Phosphocalcic metabolism and its potential association with biomarkers of kidney disease in dogs with spontaneous hyperadrenocorticism.

The pathogenesis of increased serum phosphate concentration and proteinuria in dogs with spontaneous hyperadrenocorticism (HAC) is unclear. A potential link between proteinuria and calcium/phosphate metabolism has never been studied in dogs with HAC. The aims of the study were: (1) To evaluate calcium/phosphate metabolism in dogs with spontaneous HAC and compare to healthy dogs as well as to dogs with non-HAC illness; (2) to look for associations between markers of calcium/phosphate metabolism and biomarkers of kidney disease in dogs with HAC. Fifty-four dogs were included in the study, classified as HAC (n=27), non-HAC disease (n=17), and healthy (n=10). Serum calcium, phosphate, 25(OH)Vitamin D, 1,25(OH)2Vitamin D, plasma intact parathyroid hormone concentration (iPTH), FGF23, and urinary fractional excretion of calcium and phosphate were evaluated in all dogs at diagnosis and compared between each group. The correlation between these variables and urine protein-to-creatinine ratio (UPC) and urinary N-acetylglucosaminidase-to-creatinine ratio (uNAG/C) was evaluated in the HAC group. Medians [range] of serum phosphate concentration, urinary fractional excretion of calcium (FE(Ca)), and iPTH were significantly higher in dogs with HAC than in dogs with non-HAC illness (P<0.01) and healthy dogs (P<0.01). Increased 1,25(OH)2Vitamin D/25(OH)Vitamin D was also observed (P<0.001). In HAC group, UPC was significantly negatively correlated with 25(OH)Vitamin D (r(s): -0.54; P<0.01). Urinary NAG/C was significantly positively correlated with serum phosphate (r(s): 0.46; P=0.019). Increased serum phosphate, urinary excretion of calcium, and hyperparathyroidism were observed in dogs with HAC. Vitamin D metabolism may be shifted towards increased 1-alpha hydroxylation.

Description of serum symmetric dimethylarginine concentration and of urinary SDS-AGE pattern in dogs with ACTH dependent hyperadrenocorticism.

Serum symmetric dimethylarginine (SDMA) and patterns of urinary protein separated by sodium dodecyl sulfate agarose gel electrophoresis (SDS-AGE) have not been investigated as biomarkers in dogs with ACTH-dependent hyperadrenocorticism (ADHAC). This exploratory prospective study aimed to evaluate SDMA, serum creatinine (sCR), and SDS-AGE in dogs with ADHAC with and without proteinuria (ADHAC-P and ADHAC-nP, respectively). Thirty-five pet dogs classified as ADHAC-P (n=16), ADHAC-nP (n=6) and healthy (n=13) were included. Renal biomarkers were evaluated in all dogs at diagnosis. Baseline concentration of SDMA was not significantly different between the three groups (P = 0.15) whereas sCr was significantly lower in dogs in ADHAC dogs compared to healthy dogs (88.0 µmol/L [70.4-132.6; 79.2-114.4]) whether they had proteinuria or not (P = 0.014 and 0.002, respectively). However, baseline concentrations of sCr and SDMA were not significantly different between dogs with ADHAC-P dogs (SDMA, 8 µg/dL [5-12; 7-9]; sCr, 57.2 µmol/L [35.2-212.2; 52.8-92.4]) and ADHAC-nP dogs (SDMA, 8.5 µg/dL [7-13; 8-10]; sCr, 70.4 µmol/L [61.6-79.2; 61.6-70.4]) (P = 0.35 and P = 0.41, respectively). Proteinuria in dogs with ADHAC-P was mainly of glomerular origin (SDS-AGE pattern: glomerular in 10/16 dogs; mixed glomerular/tubular in four dogs). In our study, SDMA was neither significantly different in dogs with ADHAC whether they were proteinuric or not, nor between ADHAC and healthy dogs. Urinary electrophoresis provides additional information to the UPC and further investigations are needed to determine whether it may help identify dogs with ADHAC-P requiring specific antiproteinuric treatment.

Hypercoagulability based on thromboelastography is common in dogs undergoing adrenalectomy.

OBJECTIVE: Thromboelastography (TEG) is a whole blood assay that yields global assessment of hemostasis, as it evaluates clot time, strength, and kinematics of clot formation and lysis. The main objective was to describe preoperative TEG findings in dogs that had an adrenalectomy performed and, secondarily, to describe TEG findings in the dogs with or without hyperadrenocorticism (HAC). ANIMALS: 30 dogs that had preoperative TEG and adrenalectomy performed. METHODS: Medical records between 2018 and 2022 were reviewed. Signalment, diagnostic data, and perioperative treatment were abstracted. RESULTS: 53% (16/30) of the dogs were hypercoagulable, and none were hypocoagulable. Based on histopathology, 6 of 9 dogs with adenocarcinoma were hypercoagulable, 4 of 8 with pheochromocytoma were hypercoagulable, and 6 of 10 with adenoma were hypercoagulable. None of the 3 dogs with other histopathologic diagnoses or combinations of diagnoses (adrenocortical hyperplasia, poorly differentiated sarcoma, and both adrenocortical adenocarcinoma and pheochromocytoma) were hypercoagulable. Of the 14 dogs tested preoperatively for HAC, 4 of 8 HAC dogs were hypercoagulable and 2 of 6 non-HAC dogs were hypercoagulable. CLINICAL RELEVANCE: The present report describes for the first time TEG findings for dogs undergoing adrenalectomy and suggests that the majority of dogs with adrenal neoplasia are hypercoagulable based on TEG results.

Long-term efficacy and safety of osilodrostat in patients with Cushing's disease: results from the LINC 4 study extension.

Objective: To evaluate the long-term efficacy and safety of osilodrostat in patients with Cushing's disease. Methods: The multicenter, 48-week, Phase III LINC 4 clinical trial had an optional extension period that was initially intended to continue to week 96. Patients could continue in the extension until a managed-access program or alternative treatment became available locally, or until a protocol amendment was approved at their site that specified that patients should come for an end-of-treatment visit within 4 weeks or by week 96, whichever occurred first. Study outcomes assessed in the extension included: mean urinary free cortisol (mUFC) response rates; changes in mUFC, serum cortisol and late-night salivary cortisol (LNSC); changes in cardiovascular and metabolic-related parameters; blood pressure, waist circumference and weight; changes in physical manifestations of Cushing's disease; changes in patient-reported outcomes for health-related quality of life; changes in tumor volume; and adverse events. Results were analyzed descriptively; no formal statistical testing was performed. Results: Of 60 patients who entered, 53 completed the extension, with 29 patients receiving osilodrostat for more than 96 weeks (median osilodrostat duration: 87.1 weeks). The proportion of patients with normalized mUFC observed in the core period was maintained throughout the extension. At their end-of-trial visit, 72.4% of patients had achieved normal mUFC. Substantial reductions in serum cortisol and LNSC were also observed. Improvements in most cardiovascular and metabolic-related parameters, as well as physical manifestations of Cushing's disease, observed in the core period were maintained or continued to improve in the extension. Osilodrostat was generally well tolerated; the safety profile was consistent with previous reports. Conclusion: Osilodrostat provided long-term control of cortisol secretion that was associated with sustained improvements in clinical signs and physical manifestations of hypercortisolism. Osilodrostat is an effective long-term treatment for patients with Cushing's disease. Clinical trial registration: ClinicalTrials.gov, identifier NCT02180217.

Trismus due to myotonia associated with hyperadrenocorticism in a dog.

We present the report of trismus due to hyperadrenocorticism-associated myotonia diagnosed by electromyography in a dog. An intact female Miniature Dachshund, 13 years and 9 months old, presented with stiff gait and trismus as well as polyuria and polydipsia. Abdominal ultrasonography showed enlarged adrenal glands. An adrenocorticotropic hormone stimulation test revealed an exaggerated response. Based on these findings, this case was diagnosed with hyperadrenocorticism. Electromyography revealed myotonic discharge in the temporalis muscle and limbs. Therefore, trismus was considered to be caused by hyperadrenocorticism-associated myotonia, and the case was treated with oral trilostane (1.3 mg/kg, once daily). During the 4-month follow-up period, despite the partial improvement in stiff gait, trismus did not recover. Long-term data on more cases are warranted to assess the prognosis and clinical characteristics of trismus due to hyperadrenocorticism-associated myotonia.

Effect of pituitary-dependent hypercortisolism on the survival of dogs treated with radiotherapy for pituitary macroadenomas.

BACKGROUND: Radiotherapy (RT) is an effective treatment for dogs presented with neurologic signs caused by pituitary tumors. However, its impact on the outcome of concurrent pituitary-dependent hypercortisolism (PDH) is controversial. OBJECTIVES: Determine whether dogs with PDH have longer survival after pituitary RT compared with dogs with nonhormonally active pituitary masses and to evaluate whether clinical, imaging, and RT variables affect survival. ANIMALS: Ninety-four dogs divided into 2 groups: PDH and non-PDH, based on the presence of hypercortisolism. Forty-seven dogs were allocated to the PDH group and 47 to the non-PDH group. METHODS: Retrospective cohort study in which clinical records of dogs undergoing RT for pituitary macroadenomas between 2008 and 2018 at 5 referral centers were retrospectively evaluated. RESULTS: Survival was not statistically different between PDH and non-PDH groups (median survival time [MST], 590 days; 95% confidence interval [CI], 0-830 days and 738 days; 95% CI, 373-1103 days, respectively; P = .4). A definitive RT protocol was statistically associated with longer survival compared with a palliative protocol (MST 605 vs 262 days, P = .05). The only factor statistically associated with survival from multivariate Cox proportional hazard analysis was total radiation dose (Gy) delivered (P < .01). CONCLUSIONS AND CLINICAL IMPORTANCE: No statistical difference in survival was identified between the PDH and non-PDH groups, and longer survival was associated with higher Gy delivered.

2023 AAHA Selected Endocrinopathies of Dogs and Cats Guidelines.

Canine and feline endocrinopathies reflect an endocrine gland disease or dysfunction with resulting hormonal abnormali ties that can variably affect the patient's wellbeing, quality of life, and life expectancy. These guidelines provide consensus recommendations for diagnosis and treatment of four canine and feline endocrinopathies commonly encountered in clini cal practice: canine hypothyroidism, canine hypercortisolism (Cushing's syndrome), canine hypoadrenocorticism (Addi son's disease), and feline hyperthyroidism. To aid the general practitioner in navigating these common diseases, a stepwise diagnosis and treatment algorithm and relevant background information is provided for managing each of these diseases. The guidelines also describe, in lesser detail, the diagnosis and treatment of three relatively less common endo crinopathies of cats: feline hyperaldosteronism, feline hypothyroidism, and feline hyperadrenocorticism. Additionally, the guidelines present tips on effective veterinary team utilization and client communication when discussing endocrine cases.

A cohort study on the association between changing occupational stress, hair cortisol concentration, and hypertension.

OBJECTIVE: To explore the relationship between changing occupational stress levels, hair cortisol concentration (HCC), and hypertension. METHODS: Baseline blood pressure of 2520 workers was measured in 2015. The Occupational Stress Inventory-Revised Edition (OSI-R) was used to assess changes in occupational stress. Occupational stress and blood pressure were followed up annually from January 2016 to December 2017. The final cohort numbered 1784 workers. The mean age of the cohort was 37.77±7.53 years and the percentage male was 46.52%. At baseline, 423 eligible subjects were randomly selected for hair sample collection to determine cortisol levels. RESULTS: Increased occupational stress was a risk factor for hypertension [risk ratio (RR) = 4.200, 95% confidence interval (CI): 1.734-10.172]. The HCC of workers with elevated occupational stress was higher than that of workers with constant occupational stress [(ORQ score ≥70: geometric mean±geometric standard deviation = 5.25±3.59 ng/g hair; 60-90: 5.02±4.00; 40-59: 3.45±3.41; <40: 2.73±3.40) x2 = 5.261]. High HCC increased the risk of hypertension (RR = 5.270, 95% CI: 2.375-11.692) and high HCC was associated with higher rates of elevated diastolic and systolic blood pressure. The mediating effect of HCC was 0.51[(95% CI: 0.23-0.79, odds ratio(OR) = 1.67] and accounted for 36.83% of the total effect. CONCLUSIONS: Increased occupational stress could lead to an increase in hypertension incidence. High HCC could increase the risk of hypertension. HCC acts as a mediator between occupational stress and hypertension.

Iatrogenic symptomatic hypoadrenocorticism after treatment with trilostane for hyperadrenocorticism in dogs: eight cases (2008-2019).

OBJECTIVES: Trilostane is the medical treatment of choice for hyperadrenocorticism. Iatrogenic hypoadrenocorticism is thought to be rare, with most cases being transient and only a few cases of permanent hypoadrenocorticism have been reported. This study reports findings from eight cases of iatrogenic hypoadrenocorticism and examines the presence of concurrent diseases at the time of diagnosis. MATERIALS AND METHODS: Medical records of dogs treated for hyperadrenocorticism with trilostane since 2008 were reviewed, and cases of clinical iatrogenic hypoadrenocorticism were extracted. Cases were considered permanent if long-term replacement therapy was required. RESULTS: Eight dogs met the inclusion criteria. The time between the beginning of trilostane treatment and the diagnosis of hypoadrenocorticism ranged from 4 days to 13 months, and the dosage of trilostane ranged between 1 and 8 mg/kg/day. Six dogs had a suspicion of concurrent disease at the time of hypoadrenocorticism diagnosis. The trilostane dose was decreased in two dogs; trilostane was withdrawn in one case without further relapse of hyperadrenocorticism; and glucocorticoids with or without mineralocorticoid supplementation were prescribed in five dogs. Two of these five dogs were lost to follow-up, and the other three had a diagnosis of permanent hypoadrenocorticism. Adrenal gland ultrasonography in these three dogs showed a progressive reduction in gland sizes with heterogeneous echogenicity. CLINICAL SIGNIFICANCE: Iatrogenic hypoadrenocorticism is a rare but potentially life-threatening complication of trilostane treatment in dogs with hyperadrenocorticism. The occurrence of a concurrent disease might trigger the development of clinical signs of hypoadrenocorticism in previously subclinical dogs.

Reference intervals for plasma, urinary, and salivary concentrations of free metanephrines in dogs: Relevance to the diagnosis of pheochromocytoma.

BACKGROUND: Measurement of free metanephrines is recommended for screening of pheochromocytoma (PCC) but requires appropriate reference intervals (RIs). HYPOTHESIS/OBJECTIVES: To report RIs for plasma, urinary and salivary concentrations of free metanephrines and to determine the diagnostic performance of plasma free normetanephrine (pNMN) and metanephrine (pMN) concentrations in dogs with PCC, hypercortisolism (HC), and nonadrenal illness (NAI). ANIMALS: Eighty healthy dogs, 11 PCC dogs, 25 HC dogs, 6 NAI dogs. METHODS: Plasma, urine, and saliva were collected prospectively from healthy dogs, and free metanephrine concentrations were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). In addition, medical records of dogs that had plasma free metanephrine concentrations measured by LC-MS/MS between 2018-2021 were studied retrospectively. RESULTS: The RIs for free metanephrines in plasma, urine and saliva are reported. Dogs with PCC had significantly higher pNMN than dogs with HC (P < .001) and NAI (P = .002). The PCC dogs had significantly higher pMN than HC dogs (P < .001), but not higher than NAI dogs (P = .29). Using the upper reference limit, pNMN (>3.56 nmol/L) showed high sensitivity (100%, 95% confidence interval [CI]: 72-100) and specificity (94%, 95% CI: 79-99) for diagnosis of PCC, whereas pMN (>2.49 nmol/L) showed moderate sensitivity (73%, 95% CI: 39-94) and high specificity (94%, 95% CI: 79-99). CONCLUSIONS AND CLINICAL IMPORTANCE: With establishment of these RIs, biochemical testing for PCC in dogs can be substantially improved. Measurement of pNMN is superior to pMN in dogs with PCC.

Regression of venous thrombus after trans-sphenoidal hypophysectomy for pituitary-dependent hyperadrenocorticism in a dog.

An 8.0-kg 8-year-old male dachshund was presented for surgical treatment of suspected pituitary-dependent hyperadrenocorticism with portal vein thrombosis. Advanced diagnostic imaging revealed a thrombus in the splenic and portal veins. For the portal vein thrombus, CT angiography showed an enhanced timing delay in the lateral right and caudate liver lobes. Blood tests showed a marked increase in the liver panel, including total bile acid. Brain MRI revealed a pituitary mass, suggesting pituitary-dependent hyperadrenocorticism. The mass was completely resected. The preoperative antithrombotic therapy of rivaroxaban (0.66 mg/kg, PO, once per day) and clopidogrel sulphate (1.66 mg/kg, PO, once per day) was continued postoperatively. Six months after resection of the pituitary mass, the thrombus had disappeared. Further studies are required to prove a causal association between the disappearance of the thrombus and the treatments provided.

Resolution of Signs of Epiglottic Retroversion Following Medical Management of Hyperadrenocorticism in a Dog.

A 6 yr old spayed female Chihuahua was referred for a 10 mo history of chronic respiratory compromise. Decreased serum thyroxine and thyroid-stimulating hormone concentrations had been confirmed at a primary clinic, but no treatment was initiated. Serum biochemistries revealed elevated alkaline phosphatase and cholesterol concentrations. An adrenocorticotropic hormone-stimulating test revealed elevated preserum and postserum cortisol concentrations. Fluoroscopy revealed marked epiglottic retroversion (ER) during inhalation. Enlarged bilateral adrenal glands were found on abdominal ultrasonography. Based on these findings, ER and hyperadrenocorticism (HAC) were diagnosed and surgical correction of the ER was planned. Trilostane administration was initiated before surgery to reduce the risk of thrombosis due to HAC. Seven days after the initiation of trilostane therapy, clinical signs of chronic respiratory compromise were resolved. The patient had remained clinically stable without recurrence of respiratory compromise for at least 15 mo at the time of this case report. This case suggests that HAC could contribute to the development of clinical signs of ER, which could potentially be successfully controlled by medical treatment of HAC.

Successful treatment of feline hyperadrenocorticism with pituitary macroadenoma using radiation therapy: a case study.

A 10-year-old castrated male cat showing behavioral (irritation, prowling, and tumbling) and cutaneous abnormalities such as dermal fragility was diagnosed as hyperadrenocorticism with pituitary macroadenoma, concurrent with insulin dependent diabetes mellitus. Pituitary enlargement (18.0 mm) was observed during magnetic resonance imaging. High endogenous adrenocorticotropic hormone levels (>2,500 pg/ml) were also observed. Although trilostane treatment (5-10 mg/head, daily) was commenced, the clinical signs did not disappear. Insulin and trilostane treatment were discontinued on day 86 after first day of radiation therapy (4 Gy/12 fractions). After radiation therapy, a decreased pituitary tumor size (10.7 mm) was observed on day 301; neurological and dermatological signs exhibited remission. Radiation therapy is the treatment of choice for feline hyperadrenocorticism with pituitary macroadenoma with neurological signs.

2022 Update of the Consensus on the Rational Use of Antithrombotics and Thrombolytics in Veterinary Critical Care (CURATIVE) Domain 1- Defining populations at risk.

OBJECTIVES: To expand the number of conditions and interventions explored for their associations with thrombosis in the veterinary literature and to provide the basis for prescribing recommendations. DESIGN: A population exposure comparison outcome format was used to represent patient, exposure, comparison, and outcome. Population Exposure Comparison Outcome questions were distributed to worksheet authors who performed comprehensive searches, summarized the evidence, and created guideline recommendations that were reviewed by domain chairs. The revised guidelines then underwent the Delphi survey process to reach consensus on the final guidelines. Diseases evaluated in this iteration included heartworm disease (dogs and cats), immune-mediated hemolytic anemia (cats), protein-losing nephropathy (cats), protein-losing enteropathy (dogs and cats), sepsis (cats), hyperadrenocorticism (cats), liver disease (dogs), congenital portosystemic shunts (dogs and cats) and the following interventions: IV catheters (dogs and cats), arterial catheters (dogs and cats), vascular access ports (dogs and cats), extracorporeal circuits (dogs and cats) and transvenous pacemakers (dogs and cats). RESULTS: Of the diseases evaluated in this iteration, a high risk for thrombosis was defined as heartworm disease or protein-losing enteropathy. Low risk for thrombosis was defined as dogs with liver disease, cats with immune-mediated hemolytic anemia, protein-losing nephropathy, sepsis, or hyperadrenocorticism. CONCLUSIONS: Associations with thrombosis are outlined for various conditions and interventions and provide the basis for management recommendations. Numerous knowledge gaps were identified that represent opportunities for future studies.

Hyperadrenocorticism treatment of a dog with high dilution: case report

Hyperadrenocorticism is a common endocrinopathy in dogs, associated to an excessive production or administration of cortisol.Aims:Report the evolution of homeopathic treatment in spontaneous hyperadrenocorticism analyzing with basal and post-acth stimulation cortisol values of a yorkshire male dog with 10 years old, diagnosed from the suppression test with low dose of dexamethasone and stimulation with ACTH, as well as complementary tests.Methodology: Homeopathic treatment was chosen, based on the principle of similitude usingIgnatia amarabecause the patient presents repertorized mental symptoms such as separation anxiety syndrome, docility, annoyances and jealousy and also because it is efficient and less harmful. It was associated to cortisol biotherapy to inhibit cortisol production and adrenal biotherapy to control the response of excess of the cortisol producted by the gland. The exposed information is consented by the tutor.Results:The dog was in convencional treatment with trilostane but didn't response to the therapy, showing 5,41 µg/dL of basal result and 11,8 µg/dL of post-acth result and the symptoms were worst on 12/12/2021, presenting lethargic, panting, more evident alopecia and severe muscle weakness which the patient unable to stand. Therefore, the protocol was recommended for 3 months, included 3 globules ofIgnatia amara30cH orally, every 12 hours, 3 globules of cortisol biotherapy 30 cH and also of adrenal biotherapy 6 cH every 24 hours. On 03/28/2022 the basal and post-acth stimulation results was 3,71 µg/dL e 5,79 µg/dL respectively and the patient was more active, the skin was better and even with difficulty it was movingand having more independence.Conclusion: Homeopathic treatment with high dilution was effective, keeping the indices with the recommended range of post acth between 2.0 and 5.0, confirming an adequate therapeutic monitoring and symptomatic improvement.

Survival of dogs with pituitary-dependent hyperadrenocorticism treated twice daily with low doses of trilostane.

BACKGROUND: Twice daily low trilostane doses have proven to be effective to manage canine Cushing's syndrome. However, survival and prognostic factors in dogs treated with this protocol have not been evaluated. The aim of the study was to evaluate survival and prognostic factors, including systolic blood pressure (SBP) at diagnosis, in dogs with pituitary-dependent hypercortisolism (PDH) treated with low trilostane doses. METHODS: Medical records of 91 dogs newly diagnosed with PDH initially treated with 0.2-1.1 mg/kg of trilostane twice daily were retrospectively included. Survival times were calculated using the Kaplan-Meier estimator. Univariable and multivariable analysis were performed using the Cox proportional hazard regression analysis. RESULTS: Overall, median survival was 998 days (range 26-1832 days, 95% confidence interval = 755-1241 days). In the multivariable analysis, age (hazard ratio [HR] = 1.337, p < 0.001), presence of calcinosis cutis (HR = 5.271, p < 0.001), body condition score (BCS) ≤3/9 (HR = 8.100, p < 0.001) and higher platelet count (HR = 1.002, p = 0.022) were negatively correlated with survival. SBP was not associated with survival. CONCLUSIONS: Low-dose trilostane treatment twice daily provides slightly longer survival than previously reported for dogs with PDH treated once or twice daily at higher doses. Older age, presence of calcinosis cutis, low BCS and higher platelet count, but not systemic hypertension, are predictive of poorer prognosis in dogs with PDH.

Utility of a corticotropin-releasing hormone test to differentiate pituitary-dependent hyperadrenocorticism from cortisol-producing adrenal tumors in dogs.

BACKGROUND: Hyperadrenocorticism (HAC) is a common endocrine disorder in dogs; however, there are no reports on the use of the corticotropin-releasing hormone test (CRHT) to differentiate between pituitary-dependent hyperadrenocorticism (PDH) and cortisol-producing adrenal tumors (CPATs), both causative of HAC. OBJECTIVES: To evaluate the usefulness of CRHT as a tool to differentiate between PDH and CPAT in dogs and to determine the reference intervals for CRHT in healthy, PDH, and CPAT dogs. ANIMALS: Dogs diagnosed with PDH (n = 21), CPAT (n = 6), and healthy beagle dogs (n = 33). METHODS: This prospective study included dogs with a definitive diagnosis of PDH and CPAT and healthy beagle dogs, in which CRHT was performed, were prospectively evaluated. We investigated the correlations of CRHT (endogenous adrenocorticotropic hormone [ACTH] concentration, endogenous ACTH concentration [EAC], and poststimulation ACTH concentration [PAC]) with pituitary-to-brain ratio (PBR) (in PDH) and with indices of adrenal ultrasonography (smaller and larger adrenal gland dorsoventral thickness in PDH and CPAT). RESULTS: For EAC, the area under the curve (AUC) was 0.95, with a cutoff value of 26.3 pg/mL (sensitivity: 90.62%, specificity: 87.50%). The AUC for PAC was 0.96 with a cutoff value of 54.5 pg/mL (sensitivity: 100.00%, specificity: 66.67%). The 95% reference interval for CRHT in healthy (control) dogs ranged 5.00 to 79.8 pg/mL (1.10-17.57 pmol/L) for EAC, and 1.92 to 153.42 pg/mL (0.42-33.78 pmol/L) for PAC. There was no significant correlation between PBR and CRHT, nor adrenal size and CRHT. CONCLUSIONS AND CLINICAL IMPORTANCE: CRHT appears to be a rapid and reliable test for differentiating PDH from CPAT in dogs.

Old Problem, New Concerns: Hypercortisolemia in the Time of COVID-19.

The ongoing coronavirus disease 2019 (COVID-19) pandemic forced a change in the way we provide medical treatment. Endocrinology in the era of COVID-19 had to transform and reduce its vast potential to the absolute necessities. Medical professionals needed to update their clinical practice to provide their patients as much support and as little harm as possible in these increasingly difficult times. International expert statements were published to offer guidance regarding proper care. It was suggested to simplify the diagnostic scheme of hypercortisolemia and to modify the approach to treatment. Hypercortisolemic patients with COVID-19 and iatrogenic hypercortisolemia due to glucocorticoid use are important clinical scenarios - we aimed to provide a cohesive summary of issues to consider.

Morphologic and Molecular Characterization of Adrenals and Adrenal Rest Affected by Congenital Adrenal Hyperplasia.

Introduction: Adrenocortical hyperplasia and adrenal rest tumor (ART) formation are common in congenital adrenal hyperplasia (CAH). Although driven by excessive corticotropin, much is unknown regarding the morphology and transformation of these tissues. Our study objective was to characterize CAH-affected adrenals and ART and compare with control adrenal and gonadal tissues. Patients/Methods: CAH adrenals, ART and control tissues were analyzed by histology, immunohistochemistry, and transcriptome sequencing. We investigated protein expression of the ACTH receptor (MC2R), steroidogenic (CYP11B2, CYP11B1, CYB5A) and immune (CD20, CD3, CD68) biomarkers, and delta-like 1 homolog (DLK1), a membrane bound protein broadly expressed in fetal and many endocrine cells. RNA was isolated and gene expression was analyzed by RNA sequencing (RNA-seq) followed by principle component, and unsupervised clustering analyses. Results: Based on immunohistochemistry, CAH adrenals and ART demonstrated increased zona reticularis (ZR)-like CYB5A expression, compared to CYP11B1, and CYP11B2, markers of zona fasciculata and zona glomerulosa respectively. CYP11B2 was mostly absent in CAH adrenals and absent in ART. DLK1 was present in CAH adrenal, ART, and also control adrenal and testis, but was absent in control ovary. Increased expression of adrenocortical marker MC2R, was observed in CAH adrenals compared to control adrenal. Unlike control tissues, significant nodular lymphocytic infiltration was observed in CAH adrenals and ART, with CD20 (B-cell), CD3 (T-cell) and CD68 (macrophage/monocyte) markers of inflammation. RNA-seq data revealed co-expression of adrenal MC2R, and testis-specific INSL3, HSD17B3 in testicular ART indicating the presence of both gonadal and adrenal features, and high expression of DLK1 in ART, CAH adrenals and control adrenal. Principal component analysis indicated that the ART transcriptome was more similar to CAH adrenals and least similar to control testis tissue. Conclusions: CAH-affected adrenal glands and ART have similar expression profiles and morphology, demonstrating increased CYB5A with ZR characteristics and lymphocytic infiltration, suggesting a common origin that is similarly affected by the abnormal hormonal milieu. Immune system modulators may play a role in tumor formation of CAH.

Diagnostic accuracy of the different hormonal tests used for the diagnosis of autonomous cortisol secretion.

To evaluate the diagnostic accuracy of the different tests commonly used in the evaluation of adrenal incidentalomas (AIs) for the identification of autonomous cortisol secretion (ACS) and comorbidities potentially related to ACS. In a retrospective study of patients with AIs ≥ 1 cm, we evaluated the diagnostic reliability and validity of the dexamethasone suppression test (DST), urinary free cortisol (UFC), ACTH, late-night salivary cortisol (LNSC), and dehydroepiandrosterone-sulphate (DHEAS) for the diagnosis of comorbidities potentially related to ACS. Diagnostic indexes were also calculated for UFC, ACTH, LNSC, and DHEAS considering DST as the gold standard test for the diagnosis of ACS, using three different post-DST cortisol thresholds (138 nmol/L, 50 nmol/L and 83 nmol/L). We included 197 patients with AIs in whom the results of the five tests abovementioned were available. At diagnosis, 85.9% of patients with one or more AIs had any comorbidity potentially related to ACS, whereas 9.6% had ACS as defined by post-DST cortisol > 138 nmol/L. The reliability of UFC, ACTH, LNSC, and DHEAS for the diagnosis of ACS was low (kappa index < 0.30). Of them, LNSC reached the highest diagnosis accuracy for ACS identification (AUC = 0.696 [95% CI 0.626-0.759]). The diagnostic performances of these tests for comorbidities potentially related to ACS was poor; of them, the DST was the most accurate (AUC = 0.661 [95% CI 0.546-0.778]) and had the strongest association with these comorbidities (OR 2.6, P = 0.045). Patients presenting with increased values of both DST and LNSC had the strongest association with hypertension (OR 7.1, P = 0.002) and with cardiovascular events (OR 3.6, P = 0.041). In conclusion, LNSC was the test showing the highest diagnosis accuracy for the identification of ACS when a positive DST was used as the gold standard for its diagnosis. The DST test showed the strongest association with comorbidities potentially related to ACS. The definition of ACS based on the combination of elevated DST and LNSC levels improved the identification of patients with increased cardiometabolic risk.