Key words
aldosterone - adrenal - renin - secondary hypertension
Introduction
Primary aldosteronism (PA) is hypertension caused by inappropriately high aldosterone
secretion, consecutively low plasma renin, and elevated aldosterone-to-renin ratio
(ARR). It represents the most frequent cause of endocrine arterial hypertension and
is found in 5.8% of unselected hypertensive patients in primary care,
6–12% in hypertension centers, and up to 30% in patients
with resistant hypertension [1]. Although
the disease was previously considered to be present only in patients with severe
hypertension and hypokalemia, it is now well known that PA is also common in
patients with mild forms of hypertension and normokalemia.
As patients with PA suffer from an increased risk of cardio- and cerebrovascular
events and metabolic abnormalities, early identification and therapy of the affected
patients are of great importance [2].
Most of the patients are affected by sporadic forms: unilateral aldosteronism,
mainly caused by aldosterone-producing adenoma (APA), which can be cured by
adrenalectomy; and bilateral hyperaldosteronism, mostly caused by idiopathic adrenal
hyperplasia (IAH), which can be managed by life-long administration of
mineralocorticoid receptor (MR) antagonists [3]. A recent meta-analysis found a good long-term prognosis after
specific therapy; at years 5 and 7, the mortality decreased progressively below the
level of essential hypertension (EH). This effect was even more pronounced in
patients with APA following unilateral adrenalectomy [4]. In this line, Hundemer et al.
demonstrated that medically treated PA patients had a higher cardiovascular risk
compared to adrenalectomized patients, despite similar blood pressure (BP) levels
[5]. Yet, those patients with
medically induced renin stimulation had a similar risk compared to those who were
operated upon. Medically treated PA patients have a higher risk of atrial
fibrillation compared to those with EH, whereas adrenalectomized patients do not
display an increased risk [6].
With the widespread introduction of the sensitive screening method using ARR,
awareness has increased in primary care [7]. Nevertheless, PA still remains an underdiagnosed and undertreated
disease because screening is not universally followed [8].
We aimed to identify the prevalence of PA in newly diagnosed hypertensive patients
in
primary care in Southern Germany.
Patients and Methods
Study population
A total of 27 primary care centers in Munich agreed to participate in the study.
The study was performed from 2012–2016. The primary care centers were
part of a medical school teaching network at LMU for general medicine. We sent
out a call to the 100 primary care centers of this network to participate, and
27 responded. In these centers, subjects with routine appointments and no known
diagnosis of arterial hypertension were checked for elevated BP. If positive,
our study team was contacted, and the patient was seen again in the primary care
center for informed consent, blood pressure (BP) control, and blood withdrawal.
The diagnosis of hypertension was obtained by three consecutive office BP
measurements in the sitting position on each arm using a mercury
sphygmomanometer, according to European Society of Hypertension guidelines [9]. The classification of BP for
adults was according to the Joint National Committee VI, which has established
three different stages: stage 1, systolic BP (SBP) 140 to 159, diastolic BP
(DBP) 90 to 99; stage 2, SBP 160 to 179, DBP 100 to 109; and stage 3,
SBP≥180, DBP≥110 mm Hg. When the systolic and diastolic
BP of the patient were in different categories, the higher category was selected
to classify the BP status of the individual. When a patient had newly diagnosed
arterial hypertension, ARR, sodium, potassium, and creatinine was determined and
analyzed in the endocrine laboratory of the Medical Department 4 of the
Ludwig-Maximilians-University, Munich. Hypokalemia was defined as serum
potassium<3.5 mmol/l. Diagnosis of PA was made according
to the criteria outlined in the guidelines of the Endocrine Society as described
before [10]
[11]
[12]. In short, PA patients had an
elevated ARR (>12 ng/mU) with an elevated aldosterone
(>5 ng/dL) and an abnormal confirmatory test (saline
infusion test in the seated position or captopril test). Criteria for abnormal
saline infusion testing was a plasma aldosterone>5 ng/dL
at 240 minutes, and for abnormal captopril testing, a drop in plasma
aldosterone of<30% in the presence of a continuously suppressed
plasma renin concentration. Subtypes were differentiated by adrenal imaging
followed by adrenal vein sampling (AVS) without adrenocorticotropic hormone
stimulation, as described earlier [13]
[14]. We used a
selectivity index of≥2 and a lateralization index of≥4 for the
diagnosis of unilateral aldosterone excess.
Analytical methods
Blood samples were drawn in a fasting state in a sitting position. Plasma
aldosterone measurements were performed with the radioimmunoassay
“aldosterone Coat-a-Count” (Biermann DPC). Direct renin
concentration was measured by the Liaison chemiluminescence assay (Diasorin). In
our hands, the respective within- and between-assay coefficients of variation
were less than 9 and 12% for aldosterone and less than 5.6 and
12.2% for renin. All other analyses were performed in our central
laboratory using standard methods.
Statistics and Ethics
A sample size of 200 was calculated to estimate the prevalence of
hyperaldosteronism with a two-sided 95% confidence interval of maximal
width of 10% (+/−5%). If not stated
otherwise, results were expressed as median and 25th –
75th percentiles. Data between groups were compared using the
Mann-Whitney U test. Within group changes from baseline to follow-up were
calculated by the Wilcoxon signed-rank-test. χ2 test was used to compare
frequency distributions. P<0.05 was considered to be statistically
significant. Statistical analysis was performed using standard statistical
software (SPSS 27, IBM USA). The study and the German Conn’s registry
have been approved by the local ethical committee (358–12). All subjects
agreed to participate in the study.
Results
Characteristics of the study population at diagnosis
Two-hundred thirty-five patients with newly discovered arterial hypertension were
initially screened for PA. Of these patients, 35 were excluded because the
chronic medication indicated pre-existing treated arterial hypertension or they
were on interfering antihypertensive medication. The final cohort consisted of
200 patients. Four (2.0%) of the patients had hypokalemia at the first
screening. The characteristics of these 200 patients are described in [Table 1]. One-hundred and seven
(53.5%) of the patients had hypertension stage 1, 68 (34.0%) had
hypertension stage 2, and 25 (12.5%) had hypertension stage 3.
Table 1 Characteristics of the 200 patients included in
the study and comparison of patients with PA and EH. Nine patients
had positive ARR but did not undergo confirmatory testing for PA and
were lost to follow-up.
|
Patients (n=200)
|
PA (n=11)
|
EH (n=180)
|
p
|
|
Age (years)
|
42 (32; 53)
|
46 (41; 60)
|
42 (31; 53)
|
0.126
|
|
Sex (male/female)
|
127/73
|
7/4
|
118/62
|
0.897
|
|
SBP (mmHg)
|
149 (140; 158)
|
156 (140; 160)
|
149 (140; 157)
|
0.369
|
|
DBP (mmHg)
|
95 (90; 100)
|
94 (90; 100)
|
94 (90; 100)
|
0.793
|
|
BMI (kg/m2)
|
26.0 (24.1; 29.9)
|
26.2 (24.5; 33.3)
|
26.3 (24.2; 30.1)
|
0.734
|
|
Serum aldosterone (ng/dL)
|
8.8 (5.5; 13.7)
|
11.2 (8.3; 15.9)
|
8.5 (5.1; 13.3)
|
0.027
|
|
Renin mU/L
|
14.2 (8.6; 24.4)
|
4.4 (2.0; 6.5)
|
15.8 (9.7; 25.5)
|
0.001
|
|
ARR (ng/mU)
|
5.8 (3.7; 10.7)
|
39.0 (14.5; 64.1)
|
5.4 (3.6; 9.5)
|
0.001
|
|
Serum potassium (mmol/L)
|
4.0 (3.8; 4.2)
|
3.9 (3.6; 4.4)
|
4.0 (3.8; 4.2)
|
0.468
|
|
Hypokalemic at screening
|
4
|
0
|
4
|
0.617
|
|
Serum creatinine (mg/dL)
|
0.9 (0.7; 1.0)
|
0.9 (0.7; 1.1)
|
0.9 (0.7; 1.0)
|
0.417
|
Data are given as median (25th to 75th percentile).; Abbreviations: EH,
essential hypertension; PA, primary aldosteronism; SBP, systolic blood
pressure; DBP, diastolic blood pressure; ARR, aldosterone-to-renin
ratio.
Incidence of elevated aldosterone to renin ratio in the study
population
Of the 200 patients with newly discovered arterial hypertension, 42 (21%)
had an elevated ARR (>12 ng/mU) and a plasma aldosterone
concentration>5 ng/dL ([Fig. 1]). Patients with pathological
ARR were older (48.0 (39.5; 58.0) years) than patients with normal ARR (40.0
(31.0; 53.0) years) (p=0.07). The incidence of the presence of
hypokalemia did not differ according to normal or pathological ARR
(p=0.298). The prevalence of an elevated ARR was higher in stage 2
hypertension (27.9%) than in stage 1 (19.6%), but was low in
stage 3 (8%, p=0.098, [Fig. 2]).
Fig. 1 Study Flow chart.
Fig. 2 Prevalence of pathological ARR depending on Hypertension
Stage.
Incidence of primary aldosteronism in the study population
All 42 patients with elevated ARR were contacted to perform confirmatory testing.
Nine patients (21.4%) did not show up for further testing and were lost
to follow-up, and 33 of 42 patients underwent a saline infusion test (seven
patients had an additional captopril test when the results were inconclusive).
Of these, 11 patients were diagnosed with PA ([Fig. 1]), leading to a prevalence of
at least 5.5% of PA in the collective. None of the diagnosed PA patients
was hypokalemic at screening. A study by Kanaan et al. showed that a potassium
concentration of 3.8 mmol/L or lower
(“<3.9 mmol/L”) best-discriminated
patients with PA from with EH when only this information is available [15]. In our study, 5 (45.5%)
of patients with PA had a serum-K below 3.9 mmol/L compared to
48 (26.7%) (p=0.179) of the non-PA subjects. The patients with
EH and those with PA did not differ in their BP levels (see [Table 1]). Five of the patients with
PA had hypertension stage 1, five had stage 2, and one patient had stage 3.
According to current guideline recommendations, AVS and CT were proposed to the
11 newly diagnosed PA patients. A minority of four patients chose to perform
further subtyping. One of these patients was diagnosed with unilateral PA and
treated by unilateral adrenalectomy. Three patients were diagnosed with
bilateral PA, and treatment with MR-antagonist was started. In the remaining
seven patients without AVS, MRA therapy was recommended; five of these patients
were lost to follow-up.
Discussion
In one retrospective study of patients with resistant hypertension in California
(n+= 4660), the screening rate for PA was
2.1% [16]. Similarly, a
retrospective study of veterans in the USA with treatment-resistant hypertension
(n+= 269 010) showed that 1.6% of
the participants had PA. A visit to a nephrologist or an endocrinologist was
associated with a higher likelihood of testing compared with primary care [17]. Testing was associated with a 4-fold
higher likelihood of MRA treatment and better BP control. This underlines the
importance of implementing guideline-recommended practices in managing patients with
treatment-resistant hypertension. Yet, currently, many PA patients are not diagnosed
due to missing screening procedures. The 2016 Endocrine Society guideline recommends
screening for PA in all hypertensive patients with a high risk of PA, which applies
to more than half of the hypertensive population [3]. According to a recent survey, renin
and aldosterone measurements are only performed in 7% of general
practitioners in Italy and 8% in Germany, with accordingly low PA prevalence
of 1% and 2%, respectively [8]. Along the same line, measurement of potassium levels at diagnosis of
hypertension occurred in only 43% of the general practitioners in Italy and
58% in Germany.
Previous data estimated a 2.6–12.7% prevalence of PA in unselected
hypertensives [1]
[18]
[19] and up to 20% in patients with resistant hypertension [20]. Our data on untreated, newly
diagnosed patients with hypertension perfectly align with these data; based on
confirmatory testing, 5.5% of the total cohort had PA. When analyzing the
prevalence of PA according to hypertension grade, the literature reports a
prevalence of 2.0–6.6 in grade I, 8.0–15.5 in grade II, and
11.8–19% in grade III hypertension [1]
[18]
[19]
[21]. In our study, the rate of
pathological ARR did not differ according to the hypertension stage. This could be
caused by the low number of patients.
In the Primary Aldosteronism in Torino (PATO) study, unselected hypertensive patients
(n+= 1672) in primary care were prospectively
screened. They reported a prevalence of 5.9% of patients with a diagnosis of
PA [18], similar to 5.5% in our
study. PA prevalence increased with the severity of hypertension, but 44% of
the identified cases were affected by stage I hypertension, very close to
45.5% in our study. A meta-analysis comprising 36, 614 patients from
hypertension units and 5896 patients from primary care reported a prevalence of PA
in hypertension units in the range of 0.7−29.8% and
3.2–12.7% in primary care [22]. Our data showed a prevalence of 5.5% of PA in this cohort of
newly diagnosed hypertensive patients in primary care.
In the PATO study cohort, 65% of patients were diagnosed with bilateral
disease compared with 27% with unilateral PA; 8% had an undetermined
subtype because either these patients refused AVS or the AVS results were
inconclusive. In our study, 27% of the patients were diagnosed with
bilateral disease, and only 9% with APA; 64% did not perform AVS and
directly started therapy with MRA without further subtyping or were lost to
follow-up.
Hypokalemia is observed in only 25–40% of PA patients [18]
[23]. In our study, none of the patients with PA was hypokalemic, while
2.2% had EH.
Our goal was to analyze the incidence of PA in newly diagnosed, untreated
hypertensive patients in primary care. In conclusion, our data of untreated newly
diagnosed patients with hypertension confirm a prevalence of 5.5% of PA,
quite similar to other studies on treated patients with hypertension in primary
care. The data can be used to address health care providers and to advance the care
of hypertensive patients who are affected by an endocrine disease. The early
identification of PA patients is crucial due to the high burden of cardiovascular
comorbidities that these patients display at the time of diagnosis, which are
reversible through adequate therapy.
Limitations of the study
The total number of total patients was low. Nine of 42 patients with elevated ARR
were lost to follow-up and could not be further evaluated, possibly leading to a
slightly lower prevalence of PA. Five of the 11 patients with PA were lost to
follow up, leading to a low fraction of subtyping. The collection of outcome
data was not a part of the protocol (cardiovascular outcome data).
