Biliary Diseases
Laparoscopic Cholecystectomy. Postcholecystectomy Syndrome.
Treatment: Celecoxib and Ursodeoxycholic acid

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Biliary diseases (gallbladder dysfunction, chronic acalculous cholecystitis, chronic calculous cholecystitis, gallstone disease, postcholecystectomy syndrome) are very widespread diseases of the digestive apparatus [1-8].

Currently in the U.S. there are approximately 30 million patients with cholelithiasis, and about 15 million patients recovering from surgery, which is 14.3% of the total population, in Canada – 25.0% (8.7 million), in Chile – 21.6-35.2% ( 4.8 million), in Peru – 14.3% (4.2 million), in South Africa – 10.0% (4.9 million), in Italy – 13.8% (8.3 million), in Sweden – 15.0-50.5% (2.4 million), in Denmark – 8.8-24.0% (about 1.0 million), in Norway – 21.9% (about 1.0 million), in the Great Britain – 7.5-21.7% (9.1 million), in Austria – 25.5% (2.1 million), in Germany – 19.7% (16.1 million), in Poland – 19.5% (7.4 million), in Romania – 10.9% (2.3 million), in France – 15.7% (10.3 million), in Russia – 5.0- 25.0% (20.1 million), in India – 6.1% (74.0 million), in China – 3.5% (47.1 million), in Japan – 3.2% (4.1 million), etc. [10-14]. Cholesterol cholelithiasis is 70-80% of the total number of gallstone disease [10-14].

Early diagnosis and treatment of pathology of biliary system is of great clinical importance because of the transformation of functional disorders of the biliary system in organic pathology - the gallbladder dysfunction → chronic cholecystitis acalculous without biliary sludge → chronic acalculous cholecystitis with biliary sludge → chronic calculous cholecystitis, which occurs as a result violation of colloidal stability of bile and join the inflammatory process [1-9].

Chronic calculous cholecystitis and cholesterol gallstone disease as diseases requiring surgical treatment, considered one of the main problems in gastroenterology. Laparoscopic cholecystectomy is considered the "gold" standard in the treatment of chronic calculous cholecystitis [15-23]. Annually in the U.S. operated by 750,000 patients [10-14], in Germany - 190,000 [10-14], Russia - 160.000 [4].

The absence of the gallbladder leads to functional biliary hypertension and increased hepatic and common bile duct [8, 24-31]. 3-5 years after cholecystectomy increases right and left hepatic ducts equity [8, 24-31].

Functional hypertension in the common bile duct contributes to the appearance of functional and hypertension in Wirsung's pancreatic duct with the development of the phenomena of chronic pancreatitis [8, 24-31]. At the same time period in some patients this is accompanied by the progression of chronic pancreatitis, sphincter of Oddi dysfunction and duodenogastric reflux [8, 24-45].

Duodenogastric reflux of mixture of bile with pancreatic juice promotes atrophic gastritis in the antral part of stomach [8, 24-45].

From 40% to 60% of patients after cholecystectomy dyspeptic suffering from various disorders, from 20% to 40% of pains of different localization [32-45].

Up to 70% of patients after cholecystectomy have chronic effects of "bland" cholestasis, chronic cholestatic hepatitis and chronic compensatory bile acid-dependent apoptosis of hepatocytes [31-36].

Patients undergoing cholecystectomy had an increased prevalence of metabolic risk factors for cardiovascular disease, including type 2 diabetes mellitus, high blood pressure, and high cholesterol levels [46-50].

Part of patients after cholecystectomy with increased concentration of hydrophobic hepatotoxic co-carcinogenic deoxicholic bile acid in serum and/or feces with increased risk of colon cancer [51-60].

For the treatment of biliary sludge and dissolution of cholesterol gallstones is used ursodeoxycholic bile acid [61-64]. When using the ursodeoxycholic bile acid the dissolution efficiency varies from 20% to 70%, the dissolution time is from 6 to 24 months, and the recurrence of cholelithiasis is 10% per annum or 50% within 5 years [61-64].

Absorption and concentration and evacuation function of the gall bladder plays an important role in the physiology of the formation of gallbladder bile. The mechanism of formation of lithogenic gallbladder bile was due to lower absorption and concentration functions of the gallbladder. Reducing the concentration of bile acids in gallbladder bile associated with lower water absorption of the gallbladder mucosa. Increasing the concentration of cholesterol in phospholipid vesicles - a decrease in absorbance phospholipid vesicles [9, 65-70].

Pathogenesis of cholesterol gall stones include the presence of:

1. chronic "bland" intragallbladder cholestasis (reduced absorption, concentration and evacuation function of the gall bladder), contributing to the formation of lithogenic gallbladder bile, and
2. chronic "bland" intrahepatic cholestasis (reduced excretory function of the liver), may influence the formation of lithogenic hepatic bile. These factors contribute to the formation of cholesterol gallstones in the gall bladder [9, 65-70].

Absorption, concentration and evacuation function of the gall bladder plays an important role in the regulation of gallbladder-dependent and gallbladder-independent enterohepatic circulation of bile acids. The gallbladder in humans, accumulating bile acids and excluding them from the enterohepatic circulation, helps reduce the formation of secondary hydrophobic hepatotoxic bile acids (lithocholic and deoxycholic bile acids) and thus protects the liver, gastric mucosa, gallbladder, and colon cancer from exposure to them.

Absorption and concentration and evacuation function of the gallbladder, the functional state of the sphincter of Oddi and anatomical features of the sphincter of Oddi hepatopancreatic ampulla determine development and dominance of a certain type of pathology in each individual patient with biliary tract disease [9, 65-96].

Celecoxib, effectively blocking the inflammation in the gallbladder wall, significantly reduces the risk of cholesterol gallstones [97].

Ursodeoxycholic acid during chronic administration, blocking the inflammation in the gallbladder wall [98-101], dissolving the crystals of monohydrate cholesterol [102-103], reducing the gallbladder bile lithogenicity [104-108], restoring the evacuation function of the gallbladder [109-114], improving accumulative-excretory function of the liver [115-119], increasing blood flow to the liver [120-128] and reducing lithogenicity hepatic bile [115, 117], significantly reduces the risk of biliary sludge in the transformation of cholesterol gallstones [129], the risk of acute calculous cholecystitis and biliary colic [130-131], the risk of acute biliary pancreatitis and recurrent pancreatitis [130-135] in patients with cholelithiasis.

And also, ursodeoxycholic acid during chronic administration, restoring the "passage" of hepatic bile in the gall bladder and reducing the "passage" of hepatic bile into the duodenum, eliminates the mechanism of duodenal-gastric reflux of bile, reduces the risk of bile-reflux gastritis (atrophic antral gastritis) and the appearance of intestinal metaplasia in gastric antral [136-143].

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Patents (Russia)

1. Agent for prophylaxis of stone formation in gallbladder (Salsola collina Pall.): Patent RU 2020947 C1 // Publication Date: 1994.10.15 / Semenov AA, Kuznetsov IG, Syrchina AI, Tjurjumin JaL, Nikiforov SB, Lokheh EV.
2. Medical-prophylaxis agent of cholesterol-regulating action and a method of disease treatment caused cholesterol metabolism damage in organism (Salsola collina Pall.): Patent RU 2043111 C1 // Publication Date: 1995.09.10 / Chupin SP.
3. Method for treating the cases of hypomotor hypokinetic dyskinesia of biliary tract: Patent RU 2105577 C1 // Publication Date: 1998.02.27 / Paltsev AI.
4. Method of treatment of patients with calculous cholecystitis (MTBE): Patent RU 2129026 C1 // Publication Date: 1999.04.20 / Shanturov VA, Tjurjumin JaL, Maltsev AB.
5. Method for rehabilitating patients after cholecystectomy: Patent RU 2221576 C1 // Publication Date: 2004.01.20 / Sidorov VV, Korjukina IP, Tuev AV, Guseva TP, Zavrazhnykh LA, Popova TN, Ovchinnikova SM, Bukina NM, Smirnov VV.
6. Method for setting differential diagnosis of Oddi sphincter dysfunction: Patent RU 2245102 C1 // Publication Date:  2005.01.27 Bull. №3 / Deripaskina AV, Jakovlev AA, Nelasov NJu.
7. Method for predicting functional disorders of Oddi’s sphincter by applying dynamic sonography: Patent RU 2247535 C2 // Publication Date: 2005.03.10 Bull. №7 / Akhmedov VA, Zhukov NA.
8. Method for diagnosis biliary dyskinesia cases: Patent RU 2269292 C2 // Publication Date: 2006.02.10 Bull. №4 / Butov MA, Kuznetsov PS, Shelukhina SV, Eremina JO, Ardatova VB.
9. Method for evaluating functional state of biliary system in patients after cholecystectomy: Patent RU 2283032 C1 // Publication Date: 2006.09.10 Bull. № 25 / Gibadulina IO, Gibadulin NV, Bogoutdinov MS, Grjaznov SV, Tupitsyna TJ.
10. Drug possessing hepatoprotective activity (Salsola collina Pall.): Patent RU 2277925 C2 // Publication Date: 2006.12.20 Bull. № 17 / Semenov A.A., Syrchina A.I., Azhunova T.A., Tolstikhina V.V.
11. Method for treatment of diseases caused and accompanying disturbance in metabolism of bile acids and cholesterol: Patent RU 2294207 C2 // Publication Date: 2007.02.27 Bull. №6 / Ardatskaja MD, Minushkin ON, Maksimov VA, Sazonova II, Maslovskij LV.
12. Differential diagnosis method for distinguishing chronic pancreatitis cases of alcoholic and biliary etiology:   Patent RU 2302003 C1 // Publication Date: 2007.06.27 Bull. №18 / Lazebnik LB, Tsaregorodtseva TM, Vasilev JV, Zhivaeva NS, Vinokurova LV, Serova TI, Lychkova AE.
13. Method for diagnosing chronic pancreatitis of alcoholic etiology:  Patent RU 2320997 C2 // Publication Date: 2008.03.27 Bull. № 9 / Lazebnik LB, Vinokurova LV, Trubitsyna IE, Lychkova AE, Gubina AV.
14. Method of treatment of chronic pancreatitis with stenosis of main Wirsung’s duct: Patent RU 2341203 C1 // Publication Date: 2008.12.20 Bull. № 35 / Pogrebnjakov VJ, Ivanov PA, Likhanov ID, Berditskij AA, Goncharov SA.
15. Method of treatment of chronic cholecystitis exacerbation: Patent RU 2348405 C2 // Publication Date: 2009.03.10 Bull. №7 / Kozlova NM, Tjurjumin JL.
16. Method of determining dyskinesis of gallbladder and Oddi’s sphincter: Patent RU 2369333 C2 // Publication Date: 2009.10.10 Bull. №28 / Il'chenko AA, Maksimov VA, Chernyshev AL, Tarasov KM, Deljukina OV, Orlova JN, Lychkova AE.
17. Method of treating patients with chronic noncalculous cholecystitis and biliary dyskinesia: Patent RU 2387444 C2 // Publication Date: 2010.04.27 Bull. №12 / Safonova SL, Emeljanova EA, Platonova AA.
18. Method of correcting psychovegetative disorders in patients with cholelithiasis after cholecystectomy: Patent RU 2401659 C2 // Publication Date: 2010.10.20 Bull. № 29 / Plotnikova EJ.
19. Method for prediction of developing function-type Oddi’s sphincter dyssynergia following cholecystectomy: Patent RU 2414712 C1 // Publication Date: 2011.03.20 Bull. № 8 / Serova EV, Vinnik JS, Tepljakova OV, Kovaleva OA, Kotlovskij JV.
20. Diagnostic technique for function-type Oddi’s sphincter dyssynergia following cholecystectomy: Patent RU 2416802 C1 // Publication Date: 2011.04.20 Bull. №11 / Serova EV, Vinnik JS, Tepljakova OV.
21. Method of medical rehabilitation of patients after cholecystectomy: Patent RU 2429888 C2 // Publication Date: 2011.09.27 Bull. №27 / Kulikov AG, Sarapulova NJ, Eremeev AV, Ivanova IZ.
22. Method of treating cholelithiasis (MTBE): Patent RU 2437654 C1 // Publication Date: 2011.12.27 Bull. №36 / Sajfutdinov RG.
23. Method of treating and improving quality of life in patients with chronic pancreatitis: Patent RU 2448675 C1 // Publication Date: 2012.04.27 Bull. № 12 / Romanova MM, Babkin AP, Shirjaev OJ, Kharkina DN.

Patents (USA)

1. Method for the treatment of gallstones: PatentUS 4205086 // Publication Date: 1980.05.27 / Babayan V.K.
2. Method for therapeutic use of methyl tertiary-butyl ether (MTBE): Patent US 4758596 // Publication Date: 1988.06.19 / Thistle JL, Allen MJ.
3. Apparatus and method for removing obstructions in bodily organs or cavities: Patent US 4902276 // Publication Date: 1990.02.20 / Zakko S.F.
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5. Therapeutic gallstone dissolution method (MTBE): Patent US 5212202 // Publication Date: 1993.05.18 / Hofmann AF, Schteingart CD.
6. Compositions and methods for treating gastrointestinal hypomotility and associated disorders: Patent US 20070010543 A1 // Publication Date: 2007.01.11 / Ashburn TT.
7. FXR agonists for the treatment of nonalcoholic fatty liver and cholesterol gallstone diseases: Patent US 20090163474 A1 // Publication Date: 2009.06.25 / Zhang S, Harnish D, Evans MJ, Wang J.
8. Method for the treatment of gallstones: Patent US 20090248033 A1 // Publication Date: 2009.10.01 / Forsell P.
9. Use of Ezetimibe in the prevention and treatment of cholesterol gallstones: Patent US 20100016273 A1 // Publication Date: 2010.01.21 / Miquel Poblete JF, Nervi Oddone F, Gigotti Rivera AG, Zanlungo Matsuhiro S.
10. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases: Patent US 20100152118 A1 // Publication Date: 2010.06.17 / Shailubhai K.
11. Farnesoid X receptor agonists: Patent US 8158665 // Publication Date: 2012.04.17 / Caldwell R, Deaton  DN, Mcfadyen RB, Navas III F, Spearing PK.