L-carnitine supplementation in non-alcoholic fatty liver disease: A systematic review and meta-analysis

BACKGROUNDNon-alcoholic fatty liver disease (NAFLD) dominates the landscape of modern hepatology. Affecting 25% of the general population, there is critical unmet need to identify broadly available, safe and cost-effective treatments. Cumulative evidence in animal and human models suggests that intrahepatic and skeletal muscle fatty acid oxidation is impaired in NAFLD, such that lipid accretion is not matched by efficient utilisation. L-carnitine is a crucial mediator of fatty acid metabolism in vivo, promoting mitochondrial lipid β-oxidation and enhancing tissue metabolic flexibility. These physiological properties have generated research interest in L-carnitine as a potentially effective adjunctive therapy in NAFLD.AIMTo systematically review randomised trials reporting effects of dietary L-carnitine supplementation on liver biochemistry, liver fat and insulin sensitivity in NAFLD.METHODSSearch strategies, eligibility criteria and analytic methods were specified a priori (PROSPERO reference: CRD42018107063). Ovid MEDLINE, Ovid EMBASE, PubMed, Web of Science and the Cochrane Library were searched from their inception until April 2019. Outcome measures included serum concentrations of alanine and aspartate aminotransferase (ALT and AST), liver fat and insulin sensitivity assessed by the homeostasis model of insulin resistance (HOMA-IR). A random effects meta-analysis was performed for, ALT, AST and HOMA-IR measures separately. Between-study heterogeneity was measured using I2 statistics.RESULTSFive eligible randomised trials were included in the qualitative and quantitative synthesis (n = 338). All of the 5 included trials assessed the effect of L-carnitine on serum ALT, identified from Italy, South Korea and Iran. Weighted mean difference (WMD) for ALT between L-carnitine and control groups after intervention was -25.34 IU/L [95%CI: -41.74-(-8.94); P = 0.002]. WMD for AST between L-carnitine and control groups was -13.68 IU/L (95%CI: -28.26-0.89; P = 0.066). In three studies (n = 204), HOMA-IR was evaluated. WMD for HOMA-IR between L-carnitine and control groups was -0.74 units [95%CI: -1.02-(-0.46); P < 0.001]. Two studies using validated outcome measures reported a significant reduction in liver fat in L-carnitine vs control groups post-intervention (P < 0.001).CONCLUSIONPooled results indicate that L-carnitine supplementation attenuates ALT, liver fat and insulin resistance in NAFLD cohorts, confirming a beneficial effect of L-carnitine for a highly prevalent condition with a growing economic burden

Metabolic Imaging in Non-Alcoholic Fatty Liver Disease: Applications of Magnetic Resonance Spectroscopy

Non-alcoholic fatty liver disease (NAFLD) is poised to dominate the landscape of clinical hepatology in the 21st century. Its complex, interdependent aetiologies, non-linear disease progression and uncertain natural history have presented great challenges to the development of effective therapies. Progress will require an integrated approach to uncover molecular mediators, key pathogenic milestones and response to intervention at the metabolic level. The advent of precision imaging has yielded unprecedented insights into these processes. Quantitative imaging biomarkers such as magnetic resonance imaging (MRI), spectroscopy (MRS) and elastography (MRE) present robust, powerful tools with which to probe NAFLD metabolism and fibrogenesis non-invasively,in real time. Specific advantages of MRS include the ability to quantify static metabolite concentrations as well as dynamic substrate fluxin vivo. Thus, a vast range of key metabolic events inthe natural history of NAFLD can be explored using MRS. Here, we provide an overview of MRS for the clinician, as well as key pathways exploitable by MRS in vivo. Development, optimisation and validation of multinuclear MRS, in combination with other quantitative imaging techniques, may ultimately provide a robust, non-invasive alternative to liver biopsy for observational and longitudinal studies. Through enabling deeper insight into inflammatory and fibrogenic cascades, MRS may facilitate identification of novel therapeutic targets and clinically meaningful endpoints in NAFLD. Its widespread use in future could conceivably accelerate study design, data acquisition and availability of disease-modifying therapies at a population leve

Obesity is the most common risk factor for chronic liver disease: Results from risk stratification pathway using transient elastography

IntroductionObesity has been associated with liver fibrosis yet guidelines do not emphasise it as an independent risk factor in which to have a high index of suspicion of advanced disease. We aimed to elucidate the effect of a raised body mass index on the risk of liver disease using data from a community risk stratification pathway. MethodsWe prospectively recruited patients from a primary care practice with hazardous alcohol use and/or type 2 diabetes and/or obesity. Subjects were invited for a transient elastography reading. A threshold of ≥8.0kPa defined an elevated reading consistent with clinically significant liver disease. ResultsFive hundred and seventy six patients participated in the pathway of which, 533 patients had a reliable reading and 66 (12.4%) had an elevated reading. Thirty one percent of patients with an elevated reading had obesity as their only risk factor. The proportion of patients with an elevated reading was similar among those with obesity (8.9%) to patients with more recognised solitary risk factors (Type 2 diabetes 10.8%; Hazardous alcohol use 4.8%). Obesity in combination with other risk factors further increased the proportion of patients with an elevated reading. In multivariate logistic regression, increasing BMI and type 2 diabetes were significantly associated with an elevated reading. ConclusionObesity as a single or additive risk factor for chronic liver disease is significant. Future case finding strategies using a risk factor approach should incorporate obesity within proposed algorithms

Biomarkers of idiosyncratic drug-induced liver injury (DILI) - a systematic review

Introduction: Idiosyncratic drug-induced liver injury (DILI) is an unpredictable event, and there are no specific biomarkers that can distinguish DILI from alternative explanations or predict its clinical outcomes. Areas covered: This systematic review summarizes the available evidence for all biomarkers proposed to have a role in the diagnosis or prognosis of DILI. Following a comprehensive search, we included all types of studies in humans. We included DILI cases based on any threshold criteria but excluded intrinsic DILI, commonly caused by paracetamol overdose. We classified studies into diagnostic and prognostic categories and assessed their methodological quality. After reviewing the literature, 14 studies were eligible. Expert Opinion: Diagnostic studies were heterogeneous with regard to the study population and outcomes measured. Prognostic models were developed by integrating novel biomarkers, risk scores, and traditional biomarkers, which increased their prognostic ability to predict death or transplantation by 6 months. This systematic review highlights the case of need for non-genetic biomarkers that distinguish DILI from acute liver injury related to alternative etiology. Biomarkers with the potential to identify serious adverse outcomes from acute DILI should be validated in independent prospective cohorts with a substantial number of cases.This paper was funded by the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 821283 (www.imi.europa.eu). This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. Translational Safety Biomarker Pipeline (TransBioLine): Enabling develop- ment and implementation of novel safety biomarkers in clinical trials and diagnosis of disease’ — ‘TransBioLine’ (‘action’). Grant Number: 821283

All-cause mortality in people with cirrhosis compared with the general population: a population-based cohort study

Background: Mortality due to cirrhosis has tripled over the last 30 years in the UK. However, we lack adequate, contemporary, population-based estimates of the excess mortality patients who are at risk compared with the general population. Aim: To determine the overall survival in patients with cirrhosis compared with the general population taking into account the effects of severity and aetiology of disease and comorbidity. Methods: In a cohort study, we identified 4537 people with cirrhosis and a control cohort of 44 403 patients, matched by age, sex and general practice from the UK General Practice Research Database between June 1987 and April 2002. Results: Patients with compensated cirrhosis had a nearly five-fold [hazard ratio (HR) 4.7, 95% confidence interval (CI) 4.4–5.0] increased risk of death, while those with decompensated cirrhosis had a near 10-fold (HR 9.7, 95% CI 8.9–10.6) increased risk compared with the general population. Alcoholic cirrhosis conferred a worse prognosis than non-alcohol-related cirrhosis both in the first year following diagnosis and subsequently. Conclusion: Having a diagnosis of cirrhosis confers a substantial increased mortality risk compared with the general population, even for those with compensated disease, with 5-year survival between that seen for breast and colorectal cancer

1H MRS assessment of lipid composition at 3T and 7T

1H MRS assessment of lipid composition at 3T and 7

The Evaluation and Use of a Food Frequency Questionnaire Among the Population in Trivandrum, South Kerala, India

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. Dietary record tools such as food frequency questionnaire (FFQ) and food diaries (FD) are the most commonly used choices for assessing dietary intakes in most large-scale epidemiological studies. The authors developed a self-administered 360-item food frequency questionnaire (FFQ) to assess dietary intakes amongst a population-based cohort in South Kerala. In the validation study (n = 460), the data were collected using FFQs that were administered on three different occasions which were then compared to 7-day food records. The intake of foods and nutrients was higher as determined by the FFQ than that assessed using food records. Spearman correlations for macro-nutrients ranged from 0.72 for protein to 0.61 for carbohydrates and for micronutrients, from 0.71 for vitamin B6 to 0.34 for magnesium. The correlation was improved with energy-adjusted nutrient intakes. On average, the exact agreement for the macronutrients ranged from 48.2% to 57.1%, and that for micronutrients ranged from 66.7% to 41.9%, with the median percentage of 49.58%. The authors conclude that the FFQ has an acceptable reproducibility, however, there was a systematic trend towards higher estimates with the FFQ for most nutrients compared to the FD records

The XL probe: a luxury or a necessity? risk stratification in an obese community cohort using transient elastography

Background: Transient elastography is a non-invasive tool which can stratify patients at risk of chronic liver disease. However, a raised body mass index has been independently associated with a failed or unreliable examination.Objective: The purpose of this study was to analyse the performance of two probes (M/XL) on a portable transient elastography device within an obese community population.Method: The method involved a prospective study with recruitment from a primary care practice. Patients identified with a risk factor for chronic liver disease were invited to a community-based risk stratification pathway for transient elastography readings with both probes. A threshold of ≥8.0 kPa defined elevated liver stiffness.Results: A total of 477 patients attended the pathway. Of the patients, 21% had no valid measurements with the M probe. There was a significant difference between the probes in the proportion achieving ≥10 valid readings (M versus XL probe: 66.2% versus 90.2%; p ≤ 0.001) and in their reliability (M versus XL probe: 77.4% versus 98.5%; p = 0.028). Unreliable readings with the M probe increased as the body mass index increased. The XL probe re-stratified 5.2% of patients to have a normal reading.Conclusion: The XL probe on a portable device significantly improves the applicability of transient elastography within a community-based risk stratification pathway