Peter F. Malet

Mortality and complications associated with laparoscopic cholecystectomy. A meta-analysis.

OBJECTIVE The purpose of this study was to perform a meta-analysis of large laparoscopic cholecystectomy case-series and compare results concerning complications, particularly bile duct injury, to those reported in open cholecystectomy case-series. SUMMARY BACKGROUND DATA Since the introduction of laparoscopic cholecystectomy in the United States, hundreds of reports about the technique have been published, many including statements about the advantages of laparoscopic cholecystectomy compared with those of open cholecystectomy. There is an unevenness in scope and quality of the studies. Nevertheless, enough data have accumulated from large series to permit analyses of data regarding some of the most important issues. METHODS Articles identified via a MEDLINE (the National Library of Medicines computerized database) search were evaluated according to standard criteria. Data regarding the patient sample, study methods, and outcomes of cholecystectomy were abstracted and summarized across studies. RESULTS Outcomes of laparoscopic cholecystectomy are examined for 78,747 patients reported on in 98 studies and compared with outcomes of open cholecystectomy for 12,973 patients reported on in 28 studies. Laparoscopic cholecystectomy appears to have a higher common bile duct injury rate and a lower mortality rate. Estimated rates of other types of complications after laparoscopic cholecystectomy generally were low. Most conversions followed operative discoveries (e.g., dense adhesions) and were not the result of injury. CONCLUSIONS There is wide variability in the amount and type of data reported within any single study, and patient populations may not be comparable across studies. Except for a higher common bile duct injury rate, laparoscopic cholecystectomy appears to be at least as safe a procedure as that of open cholecystectomy.

Indications for and outcomes of cholecystectomy: a comparison of the pre and postlaparoscopic eras.

PURPOSE Examine changing patient characteristics and surgical outcomes for patients undergoing cholecystectomy at five community hospitals in 1989 and 1993. PROCEDURES In a retrospective chart review, data were gathered regarding gallstone disease severity, type of admission, patient age, number of comorbidities, American Society of Anesthesiologists (ASA) Physical Status Classification, length of stay, and multiple outcomes of surgery. MAIN FINDINGS The volume of nonincidental cholecystectomies increased 26%, from 1611 in 1989 to 2031 in 1993. Nearly all of the increase occurred among patients with uncomplicated cholelithiasis and with elective admissions. In 1993, lengths of stay were significantly shorter and percentages of complications were significantly lower for infectious, cardiac, pulmonary, and gastrointestinal complications when controlling for patient case-mix characteristics. There were more major intraoperative complications (unintended wounds or injuries to the common bile duct, bowel, blood vessel(s), or other organs) in 1993. CONCLUSIONS Different types of patients underwent cholecystectomy in 1993 compared with patients in 1989, which supports the hypothesis of changing thresholds. Statements supporting the safety of cholecystectomy in the laparoscopic era were borne out when controlling for differences in patient characteristics.

The effect of ursodiol on the efficacy and safety of extracorporeal shock-wave lithotripsy of gallstones: The dornier national biliary lithotripsy study

BACKGROUND In the treatment of gallstones with extracorporeal shock-wave lithotripsy, the bile acid ursodiol is administered to dissolve the gallstone fragments. We designed our study to determine the value of administering this agent. METHODS At 10 centers, 600 symptomatic patients with three or fewer radiolucent gallstones 5 to 30 mm in diameter, as visualized by oral cholecystography, were randomly assigned to receive ursodiol or placebo for six months, starting one week before lithotripsy. RESULTS The stones were fragmented in 97 percent of all patients, and the fragments were less than or equal to 5 mm in diameter in 46.8 percent. On the basis of an intention-to-treat analysis of all 600 patients, 21 percent receiving ursodiol and 9 percent receiving placebo (P less than 0.0001) had gallbladders that were free of stones after six months. Among those with completely radiolucent solitary stones less than 20 mm in diameter, 35 percent of the patients receiving ursodiol and 18 percent of those receiving placebo (P less than 0.001) were free of stones after six months. Biliary pain, usually mild, occurred in 73 percent of all patients but in only 13 percent of those who were free of stones after three and six months (P less than 0.01). There were few adverse events. Only diarrhea occurred with a significantly different frequency in the two groups: 32.6 percent were affected in the ursodiol group, as compared with 24.7 percent in the placebo group (P less than 0.04). Severe biliary pain occurred in 1.5 percent of all patients, acute cholecystitis in 1.0 percent, and acute pancreatitis in 1.5 percent; endoscopic sphincterotomy was performed in 0.5 percent, and cholecystectomy in 2.5 percent. CONCLUSIONS Extracorporeal shock-wave lithotripsy with ursodiol was more effective than lithotripsy alone for the treatment of symptomatic gallstones, and equally safe. Treatment was more effective for solitary than multiple stones, radiolucent than slightly calcified stones, and smaller than larger stones.

Ursodiol for Hepatobiliary Disorders

Table. SI Units and Drugs Ursodeoxycholate is a naturally occurring dihydroxy bile salt that comprises approximately 1% of the total bile salt pool in humans [1-3]. It is the 7 -epimer (Figure 1) of chenodeoxycholate, one of the major endogenous bile salts. Although oral administration of either ursodiol (ursodeoxycholic acid) or chenodiol (chenodeoxycholic acid) desaturates bile and contributes to the dissolution of cholesterol gallstones, ursodiol is better tolerated and is associated with fewer adverse effects. Additionally, recent evidence suggests that ursodiol may be an effective therapy in various chronic liver diseases, especially cholestatic disorders such as primary biliary cirrhosis. Figure 1. Biochemical structure of bile acids. left right We describe the pharmacology of ursodiol, explain the rationale for its use in the treatment of patients with cholesterol gallstones and chronic liver diseases, and describe the results obtained in clinical trials of ursodiol therapy. Pharmacology Oral administration of ursodiol (Actigall; Summit Pharmaceuticals, Summit, New Jersey) leads to enrichment of bile in a dose-dependent manner such that, at pharmacologic doses (10 to 15 mg/kg per day), it becomes the predominant biliary bile acid. About 30% to 60% of an oral dose of ursodiol is absorbed, although the percentage absorbed decreases with increasing dose [4, 5]. The proportion of ursodiol in bile plateaus at doses exceeding 10 to 12 mg/kg per day because of epimerization to chenodeoxycholic acid and because ursodiol does not inhibit hepatic synthesis of the primary bile salts [6]. Ursodiol is absorbed along the length of the jejunum and ileum by nonionic passive diffusion and is absorbed in the ileum by active transport mechanisms [4, 7]. Colonic absorption is also substantial and may account for as much as 20% of an ingested dose [8]. Even in patients who have had ileal resections, high oral doses (4 g/d) of ursodiol can increase the biliary concentration of ursodiol tenfold [9]. Once absorbed, ursodiol is efficiently taken up by the liver with first-pass clearance of more than 60% of the absorbed dose [2]. Therefore, in the absence of cholestasis or substantial liver disease, minimal levels of ursodiol appear in plasma [10]. In the liver, ursodiol is conjugated with either glycine or taurine and is rapidly secreted into bile. Peak bile concentrations of ursodiol are seen 1 to 3 hours after an oral dose [4]. Ursodiol excreted from the biliary tract is resorbed through the enterohepatic circulation or is metabolized to insoluble bile salts that are excreted in the feces. The biological half-life of ursodiol is 3.5 to 5.8 days in humans [2]. With discontinuation of the drug, serum and bile levels decline exponentially [10]. Other medications, such as cholestyramine, colestipol, charcoal, sucralfate, and antacids may impair the absorption of ursodiol, thereby decreasing its bioavailability. Cholesterol Gallstones Formation of Cholesterol Gallstones The pathogenesis of cholesterol gallstones involves the failure to maintain cholesterol in solution in the bile [11-16]. Biliary cholesterol is normally solubilized by micelles and unilamellar cholesterol-phospholipid vesicles [11-15]. A prerequisite for the formation of cholesterol gallstones is bile that is supersaturated with cholesterol. In addition to supersaturation, an excess of nucleating factors or a deficiency of antinucleating factors or both lead to nucleation of solid cholesterol crystals [11-13, 17-19]. Gallbladder mucin, free calcium ions, and gallbladder stasis may also contribute to cholesterol crystal nucleation and stone growth [11-13, 15-17]. Bile Salt Therapy for Gallstones Cholecystectomy is the treatment of choice for patients with symptomatic gallstones. For patients at high operative risk and for patients who wish to avoid surgery for personal reasons, the most widely used of the nonsurgical treatments is the bile salt ursodiol. Chenodiol (Chenix; Solvay Pharmaceuticals, Marietta, Georgia) was the first bile salt reported to dissolve gallstones [11, 20-22]. It was extensively evaluated in the 1970s, particularly in the National Cooperative Gallstone Study [23] in which more than 900 patients were randomly assigned to receive placebo, low-dose chenodiol (375 mg/d), or high-dose chenodiol (750 mg/d) for up to 2 years [23]. In the high-dose group, 13.5% complete dissolution was noted, less than the 20% to 40% complete dissolution other investigators [24] achieved with higher doses. The major drawbacks of chenodiol are the dose-related side effects of diarrhea and an increase in serum aminotransferase levels. Chenodiol was not widely prescribed in the United States, and with the introduction of ursodiol in the late 1980s, it is now rarely used as monotherapy. Ursodiol has also been studied as a gallstone dissolution agent [2, 3]. Its safety and ease of administration have made ursodiol the most common therapeutic alternative to cholecystectomy [21, 22, 25]. Ursodiol is also used after shock-wave lithotripsy to dissolve residual stone fragments in the gallbladder [22, 26, 27]. Ursodiol dissolves gallstones by solubilizing cholesterol from the stone surface. Ursodiol results in the conversion of supersaturated bile to unsaturated bile [21]. This desaturation of bile enhances the transport capacity of bile for cholesterol. Ursodiol results in biliary desaturation through several mechanisms, most of which are incompletely understood [21]. Despite somewhat conflicting results, decreased intestinal absorption of cholesterol probably occurs during ursodiol administration [2, 3]. This could be related to less effective micelle formation or to less efficient intestinal absorption from liquid crystals. Ursodiol may also decrease hepatic cholesterol synthesis by decreasing the activity of 3-hydroxy 3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme in cholesterol synthesis [21]. Lastly, there is little, if any, negative feedback inhibition of hepatic bile salt synthesis by ursodiol, such that cholesterol continues to be converted to bile salts [21, 28]. In addition to biliary desaturation, ursodiol also has the unique property of promoting the formation of a liquid crystal mesophase of phospholipid plus cholesterol [21, 29]. Such liquid crystals can form even in the presence of bile that is supersaturated with cholesterol, which probably accounts for the observation that ursodiol may dissolve gallstones in the presence of supersaturated bile. Proper patient selection is critical for optimizing gallstone dissolution with ursodiol. As already noted, cholecystectomy is the treatment of choice for patients with symptomatic gallstones. Patients with mild or infrequent episodes of biliary pain are the most appropriate candidates for ursodiol treatment. Asymptomatic patients with gallstones are not suitable candidates for therapy [30-32]. Ursodiol should not be used in the management of patients with acute gallstone complications, such as acute cholecystitis, bile duct obstruction, cholangitis, or gallstone pancreatitis. Candidates for ursodiol therapy must have radiolucent gallstones and a patent cystic duct [22]. Although dissolution with ursodiol may occur in patients with nonvisualization of the gallbladder as determined by oral cholecystographic techniques, such instances have involved small numbers of patients and have not clearly defined the cause for nonvisualization. Nonvisualization of the gallbladder during the course of ursodiol therapy is, however, associated with a very low dissolution rate [22]. After the initiation of ursodiol therapy in patients with gallstones, the proportion of total biliary bile salts comprised by ursodiol increases within 1 to 2 weeks from 1% to a maximum of approximately 60% [21]. Although doses as low as 3 to 5 mg/kg per day have resulted in gallstone dissolution, the optimal dose is 8 to 10 mg/kg per day. Doses exceeding 10 mg/kg per day do not result in increased dissolution rates [2, 6, 21, 33-36]. Interestingly, with ursodiol therapy, symptoms such as pain, nausea, bloating, and vomiting may improve in some patients before actual gallstone dissolution [37-41]. The decrease in symptoms may be attributed to changes in gallbladder dimensions and to a resultant decrease in the likelihood of gallstones becoming impacted in the cystic duct [42]. Ursodiol leads to a reversible, dose-dependent increase in gallbladder volume within 2 days of starting treatment [42-44]. In addition, ursodiol therapy results in a decrease in gallbladder mucin, perhaps decreasing bile viscosity and improving bile flow [45]. The overall success rate for ursodiol in dissolving gallstones up to 20 mm in diameter ranges from 30% to 50% [2, 6, 33-36]. A meta-analysis of randomized trials with ursodiol [46] found that the dissolution rate was 37% for patients treated with ursodiol at doses of more than 7 mg/kg per day or of more than 500 mg/d for at least 6 months. The mean rate of decrease in gallstone diameter during oral bile salt therapy is 1.0 mm/mo, whereas the median rate is 0.7 mm/mo [47]. The diameter of the stones is a more important determinant of dissolution than is the number of stones; the size of the largest stone is rate-limiting [2, 6, 33-36]. In the meta-analysis by May and colleagues [46], dissolution with ursodiol was observed in 48.5% of patients with stones smaller than 10 mm and in 28.8% of those with larger stones. Factors other than gallstone size have been shown to affect the success of dissolution therapy. Stone buoyancy on oral cholecystography is highly correlated with successful dissolution [33, 35]. About 15% of gallstones are buoyant using oral cholecystographic techniques, and dissolution rates of up to 70% have been achieved with these types of stones [36]. Only cholesterol stones are buoyant, and these stones have a substantially lower content of calcium salts than do nonfloating cholesterol stones [48, 4

Hepatitis C Virus-Specific Immune Responses and Quasi-Species Variability at Baseline Are Associated with Nonresponse to Antiviral Therapy during Advanced Hepatitis C

Pretreatment hepatitis C virus (HCV)-specific lymphoproliferative (LP) responses, neutralizing antibody (NA) responses, intrahepatic cytotoxic T lymphocyte (CTL) responses, and HCV quasi-species (QS) diversity and complexity were examined in patients with advanced hepatic fibrosis (Ishak fibrosis score of > or = 3) and prior nonresponse to interferon (IFN)- alpha therapy who were enrolled in the initial phase of the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis Trial. Positive baseline HCV E1- and/or E2-specific NA responses (P = .01) and higher baseline HCV QS diversity (P = .01) were more commonly found in patients who did not become sustained virologic responders (SVRs) at week 72 (W72) than they were in those who did. No patients with positive results for both the LP and NA assays achieved a sustained virologic response. Multiple logistic regression analysis revealed that, when the presence of cirrhosis, prior ribavirin therapy, genotype 1 infection, log serum HCV RNA level, and receipt of >80% of the prescribed medication were controlled for, a sustained virologic response (W72) was negatively correlated with positive baseline LP assay results (P = .02) and with 1 or more positive assays (LP, NA, or CTL) (P = .02). No differences were noted in baseline intrahepatic CTL activity between SVRs and non-SVRs. Thus, in patients with advanced hepatic fibrosis due to HCV infection, pretreatment HCV-specific immune responses and increased QS variability appear to hinder viral clearance by pegylated IFN- alpha 2a and ribavirin combination therapy.

Portal hypertensive gastropathy in chronic hepatitis C patients with bridging fibrosis and compensated cirrhosis: results from the HALT-C trial.

OBJECTIVES:The clinical significance of portal hypertensive gastropathy (PHG) in patients with compensated liver disease is not well established. The aim of this study was to determine the prevalence and correlates of PHG in a large cohort of patients with chronic hepatitis C virus (HCV) infection and bridging fibrosis/compensated cirrhosis entering the randomized phase of the Hepatitis C Antiviral Long-term Treatment against Cirrhosis trial (HALT-C).METHODS:The presence and severity of PHG in 1,016 HCV patients with no prior history of gastrointestinal bleeding was determined at surveillance endoscopy using the New Italian Endoscopy Club criteria.RESULTS:Overall, 37% of HALT-C patients had PHG with 34% having mild and 3% with severe changes. The mucosal mosaic pattern was identified in 33%, red marks in 15%, and gastric antral vascular ectasia (GAVE) features in only 3%. Independent correlates of PHG included biochemical markers of liver disease severity (lower serum albumin, higher bilirubin), portal hypertension (lower platelet count), insulin resistance (higher glucose), and non-African American race. Independent correlates of GAVE included a history of smoking, nonsteroidal anti-inflammatory drugs (NSAIDs) use within the past year, and higher serum bilirubin and glucose levels. There was a strong positive association between the presence of PHG and esophageal varices ( p < 0.0001).CONCLUSIONS:PHG is associated with the histological and biochemical severity of liver disease in patients with HCV and advanced fibrosis but is mild in most patients. The clinical relevance of these findings will be further explored during the randomized phase of the HALT-C study.

Vitamin A hepatotoxicity: A cautionary note regarding 25,000 IU supplements

Vitamin A hepatotoxicity has been reported at doses exceeding 50,000 IU/day. At 25,000 IU vitamin A per day, although elevated liver enzymes may be seen, hepatotoxicity is rare. We report a case of severe hepatotoxicity associated with the habitual daily ingestion of 25,000 IU of vitamin A bought as an over-the-counter dietary supplement. With the general availability of high-dose supplements and recent literature emphasizing the importance of vitamin A adequacy, the potential for vitamin A hepatotoxicity may increase. Health professionals should remain aware of the potential for vitamin A hepatotoxicity and elicit a vitamin A history in all patients being evaluated for liver dysfunction.

Quantitative infrared spectroscopy of common bile duct gallstones

The aim of this study was to determine the composition of gallstones from the common bile duct of patients from the United States and the relationship of stone type to the time interval after cholecystectomy. We analyzed 56 sets of common bile duct gallstones collected over a 10-yr period using infrared and atomic absorption spectroscopy and chemical methods. Twenty-four sets (43%) of stones were cholesterol stones containing 85.3% cholesterol, 3.2% pigment, 0.6% phosphate, and 1.3% total calcium. Ten sets (18%) were black pigment stones containing 36.5% pigment, 11.4% cholesterol, 7.6% carbonate, 3.0% phosphate, and 6.2% total calcium. Twenty-two sets (39%) were brown pigment stones containing 52.7% pigment, 16.5% calcium palmitate, 10.1% cholesterol, 0.4% phosphate, and 3.4% total calcium. Most of the 26 stones found at the same time as or within several months after cholecystectomy were either cholesterol (69%) or black pigment (19%). In contrast, the majority (59%) of the 22 common duct stones that were diagnosed greater than or equal to 21 mo after cholecystectomy were brown pigment stones. In conclusion, brown pigment stones are a distinct type of pigment stone characterized by their content of substantial amounts of calcium palmitate. They comprise a significant proportion of common duct stones in this series of United States patients, particularly of those found greater than or equal to 21 mo after cholecystectomy.

Associations among clinical, immunological, and viral quasispecies measurements in advanced chronic hepatitis C

The relationships among host immune and viral factors and the severity of liver disease due to hepatitis C virus (HCV) are poorly understood. Previous studies have focused on individual components of the immune response to HCV, often in relatively small numbers of patients. We measured HCV‐specific lymphoproliferation (LP), intrahepatic cytotoxic T lymphocyte (CTL), and neutralizing antibody (NA) responses and HCV quasispecies (QS) diversity and complexity in a large cohort of subjects with advanced liver fibrosis (Ishak stages 3‐6) on entry into the HALT‐C (Hepatitis C Antiviral Long‐term Treatment against Cirrhosis) trial. We correlated LP, CTL, NA, and QS results with clinical characteristics, including serum alanine aminotransferase (ALT), HCV RNA level, HCV genotype, and hepatic histopathology. LP, CTL, and NA responses were detected in 37%, 22%, and 22% of subjects tested, respectively. The only association that was statistically significant was higher mean serum ALT values in patients with detectable HCV‐specific CTL responses (P = .03). In conclusion, immune responses to HCV and viral diversity showed little relationship to clinical or histological features at a single time point in this selected population of patients with advanced chronic hepatitis C for whom prior interferon treatment had failed. (HEPATOLOGY 2005;41:617–625.)

Chemical and Morphologic Characteristics of Cholesterol Gallstones That Failed to Dissolve on Chenodiol

During the National Cooperative Gallstone Study, chenodiol (chenodeoxycholate), 750 or 375 mg/day, resulted in complete gallstone dissolution in only 13.5% and 5.2% of patients, respectively. The purpose of this study was to analyze the composition and morphology of gallstones from patients who underwent cholecystectomy during the National Cooperative Gallstone Study to determine if calcium salts on the gallstone surface could have been responsible for failure of dissolution. Total gallstone calcium content was not different between the treated and placebo groups; however, surface calcium levels were different, being greater than 1.0% in 47.6% of stones from chenodiol-treated patients (n = 63) but in only 16.7% of those from placebo-treated patients (n = 18), p less than 0.02. Pigmented outer rims were found in 52.4% of the stones from the chenodiol-treated group compared with only 16.7% of stones from the placebo group, p less than 0.01. The rim calcium content of 36 stones with pigmented outer rims was 3.7% +/- 1.0%, whereas that of 45 stones with nonpigmented outer rims was only 1.0% +/- 0.3%, p less than 0.01. We conclude that the presence of rings of increased concentrations of calcium salts on the gallstone surface may impair dissolution by chenodiol.