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Clinical Therapeutics Dec 2023Alcohol-associated hepatitis (AH) is a unique presentation of cholestatic steatohepatitis with liver dysfunction and malaise preceded by heavy alcohol intake. Although...
PURPOSE
Alcohol-associated hepatitis (AH) is a unique presentation of cholestatic steatohepatitis with liver dysfunction and malaise preceded by heavy alcohol intake. Although AH exists on a spectrum, in its most severe form, 28-day mortality approaches 50%. Clinical trials of therapeutic interventions over the last 50 years have yielded few durable therapies, none of which convey benefit beyond the short term.
METHODS
A qualitative systematic review was performed via searches of PubMed, the International Clinical Trials Registry Platform, and ClinicalTrials.gov for therapeutic interventions for AH.
FINDINGS
Prior to 2005, clinical trial results for AH were identified within PubMed. From 2005 to the present, trials were well catalogued within online registries and included information regarding trial status (eg, complete, terminated, actively enrolling). Most clinical trials for AH have used existing medications broadly targeting pathogenic themes of AH (eg, inflammation, cell death) in an off-label manner. The trend of initially promising pilot studies answered by larger trials showing lack of efficacy or safety signals have ended the hopes of many new therapeutics. The emergence of theragnostics to identify patients who may benefit from existing therapies and trials of agents with novel mechanisms of action, including epigenetic modifications and hyaluronic acid signaling targeted to AH pathogenesis, are currently under investigation.
IMPLICATIONS
This review of AH treatments details the historical interventions and clinical trials that have led to the current treatment algorithm and active studies shaping the therapeutic pipeline for AH.
Topics: Humans; Hepatitis, Alcoholic; Clinical Trials as Topic
PubMed: 37980219
DOI: 10.1016/j.clinthera.2023.10.013 -
Minerva Gastroenterologica E Dietologica Sep 2020Worldwide, patients are tested for acute and chronic diseases using a series of basic blood assays. The most common liver tests are serum alanine aminotransferase (ALT)...
Worldwide, patients are tested for acute and chronic diseases using a series of basic blood assays. The most common liver tests are serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), also called transaminases. These tests are indicators of hepatocellular injury and their increase requires further investigations. The aim of this descriptive review is to highlight and remind the importance of liver transaminases in daily practice. A systematic literature search of the main international databases was performed. We looked for papers that involved transaminases, either in the normal range or in case of increased level and focused on their use in clinical practice. A narrative review of this topic was written. Multiple studies have demonstrated that the presence of an elevated ALT was associated with increased liver-related mortality. The normal ALT level ranges from 29 to 33 IU/L in males and 19 to 25 IU/L in females. The investigations imposed by a high level of transaminases includes testing for viral hepatitis A, B, C and E, assessment for nonalcoholic fatty liver disease and alcoholic liver disease, screening for autoimmune hepatitis, hemochromatosis, Wilson's disease and alpha-1 antitrypsin deficiency. Hepatotoxic drugs consumption also should be excluded. Furthermore, the utility of transaminases is evident in the assessment of the outcome after treatment of each specific liver disease. Beside the role in the first diagnostic step of liver injuries, the utility of liver transaminases is also maintained during the follow-up of liver diseases and in their prognostic assessment.
Topics: Alanine Transaminase; Algorithms; Aspartate Aminotransferases; Humans; Liver Diseases
PubMed: 31994373
DOI: 10.23736/S1121-421X.20.02660-4 -
The Cochrane Database of Systematic... Mar 2017Alcohol-related liver disease is due to excessive alcohol consumption. It includes a spectrum of liver diseases such as alcohol-related fatty liver, alcoholic hepatitis,... (Review)
Review
BACKGROUND
Alcohol-related liver disease is due to excessive alcohol consumption. It includes a spectrum of liver diseases such as alcohol-related fatty liver, alcoholic hepatitis, and alcoholic cirrhosis. Mortality associated with alcoholic hepatitis is high. The optimal pharmacological treatment of alcoholic hepatitis and other alcohol-related liver disease remains controversial.
OBJECTIVES
To assess the comparative benefits and harms of different pharmacological interventions in the management of alcohol-related liver disease through a network meta-analysis and to generate rankings of the available pharmacological interventions according to their safety and efficacy in order to identify potential treatments. However, even in the subgroup of participants when the potential effect modifiers appeared reasonably similar across comparisons, there was evidence of inconsistency by one or more methods of assessment of inconsistency. Therefore, we did not report the results of the network meta-analysis and reported the comparative benefits and harms of different interventions using standard Cochrane methodology.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform and randomised controlled trials registers until February 2017 to identify randomised clinical trials on pharmacological treatments for alcohol-related liver diseases.
SELECTION CRITERIA
Randomised clinical trials (irrespective of language, blinding, or publication status) including participants with alcohol-related liver disease. We excluded trials that included participants who had previously undergone liver transplantation and those with co-existing chronic viral diseases. We considered any of the various pharmacological interventions compared with each other or with placebo or no intervention.
DATA COLLECTION AND ANALYSIS
Two review authors independently identified trials and independently extracted data. We calculated the odds ratio (OR) and rate ratio with 95% confidence intervals (CIs) using both fixed-effect and random-effects models based on available-participant analysis with Review Manager. We assessed risk of bias according to Cochrane, controlled risk of random errors with Trial Sequential Analysis, and assessed the quality of the evidence using GRADE.
MAIN RESULTS
We identified a total of 81 randomised clinical trials. All the trials were at high risk of bias, and the overall quality of the evidence was low or very low for all outcomes. Alcoholic hepatitisFifty randomised clinical trials included 4484 participants with alcoholic hepatitis. The period of follow-up ranged from one to 12 months. Because of concerns about transitivity assumption, we did not perform the network meta-analysis. None of the active interventions showed any improvement in any of the clinical outcomes reported in the trials, which includes mortality (at various time points), cirrhosis, decompensated cirrhosis, liver transplantation. None of the trials reported health-related quality of life or incidence of hepatocellular carcinoma. Severe alcoholic hepatitisOf the trials on alcoholic hepatitis, 19 trials (2545 participants) included exclusively participants with severe alcoholic hepatitis (Maddrey Discriminat Function > 32). The period of follow-up ranged from one to 12 months. There was no alteration in the conclusions when only people with severe alcoholic hepatitis were included in the analysis.
SOURCE OF FUNDING
Eleven trials were funded by parties with vested interest in the results. Sixteen trials were funded by parties without vested interest in the results. The source of funding was not reported in 23 trials. Other alcohol-related liver diseasesThirty-one randomised clinical trials included 3695 participants with other alcohol-related liver diseases (with a wide spectrum of alcohol-related liver diseases). The period of follow-up ranged from one to 48 months. The mortality at maximal follow-up was lower in the propylthiouracil group versus the no intervention group (OR 0.45, 95% CI 0.26 to 0.78; 423 participants; 2 trials; low-quality evidence). However, this result is based on two small trials at high risk of bias and further confirmation in larger trials of low risk of bias is necessary to recommend propylthiouracil routinely in people with other alcohol-related liver diseases. The mortality at maximal follow-up was higher in the ursodeoxycholic acid group versus the no intervention group (OR 2.09, 95% CI 1.12 to 3.90; 226 participants; 1 trial; low-quality evidence).
SOURCE OF FUNDING
Twelve trials were funded by parties with vested interest in the results. Three trials were funded by parties without vested interest in the results. The source of funding was not reported in 16 trials.
AUTHORS' CONCLUSIONS
Because of very low-quality evidence, there is uncertainty in the effectiveness of any pharmacological intervention versus no intervention in people with alcoholic hepatitis or severe alcoholic hepatitis. Based on low-quality evidence, propylthiouracil may decrease mortality in people with other alcohol-related liver diseases. However, these results must be confirmed by adequately powered trials with low risk of bias before propylthiouracil can be considered effective.Future randomised clinical trials should be conducted with approximately 200 participants in each group and follow-up of one to two years in order to compare the benefits and harms of different treatments in people with alcoholic hepatitis. Randomised clinical trials should include health-related quality of life and report serious adverse events separately from adverse events. Future randomised clinical trials should have a low risk of bias and low risk of random errors.
PubMed: 28368093
DOI: 10.1002/14651858.CD011646.pub2 -
Expert Review of Gastroenterology &... 2015Humans develop various clinical phenotypes of severe alcoholic liver disease, including alcoholic hepatitis and cirrhosis, generally after decades of heavy drinking. In... (Review)
Review
Humans develop various clinical phenotypes of severe alcoholic liver disease, including alcoholic hepatitis and cirrhosis, generally after decades of heavy drinking. In such individuals, following each episode of drinking, their livers experience heightened intracellular and extracellular stresses that are closely associated with alcohol consumption and alcohol metabolism. This article focuses on the latest advances made in animal models on evolutionarily conserved homeostatic mechanisms for coping with and resolving these stress conditions. The mechanisms discussed include the stress-activated protein kinase JNK, energy regulator AMPK, autophagy and the inflammatory response. Over time, the host may respond variably to stress with protective mechanisms that are critical in determining an individual's vulnerability to developing severe alcoholic liver disease. A systematic review of these mechanisms and their temporal changes in animal models provides the basis for general conclusions, and raises questions for future studies. The relevance of these data to human conditions is also discussed.
Topics: Alcohol Drinking; Animals; Homeostasis; Humans; Liver Diseases, Alcoholic; Mice; Models, Animal; Rats; Stress, Physiological
PubMed: 26293978
DOI: 10.1586/17474124.2015.1069705 -
Expert Review of Gastroenterology &... May 2018Neutrophil to lymphocyte ratio (NLR) is widely used to assess inflammatory diseases. We performed a systematic review to explore the prognostic role of NLR for the... (Review)
Review
Neutrophil to lymphocyte ratio (NLR) is widely used to assess inflammatory diseases. We performed a systematic review to explore the prognostic role of NLR for the assessment of liver fibrosis and cirrhosis. Areas covered: We searched the PubMed and EMBASE databases for the eligible papers which explored the association between NLR and liver fibrosis/cirrhosis or investigated the prognostic value of NLR in cirrhotic patients. Expert commentary: In accordance with assessment of liver fibrosis stage, we classified papers into four subgroups by etiology. For the patients with nonalcoholic fatty liver disease (NAFLD) there was a significant association between NLR and fibrosis stage and nonalcoholic fatty liver disease activity score (NAS), while NLR had a negative correlation with fibrosis stage for the patients with chronic hepatitis B (CHB). As for the patients with and chronic hepatitis C (CHC), NLR might not be significantly associated with fibrosis stage. Moreover, NLR seemed to be significantly useful for predicting outcomes in cirrhotic patients. Hence, NLR might be associated with liver fibrosis stage, especially in patients with NAFLD. Furthermore, NLR might be a useful biomarker for evaluating the prognosis in cirrhotic patients.
Topics: Adult; Aged; Female; Humans; Liver Cirrhosis; Lymphocyte Count; Lymphocytes; Male; Middle Aged; Multivariate Analysis; Neutrophils; Non-alcoholic Fatty Liver Disease; Odds Ratio; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Risk Factors; Severity of Illness Index
PubMed: 29629626
DOI: 10.1080/17474124.2018.1463158 -
Acta Endocrinologica (Bucharest,... 2020The aim of the present study was to systematically review the effects of Realsil (silybin-phospholipid-vitamin E complex) on liver enzymes in patients with NAFLD or NASH. (Review)
Review
THE EFFECTS OF REALSIL (SILYBIN-PHOSPHOLIPID-VITAMIN E COMPLEX) ON LIVER ENZYMES IN PATIENTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) OR NON-ALCOHOLIC STEATO-HEPATITIS (NASH): A SYSTEMATIC REVIEW AND META-ANALYSIS OF RCTS.
BACKGROUND
The aim of the present study was to systematically review the effects of Realsil (silybin-phospholipid-vitamin E complex) on liver enzymes in patients with NAFLD or NASH.
METHODS
We searched Web of Science, MEDLINE, Google Scholar, Cochrane Library, Science Direct, ProQuest, Scopus, and 1868 articles were found up to December 2018. Four studies that examined the effect of Realsil intake on liver enzymes among NAFLD or NASH patients were included. Exclusion criteria include: animal studies, studies with the design other than clinical trials, studies on non-adult individuals, studies that assess the effect of vitamin E, silybin, or phospholipid solely, studies that examined the effect of Realsil on other outcomes, or studies with insufficient data.
RESULTS
The analysis demonstrated that Realsil intake led to a significant decrease in Gamma-Glutamyl Transpeptidase (GGT) levels (standardized mean difference (SMD) =-0.37; 95% confidence interval (CI]): -0.68 to -0.06). Realsil intake non-significantly decrease alanine transaminase (ALT) levels (SMD=-1.02 U/L; 95% CI: -2.23 to 0.20) and non-significantly increase aspartate aminotransferase (AST) levels (SMD = 0.17 U/L; 95% CI: -0.26-0.61).
CONCLUSION
Realsil intake was associated with a significantly decreased circulating GGT level without any significant effect on AST and ALT levels.
PubMed: 33029240
DOI: 10.4183/aeb.2020.223 -
Liver Transplantation : Official... Jul 2023Alcohol accounts for a large disease burden in hepatology and liver transplantation (LT) and across the globe. Clinical evaluations and decisions about LT candidacy are...
Alcohol accounts for a large disease burden in hepatology and liver transplantation (LT) and across the globe. Clinical evaluations and decisions about LT candidacy are challenging because they rely on detailed psychosocial assessments and interpretations of psychiatric and substance use disorder data, which often must occur rapidly according to the acuity of end-stage liver disease. Such difficulties commonly occur during the process of candidate selection and liver allocation, particularly during early LT (eLT) in patients with acute alcohol-associated hepatitis (AAH). Patients with AAH commonly have very recent or active substance use, high short-term mortality, psychiatric comorbidities, and compressed evaluation and treatment timetables. LT clinicians report that patients' alcohol-associated insight (AAI) is among the most relevant psychosocial data in this population, yet no studies exist examining how LT teams define and use AAI in eLT or its effect on clinical outcomes. In April 2022, we searched Ovid MEDLINE, Elsevier Embase, EBSCOhost PsycInfo and CINAHL, and Wiley Cochrane Central Register of Controlled Trials for reports describing AAH populations who underwent eLT, which also described psychosocial evaluation parameters. The searches retrieved 1603 unique reports. After eligibility screening, 8 were included in the qualitative analysis. This systematic review reveals that AAI is a poorly defined construct that is not measured in a standardized way. Yet it is a commonly cited parameter in articles that describe the psychosocial evaluation and decision-making of patients undergoing eLT for AAH. This article also discusses the general challenges of assessing AAI during eLT for AAH, existing AAI definitions and rating scales, how AAI has been used to date in the broader hepatology and LT literature, and future areas for clinical and research progress.
Topics: Humans; Liver Transplantation; Hepatitis, Alcoholic; Comorbidity
PubMed: 37016758
DOI: 10.1097/LVT.0000000000000144 -
European Radiology May 2016We conducted an individual participant data (IPD) pooled analysis on diagnostic accuracy of MRE to detect fibrosis stage in patients with non-alcoholic fatty liver... (Meta-Analysis)
Meta-Analysis Review
Magnetic resonance elastography for staging liver fibrosis in non-alcoholic fatty liver disease: a diagnostic accuracy systematic review and individual participant data pooled analysis.
OBJECTIVES
We conducted an individual participant data (IPD) pooled analysis on diagnostic accuracy of MRE to detect fibrosis stage in patients with non-alcoholic fatty liver disease (NAFLD).
METHODS
Through a systematic literature search, we identified studies of MRE (at 60-62.5 Hz) for staging fibrosis in patients with NAFLD, using liver biopsy as gold standard, and contacted study authors for IPD. Through pooled analysis, we calculated the cluster-adjusted AUROC, sensitivity and specificity of MRE for any (≥stage 1), significant (≥stage 2) and advanced (≥stage 3) fibrosis and cirrhosis (stage 4).
RESULTS
We included nine studies with 232 patients with NAFLD (mean age, 51 ± 13 years; 37.5% males; mean BMI, 33.5 ± 6.7 kg/m(2); interval between MRE and biopsy <1 year, 98.3%). Fibrosis stage distribution (stage 0/1/2/3/4) was 33.6, 32.3, 10.8, 12.9 and 10.4%, respectively. Mean AUROC (and 95% CIs) for diagnosis of any, significant or advanced fibrosis and cirrhosis was 0.86 (0.82-0.90), 0.87 (0.82-0.93), 0.90 (0.84-0.94) and 0.91 (0.76-0.95), respectively. Similar diagnostic performance was observed in stratified analysis based on sex, obesity and degree of inflammation.
CONCLUSIONS
MRE has high diagnostic accuracy for detection of fibrosis in NAFLD, independent of BMI and degree of inflammation.
KEY POINTS
• MRE has high diagnostic accuracy for detection of fibrosis in NAFLD. • BMI does not significantly affect accuracy of MRE in NAFLD. • Inflammation had no significant influence on MRE performance in NAFLD for fibrosis.
Topics: Biopsy; Elasticity Imaging Techniques; Female; Hepatitis; Humans; Liver; Liver Cirrhosis; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Obesity; Sensitivity and Specificity
PubMed: 26314479
DOI: 10.1007/s00330-015-3949-z -
Journal of Gastrointestinal Cancer Mar 2024Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths globally, including Australia. The absence of a consensus clinical practice guideline (CPG)...
BACKGROUND
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths globally, including Australia. The absence of a consensus clinical practice guideline (CPG) specific to HCC management poses challenges in reducing morbidity, mortality, and improving patient recovery. This systematic review aims to evaluate the existing evidence and assess the potential of published guidelines, including those with an international scope, to provide guidance for healthcare professionals in Australia.
METHODS
Electronic search of MEDLINE, Embase, Cochrane Library, Google Scholar, and PubMed was conducted. Peer-reviewed English language articles from 2005 to June 2022 were included if they described management of HCC as part of an evidence-based overall management plan or CPG. The quality of the included CPGs was assessed by the Appraisal of Guidelines for Research and Evaluation II (AGREE II) tool.
RESULTS
Twenty-one articles from 16 regions throughout the world were included in this review. All included guidelines (n = 21, 100%) recommended evaluating cirrhosis, hepatitis B, and hepatitis C as potential risk factors of HCC. Obesity and non-alcoholic fatty liver disease were recommended by 19 CPGs (91%) as risk factor for HCC. Fourteen guidelines (67%) endorsed using the BCLC staging system. Eighteen guidelines (86%) recommended a multidisciplinary approach for the management of HCC. Eighteen guidelines (86%) advised that surveillance using ultrasound should be implemented in all cirrhotic patients every 6 months regardless of the cause of cirrhosis. AGREE II mean overall assessment score was 90% indicating that all guidelines included were highly recommended in majority of domains.
CONCLUSIONS
The included CPGs provided a comprehensive approach, emphasizing the evaluation of risk factors, utilization of the BCLC staging system, and the importance of a multidisciplinary approach. Regular surveillance using ultrasound for cirrhotic patients was widely recommended. An understanding of contemporary international CPGs can prioritize aspects of the management of HCC to assist healthcare professionals to develop a national guideline to enable standardized, comprehensive, and evidence-based care for patients with HCC.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Practice Guidelines as Topic; Risk Factors; Australia
PubMed: 37480425
DOI: 10.1007/s12029-023-00961-0 -
Journal of Crohn's & Colitis Mar 2024Inflammatory bowel disease [IBD] comprises an immune-mediated group of chronic gastrointestinal disorders. Patients with IBD may experience extraintestinal... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND AIMS
Inflammatory bowel disease [IBD] comprises an immune-mediated group of chronic gastrointestinal disorders. Patients with IBD may experience extraintestinal manifestations, such as hepatobiliary complications. This meta-analysis aims to assess the prevalence of different hepatic manifestations in IBD patients.
METHODS
For this systematic review and meta-analysis, PubMed, Scopus, Web of Science, and Embase were searched until July 20, 2022, by specifying keywords for IBD, hepatic manifestations, and study type. Full texts of cohort studies in English that examined the prevalence of different hepatic manifestations were included in this study. The primary outcome was the overall prevalence of hepatic manifestations in IBD patients. For the statistical analysis, a proportion by random effect model meta-analysis was performed. The registration number for the protocol of this study in PROSPERO is CRD42022369595.
RESULTS
From the 4421 articles retrieved from the primary search, 118 met the inclusion criteria and were included in the final analysis. After a pooled analysis of 1 729 128 patients, the overall prevalence of hepatic manifestations was 3.49% (95% confidence interval [CI]: 3.31-3.68%; I2: 99.55%). The pooled prevalence of non-alcoholic fatty liver disease in 228 216 patients was 26.1% [95% CI: 22.1-30.2%; I2: 99.018%]. After pooled analysis of 9642 patients, the prevalence of primary sclerosing cholangitis was 1.67% [95% CI: 1.47-1.88%; I2: 99.10%]. The pooled prevalence of biliary stones was 4.1% [95% CI: 3.6-4.7%; I2: 97.43%]. Autoimmune hepatitis (0.51% [95% CI: 0.26-0.75%]; I2: 85.36%) and portal vein thrombosis (0.21% [95% CI: 0.08-0.33%]; I2: 97.95%) are considered as rare manifestations.
CONCLUSION
This study summarizes the prevalence and importance of different hepatic manifestations in IBD patients. These findings are crucial for the management of extraintestinal manifestations, especially hepatic manifestations, in IBD patients.
Topics: Humans; Inflammatory Bowel Diseases; Prevalence; Research Design; Liver Diseases
PubMed: 37695111
DOI: 10.1093/ecco-jcc/jjad157