Bilateral Hyperplasia Research Articles

Prophylactic thyroidectomy for MEN 2-related medullary thyroid carcinoma based on predictive testing for RET proto-oncogene mutation and basal serum calcitonin in China

Early and normative surgery is the only curative method for multiple endocrine neoplasia type 2 (MEN 2)-related medullary thyroid carcinoma (MTC). To study the timing of prophylactic total thyroidectomy (TT) for MEN 2-related MTC with different RET mutations in a Chinese population, and to compare the sensitivity and accuracy of fully-automated chemiluminescence immunoassay (FACLIA) and radioimmunoassay (RIA) for serum calcitonin (Ct). We collected 24 asymptomatic individuals from 8 unrelated Chinese families with MEN 2, and analyzed RET mutation and Ct levels. Then we performed TT on 17 of the 24 individuals, including TT (2/17), TT with bilateral level VI lymph-node dissection (B-LND(VI); 12/17) and TT with B-LND(VI)+modified unilateral/bilateral/local neck dissection (3/17). Histopathology revealed bilateral/unilateral MTC in 15/17 (88.2%; median diameter, 1.0cm) and bilateral C-cell hyperplasia in 2/17 (11.8%; p.V292M/R67H/R982C and p.C618Y). Lymph-node metastasis/fibro-adipose tissue invasion (p.C634R) or solely fibro-adipose tissue invasion (p.C634Y) were found in 2/17 (11.8%). Elevated pre-surgical Ct (pre-Ct) was identified by FACLIA in 17/17 (median age, 24.0), while pre-Ct by RIA was found in only 6/15 (P<0.001). The median follow-up was 22.0 months, during which 16/17 had no abnormality (one p.C634R individual had elevated Ct), and another 7 carriers still had consistently undetectable Ct by FACLIA. Our study highlights the importance and feasibility of individualized prophylactic TT for MEN 2-related MTC, based on predictive integrated screening of RET and pre-Ct levels. Besides, we recommend FACLIA to measure Ct for earlier diagnosis, treatment and follow-up monitoring of MTC.

Whole exome sequencing identifies mutation of EDNRA involved in ACTH-independent macronodular adrenal hyperplasia

ACTH independent macronodular adrenal hyperplasia (AIMAH) is a rare disorder characterized by bilateral macronodular hyperplasia of the adrenal glands and increased cortisol production with subclinical or overt Cushing's syndrome. Although the family clustering of AIMAH is infrequent, we have tried our best to find such a familial affected pedigree with complete clinical information and successfully collect adrenalectomy tissue samples from two members of this family. Using whole exome sequencing and several variant prioritization strategies based on disease network analysis, we identified Endothelin receptor type A (EDNRA) Ser420Thr mutation as a causative mutation of AIMAH. EDNRA is a member of G protein coupled receptor family and is involved in cardiovascular or polycystic kidney disease. Our findings indicate that the mutation of EDNRA at S420T site should be regard as a potential AIMAH causative variation in familial and sporadic affected patients.

The Role of Unilateral Adrenalectomy in Corticotropin‐Independent Bilateral Adrenocortical Hyperplasias

The objective of the present study was twofold: to demonstrate our experience with unilateral adrenalectomy in the treatment of adrenocorticotropic hormone (ACTH)-independent Cushing syndrome (CS) caused by bilateral adrenocortical hyperplasias, and to evaluate the long-term results as evidenced by the main laboratory and clinical findings. From February 2000 to August 2009, unilateral adrenalectomy was performed on 27 patients with ACTH-independent CS and bilateral adrenocortical hyperplasias, including 14 patients with ACTH-independent macronodular adrenal hyperplasia (AIMAH) and 13 patients with primary pigmented nodular adrenocortical disease (PPNAD). Signs and symptoms of CS, endocrine examinations, and radiographic imaging were evaluated preoperatively and postoperatively. At a median follow-up of 69 months (range: 23-120 months) for AIMAH and 47 months (range: 16-113 months) for PPNAD, 25 patients were cured by unilateral adrenalectomy. Serum cortisol level, daily urinary free cortisol (UFC), and plasma ACTH regained the normal range in both AIMAH and PPNAD patients at monthly follow-up visits; the circadian serum cortisol rhythm returned to normal, and a normal responsiveness to overnight low-dose dexamethasone administration (LDDST) became obvious. Both systolic and diastolic blood pressure (BP) levels were significantly reduced: 85 % of patients recovered normal BP levels, and the remaining patients need antihypertensive drugs, but at a reduced dose. No surgery-related morbidity occurred, and there was no sign of further enlargement of the residual adrenal gland after successful unilateral adrenalectomy. One patient with PPNAD and another patient with AIMAH with similar weights and sizes of the bilateral adrenals needed contralateral adrenalectomy. Unilateral adrenalectomy may be the suitable treatment for selected patients with AIMAH and PPNAD. It can achieve long-term remission of CS and improve glycemic control and BP values.

Serum dehydroepiandrosterone sulfate concentration is lower in women with primary aldosteronism

The objective of this article is to measure serum dehydroepiandrosterone sulfate (DHEA-S) concentration in both genders with primary aldosteronism (PA). The study enrolled 78 subjects with normal controls, 46 subjects with essential hypertension and 85 subjects with PA from October 2007 to June 2011. Subjects with PA were divided into three subtype groups: aldosterone-producing adenoma (APA), bilateral idiopathic hyperplasia (IHA) and PA with negative imaging findings. Women with PA (n = 49) had lower serum DHEA-S levels compared with normal controls and subjects with essential hypertension (p < 0.01). In subtype analysis, only female APAs had lower serum DHEA-S levels (p < 0.01 compared with normal controls, p < 0.01 compared with subjects with essential hypertension). In APA, a significant correlation between tumor size and serum DHEA-S was found in women (p < 0.01). Our data suggested that serum DHEA-S levels are lower in women with PA. In subtype groups, only women with APA had lower serum DHEA-S. There was no significant difference between subjects with bilateral essential hyperplasia, PA with negative imaging findings, normal controls and subjects with essential hypertension in both genders. The serum DHEA-S level is negatively correlated with the size of APA.

Immunohistochemistry improves histopathologic diagnosis in primary aldosteronism

BackgroundIn primary aldosteronism (PA) the main source of aldosterone hypersecretion is an aldosterone-producing adenoma (APA) or a bilateral hyperplasia. Histopathology of the adrenal gland from patients with PA has been...

Primary Hyperaldosteronism: Pitfalls in the Diagnosis and a not so Peculiar Evolution - Case Report

Primar y hyperaldosteronism is now assumed to account for 10-15% of all cases of non selected high blood pressure. The differential diagnosis between bilateral hyperplasia and unilateral adenoma remains however a medical challenge, and the pathogenic stimulus for hyperplasia is still unknown. HS, a female patient aged 32, presented with High Blood Pressure and hypokalemia. An elevated aldosterone/renin ratio and non-suppressed aldosterone levels after saline infusion confirmed the diagnosis of primary hyperaldosteronism. Negative adrenal scintigraphic examination and a marked aldosterone response in the postural test supported the diagnosis of bilateral hyperplasia, despite the presence of left adrenal nodule in the CT-scan. Tetracosactide stimulation revealed a minor 21-hydroxilase defect and a marked ACTH-dependence of aldosterone secretion. Effective treatment with dexamethasone 1.0 mg every other night was maintained for 9 years, while in the meantime the left adrenal nodule apparently resolved and a right adrenal nodule become apparent. Finally worsening of blood pressure levels and increasing aldosterone concentrations with a positive scintigraphic labelling on the right adrenal gland led to right adrenalectomy that was so far curative. This case report demonstrates bilateral hyperplasia-adenoma evolution and suggests ACTH to be the relevant pathogenic stimulus, allowing for effective long-term treatment with dexamethasone. doi: http://dx.doi.org/10.4021/jem113w

Optimización del uso de las imágenes en la patología suprarrenal (parte 1)

Objectives of trainingThe aim of this study is to propose an algorithm for the evaluation of adrenal lesions in order to arrive at the correct diagnosis in the shortest possible time.This method would favor the most appropriate therapeutic procedures for each pathology and may substantially modified a given treatment. In spite of the fact that the structural features of lesions are generally non-specific, it is possible with imaging techniques, to establish compatible features which could help us differentiate benign from malignant lesions and with the contribution of the endocrinologist and the laboratory, to distinguish functional from non-functional ones. Topic revisionA retrospective evaluation was carried out from May 2009 to December 2011 on 157 patients with adrenal diseases, including 95 females and 61 males, from 33 to 78 years of age (mean age 55). The study protocol consisted of non-contrasted intravenous computed tomography, with lesion density measurement, followed by contrasted intravenous computed tomography and wash out time with lesion density determination in portal time and later at 15’ during wash out.Measurements and calculations were: adrenal lesion size, medium density and absolute and relative washing percentiles. Magnetic resonance and 18F-fluorodesoxyglucose positron emission tomography was only performed on those patients who required these techniques. A comparison of the present results with those in the literature is included. Imaging findingsFifty-nine patients with non-functional adenoma were identified (49 unilateral and 10 bilateral), 29 functional adenomas, 9 with bilateral hyperplasia, 4 myelolipomas (2 in a female patient with simple virilizing congenital adrenal hyperplasia), 2 cysts, 2 hematomas, 3 lymphomas (2 secondary and 1 primary bilateral), 30 metastases, 5 adrenocortical carcinomas, 12 pheochromocytomas,1 malignant pheochromocytoma, and 1 ganglioneuroma. ConclusionThe use of an appropriate study algorithm, with proper diagnostic tools, allows the correct characterization of adrenal lesions. Moreover, this approach prevents loss of time, a wrong diagnosis, excessive irradiation of the patient, and incorrect use of resources.

Familial primary pigmented nodular adrenocortical disease without Carney complex (CNC): A case report and review of literature

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of familial Cushing's syndrome. It is characterized by bilateral adrenocortical hyperplasia with small to normal-sized adrenal glands containing multiple small adrenal cortical pigmented nodules [1,2]. PPNAD may occur in an isolated form or as familial PPNAD. Familial cases of PPNAD are usually associated with Carney complex in which Cushing’s syndrome is the most common endocrine manifestation [3]. Familial cases of PPNAD without associated Carney complex are very rare. Only a few cases of familial isolated PPNAD have been reported in the literature, mostly in females [4]. Isolated familial PPNAD has got a better prognosis than familial PPNAD associated with Carney Complex. This observation has important consequences for clinical management, follow-up and genetic counselling of such patients. Familial cases of PPNAD are rare and mostly present in females with associated Carney complex. We herein report a case of familial Cushing’s syndrome in male siblings due to PPNAD without associated Carney complex.

Trial use of mandibular exercise device developed by Yamagata University for opening exercise after coronoidectomy for bilateral coronoid hyperplasia: a case report

Trial use of mandibular exercise device developed by Yamagata University for opening exercise after coronoidectomy for bilateral coronoid hyperplasia: a case report

Primärer Hyperaldosteronismus bei Katzen

Primary hyperaldosteronism is a clinical syndrome characterized by an elevated aldosterone secretion by the adrenals. The present case series describes 7 cats with primary hyperaldosteronism, which were presented between 2002 and 2011. Common clinical symptoms were weakness, anorexia, cervical ventroflexion and blindness. All cats showed hypokalemia. In 6 cats, blood pressure was determined: 5 cats showed hypertension, of which 4 animals exhibited retinal detachment and blindness. In the ultrasonographic examination, unilateral adrenomegaly was present in 6 cats whereas one animal showed normal adrenals. In 4 cats, the serum aldosterone concentration was above the reference range. Five cats underwent unilateral adrenalectomy, which was accomplished uneventfully and returned the electrolytes back to normal. Histopathological examination of the adrenals revealed 2 carcinomas and 4 adenomas; one cat with ultrasonographic normal adrenals exhibited bilateral nodular hyperplasia.

Myocardial Ultrasound Tissue Characterization of Patients With Primary Aldosteronism

Primary aldosteronism (PA), an underdiagnosed cause of hypertension, is associated with more significant cardiac remodeling and myocardial fibrosis than is essential hypertension (EH). The aim of this study was to validate myocardial fibrosis and to evaluate factors associated with the degree of myocardial fibrosis in patients with PA. We prospectively analyzed 62 patients with PA (including 46 patients with aldosterone-producing adenoma and 16 with bilateral hyperplasia) between October 2006 and October 2010, and we enrolled 17 patients with EH as the control group. Echocardiography, including ultrasonic tissue characterization using cyclic variation of integrated backscatter (CVIBS), was performed in individuals in both groups. Among patients with PA, the diastolic blood pressures and plasma aldosterone concentrations were significantly higher than those of patients with EH. Moreover, the serum potassium levels and the plasma renin activities were significantly lower in patients with EH. As observed by echocardiography, patients with PA had greater interventricular septal thickness, greater left ventricular posterior wall thickness, and higher left ventricular mass indexes than did patients with EH. Patients with PA had significantly lower CVIBS values than patients with EH (7.1 ± 2.2 vs. 8.7 ± 1.5 dB; p = .005). In a correlation study that corrected for various clinical parameters, only log-transformed plasma renin activity values correlated significantly with CVIBS values. Ultrasonic tissue characterization with CVIBS is a useful tool for determining the extent of myocardial fibrosis. Patients with PA exhibit a more severe degree of myocardial fibrosis, as detected by CVIBS, than do patients with EH. Moreover, the severity of fibrosis, as detected by CVIBS, correlates with log-transformed plasma renin activity values.

Primärer Hyperaldosteronismus – Diagnostik und Therapie

Primary hyperaldosteronism (PHA) is characterized by an increased Aldosterone synthesis which is independent of the Renin-Angiotensin-Aldosterone-System (RAAS). The prevalence of PHA in patients who present in specialized hypertension centers is approx. 10 %. Besides patients with the classical symptoms known as "Conn-Trias" (hypertension, hypokalemia, metabolic alkalosis), the more frequent normokalemic patients with PHA also show a worse outcome compared to patients with essential hypertension. Identifying these patients is an important task in the evaluation of hypertension since targeted treatment options are available. Screening for PHA using the Aldosterone-Renin-Ratio (ARR) should be performed in patients with hypokalemic, severe or resistant hypertension. In addition, young patients with early onset of severe hypertension and/or positive family history should be screened. A positive screening result should be followed by a confirmatory test. The saline infusion test is the preferred clinical test for confirming a suspected PHA since it is accessible and time efficient. Other confirmatory tests are not used on a regular basis. After any confirmatory test, CT- or MRI-imaging and adrenal vein sampling (AVS) is used in order to differentiate between a unilateral adenoma, a bilateral hyperplasia or another cause of PHA. CT or MRI usually cannot discriminate smaller tumors form hyperplasia. Therefore AVS is used to detect lateralization of autonomous aldosterone production. Lateralization of aldosterone production indicates a unilateral adenoma. In these cases, laparoscopic adrenalectomy is the therapeutic option of choice with a hypertension cure rate of up to 60 %. If no lateralization is detectable, bilateral hyperplasia as the underlying cause of PHA is likely. Pharmacological inhibition of the mineralocorticoid receptor is the preferred treatment option in these cases. If Spironolactone is not well tolerated, Eplerenone and potassium-sparing diuretics should be prescribed. Often, however, in order to fully control hypertension, additional antihypertensive therapy is necessary.

Results of unilateral adrenalectomy in subclinical Cushing's syndrome due to adrenocorticotropic hormone‐independent macronodular adrenal hyperplasia

Adrenocorticotropic hormone (ACTH)‐independent bilateral adrenocortical macronodular adrenocortical hyperplasia (AIMAH) is a rare cause of Cushing's syndrome (CS). Traditionally, bilateral adrenalectomy with subsequent lifetime steroid replacement has been considered to be the treatment of choice. In the present study, we evaluated the long‐term results of unilateral adrenalectomy in subclinical CS (SCS) due to AIMAH, with regard to the main laboratory and clinical abnormalities. Two patients with confirmed SCS due to AIMAH underwent unilateral laparoscopic adrenalectomy to reduce the cortisol‐secreting tissue. These procedures were successfully conducted in both cases without open conversion, and no surgery‐related morbidity occurred. In both cases, the size of the remaining adrenal gland appeared quite stable, and neither of the patients showed a Cushingoid appearance. Unilateral adrenalectomy achieved satisfactory and prolonged control of cortisol secretion, and also reduced the risk of metabolic disorders and cardiovascular disease after surgery. It can be a safe and effective treatment for SCS due to AIMAH, while maintaining the patient's quality of life.

651 PERIPHERAL PLASMA LEVELS OF 18-OXO-CORTISOL PRACTICALLY DIFFERENTIATE ALDOSTERONE PRODUCING ADENOMA FROM BILATERAL HYPERPLASIA AND PRIMARY HYPERTENSION-A NONINVASIVE METHOD DETERMINING SURGICALLY CURABLE SUBTYPE WITH A HIGH SPECIFICITY

Backgrounds: Primary aldosteronism (PA) is diagnosed and treated by the long steps, such as screening, confirmation testing and subtype diagnosis (computed tomography (CT) scan and adrenal venous sampling (AVS)). Objective: The aim of the study was to determine the role of peripheral plasma levels of 18-oxo-cortisol (p18oxoF) and 18-hydroxycortisol (p18OHF) in discriminating aldosterone producing adenoma (APA), which is a major surgically curable subtype of PA, from bilateral hyperaldosteronism (BHA) or primary hypertension (PH) which should be medically treated. Patients: The study included 79 PH patients with the aldosterone/renin activity ratio (ARR) of 9.0 ± 0.5 (ng/dl per ng/ml/h) and 237 PA patients, such as 87 patients with CT-positive macro APA (ARR: 363 ± 38.7), 29 patients with CT-negative micro APA (ARR: 64.8 ± 11.1) and 121 BHA patients (ARR: 87.1 ± 4.5). Methods: All PA patients underwent AVS, and all APA were surgically proven and histopathologically confirmed including immunohistochemical analysis of steroidogenic enzymes. We measured p18oxoF and p18OHF of all patients by high sensitive LC ms/ms. Results: APA patients showed significantly higher levels of p18oxoF and p18OHF compared to BHA or PH patients. Especially, the ROC analysis of 18oxoF in macro APA versus BHA or PH demonstrated clinically significant discrimination with higher sensitivity of 0.81 and higher specificity of 0.97 by cutoff value of 4.6 ng/dl. Conclusions: Peripheral plasma levels of 18-oxo-cortisol might practically differentiate aldosterone producing adenoma from bilateral hyperplasia and primary hypertension omitting many steps of diagnostic workup for PA.

Bilateral Coronoid Process Hyperplasia With Pseudocartilaginous Joint Formation: Jacob Disease

Bilateral Coronoid Process Hyperplasia With Pseudocartilaginous Joint Formation: Jacob Disease

Bilateral diffuse uveal melanocytic hyperplasia: molecular characterization and novel association with bilateral renal papillary carcinoma

Bilateral diffuse uveal melanocytic hyperplasia: molecular characterization and novel association with bilateral renal papillary carcinoma

Évaluation de l’efficience diagnostique de la tomodensitométrie abdominale de première intention chez l’hypertendu non contrôlé

The prevalence of hypertension resistant to treatment to indicate for renal denervation. ObjectiveTo evaluate the efficiency for imaging the adrenal glands with an abdominal CT scan in first-line in subjects with resistant hypertension suspected to have an adrenal cause. MethodsOn 75 hypertensive patients uncontrolled by at least a combination therapy, but suspected to have secondary hypertension due to adrenal cause, an abdominal CT scan was performed in first intention. In all subjects, an exploration of the renin-aldosteron axis in standardized conditions, a 24-hour urinary cortisol and a WHO recommended biological analysis were also performed. ResultsAn abnormal morphology of adrenal was found by abdominal CT in 64% of patients. The abnormalities observed were: bilateral hyperplasia (27%), unilateral adenoma (15%), unilateral hyperplasia (15%), bilateral adenoma (7%). Abnormal biological and/or hormonal tests for adrenal disease were found in 29% of patients, with a primary aldosteronism (A/R corrected>23) in 11% or K less than 3.5mmol/L in 20%. According to the assessment conducted in first-line, indication to spironolactone is selected in 48% of patients investigated with CT as first-line and in 17% of patients investigated with biological tests (P<0.01) while the indication to adrenal surgery would be held in 15% and 11% of patients respectively. ConclusionIn a population of subjects with uncontrolled hypertension in which an adrenal cause is suspected, achieving a first-line abdominal CT leads to adrenal abnormality observed in 64% of patients while a specific biological abnormality is noted in 29% of subjects. This study shows that assessment that starts with an abdominal CT scan allows to indicate treatment with spironolactone more frequently than when the first assessment is limited to a biological investigation.

Bilateral Simultaneous Laparoscopic Adrenalectomy in Cushing's Syndrome: Safe, Effective, and Curative

Surgical morbidity and mortality rates are high in patients with Cushing's syndrome. Nevertheless, simultaneous bilateral laparoscopic adrenalectomy (LA) is feasible in these patients with less morbidity and good long-term results. Consecutive 22 patients who underwent LA for Cushing's syndrome between 2003 and 2010 in our institute were retrospectively studied. Ninteen patients underwent bilateral simultaneous and three underwent unilateral LA. Seven patients had Cushing's syndrome after failed pituitary surgery and five each had ectopic adrenocorticotrophic hormone dependent syndrome and bilateral macronodular hyperplasia respectively. LA was bilaterally done by lateral transabdominal adrenalectomy in 15 patients and retroperitoneal endoscopic adrenalectomy in 4 on the right side. Mean operative time for simultaneous bilateral cases was 199.45±72.43 minutes with mean blood loss of 72.72±48.6 mL. Patients were fit for discharge by the fifth postoperative day from the surgical aspect. Surgical complication rate was 26% that included wound infections in two, port site hernia, pleural effusion, and atelectasis in one each. One patient died of sepsis (5% mortality). Satisfactory metabolic control was achieved in all observable patients in the long term although Addisonian crisis and Nelson syndrome were seen in 26% and 15% respectively. LA has all advantages of minimal access surgery in patients with Cushing's syndrome who are immunocompromised and at high risk of delayed wound healing and infections. Magnification decreases the risk of retained adrenal remnants. Despite advances in minimal access surgery, perioperative morbidity continues to be significant for the procedure.

Severe trismus due to bilateral coronoid process hyperplasia in growth hormone therapy patient: a case report

J Korean Assoc Oral Maxillofac Surg 2012;38:249-54) Bilateral coronoid process hyperplasia is a rare condition characterized by an enlarged mandibular coronoid process. The painless progressive reduction of a mouth opening is caused by coronoid process impingement on the posterior aspect of the zygomatic bone. Hyperplasia of the bilateral coronoid process leads to the restriction of a mandibular opening consequent to the impingement of the enlarged coronoid process on the temporal surface of the zygomatic bone or with the medial surface of the zygomatic arch. The process has been diagnosed as developmental hyperplasia. Otherwise, the development of the coronoid process may be associated with growth hormone. This paper describes a case of trismus caused by coronoid hyperplasia in an idiopathic short-stature patient who received growth hormone therapy by somatropin injections.

Coronoid process hyperplasia: an unusual cause of mandibular hypomobility

A large number of disorders affecting the masticatory system can cause restriction of mouth opening. The most common conditions related to this problem are those involving the temporomandibular joint (TMJ) and the masticatory muscles, when facial pain also is an usual finding. Congenital or developmental mandibular disorders are also possible causes for mouth opening limitation, although in a very small prevalence. Coronoid process hyperplasia (CPH) is an example of these cases, characterized by an excessive coronoid process growing, where mandibular movements become limited by the impaction of this structure on the posterior portion of the zygomatic bone. This condition is rare, painless, usually bilateral and progressive, affecting mainly men. Diagnosis of CPH is made based on clinical signs of mouth opening limitation together with imaging exams, especially panoramic radiography and computerized tomography (CT). Treatment is exclusively surgical. This paper presents a case of a male patient with bilateral coronoid process hyperplasia, initially diagnosed with bilateral disk displacement without reduction, and successfully treated with intraoral coronoidectomy. It is emphasized the importance of differential diagnosis for a correct diagnosis and, consequently, effective management strategy.