Clinical Features Of Cushing's Syndrome Research Articles

PSAT033 Increased Risks of Atherosclerotic Heart Disease, Malignancy and Sleep Apnea with Primary Aldosteronism: A Case Report

Abstract Introduction Primary aldosteronism (PA) demonstrates an increased risk of atherosclerotic heart disease. A less commonly known fact is that PA is often associated with increased risks of malignancy, especially renal cell carcinoma (RCC) and sleep apnea. We are reporting a 51-year-old male with a long history of untreated PA caused by an adenoma (APA) who developed coronary artery disease (CAD), RCC, and sleep apnea during the course of his illness. Case presentation A 51-year-old male was evaluated in the endocrine clinic for secondary hypertension. Patient developed hypertension and hypokalemia at the age of 39 years and laboratory tests showed plasma renin activity PRA 0.06 ng/mL/hr, aldosterone 6 ng/dL, plasma metanephrines 79 pg/mL (ref 0–145), normetanephrine 22 pg/mL (ref 0-62), a serum cortisol value of 0.8 mcg/dL after 1 mg dexamethasone suppression. Despite using several anti-hypertensive medications, including quinapril, amlodipine, and potassium chloride, both his hypertension and hypokalemia remained poorly controlled. He also was diagnosed with sleep apnea at the age of 44 years, treated with CPAP. Abdominal CT showed normal adrenals and angiomyolipoma involving the right interior pole of the kidney. At the age of 47 years, a diagnosis of Liddle syndrome was considered, and the patient was placed on amiloride. At the age of 48 years, the patient developed chest pain and further diagnostic tests confirmed coronary artery disease, and a stent was placed in the left anterior descending artery. Due to the poor control of hypertension, carvedilol and eplerenone were also added to the regimen. Another abdominal CT done at the age of 50 years showed a left adrenal adenoma 1.2 cm, left kidney lower pole cyst 2.9 cm, and atherosclerotic calcification of aorta. Family history was negative for endocrine diseases. Physical examination: HR 62/min, BP 160/90 mmHg, normal examination of the heart, lungs, and abdomen. No clinical features of Cushing syndrome was observed. Repeat laboratory evaluations showed plasma renin activity < 0.167 ng/ml/hr, plasma aldosterone 111.4 ng/dL, concerning for PA. A follow-up CT of the abdomen confirmed left adrenal adenoma and a 1.8 cm left renal lesion suggestive of RCC. The patient underwent an adrenal venous sampling, which localized the left adrenal adenoma as the cause of PA. The patient underwent left adrenalectomy and left partial nephrectomy and pathology confirmed left adrenal adenoma and RCC. One week after surgery plasma aldosterone was 1.9 ng/dL and his hypertension was controlled with fewer medications and he did not require potassium supplements. Conclusion Our case illustrates that delayed diagnosis of PA (poorly treated PA) may be associated with an increased risk of CAD, malignancy and sleep apnea. Early diagnosis and surgical intervention are recommended for PA, especially caused by an adenoma. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Cushing syndrome as a failed cardiac screen in a patient with McCune–Albright syndrome: a case report

BackgroundMcCune–Albright syndrome is a complex disorder encompassing multiple endocrinopathies. These manifestations are secondary to a mutation in the stimulatory G-protein alpha subunit. Cushing syndrome is due to autonomous secretory function of the adrenal gland and is present in 7.1% of patients with McCune–Albright syndrome. Cardiac newborn screenings assist in the identification of critical congenital heart disease. These screenings have become part of routine postnatal care nationwide.Case reportA 6-week-old Caucasian male presented to a cardiologist at the University of Tennessee Health Science Center with left ventricular hypertrophy and poor feeding after a failed cardiac newborn screen. He had been previously seen at 2 weeks by a cardiologist on follow-up for abnormal critical congenital heart disease screening. Electrocardiogram and echocardiographic studies identified hypertrophic cardiomyopathy. Other examination findings revealed multiple characteristic café-au-lait lesions along with hypotonia and rounded facies. Given his cardiac disease, he was admitted to the hospital, where an evaluation was done for Cushing syndrome, showing elevated cortisol by immunoassay of 38 μg/dL (1.7–14.0 μg/dL, Vitros 5600) after a dexamethasone suppression test and urinary cortisol elevated to 35 μg/dL/24 hours (reference range 3–9 μg/dL/24 hours) (Esoterix; Calabasas, CA). He was started on metyrapone therapy to block synthesis of cortisol. His cortisol improved and was suppressed less than 2 μg/dL. His hypertension and clinical features of Cushing syndrome improved.ConclusionsThis case demonstrates a unique presentation of Cushing syndrome in a young infant. This is the first case to our knowledge showing significant left ventricular hypertrophy resulting from Cushing syndrome identified following a failure on a critical congenital heart disease screen. It highlights the importance of considering of McCune–Albright syndrome in patients with Cushing syndrome, especially if other clinical features are present. Medical therapy can be used to treat Cushing syndrome and can result in improvement in the cardiovascular pathology.

IJU this issue

This issue deals with a wide range of clinical topics of urology, and contains 14 Original Articles. Percutaneous nephrolithotomy (PCNL) is a minimally invasive endourological procedure recommended as first-line therapy for kidney stones >2 cm in diameter. In general, however, nephrectomy is carried out in patients with large stones within non-functioning atrophic kidneys. Su et al. (Beijing, China) evaluated outcomes in patients who underwent total ultrasound-guided PCNL for the management of large stones (>2 cm) within non-functioning atrophic kidneys. Their results showed that ultrasound-guided PCNL is safe and feasible, even for stones >2 cm in diameter within non-functioning atrophic kidneys. However, PCNL is not recommended for patients with diabetes. Several energy sources have been used for stone fragmentation during ureteroscopy. Nowadays, the holmium:YAG laser is a standard method that provides effective and safe disintegration of all stone types. However, it has some disadvantages, such as relatively high retropulsion (which might lead to relocation of the stone into the renal pelvis). Enikeev et al. (Moscow, Russia) estimated the efficacy and safety of SuperPulsed thulium-fiber laser ureteral lithotripsy, and identified optimal laser settings. Their results showed that the SuperPulsed thulium-fiber laser provides effective and safe lithotripsy during ureteroscopy regardless of stone density. Fiber diameter and laser frequency do not influence visibility or safety. Optimal laser settings are 0.5 J × 30 Hz for fragmentation and 0.15 J × 100 Hz for dusting. Subclinical Cushing syndrome is defined as a condition of hypercorticolism in patients with adrenal tumors in the absence of clinical features of Cushing syndrome. Although surgical removal of adrenal tumors for subclinical Cushing syndrome patients has been reported to be beneficial with the improvement of comorbidities, such as hypertension, diabetes mellitus and obesity, the surgical benefit is still controversial. Sato et al. (Chiba, Japan) retrospectively investigated whether the result of the 1-mg dexamethasone suppression test could predict the improvement of comorbidities after adrenalectomy in patients with subclinical Cushing syndrome. Their results showed that the greatest reduction of prescribed drugs is observed in patients whose serum cortisol levels are between 1.8 and 3.0 μg/dL after the 1-mg dexamethasone suppression test, implicating that the 1-mg dexamethasone suppression test can be a useful factor predicting the improvement of comorbidities after adrenalectomy. Today, it is well known that approximately half of cases of infertility are attributable to male factors. Recently, the European Association of Urology guideline for male infertility emphasized that oral anti-oxidants were associated with a significant increase in markers of sperm quality. Among the anti-oxidants, one of the elements perhaps most familiar and well known to the general public is zinc. Tsujimura et al. (Chiba, Japan) tried to clarify the factors associated with semen quality, and confirm whether there was an association between semen quality and serum zinc concentration. Although there was no significant correlation between serum zinc concentration and semen quality, the independent predictors for having values below the World Health Organization criteria for assessing sperm quality in binomial logistic regression analysis were follicle-stimulating hormone and serum zinc concentration. They suggested that semen analysis might be considered in men with a low level of serum zinc and high level of follicle-stimulating hormone when developing a reproductive life plan for fertilization. Yasuda et al. (Tokyo, Japan) developed the gasless approach as another type of minimally invasive endoscopic surgery, and applied it to many kinds of urological surgeries, including partial nephrectomy. In gasless partial nephrectomy, they prioritized clampless and sutureless surgery, if feasible, as an attempt to obtain maximal functional preservation. They investigated the outcomes and feasibilities of gasless laparoendoscopic single-port clampless sutureless partial nephrectomy. Their results showed that clampless and sutureless partial nephrectomy can be safely accomplished in most patients undergoing gasless laparoendoscopic single-port surgery, yielding favorable oncological and functional outcomes. Transurethral resection of the prostate represents the standard surgical technique for the management of benign prostatic hyperplasia with a prostate size <80 mL. However, considerable morbidities are associated with larger sizes. Higazy et al. (Cairo, Egypt) evaluated the safety, efficacy and cost-effectiveness of holmium enucleation of the prostate and bipolar transurethral enucleation of the prostate. Their results showed that both holmium enucleation of the prostate and bipolar enucleation of the prostate are safe and effective in the surgical management of large prostatic adenomas. However, holmium enucleation of the prostate has a shorter operative time and hospital stay, with an earlier catheter removal time, and is more cost-effective than bipolar enucleation of the prostate. None declared.

SUN-162 Isolated Primary Pigmented Micronodular Adrenal Disease. Unilateral or Bilateral Adrenalectomy? Two Cases Report

Background: Isolated primary pigmented nodular adrenal disease (i-PPNAD) is a particular case of micronodular bilateral hyperplasia (MiBAH) leading to Cushing syndrome (CS). We present two patients with i-PPNAD who undergone unilateral adrenalectomy with different disease outcomes. Case 1: A 56 yo man presented with typical signs and symptoms of CS, including central weight gain, proximal muscle weakness, hypertension and marked osteoporosis. A biochemical investigation showed an assessment of late-night salivary cortisol - 23 nmol/l (n <9), 24h urinary free cortisol (UFC)- 1206 nmol/24h (n-60–413). The 1 mg DST showed post-DST cortisol 617 nmol/l (n<50). ACTH concentration was suppressed at 1.1 pg/ml (n-7–66). Adrenal CT-scan was normal. PPNAD was assumed and the screening for Carney complex components was negative. After left adrenalectomy, histological examination confirmed the diagnosis of PPNAD. However, biochemical remission wasn’t achieved: postoperative UFC-860 nmol/24h. Thus, the right adrenalectomy was conducted. Case 2: A 40 yo female presented with long term drug-corrected (beta-blockers, ACE inhibitor) arterial hypertension, menstrual dysfunction and clinical features of CS (central obesity, proximal muscle weakness, hirsutism), without osteoporosis. Baseline hormonal evaluation documented slightly increased level of salivary cortisol- 9,8 nmol/l (n <9), post 1 mg DST cortisol - 470 nmol/l (n<50) and ACTH-concentration below detection <1 pg/ml (n-7–66). However, UFC was normal – 215 nmol/l (n-60–413). Abdominal CT-scan revealed micronodular hyperplasia of the left adrenal and was suggestive of possible right adrenal gland hyperplasia. We performed left adrenalectomy. In the early postoperative period, adrenal insufficiency was diagnosed and thus it required hydrocortisone replacement. Discussion: We obtained two opposite results: in case 1, an expected remission after unilateral adrenalectomy was not achieved, while patient No.2 developed adrenal insufficiency, which was a more favourable prognostic sign and attested to the successful outcome of surgical treatment. A possible explanation of the ineffectiveness of surgical intervention in patient No.1 was primary more severe hypercortisolism. It is also necessary to take into account that according to the CT data of the patient No.1, both adrenal glands were within normal ranges and did not differ from one another, while in the patient No.2, the lesion was more prominent on the right side. Conclusion: Diagnostic of i-PPNAD and choice of intervention can be precarious, consequently more studies are needed to define to which patients unilateral adrenalectomy could be an efficient treatment modality. It is possible to perform unilateral adrenalectomy with subsequent assessment of cortisol levels, in case of lack of remission the contralateral adrenalectomy is required.

OR23-03 Post-Operative Day One Morning Cortisol Value as a Biomarker to Predict the Recurrence of Cushing Disease

Tumor removal by transsphenoidal surgery (TSS) is the first line treatment for Cushing disease (CD). However, recurrence is relatively common. A one week post-operative (post-op) nadir cortisol has been used as a biomarker to predict recurrence1. We identified 299 CD patients from our longitudinal multidisciplinary clinic or our institutional RPDR search tool who met biochemical diagnostic criteria1 and had undergone TSS between May 2008 and May 2018, to evaluate post-op cortisol levels as biomarkers to predict long-term remission and to characterize clinical features of Cushing syndrome. Predictors of recurrence were identified with logistic regression, using recurrence as the dependent variable, and a Kaplan-Meier survival curve analysis was performed to compare long-term remission after TSS among the 202 patients who reached initial remission and had at least 1 year of follow-up. The post-op day 1 morning (AM) cortisol had significant association with CD recurrence (OR=1.025, 95%CI:1.002-1.048, p=0.032). The time to recurrence was significantly longer in patients with post-op day 1 AM cortisol <5 μg/dL. In contrast, one week post-op nadir cortisol (OR=1.081, 95%CI: 0.989-1.181, p=0.086), urinary free cortisol (OR=1.032,95%CI: 0.994-1.07, p=0.098), or late night salivary cortisol (OR=1.383, 95%CI:0.841-2.274, p=0.201) had no significant correlation with recurrence. There were no significant differences in time to recurrence for post-op day 2 AM cortisol <5 μg/dL. Among patients who developed post-op adrenal insufficiency, recurrence was significantly lower if glucocorticoid replacement continued for more than one year. In addition, tumor proliferative index (MIB-1) had a significant correlation with recurrence (OR=1.287, 95%CI:1.106-1.498, p=0.001). The most common symptoms and signs of initial presentation of CD were weight gain (91.6%), central obesity (79.6%), menstrual disorders (77.9%), round face (65.9%), hypertension (63.2%), mood disorders (60.2%), dorsocervical fat deposition (59.9%), supraclavicular fat deposition (59.9%), osteoporosis (58.9%), fatigue (58.2%), bruising (55.9%) and facial hirsutism (54.2%). Most of the best discriminating CD features did not have high sensitivity, such as purple striae (31.4%), facial plethora (33.4%) and proximal muscle weakness (30.8%). Our data show that post-op day one morning cortisol level above 5 μg/dL had significant association with recurrence. In contrast, the one week post-op nadir cortisol level had no significant value to predict recurrence. Our data also suggest that nonspecific symptoms and signs of CD are more common than stereotypical signs. Reference: Nieman LK, et al. Treatment of Cushing’s Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2015; 100:2807-2831

Harvey Cushing Treated the First Known Patient With Carney Complex.

Context:Carney complex (CNC) is a syndrome characterized by hyperplasia of endocrine organs and may present with clinical features of Cushing syndrome and acromegaly due to functional adrenal and pituitary gland tumors. CNC has been linked to mutations in the regulatory subunit of protein kinase A type I-alpha (PRKAR1A) gene.Design:Tissue samples were taken from the hypothalamus or thalamus or tumors of patients with pituitary adenomas seen and operated on by neurosurgeon Harvey Cushing between 1913 and 1932. Following DNA extraction, sequencing for genes of interest was attempted, including PRKAR1A, AIP, USP8, GNAS1, and GPR101, to explore the possibility that these mutations associated with acromegaly, CNC, and Cushing syndrome have been conserved over time.Results:We report a patient described by Dr. Cushing in 1914 with a clinical presentation and postmortem findings suggestive of CNC. Genetic sequencing of the hypothalamus and pituitary adenoma revealed a germline heterozygous p.Arg74His mutation in the PRKAR1A gene, a codon previously described as mutated in CNC, but with a novel amino acid change.Conclusions:This patient is, to our knowledge, the first molecularly confirmed individual with CNC. This case demonstrates the power of modern genetics in studying archived tissues and the importance of recording detailed clinical notes in the diagnosis of disease.

Surgical treatment of adrenocorticotropic hormone independent macronodular adrenal hyperplasia

Objective To study the surgical treatment of adrenocorticotropic hormone independent macronodular adrenal hyperplasia (AIMAH). Methods The clinical data of 12 AIMAH patients were analyzed retrospectively. There were 3 males and 9 females, with an average age of 55 years (range, 39-67 years). 10 cases had typical clinical features of Cushing syndrome. Endogenous hypercortisolism was confirmed on the basis of loss of circadian rhythm of serum cortisol, high late-night serum cortisol level and inadequate cortisol suppression after overnight low-dose dexamethasone suppression test. ACTH independence was established on the basis of suppressed serum ACTH levels and inadequate cortisol suppression after overnight high-dose dexamethasone suppression test. CT scan showed bilateral enlargement of the adrenal glands with multiple macronodules. Steroid supplement was given after operation. Results Surgical intervention was performed in all the patients. Seven patients underwent bilateral adrenalectomy, and unilateral adrenalectomy was performed in 5 patients, one of whom had the history of contralateral adrenalectomy. Pathological examination confirmed multinodular hyperplastic adrenal enlargement. The average duration of postoperative follow-up was 50 months (range, 1-105 months). One patient undergoing bilateral adrenalectomy died from respiratory failure and pulmonary infection one month after operation. Remission of Cushing syndrome symptoms was obtained after surgery in other 11 patients.For these 11 cases, the serum cortisol declined into normal ranges, but suppressed serum ACTH levels and inadequate cortisol suppression after overnight low-dose dexamethasone suppression test were still present.Two patients received contralateral adrenalectomy due to recurrent overt Cushing syndrome after one year and 5 years, respectively. Conclusions Unilateral adrenalectomy might be an effective and safe treatment modality for AIMAH, but subclinical hypercortisolism would be present postoperatively. Contralateral adrenalectomy may be performed in case of the recurrence of overt Cushing syndrome. Key words: Cushing syndrome; Adrenocorticotrophic hormone(ACTH); Macronodular adrenal hyperplasia; Operation

Nonsuppressible Oral Dexamethasone Suppression Tests but Not Cushing Syndrome.

In spite of the presence of definitive diagnostic criteria to diagnose Cushing syndrome diagnosis may become challenging. We report a young female with mild clinical features of Cushing syndrome, who had nonsuppressible oral dexamethasone suppression tests; also she had a suspicious pituitary lesion. She underwent pituitary surgery and a pituitary microadenoma (non-ACTH staining) was removed. Now she had come to us with similar complaints to those before. Again she had nonsuppressible oral dexamethasone suppression tests. As the diurnal variation of serum and salivary cortisol was maintained and urinary free cortisol was normal, further evaluation with IV dexamethasone suppression test was performed which clearly ruled out Cushing syndrome. The patient was not on any medicines known to alter dexamethasone metabolism. Fat malabsorption was also ruled out using appropriate tests. The reason for this discrepancy is thought to be altered (increased) metabolism of dexamethasone in this patient as it is widely variable in the general population.

Cushing disease with pregnancy

Pregnancy occurs rarely in patients with Cushing syndrome (CS) due to hypercortisolism. So far, about 150 cases of CS in pregnancy have been reported in the literature. We describe a 22-year-old female who presented in pregnancy with clinical features of CS. She delivered at 34 weeks of gestation and baby had transient adrenal insufficiency in the neonatal period. Mother underwent transsphenoidal surgery 1 year postpartum and on follow up she is under remission. Neonatal hypoadrenalism should be anticipated in maternal CS.

Surgical treatment of adrenocorticotropin-independent macronodular adrenal hyperplasia

Objective To investigate the diagnosis and treatment of adrenocorticotropin-independent macronodular adrenal hyperplasia (AIMAH). Methods The clinical data of 14 cases of AIMAH from August 1972 to July 2010 were retrospectively analyzed.The cases included 5 males and 9 females with a mean age of 45 (range 26 to 58 ) years.Ten patients demonstrated typical Cushing's syndrome (CS) and 4 patients presented with weight gain,hypertension or diabetes mellitus without any signs of CS.The circadian rhythm of serum cortisol was abnormal.Low and high dose dexamethasone suppression tests failed to suppress cortisol secretion.CT scan showed bilateral enlargement of the adrenal glands with multiple macronodules.All patients underwent open surgery,including 5 cases of unilateral adrenalectomy,6 cases of adrenalectomy combined with contralateral subtotal adrenalectomy and 3 cases of bilateral adrenalectomy.Results It was established by pathological examination that all patients had bilateral adrenal macronodular or adenomatoid hyperplasia.During the mean follow-up of 69 months (range 12 to 120 months),the clinical symptoms of CS disappeared after surgery in all cases.The 5 patients who received unilateral adrenalectomy had urinary free cortisol and serum cortisol within normal ranges and no further enlargement of the contralateral gland was noticed.Among the 3 patients who received bilateral adrenalectomy,1 case died of adrenal crisis on day seven post-operation.The remaining 2 cases presented with adrenal insufficiency but returned to normal after glucocorticoid replacement therapy.Nelson's syndrome was not observed in the other patients.Conclusions AIMAH has unique endocrinological and pathological features,presenting as an independent etiology of CS.Unilateral adrenalectomy appears to be an effective and safe alternative treatment for AIMAH and long-term remission can be achieved.Bilateral adrenalectomy or unilateral adrenalectomy combined with contralateral subtotal adrenalectomy may be performed if the symptoms have not improved or recurred after unilateral adrenalectomy. Key words: Cushing syndrome; Adrenocorticotropic hormone; Macronodular adrenal hyperplasia; Surgical procedures, operative

Diminished urinary free cortisol excretion in patients with moderate and severe renal impairment.

The diagnosis of Cushing syndrome remains a challenge for most general clinicians and even endocrinologists. Because the clinical features of Cushing syndrome overlap with those in some healthy obese individuals, biochemical investigations play an important role. The 24-h urinary free cortisol excretion is widely used because of its relatively good sensitivity and specificity (1)(2). Although salivary cortisol has been recommended for screening of Cushing syndrome (3), this assay has not been widely available. Because plasma free cortisol is filtered through the glomeruli with partial tubular reabsorption, the amount of free cortisol appearing in the urine is theoretically dependent on the glomerular filtration rate. However, the high reliability of using 24-h urinary cortisol excretion for the diagnosis of Cushing syndrome implies that urinary excretion of cortisol is relatively unaffected by renal function. In patients with confirmed Cushing disease and severe renal impairment, the urinary free cortisol excretion rate reportedly is normal despite markedly increased plasma cortisol (4)(5)(6). The relationship between glomerular filtration rate and urinary cortisol excretion has not been documented in patients with different degrees of renal impairment. We selected 100 leftover portions of urine samples that had been sent for the measurement of creatinine clearance (CrCl) in the Prince of Wales Hospital of Hong Kong during September, October, and November 2002. All patients were given clear instructions by an experienced nurse to ensure the completeness of 24-h urine collection. Simultaneous serum samples were also received for the …

A Case of Cushing Syndrome Caused by ACTH Producing Atypical Lung Carcinoid Tumor

A forty-one-year-old male who was found to have lung carcinoid tumor showed clinical features of Cushing syndrome. At the age of 38 years during a regular check-up, a chest roentgenogram showed multiple nodular shadows in the bilateral lung, and he was admitted to hospital. By open lung biopsy, he was diagnosed as having malignant carcinoid or small cell carcinoma of the lung. The abnormal lung shadows did not respond to chemotherapy (CDDP + VDS). The clinical course after discharge was uneventful until the age of 41 years, when he was readmitted to our hospital because of brain metastasis. Physical examination revealed moon face and central obesity. Plasma ACTH level was high and dexamethasone suppression test showed no cortisol suppression on 8 mg dexamethasone administration. Therefore, it was thought that the patient had ACTH producing ectopic tumor which led to Cushing syndrome. We measured the molecular weight of ACTH by column chromatography and found he had a big ACTH (molecular weight about 22,000). Reexamining him clinically and histologically, we concluded that the patient had atypical carcinoid tumor in the lung which might produce ACTH causing Cushing syndrome with metastasis to the brain.