Severe Coagulation Dysfunction caused by Vitamin K Deficiency in an Elderly Patient.

BACKGROUND: Vitamin K deficiency can lead to severe coagulation dysfunction, which may be dangerous and fatal, especially in patients undergoing surgery. METHODS: We report an 84-year-old male patient with gallstones and cholecystitis who had a severe coagulation disorder without bleeding symptoms after endoscopic papillary balloon dilation for removal of bile duct stones. After vitamin K supplementation, the coagulation dysfunction was corrected the next day. RESULTS: In this case, long-term antibiotic treatment, inadequate diet, and abnormal liver function led to coagulation dysfunction. After vitamin K supplementation, the blood coagulation disorder was corrected and serious consequences were prevented. Significantly elevated coagulation function was considered to be caused by vitamin K deficiency. CONCLUSIONS: This case indicates that coagulation dysfunction caused by vitamin K deficiency may occur within a few days. Laboratory personnel should fully understand the risks of vitamin K deficiency in elderly patients undergoing surgery with severely restricted diet, impaired absorption, and long-term use of cephalosporin anti-inflammatory therapy, and promptly remind clinical doctors.

Inhibition of PCSK9 prevents and alleviates cholesterol gallstones through PPARα-mediated CYP7A1 activation.

BACKGROUND & AIMS: Dysregulated cholesterol metabolism is the major factor responsible for cholesterol gallstones (CGS). Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a critical role in cholesterol homeostasis and its inhibitors secure approval for treating various cholesterol metabolic disorders such as hypercholesterolemia and cardiovascular diseases, but its role in CGS remains unclear. Our study aims to clarify mechanisms by which PCSK9 promotes CGS formation and explore the application of the PCSK9 inhibitor, alirocumab, in preventing and treating CGS. APPROACH & RESULTS: The expressions of PCSK9 were notably increased in CGS patients' serum, bile, and liver tissues compared to those without gallstones. Moreover, among CGS patients, hepatic PCSK9 was positively correlated with hepatic cholesterol and negatively correlated with hepatic bile acids (BAs), suggesting PCSK9 was involved in disrupted hepatic cholesterol metabolism related to CGS. Mechanistically, in vitro experiments demonstrated that inhibition of PCSK9 enhanced nuclear expression of PPARα by diminishing its lysosomal degradation and subsequently activated CYP7A1 transcription. Finally, inhibition of PCSK9 prevented CGS formation and dissolved the existing stones in CGS mice by elevating the conversion of cholesterol into BAs through PPARα-mediated CYP7A1 activation. Additionally, serum PCSK9 level may function as a prognostic signature to evaluate the therapeutic efficacy of PCSK9 inhibitors. CONCLUSIONS: Inhibition of PCSK9 exerts preventive and therapeutic effects on CGS by activating PPARα-mediated CYP7A1 expression and facilitating the conversion of cholesterol into BAs, which highlights the potential of PCSK9 inhibition as a promising candidate for preventing and treating CGS in clinical applications. IMPACT AND IMPLICATIONS: PCSK9 plays a pivotal role in cholesterol metabolism and its inhibitors are approved for clinical use in cardiovascular diseases. Our study observes inhibition of PCSK9 prevents and dissolves CGS by activating PPARα-mediated CYP7A1 expression and facilitating the conversion of cholesterol into BAs. Mechanistically, PCSK9 inhibition enhanced the nuclear expression of PPARα by diminishing its lysosomal degradation and subsequently activated CYP7A1 transcription. Our study sheds light on the new function and mechanism of PCSK9 in CGS, providing a novel preventive and therapeutic target with potential clinical applications.

The gut microbiome predicts response to UDCA/CDCA treatment in gallstone patients: comparison of responders and non-responders.

The treatment of gallbladder (GB) stones depends on condition severity. Ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) are commonly used to treat GB stones, but the factors affecting response rates have not been fully identified. Therefore, we investigated the relationship between response to UDCA/CDCA treatment and changes in the gut microbiomes of patients with GB stones with the intention of identifying gut microbiomes that predict susceptibility to UDCA/CDCA treatment and treatment response. In this preliminary, prospective study, 13 patients with GB stones were treated with UDCA/CDCA for 6 months. Patients were classified into responder and non-responder groups based on treatment outcomes. Gut microbiomes were analyzed by 16S rDNA sequencing. Taxonomic compositions and abundances of bacterial communities were analyzed before and after UDCA/CDCA treatment. Alpha and beta diversities were used to assess similarities between organismal compositions. In addition, PICRUSt2 analysis was conducted to identify gut microbial functional pathways. Thirteen patients completed the treatment; 8 (62%) were assigned to the responder group and the remainder to the non-responder group. Low abundances of the Erysipelotrichi lineage were significantly associated with favorable response to UDCA/CDCA treatment, whereas high abundances of Firmicutes phylum indicated no or poor response. Our results suggest that a low abundance of the Erysipelotrichi lineage is significantly associated with a favorable response to UDCA/CDCA and that a high abundance of Firmicutes phylum is indicative of no or poor response. These findings suggest that some gut microbiomes are susceptible to UDCA/CDCA treatment and could be used to predict treatment response in patients with GB stones.

Discovery and exploration of novel somatostatin receptor subtype 5 (SSTR5) antagonists for the treatment of cholesterol gallstones.

The shortage of cholesterol gallstones treatment intensifies the need to discover of effective small molecule drugs. Clinical follow-up and studies have found that activation of somatostatin receptor subtype 5 (SSTR5) reduce gallbladder contraction and thus increase the risk of cholesterol gallstones, implying that antagonizing SSTR5 may promote gallbladder emptying and reduce the formation of gallstones. Herein, we discovered novel SSTR5 antagonists and firstly investigated its effects on cholesterol gallstone. From loperamide, a reported seed structure with micromole activity, we identified optimal compound 23 as an SSTR5 antagonist exhibiting single-digit nanomolar potency, low hERG inhibition and oral availability. Further in vivo evaluation revealed that 23 significantly promoted gallbladder emptying. Moreover, in a mouse cholesterol gallstone model, 23 (3 mg/kg) effectively reduced the cholesterol gallstones formation, showing better efficacy than the clinical first-line drug UDCA (60 mg/kg), providing a new insight into the development of anti-gallstone drugs.

Ursodeoxycholic acid in the management of symptomatic gallstone disease: systematic review and clinician survey.

BACKGROUND: Symptomatic gallstones are common. Ursodeoxycholic acid (UDCA) is a bile acid that dissolves gallstones. There is increasing interest in UDCA for symptomatic gallstones, particularly in those unfit for surgery. METHOD: A UK clinician survey of use and opinions about UDCA in symptomatic gallstones was performed, assessing clinicians' beliefs and perceptions of UDCA effectiveness. A systematic review was performed in accordance with the PRISMA guidelines. PubMed, MEDLINE, and Embase databases were searched for studies of UDCA for symptomatic gallstones (key terms included 'ursodeoxycholic acid'; 'UDCA'; 'biliary pain'; and 'biliary colic'). Information was assessed by two authors, including bias assessment, with independent review of conflicts. RESULTS: Overall, 102 clinicians completed the survey, and 42 per cent had previous experience of using UDCA. Survey responses demonstrated clinical equipoise surrounding the benefit of UDCA for the management of symptomatic gallstones, with no clear consensus for benefit or non-benefit; however, 95 per cent would start using UDCA if there was a randomized clinical trial (RCT) demonstrating a benefit. Eight studies were included in the review: four RCTs, three prospective studies, and one retrospective study. Seven of eight studies were favourable of UDCA for biliary pain. Outcomes and follow-up times were heterogenous, as well as comparator type, with only four of eight studies comparing with placebo. CONCLUSION: Evidence for UDCA in symptomatic gallstones is scarce and heterogenous. Clinicians currently managing symptomatic gallstone disease are largely unaware of the benefit of UDCA, and there is clinical equipoise surrounding the benefit of UDCA. Level 1 evidence is required by clinicians to support UDCA use in the future.

Klebsiella pneumoniae liver abscess with endophthalmitis in a diabetic man with gallstones.

Invasive liver abscess syndrome (ILAS) is caused by Klebsiella pneumoniae and is typically seen in people from East Asia, often with diabetes and gallstones. ILAS includes metastatic sequelae of the infection, commonly to the eyes. The case described below occurred in a London hospital. The patient's abscess was diagnosed on CT and MRI and he developed endophthalmitis secondary to metastatic spread of the infection. He was treated with intravenous and intravitreal antibiotics and discharged with a plan for vitrectomy and cholecystectomy as an outpatient. We discuss the epidemiology, risk factors, pathogenesis, prognosis and management of this rare condition. There have been a number of recent reports of cases of this nature outside of Asia and we believe greater awareness is required. A high index of suspicion should be held for the potential development of metastases in patients of this demographic presenting with abscesses of this nature.

Oral Administration of Nanoiron Sulfide Supernatant for the Treatment of Gallbladder Stones with Chronic Cholecystitis.

Cholelithiasis with chronic cholecystitis is prevalent and threatens human health. Most cholecystitis caused by bacterial infection or biofilms is accompanied by gallstones in the clinic, making gallbladder removal the only effective solution. Here, we provide a strategy to eliminate gallstone biofilms and dissolve gallstones by oral administration of a supernatant derived from nanoscale iron sulfide (nFeS supernatant). First, by using gallstones obtained from the clinic, we simulated biofilm formation on gallstones and tested the antibacterial activity of a nFeS supernatant in vitro. We found that the supernatant kills bacteria with a 5-log reduction in viability and destroys the biofilm structure. Smashed gallstones coincubated with E. coli biofilms promote gallstone formation, while nFeS supernatant can inhibit this process. Second, by using a murine (C57BL/6) model of cholelithiasis and cholecystitis, we tested the antibacterial efficacy and therapeutic effects of nFeS supernatant on cholelithiasis in vivo. Animal experimental data show that oral administration of nFeS supernatant can reduce 60% of bacteria in the gallbladder and, remarkably, remove gallstones with 2 days of treatment compared with clinical drug combinations (chenodeoxycholid acid and ciprofloxacin). Third, by performing protein abundance analysis of L02 cells and mouse livers, we observed the changes in CYP7a1, HMGCR, and SCP2 expression, indicating that the nFeS supernatant can also regulate cholesterol metabolism to prevent gallstone formation. Finally, hematologic biochemistry analysis and high-throughput sequencing technology show that the nFeS supernatant possesses high biocompatibility. Therefore, our work demonstrates that the nFeS supernatant may be a potential regimen for the treatment of cholelithiasis and cholecystitis by oral administration.

Biliary adverse events in acromegaly during somatostatin receptor ligands: predictors of onset and response to ursodeoxycholic acid treatment.

PURPOSE: Somatostatin receptor ligands (SRL) are the first-line medical treatment for acromegaly. Gallbladder alterations are one of most important SRL side effect, but according to some authors growth hormone hypersecretion itself is a risk factor for gallstones. This single center, longitudinal retrospective study evaluated the incidence and the predictors of biliary adverse events (BAE) in acromegaly during SRL therapy and their response to ursodeoxycholic acid (UDCA). METHODS: 91 acromegaly patients with indication to SRL were enrolled. Evaluations of acromegaly activity (GH, IGF-I, IGF-I/ULN) and metabolic profile were collected before starting treatment, yearly during follow-up and at BAE onset. In patients developing BAE we searched for predictors of UDCA effectiveness. RESULTS: 61.5% of patients developed BAE (58.9% cholelithiasis; 41.1% only sludge). IGF-I and IGF-I/ULN proved to be positive predictor of BAE, which occur about 5 years after SRL starting. None of metabolic markers proved to be associated with BAE. Only five patients (5.5%) underwent cholecystectomy for symptomatic cholelithiasis. 71% of patients started UDCA treatment, achieving regression of BAE in 60% of cases (88% in patients developing only sludge and 30% in patients affected by cholelithiasis, p < 0.001). BMI and obesity were negative predictors of UDCA efficacy. In 50% of the subjects BAE resolved after 36 months of therapy with a lower rate if cholelithiasis was present. CONCLUSION: Biliary stone disease is a frequent SRL adverse event, although it is often symptomless. Ultrasound follow-up mainly in the first 5 years of therapy, early UDCA starting and proper lifestyle represent a valid strategy in their detection and management.

Cholesterol depletion sensitizes gallbladder cancer to cisplatin by impairing DNA damage response.

Gallbladder cancer (GBC) is the common malignancy of the bile tract system with extremely poor clinical outcomes, owing to its metastatic property and intrinsic resistance to the first-line drugs. Although it is well-established that cholesterol abnormity contributes to gallstone formation, a leading risk factor for GBC, the link of cholesterol homeostasis with GBC has not been investigated. The present study systematically examined the genes implicated in cholesterol homeostasis, and revealed altered gene expressions of de novo cholesterol biosynthesis and sterol sulfonation (SULT2B1), reduced bile acid synthesis (CYP7B1 and CYP39A1) and impaired sterol efflux (ABCA1, ABCG5, LCAT, and CETP) in GBC tissues. Suppression of cholesterol biosynthesis by lovastatin inhibited GBC cell proliferation possibly through attenuating the DNA repair process. Further investigation revealed lovastatin sensitized GBC cells to cisplatin-induced apoptosis and suppressed the activation of CHK1, CHK2, and H2AX during DNA damage response. By using chemically distinct statins, HMGCR depletion or supplementing mevalonate, the product of HMGCR, we showed the inhibitory effects on DNA repair process of lovastatin were due to the blockage of the mevalonate pathway. Subcutaneous xenograft mice model suggested lovastatin promoted the therapeutic efficacy of cisplatin, and significantly prolonged the survival times of tumor-bearing mice. Moreover, HMGCR ablation repressed tumor growth in vivo, which can be rescued partially by restored expression of HMGCR, suggesting the on-target effects of lovastatin. Therefore, our study provides the clinical relevance of cholesterol homeostasis with GBC progression, and highlights a novel intervention of combined use of lovastatin and cisplatin for GBC.

Combination treatment with n-3 polyunsaturated fatty acids and ursodeoxycholic acid dissolves cholesterol gallstones in mice.

The increasing prevalence of cholesterol gallstone disease places an economic burden on the healthcare system. To identify novel therapeutics, we assessed the effects of n-3 polyunsaturated fatty acids (PUFA) in combination with UDCA in a mouse model of cholesterol gallstones. Gallstone dissolution, gallbladder wall thickness, mucin gene expression in the gallbladder, and levels of phospholipids, cholesterol, and bile acids in bile and serum were analysed. RNA was extracted from the liver for mRNA sequencing and gene expression profiling. Combination treatment resulted in greater gallstone dissolution compared with the control group, and PUFA and combination treatments reduced the thickness of the gallbladder wall. Expression levels of mucin genes were significantly lower in the UDCA, PUFA, and combination groups. Transcriptome analyses revealed that combination treatment modulated hepatic lipid metabolism. The PUFA and combination groups showed elevated bile phospholipid and bile acid levels and a lower cholesterol saturation index. Combination treatment with PUFA and UDCA dissolves cholesterol gallstones in mice by decreasing mucin production, increasing levels of phospholipids and bile acids in bile, and decreasing cholesterol saturation. Further studies of the therapeutic effects of combination PUFA and UDCA treatment in patients with cholesterol gallstones are warranted.

Non-typhoidal salmonellosis presenting as acute calculus cholecystitis.

Non-typhoidal Salmonella spp.are Gram-negative bacilli, which typically cause a clinical picture of gastroenteritis and, less commonly, patients may become a chronic carrier of the pathogen within their gallbladder. We describe a rare clinical presentation of a non-typhoidal Salmonella spp. infection as acute calculus cholecystitis in an adult patient. Salmonella enterica subsp. Salamae (ST P4271) was grown from cholecystostomy fluid, and the patient subsequently underwent a laparoscopic cholecystectomy that demonstrated a necrotic gallbladder fundus. We advise that microbiological sampling of bile is essential, especially in the context of foreign travel, to detect unusual pathogens as in this case or common pathogens that may have unusual antimicrobial resistance. Given the necrotic gallbladder as in this case, we also advise that early cholecystectomy should be strongly considered in these patients.

Efficacy and safety of a novel topical agent for gallstone dissolution: 2-methoxy-6-methylpyridine.

BACKGROUND: Although methyl-tertiary butyl ether (MTBE) is the only clinical topical agent for gallstone dissolution, its use is limited by its side effects mostly arising from a relatively low boiling point (55 °C). In this study, we developed the gallstone-dissolving compound containing an aromatic moiety, named 2-methoxy-6-methylpyridine (MMP) with higher boiling point (156 °C), and compared its effectiveness and toxicities with MTBE. METHODS: The dissolubility of MTBE and MMP in vitro was determined by placing human gallstones in glass containers with either solvent and, then, measuring their dry weights. Their dissolubility in vivo was determined by comparing the weights of solvent-treated gallstones and control (dimethyl sulfoxide)-treated gallstones, after directly injecting each solvent into the gallbladder in hamster models with cholesterol and pigmented gallstones. RESULTS: In the in vitro dissolution test, MMP demonstrated statistically higher dissolubility than did MTBE for cholesterol and pigmented gallstones (88.2% vs. 65.7%, 50.8% vs. 29.0%, respectively; P < 0.05). In the in vivo experiments, MMP exhibited 59.0% and 54.3% dissolubility for cholesterol and pigmented gallstones, respectively, which were significantly higher than those of MTBE (50.0% and 32.0%, respectively; P < 0.05). The immunohistochemical stains of gallbladder specimens obtained from the MMP-treated hamsters demonstrated that MMP did not significantly increase the expression of cleaved caspase 9 or significantly decrease the expression of proliferation cell nuclear antigen. CONCLUSIONS: This study demonstrated that MMP has better potential than does MTBE in dissolving gallstones, especially pigmented gallstones, while resulting in lesser toxicities.

A novel pathogenic variant of ATP-binding cassette subfamily B member 4 causing gallstones in a young adult.

The low phospholipid-associated cholelithiasis (LPAC) syndrome was reported in European adults with cholelithiasis and a mutation of the ATP-binding cassette subfamily B member 4 (ABCB4). The ABCB4 encodes multidrug resistance 3, which is a phospholipid translocator. Reduced phospholipid transport can lead to the formation of biliary cholesterol stones. Here, we describe a 31-year-old Japanese man diagnosed with recurrent biliary colic. Although he recovered quickly after endoscopic treatment for the most recent presentation, he had a family history of similar problems. His mother had required endoscopic treatment for choledocholithiasis and his maternal aunt had died at age 29 years because of liver failure (etiology unknown). We, therefore, performed genetic analysis, which revealed a heterozygous ABCB4C717S. LPAC syndrome was diagnosed and the patient has received ursodeoxycholic acid for 2 years with no recurrence. The same variant was identified in the patient's mother, who was subsequently found to have a left intrahepatic calculus requiring left-sided lobectomy. She has received ursodeoxycholic acid for 1 year with no recurrence. ABCB4C717S is a novel pathogenic variant, and this is the first patient diagnosed with LPAC syndrome in Japan. We should consider LPAC syndrome in young adults with recurrent cholesterol gallstones to ensure early therapy.

Ursodeoxycholic acid in the prevention of gallstones in patients subjected to Roux-en-Y gastric bypass1.

PURPOSE: To evaluate the contribution of ursodeoxycholic acid (UDCA) in the first 12 months after Roux-en-Y gastric bypass in the prevention of gallstone formation. METHODS: A community-based clinical trial was conducted. A total of 137 patients were included in the study; 69 were treated with UDCA, starting 30 days after the surgery, at a dose of 150 mg twice daily (300 mg/day) over a period of 5 consecutive months (GROUP A), and 68 were control patients (GROUP B). The patients were followed-up, and ultrasonography was performed to determine the presence of gallstones at various times during follow-up. Demographic, anthropometric and comorbid indicators were obtained. The data were subjected to normality tests and evaluated using appropriate tests. RESULTS: Patients did not differ in their baseline characteristics. Of the 69 patients who used UDCA, only one patient developed cholelithiasis (1%), whereas 18 controls (26%) formed gallstones (OR = 24.4, p <0.001). Also, other factors were found not to influence the formation of calculi, such as pre-operative or postoperative hepatic steatosis or diabetes (p = 0.759, 0.468, 0.956). CONCLUSION: The results demonstrated that patients who did not use UDCA showed a 24.4-fold greater probability of developing cholelithiasis.

Clonorchiasis sinensis detected by laparoscopic exploration of biliary tracts in two patients with obstructive jaundice.

BACKGROUND: Hepatic clonorchiasis is one of the most prevalent food-borne parasitic diseases worldwide. Clonorchis sinensis, the pathogen, is the major parasitic trigger contributing to cholangitis, cholelithiasis, and even cholangiocarcinoma. Unfortunately, unspecific clinical manifestations of patients with hepatic clonorchiasis tend to mislead clinicians to neglect or misdiagnose them, following ignorance of appropriate therapy. Our case report may shed light on definite diagnosis of clonorchiasis with concomitant cholelithiasis, methodology for surgical drainage of the parasites, and postoperative anthelmintic therapy. CASE PRESENTATION: Two patients with habit of eating infected raw or undercooked freshwater fish were hospitalized due to right upper quadrant pain and jaundice. Magnetic resonance cholangiopancreatography (MRCP)/computed tomography (CT) detection indicated cholangiolithiasis and cholangiolithiasis with concurrent cholecystolithiasis, respectively. Fecal examinations were both negative for adult worms or eggs of parasites. However, adults of Clonrochis sinensis were detected within hepatobiliary tracts during laparoscopic cholecystectomy. Postoperative drainage and anthelmintic therapy contributed to complete recovery with good prognosis. CONCLUSIONS: Clonorchiasis provokes cholangiolithiasis and cholecystolithiasis. Standardized treatments for these gallstone patients with concomitant clonorchiasis include surgical removal of the calculus, postoperative T tubule drainage and anthelmintic therapy. Serological test or polymerase chain reaction (PCR)-based approaches might be helpful for diagnosis of clonorchiasis when no eggs are found by stool microscopy. Public health promotion on ceasing to eat raw freshwater fish is essential for prevention and control of clonorchiasis.

Ursodeoxycholic Acid for 6 Months After Bariatric Surgery Is Impacting Gallstone Associated Morbidity in Patients with Preoperative Asymptomatic Gallstones.

BACKGROUND: Obesity is a predisponing factor for gallstone formation with a prevalence > 10% in patients undergoing gastric bypass procedure. Although there is a strong recommendation for concomitant cholecystectomy in patients with symptomatic gallstones, the evidence level for patients with asymptomatic gallstones is weak. According to recent literature, up to 21% of asymptomatic gallstones become symptomatic after bariatric surgery. Secondary prophylaxis with ursodeoxycholic acid (UDCA), which is altering the composition and excretion of the bile acid pool, was the objective of this study. METHODS: Retrospective analysis of the patient records of all patients undergoing laparoscopic Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SGx) at our center between January 2007 and October 2017. RESULTS: We enrolled a total of 704 patients with routine preoperative ultrasound. In 61 patients, asymptomatic gallstones were detected and these patients were treated with UDCA for 6 months after bariatric surgery. One patient developed a single episode of symptoms 3 months after SGx, which did not require surgery. One patient developed chronic cholecystitis and underwent cholecystectomy 6 months after SGx. All other patients (n = 59; 96.8%) remained asymptomatic under UDCA therapy. CONCLUSION: UDCA for 6 months after bariatric surgery seems to reduce the incidence of gallstone-associated morbidity when compared to the current literature. Thus, our results call the concept of prophylactic concomitant cholecystectomy in patients with asymptomatic gallstones into question while at the same time paving the way for a future clinical trial.

Ursodeoxycholic acid in the prevention of gallstones in patients subjected to Roux-en-Y gastric bypass

Abstract Purpose: To evaluate the contribution of ursodeoxycholic acid (UDCA) in the first 12 months after Roux-en-Y gastric bypass in the prevention of gallstone formation. Methods: A community-based clinical trial was conducted. A total of 137 patients were included in the study; 69 were treated with UDCA, starting 30 days after the surgery, at a dose of 150 mg twice daily (300 mg/day) over a period of 5 consecutive months (GROUP A), and 68 were control patients (GROUP B). The patients were followed-up, and ultrasonography was performed to determine the presence of gallstones at various times during follow-up. Demographic, anthropometric and comorbid indicators were obtained. The data were subjected to normality tests and evaluated using appropriate tests. Results: Patients did not differ in their baseline characteristics. Of the 69 patients who used UDCA, only one patient developed cholelithiasis (1%), whereas 18 controls (26%) formed gallstones (OR = 24.4, p <0.001). Also, other factors were found not to influence the formation of calculi, such as pre-operative or postoperative hepatic steatosis or diabetes (p = 0.759, 0.468, 0.956). Conclusion: The results demonstrated that patients who did not use UDCA showed a 24.4-fold greater probability of developing cholelithiasis.

[Management of Gallstone].

Gallstones are one of the most common diseases worldwide. Recently, the incidence of gallstones has increased and the pattern of gallstones has changed in Korea. Laparoscopic cholecystectomy is the standard treatment for symptomatic gallstones. Expectant management is considered the most appropriate choice in patients with asymptomatic gallstones. The dissolution of cholesterol gallstones by oral bile acid, such as ursodeoxycholic acid, can be considered in selected patients with gallstones. Although the advent of laparoscopic cholecystectomy has moved interest away from the pharmacologic treatment of gallstones, several promising agents related to various mechanisms are under investigation.

Proteasome inhibition protects against diet-induced gallstone formation through modulation of cholesterol and bile acid homeostasis.

Gallstone disease is one of the most prevalent and costly gastrointestinal disorders worldwide. Gallstones are formed in the biliary system by cholesterol secretions in bile, which result from excess cholesterol, a deficiency in bile salts or a combination of the two. The present study examined the effects of proteasome inhibition on gallstone formation using the proteasome inhibitors bortezomib (BT) and carfilzomib (CF). C57BL/6J mice were fed a lithogenic diet to generate gallstones and injected with BT or CF for 12 weeks. After 12 weeks of the lithogenic diet, 8 out of the 10 mice in the control group had developed gallstones, whereas none of the mice who received proteasome inhibitors had developed gallstones. Notably, the expression of genes associated with cholesterol synthesis (sterol regulatory element­binding protein­2 and 3­hydroxy­3­methylglutaryl­CoA reductase), cholesterol secretion [ATP­binding cassette subfamily G member 5 (ABCG5) and ABCG8] and bile acid synthesis [cytochrome P450 family 7 subfamily A member 1 (Cyp7a1), Cyp7b1, Cyp27a1 and Cyp8b1] was reduced in the livers of mice injected with BT or CF. Cyp7a1 encodes cholesterol 7α­hydroxylase, the rate­limiting enzyme in the synthesis of bile acid from cholesterol. The present study therefore measured the expression levels of transcription factors that are known to inhibit Cyp7a1 expression, namely farnesoid X receptor (FXR), pregnane X receptor (PXR) and small heterodimer partner (SHP). Although FXR, PXR and SHP expression was predicted to increase in the presence of proteasome inhibitors, the expression levels were actually reduced; thus, it was concluded that they were not involved in the proteasome inhibition­induced regulation of Cyp7a1. Further investigation of the mitogen­activated protein kinase and protein kinase A (PKA) signaling pathways in human hepatoma cells revealed that proteasome inhibition­induced c­Jun N­terminal kinase (JNK) phosphorylation reduced CYP7A1 and CYP27A1 expression. In addition, reduced PKA phosphorylation as a result of proteasome inhibition regulated ABCG5 and ABCG8 expression. In conclusion, these findings suggest that proteasome inhibition regulates cholesterol and biliary metabolism via the JNK and PKA pathways, and is a promising therapeutic strategy to prevent gallstone disease.