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Digestive and Liver Disease : Official... Oct 2023Several ursodeoxycholic acid (UDCA) treatment response definitions have been introduced in primary biliary cholangitis (PBC). However, the lack of a gold standard... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Several ursodeoxycholic acid (UDCA) treatment response definitions have been introduced in primary biliary cholangitis (PBC). However, the lack of a gold standard results in heterogeneity in second-line treatment research and clinical practice.
AIMS
This study aimed to explore which UDCA treatment response endpoint serves as the most accurate predictive model of long-term outcome.
METHODS
A systematic review and meta-analysis of UDCA treatment response endpoints (and corresponding validations) were performed.
RESULTS
Sixteen individual UDCA treatment response endpoints and 96 external validations were found. Barcelona, Paris-1, Paris-2, Rotterdam, Toronto and GLOBE and UK-PBC Risk Scores are currently most robustly validated in external populations. The results show that the continuous models (GLOBE and UK-PBC Risk Scores) serve as the most accurate predictive models. Besides standard UDCA treatment response endpoints, the alkaline phosphatase and total bilirubin normalization has been suggested as a new therapeutic target.
CONCLUSIONS
The GLOBE and UK-PBC Risk Scores are the most suitable for the real-world allocation of second-line therapies (obeticholic acid and fibrates). However, in the wake of the recent findings, alkaline phosphatase and total bilirubin normalization should be the primary outcome in trial research in PBC.
Topics: Humans; Ursodeoxycholic Acid; Liver Cirrhosis, Biliary; Cholagogues and Choleretics; Alkaline Phosphatase; Treatment Outcome; Bilirubin; Cholangitis
PubMed: 36593158
DOI: 10.1016/j.dld.2022.12.010 -
Clinics and Research in Hepatology and... May 2021Currently, there is no pharmacotherapy for non-alcoholic steatohepatitis (NASH), a common liver disorder. In contrast, primary biliary cholangitis (PBC) is a chronic... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND AIMS
Currently, there is no pharmacotherapy for non-alcoholic steatohepatitis (NASH), a common liver disorder. In contrast, primary biliary cholangitis (PBC) is a chronic cholestatic liver disease for which ursodeoxycholic acid (UDCA) is the drug of choice. However, 50% of PBC patients may not respond to UDCA. Obeticholic acid (OCA) is emerging as a vital pharmacotherapy for these chronic disorders. We aimed to analyse the safety and efficacy of OCA.
METHODS
We performed an extensive search of electronic databases from 01/01/2000 to 31/03/2020. We included randomized controlled trials of OCA in patients with NASH, PBC, and primary sclerosing cholangitis (PSC). We assessed the histological improvement in NASH, reduction in alkaline phosphatase (≤1.67 ULN) in PBC, and the adverse effects of OCA.
RESULTS
Seven RCTs (n = 2834) were included. Of the total RCTs, there were three on both NASH and PBC and one on PSC. OCA improved NASH fibrosis [OR: 1.95 (1.47-2.59; p < 0.001)]. With the 10 mg OCA dose, the odds of improvement was 1.61 (1.03-2.51; p = 0.03), while with the 25 mg dose, it was 2.23 (1.55-3.18; p < 0.001). However, 25 mg OCA led to significant adverse events and discontinuation of the drug [2.8 (1.42-3.02); p < 0.001)] compared with 10 mg OCA [0.95 (0.6-1.5); p = 0.84] in NASH patients. In PBC patients, the response to 5 mg OCA was better than with the higher doses [5 mg: 7.66 (3.12-18.81; p < 0.001), 10 mg: 5.18 (2-13.41; p = 0.001), 25 mg: 2.36 (0.94-5.93; p = 0.06), 50 mg: 4.08 (1.05-15.78; p = 0.04)]. The risk of pruritus was lowest with 5 mg OCA.
CONCLUSIONS
Lower doses of OCA are effective and safe in NASH and cholestatic liver disease. While 10 mg OCA is effective for NASH fibrosis regression, only 5 mg OCA is required for PBC.
Topics: Chenodeoxycholic Acid; Cholestasis; Humans; Liver Cirrhosis, Biliary; Non-alcoholic Fatty Liver Disease; Pharmaceutical Preparations; Ursodeoxycholic Acid
PubMed: 33722778
DOI: 10.1016/j.clinre.2021.101675 -
Medicine Feb 2024Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NASH) is one of the primary causes of chronic liver disease worldwide. Obeticholic acid (OCA), a potent... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND AIMS
Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NASH) is one of the primary causes of chronic liver disease worldwide. Obeticholic acid (OCA), a potent farnesoid X nuclear receptor activator, has shown promise for treating NASH-related fibrosis due to its anti-fibrotic effects. This study aimed to examine the efficacy of OCA for patients with NASH as well as to investigate its impact on dyslipidemia.
METHOD
A search of databases including PubMed, Embase, and Cochrane Library from January 1, 2010, to November 1, 2022, was conducted to identify systematic reviews of randomized controlled trials involving NASH patients. Inclusion criteria comprised randomized controlled trials that specifically addressed NASH as diagnosed through magnetic resonance imaging, computed tomography, or histology. The results were then categorized, with consideration given to both biochemical and histological outcomes.
RESULT
Five NASH studies were ultimately selected for further analysis. In terms of biochemical indicators, patients receiving OCA treatment showed improvements in alanine transaminase (mean difference: -19.48, 95% confidence interval [CI]: -24.39 to 14.58; P < .05) and aspartate aminotransferase (mean difference: -9.22, 95% CI: -12.70 to 5.74; P < .05). As for histological improvement, OCA treatment reduced fibrosis (odds ratio [OR]: 1.95, 95% CI: 1.47-2.59; P = .001) and steatosis (OR: 1.95, 95% CI: 1.47-2.59; P = .001). No significant differences were observed regarding adverse events (1.44, 95% CI: 0.57-3.62; P > .001). Regarding dyslipidemia, mean differences between total cholesterol and low-density lipoprotein were found to be high (0.33, 95% CI: 0.01-0.64, P < .05; 0.39, 95% CI: 0.04-0.73, P < .05). In the case of pruritus, OCA achieved a high OR (3.22, 95% CI: 2.22-4.74) compared with placebo.
CONCLUSION
OCA also reduced several liver test markers compared to placebo, including the biochemical indicators alanine transaminase, aspartate aminotransferase, alkaline phosphatase, and γ-glutamyl transpeptidase, and improved hepatocellular ballooning, fibrosis, steatosis, and lobular inflammation. Although the incidence of adverse events did not significantly differ between OCA and placebo groups among NASH patients, OCA treatment was found to elevate total cholesterol and low-density lipoprotein levels, and the reported severity of pruritus increased with higher doses of OCA.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Alanine Transaminase; Randomized Controlled Trials as Topic; Chenodeoxycholic Acid; Fibrosis; Lipoproteins, LDL; Dyslipidemias; Pruritus; Aspartate Aminotransferases; Cholesterol
PubMed: 38363900
DOI: 10.1097/MD.0000000000037271 -
Nutrition (Burbank, Los Angeles County,... Feb 2016The aim of this study was to systematically review the association of conjugated linoleic acid (CLA) consumption in two forms of foods enriched or supplemented with CLA... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
The aim of this study was to systematically review the association of conjugated linoleic acid (CLA) consumption in two forms of foods enriched or supplemented with CLA on serum liver enzymes in human studies.
METHODS
We searched PubMed, Google Scholar, Cochrane Library, ScienceDirect, ProQuest, and Ovid up to January 2015. Studies that examined the effect of CLA supplementation or foods enriched with CLA on liver enzymes concentrations among healthy adults were included. The mean difference and SD of changes in serum liver enzymes between the intervention and control groups were used as effect size for the meta-analysis.
RESULTS
The analysis demonstrated that CLA supplementation led to slight and nonsignificant decreases in alkaline phosphatase (ALP) levels (mean difference [MD] -0.216; 95% confidence interval [CI], -0.60 to 0.17; P = 0.28). CLA intake can nonsignificantly increase alanine transaminase (ALT) levels (MD = 0.107 U/L; 95% CI, -0.29 to 0.244; P = 0.124) and can significantly increase aspartate aminotransferase (AST) levels (MD = 0.171 U/L; 95% CI, 0.034-0.307; P = 0.01). Subgroup analysis based on CLA source showed that CLA supplementation or foods enriched with CLA did not significantly alter ALT levels. Subgroup analysis showed that CLA supplementation led to significant increases in AST levels (MD = 0.224 U/L; 95% CI, 0.071-0.376; P = 0.004). However, foods enriched with CLA did not have any significant effects on AST levels.
CONCLUSION
CLA supplementation was associated with a significantly increased circulating AST without any significant effect on ALP and ALT levels. Prospective studies are necessary to assess the clinical outcomes of the association between CLA and liver enzyme concentrations.
Topics: Alanine Transaminase; Alkaline Phosphatase; Aspartate Aminotransferases; Databases, Factual; Dietary Supplements; Food, Fortified; Humans; Linoleic Acids, Conjugated; Liver; Randomized Controlled Trials as Topic
PubMed: 26541717
DOI: 10.1016/j.nut.2015.08.013 -
Food Science & Nutrition Jan 2022Bone metabolism is a complicated process, which involves bone modeling and remodeling. If this process is unbalanced, bone loss and resultant osteoporosis might occur.... (Review)
Review
Bone metabolism is a complicated process, which involves bone modeling and remodeling. If this process is unbalanced, bone loss and resultant osteoporosis might occur. Recently, nutrition supplementations such as n-3 polyunsaturated fatty acids (PUFAs) are considered to be used on improving the bone metabolism and reducing the risk of osteoporosis. To more precisely assess the effects of n-3 PUFA supplementation on bone mass and clarify its potential mechanism, we have conducted a systematic review and meta-analysis. Based on the strict inclusion and exclusion criteria, 12 articles were included in this meta-analysis. The results in articles show that n-3 PUFAs could slightly enhance the level of bone mineral density (BMD) (0.005 g/cm; 95% CI, 0.000-0.010) ( = 7), which was the primary outcome for the research in comparison with the control group. In addition, the results also illustrate that the increasing effect on BMD (0.024 g/cm; 95% CI, 0.020-0.028) became more significant for postmenopausal women. N-3 PUFAs had no significance on the level of bone-specific alkaline phosphatase (BALP) (-0.24 µg/L; 95% CI, -0.86 to 0.39) and osteocalcin (-0.63 μg/L; 95% CI, -1.84 to 0.57) ( = 5), which are the specific markers of bone formation. When compared with the eicosapentaenoic acid + docosahexaenoic acid supplementation, the supplementation form of α-linolenic acid significantly increased the content of BALP (0.396 µg/L; 95% CI, 0.069-0.724). The effects of n-3 PUFAs on bone resorption biomarkers containing type I collagen cross-linked C-terminal peptide (CTX) and type I collagen cross-linked N-terminal peptide (NTX) are considered and used in our study. Results indicated that participants who received n-3 PUFAs significantly decreased the level of CTX in the human body (-0.367 μg/L; 95% CI, -0.726 to -0.007) ( = 4). However, there was no significant difference in NTX levels in humans after supplementation with n-3 PUFA (-1.744 µg/L; 95% CI, -3.970-0.481) ( = 3). For postmenopausal women, it presented a significant decreasing level of CTX (-0.393 µg/L; 95% CI, -0.651 to -0.135) and NTX (-2.082 µg/L; 95% CI, -2.970 to -1.195) within their bodies. In conclusion, these findings suggested that n-3 PUFAs might have a beneficial effect on bone health, especially for α-linolenic acid supplementation form or for postmenopausal women.
PubMed: 35035917
DOI: 10.1002/fsn3.2655 -
Journal of Diabetes Research 2016Recent studies have shown the positive association between increased circulating BCAAs (valine, leucine, and isoleucine) and insulin resistance (IR) in obese or diabetic... (Review)
Review
Recent studies have shown the positive association between increased circulating BCAAs (valine, leucine, and isoleucine) and insulin resistance (IR) in obese or diabetic patients. However, results seem to be controversial in different races, diets, and distinct tissues. Our aims were to evaluate the relationship between BCAA and IR as well as later diabetes risk and explore the phenotypic and genetic factors influencing BCAA level based on available studies. We performed systematic review, searching MEDLINE, EMASE, ClinicalTrials.gov, the Cochrane Library, and Web of Science from inception to March 2016. After selection, 23 studies including 20,091 participants were included. Based on current evidence, we found that BCAA is a useful biomarker for early detection of IR and later diabetic risk. Factors influencing BCAA level can be divided into four parts: race, gender, dietary patterns, and gene variants. These factors might not only contribute to the elevated BCAA level but also show obvious associations with insulin resistance. Genes related to BCAA catabolism might serve as potential targets for the treatment of IR associated metabolic disorders. Moreover, these factors should be controlled properly during study design and data analysis. In the future, more large-scale studies with elaborate design addressing BCAA and IR are required.
Topics: 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide); Adaptor Proteins, Signal Transducing; Amino Acids, Branched-Chain; Diabetes Mellitus; Diet; Genotype; Humans; Insulin Resistance; Metabolome; Minor Histocompatibility Antigens; Obesity; Phenotype; Pregnancy Proteins; Protein Phosphatase 2C; Racial Groups; Sex Factors; Transaminases; Weight Loss
PubMed: 27642608
DOI: 10.1155/2016/2794591 -
Drug Design, Development and Therapy 2015Ursodeoxycholic acid (UDCA) is the standard treatment for primary biliary cirrhosis (PBC), but not all cases respond well. Evidence has shown that combination therapy of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND AIM
Ursodeoxycholic acid (UDCA) is the standard treatment for primary biliary cirrhosis (PBC), but not all cases respond well. Evidence has shown that combination therapy of UDCA with bezafibrate significantly improved liver function. A meta-analysis was performed to assess the efficacy and safety of UDCA and bezafibrate combination therapy in the treatment of PBC.
RESULTS
Nine trials, with a total of 269 patients, were included in the analysis. The bias risk of these trials was high. Compared with UDCA alone, the combination with bezafibrate improved the Mayo risk score (mean difference [MD], 0.60; 95% confidence interval [CI], 0.25-0.95; P=0.0008) and liver biochemistry: alkaline phosphatase (MD, -238.21 IU/L; 95% CI, -280.83 to -195.60; P<0.00001); gamma-glutamyltransferase (MD, -38.23 IU/L; 95% CI, -50.16 to -25.85; P<0.00001); immunoglobulin M (MD, -128.63 IU/L; 95% CI, -151.55 to -105.71; P<0.00001); bilirubin (MD, -0.20 mg/dL; 95% CI, -0.33 to -0.07; P=0.002); triglycerides (MD, -26.84 mg/dL; 95% CI, -36.51 to -17.17; P<0.0001); total cholesterol (MD, -21.58 mg/dL; 95% CI, -30.81 to -12.34; P<0.0001), and serum alanine aminotransferase (MD, -10.24 IU/L; 95% CI, -12.65 to -78.5; P<0.00001). However, combination therapy showed no significant differences in the incidence of all-cause mortality or pruritus, and may have resulted in more adverse events (risk ratio [RR], 0.22; 95% CI, 0.07-0.67; P=0.008).
CONCLUSION
Combination therapy improved liver biochemistry and the prognosis of PBC, but did not improve clinical symptoms or incidence of death. Attention should be paid to adverse events when using bezafibrate.
Topics: Bezafibrate; Biomarkers; Chi-Square Distribution; Drug Therapy, Combination; Humans; Liver; Liver Cirrhosis, Biliary; Odds Ratio; Risk Factors; Treatment Outcome; Ursodeoxycholic Acid
PubMed: 26491252
DOI: 10.2147/DDDT.S92041 -
European Journal of Gastroenterology &... Sep 2020Although the efficacy of ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) for primary biliary cholangitis (PBC) has been suggested by small trials, a meta-analysis... (Meta-Analysis)
Meta-Analysis
Combination therapy of obeticholic acid and ursodeoxycholic acid in patients with primary biliary cholangitis who respond incompletely to ursodeoxycholic acid: a systematic review.
BACKGROUND
Although the efficacy of ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) for primary biliary cholangitis (PBC) has been suggested by small trials, a meta-analysis to summarize the evidence has not yet been carried out. The aim of this study was to evaluate the clinical outcomes of the combination therapy of UDCA and OCA compared with UDCA monotherapy in patients with PBC.
METHODS AND MATERIALS
We searched the PubMed, EMBASE, the web of science, and the Cochrane Library databases for English-language studies published before September 2018. Studies were included if they were randomized controlled trials (RCTs) and reported relative risk (RR) estimates with 95% confidence intervals (CIs) or related data for the clinical outcomes of different therapies in patients with PBC.
RESULTS
Of the 1169 titles identified, two studies meeting the inclusion criteria were included in the meta-analysis. Approximately 222 patients with PBC were included in this analysis. The results of this study indicated that combination therapy was significantly superior to monotherapy in reducing serum alanine transaminase (mean difference: -15.63 IU/L; 95% CI, -21.59 to -9.68), aspartate transaminase (mean difference: -6.63 IU/L; 95% CI, -11.03 to -2.24), gamma-glutamyl transpeptidase (mean difference: -131.30 IU/L; 95% CI, -177.52 to -85.08), and C-reactive protein (mean difference = -1.17 mg/L; 95% CI, -2.19 to -0.14), but NS in improving primary endpoints of alkaline phosphatase level with 15.0% reduction from baseline, and equal or higher than the upper limit of normal serum total bilirubin (RR = 2.75; 95% CI, 0.43-17.68), conjugated bilirubin (mean difference = -0.06 mg/dL; 95% CI, -0.28 to 0.15), IgM (mean difference = -41.18 mg/dL; 95% CI, -244.45 to 162.09), and adverse events (P > 0.05).
CONCLUSION
This meta-analysis demonstrated that combination therapy with UDCA and OCA provided satisfactory clinical outcomes, which may be a promising alternative for patients with PBC who had an inadequate response to UDCA therapy. Therefore, high-quality RCTs on the safety and efficacy of the combination therapy of UDCA and OCA compared with UDCA monotherapy in patients with PBC should be performed in the future.
Topics: Alanine Transaminase; Chenodeoxycholic Acid; Humans; Liver Cirrhosis, Biliary; Randomized Controlled Trials as Topic; Ursodeoxycholic Acid
PubMed: 32649329
DOI: 10.1097/MEG.0000000000001785 -
The Cochrane Database of Systematic... Apr 2005Vitamins have been reported to be effective in controlling certain types of seizures and to prevent some of the harmful effects of antiepileptic drugs (AEDs). In this... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Vitamins have been reported to be effective in controlling certain types of seizures and to prevent some of the harmful effects of antiepileptic drugs (AEDs). In this review we will summarize evidence from randomized controlled trials.
OBJECTIVES
To assess if vitamins improve seizure control, reduce adverse effects of AEDs or improve the quality of life in people with epilepsy.
SEARCH STRATEGY
We searched MEDLINE from 1966 to 2004, the Cochrane Epilepsy Group trials register (December 2004), CENTRAL (the Cochrane Controlled Trials Register) (TheCochraneLibrary Issue 4, 2004), and cross-references from identified studies.
SELECTION CRITERIA
Randomized or quasi-randomized studies investigating the effects of one or more vitamins given alone or in addition to AEDs to people of any age with any type of epilepsy.
DATA COLLECTION AND ANALYSIS
Both reviewers assessed the trials for inclusion and extracted the data. Outcomes assessed included seizure frequency, gingival hyperplasia, neuropathy, changes in bone mineral content, serum calcium, alkaline phosphatase, hemogram, serum levels of AEDs, neuropsychological and quality of life outcomes. Primary analyses were by intention to treat.
MAIN RESULTS
Fifteen studies met our inclusion criteria and were of poor methodological quality. None described randomization methods and most enrolled small numbers of participants. Nine studies (331 participants) investigated folic acid. Two studies (75 participants) found no effect for the outcome 50% or greater reduction in seizure frequency (OR 0.96; 95% CI 0.32 to 2.29). Also, no evidence was found for an effect on gingival health, intelligence, behavior, mental health or personality, or measures of red blood volume and hemoglobin content. Folic acid was not associated with any consistent changes in serum phenytoin or phenobarbitone levels or improvement in the mean motor conduction velocities of peripheral nerves. One small study (72 participants) found that thiamine improves neuropsychological functions related to psychomotor speed, visuospatial abilities, selective attention and verbal abstracting ability. One study (226 participants) found a significantly higher bone mineral content (BMC) among patients with epilepsy taking AEDs with vitamin D supplementation compared to controls who were not given supplementation (OR 3.6; 95% CI 2.48 to 4.72; p < 0.00001). The studies found no significant effects on serum calcium, alkaline phosphatase or general well-being. One small study (24 participants) found a significant decrease in seizure frequency in those treated with vitamin E compared to placebo (p = 0.00005; Peto OR 26.73; 95% CI 5.46 to 130.92).
AUTHORS' CONCLUSIONS
In view of methodological deficiencies and limited number of individual studies, we have found no reliable evidence to support the routine use of vitamins in patients with epilepsy. Further trials are needed, especially to assess the utility of vitamin D supplementation to prevent osteomalacia and the role of vitamin E on seizures and thiamine in improving cognitive functions.
Topics: Anticonvulsants; Epilepsy; Folic Acid; Humans; Randomized Controlled Trials as Topic; Thiamine; Vitamin A; Vitamin D; Vitamins
PubMed: 15846704
DOI: 10.1002/14651858.CD004304.pub2 -
Alcohol and Alcoholism (Oxford,... Mar 2015The aim of this review was to focus on the knowledge of the role of lipin-1 in the pathogenesis of alcoholic fatty liver. (Review)
Review
AIMS
The aim of this review was to focus on the knowledge of the role of lipin-1 in the pathogenesis of alcoholic fatty liver.
METHODS
Systematic review of animal clinical and cell level studies related to the function of lipin-1 on alcoholic fatty liver, alcoholic hepatitis and alcoholic liver cirrhosis disease.
RESULT
Ethanol could increase the expression of lipin-1 through the AMPK-SREBP-1 signaling and dramatically increase the ratio of Lpin1β to Lpin1α by SIRT1-SFRS10-Lpin1β/α axis in the liver. Moreover, research has shown that over-expression of lipin-1 could also remarkably suppress very low density lipoprotein-triacylglyceride secretion. Last, lipin-1 has potent anti-inflammatory property.
CONCLUSION
In conclusion, lipin-1 has dual functions in lipid metabolism. In the cytoplasm, lipin-1β functions as a Mg(2+)-dependent phosphatidic acid phosphohydrolase (PAP) enzyme in triglyceride synthesis pathways. In the nucleus, lipin-1α acts as a transcriptional co-regulator to regulate the capacity of the liver for fatty acid oxidation and activity of the lipogenic enzyme. In hepatocytes of alcoholic fatty liver disease (AFLD), ethanol increases the expression of lipin-1 through the AMPK-SREBP-1 signaling and the Lpin1β/α ratio by SIRT1-SFRS10- Lpin1β/α axis. Of course, in addition to that, ethanol could also produce the PAP activity and interrupt the nucleus function of lipin-1. Furthermore, over-expression of lipin-1 could remarkably suppress very low-density lipoprotein-triacylglyceride (VLDL-TAG) secretion. In the end, endogenous lipin-1 has potent anti-inflammatory property. Increased synthesis of TAG, decreased fatty acid oxidation, impaired VLDL-TAG secretion and activated inflammatory factors act together to exacerbate the development of AFLD.
Topics: AMP-Activated Protein Kinases; Animals; Fatty Liver, Alcoholic; Hepatitis, Alcoholic; Lipid Metabolism; Lipoproteins, LDL; Liver; Liver Cirrhosis, Alcoholic; Mice; Nuclear Proteins; Phosphatidate Phosphatase; RNA-Binding Proteins; Serine-Arginine Splicing Factors; Signal Transduction; Sirtuin 1; Sterol Regulatory Element Binding Protein 1; Triglycerides
PubMed: 25595739
DOI: 10.1093/alcalc/agu102