Skip to main content

Outcome after surgery for primary hyperaldosteronism may depend on KCNJ5 tumor mutation status: a population-based study from Western Norway

Abstract

Background

Primary aldosteronism (PA) is a frequent cause (about 10 %) of hypertension. Some cases of PA were recently found to be caused by mutations in the potassium channel KCNJ5. Our objective was to determine the mutation status of KCNJ5 and seven additional candidate genes for tumorigenesis: YY1, FZD4, ARHGAP9, ZFP37, KDM5C, LRP1B, and PDE9A and, furthermore, the surgical outcome of PA patients who underwent surgery in Western Norway.

Methods

Twenty-eight consecutive patients with aldosterone-producing adrenal tumors (20 patients with single adenoma, 8 patients with unilateral multiple adenomas or hyperplasia) who underwent surgery were included in this study. All patients were operated on by uncomplicated laparoscopic total adrenalectomy. Genomic DNA was isolated from tumor and non-tumor adrenocortical tissue, and DNA sequencing revealed the mutation status.

Results

Ten out of 28 (36 %) patients with PA displayed tumor mutations in KCNJ5 (p. G151R and L168R) while none were found in the corresponding non-tumor samples. No mutations were found in the other seven candidate genes screened. The presence of KCNJ5 mutations was associated with lower blood pressure and a higher chance for cure by surgery when compared to patients harboring the KCNJ5 wild type.

Conclusions

KCNJ5 mutations are associated with a better surgical outcome. Preoperative identification of the mutation status might have impact on surgical strategy (total vs. subtotal adrenalectomy).

This is a preview of subscription content, access via your institution.

Fig. 1

References

  1. Young WF (2007) Primary aldosteronism: renaissance of a syndrome. Clin Endocrinol (Oxf) 66(5):607–618

    Article  CAS  Google Scholar 

  2. Milliez P, Girerd X, Plouin PF, Blacher J, Safar ME, Mourad JJ (2005) Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol 45(8):1243–1248

    Article  PubMed  CAS  Google Scholar 

  3. Conn JW (1955) Presidential address. I. Painting background. II. Primary aldosteronism, a new clinical syndrome. J Lab Clin Med 45(1):3–17

    PubMed  CAS  Google Scholar 

  4. Loh KC, Koay ES, Khaw MC, Emmanuel SC, Young WF Jr (2000) Prevalence of primary aldosteronism among Asian hypertensive patients in Singapore. J Clin Endocrinol Metab 85(8):2854–2859

    Article  PubMed  CAS  Google Scholar 

  5. Mulatero P, Stowasser M, Loh KC, Fardella CE, Gordon RD, Mosso L et al (2004) Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab 89(3):1045–1050

    Article  PubMed  CAS  Google Scholar 

  6. Rossi GP, Bernini G, Caliumi C, Desideri G, Fabris B, Ferri C et al (2006) A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. J Am Coll Cardiol 48(11):2293–2300

    Article  PubMed  CAS  Google Scholar 

  7. Stowasser M (2009) Update in primary aldosteronism. J Clin Endocrinol Metab 94(10):3623–3630

    Article  PubMed  CAS  Google Scholar 

  8. Choi M, Scholl UI, Yue P, Bjorklund P, Zhao B, Nelson-Williams C et al (2011) K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science 331(6018):768–772

    Article  PubMed  CAS  Google Scholar 

  9. Krapivinsky G, Gordon EA, Wickman K, Velimirovic B, Krapivinsky L, Clapham DE (1995) The G-protein-gated atrial K+ channel IKACh is a heteromultimer of two inwardly rectifying K(+)-channel proteins. Nature 374(6518):135–141

    Article  PubMed  CAS  Google Scholar 

  10. Geller DS, Zhang J, Wisgerhof MV, Shackleton C, Kashgarian M, Lifton RP (2008) A novel form of human mendelian hypertension featuring nonglucocorticoid-remediable aldosteronism. J Clin Endocrinol Metab 93(8):3117–3123

    Article  PubMed  CAS  Google Scholar 

  11. Mulatero P (2008) A new form of hereditary primary aldosteronism: familial hyperaldosteronism type III. J Clin Endocrinol Metab 93(8):2972–2974

    Article  PubMed  CAS  Google Scholar 

  12. Akerstrom T, Crona J, Delgado VA, Starker LF, Cupisti K, Willenberg HS et al (2012) Comprehensive re-sequencing of adrenal aldosterone producing lesions reveal three somatic mutations near the KCNJ5 potassium channel selectivity filter. PLoS One 7(7):e41926

    Article  PubMed  Google Scholar 

  13. Azizan EA, Murthy M, Stowasser M, Gordon R, Kowalski B, Xu S et al (2012) Somatic mutations affecting the selectivity filter of KCNJ5 are frequent in 2 large unselected collections of adrenal aldosteronomas. Hypertension 59(3):587–591

    Article  PubMed  CAS  Google Scholar 

  14. Boulkroun S, Beuschlein F, Rossi GP, Golib-Dzib JF, Fischer E, Amar L et al (2012) Prevalence, clinical, and molecular correlates of KCNJ5 mutations in primary aldosteronism. Hypertension 59(3):592–598

    Article  PubMed  CAS  Google Scholar 

  15. Monticone S, Hattangady NG, Nishimoto K, Mantero F, Rubin B, Cicala MV et al (2012) Effect of KCNJ5 mutations on gene expression in aldosterone-producing adenomas and adrenocortical cells. J Clin Endocrinol Metab 97(8):E1567–E1572

    Article  PubMed  CAS  Google Scholar 

  16. Mulatero P, Tauber P, Zennaro MC, Monticone S, Lang K, Beuschlein F et al (2012) KCNJ5 mutations in European families with nonglucocorticoid remediable familial hyperaldosteronism. Hypertension 59(2):235–240

    Article  PubMed  CAS  Google Scholar 

  17. Taguchi R, Yamada M, Nakajima Y, Satoh T, Hashimoto K, Shibusawa N et al (2012) Expression and mutations of KCNJ5 mRNA in Japanese patients with aldosterone-producing adenomas. J Clin Endocrinol Metab 97(4):1311–1319

    Article  PubMed  CAS  Google Scholar 

  18. Knappskog S, Chrisanthar R, Lokkevik E, Anker G, Ostenstad B, Lundgren S et al (2012) Low expression levels of ATM may substitute for CHEK2/TP53 mutations predicting resistance towards anthracycline and mitomycin chemotherapy in breast cancer. Breast Cancer Res 14(2):R47

    Article  PubMed  CAS  Google Scholar 

  19. Fu B, Zhang X, Wang GX, Lang B, Ma X, Li HZ et al (2011) Long-term results of a prospective, randomized trial comparing retroperitoneoscopic partial versus total adrenalectomy for aldosterone producing adenoma. J Urol 185(5):1578–1582

    Article  PubMed  Google Scholar 

  20. Walz MK, Gwosdz R, Levin SL, Alesina PF, Suttorp AC, Metz KA et al (2008) Retroperitoneoscopic adrenalectomy in Conn's syndrome caused by adrenal adenomas or nodular hyperplasia. World J Surg 32(5):847–853

    Article  PubMed  Google Scholar 

  21. Fendrich V, Ramaswamy A, Nies C (2003) Hyperaldosteronism persisting after subtotal adrenalectomy. Chirurg 74(5):473–477, Article in German

    Article  PubMed  CAS  Google Scholar 

  22. Eloubeidi MA, Black KR, Tamhane A, Eltoum IA, Bryant A, Cerfolio RJ (2010) A large single-center experience of EUS-guided FNA of the left and right adrenal glands: diagnostic utility and impact on patient management. Gastrointest Endosc 71(4):745–753

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to thank the Western Norway Regional Health Authority for financial support (grant to J.E.V. and M.B.).

Conflicts of interest

None.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Michael Brauckhoff.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Arnesen, T., Glomnes, N., Strømsøy, S. et al. Outcome after surgery for primary hyperaldosteronism may depend on KCNJ5 tumor mutation status: a population-based study from Western Norway. Langenbecks Arch Surg 398, 869–874 (2013). https://doi.org/10.1007/s00423-013-1093-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00423-013-1093-2

Keywords

  • Primary aldosteronism
  • Aldosterone-producing tumors
  • Conn's syndrome
  • KCNJ5
  • Somatic mutations
  • Western Norway