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Annales d’Endocrinologie xxx (2016) xxx-xxx
Consensus
SFE/SFHTA primary aldosteronism consensus, group 4: Subtype diagnosis in primary aldosteronism
Consensus hyperaldosteronisme primaire SFE/SFHTA groupe 4 : diagnostic étiologique des hyperaldosteronismes primaires
Stéphane Bardetª, Bernard Chamontinb, Claire Douillard®, Jean-Yves Pagnyd, Anne Hernigoud, Francis Joffree, Pierre-François Plouinf,*, Olivier Steicheng
a Service de médecine nucléaire, centre François-Baclesse, 3, avenue du Général-Harris, 14076 Caen cedex 05, France b Service de médecine interne et d’hypertension artérielle, centre hospitalo-universitaire Rangueil, 31059 Toulouse, France
” Service d’endocrinologie et des maladies métaboliques, hôpital Huriez, centre hospitalier régional universitaire de Lille, rue Polonovski, 59037 Lille, France d Département de radiologie, hôpital européen Georges-Pompidou, Assistance publique-Hôpitaux de Paris, 75908 Paris, France e Département de radiologie, centre hospitalo-universitaire Rangueil, 31059 Toulouse, France
f Unité d’hypertension, Assistance publique-Hôpitaux de Paris, hôpital européen Georges-Pompidou, 20, rue Leblanc, 75908 Paris cedex 15, France % Assistance publique-Hôpitaux de Paris, hôpital Tenon, service de médecine interne, rue de la Chine, 75020 Paris, France
Abstract
To establish the cause of primary aldosteronism (PA), it is essential to distinguish unilateral from bilateral adrenal aldosterone secretion, as adrenalectomy improves aldosterone secretion and controls hypertension and hypokalemia only in the former. Except in the rare cases of type 1 or 3 familial hyperaldosteronism, which can be diagnosed genetically and are not candidates for surgery, lateralized aldosterone secretion is diagnosed on adrenal CT or MRI and adrenal venous sampling. Postural stimulation tests and 131 I-norcholesterol scintigraphy have poor diagnostic value and 11C-metomidate PET is not yet available. We recommend that adrenal CT or MRI be performed in all cases of PA. Imaging may exceptionally identify adrenocortical carcinoma, for which the surgical objectives are carcinologic, and otherwise shows either normal or hyperplastic adrenals or unilateral adenoma. Imaging alone carries a risk of false positives in patients over 35 years of age (non-aldosterone-secreting adenoma) and false negatives in all patients (unilateral hyperplasia). We suggest that all candidates for surgery over 35 years of age undergo adrenal venous sampling, simultaneously in both adrenal veins, without ACTH stimulation, to confirm the unilateral form of the hypersecretion. Sampling results should be confirmed on adrenal vein cortisol assay showing a concentration at least double that found in peripheral veins. Aldosterone secretion should be considered lateralized when aldosterone/cortisol ratio on the dominant side is at least 4-fold higher than contralaterally. Published by Elsevier Masson SAS.
Keywords: Aldosterone; Aldosterone-secreting adenoma; Aldosteronism; Primary; Adrenal vein sampling
1. Rationale
Etiological diagnosis concerns only those patients in whom primary aldosteronism (PA) has been confirmed (see previous
chapters). Etiology is known in 2 rare single-gene forms of PA in which aldosterone hypersecretion is related either to abnormali- ties in synthesis regulation (familial hyperaldosteronism type 1, FH1), or to hereditary activation (FH3) [1]; these forms account for less than 1% of cases. Even rarer is adrenocortical carcinoma (ACC), with prevalence of 1-9 per million and only 3% showing isolated aldosterone hypersecretion, most predominantly involv- ing cortisol secretion [2].
Etiological diagnosis mainly aims to distinguish PA with and without lateralized secretion [3]. The former can be man- aged surgically, and comprises aldosterone-secreting adenoma (ASA) or in some cases no visible adenoma (unilateral primary
* Corresponding author. E-mail addresses: sbardet@baclesse.unicancer.fr (S. Bardet),
chamontin.b@chu-toulouse.fr (B. Chamontin), douillard.claire@gmail.com
(C. Douillard), jean-yves.pagny@egp.aphp.fr (J .- Y. Pagny),
anne.hernigou@egp.aphp.fr (A. Hernigou), francis.joffre0626@orange.fr
(F. Joffre), pierre-francois.plouin@egp.aphp.fr (P .- F. Plouin), olivier.steichen@tnn.aphp.fr (O. Steichen).
http://dx.doi.org/10.1016/j.ando.2016.01.008
S. Bardet et al. / Annales d’Endocrinologie xxx (2016) xxx-xxx
hyperplasia). Surgery has the aim of controlling the con- sequences of hypersecretion (hypertension, and possibly hypokalemia), rather than the oncologic aim in ACC. PA without lateralized secretion is managed medically. Etiological explo- ration distinguishes candidates for adrenalectomy (lateralized PA) and those (non-lateralized) in which it would serve no pur- pose.
Even in lateralized PA, the risk/benefit ratio of surgery may be poor: comorbidity exacerbates operative risk and prevents postoperative termination of treatment, hypertension continues to need controlling, and patients may prefer medical treatment. Etiological exploration is thus warranted only in candidates for surgery. Patients presenting FH1 or FH3 have bilateral secretion, and are not candidates for surgery and etiological testing is not suitable.
Etiological tests to detect or predict lateralized hypersecretion comprise CT and MRI, adrenal vein sampling (AVS), functional imaging and posture tests.
2. CT/MRI
R 4.1 CT (or MRI when CT is contraindicated) should be performed in all cases of PA. Level of evidence: +.
2.1. Technique
Fine imaging is required, as ACCs are small (around 10 mm). Rapid CT (≥ 64-row) is the first choice. MRI has poorer reso- lution and slower acquisition, with risk of respiratory artifacts, and is reserved to contraindications for CT.
2.2. Performance
Systematic analysis of the literature (38 articles published between 1982 and 2008; 950 patients) compiled CT and MRI results in patients undergoing AVS, with lateralization on AVS as gold-standard [4]. In 38% of cases, imaging was discordant with respect to AVS, either failing to detect the origin of lateralized secretion (19.1%), or indicating a unilateral lesion when AVS found no lateralization (14.6%) or even a lesion contralateral to the lateralization found on AVS (3.9%). Several subsequent stud- ies confirmed the frequency of false positives and false negatives on CT [5-8], but few described the typical image correspond- ing to ASA [6,7,9-11]. Table 1 presents articles with precisely reported CT data with comparison to AVS or PA resolution after adrenalectomy [6,7,10,11].
2.3. Indications
The surgeon needs CT (or MRI) in order to choose the surgical approach; some find it useful for AVS, locating the right adrenal vein. These indications are restricted to candidates for surgery,
and involve contrast enhancement. The Endocrine Society con- siders imaging indicated in all cases of PA, to rule out ACC [3]. This recommendation leads to multiple examinations in patients without indications or who are not candidates for surgery, as the rate of PA in specialized centers is around 10%, whereas that of ACC with mineralocorticoid expression is nearer 10-6.
3. Adrenal vein sampling
R 4.2 We do not recommend AVS in non- candidates for surgery. Level of evidence: +.
R 4.3 When AVS is indicated, both adrenal veins should be sampled simultaneously, without adrenocorticotropic hormone (ACTH) stimulation, with selectivity index threshold ≥ 2 and lateraliza- tion index threshold ≥ 4.
Level of evidence: ++.
R 4.4 We suggest performing AVS in candidates for surgery aged > 35 years, whatever the imaging findings.
Level of evidence: ++.
3.1. Principle
AVS compares aldosterone/cortisol ratio between the two adrenal veins (lateralization index: LI) to screen for lateral- ized secretion. Treatments (antihypertensive agents, potassium supplementation) should be adapted in advance, as in peripheral aldosterone assay. AVS is the gold-standard test, as adrenalec- tomy, if performed, aims to suppress unilateral hypersecretion rather than unilateral nodules.
3.2. Technique
AVS consists in measuring cortisol and aldosterone concen- trations in the two adrenal veins and downstream blood (inferior vena cava or a peripheral vein). Variants comprise simultaneous or sequential sampling in the two adrenal veins [12,13], and associated pharmacologic stimulation (ACTH bolus or infu- sion, or metoclopramide; see [12] for a review). Stimulation sets a ceiling to and thus neutralizes ACTH-dependent varia- tion in stress-induced steroids [14], and is therefore warranted in sequential AVS. The ratio between adrenal vein and inferior vena cava or peripheral vein cortisol levels represents a selectiv- ity index (SI) to check that AVS was selective. LI is calculated
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| Author | n | Definition of CT data | Endpoint and result |
|---|---|---|---|
| Minami et al. (2008) [10] | 33 | A: 2 normal adrenals; B: distinct unilateral nodule ≥ 8 mm or increased thickness; C: as B, but bilateral | LI>4 on AVS in 1 case A out of 7, 14 cases B out of 23, and 3 cases C out of 5 |
| Lau et al. (2012) [6] | 55 | Scale: 1 (confirmed bilateral lesions) to 5 (single nodule, other arm of the adrenal <5 mm) | PA resolved if surgery or LI>5 on AVS. Se and Sp 100% if grade 5 |
| Kupers et al. (2012) [11] | 87 | Typical nodule: hypodense (< 10 HU), diameter ≥ 8 mm, the rest of the AG and contralateral adrenal being thin and regular | LI>4 on AVS. Typical nodule Se and Sp, 55% and 87% |
| Riester et al. (2014) [7] | 194 | Typical nodule: hypodense (<10 HU), diameter ≥ 10 mm, the rest of the adrenal and contralateral adrenal being thin and regular | LI>4 on AVS. Typical nodule Se and Sp, 39% and 64%a |
AVS: adrenal vein sampling; HU: Hounsfield unit; LI: lateralization index; Se and Sp: sensitivity and specificity.
a Estimated from incomplete data.
only if SI reaches a predetermined threshold; most centers use an SI threshold of ≥ 2 without ACTH or ≥ 3 with ACTH, and an LI threshold of ≥ 2 without ACTH and ≥ 2.6 with ACTH [6,7,10-12,15].
3.3. Results
A recent international consensus statement [12] proposed an SI threshold of ≥ 2 to validate AVS and an LI threshold of ≥ 2 to confirm lateralization of hypersecretion [12], adding that a stricter LI threshold “undoubtedly leads to selection of a popu- lation with a higher chance of being cured with adrenalectomy”. Various SI and LI threshold values were compared in a cooper- ative study in which the endpoint was concordant between two AVSs in a single patient; however, the second AVS was per- formed because the first was “non-satisfactory”, which biased the findings [15]. As expected, stricter thresholds gave lower rates of lateralization: 67% for SI ≥ 1.1+LI ≥ 2, versus 36% for SI ≥ 2+LI ≥ 4. The respective performance of these thresh- olds was not validated against adrenalectomy. Despite the lack of good-quality data, we suggest an LI threshold of ≥ 4, for rea- sons of efficacy (increased probability of cure by adrenalectomy, as seen above [12]) and of safety (stricter thresholds reducing the number of patients exposed to operative risk, in a procedure aiming not at tumor prevention but functional improvement that stands comparison with medical management). Simultaneous and sequential AVS was compared in 2 articles; but sample sizes were unclear and there was no assessment criterion indepen- dent of AVS itself, so that no conclusion can be drawn [13,14]. Studies assessing SI and LI before and after ACTH or metoclo- pramide stimulation generally reported increase in SI but not LI and mentioned no impact on the decision to operate (Table 2, adapted from [12]).
3.4. Predictive value of AVS for outcome of surgery
Assessing the performance of AVS requires an independent assessment criterion, i.e. the results of adrenalectomy on hyper- secretion, blood pressure and kalemia. This allows assessment of specificity, but not of sensitivity, as patients without lateral- ization do not undergo surgery. Few studies have applied this
criterion in patients in whom adrenalectomy was indicated on the basis of positive AVS [5-8]; the number of patients fol- lowed up after positive AVS, the definition of positivity and the results of surgery were poorly defined, hindering the calculation of specificity. Specificity is not 100%, as PA may persist after adrenalectomy indicated by lateralized AVS [4,5,8].
3.5. Should AVS be systematic?
The lack of a gold-standard means that whether AVS is warr- anted can be judged only theoretically and not on hard data. The procedure is invasive, and entails a risk of adrenal vein lesion (estimated at 0.6% in expert center reports [16]). It is costly: at least 1 day’s hospital stay, with interventional radi- ology using a single-use probe, and at least 6 steroid assays. It is complicated to perform: the right adrenal vein is diffi- cult to catheterize; and the 6 samples, 6 blood tubes and 6 plasma tubes need to be meticulously labeled. Consequently, AVS is routine in only a few centers. A risk/benefit analysis should be enabled by the ongoing SPARTACUS [17] random- ized controlled trial, comparing hormonal and blood pressure results of adrenalectomy indicated by CT alone or by CT confirmed by AVS; meanwhile, different situations may be distinguished.
3.5.1. CT finds a typical unilateral nodule
A typical unilateral nodule is a hypodense ≥ 10 mm or ≥ 8 mm nodule with normal contralateral adrenal ([7,9,11] and Table 1). In this situation, failing to perform AVS entails a risk of unnecessary surgery due to an associated non-secreting adenoma [3,4]. However, incidentaloma rate is age-dependent, and recent studies indicate that, in PA, a typical unilateral nodule before the age of 40 [11,18] or 35 years [8] is very probably an ASA. AVS can be omitted in this age range, although the above findings were based on small patient samples and the double criterion (typical nodule + young age) applies to less than 10% of cases (Table 3).
3.5.2. CT does not find a typical unilateral nodule
The aspect may be of normal adrenals, bilateral nodules or a unilateral nodule that is atypical in being small (<10 or <8 mm)
| n validated AVSs | Simultaneous bilateral AVS | Impact on SI | Impact on LI | |
|---|---|---|---|---|
| ACTH | ||||
| Monticone et al. (2012) [23] | 76 | No | Increased | Unchanged |
| Mathur et al. (2010) [24] | 114 | Yes | Reduced on right | Unchanged on right |
| Unchanged on left | Increased on left | |||
| Seccia et al. (2012) [14] | 63 | Yes | Increased | Unchanged |
| Tanemoto et al. (2009) [25] | 10 | Yes | Unchanged | Unchanged |
| Rossi et al. (2008) [26] | 46 | Yes | Increased | Reduced |
| Satoh et al. (2007) [27] | 87 | Yes | Increased | Reduced |
| Harvey et al. (2006) [28] | 12? | Yes | Increased | NR |
| Carr et al. (2004) [13] | 11 | Yes | NR | NR |
| Metoclopramide | ||||
| Wu et al. (2001) [29] | 20 | Yes | NR | Unchanged |
AVS: adrenal vein sampling; LI: lateralization index; SI: selectivity index; NR: not reported; see detail and individual study references in [7].
| Total | With typical nodule ≤ 40 yrs | Lateralization criterion | n lateralized | |
|---|---|---|---|---|
| Mulatero et al. (2008) [18] | 70 | 5 | IS ≥ 2, IL ≥4 | 5/5 |
| Kupers et al. (2012) [11] | 87 | 9 | IS ≥ 2, IL ≥4 | 9/9 |
| Riester et al. (2014) [7] | 193 | 6 | IS ≥ 2, IL ≥4 | 5/6 |
| Lim et al. (2014) [8] | 133 | 21 | PA resolved by adrenalectomy | 15/21ª |
| Total | 483 | 41/483 (8%) | 34/41 (83%) |
a Including 6/6 under 35 years of age.
or associated with an abnormal contralateral adrenal. In this sit- uation, failing to perform AVS entails a loss of opportunity in 19-35% of cases [4,19]. The decision to operate, and therefore to perform AVS, depends on operative risk, expected benefit of surgery, and the patient’s wishes. If the risk/benefit ratio is negative, AVS should not be performed. Otherwise, exploration should be continued to the end and the patient referred to a center experienced in AVS.
3.5.3. Special cases
AVS is not contributive in suspected ACC (usually, ≥ 4 cm heterogeneous nodule, often with co-secretion of cortisol or androgens), as tumor resection is in any case mandatory. Nor is it useful in FH1 or FH3, as unilateral adrenalectomy is not curative in these cases. In FH2, the situation is, in the present state of knowledge, unclear, as PA may be associated with a unilateral typical nodule.
To sum up, AVS is not useful in patients who are not candi- dates for adrenalectomy, including those with FH1 or FH3, or who present a large tumor or tumor associated with cortisol or androgen secretion, as surgery is indicated regardless of AVS. Abstention is also probably possible in under 35-year-olds with typical nodules. Otherwise, the indication for surgery should be confirmed by AVS, whether adrenal nodules are present or not. The literature is silent on how to proceed after invalid AVS. One option is to repeat the AVS, as in some cases in the study by Mulatero et al. [15]; alternatively, isolated medical treatment may be pursued. In either case, the patient must be informed.
4. Functional imaging: 131 I-norcholesterol and 11 C-metomidate
R4.5 We suggest not using functional imaging for etiologic diagnosis of PA. Level of evidence: +.
Two radiopharmaceuticals (RP) have been described: 131I- methylnorcholesterol, which accumulates in the adrenocortical gland under the influence of ACTH, and 11C-metomidate, an 11ß hydroxylase and aldosterone-synthase inhibitor.
4.1. Technique
131 I-methylnorcholesterol (Norchol®) scintigraphy is per- formed under dexamethasone (DXM) suppression. Spironolac- tone, diuretics and oral contraceptives should be interrupted 4-6 weeks ahead of examination. The thyroid should be pre- saturated with iodine. Images are acquired at D2 and D4 or D5 on tomoscintigraphy coupled to CT. Normal adrenals are not seen before D4-5. Early unilateral fixation suggests ASA.
11C-metomidate PET-scan uses a short half-life radiophar- maceutical, and therefore needs to be conducted near the site producing the RP. In the only clinical study to date [20], 150-500 MBq 11C-metomidate was injected, with dynamic recording for the first 45 min. DXM suppression increased adrenal tumor uptake (versus normal adrenal tissue) by 25%.
S. Bardet et al. / Annales d’Endocrinologie xxx (2016) xxx-xxx
4.2. Performance
The published 131 I-methylnorcholesterol scintigraphy stud- ies are all old, retrospective, with varying assessment criteria, and poor resolution. A single, retrospective study reported a comparison against CT, in 27 PA patients, all with CT and 8 with non-conclusive AVS [21]. The assessment criteria were histologic results and response to surgery. Sensitivity was bet- ter on scintigraphy than CT (82% vs. 41% for histology, 100% vs. 40% for response to surgery), but specificity did not differ (respectively, 67% and 67% for histology, 54% and 62% for response to surgery).
Burton et al. assessed 11C-metomidate PET in 44 patients: 39 with PA and 5 with incidentaloma [20]. In the 25 patients with unilateral adenoma, 11C-metomidate uptake [SUVmax] was greater in tumoral than normal adrenal tissue. At a 1.25 tumoral/normal adrenal SUVmax ratio threshold, PET showed 76% sensitivity and 87% specificity.
4.3. Indications
131I-methylnorcholesterol scintigraphy is indicated in case of failure of AVS. It is long, costly and requires several days’ prior DXM suppression. It is not without risk: DXM raises blood pressure and lowers kalemia in hypertensive and hypokalemic patients. 11C-metomidate is not commercially available, and its contribution remains to be determined.
5. Postural stimulation tests
R4.6 We do not recommend posture tests for etiological diagnosis of PA. Level of evidence: ++.
5.1. Technique
We are concerned here with the contribution of postural stimulation tests to etiological rather than positive diagnosis of PA: 40 mg/iv furosemide response after 2 hours’ walking and response to upright stance after 2 or 4 hours’ walking.
5.2. Performance
Lau et al., in a prospective study, compared CT (1.25 mm slices with and without contrast enhancement) versus postural stimulation test (≥ 30% reduction in aldosterone concentration after 4 hours’ walking as indicating ASA) in 50 consecutive patients with non-suppressible PA [6]. The endpoints were hormonal resolution in the 24 operated patients and AVS lat- eralization after 1 hour’s 50 µg/h synacthen (SI ≥ 5 and LI ≥ 4) in the 26 non-operated patients. Sensitivity and specificity were respectively <56% and 75% on postural test, versus 77% and 80% for CT. CT sensitivity and specificity were 100% in case
of > 10 mm unilateral nodule without contralateral abnormality. The authors concluded that the posture test contributed noth- ing to CT, the latter being contributive in all surgery candidates. They briefly analyzed and discounted previous studies, which had been retrospective.
Nanba et al. [22] compared the captopril test, postural stim- ulation + furosemide test and intravenous saline infusion in 120 patients. In a subgroup of 57 patients, they reported sensi- tivity and specificity for a composite lateralization criterion consisting of AVS after synacthen (SI ≥ 5 and LI ≥ 2.6) or scintigraphy (without details) or response to surgery (without details). Sensitivity was 93% for postural test + furosemide, but with incomplete data, specificity could not be calculated in a subgroup of 48% of the patients.
Disclosure of interest
The authors declare that they have no competing interest.
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