroidism and hyperthyroidism. This study aimed to elucidate whether iodine intake is associated with mortality among U.S. adults. METHODS This was an observational study to estimate mortality risks according to urinary iodine concentration (UIC) utilizing a nationally representative sample of 12,264 adults aged 20-80 years enrolled in the National Health and Nutrition Examination Survey (NHANES) III. Crude and multivariable Cox proportional hazards regression models were employed to investigate the association between UIC (<50, 50-99, 100-299, 300-399, and ≥400 μg/L) and mortalities (all-cause, cardiovascular, and cancer). In sensitivity analyses, the study adjusted for total sodium intake and fat/calorie ratio in addition to other potential confounders. Stratum-specific analyses were also conducted to estimate the effects of UIC on mortality according to age, sex, race/ethnicity, and estimated glomerular filtration rate category. RESULTS Over a median follow-up of 19.2 years, there were 3159 deaths from all causes. Participants with excess iodine exposure (UIC ≥400 μg/L) were at higher risk for all-cause mortality compared to those with adequate iodine nutrition (hazard ratio = 1.19 [confidence interval 1.04-1.37]). Elevated hazard ratios of cardiovascular and cancer mortality were also found, but the confidence interval of the effect estimates included the null value for both outcomes. Low UIC was not associated with increased mortality. Restricted cubic spline models showed similar results for all outcomes. The results did not change substantially after adjusting for total sodium intake and fat/calorie ratio. None of the potential interactions were statistically significant on a multiplicative scale. CONCLUSION Higher all-cause mortality among those with excess iodine intake compared to individuals with adequate iodine intake highlights the importance of monitoring population iodine status. Further studies with longitudinal measures of iodine status are needed to validate these results and to assess the potential risks excess iodine intake may have on long-term health outcomes.

Aldosterone Suppression by Dexamethasone in Patients with KCNJ5-Mutated Aldosterone-producing Adenoma.

Context Aldosterone biosynthesis is regulated principally by ACTH and gene mutations as well as by angiotensin II and serum potassium. In addition, previous studies have reported the potential effects of KCNJ5 mutations in aldosterone-producing adenoma (APA) on cardiovascular diseases. However, responsiveness to ACTH in APAs according to potassium inwardly rectifying channel, subfamily J, member 5 (KCNJ5) mutations remains unknown. Objective To investigate KCNJ5 genotype-specific differences in aldosterone biosynthesis in response to ACTH stimulation. Design and Setting A cross-sectional study through retrieval of clinical records. Participants One hundred forty-one patients aged ≥20 years with APA were examined. Main Outcome Measures Associations between KCNJ5 mutations and clinical parameters reflecting the renin-angiotensin system [saline infusion test (SIT)] and ACTH pathways [dexamethasone suppression test (DST)]. Results KCNJ5 mutations were detected in 107 cases. In the crude comparison, patients with mutations in KCNJ5 had higher plasma aldosterone concentrations (PACs) both at baseline and after the SIT. PAC after the DST showed a significant inverse association with KCNJ5 genotypes after controlling for age, sex, tumor size, and PAC after the SIT. Immunohistochemical analysis of 101 cases revealed more abundant immunoreactivity of CYP11B1 and CYP17 in the KCNJ5-mutated group than in the KCNJ5 wild-type group. Conclusion This report of marked suppression of PAC by dexamethasone in patients with KCNJ5-mutated APAs indicates that such APAs respond to endogenous ACTH more readily than APAs in nonmutated cases. Further molecular and epidemiologic studies are required to validate our results and clarify the clinical effectiveness of the DST for predicting KCNJ5 mutations before adrenalectomy.

Urinary Iodine Concentrations and Mortality Among U.S. Adults

BACKGROUND Iodine deficiency has long been recognized as an important public health problem. Global approaches such as salt iodization that aim to overcome iodine deficiency have been successful. Meanwhile, they have led to excessive iodine consumption in some populations, thereby increasing the risks of iodine-induced thyroid dysfunction, as well as the comorbidities and mortality associated with hypothyroidism and hyperthyroidism. This study aimed to elucidate whether iodine intake is associated with mortality among U.S. adults. METHODS This was an observational study to estimate mortality risks according to urinary iodine concentration (UIC) utilizing a nationally representative sample of 12,264 adults aged 20-80 years enrolled in the National Health and Nutrition Examination Survey (NHANES) III. Crude and multivariable Cox proportional hazards regression models were employed to investigate the association between UIC (<50, 50-99, 100-299, 300-399, and ≥400 μg/L) and mortalities (all-cause, cardiovascular, and cancer). In sensitivity analyses, the study adjusted for total sodium intake and fat/calorie ratio in addition to other potential confounders. Stratum-specific analyses were also conducted to estimate the effects of UIC on mortality according to age, sex, race/ethnicity, and estimated glomerular filtration rate category. RESULTS Over a median follow-up of 19.2 years, there were 3159 deaths from all causes. Participants with excess iodine exposure (UIC ≥400 μg/L) were at higher risk for all-cause mortality compared to those with adequate iodine nutrition (hazard ratio = 1.19 [confidence interval 1.04-1.37]). Elevated hazard ratios of cardiovascular and cancer mortality were also found, but the confidence interval of the effect estimates included the null value for both outcomes. Low UIC was not associated with increased mortality. Restricted cubic spline models showed similar results for all outcomes. The results did not change substantially after adjusting for total sodium intake and fat/calorie ratio. None of the potential interactions were statistically significant on a multiplicative scale. CONCLUSION Higher all-cause mortality among those with excess iodine intake compared to individuals with adequate iodine intake highlights the importance of monitoring population iodine status. Further studies with longitudinal measures of iodine status are needed to validate these results and to assess the potential risks excess iodine intake may have on long-term health outcomes.

Life Expectancy of Patients With Low-Normal Thyroid Function

Life Expectancy of Patients With Low-Normal Thyroid Function To the Editor Using the multistate life table method with data from the Rotterdam Study, Bano and colleagues,1 in a recent issue of JAMA Internal Medicine, showed that participants with low-normal thyroid function had longer life expectancy compared with those with high-normal thyroid function. Although we agree that the results of this study would contribute to reevaluating the reference range of thyroid hormones, Bano and colleagues1 need to provide more information about the association between thyroid hormone levels (within reference range) and mortality. Bano et al1 calculated life expectancy among tertiles of thyrotropin and free thyroxine considering the following 3 transitions: (1) incident cardiovascular disease (CVD), (2) mortality among those without CVD, and (3) mortality among those with CVD. It means that participants who already had a history of CVD at baseline and those who acquired CVD during the study period contributed to the number of “persons at risk” of mortality among those with CVD. However, it is not clear whether the effect of baseline thyroid hormone levels on mortality risk would last after the CVD event or would be homogenous among those who already had a history of CVD at baseline and those who acquired CVD during the study period. It is also unclear why person-years at risk are different between the 2 transitions: (1) incident CVD and (2) mortality among those without CVD. Providing the additional information, the comparison between the results of this study1 and those of previous studies would be more straightforward.2,3 It has been reported that subclinical hypothyroidism is associated with increased risk of CVD and mortality.4 Moreover, we previously reported that low-normal thyroid function had higher risks of cardiovascular and all-cause mortality than median-normal thyroid function.3 Physiologically, low thyroid function has been known to weaken cardiac function and increase systemic vascular resistance by regulating calcium uptake and inducing endothelial dysfunction, which can eventually cause CVD.5 Additionally, the association between low thyroid function and metabolic syndrome has been reported within the reference range.3 Therefore, Bano et al1 would need to explain how they interpreted the prolonged life expectancy of participants with low-normal thyroid function despite these physiological mechanisms.

Prenatal Exposure to Perfluoroalkyl Substances and Birth Outcomes; An Updated Analysis from the Danish National Birth Cohort

Perfluoroalkyl substances (PFASs) are widespread industrial pollutants that are extremely persistent in the environment. A previous study in the Danish National Birth Cohort (DNBC) found prenatal perfluorooctanoate (PFOA) exposure was associated with decreased birth weight, but had insufficient statistical power to evaluate adverse birth outcomes. Here, we conducted additional analyses in three samples originating from the DNBC for 3535 mothers and infant pairs to evaluate associations between prenatal PFASs exposures and low birth weight and preterm birth. Maternal plasma concentrations were measured for six types of PFASs in early pregnancy. Several PFASs were associated with a reduction in birth weight and gestational age. We estimated a nearly 2-fold increase in risks of preterm birth for the higher quartiles of PFOA and perflourooctanesulfonate (PFOS) exposure. In spline models, risk of preterm birth was increased for perfluorononanoic acid (PFNA), perfluoroheptane sulfonate (PFHpS) and perfluorodecanoic acid (PFDA) in higher exposure ranges. We also observed some elevated risks for low birth weight but these estimates were less precise. Our findings strengthen the evidence that in-utero PFASs exposures affect fetal growth. Future studies are needed to evaluate whether these associations persist with the decline of PFOA and PFOS in populations and should also investigate newer types of fluorinated compounds introduced more recently.

Amiodarone-induced Thyrotoxicosis with Cardiopulmonary Arrest

We describe a case of amiodarone-induced thyrotoxicosis (AIT) with cardiopulmonary arrest (CPA) in a 49-year-old woman. The patient had been treated with amiodarone for non-sustained ventricular tachycardia. Two weeks prior to her admission, she developed thyrotoxicosis and prednisolone (PSL, 30 mg daily) was administered with the continuation of amiodarone. However, she was admitted to our hospital for CPA. We performed total thyroidectomy to control her thyrotoxicosis and the pathological findings were consistent with type 2 AIT. She gradually improved and was discharged on day 84. This case demonstrates the importance of considering immediate total thyroidectomy for patients with uncontrollable AIT.

Increased Serum Dihomo-γ-linolenic Acid Levels Are Associated with Obesity, Body Fat Accumulation, and Insulin Resistance in Japanese Patients with Type 2 Diabetes

Objective To clarify the associations between serum omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acid (PUFA) levels and obesity-related metabolic abnormalities in patients with type 2 diabetes. Methods and Materials Data from 225 Japanese patients with type 2 diabetes were cross-sectionally analyzed. The serum levels of n-6 PUFAs [dihomo-γ-linolenic acid (DGLA) and arachidonic acid (AA)] and n-3 PUFAs (eicosapentaenoic acid and docosahexaenoic acid) were measured, and the estimated Δ-5 desaturase (D5D) activity was calculated based on the AA to DGLA ratio. The associations between the composition of PUFAs and obesity-related parameters, including the body mass index (BMI), waist circumference, alanine amino transferase (ALT) level, homeostatic model assessment of insulin resistance (HOMA-IR), and body fat percentage, as measured by a bioelectrical impedance analysis, were analyzed. Results Among the PUFAs, the DGLA level had the strongest correlations with BMI (p＜0.001), waist circumference (p＜0.001), ALT level (p＜0.001), HOMA-IR (p＜0.001), and body fat percentage (p＜0.01). AA was positively correlated and D5D was negatively correlated with several obesity-related parameters, while n-3 PUFAs did not have a constant correlation. A multivariate regression analysis revealed that the DGLA level was an independent determinant for HOMA-IR (β=0.195, p=0.0066) after adjusting for sex, age, BMI, and the ALT, triglyceride, and HbA1c levels. Conclusion A high serum DGLA level was associated with obesity, body fat accumulation, a high ALT level, and insulin resistance in patients with type 2 diabetes. The measurement of the serum PUFA levels may be useful for evaluating metabolic abnormalities and estimating the dietary habits of patients.