Diagnostic accuracy of AGILE 3+ score for advanced fibrosis in patients with NAFLD: A systematic review and meta-analysis.

BACKGROUND AND AIMS: A simple noninvasive score, the Agile 3+ score, combining liver stiffness measurement, aspartate aminotransferase/alanine aminotransferase ratio, platelet count, diabetes status, sex, and age, has been proposed for the identification of advanced fibrosis in patients with suspected NAFLD. We performed a systematic review and meta-analysis of observational studies to evaluate the diagnostic accuracy of the Agile 3+ score in identifying patients with NAFLD and advanced fibrosis. Recently, an International consensus changed the nomenclature of NAFLD into metabolic-associated steatotic liver disease, so currently, the two terms are interchangeable. APPROACH AND RESULTS: We systematically searched MEDLINE, Ovid Embase, Scopus, and Cochrane Library electronic databases for full-text published articles in any language from the inception to the April 24, 2023. We included original articles reporting data on the sensitivity and specificity of the Agile 3+ score, according to previously described rule-out (≤ 0.451) and rule-in (≥ 0.679) cutoffs. We included 6 observational studies (total of 6955 participants) with biopsy-proven NAFLD [mean age 53 (SE 4) years, mean body mass index 30.9 (SE 2.3) kg/m 2 , 54.0% men, prevalence of diabetes 59.6%]. The pooled prevalence of advanced fibrosis (≥ F3) was 42.1%. By the rule-out cutoff, the overall sensitivity and specificity were 88% (95% CI: 81-93%; I2 = 89.2%) and 65% (95% CI: 54-75%; I2 = 97.6%), respectively. By the rule-in cutoff, the overall sensitivity and specificity were 68% (95% CI: 57-78%; I2 =91.1%) and 87% (95% CI: 80%-92%; I2 =96.7%), respectively. Meta-regression analyses reported that the diagnostic accuracy was partly mediated by age ( p < 0.01), body mass index ( p < 0.01), and, although not statistically significant, sex ( p = 0.06). CONCLUSIONS: Our systematic review and meta-analysis suggests that Agile 3+ accurately diagnoses NAFLD with advanced fibrosis and can identify patients eligible for biopsy and emerging pharmacotherapies.

Prevalence of portal vein thrombosis in non-alcoholic fatty liver disease: a meta-analysis of observational studies.

Portal vein thrombosis (PVT) is a common complication of cirrhosis as a result of portal hypertension and modification in the hemostatic balance. Accumulating evidence now suggests that patients with non-alcoholic fatty liver disease (NAFLD), especially those with advanced forms, have an increased risk of PVT. Hence, we performed a meta-analysis of observational studies to estimate the overall prevalence of PVT in patients with NAFLD and its advanced forms compared with patients with advanced liver diseases from other etiologies. We systematically searched PubMed, Scopus and Web of Science databases from the inception date to December 30th 2022, using predefined keywords, to identify observational studies. Meta-analysis was performed using random-effects modeling. We included five observational studies for a total of 225,571 patients. Of these, 26,840 (11.9%) patients had NAFLD, whereas the PVT prevalence was 8.5% (n = 2,280). When compared with patients with advanced liver diseases from other etiologies, patients with NAFLD and its advanced forms had a higher risk of prevalent PVT (OR 1.34, 100% CI 1.07-1.67 p < 0,01). The between-study heterogeneity was substantial (I2 = 88%). This meta-analysis suggests that compared with patients with advanced liver diseases from other etiologies, patient with NAFLD and its advanced forms had a higher risk of prevalent PVT. Further research is required to understand the complex link between NAFLD/NASH and PVT development.

Glomerular Hyperfiltration: A Marker of Fibrosis Severity in Metabolic Associated Steatotic Liver Disease in an Adult Population.

Glomerular hyperfiltration (GH) is an increase in the glomerular filtration rate, possibly progressing to chronic kidney disease (CKD). Metabolic-associated steatotic liver disease (MASLD) is linked to an increased risk of CKD, especially if fibrosis is present; however, the association between GH and MASLD has not been explored. To evaluate GH prevalence in MASLD and its possible correlation with liver fibrosis. 772 consecutive patients with ultrasound MASLD (mean age 47.3 ± 8.9 years, 67.1% males) were enrolled. GH was defined as estimated glomerular filtration rate (eGFR) greater than the upper quartile of values in the cohort. Liver stiffness measurement (LSM) by FibroScan ≥ 7.2 kPa suggested liver fibrosis. GH was present in 20% of patients, liver fibrosis in 30%. In total, 53.4% of the cohort was obese, 40.9% hypertensive, 36.3% diabetic and 70.8% dyslipidaemic. GH patients compared to non-GH were significantly younger (38.4 ± 8.3 vs. 49.5 ± 7.7, p < 0.001), with higher prevalence of LSM > 7.2 kPa (35.5% vs. 29%, p < 0.001), without any difference in metabolic comorbidities. In multivariate analysis, age (OR 0.85, CI 95% 0.82-0.87) and significant fibrosis (OR 1.83; CI 95%1.10-3.03) remained independently associated with GH, regardless of the presence of metabolic alterations and nephrotoxic drugs. GH, an early marker of renal damage, is highly prevalent in MASLD and is associated with hepatic fibrosis. GH may be considered an early marker of both liver and renal disease and its recognition could prompt the management of risk factors aimed at preventing the progression of both hepatic and renal disease.

Factors affecting long-term changes of liver stiffness in direct-acting anti-hepatitis C virus therapy: A multicentre prospective study.

The long-term changes of liver stiffness (LS) in patients who achieve viral clearance after direct-acting anti-HCV therapy remain undefined. We conducted a multicentre prospective study to investigate this aspect. Patients with HCV infection treated with DAAs were enrolled from six Italian centres; they underwent clinical, biochemical, ultrasound and transient elastography evaluations before treatment (T0), 12 weeks (SVR12) and 24 months (T24) after the end of therapy. Among the 516 consecutive patients enrolled, 301 had cirrhosis. LS significantly decreased from T0 to SVR (14.3 vs 11.1 kPa, p = .002), with a progressive reduction until T24 (8.7 kPa, p < .001). However, only patients with steatosis and those who developed HCC did not experience a late improvement in LS. Multivariate analysis of baseline and follow-up variables identified steatosis as the only independent predictor of failure of LS improvement (OR 1.802, p = .013). ROC curve analysis of the association of LS with the risk of developing HCC showed that SVR12 ≥14.0 kPa had the highest accuracy (sensitivity 82%, specificity 99%; AUC: 0.774). Multivariate analysis revealed that LS was the only variable independently associated with an increased risk of developing HCC (OR 6.470, p = .035). Achieving an SVR was associated with a progressive, long-term decline of LS, suggesting a late improvement in liver fibrosis, besides the resolution of inflammation. Fatty liver and the development of HCC interfered with late reduction of LS. Patients with an LS ≥14 kPa at 12 weeks after the end of treatment were at higher risk for developing HCC.

The role of hypoxia and inflammation in the regulation of iron metabolism and erythropoiesis in COVID-19: The IRONCOVID study.

Coronavirus Disease (COVID-19) can be considered as a human pathological model of inflammation combined with hypoxia. In this setting, both erythropoiesis and iron metabolism appear to be profoundly affected by inflammatory and hypoxic stimuli, which act in the opposite direction on hepcidin regulation. The impact of low blood oxygen levels on erythropoiesis and iron metabolism in the context of human hypoxic disease (e.g., pneumonia) has not been fully elucidated. This multicentric observational study was aimed at investigating the prevalence of anemia, the alterations of iron homeostasis, and the relationship between inflammation, hypoxia, and erythropoietic parameters in a cohort of 481 COVID-19 patients admitted both to medical wards and intensive care units (ICU). Data were collected on admission and after 7 days of hospitalization. On admission, nearly half of the patients were anemic, displaying mild-to-moderate anemia. We found that hepcidin levels were increased during the whole period of observation. The patients with a higher burden of disease (i.e., those who needed intensive care treatment or had a more severe degree of hypoxia) showed lower hepcidin levels, despite having a more marked inflammatory pattern. Erythropoietin (EPO) levels were also lower in the ICU group on admission. After 7 days, EPO levels rose in the ICU group while they remained stable in the non-ICU group, reflecting that the initial hypoxic stimulus was stronger in the first group. These findings strengthen the hypothesis that, at least in the early phases, hypoxia-driven stimuli prevail over inflammation in the regulation of hepcidin and, finally, of erythropoiesis.

Subclinical and clinical atherosclerosis in non-alcoholic fatty liver disease is associated with the presence of hypertension.

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is associated with increased cardiovascular (CV) risk. However, it is unclear whether NAFLD contributes independently to the development of CV disease. Our study aimed at assessing the differences in several indices of atherosclerosis, arterial stiffness and cardiac morphology among patients with isolated NAFLD, isolated hypertension (HT) or a combination of the two conditions. METHODS AND RESULTS: A total of 169 participants (mean age = 50.4 ± 10.2 yrs; males = 73.6%) were divided according to the presence of NAFLD and HT into three groups: only NAFLD (55 patients), only HT (49 patients), and NAFLD + HT (65 patients). Exclusion criteria were a BMI≥35 kg/m2 and a diagnosis of diabetes mellitus. Carotid ultrasonography was performed to measure markers of atherosclerosis and arterial stiffness. Cardiac remodeling was analyzed using echocardiography. The prevalence of subclinical and overt atherosclerosis was significantly higher in the NAFLD + HT patients as compared to the other two groups (atherosclerotic plaques: 43.1%, 10.9%, and 22.4% (p < 0.001) in NAFLD + HT, NAFLD, and HT groups, respectively). No differences were found among indices of arterial stiffening and cardiac remodeling across the three groups. In multivariate regression analysis, the coexistence of NAFLD and HT was an independent risk factor for overt atherosclerosis (OR = 4.88, CI 95% 1.14-20.93), while no association was found when either NAFLD or HT was considered alone. CONCLUSION: Overt atherosclerosis was significantly present only in NAFLD + HT patients, but not in patients with isolated NAFLD. This implies that the impact of NAFLD on vascular structure and function could depend on the coexistence of other major CV risk factors, such as HT.

MAFLD and CKD: An Updated Narrative Review.

Accumulating evidence now indicates that non-alcoholic fatty liver disease (NAFLD), which is the most common chronic liver disease observed in clinical practice worldwide, is independently associated with an increased risk of incident chronic kidney disease (CKD). Given that NAFLD is linked to insulin resistance, obesity and type 2 diabetes mellitus, an international panel of experts have recently proposed a name change from NAFLD to metabolic associated fatty liver disease (MAFLD). Since the diagnostic criteria for NAFLD and MAFLD are different, observational studies assessing the potential concordance (or even superiority) of MAFLD, compared with NAFLD, in detecting patients at increased risk of hepatic and extra-hepatic complications (including CKD) are required. Hence, in the last two years, some observational studies have investigated the potential relationship between MAFLD and CKD. The result is that, at present, evidence regarding the concordance or even superiority of MAFLD, compared with NAFLD, in detecting patients at higher risk of CKD is still preliminary, although some data indicate that MAFLD identifies patients with CKD as accurately as NAFLD. In this narrative review, we will discuss: (a) the epidemiological evidence assessing the association between NAFLD and risk of incident CKD, (b) the epidemiological data investigating the association between MAFLD and risk of CKD and (c) the biological mechanisms underlying the association between NAFLD/MAFLD and CKD.

PD-1/PD-L1 Immuno-Mediated Therapy in NAFLD: Advantages and Obstacles in the Treatment of Advanced Disease.

Non-alcoholic fatty liver disease (NAFLD) is characterized by an enhanced activation of the immune system, which predispose the evolution to nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Resident macrophages and leukocytes exert a key role in the pathogenesis of NAFLD. In particular, CD4+ effector T cells are activated during the early stages of liver inflammation and are followed by the increase of natural killer T cells and of CD8+ T cytotoxic lymphocytes which contribute to auto-aggressive tissue damage. To counteract T cells activation, programmed cell death 1 (PD-1) and its ligand PDL-1 are exposed respectively on lymphocytes and liver cells' surface and can be targeted for therapy by using specific monoclonal antibodies, such as of Nivolumab, Pembrolizumab, and Atezolizumab. Despite the combination of Atezolizumab and Bevacizumab has been approved for the treatment of advanced HCC, PD-1/PD-L1 blockage treatment has not been approved for NAFLD and adjuvant immunotherapy does not seem to improve survival of patients with early-stage HCC. In this regard, different ongoing phase III trials are testing the efficacy of anti-PD-1/PD-L1 antibodies in HCC patients as first line therapy and in combination with other treatments. However, in the context of NAFLD, immune checkpoints inhibitors may not improve HCC prognosis, even worse leading to an increase of CD8+PD-1+ T cells and effector cytokines which aggravate liver damage. Here, we will describe the main pathogenetic mechanisms which characterize the immune system involvement in NAFLD discussing advantages and obstacles of anti PD-1/PDL-1 immunotherapy.

Impact of direct acting antivirals (DAAs) on cardiovascular events in HCV cohort with pre-diabetes.

BACKGROUND AND AIMS: Beyond type 2 diabetes, even a condition of prediabetes is associated with an increased cardiovascular (CV) risk, and HCV infection coexistence represents an exacerbating factor. CV prognosis improvement in prediabetes represents a challenge, due to the increasing prevalence of this metabolic condition worldwide. Hence, we aimed to prospectively assess how direct acting antivirals (DAAs) could affect major cardiovascular events (MACE) in a prediabetic HCV positive cohort. METHODS AND RESULTS: In this prospective multicenter study, we enrolled HCV patients with overt prediabetes. We compared a subgroup of patients treated with DAAs with untreated prediabetic controls. We recorded all CV events occurred during an overall median follow-up of 24 months (IQR 19-34). 770 HCV positive prediabetic patients were enrolled, 398 untreated controls and 372 DAAs treated patients. Overall, the CV events annual incidence was much higher among prediabetic treated patients (1.77 vs. 0.62, p < 0.001), and HCV clearance demonstrated to significantly reduce CV events (RR: 0.411, 95%CI 0.148-1.143; p < 0.001), with an estimated NNT for one additional patient to benefit of 52.1. Moreover, an independent association between a lower rate of CV events and HCV clearance after DAAs was observed (OR 4.67; 95%CI 0.44-53.95; p = 0.016). CONCLUSIONS: HCV eradication by DAAs allows a significant reduction of MACEs in the prediabetic population, and therefore represents a primary objective, regardless of the severity of liver disease and CV risk factors.

FibroScan Identifies Patients With Nonalcoholic Fatty Liver Disease and Cardiovascular Damage.

Patients with nonalcoholic fatty liver disease (NAFLD), particularly in the presence of nonalcoholic steatohepatitis or fibrosis, are at high cardiac and cerebrovascular risk.1.

Liver fibrosis by FibroScan® independently of established cardiovascular risk parameters associates with macrovascular and microvascular complications in patients with type 2 diabetes.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are closely associated, and liver fibrosis has been related to macrovascular complications. We examined whether liver fibrosis, diagnosed by FibroScan® , correlates with chronic vascular complications in a cohort of T2DM. METHODS: We recruited 394 outpatients with T2DM attending five Italian diabetes centres who underwent liver ultrasonography (US), FibroScan® and extensive evaluation of macrovascular and microvascular diabetic complications. RESULTS: Steatosis by US was present in 89%. Almost all patients (96%) were on hypoglycaemic drugs, 58% had at least one chronic vascular complication, 19% a macrovascular complication (prior myocardial infarction and/or ischaemic stroke) and 33% a microvascular one (26% chronic kidney disease [CKD]; 16% retinopathy; 6% neuropathy). In all, 171 (72%) patients had CAP ≥ 248dB/m (ie hepatic steatosis), whereas 83 (21%) patients had LSM ≥ 7.0/6.2 kPa (M/XL probes) (significant liver fibrosis). CAP was not associated with any macro/microvascular complications, whereas LSM ≥ 7.0/6.2 kPa was independently associated with prior cardiovascular disease (adjusted OR 3.3, 95%CI 1.2-8.8; P = .02) and presence of microvascular complications (adjusted OR 4.2, 95%CI 1.5-11.4; P = .005), mainly CKD (adjusted OR 3.6, 95%CI 1.3-10.1; P = .01) and retinopathy (adjusted OR 3.7, CI 95% 1.2-11.9; P = .02). Neither diabetes duration nor haemoglobin A1c differed according to CAP or LSM values. CONCLUSION: Significant fibrosis, detected by FibroScan® , is independently associated with increased prevalence of macrovascular and microvascular complications, thus opening a new scenario in the use of this tool for a comprehensive evaluation of hepatic and vascular complications in patients with T2DM.

Reduced incidence of type 2 diabetes in patients with chronic hepatitis C virus infection cleared by direct-acting antiviral therapy: A prospective study.

AIM: To assess the effect of hepatitis C virus (HCV) eradication on type 2 diabetes mellitus (T2DM). incidence. METHODS: A prospective multicentre case-control study was performed, which included 2426 patients with HCV, 42% of whom had liver fibrosis stage F0-F2 and 58% of whom had liver fibrosis stage F3-F4. The study population consisted of a control group including 1099 untreated patients and 1327 cases treated with direct-acting antivirals (DAAs). T2DM incidence was assessed during a median (interquartile range) follow-up period of 30 (28-42) months. Risk factors for T2DM were assessed using a Cox regression model (relative risk [RR], hazard ratio [HR], Kaplan-Meier analysis). Insulin sensitivity was evaluated by homeostatic model assessment (HOMA) and changes by repeated-measures ANOVA. Factors independently associated with T2DM were assessed by multivariate analysis. RESULTS: The absolute incidence of T2DM for controls and cases was 28 and 7/1000 person-years, respectively (P = 0.001). In cases compared to controls, HCV clearance reduced the RR and HR of T2DM by 81% and 75% to 93%, respectively (P = 0.001). It was calculated that, for every 15 patients who obtained HCV clearance, one case of T2DM was saved. HCV clearance was associated with significant reductions in HOMA-insulin resistance and HOMA-ß-cell function and an increase in HOMA-insulin sensitivity, as assessed in 384 patients before and after HCV clearance. At multivariate analysis, HCV clearance emerged as independently associated with a reduced T2DM risk. CONCLUSION: The results showed that HCV clearance by DAA treatment reduces T2DM incidence probably by restoring the HCV-induced alteration of glucose homeostasis mechanisms.

Nutrients, Genetic Factors, and Their Interaction in Non-Alcoholic Fatty Liver Disease and Cardiovascular Disease.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries and expose patients to increased risk of hepatic and cardiovascular (CV) morbidity and mortality. Both environmental factors and genetic predisposition contribute to the risk. An inappropriate diet, rich in refined carbohydrates, especially fructose, and saturated fats, and poor in fibers, polyunsaturated fats, and vitamins is one of the main key factors, as well as the polymorphism of patatin-like phospholipase domain containing 3 (PNPLA3 gene) for NAFLD and the apolipoproteins and the peroxisome proliferator-activated receptor (PPAR) family for the cardiovascular damage. Beyond genetic influence, also epigenetics modifications are responsible for various clinical manifestations of both hepatic and CV disease. Interestingly, data are accumulating on the interplay between diet and genetic and epigenetic modifications, modulating pathogenetic pathways in NAFLD and CV disease. We report the main evidence from literature on the influence of both macro and micronutrients in NAFLD and CV damage and the role of genetics either alone or combined with diet in increasing the risk of developing both diseases. Understanding the interaction between metabolic alterations, genetics and diet are essential to treat the diseases and tailoring nutritional therapy to control NAFLD and CV risk.

Impact of Obesity and Alanine Aminotransferase Levels on the Diagnostic Accuracy for Advanced Liver Fibrosis of Noninvasive Tools in Patients With Nonalcoholic Fatty Liver Disease.

INTRODUCTION: Some evidence suggests an interference of obesity and alanine aminotransferase (ALT) levels on the diagnostic accuracy for advanced fibrosis of noninvasive tools such as liver stiffness measurement (LSM) by FibroScan, Fibrosis-4 (FIB-4), and nonalcoholic fatty liver disease fibrosis score (NFS). We assessed whether the diagnostic accuracy of LSM, Fibrosis-4 (FIB-4), and NFS and strategies based on the combination of these tools is affected by obesity and/or ALT levels. METHODS: We analyzed data from 968 patients with a histological diagnosis of nonalcoholic fatty liver disease. FIB-4, NFS, and LSM by FibroScan were measured. RESULTS: LSM was better than both FIB-4 and NFS for staging F3-F4 fibrosis area under the receiver operating characteristic curve test (AUC) 0.863, 0.777, and 0.765, respectively; P < 0.001 for both), showing higher accuracy and higher negative predictive value (NPV), but lower positive predictive value (PPV). LSM worked less well in high ALT (>100 IU) (AUC 0.811 vs 0.877, P = 0.04; PPV 57.5% vs 62.4%; NPV 90.7% vs 94%) or obese patients (AUC 0.786 vs 0.902, P < 0.001; PPV 58.7% vs 64.8%; NPV 88.3% vs 95.2%), the latter not being affected by the M or XL probe. Consistently, LSM worked better in terms of AUC and accuracy compared with both FIB-4 and NFS only in nonobese or high ALT patients, even with always keeping a slightly lower PPV. A serial combination of FIB-4 or NFS with LSM as the second test in patients in the gray area of the first test retained-in most scenarios-similar PPV and NPV compared with LSM alone. These strategies also increased the diagnostic accuracy of about 20% in all groups of patients, even if with a lower overall accuracy in obese patients (71.3% and 67.1% for FIB-4 and NFS as the first test, respectively) compared to nonobese patients (81.9% and 82.4% for FIB-4 and NFS as the first test, respectively). CONCLUSIONS: All tested noninvasive tools have overall better NPV than PPV. LSM has a better diagnostic accuracy for advanced fibrosis than both FIB-4 and NFS only in nonobese and/or low ALT patients. Serial combination strategies are better than a single tool strategy, regardless of obesity and ALT levels, although the accuracy is lower in obese patients.

Procoagulant imbalance influences cardiovascular and liver damage in chronic hepatitis C independently of steatosis.

BACKGROUND & AIMS: Patients with chronic HCV infection besides hepatitis often present cardiovascular damage, the pathogenesis of which is not defined. In chronic liver diseases, including NAFLD and cirrhosis, a procoagulant imbalance, potentially responsible for atherosclerosis has been reported. We aimed at evaluating whether a procoagulant imbalance is present also in non-cirrhotic patients with HCV infection and whether the procoagulant imbalance correlates with cardiovascular damage. The correlation between the procoagulant imbalance, coexisting steatosis, and liver fibrosis was analysed. METHODS: From 2014 to 2018, 393 subjects (205 patients with chronic HCV infection from two liver units and 188 controls) were enrolled. Metabolic, cardiovascular, liver assessment and coagulation parameters-procoagulants (FII and FVIII) and anticoagulants (antithrombin and protein C [PC]), endogenous thrombin potential (ETP), peak-thrombin and their ratios (with/without thrombomodulin)-were determined. RESULTS: The procoagulant imbalance (defined as high FVIII, FVIII/PC ratio, ETP-ratio and peak-thrombin-ratio (with/without thrombomodulin)) was significantly higher in patients with chronic HCV than controls. Steatosis was detected in 87 patients (42%). No difference in coagulation imbalance, carotid and cardiac parameters and severity of liver fibrosis was observed in patients with or without steatosis, despite the latter had less severe metabolic alterations. The FVIII/PC ratio was independently associated with carotid intima-media thickness (coefficient 0.04, 95% CI 0.002-0.07, P = .04) and liver fibrosis (coefficient 0.64, 95% CI 0.37-0.92, P < .0001). CONCLUSION: Patients with HCV infection, even in the absence of cirrhosis have a procoagulant-imbalance that possibly plays a role in increasing the risk of cardiovascular disease and progression of fibrosis.

Liver and Cardiovascular Damage in Patients With Lean Nonalcoholic Fatty Liver Disease, and Association With Visceral Obesity.

BACKGROUND & AIMS: Lean nonalcoholic fatty liver disease (NAFLD) is defined as NAFLD that develops in patients with a body mass index (BMI) less than 25 kg/m2. We investigated the differences between lean NAFLD and NAFLD in overweight and obese persons, factors associated with the severity of liver and cardiovascular disease, and the effects of visceral obesity. METHODS: We performed a retrospective cohort study of 669 consecutive patients with biopsy-proven NAFLD seen at 3 liver centers in Italy. We collected anthropometric, clinical, and biochemical data, as well as information on carotid atherosclerosis (artery intima-media thickness and plaque), liver histology (nonalcoholic steatohepatitis [NASH] and fibrosis), insulin resistance, and diabetes. Overweight was defined as a BMI of 25 to 29.9 kg/m2, and obese was defined as a BMI of 30 kg/m2 or greater. Patients were assigned to groups based on waist circumference, a marker of visceral obesity (low: men, <94 cm, women <80 cm; medium: men, 94-102 cm, women 80-88 cm; or high: men >102 cm, women >88 cm). DNA samples were analyzed for the rs738409 C>G (I148M in PNPLA3), the rs58542926 C>T (E167K in TM6SF2), and single-nucleotide polymorphisms. Variables in men and women were analyzed using chi-squared analysis and the Mann-Whitney or Kruskal-Wallis tests. Multiple linear or logistic regression analyses were adjusted for all the variables of clinical relevance or statistically significant at univariate analyses. The primary outcome was the difference in liver and cardiovascular disease between lean NAFLD and NAFLD in overweight and obese persons. Secondary outcomes were effects of visceral obesity, based on waist circumference, on hepatic, vascular, and metabolic features. RESULTS: Significantly lower proportions of patients with lean NAFLD (143 patients; 43 women; mean age, 46 ± 13 y) had hypertension (P = .001), diabetes (P = .0001), and metabolic syndrome (P = .0001) than overweight or obese patients with NAFLD (526 patients; 149 women; mean age, 49 ± 12 y). Significantly lower proportions of patients with lean NAFLD had NASH (17% vs 40% of obese or overweight patients with NAFLD; P = .0001), fibrosis of F2 or higher (17% vs 42%; P = .0001), or carotid plaques (27% vs 39%; P = .03). Patients with lean NAFLD had significantly thinner carotid intima-media (0.74 ± 0.1 mm) than obese or overweight patients with NAFLD (0.84 ± 0.3 mm; P = .0001). There was no significant difference in the proportions of patients with rs738409 C>G in PNPLA3, but a significantly greater proportion of patients with lean NAFLD carried rs58542926 C>T in TM6SF2 (4%) than obese or overweight individuals with NAFLD (0.3%; P = .001). Of the 143 patients with lean NAFLD, 27 had grade 3 steatosis, 24 had a lobular inflammation score greater than 2, 10 had a ballooning score of 2, and 25 had a fibrosis score of 2 or higher. In patients with lean NAFLD, the only variable associated independently with NASH and a fibrosis score of 2 or higher was rs738409 C>G in PNPLA3. Patients with lean NAFLD and a medium waist circumference had a significantly higher risk of diabetes (odds ratio, 11; 95% confidence interval [CI], 1.2-106; P = .03) than overweight or obese patients with a similar waist circumference (odds ratio, 1.3; 95% CI, 0.4-4.2; P = .6). Lean and overweight or obese patients with high waist circumferences had significant increases in risk compared with patients with low and medium circumference and diabetes, hypertension, and fibrosis scores of 2 or higher. CONCLUSIONS: In a retrospective study of patients with lean NAFLD vs obese or overweight persons with NAFLD, we found 20% of patients with lean NAFLD to have NASH, fibrosis scores of 2 or higher, and carotid atherosclerosis. Lean patients with rs738409 C>G in PNPLA3 should be monitored for liver disease progression; studies including large series of patients with lean NAFLD will clarify the possible role of TM6SF2 polymorphisms.

Pharmacological interventions for non-alcohol related fatty liver disease (NAFLD): an attempted network meta-analysis.

BACKGROUND: Non-alcohol related fatty liver disease (commonly called non-alcoholic fatty liver disease (NAFLD)) is liver steatosis in the absence of significant alcohol consumption, use of hepatotoxic medication, or other disorders affecting the liver such as hepatitis C virus infection, Wilson's disease, and starvation. NAFLD embraces the full spectrum of disease from pure steatosis (i.e. uncomplicated fatty liver) to non-alcoholic steatohepatitis (NASH), via NASH-cirrhosis to cirrhosis. The optimal pharmacological treatment for people with NAFLD remains uncertain. OBJECTIVES: To assess the comparative benefits and harms of different pharmacological interventions in the treatment of NAFLD through a network meta-analysis and to generate rankings of the available pharmacological treatments according to their safety and efficacy. However, it was not possible to assess whether the potential effect modifiers were similar across different comparisons. Therefore, we did not perform the network meta-analysis, and instead, assessed 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, the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.com to August 2016. SELECTION CRITERIA: We included only randomised clinical trials (irrespective of language, blinding, or publication status) in participants with NAFLD. We excluded trials which included participants who had previously undergone liver transplantation. We considered any of the various pharmacological interventions compared with each other or with placebo or no intervention. DATA COLLECTION AND ANALYSIS: We calculated the odds ratio (OR) and rate ratio with 95% confidence intervals (CI) using both fixed-effect and random-effects models based on an available participant analysis with Review Manager. We assessed risk of bias according to the Cochrane risk of bias tool, controlled risk of random errors with Trial Sequential Analysis, and assessed the quality of the evidence using GRADE. MAIN RESULTS: We identified 77 trials including 6287 participants that met the inclusion criteria of this review. Forty-one trials (3829 participants) provided information for one or more outcomes. Only one trial was at low risk of bias in all domains. All other trials were at high risk of bias in one or more domains. Overall, all the evidence was very low quality. Thirty-five trials included only participants with non-alcohol related steatohepatitis (NASH) (based on biopsy confirmation). Five trials included only participants with diabetes mellitus; 14 trials included only participants without diabetes mellitus. The follow-up in the trials ranged from one month to 24 months.We present here only the comparisons of active intervention versus no intervention in which two or more trials reported at least one of the following outcomes: mortality at maximal follow-up, serious adverse events, and health-related quality of life, the outcomes that determine whether a treatment should be used. Antioxidants versus no interventionThere was no mortality in either group (87 participants; 1 trial; very low quality evidence). None of the participants developed serious adverse events in the trial which reported the proportion of people with serious adverse events (87 participants; 1 trial; very low quality evidence). There was no evidence of difference in the number of serious adverse events between antioxidants and no intervention (rate ratio 0.89, 95% CI 0.36 to 2.19; 254 participants; 2 trials; very low quality evidence). None of the trials reported health-related quality of life. Bile acids versus no interventionThere was no evidence of difference in mortality at maximal follow-up (OR 5.11, 95% CI 0.24 to 107.34; 659 participants; 4 trials; very low quality evidence), proportion of people with serious adverse events (OR 1.56, 95% CI 0.84 to 2.88; 404 participants; 3 trials; very low quality evidence), or the number of serious adverse events (rate ratio 1.01, 95% CI 0.66 to 1.54; 404 participants; 3 trials; very low quality evidence) between bile acids and no intervention. None of the trials reported health-related quality of life. Thiazolidinediones versus no interventionThere was no mortality in either group (74 participants; 1 trial; very low quality evidence). None of the participants developed serious adverse events in the two trials which reported the proportion of people with serious adverse events (194 participants; 2 trials; very low quality evidence). There was no evidence of difference in the number of serious adverse events between thiazolidinediones and no intervention (rate ratio 0.25, 95% CI 0.06 to 1.05; 357 participants; 3 trials; very low quality evidence). None of the trials reported health-related quality of life. Source of fundingTwenty-six trials were partially- or fully-funded by pharmaceutical companies that would benefit, based on the results of the trial. Twelve trials did not receive any additional funding or were funded by parties with no vested interest in the results. The source of funding was not provided in 39 trials. AUTHORS' CONCLUSIONS: Due to the very low quality evidence, we are very uncertain about the effectiveness of pharmacological treatments for people with NAFLD including those with steatohepatitis. Further well-designed randomised clinical trials with sufficiently large sample sizes are necessary.