A new look at the classification of gallstone disease

Given the new diagnostic possibilities using endoultrasonography, the authors propose to supplement the definition of “gall-stone disease” (GSD), i.e. to consider it as a chronic hepatobiliary disease, in which not only stones, but also microcholelithiasis (microcholecysto- and/or microcholedocholithiasis), and biliary sludge are forming in the bile ducts. The article discusses a new draft classification of GSD, diagnostic criteria, and features of the clinical course of different stages of GSD. The therapy with a fixed-dose combination of GA and UDCA has become one of the promising approaches to the treatment of GSD, which reduces the risk of progression and complications of the disease at all its stages, as well as after cholecystectomy. Based on the analysis of available research papers and our own clinical experience, this topical article discusses a new draft classification of GSD based on new diagnostic methods, which is proposed for consideration by surgical and non-surgical specialists. The work presents diagnostic criteria, features of the clinical course of different stages of GSD, and points to the fact that complications such as acute pancreatitis and cholangitis may develop even with stage I GSD. Attention was also being given to the question of incorporating a section on different post-cholecystectomy conditions into the classification of GSD. The article presents the principles of pharmacotherapy for GSD based on the pathogenetic mechanisms by which it develops. The ursodeoxycholic acid is a multi-purpose combination drug, whose effect is potentiated by glycyrrhizic acid added to it. Improvement of the classification of GSD, including its stage I and the post-cholecystectomy condition, is needed to study the features of the clinical picture, prognosis for stone formation and the risks for complications, as well as optimization of disease management.

1. Ivashkin VT, Mayev IV, Baranskaya YeK, Okhlobystin AV, Shulpekova YuO, Trukhmanov AS et al. Gallstone disease diagnosis and treatment: guidelines of the Russian gastroenterological association. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2016;26(3):6–80. (In Russ.) https://doi.org/10.22416/1382-4376-2016-26-3-64-80.

2. EASL Clinical Practice Guidelines on the prevention, diagnosis and treatment of gallstones. J Hepatol. 2016;65(1):146–181. https://doi.org/10.1016/j.jhep.2016.03.005

3. Ильченко АА. Болезни желчного пузыря и желчных путей. 2-е изд., перераб. и доп. М.: МИА; 2011. 880 с. Режим доступа: https://djvu.online/file/e1rPOssLLJk4i.

4. Żorniak M, Sirtl S, Beyer G, Mahajan UM, Bretthauer K, Schirra J et al. Consensus definition of sludge and microlithiasis as a possible cause of pancreatitis. Gut. 2023;72(10):1919–1926. https://doi.org/10.1136/gutjnl-2022-327955.

5. Thevenot A, Bournet B, Otal P, Canevet G, Moreau J, Buscail L. Endoscopic ultrasound and magnetic resonance cholangiopancreatography in patients with idiopathic acute pancreatitis. Dig Dis Sci. 2013;58(8):2361–2368. doi:10.1007/s10620-013-2632-y

6. Quispel R, Schutz HM, Hallensleben ND, Bhalla A, Timmer R, van Hooft JE et al. Do endosonographers agree on the presence of bile duct sludge and the subsequent need for intervention? Endosc Int Open. 2021;9(6):E911–E917. https://doi.org/10.1055/a-1452-8919.

7. Fujita N, Yasuda I, Endo I, Isayama H, Iwashita T, Ueki T et al. Evidence-based clinical practice guidelines for cholelithiasis 2021. J Gastroenterol. 2023;58(9):801–833. https://doi.org/10.1007/s00535-023-02014-6.

8. Meeralam Y, Al-Shammari K, Yaghoobi M. Diagnostic accuracy of EUS compared with MRCP in detecting choledocholithiasis: a meta-analysis of diagnostic test accuracy in head-to-head studies. Gastrointest Endosc. 2017;86(6):986–993. https://doi.org/10.1016/j.gie.2017.06.009.

9. Avalueva EB, Karpenko AK, Serkova MY, Sazhina IV, Bakulin IG, Sitkin SI. Magnetic resonance imaging and other medical imaging techniques in the diagnosis of gallstones. Experimental and Clinical Gastroenterology. 2021;(12):28–34. (In Russ.) https://doi.org/10.31146/1682-8658-ecg-196-12-28-34

10. Cotton PB, Elta GH, Carter CR, Pasricha PJ, Corazziari ES. Rome IV. Gallbladder and Sphincter of Oddi Disorders. Gastroenterology. 2016;150(6):1420–1429. e2. https://doi.org/10.1053/j.gastro.2016.02.033.

11. Minushkin ON, Topchiy TB, Burdina EG, Novozhenova EV, Tugova YE. Biliary slage as a stage of gallstone disease: the successes and difficulties of treatment. Meditsinskiy Sovet. 2020;(21):110–116. (In Russ.) https://doi.org/10.21518/2079-701X2020-21-110-116

12. Bakulin IG, Avalueva EB, Serkova MU, Skvortsova TE, Seliverstov PV, Shevyakov MA, Sitkin SI. Biliary sludge: pathogenesis, etiology and drug therapy. Terapevticheskii Arkhiv. 2021;93(2):179–186. (In Russ.) https://doi.org/10.26442/00403660.2021.02.200638.

13. Авалуева ЕБ, Ситкин СИ, Бакулин ИГ. Желчнокаменная болезнь и билиарный сладж: современные подходы к диагностике, лечению и профилактике. М.: Прима Принт; 2021. 100 с.

14. Wang JY, Wu SD. Ursodeoxycholic Acid for the Treatment of Liver Diseases. In: Liver Pathophysiology: Therapies and Antioxidants. Elsevier; 2017, pp. 767–779. https://doi.org/10.1016/B978-0-12-804274-8.00055-2.

15. Kucheryavyy YA, Cheremushkin SV. Therapeutic efficacy evaluation of the reference drug ursodeoxycholic acid and its analogues in the biliary sludge dissolution: a meta-analysis. Consilium Medicum. 2022;24(12):860–864. https://doi.org/10.26442/20751753.2022.12.201429.

16. Okoro N, Patel A, Goldstein M, Narahari N, Cai Q. Ursodeoxycholic acid treatment for patients with postcholecystectomy pain and bile microlithiasis. Gastrointest Endosc. 2008;68(1):69–74. https://doi.org/10.1016/j.gie.2007.09.046.

17. Reichelson KL, Kondrashina EA, Pazenko EV. Ursodeoxycholic acid effect on the symptoms and life quality of patients with biliary sludge (AURA study). RMJ. 2024;(6):26–30. (In Russ.) Available at: https://www.rmj.ru/articles/gastroenterologiya/Vliyanie_ursodezoksiholevoy_kisloty_na_simptomy_i_kachestvo_ghizni_pacientov_s_biliarnym_sladghem_issledovanie_AURA.

18. Gubergrits NB, Belyaeva NV, Lukashevich GM, Fomenko PG, Borodiy KN. Diagnosis and treatment of patients with biliary sludge causing pancreatitis. Bulletin of the Pancreatologists Club. 2021;(1):69–76. (In Russ.) Available at: https://elibrary.ru/qhsste.

19. Alvisi V, Tralli M, Loponte A, D’Ambrosi A, Pavani F, Ruina M. Ursodeoxycholic acid in the treatment of dyspeptic-painful disorders of biliary origin: report of a controlled multicenter study. Clin Ter. 1982;100(1):21–33. Available at: https://pubmed.ncbi.nlm.nih.gov/6759007.

20. Hempfling W, Dilger K, Beuers U. Systematic review: ursodeoxycholic acid – adverse effects and drug interactions. Aliment Pharmacol Ther. 2003;18(10):963–972. https://doi.org/10.1046/j.1365-2036.2003.01792.x.

21. Realini S, Reiner M, Frigerio G. Treatment of dyspeptic disorders, lithiasis and biliary dyskinesia with ursodeoxycholic acid. Analysis of a controlled multicenter study. Schweiz Med Wochenschr. 1980;110(22):879–880. Available at: https://pubmed.ncbi.nlm.nih.gov/6996086.

22. Selyutina OY, Polyakov NE. Glycyrrhizic acid as a multifunctional drug carrier – From physicochemical properties to biomedical applications: A modern insight on the ancient drug. Int J Pharm. 2019;559:271–279. https://doi.org/10.1016/j.ijpharm.2019.01.047.

23. Mekhtiev SN, Mekhtieva OA, Ibragimova ZM, Ukhova MV, Volnukhin AV. Possibilities of combined therapy in patients with functional biliary sphincter of Oddi disorder. Meditsinskiy Sovet. 2021;(5):102–110. (In Russ.) https://doi.org/10.21518/2079-701X-2021-5-102-110.

24. Nikitin IG, Volnukhin AV. Cholelithiasis: epidemiological data, key aspects of pathogenesis and comorbidity, current therapeutic targets. RMJ. Medical Review. 2020;4(5):290–296. (In Russ.) Available at: https://www.rmj.ru/articles/gastroenterologiya/Ghelchnokamennaya_bolezny_epidemiologicheskie_dannye_klyuchevye_aspekty_patogeneza_i_komorbidnosti_aktualynye_ terapevticheskie_misheni.

25. Okus A, Tanrikulu Y, Gemici K, Alptekin H, Sevinç B. Effectiveness of ursode-oxycholic acid for the treatment of gall bladder stones and sludge in pregnant women. Ann Med Res. 2021;28(3):593–596. https://doi.org/10.5455/annalsmedres.2020.02.111.