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რეგისტრ.: 25-November 05
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#3855994 · 29 Sep 2006, 20:44 · · პროფილი · პირადი მიმოწერა · ჩატი
ტანკე
| QUOTE | | არადა ყველაზე საინტერესო ის არის,რომ 140 წნევას ვერ ვგრძნობ და თავს კარგად ვგრძნობ |
არ არის კარგი. წნევის წამლის ემპირიული მიღება თქვენს შემთხვევაში გამართლებული არ არის... უსათუოდ უნდა მოიძიოთ მიძეზი. აქ ძალიან ბევრია სალაპარაკო ამიტომ მოდით აქ დავდებ ყველაზე ცნობილი კარდიოლოგიური წიგნიდან ტექსტს მეორად ჰიპერტენზიაზე. გადახედეთ და თუ შეკითხვები გაგიჩნდებათ გიპასუხებთ. შაბათს და კვირას მორიგე ვარ. ორშაბათს ისევ ფორუმზე ვიქნები.
ასე რომ დროებით.
Zipes: Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 7th ed., Copyright © 2005 Saunders, An Imprint of Elsevier
Identifiable (Secondary) Forms of Hypertension (see Table 37-5 and Table 37-7 )
Oral Contraceptive and Postmenopausal Estrogen Use
The use of estrogen-containing oral contraceptive pills is probably the most common cause of secondary hypertension in young women. Most women who take them experience a slight rise in blood pressure. In a prospective cohort study of almost 70,000 nurses, over the 4 years between 1989 and 1993, those who were current users of oral contraceptives had an overall risk for hypertension 50 percent higher than never-users and 10 percent higher than former users.[105] The 50 percent increase in relative risk translated to 41 cases per 10,000 person-years of oral contraceptive use. The incidence of hypertension is likely even less with present-day lower dose formulations.
The dangers of oral contraceptives should be kept in proper perspective. While it is true that use of these drugs is associated with increased morbidity and mortality, the absolute numbers are quite small, as noted in the nurses study.[105] Most adverse effects, including hypertension, occur in women older than 35 years of age who smoke and have other cardiovascular risk factors.[106]
CLINICAL FEATURES.
In most women, the hypertension is mild; however, in some, it may accelerate rapidly and cause severe renal damage. When use of the pill is discontinued, blood pressure falls to normal within 3 to 6 months in about half the patients. Whether the pill caused permanent hypertension in the other half or just uncovered primary hypertension at an earlier time is not clear.
MECHANISMS OF HYPERTENSION.
Oral contraceptive use probably causes hypertension by volume expansion, since both estrogens and the synthetic progestogens used in oral contraceptive pills cause sodium retention. Although plasma renin levels rise in response to increased levels of angiotensinogen, angiotensin-converting enzyme (ACE) inhibition did not alter blood pressure any more in women with oral contraceptive-induced hypertension than in women with essential hypertension.[107]
MANAGEMENT.
The use of estrogen-containing oral contraceptives should be restricted in women older than 35 years, particularly if they also smoke or are hypertensive or obese. Women given the pill should be properly monitored as follows: (1) The initial supply should be limited; (2) they should be asked to return for a blood pressure check before an additional supply is provided; and (3) if blood pressure has risen, an alternative contraceptive method should be offered. If the pill remains the only acceptable contraceptive method, the elevated blood pressure can be reduced with appropriate therapy. In view of the possible role of aldosterone, use of a diuretic-spironolactone combination seems appropriate. In women who stop taking oral contraceptives, evaluation for secondary hypertensive diseases should be postponed for at least 3 months to allow changes in the reninangiotensin-aldosterone system to remit. If the hypertension does not recede, additional work-up and therapy may be needed.
POSTMENOPAUSAL ESTROGEN USE.
Millions of women take estrogen replacement therapy after menopause. Estrogen replacement therapy does not appear to induce hypertension, even though it does induce the various changes in the renin-angiotensin-aldosterone system seen with oral contraceptive use. In fact, most controlled trials find a decrease in daytime ambulatory blood pressure and a greater dipping of nocturnal blood pressure in estrogen replacement therapy users[108] and most hypertensive women have a fall in blood pressure with transdermal estradiol.[109] Such lower blood pressures may reflect a number of effects, including improved endothelium-dependent vasodilation and reduced muscle sympathetic nerve activity.
Renal Parenchymal Disease (see Chap. 86 )
Subtle renal dysfunction has been previously described as a likely initiator of primary hypertension, and renal parenchymal disease is the most common cause of secondary hypertension, responsible for 2 to 5 percent of cases. As chronic glomerulonephritis has become less common, hypertensive nephrosclerosis and, to an even greater degree, diabetic nephropathy have become the most common causes of chronic renal disease.[110] The prevalence of chronic renal disease, defined by a reduction in glomerular filtration rate to less than 60 ml/min/1.73 m2 or persistent albuminuria of more than 300 mg/day, is estimated to be 11 percent (19.2 million) of the adult U.S. population.[111] The higher prevalence of hypertension among U.S. blacks is probably responsible for their significantly higher rate of end-stage renal disease with hypertension as the underlying cause in as many as half of these patients.
As previously noted, even microalbuminuria, 30 to 300 mg/day, is closely related to target organ damage in hypertensive persons,[50] and it likely should be looked for routinely in the evaluation of every new hypertensive patient in a "spot" urine collection. Measurement of serum creatinine is routine but by itself is an inadequate screening test for significant renal damage, particularly in elderly patients.[112] Therefore, a creatinine clearance should be calculated with either the Cockcroft-Gault formula or the Modification of Diet in Renal Disease (MDRD) equation, taking age, gender, and body weight into account.
Once it begins, renal disease is usually progressive, following the concept that a loss of filtration surface leads to both glomerular and systemic hypertension, which engenders more glomerular sclerosis, setting up a cycle of progressive disease (see Fig. 37-12 ). Therefore, it is critical to identify renal damage early, since removal of causal or aggravating factors can prevent the otherwise inexorable progress of renal damage. These factors include obstruction of the urinary tract, depletion of effective circulating volume, nephrotoxic agents, and, most importantly, uncontrolled hypertension.
In addition to these and other factors involved in chronic renal disease, a number of acute conditions may be responsible for renal damage and hypertension.
ACUTE RENAL DISEASES.
Hypertension may appear with any sudden, severe insult to the kidneys that either markedly impairs excretion of salt and water, which leads to volume expansion, or reduces renal blood flow, which sets off the renin-angiotension-aldosterone mechanism. Bilateral ureteral obstruction is an example of the former; sudden bilateral renal artery occlusion, as by cholesterol emboli, is an example of the latter. Relief of either may dramatically reverse severe hypertension. Such reversal of hypertension has been particularly striking in men with high-pressure chronic retention of urine, who may manifest both renal failure and severe hypertension, both of which may be ameliorated by relief of the obstruction.[113] Some collagen diseases may also produce rapidly progressive vasculitis and renal damage.
Two commonly used classes of drugs—nonsteroidal antiinflammatory drugs and inhibitors of the renin-angiotensin system—may suddenly worsen renal function in patients with preexisting renal diseases. Nonsteroidal antiinflammatory drugs, by blocking synthesis of prostaglandins, which act as vasodilators within the kidney, may cause an abrupt loss of renal function. Renin-angiotensin inhibitors, both ACE inhibitors and angiotensin II receptor blockers (ARBs), may precipitate acute renal failure in patients with bilateral renovascular disease whose renal profusion is dependent on high levels of renin-angiotensin.[114]
CHRONIC RENAL DISEASES.
All chronic renal diseases are associated with a higher prevalence of hypertension, and the presence of hypertension accelerates the progression of renal damage. Although it is uncertain that hypertension by itself can lead to renal failure in persons who are not black, there is no doubt that hypertension can accelerate the progress of all underlying renal diseases.
The control of hypertension can slow or stop the progression of renal diseases and of cardiovascular sequelae ( Fig. 37-17 ).[115] As noted in the Heart Outcomes Prevention Evaluation (HOPE) trial,[116] the presence of microalbuminuria was associated with an increase in cardiovascular morbidity and mortality in subjects with microalbuminuria (26.4 percent) compared with those without microalbuminuria (15.4 percent). With the further lowering of blood pressure by the addition of the ACE inhibitor ramipril, individuals with microalbuminuria had even greater reduction in their risk. This protection may reflect special advantages of ACE inhibition, but the lowering of blood pressure must also be a factor.
Uncertainty remains as to the goal of antihypertensive therapy in patients with chronic renal disease. In two large trials of nondiabetic patients with chronic renal disease, more intensive therapy to reach a goal of 125/75 mm Hg did not slow the rate of fall of glomerular filtration rate more than did less intensive therapy to a level of 140/85 mm Hg, except in patients with more than 1 g of proteinuria per day.[117][118]
Issues as to the preferred choices of antihypertensive agents in patients with chronic renal disease are addressed in Chapter 38 . Suffice it to note that an ACE inhibitor or an ARB is always indicated as the initial choice, almost always in combination with a diuretic. With whatever drugs chosen, but particularly with ACE inhibitors and ARBs, caution is needed in lowering blood pressure in the presence of previously unrecognized bilateral renovascular disease, which has been found in as many as 20 percent of patients with progressive renal damage.[114] However, a modest increase in serum creatinine, averaging 30 percent above baseline, has been found to predict a better preservation of renal function, presumably reflecting a successful reduction in intraglomerular pressure.[119]
DIABETIC NEPHROPATHY (see Chap. 51 and Chap. 86 ).
The most impressive protection against progressive renal damage by reduction of elevated blood pressure has been seen in patients with diabetic nephropathy.[110] Such protection has been observed to extend to diabetic retinopathy and neuropathy, both in normotensive[120] and hypertensive[121] type 2 diabetic patients with proteinuria. The consensus advice is to start antihypertensive therapy in diabetic patients with or without nephropathy at a blood pressure of 140/90 mm Hg or higher and to reach a level of 130/80 mm Hg or lower.[115] Such intensive control of hypertension has been shown to be much more cost-effective than either intensive glycemic control or reduction in hypercholesterolemia.[122]
Hypertension During Chronic Dialysis and after Renal Transplantation
In patients with end-stage renal disease who are on dialysis, hypertension is a significant risk factor for mortality. Beyond the primary influence of excess fluid volume, hypertension can be accentuated by the accumulation of endogenous inhibitors of nitric oxide synthase. With neither the vasoconstrictor effects of renal renin nor the vasodepressor actions of various renal hormones, blood pressure may be particularly labile and sensitive to changes in fluid volume. Among patients receiving maintenance hemodialysis every 48 hours, elevated blood pressures tend to fall progressively after dialysis is completed, remain depressed during the remainder of the first 24 hours, and rise again during the second day as a consequence of excessive fluid retention. By increasing the time of dialysis treatment and thereby reducing dry weight, blood pressure can be better controlled.[123] As with other forms of renal disease, ACE inhibitors may provide special benefits to hemodialysis patients.[124]
Although successful renal transplantation may cure primary hypertension, various problems can result, with about half of the recipients becoming hypertensive within 1 year. These problems include stenosis of the renal artery at the site of anastomosis, rejection reactions, high doses of adrenal steroids and cyclosporine or tacrolimus, and excess renin derived from the retained diseased kidneys. ACE inhibitor therapy may obviate the need to remove the native diseased kidneys to relieve hypertension caused by their persistent secretion of renin. The source of the donor kidney may also play a role in the subsequent development of hypertension in the recipient. More hypertension has been observed when donors had a family history of hypertension or when the donors had died of subarachnoid hemorrhage and had probably been hypertensive.
Renovascular Hypertension
Renovascular hypertension is among the most common secondary forms of hypertension and is not easily recognizable. The prevalence of proven renovascular hypertension in the overall hypertensive population is unknown, but significant renal artery disease (defined as a 60 percent or greater reduction of diameter on duplex sonography) has been found in 6.8 percent of 824 elderly people in North Carolina[125] and in 7 percent of hypertensive patients undergoing coronary angiography (defined as a 70 percent or greater stenosis on renal angiography).[126]
It has long been known that the presence of renovascular disease does not, in itself, prove that the renovascular lesion is responsible for renovascular hypertension. Therefore, screening should focus on those hypertensive patients who have multiple features known to be associated with renovascular hypertension. The greater the number of clues, the more extensive the search ( Table 37-12 ). The search likely should start with renal arteriography in those who are at high likelihood, since no other screening study can rule out the presence of the disease.
Table 37-12 -- Clinical Clues for Renovascular Hypertension
History
Onset of hypertension before 30 or after 50 years of age
Abrupt onset of hypertension
Severe or resistant hypertension
Symptoms of atherosclerotic disease elsewhere
Negative family history of hypertension
Smoker
Worsening renal function with angiotensin-converting enzyme inhibition
Recurrent flash pulmonary edema
Examination
Abdominal bruits
Other bruits
Advanced fundal changes
Laboratory
Secondary aldosteronism
Higher plasma renin
Low serum potassium
Low serum sodium
Proteinuria, usually moderate
Elevated serum creatinine
>1.5 cm difference in kidney size on sonography
Adapted from McLaughlin K, Jardine AG, Moss JG. Renal artery stenosis. Br Med J 320:1124, 2000.
Classification
In adults, the two major types of renovascular disease tend to appear at different times and affect the sexes differently ( Table 37-13 ). Atherosclerotic disease affecting mainly the proximal third of the main renal artery is seen mostly in older men. Fibroplastic disease involving mainly the distal two-thirds and branches of the renal arteries appears most commonly in younger women. As the population grows older, 80 percent of cases are caused by atherosclerotic disease and fewer than 20 percent by fibroplastic disease. Although the nonatherosclerotic stenoses may involve all layers of the renal artery, the most common is medial fibroplasia.
Table 37-13 -- Features of the Two Major Forms of Renal Artery Disease
Cause Incidence (%) Age (yr) Location of Lesion in Renal Artery Natural History
Atherosclerosis 80–90 >50 Proximal 2 cm; branch disease rare Progression in 50%, often to total occlusion
Fibromuscular dysplasias
Intimal 1–2 Birth-25 Midportion of main renal artery and/or branches Progression in most cases; dissection and/or thrombosis common
Medial 10–20 25–50 Distal segment of main renal artery and/or branches Progression in 33%; dissection and/or thrombosis rare
Periarterial 1–2 15–30 Middle to distal segments of main renal artery or branches Progression in most cases; dissection and/or thrombosis common
From Kaplan NM: Kaplan's Clinical Hypertension. 8th ed. Baltimore, Lippincott Williams & Wilkins, 2002, p 385.
A number of other intrinsic and extrinsic causes of renovascular hypertension are known, including cholesterol emboli within the renal artery or compression of this vessel by nearby tumors. Most renovascular hypertension develops from partial obstruction of one main renal artery, but only a branch need be involved; segmental disease has been found in about 10 percent of cases. On the other hand, if apparent complete occlusion of the renal artery is slow in developing, enough collateral flow will become available to preserve the viability of the kidney. In this way, the seemingly nonfunctioning kidney may be responsible for continued renin secretion and hypertension. If recognized, such totally occluded vessels can sometimes be repaired, with return of renal function and relief of hypertension.[127]
Renovascular stenosis is often bilateral, although usually one side is clearly predominant. The possibility of bilateral disease should be suspected in those with renal insufficiency, particularly if rapidly progressive oliguric renal failure develops without evidence of obstructive uropathy and even more so if it develops after the start of ACE inhibitor or ARB therapy.[114]
Mechanisms
The sequence of changes in patients with renovascular hypertension starts with the release of increased amounts of renin when sufficient ischemia is induced to diminish pulse pressure against the juxtaglomerular cells in the renal afferent arterioles. A reduction in renal perfusion pressure by 50 percent leads to an immediate and persistent increase in renin secretion from the ischemic kidney, along with suppression of secretion from the contralateral one. With time, renin levels fall (but not to the low level expected from the elevated blood pressure), accompanied by an expanded body fluid volume and increased cardiac output.
Diagnosis
The presence of the clinical features listed in Table 37-12 , found in perhaps 5 to 10 percent of all hypertensive persons, indicates the need for a screening test for renovascular hypertension. A positive screening test result, or very strong clinical features, calls for more definitive confirmatory tests. Recurrent flash pulmonary edema has been associated with renovascular hypertension, so this clinical manifestation has been added to the indication for diagnostic work-up.[128] The initial diagnostic study in most patients should be noninvasive and, if abnormal, followed by a study of renal perfusion to ensure that any renovascular lesion is pathogenic, to decide whether revascularization is indicated There are problems with all screening studies. Considerable asymmetry of renal blood flow, 25 percent or more, was found in 148 hypertensive patients with patent renal arteries on prior angiography.[130] Such normal asymmetry likely is responsible for the low sensitivity and specificity of captopril-enhanced renal scans. On the other hand, the sensitivity of renal duplex sonography for the detection of hemodynamically significant renovascular disease has been reported to be only 50 percent.[131] The accuracy of ultrasonography is very much operator-dependent, often requiring scanning times of 1 hour or longer, so its use has been limited. However, a strong association with the outcome of revascularization has been reported with the use of a resistance index to assess flow in segmental arteries.[132] Patients with high resistance-index values above 80, reflecting marked intrarenal vascular disease, had generally poor outcomes. Those with lower values had generally good outcomes.
Over the past few years, both contrast-enhanced computed tomography and magnetic resonance angiography have been increasingly used to screen for renovascular hypertension. Magnetic resonance angiography will likely be more widely used, since it avoids the possibility of dye-induced nephrotoxicity and ionizing radiation as well as its greater potential for an assessment of renal function.
Management
MEDICAL.
The availability of ACE inhibitors can be considered a two-edged sword; one edge provides better control of renovascular hypertension than may be possible with other antihypertensive medications, while the other edge exposes the already ischemic kidney to further loss of blood flow by removing the high level of angiotensin II that was supporting its circulation. Other antihypertensive drugs may be almost as effective as ACE inhibitors and perhaps safer, but there are no comparative data.
ANGIOPLASTY (see Chap. 55 ).
Angioplasty has been shown to improve blood pressure (at least transiently) in 60 to 70 percent of patients, more with fibromuscular disease than with atherosclerosis, as is also the case for surgery. In three small but controlled trials, balloon angioplasty was shown to provide a modest but significantly greater reduction in blood pressure than medical therapy.[133] Placement of an arterial stent reduced the likelihood of restenosis and is increasingly performed as the initial procedure to preserve renal function.[134]
SURGERY.
Revascularization by surgery is indicated in patients whose hypertension is not well controlled or whose renal function deteriorates with medical therapy and in those with only a transient response to angioplasty or in whom lesions are not amenable to that procedure. Surgery is recommended more to preserve renal function than to relieve hypertension and should be undertaken before serum creatinine level rises above 3 mg/dl.[129]
Renin-Secreting Tumors
Made up of juxtaglomerular cells or hemangiopericytomas, renin-secreting tumors have been found mostly in young patients with severe hypertension, very high renin levels in both peripheral blood and the kidney harboring the tumor, and secondary aldosteronism manifested by hypokalemia.[135] The tumor can generally be recognized by selective renal angiography, usually performed for suspected renovascular hypertension, although a few are extrarenal. More commonly, children with Wilms tumors (nephroblastoma) may have hypertension and high plasma renin and prorenin levels that revert to normal after nephrectomy.[136]
Adrenal Causes of Hypertension
Adrenal causes of hypertension include primary excesses of aldosterone, cortisol, and catecholamines; more rarely, excess deoxycorticosterone is present along with congenital adrenal hyperplasia. Together, these conditions cause less than 1 percent of all hypertensive diseases, although, as will be noted, primary aldosteronism may be more common than previously thought. Each can usually be recognized with relative ease, and patients suspected of having these disorders can be screened by readily available tests.
More of a problem than the diagnosis of these adrenal disorders is the need to exclude their presence because of the increasing identification of incidental adrenal masses when abdominal computed tomography (CT) is done to diagnose intraabdominal pathological conditions. Unsuspected adrenal tumors have been found on about 1 percent of abdominal CT scans obtained for reasons unrelated to the adrenal gland. As delineated in Table 37-7 , screening for hormonal excess should be performed if an adrenal tumor is found. Most of these "incidentalomas" appear to be nonfunctional on the basis of normal basal adrenal hormone levels. When more detailed studies are done, however, a significant number show incomplete suppression of cortisol by dexamethasone, that is, subclinical Cushing disease that does not appear to progress to overt hypercortisolism but may be associated with insulin resistance and osteopenia.[137]
The benign nature of smaller tumors can usually be assured by appropriate imaging studies. The threat of malignancy can probably be best excluded by adrenal scintigraphy with NP-59, a radioiodinated derivative of cholesterol. Benign lesions almost always take up the isotope, whereas malignant ones almost always do not. Most tumors larger than 4 cm are resected, since a significant number of them are malignant.
Primary Aldosteronism
This disease has been considered to be relatively rare in unselected populations, but it has been recognized in considerably more patients screened by a plasma aldosterone/renin activity ratio.[138]
PATHOPHYSIOLOGY OF MINERALOCORTICOID EXCESS.
A number of syndromes with mineralocorticoid excess have been recognized ( Table 37-14 ), with primary aldosteronism being by far the most common. Until recently, the most frequently found source of hyperaldosteronism was a solitary aldosterone-producing adenoma. Recently, as milder forms of hyperaldosteronism have been recognized by measurements of plasma renin and aldosterone, bilateral adrenal hyperplasia (BAH) has become far more common.
Table 37-14 -- Syndromes of Mineralocorticoid Excess
Adrenal origin
Aldosterone excess (primary)
Aldosterone-producing adenoma
Bilateral hyperplasia
Primary unilateral adrenal hyperplasia
Glucocorticoid-remediable aldosteronism (familial hyperaldosteronism, type I)
Adrenal carcinoma
Extraadrenal tumors
Deoxycorticosterone excess
Deoxycorticosterone-secreting tumors
Congenital adrenal hyperplasia
11β-hydroxylase deficiency
17α-hydroxylase deficiency
Cortisol excess
Cushing syndrome from ACTH-producing tumor
Glucocorticoid receptor resistance
Renal origin
Activating mutation of mineralocorticoid receptor
Pseudohypoaldosteronism, type II (Gordon)
11β-hydroxysteroid dehydrogenase deficiency
Congenital: apparent mineralocorticoid excess
Acquired: licorice, carbenoxolone
Aldosterone excess from any source causes hypertension and renal potassium wastage, which should induce hypokalemia ( Fig. 37-19 ). However, the majority of patients with aldosteronism caused by BAH are normokalemic.[138] The lack of overt hypokalemia could be explained in numerous ways: (1) potassium wastage has lowered the serum potassium level, but not yet to hypokalemic levels; (2) with milder degrees of aldosteronism, as are typical with BAH, the excess of aldosterone induces hypertension without causing potassium wastage, a scenario that has never been experimentally or clinically recognized; or (3) the BAH is related to the typical progressive increase in adrenal nodular hyperplasia with age that has no relationship to hypertension.[139] The third explanation would fit with the long-held belief that BAH is simply a form of low-renin hypertension, that is, primary (essential) hypertension with plasma renin levels that are known to fall progressively with age while plasma aldosterone levels remain stable.[140]
This third explanation could account for the common finding of an increased aldosterone/renin ratio, due not to increased aldosterone but to decreased renin as well as the presence of BAH in the majority of normokalemic hypertensive patients reported in recent series.[138] In an analysis of the aldosterone/renin ratio in 505 patients with essential hypertension, an elevated ratio was found to be a measure of low renin alone without increased aldosterone in 36 percent and the positive predictive value of the ratio to identify patients with increased aldosterone and low renin was only 34 percent.[141]
This examination of the pathophysiology of hyperaldosteronism does not deny the existence of autonomous hypersecretive from hyperplastic glands. However, most patients with an elevated aldosterone/renin ratio and BAH do not have autonomous hyperaldosteronism.[142]
DIAGNOSIS.
Despite the enthusiasm to screen virtually all hypertensive patients with an aldosterone/renin ratio measurement,[138] there are good reasons to limit use of the test and, rather than using a ratio that could be high entirely because of a low renin level, to simply confirm an elevated plasma aldosterone level, above 15 ng/dl, and a low renin level. This more conservative view is based on the strong likelihood that only a very few normokalemic patients harbor an adenoma that should be resected and that there is no need to identify the presence of bilateral hyperplasia in normokalemic patients, mainly because identification of BAH usually requires an expensive, difficult, and occasionally harmful study, bilateral adrenal venous sampling.[143]
Therefore, screening is recommended only for hypertensive subjects who have a higher likelihood of primary aldosteronism, including those with (1) unprovoked, unexplainable hypokalemia; (2) hypokalemia induced by diuretics but resistant to correction; (3) family history of aldosteronism; or (4) hypertension resistant to appropriate therapy wherein the resistance cannot be explained. Hyperaldosteronism has been found in as many as 20 percent of resistant hypertensive patients, but BAH is the usual finding and therapy with the aldosterone blocker spironolactone significantly reduced blood pressure,[144] alleviating the need for extensive evaluation for aldosteronism in most such patients.
If the screening plasma aldosterone and renin levels are suggestive, a saline suppression study, either oral or intravenous, should be done to document autonomy of hyperaldosteronism ( Fig. 37-20 ). If the aldosteronism persists, either a CT or an MRI scan should look for adrenal pathological lesions. If a solitary adenoma larger than 1 cm is present, the diagnosis of an aldosterone-producing adenoma can be reasonably ensured and consideration given to adrenalectomy. Because some nodularity is common even with a single hypersecreting adenoma, however, most experts suggest adrenal venous sampling before surgery is recommended.[145]
Figure 37-20 A diagnostic flow chart for evaluating and treating patients with primary aldosteronism. 1° Aldo = primary aldosteronism; ACEI = angiotensin-converting enzyme inhibitor; APA = aldosterone-producing adenoma; ARB = angiotensin II receptor blocker; BAH = bilateral adrenal hyperplasia; CT = computed tomography; MRI = magnetic resonance imaging; 18-OH-B, 18-hydroxycorticosterone. (Modified from Kaplan NM: Kaplan's Clinical Hypertension. 8th ed. Baltimore, Lippincott Williams & Wilkins, 2002, p 464.)
OTHER FORMS OF MINERALOCORTICOID EXCESS.
Table 37-14 lists a number of other causes for real or apparent mineralocorticoid excess. One, familial glucocorticoid-remediable aldosteronism, is caused by a mutation in the genes involved in coding for the aldosterone synthase enzyme normally found only in the outer zona glomerulosa and the 11-beta-hydroxylase enzyme in the zona fasciculata. The chimeric gene induces an enzyme that catalyzes the synthesis of 18-hydroxylated cortisol in the zona fasciculata. Since this zone is under the control of adrenocorticotropic hormone (ACTH), the glucocorticoid suppressibility of the syndrome is explained. The diagnosis should be made by genetic testing for the chimeric gene and treatment provided with glucocorticoid suppression.[146]
Another rare form is apparent mineralocorticoid excess caused by deficiency of the enzyme 11-beta-hydroxysteroid dehydrogenase type 2 (11β-OHSD2) in the renal tubule, where it normally converts cortisol (which has the ability to act on the mineralocorticoid receptor) to cortisone (which does not). Persistence of high levels of cortisol induces all the features of mineralocorticoid excess. The 11β-OHSD enzyme may be congenitally absent (the syndrome of apparent mineralocorticoid excess) or inhibited by the glycyrrhetenic acid contained in licorice.[147] Another unusual syndrome with hypertension and hypokalemia but suppressed mineralocorticoid secretion is Liddle syndrome, wherein the kidney reabsorbs excess sodium and wastes potassium because of a mutation in the beta or gamma subunits of the epithelial sodium channel.[148]
THERAPY.
Once the diagnosis of primary aldosteronism is made and the type of adrenal disorder has been established, the choice of therapy is easy: Patients with a solitary adenoma should have the tumor resected, now more and more frequently done by laparoscopic surgery, and those with bilateral hyperplasia should be treated with an aldosterone blocker, either spironolactone or eplerenone and, if necessary, a thiazide diuretic or other antihypertensive drugs.[149] When an adenoma is resected, about half the patients will become normotensive, whereas the others, although improved, remain hypertensive, either from preexisting primary hypertension or from renal damage caused by prolonged secondary hypertension.
Cushing Syndrome (see Chap. 79 )
Hypertension occurs in about 80 percent of patients with Cushing syndrome. If left untreated, it can cause marked LVH and CHF. As with hypertension of other endocrine causes, the longer it is present, the less likely it is to disappear when the underlying cause is relieved.
MECHANISM OF HYPERTENSION.
Blood pressure can increase for a number of reasons.[150] Secretion of mineralocorticoids can also be increased along with cortisol. The excess cortisol can overwhelm the ability of renal 11β-OHSD2 to convert it to the inactive cortisone, and renal mineralocorticoid receptors are activated by the excess cortisol to retain sodium and expand fluid volume. Cortisol stimulates the synthesis of renin substrate and the expression of angiotensin II receptors, which may be responsible for enhanced pressor effects.
DIAGNOSIS.
The syndrome should be suspected in patients with truncal obesity, thin skin, muscle weakness, and osteoporosis. If clinical features are suggestive, the diagnosis can be either ruled out or virtually ensured by the measurement of free cortisol in a 24-hour urine sample or the simple overnight dexamethasone suppression test.[151] In normal subjects, the level of plasma cortisol in a sample drawn at 8 am after a bedtime dose of 1 mg of dexamethasone should be lower than 2 µg/100 ml. If the level is higher, additional work-up is in order to establish both the diagnosis of cortisol excess and the pathological type. A lack of suppression may be noted in patients who are depressed or are alcohol abusers.
When an abnormal screening test result is present, most authorities continue to recommend an additional high-dose dexamethasone suppression test at 2.0 mg every 6 hours for 2 days, with measurement of urinary free cortisol excretion and plasma cortisol levels. If Cushing syndrome is caused by excess pituitary ACTH drive with bilateral adrenal hyperplasia, urinary free cortisol will be suppressed to below 40 percent of the control value with the 2.0 mg dose. Plasma ACTH assays provide an additional means of differentiating pituitary and ectopic ACTH excess from adrenal tumors with ACTH suppression. The response to corticotropin-releasing hormone and inferior petrosal sinus sampling may be needed to identify a pituitary cause of the syndrome.
THERAPY.
In about two-thirds of patients with Cushing syndrome, the process begins with overproduction of ACTH by the pituitary, which leads to bilateral adrenal hyperplasia. Although pituitary hyperfunction may reflect a hypothalamic disorder, the majority of patients have discrete pituitary adenomas that can usually be resected by selective transsphenoidal microsurgery.
If an adrenal tumor is present, it should be removed surgically. With earlier diagnosis and more selective surgical therapy, it is hoped that more patients with Cushing syndrome will be cured without a need for lifelong glucocorticoid replacement therapy and with permanent relief of their hypertension. Temporarily, and rarely permanently, therapy may require one of a number of drugs.[152]
Congenital Adrenal Hyperplasia
Enzymatic defects may induce hypertension by interfering with cortisol biosynthesis. Low levels of cortisol lead to increased ACTH, which increases the accumulation of precursors proximal to the enzymatic block, specifically deoxycorticosterone, which induces mineralocorticoid hypertension. The more common of these is 11-hydroxylase deficiency, which has been attributed to various mutations in the gene[153] and leads to virilization (from excessive androgens) and hypertension with hypokalemia (from excessive deoxycorticosterone). The other is 17-hydroxylase deficiency, which also causes hypertension from excess deoxycorticosterone but, in addition, causes failure of secondary sexual development because sex hormones are also deficient.[154] Affected children are hypertensive, but the defect in sex hormone synthesis may not become obvious until after puberty. Thereafter, affected males display ambiguity of sexual development and fail to mature.
Pheochromocytoma (see Chap. 79 )
The wild fluctuations in blood pressure and dramatic symptoms of pheochromocytoma usually alert both the patient and the physician to the possibility of this diagnosis. However, such fluctuations may be missed, or, as occurs in half the patients, the hypertension may be persistent, with headache, sweating, and palpitations. On one hand, the spells that are typical of a pheochromocytoma may be incorrectly attributed to migraine, menopause, or panic attacks. On the other, some patients with severe paroxysmal hypertension do not have a pheochromocytoma but rather marked anxiety.[155] Unfortunately, if the diagnosis of pheochromocytoma is missed, severe complications can arise from exceedingly high blood pressure and damage to the heart by catecholamines. Stroke and hypertensive crises with encephalopathy and retinal hemorrhage may occur, probably because blood pressure levels soar in vessels unprepared by a chronic hypertensive condition. Fortunately, a single blood test will detect the disease with virtual certainty,[156] so diagnostic indecision should be minimized.
PATHOPHYSIOLOGY.
Tumors arising from chromaffin cells, that is, pheochromocytomas, occur at all ages anywhere along the sympathetic chain and rarely in aberrant sites. About 15 percent of pheochromocytomas are extraadrenal, that is, paragangliomas. Paragangliomas below the head and neck are often functional; those in the head and neck usually present with a mass effect.
Of the 85 percent of pheochromocytomas that arise in the adrenal medulla, 10 percent are bilateral and another 10 percent are malignant. Familial pheochromocytomas are inherited as an autosomal dominant trait alone or in one of four syndromes with recognized genetic mutations: in about half of patients with multiple endocrine neoplasia types 2A or 2B, in 25 percent of those with von Hippel-Lindau disease, and rarely in those with neurofibromatosis type 1. Such germ-line mutations have been found in 25 percent of 271 patients with sporadic, nonsyndromic, nonfamilial pheochromocytoma, a much higher prevalence than the generally reported 10 percent of pheochromocytomas.[157] Therefore, a higher index of suspicion for familial syndromes is needed, particularly in young patients or those with multiple extraadrenal tumors, prompting a thorough family history and a careful search for other components of a hereditary syndrome. Genetic testing should become more readily available.
Secretion from nonfamilial pheochromocytomas varies considerably, with small tumors tending to secrete larger proportions of active catecholamines. If the predominant secretion is epinephrine, which is formed primarily in the adrenal medulla, the symptoms reflect its effects, mainly systolic hypertension caused by increased cardiac output, tachycardia, sweating, flushing, and apprehension. If norepinephrine is predominantly secreted, as from some of the adrenal tumors and from almost all extraadrenal tumors, the symptoms include both systolic and diastolic hypertension from peripheral vasoconstriction but less tachycardia, palpitations, and anxiety.
DIAGNOSIS.
Many more hypertensive patients have variable blood pressure and "spells" than the 0.1 percent or so who harbor a pheochromocytoma. Spells with paroxysmal hypertension may occur with a number of stresses, and a large number of conditions may involve transient catecholamine release. A pheochromocytoma should be suspected in patients with hypertension that is either paroxysmal or persistent and accompanied by the symptoms and signs listed in Table 37-15 . In addition, children and patients with rapidly accelerating hypertension should be screened. Those whose tumors secrete predominantly epinephrine are prone to postural hypotension from a contracted blood volume and blunted sympathetic reflex tone. Suspicion should be heightened if activities such as bending over, exercise, palpation of the abdomen, smoking, or dipping snuff cause repetitive spells that begin abruptly, advance rapidly, and subside within minutes.
Table 37-15 -- Features Suggestive of Pheochromocytoma
Hypertension: Persistent or Paroxysmal
Markedly variable blood pressures (± orthostatic hypotension)
Sudden paroxysms (± subsequent hypertension) in relation to
Stress: anesthesia, angiography, parturition
Pharmacological provocation: histamine, nicotine, caffeine, beta blockers, glucocorticoids, tricyclic antidepressants
Manipulation of tumors: abdominal palpation, urination
Rare patients persistently normotensive
Unusual settings
Childhood, pregnancy, familial
Multiple endocrine adenomas: medullary carcinoma of the thyroid (MEN-2), mucosal neuromas (MEN-2B)
von Hippel-Lindau syndrome
Neurocutaneous lesions: neurofibromatosis
Associated Symptoms
Sudden spells with headache, sweating, palpitations, nervousness, nausea, and vomiting
Pain in chest or abdomen
Associated Signs
Sweating, tachycardia, arrhythmia, pallor, weight loss
MEN = multiple endocrine neoplasia.
High levels of catecholamines can induce myocarditis (see Chap. 60 ), which can progress to cardiomyopathy and left ventricular failure. Electrocardiographic changes of ischemia can also be seen. Beta blockers given to such patients can raise the pressure and induce coronary spasm through blockade of beta-mediated vasodilation.
LABORATORY CONFIRMATION.
The easiest and best procedure is a plasma free metanephrine assay,[156] which provides better sensitivity and specificity than other blood or urine catecholamine assays. The test has been found to be equally sensitive for detection of pheochromocytomas in children as part of one of the autosomal dominant familial disorders.[158]
At the Mayo Clinic, measures of urinary metanephrine and catecholamine excretion provided equal sensitivity and better specificity than plasma free metanephrine assays, so the urinary assays are recommended for testing low-risk patients to avoid false-positive results.[159]
If basal levels are equivocal, a clonidine suppression test can be performed, using the plasma free metanephrine assay.[160]
LOCALIZATION OF THE TUMOR.
Once the diagnosis has been made, medical therapy should be started and the tumor localized by CT or MRI, which usually demonstrates these typically large tumors with ease. In the few patients in whom localization is not possible by CT or MRI, radioisotopes that localize in chromaffin tissue are available for imaging.
THERAPY.
Once diagnosed and localized, pheochromocytomas should be resected. Although preoperative alpha-adrenergic blockade has been recommended, fewer operative and postoperative problems were encountered in one series of patients who had been treated with a calcium channel blocker.[161] If the tumor is unresectable, chronic medical therapy with the alpha blocker phenoxybenzamine (Dibenzyline) or the inhibitor of catechol synthesis alpha-methyltyrosine (Demser) can be used.
Other Causes of Hypertension
A host of other causes of hypertension are known (see Table 37-5 ). One that is probably becoming more common is ingestion of various drugs, prescribed (e.g., cyclosporine, tacrolimus, and erythropoietin), over-the-counter (e.g., ephedra), and illicit (e.g., cocaine). As previously noted, obstructive sleep apnea has been well characterized as a cause of significant, and reversible, hypertension.
Coarctation of the Aorta (see Chap. 56 )
Congenital narrowing of the aorta can occur at any level of the thoracic or abdominal aorta. It is usually found just beyond the origin of the left subclavian artery or distal to the insertion of the ligamentum arteriosum. With less severe postductal lesions, symptoms may not appear until the teenage years or later, particularly during pregnancy.
Hypertension in the arms, weak or absent femoral pulses, and a loud murmur heard over the back are the classic features of coarctation. The pathogenesis of the hypertension can be more complicated than simple mechanical obstruction; a generalized vasoconstrictor mechanism is likely involved. The lesion can be detected by two-dimensional echocardiography, and aortography proves the diagnosis. Once repaired, patients may continue to have hypertension that should be carefully monitored[162] and treated.
Hormonal Disturbances
Hypertension is seen in as many as half of patients with a variety of hormonal disturbances, including acromegaly,[163] hypothyroidism,[164] and hyperparathyroidism.[165] Diagnosis of the latter two conditions has been made easier by readily available blood tests, and affected hypertensive patients can be relieved of their high blood pressure by correction of the hormonal disturbance. Such relief happens more frequently in patients with hypothyroidism than in those with hyperparathyroidism.
Perioperative Hypertension
If at all possible, preexisting hypertension should be well controlled before elective surgery, with particular attention to correction of diuretic-induced hypokalemia. Caution is advised in abruptly discontinuing antihypertensive agents preoperatively, in particular beta-blockers or clonidine. Fortunately, intravenous formulations of most classes are available if oral intake is not possible. A skin patch of clonidine can treat the patient through surgery.
Hypertension may appear or worsen in the perioperative period, perhaps more commonly with cardiac than noncardiac surgery ( Table 37-16 ).[166] Patients at high risk for cardiac events have been found to be protected by the use of beta-blockers prior to either cardiac or noncardiac surgery.[167]
Table 37-16 -- Hypertension Associated with Cardiac Surgery
Preoperative
Anxiety, angina, etc.
Discontinuation of antihypertensive therapy
Rebound from beta blockers in patients with coronary artery disease
Intraoperative
Induction of anesthesia: tracheal intubation; nasopharyngeal, urethral, or rectal manipulation
Precardiopulmonary bypass (during sternotomy and chest retraction)
Cardiopulmonary bypass
Postcardiopulmonary bypass (during surgery)
Postoperative
Early (within 2 h)
Obvious cause: hypoxia, hypercarbia, ventilatory difficulties, hypothermia, shivering, arousal from anesthesia
With no obvious cause: after myocardial revascularization; less frequently after valve replacement; after resection of aortic coarctation
Late (weeks to months)
After aortic valve replacement by homografts
Data from Estafanous FG, Tarazi RC: Systemic arterial hypertension associated with cardiac surgery. Am J Cardiol 46:685, 1980.
Hypertension is of particular concern after heart transplantation, appearing for a number of reasons but in particular because the denervation of cardiac volume receptors prevents the normal suppression of the renin-angiotensin mechanism with volume expansion.[168] Reduction of dietary sodium intake and ACE inhibitor or ARB therapy should be especially beneficial.
Hypertension During Pregnancy (see Chap. 74 )
In about 12 percent of first pregnancies in previously normotensive women, hypertension appears after 20 weeks (gestational hypertension) and in about half this hypertension will progress to preeclampsia when complicated by proteinuria, edema, or hematological or hepatic abnormalities, which, in turn, increase the risk of progress to eclampsia, defined by the occurrence of convulsions. Women with hypertension predating pregnancy have an even higher incidence of preeclampsia and a greater likelihood of early delivery of small-for-gestational-age babies.
Preeclampsia is of unknown cause but occurs more frequently in primigravid women and in pregnancies involving either men or women who were the product of a pregnancy complicated by preeclampsia,[169] supporting a genetic role. Additional predisposing factors include increased age, black race, multiple gestations, concomitant heart or renal disease, and chronic hypertension.
The diagnosis is usually based on a rise in pressure of 30/15 mm Hg or more to a level above 140/90 mm Hg. As with other forms of hypertension, the diagnosis is most precisely made by ambulatory blood pressure monitoring.[170]
Clinical Features
The features shown in Table 37-17 should help distinguish gestational hypertension and preeclampsia from chronic, primary hypertension. The distinction should be made because management and prognosis are different: Gestational hypertension is self-limited and less commonly recurs in subsequent pregnancies, whereas chronic hypertension progresses and usually complicates subsequent pregnancies. Separation may be difficult because of a lack of knowledge of prepregnancy blood pressure and because of the usual tendency for high pressure to fall considerably during the middle trimester so that hypertension present before pregnancy may not be recognized.
Table 37-17 -- Differences Between Preeclampsia and Chronic Hypertension
Feature Preeclampsia Chronic Hypertension
Age (yr) Young (<20) Older (>30)
Parity Primigravida Multigravida
Onset After 20 wk of pregnancy Before 20 wk of pregnancy
Weight gain and edema Sudden Gradual
Systolic blood pressure <160 mm Hg >160 mm Hg
Funduscopic findings Spasm, edema Arteriovenous nicking, exudates
Left ventricular hypertrophy Rare More common
Proteinuria Present Absent
Plasma uric acid Increased Normal
Blood pressure after delivery Normal Elevated
Mechanisms
The hemodynamic features of gestational hypertension are a further rise in cardiac output than usually seen in normal pregnancy, accompanied by profound vasoconstriction that reduces intravascular capacity even more than blood volume that may reflect increased central and peripheral sympathetic activity.[171] The mother may be particularly vulnerable to encephalopathy because of her previously normal blood pressure. As is described in more detail under Hypertensive Crisis, cerebral blood flow is normally maintained constant over a fairly narrow range of mean arterial pressure, roughly between 60 and 100 mm Hg in normotensive individuals. In a previously normotensive young woman, an acute rise in blood pressure to 150/100 mm Hg can exceed the upper limit of autoregulation and result in a "breakthrough" of cerebral blood flow (acute dilation) that leads to cerebral edema and convulsions.
Increasingly strong evidence indicates that preeclampsia starts from deficient trophoblast invasion that, in some manner, sets off a systemic maternal inflammatory response. A variety of triggers have been proposed,[172] but the specific mechanisms remain unknown.
Prevention
Beyond delay of pregnancy until after the teens and better prenatal care, the only other maneuver that has been shown to prevent preeclampsia is the use of low doses of aspirin.[173]
Treatment
The only cure for preeclampsia is delivery, which removes the diseased placenta. To achieve this apparently simple end, the clinician must detect the symptomless prodromal condition by screening all pregnant women, admit to hospital those with advanced preeclampsia so as to keep track of an unpredictable situation, and time preemptive delivery to maximize the safety of mother and baby.
Caution is advised in the use of drugs for gestational hypertension, traditionally limited to methyldopa. Drug treatment of maternal blood pressure does not improve perinatal outcome and may be associated with fetal growth retardation. Most authorities recommend antihypertensive drugs only if diastolic pressures remain above 100 mm Hg.[174] The only drugs that are contraindicated are ACE inhibitors and ARB because of their propensity to induce neonatal renal failure.
Chronic Hypertension
If pregnancy begins while a woman is receiving antihypertensive drug therapy, the medications, including diuretics but excluding ACE inhibitors and ARBs, are usually continued in the belief that the mother should be protected and that the fetus will not suffer from any sudden hemodynamic shifts such as occur when therapy is first begun. However, despite modern treatment, the incidence of perinatal mortality and fetal growth retardation remains higher in patients with chronic hypertension.
Management of Eclampsia
With appropriate care of gestational hypertension, eclampsia hardly ever supervenes; when it does, however, maternal and fetal mortality increase markedly. Excellent results have been reported with the use of magnesium sulfate to prevent and treat convulsions.[175] Caution is needed to avoid volume overload, since pulmonary edema is the most common cause of maternal mortality. When compared with women who were normotensive, the overall prognosis for women who had hypertension during pregnancy is not as good, probably because of causes other than preeclampsia, including unrecognized chronic primary hypertension.
After delivery, transient or persistent hypertension can develop in the mother. In many, early primary hypertension may have been masked by the hemodynamic changes of pregnancy. Peripartum cardiomyopathy is a rare form of left ventricular systolic dysfunction appearing during the last month of pregnancy or within a few months after delivery in the absence of known causes.[176]
გადახედეთ იქნებ იპოვოთ თქვენი სიმპტომების მსგავსი პათოლოგია.
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