XIV. Treatment of Secondary Hypertension Due to Endocrine Causes

Prevention and Treatment

Subgroup Members: Ernesto L. Schiffrin, MD, PhD; Ally Prebtani, MD
Central Review Committee: Doreen M. Rabi, MD, MSc; Stella S. Daskalopoulou, MD, PhD; Kaberi Dasgupta, MD, MSc; Kelly B. Zarnke, MD, MSc; Kara Nerenberg, MD, MSc; Kerry McBrien, MD, MPH; Kevin C. Harris, MD, MHSc; Alexander A. Leung, MD, MPH
Chair: Raj Padwal, MD, MSc

This information is based on the Hypertension Canada guidelines published in Leung, Alexander A. et al. Hypertension Canada’s 2016 Canadian Hypertension Education Program Guidelines for Blood Pressure Measurement, Diagnosis, Assessment of Risk, Prevention, and Treatment of Hypertension. Can J Cardiol 2016; 32(5): 569-588.

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 and diagnosis
Screening
Re-printed with permission of the Canadian Hypertension Education Program.
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markedly affect the results of testing (aldosterone antagonists, potassium sparing and wasting diuretics) should be withdrawn at least 4-6 weeks prior.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 two weeks after withdrawing the following medications that can interfere with test accuracy: beta-blockers, centrally acting alpha-2 agonists, angiotensin receptor blockers, angiotensin converting enzyme inhibitors, directly acting renin inhibitors, dihydropyridine calcium channel blockers.
ii. Renin, Aldosterone and Ratio 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. Definition of a positive screening test: plasma aldosterone-to-renin activity ratio greater than 750 pmol/L/ng/ml/hr (or 144 pmol/L/ng/L when renin is measured as renin mass or concentration).
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 two litres of normal saline intravenously over 4h with the patient in a recumbent position. Primary hyperaldosteronism is defined as a post-infusion plasma aldosterone >280 pmol/L. If <140 pmol/L, primary hyperaldosteronism is unlikely. Values in between are considered indeterminate;
    2. Administer oral sodium, 200 mmol/day for three days, with primary hyperaldosteronism 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 hyperaldosteronism is unlikely.
  2. a plasma aldosterone to PRA ratio greater than 1400 pmol/L/ng/ml/hr (or 270 pmol/L/ng/L), with a plasma aldosterone greater than 440 pmol/L.
  3. captopril suppression test: Administer 25-50mg 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 1-2 hours after ingestion. Primary hyperaldosteronism is unlikely if plasma aldosterone is suppressed by >30% following captopril ingestion. In primary hyperaldosteronism, plasma aldosterone remains elevated, while renin remains suppressed.
Subtype Classification
v. Differentiating potential causes of confirmed primary hyperaldosteronism (unilateral vs bilateral secretion):
  1. Adrenal CT-scanning or MRI can help localize the 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 hyperaldosteronism 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, negative imaging studies, 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. In patients with confirmed primary hyperaldosteronism and either:
    1. a family history of primary hyperaldosteronism or stroke at young age (≤40y);
    2. onset of hypertension ≤20y and negative imaging; we suggest genetic testing for Glucocorticoid Remediable Aldosteronism
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/unilateral adrenal hyperplasia). Post–operatively, consider stopping/reducing antihypertensive therapy (especially MRA’s, ACEI/ARBs) & potassium supplements and closely following the blood pressure, potassium, and creatinine due to a subset developing transient hypoaldosteronism and worsening renal dysfunction.
  2. Patients should be followed in the long term after surgery as a proportion may remain hypertensive.
  3. Post-operative measurement of the aldosterone-renin ratio is recommended as part of the post-operative assessment; a curative surgery should result in ARR normalization.
  4. Mineralocorticoid receptor antagonists (MRAs), particularly spironolactone in low to moderate doses, are quite effective for those with bilateral disease (e.g., idiopathic hyperaldosteronism/bilateral adrenal hyperplasia). Monitoring of potassium/creatinine is required, especially if used with ACEI/ARBs.
  5. MRAs should be considered for individuals who are not surgical candidates or for those who refuse surgery (even with confirmed unilateral hypersecretion). Other antihypertensives (e.g., amiloride, angiotensin receptor blockers, angiotensin converting enzyme inhibitors, and calcium channel blockers) are considered second line because they do not lower blood pressure as well as the MRAs. Amiloride is more effective than the other non-MRAs. Beta blockers are not very effective in this setting.
  6. Glucocorticoid Remediable Hyperaldosteronism (GRA) is best treated with a glucocorticoid, preferably dexamethasone or prednisone, at the lowest effective dose. If needed, MRAs may be added to achieve additional blood pressure control and normokalemia.
  7. Adrenal carcinoma most often requires surgical resection plus MRAs +/- mitotane therapy and other anti-neoplastic therapies depending on the stage of the disease. This is best done in a multidisciplinary Oncology setting.
Supplemental Table S8. Pheochromocytoma: Screening and diagnosis
Screening
Re-printed with permission of the Canadian Hypertension Education Program.
Biochemical screening tests for pheochromocytoma:
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 100%) 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. mild elevation of screening values (i.e., less than two-fold upper limit of normal)
  3. normal values on repeat testing
  4. only 1 abnormal biochemical test in the panel of assays
  5. atypical imaging results for pheochromocytoma
  6. a low pre-test probability of pheochromocytoma
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 should generally be only done after biochemical confirmation eg. CT, MRI, ± MIBG
Treatment
v. Definitive treatment is with surgical resection. Preoperative planning is recommended for blood pressure control and volume expansion:
  1. Alpha blockade should be started 10-14 days preoperatively. Typical options include oral phenoxybenzamine (a long-acting, non-selective, irreversible alpha- blocker), prazosin, or doxazosin.
  2. Other anti-hypertensives may be added as necessary but diuretics should be avoided if possible. Dihdydropyridine calcium channel blockers are most commonly used add on agents for blood pressure control. Oral beta-blockers may be considered after achieving adequate alpha 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.
  4. Immediately post-op, consider stopping anti-hypertensives. Patients may also need aggressive intravenous fluids post-op.
vi. Postoperatively, annual 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, paragangliomas, or a family history of pheochromocytoma or paraganglioma.