JS-1：ESROC-TSA Joint Symposium

JS1-1 THE LONG TERM OUTCOME OF PRIMARY ALDOSTERONISM

VIN-CENT WU

Department of internal medicine, National Taiwan University Hospital, Taiwan

Although the role of primary aldosteronism (PA) in increasing cardiovascular risk and the potential of targeted therapy for PA have gained recognition, there exists a great knowledge gap in terms of long-term effects of various surgical and pharmacological treatments on outcomes among PA patients. For instance, it remains unclear whether certain targeted treatments for PA can yield everlasting elimination of high blood pressure and regression of the adverse cardiovascular changes. However, patients with IHA may have a different genotype and phenotype compared to APA, the clinical decision of targeted treatments for APA and long term outcome retained unmet study. Previous studies showed impaired glucose homeostasis and insulin resistance (IR) in PA patients, leading to increased prevalence of metabolic syndrome (MS), which could be improved after adrenalectomy.

A cohort study reported a higher risk of cardiometabolic events and death in all PA patients than in essential hypertension counterparts in the follow–up after treatment with a mineralocorticoid receptor antagonist (MRA). In a cohort of PA patients with or without adrenal adenoma, surgical or medical treatment has a compatible cardiovascular outcome in the long term. While we had showed adrenalectomy could decreases long-term all-cause mortality independently from cure from hypertension in all PA patients from a claims database, whether MRA treatment produce a similar effect as adrenalectomy in terms of prevention of cardiovascular events or mortality among APA is unclear.

JS1-2 ADRENAL VENOUS SAMPLING: TECHNIQUES AND INTERPRETATION

CHIN-CHEN CHANG

Department of Medical Imaging, National Taiwan University Hospital, Taiwan.

Adrenal venous sampling (AVS) was introduced in late 1960s as a test to distinguish unilateral from bilateral primary aldosteronism (PA). AVS is held to be the “gold standard” diagnostic procedure for assessing lateralization of aldosterone secretion and thereby identifying the surgically curable forms of primary aldosteronism.

The successful cannulation of both adrenal veins continues to be challenging clinical issues. Adequate adrenal sampling is based on higher cortisol concentration compared with peripheral sampling. Dyna-CT and on-site quick cortisol assay could be helpful to improve the successful rate.

Cortisol is used for AVS data interpretation, but it has several pitfalls, including time- and stressrelated variation, and co-secretion in ipsilateral or contralateral adrenal with hyperaldosteronism. Multiple steroid panels are suggested for stratified PA subtyping and have the potential to circumvent AVS in a subset of patients with PA.

We will share our experiences and the recent literature reviews in this speech.

JS1-3 CLINICAL APPLICATION OF NUCLEAR MEDICINE IN PRIMARY ALDOSTERONISM

CHING-CHU LU

Department of Nuclear Medicine, National Taiwan University Hospital, Taiwan

Primary aldosteronism (PA), characterized by an excessive production of aldosterone, affects 10% of patients with hypertension. Accurate strategies are needed for the timely diagnosis of PA to allow curability and prevention of excessive cardiovascular events and related damage. Adrenal venous sampling (AVS) is the gold standard for lateralization but it is technically dependent and invasive. Conventional imaging modality such as computed tomography (CT) is widely available and could be used to exclude malignancy. Traditionally CT is considered useless in lateralization since lesion morphology is not correlated with functional status. However, in SPARTACUS trial, treatment based on CT or AVS did not show significant differences in intensity of antihypertensive medication or clinical benefits for patients after 1 year of follow-up. NP-59 adrenal scintigraphy (NP-59) is a molecular imaging evaluating adrenal cortical function based on the activity of cholesterol uptake and transfer. Studies revealed prognostic value of NP-59, but it is commonly considered out-of-date due to low resolution, limited availability and high radiation. Positron emission tomography (PET) using C11-metomidate, which is a CYP11B1 and CYP11B2 inhibitor, showed delicate imaging resolution with some preliminary report of lateralization ability. Specific CYP11B2 PET tracer labelled with fluorine-18 (F18-CDP2230) is currently under investigation in animal model. No steroid suppression is required due to its high affinity to CYP11B2. A novel PET tracer, Ga68-CXCR4 was found uptake by aldosterone-producing adenoma (APA) in human studies. CXCR4 was elevated in APA tissue its expression is closely associated with the expression of CYP11B2. The current review will introduce the history and the future of nuclear medicine in PA.

JS1-4 AUTONOMOUS CORTISOL SECRETION IN PRIMARY ALDOSTERONISM

WAN-CHEN WU

Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

Primary aldosteronism (PA) is considered to be the most common reason for secondary hypertension and also recognized as a result of a heterogeneous group of disorders, including aldosterone-producing adenomas (APAs), idiopathic uni- or bilateral adrenal hyperplasia, or from inherited forms of familial hyperaldosteronism (FHA). Among adrenal disorders that lead to PA, the subtype of aldosterone- and cortisol-co-secreting tumors can be recognized separately.

A term widely used in the context of adrenal incidentaloma (AI) was “subclinical CS”. However, this terminology has become somewhat obsolete and it is currently more advisable to talk about autonomous cortisol secretion (ACS). This term aims to define AI patients with biochemical evidence of excess of cortisol, but without typical symptoms and signs of CS (mainly the lack of catabolic characteristics such as myopathy and skin fragility).

ACS is associated with increased morbidity (diabetes, obesity, hypertension, osteoporosis, and cardiovascular events) and mortality. Concurrent ACS in subjects with PA is reported in an increase number, characterized by a high cardiovascular risk, which reflects the combined damaging effects of the two steroid excess.

However, ACS is not easy to diagnose, mainly due to the lack of consensus on its definition and the fact that the detection of “specific” findings of CS is doctor dependent. The dexamethasone suppression test is the most accepted for screening. Low levels of ACTH and DHEA-S and high urinary free cortisol are also associated with ACS, but in isolation they are of little value to establish the diagnosis.

Several somatic mutations (KCN5J, ATP1A1, ATP2B3, CACNA1D, CTNNB1) have been showed causative for APAs, and two somatic mutations of PRKACA (catalytic subunit of protein kinase A) and GNAS (guanine nucleotide binding protein α stimulating) have been identified in cortisol-producing adenomas (CPAs). The presence of PRKACA or GNAS mutations in APAs, especially with ACS is not well known.

JS1-5 GENETIC AND HISTOPATHOLOGIC CHARACTERIZATION OF SPORADIC PRIMARY ALDOSTERONISM

KANG-YUNG PENG

Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan.

Primary aldosteronism (PA) is a major cause of secondary hypertension characterized by inappropriate secretion of aldosterone from unilateral or bilateral abnormal adrenal glands. The majority cases of PA are sporadic due to a unilateral aldosterone-producing adenoma (APA) or bilateral adrenal hyperplasia (BAH, also known as idiopathic hyperaldosteronism, IHA). During the last ten years, a better knowledge of the pathophysiology of PA came from the discovery of somatic and germline mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, CTNNB1, CLCN2 and CACNA1H in sporadic and familial forms of the disease. These genes (except for CTNNB1 which encodes β-catenin) encode ion channels or pumps in adrenal cell membranes, mutations in these genes lead to membrane depolarization, increased calcium influx and activation of calcium signaling which in turn activates aldosterone synthase (CYP11B2) expression and aldosterone production. Histologically, APA has been reported to be mainly composed of clear cells (ZF-like, lipid-rich cells) and compact cells (ZG-like, spherical small cells). Some studies have described APA with KCNJ5 mutations have more ZF-like phenotype with high expression of CYP17A1, while APA with ATP1A1, ATP2B3 and CACNA1D mutations presented more frequently a ZG-like phenotype with high expression of CYP11B2. It is unclear whether somatic mutations completely cause the development of APA, leading to both excessive aldosterone production and nodule formation. Recent studies suggested that APA may derive from aldosterone-producing cell clusters (APCCs), CYP11B2-positive cell foci found in normal adrenal glands, which harbored APA-associated somatic mutations. In addition to APA, APCCs have also been implicated in IHA. The APCC hypothesis is also supported by the description of possible APCC to APA translational lesions (pAATL), which also carry APA-associated somatic mutations. Other studies suggest a two-hit hypothesis, where a specific genetic or epigenetic event stimulates adrenocortical cell proliferation and somatic mutations are secondary events leading to excessive aldosterone secretion. These two hypotheses may coexist, and both contribute to sporadic PA development.