Secondary Causes of Hypertension

Randy Laine

Patricia F. Kao

Introduction

This chapter will cover nonrenovascular etiologies of secondary hypertension (sHTN), focusing specifically on hormonal and monogenic causes.
The work-up for secondary causes can be expensive and time consuming. Thus, the cost-effective diagnosis and management of sHTN requires a thorough knowledge of the clinical signs and symptoms, risk factors, and diagnostic tools available.
sHTN is defined as high blood pressure (BP) from an identifiable cause, unlike primary, or essential hypertension, which has no clear identifiable etiology.
A secondary cause can be identified in about 15% of prevalent patients with hypertension (HTN).¹
In hypertensive adults <age 40 the prevalence of sHTN is approximately 30%.
The prevalence rates of specific forms of sHTN are highly variable and remain unclear, likely due to heterogeneity in diagnostic criteria and sampling bias.
Renal parenchymal disease has been reported as the most common cause of sHTN. It is unclear whether HTN is the cause or the result for the chronic kidney disease (CKD) in most patients.
- All patients who present with HTN should be screened for renal disease.
- In the large longitudinal Chronic Renal Insufficiency Cohort (CRIC) the prevalence of HTN increased with decreasing glomerular filtration rate (GFR): 67% in patients with an estimated GFR (eGFR) >60 mL/min/1.73 m², 92% in those with eGFR <30 mL/min/1.73 m².²
- The various forms of renal parenchymal diseases that are classically associated with HTN are discussed in other chapters extensively, and will not be discussed further here. These are typically a high renin type of HTN and may cause a secondary hyperaldosteronism.
Renal artery stenosis has been reported as the second most common cause of sHTN. (See Chapter 17.)
Various medications, as outlined in Table 18-1, are associated with secondary or resistant hypertension and patients should be asked about use of these medications during evaluation.³
This chapter will focus primarily on endocrine/hormonal causes of sHTN: primary and familial hyperaldosteronism, Cushing syndrome, and rare conditions, such as pheochromocytoma, syndrome of apparent mineralocorticoid excess (SAME), Liddle syndrome, glucocorticoid-remediable aldosteronism (GRA), pseudohypoaldosteronism type II (Gordon syndrome), and activation mutation of mineralocorticoid receptor (MR, sometimes referred to as Geller syndrome).
Obstructive sleep apnea (OSA) and thyroid disease are two common and important medical conditions that are often overlooked as causes of sHTN. Since etiology of hypertension associated with these conditions does not have a direct correlation with renal pathophysiology, they are outside of the scope of this chapter, and will not be discussed. Patients who have risk factors for OSA and have uncontrolled HTN should be referred for a sleep study.
A comprehensive list of causes of secondary and resistant HTN is shown in Table 18-1.

TABLE 18-1 COMMON ETIOLOGIES OF SECONDARY OR RESISTANT HYPERTENSION

Renal disorders	Renal disease of any etiology Glomerular disease Polycystic kidney disease Renal artery stenosis (fibromuscular dysplasia or atherosclerotic disease)
Systemic disorders	Obstructive sleep apnea Hypo- or hyperthyroidism Coarctation of the aorta Pheochromocytoma
Medications	Oral contraceptives Attention deficit disorder medications (e.g., amphetamine, methylphenidate, etc.) NSAIDs Corticosteroids Nasal decongestants (sympathomimetic agents such as phenylephrine and pseudoephedrine) Erythropoietin-stimulating agents (i.e., erythropoietin, darbepoetin) Tyrosine kinase inhibitors Calcineurin inhibitors Herbal products (e.g., ephedra, ginseng) Caffeine (excessive use) Weight loss agents (e.g., phentermine) Illicit drugs (e.g., cocaine, methamphetamine) Anabolic steroids
Disorders associated with renin–aldosterone–angiotensin system	Primary hyperaldosteronism Adrenal adenoma (aldosteronoma or Conn syndrome) Idiopathic aldosteronism Unilateral or bilateral adrenal hyperplasia Adrenal carcinoma Glucocorticoid-remediable aldosteronism Syndrome of apparent mineralocorticoid excess Renin-secreting tumor Congenital adrenal hyperplasia Liddle syndrome Gordon syndrome Activating mutation of mineralocorticoid receptor gene

Primary Aldosteronism

General Principles

Primary aldosteronism (PA, also known as Conn syndrome) occurs when aldosterone secretion is independent of the normal regulatory pathway of the renin–angiotensin–aldosterone system. Specifically, the feedback signals that normally suppress aldosterone, such as volume expansion an increased sodium intake are ineffective in PA.
Aldosterone secretion is autonomous. Renin levels are low due to negative feedback exerted by the excess aldosterone.
PA is one of the few potentially curable forms of sHTN, so it is important to detect and initiate treatment in a timely manner.
Prevalence is unclear but it has been estimated that PA is present in about 5% to 10% of patients with HTN.
Aldosterone is a mineralocorticoid that is produced by the zona glomerulosa, the outer region of the adrenal gland.
The primary action of aldosterone is on the principal cell of the cortical collecting tubule (CCT). When it binds the MR, this results in increased activity of basolateral Na-K-ATPase, the epithelial sodium channel (ENaC), and the renal outer medullary potassium channel (ROM-K). The net effect is increased reabsorption of sodium and increased secretion of potassium in the renal CCT.
There are several pathophysiologic etiologies of PA. In PA, aldosterone secretion is independent of renin.
The most common cause of PA is hyperactivity of one or both adrenal glands.
- Unilateral disease is typically the result of an aldosterone-producing adenoma (APA, also referred to as an adrenal adenoma, adrenocortical adenoma, or aldosteronoma). These benign tumors are generally <2 cm in diameter. They are more common in women than men.
- Bilateral disease is typically characterized by bilateral micro- or macronodular adrenal hyperplasia. This is also sometimes referred to as idiopathic aldosteronism. This is more common in men than women, and presents later in life.
- There are conflicting reports in the literature as to whether adrenal adenomas or bilateral adrenal hyperplasia is more common, but these are the two most common causes of PA.
Less common causes of PA include unilateral adrenal hyperplasia, malignant adrenal carcinoma, familial hyperaldosteronism, and ectopic aldosterone-producing tumor, each of which account for only 1% to 2% of cases of PA.
- Familial hyperaldosteronism type I (FH-I) is a rare, genetic, autosomal dominant form of PA and is also referred to as glucocorticoid-remediable aldosteronism (GRA).⁴ In this disease, a chimeric gene encoding 11-beta hydroxylase and aldosterone synthase results in a hybrid form of aldosterone synthase that is adrenocorticotropic hormone (ACTH)-sensitive. Normally, ACTH is only a minor regulator of aldosterone secretion in an acute and transient fashion. However, in GRA, secretion of aldosterone is regulated completely by ACTH rather than by the renin–angiotensin system. This results in oversecretion of aldosterone.
- Other forms of hyperaldosteronism such as FH-II (familial occurrence of aldosterone adenomas), FH-III (mutations of the potassium channel) and the newly characterized FH IV (mutations of genes that code for calcium channel) are exceedingly rare.⁵^,⁶

Diagnosis

Clinical Presentation

The classic presentation of PA is moderate or severe hypertension, hypokalemia, and metabolic alkalosis.
However, patients may be asymptomatic, some patients are normotensive, and most patients are not overtly hypokalemic.⁷^,⁸
Patients rarely present with malignant hypertension.
Serum sodium levels are normal or on the high end of the normal range.

OSA prevalence is increased in patients with PA.⁹

TABLE 18-2 HIGH-RISK PATIENTS WHO SHOULD BE SCREENED FOR PRIMARY ALDOSTERONISM

Sustained elevated BP (SBP ≥150 mm Hg and/or DBP ≥100 mm Hg)
Hypertension (BP >140/90 mm Hg) resistant to three conventional antihypertensive drugs, including a diuretic
Controlled BP (BP <140/90 mm Hg) with ≥4 antihypertensive drugs
HTN and spontaneous or diuretic-induced hypokalemia
HTN and adrenal incidentaloma identified on imaging
HTN and OSA
HTN and a family history of early-onset HTN or cerebrovascular accident (<40 yrs old)
Case detection for all hypertensive first-degree relatives of patients with PA

BP, blood pressure; DBP, diastolic blood pressure; HTN, hypertension; OSA, obstructive sleep apnea; SBP, systolic blood pressure.
Adapted from Young WF, Calhoun DA, Lenders JWM, et al. Screening for endocrine hypertension: an Endocrine Society Scientific Statement. Endocr Rev. 2017;38:103–122.

Most patients with PA present in their third to sixth decades of life.
In children with hypertension, with or without a family history of HTN, GRA should be suspected. Patients may be asymptomatic or they may present with failure to thrive, weakness, and hypokalemia in infancy.

Diagnostic Testing

Evaluation for PA involves initial screening tests, followed by confirmatory testing in some cases, and then localization using radiologic techniques and imaging.
Table 18-2 shows which high-risk patients should be screened for PA, as recommended by the Endocrine Society clinical practice guideline.¹⁰
Other guidelines have also recommended screening for PA in any patient with untreated HTN with low normal serum potassium levels of unknown cause.

Laboratories

In PA, the plasma renin level is low, due to the effect of negative feedback from excess aldosterone. However, random plasma renin and aldosterone levels are not sensitive for detection of PA.

The aldosterone to renin ratio (ARR) is the most readily available and commonly used screening test for PA. ARR >30 is highly suggestive of PA, with some studies reporting 1-hour upright ARR ≥35.90 as having 100% sensitivity and 92.3% specificity.¹¹ In order to maximize the sensitivity of the ratio, the ARR should be repeated more than once and should be checked under the following conditions:

Hypokalemia must be corrected
Encourage the patient to follow a liberal sodium diet, which suppresses aldosterone in normal circumstances
Secretion of aldosterone is positional and follows a circadian rhythm (peaks during sleep), so plasma levels of aldosterone and renin should be checked in the morning in seated patients who have been in the upright position (i.e., sitting, standing, or walking) for 2 to 4 hours
Diuretics should be withdrawn for at least 4 weeks

Antihypertensive medications that block the renin–angiotensin system, dihydropyridine calcium channel blockers, β-blockers, and clonidine should be held for 2 weeks
prior to testing if possible. If antihypertensive medications are required during this period, use nondihydropyridine calcium channel blockers (e.g., verapamil), hydralazine, and prazosin or doxazosin, where possible

TABLE 18-3 FACTORS THAT AFFECT THE RELIABILITY OF THE ALDOSTERONE TO RENIN RATIO (ARR)

False-Negative ARR	False-Positive ARR
Dietary salt restriction Uncorrected hypokalemia Concomitant malignant or renovascular hypertension Pregnancy Potassium sparing diuretics Dihydropyridine calcium channel blockers Angiotensin-converting enzyme inhibitors (ACE-I) Angiotensin receptor antagonists (ARB) Selective serotonin reuptake inhibitors (SSRI)	β-Adrenergic blockers α-Methyldopa Clonidine Nonsteroidal anti-inflammatories CKD Age >65 yrs old Luteal phase of menstruation Familial hyperkalemic hypertension (pseudohypoaldosteronism type II, Gordon syndrome)

In cases where antihypertensive medications cannot be altered or held prior to testing, refer to Table 18-3 for the potential effects of interfering medications on the ARR.
Note that screening for PA using an ARR is not recommended in all patients with hypertension, since the prevalence of this disease remains relatively low compared to essential hypertension and this testing is not cost effective in low clinical suspicion. In addition, it is important to screen with the ARR only in high-risk patients, as the withdrawal of hypertensive agents in preparation of collecting the ARR may lead to adverse outcomes in patients with severe hypertension.

If a patient has a positive blood or urine screening test for PA, confirmatory testing may be performed using one of four methods or the patient may proceed directly to lateralization methods discussed in Imaging (this will also depend on the medical center and the availability of specific lateralization techniques). There is no established gold standard for confirmatory testing and some authors suggest that confirmatory testing does not add additional diagnostic value and that all patients should proceed to imaging and lateralization.

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