ACTH-independent Macronodular Adrenocortical Hyperplasia Research Articles

A Case of ACTH Independent Macronodular Adrenocortical Hyperplasia Presenting with Conns Syndrome

Backgound: ACTH Independent macronodular adrenocortical hyperplasia (AIMAH)is a rare cause of hyperaldosteronism and is characterised by bilateral adrenal hyperplasia . One of the most common presenting symptoms is refractory hypertension. Clinical features and hypertension usually resolve following adrenalectomy. Timely diagnosis of such conditions are pertinent as they are completely treatable and thus prevents further comorbidities associated with hypertension and hypokalemia like arrhythmia.
 Case Presentation: A 57 year old male patient presented with unresolved hypertension since 15 years even after treatment with three different antihypertensives drugs since last one year. He was detected with raised serum aldosterone levels. Adrenal venous sampling showed lateralisation to the left adrenal. CT abdomen and pelvis revealed enlarged and nodular left adrenal gland and a bulky right adrenal gland. Laparoscopic left adrenalectomy was performed. Grossly left adrenal showed multiple well circumscribed yellow coloured nodules restricted to the cortex. Microscopy showed multiple well circumscribed unencapsulated nodules comprising of compact cells with clear to vacuolated cytoplasm and round central nucleus along with few foci of myelometaplasia.
 Conclusion: Conns syndrome causes a high rate of mortality and morbidity of left untreated. Serum aldosterone, serum cortisol and serum electrolyte levels should be carried out in every case of refractory hypertension to rule out adrenocortical lesions. Timely diagnosis goes a long way in reducing morbidities associated with hypertension and dyselectrolytemia.

ACTH-independent macronodular adrenocortical hyperplasia reveals prevalent aberrant in vivo and in vitro responses to hormonal stimuli and coupling of arginine-vasopressin type 1a receptor to 11β-hydroxylase

BackgroundAdrenal Cushing’s syndrome caused by ACTH-independent macronodular adrenocortical hyperplasia (AIMAH) can be accompanied by aberrant responses to hormonal stimuli. We investigated the prevalence of adrenocortical reactions to these stimuli in a large cohort of AIMAH patients, both in vivo and in vitro.MethodsIn vivo cortisol responses to hormonal stimuli were studied in 35 patients with ACTH-independent bilateral adrenal enlargement and (sub-)clinical hypercortisolism. In vitro, the effects of these stimuli on cortisol secretion and steroidogenic enzyme mRNA expression were evaluated in cultured AIMAH and other adrenocortical cells. Arginine-vasopressin (AVP) receptor mRNA levels were determined in the adrenal tissues.ResultsPositive serum cortisol responses to stimuli were detected in 27/35 AIMAH patients tested, with multiple responses within individual patients occurring for up to four stimuli. AVP and metoclopramide were the most prevalent hormonal stimuli triggering positive responses in vivo. Catecholamines induced short-term cortisol production more often in AIMAH cultures compared to other adrenal cells. Short- and long-term incubation with AVP increased cortisol secretion in cultures of AIMAH cells. AVP also increased steroidogenic enzyme mRNA expression, among which an aberrant induction of CYP11B1. AVP type 1a receptor was the only AVPR expressed and levels were high in the AIMAH tissues. AVPR1A expression was related to the AVP-induced stimulation of CYP11B1.ConclusionsMultiple hormonal signals can simultaneously induce hypercortisolism in AIMAH. AVP is the most prevalent eutopic signal and expression of its type 1a receptor was aberrantly linked to CYP11B1 expression.

Improvement of hypercortisolism by β-blocker therapy in subclinical Cushing’s syndrome associated with ACTH-independent macronodular adrenocortical hyperplasia

A 61-year-old man with hypertension and diabetes was referred for the evaluation of multiple bilateral adrenal tumors. While Cushingoid features were not apparent, an elevated cortisol level in response to a low-dose dexamethasone suppression test (187.7nmol/l), an elevated urinary cortisol level (170.9nmol/day), and a weak response to a cosyntropin-releasing hormone (CRH) provocation test were observed. Furthermore, the serum cortisol level increased in response to a posture test or isoproterenol infusion. Accordingly, the patient was diagnosed as having ACTH-independent macronodular adrenal hyperplasia (AIMAH) with subclinical Cushing's syndrome associated with the aberrant expression of β-adrenergic receptors. After 2months of propranolol therapy, the serum cortisol responses to a posture test and isoproterenol infusion, the cortisol level in response to a low-dose dexamethasone suppression test (102.1nmol/l), and the urinary cortisol level (165.9nmol/day) all normalized. While the suppression of cortisol secretion was sustained for 24months, glucose metabolism and adrenal size were unaffected. To our knowledge, this is the first report of AIMAH accompanied by subclinical Cushing's syndrome associated with the aberrant expression of β-adrenergic receptors. Furthermore, propranolol inhibited cortisol hypersecretion in the present case. Additional cases or controlled studies are needed to determine the potential effect of propranolol on metabolic disorders and adrenal size in patients with AIMAH.

Cushing's disease

Cushing's syndrome refers to the clinical manifestations induced by chronic exposure to excess glucocorticoids. There are three pathological conditions that can result in the chronic overproduction of endogenous cortisol in man: the most frequent is Cushing's disease where adrenocorticotropic hormone (ACTH) is overproduced by a pituitary corticotroph adenoma, rarely ACTH can be produced in an 'ectopic' manner by a non-pituitary tumour, finally cortisol can be directly over-secreted by one or (rarely) the two adrenals that have become tumourous, either benign or malignant. The positive diagnosis of Cushing's syndrome requires that chronic hypercortisolism is unequivocally demonstrated biologically, using 24-h urinary cortisol, late-evening plasma or salivary cortisol, midnight 1-mg or the classic 48-h-low-dose dexamethasone suppression test, etc., all with essentially the same diagnosis potencies. The search for the responsible tumour then relies on the assessment of the corticotroph function, and imaging: suppressed ACTH plasma levels indicate an 'adrenal' Cushing, and the responsible unilateral adrenocortical tumour is always visible at computed tomography (CT) scan, whereas its benign or malignant nature may be difficult to diagnose before surgery. Imaging can suspect bilateral 'adrenal' Cushing, when the two adrenals are small, as in the primary pigmented nodular adrenal dysplasia associated with Carney complex, or enlarged, as in the ACTH-independent macronodular adrenocortical hyperplasia. Measurable or increased ACTH plasma levels indicate either Cushing's disease or the ectopic ACTH syndrome. When the dynamics of the corticotroph function (high-dose dexamethasone suppression test, the CRH test) are equivocal, and/or the imaging is non-contributive, it may be difficult to distinguish between the two. This is the situation where sampling ACTH plasma levels in the inferior petrosal sinus may be necessary. The best treatment option of Cushing's disease is when the responsible corticotroph adenoma can be entirely removed by the trans-sphenoidal approach, with sufficient skill to preserve the normal anterior pituitary function. When it fails, all other options directed towards the pituitary (radiation therapies), or the adrenals (medications or surgery), have numerous side effects. There is at present no recognised efficient medical treatment towards the corticotroph adenoma -still an orphan disease.

Phosphodiesterase 11A (PDE11A) and Genetic Predisposition to Adrenocortical Tumors

We have reported previously nonsense inactivating mutations of the phosphodiesterase 11A (PDE11A) gene in patients with micronodular adrenocortical hyperplasia and Cushing syndrome. The aim of this study is to investigate the presence of somatic or germ-line PDE11A mutations in various types of adrenocortical tumors: ACTH-independent macronodular adrenocortical hyperplasia (AIMAH), adrenocortical adenoma (ACA), and adrenocortical cancer (ACC). PDE11A was sequenced in 117 adrenocortical tumors and 192 controls subjects; immunohistochemistry for PDE11A and tumor cyclic AMP levels were studied in a subgroup of adrenocortical tumors. One PDE11A inactivating mutation (R307X) was found in one ACA, 22 germ-line missense variants (18.8%) were found in adrenocortical tumors, and only 11 missense variants (5.7%) were found in controls. By comparing the common mutations, a higher frequency of mutations in adrenocortical tumors than in age/sex-matched controls were observed [16% versus 10% in ACC, 19% versus 10% in ACA, and 24% versus 9% in AIMAH; odds ratio (OR), 3.53; P = 0.05]. Somatic DNA from adrenocortical tumors with missense variants showed a wild-type allelic loss. A significant difference between ACC and controls was observed for a polymorphism in exon 6 (E421E; OR, 2.1; P = 0.03) and three associated polymorphisms located in intron 10-exon 11-intron 11 (OR, 0.5; P = 0.01). In AIMAH/ACA, cyclic AMP levels were higher than in normal adrenals and decreased PDE11A immunostaining was present in adrenocortical tumors with PDE11A variants. The present investigation of a large cohort of adrenocortical tumors suggests that PDE11A sequence defects predispose to a variety of lesions (beyond micronodular adrenocortical hyperplasia) and may contribute to the development of these tumors in the general population.

Familial adrenocorticotropin-independent macronodular adrenal hyperplasia with aberrant serotonin and vasopressin adrenal receptors

ACTH-independent macronodular adrenocortical hyperplasia (AIMAH) is rare and generally presents as a sporadic disease. We describe a familial case of AIMAH with in vivo and in vitro demonstration of aberrant 5-HT4 and vasopressin adrenal receptors. Two sisters presented with clinical and biological features of mild Cushing's syndrome with bilateral macronodular adrenal enlargement on computerized tomography (CT)-scan evaluation. In vivo pharmacological tests showed a significant increase in plasma cortisol after terlipressin and metoclopramide administration. Unilateral adrenalectomy was performed in one of these patients. Reverse transcriptase-PCR analysis of the hyperplastic tissue revealed expression of 5-HT4 receptor isoforms (a), (b), (c), (i), and (n), and of vasopressin receptors, V1 and V2. Their father and brother were overweight, had easy bruisability and presented with biological features of subclinical Cushing's syndrome. CT scan showed moderate adrenal enlargement. In vivo pharmacological screening tests for the detection of adrenal aberrant receptors in the brother were negative. Finally, three out of the two sisters' children were evaluated. They had neither clinical nor biological features of Cushing's syndrome. Their adrenal glands were normal on CT-scan evaluation. In vivo evaluation for the detection of aberrant adrenocortical receptors performed in one of these subjects was negative. In conclusion, this study shows that (i) familial AIMAH could be an autosomal dominantly inherited disorder; (ii) aberrant 5-HT4 serotonin and vasopressin receptors can be expressed in familial AIMAH; and (iii) phenotypic expression of familial AIMAH could be varied in a same family and more pronounced in female than in male patients.

Vasopressin responsiveness of subclinical Cushing's syndrome due to ACTH-independent macronodular adrenocortical hyperplasia.

Vasopressin (AVP) is reported to be an important factor for regulating cortisol secretion in patients with Cushing's syndrome due to ACTH-independent macronodular adrenocortical hyperplasia (AIMAH). Recently, there have been several case reports of subclinical Cushing's syndrome due to AIMAH, in which the pathophysiological role of AVP has been unknown. The aim was to conduct an extensive investigation of AVP in the autonomous secretion of cortisol in subclinical Cushing's syndrome due to AIMAH. Five cases of AIMAH with subclinical Cushing's syndrome underwent prospective study including physical examination, imaging (MRI, CT and 131I-adosterol scintigraphy) and endocrinological evaluation that comprised basal plasma cortisol levels and urinary excretions of steroid metabolites, a dexamethasone suppression test and an AVP stimulation test. In case 1, left adrenalectomy was performed and the pathological diagnosis of AIMAH was established. An in vitro experiment using the cultured AIMAH adrenal cells was conducted to investigate cortisol secretion and expression of the V1-AVP receptor, mRNA by RT-PCR. All five cases were discovered incidentally to have bilateral adrenal nodules. Imaging by MRI and CT revealed large multinodular lesions in both adrenal glands, which showed positive uptake on 131I-adosterol scintigraphy. Although the basal values of plasma cortisol and urinary excretions of steroid metabolites were within normal limits, autonomous secretion of cortisol was assumed to occur because of lack of suppression during dexamethasone suppression. The five patients had no overt signs of Cushing's syndrome, and they were therefore diagnosed with subclinical Cushing's syndrome due to AIMAH. In all five patients, AVP stimulated cortisol secretion in vivo, whereas desmopressin acetate failed to affect cortisol secretion. In case 1, AVP stimulated cortisol secretion from cultured AIMAH adrenal cells, but this secretion had no relationship with cAMP production. In addition, over-expression of V1-AVP receptor mRNA in AIMAH tissue was determined by RT-PCR. Patients with subclinical Cushing's syndrome due to AIMAH commonly exhibit cortisol responsiveness to AVP, and this is probably mediated through activation of overexpressed V1-AVP receptors.

Eutopic overexpression of vasopressin v1a receptor in adrenocorticotropin-independent macronodular adrenal hyperplasia.

Arginine vasopressin (AVP) stimulates cortisol secretion through its vascular type V(1a) receptor in the adrenal glands, in addition to stimulating ACTH secretion through pituitary V(3) receptor. Because hyper-response of plasma cortisol to vasopressin is documented in some patients with Cushing's syndrome due to adrenal adenoma (CS) or ACTH-independent macronodular adrenocortical hyperplasia (AIMAH), we analyzed the expression of V(1a), V(2), V(3) receptor and AVP mRNA in human adrenal tissues by quantitative competitive RT-PCR or real-time PCRs. V(1a) receptor mRNA levels (ratio against glyceraldehyde 3-phosphate dehydrogenase) were 0.378 +/- 0.143 (mean +/- SE) in preclinical CS (n = 5) and 0.630 +/- 0.072 in AIMAH (n = 4), which were significantly higher than those (0.046 +/- 0.012; n = 9) in control adrenals, whereas those in overt CS (0.143 +/- 0.048; n = 10) or aldosterone-producing adenomas (0.069 +/- 0.018; n = 12) were similar to control adrenals. Although ectopic expression of V(2) or V(3) receptor was detected in half of AIMAH cases, the absolute levels were low. Furthermore, V(1a) receptor mRNA levels in the adjacent adrenal glands (0.190 +/- 0.039, n = 9) of aldosterone-producing adenomas were higher than those in control adrenals and in the corresponding tumor portions (0.079 +/- 0.024). In contrast, there were no significant differences in AVP mRNA levels among these groups. These results suggest that eutopic V(1a) receptor overexpression is involved in the etiology of AIMAH and a subset of adrenal adenomas causing overt or preclinical Cushing's syndrome. Our results imply a possible association of V(1a) receptor expression with adrenal hyperplasia.

Section 3. Adrenal: Laparoscopic bilateral adrenalectomy for Cushing’s syndrome due to ACTH-independent macronodular adrenocortical hyperplasia

We performed simultaneous bilateral laparoscopic total adrenalectomy in two patients with Cushing’s syndrome due to ACTH-independent macronodular adrenocortical hyperplasia (AIMAH). Preoperative serum cortisol in the patients was 29.5 and 53.2 μg/dl, respectively. The clinical symptoms of the latter patient were advanced, and respiration was labored with orthopnea. Laparoscopic adrenalectomies were performed transabdominally in the sequential lateral decubitus positions with extension of the lateral abdominal wall of the affected side. Three 12-mm and three 5-mm trocars were positioned, and two trocar sites in the midline were used on both sides. The flexible fiberscope was inserted through the umbilical port. The adrenal glands were large, fragile, and multinodular. The maximal diameters of the removed glands were 7.8 and 8.7 cm, respectively. In both patients, the adrenal glands were successfully removed without fragmentation. The operation times were 505 and 320 min, and the estimated blood loss was 150 and 5 ml, respectively. Neither intraoperative nor postoperative complications occurred, although the latter patient required muscle training before ambulation on postoperative day 42. The procedures resulted in marked clinical improvements. Compliance with the substitutive therapy remained excellent, and the patients expressed a very high degree of satisfaction with the laparoscopic adrenal surgery. The procedures of bilateral laparoscopic adrenalectomy were successful, and provided increased experience with the laparoscopic techniques.

Adrenocorticotropin-independent macronodular adrenal hyperplasia: an uncommon cause of primary adrenal hypercortisolism.

To describe the imaging findings in the adrenal glands of 12 patients with adrenocorticotropin (ACTH)-independent macronodular adrenocortical hyperplasia (AIMAH). Computed tomographic (CT) and magnetic resonance (MR) imaging findings in the adrenal glands were reviewed retrospectively in 12 patients (three men, nine women) with ACTH-independent Cushing syndrome and with bilateral nonpigmented multinodular adrenal hyperplasia. The results of pituitary MR imaging, adrenal scintigraphy, and petrosal sampling were available in nine, five, and six patients, respectively. Eleven patients underwent bilateral and one patient underwent unilateral adrenalectomy. Eleven patients had enlarged multinodular adrenal glands: Nodules were 0.1-5.5 cm. The combined weight of both adrenal specimens for the 11 bilateral adrenalectomy specimens was 28-297 g, with a mean weight of 122 g. Glands were hypointense compared with the liver on T1-weighted images and were hyperintense on T2-weighted images. Pituitary MR imaging findings were negative in nine of nine patients. Iodomethylnorcholesterol scintigraphy showed bilateral uptake in four of five patients. Petrosal sinus sampling revealed no petrosal-to-peripheral ACTH gradients before corticotropin-releasing hormone (CRH) stimulation in six of six patients, but three patients had gradients after CRH stimulation. After undergoing bilateral or unilateral adrenalectomy, all patients were cured. AIMAH is a rare cause of ACTH-independent Cushing syndrome, with characteristic CT findings of massively enlarged multinodular adrenal glands. Bilateral adrenalectomy is indicated on the basis of clinical and CT findings.