Endocrine hypertension

ADRENAL DISORDERS

Endocrine hypertension

Key points

Mark Sherlock

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Endocrine causes of secondary hypertension are common

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Endocrine hypertension is the aetiology in up to 10% of patients with hypertension, and more in patients with resistant hypertension

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Screening for secondary causes of hypertension is suggested for high-risk groups

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Appropriate screening for primary hyperaldosteronism can lead to targeted therapy (medical and surgical), which can lead to resolution of hypertension

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Appropriate perioperative management of phaeochromocytomas/paragangliomas (PPGLs) is essential, and these tumours should be managed in specialist centres

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PPGLs are increasingly recognized as having an underlying genetic aetiology

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Diagnosis offers the potential for cure of hypertension and identification of important familial disorders (e.g. PPGL syndrome)

Isolda Frizelle

Abstract Up to 10% of patients have a secondary cause for hypertension. Endocrine conditions associated with hypertension include diseases associated with mineralocorticoid excess, phaeochromocytomas/paragangliomas, acromegaly and primary hyperparathyroidism. Primary hyperaldosteronism (PH) is the most common endocrine cause of hypertension. If not appropriately managed, PH has an unfavourable cardiovascular morbidity and mortality profile. It is treatable by medical or surgical approaches. Phaeochromocytomas and paragangliomas are rare neuro-endocrine tumours frequently associated with genetic abnormalities.

Keywords Adrenal adenoma; Cushing’s syndrome; endocrine hypertension MRCP; paraganglioma; phaeochromocytoma; primary hyperaldosteronism

Introduction Endocrine disorders are estimated to account for up to 10% of all hypertension (Table 1). A low index of suspicion is therefore required to avoid overlooking a potentially curable cause. In recent years, the molecular basis of many causes of endocrine hypertension has been established, in particular the underlying aetiology of primary hyperaldosteronism (PH) and phaeochromocytomas/paragangliomas (PPGLs).

somatic mutations in a variety of genes, including KCNJ5, ATP1A1 and CACNA1D, which increase intracellular calcium and thus facilitate aldosterone secretion.1 Screening for primary hyperaldosteronism In line with the most recent Endocrine Society guidelines,2 screening is recommended for high-risk groups (Table 2). This

Primary hyperaldosteronism PH is the most common cause of endocrine hypertension, and is most commonly the result of hyperplasia of, or an adenoma arising from, the zona glomerulosa of the adrenal gland. Increased aldosterone secretion leads to retention of sodium and water in the distal renal tubule, resulting in hypertension with an associated suppression of plasma renin activity. Increased understanding of the molecular mechanisms of PH have revealed

Endocrine conditions associated with hypertension Mineralocorticoid excess Low renin, high aldosterone C Aldosterone-producing adenoma (Conn’s syndrome) C Bilateral adrenal hyperplasia C Glucocorticoid-remediable (suppressible) (hyper)aldosteronism C Adrenal carcinoma e rare Low renin, low aldosterone C Congenital adrenal hyperplasia C 11b
Hydroxylase deficiency C Liddle’s syndrome C Apparent mineralocorticoid excess Mineralocorticoid/glucocorticoid excess C Cushing’s syndrome C Corticosteroid therapy Other C Phaeochromocytomas/paragangliomas C Acromegaly C Primary hyperparathyroidism

Mark Sherlock MB BCh BAO MRCPI MD PhD is a Consultant Endocrinologist and Clinical Senior Lecturer at Tallaght Hospital Dublin and Trinity College Dublin, Ireland. He received his postgraduate endocrine training at Beaumont Hospital, Dublin and the Queen Elizabeth Hospital/University of Birmingham, UK. He obtained a postgraduate MD for a thesis studying morbidity and mortality in patients with acromegaly, and a PhD for studies relating to cortisol metabolism in muscle and in patients receiving hydrocortisone therapy. His main clinical and research interests are pituitary and adrenal disease and salt and water homeostasis. Competing interests: none declared. Isolda Frizelle MB BCh BAO MRCPI is a Specialist Registrar in the Department of Endocrinology, Tallaght Hospital Dublin, Ireland. Competing interests: none declared.

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Table 1

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ADRENAL DISORDERS

Confirmatory tests for primary hyperaldosteronism No single test is universally accepted as the gold standard to confirm PH; possible confirmatory tests include oral sodium loading, intravenous saline suppression and the fludrocortisone suppression test. Whichever test is used, the premise is to demonstrate failure of aldosterone suppression, which confirms PH.

Case detection for PH: who should be screened?2 C

C

C C C

C

Sustained blood pressure (BP) >150/100 mmHg, at three measurements obtained on different days, Hypertension (BP >140/90 mmHg) resistant to three conventional antihypertensive drugs, or BP controlled when taking four or more antihypertensive medications Hypertension and spontaneous (or diuretic-induced) hypokalaemia Hypertension and adrenal incidentaloma Hypertension and sleep apnoea Hypertension and family history of early-onset hypertension or cerebrovascular accident at <40 years of age Hypertensive first-degree relatives of patients with PH

Imaging for primary hyperaldosteronism Non-contrast computed tomography (CT) of the adrenal glands is indicated once confirmatory testing is complete. Adrenal vein sampling and/or functional positron-emission tomography (PET) may be required to confirm unilateral secretion of aldosterone, but is only required when surgery is planned (Figure 1). Management of primary hyperaldosteronism (Figure 1)2 Options for treatment of PH caused by an aldosterone-secreting adenoma include laparoscopic surgical excision; for patients who are not surgical candidates, a mineralocorticoid receptor antagonist (spironolactone, eplerenone) is indicated. Surgery is not indicated in bilateral adrenal hyperplasia (treatment is with spironolactone or eplerenone).

Table 2

comprises determination of plasma aldosterone:renin ratio (ARR), and, if the result is positive, one of the confirmatory tests to definitively confirm the diagnosis of PH before imaging. Importantly, patients must be potassium-replete before testing as hypokalaemia suppresses aldosterone production and can give a false-negative result. Several medications lead to alterations in ARR, and this should be taken into account when interpreting the results (Table 3). A positive screening test for PH is a high plasma ARR with plasma aldosterone >15 ng/dl (420 pmol/ litre). In the setting of spontaneous hypokalaemia and hypertension, undetectable renin and plasma aldosterone concentration >20 ng/dl (550 pmol/litre), it is suggested that confirmatory testing is not required.2

Glucocorticoid-remediable aldosteronism (GRA) The genes encoding aldosterone synthase and the adrenocorticotropic hormone (ACTH)-sensitive 11b-hydroxylase enzyme are 95% identical. In GRA, the promoter of the 11b-hydroxylase gene is fused to the coding region of aldosterone synthase. The product of this hybrid gene is an aldosterone synthase enzyme that is ACTH-sensitive. In individuals with GRA, ACTH increases the activity of aldosterone synthase, resulting in hyperaldosteronism. Treatment with glucocorticoids (to suppress ACTH) is highly effective.

Apparent mineralocorticoid excess (AME)

Interfering medications that can lead to false-positive or false-negative ARR results while screening for PH2 Agent

Effect on testing

Mineralocorticoid antagonism (e.g. spironolactone, eplerenone, amiloride) b-Adrenoceptor blockers, non-steroidal anti-inflammatory drugs Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, dihydropyridine calcium channel antagonists Direct renin inhibitors

Increased plasma renin activity, variable effect on plasma aldosterone Reduce/suppress plasma renin activity more than aldosterone Reduce plasma aldosterone, increase plasma renin activity

Products derived from liquorice root Oestrogen or hormone replacement therapy preparations

AME is an autosomal recessive condition associated with a defective 11b-hydroxysteroid dehydrogenase type II enzyme. This enzyme inactivates cortisol through conversion to cortisone in the kidney, preventing cortisol binding to the mineralocorticoid receptor (for which cortisol has the same affinity as aldosterone). In AME, cortisol is able to activate the mineralocorticoid receptor, leading to hypertension and hypokalaemia.

Liddle’s syndrome (pseudohyperaldosteronism) Liddle’s syndrome is an autosomal dominant condition in which mutation of the renal epithelial sodium channel (ENaC) produces loss of ability to degrade ENaC, leading to increased sodium retention and resultant hypertension.

Reduce plasma aldosterone, can increase or decrease plasma renin concentrations Decrease plasma renin concentrations Increase renin substrate

Phaeochromocytomas/paragangliomas Phaeochromocytomas and paragangliomas are catecholaminesecreting tumours arising from the adrenal medulla and extraadrenal ganglia, respectively. Chromaffin cells produce one or more catecholamines, which are degraded to normetanephrines, metanephrines and 3-methoxytyramine. In recent years, there has been increased understanding of the pathophysiology of PPGLs. A significant proportion of patients harbour an underlying germline mutation, including in the

Source: Modified from Funder et al.2

Table 3

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ADRENAL DISORDERS

Source: Adapted from Funder et al.2 Figure 1 Unilateral laparoscopic adrenalectomy is recommended for patients with documented unilateral PH (i.e. aldosterone-producing adenoma, unilateral adrenal hyperplasia) (1j555). If a patient is unable or unwilling to undergo surgery, medical treatment is recommended including a mineralocorticoid receptor (MR) antagonist (1j555). If an ARR-positive patient is unwilling or unable to undergo further investigations, it is recommended that medical treatment including an MR antagonist be initiated (1j55). Instead of proceeding directly to subtype classification, it is recommended that patients with a positive ARR undergo one or more confirmatory tests to definitively confirm or exclude the diagnosis (1j55). However, in the setting of spontaneous hypokalaemia, undetectable renin, and plasma aldosterone concentration (PAC) >20 ng/dl (550 pmol/litre), it is suggested that there may be no need for further confirmatory testing (2j5). It is recommended that, when surgical treatment is feasible and desired by the patient, an experienced radiologist should use adrenal vein sampling (AVS) to make the distinction between unilateral and bilateral adrenal disease (1j555). Younger patients (<35 years) with spontaneous hypokalaemia, marked aldosterone excess and unilateral adrenal lesions with radiological features consistent with a cortical adenoma on adrenal CT may not need AVS before proceeding to unilateral adrenalectomy (2j5).

succinate dehydrogenase family (SDHx) or related to neurofibromatosis, multiple endocrine neoplasia type 2 or Von Hippel eLindau syndrome (Figure 2).3 The clinical features of PPGLs are shown in Table 4.

Imaging of phaeochromocytomas/paragangliomas CT offers excellent spatial resolution of the thorax, abdomen and pelvis. Meta-iodobenzylguanidine (MIBG) scanning and magnetic resonance imaging (MRI) are also helpful in assessing these lesions. PET (e.g. using 18fluorine-labelled fluorodeoxyglucose) may be indicated pre- or postoperatively to establish the presence or absence of metastases (particularly in patients with SDHx disease).

Diagnosis of phaeochromocytomas/paragangliomas A high index of clinical suspicion is required to diagnose these rare tumours. Assessment of plasma or urinary concentrations of catecholamine secretion and metabolism are acceptable.3 Plasma metanephrine/normetanephrine concentrations offer the highest sensitivity, and are less susceptible to assay interference and more convenient for patient collection. Chromogranin A can serve as a useful postoperative tumour marker. Genetic testing is an important part of the management of patients with PPGLs and should be tailored to disease presentation, biochemical analysis and family history given the current spectrum of mutations in predisposing genes (Figure 2).

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Management of phaeochromocytomas/paragangliomas Surgical management remains the first-line treatment. Caution must be exercised in preparation for surgery, with appropriate aadrenoceptor blockade to prevent an intraoperative hypertensive crisis. A number of a-adrenoceptor blockers have been used, including phenoxybenzamine, which is introduced slowly and titrated upwards from 10 mg two or three times daily to a usual maximum dose of 1e2 mg/kg per day, the dose depending on

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ADRENAL DISORDERS

Decisional algorithm for genetic testing in patients with a proven PPGL PPGL diagnosis Syndromic presentation Metastatic

Targeted genetic testing

SDHB

SDHD, SDHC, VHL, MAX

Nonmetastatic

Skull base and neck

SDHD, SDHB, SDHC

Dopaminergic

SDHB, SDHD, SDHC

Noradrenergic

SDHB, SDHD, SDHC, VHL, MAX

Dopaminergic

SDHD, SDHB, SDHC

Noradrenergic

VHL

SDHD, SDHB, SDHC, MAX

Adrenergic

RET

TMEM127, MAX

Extra-adrenal

Adrenal

Dopaminergic, noradrenergic, and adrenergic phenotypes are defined as significant production of 3-methoxytyramine, normetanephrine and metanephrine, respectively, relative to combined production of all three metabolites.3 Reproduced from Lenders JW et al.3

Figure 2

when the patient is clinically a-blocked. Caution is required while titrating a-blockade upwards as patients with PPGLs are often volume-depleted; therefore volume expansion (intravenous, oral) is required in conjunction with a-blockade. Careful monitoring for postural hypotension/tachycardia is required. b-Adrenoceptor blockade should not be commenced until patients are adequately a-blocked, as unopposed b-blockade can lead to a hypertensive crisis. Non-cardioselective short-acting b-adrenoceptor blockers (e.g. propanolol) are usually initiated at low doses that are titrated slowly upwards as required before surgery. Surgery should be performed in a specialist centre with experienced endocrine, surgical and anaesthetist/intensivist support.

Clinical features of PPGLs Symptoms are often paroxysmal; patients can be asymptomatic C Headache (80%) C Sweating (70%) C Palpitations (70%) C Pallor (40%) C Nausea (40%) C Tremor (30%) C Weakness (30%) C Anxiety (20%) C Epigastric pain (20%) C Chest pain and dyspnoea (20%) Metastases can be present at diagnosis (10%) Bilateral tumours can be present (10%) Extra-adrenal tumours can occur (10%)

Cushing’s syndrome (CS) CS occurs in patients who have chronic glucocorticoid excess. It can be:  ACTH-dependent e usually from a pituitary adenoma (Cushing’s disease), but sometimes from non-pituitary

Table 4

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ADRENAL DISORDERS

(although around 30% of scans are ‘negative’, while pituitary incidentalomas can be mistakenly identified as the cause). In ectopic ACTH secretion, CT scanning of the neck, thorax, abdomen and pelvis is required, often in conjunction with isotope (e.g. octreotide) imaging. Adrenal CT scanning is required if biochemical testing suggests ACTH-independent CS.

tumours producing ectopic ACTH (small-cell carcinoma of the bronchus, neuro-endocrine tumours)  ACTH-independent e the most common cause being iatrogenic from prolonged exogenous glucocorticoid exposure or an adrenal adenoma (rarely adrenal carcinoma). Clinical presentation of Cushing’s syndrome Presentation can be with ‘classical’ manifestations of centripetal obesity, moon face, hirsutism and plethora, but findings can be more subtle than in classic textbook cases. Hypertension is present in approximately 75% of patients with CS, caused by a number of factors including increased mineralocorticoid activity and vasoconstriction.

Treatment of Cushing’s syndrome Surgical excision of the lesion causing CS is, if possible, first-line treatment. Excision via a trans-sphenoidal approach is recommended for pituitary adenomas. In CS caused by ectopic ACTH, surgical removal of the tumour can lead to cure, but this is not always possible. In CS caused by an adrenal tumour, resection, via either a laparoscopic (most cases) or an open approach (malignant tumours), is recommended depending on the size of tumour and whether it is malignant.5 Medical management is considered second line and involves drugs that interfere with cortisol synthesis (e.g. metyrapone, ketoconazole).5 A

Screening tests for Cushing’s syndrome These can include:4  elevated urine free cortisol (at least two measurements)  elevated late-night salivary cortisol (at least two measurements)  failure to suppress 09:00 hours cortisol to <50 nmol/litre following a 1 mg overnight dexamethasone suppression test (DST)  failure to suppress 09:00 hours cortisol to <50 nmol/litre following a low-dose DST (2 mg per day for 48 hours)

KEY REFERENCES 1 Choi M, Scholl UI, Yue P, et al. Kþ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science 2011; 331: 768e72. 2 Funder JW, Carey RM, Mantero F, et al. The management of primary aldosteronism: case detection, diagnosis, and treatment: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2016; 101: 1889e916. 3 Lenders JW, Duh QY, Eisenhofer G, et al. Pheochromocytoma and paraganglioma: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2014; 99: 1915e42. 4 Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2008; 93: 1526e40. 5 Nieman LK, Biller BM, Findling JW, et al. Treatment of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2015; 100: 2807e31.

Diagnosing the underlying cause of Cushing’s syndrome ACTH-dependent causes can be distinguished from ACTHindependent causes by measuring plasma ACTH (09:00 hours sample). If ACTH is low, the likely aetiology is exogenous glucocorticoids or adrenal pathology. Determining whether elevated ACTH originates from the pituitary (Cushing’s disease) or an ectopic source can be challenging and can require a number of tests including inferior petrosal sinus sampling.

Imaging in Cushing’s syndrome If biochemical testing suggests a pituitary source of ACTH, contrast-enhanced pituitary MRI is the investigation of choice

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