Bilateral Adrenal Hyperplasia Research Articles

Adrenal lesions do matter in the course of primary aldosteronism: a comparative analysis of Conn's adenoma vs bilateral adrenal hyperplasia

Adrenal lesions do matter in the course of primary aldosteronism: a comparative analysis of Conn's adenoma vs bilateral adrenal hyperplasia

Bilateral adrenal hyperplasia as a paraneoplastic phenomenon - a cadaveric case report

Bilateral adrenal hyperplasia as a paraneoplastic phenomenon - a cadaveric case report

Results of systematic KDM1A genotyping in a large series of Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH) patients and analysis of the genotype/phenotype correlation

Results of systematic KDM1A genotyping in a large series of Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH) patients and analysis of the genotype/phenotype correlation

Primary bilateral macronodular adrenal hyperplasia caused by a novel variant in the ARMC5 gene

Primary bilateral macronodular adrenal hyperplasia caused by a novel variant in the ARMC5 gene

Long term management of adult bilateral adrenal hyperplasia with mild autonomous cortisol secretion - data from a Romanian tertiary center

Long term management of adult bilateral adrenal hyperplasia with mild autonomous cortisol secretion - data from a Romanian tertiary center

A Cadaveric Case of Bilateral Adrenal Hyperplasia With Lung Cancer: A Paraneoplastic Syndrome?

A Cadaveric Case of Bilateral Adrenal Hyperplasia With Lung Cancer: A Paraneoplastic Syndrome?

Bilateral adrenal macronodular hyperplasia successfully treated by unilateral adrenalectomy.

Bilateral adrenal macronodular hyperplasia successfully treated by unilateral adrenalectomy.

Bilateral adrenal macronodular hyperplasia successfully treated by unilateral adrenalectomy

Bilateral adrenal macronodular hyperplasia successfully treated by unilateral adrenalectomy

Familial bilateral macronodular adrenal hyperplasia due to a novel ARMC 5 germline mutation: Clinical status and possible association with other neoplasms

Introduction/ObjectivesMutations in the ARMC5 (armadillo repeat containing 5, OMIM 615549) gene, a putative tumor suppressor gene, have recently been identified as a common cause of sporadic and familial bilateral macronodular adrenal hyperplasia (BMAH). Familial BMAH is thought to be caused by two mutations, one germline and the other somatic, as suggested by the 2-hit theory. The objective is to describe a new mutation and develop its clinical characteristics and implications. Methods, Results and ConclusionsWe present an affected family with 11 members carrying a novel mutation of the ARMC5 gene (NM_001288767.1): c.2162T>C p. (Leu721Pro). Two of the carriers developed clinical Cushing's syndrome (CS), two mild autonomous cortisol secretion (MACS) and one presented with autonomous cortisol secretion (ACS). Four patients developed other tumors, three of whom died from this cause. It is not known whether these tumors could be related to the described mutation.

The importance of novel histopathological classification and its association with outcomes of primary aldosteronism: What you need to know from a urologist’s perspective

Primary aldosteronism (PA), the most important cause of secondary endocrine hypertension, is hallmarked by excessive aldosterone secretion. There were 2 subtypes of PA—unilateral aldosterone-producing adenoma and bilateral adrenal hyperplasia, which are now outdated. Since conventional adrenal pathological reports only examined hematoxylin and eosin staining, the secretory function of the structural adenoma(s) could not be determined. Several enzymes produce aldosterone-related steroids, and 2 isoforms of 11β-hydroxylase, namely CYP11B1 and CYP11B2 (aldosterone synthase), are responsible for producing cortisol and aldosterone, respectively. Since the availability of specifically selective antibodies for targeting CYP11B1 and CYP11B2, the diagnosis/nomenclature of PA-related adrenal pathology has been revolutionized by using immunohistochemistry staining for CYP11B2 to identify the aldosterone production site in the human adrenal cortex. The significance of immunohistochemical staining of formalin-fixed paraffin-embedded adrenal tissue sections has become “mandatory” for precisely detecting the lesions responsible for PA. Recently, the histopathology of PA consensus, based on immunochemical findings, was established to define the nomenclature and adrenal histopathological features in unilateral PA. In this study, we further investigate the association between the pathological subtypes and the surgical outcomes of PA as per the criteria of the Primary Aldosteronism Surgery Outcome consensus. Unfortunately, a significant lag is seen in the adaptation of Taiwan’s pathologists to the histopathology of PA consensus. Furthermore, a strong push from all urologists across Taiwan and the governmental health care authorities is required to elevate the care level provided to all patients with PA in Taiwan to exceptional.

Cabergoline therapy against hyperadrenocorticism in a dog

A 9-year-old male Labrador dog was presented to Small Animal Medicine Unit of Veterinary Clinical Complex, Veterinary College and Research Institute, Orathanadu with a history of chronic skin infection for the past 6 months. Clinical examination revealed alopecia, skin thinning, calcinosis cutis and comedone with pendulous abdomen. Laboratory examination revealed increased ALP and hyperglycemia. Hepatomegaly and bilateral adrenal gland hyperplasia were noticed on ultrasonography. Based on clinical and ultrasonographic findings it was diagnosed as hyperadrenocorticism. The dog was treated with Cabergoline @ 0.07 mg/kg P.O every 3 days for 3 months. The clinical signs were gradually subsided and animal recovered uneventfully with 3 months of treatment. Cabergoline found to be an alternative treatment of choice for the management of hyperadrenocorticism in dogs.

Familial bilateral macronodular adrenal hyperplasia due to a novel ARMC 5 germline mutation: Clinical status and possible association with other neoplasms

Introduction/ObjectivesMutations in the ARMC5 (armadillo repeat containing 5, OMIM 615549) gene, a putative tumor suppressor gene, have recently been identified as a common cause of sporadic and familial bilateral macronodular adrenal hyperplasia (BMAH). Familial BMAH is thought to be caused by two mutations, one germline and the other somatic, as suggested by the 2-hit theory. The objective is to describe a new mutation and develop its clinical characteristics and implications. Methods, Results and ConclusionsWe present an affected family with 11 members carrying a novel mutation of the ARMC5 gene (NM_001288767.1): c.2162T>C p. (Leu721Pro). Two of the carriers developed clinical Cushing's syndrome (CS), two mild autonomous cortisol secretion (MACS) and one presented with autonomous cortisol secretion (ACS). Four patients developed other tumors, three of whom died from this cause. It is not known whether these tumors could be related to the described mutation.

Determination of three C18-oxygenated steroids in adrenal lesion segments in primary aldosteronism by super-selective adrenal venous sampling and LC/ESI-MS/MS.

Super-selective adrenal venous sampling (ssAVS) can collect the adrenal tributary venous blood in the aldosterone (ALD)-hypersecreting segments in primary aldosteronism. The concentrations of the C18-oxygenated steroids, especially 18-oxocortisol (18-oxoF), in the lesion segments might be more useful indices than those in the peripheral or adrenal central veins (current candidate indexes) for the differential diagnosis of unilateral ALD-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH). To verify this hypothesis, we developed a liquid chromatography/electrospray ionization-tandem mass spectrometry (LC/ESI-MS/MS) method for simultaneously quantifying ALD, 18-oxoF and 18-hydroxycortisol in the adrenal tributary venous serum sample collected by ssAVS (ssAVS serum) and compared their concentrations between APA and BAH patients. Only deproteinization was required for a 10 μl sample prior to the LC/ESI-MS/MS analysis. Endogenous corticoids did not interfere with the quantifications, and the intra-assay and interassay precisions (≤ 8.3%) and accuracies (94.2-102.7%) were acceptable. The clinical study revealed that the 18-oxoF concentration was significantly higher in the ALD-producing tumor tissues (from APA patients) than in the hyperplastic tissues (from BAH patients). However, in conclusion, the 18-oxoF concentration in the ssAVS serum sample can be a rough indication but cannot be decisive for the differential diagnosis between APA and BAH owing to the significant individual difference.

KDM1A genotyping and expression in 146 sporadic somatotroph pituitary adenomas.

A paradoxical increase of growth hormone (GH) following oral glucose load has been described in ∼30% of patients with acromegaly and has been related to the ectopic expression of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in somatotropinomas. Recently, we identified germline pathogenic variants and somatic loss of heterozygosity of lysine demethylase 1A (KDM1A) in patients with GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome. The ectopic expression of GIPR in both adrenal and pituitary lesions suggests a common molecular mechanism. We aimed to analyze KDM1A gene sequence and KDM1A and GIPR expressions in somatotroph pituitary adenomas. We conducted a cohort study at university hospitals in France and in Italy. We collected pituitary adenoma specimens from acromegalic patients who had undergone pituitary surgery. We performed targeted exome sequencing (gene panel analysis) and array-comparative genomic hybridization on somatic DNA derived from adenomas and performed droplet digital PCR on adenoma samples to quantify KDM1A and GIPR expressions. One hundred and forty-six patients with sporadic acromegaly were studied; 72.6% presented unsuppressed classical GH response, whereas 27.4% displayed a paradoxical rise in GH after oral glucose load. We did not identify any pathogenic variant in the KDM1A gene in the adenomas of these patients. However, we identified a recurrent 1p deletion encompassing the KDM1A locus in 29 adenomas and observed a higher prevalence of paradoxical GH rise (P = .0166), lower KDM1A expression (4.47 ± 2.49 vs 8.56 ± 5.62, P < .0001), and higher GIPR expression (1.09 ± 0.92 vs 0.43 ± 0.51, P = .0012) in adenomas from patients with KDM1A haploinsufficiency compared with those with 2 KDM1A copies. Unlike in GIP-dependent primary bilateral macronodular adrenal hyperplasia, KDM1A genetic variations are not the cause of GIPR expression in somatotroph pituitary adenomas. Recurrent KDM1A haploinsufficiency, more frequently observed in GIPR-expressing adenomas, could be responsible for decreased KDM1A function resulting in transcriptional derepression on the GIPR locus.

Diverse presentations of Cushing's syndrome during pregnancy - A case series.

Cushing's syndrome (CS) encompasses various causes of hypercortisolism including adrenocorticotropic hormone (ACTH) secreting pituitary adenoma with or without bilateral adrenal hyperplasia, an adrenal adenoma or carcinoma, ectopic ACTH or corticotrophin-releasing hormone (CRH) secretion by a neoplasm or exogenous corticosteroid therapy. The diagnosis of CS in pregnancy presents a challenge due to overlapping clinical features of pregnancy (weight gain, striae, acne). If untreated, CS in pregnancy is associated with increased risk of maternal and fetal complications. With fewer than 250 cases currently published, we aim to review the clinical presentations, diagnostic methods, management, and outcomes of patients with CS in pregnancy to help optimise our clinical practice. This is a single-centre, retrospective review of woman with documented hypercortisolism receiving antenatal care at a tertiary maternity hospital in Perth between 2006 to 2022. Data were collated from electronic and chart reviews. OMNI calculator was used for birthweight calculations. Local ethics and patient consent were obtained. Five women and seven pregnancies were identified. Four women had a pituitary source of ACTH-dependent CS as confirmed by brain magnetic resonance imaging. One woman had an ectopic source of ACTH. Two women were diagnosed during pregnancy. All pregnancies occurring prior to treatment of the Cushing's disease were complicated by secondary hypertension and diabetes. CS represents a rare and difficult to diagnose condition in pregnancy. When untreated, maternal and fetal outcomes are compromised. Close monitoring of the associated complications with involvement of a multidisciplinary team are recommended.

O-02 Inactivation of KDM1A with the concurrent presence of MGUS in a patient with GIP-dependent Cushing's syndrome and the vanishing effect of octreotide therapy

Abstract Introduction Glucose-dependent insulinotropic peptide (GIP)-dependent primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of Cushing's syndrome. It has germline genetic predisposition and requires for personalized approaches to investigation and therapy. We aimed to present the rare case of a GIP-dependent PBMAH patient with unusually severe cortisol secretion and a KDM1A inactivation with an accompanying haematological co-morbidity related to that mutation. Clinical Case A 41-year-old woman presented with a 5-kg weight gain in last 6 months, irritability and fatique. Physical examination revealed elevated blood pressure, increased supraclavicular fat pads, and abdominal obesity. The cortisol level was 25.9 (6.7-22.6) µg/dL in the morning, 16.9 µg/dL in the late night, and 6.5 µg/dL in the morning after an overnight 1 mg of dexamethasone. Urinary free cortisol (UFC) level was also elevated to 2150 (58-403) µg/24-h. The early morning plasma ACTH level was 1.5 (7-63) pg/mL. Abdominal imaging revealed 29×23 mm adenomas on the right and 46×35 mm on the left with high fat content. Cortisol was stimulated by the administration of mixed meals (+537%) but not by TRH, GnRH, metoclopramide or upright posture. The response to mixed meals was blunted by pretreatment with subcutaneous 100 mg octreotide. Following the patient's diagnosis of GIP-dependent PBMAH, octreotide LAR therapy was initiated. Although inducing a significant acute suppression of UFC and improvement in symptoms during the first 3 months, the UFC began to rise due to the resistance in the following period (Figure 1). After 9 months of octreotide LAR treatment, left adrenalectomy was performed according to the adrenal volumetric assessment. Histopathology was reported as diffuse macronodular adrenal hyperplasia without internodular atrophy. Even though the patient had a unilateral adrenalectomy, adrenal insufficiency occurred in the postoperative period. Subsequently, the patient has been closely monitored and followed up with a physiological, divided-dose hydrocortisone replacement regimen for 7 months. A germline heterozygous variant in the KDM1A gene in the patient's blood sample and a recurrent deletion in the short p arm of chromosome 1 harboring the KDM1A locus in the adrenal sample were identified. When screened for diseases associated with the KDM1A mutation, monoclonal gammopathy of undetermined significance (MGUS) was detected in the patient with mild anemia, and genetic counseling was also provided. Conclusion The management of GIP-dependent PBMAH remains controversial, and further therapeutic options are under investigation. Due to the very limited number of case reports and the heterogeneous nature of the disease, special features of our case, which are severe cortisol excess, accompanying MGUS, the vanishing effect of octreotide, and adrenal insufficiency after unilateral adrenalectomy, might contribute to the existing literature.Figure 1.Urinary free cortisol levels following octreotide therapyUFC: Urinary free cortisol, ULN: Upper limit normal, LAR: Long acting release

Conn´s syndrome after kidney transplantation.

Conn's syndrome, defined as unilateral aldosterone-producing adenoma, accounts for 35-40% of cases of primary hyperaldosteronism. Primary hyperaldosteronism typically occurs in younger patients with poorly controlled arterial hypertension due to extracellular fluid retention, in whom at least atriple combination of antihypertensives, including adiuretic, is needed to maintain normotension. The clinical picture of arterial hypertension may be complemented by symptoms associated with hypokalaemia, such as weakness, fatigue, palpitations, convulsions, polydipsia, or polyuria. In addition to arterial hypertension and hypokalaemia, the diagnosis of Conn's syndrome relies on examination of serum renin and aldosterone concentrations, plasma renin activity, exercise or furosemide stimulation tests, and imaging studies, preferably computed tomography. The method of treatment of Conn's syndrome is adrenalectomy. In patients with primary hyperaldosteronism with underlying bilateral adrenal cortical hyperplasia or patients contraindicated for surgery, mineralocorticoid receptor antagonists are administered in combination with antihypertensives targeted for optimal blood pressure control.In the group of patients after kidney transplantation, the exact incidence of primary hyperaldosteronism is unknown. Based on across-sectional study performed in 2020, it is estimated to be approximately 15% in the group of patients with unsatisfactorily compensated arterial hypertension; in the cohort of normotensive recipients, the incidence of primary hyperaldosteronism is not documented. Diagnosis of Conn's syndrome in patients in the early period after kidney transplantation is problematic, as the prevalence of arterial hypertension in transplanted patients is high (70-90%) according to the literature. Mineral abnormalities, including hypokalaemia, are also common in the early post-transplant period, mainly due to factors such as duration of cold ischaemia, onset of graft function, donor parameters, post-transplant tubulopathy, and diuretics, the effects of immunosuppressive drugs (especially calcineurin inhibitors and corticosteroids), and possibly potassium-restricted dietary habits that the patient brings from the pre-transplant period, which may mask the effect of hyperaldosteronism on potassium.We present the case of apatient who was diagnosed with Conn's syndrome 7 months after primary kidney transplantation from adeceased donor based on persistent hypokalaemia unresponsive to replacement therapy. At the time of the first manifestation of severe hypokalaemia, the patient was treated with adual combination of antihypertensives (amlodipine at adaily dose of 5 mg and carvedilol at adaily dose of 50 mg), without the need for adiuretics.We consider the case interesting because the spectrum of mineral and acid-base abnormalities in advanced renal failure and in the early post-transplant period, as well as acid-base and mineral imbalances, including hypokalaemia, and the high prevalence of arterial hypertension in the post-transplant period, may mask the picture of Conn's syndrome (Fig. 3, Ref. 19). Text in PDF www.elis.sk Keywords: kidney transplantation, primary hyperaldosteronism, hypokalaemia, metabolic alkalosis, secondary arterial hypertension.

Delineating endogenous Cushing’s syndrome by GC-MS urinary steroid metabotyping

BackgroundDiagnosing Cushing’s syndrome (CS) is highly complex. As the diagnostic potential of urinary steroid metabolome analysis by gas chromatography-mass spectrometry (GC-MS) in combination with systems biology has not yet been fully exploited, we studied a large cohort of patients with CS. MethodsWe quantified daily urinary excretion rates of 36 steroid hormone metabolites. Applying cluster analysis, we investigated a control group and 168 patients: 44 with Cushing’s disease (CD) (70% female), 18 with unilateral cortisol-producing adrenal adenoma (83% female), 13 with primary bilateral macronodular adrenal hyperplasia (PBMAH) (77% female), and 93 ruled-out CS (73% female). FindingsCluster-Analysis delineated five urinary steroid metabotypes in CS. Metabotypes 1, 2 and 3 revealing average levels of cortisol and adrenal androgen metabolites included patients with exclusion of CS or and healthy controls. Metabotype 4 reflecting moderately elevated cortisol metabolites but decreased DHEA metabolites characterized the patients with unilateral adrenal CS and PBMAH. Metabotype 5 showing strong increases both in cortisol and DHEA metabolites, as well as overloaded enzymes of cortisol inactivation, was characteristic of CD patients. 11-oxygenated androgens were elevated in all patients with CS. The biomarkers THS, F, THF/THE, and (An + Et)/(11β-OH-An + 11β-OH-Et) correctly classified 97% of patients with CS and 95% of those without CS. An inverse relationship between 11-deoxygenated and 11-oxygenated androgens was typical for the ACTH independent (adrenal) forms of CS with an accuracy of 95%. InterpretationGC-MS based urinary steroid metabotyping allows excellent identification of patients with endogenous CS and differentiation of its subtypes. FundingThe study was funded by the Else-Kröner-Fresenius-Stiftung and the Eva-Luise-und-Horst-Köhler-Stiftung.

Primary hyperaldosteronism: the choice in favor of conservative surgery

Primary hyperaldosteronism (PHA) is the most common cause of secondary arterial hypertension among endocrine disorders. Given that patients with this pathology are at a higher risk of developing fatal and non-fatal cardiovascular events, early diagnosis and timely treatment are of great importance. Currently, the two main forms of PHA are aldosterone-producing adenoma and bilateral adrenal hyperplasia, which are treated with laparoscopic adrenalectomy or pharmacotherapy with mineralocorticoid receptor antagonists. Although most patients experience restoration of their functional and metabolic status after surgical intervention, some may develop postoperative adrenal insuffi ciency, which requires long-term hormone replacement therapy. This review examines the options for organ-preserving surgeries, such as partial adrenalectomy and selective embolization of the adrenal artery.

Adrenal Cushing's syndrome in children.

Adrenal Cushing's syndrome is a rare cause of endogenous hypercortisolism in neonatal and early childhood stages. The most common causes of adrenal CS are hyperfunctioning adrenal tumours, adenoma or carcinoma. Rarer causes are primary bilateral macronodular adrenal hyperplasia (PBAMH), primary pigmented adrenocortical disease (PPNAD) and McCune Albright syndrome. The diagnosis represents a challenge for clinicians. In cases of clinical suspicion, confirmatory tests of hypercortisolism should be performed, similarly to those performed in adults. Radiological imaging should be always combined with biochemical confirmatory tests, for the differential diagnosis of adrenal CS causes. Treatment strategies for adrenal CS include surgery and in specific cases medical drugs. An adequate treatment is associated to an improvement of growth, bone health, reproduction and body composition from childhood into and during adult life. After cure, lifelong glucocorticoid replacement therapy and endocrine follow-up are required, notably in patients with Carney's complex disease.