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Biochemical Pharmacology Feb 2022Cholesterol esterification proteins Sterol-O acyltransferases (SOAT) 1 and 2 are emerging prognostic markers in many cancers. These enzymes utilise fatty acids... (Meta-Analysis)
Meta-Analysis
Cholesterol esterification proteins Sterol-O acyltransferases (SOAT) 1 and 2 are emerging prognostic markers in many cancers. These enzymes utilise fatty acids conjugated to coenzyme A to esterify cholesterol. Cholesterol esterification is tightly regulated and enables formation of lipid droplets that act as storage organelles for lipid soluble vitamins and minerals, and as cholesterol reservoirs. In cancer, this provides rapid access to cholesterol to maintain continual synthesis of the plasma membrane. In this systematic review and meta-analysis, we summarise the current depth of understanding of the role of this metabolic pathway in pan-cancer development. A systematic search of PubMed, Scopus, Web of Science, and Cochrane Library for preclinical studies identified eight studies where cholesteryl ester concentrations were compared between tumour and adjacent-normal tissue, and 24 studies where cholesterol esterification was blocked by pharmacological or genetic approaches. Tumour tissue had a significantly greater concentration of cholesteryl esters than non-tumour tissue (p < 0.0001). Pharmacological or genetic inhibition of SOAT was associated with significantly smaller tumours of all types (p ≤ 0.002). SOAT inhibition increased tumour apoptosis (p = 0.007), CD8 + lymphocyte infiltration and cytotoxicity (p ≤ 0.05), and reduced proliferation (p = 0.0003) and metastasis (p < 0.0001). Significant risk of publication bias was found and may have contributed to a 32% overestimation of the meta-analysed effect size. Avasimibe, the most frequently used SOAT inhibitor, was effective at doses equivalent to those previously reported to be safe and tolerable in humans. This work indicates that SOAT inhibition should be explored in clinical trials as an adjunct to existing anti-neoplastic agents.
Topics: Animals; Anticholesteremic Agents; Antineoplastic Agents; Cholesterol; Clinical Trials as Topic; Esterification; Humans; Organic Anion Transporters; Tumor Burden; Urea; Xenograft Model Antitumor Assays
PubMed: 34407453
DOI: 10.1016/j.bcp.2021.114731 -
Lipids in Health and Disease Jul 2021LCAT (lecithin-cholesterol acyltransferase) deficiency is characterized by two distinct phenotypes, familial LCAT deficiency (FLD) and Fish Eye disease (FED). This is...
BACKGROUND
LCAT (lecithin-cholesterol acyltransferase) deficiency is characterized by two distinct phenotypes, familial LCAT deficiency (FLD) and Fish Eye disease (FED). This is the first systematic review evaluating the ethnic distribution of LCAT deficiency, with particular emphasis on Latin America and the discussion of three Mexican-Mestizo probands.
METHODS
A systematic review was conducted following the PRISMA (Preferred Reporting Items for Systematic review and Meta-Analysis) Statement in Pubmed and SciELO. Articles which described subjects with LCAT deficiency syndromes and an assessment of the ethnic group to which the subject pertained, were included.
RESULTS
The systematic review revealed 215 cases (154 FLD, 41 FED and 20 unclassified) pertaining to 33 ethnic/racial groups. There was no association between genetic alteration and ethnicity. The mean age of diagnosis was 42 ± 16.5 years, with fish eye disease identified later than familial LCAT deficiency (55 ± 13.8 vs. 41 ± 14.7 years respectively). The prevalence of premature coronary heart disease was significantly greater in FED vs. FLD. In Latin America, 48 cases of LCAT deficiency have been published from six countries (Argentina (1 unclassified), Brazil (38 FLD), Chile (1 FLD), Columbia (1 FLD), Ecuador (1 FLD) and Mexico (4 FLD, 1 FED and 1 unclassified). Of the Mexican probands, one showed a novel LCAT mutation.
CONCLUSIONS
The systematic review shows that LCAT deficiency syndromes are clinically and genetically heterogeneous. No association was confirmed between ethnicity and LCAT mutation. There was a significantly greater risk of premature coronary artery disease in fish eye disease compared to familial LCAT deficiency. In FLD, the emphasis should be in preventing both cardiovascular disease and the progression of renal disease, while in FED, cardiovascular risk management should be the priority. The LCAT mutations discussed in this article are the only ones reported in the Mexican- Amerindian population.
Topics: Ethnicity; Genetic Predisposition to Disease; Humans; Indians, North American; Lecithin Cholesterol Acyltransferase Deficiency; Mexico; Phosphatidylcholine-Sterol O-Acyltransferase; Racial Groups
PubMed: 34256778
DOI: 10.1186/s12944-021-01498-6 -
Liver International : Official Journal... Nov 2021Previous studies investigating the prevalence of celiac disease (CD) in individuals with autoimmune hepatitis (AIH) have shown highly variable results. We therefore... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Previous studies investigating the prevalence of celiac disease (CD) in individuals with autoimmune hepatitis (AIH) have shown highly variable results. We therefore aimed to examine the prevalence of CD in individuals with AIH.
METHODS
Two professional librarians searched PubMed, EMBASE, Cochrane and Web of Science Core Collection up until 7 February 2020. The search terms included 'celiac disease', 'celiac', 'transglutaminases', 'gluten', 'gliadin', 'EMA', 'TTG' and 'villous' combined with 'autoimmune', 'hepatitis', 'ANA', 'SMA' and 'LKM'. This search yielded 2419 unique publications. A systematic review based on the PRISMA guidelines resulted in 31 articles eligible for full text review. Fifteen articles were deemed relevant, with 8 being included in our main analysis. A fixed-effect inverse variance-weighted model was used, and heterogeneity was calculated.
RESULTS
Our main analysis included 567 individuals with AIH from eight studies, where biopsy-verified CD (equivalent to Marsh III) was seen in 23 individuals (4.1%). The pooled prevalence of CD in AIH was 3.5% (95% CI = 1.6%-5.3%) (heterogeneity: P = .874; I = 0.0%), which is clearly higher than the 1% CD seen in most general populations. When also including studies where CD had been diagnosed through positive serology without biopsy (15 studies: n = 1817 individuals with AIH), the pooled prevalence of CD was 2.9% (95% CI = 2.1%-3.8%) (heterogeneity: P < .001; I = 66.8%).
CONCLUSION
Our results demonstrate a higher prevalence of CD in individuals with AIH compared to the general population. CD screening may be considered in patients with AIH.
Topics: Biopsy; Celiac Disease; Hepatitis, Autoimmune; Humans; Prevalence; Transglutaminases
PubMed: 34219350
DOI: 10.1111/liv.15000 -
The British Journal of Nutrition Oct 2022Elevated levels of liver enzymes are the main markers of liver dysfunction. Liver enzymes are the important indicators of non-alcoholic fatty liver disease (NAFLD) in... (Meta-Analysis)
Meta-Analysis
Elevated levels of liver enzymes are the main markers of liver dysfunction. Liver enzymes are the important indicators of non-alcoholic fatty liver disease (NAFLD) in the general population. Previous randomised clinical trials (RCT) investigated the effects of Mediterranean diet (MedDiet) as a plant-based diet on features of NAFLD like liver enzymes, but their results are contradictory. This study aimed to systematically review and meta-analyse RCT investigating the effect of MedDiet on liver enzymes. PubMed, Web of Science, Scopus and Google Scholar were searched until December 2020. A total of ten RCT ( 705 participants) evaluating the effect of MedDiet on liver enzymes including aspartate aminotransferase (AST), alanine transaminase (ALT) and -glutamyltransferase (GGT) were included. A random effects model was used to estimate the pooled effect size. To evaluate the heterogeneity among the included studies, the Cochran's -test and I-squared test were used. The MedDiet significantly reduced AST (weighted mean difference (WMD) = -0·38 IU/l; 95 % CI - 0·73, -0·03 IU/l; = 0·03) and GGT (WMD = -0·16 IU/l; 95 % CI - 0·32, -0·006 IU/l; = 0·04) but had no significant effect on ALT (WMD = -0·55 IU/l; 95 % CI - 1·25, 0·13 IU/l; = 0·11). However, sensitivity analysis revealed that the overall effects of MedDiet on AST, GGT and ALT were significantly influenced by removing some studies. There was no publication bias based on Begg's and Egger's tests. Generally, MedDiet can improve liver enzymes. To better conclusion, further RCT investigating the effect of MedDiet on liver enzymes, especially in patients with NAFLD, are still required.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Liver; Diet, Mediterranean; gamma-Glutamyltransferase; Alanine Transaminase; Aspartate Aminotransferases; Randomized Controlled Trials as Topic
PubMed: 34165054
DOI: 10.1017/S0007114521002270 -
British Journal of Clinical Pharmacology Feb 2022Statin liver safety in non-alcoholic fatty liver disease (NAFLD) patients is not well defined. We analysed differences in liver function tests, including alanine... (Meta-Analysis)
Meta-Analysis Review
AIMS
Statin liver safety in non-alcoholic fatty liver disease (NAFLD) patients is not well defined. We analysed differences in liver function tests, including alanine transaminase aminotransferase (ALT), aspartate transaminase (AST) and gamma-glutamyl transpeptidase (GGT) in NAFLD patients treated or not treated with statins.
METHODS
We performed a systematic review of MEDLINE via PubMed and EMBASE databases and metanalysis of clinical studies investigating levels of ALT, AST and GGT in NAFLD according to statin treatment. Mean difference (MD) and percentage MD were calculated between the two groups.
RESULTS
We included 22 studies with 2345 NAFLD patients. Overall, 16 were before-after interventional, five were cross-sectional and one was combined cross-sectional/interventional study. In all interventional studies, except one, patients had raised ALT, AST and GGT at baseline. Interventional studies showed reduced ALT values with an MD reduction of -27.2 U/L (95% CI -35.25/-19.15) and a percentage MD reduction of -35.41% (95% CI -44.78/-26.04). Also, AST values were reduced after statin treatment in interventional studies with an MD of -18.82 U/L (95% CI -25.63/-12.02) (percentage -31.78%, 95% CI -41.45/-22.11). Similarly, GGT levels were reduced after statin treatment with an MD of -19.93 U/L (95% CI -27.10/-12.77) (percentage -25.57%, 95% CI -35.18/-15.97). Cross-sectional studies showed no difference in AST and GGT values between patients treated with and without statins.
CONCLUSION
In interventional studies, ALT, AST and GGT were reduced after statin treatment with a percentage mean difference of -35.41%, -31.78% and -25.57%, respectively, while observational studies showed a null effect, suggesting liver safety of statins in NAFLD patients.
Topics: Alanine Transaminase; Aspartate Aminotransferases; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Liver; Non-alcoholic Fatty Liver Disease; gamma-Glutamyltransferase
PubMed: 34133035
DOI: 10.1111/bcp.14943 -
European Journal of Pharmacology Aug 2021Melatonin has shown promising effects in controlling the progress of non-alcoholic fatty liver disease (NAFLD), introducing it as a possible candidate for NAFLD... (Meta-Analysis)
Meta-Analysis
Melatonin has shown promising effects in controlling the progress of non-alcoholic fatty liver disease (NAFLD), introducing it as a possible candidate for NAFLD treatment. In this context, the current study is aimed to evaluate melatonin's effect on the plasma levels of Gamma-glutamyl transpeptidase, cholesterol, triglyceride, and liver aminotransferases in NAFLD patients. NAFLD and melatonin, as well as their related terms, were searched in electronic databases, until May 1st, 2020. The initial search identified 1152 studies. Considering inclusion and exclusion criteria, the final seven articles were included in the study. The methodology of the articles was assessed by the Newcastle-Ottawa Scale. Alanine transaminase levels were significantly lowered with melatonin treatment but not earlier than the 4th week (P = 0.010 and 0.519, respectively). Aspartate aminotransferase levels didn't show significant alteration before 4 weeks, although exhibiting substantial decline in total (P = 0.697 and 0.008, respectively). Alkaline phosphatase changes under 4 weeks of follow-up were not significant (P = 0.3), however, it decreased significantly in total (P = 0.006). A significant decline was detected in triglyceride levels after melatonin treatment (P = 0.015). There was a significant reduction in cholesterol levels (P = 0.005). Gamma-glutamyl transpeptidase levels were also significantly different after the administration of melatonin (P < 0.001). Melatonin could reduce the progress of NAFLD. It might also decrement hepatic function parameters. Thus, it could be used for managing NAFLD and possibly as part of the treatment plan for patients with NAFLD.
Topics: Alanine Transaminase; Alkaline Phosphatase; Aspartate Aminotransferases; Humans; Lipids; Liver; Melatonin; Non-alcoholic Fatty Liver Disease; gamma-Glutamyltransferase
PubMed: 34058202
DOI: 10.1016/j.ejphar.2021.174154 -
Alcohol and Alcoholism (Oxford,... Feb 2021Alcohol dependence affects over 240 million people worldwide and attributed to 3 million deaths annually. Early identification and intervention are key to prevent harm.... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND AIMS
Alcohol dependence affects over 240 million people worldwide and attributed to 3 million deaths annually. Early identification and intervention are key to prevent harm. We aim to systematically review literature on the effectiveness of adding advice based on biomarkers of liver injury or non-invasive tests of liver fibrosis (intervention-based advice) to prevent alcohol misuse.
METHODS
Electronic search was conducted on Ovid Medline, PubMed, EMBASE, Psychinfo and CINAHL for articles published up to end of February 2020. Additionally, we searched study citations, Scopus, Ethos and Clinical trials. The primary outcome measure was changed in self-reported alcohol consumption analysed by random-effects meta-analysis. Secondary outcomes included change to liver blood markers and alcohol-related health outcomes.
RESULTS
Fourteen randomized controlled trials (RCTs) and two observational studies comprising n = 3763 participants were included. Meta-analyses showed a greater reduction in alcohol consumption and liver biomarkers for the intervention compared to control group: mean difference for weekly alcohol intake was -74.4 g/week (95% confidence interval (CI) -126.1, -22.6, P = 0.005) and mean difference for gamma-glutamyl transferase (GGT) -19.7 IU/l (95% CI -33.1, -6.4, P = 0.004). There was a higher incidence of alcohol-attributed mortality, number of days spent in the hospital, physician visits and sickness absence in the non-intervention group. The quality of the included studies was moderate for RCTs and high for observational studies.
CONCLUSIONS
The review confirmed a significant association between the addition of intervention-based advice in routine care to the reduction of harmful alcohol consumption, GGT and alcohol-related mortality. The findings support the inclusion of this type of advice in routine alcohol care.
Topics: Adult; Alcohol Drinking; Biomarkers; Crisis Intervention; Erythrocyte Indices; Female; Humans; Liver Cirrhosis; Male; Middle Aged; gamma-Glutamyltransferase
PubMed: 33479737
DOI: 10.1093/alcalc/agaa143 -
European Review For Medical and... Dec 2020Liver involvement of SARS-CoV-2 infection has been reported in several papers, but without homogeneous findings. We aimed to systematically review the prevalence of... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Liver involvement of SARS-CoV-2 infection has been reported in several papers, but without homogeneous findings. We aimed to systematically review the prevalence of liver involvement in patients with SARS-CoV-2 infection at their hospital admission, and its correlation with disease severity and clinical outcomes in patients with or without pre-existing chronic liver disease.
MATERIALS AND METHODS
We systematically searched PubMed, Embase, Web of Science, Medline, PMC, clinical trial registries, and other Coronavirus family publications for studies reporting data on SARS-CoV-2 infection or COVID-19 and liver function tests (LFTs) alterations, as well as clinical course of patients with chronic liver disease or cirrhosis. Case reports, preprints, editorials, reviews were excluded. We also revised literature to describe the background of liver involvement during SARS-CoV-2 infection.
RESULTS
36 studies, including 20724 patients with SARS-CoV-2 infection, were included. The pooled prevalence of LFTs abnormalities at admission was 46.9% (AST 26.5%, ALT 22.8%, GGT 22.5%, ALP 5.7%, tBIL 8.0%). ALT, AST, tBIL were independent predictors of disease severity (ALT OR 1.54, 95% CI 1.17-2.03; AST OR 3.17, 95% CI 2.10-4.77; tBIL OR 2.32, 95% CI 1.18-4.58) and in-hospital mortality (ALT OR 1.48, 95% CI 1.12-1.96; AST OR 4.39, 95% CI 2.68-7.18; tBIL OR 7.75, 95% CI 2.28-26.40). Heterogeneity among studies was high. The few available data also reported that COVID-19 was associated with increased risk of liver decompensation and mortality in patients with liver cirrhosis.
CONCLUSIONS
LFTs alterations were reported in up to 47% of unselected patients with COVID-19 and were associated with severe disease or in-hospital mortality. In cirrhotic patients, COVID-19 was associated with high risk of liver decompensation or mortality.
Topics: Alanine Transaminase; Alkaline Phosphatase; Aspartate Aminotransferases; Bilirubin; COVID-19; Hospital Mortality; Humans; Liver Diseases; Liver Function Tests; Odds Ratio; Prevalence; Prognosis; SARS-CoV-2; Severity of Illness Index; gamma-Glutamyltransferase
PubMed: 33378061
DOI: 10.26355/eurrev_202012_24215 -
Thyroid : Official Journal of the... Jun 2021Abnormal liver blood tests (LBTs) in hyperthyroid patients are not uncommonly encountered. One major adverse event of antithyroid drug (ATD) therapy is drug-induced... (Meta-Analysis)
Meta-Analysis
Abnormal liver blood tests (LBTs) in hyperthyroid patients are not uncommonly encountered. One major adverse event of antithyroid drug (ATD) therapy is drug-induced hepatotoxicity. Abnormal LBT in the hyperthyroidism scenario is a main diagnostic and therapeutic dilemma. We aimed to assess the prevalence and the response to ATD therapy of LBT abnormalities in newly diagnosed and uncomplicated hyperthyroidism through a systematic review and meta-analysis. A literature search was performed reporting LBTs at presentation and after ATD therapy in hyperthyroid patients. A proportion meta-analysis was performed with random-effects model. Pooled data were presented with 95% confidence intervals (CI). I statistic index was used to quantify the heterogeneity. Sensitivity analyses for prevalence of hyperthyroid patients with at least one abnormal LBT were performed. -Value of <0.05 was regarded as significant. The literature search yielded 2286 studies, of which 25 were included for systematic review and meta-analysis. The prevalence of untreated hyperthyroid and Graves' disease patients with at least one abnormal LBT was 55% ([CI 46-63%], I 96%) and 60% ([CI 53-67%], I 92%), respectively. The prevalence of alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), total bilirubin (BIL), and γ-glutamyltransferase (GGT) abnormalities in hyperthyroid patients were 33% ([CI 24-44%], I 95%), 23% ([CI 17-29%], I 89%), 44% ([CI 35-52%], I 93%), 12% ([CI 7-20%], I 92%), and 24% ([CI 16-36%], I 95%), respectively. ATD therapy, along with euthyroidism restoration, was accompanied by normalization of LBT abnormalities in the following percentage of cases: ALT 83% ([CI 72-90%], I 46%), AST 87% ([CI 74-94%], I 2%), ALP 53% ([CI 32-73%], I 76%), BIL 50% (CI cannot be calculated), and GGT 70% ([CI 47-87%], I 74%). The sensitivity analyses showed similar results as those of the main analyses. The publication bias was not statistically significant for all outcomes, except for the prevalence of resolved BIL abnormalities that was not calculable. LBT abnormalities are common in newly diagnosed and untreated hyperthyroidism setting. A high chance of safely normalizing elevated transaminases, up to fivefold above the upper limit of normal, accompanies the use of ATDs in the treatment of hyperthyroidism.
Topics: Alanine Transaminase; Alkaline Phosphatase; Antithyroid Agents; Aspartate Aminotransferases; Bilirubin; Graves Disease; Humans; Hyperthyroidism; Liver Diseases; Liver Function Tests; Prevalence; gamma-Glutamyltransferase
PubMed: 33327837
DOI: 10.1089/thy.2020.0715 -
Pharmacology & Therapeutics Jun 2021Chronic kidney disease (CKD) is a global health problem with a prevalence of 10-15%. Progressive fibrosis of the renal tissue is a main feature of CKD, but current... (Review)
Review
Chronic kidney disease (CKD) is a global health problem with a prevalence of 10-15%. Progressive fibrosis of the renal tissue is a main feature of CKD, but current treatment strategies are relatively unspecific and delay, but do not prevent, CKD. Exploration of novel pharmacological targets to inhibit fibrosis development are therefore important. Transglutaminase 2 (TG2) is known to be central for extracellular collagenous matrix formation, but TG2 is a multifunctional enzyme and novel research has broadened our view on its extra- and intracellular actions. TG2 exists in two conformational states with different catalytic properties as determined by substrate availability and local calcium concentrations. The open conformation of TG2 depends on calcium and has transamidase activity, central for protein modification and cross-linking of extracellular protein components, while the closed conformation is a GTPase involved in transmembrane signaling processes. We first describe different methodologies to assess TG2 activity in renal tissue and cell cultures such as biotin cadaverine incorporation. Then we systematically review animal CKD models and preliminary studies in humans (with diabetic, IgA- and chronic allograft nephropathy) to reveal the role of TG2 in renal fibrosis. Mechanisms behind TG2 activation, TG2 externalization dependent on Syndecan-4 and interactions between TG and profibrotic molecules including transforming growth factor β and the angiotensin II receptor are discussed. Pharmacological TG2 inhibition shows antifibrotic effects in CKD. However, the translation of TG2 inhibition to treat CKD in patients is a challenge as clinical information is limited, and further studies on pharmacokinetics and efficacy of the individual compounds are required.
Topics: Animals; Fibrosis; Humans; Protein Glutamine gamma Glutamyltransferase 2; Renal Insufficiency, Chronic
PubMed: 33307141
DOI: 10.1016/j.pharmthera.2020.107787