Clarification of hypertension – Diagnosis of
primary hyperaldosteronism

Marc Beineke
The significance of the aldosterone/renin
ratio (ARR) in the diagnosis of normo-
alaemic and hypokalaemic primary hyper-
aldosteronism, the most common causes
of secondary hypertension
Epidemiology of primary
On the basis of the new data, which were ob- hyperaldosteronism
tained by determining the aldosterone/renin ratio (ARR), the frequency of PH in hyper- Primary hyperaldosteronism (PH) is the most tensives – 5-13% – is much higher than previ- Apart from hypertension, hypokalaemia was hitherto considered to be the classical cardinal On the cautious assumption that PH is the un- symptom. Its presence was therefore also derlying cause in 5% of al hypertensives, over usual y a prerequisite for further diagnostic 800,000 people in Germany would be affected clarification in respect of PH. However, numer- by this diagnosis. Aldosterone-producing adenoma as a cause of hypertension can in potassium levels are within the reference range in approximately 90% of PH patients. ■ Aetiology of primary hyperaldosteronism

Aldosterone-producing adenoma (APA = Conn’s syndrome) (approx. 30-40%), unilateral Idiopathic hyperaldosteronism (IH) (approx. 60%), bilateral Macronodular adrenocortical hyperplasia (MNH), (1-5%), unilateral or bilateral Aldosterone-producing carcinoma (adrenal or ectopic, e.g. ovarian) (1%) Familial hyperaldosteronism (FH)* (1-5%), type I (= GSH**) and II : Classification of primary hyperaldosteronism (PH) [1, 2] The stated frequencies refer to the total PH group (normokalaemic and hypokalaemic). If – as before – only the hypokalaemic PH patients are included, APA is the most common cause, at around 70% [3]. * For details of diagnosis and treatment, see [3]. ** GSH = glucocorticoid-suppressible hyperaldosteronism ■ Optimized PH screening: the
aldosterone/renin ratio (ARR)
Since the diagnosis of PH opens up effective, inexpensive treatment options [4, 5], ex- tended laboratory screening with additional determination of the aldosterone/renin ratio (ARR), including normokalaemic patients, is Fig. 1: Classification of disturbances of the renin-angiotensin-aldosterone system using the aldosterone/renin ratio (ARR) and aldosterone. Marked in are the limits recommended by our laboratory for the identification of patients with PH (ARR: 30; aldosterone 15 ng/dl), according to [2, 9, 10, 17]. If the ARR is > 30 and aldosterone is < 15 ng/dl, further clarification in respect of PH may also be indicated and successful. ■ Optimized PH screening:
tween 8 and 12 o’clock (contraindication: target groups
heart failure, state after myocardial infarct; severe, uncontrol ed hypertension). In the fol owing groups of patients, optimized At 8 o’clock and 12 o’clock blood is col ected PH screening with additional determination of for analysis of plasma aldosterone and plasma the aldosterone/renin ratio (ARR) is recom- In patients without autonomous aldosterone secretion, plasma aldosterone is suppressed by at least 50% by the infusion of saline, or aldosterone levels normalize. In PH, there is no, or no clear, suppression of the elevated baseline aldosterone values. The salt loading medication as the screening test [15]. The fludrocortisone suppression test, which has age) with a positive familial history or a likewise been wel evaluated in the literature, is very expensive, because of the need to spend 5 days in hospital. Analysis of aldoster- one-18-glucuronide in 24-h urine under oral salt loading should only be carried out as an alternative if the salt loading test is contraindi- cated/impracticable. Administration of 3 x 2 g NaCl/day in addition to the normal diet (ap- proximately 9 g NaCl/day) for a period of 3 days is recommended for this, to give a daily sodium intake of roughly 260 nmol/day. Since aldosterone-18-glucuronide represents only about 20% of total aldosterone secretion and there are no up-to-date evaluation stud- ies, this test is less conclusive than the salt loading test [15]. On the 3rd day of oral salt loading, aldosterone-18-glucuronide must be in the normal range and urinary sodium in the check on salt supply must be > 200 mmol/ ■ Procedure if a pathological result
Clarification of the aetiology in
is obtained in the PH screening
cases of confirmed diagnosis
Confirmation of diagnosis
firmed, the aetiology is further investigated After a positive result in screening, the diag- using biochemical methods (analysis of aldos- nosis of PH must be confirmed with further terone, renin, and cortisol in the orthostasis test; 8 o'clock (recumbent position), 12 o'clock (standing)) and imaging techniques (CT or The principal confirmatory test recommended, MRI) [see 1, 2, 3]. For the orthostasis test, on the basis of its practicability (for out- care must be taken to ensure that the patient patients) and evaluation [15], is the salt load- remains constantly in horizontal position for at ing test: 2 litres of isotonic saline is infused into the patient, in a recumbent position, be- inpatient setting. After col ection of the first For patients with bilateral idiopathic hyperpla- sample of blood in the recumbent position, sia, the only thing left is drug treatment with a the patient is to adopt an erect posture for 4 mineralocorticoid receptor antagonist (e.g. h. Another blood sample is then col ected for spironolactone), possibly in combination with the analysis of aldosterone, renin, and cortisol A typical sign of an aldosterone-producing adenoma is an apparently paradoxical drop in ■ Pre-analysis and sampling for
determination of the ARR
o'clock [recumbent position] and 12 o'clock [standing] in the orthostasis test, which can be explained by ACTH-dependence on In bilateral adrenocortical hyperplasia, on the other hand, preserved angiotensin II-depend- ence on aldosterone secretion with an in- sition between 8 and 10 o’clock in the orthostasis is typical. 30% of adenomas also show an increase in aldosterone in orthosta- sis, however. If the results of the orthostasis test and imaging techniques agree, the aim is to give the relevant specific therapy (adrena- lectomy or spironolactone therapy). If a clear differential diagnosis between adenoma and hyperplasia is not possible with these tests, with analysis of aldosterone and cortisol is in- sampling should always be carried out, how- ever, if surgical treatment is probable [17]. Patients with aldosterone-producing adenoma typical y show an aldosterone/ cortisol ratio name of the material (“EDTA plasma”) gradient of more than 5:1 to the adenoma- affected side. [2]. Other sources speak of more than 2:1 [15, 16] or more than 3:1 [18]. ■ Some antihypertensives should be dis- present, the treatment of choice is (laparo-scopic) adrenalectomy; long-term therapy ■ Flow diagram: Procedure to be followed if primary hyperaldosteronism is
suspected/to be excluded
2 Differential diagnosis and clarification of PH [according to 1, 2] Before surgical treatment, selective adrenal venous blood sampling with determination of the aldosterone/cortisol ratio should always be performed to confirm the diagnosis. Imidazoline receptor antagonists (e.g. clonidine) Alpha receptor blockers (e.g. doxazosin) Spironolactone, eplerenons, drospirenone, amiloride, triamterene References
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Clinical Pathologist
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