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Open access

Confirmatory testing of primary aldosteronism with saline infusion test and LC-MS/MS

Carmina Teresa Fuss, Katharina Brohm, Max Kurlbaum, Anke Hannemann, Sabine Kendl, Martin Fassnacht, Timo Deutschbein, Stefanie Hahner, and Matthias Kroiss

Objective

Saline infusion testing (SIT) for confirmation of primary aldosteronism (PA) is based on impaired aldosterone suppression in PA compared to essential hypertension (EH). In the past, aldosterone was quantified using immunoassays (IA). Liquid chromatography tandem mass spectrometry (LC-MS/MS) is increasingly used in clinical routine. We aimed at a method-specific aldosterone threshold for the diagnosis of PA during SIT and explored the diagnostic utility of steroid panel analysis.

Design

Retrospective cohort study of 187 paired SIT samples (2009–2018). Diagnosis of PA (n = 103) and EH (n = 84) was established based on clinical routine workup without using LC-MS/MS values.

Setting

Tertiary care center.

Methods

LC-MS/MS using a commercial steroid panel. Receiver operator characteristics analysis was used to determine method-specific cut-offs using a positive predictive value (PPV) of 90% as criterion.

Results

Aldosterone measured by IA was on average 31 ng/L higher than with LC-MS/MS. The cut-offs for PA confirmation were 54 ng/L for IA (sensitivity: 95%, 95% CI: 89.0–98.4; specificity: 87%, 95% CI: 77.8–93.3; area under the curve (AUC): 0.955, 95% CI: 0.924–0.986; PPV: 90%, 95% CI: 83.7–93.9) and 69 ng/L for LC-MS/MS (79%, 95% CI: 69.5–86.1; 89%, 95% CI: 80.6–95.0; 0.902, 95% CI: 0.857–0.947; 90%, 95% CI: 82.8–94.4). Other steroids did not improve SIT.

Conclusions

Aldosterone quantification with LC-MS/MS and IA yields comparable SIT-cut-offs. Lower AUC for LC-MS/MS is likely due to the spectrum of disease in PA and previous decision making based on IA results. Until data of a prospective trial with clinical endpoints are available, the suggested cut-off can be used in clinical routine.

Open access

Treatment of symptomatic hyponatremia with hypertonic saline: a real-life observational study

Irina Chifu, Amelie Gerstl, Björn Lengenfelder, Dominik Schmitt, Nils Nagler, Martin Fassnacht, and Dirk Weismann

Objective

Treatment of symptomatic hyponatremia is not well established. The European guidelines recommend bolus-wise administration of 150 mL of 3% hypertonic saline. This recommendation is, however, based on low level of evidence.

Design

Observational study.

Methods

Sixty-two consecutive hyponatremic patients admitted to the emergency department or intensive care unit of the University Hospital Wuerzburg were divided in subgroups according to treatment (150 mL bolus of 3% hypertonic saline or conventional treatment) and symptom severity. Treatment target was defined as an increase in serum sodium by 5–10 mEq/L within first 24 h and maximum 8 mEq/L during subsequent 24 h.

Results

Thirty-three out of sixty-two patients (53%) were presented with moderate symptoms and 29/62 (47%) with severe symptoms. Thirty-six were treated with hypertonic saline and 26 conventionally. In the hypertonic saline group, serum sodium increased from 116 ± 7 to 123 ± 6 (24 h) and 127 ± 6 mEq/L (48 h) and from 121 ± 6 to 126 ± 5 and 129 ± 4 mEq/L in the conventional group, respectively. Overcorrection at 24 h occurred more frequent in patients with severe symptoms than with moderate symptoms (38% vs 6%, P < 0.05). Diuresis correlated positively with the degree of sodium overcorrection at 24 h (r = 0.6, P < 0.01). Conventional therapies exposed patients to higher degrees of sodium fluctuations and an increased risk for insufficient sodium correction at 24 h compared to hypertonic saline (RR: 2.8, 95% CI: 1.4–5.5).

Conclusion

Sodium increase was more constant with hypertonic saline, but overcorrection rate was high, especially in severely symptomatic patients. Reducing bolus-volume and reevaluation before repeating bolus infusion might prevent overcorrection. Symptoms caused by hypovolemia can be misinterpreted as severely symptomatic hyponatremia and diuresis should be monitored.

Open access

MANAGEMENT OF ENDOCRINE DISEASE: Imaging for the diagnosis of malignancy in incidentally discovered adrenal masses: a systematic review and meta-analysis

Jacqueline Dinnes, Irina Bancos, Lavinia Ferrante di Ruffano, Vasileios Chortis, Clare Davenport, Susan Bayliss, Anju Sahdev, Peter Guest, Martin Fassnacht, Jonathan J Deeks, and Wiebke Arlt

Objective

Adrenal masses are incidentally discovered in 5% of CT scans. In 2013/2014, 81 million CT examinations were undertaken in the USA and 5 million in the UK. However, uncertainty remains around the optimal imaging approach for diagnosing malignancy. We aimed to review the evidence on the accuracy of imaging tests for differentiating malignant from benign adrenal masses.

Design

A systematic review and meta-analysis was conducted.

Methods

We searched MEDLINE, EMBASE, Cochrane CENTRAL Register of Controlled Trials, Science Citation Index, Conference Proceedings Citation Index, and ZETOC (January 1990 to August 2015). We included studies evaluating the accuracy of CT, MRI, or 18F-fluoro-deoxyglucose (FDG)-PET compared with an adequate histological or imaging-based follow-up reference standard.

Results

We identified 37 studies suitable for inclusion, after screening 5469 references and 525 full-text articles. Studies evaluated the accuracy of CT (n=16), MRI (n=15), and FDG-PET (n=9) and were generally small and at high or unclear risk of bias. Only 19 studies were eligible for meta-analysis. Limited data suggest that CT density >10HU has high sensitivity for detection of adrenal malignancy in participants with no prior indication for adrenal imaging, that is, masses with ≤10HU are unlikely to be malignant. All other estimates of test performance are based on too small numbers.

Conclusions

Despite their widespread use in routine assessment, there is insufficient evidence for the diagnostic value of individual imaging tests in distinguishing benign from malignant adrenal masses. Future research is urgently needed and should include prospective test validation studies for imaging and novel diagnostic approaches alongside detailed health economics analysis.

Open access

Adrenal wash-out CT: moderate diagnostic value in distinguishing benign from malignant adrenal masses

Wiebke Schloetelburg, Ines Ebert, Bernhard Petritsch, Andreas Max Weng, Ulrich Dischinger, Stefan Kircher, Andreas Konrad Buck, Thorsten Alexander Bley, Timo Deutschbein, and Martin Fassnacht

Objective

Reliable results of wash-out CT in the diagnostic workup of adrenal incidentalomas are scarce. Thus, we evaluated the diagnostic accuracy of delayed wash-out CT and determined thresholds to accurately differentiate adrenal masses.

Design

Retrospective, single-center cohort study including 216 patients with 252 adrenal lesions who underwent delayed wash-out CT. Definitive diagnoses based on histopathology (n = 92) or comprehensive follow-up.

Methods

Size, average attenuation values of the adrenal lesions in all CT scan phases, and absolute and relative percentage wash-out (APW/RPW) were determined by an expert radiologist blinded for clinical data. Adrenal lesions with unenhanced attenuation values >10 Hounsfield units (HU) built a subgroup (n = 142). Diagnostic accuracy was calculated.

Results

The study group consisted of 171 adenomas, 32 other benign tumors, 11 pheochromocytomas, 9 adrenocortical carcinomas, and 29 other malignant tumors. All (potentially) malignant and 46% of benign lesions showed unenhanced attenuation values >10 HU. In this most relevant subgroup, the established thresholds of 60% for APW and 40% for RPW misclassified 35.9 and 35.2% of the masses, respectively. When we applied optimized cutoffs (APW >83%; RPW >58%) and excluded pheochromocytomas, we missed only one malignant tumor by APW and none by RPW. However, only 11 and 15% of the benign tumors were correctly identified.

Conclusions

Wash-out CT with the established thresholds for APW and RPW is insufficient to reliably diagnose adrenal masses. Using the proposed cutoff of 58% for RPW, malignant tumors will be correctly identified, but the added value is limited, namely 15% of patients with benign tumors can be prevented from additional imaging or even unnecessary surgery.

Open access

Plasma methoxytyramine: clinical utility with metanephrines for diagnosis of pheochromocytoma and paraganglioma

Dipti Rao, Mirko Peitzsch, Aleksander Prejbisz, Katarzyna Hanus, Martin Fassnacht, Felix Beuschlein, Christina Brugger, Stephanie Fliedner, Katharina Langton, Christina Pamporaki, Volker Gudziol, Anthony Stell, Andrzej Januszewicz, Henri J L M Timmers, Jacques W M Lenders, and Graeme Eisenhofer

Context

Measurements of plasma methoxytyramine, the O-methylated dopamine metabolite, are useful for detecting rare dopamine-producing pheochromocytomas and paragangliomas (PPGLs) and head and neck paragangliomas (HNPGLs), but utility for screening beyond that achieved using standard measurements of normetanephrine and metanephrine is unclear.

Objective

Evaluation of the additional utility of methoxytyramine compared to plasma normetanephrine and metanephrine for diagnosis of PPGLs and HNPGLs.

Design

Comparative prospective study.

Methods

Comparison of mass spectrometric-based measurements of plasma methoxytyramine, normetanephrine and metanephrine in 1963 patients tested for PPGLs at six tertiary medical centers according to reference intervals verified in 423 normotensive and hypertensive volunteers.

Results

Of the screened patients, 213 had PPGLs and 38 HNPGLs. Using an upper cut-off of 0.10 nmol/L for methoxytyramine, 0.45 nmol/L for metanephrine and age-specific upper cut-offs for normetanephrine, diagnostic sensitivity with the addition of methoxytyramine increased from 97.2% to 98.6% for patients with PPGLs and from 22.1% to 50.0% for patients with HNPGLs, with a small decrease in specificity from 95.9% to 95.1%. Addition of methoxytyramine did not significantly alter areas under receiver operating characteristic curves for patients with PPGLs (0.984 vs 0.991), but did increase (P < 0.05) areas for patients with HNPGLs (0.627 vs 0.801). Addition of methoxytyramine also increased the proportion of patients with PPGLs who showed highly positive predictive elevations of multiple metabolites (70.9% vs 49.3%).

Conclusions

While the benefit of additional measurements of plasma methoxytyramine for the detection of PPGLs is modest, the measurements do assist with positive confirmation of disease and are useful for the detection of HNPGLs.