Natural history of NASH Armandi, Angelo; Bugianesi, Elisabetta; Valenti, Luca
Liver international,
June 2021, 2021-06-00, 20210601, Letnik:
41, Številka:
S1
Journal Article
Recenzirano
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Non‐alcoholic fatty liver disease (NAFLD) is the fastest growing cause of chronic liver disease worldwide. Although only a small proportion of NAFLD patients will progress to end‐stage liver disease ...and death, the clinical burden of NAFLD is substantial due the sheer number of individuals affected worldwide. In fact, recent estimates suggest that 25% of the world have NAFLD, which is now one of the leading causes of cirrhosis and indications for liver transplantation. Although liver‐related mortality is common, the most common cause of death in patients with NAFLD is related to cardiovascular diseases, followed by extra‐hepatic cancers. There is a significant interindividual variability in the susceptibility to liver disease. The severity of metabolic alterations is the main risk factor for progressive NAFLD, but the qualitative components of diet, physical activity and genetic factors also play an important role. In particular, common variants in patatin‐like phospholipase domain‐containing 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2), membrane bound O‐acyl transferase 7 (MBOAT7) and glucokinase regulator (GCKR) have been shown to contribute to the full spectrum of NAFLD. In those at risk of a potentially progressive form of NAFLD or non‐alcoholic steatohepatitis or in those with hepatic fibrosis, additional assessment must be made.
Current treatment recommendations for non-alcoholic fatty liver disease (NAFLD) rely heavily on lifestyle interventions. The Mediterranean diet and physical activity, aiming at weight loss, have ...shown good results in achieving an improvement of this liver disease. However, concerns related to compliance and food accessibility limit the feasibility of this approach, and data on the long-term effects on liver-related outcomes are lacking. Insulin resistance is a central aspect in the pathophysiology of NAFLD; therefore, interventions aiming at the improvement of insulin sensitivity may be preferable. In this literature review, we provide a comprehensive summary of the available evidence on nutritional approaches in the management of NAFLD, involving low-calorie diets, isocaloric diets, and the novel schemes of intermittent fasting. In addition, we explore the harmful role of single nutrients on liver-specific key metabolic pathways, the role of gene susceptibility and microbiota, and behavioral aspects that may impact liver disease and are often underreported in clinical setting. At present, the high variability in terms of study populations and liver-specific outcomes within nutritional studies limits the generalizability of the results and highlights the urgent need of a tailored and standardized approach, as seen in regulatory trials in Non-Alcoholic Steatohepatitis (NASH).
Insulin resistance (IR) is defined as a lower-than-expected response to insulin action from target tissues, leading to the development of type 2 diabetes through the impairment of both glucose and ...lipid metabolism. IR is a common condition in subjects with nonalcoholic fatty liver disease (NAFLD) and is considered one of the main factors involved in the pathogenesis of nonalcoholic steatohepatitis (NASH) and in the progression of liver disease. The liver, the adipose tissue and the skeletal muscle are major contributors for the development and worsening of IR. In this review, we discuss the sites and mechanisms of insulin action and the IR-related impairment along the spectrum of NAFLD, from simple steatosis to progressive NASH and cirrhosis.
Sarcopenia is a common muscular affection among elderly individuals. More recently, it has been recognized as the skeletal muscle (SM) expression of the metabolic syndrome. The prevalence of ...sarcopenia is increasing along with visceral obesity, to which it is tightly associated. Nonetheless, it is a still underreported entity by clinicians, despite the worsening in disease burden and reduced patient quality of life. Recognition of sarcopenia is clinically challenging, and variability in study populations and diagnostic methods across the clinical studies makes it hard to reach a strong evidence. Impaired insulin activity in SM is responsible for the altered molecular pathways and clinical manifestations of sarcopenia, which is morphologically expressed by myosteatosis. Lipotoxicity, oxidative stress and adipose tissue-derived inflammation lead to both alterations in glucose disposal and protein synthesis in SM, with raising insulin resistance (IR) and SM atrophy. In particular, hyperleptinemia and leptin resistance interfere directly with SM activity, but also with the release of Growth Hormone from the hypohysis, leading to a lack in its anabolic effect on SM. Moreover, sarcopenia is independently associated to liver fibrosis in Non-Alcoholic Fatty Liver Disease (NAFLD), which in turn worsens SM functionality through the secretion of proinflammatory heptokines. The cross-talk between the liver and SM in the IR setting is of crucial relevance, given the high prevalence of NAFLD and the reciprocal impact of insulin-sensitive tissues on the overall disease burden. Along with the efforts of non-invasive diagnostic approaches, irisin and myostatin are two myokines currently evaluated as potential biomarkers for diagnosis and prognostication. Decreased irisin levels seem to be potentially associated to sarcopenia, whereas increased myostatin has shown to negatively impact on sarcopenia in pre-clinical studies. Gene variants in irisin have been explored with regard to the impact on the liver disease phenotype, with conflicting results. The gut-muscle axis has gain relevance with the evidence that insulin resistance-derived gut dysbiosis is responsible for increased endotoxemia and reduction in short-chain free fatty acids, directly affecting and predisposing to sarcopenia. Based on the current evidence, more efforts are needed to increase awareness and improve the management of sarcopenic patients.
Behavioral programs are needed for prevention and treatment of NAFLD and the effectiveness of a web-based intervention (WBI) is similar to a standard group-based intervention (GBI) on liver disease ...biomarkers.
We aimed to test the long-term effectiveness of both programs on diabetes incidence, a common outcome in NAFLD progression.
546 NAFLD individuals (212 WBI, 334 GBI) were followed up to 60 months with regular 6- to 12-month hospital visits. The two cohorts differed in several socio-demographic and clinical data. In the course of the years, the average BMI similarly decreased in both cohorts, by 5% or more in 24.4% and by 10% or more in 16.5% of cases available at follow-up. After excluding 183 cases with diabetes at entry, diabetes was newly diagnosed in 48 cases during follow-up (31 (16.6% of cases without diabetes at entry) in the GBI cohort vs. 17 (9.7%) in WBI;
= 0.073). Time to diabetes was similar in the two cohorts (mean, 31 ± 18 months since enrollment). At multivariable regression analysis, incident diabetes was significantly associated with prediabetes (odds ratio (OR) 4.40; 95% confidence interval (CI) 1.97-9.81;
< 0.001), percent weight change (OR 0.57; 95% CI 0.41-0.79;
< 0.001) and higher education (OR 0.49; 95% CI 0.27-0.86;
= 0.014), with no effect of other baseline socio-demographic, behavioral and clinical data, and of the type of intervention. The importance of weight change on incident diabetes were confirmed in a sensitivity analysis limited to individuals who completed the follow-up.
In individuals with NAFLD, WBI is as effective as GBI on the pending long-term risk of diabetes, via similar results on weight change.
The prevalence of metabolic risk factors and non-alcoholic fatty liver disease (NAFLD) is high among people living with HIV (PLWH). Data on the recently proposed definition of metabolic ...dysfunction-associated fatty liver disease (MAFLD) in PLWH receiving antiretroviral therapy (ART) remains unknown. A total of 282 PLWH were included in this cross-sectional cohort study. Vibration-controlled transient elastography (VCTE) was used to assess hepatic steatosis and fibrosis. MAFLD and its subgroups (overweight/obese, lean/normal weight, and type 2 diabetes) were defined according to a recently published international consensus statement. The majority of this cohort was male (n = 198, 70.2%), and the median age was 51.5 years. The median BMI was 25 kg/m
, and obesity was prevalent in 16.2% (n = 44). A total of 207 (73.4%) PLWH were classified as non-MAFLD while 75 (26.6%) qualified as MAFLD. The median CAP in the MAFLD group was 320 dB/m. PLWH with MAFLD showed a higher median LSM (p < 0.008) and were older (p < 0.005) compared to the non-MAFLD group. Overall, the metabolic risk profile was comparable between MAFLD and NAFLD. The majority of PLWH and MAFLD were overweight or obese (n = 58, 77.3%). The highest median LSM values were observed in the subgroup with MAFLD and type 2 diabetes. HIV-related parameters did not differ between non-MAFLD and MAFLD. The prevalence of MAFLD in PLWH is high and comparable to NAFLD. PLWH may be characterized according to the novel MAFLD criteria and its subgroups to identify patients at risk for chronic liver disease.
Several features of the modern lifestyle, such as weekly schedules or irregular daily eating patterns, have become major drivers of global health problems, including non-alcoholic fatty liver disease ...(NAFLD). Sleep is an essential component of human well-being, and it has been observed that when circadian rhythms are disrupted, or when sleep quality decreases, an individual's overall health may worsen. In addition, the discrepancy between the circadian and social clock, due to weekly work/study schedules, is called social jetlag and has also been associated with adverse metabolic profiles. Current management of NAFLD is based on dietary intake and physical activity, with circadian preferences and other environmental factors also needing to be taken into account. In this regard, dietary approaches based on chrononutrition, such as intermittent fasting or time-restricted feeding, have proven to be useful in realigning lifestyle behaviors with circadian biological rhythms. However, more studies are needed to apply these dietary strategies in the treatment of these patients. In this review, we focus on the impact of circadian rhythms and the role of sleep patterns on the pathogenesis and development of NAFLD, as well as the consideration of chrononutrition for the precision nutrition management of patients with NAFLD.
Late chronotype, the individual's aptitude to perform daily activities late in the day, has been associated with low adherence to the Mediterranean diet (MedDiet) and metabolic syndrome. The aim of ...this work was to investigate the potential association of chronotype and adherence to the MedDiet with the liver fibrosis risk in patients with non-alcoholic fatty liver disease (NAFLD). Liver stiffness was assessed in 126 patients by FibroScan
530. Significant (F ≥ 2) and advanced (F ≥ 3) hepatic fibrosis were defined according to liver stiffness values ≥7.1 kPa and ≥8.8 kPa, respectively. Chronotype (MSFsc) was defined by the Munich Chronotype Questionnaire, and adherence to the MedDiet was defined by the Mediterranean diet score (MDS). Overall, the median age was 55 (46-63) years, and 57.9% of participants were male. The principal comorbidities were type-2 diabetes mellitus (T2DM) (26.1%), arterial hypertension (53.1%), dyslipidaemia (63.4%), obstructive sleep apnoea (5.5%) and depression (5.5%). Most subjects (65.0%) had intermediate + late chronotype and showed higher mid-sleep on workdays (
< 0.001) and on work-free days (
< 0.001) compared to those with early chronotype. In the logistic regression model, intermediate + late chronotype (
= 0.024), MDS (
= 0.019) and T2DM (
= 0.004) were found to be significantly and independently associated with the risk of both F ≥ 2 And F ≥ 3. We observed that the intermediate + late chronotype and low adherence to the MedDiet were associated with both significant and advanced liver fibrosis in patients with NAFLD.
Current surveillance strategy for patients with nonalcoholic fatty liver disease (NAFLD) at risk of hepatocellular carcinoma (HCC) development is unsatisfactory. We aimed to investigate the ...diagnostic accuracy of alpha-fetoprotein (AFP), protein induced by vitamin K absence or antagonist-II (PIVKA-II), glypican-3 (GPC-3), adiponectin, leptin and interleukin-6 (IL-6), alone or in combination, for the discrimination between NAFLD patients with or without HCC. The biomarkers were investigated in a cohort of 191 NAFLD patients (median age 62, 54–68 years; 121 males and 70 females) with advanced fibrosis/cirrhosis, 72 of whom had a diagnosis of HCC. PIVKA-II showed the best performance for the detection of HCC with an area under the curve (AUC) of 0.853, followed by adiponectin (AUC = 0.770), AFP (AUC = 0.763), GPC-3 (AUC = 0.759) and by IL-6 (AUC = 0.731), while the leptin values were not different between patients with and without HCC. The accuracy of the biomarkers’ combination was assessed by a stratified cross-validation approach. The combination of age, gender, PIVKA-II, GPC-3 and adiponectin further improved the diagnostic accuracy (AUC = 0.948); the model correctly identified the 87% of the patients. In conclusion, we developed a model with excellent accuracy for the detection of HCC that may be useful to improve the surveillance of NAFLD patients at risk of tumor development.
Intrahepatic oxidative stress is a key driver of inflammation and fibrogenesis in non-alcoholic fatty liver disease (NAFLD). We aimed to investigate the role of extracellular Nicotinamide ...phosphoribosyltransferase (eNAMPT) and extracellular nicotinic acid phosphoribosyltransferase (eNAPRT) for the detection of advanced fibrosis. eNAMPT and eNAPRT were tested in 180 consecutive biopsy-proven NAFLD patients and compared with liver stiffness (LS) and the FIB-4 score. eNAMPT was similarly distributed across fibrosis stages, whereas eNAPRT was increased in patients with advanced fibrosis (
= 0.036) and was associated with advanced fibrosis (OR 1.08,
= 0.016). A multiple stepwise logistic regression model containing significant variables for advanced fibrosis (eNAPRT, type 2 diabetes, age, male sex, ALT) had an area under the curve (AUC) of 0.82 (Se 89.6%, Sp 67.3%, PPV 46.7%, NPV 93.8%) when compared to that of LS (0.79; Se 63.5%, Sp 86.2%, PPV 66.0%, NPV 84.8%) and to that of the FIB-4 score (0.73; Se 80.0%, Sp 56.8%, PPV 44.9%, NPV 86.6%). The use of eNAPRT in clinical practice might allow for the better characterization of NAFLD patients at higher risk of disease progression.
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