Adrenal Causes of Hypertension
Norman N. Kaplan, MD, Dallas
Adrenal diseases are responsible for only about 1% of cases of hypertension. How- ever, these diseases need to be considered in many more patients with unusual symp- toms, signs, and laboratory data. Procedures are readily available to rule out these dis- eases with relative ease and great accuracy. Those patients with positive screening tests can be subjected to more intensive work-up to confirm the diagnosis. Definitive therapy, either medical or surgical, usually relieves the hypertension.
T Though subtle abnormalities of the adrenal may be involved in the pathogenesis of essential hyperten- sion, currently recognizable diseases of the adrenal are responsible for no more than about 1% of the cases of hypertension. These diseases are cor- tical including Cushing syndrome, primary aldosteronism, and congen- ital adrenal hyperplasia, and medul- lary including pheochromocytoma.
The definitive diagnosis of these four adrenal causes of hypertension sometimes requires the application of sophisticated hormone analyses that can be done only in research labora- tories. The practicing physician can, however, by use of fairly simple clini- cal criteria and laboratory tests that are readily available, exclude these diseases in most hypertensives with relative certainty, and identify those few patients who deserve additional work-up.
Cushing Syndrome
Frequency .- Hypertension occurs in 85% of patients with idiopathic Cush- ing syndrome but in only about 20%
Received for publication Oct 23, 1973; accepted Jan 28, 1974.
From the Department of Medicine, the Uni- versity of Texas Health Science Center at Dal- las.
Reprint requests to Department of Medicine, the University of Texas Health Science Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75235 (Dr. Kaplan).
of patients with the iatrogenic dis- ease. The lesser frequency with the use of exogenous glucocorticoids re- flects the use of cortisol derivatives with greater antiinflammatory and lesser salt-retaining properties than the natural hormone.
The hypertension can be severe. In a series of 50 patients, six had a dia- stolic pressure above 130 mm Hg and four of the seven deaths were from cardiovascular complications.1 Of the 24 patients over age 40, 23 were hy- pertensive and 11 of these developed congestive heart failure.
If present for a long time, the hy- pertension may persist despite re- moval of the source of excess cortisol and cure of the syndrome. In a series of 64 patients, 26% of those with bi- lateral adrenal hyperplasia remained hypertensive after curative adrenal surgery.2 The persistence of hyper- tension was attributed to arteriolar nephrosclerosis that developed sec- ondarily.
Thus, hypertension may be a promi- nent part of the pathologic findings of Cushing syndrome. The syndrome should be recognized and treated quickly to prevent permanent dam- age from hypertension.
Mechanism .- Cortisol, the natural hormone that is in greatest excess in most patients with Cushing syn- drome, has about 1:100 to 1:200 of the mineralocorticoid activity of aldoste- rone. In the normal person, however, 200 times more cortisol is secreted than aldosterone. Thus, under rela- tively basal conditions, much of the steroid-mediated retention of sodium is effected by cortisol. When shrink- age of fluid volume elicits additional mineralocorticoid activity, aldoste- rone and not cortisol is stimulated by the renin-angiotensin mechanism.
The twofold to fourfold increased levels of cortisol present in most cases of Cushing syndrome are sufficient to
cause salt retention and expansion of extracellular fluid volume and, thereby, hypertension. In those syn- dromes with high cortisol secretion, ectopic adrenocorticotropic hormone (ACTH) producing tumors, and adre- nal carcinomas, hypertension and se- rious hypokalemic alkalosis may arise secondary to both the miner- alocorticoid activity of cortisol and the presence of other adrenal steroids such as deoxycorticosterone and corti- costerone B.ª Aldosterone secretion is not elevated, even in those patients with pronounced hypokalemic alka- losis.+
Diagnosis .- Clinical features can usually separate the many hyperten- sive patients with cushingoid fea- tures from the few who have the dis- ease. In an analysis of 52 patients with Cushing syndrome and 159 oth- ers suspected of having the syn- drome, the following features were shown to have the greatest differ- ential value, being present in most patients with Cushing syndrome but in few of those suspected of having it®: central obesity; osteoporosis shown by x-ray film; muscular weak- ness demonstrated by the inability to arise from a knee-bend; plethora; and ecchymoses.
On the other hand, features that were of little discriminatory value since almost as many patients with- out Cushing syndrome had them as did patients with the syndrome in- cluded leukocytosis, acne, striae, edema, hirsutism, oligomenorrhea, and an abnormal glucose tolerance test.
Hypertension in itself was also of little diagnostic value. Of the patients with Cushing syndrome, 39% had di- astolic pressures above 104 mm Hg but so did 17% of those without the syndrome.
Laboratory tests are often needed to confirm the clinical impression and are always needed to establish the diagnosis. The following procedures can be performed with readily avail- able steroid analyses.
Plasma cortisol or 17-hydroxy- corticoid (17-OHCS) is determined in a specimen obtained the morning after the patient is given 1.0 mg of dexamethasone, taken orally at bed-
Hypertension + Hypokalemia
Urine K+
< 30 mEq/day
> 30 mEq/day
Prior Diuretic Therapy Gl Losses
Plasma Renin Activity
High
Low
Estrogen Therapy Renovascular Hypertension Accelerated-Malignant Hypertension Salt-Wasting Renal Disease
Aldosterone
Low
High
Primary Aldosteronism
Licorice Ingestion Excess of Deoxycorticosterone or Other Mineralocorticoid Liddle Syndrome
time.” Normal patients not under un- due stress will suppress below 10ug/ 100 ml; patients with Cushing syn- drome rarely suppress below 15µg/ 100 ml.
Urinary 17-OHCS excretion mea- sured on the second day of adminis- tration of 0.5 mg of dexamethasone every six hours.7 Patients with Cush- ing syndrome rarely suppress below 4 mg per 24-hour specimen. Once the diagnosis of Cushing syndrome is made, the type of adrenal pathologic findings can usually be ascertained by measuring urinary 17-OHCS excre- tion on the second day of adminis- tration of 2.0 mg of dexamethasone every six hours. Patients with adrenal tumors fail to suppress below 50% of the basal level, while those with bilat- eral hyperplasia usually do so. A few patients with nodular adrenal hyper-
plasia fail to suppress8 and would, therefore, be considered candidates for adrenalectomy, but this is of little concern, since adrenal excision is ac- ceptable therapy for bilateral hyper- plasia.
Caution is needed in the perform- ance and interpretation of laboratory tests for Cushing syndrome. Basal plasma and urinary 17-OHCS levels are of little value; plasma levels vary from minute to minute,9 and plasma and urinary levels may be affected by various factors affecting steroid me- tabolism (Table). Normal patients un- der the stress of hospitalization may fail to suppress their plasma 17- OHCS with the 1.0 mg dexametha- sone test.1º Rarely, normal suppres- sion is seen with bilateral hyper- plasia.11 Other procedures such as the metyrapone test, using stimulation
by endogenous ACTH, or the re- sponse to stimulation by exogenous ACTH, seem to provide little addi- tional help.
Recognizing these precautions, the diagnosis of Cushing syndrome is usually easy. The process can be ex- cluded as a cause of hypertension in most suspects by use of the plasma suppression test alone.
Treatment .- Adrenal adenomas should be removed and adrenal carci- nomas resected if possible. Bilateral adrenal hyperplasia can be cured by pituitary irradiation in some patients with relatively mild disease; bilateral adrenalectomy is the treatment of choice with more severe disease or af- ter failure of pituitary irradiation.12 Partial destruction of cortisol-produc- ing adrenal tissue with ortho, para DDD has proved to be less satisfac-
tory than originally claimed. If adre- nalectomies are done, part of one gland should be autotransplanted to the patient’s thigh since it may occa- sionally function adequately enough to preclude the need for life-long re- placement therapy.1.3
Primary Aldosteronism
Frequency .- As many as 7% of the hypertensives referred to the Univer- sity of Michigan medical center have primary aldosteronism.14 In most other centers, the frequency is less than 1% of the hypertensive popu- lation.15-18 The lower figure does not appear to reflect the use of less exten- sive diagnostic studies but rather the lesser degree of selection of patients for study. Among a truly unselected population, the frequency is probably considerably below 1%.
With the wider application of as- says for renin activity and plasma al- dosterone, adrenal venography, and scintillation scanning, more cases may be uncovered. But the practicing physician need be concerned only about those hypertensive patients with hypokalemia. When the hypoka- lemia has not been provoked by thia- zide diuretics, laxative use, or con- cealed vomiting, as many as half of the patients may have primary al- dosteronism.16 When the hypokalemia has been provoked, the likelihood is sharply reduced.15
Every hypertensive should have a plasma potassium level determined before institution of diuretic therapy. Those patients found to have hypoka- lemia should be extensively evaluated for aldosteronism. Those who are found to be hypokalemic after use of thiazides may deserve evaluation if their hypokalemia cannot be easily corrected by discontinuation of di- uretics and administration of ade- quate supplemental potassium while on a low sodium diet. Since mild hy- pokalemia is seldom dangerous in the absence of digitalis therapy, it may be more sensible simply to change the diuretic therapy to a combination of a thiazide with either of the potassium- sparing agents, spironolactone (Al- dactazide) or triamterene (Dyazide).
Mechanism .- Primary aldosteron-
ism may arise either from benign adenomas, usually solitary, or from bilateral hyperplasia. Interestingly, some degree of hyperplasia is almost always found in those glands harbor- ing an adenoma.19 The two causes, however, can be separated anatomi- cally and, usually, clinically. The sepa- ration is important since surgical ex- cision is probably indicated in most patients with an adenoma but not in those with bilateral hyperplasia.
With either type of pathologic find- ings, the excess of aldosterone causes increased retention of sodium in the distal portion of the renal tubule. These major consequences follow. Plasma and extracellular fluid volume expands, causing hypertension and a suppression of renin release. Potas- sium is exchanged and swept into the urine, resulting in hypokalemia and a metabolic alkalosis.
Adenomas usually secrete more al- dosterone than do hyperplastic glands. All of the aforementioned features are, therefore, more overt and pronounced in those patients with aldosteronism caused by an ade- noma.2º Since an extensive work-up seems necessary only for those with an adenoma who would benefit from surgical excision of their tumor, there appears to be even greater justifica- tion not to subject those hyperten- sives without unprovoked hypoka- lemia to a work-up for aldosteronism. If the work-up uncovers mild aldoste- ronism caused by bilateral hyper- plasia, therapy will probably differ little from what it would have been otherwise, though more spiro- nolactone might be indicated.
A small number of patients with al- dosteronism caused by bilateral hy- perplasia have either an enzymatic defect or some other reason for sup- pressibility by exogenous glucocorti- coids.21 There may be value in giving a seven to ten day course of dexa- methasone, 0.5 mg given twice daily, to all patients with aldosteronism, particularly those with mild features suggesting bilateral hyperplasia. Those patients whose blood pressures become normal should probably be maintained on such suppression ther- apy.
Diagnosis .- The flow diagram (Fig-
ure) describes a reasonable approach to the differential diagnosis of a hypokalemic hypertensive patient. The work-up involves three proce- dures, done in this sequence: mea- surement of urinary potassium excre- tion; assay of plasma renin activity; and assay of aldosterone levels.
There are factors to consider in the proper use of each of these three pro- cedures.
Urinary potassium should be mea- sured in a 24-hour urine specimen col- lected while the patient is hypokale- mic, has not taken diuretics for at least four days and is receiving salt intake adequate to deliver 100 mEq of sodium into the urine so that potas- sium wastage can be accurately quantitated. Most patients with al- dosteronism excrete more than 30 mEq of potassium.22
Plasma renin activity (PRA) should be suppressed by the expanded plasma volume and hypertension of primary aldosteronism. Some stimu- lus that usually raises PRA must be applied to demonstrate a suppressed level. A 500-mg low-salt diet adhered to for three days followed by two hours of upright posture has been the most frequently used stimulus,23 but upright posture alone16 or adminis- tration of a potent diuretic24.25 has also been used to provide a moderate shrinkage of effective plasma volume, which increases renin release in most hypertensives but not in those with expanded volumes due to aldosterone excess.
Unfortunately, 12% to 45% of hy- pertensive patients without primary aldosteronism have a suppressed PRA after application of these various stimuli.26 Though some of these pa- tients may have an excess of another mineralocorticoid, most have not been found to have a recognizable cause for their low-renin state. Extensive investigation is being performed to elucidate the mechanism of low-renin hypertension. For now, the clinician must be aware of its presence and its meaning.
A suppressed PRA is seen in all pa- tients with primary aldosteronism but it also occurs in many hyperten- sives without this disease.
Aldosterone assays need only be
| Factors Affecting Steroid Metabolism* | |||
|---|---|---|---|
| Condition | Primary Mechanism | Plasma 17-OHCS | Urinary 17-OHCS |
| Hypothyroidism | I Degradation | Normal | Low |
| Hyperthyroidism | 1 Degradation | Normal | High |
| Liver disease | Į Degradation | Normal | Low |
| Obesity | t Body mass | Normal | High |
| Pregnancy | 1 Binding protein | High | Normal |
| Estrogen therapy | î Binding protein | High | Normal |
| Diphenylhydantoin therapy | 1 Degradation of dexamethasone | Failure to suppress | Failure to suppress |
* From Kaplan.26
done in those hypokalemic hyperten- sives who waste potassium and have a suppressed PRA. The tedious double isotopic derivative assay for urinary aldosterone is being replaced by ra- dioimmunoassays that can measure the nanogram quantities in plasma.27 Since the aldosterone levels in plasma vary from minute to minute, the as- say of a single specimen may not pro- vide an adequate measure of adrenal secretion. As with plasma cortisol as- says in the diagnosis of Cushing syn- drome, a rapid suppression test ap- pears to provide excellent diagnostic accuracy.28 Plasma aldosterone is first raised by the patient maintaining up- right posture for two hours and is then suppressed by infusion of 2 liters of normal saline over four hours. Hy- pertensives without primary aldoste- ronism suppress their plasma aldoste- rone concentration below 5 ng/100 ml, while concentrations of those with the disease remain elevated.
Since hypokalemia may suppress aldosterone production even from an adenoma, these assays should proba- bly not be done until potassium re- placement has been achieved. Supple- mental potassium should be stopped for at least three days before aldoste- rone is measured since it will stimu- late secretion even from normal glands.
Numerous other procedures have been advocated for the diagnosis of primary aldosteronism. These include the pattern of electrolyte excretion after saline infusion, suppression of urinary aldosterone by deoxycorti- costerone or fludrocortisone (Fluri- nef), and the response of the blood pressure to 400 mg of spironolactone administered daily for up to six weeks.
Only the latter procedure seems to be needed now that plasma renin and aldosterone assays are so readily available. The spironolactone test not only helps in diagnosis but also pre- dicts surgical curability and helps cor- rect the hypokalemia and other dis- turbances of aldosterone excess.29
Once the diagnosis is established, an attempt to visualize the adrenals by venography30 or scintillation scanning31 should be attempted to es- tablish the pathologic findings, and to decide upon the proper therapy. As- say of aldosterone in venous blood ob- tained at venography discriminates even more between adenoma and hy- perplasia.32
Therapy .- The ability of spiro- nolactone to return the blood pressure and body composition to normal in most patients with primary aldoste- ronism has prompted its long-term use as definitive therapy for the dis- ease. Smaller doses than the 400 mg daily needed for a diagnostic test are usually adequate and do not cause the nausea, gynecomastia, menstrual ir- regularities, and impotence seen with long-term use of large doses.
Surgery still seems indicated if the patient has an adenoma, is young and in good condition, has pronounced hy- pertension and hypokalemia, or is unable to tolerate spironolactone. If the work-up indicates bilateral hyper- plasia, long-term medical therapy should be continued.29
Congenital Adrenal Hyperplasia
Frequency .- One or another en- zymatic defect in the synthesis of cor- tisol may lead to the compensatory secretion of large amounts of miner- alocorticoid hormones that cause hy- pertension. Such defects are usually
present at birth but may not become manifest until adult life. They are very rare and no work-up aimed at their recognition is needed in most hypertensives.
Mechanism and Diagnosis .- Prior mention was made of glucocorticoid- suppressible adrenal hyperplasia, which is a rare cause of primary al- dosteronism. This may well represent a congenital enzymatic block but some cases do not display clear evi- dence for such a mechanism.21
Two forms of congenital adrenal hyperplasia have hypertension as part of their clinical presentation.
The 11-hydroxylase deficiency, pro- duces a block in the formation of cor- tisol from its precursor 11-deoxy- cortisol and in the conversion of deoxycorticosterone to corticosterone. The decrease in cortisol synthesis ac- tivates the release of ACTH, which stimulates the secretion of adrenal androgens, causing virilization of the infant. The excess of deoxycorticoste- rone induces hypertension and hy- pokalemia.
The syndrome should be suspected in virilized infants with hypertension and proved by the finding of high lev- els of 11-deoxycortisol and deoxy- corticosterone in urine or blood.
The 17-hydroxylase deficiency, in addition to blocking the synthesis of cortisol, also blocks the synthesis of adrenal androgens and estrogens.33 Therefore, virilization is not seen. In- stead, a failure of secondary sexual development at puberty with hypogo- nadism and amenorrhea in affected females and ambiguous genitalia in male patients occurs.34 These defects in sexual development are not notice- able until after the expected time of puberty. From birth, however, the block in cortisol synthesis does allow excessive ACTH stimulation of the synthesis of the potent mineralocor- ticoid, deoxycorticosterone. Therefore, hypertension and hypokalemia ap- pear.
This syndrome should be suspected in hypertensive infants but may not be recognized until hypogonadism be- comes obvious during adolescence. The diagnosis is established by finding low urinary 17-ketosteroids and high levels of deoxycorticosterone.
Therapy .- Replacement therapy with cortisol in doses of 10 mg to 30 mg daily should relieve the hyperten- sion, stop virilization in the patient having an 11-hydroxylase defect, and start sexual development in the pa- tient with 17-hydroxylase defect.
Pheochromocytoma
Frequency .- About 0.5% of hyper- tensives have a pheochromocytoma. The disease is more common among those patients with one or more of these features: widely fluctuating hy- pertension; paroxysms of headache, sweating, and palpitations; hyper- metabolic state without hyperthy- roidism; neurofibromatosis; a family history of pheochromocytoma; medul- lary carcinoma of the thyroid; hyper- parathyroidism; or facial neuromas (Sipple syndrome or multiple endo- crine adenomatosis, type 2).35
The disease is found in fewer than 5% of those suspected on the basis of clinical features. On the other hand, in patients with pheochromocytoma, the hypertension may be persistent and few if any paroxysmal symptoms may be present. In view of the rela- tive ease and accuracy of the urinary metanephrine assay, some clinicians perform this test on all hyperten- sives.
Mechanism .- Tumors may arise from chromaffin cells, which synthe- size epinephrine and norepinephrine, wherever they are located. About 90% of these tumors arise from the adre- nal medulla, while the other 10% occur in sympathetic ganglia in the thorax and abdomen, in the organ of Zuck- erkandl at the bifurcation of the aorta, and in the wall of the bladder. About 10% of these tumors are malig- nant.
The manifestations of the disease depend in part on the nature of cate- cholamine secretion. Adrenal medul- lary tumors can synthesize epineph- rine. If epinephrine is the major secretion, the symptoms usually in- clude predominantly systolic hyper- tension, tachycardia, sweating, flush- ing, and tremulousness. Rarely, hypotension to the point of shock can occur with predominant epinephrine secretion.36 Very rarely, extra-adre- nal pheochromocytomas may also se-
crete epinephrine.37
Some adrenal and most extra-adre- nal tumors secrete mainly norepi- nephrine; their manifestations in- clude both diastolic and systolic hypertension that may be persistent, less tachycardia and fewer paroxysms of headache, sweating, and palpita- tion.
Rarely occurring pheochromocyto- mas may secrete, in addition, large amounts of the catecholamine pre- cursors, dopa and dopamine, which, because of their hypotensive action, may keep the patient normotensive.38 Such tumors are usually found as ab- dominal masses.
Diagnosis .- The following tabula- tion lists the frequency of various symptoms and signs found in over 300 published cases of pheochromocy- toma.39
Common
Hypertension, probably over 98% Intermittent only, 2% to 50% Sustained, 50% to 60%
Paroxysms superimposed, about 50%
Headache, 80% to 85%
Sweating, 65% to 70%
Palpitations, 60% to 65% Nervousness, 35% to 40%
Nausea and vomiting, 35% to 60% Weight loss, 40% to 70%
Funduscopic changes, 50% to 70% Less Common
Abdominal pain Chest pain
Polydipsia, polyuria Flushing Acrocyanosis
Pallor Dyspnea
Dizziness
Convulsions Bradycardia
An assay of catecholamine excretion should be done on patients with these symptoms and signs or with a neu- rocutaneous syndrome or a familial history of endocrine tumors.
A total metanephrine-normeta- nephrine assay on a single voided urine specimen, performed by the Pi- sano technique4º and expressed as mi- crograms of metanephrine per milli- gram of creatinine has proved to be a simple, inexpensive, and highly re- liable procedure.” The normal level is less than 1.0ug/mg of creatinine.
Only a few things interfere with
this test. Radiopaque dyes containing methylglucamine42 cause falsely low readings, and administration of chlorpromazine43 produces falsely high readings. Monoamine oxidase in- hibitors increase the levels by in- creasing the conversion of cate- cholamines into the metanephrine metabolites. However, no dietary in- gredients or antihypertensive drugs cause interference. Neither the pa- tient nor the urine specimen need be put through special maneuvers for this assay. It should replace the 24- hour urinary vanilmandelic acid de- termination as a screening test for pheochromocytoma.
If an elevated metanephrine level is found in a spot urine test, the pro- cedure should be repeated and, if that too shows a high level, catecholamines should be assayed by another proce- dure.
If the clinical and laboratory find- ings are positive, an intravenous pyelogram should be done and a chest x-ray film should be taken to localize the tumor. More sophisticated proce- dures have been advocated including adrenal arteriography” and venog- raphy.” Since neither of these proce- dures is capable of demonstrating multiple, small, and extra-adrenal tu- mors, their value seems doubtful. They may be of greater diagnostic usefulness when combined with as- says of catecholamines in blood sam- ples taken from multiple sites. Re- liable and simpler assays for blood catecholamines have been recently re- ported.46
Pharmacologie tests have no place in the diagnosis of pheochromocy- toma.
Therapy .- Surgical excision is al- most always indicated though chronic medical therapy with a- and B-ad- renergie antagonists is feasible.47 Sur- geons, anesthesiologists, and inter- nists responsible for management of patients with pheochromocytoma should be aware of the many hazards and pitfalls involved. Articles by Ross et al48 and Gitlow et al49 provide excel- lent guidance and should be con- sulted.
This work was supported by Public Health Service grant 5 R01 HL 4863-02.
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