American Association of Clinical Endocrinology Disease State Clinical Review on the Evaluation and Management of Adrenocortical Carcinoma in an Adult: a Practical Approach

Objective: The aim of this Disease State Clinical Review is to provide a practical approach to patients with newly diagnosed adrenocortical carcinoma, as well as to follow-up and management of patients with persistent or recurrent disease.Methods: This is a case-based clinical review. The provided recommendations are based on evidence available from randomized prospective clinical studies, cohort studies, cross-sectional and case-based studies, and expert opinions.Results: Adrenocortical carcinoma is a rare malignancy, often with poor outcomes. For any patient with an adrenal mass suspicious for adrenocortical carcinoma, the approach should include prompt evaluation with detailed history and physical exam, imaging, and biochemical adrenal hormone assessment. In addition to adrenal-focused imaging, patients should be evaluated with chest-abdomen-pelvis cross-sectional imaging to define the initial therapy plan. Patients with potentially resectable disease limited to the adrenal gland should undergo en bloc open surgery by an expert surgeon. For patients presenting with advanced or recurrent disease, a multidisciplinary approach considering curative repeat surgery, local control with surgery, radiation therapy or radiofrequency ablation, or systemic therapy with mitotane and/or cytotoxic chemotherapy is recommended.Conclusion: As most health care providers will rarely encounter a patient with adrenocortical carcinoma, we recommend that patients with suspected adrenocortical carcinoma be evaluated by an expert multidisciplinary team which includes clinicians with expertise in adrenal tumors, including endocrinologists, oncologists, surgeons, radiation oncologists, pathologists, geneticists, and radiologists. We recommend that patients in remote locations be followed by the local health care provider in collaboration with a multidisciplinary team at an expert adrenal tumor program.Abbreviations: ACC = adrenocortical carcinoma; ACTH = adrenocorticotropic hormone; BRACC = borderline resectable adrenocortical carcinoma; CT = computed tomography; DHEAS = dehydroepiandrosterone sulfate; EDP = etoposide, doxorubicin, cisplatin; FDG = ¹⁸F-fluorodeoxyglucose; FNA = fine-needle aspiration; HU = Hounsfield units; IVC = inferior vena cava; LFS = Li-Fraumeni syndrome; MEN1 = multiple endocrine neoplasia type 1; MRI = magnetic resonance imaging; OAC = oncocytic adrenocortical carcinoma; PC = palliative care; PET = positron emission tomography     

Clinical Outcomes in Adrenal Incidentaloma: Experience From one Center

Objective: To investigate the outcome in patients with adrenal incidentaloma (AI).Methods: A retrospective evaluation of 637 patients with AI referred to a tertiary center over 8 years. Radiologic and hormonal evaluations were performed at baseline. Follow-up imaging was carried out if necessary, and hormonal evaluation was performed at 24 months according to national guidelines.Results: The mean age was 62.7 ± 11.6 years, and the mean AI size was 25.3 ± 17.0 mm at presentation. Hormonal evaluation revealed that 85.4% of all tumors were nonfunctioning adenomas, 4.1% subclinical Cushing syndrome (SCS), 1.4% pheochromocytoma, 1.4% primary hyperaldosteronism, 0.8% Cushing syndrome, 0.6% adrenocortical carcinoma, 0.3% congenital adrenal hyperplasia, 2.2% metastasis to adrenals, and 3.8% other lesions of benign origin. Bilateral tumors were found in 11%, and compared to unilateral tumors, SCS was more prevalent. Only 2 cases were reclassified during follow-up, both as SCS, but neither had had a dexamethasone suppression test performed at initial work-up. In patients diagnosed with an adrenal metastasis, 92.9% were deceased within 2 years. Excluding those with malignant tumors, 12.9% of patients died during the study period of up to 11 years due to other causes than adrenal.Conclusion: Most AIs were benign, but a small fraction of tumors were functional and malignant. The prognosis of patients with adrenal metastasis was extremely poor, but otherwise, the mortality rate was similar to that for the general population. Follow-up of AIs <4 cm with an initial nonfunctional profile and benign radiologic appearance appears unwarranted, but screening for congenital adrenal hyperplasia should be considered.Abbreviations: 17OHP = 17-hydroxyprogesterone ACC = adrenal cortical carcinoma ACTH = adrenocorticotropic hormone AI = adrenal incidentaloma CAH = congenital adrenal hyperplasia CT = computed tomography CS = Cushing syndrome DST = dexamethasone suppression test HPA = hypothalamic-pituitary-adrenal axis MRI = magnetic resonance imaging SCS = subclinical Cushing syndrome T2DM = type 2 diabetes mellitus UFC = urinary free cortisol     

The Low-Dose Acth Stimulation Test: is 30 Minutes Long Enough?

Objective: Controversy persists regarding the use of the low-dose adrenocorticotropic hormone (ACTH) stimulation test (LDST) for the diagnosis of adrenal insufficiency (AI) and optimal test result interpretation. However, many centers are now using the LDST to assess cortisol secretion adequacy, and some only use a 30-minute cortisol level to determine adrenal sufficiency or AI. This study examined both 30- and 60-minute cortisol levels to assess whether the interpretation of the test was affected when both cortisol levels were taken into consideration.Methods: Data were obtained by retrospective chart review from a single pediatric endocrinology unit over a 7-year period. We identified 82 patients who completed the LDST. Their mean age was 11.7 years, and 37% were female. Cortisol levels were evaluated at baseline and 30 and 60 minutes after cosyntropin administration. A cutoff value ≥18 μg/dL was used to define adrenal sufficiency.Results: We found that 54% of patients reached peak cortisol levels at 60 minutes, and 11 patients who did not pass the test at 30 minutes did so at 60 minutes. The only predictive characteristic was weight status; overweight and obese individuals tended to peak at 30 minutes, and normal and underweight individuals tended to peak at 60 minutes.Conclusion: Although further studies are necessary to confirm our findings, it appears that measuring cortisol both 30 and 60 minutes following synthetic ACTH administration may be necessary to avoid overdiagnosing AI.Abbreviations: ACTH = adrenocorticotropic hormone AI = adrenal insufficiency BMI = body mass index LDST = low-dose ACTH stimulation test MRI = magnetic resonance imaging     

Active Surveillance for Papillary Thyroid Microcarcinoma: New Challenges and Opportunities for The Health Care System

Objective: The dramatic increase in papillary thyroid carcinoma (PTC) is primarily a result of early diagnosis of small cancers. Active surveillance is a promising management strategy for papillary thyroid microcarcinomas (PTMCs). However, as this management strategy gains traction in the U.S., it is imperative that patients and clinicians be properly educated, patients be followed for life, and appropriate tools be identified to implement the strategy.Methods: We review previous active surveillance studies and the parameters used to identify patients who are good candidates for active surveillance. We also review some of the challenges to implementing active surveillance protocols in the U.S. and discuss how these might be addressed.Results: Trials of active surveillance support nonsurgical management as a viable and safe management strategy. However, numerous challenges exist, including the need for adherence to protocols, education of patients and physicians, and awareness of the impact of this strategy on patient psychology and quality of life. The Thyroid Cancer Care Collaborative (TCCC) is a portable record keeping system that can manage a mobile patient population undergoing active surveillance.Conclusion: With proper patient selection, organization, and patient support, active surveillance has the potential to be a long-term management strategy for select patients with PTMC. In order to address the challenges and opportunities for this approach to be successfully implemented in the U.S., it will be necessary to consider psychological and quality of life, cultural differences, and the patient's clinical status.Abbreviations:CT = computed tomographyPTC = papillary thyroid carcinomaPTMC = papillary thyroid microcarcinomaTCCC = Thyroid Cancer Care Collaborative     

Germline Deletion of Armc5 In Familial Primary Macronodular Adrenal Hyperplasia

Objective: Primary macronodular adrenal hyperplasia (PMAH) is considered a predominantly sporadic disease, but familial forms are well recognized. Genetic studies revealed germline mutations in the armadillo repeat containing 5 gene (ARMC5) in the majority of PMAH cases. Furthermore, somatic ARMC5 mutations, as different types of second-hit mutations and loss of heterozygosity have been reported in each adrenal nodule in PMAH. Here, we describe the involvement of ARMC5 alteration in a familial case of PMAH.Methods: In our study, we performed clinical and genetic evaluations in a mother and her son with familial PMAH. To search for mutations and deletion of ARMC5, we used Sanger sequencing and droplet digital polymerase chain reaction (ddPCR), respectively.Results: Both patients showed the same phenotype of subclinical Cushing syndrome, with mild excess of mineralocorticoids and vasopressin-responsive cortisol secretion. The ddPCR analysis demonstrated that both mother and son had germline deletions in exons 1 to 5 of the ARMC5 gene locus. Furthermore, Sanger sequencing of DNA from the right and left adrenal nodules as well as peripheral blood of the son revealed the presence of another germline, missense mutation in ARMC5 exon 3 (p.P347S).Conclusion: This is the first report demonstrating germline deletion of ARMC5 in familial PMAH. In addition to investigating mutations, germline and somatic deletions of ARMC5 could be examined by ddPCR, which permits rapid and accurate evaluation of the ARMC5 allelic status.Abbreviations: ACTH = adrenocorticotropic hormone ARMC5 = armadillo repeat containing 5 CT = computed tomography ddPCR = droplet digital polymerase chain reaction LOH = loss of heterozygosity PMAH = primary macronodular adrenal hyperplasia     

Genetic Basis of Bilateral Macronodular Hyperplasia

Objective: To review the genetic basis of bilateral macronodular hyperplasia (BMAH).Methods: Case presentation, review of literature, table, and bullet point conclusions.Results: BMAH, also known as adrenocorticotropic hormone (ACTH)-independent macronodular hyperplasia (AIMH), can cause Cushing syndrome or mild hypercortisolism. Recent studies have demonstrated that hyperplastic tissue reproduces ectopic ACTH, implying that BMAH is the more proper term, as the syndrome is not ACTH-independent. BMAH was thought to be sporadic, but recent data have shown that there is likely a genetic component in the majority of cases. Mutations in ARMC5, a putative suppressor gene, have been found in many familial cases of BMAH and are thought to be responsible for the disorder. As these nodules inefficiently produce cortisol, large nodules are required to produce a clinical syndrome. ARMC5 likely requires a second somatic mutation to become clinically apparent. Clinical manifestations are not generally noted until the fifth to sixth decades of life.Conclusion: BMAH is an underrecognized genetic condition that can lead to Cushing syndrome and should be screened for in patients and susceptible family members.Abbreviations: ACTH = adrenocorticotropic hormone AIMAH = ACTH-independent macronodular adrenal hyperplasia ARMC5 = armadillo-repeat containing 5 BMAH = bilateral macronodular adrenal hyperplasia CAH = congenital adrenal hyperplasia CT = computed tomography MEN1 = multiple endocrine neoplasia 1 UFC = urinary free cortisol     

Primary Adrenal Lymphoma: a Single-Center Experience

Objective: To describe the clinical presentation, biochemistry, imaging features, and treatment outcome of patients with primary adrenal lymphoma (PAL) presenting to a single tertiary care center.Methods: We performed a retrospective analysis of case records of 7 patients diagnosed with PAL between January 2011 and May 2014 at our institution in Mumbai, India.Results: Median age of presentation in our series was 48 years (range, 41 to 60 years), with a male to female ratio of 6:1. Bilateral adrenal involvement was seen in 4 of 7 patients (58%). Adrenal insufficiency (AI) was seen in 3 of the 4 patients with bilateral involvement (75%). Computed tomography showed slight to moderate contrast enhancement of adrenal masses in 4 of 5 patients (80%). Diffuse, large, B-cell lymphoma (DLBCL) was the most common immunophenotype (85%). One patient died due to rapid disease progression even before starting chemotherapy. Six patients were treated with chemotherapy and/or external beam radiotherapy. After 1 year, 2 more patients had died, whereas 4 patients were in remission.Conclusion: PAL should always be considered in differential diagnosis of bilateral adrenal mass with AI. DLBCL is the most common histologic subtype of PAL. Despite treatment, long-term prognosis of PAL remains poor.Abbreviations: AI = adrenal insufficiency B/L = bilateral CT = computed tomography DLBCL = diffuse, large, B-cell lymphoma EBRT = external beam radiotherapy ¹⁸F-FDG PET/CT= ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography PAL = primary adrenal lymphoma T/NK = T cell/natural killer cell     

Mifepristone Treatment for Mild Autonomous Cortisol Secretion Due to Adrenal Adenomas: A Pilot Study

Objective: Adrenal incidentalomas are increasingly detected with the widespread use of thoracic and abdominal imaging. The most common secretory syndrome in adrenal nodules is autonomous cortisol secretion (ACS). Recent data show that even mild cortisol excess is associated with adverse outcomes. The glucocorticoid receptor antagonist mifepristone has been used in patients with overt Cushing syndrome and hyperglycemia. The purpose of our study was to determine the effect of mifepristone on metabolic parameters in patients with ACS and concomitant prediabetes or diabetes.Methods: Eight patients with either unilateral or bilateral adrenal nodules with ACS were included in the study. Fasting laboratory tests including glucose and insulin levels to calculate homeostatic model assessment for insulin resistance (HOMA-IR) were performed at baseline and again after either 3 months (3 patients) or 6 months (5 patients) on mifepristone 300 mg daily treatment. Patients also completed several validated surveys on mood and quality of life at baseline and follow-up.Results: There were significant reductions in fasting glucose measurements and insulin resistance as measured by HOMA-IR in the 6 of 8 study patients in whom these measurements were available (P = .03).Conclusion: This pilot study demonstrates that mifepristone treatment of ACS is associated with a significant decrease in fasting glucose and insulin resistance as measured by HOMA-IR scores. Mifepristone treatment of ACS may be considered as a medical option for patients with ACS due to adrenal adenomas with concomitant abnormal glucose parameters in whom surgical removal is not being considered.Abbreviations: ACS = autonomous cortisol secretion; ACTH = adrenocorticotropic hormone; AI = adrenal incidentaloma; DHEAS = dehydroepiandrosterone sulfate; GR = glucocorticoid receptor; HbA1c = hemoglobin A1c; HOMA-IR = homeostatic model assessment for insulin resistance; ODT = overnight dexamethasone suppression test; QoL = quality of life; STAI = state trait anxiety inventory; TSH = thyroid stimulating hormone; UFC = urinary free cortisol     

Implementing Key Changes in The American Thyroid Association 2015 Thyroid Nodules/Differentiated Thyroid Cancer Guidelines Across Practice Types

Objective: This article provides suggestions to help clinicians implement important changes in the 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Carcinoma (“ATA 2015”) across diverse settings.Methods: Key ATA 2015 changes are summarized regarding: (1) thyroid nodule management; (2) lobectomy versus thyroidectomy for differentiated thyroid carcinoma (DTC); and (3) surveillance following primary treatment of DTC. Advice to facilitate implementation is based on clinical experience and selected literature.Results: Strategies are described to enhance acquisition of high-quality information that helps identify patients who may possibly avoid fine-needle aspiration (FNA) of thyroid nodules or total thyroidectomy for DTC, or undergo less intense postoperative surveillance. Sonographic imaging of nodules may improve if sonograms are obtained by clinicians ordering or performing FNA or trusted high-volume sonographers. Cytopathologic assessment and reporting can be improved by working with regional or national experts. Pre-operative evaluation by endocrinologists is important so that patients are referred to experienced, proficient surgeons and assisted with well-informed decision-making regarding surgical radicality. Endocrinologists and surgeons should ensure performance of pre-operative neck ultrasonography, voice/laryngeal evaluation, and contrast-enhanced cross-sectional imaging when appropriate. Findings should be disseminated to all healthcare team members, ideally through a comprehensive medical record accessible to the entire team.Conclusion: Optimization of the sequence of specialist visits and assembly of interactive multidisciplinary teams coupled with intensified interdisciplinary and patient communication may enable clinicians to more effectively implement ATA 2015, which calls for more individualized, and often, less “invasive” management of thyroid nodules and DTC.Abbreviations: ATA 2009 = 2009 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Carcinoma; ATA 2015 = 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Carcinoma; DTC = differentiated thyroid carcinoma; FNA = fine-needle aspiration; PET/CT = positron emission tomography/computed tomography     

Serum Morning Cortisol as A Screening Test for Adrenal Insufficiency

Objective: To evaluate the performance of morning serum cortisol (MSC) compared to a 10 mg adrenocortico-tropic hormone (ACTH) stimulation test in the diagnosis of adrenal insufficiency (AI).Methods: A retrospective, cross-sectional analysis of ACTH stimulation tests were conducted. From a total of 312 potentially eligible ACTH stimulation tests, 306 met the inclusion criteria. The population was randomized into 2 groups: test (n = 159) and validation (n = 147). In the test group, the receiver operating characteristics curve test evaluated the diagnostic performance of MSC.Results: A subnormal cortisol response to ACTH was found in 25.8% of the test group. The area under the curve values of MSC to predict AI at +30 minutes, +60 minutes, or at maximal cortisol response were 0.874, 0.897, and 0.925 (95% confidence interval &lsqb;CI] 0.81 to 0.92, 0.83 to 0.93, and 0.87 to 0.96). The Youden index was 234.2 mmol/L with a sensitivity of 83.3% (95% CI 65.2 to 94.3%), and a specificity of 89.1% (95% CI 82.4 to 93.9%). Positive and negative predictive values were 64.1% (95% CI 47.1 to 78.8%) and 95.8% (95% CI 90.5 to 98.6%). There was no difference in age, gender, AI prevalence, or mean serum cortisol at +30 or +60 minutes in the validation group; however, a lower mean MSC value was found. Lower sensitivity and specificity values (88.3% and 60%, respectively) were found for the 234.2 mmol/L cutoff value.Conclusion: This study supports the role of MSC as a first-step diagnostic test in patients with clinically suspected AI. The short stimulation test could be omitted in almost half of the cases. Prospective and longitudinal studies to reproduce and confirm the cutoff values proposed are warranted.Abbreviations: ACTH = adrenocorticotropic hormone; AI = adrenal insufficiency; AUC = area under the curve; CI = confidence interval; HPA = hypothalamic pituitary adrenal; ITT = insulin tolerance test; MSC = morning serum cortisol     

Clinical Features and Retroperitoneal Laparoscopic Resection of Adrenal Schwannoma in 19 Patients

Objective: To explore the diagnostic and therapeutic principles of the rare adrenal schwannoma.Methods: We objectively analyzed the detailed clinical data of 19 patients with adrenal schwannoma treated in a large comprehensive medical center in China between January 2009 and March 2014, including general information, clinical manifestations, imaging, adrenal-related endocrine tests, treatment, pathology, and follow-up records.Results: Patients included 16 females and 3 males ranging from 23 to 66 years of age (mean, 48.3 ± 12.6 years), of whom 15 were discovered incidentally. Four patients reported mild abdominal discomfort. Each patient had one unilateral lesion, ranging in diameter from 4.0 to 8.8 cm (mean, 6.2 ± 1.2 cm). Lesions were hypoechoic in 16 patients and cystic-solid in 3 patients. Computed tomography (CT) scanning revealed soft tissue density, mostly with calcifications and clear boundaries. Average values in normal and enhanced CT were 28.7 ± 7.2 Hounsfield units (HU) and 59.7 ± 5.4 HU, respectively. Indicators of adrenal-related endocrine tests were normal, except that catecholamines levels were slightly low in 2 patients with excessively large lesions. All patients underwent uncomplicated retroperitoneal laparoscopic surgery, with subsequent pathology confirmation of adrenal schwannoma. The patients have been followed for 6 months to 4 years, with no recurrence.Conclusion: Our results demonstrate that the onset of adrenal schwannoma is always occult, without typical clinical manifestations and adrenal-related endocrine abnormalities, and the pre-operative diagnosis depends primarily on imaging features of hypoechoic calcifications and mild enhancement. Diagnosis can be confirmed by postoperative pathology. Even with large diameter lesions, retroperitoneal laparoscopic surgery is still the preferred approach, with good prognosis.Abbreviations: CT = computed tomography DA = dopamine E = epinephrine HE = hematoxylin-eosin HU = Hounsfield unit NE = norepinephrine PET/CT = positron emission tomography/computed tomography S-100 = soluble protein-100     

Large Adrenal Incidentalomas Require a Dedicated Diagnostic Procedure

Objective: The management of large nonsecreting adrenal tumors (at least 4 cm) is still a matter of debate as it is unclear whether imaging, especially ¹⁸F-fluorodeoxyglucose (FDG), can be used to characterize their potential malignancy. Moreover, the risk of new hypersecretion in nonoperated tumors is uncertain. Our aim was to better characterize these large adrenal incidentalomas.Methods: Patients followed in our center for a nonsecreting large (at least 4 cm) adrenal incidentaloma, with an initial computed tomography (CT) and ¹⁸F-FDG positron emission tomography (PET) CT, were retrospectively included. Patients who were not operated after initial diagnosis had to be followed with clinical, biological, and imaging evaluations for at least 3 years or until delayed surgery.Results: Eighty-one patients were included in the study: 44 patients (54.3%) had initial surgery while 37 were followed, including 21 (25.9%) who were operated after a mean of 19 months. Among the 65 operated patients, 13 (20%) had a malignant lesion (3 with metastasis, and 10 with adrenocortical carcinoma). Unenhanced CT <10 showed 85.6% sensitivity and 78.8% specificity; all had a ¹⁸F-FDG uptake ratio >1.5. Among the 24 patients who were followed for at least 3 years, 5 (20.8%) finally presented hypercortisolism (4 subclinical).Conclusion: As expected, large adrenal tumors are at a higher risk of malignancy. The combination of unenhanced CT <10 and ¹⁸F-FDG PET ratio <1.5 prove to be reassuring and might lead to a close follow-up rather than immediate surgery. Hormonal follow-up should be focused on the risk of hypercortisolism.Abbreviations: CI = confidence interval; CT = Computed Tomography; ENSAT = European Network for the Study of Adrenal Tumors; ESE = European Society of Endocrinology; FDG = fluorodeoxyglucose; HU = Hounsfield units; PET = positron emission tomography; ROI = regions of interest; SUV = standard uptake value     

American Association of Clinical Endocrinologists And American College of Endocrinology Disease State Clinical Review: Postoperative Management Following Pituitary Surgery

Pituitary lesions are common in the general population. Patients can present with a wide range of signs and symptoms that can be related to tumor mass effects or pituitary hormonal alterations. Evaluation involves assessing patients for the extent of tumor burden and pituitary hyper- or hypofunction and includes clinical exams, hormonal testing, and brain imaging. Preoperative diagnosis and treatment planning generally require a multidisciplinary team approach with expertise from endocrinologists, neurosurgeons, neuro-ophthalmologists, and neuroradiologists. This review will outline considerations for the evaluation and management of patients with pituitary masses at each stage in their treatment including the pre-, peri- and postoperative phases.Abbreviations: ADH = antidiuretic hormone CSF = cerebrospinal fluid DDAVP = desmopressin DI = diabetes insipidus GH = growth hormone MRI = magnetic resonance imaging SIADH = syndrome of inappropriate ADH release TSS = transsphenoidal surgery     

Genetic Forms of Adrenal Insufficiency

Objective: The American Association of Clinical Endocrinologists Adrenal Scientific Committee has developed a series of articles to update members on the genetics of adrenal diseases.Methods: Case presentation, discussion of literature, table, and bullet point conclusions.Results: The genetic mutations associated with several familial causes of adrenal insufficiency have now been identified. The most common ones that will be discussed here include Allgrove syndrome, adrenoleukodystrophy, adrenal hypoplasia congenita, autoimmune polyglandular syndrome type 1, congenital adrenal hyperplasia (CAH), lipoid CAH, and familial glucocorticoid deficiency. Although these diseases most commonly present in childhood, some rarely present in adulthood, and thus all endocrinologists must be familiar with these syndromes. Some patients only develop glucocorticoid deficiency, and others have both glucocorticoid and mineralocorticoid deficiency. These diseases may be associated with other conditions, especially neurologic disease, hypogonadism, or dermatologic problems. Diagnosis is suspected based on clinical presentation and laboratory findings. Gene testing may be necessary for confirmation of a diagnosis and/or screening of family members.Conclusion: This article briefly reviews the various familial adrenal insufficiency syndromes and the specific associated gene defects.Abbreviations: AAA = Allgrove syndrome (alachrima-achalasiaadrenal insufficiency) ACTH = adrenocorticotropic hormone AHC = adrenal hypoplasia congenita ALD = adrenoleukodystrophy CAH = congenital adrenal hyperplasia DAX1 = dosage-sensitive sex reversal, adrenal hypoplasia congenita, X-chromosome FGD = familial glucocorticoid deficiency LCAH = lipoid CAH MCM4 = mini-chromosome maintenancedeficient 4 SF1 = steroidogenic factor 1 VLCFA = very-long-chain fatty acid     

Glucocorticoid-Induced Adrenal Insufficiency: A Study of the Incidence in Hospital Patients and A Review of Peri-Operative Management

Objective: Glucocorticoid (GC) pharmacotherapy is an effective treatment for a range of diseases, but exposure can suppress the hypothalamic-pituitary-adrenal axis, leading to glucocorticoid-induced adrenal insufficiency (GC-AI) in some patients. However, the incidence of diagnosed GC-AI and the associated health burden, including the incidence of adrenal crises (ACs), are unknown. Although GC-AI treatment is based on well-established principles, there are no agreed protocols regarding the peri-operative management of exposed patients. The aims of this study were to assess the incidence of diagnosed GC-AI in hospital patients and review current approaches to peri-operative management of surgical patients with GC exposure.Methods: An analysis of hospital admission data concerning adult patients diagnosed with GC-AI and a review of published recommendations for peri-operative GC cover.Results: Between 2001 and 2013, admission with a diagnosis of GC-AI in New South Wales, Australia was rare (annual average of 22.5 admissions/year) and ACs were even more rare (n = 3). Almost two-thirds (64.4%, n = 188) of the patients with diagnosed GC-AI were aged between 50 and 79 years and 45.2% (n = 132) had a comorbid infection. The current approach to peri-operative management of patients with GC exposure appears to be influenced by both the absence of clear guidelines and historic practices. This results in the exposure of some patients to supraphysiologic doses of GCs during the peri-operative period.Conclusion: Hospital admission with a diagnosis of GC-AI (with or without an AC) is very rare. Clear guidelines on peri-operative GC cover are necessary to avoid overreplacement with supraphysiologic doses in susceptible patients.Abbreviations: AC = adrenal crisis; ACTH = adrenocorticotropic hormone; AI = adrenal insufficiency; CI = confidence interval; GC = glucocorticoid; GC-AI = glucocorticoid-induced adrenal insufficiency; HPA = hypothalamic-pituitary-adrenal; OR = odds ratio     

UPDATE ON THE CLINICOPATHOLOGY OF PITUITARY ADENOMAS

Objective: Pituitary adenomas are the third most common central nervous system tumors and arise from the anterior pituitary within the pituitary fossa.Methods: Literature review and discussion.Results: The signs and symptoms of patients with pituitary adenomas vary from ‘mass effects’ caused by a large adenoma to features secondary to excess pituitary hormones produced by the functioning pituitary adenoma. Detailed histopathologic assessment, based on novel classifications and the latest World Health Organization guidelines, helps to categorize pituitary adenomas into different subtypes and identify features that, in some cases, help to predict their behavior. Most of the pituitary tumors occur sporadically without known genetic predisposition, but in a significant minority of cases, somatic mutations can be identified in the GNAS and USP8 genes. A small proportion of the cases have germline genetic defects or embryonic mutations leading to mosaicism. Genes with germ-line mutations predisposing to pituitary adenomas include AIP, GPR101, MEN1, CDKN1B, PRKAR1A, PRKAR2A, DICER1, NF1, and SDHx, whereas more recently, CABLES1 has also been implicated.Conclusion: Understanding the pathogenesis of pituitary adenomas will allow clinicians to correlate the pathologic and genetic features with clinical data, helping decisions on the best management of these tumors.Abbreviations: ACTH = adrenocorticotropic hormone; AIP = aryl hydrocarbon receptor-interacting protein; αSU = alpha-subunit; EGFR = epithelial growth factor receptor; ER = estrogen receptor; FSH = follicle-stimulating hormone; GH = growth hormone; GHRH = growth hormone–releasing hormone; IGF-1 = insulin-like growth factor 1; LH = luteinizing hormone; MEN1 = multiple endocrine neoplasia 1; MRI = magnetic resonance imaging; NFPA = nonfunctioning pituitary adenoma; PRL = prolactin; TSH = thyroid-stimulating hormone; USP8 = ubiquitin-specific peptidase 8; WHO = World Health Organization     

Pheochromocytoma in Patients Suspected of Harboring Adrenal Meta stasis: Management and Clinical Predictors

ObjectiveTo study clinical management of patients with suspected adrenal metastasis and to assess whether there are clinical predictors of pheochromocytoma in this patient population.MethodsIn this retrospective cross-sectional study, we reviewed medical records of patients who had adrenalectomy for adrenal lesions or had adrenal biopsy performed between January 1997 and July 2007 in a large academic hospital. Patients who harbored adrenal masses that were suspected of being metastases were identified on clinical findings. Pathologic diagnosis, demographic data, clinical history, imaging studies, and laboratory test results were reviewed and compared among patients whose adrenal mass was determined to be metastasis, adenoma, or pheochromocytoma.ResultsOne-hundred sixty-three patients had adrenalectomy or had adrenal biopsy during the study period. Thirty patients (18%) had adrenal masses that were suspected of being metastases. Of the adrenal masses, 18 (60%) were metastases, 8 (27%) were benign adenomas, and 4 (13%) were pheochromocytomas. Eleven patients (37%) had biochemical testing for pheochromocytoma. Adrenal biopsy was performed without biochemical testing for pheochromocytoma in 9 patients (30%), including 2 subsequently found to have this tumor. Adrenalectomy was performed in 10 patients (33%) without biochemical testing for pheochromocytoma. Clinical parameters were similar among patients with metastasis, adenoma, or pheochromocytoma. There were no clinical predictors to suggest pheochromocytoma.ConclusionsPheochromocytoma occurs frequently in patients suspected of harboring adrenal metastasis, but this tumor is often not considered in clinical practice. The size and imaging characteristics of the adrenal mass and history of known metastasis may help clinicians in decision-making. Biochemical testing for pheochromocytoma should ideally be performed in all patients suspected of having adrenal metastasis. (Endocr Pract. 2008;14:967-972)     

Increasing Prevalence Of Addison Disease: Results From A Nationwide Study

Objective: Primary adrenal insufficiency is a life-threatening endocrine disease unless properly treated. However, few studies on the prevalence, concomitances of the disease, and prescribing of drugs have been published. The goal of the study was to establish the prevalence of primary adrenal insufficiency in Iceland and additionally, to study the most common concomitant diseases in patients with primary adrenal insufficiency, as well as the mode of glucocorticoid replacement therapies.Methods: To achieve this, the medical records of all patients in Iceland who had received the International Classification of Diseases and Related Health Problems, 10th Revision, diagnosis code E27, were evaluated for true primary adrenal insufficiency. Additionally, these records were evaluated for concomitant diseases, as well as the mode of glucocorticoid replacement therapy. The study covered the whole population of Iceland over 18 years of age. It was thus a nationwide study. The records were retrieved from large hospitals and clinics and every practicing specialist in endocrinology.Results: Primary adrenal insufficiency was found in 53 individuals, 26 women and 27 men, yielding a prevalence of 22.1 per 100,000 population. Hypothyroidism was by far the most common concomitant disease. Most patients had their glucocorticoid deficiency replaced with shortacting glucocorticoids.Conclusion: The prevalence of primary adrenal insufficiency in Iceland is higher than in earlier reports, with comorbidities being in line with recent studies. Treatment is according to the latest protocols.Abbreviations:CAH = congenital adrenal hyperplasiaCVD = cardiovascular diseaseDM = diabetes mellitusGC = glucocorticoidLSH = Landspitali National University HospitalPAI = primary adrenal insufficiencyPAS = polyendocrine autoimmune syndrome     

Genetics of Primary Aldosteronism

Objective: The American Association of Clinical Endocrinologists Adrenal Scientific Committee has developed a series of articles to update members on the genetics of adrenal diseases.Methods: Case presentation, discussion of literature, table, and bullet point conclusions.Results: Primary aldosteronism (PA) is the most common form of secondary hypertension. Early detection, surveillance, and treatment of PA may mitigate future cardiovascular risk. The genetics of PA are rapidly evolving, and the consideration for genetic causes of PA are growing. Three inheritable forms of PA are now recognized: familial hyperaldosteronism type I (glucocorticoidremediable aldosteronism), familial hyperaldosteronism type II, and familial hyperaldosteronism type III. The recent discovery of familial hyperaldosteornism type III spurred a flurry of international and collaborative research that is identifying more genetic and molecular causes of PA that relate to mutations in membrane electrolyte transport channels of zona glomerulosa cells.Conclusion: This article reviews the various genetic forms of PA, including a focus on the molecular mechanisms involved, diagnosis, and treatment.Abbreviations: ACTH = adrenocorticotropic hormone ARR = aldosterone to renin ratio FH-I = familial hyperaldosteronism type I FH-II = familial hyperaldosteronism type II FH-III = familial hyperaldosteronism type III GRA = glucocorticoidremediable aldosteronism PA = primary aldosteronism PRA = plasma renin activity