The first experience of using beta-hydroxybutyrate analysis of capillary blood in the diagnosis of non-diabetic hypoglycemia in adults

Background: The diagnostic threshold of β-hydroxybutyrate (BHB) at the moment of hypoglycemia in insulinoma was developed for venous blood many years ago, when there were no alternative ways to measure ketones. Number of works, mainly on patients with diabetes mellitus, found differences in the measurement of this indicator in venous and capillary blood, but the results were contradictory. Moreover, this study was not previously used in the diagnosis of non-diabetic hypoglycemia (NDH) in adults on the territory of the Russian Federation.

Aim: To estimate the effectiveness of the method for determining BHB in capillary blood and its place in the diagnosis of NDH.

Materials and methods: We conducted an experimental, cross-sectional, comparative study and included patients with suspected NDH who underwent a standard fast test. The BHB level in capillary blood was determined every 6 hours during the fast test and at its completion.

Results: Based on the results of the fast test, the participants (n=154) were divided into groups: with hyperinsulinemic variant of NDH and IFRoma (n=98; group 1), with hypoinsulinemic variant of NDH /absence of NDH (n=56; group 2). When comparing the level of BHB at the moment of fasting completion, significant differences were obtained between groups 1 and 2 (p<0.001). According to the ROC analysis, the determination of BHB for differentiation the hyper- and hypoinsulinemic variants of hypoglycemia is characterized by excellent quality of model (AUC=99,1% [98,0%; 100,0%]). The BHB determination in capillary blood has the maximum diagnostic accuracy at a cut-off point of ≤ 1.4 mmol/L (Se 98.0%, Sp 96.4%, PPV 98.0%, NPV 96.4%, Ac 97.4%). Exceeding the diagnostic threshold of BHB was first recorded after 24h of fasting; at the same point, a significant difference was determined when comparing BHB indicators between two consecutive measurements (between 18h and 24h).

Conclusion: The BHB determination in capillary blood is a highly sensitive and highly specific additional method for the differential diagnosis of NDH variants. The diagnostic threshold for BHB of capillary blood, which allows differentiating hyper- and hypoketonemic variants of NDH, is ≤1.4 mmol / L. It is advisable to initiate control of BHB in the blood no earlier than 18 hours after the start of the fast test.

1. Cryer PE, Axelrod L, Grossman AB, et al. Evaluation and Management of Adult Hypoglycemic Disorders: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2009;94(3):709-728. doi: https://doi.org/10.1210/jc.2008-1410

2. Kapoor RR, Flanagan SE, James C, et al. Hyperinsulinaemic hypoglycaemia. Arch Dis Child. 2009;94(6):450-457. doi: https://doi.org/10.1136/adc.2008.148171

3. Bonaventura A, Montecucco F, Dallegri F. Update on strategies limiting iatrogenic hypoglycemia. Endocr Connect. 2015;4(3):R37-R45. doi: https://doi.org/10.1530/EC-15-0044

4. Nedoboy PE, Cohen M, Farnham MM-J. Slow but Steady— The Responsiveness of Sympathoadrenal System to a Hypoglycemic Challenge in Ketogenic Diet-Fed Rats. Nutrients. 2021;13(8):2627. doi: https://doi.org/10.3390/nu13082627

5. Placzkowski KA, Vella A, Thompson GB, et al. Secular Trends in the Presentation and Management of Functioning Insulinoma at the Mayo Clinic, 1987–2007. J Clin Endocrinol Metab. 2009;94(4):1069-1073. doi: https://doi.org/10.1210/jc.2008-2031

6. Norgren J, Sindi S, Sandebring-Matton A, et al. Capillary blood tests may overestimate ketosis: triangulation between three different measures of β-hydroxybutyrate. Am J Physiol Endocrinol Metab. 2020;318(2):E184-E188. doi: https://doi.org/10.1152/ajpendo.00454.2019

7. Armer J, Hunt N, Kaushal K, et al. Limitations to using point of care blood ketone testing to monitor DKA treatment. Pract Diabetes. 2013;30(9):380-383. doi: https://doi.org/10.1002/pdi.1818

8. Service FJ, O’Brien PC. Increasing Serum Betahydroxybutyrate Concentrations during the 72-Hour Fast: Evidence against Hyperinsulinemic Hypoglycemia. J Clin Endocrinol Metab. 2005;90(8):4555-4558. doi: https://doi.org/10.1210/jc.2005-0033

9. O’Brien T, O’Brien PC, Service FJ. Insulin surrogates in insulinoma. J Clin Endocrinol Metab. 1993;77(2):448-451. doi: https://doi.org/10.1210/jcem.77.2.8345050

10. Chammas N, Teale J, Quin J. Insulinoma: how reliable is the biochemical evidence? Ann Clin Biochem Int J Lab Med. 2003;40(6):689-693. doi: https://doi.org/10.1258/000456303770367315

11. Popa SG, Ungureanu BS, Săftoiu A, et al. Pitfalls in diagnosing a pancreatic neuroendocrine tumor: a case report. Rom J Morphol Embryol. 2015;56(4):1495-1502.

12. Garla V, Sonani H, Palabindala V, et al. Nonislet Cell Hypoglycemia: Case Series and Review of the Literature. Front Endocrinol (Lausanne). 2019;10:316. doi: https://doi.org/10.3389/fendo.2019.00316

13. Dynkevich Y, Rother KI, Whitford I, et al. Tumors, Igf-2, And Hypoglycemia: Insights From The Clinic, The Laboratory, And The Historical Archive. Endocrine Reviews. 2013;34(6):798-826. doi: https://doi.org/10.1210/er.2012-1033

14. Vice E, Privette JD, Hickner RC, Barakat HA. Ketone body metabolism in lean and obese women. Metabolism: Clinical and Experimental. 2005;54(11):1542-1545. doi: https://doi.org/10.1016/j.metabol.2005.05.023

15. Buffet A, Vezzosi D, Maiza JC, et al. Increased plasma β-hydroxybutyrate levels during the fasting test in patients with endogenous hyperinsulinaemic hypoglycaemia. Eur J Endocrinol. 2013;169(1):91-97. doi: https://doi.org/10.1530/EJE-13-0020

16. Newman JC, Verdin E. β-Hydroxybutyrate: A Signaling Metabolite. Annu Rev Nutr. 2017;37(1):51-76. doi: https://doi.org/10.1146/annurev-nutr-071816-064916

17. Schneider DA, Zare M, Behnia F, et al. Biochemical and Clinical Features of Insulinoma in a Patient with Turner Syndrome. Case Rep Endocrinol. 2019;2019(1):1-4. doi: https://doi.org/10.1155/2019/6809479

18. Wiesli P, Spinas G, Pfammatter T, et al. Glucoseinduced hypoglycaemia. Lancet. 2002;360(9344):1476. doi: https://doi.org/10.1016/S0140-6736(02)11475-9

19. Hermansen K. Stimulatory effect of beta-hydroxybutyrate on the release of somatostatin from the isolated pancreas of normal and streptozotocin-diabetic dogs. Diabetes. 1982;31(3):270-274. doi: https://doi.org/10.2337/diab.31.3.270

20. Zhang Z, Liang X, Tong L, et al. The Metabolite β-Hydroxybutyrate of Lactobacillus Plantarum YZX21 Improves Type 2 Diabetes By Promoting Intestinal Secretion of GLP-1. Preprint. 2021. doi: https://doi.org/10.21203/rs.3.rs-850464/v1

21. Ferrara C, Patel P, Becker S, et al. Biomarkers of Insulin for the Diagnosis of Hyperinsulinemic Hypoglycemia in Infants and Children. J Pediatr. 2016;168:212-219. doi: https://doi.org/10.1016/j.jpeds.2015.09.045

22. de León DD, Stanley CA. Determination of Insulin for the Diagnosis of Hyperinsulinemic Hypoglycemia. Best Pract Res Clin Endocrinol Metab. 2013;27(6):763-769. doi: https://doi.org/10.1016/j.beem.2013.06.005

23. Yukina MY, Nuralieva NF, Troshina EA, et al. Genetically determined causes of hypoglycemic syndrome in adults without diabetes. Med Counc. 2018;168(4):66-73. (In Russ.). doi: https://doi.org/10.21518/2079-701X-2018-4-66-73