Faculty Bibliography

BACKGROUND:There is a bidirectional association between primary aldosteronism and obstructive sleep apnea, with evidence suggesting that the treatment of primary aldosteronism can reduce obstructive sleep apnea severity. Current guidelines recommend screening for primary aldosteronism in patients with comorbid hypertension and obstructive sleep apnea, identifying potential candidates for treatment. However, emerging data suggest current screening practices are unsatisfactory. Moreover, data regarding the true incidence of primary aldosteronism among this population are limited. This study aimed to assess the primary aldosteronism screening rate among patients with obstructive sleep apnea and hypertension at our institution and estimate the prevalence of primary aldosteronism among this population. METHODS:Sleep studies conducted at our institution between January and September 2021 were retrospectively reviewed. Adult patients with a sleep study diagnostic of obstructive sleep apnea (respiratory disturbance index ≥5) and a diagnosis of hypertension were included. Patient medical records were reviewed and laboratory data of those with biochemical screening for primary aldosteronism were assessed by an experienced endocrinologist. Screening rates were compared before and after initiation of a screening protocol in accordance with the 2016 Endocrine Society guidelines. RESULTS:A total of 1,005 patients undergoing sleep studies were reviewed; 354 patients had comorbid obstructive sleep apnea and hypertension. Patients were predominantly male (67%), with a mean age of 58 years (standard deviation = 12.9) and mean body mass index of 34 (standard deviation = 8.1). The screening rate for primary aldosteronism among included patients was 19% (n = 67). The screening rate was significantly higher after initiation of a dedicated primary aldosteronism screening protocol (23% vs 12% prior; P = .01). Fourteen screens (21%) were positive for primary aldosteronism, whereas 45 (67%) were negative and 8 (12%) were indeterminate. Four had prior abdominal cross-sectional imaging, with 3 revealing an adrenal adenoma. Compared with patients without primary aldosteronism, patients with positive primary aldosteronism screens were more likely to have a history of hypokalemia (36% vs 4.4%; P = .002). The frequency of hyperlipidemia, diabetes mellitus, and left ventricular hypertrophy did not differ between patients with positive versus negative screens. CONCLUSION/CONCLUSIONS:Current screening practices for primary aldosteronism among patients with comorbid obstructive sleep apnea and hypertension are suboptimal. Patients evaluated at sleep centers may represent an optimal population for screening, as the prevalence of primary aldosteronism among this cohort appears high.

Endogenous Cushing's syndrome (CS) is a rare disease characterized by prolonged glucocorticoid excess. Timely diagnosis is critical to allow prompt treatment and limit long-term disease morbidity and risk for mortality. Traditional biochemical diagnostic modalities each have limitations and sensitivities and specificities that vary significantly with diagnostic cutoff values. Biochemical evaluation is particularly complex in patients whose hypercortisolemia fluctuates daily, often requiring repetition of tests to confirm or exclude disease, and when delineating CS from physiologic, nonneoplastic states of hypercortisolism. Lastly, traditional pituitary MRI may be negative in up to 60% of patients with adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (termed "Cushing's disease" [CD]) whereas false positive pituitary MRI findings may exist in patients with ectopic ACTH secretion. Thus, differentiating CD from ectopic ACTH secretion may necessitate dynamic testing or even invasive procedures such as bilateral inferior petrosal sinus sampling. Newer methods may relieve some of the diagnostic uncertainty in CS, providing a more definitive diagnosis prior to subjecting patients to additional imaging or invasive procedures. For example, a novel method of cortisol measurement in patients with CS is scalp hair analysis, a non-invasive method yielding cortisol and cortisone values representing long-term glucocorticoid exposure of the past months. Hair cortisol and cortisone have both shown to differentiate between CS patients and controls with a high sensitivity and specificity. Moreover, advances in imaging techniques may enhance detection of ACTH-secreting pituitary adenomas. While conventional pituitary MRI may fail to identify microadenomas in patients with CD, high-resolution 3T-MRI with 3D-spoiled gradient-echo sequence has thinner sections and superior soft-tissue contrast that can detect adenomas as small as 2 mm. Similarly, functional imaging may improve the identification of ACTH-secreting adenomas noninvasively; Gallium-68-tagged corticotropin-releasing hormone (CRH) combined with PET-CT can be used to detect CRH receptors, which are upregulated on corticotroph adenomas. This technique can delineate functionality of adenomas in patients with CD from patients with ectopic ACTH secretion and false positive pituitary lesions on MRI. Here, we review emerging methods and imaging modalities for the diagnosis of CS, discussing their diagnostic accuracy, strengths and limitations, and applicability to clinical practice.

Cushing's syndrome results from supraphysiological exposure to glucocorticoids and is associated with significant morbidity and mortality. The pathogenesis includes administration of corticosteroids (exogenous Cushing's syndrome) or autonomous cortisol overproduction, whether or not adrenocorticotropin hormone (ACTH) dependent (endogenous Cushing's syndrome). An early diagnosis of Cushing's syndrome is warranted, however, in clinical practice very challenging partly due to resemblance with other common conditions (i.e. pseudo-Cushing's syndrome). Initial workup should start with excluding local and systemic corticosteroid use. First-line screening tests including the 1-mg dexamethasone suppression test, 24-hour urinary free cortisol excretion, and late-night salivary cortisol measurement should be performed to screen for endogenous Cushing's syndrome. Scalp-hair cortisol/cortisone analysis helps in the assessment of long-term glucocorticoid exposure as well as in detection of transient periods of hypercortisolism as observed in cyclical Cushing's syndrome. Interpretation of results can be difficult due to individual patient characteristics and hence requires awareness of test limitations. Once endogenous Cushing's syndrome is established, measurement of plasma ACTH concentrations differentiates between ACTH-dependent (80-85%) or ACTH-independent (15-20%) causes. Further assessment with different imaging modalities and dynamic biochemical testing including bilateral inferior petrosal sinus sampling helps further pinpoint the cause of Cushing's syndrome. In this issue of 'Approach to the patient' the diagnostic workup of Cushing's syndrome is discussed with answering the questions when to screen, how to screen and how to differentiate the different causes. In this respect, latest developments in biochemical and imaging techniques are discussed as well.

The histologic diagnosis of sellar masses can be challenging, particularly in rare neoplasms and tumors without definitive biomarkers. Moreover, there is significant inter-observer variability in the histopathological diagnosis of many tumors of the CNS, and some rare tumors risk being misclassified. DNA methylation has recently emerged as a useful diagnostic tool. To illustrate the clinical utility of machine-learning-based DNA methylation classifiers, we report a rare case of primary sellar esthesioneuroblastoma histologically mimicking a non-functioning pituitary adenoma. The patient had multiple recurrences, and the resected specimens had unusual histopathology. A portion of the resected sellar lesion was profiled using clinically validated whole-genome DNA methylation and classification. DNA was extracted from the tissue, hybridized on DNA methylation chips, and analyzed using a clinically validated classifier. DNA methylation profiling of the lesion showed that the tumor classified best with the esthesioneuroblastoma reference cohort. This case highlights the difficulty in diagnosing atypical sellar lesions by standard histopathological methods. However, when phenotypic analyses were nonconclusive, DNA methylation profiling resulted in a change in diagnosis. We discuss the growing role of DNA methylation profiling in the classification and diagnosis of CNS tumors, finding that utilization of DNA methylation studies in cases of atypical presentation or diagnostic uncertainty may improve diagnostic accuracy with therapeutic and prognostic implications.

PURPOSE/OBJECTIVE:Hypophysitis can clinically and radiologically mimic other nonfunctioning masses of the sella turcica, complicating preoperative diagnosis. While sellar masses may be treated surgically, hypophysitis is often treated medically, so differentiating between them facilitates optimal management. The objective of our study was to develop a scoring system for the preoperative diagnosis of hypophysitis. METHODS:A thorough literature review identified published hypophysitis cases, which were compared to a retrospective group of non-functioning pituitary adenomas (NFA) from our institution. A preoperative hypophysitis scoring system was developed and internally validated. RESULTS:Fifty-six pathologically confirmed hypophysitis cases were identified in the literature. After excluding individual cases with missing values, 18 hypophysitis cases were compared to an age- and sex-matched control group of 56 NFAs. Diabetes insipidus (DI) (p < 0.001), infundibular thickening (p < 0.001), absence of cavernous sinus invasion (CSI) (p < 0.001), relation to pregnancy (p = 0.002), and absence of visual symptoms (p = 0.007) were significantly associated with hypophysitis. Stepwise logistic regression identified DI and infundibular thickening as positive predictors of hypophysitis. CSI and visual symptoms were negative predictors. A 6-point hypophysitis-risk scoring system was derived: + 2 for DI, + 2 for absence of CSI, + 1 for infundibular thickening, + 1 for absence of visual symptoms. Scores ≥ 3 supported a diagnosis of hypophysitis (AUC 0.96, sensitivity 100%, specificity 75%). The scoring system identified 100% of hypophysitis cases at our institution with an estimated 24.7% false-positive rate. CONCLUSIONS:The proposed scoring system may aid preoperative diagnosis of hypophysitis, preventing unnecessary surgery in these patients.

Adult growth hormone (GH) deficiency is rare and requires replacement with extrinsic/synthetic injection. GH hypersensitivity has been reported; specifically, atopic patients may develop rashes from somatotropin therapy. Allergic and non-allergic skin reactions to recombinant human GH are uncommon and infrequently reported. We describe a graded-dose challenge with intravenous Norditropin® in a 65-year-old atopic adult woman who developed a severe whole-body rash with Norditropin FlexPro® administration on several occasions but was negative on skin-prick testing to Norditropin® percutaneously and intradermally, but the patch testing was positive for gold and nickel. The patient was registered as a direct admission to the emergency room at a university hospital for a rapid antigen coronavirus disease 2019 (COVID-19) testing after having received two COVID-19 vaccinations and re-testing four months after vaccination. She was then directly admitted to a non-COVID-19 intensive care unit with direct bedside supervision by a registered nurse and a physician board certified in internal medicine, allergy/immunology, and pulmonary diseases. The patient brought a Norditropin® pen which our pharmacy team attached to a compatible syringe for dilutions. A graded dose challenge at a final dosage of 0.1 mL was performed and the patient was monitored for allergic and other adverse drug reactions, which did not occur. At the time of writing this case report, the patient has been maintained on Norditropin FlexPro® 0.1 mL and has not experienced any adverse reactions, including recurrent skin eruptions. The case presented is the first to describe a patient who successfully tolerated a graded dose challenge of an adult patient to GH replacement therapy (as Norditropin®) under supervision in an intensive care unit, whereas prior to reporting of this case, a graded dose challenge to GH replacement therapy had only been successfully performed in a child using another formulation of somatotropin (Humatrope®). Hence, this case lends support that graded dose challenge with somatotropin analogs may be considered for patients with isolated GH deficiency such as in the case presented here.

OBJECTIVE:Silent corticotroph adenomas (SCAs) behave more aggressively than other non-functioning adenomas (NFAs). This study aims to expand the body of knowledge of the behavior of SCAs. METHODS:Retrospective analysis of 196 non-corticotroph NFAs and 20 SCAs from 2012-2017 was completed. Demographics, clinical presentation, imaging and biochemical data were gathered. The primary endpoint was to identify features of SCAs vs. other NFAs that suggest aggressive disease, including pre-surgical comorbidities, postoperative complications, extent of tumor and recurrence. GRASP MRI images were obtained from a subset of SCAs and NFAs. Permeability data was obtained to compare signal-to-time curve variation between the two groups. RESULTS:With multivariate regression analysis, SCAs showed higher rates of hemorrhage on preoperative imaging than NFAs (p=0.017). SCAs presented more frequently with headache, vision changes and fatigue (p=0.012, p=0.041, p=0.028). SCAs exhibited greater extent of tumor burden with increased occurrence of stalk deviation, suprasellar invasion, optic chiasm compression and cavernous sinus invasion (p=0.008, p=0.021, p=0.022, p=0.015). On GRASP imaging, SCAs had significantly lower permeability of contrast than NFAs (p=0.001). 30% of SCAs were noted to recur with a 14% recurrence rate in other NFAs, though this difference was not of statistical significance (p=0.220). CONCLUSIONS:SCAs exhibit features of more aggressive disease. Interestingly, a significant increase in recurrence was not seen despite these features. The results of this study support the growing body of evidence that SCAs behave more aggressively than other NFPAs and was able to provide some insight into factors that may contribute to recurrence.