Introduction
Early case detection and adequate therapeutic management of primary aldosteronism
(PA) are crucial to reducing the associated increased risk of metabolic and
cardiovascular complications of PA [1]
[2]
[3]. In a classic dichotomous manner, PA
was believed to be mostly secondary, in almost equal proportions, to either
unilateral single aldosterone-producing adenomas (or aldosteronomas) (APA) or
bilateral idiopathic hyperaldosteronism (IHA) [1]
[4]
[5]. Adrenal vein sampling (AVS) has been
performed to distinguis between both etiologies and recommending surgical therapy in
unilateral APA or medical therapy in bilateral IHA [4]. Patient preferences, comorbidities,
and co-secretion of cortisol also affect the final therapeutic decision. To date,
AVS remains the gold-standard localization test for adequate subtyping of PA and
tailoring of therapeutic management [4]
[6]
[7]. In one systematic review, compared to
AVS, conventional imaging led to an incorrect diagnosis in 37.8% of PA
patients [8], with similar discordance
rates in other studies [9]
[10]
[11]. Additionally, recent studies have shown that, even in younger
patients in which AVS could potentially be avoided [4]
[6], imaging alone cannot undoubtedly confirm lateralized PA [12]
[13]
[14]. Thus, AVS remains
indispensable for a correct diagnosis, regardless of age, when the patient is able
and accepts an adrenalectomy if a lateralized source of aldosterone excess is
demonstrated. The main limitation of AVS resides in the successful cannulation of
the right adrenal vein (RAV) because it is smaller and shorter compared to the left
adrenal vein (LAV), and it drains directly into the inferior vena cava (IVC). It can
also share a common trunk with a hepatic accessory vein in 8–12%,
thus diluting the cortisol concentration and decreasing the selectivity index (SI)
[15]
[16]. Therefore, AVS should be done by an
experienced interventional radiologist in referral centers to increase rates of
successful RAV cannulation and limit procedure-related complications. Additionally,
no standardized protocol has been agreed upon, and protocols vary from one center to
another, especially regarding the sampling procedure, the use of adrenocorticotropic
hormone (ACTH) stimulation, and their interpretation criteria, including expert
consensus opinions on the conduct of AVS ([Table 1]) [5]
[17]
[18].
Table 1 Different AVS protocols and interpretations, according
to National Societies and cited expert centers.
Expert Authority
|
AVS Procedure
|
Success Criteria
|
Unilateral PA Diagnosis
|
International and national endocrine societies
|
European Society of Hypertension (2020)
|
Unstimulated or continuous ACTH infusion
|
Unstimulated SI ≥ 2
|
Unstimulated LR ≥2 [4]
|
ACTH-stimulated SI ≥ 5
|
ACTH-stimulated LR ≥ 4
|
Endocrine Society (2016)
|
Unstimulated (sequential or simultaneous), continuous ACTH
infusion, or ACTH bolus
|
Unstimulated SI ≥ 2
|
Unstimulated LR ≥ 2
|
ACTH-stimulated SI ≥ 5
|
ACTH-stimulated LR ≥ 4
|
French Society of Endocrinology (2016)
|
Unstimulated, simultaneous
|
Unstimulated SI ≥ 2
|
Unstimulated LR ≥ 4
|
Japan Society of Endocrinology (2009)
|
ACTH bolus
|
ACTH-stimulated SI ≥ 5
|
ACTH-stimulated LR ≥ 2.6, or aldosterone
concentration>1400 ng/dL on one side
|
AACE (2006)
|
Continuous ACTH infusion
|
ACTH-stimulated SI ≥ 10
|
ACTH-stimulated LR ≥ 3
|
Expert centers*
|
Munich and Paris
|
Unstimulated
|
Unstimulated SI ≥ 2
|
ACTH-stimulated LR ≥ 4
|
Torino
|
Unstimulated and continuous ACTH infusion
|
Unstimulated SI ≥2–3 [47]
|
LR ≥ 4 or ≥ 3 and
CLS≤1
|
Brisbane
|
Unstimulated
|
Unstimulated SI ≥ 3
|
LR ≥ 2.5 and CLS≤1
|
Rochester
|
Continuous ACTH infusion
|
ACTH-stimulated SI ≥ 5
|
ACTH-stimulated LR ≥ 4
|
Sendai
|
ACTH bolus
|
ACTH-stimulated SI ≥ 5
|
ACTH-stimulated LR ≥ 2.6
|
Yokohama City
|
ACTH bolus and continuous infusion
|
AV[Cortisol]>200 mcg/dL
|
Ipsilateral AV[PAC]>1400 ng/dL
|
Abbreviations: AV: adrenal vein; AVS: adrenal vein sampling; Ipsilateral AV:
ipsilateral adrenal vein; LR: lateralization ratio; PA: primary
aldosteronism; PAC: plasma aldosterone concentration; SI: selectivity
index.; *Adapted from reviews by Williams and Reincke [100] and
Reincke et al. [5].
Although the use of ACTH stimulation improves the SI [18], its influence on the lateralization
ratio (LR) is still somewhat controversial in the literature [18]
[19]
[20]
[21], leading several centers, particularly
in Europe, to abandon ACTH stimulation and adopt only unstimulated values for
interpretation of lateralization. In this review, we will discuss the different
techniques of AVS, the numerous interpretation criteria, and the clinical and
biochemical outcomes of AVS-guided surgery.
Classical dichotomy between uniform phenotypes of aldosteronoma and
idiopathic hyperaldosteronism revisited
The traditional classification of PA into either APA or
unilateral/bilateral IHA was challenged and revamped into a modern
classification based on both morphology and functionality, determined by CYP11B2
IHC. The recent development of monoclonal antibodies targeting CYP11B2 [22] allowed for a better understanding
of the pathophysiological mechanisms governing PA. In fact, areas within the
adrenal cortex, known as aldosterone-producing micronodules (previously
aldosterone-producing cell clusters), express CYP11B2 and can produce
aldosterone in excess without being necessarily restricted to a well-defined
radiologically detected nodule or hyperplasia [23]
[24]
[25]. Such micronodules are often found
adjacent to a dominant APA in resected adrenals based on lateralized AVS, which
had suggested that a unique APA would be found [26]. The modern classification
suggested by the international HISTALDO consensus includes, in addition to
classical APA, non-classical PA histology including either multiple
aldosterone-producing nodules, aldosterone-producing micronodules, or rarely,
diffuse hyperplasia of zona glomerulosa [[5]
[25]. Accordingly, bilateral PA is
explained by multiple aldosterone-producing micronodules/nodules
harboring somatic driver mutations, most frequently CACNA1D mutations
[14]
[25]
[27]
[28]
[29]. However, it can be presumed that
micronodules found adjacent to an APA can also be present in the contralateral
adrenal, further explaining the persistence of PA after adrenalectomy and
highlighting the role of CYP11B2 IHC in the post-operative follow-up of patients
[25]
[30]
[31].
b. Variable expression of melanocortin type 2 receptors (MC2R) in
primary aldosteronism
ACTH stimulatory effects on AVS results vary greatly in part due to the variable
expression of ACTH receptors, or MC2R, in APAs and PA micronodules compared to
normal zona glomerulosa
[32].
It has been shown that while APAs with ATPase somatic mutations demonstrate a
high MC2R expression, those with KCNJ5 mutations tend to be poor in MC2R
[1]. In the former case, this
results in an increased ipsilateral aldosterone secretion, and in the latter, a
relatively higher aldosterone secretion from the surrounding (and contralateral)
cortex following ACTH stimulation [1]. Independently of the underlying driving somatic mutations, other
authors have noted in contrast, that only a minority of florid PA cases
overexpress MC2R, while about two-thirds under-expressed it [20]. Thus, the MC2R expression
variability impacts ACTH-stimulated LR and can contribute to discordance between
unstimulated and ACTH-stimulated LR, as will be discussed in a further
section.
c. AVS without adrenocorticotropic hormone stimulation
Several centers discontinued the use of ACTH stimulation during AVS following
initial reports of discordant lateralization between unstimulated values and
ACTH-stimulated values [33] and only
collected unstimulated samples for cortisol and aldosterone measurements. The
most recent studies on AVS without ACTH stimulation and their essential
conclusions are summarized in [Table
2]
. The 2014 expert consensus statement on the use of AVS for
subtyping PA [17] recommended that
unstimulated AVS be performed in the morning to minimize false-negatives caused
by the diurnal variations of aldosterone secondary to endogenous diurnal rhythm
of ACTH [34]. Moreover, the
selectivity and lateralization indices are influenced by the transitory stress
reaction at the beginning of the procedure. The increase in cortisol in both
adrenal veins at the start of AVS would generate different ratios between
samples taken 15 min apart, with higher values on the first samples
[35]
[36]. Even in the absence of a stress
reaction, aldosterone levels are highly variable and not persistently elevated
during AVS. In fact, Yozamp et al. [37] recently showed that unstimulated triplicate measurements of
aldosterone had a mean percent difference of 57% and 73% in the
left and right adrenal veins, respectively. This resulted in discordant
lateralization in 17% of patients, mostly from lateralized to bilateral
PA, when using only one of the three unstimulated samples for
aldosterone-to-cortisol (A/C) ratio calculation [37].
Table. 2 Studies on AVS performed without ACTH
stimulation.
Study
|
Country
|
Patients’ Selection
|
Simultaneous or Sequential
|
SI
|
LR
|
CLS
|
Essential Conclusions
|
Benoit et al., 2022 [53]
|
France
|
188
|
Sequential or bilateral simultaneous
|
≥2
|
≥4
|
N/A
|
Adequate cannulation in 82.3%
|
2018–2020 prospective
|
Lateralization in 38 patients (24.6%)
|
Concordance between lateralization and CT in
35.4%
|
Cure in 83.3% of patients with radical treatment
|
Clinical recovery higher in women (88.9 vs. 38.9%;
p 0.0153)
|
Huang et al., 2020 [45]
|
Taiwan
|
54
|
Sequential
|
≥2
|
≥2
|
A/C non dominant side<A/C
peripheral vein
|
Complete clinical success in 57.4% (PASO
criteria)
|
2011–2016 retrospective
|
Complete biochemical success in 80.8% (of 52
evaluated)
|
LR>4: significantly associated with complete clinical
success (OR 4.30, 95% CI 1.18–15.68) and
biochemical success (OR 7.55, 95% CI
1.28–44.47)
|
Contralateral suppression: an independent predictor of
complete biochemical success only
|
Aono et al., 2019 [10]
|
Japan
|
362
|
Bilateral simultaneous
|
>2
|
≥2
|
<1
|
No nodules on CT: 88% successful AVS and 36%
lateralized
|
2005–2016 retrospective
|
Bilateral nodules on CT: 100% successful AVS and
17% lateralized
|
Unilateral nodules on CT: 85% successful AVS and
41% ipsilateral PA
|
Concordance rate between CT and AVS: 53%
|
Bilateral nodules on CT+lateralized disease on AVS
(n=17) had a complete biochemical success
rate<unilateral nodules on CT+ipsilateral
disease on AVS (n=30) (41% vs. 80%,
p 0.01)
|
Rossitto et al., 2018 [36]
|
Italy
|
138
|
Bilateral simultaneous and simulated sequential R->L
and L->R
|
≥2
|
≥2
|
N/A
|
Simultaneous is superior to sequential AVS for APA
diagnosis
|
2007–2015 prospective
|
Of 37 patients who lateralized on AVS: 100% had a
biochemical cure
|
Pedersen et al., 2016 [101]
|
Denmark
|
50 1992–2006 retrospective
|
Sequential
|
N/A
|
N/A
|
N/A
|
Lateralized PA: 39/50 patients
|
28% with lateralized PA on AVS had normal imaging
|
Citton et al., 2015 [102]
|
Italy
|
128
|
Bilateral simultaneous
|
>1.1
|
>2
|
N/A
|
56 patients underwent AVS-guided unilateral adrenalectomy
|
1990–2013 retrospective
|
The combination of AVS/scintigraphy and
CT/MRI reduced the failure rate from 10.6 to
1.4%
|
PPV of scintigraphy for the biochemical cure: 93%
|
PPV of AVS 100%
|
Recurrence of PA in 3.7%
|
Haase et al., 2014 [103]
|
Germany
|
4
|
Sequential
|
≥2
|
≥4
|
N/A
|
Four patients had AVS under MR antagonist: all four had
persistent suppressed renin despite MR antagonists and
lateralized PA and underwent adrenalectomy
|
2008–2014 retrospective
|
6 months after surgery: all patients showed remission of
PA
|
Wolley et al., 2013 [104]
|
Australia
|
1439
|
Sequential
|
≥3
|
A/Cone side≥2-fold peripheral
ratio
|
A/Cone side≤peripheral ratio
|
1200 satisfactory AVS
|
1978–2012 retrospective
|
Samples drawn at t-15 and t0 min
|
37 (2.5%) had adequate samples but bilateral
A/C≤A/C peripheral
|
22/37 had repeat AVS with 18 diagnostic AVS
|
9/22 had concordant imaging and 10/22 had
lateralized disease
|
Seccia et al., 2012 [35]
|
Italy
|
34
|
Bilateral simultaneous and Simulated sequential
|
≥1.10–2
|
N/A
|
N/A
|
Simultaneous>sequential for AVS selectivity
|
prospective
|
All 34 patients had an APA and a PAC decrease, PRA increase,
normalization of the ARR and K+plasma levels post
adrenalectomy
|
Vonend et al., 2011 [41]
|
Germany
|
200 1990–2007 retrospective phase
|
Sequential
|
≥2
|
≥3
|
N/A
|
Bilaterally selective: 30.5% (retrospective);
61.3% (prospective)
|
106 2008–2009 prospective phase
|
Bilaterally nonselective: 16.5% (retrospective);
8.5% (prospective)
|
The rate of unsuccessful bilateral cannulation rose from
4% to 45% with a stringent cut-off of 5.0
compared to 1.1.
|
178 patients (retrospective) also had cross-sectional
imaging: the agreement between AVS and imaging was
27%
|
A/C: Aldosterone/Cortisol; ACTH: adrenocorticotropin
hormone; APA: Aldosterone-producing adenoma; ARR: Aldosterone-to-renin
ratio; AVS: Adrenal vein sampling; CLS: Contralateral suppression; CT:
Computed tomography; L: Left; LR: Lateralization ratio; MR:
Mineralocorticoid receptor; MRI: Magnetic resonance imaging;
N/A: Not available; OR: odds ratio; PA: Primary aldosteronism;
PAC: Plasma aldosterone concentration; PASO: Primary Aldosteronism
Surgical Outcome; PPV: Positive predictive value; PRA: Plasma renin
activity; R: Right; SI: Selectivity index.
Additionally, peripheral aldosterone values were also found to fluctuate
importantly, often reaching normal values in a high proportion of patients
during AVS, without hypokalemia, but potential fluctuations in ACTH, posture, or
other aberrant regulators of aldosterone secretion may be implicated [32]
[37]
[38]. These findings led to
recommending the collection of at least 2 or 3 unstimulated samples during the
AVS procedure to overcome the variability of aldosterone.
The question of whether simultaneous or sequential sampling achieves better
results in unstimulated AVS is rather controversial. In fact, a large
retrospective study, including 188 patients undergoing simultaneous bilateral
AVS and simulated sequential AVS, did not report significant differences in both
selectivity and lateralization indices between the two procedures [39], confirming the results of a
previous smaller study [40]. However,
two prospective studies from the same group [35]
[36] reported better accuracy for the
diagnosis of lateralized PA with simultaneous bilateral sampling and discouraged
sequential sampling unless samples can be successfully drawn from both adrenal
veins within 15 min at most. The discordance between these studies might
be due to the differences in the timing of samples, where Almarzooqi et al.
suggested a maximal delay of 5 min between sampling of both sides in
sequential AVS, after which possible inaccurate ratios might derive [39]. In inexperienced hands, this time
interval could be difficult to achieve, rendering sequential AVS longer and less
accurate.
As discussed earlier, successful cannulation of both adrenal veins is required to
accurately interpret AVS results. This is measured by calculating the SI, which
is the ratio of the serum cortisol concentration in the adrenal vein (AV) to
that in the IVC. No approved cut-off exists for SI interpretation, and each
center uses its own criteria, with variations from 1.1 to a more stringent SI of
3 for unstimulated ratios ([Table
2]
). When using a strict cut-off of 5 compared to 1.1, the rate
of unsuccessful cannulation increased from 4% to 45% [41]. This is concordant with a
previous study demonstrating that while a permissive SI cut-off increased the
rate of successful cannulation from 34 to 91%, an SI of<2.75 had
poor diagnostic reproducibility and could lead to incorrect PA subtyping [42]. In contrast, Mailhot et al.
reported no difference in specificity between cut-offs 2 and 3 for unstimulated
SI, and no false positives were found with either (i. e., 100%
specificity), but sensitivity increased from 50.4% to 70.8% with
a more permissive cut-off of 2 [43].
The LR, the ratio of A/C on the dominant side to A/C on the
contralateral side, is also subject to different criteria ([Table 2]). The basal or unstimulated
LR varies between 2 and 4 depending on the center where AVS is performed.
Monticone et al. [18] recommended an
LR>4 for the diagnosis of lateralized PA and<3 for bilateral PA,
for both stimulated and unstimulated ratios, while an unstimulated LR
of>2 for lateralized PA was suggested by others [21]
[44]. In the case of intermediate LR
(=3–4), patient-related clinical and biochemical characteristics
should be used to achieve a final decision regarding treatment [18]. Additionally, El Ghorayeb et al.
[21], concluded that unstimulated
LR plays a major role in the treatment decision and suggested that when
unstimulated and stimulated LR were discordant, as is the case in up to
28% of patients, unilateral adrenalectomy could still be considered even
when ACTH-stimulated LR was<4 but unstimulated LR was≥2.
Recently, an unstimulated LR>4 was found to be significantly associated
with complete clinical (OR 4.30, 95% CI
1.18–15.68) and biochemical success (OR 7.55, 95% CI
1.28–44.47) [45].
Nonetheless, some cases of lateralized PA that would benefit from surgery could
be missed when choosing a higher LR cut-off.
One other important limitation of unstimulated AVS is that presence of a
quiescent phase of aldosterone secretion in some lateralized cases of PA leads
to a missed diagnosis, and lateralization can only be revealed after ACTH
administration (see later section).
AVS with sampling performed only under adrenocorticotropic hormone
perfusion
The theoretical benefits of ACTH administration during AVS include increased
identification of successful AV cannulations due to improved SI, reduced
fluctuations in aldosterone and cortisol secretion (especially if
non-simultaneous sampling), identification of aldosterone source when secretion
is in a quiescent phase basally, and possibly increased aldosterone secretion
and LR from an APA [46]
[47]. ACTH is also necessary for
patients with contrast media allergy who are premedicated with glucocorticoids,
as well as for patients undergoing AVS at times other than in the early morning
[18]
[48].
[Table 3] summarizes the most recent
studies on AVS with ACTH administration, their protocols, and their main
conclusions. Protocols of ACTH administration during AVS vary between centers.
Notably, only one of the recent studies in [Table 3a], mentioned simultaneous
bilateral sampling for post-ACTH infusion only measurements [49], while Dekkers et al. [50] performed sequential AVS, and the
other two studies did not specify their sampling technique [9]
[51]. Whenever ACTH stimulation is
used, Monticone et al. recommended that continuous perfusion be favored because
the ACTH bolus might excessively stimulate aldosterone release from the
contralateral adrenal gland [18]. All
four studies in [Table 3a] performed
AVS under ACTH infusion at a rate of 50 mcg/h. However, only one
compared ACTH bolus (250 mcg) and ACTH infusion
(50 mcg/h) and reported a higher SI in the RAV in the bolus
subgroup [49]. No other differences
in terms of cannulation success, LR, or surgical outcomes were demonstrated
between the two subgroups [49]. While
the SI cut-offs varied between 3 and 5 (post-ACTH), they tended to be closer to
3 in most recent studies [49]
[50]. The cut-off for ACTH-stimulated
LR, in studies only using post-ACTH infusion samples, also differed from center
to center, with ratios from 3 to 4. The latter had the best sensitivity and
specificity for lateralized disease, according to the study by Young et al.,
which was one of the first studies attempting to prospectively determine the
optimal ACTH-stimulated LR [51].
ACTH-stimulated LR was higher on average in cured adrenalectomized PA patients
than in those with residual post-operative disease and was concordant with
surgical pathology results in all cases [9]. Although the prospective SPARTACUS trial challenged the
importance of AVS in the management of PA, finding no significant difference in
clinical or biochemical outcomes between patients managed according to either
computed tomography (CT) scan or post-ACTH infusion AVS results, the latter
demonstrated a trend in favor of reducing biochemical failure among patients who
had AVS-guided adrenalectomy [50].
However, several limitations should be mentioned regarding the SPARTACUS trial.
First, it mostly included florid and severe cases of PA, which could have
reduced the odds of cure or significant improvement following surgical
management in both groups. Second, the number of patients in each subgroup
(n=46) may have been insufficient to detect a significant difference
between the two groups when one possibly exists. In addition, it cannot be
excluded that the management of patients in the CT subgroup with normal or
bilaterally enlarged adrenals may have been different if AVS were used. Finally,
the authors should have concluded that AVS performed under ACTH infusion may not
be superior to CT scan only, but this study did not compare other techniques of
AVS with adrenal imaging. Regardless of the criteria used to interpret sampling,
AVS-guided surgery led to significantly more hypertension cures compared with
non-AVS-guided (40.0% compared to 30.5%; p=0.027)
in a large multicenter analysis of 1625 cases [52]. Women were more likely to be
cured following adrenalectomy [52]
[53].
Table 3 Studies on AVS performed with ACTH
stimulation.
3a. ACTH-stimulated only
|
Study
|
Country
|
Patients’ Selection
|
ACTH
|
Simultaneous or Sequential
|
SI
|
LR
|
CLS
|
Essential Conclusions
|
Hu et al., 2021
[49]
|
China
|
174
|
250 mcg bolus (n=80) or continuous infusion 50
mcg/h (n=94)
|
Simultaneous bilateral
|
>3
|
>4 or >3-4 if CLS present
|
A/C nondominant side < A/C
IVC
|
Comparable number of patients with LR <3, 3-4,
>4 between the bolus and infusion groups.
|
2016–2021 retrospective
|
Post-adrenalectomy, the rate of complete biochemical
remission was not significantly different between the bolus
(97.7%) and infusion groups (100%,
p0.454).
|
Dekkers et al., 2016
[50]
|
Netherlands, Poland
|
184
|
Continuous infusion 50 mcg/h
|
Sequential
|
≥3.0
|
≥4.0
|
≤1.0
|
At 1 year F/U: No difference between CT-guided and
AVS-guided treatment regarding the number of
antihypertensive medications, biochemical and clinical
outcomes (non-PASO criteria).
|
2010–2013 RCT
|
Lim et al., 2014
[9]
|
USA
|
263 (213 had AVS)
|
Continuous infusion 50 mcg/h
|
N/A
|
>5
|
>4
|
A/C nondominant < A/C
IVC
|
44.9% discordance between AVS and CT
|
1993–2011 retrospective
|
In lateralized PA: 100% concordance rate between AVS
and the surgical side.
|
ACTH-stimulated LR in cured PA (14.8, 95%CI 7.4-26.3)
is higher than ACTH-stimulated LR in non-cured PA (5.5,
95% CI 3.2-7.4, p0.02).
|
Young et al., 2004
[51]
|
USA
|
203
|
Continuous infusion 50 mcg/h
|
N/A
|
>5
|
Study outcome
|
N/A
|
LR >4.0: sensitivity 95.2%, and specificity
100% for lateralized PA.
|
1990–2003 prospective
|
Based on CT alone: 21.7 %: missed lateralization,
24.7 %: unnecessary adrenalectomy.
|
3b. Unstimulated and ACTH-stimulated (bolus)
samplings.
|
Study
|
Country
|
Patients’ Selection
|
ACTH
|
Simultaneous OR Sequential
|
SI
|
LR
|
CLS
|
Essential Conclusions
|
Yozamp et al., 2021
[56]
|
USA
|
340
|
Bolus of ACTH (250 mcg)
|
Simultaneous bilateral
|
≥3
|
Unstimulated ≥2
|
N/A
|
90% of patients with concordant unstimulated and
ACTH-stimulated AVS underwent unilateral adrenalectomy:
– clinical success: 61% partial, 24%
complete – biochemical success: 6% partial,
92% complete
|
2005–2019 retrospective
|
ACTH-stimulated ≥4
|
49% of patients with discordant unstimulated and
ACTH-stimulated AVS underwent unilateral adrenalectomy:
– clinical success: 68% partial, 0%
complete – biochemical success: 8% partial,
75% complete.
|
Desrochers et al., 2020
[65]
|
Canada
|
192 (Montréal)2009–2018
|
Bolus of ACTH (250 mcg)
|
Simultaneous bilateral
|
ACTH-stimulated >5
|
Unstimulated >2
|
ACL/Ap: <1.0 and
<1.5
|
ACL/Ap of 2.15 and 6.15 had the
best sensitivity and specificity for clinical and
biochemical cures at 1 year, respectively.
|
138 (Calgary)2005–2018
|
Calgary: bolus + infusion
|
ACTH-stimulated >4 (Montréal) or >3
(Calgary)
|
(A/C) CL / (A/C)
P <0.66
|
22% discordance rate between unstimulated and
ACTH-stimulated.
|
retrospective
|
Both unstimulated LR and ACTH-stimulated LR are associated
with a clinical cure.
|
Only ACTH-stimulated LR is associated with a biochemical
cure.
|
Yatabe et al., 2020
[19]
|
Japan
|
185
|
Bolus of ACTH (250 mcg)
|
Sequential
|
Unstimulated ≥2
|
Unstimulated ≥2
|
<1.0
|
Stimulated LR ≥ 2.6 had a better clinical
outcome.
|
2000–2015 retrospective
|
ACTH-stimulated ≥5
|
A dominant side ≥14,000 pg/mL
|
ACTH decreased the lateralization rate from 72.4% to
36.2%.
|
ACTH-stimulated ≥2.6
|
26.5% discordance between unstimulated and
ACTH-stimulated LR.
|
81/185 had unilateral adrenalectomy: 49% had
complete clinical success and 27% partial. Mostly,
all had biochemical success.
|
Rossitto et al., 2018
[20]
|
Italy
|
53
|
Bolus of ACTH (250 mcg)
|
Simultaneous bilateral
|
SI = primary outcome
|
Unstimulated >2.0
|
Secondary outcome
|
ACTH facilitates ascertainment of selectivity but lessens
LR.
|
2000–2016 retrospective
|
62% of patients had HTN cure post adrenalectomy.
|
Durivage et al., 2017
[84]
|
Canada
|
197 (with repeat AVS in 11 patients)
|
Bolus of ACTH (250 mcg)
|
Simultaneous bilateral
|
ACTH-stimulated ≥5
|
Unstimulated ≥2
|
N/A
|
Multinomial regression modeling could correctly
lateralize:
|
1989–2015 retrospective
|
ACTH-stimulated ≥4
|
- to the right: 65.5% with unstimulated AVS and
77.2% with ACTH-stimulated AVS.
|
- to the left: 62.7% with unstimulated AVS and
72.9% with ACTH-stimulated AVS.
|
El Ghorayeb et al., 2016
[21]
|
Canada
|
175
|
Bolus of ACTH (250 mcg)
|
Simultaneous bilateral
|
ACTH-stimulated >5
|
Unstimulated >2
|
Primary outcome
|
CLS of 1.44: highest specificity and sensitivity.
|
1989–2014 retrospective
|
ACTH-stimulated >4
|
ACTH increases selectivity on both sides.
|
28 % discordance between unstimulated and
ACTH-stimulated LR (lateralized to bilateral PA after
ACTH).
|
Wolley et al., 2016
[60]
|
Australia
|
47
|
Bolus of ACTH (250 mcg)
|
Sequential
|
Unstimulated ≥3
|
ACTH-stimulated ≥2
|
≤1
|
91% concordance between unstimulated and
ACTH-stimulated LR.
|
prospective and retrospective
|
ACTH-stimulated ≥5
|
13/15 underwent unilateral adrenalectomy: 5 had a
biochemical cure.
|
Rossi et al., 2006
[33]
|
Italy
|
24 prospective
|
Bolus of ACTH (250 mcg)
|
Simultaneous bilateral
|
>1.1
|
>2
|
N/A
|
ACTH increased aldosterone secretion from the contralateral
adrenal but not from APA and does not improve diagnostic
accuracy for APA.
|
Kometani et al., 2022
[85]
|
Japan
|
4057 enrolled
|
159: Unstimulated
|
N/A
|
Unstimulated >2
|
Unstimulated >2
|
N/A
|
Real-time intraprocedural cortisol measurements increase the
success rate of unstimulated AVS and ACTH-stimulated
AVS.
|
2006–2018 retrospective
|
473: ACTH
|
ACTH-stimulated >5
|
ACTH-stimulated >4
|
No effect on subtype diagnosis.
|
2396: both
|
250 mcg bolus or continuous infusion or bolus +
infusion
|
Sung et al., 2020
[59]
|
USA
|
76
|
Pre and post-250 mcg bolus of ACTH + infusion
(0.25 mg in 250 mL NS)
|
Simultaneous bilateral
|
≥2
|
>2 and >4 (outcome)
|
N/A
|
ACTH stimulation increased SI.
|
1984–2009 retrospective
|
Mean ACTH-stimulated LR > unstimulated LR.
|
When LR >4 was used: 9.2% of patients who did
not lateralize with ACTH stimulation, lateralized without
ACTH.
|
76/76: had adrenalectomy: all had a biochemical cure,
34% complete success and 66% partial success
(PASO criteria).
|
Kobayashi et al., 2020
[61]
|
Japan
|
1834 (314 adrenalectomy)
|
Pre and post-ACTH
|
Sequential
|
Unstimulated ≥2
|
Unstimulated ≥2
|
A/C nondominant < A/C
IVC
|
40.6 % had discordant LR: 37.9% from
lateralized to bilateral, 2% from bilateral to
lateralized, and 0.6% from lateralized to
contralateral lateralized
|
2006–2018
|
Bolus or continuous infusion or bolus + infusion
|
ACTH-stimulated ≥5
|
ACTH-stimulated ≥4
|
22% of those who underwent adrenalectomy had
discordant unstimulated and ACTH-stimulated LR: mostly
driven by lateralized to bilateral PA post-ACTH.
|
Basal CLS = 0.40 was significantly associated with
clinical and biochemical success post-surgery;
ACTH-stimulated CLS= 0.81 was not.
|
Chee et al., 2020
[57]
|
Australia
|
201
|
Pre and post-250 mcg bolus of ACTH + infusion (50
mcg/h)
|
Sequential
|
Unstimulated >2
|
Unstimulated >3
|
<1
|
ACTH stimulation decreased lateralization: 70% with
unstimulated to 52% with ACTH-stimulated.
|
(102 pre- and post-ACTH successful AVS)
|
ACTH-stimulated >3
|
ACTH-stimulated >4
|
23% discordance between unstimulated and
ACTH-stimulated LR in bilaterally successful AVS, mostly
driven by lateralized to the bilateral pattern.
|
2001–2018 retrospective
|
|
Wannachalee et al., 2020
[11]
|
USA
|
234
|
Pre and post-125 mcg bolus of ACTH + infusion (75-125
mcg/h
|
Simultaneous bilateral
|
Unstimulated >2
|
Unstimulated and/or ACTH-stimulated ≥ 4
|
<1
|
62% concordance between AVS and cross-sectional
imaging, highest in unilateral lesions on both.
|
2009–2019 retrospective
|
ACTH-stimulated >5
|
89% of patients had a clinical benefit and
83% biochemical cure (PASO criteria).
|
Wannachalee et al., 2019
[62]
|
USA
|
222
|
Pre and post-125 mcg bolus of ACTH + infusion (75-125
mcg/h
|
Simultaneous bilateral
|
Unstimulated >2
|
Unstimulated and/or ACTH-stimulated ≥ 4
|
<1
|
24% discordance between unstimulated and
ACTH-stimulated LR (lateralized to the bilateral pattern)
|
2009–2018 retrospective
|
ACTH-stimulated >5
|
LR increased after ACTH stimulation in 27%, decreased
in 33%, and remained stable in 40%.
|
ATP1A1 and ATP2B3 mutations associated with ascending LR.
KCNJ5 associated with descending LR.
|
Takeda et al., 2019
[58]
|
Japan
|
2197
|
Pre and post-bolus of ACTH, or continuous infusion, or bolus
+ infusion
|
24 centers: sequential
|
Unstimulated ≥2
|
Unstimulated ≥2
|
N/A
|
ACTH improved the success rate (67 to 89%) but
decreased LR (62 to 28%).
|
2006–2016 retrospective
|
4 centers: Simultaneous bilateral
|
ACTH-stimulated ≥5
|
ACTH-stimulated ≥4
|
The method of ACTH administration did not affect SI or
LR.
|
Clinical success: absent in 33%.
|
Biochemical success: absent in 15%.
|
ACTH did not influence clinical and biochemical outcomes.
|
Shibayama et al., 2018
[64]
|
Japan
|
1689
|
Pre and post-ACTH
|
23 centers: Simultaneous bilateral
|
Unstimulated >2
|
Unstimulated >4
|
N/A
|
Apparent bilateral aldosterone suppression (ABAS) is the
outcome.
|
2006–2016 retrospective
|
18 centers: 250 mcg bolus
|
4 centers: sequential
|
ACTH-stimulated >5
|
ACTH-stimulated >4
|
- prevalence of ABAS post-ACTH (7.6%) lower than
unstimulated ABAS (18.0%, p0.001).
|
8 centers: 200 or 250 mcg bolus + infusion
|
- 20/45 patients with some degree of ABAS had an
adrenalectomy.
|
- 15/20 with available outcome data post-op: complete
clinical success in 5 (33.3%), partial clinical
success in 8 (53.3%), and absent clinical success in
2 (13.3%).
|
- 13/20 with available biochemical data post-op:
complete biochemical success in 12 (92.3%).
|
Kline et al., 2013
[105]
|
Canada
|
32
|
Pre and post-infusion of ACTH 250 mcg over 15 minutes
|
Simultaneous bilateral
|
Unstimulated >3
|
Unstimulated >3
|
N/A
|
Post ACTH SI is preferred for confirmation of successful
AVS.
|
2005–2011 retrospective
|
ACTH-stimulated >3
|
ACTH-stimulated >3
|
Post adrenalectomy: hypokalemia resolved in all patients who
had pre-operative hypokalemia; ARR normalized in 19
patients; 34% had normotension.
|
Monticone et al., 2012
[106]
|
Italy, Japan
|
76
|
Pre and post-ACTH
|
Japan: Simultaneous bilateral
|
Unstimulated strict >3 permissive >1.1
|
Unstimulated strict >4 permissive >2
|
<1
|
The diagnosis did not change: – in 88% of
patients before and after ACTH infusion – in
78% of patients before and after ACTH IV bolus.
|
prospective
|
Japan: bolus 250 mcg
|
Italy: N/A
|
ACTH-stimulated strict >4 intermediate >2
|
ACTH-stimulated strict >4 intermediate >3
|
Discordance was more driven by the switch from lateralized PA
to bilateral PA post-ACTH.
|
Italy: continuous infusion
|
When permissive criteria were used: concordance between
unstimulated and stimulated diagnoses was reduced from
13% to 26% according to ACTH infusion
protocol.
|
Webb et al., 2012
[107]
|
USA
|
108
|
Pre and post-250 mcg bolus of ACTH + infusion (250
mcg in 250 mL NS)
|
Simultaneous bilateral
|
Unstimulated >1.1-3
|
Unstimulated >1-4
|
N/A
|
ACTH-stimulated LR criterium of >4 was the most
accurate in diagnosing lateralization.
|
1991–2010 retrospective
|
ACTH-stimulated >2 or >5
|
ACTH-stimulated >4 or >10
|
89/91 patients with post-op clinical data had
documented improvement in at least one clinical endpoint
(non-PASO criteria).
|
Mathur et al., 2010
[108]
|
USA
|
114
|
Pre and post-250 mcg bolus of ACTH + infusion (250
mcg in 250 mL NS)
|
Simultaneous bilateral
|
>2
|
≥ 4
|
<1.0
|
19.3% of patients had discordant AVS and CT results.
|
Timeline N/A retrospective
|
ACTH-stimulated LR was more accurate for lateralization.
|
85 patients underwent adrenalectomy: 80 with a cure orbetter
symptom control and 17 with normal blood pressurewithout
medication
|
Seccia et al., 2009
[54]
|
Italy
|
67
|
Pre and post-ACTH: High dose (HD) bolus: 250 mcg
(n=47)
|
Simultaneous bilateral
|
≥1.1
|
≥2
|
N/A
|
HD and ID improved the selectivity of AVS but influenced
lateralization.
|
2001–2007 prospective
|
Intermediate dose (ID): 100 mcg + infusion 50
μg/h (n=14)
|
Lateralization was on the wrong side in 3.0% and
12.5% with HD and ID, respectively.
|
Very low dose (VLD) 250 pg + infusion 0.5
pg/min (n=6).
|
HD group misdiagnosed APA as idiopathic hyperaldosteronism in
19.4% more cases than based on unstimulated AVS.
|
All 35 patients who underwent adrenalectomy had complete
biochemical success, and hypertension was cured in
33% (non-PASO criteria).
|
A: aldosterone concentration; A/C: Aldosterone/Cortisol;
ACL/Ap: aldosterone in contralateral
adrenal vein/aldosterone in peripheral vein; (A/C)
CL/(A/C) P :
(aldosterone/cortisol in contralateral adrenal
vein)/(aldosterone/cortisol in peripheral vein); ACTH:
adrenocorticotropin hormone; ABAS: Apparent bilateral aldosterone
suppression; APA: Aldosterone-producing adenoma; ARR:
Aldosterone-to-renin ratio; AVS: Adrenal vein sampling; CLS:
Contralateral suppression; CT: Computed tomography; F/U:
follow-up; HD: high dose; HTN: Hypertension; ID: intermediate dose; IVC:
inferior vena cava; LR: Lateralization ratio; N/A: Not
available; NS: normal saline; PA: Primary aldosteronism; PASO: Primary
Aldosteronism Surgical Outcome; post-op: post-operatively; SI:
Selectivity index; VLD: very low dose.
AVS performed with both basal and post-adrenocorticotropic hormone
sampling
The majority of AVS studies presented in [Table 3b, c] are from centers performing AVS under basal (without
stimulation) and post-ACTH stimulation conditions, mostly using a simultaneous
bilateral sampling technique. An intravenous (IV) bolus of 250 mcg of
ACTH was the most common administration method ([Table 3b]), but some centers used
either smaller bolus doses, a continuous infusion, or a sequence of bolus
followed by continuous infusion (see details in [Table 3c]). Most studies used an
unstimulated SI ratio of 2 or 3 and a stimulated ratio between 3 and 5. Few,
such as Seccia et al., used less stringent criteria [54]. The SI consistently increases
after ACTH stimulation [20]
[21]. As demonstrated by Deinum et al.
in their debate article on ACTH use in AVS, the rate of successful AV
cannulation is increased by 20 to 30% after ACTH stimulation, and this
is directly due to the manifest increase in adrenal cortisol secretion [55]. In other words, depending on the
stringency of unstimulated SI criteria, a significant percentage of unstimulated
AVS procedures are inappropriately concluded as non-selective; thus; these
patients would not benefit from further AVS interpretation.
Meanwhile, the effect of ACTH on LR is variable in the literature, with possibly
a general tendency to a decreased LR following ACTH administration compared to
baseline [19]
[54]
[56]
[57]
[58]. One study, however, found a
tendency to increased ACTH-stimulated LR [59]. Similarly, many studies examined the discordance rate of LR
between individual unstimulated and ACTH- stimulated samplings. This discordance
varies greatly between studies, from around 9% [59]
[60] up to 41% [61]. In their review of the last 12
studies, Yozamp et al. estimated the discordance in lateralization to be around
26% [56]. In many cases, the
discordance was driven by a loss of lateralization following ACTH administration
(i. e., lateralized-to-bilateral) [11]
[19]
[21]
[47]
[54]
[56]
[57]
[58]
[61]
[62]. However, a large retrospective
cohort of 222 patients demonstrated roughly equal proportions of patients with
increasing (27%), decreasing (33%), and stable LR (40%)
following ACTH stimulation [62]. This
variability in discordant AVS results might be explained by the variable
individual under- or upregulation of MC2R in APA and adjacent hyperplastic
micronodular adrenal tissue, itself driven by certain somatic mutations, as
discussed above [1]
[55]
[62]. Indeed, the presence of an
ATP1A1 or an ATP2B3 somatic mutation in adrenalectomized
glands was associated with an increasing ACTH-stimulated LR, while the presence
of a KNCJ5 mutation was associated with a decreasing LR [62]. The latter would lead to
relatively more aldosterone secretion from the contralateral gland following
ACTH administration, thus revealing the bilateral nature of the disease (albeit
possibly asymmetrical) [32]. However,
some patients with true lateralized PA may be missed if ACTH stimulation were to
be discarded. As shown by El Ghorayeb et al., 5% of patients with
bilateral PA, according to unstimulated LR (cut-off of 2), had lateralized PA
after ACTH (LR cut-off of 4) [21].
While up to 91% of discordant LR results were driven by a lateralized to
the bilateral pattern (depending on the stringency of LR cut-offs),
2.35% lateralized only after ACTH stimulation [56]. Another study (not shown in [Table 3]) found a high percentage of
patients (18.8%), with lateralized PA, based exclusively on
ACTH-stimulated LR, compared to 22% based on baseline ratios
(LR>4) [63]. Moreover,
Shibayama et al. demonstrated that ACTH stimulation reduced rates of apparent
bilateral aldosterone suppression (see [Table 3c]) [64]. These
cases underline the importance of interpreting AVS according to both
unstimulated and ACTH-stimulated samples. In addition, it clearly suggests that
performing AVS only under ACTH perfusion may deprive 25–30% of
patients with basal lateralization (appearing as bilateral during ACTH infusion)
from possible beneficial surgical therapy.
Biochemical and clinical outcomes post adrenalectomy were studied by some groups
and are included in [Table 3].
Overall, a strong majority of patients chosen to undergo adrenalectomy succeeded
in achieving a complete biochemical cure. In the study by Desrochers et al.,
83% and 4% of the total cohort had, respectively, complete and
partial biochemical success at 12 months post-operatively [65]. On the other hand, only
29% and 67% had complete and partial clinical success,
respectively [65]. This discrepancy
between biochemical and clinical success, and between complete and partial
clinical success, is consistent across all studies of the post-Primary
Aldosteronism Surgical Outcome (PASO) criteria era [11]
[19]
[56]
[58]
[59]
[61]
[64]
[65]
[66]
[67]. This trend is difficult to
extrapolate to studies with post-operative outcomes of the pre-PASO era, as the
criteria for PA cure varied from one study to another. Interestingly, patients
with a lateralized-to-bilateral AVS pattern had less favorable post-operative
clinical and biochemical outcomes (57.5% and 79.5%,
respectively) than patients who maintained a lateralized pattern after ACTH
injection (72.6% and 94.3%, respectively) [61]. In the lateralized-to-bilateral
subgroup of patients, a higher unstimulated LR was predictive of better surgical
outcomes [61]. Chee et al. also
reported complete biochemical success in 3 out of 7 patients with discordant LRs
(lateralized-to-bilateral pattern) who underwent adrenalectomy. Even though all
7 patients had other characteristics suggestive of lateralized disease (a
unilateral adenoma on CT scan or hypokalemia), and all had a CLS
index<1, the only significant difference was an ACTH-stimulated LR
of>2 in the 3 patients with biochemical success [57].
Contralateral adrenal suppression
Contralateral aldosterone suppression (CLS) has been extensively studied by
several groups [21]
[65]
[68]
[69]
[70]
[71]
[72] and found to be helpful in
ascertaining aldosterone lateralization [69]
[70]
[71]
[72], especially in cases where the LR
is lower than 4 [69], as it is
expected that a single APA would suppress renin and consequently suppress
aldosterone in the contralateral adrenal gland. Although some authors did not
report better outcomes when CLS is present [68]
[73], in particular for
patients with clear lateralization on AVS [68], others found that it can predict surgical outcomes [21]
[65]
[69]
[72].
However, in most studies, CLS was calculated by dividing A/C in the
non-dominant AV by the A/C ratio in the IVC and was considered
suppressed if the ratio was<1, some at baseline and some after ACTH
stimulation. Yet, when we examined aldosterone concentrations in the
contralateral AV in our lateralized cases, it became evident that aldosterone
concentrations were higher than in peripheral veins, on average 2.4 times that
of IVC levels [21]. We reasoned that
there was no rationale for correcting aldosterone with cortisol concentrations
in the IVC. In fact, to estimate LR, aldosterone is divided by cortisol to
correct for the variable blood flow and dilution in each AV, while no such
correction is required when examining the concentration of aldosterone in the
IVC. We believe it is also inappropriate to estimate CLS under ACTH stimulation
as one is searching for a suppressed status. Despite all of this, Monticone et
al. had previously reported that 82% of lateralized PA patients had CLS
using A/C corrected ratios and, surprisingly, a higher percentage with
ACTH stimulation compared to baseline (90% and 77%,
respectively) [68]. The authors did
not report a change in post-operative outcomes in terms of blood pressure
reduction nor a reduction in clinical and biochemical response to adrenalectomy
when CLS was absent, more so when the LR was>4 [68].
When using the unstimulated ratio of aldosterone (A)contralateral
(CL)/A peripheral (P), with a cut-off of 1, the
prevalence of CLS in PA was reduced from 45 to 6%, as compared to
(A/C)CL/(A/C)P
[65]. Another previous study also
demonstrated a reduction from 77% to 30% in basal CLS with a
cut-off of 1.5 when using corrected and absolute ratios, respectively [21]. Therefore, true CLS is rare in PA
and when absent, patients responded less to adrenalectomy [21]
[45]
[65]
[74]. A basal CLS of<2.15 was
associated with the best clinical outcomes at 12 months following adrenalectomy
[65]. While these studies
encourage clinicians to factor in CLS in their decision-making, some authors
consider it not required to decide when to offer surgery because as much as
32% of IHA had a CLS ratio<1 [51]
[75]. It is, however, important to
mention that CLS was calculated with corrected rather than absolute ratios in
the Young et al. study [51], which in
fact, overestimates CLS [21], thus
explaining their high percentage of CLS in IHA.
The rarity of true CLS in PA supports the hypothesis that bilateral, asymmetrical
aldosterone production is frequent in PA and precludes the occurrence of
hypotension and hyperkalemia in the immediate post-operative period. Therefore,
CLS, as generally estimated by A/C ratios in most studies, does not
consistently predict outcomes after adrenalectomy, and long-term follow-up
should be implemented to detect cases of residual PA secondary to the
asymmetrical bilateral source of aldosterone excess instead of relying solely on
AVS, in general, to predict recurrence or persistence after surgery [1]
[68]
[73]
[76].
Other methods for performing and interpreting AVS
Super selective AVS or segmental AVS (sAVS) is performed in some specialized
centers in Japan by sampling adrenal tributary veins to detect possible
heterogeneity in aldosterone production within the adrenal glands and possibly
offer partial unilateral adrenalectomy to some patients with bilateral PA [77]
[78]
[79]. sAVS had a success rate of
98% and was able to successfully detect distal APAs and differentiate
between bilateral PA secondary to either APAs/nodules or diffuse
hyperplasia, thus allowing for good biochemical and clinical outcomes
post-adrenalectomy in the former group [77]
[78]
[80]. In one recent study, sAVS
detected a unilateral elevation in aldosterone in 85% of APA with a
positive predictive value (PPV) of 97.1% for APA, compared to
conventional central AVS, which only detected 73%, based on an
ACTH-stimulated LR of>4 [81].
This method could also be used in specific groups of patients with associated
subclinical cortisol co-secretion [82]. However, it is more difficult and time-consuming, especially in
inexperienced hands. Conventional AVS can also present with some difficulties,
especially regarding RAV cannulation. If unsuccessful, AVS results could still
be interpreted using the ratio of (A/C) LAV to (A/C)
IVC. When≥5.5, it depicts left adrenal disease
and≤0.5 right adrenal disease, with a sensitivity of 77% and
specificity of 100% [83].
However, values between 0.5 and 5.5 cannot reliably differentiate between
lateralized and bilateral disease [83]. Considering the frequent multiplicity of micronodules in
addition to the dominant aldosterone-secreting one, it appears that a total
adrenalectomy would be more logical than a selective adrenalectomy for long-term
remission of PA, but this will require longer-term prospective studies. Another
method allowing for successful interpretation of AVS when RAV cannulation has
failed, is the multinomial regression modeling of peripheral and LAV samplings,
which was able to successfully detect lateralization of PA with a 95%
specificity and obviated the need for a repeat AVS [84] ([Table 3b]).
Intraprocedural cortisol measurement during AVS is another method suggested for
improving selectivity, in particular for unstimulated samples [85]. In addition, steroid profiling
using liquid chromatography with tandem mass spectrometry (LC-MS/MS) for
15 different adrenal steroids during AVS reported higher AV to peripheral vein
ratios, both before and after ACTH stimulation, compared to that for cortisol,
with the exceptions of DHEAS, cortisone, and 18-hydroxycortisol [86]. This may be beneficial to use in
place of cortisol in patients with significant cortisol co-secretion, but
extensive data on this issue are still scarce, and modest cortisol co-secretion
has little impact on interpretation [87]
[88]. While there is
some evidence that high cortisol co-secretion can increase the
non-ACTH-stimulated LR contralateral to it and misclassify some cases as
bilateral [88], another study
suggests that the LR is not significantly influenced by cortisol co-secretion
when performed only under ACTH perfusion [87]. Recently, LC-MS/MS was shown to be superior to
immunoassays for lateralization diagnosis, particularly for ACTH-stimulated
samples where the discordance between the two methods was higher [89]. The steroids measured by
LC-MS/MS could potentially be used for aldosterone correction and
assessment of selectivity instead of cortisol. In fact, as much as 43 to
73% of failed AVS based on SI using cortisol concentrations can be
salvaged by using 17-α-hydroxyprogesterone or androstenedione for
correction, respectively [90].
Specifically, androstenedione conceded more successful AVS because the SI was
16-fold higher than with cortisol [90]. Metanephrines were also extensively studied as an alternative to
cortisol for selectivity assessment and were found to be better than cortisol in
detecting successful cannulation in the unstimulated state [91]
[92]
[93]. Both androstenedione and
metanephrines were superior to cortisol and increased the rate of successful AVS
by 14 and 15%, respectively, without any gender differences and without
influencing the LR [94]. However,
androstenedione, and possibly 17-α-hydroxyprogesterone, also respond to
the stress reaction occurring at the beginning of AVS, leading to higher SI
immediately after cannulation compared to 15 min later; similar to what
is seen with cortisol, thus a possible limitation for their use in AVS without
ACTH stimulation [94]. An even higher
percentage of missed AVS with cortisol was recently found (36.6%)
compared to free metanephrine, with an SI cut-off suggested at 10 for free
metanephrines [93]. Finally, although
epinephrine measurement in AV>364 pg/mL predicts
successful AVS, there is a wide variability in what is considered to be normal
values for the adrenal veins, with a significant difference between the RAV and
LAV, thus probably limiting its use in AVS [95]
[96]. Without any
prospective studies comparing outcomes when using these newer parameters for
aldosterone correction in AVS to standard cortisol measurements, it is difficult
to recommend their wider use in clinical practice.