CHAPTER 5
ENDOCRINE HYPERTENSION
Sam
Dagogo-Jack, MD, FRCP
Professor of
Medicine
Friday,
January 17, 2003
(9:15a.m.-9:50a.m.)
Objectives:
- To recognize
hypertension as a major public health problem, and understand its
classification.
- To appreciate the current
lack of specific knowledge regarding etiology of essential hypertension.
- To identify possible
endocrine mechanisms which have been implicated in essential hypertension.
- To delineate the
leading systemic causes of secondary hypertension and understand their
rarity.
- To recall the major
endocrine causes of hypertension and the pathophysiologic mechanisms for
elevation of blood pressure in these conditions.
OVERVIEW OF HYPERTENSION
Hypertension (elevated blood pressure,
conventionally defined as a systolic blood pressure > 140 mm Hg, a diastolic
blood pressure >90 mm Hg, or both) affects about 50 million Americans. It is important because it markedly increases the risk of stroke, heart
failure, myocardial infarction (heart attack) and renal failure. High blood
pressure itself causes no symptoms,
except when extremely high. In more than 95% of patients, no underlying cause
can be determined – they have essential
hypertension (“essential’ is a synonym for “idiopathic” and also means “we
don’t know the cause”), and are treated to lower blood pressure and risk of the
diseases above. A small fraction
(<5%) of patients with hypertension have diagnosable causes (secondary hypertension). Essential hypertension is currently
considered an incurable disorder that requires life-long medical management.
Endocrine Aspects of Essential hypertension
Although
the underlying cause(s) of essential hypertension are unknown, there are
definite alterations of endocrine systems in this condition. Many patients with
essential hypertension have demonstrable alterations of the
renin-angiotensin-aldosterone system that permits them to be classified as
having Low-, Normal-, or High-Renin Hypertension. The plasma renin activity is
used for this classification. This subclassification of essential hypertension
has therapeutic and prognostic implications. For instance, cardiovascular risk
is markedly higher in high-renin patients than in low-renin patients. Also, the
BP response to diuretics and calcium channel blockers is better in patients
with low-renin hypertension compared with high-renin patients, whereas the
latter respond better to angiotensin converting enzyme inhibitors. In addition
to the renin-angiotensin-aldosterone system, alterations in catecholamines
(sympathetic nervous system) have been noted in some patients with essential
hypertension. In general, circulating levels of epinephrine and norepinephrine
and urinary norepinephrine excretion tend to be higher in patients with
essential hypertension than in normotensive subjects, although there is
considerable overlap. The overlap is so large as to make this test not useful
for diagnostic purposes. There may also be a defect in the vasodilatory
kallikrein-bradykinin system in some familial forms of essential hypertension.
Thus, although no single hormone or hormonal system appears to be the culprit,
many patients with essential hypertension have some alterations in one or more
endocrine systems.
Secondary hypertension
In
the general populace, approximately <5% of patients with hypertension have
an identifiable underlying cause; this form is referred to as “Secondary
Hypertension”. In the Hypertension Detection and Follow-Up Program conducted in
the 1970’s, 0.18% of 15,000 participants had secondary hypertension. Because secondary
hypertension is extremely uncommon, current clinical practice discourages
routine search or an elaborate work up for underlying causes in a typical
patient with hypertension. The clinical importance of identifying cases of
secondary hypertension is obvious, however. Unlike essential hypertension
(which is an incurable, lifelong disorder) successful treatment of the
underlying cause may provide a cure for patients with secondary hypertension.
Causes of secondary hypertension
·
Renal
parenchymal disease: e.g., acute nephritis, chronic glomerulonephritis, etc.
·
Renovascular
disease: e.g., renal artery stenosis, atherosclerosis, fibroplasia, etc.
·
Endocrine
causes
ENDOCRINE HYPERTENSION
Three
endocrine diseases cause hypertension in the majority of patients who have them: primary
hyperaldosteronism, pheochromocytoma and Cushing’s syndrome. Each of
these is a rare cause of
hypertension, accounting for <1%. Renal artery stenosis also causes
hypertension. Although increased angiotensin II and secondary
hyperaldosteronism contribute to hypertension in patients with renal artery
stenosis, this condition is not considered an endocrine cause of
hypertension. On the other hand, there
is a long list of endocrine conditions that have been associated with hypertension.
The evidence for causality is not equally strong across all of these
conditions. A partial list of such conditions is presented, followed by a
fuller discussion of the more characteristic (or more common) examples of
endocrine hypertension.
Endocrine conditions associated with hypertension
·
Pheochromocytoma
·
Mineralocorticoid
excess (e.g., primary hyperaldosteronism)
·
Glucocorticoid
excess (e.g., Cushing’s syndrome)
·
Acromegaly
·
Diabetes
mellitus
·
Obesity
·
Congenital
adrenal hyperplasia
·
Estrogen-induced
hypertension
·
Pregnancy-induced
hypertension
·
Renin-secreting
tumors
·
Hypothyroidism
·
Hyperthyroidism
·
Liddle
syndrome
PHEOCHROMOCYTOMA
The sympathochromaffin (sympathoadrenal) system is
the prototype neuroendocrine system. It
has two components: 1) The sympathetic
nervous system including its postganglionic neurons, the vast majority of which
release norepinephrine (noadrenaline)
among other neurotransmitters. 2) The
chromaffin tissues including particularly the adrenal medullae (conceptually
postganglionic neurons without axons), which are the major source of
circulating epinephrine (adrenaline) among other hormones. Norepinephrine and
epinephrine (along with dopamine) are catecholamines;
their structures include a dihydroxyphenly (“catechol”) nucleus and an amine
side chain. The sympathochromaffin
system and the parasympathetic nervous system comprise the autonomic nervous system.
Catecholamines:
The
catecholamines—dopamine (DA), norepinephrine (NE) and ephinephrine (E) are
synthesized from tyrosine which is hydroxylated to dihydroxyphenylalamine
(DOPA) in the presence of tyrosine hydroxylase, the rate-limiting enzyme in
catecholamine biosynthesis (figure 1).
DOPA is decarboxylated by a nonspecific enzyme to form DA. Dopamine b-hydroxylase (DbH) converts DA to
NE, phenylethanolamine-N-menthyl transferase (PNMT) NE to E. Some systems (e.g. most cells of the adrenal
medullae) contain all of these enzymes, and release E. Others (e.g. most sympathetic postganglionic
neurons) lack PNMT, and release NE. Still
others (particularly in the brain) lack both DbH and PNMT and release DA.
The catecholamines are degraded by two principal
enzyme systems, catechol-O-methyl transferase (COMT) and monoamine oxidase
(MAO). COMT converts NE and E to their
O-methyl metabolites, normetanephrine and
metanephrine respectively; after
further metabolism these serve as substrates for MAO leading to formation of
3-methoxy 4-hydroxymandelic acid, better known as vanillylmandelic acid (VMA), the major end product of catecholamine
metabolism.
Catecholamines act through plasma membrane receptors
of two broad types, a- and b-adrenergic receptors (adrenoceptors). Each type
includes multiple subtypes (a1 and a2 and b1
, b2 and b3 );
cloning has revealed further divisions of these subtypes. NE and E are mixed agonists. They interact with both a-and b-adrenergic
receptors although NE has a relatively low affinity for b2 –adrenergic
receptors including those that mediate vasodilation in skeletal muscles. This probably explains the differences in
the
hemodynamic responses to E (increased systolic, but
not diastolic, blood pressure and increased heart rate) and NE (increased
systolic and diastolic blood pressure with reflex restraint of the increase in
heart rate).
Although extra-adrenal epinephrine secretion occurs,
the adrenal medullae are the source of biologically effective plasma levels of
E. Thus, E is a hormone in the
traditional sense. In contrast, NE
functions primarily as a neurotransmitter. Because most (~90%) of the NE released
from sympathetic axon terminals is dissipated locally (by re-uptake or local
metabolism) and does not enter the circulation, there is a steep NE
concentration gradient from the synaptic clefts to the plasma when NE is
released from the terminals in quantities sufficient to produce biologic
effects (e.g. an increase n BP). This gradient must be reversed in order for
circulating NE to raise blood pressure.
Therefore, substantial increments over basal plasma NE levels are
required to produce biological effects (e.g. hypertension) if the NE is
released directly into the circulation (as from a pheochromocytoma).
PHEOCHROMOCYTOMA: Pheochromocytomas are catecholamine producing tumors, composed of chromaffin cells, that typically produce labile hypertension and paroxysmal symptoms. They are rare (perhaps 0.1% of hypertensive patient) but important to detect because: 1) The hypertension is usually curable. 2) The untreated patient is at risk for a lethal hypertensive paroxysm. 3) Some (perhaps 5-10%) are malignant. 4) They can
be a clue to the presence of a familial, often autosomal dominant, syndrome. The latter include multiple endocrine neoplasia (type 2A with hyperparathyroidism and medullary carcinoma of the thyroid, and type 2B, with multiple mucosal neuromas and medullary carcinoma of the thyroid). Familial pheochromocytoma also occurs without associated disorders, in some kindred with von Hippel-Lindau disease and, uncommonly, in persons with neurofibromatosis.
Diagnosis: The diagnosis of pheochromocytoma is based
upon clinical suspicion and biochemical confirmation and then (and generally
only then) anatomical localization. Clinical: Pheochromocytoma is suspected in a patient with paroxysmal
symptoms (especially headache, diaphoresis and palpitations), labile (and
sometimes truly paroxysmal) hypertension, a family history of pheochromocytoma
or some combination of these. These
paroxysms may be precipitated by a variety of stimuli: positional changes, emotional
stress, abdominal pressure, direct pressure on tumor, medications, etc. Metabolic
features of pheochromocytoma include signs of hypercatabolism: increased
metabolic rate, profuse sweating, hyperglycemia, and weight loss (despite good
appetite). The hyperglycemia may be accompanied by glycosuria, both being due
to catecholamine stimulation of hepatic glucose production and inhibition of
insulin secretion and action. Hematological manifestations (attributable
to catecholamine-induced vasoconstriction and plasma volume reduction) include
orthostatic hypotension, which may also be due, in part, to blunted sympathetic
reflexes. Patients with pheochromocytoma may have an elevated hematocrit, from
plasma volume contraction and hemoconcentration. Rarely, true erythrocytosis
(polycythemia) occurs from
paraneoplastic production of erythropoietin by the tumor. Thus clinical clues
in some patients include orthostatic hypotension, hyperglycemia, and
erythrocytosis. Routine testing for pheochromocytoma in patients with
hypertension is both cost-inefficient and unwise – false positive tests would
outweigh true positives by a large margin.
SYMPTOMS
DURING PAROXYSMAL ATTACKS (% of Adults)
Headache 59
Sweating 52
Palpitations 49
Pallor 42
Nausea 34
Tremor 33
Anxiety 28
Abdominal pain 25
Chest pain 25
Weakness 19
Dyspnea 17
Weight loss 16
Flushing 14
Visual disturbance 12
_______________________________________________________
adapted from Ross EJ, Griffith DNW. Quart J Med
1989;71(266): 485-496
Biochemical: Confirmation of the
presence of a pheochromocytoma is traditionally accomplished with 24h urine
catecholamine (NE and E). Although
measurements of metabolites (preferably total metanephrines rather than VMA)
can be used, specific measurements of catecholamines are preferable. These values are more than twice the upper
limit of normal in >90% of patients with proven pheochromocytomas. Plasma
catecholamine measurements (NE, E) can also be used. Recent data suggest a slight advantage to urinary catecholamine
measurements (which provide information integrated over time), although plasma
catecholamine measurements (which provide information only about a short time
frame since the plasma half times are ~ 1-2 minutes) are effective and simpler
for the patient. Initial plasma NE and
E levels in thirty patients with pheochromocytomas are shown in Figure 2.
Plasma samples should be obtained in the drug-free
state if at all possible since many medications might elevate catecholamine
levels producing false positive results.
If hypertension must be treated, clonidine, which does not produce fale
positives, should be used. Samples
should be obtained in the basal state (for which reference values are well
established and in which most affected patients have elevated levels) as well
as during paroxysms.
Most patients with a pheochromocytoma have elevated plasma and urinary catecholamine (especially NE) values whenever sampled. Occasional patients have normal value when sampled when they are normotensive and asymptomatic. If clinical suspicion is high, plasma samples should be obtained during a paroxysm, if possible, and urinary NE should be measured. On the other hand, normal or slightly elevated catecholamine levels are good evidence against pheochromocytoma in a patient hypertensive at the time of sampling.
Localization: Although described in
regions ranging from the carotid body to the pelvic floor, 90% of
pheochromocytomas are in the adrenal medullae and 99% are in the abdomen. Most of the remainder are in the
mediastinum. Pheochromocytomas are
usually localized by computed tomography or magnetic resonance imaging.
Iodobenzylguanidine scintigraphy is expensive, time consuming, less sensitive
for
intra-adrenal tumors and of somewhat limited
availability, but has localized tumors not detected by CT (especially
extra-adrenal, metastatic and recurrent pheochromocytomas). Although multiple tumors are found in less
than 10% of patients with sporadic pheochromocytomas, bilateral adrenomedullary
disease is the rule in familial pheochromocytoma.
In summary, the diagnosis of pheochromocytoma is
based upon suggestive clinical findings, measurement of urinary and/or plasma
catecholamines, followed by localization by CT or MRI scans.
Treatment: Briefly, the treatment of pheochromocytoma is surgical excision
by an experienced surgeon working with a vigilant anesthesiologist. Pre-operative control of blood pressure with
an alpha-adrenergic antagonist (e.g. phenoxybenzamine, prazosin) helps prevent
catastrophic rise in blood pressure during surgical handling of the tumor. The prompt resolution of hypertension
following successful resection of a pheochromocytoma is one of the most
gratifying clinical experiences.
MINERALOCORTICOID EXCESS
MINERALOCORTICOIDS stimulate the distal renal
tubules to reabsorb sodium from
tubular fluid (ie,excrete less sodium) and excrete
more potassium and hydrogen ions
(acid). They increase open sodium
and potassium channels in the luminal membrane of tubular cells and increase
synthesis of basolateral membrane Na+/K+ ATPase, which generates the gradients
that drive ion movement.
Mineralocorticoids
expand extracellular fluid (ECF) volume by
increasing the amount of sodium in the body, and increase blood pressure due to greater intravascular volume and
increased arteriolar resistance. They lower plasma potassium levels and
increase plasma pH. There is some
evidence that effects on the brain contribute to hypertension.
The mineralocorticoid
receptor is activated by both cortisol and aldosterone. Aldosterone is the primary mineralocorticoid
because an enzyme (11 – beta
hydroxysteroid dehydrogenase) coexists with this receptor in the renal
tubule and coverts cortisol to inactive cortisone. Hereditary defects or drug inhibition
of this enzyme produces a syndrome of apparent
mineralocorticoid excess, due to receptor activation by normal levels of
cortisol. Licorice contained in some candies and tobacco products has a
metabolite (glycyrrhetinic acid) that produces mineralocorticoid excess by
inhibiting 11-beta hydroxysteroid dehydrogenase. Severe cortisol excess causes
mineralocorticoid effects, including hypertension and hypokalemia.
Aldosterone is the primary
mineralocorticoid in man. Cortisol has
mineralocorticoid activity that is clinically important at high
concentrations. 11-deoxycorticosterone,
an aldosterone precursor, is also a mineralocorticoid.
•
Mineralocorticoid excess causes hypertension and hypokalemic alkalosis. Two things you might expect,
hypernatremia and edema (excess fluid in subcutaneous tissue, producing
swelling of the feet and ankles) don’t occur.
Plasma sodium increases only slightly (and usually remains normal)
because it is regulated by antidiuretic hormone and thirst that control water
balance. ECF expansion stops before
edema develops, in part because atrial natriuretic hormone levels rise and
limit sodium retention.
Aldosterone secretion is regulated by
the volume of the extracellular fluid
(ECF) (Fig 3a and 3b). This is sensed by receptors in the
juxtaglomerular apparatus of the kidney, through changes in renal arteriolar
blood pressure and sodium concentration of renal tubular fluid. ECF volume contraction (“dehydration”)
stimulates secretion of the enzyme renin. Renin cleaves the circulating protein
angiotensinogen to release angiotensin 1, which is converted to angiotensin II by angiotensin converting enzyme (ACE)
on endothelial cells. Angiotensin II stimulates aldosterone
secretion, which then decreases sodium excretion, tending to increase ECF
volume and suppress renin secretion, forming a negative feedback loop. Conversely expansion of ECF volume by high
salt intake or intravenous infusion of saline suppresses renin and aldosterone
secretion, increasing sodium excretion and tending to correct ECF volume
expansion.
Angiotensin ll
is also a potent vasoconstrictor, and increases
blood pressure directly. In summary,
the regulatory steps in aldosterone secretion are:
Renin ACE
angiotensinogen angiotensin I
angiotensin II stimulation of aldosterone
The renin-angiotensin-aldosterone system maintains
ECF volume by responding to decreased salt intake or increased salt loss (eg
sweating) to limit further sodium loss in the urine. Pathological causes of sodium loss (vomiting, diarrhea), diuretic
therapy and other conditions in which renal blood flow is decreased
hypotension, renal artery stenosis, heart failure) increase renin and
aldosterone secretion.
Renin secretion is also stimulated by the sympathetic nervous system, via
beta-adrenergic receptors. This increases renin and aldosterone levels on
standing, and contributes to the response to hypotension. Hyperkalemia
stimulates aldosterone secretion and hypokalemia suppresses it, but this
regulatory mechanism is less important than ECF volume. ACTH
is not part of the physiologic control of aldosterone, so patients with
ACTH deficiency lack cortisol, but aldosterone secretion is intact.
•
Mineralocorticoid excess may be due to autonomous aldosterone secretion, eg by an adrenal
adenoma (primary hyperaldosteronism),
in which case plasma renin and angiotensin are suppressed by negative
feedback. It may also be due to
increased renin secretion (secondary
hyperaldosteronism). Secondary hyperaldosteronism may be an adaptive
physiologic response to ECF volume depletion, or cause some symptoms of
disorders in which renal perfusion is decreased (eg congestive heart failure).
Plasma levels of renin and aldosterone vary widely
due to differences in salt intake, and whether patients were standing before
samples were drawn. This means that
random plasma levels of either one alone are seldom helpful. The ratio
of plasma aldosterone to plasma
renin activity is used to diagnose primary hyperaldosteronism. During physiologic increases in aldosterone
secretion due to increased renin secretion, the ratio remains unchanged. In primary hyperaldosteronism, plasma
aldosterone increases while renin is suppressed by negative feedback, so the
aldosterone to renin ratio is much higher than
normal.
Manipulation of ECF volume is also used for diagnosis – intravenous
infusion of saline suppresses normal secretion of renin and aldosterone.
PRIMARY HYPERALDOSTERONISM
Primary hyperaldosteronism is
excessive production of aldosterone due to an adrenal disorder, and not due to excess renin secretion. It results in ECF expansion, hypertension
and marked suppression of renin secretion.
Secondary
hyperaldosteronism is increased secretion of both renin and aldosterone. It is a normal response to deficient salt
intake, and is a compensatory mechanism in diseases that decrease ECF volume
(eg, vomiting, diarrhea) or reduce perfusion of the kidneys (eg, cirrhosis,
heart failure, renal artery stenosis).
It contributes to clinical findings such as edema in the latter
diseases, and the aldosterone antagonist spironalactone is sometimes used to
treat them.
ETIOLOGY OF
PRIMARY HYPERALDOSTERONISM: About 2/3 of cases are due to
an aldosterone-secreting adrenal
adenoma. These tumors tend to be
small – average diameter <2 cm.
Remaining cases are due to bilateral adrenal hyperplasia of unknown
cause (idiopathic hyperaldosteronism).
CLINICAL
FINDINGS in
primary hyperaldosteronism are hypertension,
and hypokalemia. Hypertension in
this disorder is due to increased body sodium, which increases ECF volume and
vascular resistance. Patients rarely
have symptoms, although severe hypokalemia may cause muscle weakness, cramps,
and polyuria. Edema does not occur,
since compensatory mechanisms limit the degree of ECF expansion. Plasma sodium concentration is usually
normal, not increased.
DIAGNOSIS: This disorder is suspected in a patient with hypertension and spontaneous hypokalemia. Since diuretics used to treat hypertension
(eg thiazides) are a much more common cause of hypokalemia than primary
hyperaldosteronism, serum potassium should be measured while the patient is not
taking diuretics (or after they have been stopped for several weeks).
In a patient with hypertension and hypokalemia not due
to diuretics, urine potassium is measured to be sure hypokalemia is due to
excess renal potassium excretion (rather than to excess gastrointestinal loss,
eg in diarrhea or laxative abuse).
Urine potassium >30 mmo1/24 hr indicates renal potassium wasting.
Tests for primary hyperaldosteronism are based on
the fact that excess aldosterone secretion is not under normal control by
renin. Plasma renin activity (PRA) is
low, and the ratio of plasma aldosterone
to PRA is increased. Measuring the
ratio minimizes diagnostic problems caused by normal variation of these two
hormones with body position (supine vs standing), salt intake and other factors
that affect ECF volume. In essential
hypertension, renin and aldosterone tend to change in parallel, and the ratio
between them remains fairly constant.
Likewise, the ratio is not elevated in secondary hyperaldosteronism.
The optimum ratio for separating primary
hyperaldosteronism from essential hypertension is debated, but if the ratio is
>30, primary hyperaldosteronism is very likely; if the ratio is >50, it
is almost certain. The ratio may be
affected by many antihypertensive drugs, which should be stopped several weeks
before testing. If the aldosterone/renin ratio is elevated, the diagnosis of
primary hyperaldosteronism is confirmed by demonstrating that plasma aldosterone cannot be normally
suppressed by ECF volume expansion. IV infusion of saline is usually used
for this purpose.
DIAGNOSTIC TESTS FOR PRIMARY HYPERALDOSTERONISM
Screening:
• plasma potassium (while not
treated with diuretics)
Definitive:
• plasma aldosterone (ng/dl) /
plasma renin activity (ng/ml/hr) ratio:
<30: probably not primary hyperaldosteronism
>50: almost certainly primary hyperaldosteronism
• aldosterone suppression: 2 liters 0.9% (normal) saline IV over 4 hrs
with
patient supine. Normal: plasma aldosterone <4 ng/dl
_________________________________________________________
DIFFERENTIAL
DIAGNOSIS: Although small, adrenal adenomas are usually
seen on CT scans, remember that non-functioning, incidental adrenal nodules are common. Primary hyperaldosteronism
is diagnosed by endocrine testing, not radiology. There are some differences in regulation of aldosterone secretion
by adenomas and idiopathic hyperaldosteronism that may help in differential
diagnosis.
Occasionally, adrenal venous aldosterone
measurements are necessary.
TREATMENT: Resection of an aldosterone-secreting adenoma cures
hypokalemia and, in most cases, hypertension.
In idiopathic hyperaldosteronism, even bilateral adrenalectomy doesn’t
cure hypertension, so it is treated with the aldosterone antagonist
spironolactone, and other antihypertensives as needed to control blood
pressure.
GLUCOCORTICOID EXCESS
GLUCOCORTICOIDS have multiple actions,
including effects on glucose metabolism (hence their name). In high concentrations, they cause profound catabolic effects on protein
metabolism, especially in skeletal muscle and connective tissue, and suppress immunity and inflammation. They are necessary for normal cardiovascular function. They have effects on the brain,
including increased appetite. Cortisol is the primary glucocorticoid
in man. Synthetic glucocorticoids are
widely used to treat allergic and inflammatory disorders, and to suppress
autoimmune diseases and rejection of organ transplants. When physicians say
“steroids’< they mean this pharmacologic use of glucocorticoid drugs. Prednisone
is most commonly used glucocorticoid.
Dexamethasone is a potent
synthetic glucocorticoid used to produce negative feedback in diagnostic tests
because it interferes very little with measurement of cortisol. Treatment with
excessive doses of prednisone or dexamethasone or other glucocorticoid agent
produces a syndrome that is clinically similar to that produced by endogenous
cortisol excess.
• Glucocorticoid excess (known as Cushing’s syndrome
after the neurosurgeon who described it) causes a variety of clinical effects,
some of which can be explained by known actions of cortisol. Obesity is due
mainly to stimulation of appetite, while catabolic effects cause weakness of
skeletal muscle and connective tissue of the skin. Bone mass decreases and fractures are common.
Glucocorticoid excess and
Hypertension
General information on
Cushing’s syndrome is discussed more fully elsewhere. Up
to 80% of patients with Cushing’s syndrome have hypertension (high blood
pressure occurs less frequently in drug-induced cases of the syndrome). The exact mechanism of hypertension in
Cushing’s syndrome is unknown. Some suggested pathways include direct effects
of excess cortisol, acting via three mechanisms: 1) angiotensin, 2)
mineralocorticoid, and 3) vascular reactivity.
Angiotensin mechanism: Glucocorticoids stimulate
hepatic synthesis of angiotensinogen, wich is acted upon by renin and
angiotensin converting enzyme to the potent vasoconstrictor angiotensin II.
This mechanism probably operates in some but not all patients with Cushing’s
syndrome.
Mineralocorticoid: High concentrations of
cortisol can bind to and cross-activate mineralocorticoid receptors, resulting
in typical mineralocortocid effects-hypertension and hypokalemia. The sodium and
fluid retention from this mechanism
also will suppress plasma renin. However, most patients with Cushing’s disease
(from pituitary tumor) or syndrome from adrenal adenoma do not have hypokalemia
or suppressed renin. Interestingly, when the Cushing’s syndrome results from
ectopic paraneoplastic production of ACTH, hypokalemia and renin become more
prominent features. One possible explanation may the effect of high levels of
ACTH on the biosynthesis of cortisol precursors with enhanced mineralocorticoid
activity (e.g. 11-deoxycortisol). Furthermore, the renal enzyme 11
beta-hydroxysteroid dehydrogenase (which breaks down cortisol) has been found
deficient in some patients with paraneoplastc (ectopic) ACTH syndromes.
Deficiency in 11 beta-HSD allows high intrarenal levels of cortisol to activate
the mineralocorticoid receptor, resulting is hypertension and hypokalemia.
Vascular reactivity: Administration of cortisol
to normal subjects enhances vascular reactivity to pressors, resulting in
vasocontriction, increased peripheral resistance, and elevation in BP. This is
likely to be a more general mechanism than the alterations of specific hormone
pathways discussed earlier.
Diagnosis: The
diagnosis of Cushing’s syndrome is covered elsewhere in this syllabus.
Treatment: In patients without a family
history of hypertension, blood pressure often returns promptly to normal, or
becomes easier to control with few drugs, once the underlying cause of
Cushing;s syndrome has been localized and removed.
Suggested reading
Weber KT. Mechanisms of disease: Aldosterone in congestive heart failure. N Engl J Med 345:1689-1700, 2001.
Cryer PE: Diseases of the sympathochromaffin system. In Endocrinology and Metabolism, Third
Edition. Felig P, Baxter J, Frohman L (eds). McGraw-Hill, New York, 1994.
Bravo EL, Gifford RW Jr: Pheochromocytoma. Endocrnol Metab Clinics NA 22:329-341, 1993.
Ross EJ, Griffith DNW. The clinical presentation of pheochromocytoma. Quart J Med 71(266): 485-496, 1989.
White PC. Disorders of aldosterone biosynthesis and action. N Engl J Med 331:250, 1994.
Finder JW. Glucocorticoid and mineralocorticoid receptors: biology and clinicial relevance. Ann Rev Med
48:231, 1997.
Sam Dagogo-Jack, MD, FRCP
Friday, January 17, 2003
(9:15a.m.-9:50a.m.)
ENDOCRINE HYPERTENSION
CASE # 1
A 47-year-old woman is referred because of poorly controlled hypertension. She has leg
Cramps and polyuria, but no episodes of headache, sweating or palpitations. There is no family history of hypertension.
She is not obese. HR is 78/min and BP 160/98 mm; the exam is otherwise normal.
Plasma potassium: 2.5 mM
1) What symptoms are caused by hypertension? By severe hypokalemia?
2) What are the three major endocrine causes of hypertension (ie, disorders in which the majority of
patients have high blood pressure)? How common are they in patients with hypertension?
3) Which endocrine cause of hypertension is most likely in this patient? What test should be done now?
______________________________________________________________________________________________________________________________________________________________________________________________________
A blood sample is drawn with the patient seated:
Plasma aldosterone: 25 ng/dl plasma renin activity: <0.5 ng/ml/hr
After these results are available, another test is performed. With the patient supine, 2 liters of normal
Saline (0.9% NaCl) is infused IV over 4 hr. Plasma aldosterone at the end of the infusion is 20 ng/dl.
______________________________________________________________________________________________________________________________________________________________________________________________________
4) Do these results establish a diagnosis? Why were aldosterone and renin activity measured
simultaneously? Can a diagnosis be made by measuring either hormone level alone?
5) What is the purpose of saline infusion?
6) What are the major causes of this syndrome? Why is it important to distinguish between them, and
how can this be done?
______________________________________________________________________________________________________________________________________________________________________________________________________
Abdominal CT shows a 2 cm mass in the right adrenal
______________________________________________________________________________________________________________________________________________________________________________________________________
Sam Dagogo-Jack, MD, FRCP
Friday, January 17, 2003
(9:15a.m.-9:50a.m.)
ENDOCRINE HYPERTENSION CASE #2
A 34-year-old man complains of episodes of palpitations and severe, pounding headache,
usually lasting less than 30 minutes. He has no history of hypertension or other medical problems.
BP is 160/95 and HR 78/min; otherwise the exam is normal.
Plasma potassium is 4.4 mM
1) What endocrine disorder can cause this man’s symptoms? Excessive secretion of what compound
causes hypertension in this disorder?
2) What diagnostic tests can be done to confirm this diagnosis?
______________________________________________________________________________________________________________________________________________________________________________________________________
24 hr urine norepinephrine: 280 μg (normal 15-80) epinephrine: 5 μg (normal <15)
______________________________________________________________________________________________________________________________________________________________________________________________________
3) What are the pathologic features of this disorder?
4) Should all patients with hypertension be tested for this disorder?
4
