Contrast-enhanced ultrasound for the diagnosis of hepatocellular carcinoma in adults with chronic liver disease.

BACKGROUND: Hepatocellular carcinoma occurs mostly in people with chronic liver disease. Worldwide, it ranks sixth in terms of incidence of cancer, and fourth in terms of cancer-related deaths. Contrast-enhanced ultrasound (CEUS) is used as an add-on test to confirm the presence of focal liver lesions suspected as hepatocellular carcinoma after prior diagnostic tests such as abdominal ultrasound or measurement of alpha-foetoprotein, or both. According to guidelines, a single contrast-enhanced imaging investigation, with either computed tomography (CT) or magnetic resonance imaging (MRI), may show the typical hepatocellular carcinoma hallmarks in people with cirrhosis, which will be sufficient to diagnose hepatocellular carcinoma. However, a significant number of hepatocellular carcinomas show atypical imaging features, and therefore, are missed at imaging. Dynamic CEUS images are obtained similarly to CT and MRI images. CEUS differentiates between arterial and portal venous phases, in which sonographic hepatocellular carcinoma hallmarks, such as arterial hyperenhancement and subsequent washout appearance, are investigated. The advantages of CEUS over CT and MRI include real-time imaging, use of contrast agents that do not contain iodine and are not nephrotoxic, and quick image acquisition. Despite the advantages, the use of CEUS in the diagnostic algorithm for HCC remains controversial, with disagreement on relevant guidelines. There is no clear evidence of the benefit of surveillance programmes in terms of overall survival as the conflicting results can be a consequence of an inaccurate detection, ineffective treatment, or both. Therefore, assessing the diagnostic accuracy of CEUS may clarify whether the absence of benefit could be related to underdiagnosis. Furthermore, an assessment of the accuracy of CEUS for the diagnosis of hepatocellular carcinoma is needed for either diagnosing hepatocellular carcinoma or ruling it out in people with chronic liver disease who are not included in surveillance programmes. OBJECTIVES: 1. To assess the diagnostic accuracy of contrast-enhanced ultrasound (CEUS) for the diagnosis of hepatocellular carcinoma of any size and at any stage in adults with chronic liver disease, in a surveillance programme or in a clinical setting. 2. To assess the diagnostic accuracy of CEUS for the diagnosis of resectable hepatocellular carcinoma in people with chronic liver disease and identify potential sources of heterogeneity in the results. SEARCH METHODS: We used standard, extensive Cochrane search methods. The last date of search was 5 November 2021. SELECTION CRITERIA: We included studies assessing the diagnostic accuracy of CEUS for the diagnosis of hepatocellular carcinoma in adults with chronic liver disease, with cross-sectional designs, using one of the acceptable reference standards, such as pathology of the explanted liver, and histology of resected or biopsied focal liver lesion with at least a six-month follow-up. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods to screen studies, extract data, and assess the risk of bias and applicability concerns, using the QUADAS-2 checklist. We used the bivariate model and provided estimates of summary sensitivity and specificity. We assessed the certainty of the evidence using GRADE. We presented uncertainty-of-the-accuracy estimates using 95% confidence intervals (CIs). MAIN RESULTS: We included 23 studies with 6546 participants. Studies were published between 2001 and 2021. We judged all 23 studies at high-risk of bias in at least one domain, and 13/23 studies at high concern for applicability. Most studies used different reference standards to exclude the presence of the target condition. The time interval between the index test and the reference standard was rarely defined. We also had major concerns on their applicability due to the characteristics of the participants. - CEUS for hepatocellular carcinoma of any size and stage: sensitivity 77.8% (95% CI 69.4% to 84.4%) and specificity 93.8% (95% CI 89.1% to 96.6%) (23 studies, 6546 participants; very low-certainty evidence). - CEUS for resectable hepatocellular carcinoma: sensitivity 77.5% (95% CI 62.9% to 87.6%) and specificity 92.7% (95% CI 86.8% to 96.1%) (13 studies, 1257 participants; low-certainty evidence). The observed heterogeneity in the results remains unexplained. The sensitivity analyses, including only studies with clearly prespecified positivity criteria and only studies in which the reference standard results were interpreted with no knowledge of the results about the index test, showed no differences in the results. AUTHORS' CONCLUSIONS: We found that by using CEUS, as an add-on test following abdominal ultrasound, to diagnose hepatocellular carcinoma of any size and stage, 22% of people with hepatocellular carcinoma would be missed, and 6% of people without hepatocellular carcinoma would unnecessarily undergo further testing or inappropriate treatment. As to resectable hepatocellular carcinoma, we found that 23% of people with resectable hepatocellular carcinoma would incorrectly be unresected, while 8% of people without hepatocellular carcinoma would undergo further inappropriate testing or treatment. The uncertainty resulting from the high risk of bias of the included studies, heterogeneity, and imprecision of the results and concerns on their applicability limit our ability to draw confident conclusions.

Magnetic resonance imaging for the diagnosis of hepatocellular carcinoma in adults with chronic liver disease.

BACKGROUND: Hepatocellular carcinoma occurs mostly in people with chronic liver disease and ranks sixth in terms of global incidence of cancer, and third in terms of cancer deaths. In clinical practice, magnetic resonance imaging (MRI) is used as a second-line diagnostic imaging modality to confirm the presence of focal liver lesions suspected as hepatocellular carcinoma on prior diagnostic test such as abdominal ultrasound or alpha-fetoprotein, or both, either in surveillance programmes or in clinical settings. According to current guidelines, a single contrast-enhanced imaging study (computed tomography (CT) or MRI) showing typical hallmarks of hepatocellular carcinoma in people with cirrhosis is considered valid to diagnose hepatocellular carcinoma. The detection of hepatocellular carcinoma amenable to surgical resection could improve the prognosis. However, a significant number of hepatocellular carcinomas do not show typical hallmarks on imaging modalities, and hepatocellular carcinoma may, therefore, be missed. There is no clear evidence of the benefit of surveillance programmes in terms of overall survival: the conflicting results can be a consequence of inaccurate detection, ineffective treatment, or both. Assessing the diagnostic accuracy of MRI may clarify whether the absence of benefit could be related to underdiagnosis. Furthermore, an assessment of the accuracy of MRI in people with chronic liver disease who are not included in surveillance programmes is needed for either ruling out or diagnosing hepatocellular carcinoma. OBJECTIVES: Primary: to assess the diagnostic accuracy of MRI for the diagnosis of hepatocellular carcinoma of any size and at any stage in adults with chronic liver disease. Secondary: to assess the diagnostic accuracy of MRI for the diagnosis of resectable hepatocellular carcinoma in adults with chronic liver disease, and to identify potential sources of heterogeneity in the results. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Hepato-Biliary Group Diagnostic Test of Accuracy Studies Register, the Cochrane Library, MEDLINE, Embase, and three other databases to 9 November 2021. We manually searched articles retrieved, contacted experts, handsearched abstract books from meetings held during the last 10 years, and searched for literature in OpenGrey (9 November 2021). Further information was requested by e-mails, but no additional information was provided. No data was obtained through correspondence with investigators. We applied no language or document-type restrictions. SELECTION CRITERIA: Studies assessing the diagnostic accuracy of MRI for the diagnosis of hepatocellular carcinoma in adults with chronic liver disease, with cross-sectional designs, using one of the acceptable reference standards, such as pathology of the explanted liver and histology of resected or biopsied focal liver lesion with at least a six-month follow-up. DATA COLLECTION AND ANALYSIS: At least two review authors independently screened studies, extracted data, and assessed the risk of bias and applicability concerns, using the QUADAS-2 checklist. We presented the results of sensitivity and specificity, using paired forest plots, and we tabulated the results. We used a hierarchical meta-analysis model where appropriate. We presented uncertainty of the accuracy estimates using 95% confidence intervals (CIs). We double-checked all data extractions and analyses. MAIN RESULTS: We included 34 studies, with 4841 participants. We judged all studies to be at high risk of bias in at least one domain because most studies used different reference standards, often inappropriate to exclude the presence of the target condition, and the time interval between the index test and the reference standard was rarely defined. Regarding applicability, we judged 15% (5/34) of studies to be at low concern and 85% (29/34) of studies to be at high concern mostly owing to characteristics of the participants, most of whom were on waiting lists for orthotopic liver transplantation, and due to pathology of the explanted liver being the only reference standard. MRI for hepatocellular carcinoma of any size and stage: sensitivity 84.4% (95% CI 80.1% to 87.9%) and specificity 93.8% (95% CI 90.1% to 96.1%) (34 studies, 4841 participants; low-certainty evidence). MRI for resectable hepatocellular carcinoma: sensitivity 84.3% (95% CI 77.6% to 89.3%) and specificity 92.9% (95% CI 88.3% to 95.9%) (16 studies, 2150 participants; low-certainty evidence). The observed heterogeneity in the results remains mostly unexplained. The sensitivity analyses, which included only studies with clearly prespecified positivity criteria and only studies in which the reference standard results were interpreted without knowledge of the results of the index test, showed no variation in the results. AUTHORS' CONCLUSIONS: We found that using MRI as a second-line imaging modality to diagnose hepatocellular carcinoma of any size and stage, 16% of people with hepatocellular carcinoma would be missed, and 6% of people without hepatocellular carcinoma would be unnecessarily treated. For resectable hepatocellular carcinoma, we found that 16% of people with resectable hepatocellular carcinoma would improperly not be resected, while 7% of people without hepatocellular carcinoma would undergo inappropriate surgery. The uncertainty resulting from the high risk of bias in the included studies and concerns regarding their applicability limit our ability to confidently draw conclusions based on our results.

Abdominal ultrasound and alpha-foetoprotein for the diagnosis of hepatocellular carcinoma in adults with chronic liver disease.

BACKGROUND: Hepatocellular carcinoma (HCC) occurs mostly in people with chronic liver disease and ranks sixth in terms of global instances of cancer, and fourth in terms of cancer deaths for men. Despite that abdominal ultrasound (US) is used as an initial test to exclude the presence of focal liver lesions and serum alpha-foetoprotein (AFP) measurement may raise suspicion of HCC occurrence, further testing to confirm diagnosis as well as staging of HCC is required. Current guidelines recommend surveillance programme using US, with or without AFP, to detect HCC in high-risk populations despite the lack of clear benefits on overall survival. Assessing the diagnostic accuracy of US and AFP may clarify whether the absence of benefit in surveillance programmes could be related to under-diagnosis. Therefore, assessment of the accuracy of these two tests for diagnosing HCC in people with chronic liver disease, not included in surveillance programmes, is needed. OBJECTIVES: Primary: the diagnostic accuracy of US and AFP, alone or in combination, for the diagnosis of HCC of any size and at any stage in adults with chronic liver disease, either in a surveillance programme or in a clinical setting. Secondary: to assess the diagnostic accuracy of abdominal US and AFP, alone or in combination, for the diagnosis of resectable HCC; to compare the diagnostic accuracy of the individual tests versus the combination of both tests; to investigate sources of heterogeneity in the results. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Hepato-Biliary Group Diagnostic-Test-Accuracy Studies Register, Cochrane Library, MEDLINE, Embase, LILACS, Science Citation Index Expanded, until 5 June 2020. We applied no language or document-type restrictions. SELECTION CRITERIA: Studies assessing the diagnostic accuracy of US and AFP, independently or in combination, for the diagnosis of HCC in adults with chronic liver disease, with cross-sectional and case-control designs, using one of the acceptable reference standards, such as pathology of the explanted liver, histology of resected or biopsied focal liver lesion, or typical characteristics on computed tomography, or magnetic resonance imaging, all with a six-months follow-up. DATA COLLECTION AND ANALYSIS: We independently screened studies, extracted data, and assessed the risk of bias and applicability concerns, using the QUADAS-2 checklist. We presented the results of sensitivity and specificity, using paired forest-plots, and tabulated the results. We used a hierarchical meta-analysis model where appropriate. We presented uncertainty of the accuracy estimates using 95% confidence intervals (CIs). We double-checked all data extractions and analyses. MAIN RESULTS: We included 373 studies. The index-test was AFP (326 studies, 144,570 participants); US (39 studies, 18,792 participants); and a combination of AFP and US (eight studies, 5454 participants). We judged at high-risk of bias all but one study. Most studies used different reference standards, often inappropriate to exclude the presence of the target condition, and the time-interval between the index test and the reference standard was rarely defined. Most studies with AFP had a case-control design. We also had major concerns for the applicability due to the characteristics of the participants. As the primary studies with AFP used different cut-offs, we performed a meta-analysis using the hierarchical-summary-receiver-operating-characteristic model, then we carried out two meta-analyses including only studies reporting the most used cut-offs: around 20 ng/mL or 200 ng/mL. AFP cut-off 20 ng/mL: for HCC (147 studies) sensitivity 60% (95% CI 58% to 62%), specificity 84% (95% CI 82% to 86%); for resectable HCC (six studies) sensitivity 65% (95% CI 62% to 68%), specificity 80% (95% CI 59% to 91%). AFP cut-off 200 ng/mL: for HCC (56 studies) sensitivity 36% (95% CI 31% to 41%), specificity 99% (95% CI 98% to 99%); for resectable HCC (two studies) one with sensitivity 4% (95% CI 0% to 19%), specificity 100% (95% CI 96% to 100%), and one with sensitivity 8% (95% CI 3% to 18%), specificity 100% (95% CI 97% to 100%). US: for HCC (39 studies) sensitivity 72% (95% CI 63% to 79%), specificity 94% (95% CI 91% to 96%); for resectable HCC (seven studies) sensitivity 53% (95% CI 38% to 67%), specificity 96% (95% CI 94% to 97%). Combination of AFP (cut-off of 20 ng/mL) and US: for HCC (six studies) sensitivity 96% (95% CI 88% to 98%), specificity 85% (95% CI 73% to 93%); for resectable HCC (two studies) one with sensitivity 89% (95% CI 73% to 97%), specificity of 83% (95% CI 76% to 88%), and one with sensitivity 79% (95% CI 54% to 94%), specificity 87% (95% CI 79% to 94%). The observed heterogeneity in the results remains mostly unexplained, and only in part referable to different cut-offs or settings (surveillance programme compared to clinical series). The sensitivity analyses, excluding studies published as abstracts, or with case-control design, showed no variation in the results. We compared the accuracy obtained from studies with AFP (cut-off around 20 ng/mL) and US: a direct comparison in 11 studies (6674 participants) showed a higher sensitivity of US (81%, 95% CI 66% to 90%) versus AFP (64%, 95% CI 56% to 71%) with similar specificity: US 92% (95% CI 83% to 97%) versus AFP 89% (95% CI 79% to 94%). A direct comparison of six studies (5044 participants) showed a higher sensitivity (96%, 95% CI 88% to 98%) of the combination of AFP and US versus US (76%, 95% CI 56% to 89%) with similar specificity: AFP and US 85% (95% CI 73% to 92%) versus US 93% (95% CI 80% to 98%). AUTHORS' CONCLUSIONS: In the clinical pathway for the diagnosis of HCC in adults, AFP and US, singularly or in combination, have the role of triage-tests. We found that using AFP, with 20 ng/mL as a cut-off, about 40% of HCC occurrences would be missed, and with US alone, more than a quarter. The combination of the two tests showed the highest sensitivity and less than 5% of HCC occurrences would be missed with about 15% of false-positive results. The uncertainty resulting from the poor study quality and the heterogeneity of included studies limit our ability to confidently draw conclusions based on our results.

Computed tomography for the diagnosis of hepatocellular carcinoma in adults with chronic liver disease.

BACKGROUND: Hepatocellular carcinoma occurs mostly in people with chronic liver disease and ranks sixth in terms of global incidence of cancer, and fourth in terms of cancer deaths. In clinical practice, computed tomography (CT) is used as a second-line diagnostic imaging modality to confirm the presence of focal liver lesions suspected as hepatocellular carcinoma on prior diagnostic test such as abdominal ultrasound or alpha-foetoprotein, or both, either in surveillance programmes or in clinical settings. According to current guidelines, a single contrast-enhanced imaging study CT or magnetic resonance imaging (MRI) showing typical hallmarks of hepatocellular carcinoma in people with cirrhosis is valid to diagnose hepatocellular carcinoma. However, a significant number of hepatocellular carcinomas do not show typical hallmarks on imaging modalities, and hepatocellular carcinoma is, therefore, missed. There is no clear evidence of the benefit of surveillance programmes in terms of overall survival: the conflicting results can be a consequence of inaccurate detection, ineffective treatment, or both. Assessing the diagnostic accuracy of CT may clarify whether the absence of benefit could be related to underdiagnosis. Furthermore, an assessment of the accuracy of CT in people with chronic liver disease, who are not included in surveillance programmes is needed for either ruling out or diagnosing hepatocellular carcinoma. OBJECTIVES: Primary: to assess the diagnostic accuracy of multidetector, multiphasic contrast-enhanced CT for the diagnosis of hepatocellular carcinoma of any size and at any stage in adults with chronic liver disease, either in a surveillance programme or in a clinical setting. Secondary: to assess the diagnostic accuracy of CT for the diagnosis of resectable hepatocellular carcinoma in adults with chronic liver disease. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Trials Register, Cochrane Hepato-Biliary Diagnostic-Test-Accuracy Studies Register, the Cochrane Library, MEDLINE, Embase, LILACS, Science Citation Index Expanded, and Conference Proceedings Citation Index - Science until 4 May 2021. We applied no language or document-type restrictions. SELECTION CRITERIA: Studies assessing the diagnostic accuracy of CT for the diagnosis of hepatocellular carcinoma in adults with chronic liver disease, with cross-sectional designs, using one of the acceptable reference standards, such as pathology of the explanted liver and histology of resected or biopsied focal liver lesion with at least a six-month follow-up. DATA COLLECTION AND ANALYSIS: At least two review authors independently screened studies, extracted data, and assessed the risk of bias and applicability concerns, using the QUADAS-2 checklist. We presented the results of sensitivity and specificity, using paired forest plots, and tabulated the results. We used a hierarchical meta-analysis model where appropriate. We presented uncertainty of the accuracy estimates using 95% confidence intervals (CIs). We double-checked all data extractions and analyses. MAIN RESULTS: We included 21 studies, with a total of 3101 participants. We judged all studies to be at high risk of bias in at least one domain because most studies used different reference standards, often inappropriate to exclude the presence of the target condition, and the time-interval between the index test and the reference standard was rarely defined. Regarding applicability in the patient selection domain, we judged 14% (3/21) of studies to be at low concern and 86% (18/21) of studies to be at high concern owing to characteristics of the participants who were on waiting lists for orthotopic liver transplantation. CT for hepatocellular carcinoma of any size and stage: sensitivity 77.5% (95% CI 70.9% to 82.9%) and specificity 91.3% (95% CI 86.5% to 94.5%) (21 studies, 3101 participants; low-certainty evidence). CT for resectable hepatocellular carcinoma: sensitivity 71.4% (95% CI 60.3% to 80.4%) and specificity 92.0% (95% CI 86.3% to 95.5%) (10 studies, 1854 participants; low-certainty evidence). In the three studies at low concern for applicability (861 participants), we found sensitivity 76.9% (95% CI 50.8% to 91.5%) and specificity 89.2% (95% CI 57.0% to 98.1%). The observed heterogeneity in the results remains mostly unexplained. The sensitivity analyses, which included only studies with clearly prespecified positivity criteria and only studies in which the reference standard results were interpreted without knowledge of the results of the index test, showed no variation in the results. AUTHORS' CONCLUSIONS: In the clinical pathway for the diagnosis of hepatocellular carcinoma in adults with chronic liver disease, CT has roles as a confirmatory test for hepatocellular carcinoma lesions, and for staging assessment. We found that using CT in detecting hepatocellular carcinoma of any size and stage, 22.5% of people with hepatocellular carcinoma would be missed, and 8.7% of people without hepatocellular carcinoma would be unnecessarily treated. For resectable hepatocellular carcinoma, we found that 28.6% of people with resectable hepatocellular carcinoma would improperly not be resected, while 8% of people without hepatocellular carcinoma would undergo inappropriate surgery. The uncertainty resulting from the high risk of bias in the included studies and concerns regarding their applicability limit our ability to confidently draw conclusions based on our results.

Diclofenac sodium versus ceftazidime for preventing pancreatitis after endoscopic retrograde cholangiopancreatography: a prospective, randomized, controlled trial.

BACKGROUND AND AIMS: We aimed to compare the efficacy of prophylactic, parenterally administered ceftazidime and rectally applied diclofenac sodium for the prophylaxis of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). METHODS: We prospectively enrolled patients who underwent ERCP. In a double-blind, randomized, controlled trial, patients received a suppository containing diclofenac sodium rectally (100 mg) and placebo intravenously (group A) or ceftazidime intravenously (1 g) and placebo rectally (group B) immediately before the procedure. The serum and urine amylase levels were recorded and the patients were clinically evaluated after ERCP. RESULTS: Of the 272 patients enrolled (group A: 129; group B: 143), 32 developed pancreatitis (group A: 11 [8.5 %]; group B: 21 [14.7 %]; P = 0.17; relative risk = 1.72; 95 % confidence interval [CI] = 0.86-3.43). The severity of the pancreatitis or complications did not significantly differ between the groups. A serum amylase level of ≥560 U/L and urine amylase level of ≥1150 U/L indicated a positive likelihood ratio for post-ERCP pancreatitis of ≥10. Moreover, the threshold visual analog scale score of ≤5 for abdominal pain after ERCP had excellent diagnostic potential for predicting the presence or absence of post-ERCP pancreatitis. CONCLUSIONS: The PEP incidence did not differ between the ceftazidime and diclofenac sodium groups. In patients with nonsteroidal anti-inflammatory drug contraindications, antibiotics can be considered a safe alternative to diclofenac sodium for PEP prevention. Moreover, the visual analog scale for abdominal pain has excellent diagnostic value for predicting PEP. CLINICAL TRIALS. GOV NUMBER: NCT 01784445.

Diagnostic Accuracy of Abdominal Ultrasound for Diagnosis of Acute Appendicitis: Systematic Review and Meta-analysis.

BACKGROUND: To determine the diagnostic accuracy of abdominal ultrasound (US) for the diagnosis of acute appendicitis (AA), in terms of sensitivity, specificity and post-test probabilities for positive and negative result. METHODS: A systematic search of MEDLINE, Embase, The Cochrane library and Science Citation Index Expanded from January 1994 to October 2014 was performed. Two authors independently evaluated studies for inclusion, extracted data and performed analyses. The reference standard for evaluation of final diagnosis was pathohistological report on tissue obtained at appendectomy. Summary sensitivity, specificity and post-test probability of AA after positive and negative result of US with corresponding 95% confidence intervals (CI) were calculated. RESULTS: Out of 3306 references identified through electronic searches, 17 reports met the inclusion criteria, with 2841 included participants. The summary sensitivity and specificity of US for diagnosis of AA were 69% (95% CI 59-78%) and 81% (95% CI 73-88%), respectively. At the median pretest probability of AA of 76.4%, the post-test probability for a positive and negative result of US was 92% (95% CI 88-95%) and 55% (95% CI 46-63%), respectively. CONCLUSIONS: Abdominal ultrasound does not seem to have a role in the diagnostic pathway for diagnosis of AA in suspected patients. The summary sensitivity and specificity of US do not exceed that of physical examination. Patients that require additional diagnostic workup should be referred to more sensitive and specific diagnostic procedures, such as computed tomography.

Enteral nutrition formulations for acute pancreatitis.

BACKGROUND: Acute pancreatitis is a common and potentially lethal disease with increasing incidence. Severe cases are characterised by high mortality, and despite improvements in intensive care management, no specific treatment relevantly improves clinical outcomes of the disease. Meta-analyses suggest that enteral nutrition is more effective than conventional treatment consisting of discontinuation of oral intake with use of total parenteral nutrition. However, no systematic review has compared different enteral nutrition formulations for the treatment of patients with acute pancreatitis. OBJECTIVES: To assess the beneficial and harmful effects of different enteral nutrition formulations in patients with acute pancreatitis. SEARCH METHODS: We searched the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group Specialised Register of Clinical Trials, the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 7), MEDLINE (from inception to 20 August 2013), EMBASE (from inception to 2013, week 33) and Science Citation Index-Expanded (from 1990 to August 2013); we conducted full-text searches and applied no restrictions by language or publication status. SELECTION CRITERIA: We considered randomised clinical trials assessing enteral nutrition in patients with acute pancreatitis. We allowed concomitant interventions if they were received equally by all treatment groups within a trial. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and extracted data. We performed the analysis using Review Manager 5 (Review Manager 2013) and both fixed-effect and random-effects models. We expressed results as risk ratios (RRs) for dichotomous data, and as mean differences (MDs) for continuous data, both with 95% confidence intervals (CIs). Analysis was based on an intention-to-treat principle. MAIN RESULTS: We included 15 trials (1376 participants) in this review. We downgraded the quality of evidence for many of our outcomes on the basis of high risk of bias. Low-quality evidence suggests that immunonutrition decreases all-cause mortality (RR 0.49, 95% CI 0.29 to 0.80). The effect of immunonutrition on other outcomes from a subset of the included trials was uncertain. Subgrouping trials by type of enteral nutrition did not explain any variation in effect. We found mainly very low-quality evidence for the effects of probiotics on the main outcomes. One eligible trial in this comparison reported a higher rate of serious adverse events leading to increased organ failure and mortality due to low numbers of events and low risk of bias. When we excluded this study as a post hoc sensitivity analysis, risks of mortality (RR 0.30, 95% CI 0.10 to 0.84), organ failure (RR 0.74, 95% CI 0.59 to 0.92) and local septic complications (RR 0.40, 95% CI 0.22 to 0.72) were lower with probiotics. In one trial assessing immunonutrition with probiotics and fibres, no deaths occurred, but hospital stay was shorter with immunonutrition (MD -5.20 days, 95% CI -8.73 to -1.67). No deaths were reported following semi-elemental enteral nutrition (EN), and the effect on length of hospital stay was small (MD 0.30 days, 95% CI -0.82 to 1.42). Fibre-enriched formulations reduced the number of other local complications (RR 0.52, 95% CI 0.32 to 0.87) and length of hospital stay (MD -9.28 days, 95% CI -13.21 to -5.35) but did not significantly affect all-cause mortality (RR 0.23, 95% CI 0.03 to 1.84) and other outcomes. Very low-quality evidence from the subgroup of trials comparing EN versus no intervention showed a decrease in all-cause mortality with EN (RR 0.50, 95% CI 0.29 to 0.86). AUTHORS' CONCLUSIONS: We found evidence of low or very low quality for the effects of immunonutrition on efficacy and safety outcomes. The role of supplementation of enteral nutrition with potential immunomodulatory agents remains in question, and further research is required in this area. Studies assessing probiotics yielded inconsistent and almost contrary results, especially regarding safety and adverse events, and their findings do not support the routine use of EN enriched with probiotics in routine clinical practice. However, further research should be carried out to try to determine the potential efficacy or harms of probiotics. Lack of trials reporting on other types of EN assessed and lack of firm evidence regarding their effects suggest that additional randomised clinical trials are needed. The quality of evidence for the effects of any kind of EN on mortality was low, and further studies are likely to have an impact on the finding of improved survival with EN versus no nutritional support. Evidence remains insufficient to support the use of a specific EN formulation.

Endoscopic retrograde cholangiopancreatography versus intraoperative cholangiography for diagnosis of common bile duct stones.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) and intraoperative cholangiography (IOC) are tests used in the diagnosis of common bile duct stones in people suspected of having common bile duct stones. There has been no systematic review of the diagnostic accuracy of ERCP and IOC. OBJECTIVES: To determine and compare the accuracy of ERCP and IOC for the diagnosis of common bile duct stones. SEARCH METHODS: We searched MEDLINE, EMBASE, Science Citation Index Expanded, BIOSIS, and Clinicaltrials.gov to September 2012. To identify additional studies, we searched the references of included studies and systematic reviews identified from various databases (Database of Abstracts of Reviews of Effects (DARE)), Health Technology Assessment (HTA), Medion, and ARIF (Aggressive Research Intelligence Facility)). We did not restrict studies based on language or publication status, or whether data were collected prospectively or retrospectively. SELECTION CRITERIA: We included studies that provided the number of true positives, false positives, false negatives, and true negatives for ERCP or IOC. We only accepted studies that confirmed the presence of common bile duct stones by extraction of the stones (irrespective of whether this was done by surgical or endoscopic methods) for a positive test, and absence of common bile duct stones by surgical or endoscopic negative exploration of the common bile duct, or symptom-free follow-up for at least six months for a negative test as the reference standard in people suspected of having common bile duct stones. We included participants with or without prior diagnosis of cholelithiasis; with or without symptoms and complications of common bile duct stones; with or without prior treatment for common bile duct stones; and before or after cholecystectomy. At least two authors screened abstracts and selected studies for inclusion independently. DATA COLLECTION AND ANALYSIS: Two authors independently collected data from each study. We used the bivariate model to summarise the sensitivity and specificity of the tests. MAIN RESULTS: We identified five studies including 318 participants (180 participants with and 138 participants without common bile duct stones) that reported the diagnostic accuracy of ERCP and five studies including 654 participants (125 participants with and 529 participants without common bile duct stones) that reported the diagnostic accuracy of IOC. Most studies included people with symptoms (participants with jaundice or pancreatitis) suspected of having common bile duct stones based on blood tests, ultrasound, or both, prior to the performance of ERCP or IOC. Most studies included participants who had not previously undergone removal of the gallbladder (cholecystectomy). None of the included studies was of high methodological quality as evaluated by the QUADAS-2 tool (quality assessment tool for diagnostic accuracy studies). The sensitivities of ERCP ranged between 0.67 and 0.94 and the specificities ranged between 0.92 and 1.00. For ERCP, the summary sensitivity was 0.83 (95% confidence interval (CI) 0.72 to 0.90) and specificity was 0.99 (95% CI 0.94 to 1.00). The sensitivities of IOC ranged between 0.75 and 1.00 and the specificities ranged between 0.96 and 1.00. For IOC, the summary sensitivity was 0.99 (95% CI 0.83 to 1.00) and specificity was 0.99 (95% CI 0.95 to 1.00). For ERCP, at the median pre-test probability of common bile duct stones of 0.35 estimated from the included studies (i.e., 35% of people suspected of having common bile duct stones were confirmed to have gallstones by the reference standard), the post-test probabilities associated with positive test results was 0.97 (95% CI 0.88 to 0.99) and negative test results was 0.09 (95% CI 0.05 to 0.14). For IOC, at the median pre-test probability of common bile duct stones of 0.35, the post-test probabilities associated with positive test results was 0.98 (95% CI 0.85 to 1.00) and negative test results was 0.01 (95% CI 0.00 to 0.10). There was weak evidence of a difference in sensitivity (P value = 0.05) with IOC showing higher sensitivity than ERCP. There was no evidence of a difference in specificity (P value = 0.7) with both tests having similar specificity. AUTHORS' CONCLUSIONS: Although the sensitivity of IOC appeared to be better than that of ERCP, this finding may be unreliable because none of the studies compared both tests in the same study populations and most of the studies were methodologically flawed. It appears that both tests were fairly accurate in guiding further invasive treatment as most people diagnosed with common bile duct stones by these tests had common bile duct stones. Some people may have common bile duct stones in spite of having a negative ERCP or IOC result. Such people may have to be re-tested if the clinical suspicion of common bile duct stones is very high because of their symptoms or persistently abnormal liver function tests. However, the results should be interpreted with caution given the limited quantity and quality of the evidence.

Ultrasound versus liver function tests for diagnosis of common bile duct stones.

BACKGROUND: Ultrasound and liver function tests (serum bilirubin and serum alkaline phosphatase) are used as screening tests for the diagnosis of common bile duct stones in people suspected of having common bile duct stones. There has been no systematic review of the diagnostic accuracy of ultrasound and liver function tests. OBJECTIVES: To determine and compare the accuracy of ultrasound versus liver function tests for the diagnosis of common bile duct stones. SEARCH METHODS: We searched MEDLINE, EMBASE, Science Citation Index Expanded, BIOSIS, and Clinicaltrials.gov to September 2012. We searched the references of included studies to identify further studies and systematic reviews identified from various databases (Database of Abstracts of Reviews of Effects, Health Technology Assessment, Medion, and ARIF (Aggressive Research Intelligence Facility)). We did not restrict studies based on language or publication status, or whether data were collected prospectively or retrospectively. SELECTION CRITERIA: We included studies that provided the number of true positives, false positives, false negatives, and true negatives for ultrasound, serum bilirubin, or serum alkaline phosphatase. We only accepted studies that confirmed the presence of common bile duct stones by extraction of the stones (irrespective of whether this was done by surgical or endoscopic methods) for a positive test result, and absence of common bile duct stones by surgical or endoscopic negative exploration of the common bile duct, or symptom-free follow-up for at least six months for a negative test result as the reference standard in people suspected of having common bile duct stones. We included participants with or without prior diagnosis of cholelithiasis; with or without symptoms and complications of common bile duct stones, with or without prior treatment for common bile duct stones; and before or after cholecystectomy. At least two authors screened abstracts and selected studies for inclusion independently. DATA COLLECTION AND ANALYSIS: Two authors independently collected data from each study. Where meta-analysis was possible, we used the bivariate model to summarise sensitivity and specificity. MAIN RESULTS: Five studies including 523 participants reported the diagnostic accuracy of ultrasound. One studies (262 participants) compared the accuracy of ultrasound, serum bilirubin and serum alkaline phosphatase in the same participants. All the studies included people with symptoms. One study included only participants without previous cholecystectomy but this information was not available from the remaining studies. All the studies were of poor methodological quality. The sensitivities for ultrasound ranged from 0.32 to 1.00, and the specificities ranged from 0.77 to 0.97. The summary sensitivity was 0.73 (95% CI 0.44 to 0.90) and the specificity was 0.91 (95% CI 0.84 to 0.95). At the median pre-test probability of common bile duct stones of 0.408, the post-test probability (95% CI) associated with positive ultrasound tests was 0.85 (95% CI 0.75 to 0.91), and negative ultrasound tests was 0.17 (95% CI 0.08 to 0.33).The single study of liver function tests reported diagnostic accuracy at two cut-offs for bilirubin (greater than 22.23 µmol/L and greater than twice the normal limit) and two cut-offs for alkaline phosphatase (greater than 125 IU/L and greater than twice the normal limit). This study also assessed ultrasound and reported higher sensitivities for bilirubin and alkaline phosphatase at both cut-offs but the specificities of the markers were higher at only the greater than twice the normal limit cut-off. The sensitivity for ultrasound was 0.32 (95% CI 0.15 to 0.54), bilirubin (cut-off greater than 22.23 µmol/L) was 0.84 (95% CI 0.64 to 0.95), and alkaline phosphatase (cut-off greater than 125 IU/L) was 0.92 (95% CI 0.74 to 0.99). The specificity for ultrasound was 0.95 (95% CI 0.91 to 0.97), bilirubin (cut-off greater than 22.23 µmol/L) was 0.91 (95% CI 0.86 to 0.94), and alkaline phosphatase (cut-off greater than 125 IU/L) was 0.79 (95% CI 0.74 to 0.84). No study reported the diagnostic accuracy of a combination of bilirubin and alkaline phosphatase, or combinations with ultrasound. AUTHORS' CONCLUSIONS: Many people may have common bile duct stones in spite of having a negative ultrasound or liver function test. Such people may have to be re-tested with other modalities if the clinical suspicion of common bile duct stones is very high because of their symptoms. False-positive results are also possible and further non-invasive testing is recommended to confirm common bile duct stones to avoid the risks of invasive testing.It should be noted that these results were based on few studies of poor methodological quality and the results for ultrasound varied considerably between studies. Therefore, the results should be interpreted with caution. Further studies of high methodological quality are necessary to determine the diagnostic accuracy of ultrasound and liver function tests.

Endoscopic ultrasound versus magnetic resonance cholangiopancreatography for common bile duct stones.

BACKGROUND: Endoscopic ultrasound (EUS) and magnetic resonance cholangiopancreatography (MRCP) are tests used in the diagnosis of common bile duct stones in patients suspected of having common bile duct stones prior to undergoing invasive treatment. There has been no systematic review of the accuracy of EUS and MRCP in the diagnosis of common bile duct stones using appropriate reference standards. OBJECTIVES: To determine and compare the accuracy of EUS and MRCP for the diagnosis of common bile duct stones. SEARCH METHODS: We searched MEDLINE, EMBASE, Science Citation Index Expanded, BIOSIS, and Clinicaltrials.gov until September 2012. We searched the references of included studies to identify further studies and of systematic reviews identified from various databases (Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment (HTA), Medion, and ARIF (Aggressive Research Intelligence Facility)). We did not restrict studies based on language or publication status, or whether data were collected prospectively or retrospectively. SELECTION CRITERIA: We included studies that provided the number of true positives, false positives, false negatives, and true negatives for EUS or MRCP. We only accepted studies that confirmed the presence of common bile duct stones by extraction of the stones (irrespective of whether this was done by surgical or endoscopic methods) for a positive test, and absence of common bile duct stones by surgical or endoscopic negative exploration of the common bile duct or symptom free follow-up for at least six months for a negative test, as the reference standard in people suspected of having common bile duct stones. We included participants with or without prior diagnosis of cholelithiasis; with or without symptoms and complications of common bile duct stones, with or without prior treatment for common bile duct stones; and before or after cholecystectomy. At least two authors independently screened abstracts and selected studies for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently collected the data from each study. We used the bivariate model to obtain pooled estimates of sensitivity and specificity. MAIN RESULTS: We included a total of 18 studies involving 2366 participants (976 participants with common bile duct stones and 1390 participants without common bile duct stones). Eleven studies evaluated EUS alone, and five studies evaluated MRCP alone. Two studies evaluated both tests. Most studies included patients who were suspected of having common bile duct stones based on abnormal liver function tests; abnormal transabdominal ultrasound; symptoms such as obstructive jaundice, cholangitis, or pancreatitis; or a combination of the above. The proportion of participants who had undergone cholecystectomy varied across studies. Not one of the studies was of high methodological quality. For EUS, the sensitivities ranged between 0.75 and 1.00 and the specificities ranged between 0.85 and 1.00. The summary sensitivity (95% confidence interval (CI)) and specificity (95% CI) of the 13 studies that evaluated EUS (1537 participants; 686 cases and 851 participants without common bile duct stones) were 0.95 (95% CI 0.91 to 0.97) and 0.97 (95% CI 0.94 to 0.99). For MRCP, the sensitivities ranged between 0.77 and 1.00 and the specificities ranged between 0.73 and 0.99. The summary sensitivity and specificity of the seven studies that evaluated MRCP (996 participants; 361 cases and 635 participants without common bile duct stones) were 0.93 (95% CI 0.87 to 0.96) and 0.96 (95% CI 0.90 to 0.98). There was no evidence of a difference in sensitivity or specificity between EUS and MRCP (P value = 0.5). From the included studies, at the median pre-test probability of common bile duct stones of 41% the post-test probabilities (with 95% CI) associated with positive and negative EUS test results were 0.96 (95% CI 0.92 to 0.98) and 0.03 (95% CI 0.02 to 0.06). At the same pre-test probability, the post-test probabilities associated with positive and negative MRCP test results were 0.94 (95% CI 0.87 to 0.97) and 0.05 (95% CI 0.03 to 0.09). AUTHORS' CONCLUSIONS: Both EUS and MRCP have high diagnostic accuracy for detection of common bile duct stones. People with positive EUS or MRCP should undergo endoscopic or surgical extraction of common bile duct stones and those with negative EUS or MRCP do not need further invasive tests. However, if the symptoms persist, further investigations will be indicated. The two tests are similar in terms of diagnostic accuracy and the choice of which test to use will be informed by availability and contra-indications to each test. However, it should be noted that the results are based on studies of poor methodological quality and so the results should be interpreted with caution. Further studies that are of high methodological quality are necessary to determine the diagnostic accuracy of EUS and MRCP for the diagnosis of common bile duct stones.

Gastrointestinal stromal tumors characteristics in Croatian Northern Adriatic region.

BACKGROUND/AIMS: Gastrointestinal stromal tumors (GISTs) have fairly recently been identified as a new type of tumor, thanks to advances in immunohistochemistry. Aim of our work was to investigate and describe GISTs in our hospital in a 10-year period. METHODOLOGY: Records of patients treated for GIST were analyzed and data describing demographics, comorbidities, primary tumor site, initial symptoms, immunohistochemical characteristics, method of detection and grade of malignancy were shown for each patient. RESULTS: A total of 31 patients were analyzed. There was 54.8% of women and 46.7% of men with GIST. The mean age was 61.9±12.8 years. Predominant symptoms and signs were abdominal pain and anemia, bloody stool or melena, even though a significant portion of patients did not have any, or only mild symptoms. Stomach was the most frequent location of the tumor. CD117 was positive in all but two biopsy specimens. CONCLUSIONS: We observed approximately the same incidence of GISTs as in other published data. However, we reported less asymptomatic cases at the time of diagnosis. Also, we reported more women diagnosed with GIST in our population. Even though many tumors were diagnosed by other methods, immunohistochemistry remains the definitive diagnostic method.

Bile acids for primary sclerosing cholangitis.

BACKGROUND: Primary sclerosing cholangitis is a progressive chronic cholestatic liver disease that usually leads to the development of cirrhosis. Studies evaluating bile acids in the treatment of primary sclerosing cholangitis have shown a potential benefit of their use. However, no influence on patients survival and disease outcome has yet been proven. OBJECTIVES: To assess the beneficial and harmful effects of bile acids for patients with primary sclerosing cholangitis. SEARCH STRATEGY: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Library, MEDLINE, EMBASE and Science Citation Index Expanded generally from inception through to October 2010. SELECTION CRITERIA: Randomised clinical trials comparing any dose of bile acids or duration of treatment versus placebo, no intervention, or another intervention were included irrespective of blinding, language, or publication status. DATA COLLECTION AND ANALYSIS: Two authors extracted data independently. We evaluated the risk of bias of the trials using prespecified domains. We performed the meta-analysis according to the intention-to-treat principle. We presented outcomes as relative risks (RR) or mean differences (MD), both with 95% confidence intervals (CI). MAIN RESULTS: Eight trials evaluated ursodeoxycholic acid versus placebo or no intervention (592 patients). The eight randomised clinical trials have a high risk of bias. Patients were treated for three months to six years (median three years). The dosage of ursodeoxycholic acid used in the trials ranged from low (10 mg/kg body weight/day) to high (28 to 30 mg/kg body weight/day). Ursodeoxycholic acid did not significantly reduce the risk of death (RR 1.00; 95% CI 0.46 to 2.20); treatment failure including liver transplantation, varices, ascites, and encephalopathy (RR 1.22; 95% CI 0.91 to 1.64); liver histological deterioration (RR 0.89; 95% CI 0.45 to 1.74); or liver cholangiographic deterioration (RR 0.60; 95% CI 0.23 to 1.57). Ursodeoxycholic acid significantly improved serum bilirubin (MD -14.6 µmol/litre; 95% CI -18.7 to -10.6), alkaline phosphatases (MD -506 IU/litre; 95% CI -583 to -430), aspartate aminotransferase (MD -46 IU/litre; 95% CI -77 to -16), and gamma-glutamyltranspeptidase (MD -260 IU/litre; 95% CI -315 to -205), but not albumin (MD -0.20 g/litre; 95% CI -1.91 to 1.50). Ursodeoxycholic acid was safe and well tolerated by patients with primary sclerosing cholangitis. AUTHORS' CONCLUSIONS: We did not find enough evidence to support or refute the use of bile acids in the treatment of primary sclerosing cholangitis. However, bile acids seem to lead to a significant improvement in liver biochemistry. Therefore, more randomised trials are needed before any of the bile acids can be recommended for this indication.

Bisphosphonates for osteoporosis in primary biliary cirrhosis.

BACKGROUND: Bisphosphonates are widely used for treatment of postmenopausal osteoporosis. Patients with primary biliary cirrhosis often have osteoporosis - either postmenopausal or secondary to the liver disease. No systematic review or meta-analysis has assessed the effects of bisphosphonates for osteoporosis in patients with primary biliary cirrhosis. OBJECTIVES: To assess the beneficial and harmful effects of bisphosphonates for osteoporosis in primary biliary cirrhosis. SEARCH METHODS: The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS, clinicaltrials.gov, the WHO International Clinical Trials Registry Platform, and full text searches were conducted until November 2011. Manufacturers and authors were contacted for additional studies during the conductance of the review. SELECTION CRITERIA: All randomised clinical trials of bisphosphonates in primary biliary cirrhosis compared with placebo or no intervention, or another bisphosphonate, or any other drug. DATA COLLECTION AND ANALYSIS: Two authors extracted data. RevMan Analysis was used for statistical analysis of dichotomous data with risk ratio (RR) or risk difference (RD) and of continuous data with mean difference (MD) or standardised mean difference (SMD), all with 95% confidence intervals (CI). Methodological components were used to assess risk of systematic errors (bias). Trial sequential analysis was also used to control for random errors (play of chance). MAIN RESULTS: Six trials were included. Three trials with 106 participants, of which two trials with high risk of bias, did not demonstrate significant effects of bisphosphonates (etidronate or alendronate) versus placebo or no intervention regarding mortality (RD 0.00; 95% CI -0.12 to 0.12, I² = 0%), fractures (RR 0.87; 95% CI 0.29 to 2.66, I² = 0%), or adverse events (RR 1.00; 95% CI 0.49 to 2.04). Two trials with 62 participants with high risk of bias compared one bisphosphonate (etidronate or alendronate) versus another (alendronate or ibandronate) and found no significant difference regarding mortality (RD -0.03; 95% CI -0.14 to 0.07, I² = 0%), fractures (RR 0.95; 95% CI 0.18 to 5.06, I² = 0%), or adverse events (RR 1.00; 95% CI 0.49 to 2.04, I² = 0%). Bisphosphonates had no significant effect on liver-related mortality, liver transplantation, or liver-related morbidity compared with placebo or no intervention, or another bisphosphonate. Bisphosphonates had no significant effect on bone mineral density compared with placebo or no intervention, or another bisphosphonate. Bisphosphonates compared with placebo or no intervention seem to decrease the urinary amino telopeptides of collagen I (NTx) concentration (MD -16.93 nmol bone collagen equivalents/mmol creatinine; 95% CI -23.77 to -10.10; 2 trials with 88 patients; I² = 0%) and serum osteocalcin (SMD -0.81; 95% CI -1.22 to -0.39; 3 trials with 100 patients; I² = 34 %) concentration. The former result was supported by trial sequential analysis, but not the latter. Alendronate compared with another bisphosphonate (ibandronate) had no significant effect on serum osteocalcin concentration (MD -3.61 ng/ml, 95% CI -9.41 to 2.18; 2 trials with 47 patients; I² = 82%) in a random-effects meta-analysis, but it significantly decreased serum osteocalcin (MD -4.40 ng/ml, 95% CI -6.75 to -2.05; 2 trials with 47 patients; I² = 82%), the procollagen type I N-terminal propeptide (MD -8.79 ng/ml, 95% CI -15.96 to -1.63; 2 trials with 47 patients; I² = 38%), and NTx concentration (MD -14.07 nmol bone collagen equivalents/mmol creatinine, 95% CI -24.23 to -3.90; 2 trials with 46 patients; I²=0%) in a fixed-effect model. The latter two results were not supported by trial sequential analyses. There was no statistically significant difference in the number of patients having bisphosphonates withdrawn due to adverse events compared with placebo or no intervention (RD -0.04; 95% CI -0.21 to 0.12; 2 trials with 46 patients; I² = 0%), or another bisphosphonate (RR 0.56; 95% CI 0.14 to 2.17; 2 trials with 62 patients; I² = 0%). One trial with 32 participants and with high risk of bias compared etidronate versus sodium fluoride without finding significant difference regarding mortality, fractures, adverse events, or bone mineral density. Etidronate compared with sodium fluoride significantly decreased serum osteocalcin, urinary hydroxyproline, and parathyroid hormone concentration. AUTHORS' CONCLUSIONS: We did not find evidence to support or refute the use of bisphosphonates for patients with primary biliary cirrhosis. The data seem to indicate a possible positive intervention effect of bisphosphonates on decreasing urinary amino telopeptides of collagen I concentration compared with placebo or no intervention with no risk of random error. There is need for more randomised clinical trials assessing the effects of bisphosphonates for osteoporosis on patient-relevant outcomes in primary biliary cirrhosis.

Bile acids for liver-transplanted patients.

BACKGROUND: Liver transplantation has become a widely accepted form of treatment for numerous end-stage liver diseases. Bile acids may decrease allograft rejection after liver transplantation by changing the expression of major histocompatibility complex class molecules in bile duct epithelium and central vein endothelium. OBJECTIVES: To assess the beneficial and harmful effects of bile acids for liver-transplanted patients. SEARCH STRATEGY: We performed searches of The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Expanded to September, 2009. SELECTION CRITERIA: Randomised clinical trials comparing any dose of bile acids or duration of treatment in liver-transplanted patients versus placebo, no intervention, or another intervention. We included randomised clinical trials irrespective of blinding, language, and publication status. DATA COLLECTION AND ANALYSIS: Two review authors extracted and checked data independently. We evaluated the risk of bias of the trials from the method of allocation sequence generation, allocation concealment, blinding, outcome data analysis, outcome data reporting, and other potential sources of bias. We used the intention-to-treat principle to perform meta-analyses and presented the outcomes as relative risks (RR) or mean differences (MD), both with 95% confidence intervals (CI). MAIN RESULTS: The updated search resulted in no new trials meeting the inclusion criteria of this review, thus leaving it to the seven already included randomised trials (six evaluating ursodeoxycholic acid versus placebo or no intervention, and one evaluating tauro-ursodeoxycholic acid versus no intervention) enrolling a total of 335 participants. The administration of bile acids began one day or more after liver transplantation. All patients received the standard triple-drug immunosuppressive regimen (steroids, azathioprine, and cyclosporine or tacrolimus) to suppress the allograft rejection response after liver transplantation. Bile acids compared with placebo or no intervention did not significantly change all-cause mortality (RR 0.85, 95% CI 0.53 to 1.36), mortality related to allograft rejection (RR 0.30, 95% CI 0.01 to 7.12), retransplantation (RR 0.76, 95% CI 0.20 to 2.86), acute cellular rejection, or number of patients with steroid-resistant rejection. Bile acids significantly reduced the number of patients who had chronic rejection in a fixed-effect model but not in a random-effects model meta-analysis. Bile acids were safe and well tolerated by liver-transplanted patients. However, this observation is based on data analysis from three trials with only 187 patients. AUTHORS' CONCLUSIONS: We did not find evidence to support or refute bile acids for liver-transplanted patients. Further randomised trials are necessary before bile acids can be recommended to liver-transplanted patients.

Glucocorticosteroids for primary sclerosing cholangitis.

BACKGROUND: Primary sclerosing cholangitis is a chronic cholestatic disease of intrahepatic and extrahepatic biliary ducts, characterised by chronic periductal inflammation and sclerosis of the ducts, which results in segmental stenoses of bile ducts, cholestasis, fibrosis, and ultimately, liver cirrhosis. Patients with primary sclerosing cholangitis are at higher risk of cholangiocarcinoma as well as of colonic neoplasia, since primary sclerosing cholangitis is associated with inflammatory bowel disease in more than 80% of the patients. Several therapeutic modalities have been proposed for primary sclerosing cholangitis, like ursodeoxycholic acid, glucocorticosteroids, and immunomodulatory agents, but none has been successful in reversing the process of the disease. To date, liver transplantation is the only definite therapeutic solution for patients with advanced primary sclerosing cholangitis with liver cirrhosis. OBJECTIVES: To assess the beneficial and harmful effects of glucocorticosteroids for patients with primary sclerosing cholangitis. SEARCH STRATEGY: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE, EMBASE, and LILACS from their inception until September 2009, as well as reference lists. SELECTION CRITERIA: Randomised clinical trials comparing any dose or duration of glucocorticosteroids versus placebo, no intervention, or other immunosuppressive agents. We included trials irrespective of language, blinding, or publication status. DATA COLLECTION AND ANALYSIS: Authors extracted data independently and assessed the methodological quality by the generation of the allocation sequence, allocation concealment, double blinding, follow-up, incomplete outcome data reporting, selective reporting, baseline imbalance, and early stopping. The results of the meta-analyses were presented as relative risks (RR) or mean difference (MD), both with 95% confidence intervals (CI). The primary outcome measures were mortality and liver-related morbidity. MAIN RESULTS: Two randomised clinical trials were eligible for inclusion. One trial compared biliary lavage with hydrocortisone versus saline in 17 patients. Hydrocortisone tended to increase adverse events (pancreatitis, cholangitis with septicaemia, paranoid ideas, fluid retention) (RR 3.43, 95% CI 0.51 to 22.9) and had no cholangiographic improvement, which led to termination of the trial. The other trial compared budesonide versus prednisone in 18 patients. Patients had statistically significant higher serum bilirubin concentration after treatment with prednisone compared with budesonide (MD 10.4 micromol/litre, 95% CI 1.16 to 19.64 micromol/litre). No other statistically significant effects on clinical or biochemical outcomes were reported on any of the evaluated interventions. AUTHORS' CONCLUSIONS: There is no evidence to support or refute peroral glucocorticosteroids for patients with primary sclerosing cholangitis. The intrabiliary application of corticosteroids via nasobiliary tube seems to induce severe adverse effects.

Methotrexate for primary biliary cirrhosis.

BACKGROUND: Methotrexate has been used to treat patients with primary biliary cirrhosis as it possesses immunosuppressive properties. The previously prepared version of this review from 2005 showed that methotrexate seemed to significantly increase mortality in patients with primary biliary cirrhosis. Since that last review version, follow-up data of the included trials have been published. OBJECTIVES: To assess the beneficial and harmful effects of methotrexate for patients with primary biliary cirrhosis. SEARCH STRATEGY: Randomised clinical trials were identified by searching The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, and EMBASE (from their inception until September 2009). Reference lists were also read through. Authors of trials were contacted. SELECTION CRITERIA: We searched to include randomised clinical trials comparing methotrexate with placebo, no intervention, or another drug irrespective of blinding, language, year of publication, or publication status. DATA COLLECTION AND ANALYSIS: Our primary outcomes were mortality, and mortality or liver transplantation combined. Dichotomous outcomes were reported as relative risks (RR) and hazard ratios (HR) if applicable. Continuous outcomes were reported as mean differences (MD). MAIN RESULTS: Five trials were included. Four trials with 370 patients compared methotrexate with placebo or no intervention (three trials added an equal dose of ursodeoxycholic acid to the intervention groups). The bias risk of these trials was high. We did not find statistically significant effects of methotrexate on mortality (RR 1.32, 95% CI 0.66 to 2.64), mortality or liver transplantation combined, pruritus, fatigue, liver complications, liver biochemistry, liver histology, or adverse events. The pruritus score (MD - 0.17, 95% CI - 0.25 to - 0.09) was significantly lower in patients receiving methotrexate. The prothrombin time was significantly worsened in patients receiving methotrexate (MD 1.60 s, 95% CI 1.18 to 2.02). One trial with 85 patients compared methotrexate with colchicine. The trial had low risk of bias. Methotrexate, when compared to colchicine, did not significantly effect mortality, fatigue, liver biopsy, or adverse events. Methotrexate significantly benefited pruritus score (MD - 0.68, 95% CI - 1.11 to - 0.25), serum alkaline phosphatases (MD - 0.41 U/l, 95% CI - 0.70 to - 0.12), and plasma immunoglobulin M (MD - 0.47 mg/dl, 95% CI - 0.74 to - 0.20) compared with colchicine. Other outcomes showed no statistical difference. AUTHORS' CONCLUSIONS: Methotrexate had no statistically significant effect on mortality in patients with primary biliary cirrhosis nor the need for liver transplantation. Although methotrexate may benefit other outcomes (pruritus score, serum alkaline phosphatase, immunoglobulin M levels), there is no sufficient evidence to support methotrexate for patients with primary biliary cirrhosis.

Acute renal failure due to pericardial tamponade in a 60-year-old male patient.

Acute renal failure (ARF) is still a considerable factor in hospital morbidity and mortality. This clinical condition occurs in up to 25% of critically ill patients. Mortality in these patients varies widely depending on the cause. ARF in the context of a large pericardial effusion and pericardial tamponade has not often been reported. This paper presents a case of life-threatening pericardial tamponade and a consecutive rapid onset of ARF. Successful treatment with pericardiocentesis was performed, which was followed by restitution of renal function.