Gallstone Dissolution Effects of Combination Therapy with n-3 Polyunsaturated Fatty Acids and Ursodeoxycholic Acid: A Randomized, Prospective, Preliminary Clinical Trial
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Background/Aims: Ursodeoxycholic acid (UDCA) is the only well-established and widely used agent for dissolving gallstones. Epidemiological and animal studies have suggested potential therapeutic benefits of n-3 polyunsaturated fatty acids (PUFA) for dissolving cholesterol gallstones. We evaluated whether adding PUFA to UDCA improves gallstone dissolution in patients with cholesterol gallstones. Methods: This randomized, prospective, preliminary clinical trial compared the efficacy and safety of UDCA plus PUFA combination therapy (combination group) with those of UDCA monotherapy (monotherapy group). The inclusion criteria were a gallstone diameter ≤15 mm on ultrasonography, radiolucent stones on plain X-ray, and no to mild symptoms. Gallstone dissolution rates, response rates, and adverse events were evaluated. Results: Of the 59 screened patients, 45 patients completed treatment (24 and 21 in the monotherapy and combination groups, respectively). The gallstone dissolution rate tended to be higher in the combination group than in the monotherapy group (45.7% vs 9.9%, p=0.070). The radiological response rate was also significantly higher in the combination group (90.5% vs 41.7%, p=0.007). In both groups, dissolution and response rates were higher in patients with gallbladder sludge than in those with distinct stones. Four adverse events (two in each group) were observed, none of which were study drug-related or led to drug discontinuation. The incidence of these adverse events was similar in both groups (combination vs monotherapy: 9.5% vs 8.3%, p=0.890). Conclusions: UDCA plus PUFA therapy dissolves cholesterol gallstones more effectively than UDCA monotherapy, without significant complications. Further prospective, large-scale studies of this combination therapy are warranted.
Abstract
Background/Aims: Ursodeoxycholic acid (UDCA) is the only well-established and widely used agent for dissolving gallstones. Epidemiological and animal studies have suggested potential therapeutic benefits of n-3 polyunsaturated fatty acids (PUFA) for dissolving cholesterol gallstones. We evaluated whether adding PUFA to UDCA improves gallstone dissolution in patients with cholesterol gallstones. Methods: This randomized, prospective, preliminary clinical trial compared the efficacy and safety of UDCA plus PUFA combination therapy (combination group) with those of UDCA monotherapy (monotherapy group). The inclusion criteria were a gallstone diameter ≤15 mm on ultrasonography, radiolucent stones on plain X-ray, and no to mild symptoms. Gallstone dissolution rates, response rates, and adverse events were evaluated. Results: Of the 59 screened patients, 45 patients completed treatment (24 and 21 in the monotherapy and combination groups, respectively). The gallstone dissolution rate tended to be higher in the combination group than in the monotherapy group (45.7% vs 9.9%, p=0.070). The radiological response rate was also significantly higher in the combination group (90.5% vs 41.7%, p=0.007). In both groups, dissolution and response rates were higher in patients with gallbladder sludge than in those with distinct stones. Four adverse events (two in each group) were observed, none of which were study drug-related or led to drug discontinuation. The incidence of these adverse events was similar in both groups (combination vs monotherapy: 9.5% vs 8.3%, p=0.890). Conclusions: UDCA plus PUFA therapy dissolves cholesterol gallstones more effectively than UDCA monotherapy, without significant complications. Further prospective, large-scale studies of this combination therapy are warranted.
참고문헌 (48)
- Branch of Biliary Surgery, Chinese Society of Surgery, Chinese Medical Association, "Consensus on the surgical management of benign gallbladder diseases(2021 edition)", Zhonghua Wai Ke Za Zhi, 60, pp.4~9 (2022)
- Scollay JM, "Mortality associated with the treatment of gallstone disease : a 10-year contemporary national experience", World J Surg, 35, pp.643~647 (2011)
- McMahon AJ, "Impact of laparoscopic cholecystectomy : a population-based study", Lancet, 356, pp.1632~1637 (2000)
- Stinton LM, "Epidemiology of gallbladder disease : cholelithiasis and cancer", Gut Liver, 6, pp.172~187 (2012)
- Zheng Y, "Gallstone disease and increased risk of mortality : two large prospective studies in US men and women", J Gastroenterol Hepatol, 33, pp.1925~1931 (2018)
- Su CH, "Relative prevalence of gallstone diseases in Taiwan : a nationwide cooperative study", Dig Dis Sci, 37, pp.764~768 (1992)
- Zhu L, "Prevalence of and risk factors for gallstones in Uighur and Han Chinese", World J Gastroenterol, 20, pp.14942~14949 (2014)
- Tamimi TM, "Increased cholecystectomy rates in Saudi Arabia", Lancet, 336, pp.1235~1237 (1990)
- Jeon CH, "Chronological trends in patients undergoing cholecystectomy in Korea : a nationwide health insurance claims study", Ann Surg Treat Res, 102, pp.205~213 (2022)
- Sabour AF, "Nationwide trends in the use of subtotal cholecystectomy for acute cholecystitis", Surgery, 167, pp.569~574 (2020)
- Kaneta A, "Efficacy of endoscopic gallbladder drainage in patients with acute cholecystitis", BMC Surg, 22, pp.224~ (2022)
- Petroni ML, "Ursodeoxycholic acid alone or with chenodeoxycholic acid for dissolution of cholesterol gallstones : a randomized multicentre trial. The British-Italian Gallstone Study group", Aliment Pharmacol Ther, 15, pp.123~128 (2001)
- Tomida S, "Long-term ursodeoxycholic acid therapy is associated with reduced risk of biliary pain and acute cholecystitis in patients with gallbladder stones : a cohort analysis", Hepatology, 30, pp.6~13 (1999)
- Guarino MP, "Ursodeoxycholic acid improves muscle contractility and inflammation in symptomatic gallbladders with cholesterol gallstones", Gut, 56, pp.815~820 (2007)
- May GR, "Efficacy of bile acid therapy for gallstone dissolution : a meta-analysis of randomized trials", Aliment Pharmacol Ther, 7, pp.139~148 (1993)
- Wang HH, "Effect of ezetimibe on the prevention and dissolution of cholesterol gallstones", Gastroenterology, 134, pp.2101~2110 (2008)
- Lee BJ, "Effects of sphingolipid synthesis inhibition on cholesterol gallstone formation in C57BL", 6J mice, 2010, pp.25, 1105~1110
- Simopoulos AP, "Importance of the ratio of omega-6", omega-3 essential fatty acids : evolutionary aspects, 2003, pp.92, 1~22
- Lee DK, "Can fish oil dissolve gallstones?", J Gastroenterol Hepatol, 27, pp.1649~1651 (2012)
- Kim JK, "N-3 polyunsaturated fatty acid attenuates cholesterol gallstones by suppressing mucin production with a high cholesterol diet in mice", J Gastroenterol Hepatol, 27, pp.1745~1751 (2012)
- Jang SI, "Combination treatment with n-3 polyunsaturated fatty acids and ursodeoxycholic acid dissolves cholesterol gallstones in mice", Sci Rep, 9, pp.12740~ (2019)
- Kiriyama S, "Tokyo Guidelines 2018 : diagnostic criteria and severity grading of acute cholangitis(with videos)", J Hepatobiliary Pancreat Sci, 25, pp.17~30 (2018)
- Yokoe M, "Tokyo Guidelines 2018 : diagnostic criteria and severity grading of acute cholecystitis(with videos)", J Hepatobiliary Pancreat Sci, 25, pp.41~54 (2018)
- Seger D, "Misuse of the Naranjo adverse drug reaction probability scale in toxicology", Clin Toxicol(Phila), 51, pp.461~466 (2013)
- "Common Terminology Criteria for Adverse Events (CTCAE) Version 5" (2020)[URL]
- Guarino MP, "Ursodeoxycholic acid therapy in gallbladder disease, a story not yet completed", World J Gastroenterol, 19, pp.5029~5034 (2013)
- Fromm H, "Comparative efficacy and side effects of ursodeoxycholic and chenodeoxycholic acids in dissolving gallstones : a doubleblind controlled study", Gastroenterology, 85, pp.1257~1264 (1983)
- Erlinger S, "Franco-Belgian cooperative study of ursodeoxycholic acid in the medical dissolution of gallstones : a double-blind, randomized, doseresponse study, and comparison with chenodeoxycholic acid", Hepatology, 4, pp.308~314 (1984)
- Caroli A, "Computed tomography in predicting gall stone solubility : a prospective trial", Gut, 33, pp.698~700 (1992)
- Pereira SP, "Gallstone dissolution with oral bile acid therapy : importance of pretreatment CT scanning and reasons for nonresponse", Dig Dis Sci, 42, pp.1775~1782 (1997)
- Filly RA, "In vitro investigation of gallstone shadowing with ultrasound tomography", J Clin Ultrasound, 7, pp.255~262 (1979)
- Ward A, "Ursodeoxycholic acid : a review of its pharmacological properties and therapeutic efficacy", Drugs, 27, pp.95~131 (1984)
- Xiang Z, "The role of ursodeoxycholic acid in non-alcoholic steatohepatitis : a systematic review", BMC Gastroenterol, 13, pp.140~ (2013)
- Dufour JF, "Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin e in nonalcoholic steatohepatitis", Clin Gastroenterol Hepatol, 4, pp.1537~1543 (2006)
- Pietu F, "Ursodeoxycholic acid with vitamin E in patients with nonalcoholic steatohepatitis : long-term results", Clin Res Hepatol Gastroenterol, 36, pp.146~155 (2012)
- Kris-Etherton PM, "American Heart Association. Omega-3 fatty acids and cardiovascular disease : new recommendations from the American Heart Association", Arterioscler Thromb Vasc Biol, 23, pp.151~152 (2003)
- Siscovick DS, "Omega-3polyunsaturated fatty acid(fish oil)supplementation and the prevention of clinical cardiovascular disease : a science advisory from the American Heart Association", Circulation, 135, pp.e867~e884 (2017)
- Skulas-Ray AC, "Omega-3 fatty acids for the management of hypertriglyceridemia : a science advisory from the American Heart Association", Circulation, 140, pp.e673~e691 (2019)
- Ginty AT, "Short-term supplementation of acute long-chain omega-3 polyunsaturated fatty acids may alter depression status and decrease symptomology among young adults with depression : a preliminary randomized and placebo controlled trial", Psychiatry Res, 229, pp.485~489 (2015)
- Su KP, "Association of use of omega-3polyunsaturated fatty acids with changes in severity of anxiety symptoms : a systematic review and meta-analysis", JAMA Netw Open, 1, pp.e182327~ (2018)
- Liao Y, "Efficacy of omega-3 PUFAs in depression : a meta-analysis", Transl Psychiatry, 9, pp.190~ (2019)
- Dasarathy S, "Double-blind randomized placebo-controlled clinical trial of omega 3 fatty acids for the treatment of diabetic patients with nonalcoholic steatohepatitis", J Clin Gastroenterol, 49, pp.137~144 (2015)
- Alwayn IP, "Omega-3 fatty acid supplementation prevents hepatic steatosis in a murine model of nonalcoholic fatty liver disease", Pediatr Res, 57, pp.445~452 (2005)
- Ministry of Food and Drug Safety (MFDS), "Manual for MFDS notification health functional food", MFDS, ~ (2020)
- Ministry of Food and Drug Safety (MFDS), "Recognition on the functionality of ingredients of the health functional food", MFDS, ~ (2020)
- Shabanzadeh DM, "A prediction rule for risk stratification of incidentally discovered gallstones : results from a large cohort study", Gastroenterology, 150, pp.156~167 (2016)
- Festi D, "Natural history of gallstone disease: expectant management or active treatment? Results from a population-based cohort study", J Gastroenterol Hepatol, 25, pp.719~724 (2010)
- Riall TS, "The risk paradox : use of elective cholecystectomy in older patients is independent of their risk of developing complications", J Am Coll Surg, 220, pp.682~690 (2015)