Abstract
Objective. To search for primary hyperaldosteronism (PHA) among previously known hypertensive patients in primary care, using the aldosterone/renin ratio (ARR), and to evaluate clinical and biochemical characteristics in patients with high or normal ratio. Design. Patient survey study. Setting and subjects. The study population was recruited by written invitation among hypertensive patients in two primary care areas in Sweden. A total of 200 patients met the criteria and were included in the study. Main outcome measures. The ARR was calculated from serum aldosterone and plasma renin concentrations. The cut-off level for ARR was set to 100, as confirmed in 28 healthy subjects. Patients with increased ARR were considered for a confirmatory test, using the fludrocortisone suppression test. Results. Of 200 patients, 50 patients had ARR > 100; 26 patients were further evaluated by fludrocortisone suppression test. Seventeen of these patients had an incomplete aldosterone inhibition. Conclusion. In total 17 of 200 evaluated patients (8.5%) had an incomplete suppression with fludrocortisone. This confirms previous reports on a high frequency of PHA. No significant biochemical or clinical differences were found among hypertensive patients with PHA compared with the whole sample.
Hypertension is a major modifiable risk factor contributing to global cardiovascular mortality. Arterial hypertension affects 10–15% of the Swedish population Citation[1–4] and is in the vast majority classified as essential hypertension, evaluated and treated in primary care. Identifying patients with curable causes of hypertension is of great importance.
Primary hyperaldosteronism (PHA) was described in 1955 by Jeromy Conn Citation[5]. The syndrome is characterized by hypertension and hypokalemia, due to autonomous increase of aldosterone secretion. The most common causes are an aldosterone producing benign adrenal adenoma or bilateral hyperplasia of the adrenal cortex Citation[6]. Reversion of hypertension may be achieved by surgery in adenoma while medical treatment with an aldosterone antagonist is preferred in bilateral hyperplasia. Historic data estimated the prevalence of PHA to be less than 1–2%. Several international studies suggest, however, that PHA is more prevalent than previously believed and is suggested to be the most common, potentially curable cause of hypertension Citation[7–12].
Primary hyperaldosteronism (PHA) is the most common form of secondary hypertension with international prevalence rates between 5% and 10%.
Among 200 evaluated patients, 17 (8.5%) had an incomplete suppression test with fludrocortisone. This confirms previous reports on a high frequency of PHA.
It is important to consider PHA among hypertensive patients since they are potentially curable and/or specifically treatable.
It is convenient and appropriate to look for PHA among hypertensive patients in primary healthcare.
The aldosterone to renin ratio (ARR) is considered to be the best screening test for PHA Citation[13]. However, the ratio has not been standardized due to different analytical methods for aldosterone and renin Citation[14]. Furthermore, most drugs used for treatment of hypertension alter the ARR since they influence the renin angiotensin aldosterone system. Therefore withdrawal of antihypertensive drugs is strongly suggested before screening Citation[15]. To the best of our knowledge no studies have reported the prevalence of PHA in primary care in Sweden. The principal aim of this study was, therefore, to estimate how common PHA is among a group of hypertensive patients in a primary care area. The study also compared clinical and biochemical characteristics in patients with high or normal ARR. For study purposes, we established reference values for aldosterone and renin in healthy subjects, thereby obtaining an appropriate cut-off level for ARR. To confirm PHA, patients with a high ARR were referred for a fludrocortisone suppression test.
Material and methods
Study population
The study population was recruited from two primary care areas in Lund, Sweden, with a catchment area of 13 000 inhabitants. A database identified 482 patients, 75 years of age or younger, with the diagnosis of essential hypertension (ICD-10). Some 76 patients were excluded because of insulin-treated diabetes mellitus, dementia, stroke, psychiatric illness, mental disorder or malignant tumours. Hence, 406 patients were invited to participate in the study by letter. Non-responders were addressed twice. Twenty-seven patients answered no and 135 patients did not respond. In total, 244 patients declared an interest in participating, but 44 of these patients were unwilling to withdraw treatment. Thus 200 patients were recruited. There was no difference in age or gender between the 200 patients that chose to participate in the study and the 206 patients who did not.
The study was approved by the Ethical Committee of the Faculty of Medicine, Lund University. After receiving oral and written information, informed consent was obtained from all patients participating in the study.
Study design
Antihypertensive drugs that interfere with the aldosterone and renin axis, such as beta blockers, diuretics, ACE inhibitors, alfa-1-receptor blockers and angiotensin II-antagonists were withdrawn two weeks before blood sampling. Calcium channel blockers were continued.
The blood pressure was measured at least once during the withdrawal period. If blood pressure increased to > 200/110 mm Hg, the patient was offered treatment with a calcium channel blocker. If the patient did not accept this medication, the investigation was discontinued. Medical history concerning the duration of hypertension, heredity, current medication, and diseases was recorded by a physician, as well as results of the physical examination.
Biochemical methods
After an overnight fast, blood samples for serum aldosterone concentration and plasma renin concentration were drawn in the morning in a sitting position, after 5–10 minutes’ rest. Renin was analyzed by the Pasteur method (ref. value 3–20 ng/L, Elektrabox). Aldosterone was analyzed with a radio immunological test (RIA) (ref. value 110–860 pmol/L, DPC Skafte AB). Haemoglobin (ref. value122–166 g/L), the plasma concentration of creatinine (ref. value 45–116 umol/L), potassium (ref. value 3.2–4.7 mmol/L), sodium (ref. value 136–146 mmol/L), and urine-albumin/creatinine excretion (ref. value < 3.8g/mol creatinine), were analyzed by routine laboratory methods.
ARR in healthy subjects
The cut-off level for ARR, using the same analytical method to measure aldosterone and renin as in the present study, has been suggested to be 100 Citation[16].
To confirm the accuracy of this cut-off level, 28 healthy subjects were tested, 11 men and 17 women, aged 21–57 years. Blood samples for aldosterone and renin were analyzed under the same conditions as for the patients. The upper limit for ARR was determined by the mean value for the ratio + 2 SD.
Confirmatory testing
The logistic for further evaluation for patients with increased ARR is shown in .
Figure 1. Flow diagram of patients with increased ARR.
Briefly, patients with increased ARR at screening were referred for confirmatory tests. The fludrocortisone suppression test was performed in patients with no medical contraindications. These patients were administered fludrocortisone acetate (Florinef) for 4 days. A serum aldosterone level at day 5 in the morning exceeding 160 pmol/L in sitting position after 15 minutes’ rest was consistent with PHA Citation[17]. Patients who had a positive fludrocortisone suppression test were investigated with adrenal computer tomography.
Radiology
The computer tomography examined the adrenal glands with 3 mm cuts and a contrast medium, Xenetic, was infused.
Statistics
For numeric data, results are given as mean±SD and for categorical data, numbers and percentage if not stated otherwise. Statistical analysis was performed using Stat-View for Windows, version 5.0.1, (SAS Institute Incorporation). For analyzing differences between groups, the Mann–Whitney U-test was used for numerical data. For categorical data, the chi-squared test or Fischer's exact test was used when appropriate. A probability level of p < 0.05 was considered significant.
Results
ARR in healthy subjects
The mean (±SD) serum aldosterone concentration among 28 healthy subjects was 252±172 pmol/L. The upper limit of the 95 CI for the mean value of aldosterone was > 317 pmol/L. For plasma renin concentration the mean (±SD) value was 7.5±4.8 ng/L. The mean (±SD) value for ARR was 40±32. Thus the upper limit for ARR was calculated at 104 (mean value + 2SD). For the screening purpose of the study, a ratio > 100 was considered increased and used as a cut-off level.
ARR at screening
Of the 200 screened patients, 50 (25%) had an ARR > 100. Patients with an increased ARR were more likely to receive medical treatment with calcium channel blockers than patients with a normal ratio (p = 0.002) (). Furthermore, although not significant, patients with a ratio of more than 100 had a tendency towards increased heredity (p = 0.15) (). Otherwise, there were no significant differences in medication, in blood pressure or in the biochemical variables measured (), and no difference in medical history (data not shown).
Table I. Clinical and biochemical variables in patients screened for primary aldosteronism with a raised (>100) and normal (<100) aldosterone/renin ratio.
Confirmatory testing
Of the 50 patients with an ARR > 100, 34 were further evaluated at the Endocrine Unit at Lund University Hospital. Sixteen patients were not investigated because they were considered unlikely to have PHA (low aldosterone < 317 pmol/L, n = 12) or were otherwise medically unsuitable for further evaluation (n = 4).
Of the 34 patients who were offered further evaluation, three patients refused the fludrocortisone suppression test, one patient was previously diagnosed with PHA and the diagnosis was confirmed at the endocrine unit. Four patients were unsuitable on clinical grounds for fludrocortisone suppression test because of earlier stroke, oedema, or unwillingness to withdraw their antihypertensive treatment once more. Thus, in total 26 of 34 patients were further evaluated with a fludrocortisone suppression test.
A high level of ARR was confirmed in 11 of the 26 patients. The mean±SE value for ARR was 200±19 at the initial screening and 108±12 at the endocrine unit, in both occasions higher than in controls.
Sixteen of the 26 patients undergoing a fludrocortisone suppression test (62%) had incomplete aldosterone inhibition (>160 pmol/L), i.e. a positive test. The potassium value at the initial screening was lower in patients with a positive fludrocortisone suppression test compared with patients with a negative test, p = 0.02 (). Otherwise there were no significant differences with regard to clinical characteristics at screening between the patients with a positive and a negative fludrocortisone suppression test ().
Table II. Clinical and biochemical variables in patients with a positive and a negative fludrocortisone suppression test.
However, the mean (±SE) basal aldosterone value before the fludrocortisone suppression test was significantly higher in patients with a positive test compared with those with a negative fludrocortisone suppression test, 344±32 pmol/L versus 211±31 pmol/L, (p < 0.01). There was no significant difference in blood pressure control in fludrocortisone suppression test positive patients compared with patients with a normal ARR (<100), (p = 0.85).
Total outcome
In total, 17 of 200 evaluated patients (8.5%) had incomplete suppression with fludrocortisone (n = 16) or had previously diagnosed PHA (n = 1).
Radiology
Computer tomography of the adrenals was done in the 16 patients with a positive fludrocortisone suppression test. Ten CT scans were normal, five scans showed a wide adrenal limb and in one patient an adrenal tumour was diagnosed. Thus, in 38% of investigated patients, the CT scan was abnormal.
Discussion
To our knowledge, no studies identifying patients at risk of having PHA in a primary care setting have been published from the Scandinavian countries. This study of a cohort of hypertensive patients in primary care suggests that PHA may be as frequent as 8.5%, confirming previous reports of a 5–10% prevalence of PHA from more specialized centres.
The strength of the study is that the patients were recruited from two well-defined primary care areas. The patients had close contact with primary care and were well diagnosed. Therefore, the patients studied were considered to be representative of those patients being diagnosed and treated for hypertension. The weakness is the moderate inclusion of patients, though the dropouts were random among those invited.
There is debate over the optimal methods for detecting PHA Citation[18–21]. The denominator in ARR, renin, has a huge impact on the ratio. Therefore, it is of paramount importance to use sensitive methods for the renin analysis. In order to obtain an accurate ARR, we investigated 28 healthy subjects with aldosterone expressed in pmol/L and renin in ng/L. Our results confirmed that a ratio of 100 is a reliable cut-off level.
The renin angiotensin system is easily disturbed by pharmacological intervention. Before testing, all hypertensive drugs were withdrawn except for calcium channel blockers. Interestingly, most patients experienced no adverse effect of the drug withdrawal. Therefore, a temporary carefully supervised withdrawal of antihypertensive treatment also seems possible in a primary care setting.
In the present investigation, we found that the plasma aldosterone concentration and ARR varied between samples taken in the primary care setting compared with a second testing performed at the endocrine unit. This suggests that the concentration of aldosterone fluctuates more than the concentration of renin and that renin seems to be continuously suppressed in patients with PHA. This finding is in agreement with a previous report Citation[22] in which only about two-thirds of the patients had consistently elevated ARR. To avoid a high number of false-positive screening tests for PHA, the combination of increased ratio and high aldosterone levels has been suggested Citation[21]. Using the present method, an aldosterone concentration above the 95% CI for the mean value among healthy subjects, 317 pmol/L, could serve as a reasonable threshold together with ARR > 100. Furthermore, possibly two or more samples should be analyzed before referring the patient for confirmatory testing.
Patients with an increased ARR and a high PAC did not differ in clinical characteristics compared with patients with a ratio below 100. Furthermore, there were no differences between the two groups with regard to plasma potassium concentration. This is in accordance with several studies showing a significant number of normocalemic patients proven to have PHA Citation[17].
In conclusion, our study has shown that among 200 patients undergoing treatment for hypertension in a primary care setting in Sweden almost 25% had an increased ARR and 8.5% had a positive fludrocortisone suppression test. These patients cannot, however, be recognized from clinical characteristics. Since the frequency of PHA is so high, and these patients are first seen in primary care before treatment is started, it should be highly relevant for the family practitioner to incorporate ARR screening for PHA in the initial evaluation of patients with hypertension. This study also shows that it is convenient and accurate for doctors in primary care to use the analysis of aldosterone, renin, and ARR for the diagnosis of PHA.
Related Research Data
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