Functional imaging by 11C-metomidate PET: a really useless technique for primary aldosteronism subtyping?

in European Journal of Endocrinology
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  • 1 Institute of Radiology, Specialized Hypertension Centre of Regione Veneto, Department of Medicine – DIMED, University of Padova, Padova, Italy
  • 2 Nuclear Medicine Unit, Specialized Hypertension Centre of Regione Veneto, Department of Medicine – DIMED, University of Padova, Padova, Italy
  • 3 Internal Medicine Emergency Unit, Specialized Hypertension Centre of Regione Veneto, Department of Medicine – DIMED, University of Padova, Padova, Italy

Correspondence should be addressed to F Crimì; Email: filippo.crimi@unipd.it

Dear Editor,

Soinio et al. (1) recently compared the diagnostic accuracy of 11C-metomidate PET (11C-MTO-PET) and cosyntropin-stimulated adrenal venous sampling (AVS) for the subtyping of patients with primary aldosteronism (PA), who were diagnosed according to the 2008 Endocrine Society guidelines (2). Metomidate, the methyl ester of 1-[(1R)-1phenylethyl]-1H-imidazol-5-carboxylic acid, inhibits both steroid-11-beta-hydroxylase (CYP11B1) and aldosterone-synthase (CYP11B2) in human adrenocortical tissues with similar IC50 (0.24 vs 0.6 nM) (3). Because of this poor selectivity, the compound was not further considered as a therapeutic tool to decrease high plasma aldosterone in humans. However, it was pursued for functional imaging based on promising results in pilot studies (4, 5).

Soinio et al. concluded that 11C-MTO-PET offered no diagnostic usefulness in PA patients. In our view, this conclusion needs to be taken with great caution owing to a number of concerns that can be raised concerning their study.

First, notwithstanding the poor selectivity for CYP11B2, they performed 11C-MTO-PET without prior suppression of background uptake of the radiotracer in the glucocorticoid-producing zona fasciculata of the normally functioning adrenocortical tissue adjacent to an aldosterone-producing adenoma (APA) by means of dexamethasone administration (5). This is, in our view, of key importance in order to avoid excess background radiotracer uptake inasmuch as 11C-MTO binds also to CYP11B1, which is widely expressed in the adrenocortical tissue (6). Accordingly, in previous studies on 11C-MTO-PET, which highlighted its potential for functional imaging of PA, dexamethasone suppression was systematically administered (4, 5). The lack of background suppression could explain the low SUVmax-ratio cutoff of 1.16 identified by Soinio et al. (1) in their ROC curve analysis, as compared to the 1.25 found by Burton (5) and used by O’Shea (4).

Therefore, the negative results of Soinio et al. (1) are somehow expected and by no means contradict previous positive studies (4, 5). Considering this bias in their study design, the authors repeated seven PET examinations (13% of the whole population) after dexamethasone suppression using a protocol identical to that used in the previous studies by Burton (5) and used by O’Shea (4). However, this further testing was undertaken only in patients with no lateralization at AVS in whom an increased uptake in one of the adrenal glands could be expected to be highly unlikely.

Secondly, although the radiotracer activity used by Soinio et al. was presumably similar to that used by O’Shea et al. and Burton et al., the PET images acquisition protocol differed markedly. Soinio et al. performed a 20 min acquisition starting 15 min after the radiotracer injection, while O’Shea et al. and Burton et al. performed dynamic acquisitions to select the time frame that warranted the best SUV values. Burton suggested to start the acquisition of PET images 35 min after tracer injection and to acquire data for 10 min and O’Shea replicated the same protocol. Therefore, the acquisition protocol used by Soinio et al.is markedly different from previous literature and does not take into account kinetic dynamic properties of the tracer. Moreover, cosyntropin was shown to confound or even invert the lateralization in about 24% of patients (7) and therefore the results obtained by AVS could have been biased in a certain number of patients causing a misclassification of PA subtype.

Finally, in these studies (1, 4, 5) the lateralization index (LI) used thus far was ≥4. In the AVIS-2 Selectivity study (8) adoption of less restrictive cutoffs was associated with similarly good clinical outcomes. Thus, it is quite likely that all these studies selected patients with the most florid phenotype of unilateral PA, which likely led to overestimating the diagnostic accuracy of 11C-MTO-PET functional imaging.

In summary, functional imaging of PA with 11C-MTO-PET certainly has some limitations and negative studies are equally important as positive studies to obtain a balanced view of its diagnostic usefulness. However, it seems premature to draw definitive conclusions based on protocols that failed to meet basic methodological requirements.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

References

  • 1

    Soinio M, Luukkonen AK, Seppänen M, Kemppainen J, Seppänen J, Pienimäki JP, Leijon H, Vesterinen T, Arola J & Lantto E et al. Functional imaging with 11C-metomidate PET for subtype diagnosis in primary aldosteronism. European Journal of Endocrinology 2020 183 539550. (https://doi.org/10.1530/EJE-20-0532)

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  • 2

    Funder JW, Carey RM, Fardella C, Gomez-Sanchez CE, Mantero F, Stowasser M, Young WF, Montori VMEndocrine Society. Case detection, diagnosis, and treatment of patients with primary aldosteronism: an Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 2008 93 32663281. (https://doi.org/10.1210/jc.2008-0104)

    • Search Google Scholar
    • Export Citation
  • 3

    Lenzini L, Zanotti G, Bonchio M & Rossi GP Aldosterone synthase inhibitors for cardiovascular diseases: a comprehensive review of preclinical, clinical and in silico data. Pharmacological Research 2020 163 105332. (https://doi.org/10.1016/j.phrs.2020.105332)

    • Search Google Scholar
    • Export Citation
  • 4

    O’Shea PM, O’Donoghue D, Bashari W, Senanayake R, Joyce MB, Powlson AS, Browne D, O’Sullivan GJ, Cheow H & Mendichovszky I et al. 11C-metomidate PET/CT is a useful adjunct for lateralization of primary aldosteronism in routine clinical practice. Clinical Endocrinology 2019 90 670679. (https://doi.org/10.1111/cen.13942)

    • Search Google Scholar
    • Export Citation
  • 5

    Burton TJ, Mackenzie IS, Balan K, Koo B, Bird N, Soloviev DV, Azizan EAB, Aigbirhio F, Gurnell M & Brown MJ Evaluation of the sensitivity and specificity of 11C-metomidate positron emission tomography (PET)-CT for lateralizing aldosterone secretion by Conn’s adenomas. Journal of Clinical Endocrinology and Metabolism 2012 97 100109. (https://doi.org/10.1210/jc.2011-1537)

    • Search Google Scholar
    • Export Citation
  • 6

    Bergström M, Bonasera TA, Lu L, Bergström E, Backlin C, Juhlin C & Långström B In vitro and in vivo primate evaluation of carbon-11-etomidate and carbon-11-metomidate as potential tracers for PET imaging of the adrenal cortex and its tumors. Journal of Nuclear Medicine 1998 39 982989.

    • Search Google Scholar
    • Export Citation
  • 7

    Wannachalee T, Zhao L, Nanba K, Nanba AT, Shields JJ, Rainey WE, Auchus RJ & Turcu AF Three discrete patterns of primary aldosteronism lateralization in response to cosyntropin during adrenal vein sampling. Journal of Clinical Endocrinology and Metabolism 2019 104 58675876. (https://doi.org/10.1210/jc.2019-01182)

    • Search Google Scholar
    • Export Citation
  • 8

    Rossitto G, Amar L, Azizi M, Riester A, Reincke M, Degenhart C, Widimsky J, Naruse M, Deinum J & Schultzekool L et al. Subtyping of primary aldosteronism in the AVIS-2 study: assessment of selectivity and lateralization. Journal of Clinical Endocrinology and Metabolism 2020 105 20422052. (https://doi.org/10.1210/clinem/dgz017)

    • Search Google Scholar
    • Export Citation

 

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  • 1

    Soinio M, Luukkonen AK, Seppänen M, Kemppainen J, Seppänen J, Pienimäki JP, Leijon H, Vesterinen T, Arola J & Lantto E et al. Functional imaging with 11C-metomidate PET for subtype diagnosis in primary aldosteronism. European Journal of Endocrinology 2020 183 539550. (https://doi.org/10.1530/EJE-20-0532)

    • Search Google Scholar
    • Export Citation
  • 2

    Funder JW, Carey RM, Fardella C, Gomez-Sanchez CE, Mantero F, Stowasser M, Young WF, Montori VMEndocrine Society. Case detection, diagnosis, and treatment of patients with primary aldosteronism: an Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 2008 93 32663281. (https://doi.org/10.1210/jc.2008-0104)

    • Search Google Scholar
    • Export Citation
  • 3

    Lenzini L, Zanotti G, Bonchio M & Rossi GP Aldosterone synthase inhibitors for cardiovascular diseases: a comprehensive review of preclinical, clinical and in silico data. Pharmacological Research 2020 163 105332. (https://doi.org/10.1016/j.phrs.2020.105332)

    • Search Google Scholar
    • Export Citation
  • 4

    O’Shea PM, O’Donoghue D, Bashari W, Senanayake R, Joyce MB, Powlson AS, Browne D, O’Sullivan GJ, Cheow H & Mendichovszky I et al. 11C-metomidate PET/CT is a useful adjunct for lateralization of primary aldosteronism in routine clinical practice. Clinical Endocrinology 2019 90 670679. (https://doi.org/10.1111/cen.13942)

    • Search Google Scholar
    • Export Citation
  • 5

    Burton TJ, Mackenzie IS, Balan K, Koo B, Bird N, Soloviev DV, Azizan EAB, Aigbirhio F, Gurnell M & Brown MJ Evaluation of the sensitivity and specificity of 11C-metomidate positron emission tomography (PET)-CT for lateralizing aldosterone secretion by Conn’s adenomas. Journal of Clinical Endocrinology and Metabolism 2012 97 100109. (https://doi.org/10.1210/jc.2011-1537)

    • Search Google Scholar
    • Export Citation
  • 6

    Bergström M, Bonasera TA, Lu L, Bergström E, Backlin C, Juhlin C & Långström B In vitro and in vivo primate evaluation of carbon-11-etomidate and carbon-11-metomidate as potential tracers for PET imaging of the adrenal cortex and its tumors. Journal of Nuclear Medicine 1998 39 982989.

    • Search Google Scholar
    • Export Citation
  • 7

    Wannachalee T, Zhao L, Nanba K, Nanba AT, Shields JJ, Rainey WE, Auchus RJ & Turcu AF Three discrete patterns of primary aldosteronism lateralization in response to cosyntropin during adrenal vein sampling. Journal of Clinical Endocrinology and Metabolism 2019 104 58675876. (https://doi.org/10.1210/jc.2019-01182)

    • Search Google Scholar
    • Export Citation
  • 8

    Rossitto G, Amar L, Azizi M, Riester A, Reincke M, Degenhart C, Widimsky J, Naruse M, Deinum J & Schultzekool L et al. Subtyping of primary aldosteronism in the AVIS-2 study: assessment of selectivity and lateralization. Journal of Clinical Endocrinology and Metabolism 2020 105 20422052. (https://doi.org/10.1210/clinem/dgz017)

    • Search Google Scholar
    • Export Citation