Download Endocrine Causes of Hypertension

Endocrine Causes of Hypertension
A large number of secondary causes of hypertension are known (see table 1). Hyperaldosteronism is probably the
commonest secondary cause of hypertension and appropriate investigation requires a careful understanding of
the physiology of aldosterone secretion and the effects of anti-hypertensive medications on regulation of the reninangiotensin system.
Aldosterone, a salt retaining hormone produced by the
adrenal cortex, may be secreted in excess and independent
of salt, water balance or renin/angiotensin 1. Consequently,
in appropriately prepared patients, the measurement
of renin plus aldosterone and the calculation of the
aldosterone renin ratio (ARR) is extremely helpful in the initial
investigation of patients suspected of suffering from primary
hyperaldosteronism (PHA) 2.
ARR as a screening test was first introduced in 1983 3.
With the use of ARR, it was recognised that PHA was more
common than previously appreciated (>5% of hypertensive
patients) and the presence of hypokalemia was less
common than normokalemia in patients proven to have PHA
(10-30% have hypokalemia in PHA) 4. More recently, PHA
has been associated with excess cardiovascular morbidity
due to cerebrovascular disease, myocardial infarction or
arrhythmia compared to patients with essential hypertension
and similar blood pressure control 5. The frequency of
these co-morbidities is reversed by surgery or specific
medications that antagonise aldosterone action 6. Case
detection therefore offers the dual potential of surgical cure
of the patient and/or minimisation of morbidity.
When should you test the ARR?
Recent guidelines have suggested the following patient
categories should be considered for screening for PHA 7:
1. Moderate, severe or resistant hypertension: BP > 160/100
or BP >140/90 despite 3 anti-hypertensive medications
2. Hypertension with spontaneous or diuretic induced
hypokalemia
3.Presence of adrenal adenoma: note such adrenal masses
could represent non-functioning “incidentalomas”–
see later.
4. Hypertension and family history of early onset
hypertension or CVA at age < 40
5.Hypertensive 1st degree relatives of patients with
previous proven PHA
Some have argued that all hypertensive patients should
be screened for PHA as the longer the diagnosis is missed,
the higher likelihood of irreversible morbidity, the lower
likelihood of curative surgery and screening before the
introduction of anti-hypertensive medications makes ARR
interpretation easier 8.
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Table 1 – Secondary Causes of Hypertension
• Hyperaldosteronism: Primary 5%
• Phaeochromocytoma
• Cushings syndrome
• Congenital Adrenal Hyperplasia
• Adrenal virilising tumours
• Acromegaly
• PCOS: metabolic syndrome complication
• Thyroid disease
• Primary hyperparathyroidism:
not used as criteria for surgery
• B-type naturetic peptide
Measuring renin and aldosterone
Whilst renin is the main regulator of aldosterone secretion,
serum potassium, ACTH and changes in hepatic blood flow
can also effect aldosterone secretion. A number of factors
can affect renin release as well as aldosterone secretion
and consequently the ARR. There is a need to control these
extraneous factors, where possible.
The ARR is a simple ratio of the serum aldosterone,
usually measured in pmol/L divided by the plasma renin,
usually measured in mU/L. Consequently, similar to
other ratios, such as FAI etc, it is the denominator, that
is the plasma concentration of renin, that dominates the
calculation of the ratio. Consequently, one limitation of ARR
is that the ratio can be elevated purely in the presence of a
very low renin concentration, such as occurs in advancing
renal failure or in low renin, essential hypertension. Some
laboratories, therefore, don’t report the ratio when the
aldosterone values are very low (<300 pmol/L) to minimise
the risk of over-interpretation of the result.
In a patient with PHA, renin is usually less than 10mU/L
and typically often less than 5 mU/L. Serum aldosterone is
typically greater than 420 pmol/L and as a consequence,
an ARR of >50-70 is used by some laboratories. The lack of
consensus regarding the specific value of the ratio can be
partially explained by some differences between methods
of renin and aldosterone analysis but also emphasises the
divided literature in this area of diagnosis 7.
Endocrine Causes of Hypertension continued
Posture
Upright posture results in a rise in serum aldosterone due
to a secondary increase in renin release. This effect occurs
in healthy normotensive individuals as well as most patients
with PHA. In practice, most centres measuring ARR use a
mid-morning ambulant sample usually obtained after sitting
for 5 to 10 minutes.
Time of day
In patients with PHA, renin is suppressed so aldosterone
concentration may be influenced by ACTH levels which
show a circadian rhythm. Consequently, ARR is more likely
to be elevated in the morning in PHA as ACTH is highest at
this time of day 9.
Dietary Na and serum/plasma K
Dietary sodium restriction may stimulate renin release and
consequently lower the ARR. The sensitivity of the ARR can
be improved by ensuring a liberal dietary salt intake.
Since potassium can stimulate aldosterone secretion,
hypokalemia can be associated with a false negative ARR in
PHA. Consequently, correction of serum K before assessing
ARR is important. Concomitant assessment of creatinine
and K with renin and aldosterone measurement is advisable.
Anti-hypertensive medications:
beware the false positives!
Beta blockers inhibit renin output as sympathoadrenal
function is an additional important regulator of renin. Renin
output can be reduced with aldosterone concentrations
being less affected. The latter may be due to continued
stimulatory effects of serum potassium and ACTH on
aldosterone production. As a consequence, false positive
ARR may occur 10. Methyldopa and clonidine may have
similar effects to beta blockers on the ARR 11.
Anti-hypertensive medications:
beware the false negatives!
Diuretics, dihydropyridine calcium antagonists (DHCA’s),
angiotensin converting enzyme (ACE) inhibitors and
angiotensin receptor blockers (ARB’s) can all increase renin
more than aldosterone and in cases with PHA can result
in false negative diagnoses 12. Diuretics induce volume
contraction and consequent sympathoadrenal activation,
DHCA’s induce reflex sympathoadrenal activation and ACE
inhibitors or ARB’s may potentially interfere in the negative
feed-back effect of angiotensin II on renin production.
Other medications
NSAID’s can suppress renin while concomitantly
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promoting potassium retention leading to stimulation
of aldosterone production and an elevation in the ARR.
Oral contraceptive agents probably have little effect
on ARR when older renin activity assays were in use.
However, newer mass renin assays could be affected as
potentially, oestrogen could increase hepatic production
of angiotensinogen resulting in increased angiotensin I,
angiotensin II and consequently, greater feedback inhibition
on renin. Newer oral ocps containing drosperinone or
gestodene (Yasmin, Yaz,) could equally and falsely
increase ARR 13.
Other physiological effects
One recent study has indicated that ARR is higher
in the luteal compared with the follicular phase but only
when measuring renin using a mass and not an activity
assay 14. Further studies are needed, but it is probably
preferable to measure ARR in the follicular phase pending
further data. Renal failure may result in false positive ARR
due to reduction in renin secretory mass or salt and water
retention. Pregnancy or renal artery stenosis may result in
false negative ARR due to physiological renin stimulation.
Suggested testing of ARR and correction of
pre-analytical factors
It is preferable to correct serum K before analysis of ARR
and collect a sample for serum K and creatinine whenever
measuring ARR. Normal unrestricted diet is preferred and
medications which significantly affect the ARR should be
listed on the request form.
If, for example, renin is relatively high (>10mU/L) whilst
taking beta blockers, clonidine or methyldopa and assuming
no other medication use or physiological effects, then the
likelihood of PHA is low if the ARR is low. Consequently,
further investigation may be unnecessary. Alternatively, if the
ARR is high in the presence of diuretics, DHCA’s or ARB’s
then PHA is likely.
If anti-hypertensive medication effects are causing
possible interference then withdrawal of beta blockers plus
most other agents for at least two weeks, diuretics for at
least four weeks and specifically spironolactone for 6 weeks
may be required. Prazosin, verapamil SR or hydralazine
have been shown to have least effects on the ARR and
can be used as alternative anti-hypertensive agents in the
meantime.
A number of additional tests including oral salt loading,
saline suppression, fludrocortisone suppression and captopril
challenge are currently used to confirm PHA with recent
consensus guidelines concluding that there is insufficient
direct evidence to recommend one specific test 7.
Endocrine Causes of Hypertension continued
Lateralisation and the role of imaging
Adrenal CT scanning is recommended once the ARR has
been proven to be consistently and unequivocally elevated.
Unfortunately, some aldosterone producing adenomas (APA’s)
are too small to identify, small APA’s can be misinterpreted as
representing hyperplasia and non-functioning, incidentalomas
cannot be distinguished from APA’s on CT imaging. MR
imaging has no advantage over CT imaging and is more
expensive. However, CT imaging will exclude adrenocortical
carcinomas which are fortunately rare.
Further testing is required in order to confirm lateralisation
of aldosterone production. Adrenal venous sampling
(AVS) involves bilateral adrenal vein cannulation to confirm
unilateral as opposed to bilateral aldosterone production.
The interpretation of AVS is beyond the scope of this article
but it should be performed in a centre with extensive
radiological experience and interpreted by pathologists with
an understanding of the limitations of this methodology 15.
Consequently, referral to an endocrinologist with experience
and understanding of AVS is advisable when a diagnosis of
PHA is suspected in general practice.
Treatment
Unilateral, laparoscopic adrenalectomy is advisable if
unilateral aldosterone production is confirmed by AVS 7.
50% of patients may be cured of hypertension (BP<140/90
without anti-hypertensive agents) following successful
surgery and 100% have improvement in BP control and
serum potassium concentration 16. Laparoscopy compared
to open adrenalectomy is associated with shorter hospital
stay and fewer complications 17.
In patients who decide against surgery, where AVS
fails to lateralise aldosterone production or if AVS is
unsuccessful due to lack of successful cannulisation of
both adrenal veins, medical management can be pursued
with either spironolactone, amiloride or eplerenone 18. Whilst
epleronone is a newer and more selective aldosterone
antagonist it is only PBS listed in Australia for the
management of heart failure so there are cost implications
for patients who chose this treatment.
Conclusions
PHA should be considered in higher risk groups of
hypertensive patients and in the presence of spontaneous
or diuretic induced hypokalemia. ARR is ideally measured
in the morning, in the early follicular phase of premenopausal women and should be interpreted carefully
taking into consideration the effects of anti-hypertensive
and other medications which can alter the renin-angiotensin
system. Withdrawl of interfering medications should be
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considered where appropriate. All patients with PHA
should undergo CT imaging and the presence of unilateral
aldosterone production should be established or excluded
by AVS. Laparoscopic unilateral adrenalectomy is optimal
management for PHA due to an APA. Patients with bilateral
adrenal hyperplasia or who are unsuitable for surgery
should be offered medical treatment with mineralocorticoid
receptor antagonists.
References
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Dr Paul Glendenning
Consultant Endocrinologist and Chemical Pathologist
T: 08 9476 5222
E: [email protected]