BACKGROUND: The prevalence of non-alcoholic fatty liver disease (NAFLD) keeps increasing annually worldwide. Non-invasive assessment tools for evaluating the risk and severity of the disease are still limited. Insulin resistance (IR) and abdominal obesity (ABO) are closely related to NAFLD.
METHODS: A retrospective large-scale, population-based study was conducted based on the data from the 2017-2018 cycle of the National Health and Nutrition Examination Survey (NHANES). Three ABO indices, namely lipid accumulation product (LAP), visceral obesity index (VAI), waist circumference-triglyceride index (WTI), and three IR indices, including triglyceride glucose index (TyG), homeostasis model assessment of insulin resistance (HOMA-IR) and metabolic score for insulin resistance (METS-IR), were analyzed and compared for their relationships with NAFLD based on weighted multivariable logistic regression, spearman correlation heatmap, smooth curve fittings. The area under the curve (AUC) of receiver-operating characteristic (ROC) curve was used to evaluate the diagnostic capability of these indices for NAFLD. Differences among the AUCs were calculated and compared by Delong test.
RESULTS: In total, 3095 participants were included in our study among which 1368 adults were diagnosed with NAFLD. All six indices presented positive associations with NAFLD. There was a claw-shaped curve between HOMA-IR, VAI, LAP and NAFLD while a smooth semi-bell curve was observed in TyG, METS-IR and WTI. LAP and HOMA-IR had the best diagnostic capability for NAFLD (LAP: AUC = 0.8, Youden index = 0.48; HOMA-IR: AUC = 0.798, Youden index = 0.472) while VAI (AUC = 0.728, Youden index = 0.361) showed the lowest predictive value. The correlation heat map indicated positive correlations between all six indices and liver function, hepatic steatosis and fibrosis severity. In the NAFLD group, IR indicators presented a stronger association with alanine aminotransferase (ALT) compared with ABO indices.
CONCLUSIONS: All six indices can screen NAFLD withLAP and HOMA-IR being possibly optimal predictors. IR indices may be more sensitive to identify acute hepatic injury in NAFLD patients than ABO indices.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver ailment worldwide, in which nonpharmacological strategies have a considerable role in the treatment. Probiotic supplementation as well as physical exercise can improve cardiometabolic parameters, but further research is needed to determine the effects of combined treatment versus exercise alone in managing NAFLD-associated biomarkers, primarily liver enzymes, lipid markers, and insulin resistance.
OBJECTIVE: This systematic review and meta-analysis aimed to evaluate the effects of probiotic supplementation, combined with exercise versus exercise alone, on liver enzymes and cardiometabolic markers in patients with NAFLD.
METHODS: A systematic review and meta-analysis of randomized clinical trials was performed by searching PubMed, Scopus, and Web of Science databases up to April 2024. The search was restricted to articles published in the English language and human studies. Random effects models were used to calculate weighted mean differences (WMD).
RESULTS: Pooled estimates (9 studies, 615 patients, intervention durations ranging from 8 to 48 weeks) revealed that probiotics plus exercise decreased aspartate transaminase (AST) [WMD=-5.64 U/L, p = 0.02], gamma-glutamyl transferase (GGT) [WMD=-7.09 U/L, p = 0.004], low-density lipoprotein (LDL) [WMD=-8.98 mg/dL, p = 0.03], total cholesterol (TC) [WMD=-16.97 mg/dL, p = 0.01], and homeostatic model assessment for insulin resistance (HOMA-IR) [WMD=-0.94, p = 0.005] significantly more than exercise only. However, probiotics plus exercise did not significantly change high-density lipoprotein (HDL) [WMD = 0.07 mg/dL, p = 0.9], fasting insulin [WMD=-1.47 µIU/mL, p = 0.4] or fasting blood glucose (FBG) [WMD=-1.57 mg/dL, p = 0.3] compared with exercise only. While not statistically significant, there were clinically relevant reductions in alanine aminotransferase (ALT) [WMD=-6.78 U/L, p = 0.1], triglycerides (TG) [WMD=-21.84 mg/dL, p = 0.1], and body weight (BW) [WMD=-1.45 kg, p = 0.5] for probiotics plus exercise compared with exercise only. The included studies exhibited significant heterogeneity for AST (I2 = 78.99%, p = 0.001), GGT (I2 = 73.87%, p = 0.004), LDL (I2 = 62.78%, p = 0.02), TC (I2 = 72.41%, p = 0.003), HOMA-IR (I2 = 93.86%, p = 0.001), HDL (I2 = 0.00%, p = 0.9), FBG (I2 = 66.30%, p = 0.01), ALT (I2 = 88.08%, p = 0.001), and TG (I2 = 85.46%, p = 0.001). There was no significant heterogeneity among the included studies for BW (I2 = 0.00%, p = 0.9).
CONCLUSIONS: Probiotic supplementation combined with exercise training elicited better results compared to exercise alone on liver enzymes, lipid profile, and insulin resistance in patients with NAFLD.
BACKGROUND: PROSPERO registration number CRD42023424290.

In this editorial, we comment on the article by Chen et al recently published in 2024. We focus the debate on whether reducing the upper limit of normal of alanine aminotransferase (ALT) would effectively identify cases of fibrosis in metabolic-dysfunction associated fatty liver disease (MAFLD). This is important given the increasing prevalence of MAFLD and obesity globally. Currently, a suitable screening test to identify patients in the general population does not exist and most patients are screened after the finding of an abnormal ALT. The authors of this paper challenge the idea of what a normal ALT is and whether that threshold should be lowered, particularly as their study found that 83.12% of their study population with a diagnosis of MAFLD had a normal ALT. The main advantages of screening would be to identify patients and provide intervention early, the mainstay of this being changing modifiable risk factors and monitoring for liver fibrosis. However, there is not enough suitable therapeutic options available as of yet although this is likely to change in the coming years with more targets for therapy being discovered. Semaglutide is one example of this which has demonstrated benefit with an acceptable side effect profile for those patients with MAFLD and obesity, although studies have not yet shown a significant improvement in fibrosis regression. It would also require a huge amount of resource if a reduced ALT level alone was used as criteria; it is more likely that current scoring systems such as fibrosis-4 may be amended to represent this additional risk. Currently, there is not a good argument to recommend widespread screening with a reduced ALT level as this is unlikely to be cost-effective. This is compounded by the fact that there is a significant heterogeneity in what is considered a normal ALT between laboratories. Although studies previously have suggested a more pragmatic approach in screening those over the age of 60, this is likely to change with the increasing incidence of obesity within the younger age groups. The main message from this study is that those who have hypercholesterolemia and high body metabolic index should have these risk factors modified to maintain a lower level of ALT to reduce the risk of progression to fibrosis and cirrhosis.

In this editorial, we offer commentary on the article published by Chen et al in a recent issue of the World Journal of Gastroenterology (2024; 30: 1346-1357). The study highlights a noteworthy association between persistently elevated, yet high-normal levels of alanine transaminase (ALT) and an escalated cumulative risk of developing metabolic dysfunction-associated fatty liver disease (MAFLD). MAFLD has emerged as a globally prevalent chronic liver condition, whose incidence is steadily rising in parallel with improvements in living standards. Left unchecked, MAFLD can progress from hepatic steatosis to liver fibrosis, cirrhosis, and even hepatocellular carcinoma, underscoring the importance of early screening and diagnosis. ALT is widely recognized as a reliable biomarker for assessing the extent of hepatocellular damage. While ALT levels demonstrate a significant correlation with the severity of fatty liver disease, they lack specificity. The article by Chen et al contributes to our understanding of the development of MAFLD by investigating the long-term implications of high-normal ALT levels. Their findings suggest that sustained elevation within the normal range is linked to an increased likelihood of developing MAFLD, emphasizing the need for closer monitoring and potential intervention in such cases.

BACKGROUND: As one of the most requested profiles of blood tests, there is a need for standardization among liver function tests (LFT). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are key markers of hepatocellular injury. ALT and AST are used to calculate a Fibrosis-4 (FIB-4) score for assessing liver fibrosis. Despite recommendations by the International Federation of Clinical Chemistry (IFCC) to include pyridoxal-5-phosphate in ALT and AST assay methodologies, most laboratories continue to omit this.
METHODS: Data from the UK NEQAS for Clinical Chemistry Scheme, Distribution 1160 (November 2023), was reviewed to investigate variation in practice regarding liver blood tests in relation to ALT, AST and FIB-4. In addition, a series of questions audited laboratory practice in relation to liver enzymes.
RESULTS: Wide variation was seen in LFT profiles offered by laboratories, with 32 different combinations of tests used. The IFCC-recommended methods for ALT and AST are used by one-third of laboratories and give significantly higher results than non-IFCC methods. Laboratories using IFCC methods also reported significantly higher FIB-4 scores. Reference ranges and cut-offs for these tests also varied, and did not account for method-related differences in results.
CONCLUSIONS: The lack of standardization of LFTs can have a significant impact on patient care. The difference in results for ALT, AST and FIB-4 in laboratories not using IFCC-recommended methods may lead to misdiagnosis. This issue should be addressed by laboratories using methods including pyridoxal-5-phosphate. Until then, method-related reference ranges and cut-offs for ALT, AST and FIB-4 are required.

Studies have indicated that reduced serum ALT levels are commonly linked to aging and are known to predict poor outcomes in many clinical conditions as potential frailty indicators. There are close connections between the brain and peripheral organs, particularly the liver. In patients with acute ischemic stroke (AIS), the interactive effects may change ALT levels, which in turn influence stroke outcomes. Whether ALT has potential neuroprotective effects or is an indicator of frailty in AIS patients remains unknown. This retrospective analysis examined 572 AIS patients in Beijing Luhe Hospital between August 2020 and June 2021. Patient demographics and laboratory results were assembled. The National Institutes of Health Stroke Scale (NIHSS) was used to analyze stroke severity. Modified Rankin Score (mRS) determined stroke outcome 3 months after AIS, with mRS≤2 indicating a favorable outcome. Based on serum ALT measurements, patients were classified into three tertiles (T1-T3). Binary logistic regression analysis evaluated the correlation between ALT tertiles and AIS outcomes. Of the patients, 66 exhibited unfavorable outcomes. The median ALT level in this group was 13 (IQR: 11-18.25), which was lower than in the favorable outcomes cohort (16; IQR: 11-22). A decline in ALT corresponded with a higher incidence of poor outcomes at 3 months (T1, 15.5 %; T2, 11.4 %; T3, 7.0 %; p = 0.03). The lowest ALT tertile (T1) was independently linked to an adverse 3-month outcome (OR 2.50 95 %CI 1.24-5.07, p = 0.038) compared to the highest tertile. ALT levels demonstrated no correlation with age (T1, 62.59 ± 12.64; T2, 64.01 ± 11.47; T3, 65.12 ± 11.27; p > 0.05). Regardless of age, lower serum ALT levels are independently associated with poorer outcomes in AIS patients. This finding suggests the potential pivotal part of the liver in AIS outcomes, highlighting the need to consider both neurological and liver functions post-stroke.

In this editorial, we comment on the article by Chen et al. Metabolic dysfunction-associated fatty liver disease (MAFLD) is a global public health burden whose incidence has risen concurrently with overweight and obesity. Given its detrimental health impact, early identification of at-risk individuals is crucial. MAFLD diagnosis is based on evidence of hepatic steatosis indicated by liver biopsy, imaging, or blood biomarkers, and one of the following conditions: Overweight/ obesity, type 2 diabetes mellitus, or metabolic dysregulation. However, in large-scale epidemiological studies, liver biopsies are not feasible. The application of techniques such as ultrasonography, computed tomography, magnetic resonance imaging, and magnetic resonance spectroscopy is restricted by their limited sensitivity, low effectiveness, high costs, and need for specialized software. Blood biomarkers offer several advantages, particularly in large-scale epidemiological studies or clinical scenarios where traditional imaging techniques are impractical. Analysis of cumulative effects of excess high-normal blood alanine aminotransferase (ALT) levels of blood ALT levels could facilitate identification of at-risk patients who might not be detected through conventional imaging methods. Accordingly, investigating the utility of blood biomarkers in MAFLD should enhance early detection and monitoring, enabling timely intervention and management and improving patient outcomes.

This study assessed the acute and sub-chronic toxicity of Camelina oil, a well-known oil rich in polyunsaturated fatty acids that enhance cellular immunity and human health, in Wistar rats. Wistar rats, 5 per sex per group, were randomly assigned to three groups for acute (14 days) toxicity studies and five groups for sub-chronic (90 days) toxicity studies. In the acute study, Camelina sativa oil was administered orally at a single dose of 5000 mg/kg of body weight (BW). The positive control group received a single dose of 5 000 mg/kg BW Canola oil by gavage. In the sub-chronic study, Groups III-V received 250, 500, and 1 000 mg/kg BW of Camelina oil, while Groups I and II received ultra-pure water and Canola oil at a dose of 500 mg/kg BW, respectively. Throughout the experiment, clinical signs, mortality, and body weight were monitored. At the end of the sub-chronic study, hematological, biochemical, and histopathological investigations were conducted. Administration of Camelina oil and Canola had no significant effect on daily weight gain (P > 0.05) of the test rats. Serum calcium levels decreased while phosphorous levels increased in male rats treated with Camelina oil. Other hematological and biochemical parameters showed no significant differences or dose-response effects between control and seed oil groups in both sexes (P < 0.05). Moreover, in animal necropsy, there were no apparent lesions in the liver, heart, and kidney organs in any of the doses administered. In conclusion, the results suggest that oral administration of Camelina oil is unlikely to be toxic. Therefore, the possibility for the development of future human nutrition should be considered.

Alanine aminotransferase (ALT) serum levels increase because of hepatocellular damage. Metabolic dysfunction-associated fatty liver disease (MAFLD), which identifies steatotic liver disease (SLD) associated with ≥ 2 metabolic abnormalities, has prominent sexual differences. The Metabolic Syndrome defines a cluster comprising abdominal obesity, altered glucose metabolism, dyslipidemia, and hypertension. Male sex, body mass index, glucose, lipids, ferritin, hypertension, and age independently predict ALT levels among blood donors. Over the last few decades, the reference range of ALT levels has been animatedly debated owing to attempts to update sex-specific reference ranges. With this backset, Chen et al have recently published a study which has two main findings. First, > 80% of individuals with MAFLD had normal ALT levels. Second, there was a linear increasing trend in the association between cumulative excess high-normal ALT levels and the rate of incident MAFLD. This study has biologically credible findings. However, it inaccurately considered sex differences in the MAFLD arena. Therefore, future studies on SLD owing to metabolic dysfunction should adopt locally determined and prospectively validated reference ranges of ALT and carefully consider sex differences in liver enzymes and MAFLD pathobiology.

UNASSIGNED: Despite extensive research on hyperuricemia (HUA) in adults, there remains a dearth of studies examining this condition in youth. Consequently, our objective was to investigate the prevalence of HUA among youth in the United States, as well as identify the corresponding risk factors.
UNASSIGNED: This study employed a nationally representative subsample of 1,051 youth aged 13-20 from the US National Health and Nutrition Examination Survey (NHANES) conducted between January 2017 and March 2020. Univariate and multivariate techniques were utilized to examine the association between HUA and obesity, dietary nutrients, liver and kidney function, glucose and lipid metabolism, inflammation, and other indicators in the adolescent population.
UNASSIGNED: The study encompassed a cohort of 1,051 youth aged 13-20 years, comprising 538 boys and 513 girls. The overall prevalence of HUA was found to be 7% (74 out of 1,051). Univariate analysis revealed that the HUA group exhibited greater age, body mass index (BMI), waist circumference (WC), hip circumference (HC), and waist-to-hip ratio (WHR). Additionally, the prevalence of obesity was significantly higher in the HUA group compared to the non- HUA group (all p < 0.05). Regarding biochemical indicators, the levels of urea nitrogen, creatinine (Cr), alanine aminotransferase (ALT), glutamic oxalic aminotransferase (AST), gamma-glutamyl transferase (GGT), total cholesterol (TC), triglyceride (TG), and HS C reactive protein (Hs CRP) were found to be significantly higher in the HUA group compared to the non-HUA group (all p < 0.05). Further analysis using binary logistics regression showed that BMI (p = 0.024, OR1.158, 95%CI1.019-1.316), ALT (p = 0.020, OR1.032, 95%CI1.005-1.059), and Cr (p = 0.016, OR1.028, 95%CI1.005-1.051) were identified as risk factors for HUA, after controlling for age, gender, BMI, WC, HC, WHR, ALT, AST, GGT, TG, TC, Cr, Hs CRP, and other indicators. Interestingly, neither univariate nor multivariate analysis found any association between dietary nutrients and the risk of HUA (all p > 0.05).
UNASSIGNED: High BMI remains a major risk factor for HUA in US youth aged 13-20 years, and ALT and Cr levels should be closely monitored along with serum uric acid.