Identifiable Hypertension: A New Spectrum

Authors


Address for correspondence: Lawrence R. Krakoff, MD, Professor of Medicine, Icahn School of Medcine at Mount Sinai, Cardiovascular Center, Box 3000, 5 East 98th Street, New York, NY 10029-6574.

E-mail: Lawrence.Krakoff@mssm.edu

Since the original description of hypertension as Bright's disease, there has been a distinction between high blood pressure related to an underlying condition and high blood pressure that occurs on its own: “secondary hypertension” and “primary or essential hypertension,” respectively.[1] In 2003, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) introduced “identifiable hypertension,” replacing “secondary hypertension.”[2] However, the implications of the two terms may not be exactly the same. “Secondary” suggests a specific pathologic and curable cause such as pheochromocytoma. However, “identifiable,” as used in JNC 7, has a broader context that often includes found disorders strongly associated with hypertension with multiple causes. Each form of identifiable hypertension, even when not curable, can be linked to specific characteristics and strategies for management that go beyond the usual treatment of hypertension.

Identifiable hypertension has not displaced secondary hypertension in publications since 2003, as indicated in Table 1. However, the landscape of identifiable hypertension has expanded. First, there is general recognition that several very common disorders, obesity, the metabolic syndrome, adult type 2 diabetes, and sleep apnea syndrome are often coexistent with hypertension. Comprehensive management of these conditions adds several modalities in addition to lowering blood pressure. Second, the causes of classic secondary hypertension are more easily found, either by intention or by accident (eg, incidenalomas) with modern biochemical screening and noninvasive imaging. Third, several rare forms of hypertension occurring in family clusters have become extensively defined by genetic studies that can be applied to family screening and to selection of highly specific monotherapy. The window into monogenic mechanisms for control of blood pressure offered by these disorders opens potential for application to significant insights for larger populations in which heterozygous mutations may be found that raise or lower pressure.[3] Last, hypertension as an adverse effect of legal or illegal drugs has also become more frequent.

Table 1. Publications Using Either Identifiable or Secondary Hypertension
IntervalIdentifiable (I)Secondary (S)Ratio I/S
  1. PubMed search on March 20, 2013, for either “Identifiable Hypertension” or “Secondary Hypertension” for accumulation over past intervals: “10” = past 10 years. Each search excluded “glaucoma,” “pulmonary hypertension,” “portal hypertension,” and “intracranial hypertension.” Results are shown for the past 10, 5, 3, 2, and 1 year, respectively.

YearsNumberNumber%
Past 1011150382.2
Past 55728852.0
Past 35124502.1
Past 24419022.3
Past 13012942.3

This brief review will highlight how “identifiable hypertension” is a useful basis for a systematic approach to patients for whom the varied forms of identifiable hypertension can be linked to comprehensive and improved management.

Prevalent Forms of Identifiable Hypertension

Hypertension is often found in patients who also have ≥1 of the conditions that are described in Table 2. The supplemental measures for optimal therapy of these disorders are also shown. For overweight patients, greater emphasis on weight reduction through diet and exercise may suffice, but in those with definite obesity and overall low operative risk (generally younger patients), bariatric surgery may be considered and prove beneficial.[4-6] The metabolic syndrome often includes hypertension and type 2 diabetes or prediabetes with insulin resistance.[7] This syndrome demands greater attention to lipid risk and careful management for prediabetes.[8] The sleep-apnea syndrome requires supplemental management to achieve weight reduction and improve nocturnal oxygenation.[9] Adult-onset diabetes is included in this list because of its frequent occurrence with hypertension and the need for attention to enhance glucose tolerance and for consideration of appropriate goals for antihypertensive therapy.[10-12]

Table 2. Identifiable Hypertension: Most Common Forms
EntityPrevalence in HypertensionSpecial Management
Obesity hypertension20%–30%Diet, anorexigenic drugs, bariatric surgery
Metabolic syndrome: combination of overweight, low high-density lipoproteinAge-related 15%–30%Assessment and treatment for lipid disorders, prediabetes, insulin resistance
Sleep apnea syndrome5%–30% related to age and weightSomnography, obesity management. Nighttime positive pressure ventilation
Type 2 diabetes15%+Lifestyle, diet, exercise. Medications to improve glucose tolerance. Selection of appropriate blood pressure goal

Traditional Identifiable Hypertension

Table 3 lists the diagnoses that are often considered when screening for secondary hypertension is recommended. Several are curable by intervention (either surgery or endovascular procedures). Many can be identified by a careful and focused medical history, physical examination, and available laboratory tests. The diagnoses listed in Table 3 can be conveniently divided into 3 catagories: (1) Renal disorders: chronic renal diseases and renal artery stenosis; (2) Adrenal cortical disorders: primary aldosteronism and Cushing's syndrome; (3) Adrenal chromaffin tissue disease: pheochromocytoma; and (4) Vascular: coarctation of the aorta. Based on recent surveys, the most prevalent of these forms of identifiable and potentially curable forms of hypertension are primary aldosteronism[13, 14] and atherosclerotic renal artery stenosis.[15, 16] The estimated cure rates for hypertension, if available, are shown in Table 3. In general, cure rates are higher for younger patients with shorter duration of hypertension compared with older patients with longer duration of hypertension. Following successful interventions, either surgery (primary aldosteronism, Cushing syndrome, pheochromocytoma) or endovascular procedures (angioplasty or stenting for renal artery stenosis, or for coarctation of the aorta), long-term surveillance is necessary to treat subsequent hypertension and detect recurrent disease.

Table 3. The Traditional or Most Familiar Forms of Identifiable Hypertension (Once Secondary Hypertension)
DisorderPrevalence (%) in Hypertensive PopulationCurable Yes/No (%) CurableSpecial ManagementGenetic Origin
  1. Abbreviations: KEEP, Kidney Early Evaluation Program; NHANES, National Health and Nutrition Examination Survey.

  2. a

    Tolvaptan is approved for only 30 days according to recent Food and Drug Administration warnings because of hepatic toxicity. The report that this drug may reduce growth of renal cysts in adult polycystic kidney disease (APCKD) should be viewed as evidence for concept. Perhaps a safe, effective vasopressin V2 antagonist will be developed for this purpose.

Chronic renal disease including all except APCKD15% NHANES 27% KEEPNoHighly dependent on specific diagnosisMostly no. Some forms yes.
APCKD≈0.1% of populationNoTolvaptan.a Surveillance for complications, eg, cerebral aneurysmsYes. Two specific genotypes
Renal artery stenosis due to fibromuscular dysplasia0.1%Yes (50%) Age-relatedImaging, Inter-vention: balloon angioplasty, stenting Search for disease in other arteriesTrends only
Renal artery stenosis causedby atherosclerosis5%–10%Yes (10%–20%) hypertension. Possible prevention of renal failureImaging, intervention: balloon angioplasty, stenting Atherosclerotic risk factorsSome relationship to inherited hyperlipidemias
Primary aldosteronism5%–10% of hypertensionYes, especially in younger patientsEndocrine tests, imaging, AVSNo for sporadic cases. Rare familial forms
Cushing syndromeRareYesExtensive endocrine and imaging evaluation for appropriate surgeryNo. Rare familial forms
PheochromocytomaRareYes. Recurrence or malignant in 5%–10%Special biochemical and imaging, surgery, pharmacologic blockadeSometimes, MEN 2, von Hippel, neurofibromatosis
Coarctation of aortaUncertain <1%Yes. Post-coart hypertension frequentSurgery or intervention with angioplasty or stentNot known, associated with congenital abnormalities Turner's

Rare or Exotic Forms of Identifiable Hypertension With Lessons to Tell

Astute clinical observation combined with modern medical science has led to recognition of a number of very rare forms of hypertension that can now be identified and characterized with regard to pathophysiology and, in some instances, specific genetic mechanisms. These are listed in Table 4. The adrenogenital syndromes, sometimes called congenital adrenal hyperplasias are pediatric disorders associated with abnormal gender development. Loss of function mutations in either the 11-OH ase or 17-OH pathways lead to excess production of desoxycorticosterone and resultant mineralocorticoid hypertension with suppressed plasma renin activity and hypokalemia.[17-19] Another variant in the low renin group is apparent mineralocorticoid excess, caused by defective 11 steroid dehydrogenase reducing conversion of cortisol to a far less active mineralocorticoid receptor, cortisone.[17-19]

Table 4. Rare, Recently Discovered Identifiable Hypertension
DisorderApproximate Prevalence or Gene FrequencyGenetic Origin: PatternClinical FeaturesSpecific Treatment
  1. Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging.

  2. a

    Normalization by monotherapy target to specific genetic phenotype.

Congenital adrenal hyperplasia with hypertension 11-OH dehydroxylase deficiency YesVirilization, precocious pubertyGlucocorticoid management
17-OH hydroxylase deficiencyVery rareYesWomen: lack of feminizing at pubertyGlucocorticoid management
Apparent mineralocorticoid excess 11 steroid dehydrogenase deficiencyVery rareYesEarly onset, hypokalemia, low renin, low aldosterone, normal cortisolGlucocorticoid management
Glucocorticoid remediable hypertension. Type I familial aldosteronismVery rareYesEarly onset, low renin, elevated aldosterone corrects with low dose glucocorticoidsGlucocorticoid management
Familial aldosteronism, not glucocorticoid remediable hypertension. Type II familial aldosteronismVery rareYesHypertension, low potassium, low renin, high aldosteroneMineralocorticoid receptor blockade. In rare cases, adrenalectomy
Pseudohypoaldosteronism type 2, Gordon's syndromeVery rareYesHypertension with high potassium, low renin, low aldosteroneThiazide-type diuretic
Liddle syndromeVery rareNoaHypertension, low potassium, low renin and normal-low aldosteroneAmiloride monotherapy
Renin-secreting juxtaglomerlar tumor[27]UnknownNoHigh renins, secondary aldosteronism. Respond well to anti-renin therapy. CT, MRI, renal sonography reveal intra-renal tumorSurgery, partial nephrectomy
Extrarenal renin secreting tumorVery rareNoMay occur in renal cancers, germ cell tumorsSurgery to remove causative tumor

Hypertension with features suggesting primary aldosteronism, ie, tendency to low potassium and suppressed plasma renin occurring in familial patterns may be caused by mutations in the aldosterone synthase via a chaemeric gene pathway (glucocorticoids remediable aldosteronism).[20] A second rare form of familial aldosteronism without suppression by glucocorticoids has been described; the genetic mechanism has not yet been fully defined, although the mutations have been localized to chromosome 7.[21] In Liddle syndrome, gain of function mutations in the NaEC or amiloride-sensitive channel of the distal renal tubule cause hypertension, low potassium, low renin, but low aldosterone. This disorder is markedly improved by amiloride.[22] Hypertension with suppressed plasma renin, low aldosterone, and hyperkalemia (Gordon's syndrome) on the other hand, is found when mutations occur in WNK kinases that regulate the Na,K co-transport pathways.[23-25] Plasma membrane turnover of either the NaEC or Na-K-Cl co-transport channels is impaired in these disorders because of impaired ubiquitylation.[26] Thiazide diuretics inhibit the Na-K-Cl co-transport channel and are remarkably effective for treatment of hypertension and hyperkalemia in Gordon's syndrome. The pathophysiologies of these rare hypertensive disorders are matched perfectly with specific pharmacologic agents, a triumph of applied basic research in cardiovascular disease.

Renin-secreting tumors cause hypertension resulting from elevated angiotensin II levels, causing increased vascular resistance and secondary aldosteronism. Intra-renal juxta-glomerular pericytomas are caused by a neoplastic transformation of renin-secreting cells.[27-29] Alternatively, primitive renal carcinomas or nonrenal cells may retain potential for renin synthesis and secretion to initiate a pure renin mechanism for hypertension.[29-32]

The rare forms of hypertension summarized in Table 4 are lessons in modern biology that fully explain hypertension for very few patients and families. As more genetic pathways are characterized for the various systems that control blood pressure,[23] it is highly likely that pharmacologic research will keep pace in the development of specific and highly effective therapies.

Hypertension Identified With Drugs or Illicit Agents

Hypertension has clearly been linked to a variety of drugs in the past. The various synthetic steroids, oral contraceptive agents, catecholamine-like agents, and nonsteroidal anti-inflammatory drugs have been recognized for many years. Table 5 provides a list of those drugs, over-the-counter remedies, and illicit substances that now must be considered as identifiable forms of hypertension stemming from adverse reactions or unintended consequences. The most recent to join this group are the anti–vascular endothelial growth factor (VEGF) agents used in oncology and typified by bevacizumab.[33, 34] It is not yet certain as to the best strategy for prevention or treatment of hypertension caused by these agents. Calcium channel blockers have been suggested for this purpose.[35] As the list of drugs and other agents clearly related to hypertension increases, all providers who deal with clinical hypertension from emergency department to geriatric services need to be aware of these identifiable causes to either eliminate the cause or initiate appropriate therapy.

Table 5. Identifiable Hypertension Caused by Drugs or Illicit Substances
Drug or SubstanceMechanisms for Hypertension
  1. Abbreviations: AME, apparent mineralocorticoid excess; NSAIDs, nonsteroidal anti-inflammatory drugs; VEGF, vascular endothelial growth factor.

Diet pill, ephedrine, amphetamines, cocaine-like agentsCatecholamine like-actions
Glucocorticoids: multiple actionsIncreased plasma volume, increased renin substrate, altered prostaglandin, and nitric oxide effects
NSAIDs[36, 37]Impaired prostaglandin production
Oral contraceptive agents[38]Multiple actions, increased renin substrate
Licorice[39, 40]Inhibits 11-OH dehydrogenase producing acquired AME syndrome
Cyclosporine and other calcineurin inhibitors[41, 42]Multiple effects including alteration of endothelial function, NO metabolism and enhanced renal tubular Na-K-Cl cotransport via WNK pathways
Anti-VEGF bevacizumab[33]Multiple vascular effects

Summary and Conclusions

Identifiable hypertension now encompasses a large and growing spectrum of disorders from the most common associations (eg, diabetes), to rare genetic disorders and adverse reactions (eg, hypertension caused by anti-VEGF cancer therapy). Each of these disorders requires strategies for diagnosis and management that extend well beyond the usual treatment of hypertension for maximal benefit in preventing cardiovascular disease.

Ancillary