ACTH-independent Macronodular Adrenal Hyperplasia Research Articles

Experience in the treatment of patients with ACTH-independent macronodular bilateral adrenal hyperplasia

Aim to determine the optimal tactics for the examination and treatment of patients with macronadular bilateral adrenal hyperplasia.
 Material and methods. The study included 11 patients with macronodular bilateral adrenal hyperplasia (main group). To compare biochemical parameters, the results of 26 healthy people were studied (control group).
 Results. The patients with macronodular bilateral adrenal hyperplasia were characterized by deficiency of 11-hydroxylase, 21-hydroxylase, 11-hydroxysteroid dehydrogenase type 2 and increased activity of 5-reductase compared with the control group. The optimal treatment for these patients is unilateral adrenalectomy. A comparative selective blood sampling from the central veins of the adrenals is necessary to select the side of intervention in patients with bilateral macronodular adrenal hyperplasia with ACTH-independent Cushing's syndrome.
 Conclusion. The first step in the treatment of patients with bilateral macronodular adrenal hyperplasia with ACTH-independent Cushing's syndrome is unilateral adrenalectomy, which reduces the risk of developing adrenal insufficiency and subsequent hormone replacement therapy.

PS-R03-7: PARTIAL ADRENALECTOMY IN A PATIENT WITH ACTH-INDEPENDENT MACRONODULAR ADRENAL HYPERPLASIA: A CASE REPORT

Background: The standard treatment for ACTH-independent macronodular adrenal hyperplasia (AIMAH) with overt Cushing's syndrome is bilateral adrenalectomy. Here we show a case of AIMAH who underwent total adrenalectomy on one side and partial adrenalectomy on the other, resulting in the successful debulking of cortisol-secreting adrenal masses and improvement of Cushing's syndrome, yet not necessitating postoperative steroid replacement. Case presentation: A 74-year-old female patient with hypertension, type 2 diabetes and dyslipidemia developed edema of the legs. She visited her primary physician and was found to have lumbar vertebral compression fractures. The blood test and 24-hr urine collection revealed the plasma cortisol levels of 26.1 μg per dL, adrenocorticotropic hormone of 1.1 pg per mL, and urine free cortisol of 340 μg per day. Computed tomographic scan and adrenal scintigraphy confirmed bilateral adrenal nodules with notable tracer uptake. Diagnosis of AIMAH with Cushing's syndrome was made. Laparoscopic partial adrenalectomy, i.e., total removal of the left adrenal gland and partial removal of the right counterpart, was conducted aiming to avert from steroid replacement therapy. After the surgery, blood pressure and glycemic control were markedly improved and maintained for 4 years whilst adrenocortical functions were preserved. Conclusion: Partial adrenalectomy could be an effective therapy in selected cases of AIMAH.

Clinical Spectrum of Adrenal Cushing's Syndrome and the Caution for Interpretation of Adrenocorticotrophic Hormone: A Single-Center Experience.

Retrospective, single-center, observational study. Fifty-eight adrenal CS patients [Adrenocortical carcinoma (ACC), n=30; Adenoma (ACA), n=15; Primary pigmented nodular adrenocortical disease (PPNAD), n=10; ACTH independent macronodular adrenal hyperplasia (AIMAH), n=3) evaluated at a tertiary care center in western India between January 2006 to March 2020 were included. Data on demography, clinical evaluation, biochemistry, imaging, management, histopathology, and outcome were recorded in a standard format and analyzed. Cortisol secreting ACC presented at 38(1-50) years with abdominal mass in 26/30 (86.7%) and 16/30 (53.3%) had metastases at presentation. ACA with autonomous cortisol excess presented at 25(4.9-40) years with discriminating features of CS in 14/15 (93.3%), sex steroid production in 2/15, unenhanced HU <10 in only one, and relative washout >40% in 8/11 (72.7%). One ACA and eight ACC patients had plasma ACTH (by Siemens Immulite assay) > 20 pg/ml, despite hypercortisolemic state. Cortisol-secreting ACC and ACA most often present with mass effects and florid CS, respectively. Baseline HU has low sensitivity to differentiate cortisol-secreting ACA from ACC. Plasma ACTH measured by Seimens Immulite is often unsuppressed, especially in ACC patients, which can be addressed by measuring ACTH by more accurate assays.

MicroRNA expression signature and target prediction in familial and sporadic primary macronodular adrenal hyperplasia (PMAH)

BackgroundPrimary macronodular adrenal hyperplasia (PMAH), previously termed ACTH-independent macronodular adrenal hyperplasia (AIMAH), is a rare cause of Cushing’s syndrome usually characterized by functioning adrenal macronodules and increased cortisol production.MethodsTo screen and analyse the microRNA (miRNA) profile of PMAH in order to elucidate its possible pathogenesis, a miRNA microarray was used to test tissue samples from patients with familial PMAH, patients with sporadic PMAH and normal control samples of other nontumour adrenocortical tissues and identify characteristic microRNA expression signatures. Randomly selected miRNAs were validated by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). Furthermore, the key signalling pathways and miRNAs involved in PMAH pathogenesis were determined by gene ontology and pathway analysis.ResultsCharacteristic microRNA expression signatures were identified for patients with familial PMAH (16 differentially expressed microRNAs) and patients with sporadic PMAH (8 differentially expressed microRNAs). The expression of the selected miRNAs was confirmed by qRT-PCR, suggesting the high reliability of the miRNA array analysis results. Pathway analysis showed that the most enriched pathway was the renal cell carcinoma pathway. Overexpression of miR-17, miR-20a and miR-130b may inhibit glucocorticoid-induced apoptosis in PMAH pathogenesis.ConclusionWe identified the miRNA signatures in patients with familial and sporadic PMAH. The differentially expressed miRNAs may be involved in the mechanisms of PMAH pathogenesis. Specific miRNAs, such as miR-17, miR-20a and miR-130b, may be new targets for further functional studies of PMAH.

Hypokalemia associated with mifepristone use in the treatment of Cushing's syndrome.

SummaryMifepristone is a promising option for the management of hypercortisolism associated with hyperglycemia. However, its use may result in serious electrolyte imbalances, especially during dose escalation. In our patient with adrenocorticotropic hormone-independent macro-nodular adrenal hyperplasia, unilateral adrenalectomy resulted in biochemical and clinical improvement, but subclinical hypercortisolism persisted following adrenalectomy. She was started on mifepristone. Unfortunately, she missed her follow-up appointments following dosage escalation and required hospitalization at an intensive care level for severe refractory hypokalemia.Learning points:Mifepristone, a potent antagonist of glucocorticoid receptors, has a high risk of adrenal insufficiency, despite high cortisol levels.Mifepristone is associated with hypokalemia due to spill-over effect of cortisol on unopposed mineralocorticoid receptors.Given the lack of a biochemical parameter to assess improvement, the dosing of mifepristone is based on clinical progress.Patients on mifepristone require anticipation of toxicity, especially when the dose is escalated.The half-life of mifepristone is 85 h, requiring prolonged monitoring for toxicity, even after the medication is held.

Characteristic Computed Tomography Findings in Adrenocorticotropic Hormone-independent Macronodular Adrenal Hyperplasia: “Bunch of Grapes”

Characteristic Computed Tomography Findings in Adrenocorticotropic Hormone-independent Macronodular Adrenal Hyperplasia: “<i>Bunch of Grapes</i>”

Whole-genome sequencing revealed armadillo repeat containing 5 (ARMC5) mutation in a Chinese family with ACTH-independent macronodular adrenal hyperplasia.

Primary macronodular adrenal hyperplasia (PMAH), also known in the past as bilateral macronodular adrenalhyperplasia or adrenocorticotropin (ACTH)-independent macronodular adrenal hyperplasia, is a rare type of Cushing's syndrome (CS) and is associated with bilateralenlargement of the adrenal glands. It accounts for <1% of all endogenous cases of CS. In order toidentify the pathogenic mutations in the causative gene of (AIMAH pedigrees, Whole-genome sequencing of three patients in family I was used to retrieve candidate causative genes. Meanwhile, the causative gene was identified by Sanger sequencing from the two pedigrees. Sequencing of ARMC5 exons of three patients was carried out to identify somatic mutations. Moreover, haploid clone of one tumor DNA sample was conducted. ARMC5 was the causative gene of two pedigrees confirmed by whole-genome sequencing (WGA) and Sanger sequencing. The variant sites of the two families were c.C943T (p.R315W) and c.C1960T (p.R654X), respectively. Autosomal dominant inheritance of AIMAH was confirmed by genotypes of one family member. Several somatic mutations were discovered in tumor DNA samples. In addition, haploid clone of tumor DNA was confirmed by germline mutation and somaticmutation, which suggested the pathogenic mechanism of "two-hit-model." ARMC5 was the causative gene of AIMAH pedigrees. This AIMAH in this study presented autosomal dominant inheritance, fitting to Mendelian inheritance law. However, the pathogenic mode of this disease showed as compound heterozygote.

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

Therapeutic analysis of unilateral adrenalectomy for Cushing syndrome in patients with adrenocorticotropic hormone independent bilateral macronodular adrenal hyperplasia

Objective To investigate the therapeutic outcomes of unilateral adrenalectomy for Cushing syndrome in patients with adrenocorticotropic hormone(ACTH) independent bilateral macronodular adrenal hyperplasia. Methods 22 patients diagnosed with Cushing syndrome caused by ACTH independent bilateral macronodular adrenal hyperplasia from January 2005 to December 2015 were retrospectively concluded. There are 17 male patients and 5 female patients with the median age of 46.5 years. All patients were presented with Cushing syndrome such as moon face, buffalo hump and other typical symptoms of Cushing syndrome. The laboratory tests showed disappearance of cortisol rhythm, elevated 24-hour urinary free cortisol, suppressed or normal ACTH and unsuppressed low dose dexamethasone suppressing test. CT scan showed bilateral macronodular adrenal hyperplasia in all patients. Results All the patients received unilateral adrenalectomy. Pathological results showed adrenal cortex nodular hyperplasia. 16 patients had reexamination in the endocrine department. The median follow-up time was 26(17-118)months for these 16 patients. In the follow-up between 3 to 9 months after surgery, laboratory test showed serum and urinary cortisol level returned to normal range and Cushing syndrome also disappeared in these 16 patients. CT scan showed no recurrence. And no adrenal insufficiency occurred.One patient had recurrence one year after surgery and two patients turned better after surgery but had recurrence at 3 years and 10 years after surgery. Two patients received contralateral adrenalectomy and cortisol hormone replacement therapy after surgery. Another patient with recurrence refused second surgery. No recurrence was observed in other patients. Four patients were followed up by telephone, and all recovered well after surgery. 18 patients had hypertension before surgery and their blood pressure significantly decreased after surgery. Among them 13 cases blood pressure returned to normal range. 5 patients had elevated blood glucose before surgery, and 3 patients′ blood glucose returned to normal range. Conclusions Unilateral adrenalectomy for Cushing syndrome in patients with ACTH independent bilateral macronodular adrenal hyperplasia is safe and effective. Key words: Macronodular adrenal hyperplasia; Cushing syndrome; Unilateral adrenalectomy

Cushing Syndrome Caused by ACTH-independent Macronodular Adrenal Hyperplasia

Adenocorticotropic hormone-independent macronodular adrenal hyperplasia (AIMAH) is a rare cause of Cushing’s syndrome. It is characterized by multinodular enlargement of the adrenal glands and hypercortisolism. Although bilateral adrenalectomy is the standard therapy, unilateral adrenalectomy is an effective alternative. Here we present a case of a 71-year-old female referred to the Endocrinology Department for further evaluation of bilateral adrenal macronodular hyperplasia. Based on dynamic hormone tests and imaging studies, she was diagnosed with AIMAH. Due to persistent hypercortisolism, she underwent completion contralateral surgery after unilateral adrenalectomy. This case demonstrates that unilateral adrenalectomy should be considered in a patient presenting with obvious symptoms of hypercotisolism and relatively asymmetric adrenal enlargement. Keywords: Acth-independent macronodular adrenal hyperplasia; Cushing syndrome; Adrenalectomy 중심 단어: 거대 ê²°ì ˆì„± ë¶€ì‹ í”¼ì§ˆ 과증식; ì¿ ì‹±ì¦í›„êµ°; ë¶€ì‹ ì ˆì œìˆ

Etiology analysis of 522 hospitalized cases with Cushing syndrome

To summarize the characteristics of the etiology distribution of Cushing syndrome (CS) patients in Chinese PLA general hospital during the past 20 years. All data of CS patients admitted to Chinese PLA General Hospital between 1995 and 2014 were collected. The sex ratio of patients, visiting age, final diagnosis were retrospectively analyzed. From January 1995 to December 2014, 522 patients with CS were admitted, of which, 134 (25.67%) were males and 388(74.33%) were females. The overall mean age was (42±13) years old. 46.36% of the cases were adrenocorticotropic hormone (ACTH) dependent, and ACTH independent CS accounted for 53.64%. At the 41-60 age group, the proportion of ACTH independent CS was higher than that of ACTH independent CS.The proportions of ACTH-independent macronodular adrenal hyperplasia (AIMAH), ectopic ACTH syndrome and adrenal cortical carcinoma were higher in male group than in female group. The number of CS patients was gradually increased during the past 20 years. The proportion of ACTH independent CS was increased (from 32.8% to 60.4%). The proportion of ACTH dependent CS was declined (from 67.2% to 39.6%). The etiology spectrum of CS has changed. There was significant gender-related, age-related difference of etiology distribution in patients with CS.

Laparoscopic Subcutaneous Transposition of a Pedicled Adrenal for ACTH-Independent Bilateral Macronodular Adrenal Hyperplasia.

Bilateral adrenalectomy or unilateral adrenalectomy and contralateral partial adrenalectomy are indicated for the treatment of ACTH-independent macronodular adrenal hyperplasia. Independent of the surgical procedure, the prognosis is poor. This article discusses a new treatment method and its efficacy for treating nodular adrenal hyperplasia. We performed a retrospective review of the medical records of 12 patients operated on between January 2008 and October 2014 at the First Affiliated Hospital of Zhengzhou University. All patients were treated by laparoscopic subcutaneous transposition of a pedicled adrenal. We performed postoperative monitoring of patients, including clinical symptoms and 24-hour levels of serum-free and urinary-free cortisol. All 12 patients were pathologically confirmed to have nodular adrenal hyperplasia and were followed for an average of 45.5 months (range 24-60 months). The clinical symptoms of all patients disappeared, and the 24-hour plasma-free cortisol and urinary-free cortisol levels were within the normal range. Laparoscopic subcutaneous transposition of a pedicled adrenal is a new and effective method for treating bilateral macronodular adrenal hyperplasia and can achieve long-term remission of Cushing's syndrome.

AB191. Laparoscopic subcutaneous transposition of a pedicled adrenal for ACTH-independent bilateral macronodular adrenal hyperplasia

ObjectiveBilateral adrenalectomy or unilateral adrenalectomy and contralateral partial adrenalectomy are indicated for the treatment of ACTH-independent macronodular adrenal hyperplasia. Independent of the surgical procedure, the prognosis is poor. This paper discusses a new treatment method and its efficacy for treating nodular adrenal hyperplasia.MethodsWe performed a retrospective review of the medical records of 12 patients operated on between January 2008 and October 2014 at the First Affiliated Hospital of Zhengzhou University. All patients were treated by laparoscopic subcutaneous transposition of a pedicled adrenal. We performed postoperative monitoring of patients including clinical symptoms and 24-hour levels of serum free and urinary free cortisol.ResultsAll twelve patients were pathologically confirmed to have nodular adrenal hyperplasia, and were followed for an average of 45.5 months (range, 24–60 months). The clinical symptoms of all patients disappeared, and the 24-hour plasma free cortisol and urinary free cortisol levels were within the normal range.ConclusionsLaparoscopic subcutaneous transposition of a pedicled adrenal is a new and effective method for treating bilateral macronodular adrenal hyperplasia, and can achieve long-term remission of Cushing’s syndrome.

Genetics of primary macronodular adrenal hyperplasia.

ACTH-independent macronodular adrenal hyperplasia is a rare cause of Cushing's syndrome (CS), accounting for <2% of all endogenous CS cases; however it is more frequently identified incidentally with sub-clinical cortisol secretion. Recently, cortisol secretion has been shown to be regulated by ectopic corticotropin, which is in turn produced by clusters of steroidogenic cells of the hyperplastic adrenal nodules. Hence, the term 'ACTH-independent' is not entirely appropriate for this disorder. Accordingly, the disease is designated primary macronodular adrenal hyperplasia (PMAH) in this review article. The means by which cortisol production is regulated in PMAH despite the suppressed levels of ACTH of pituitary origin is exceedingly complex. Several molecular events have been proposed to explain the enhanced cortisol secretion, increased cell proliferation, and nodule formation in PMAH. Nonetheless, the precise sequence of events and the molecular mechanisms underlying this condition remain unclear. The purpose of this review is therefore to present new insights on the molecular and genetic profile of PMAH pathophysiology, and to discuss the implications for disease progression.

Clinical and Hormonal Response to Mifepristone Therapy in 2 Patients with ACTH-Independent Cushing Syndrome

ABSTRACT Objective: Cushing syndrome is an endocrine disorder resulting from prolonged exposure to excess cortisol that can lead to significant morbidity and mortality. Surgery is the first-line treatment for Cushing syndrome. Mifepristone is a glucocorticoid receptor (GR) antagonist that is used in the medical treatment of Cushing syndrome. Methods: We describe the clinical and hormonal responses of 2 patients with adrenal (adrenocorticotropic hormone lACTH]-independent) Cushing syndrome who were treated with mifepristone. The first case was a 41-year-old male with Cushing syndrome secondary to primary pigmented nodular adrenocortical disease associated with Carney complex. He was treated with mifepristone prior to definitive surgical management. During medical treatment with mifepristone, he lost 44 pounds, and his Cushingoid features resolved. The second case was a 65-year-old male with Cushing syndrome secondary to ACTH-independent macronodular adrenal hyperplasia (AIMAD). Cushing syndrome persisted after unilateral adrenalectomy, but medical comorbidities precluded a second surgery. Ketoconazole failed to adequately control his symptoms, and he was treated with mifepristone. During medical treatment with mifepristone, he lost 12 pounds, and his Cushingoid features and cortisol excessrelated comorbidities improved. In both cases, ACTH was suppressed prior to treatment and rose into the normal range within 3 months of initiating pharmacologic therapy. Conclusions: Mifepristone is a GR antagonist that can be used in the medical management of cortisol excess due to ACTH-independent Cushing syndrome. Hormonal responses indicating recovery of the hypothalamus-pituitary adrenal (HPA) axis can be seen within 3 months of therapy. Abbreviations: ACTH adrenocorticotropin hormone CT computed tomography DHEAS dehydroepiandrosterone sulfate GR glucocorticoid receptors HPA hypothalamic-pituitary adrenal axis MR mineralocorticoid receptors UFC urinary free cortisol

Actualités du syndrome de Cushing d’origine surrénalienne

The development of molecular biology tools has allowed major advances in the genetic determinism and the pathophysiology of pheochromocytomas and Conn's adenomas. However, the molecular pathophysiology of ACTH-independent Cushing's Syndrome was mostly unknown until recently. In 2014, major new insights concerning the physiopathology of ACTH-independent macronodular adrenal hyperplasias (AIMAH) and the cortisol-secreting adenomas have been published. Elsewhere, the cardiovascular consequences of the subclinical hypercortisolism due to adrenal incidentalomas, was described only in some cross-sectional studies. The natural history of these lesions has been documented in two large follow-up studies. These new data presented during the Endocrine Congress are summarized herein.

Abstract 2239: Macronodular adrenal hyperplasia due to mutations in ARMC5: New mutations in humans and modeling in zebrafish

Abstract Inactivating germline mutations of the probable tumor suppressor gene Armadillo Repeat Containing 5 (ARMC5) have recently been identified (N Engl J Med. 2013;369:2105-14) as a genetic cause of ACTH-independent macronodular adrenal hyperplasia (AIMAH) . We assessed for the presence of ARMC5 mutations in a cohort of patients with AIMAH. Blood DNA from 34 AIMAH patients was genotyped using Sanger sequencing. Germline ARMC5 mutations were found in 15 out of 34 patients (44.12%). In silico analysis of the mutations indicated that 7 (20.6%) predicted major implications for gene expression. All patients carrying ARMC5 mutation, that were predicted to be pathogenic, had clinical Cushing's Syndrome (7/7, 100%) compared to 14/27 (52%) of those without or with mutations predicted as benign (p=0.029). ARMC5 mutations are implicated in clinically severe Cushing's syndrome associated with AIMAH. Knowledge of a patient's ARMC5 status and the pathway related with this gene has important clinical implications for the diagnosis of some diseases, including Cushing's syndrome and for genetic counseling of patients and their families. To further investigate the function of ARMC5 we are investigating its function using the zebrafish model. We knocked down the zebrafish ortholog, armc5, with an antisense morpholino oligonucleotide (MO). Zebrafish embryos injected with 15 pg of our armc5 MO display phenotypes at mid- through late stages of embryogenesis; these are: hyperactive spontaneous movement at 36 hours post fertilization (hpf) and irregularities in the notochord and a “curly down” body curvature at 48 hpf. Whole mount in situ hybridization (WISH) of MO-injected embryos at an earlier stage (10 hpf/ late gastrula) reveals reductions in a marker of paraxial mesoderm and a foreshortening of labeled chordamesoderm. Intriguingly, reduction of the same paraxial mesoderm marker causes cysts to form in the embryonic zebrafish kidney and several zebrafish models of polycystic kidney disease display a curly down body shape. RNA-Seq of Armc5 MO-injected embryos reveals enrichment in genes normally expressed in the musculature and liver among the cohort of upregulated genes. Based on these preliminary findings, we hypothesize that armc5 acts to repress one or more components involved in the differentiation of muscle and liver and possibly formation of embryonic kidney cysts. Ongoing studies will examine embryonic kidney cyst incidence in armc5 MO-injected embryos and validate selected RNA-seq findings by WISH and by assessment of the armc5 overexpression phenotype in zebrafish. Citation Format: Fabio R. Faucz, Mihail Zilbermint, Guillaume Assié, Maya B. Lodish, Eva Szarek, Giampaolo Trivellin, Annabel Berthon, Ninet Sinaii, Rossella Libé, Stéphanie Espiard, Ludivine Drougat, Bruno Ragazzon, Benjamin Feldman, Jerome Bertherat, Constantine A. Stratakis. Macronodular adrenal hyperplasia due to mutations in ARMC5: New mutations in humans and modeling in zebrafish. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2239. doi:10.1158/1538-7445.AM2014-2239

Primary bilateral macronodular adrenal hyperplasia.

Primary bilateral macronodular adrenal hyperplasia is a rare cause of Cushing's syndrome and is more often diagnosed as bilateral adrenal incidentalomas with subclinical cortisol production. We summarize the recent insights concerning its epidemiology, diagnosis, genetics, pathophysiology, and therapeutic options. Recent publications have modified our notions on the genetics and pathophysiology of bilateral macronodular adrenal hyperplasia. Combined germline and somatic mutations of armadillo repeat containing 5 gene were identified in familial cases, in approximately 50% of apparently sporadic cases and in the relatives of index cases; genetic testing should allow early diagnosis in the near future. The recent finding of ectopic adrenocortical production of adrenocorticotropic hormone in clusters of bilateral macronodular adrenal hyperplasia tissues and its regulation by aberrant hormone receptors opens new horizons for eventual medical therapy using melanocortin-2 receptor and G-protein-coupled receptor antagonists. Finally, some medical and surgical treatments have been updated. Recent findings indicate that bilateral macronodular adrenal hyperplasia is more frequently genetically determined than previously believed. Considering the role of paracrine adrenocorticotropic hormone production on cortisol secretion, the previous nomenclature of adrenocorticotropic hormone-independent macronodular adrenal hyperplasia appears inappropriate, and this disease should now be named primary bilateral macronodular adrenal hyperplasia.

In Silico Analyses Reveals Nuclear Asymmetry of Spongiocytes and Compact Cells of Adrenocorticotrophic Hormone-Independent Macronodular Adrenocortical Hyperplasia

BackgroundLittle information is available about the risk of progression of seemingly benign adrenocortical hyperplasias to carcinomatous conditions. Using in silico approaches of digitally archived tissue sections, the nuclear morphometric parameters were compared to assess nuclear asymmetry as an index for nuclear atypia. MethodsFour groups of nuclei were used for the current study: spongiocytes and compact cells obtained from adrenocorticotropic hormone (ACTH)-independent macronodular hyperplasia, which were hypothesized to be high risk for nuclear asymmetry, and primary pigmented nodular adrenocortical disease and micronodular adrenocortical hyperplasia samples were used as internal controls. ResultsAnalyses reveal high nuclear irregularity index of spongiocytes and shape factor abnormalities of both spongiocytes and compact cells of ACTH-independent macronodular adrenal hyperplasia compared with the other 2 groups (high F values and very low P values after analyses of variances), thus confirming the hypothesis that ACTH-independent macronodular adrenal hyperplasia present with subtle morphometric features of nuclear atypia. ConclusionsThis probably puts this class of adrenocortical tumors at risk of dysplastic progression, and more studies are needed to test the hypothesis.

Clinical characteristics of adrenocorticotropic hormone independent macronodular adrenal hyperplasia: a report of 30 cases

To explore the clinical characteristics of adrenocorticotropic hormone (ACTH) independent macronodular adrenal hyperplasia (AIMAH). A total of 30 AIMAH patients from January 2001 to December 2011 at our hospital were reviewed retrospectively and their clinical data collected. AIMAH was equally distributed between genders. Their mean age was 44 ± 9 years and median course of disease 5 years. Hypertension was the most common clinical manifestation. Circadian rhythm of plasma cortisol disappeared in all patients, and the level of 24 hour urinary free cortisol (24 hUFC) was normal only in 4 (13.3%) patients. Both low and high dose dexamethasone suppression tests were not suppressed in 30 (100.0%) and 28 (93.3%) patients respectively. The stimulation tests for detecting aberrant expression of hormone receptors were performed in 14 patients. At least one aberrant cortisol response was identified in 12 patients. Twenty-five patients underwent adrenalectomy. Among 7 patients of bilateral adrenalectomy, 6 achieved remission while 8 patients did so among 14 patients of unilateral adrenalectomy. AIMAH should be considered in patients with massively enlarged bilateral adrenal glands. Treatment modalities should be decided according to clinical manifestations and cortisol level so as to relieve symptoms and improve prognosis.