Insights into diagnostic errors in endocrinology: a prospective, case-based, international study.

BACKGROUND: Diagnostic errors in internal medicine are common. While cognitive errors have previously been identified to be the most common contributor to errors, very little is known about errors in specific fields of internal medicine such as endocrinology. This prospective, multicenter study focused on better understanding the causes of diagnostic errors made by general practitioners and internal specialists in the area of endocrinology. METHODS: From August 2019 until January 2020, 24 physicians completed five endocrine cases on an online platform that simulated the diagnostic process. After each case, the participants had to state and explain why they chose their assumed diagnosis. The data gathering process as well as the participants' explanations were quantitatively and qualitatively analyzed to determine the causes of the errors. The diagnostic processes in correctly and incorrectly solved cases were compared. RESULTS: Seven different causes of diagnostic error were identified, the most frequent being misidentification (mistaking one diagnosis with a related one or with more frequent and similar diseases) in 23% of the cases. Other causes were faulty context generation (21%) and premature closure (17%). The diagnostic confidence did not differ between correctly and incorrectly solved cases (median 8 out of 10, p = 0.24). However, in incorrectly solved cases, physicians spent less time on the technical findings (such as lab results, imaging) (median 250 s versus 199 s, p < 0.049). CONCLUSIONS: The causes for errors in endocrine case scenarios are similar to the causes in other fields of internal medicine. Spending more time on technical findings might prevent misdiagnoses in everyday clinical practice.

Postoperative ACTH-stimulated aldosterone predicts biochemical outcome in primary aldosteronism.

OBJECTIVE: Primary aldosteronism (PA) is the most common surgically curable cause of hypertension. Unilateral aldosterone-producing adenoma can be treated with adrenalectomy. Clinical and biochemical outcomes are assessed 6-12 months after adrenalectomy according to primary aldosteronism surgical outcome (PASO) consensus criteria. Earlier prediction of biochemical remission would be desirable as it could reduce cumbersome follow-up visits. We hypothesized that postoperative adrenocorticotropic hormone (ACTH) stimulated plasma aldosterone concentrations (PAC) measured shortly after adrenalectomy can predict PASO outcomes. DESIGN: Retrospective cohort study. METHODS: We analyzed 100 patients of the German Conn's registry who underwent adrenalectomy and postoperative ACTH stimulation tests within the first week after adrenalectomy. Six to twelve months after adrenalectomy we assessed clinical and biochemical outcomes according to PASO criteria. Serum cortisol and PAC were measured by immunoassay at baseline and 30 min after the intravenous ACTH infusion. We used receiver operating characteristics (ROC) curve analysis and matched the parameters to PASO outcomes. RESULTS: Eighty-one percent of patients had complete, 13% partial, and 6% absent biochemical remission. Complete clinical remission was observed in 28%. For a cut-off of 58.5 pg/mL, stimulated PAC could predict partial/absent biochemical remission with a high sensitivity (95%) and reasonable specificity (74%). Stimulated PAC's area under the curve (AUC) (0.89; confidence interval (CI) 0.82-0.96) was significantly higher than other investigated parameters. CONCLUSIONS: Low postoperative ACTH stimulated PAC was predictive of biochemical remission. If confirmed, this approach could reduce follow-up visits to assess biochemical outcome.

Influence of cortisol cosecretion on non-ACTH-stimulated adrenal venous sampling in primary aldosteronism: a retrospective cohort study.

Objective: Cortisol measurements are essential for the interpretation of adrenal venous samplings (AVS) in primary aldosteronism (PA). Cortisol cosecretion may influence AVS indices. We aimed to investigate whether cortisol cosecretion affects non-adrenocorticotrophic hormone (ACTH)-stimulated AVS results. Design: Retrospective cohort study at a tertiary referral center. Methods: We analyzed 278 PA patients who underwent non-ACTH-stimulated AVS and had undergone at least a 1-mg dexamethasone suppression test (DST). Subsets underwent additional late-night salivary cortisol (LSC) and/or 24-h urinary free cortisol (UFC) measurements. Patients were studied from 2013 to 2020 with follow-up data of 6 months following adrenalectomy or mineralocorticoid antagonist therapy initiation. We analyzed AVS parameters including adrenal vein aldosterone/cortisol ratios, selectivity, lateralization (LI) and contralateral suppression indices and post-operative ACTH-stimulation. We classified outcomes according to the primary aldosteronism surgical outcome (PASO) criteria. Results: Among the patients, 18.9% had a pathological DST result (1.9-5 µg/dL: n = 44 (15.8%); >5 µg/dL: n = 8 (2.9%)). Comparison of AVS results stratified according to the 1-mg DST (≤1.8 vs >1.8 µg/dL: P = 0.499; ≤1.8 vs 1.8 ≤ 5 vs >5 µg/dL: P = 0.811) showed no difference. Lateralized cases with post DST serum cortisol values > 5 µg/dL had lower LI (≤1.8 µg/dL: 11.11 (5.36; 26.76) vs 1.9-5 µg/dL: 11.76 (4.9; 31.88) vs >5 µg/dL: 2.58 (1.67; 3.3); P = 0.008). PASO outcome was not different according to cortisol cosecretion. Conclusions: Marked cortisol cosecretion has the potential to influence non-ACTH-stimulated AVS results. While this could result in falsely classified lateralized cases as bilateral, further analysis of substitutes for cortisol are required to unmask effects on clinical outcome.

The metabolic phenotype of patients with primary aldosteronism: impact of subtype and sex - a multicenter-study of 3566 Caucasian and Asian subjects.

Background: Accumulating evidence suggests that primary aldosteronism (PA) is associated with several features of the metabolic syndrome, in particular with obesity, type 2 diabetes mellitus, and dyslipidemia. Whether these manifestations are primarily linked to aldosterone-producing adenoma (APA) or bilateral idiopathic hyperaldosteronism (IHA) remains unclear. The aim of the present study was to investigate differences in metabolic parameters between APA and IHA patients and to assess the impact of treatment on these clinical characteristics. Methods: We conducted a retrospective multicenter study including 3566 patients with APA or IHA of Caucasian and Asian origin. We compared the prevalence of metabolic disorders between APA and IHA patients at the time of diagnosis and 1-year post-intervention, with special references to sex differences. Furthermore, correlations between metabolic parameters and plasma aldosterone, renin, or plasma cortisol levels after 1 mg dexamethasone (DST) were performed. Results: As expected, APA patients were characterized by higher plasma aldosterone and lower serum potassium levels. Only female IHA patients demonstrated significantly worse metabolic parameters than age-matched female APA patients, which were associated with lower cortisol levels upon DST. One-year post-intervention, female adrenalectomized patients showed deterioration of their lipid profile, when compared to patients treated with mineralocorticoid receptor antagonists. Plasma aldosterone levels negatively correlated with the BMI only in APA patients. Conclusions: Metabolic alterations appear more prominent in women with IHA. Although IHA patients have worse metabolic profiles, a correlation with cortisol autonomy is documented only in APAs, suggesting an uncoupling of cortisol action from metabolic traits in IHA patients.

Renin, a marker for left ventricular hypertrophy, in primary aldosteronism: a cohort study.

CONTEXT: Primary aldosteronism (PA) causes left ventricular hypertrophy (LVH) via hemodynamic factors and directly by aldosterone effects. Specific treatment by mineralocorticoid receptor antagonists (MRA) or adrenalectomy (ADX) has been reported to improve LVH. However, the cardiovascular benefit could depend on plasma renin concentration (PRC) in patients on MRA. PATIENTS AND OBJECTIVE: We analyzed data from 184 patients from the Munich center of the German Conn's Registry, who underwent echocardiography at the time of diagnosis and 1 year after treatment. To assess the effect of PRC on cardiac recovery, we stratified patients on MRA according to suppression (n = 46) or non-suppression of PRC (n = 59) at follow-up and compared them to PA patients after ADX (n = 79). RESULTS: At baseline, patients treated by ADX or MRA had comparable left ventricular mass index (LVMI, 61.7 vs 58.9 g/m2.7, P = 0.591). Likewise, patients on MRA had similar LVMI at baseline, when stratified into treatment groups with suppressed and unsuppressed PRC during follow-up (60.0 vs 58.1 g/m2.7, P = 0.576). In all three groups, we observed a significant reduction in LVMI following treatment (P < 0.001). However, patients with suppressed PRC had no decrease in pro-BNP levels, and the reduction of LVMI was less intense than in patients with unsuppressed PRC (4.1 vs 8.2 g/m2.7, P = 0.033) or after ADX (9.3 g/m2.7, P = 0.019). Similarly, in multivariate analysis, higher PRC was correlated with the regression of LVH. CONCLUSION: PA patients with suppressed PRC on MRA show impaired regression of LVH. Therefore, dosing of MRA according to PRC could improve their cardiovascular benefit.

Single-Center Prospective Cohort Study on the Histopathology, Genotype, and Postsurgical Outcomes of Patients With Primary Aldosteronism.

[Figure: see text].

Altered Taste Perception for Sodium Chloride in Patients With Primary Aldosteronism: A Prospective Cohort Study.

[Figure: see text].

Autonomous Cortisol Secretion Influences Psychopathological Symptoms in Patients With Primary Aldosteronism.

CONTEXT: Primary aldosteronism (PA) is associated with impaired quality of life (QoL). Autonomous cortisol cosecretion (ACS) is a relevant phenotype of PA, which could contribute to depression and anxiety disorders. This has not been investigated so far. OBJECTIVE: To evaluate the prevalence of depression and anxiety in PA patients according to ACS. METHODS: We performed testing for hypercortisolism and evaluated anxiety, depression and QoL by self-rating questionnaires in newly diagnosed PA patients of the German Conn's Registry; 298 patients were reevaluated at follow-up. RESULTS: In the overall cohort, scores for anxiety (P < .001), depression (P < .001), and QoL (mental P = .021; physical P = .015) improved significantly at follow-up. This improvement was seen in both subgroups of patients with and without ACS, with the exception of the mental subscore in no-ACS patients. Analysis for sex differences showed that anxiety decreased significantly in females with ACS and no-ACS, whereas males with no-ACS failed to improve. Depression improved significantly in males and females with ACS (P = .004, P = 0.011 respectively), but not in those with no-ACS. Physical subscore of QoL improved significantly (P = .023) in females with ACS and mental subscore (P = .027) in males with ACS, whereas no differences were seen for the no-ACS groups. CONCLUSION: Improvement in depression and anxiety scores in response to treatment of PA is more pronounced in patients with ACS in contrast to no-ACS suggesting a role of ACS in the psychopathological symptoms of patients with PA. Furthermore, we observed significant differences in depression and anxiety scores between the sexes.

Atherosclerotic Burden and Arterial Stiffness are Not Increased in Patients with Milder Forms of Primary Aldosteronism Compared to Patients with Essential Hypertension.

Patients with primary aldosteronism (PA) are at increased cardiovascular risk, compared to patients with essential hypertension (EH). Cardiovascular damage could depend on PA phenotype, potentially being lower in milder forms of PA. Our aim was to assess atherosclerotic burden and arterial stiffness in 88 prospectively recruited patients, including 44 patients with mild PA and EH respectively. All patients underwent a structured study program, including measurements of ankle-brachial index, oscillometric measurement of central pulse wave velocity (cPWV) and vascular ultrasound examination of the supraaortic arteries, the abdominal aorta, and the femoropopliteal arteries. A plaque score was calculated to estimate atherosclerotic burden for each patient. This is a prospective case-control study set at a tertiary care hospital. Patients with PA and EH matched well for age, gender, blood pressure, BMI, and cardiovascular risk factors such as diabetes mellitus and smoking status. Common carotid intima-media thickness (0.77 vs. 0.75 mm; p=0.997) and cPWV (7.2 vs. 7.1 m/s; p=0.372) were comparable between patients with PA and EH. The atherosclerotic burden, as expressed by the plaque score, did not differ between the two groups (p=0.159). However, after initiation of treatment cPWV was significantly decreased in patients with PA (p=0.017). This study shows that subclinical atherosclerotic burden and arterial stiffness in patients with milder forms of PA is comparable to patients with EH. Nevertheless, specific treatment for PA significantly improved cPWV, which argues for a more liberal use of mineralocorticoid receptor antagonists in patients with arterial hypertension.

Development of a Prediction Score to Avoid Confirmatory Testing in Patients With Suspected Primary Aldosteronism.

CONTEXT: The diagnostic work-up of primary aldosteronism (PA) includes screening and confirmation steps. Case confirmation is time-consuming, expensive, and there is no consensus on tests and thresholds to be used. Diagnostic algorithms to avoid confirmatory testing may be useful for the management of patients with PA. OBJECTIVE: Development and validation of diagnostic models to confirm or exclude PA diagnosis in patients with a positive screening test. DESIGN, PATIENTS, AND SETTING: We evaluated 1024 patients who underwent confirmatory testing for PA. The diagnostic models were developed in a training cohort (n = 522), and then tested on an internal validation cohort (n = 174) and on an independent external prospective cohort (n = 328). MAIN OUTCOME MEASURE: Different diagnostic models and a 16-point score were developed by machine learning and regression analysis to discriminate patients with a confirmed diagnosis of PA. RESULTS: Male sex, antihypertensive medication, plasma renin activity, aldosterone, potassium levels, and the presence of organ damage were associated with a confirmed diagnosis of PA. Machine learning-based models displayed an accuracy of 72.9%-83.9%. The Primary Aldosteronism Confirmatory Testing (PACT) score correctly classified 84.1% at training and 83.9% or 81.1% at internal and external validation, respectively. A flow chart employing the PACT score to select patients for confirmatory testing correctly managed all patients and resulted in a 22.8% reduction in the number of confirmatory tests. CONCLUSIONS: The integration of diagnostic modeling algorithms in clinical practice may improve the management of patients with PA by circumventing unnecessary confirmatory testing.

[Primary aldosteronism - why is it still underdiagnosed in clinical practice?] / Primärer Hyperaldosteronismus ­ warum diagnostizieren wir immer noch so wenige Patienten?

Primary aldosteronism (PA) represents the leading cause of endocrine hypertension, accounting for 4-13 % of all cases. Simultaneously, it is the most common endocrine form of hypertension that can be cured by surgery. Estimates suggest that 2.5 million people in Germany are affected, yet only 8 % of hypertensive patients undergo the proper diagnostic screening for PA. The diagnosis of PA is evidently not taken into account sufficiently when it comes to the everyday management of hypertension. Since PA patients carry an increased risk of cardio- and cerebrovascular events as well as metabolic comorbidities, early screening and diagnosis is crucial.This manuscript highlights the current guidelines of screening and diagnosing PA and addresses some currently published findings regarding this area. The aim is to raise awareness when it comes to diagnosing and screening for PA in the everyday management of hypertensive patients.

Spironolactone reduces biochemical markers of bone turnover in postmenopausal women with primary aldosteronism.

CONTEXT: Primary aldosteronism (PA) is the most frequent form of endocrine hypertension. Besides its deleterious impact on cardiovascular target organ damage, PA is considered to cause osteoporosis. PATIENTS AND METHODS: We assessed bone turnover in a subset of 36 postmenopausal women with PA. 18 patients had unilateral PA and were treated by adrenalectomy, whereas 18 patients had bilateral PA and received mineralocorticoid receptor antagonist (MRA) therapy respectively. 18 age- and BMI-matched females served as controls. To estimate bone remodeling, we measured the bone turnover markers intact procollagen 1 N-terminal propeptide, bone alkaline phosphatase, osteocalcin and tartrate resistant acid phosphatase 5b in plasma by chemiluminescent immunoassays at time of diagnosis and one year after initiation of treatment. STUDY DESIGN: Observational longitudinal cohort study. SETTING: Tertiary care hospital. RESULTS: Compared with controls, patients with PA had mildly elevated osteocalcin at baseline (p = 0.013), while the other bone markers were comparable between both groups. There were no differences between the unilateral and the bilateral PA subgroup. One year after initiation of MRA treatment with spironolactone bone resorption and bone formation markers had significantly decreased in patients with bilateral PA. In contrast, patients adrenalectomized because of unilateral PA showed no significant change of bone turnover markers. CONCLUSION: This study shows that aldosterone excess in postmenopausal women with PA is not associated with a relevant increase of bone turnover markers at baseline. However, we observed a significant decrease of bone markers in patients treated with spironolactone, but not in patients treated by adrenalectomy.

The Impact of Glucocorticoid Co-Secretion in Primary Aldosteronism on Thyroid Autoantibody Titers During the Course of Disease.

Excess aldosterone is associated with the increased risk of cardio-/cerebrovascular events as well as metabolic comorbidities not only due to its hypertensive effect but also due to its proinflammatory action. Autonomous cortisol secretion (ACS) in the setting of primary aldosteronism (PA) is known to worsen cardiovascular outcome and potentially exhibit immunosuppressive effects. The aim of this study was to determine the impact of ACS status in patients with PA on kinetics of thyroid autoantibodies (anti-TPO, anti-TG) pre and post therapy initiation. Ninety-seven PA patients (43 unilateral, 54 with bilateral PA) from the database of the German Conn's Registry were included. Anti-TPO and anti-TG levels were measured pre and 6-12 months post therapeutic intervention. Patients were assessed for ACS according to their 24- hour urinary cortisol excretion, late night salivary cortisol and low-dose dexamethasone suppression test. Abnormal test results in line with ACS were identified in 74.2% of patients with PA. Following adrenalectomy, significant increases in anti-TPO levels were observed in patients with at least one abnormal test (p = 0.049), adrenalectomized patients with at least two pathological ACS tests (p = 0.015) and adrenalectomized patients with pathologic dexamethasone suppression tests (p = 0.018). No antibody increases were observed in unilateral PA patients without ACS and in patients with bilateral PA receiving mineralocorticoid antagonist therapy (MRA). Our data are in line with an immunosuppressive effect of mild glucocorticoid excess in PA on thyroid autoantibody titers. This effect is uncovered by adrenalectomy, but not by MRA treatment.

[Modern thyroid surgery - the surgeon's endocrine-surgical understanding and his responsibility for the extent of surgery and complication rate]. / Moderne Schilddrüsenchirurgie ­ das endokrin-chirurgische Verständnis des Operateurs und seine Verantwortung für Resektionsausmaß und Komplikationsrate.

High quality thyroid surgery implies a surgeon with an endocrine-surgical understanding aiming at best possible outcome. This includes an appropriate extent of the resection and a low rate of complications. It is important that the surgeon is involved at an early stage being part of the decision process for or against partial or total thyroidectomy. Furthermore, the surgeon should not only be able to perform thyroid and cervical lymph node sonography, but also to be capable to interpret cross-sectional imaging modalities and nuclear medicine imaging procedures. A thorough knowledge of modern principles of radicality is essential.Benign goiters require individualized surgical strategy: solitary nodules can be treated with a tissue-preserving selective nodular resection. However, a multinodular goiter does not necessarily require total thyroidectomy-prevention of a permanent hypoparathyroidism is of paramount importance. For recurrent goiters, removal of the dominant side and therefore, unilateral procedure is favored. Nowadays, there is an increasing tendency to set the indication for thyroid surgery separately for each lobe. Graves' disease requires thyroidectomy, and occasionally, hypertrophic Hashimoto's thyroiditis may also result in surgery.The principles of radical surgical treatment of malignant goiters have changed significantly over the past few years and, so far, strict indication for postoperative radioiodine treatment is being reconsidered. This is especially relevant for papillary thyroid microcarcinomas and minimally invasive follicular tumors. Even the radical surgical treatment of medullary thyroid carcinoma, especially considering synchronous or metachronous lateral neck dissection, is currently under review.Hypoparathyroidism is the most relevant complication in radical thyroid surgery and has devastating influence on the patients' life quality. Nowadays, permanent recurrent laryngeal nerve injury and postoperative hemorrhage rarely occur due to subtle surgical techniques. Extracervical surgical access to the thyroid is still a matter of clinical trials and should be restricted to centers. Radiofrequency ablation is an alternative method for benign lesions or hyperfunctioning nodules in patients with high surgical risk.

Salt Appetite and its Effects on Cardiovascular Risk in Primary Aldosteronism.

First described in 1955 by Jerome W. Conn, primary aldosteronism (PA) today is well established as a relevant cause of secondary hypertension and accounts for about 5-10 % of hypertensives. The importance of considering PA is based on its deleterious target organ damage far beyond the effect of elevated blood pressure and on PA being a potentially curable form of hypertension. Aside the established contributory role of high dietary salt intake to arterial hypertension and cardiovascular disease, high salt intake is mandatory for aldosterone-mediated deleterious effects on target-organ damage in patients with primary aldosteronism. Consequently, counselling patients on the need to reduce salt intake represents a major component in the treatment of PA to minimize cardiovascular damage. Unfortunately, in PA patients salt intake is high and far beyond the target values of 5 g per day, recommended by the World Health Organization. Insufficient patient motivation for lifestyle interventions can be further complicated by enhancing effects of aldosterone on salt appetite, via central and gustatory pathways. In this context, treatment for PA by adrenalectomy results in a spontaneous decrease in dietary salt intake and might therefore provide further reduction of cardiovascular risk in PA than specific medical treatment alone. Furthermore, there is evidence from clinical studies that even after sufficient treatment of PA dietary salt intake remains a relevant prognostic factor for cardiovascular risk. This review will focus on the synergistic benefits derived from both blockade of aldosterone-mediated effects and reduction in dietary salt intake on cardiovascular risk.

The laryngeal twitch response - Can it avoid unnecessary two-stage thyroidectomy? - A retrospective cohort study.

BACKGROUND: The objective of this study was to determine if the laryngeal twitch response, when compared to neuromonitoring, can predict postoperative vocal cord function and can thus be used in case of technical failure of the EMG-recording electrode. METHODS: A total of 640 nerves at risk were included in this study based on a prospective protocol. The laryngeal twitch response and the EMG-records were compared with the results of the postoperative laryngoscopy. RESULTS: Of the 640 nerves at risk, 582 showed a normal postoperative vocal cord function. A recurrent laryngeal nerve paralysis (no vocal fold movement) was observed in 39 cases and recurrent laryngeal nerve paresis (reduced vocal cord movement) was diagnosed in 19 cases. The overall negative predictive value (NPV) in final vagus nerve stimulation (V2) was 95.0% for the EMG-records and 94.8% for the laryngeal twitch response. When pareses were excluded, the NPV was 96.8% and 96.6% respectively. The positive predictive value (PPV) of vagus nerve stimulation lies between 51.4% and 57.1% excluding the pareses. It rises to values between 60.0% and 65.1% if they are included. CONCLUSIONS: The laryngeal twitch response and the EMG-records show similar results, and the NPV is good in both. Thus, in case of technical failure or displacement of the EMG-recording electrode, the laryngeal twitch can be used in decision-making for or against a two-stage thyroidectomy.

Complete and incomplete recurrent laryngeal nerve injury after thyroid and parathyroid surgery: Characterizing paralysis and paresis.

BACKGROUND: Injury of the recurrent laryngeal nerve and consequent disorder of vocal fold movement is a typical complication in thyroid and parathyroid surgery. During postoperative laryngoscopy we observed not only a complete standstill (vocal fold paralysis), but also a hypomobility (paresis). In this prospective study, we investigated the difference in incidence and prognosis as well as risk-factors, intraoperative neuromonitoring, and symptoms between vocal fold paralysis and vocal fold paresis. METHODS: Data were prospectively collected and analyzed in a single high-volume thyroid center between 2012 and 2016. Vocal fold paresis was defined as hypomobility in abduction or adduction, a reduction in range and speed of vocal fold movement. Vocal fold paralysis was defined as asymmetry and missing purposeful vocal fold movement. RESULTS: The study included 4,707 surgeries and 7,992 at-risk nerves at risk. Vocal fold paralysis was diagnosed in 374 patients (4.68% of 7,992 nerves at risk) and vocal fold paresis in 114 patients (1.43%). Exclusively in the paralysis group, 36 patients (0.45%) developed permanent loss of vocal fold function (P < .001). In follow-up, vocal fold paresis patients regain normal vocal fold function significantly earlier than vocal fold paralysis (mean duration: 6.96 ± 6.506 vs 10.77 ± 7,827 weeks) and presented with significantly less symptoms like hoarseness, diplophonia, dysphagia, and dyspnea (68.8% vs 95.9 %). In intraoperative neuromonitoring, vocal fold paresis showed a significantly higher postresectional N. vagus amplitude than vocal fold paralysis patients (0.349 mV vs 0.114 mV, P < .001). CONCLUSION: After thyroidectomy, vocal fold paresis must be distinguished from vocal fold paralysis and should be implemented as a separate outcome parameter in the postoperative quality assessment.