XIV. Treatment of Secondary Hypertension Due to Endocrine Causes

Prevention and Treatment

Subgroup Members:  Ally Prebtani, MD; Gregory Kline, MD; Ernesto L. Schiffrin, MD, PhD
Central Review Committee: Stella S. Daskalopoulou, MD, PhD; Kaberi Dasgupta, MD, MSc; Kelly B. Zarnke, MD, MSc; Kara Nerenberg, MD, MSc; Alexander A. Leung, MD, MPH; Kevin C. Harris, MD, MHSc; Kerry McBrien, MD, MPH; Sonia Butalia, BSc, MD; Meranda Nakhla, MD, MSc
Chair: Doreen M. Rabi, MD, MSc
This information is based on the Hypertension Canada guidelines published in Leung, Alexander A. et al. Hypertension Canada’s 2017 Guidelines for Diagnosis, Risk Assessment, Prevention, and Treatment of Hypertension in Adults. Can J Cardiol 2017; 33(5): 557-576.

Recommendations

  1. Treatment of hyperaldosteronism and pheochromocytoma are outlined in Supplemental Tables S7 and S8, respectively.

Background

Treatment of hyperaldosteronism and pheochromocytoma are outlined in Supplemental Tables S7 and S8, respectively.

Recommendations on diagnosis and treatment of hypertension in the setting of pheochromocytoma and hyperaldosteronism were first made in 2001. For the initial background and references, please see Part VI, recommendations A and B, which can be found in the citations – Part 1.

Supplemental Table S7. Hyperaldosteronism
Screening
i. Plasma aldosterone and plasma renin activity or renin mass/concentration (see ii below for conversion factors) should be collected as follows:
  1. In the morning after the patient has been ambulatory (sitting, standing, or walking) for at least 2 hours.
  2. Patients should be seated for 5-15 minutes prior to the blood draw.
  3. Hypokalemia should be corrected and sodium intake should be liberalized.
  4. Agents that markedly affect the results of testing (aldosterone antagonists, potassium sparing and wasting diuretics) should be withdrawn at least 4-6 weeks prior.
  5. If the results are not diagnostic, and if hypertension can be controlled with medications less likely to affect testing (slow-release verapamil, hydralazine, prazosin, doxazosin, and terazosin), repeat testing 2 weeks after withdrawing the following medications that can interfere with test accuracy: β-blockers, centrally acting α-2 agonists, angiotensin receptor blockers, angiotensin converting enzyme inhibitors, directly acting renin inhibitors, dihydropyridine calcium channel blockers.
  6. False positive results may occur with direct renin mass/concentration if the patient is a woman using an oral contraceptive pill. If possible, oral contraception should be discontinued for 1 month prior to testing, or alternately, plasma renin activity should be measured instead.
ii. Suggested Conversion Factors:
A. To estimate: B. From: Multiply (B) by:
Plasma renin concentration (ng/L) Plasma renin activity (ng/mL/hr) 0.192
Plasma renin activity (ng/L/sec) Plasma renin activity (ng/mL/hr) 0.278
Plasma aldosterone concentration (pmol/L) Plasma aldosterone concentration (ng/dL) 28
iii. Interpretation of a positive screening test is dependent upon local laboratory method for renin measurement but assumes standard reporting of aldosterone in pmol/L:
Renin method used Aldosterone-to-renin ratio: higher sensitivity, lower specificity Aldosterone-to-renin ratio: lower sensitivity, higher specificity
Plasma renin activity (ng/ml/h) 555 750
Direct renin concentration (mIU/L) 60 91
Direct renin concentration (ng/L) 100 144
Confirmatory Testing
iv. If one of the following criteria is met, autonomous hypersecretion of aldosterone is confirmed (interfering drugs should continue to be held, as outlined above):
  1. saline loading tests (perform either):
    1. Administer 2 litres of normal saline intravenously over 4h with the patient in a recumbent position. This test is conraindicated in the presence of severe, uncontrolled hypertension or congestive heart failure. Primary aldosteronism is defined as a post-infusion plasma aldosterone >280 pmol/L. If <140 pmol/L, primary aldosteronism is unlikely. Values in between are considered indeterminate.
    2. Administer 200 mmol/day of oral sodium (i.e., equivalent to >5 g/day of sodium; >12 g/day of sodium chloride; or >2 tsp/day of salt) for three days, with primary aldosteronism defined as a 24-hr urinary aldosterone >33 nmol/d (measured from the morning of Day 3 to the morning of Day 4). If <28 nmol/day, primary aldosteronism is unlikely.
  2. A plasma aldosterone to PRA ratio >1400 pmol/L/ng/ml/hr (or >270 pmol/L/ng/L), with a plasma aldosterone >440 pmol/L.
  3. Captopril suppression test: Administer 25-50 mg captopril orally after the patient has been sitting or standing for 1 hour. While seated, renin and plasma aldosterone levels should be measured at time zero and 1 to 2 hours after ingestion. Primary aldosteronism is unlikely if plasma aldosterone is suppressed by >30% following captopril ingestion. In primary aldosteronism, plasma aldosterone remains elevated, while renin remains suppressed.
Subtype Classification
v. Differentiating potential causes of confirmed primary aldosteronism (unilateral vs bilateral secretion):
  1. CT-scanning (or MRI) can help localize the presence of adrenal lesion(s). If imaging demonstrates an adrenal lesion/adenoma, it may be non-functional. Therefore, if surgery to remove a suspected unilateral source of primary aldosteronism is planned, selective adrenal venous sampling should be considered first (to verify that abnormally appearing adrenal gland is the source of hypersecretion).
  2. For patients with established primary hyperaldosteronism and in whom surgery is an option, selective adrenal venous sampling should be considered to differentiate unilateral from bilateral overproduction of aldosterone.
  3. Adrenal venous sampling should be conducted in centers with experience in performing this diagnostic technique.
  4. We suggest selective genetic testing for glucocorticoid remediable aldosteronism in patients with confirmed primary aldosteronism and either:
    1. A family history of primary aldosteronism or stroke at young age (≤40y); or
    2. Onset of hypertension ≤20y and negative imaging.
Treatment
vi. Treatment is informed by subtype classification (unilateral vs. bilateral secretion):
  1. Surgery with laparoscopic ipsilateral adrenalectomy should be considered for unilateral forms of hypersecretion (e.g., aldosterone-producing adenonas). Patients should be followed closely after surgery as a significant proportion may remain hypertensive
  2. Mineralocorticoid receptor antagonists, (particularly spironolactone in low to moderate doses) are quite effective for those with bilateral disease (e.g., idiopathic/bilateral adrenal hyperplasia). Monitoring of potassium and creatinine is required, especially if combined with angiotensin receptor blockers or angiotensin converting enzyme inhibitors.
  3. Mineralocorticoid receptor antagonists hould be considered for individuals who are not surgical candidates or for those who refuse surgery (even with confirmed unilateral hypersecretion). Blood pressure lowering responses to other antihypertensives (e.g., angiotensin receptor blockers, angiotensin converting enzyme inhibitors, and calcium channel blockers) are often only modest-to-moderate.
Supplemental Table S8. Pheochromocytoma
Screening AND DIAGNOSIS
i. To screen for pheochromocytoma
  1. 24-hr urinary total metanephrines and catecholamines (sensitivity 90-95%) or 24-hr urine fractionated metanephrines (sensitivity of about 95%) should be measured. Concomitant measurement of 24-hr urine creatinine should also be performed to confirm accurate collection.
  2. Plasma free metanephrines and free normetanephrines, where available, may also be considered (sensitivity up to 99%).
  3. Urinary VMA measurements should not be used for screening.
ii. Keep in mind that potential false positives should be considered in the setting of:
  1. Interfering drugs
  2. Incorrect patient preparation and positioning (for plasma metanephrine measures)
  3. Mild elevation of screening values (i.e., less than two-fold upper limit of normal)
  4. Normal values on repeat testing
  5. Only 1 abnormal biochemical test in the panel of assays
  6. Atypical imaging results for pheochromocytoma
  7. A low pre-test probability of pheochromocytoma
  8. Acute illness/hospitalization
iii. In the presence of borderline biochemical test results or potentially false positive results, repeat testing may be performed and/or the clonidine suppression test may be used. This should be done before imaging is requested to avoid identifying potential incidentalomas.
iv. Imaging (e.g., CT, MRI, ± MIBG) should generally be performed only done after biochemical confirmation of disease.
v. Definitive treatment is with surgical resection. Preoperative planning is recommended for blood pressure control and volume expansion:
  1. α-blockade should be started 10-14 days preoperatively. Typical options include oral phenoxybenzamine (a long-acting, non-selective, irreversible α-blocker), prazosin, or doxazosin.
  2. Other anti-hypertensives may be added as necessary but diuretics should be avoided if possible. Oral β-blockers may be considered after achieving adequate α-blockade to control tachycardia and prevent arrhythmias during surgery.
  3. Volume replacement and liberal sodium intake should be encouraged as volume contraction is common in this condition. Intravenous volume expansion in the perioperative period is recommended to prevent postoperative shock.
vi. Postoperatively, long-term follow-up is recommended with urinary or plasma metanephrines to screen for recurrence, especially in those with a genetic predisposition.
vii. Genetic testing should be considered for individuals <50 years of age and for all patients with multiple lesions, malignant lesions, bilateral pheochromocytomas or paragangliomas, or a family history of pheochromocytoma or paraganglioma.