Secondary Hypertension: Etiology and Mechanism of Disease

SPECIAL REPORT

Secondary hypertension: etiology and mechanism of disease

Hypertension afﬂ icts up to 65 million adults in the USA. Although most cases of hypertension are without an underlying cause (i.e., primary hypertension), secondary causes of hypertension should be investigated due to the potential for cure. This article discusses the common causes of secondary hypertension. Furthermore, the etiology, mechanism of blood pressure elevation and treatment are discussed. Through an understanding of the mechanism, diagnosis and treatment of secondary hypertension, physicians can positively inﬂ uence the associated long-term morbidity and mortality.

KEYWORDS: mineralcorticoid excess syndromes, obstructive sleep apnea, Jeff rey H Freihage, pheochromocytoma, renal artery stenosis, renovascular hypertension, secondary Aravinda Nanjundappa & hypertension Robert S Dieter† †Author for correspondence: Hypertension is estimated to affect up to 65 mil- to elevation in blood pressure due to inabil- Loyola University Medical lion adults in the USA, and is the most common ity of the diseased kidney to excrete sodium Center, Maywood, IL 60153, primary diagnosis at clinic visits [1,2] . Due to the and water, resulting in volume expansion. USA rising incidence of obesity and an aging popula- Renovascular hypertension usually refers to Tel.: +1 708 216 4466 tion, the number of patients with hypertension RAS, caused either by atherosclerotic disease Fax: +1 708 216 8795 is expected to increase. Importantly, elevated or fi bro muscular dysplasia (FMD). RAS leads [email protected] blood pressure can be effectively treated and to elevated blood pressure as a result of low lead to a reduction in the incidence of heart perfusion pressure to the affected kidney, with failure, stroke and myocardial infarction [3]. resultant activation of the renin–angiotensin– The evaluation of patients with hypertension aldosterone axis. Atherosclerotic RAS, account- includes identifying other disease conditions ing for approximately 90% of cases of RAS, is a that either cause or contribute to elevation in progressive disease affecting the proximal third blood pressure. The purpose of this article is of the main renal artery, and is usually found in to discuss causes of secondary hypertension, patients with coronary artery disease and clas- along with appropriate diagnostic testing, and sic risk factors for atherosclerosis. On the other the mechanism of blood pressure elevation in hand, FMD, accounting for the remaining 10% these conditions. of cases of RAS, affects women between the age Although the vast majority (over 90%) of of 15 and 50 years, and involves the middle two- patients with hypertension have primary hyper- thirds of the main renal artery. BOX 2 lists the situ- tension, that is, hypertension without an iden- ations in which RAS should specifi cally be inves- tifi able cause, an attempt to detect secondary tigated. While most experts agree that balloon causes of hypertension is important due to the angioplasty with bail-out stenting is the optimal potential for cure with appropriate treatment. treatment strategy for patients with hypertension BOX 1 lists conditions associated with secondary due to FMD, considerable debate exists between hypertension. A thorough medical history and cardiovascular experts and nephrologists as to the physical examination can often provide clues as appropriate indications for revascularization in to the presence of secondary causes of hyper- patients with atherosclerotic RAS. Much of the tension. A review of medications, both pre- controversy is due to the lack of a perfect tool for scribed and over the counter, is important, as the assessment of the contribution of a renal artery many medications can lead to blood pressure obstruction to any individual’s hypertension. elevation and must not be overlooked. Furthermore, discrepancies exist in the literature as to the effi cacy of revascularization for improve- Renal hypertension ment in blood pressure control and preservation Hypertension of renal origin can be due to either of renal function. Currently, accepted indica- chronic renal insuffi ciency (CRI) of any etiol- tions for renal revascularization in the setting of ogy, or renal artery stenosis (RAS). CRI leads atherosclerotic RAS are listed in BOX 3 [4,5].

Box 1. Causes of secondary suspected based on physical examination signs and hypertension. symptoms, laboratory confi rmation demonstrat- Chronic renal insuffi ciency ing hypercortisolism is required to establish the Renal artery stenosis diagnosis and cause of the syndrome. The mecha- Coarctation of the aorta nism by which cortisol excess leads to elevation Mineralcorticoid excess syndromes in blood pressure is unclear [7]. However, recent Cushing’s syndrome studies have demonstrated that cortisol-induced Hypothyroid blood pressure elevation is more complicated than Hyperthyroid [8] Hyperparathyroidism simply renal sodium retention . Obstructive sleep apnea Pheochromocytoma and paraganglioma Pheochromocytoma & paraganglioma Pheochromocytoma and paraganglioma are tumors of chromaffi n cell origin that produce Mineralcorticoid excess syndromes symptoms of headache, palpitations and dia- Mineralcorticoid excess syndromes are recognized phoresis, along with elevation in blood pressure, to contribute to elevations in blood pressure due due to the release of catecholamines. Circulating to increased sodium and water retention by the levels of catecholamines, along with elevated kidney. Most cases (approximately two-thirds) of sympathetic nervous system activity, contribute mineralcorticoid excess syndromes are attributa- to persistent elevations in blood pressure due to ble to primary aldosteronism (Conn’s syndrome). increased peripheral vascular tone and impair- The other cases of mineralcorticoid hypertension ment in endothelium-dependent and -inde- are largely due to bilateral adrenal hyperplasia and pendent vasodilatation [9,10]. Establishment of adrenal carcinomas (gluco corticoid-suppressible the diagnosis of a pheochromocytoma consists hyperaldosteronism). Screening for mineralcor- of measuring 24-h urinary excretion of total or ticoid excess syndromes should be considered in fractionated metanephrines and catecholamines. patients with unprovoked hypokalemia, hypo- Once biochemical testing has confi rmed the kalemia due to diuretics but not correctable with elevation in catecholamine levels, localization replacement therapy, a family history of hyperal- of the tumor with a CT scan, MRI, iodine 131- dosteronism, and the presence of an adrenal mass or iodine 123-labeled metaiodobenzylguanidine on imaging. As the optimal method of establishing (MIBG) or PET scan should be performed prior the diagnosis of primary aldosteronism and other to surgical resection [11] . causes of mineralcorticoid excess is complicated and controversial, biochemical testing with fol- Coarctation of the aorta low-up imaging, and possibly adrenal vein blood Coarctation of the aorta should be specifi cally sampling, is best directed by specialists [6]. investigated via upper and lower extremity blood pressure measurements in all hypertensive Cushing’s syndrome patients. Most experts agree that surgical correc- Cushing’s syndrome, glucocorticoid excess syn- tion should be performed in infancy and early drome, is another cause of secondary hyper- childhood [12] . However, many adult patients tension. Although Cushing’s syndrome may be also benefi t by becoming normotensive after coarctation repair during adulthood [13] . Box 2. Situation in which renal artery stenosis should be investigated. Hyperthyroidism & hypothyroidism Onset of hypertension ≤30 years or ≥55 years Hyperthyroidism and hypothyroidism have both Malignant, accelerated or resistant been recognized as causes of secondary hyper- hypertension tension. Hyperthyroidism can lead to isolated Unexplained renal dysfunction secondary hypertension by alterations in sys- Development of azotemia with an ACE temic vascular resistance and increases in heart inhibitor or ARB medication rate and cardiac output [14] . In hypo thyroidism, Unexplained size discrepancy of ≥1.5 cm hypertension, predominantly diastolic, can between kidneys occur in up to 50% of patients. The mechanism Flash pulmonary edema (usually bilateral RAS) Refractory angina of hypertension is related to increased systemic Unexplained congestive heart failure vascular resistance and changes in aortic wall Multivessel coronary artery disease stiffness, which can become fi xed if treatment ACE: Angiotensin-converting enzyme; ARB: Angiotensin of the hypothyroid state is not initiated early in receptor blocker; RAS: Renal artery stenosis. the disease course [15] .

788 Therapy (2008) 5(6) future science group Secondary hypertension: etiology & mechanism of disease SPECIAL REPORT

Box 3. Indications for renal artery revascularization in a patient with RAS. Failure of medical therapy despite full doses of ≥3 drugs, including a diuretic Compelling need for ACE inhibition/angiotensin blockade with angiotensin-dependent GFR Recent rise in serum creatinine Loss of GFR during antihypertensive therapy (e.g., with ACE inhibition/ARB therapy) Circulatory congestion, recurrent ‘ﬂ ash’ pulmonary edema Refractory congestive heart failure with bilateral renal arterial stenosis ACE: Angiotensin-converting enzyme; ARB: Angiotensin receptor blocker; GFR: Glomerular ﬁ ltration rate; RAS: Renal artery stenosis.

Hyperparathyroidism The evaluation of the hypertensive patient The contribution of hyperparathyroidism to ele- must include a search for identifi able, and thus, vation in blood pressure has been well recognized. potentially curable, conditions. Often, a thor- However, the exact mechanism is undefi ned, but ough history and physical exam with supple- most likely relates to hypercalcemia (vasocon- mental laboratory testing will give strong clues striction) and hypercalcemia’s contribution to to the presence of an underlying disease process renal insuffi ciency (renal parenchymal damage). that is contributing to a patient’s hypertensive Importantly, in patients with primary hyperpar- state. Unfortunately, uncertainty exists as to athyroidism, hypertensive patients have a higher the best diagnostic tools and optimal therapy mortality relative to normotensive patients. for some of these conditions. Future research However, the yearly death risk after surgery in into the mechanism, diagnosis and treatment patients with hypertension decreases by dou- of secondary causes of hypertension will lead ble relative to that of the normotensive patient, to better diagnostic tests and therapies that will implying that elevated blood pressure is a major improve the long-term morbidity and mortality source of increased cardiovascular mortality in associated with hypertension. patients with hyperparathyroidism [16] .

Obstructive sleep apnea Financial & competing interests disclosure The number of patients with obstructive sleep The authors have no relevant affi liations or fi nancial apnea (OSA) and hypertension is extremely involvement with any organization or entity with a fi nan- high, ranging from 35 to 70% [17] . Hypertension cial interest in or fi nancial confl ict with the subject matter in patients with OSA is thought to be related or materials discussed in the manuscript. This includes to sympathetic activation, oxidative stress and employment, consultancies, honoraria, stock ownership or endo thelial dysfunction. Treatment of OSA options, expert testimony, grants or patents received or pend- with either weight loss or continuous positive ing, or royalties. airway pressure has been shown to improve No writing assistance was utilized in the production of blood pressure control. this manuscript.

Executive summary Hypertension is estimated to affect up to 65 million adults in the USA. An attempt to detect secondary causes of hypertension is important due to the potential for cure with appropriate treatment. A thorough medical history and physical examination can often give clues as to the presence of secondary causes of hypertension. Chronic renal insufﬁ ciency leads to elevation in blood pressure due to inability of the diseased kidney to excrete sodium and water, resulting in volume expansion. Renal artery stenosis leads to elevated blood pressure as a result of low perfusion pressure to the affected kidney, with resultant activation of the renin–angiotensin–aldosterone axis. Mineralcorticoid excess syndromes are recognized to contribute to elevations in blood pressure due to increased sodium and water retention by the kidney. Coarctation of the aorta should be speciﬁ cally investigated via upper and lower extremity blood pressure measurements in all hypertensive patients. Hypertension in patients with obstructive sleep apnea is thought to be related to sympathetic activation, oxidative stress and endothelial dysfunction.

future science group www.futuremedicine.com 789 SPECIAL REPORT Freihage, Nanjundappa & Dieter

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