Non-alcoholic fatty liver disease Powell, Elizabeth E; Wong, Vincent Wai-Sun; Rinella, Mary
The Lancet (British edition),
06/2021, Letnik:
397, Številka:
10290
Journal Article
Recenzirano
Non-alcoholic fatty liver disease (NAFLD) has a global prevalence of 25% and is a leading cause of cirrhosis and hepatocellular carcinoma. NAFLD encompasses a disease continuum from steatosis with or ...without mild inflammation (non-alcoholic fatty liver), to non-alcoholic steatohepatitis (NASH), which is characterised by necroinflammation and faster fibrosis progression than non-alcoholic fatty liver. NAFLD has a bidirectional association with components of the metabolic syndrome, and type 2 diabetes increases the risk of cirrhosis and related complications. Although the leading causes of death in people with NAFLD are cardiovascular disease and extrahepatic malignancy, advanced liver fibrosis is a key prognostic marker for liver-related outcomes and overall mortality, and can be assessed with combinations of non-invasive tests. Patients with cirrhosis should be screened for hepatocellular carcinoma and oesophageal varices. There is currently no approved therapy for NAFLD, although several drugs are in advanced stages of development. Because of the complex pathophysiology and substantial heterogeneity of disease phenotypes, combination treatment is likely to be required for many patients with NAFLD. Healthy lifestyle and weight reduction remain crucial to the prevention and treatment of NAFLD.
Over the past 2 decades, nonalcoholic fatty liver disease (NAFLD) has grown from a relatively unknown disease to the most common cause of chronic liver disease in the world. In fact, 25% of the ...world’s population is currently thought to have NAFLD. Nonalcoholic steatohepatitis (NASH) is the subtype of NAFLD that can progress to cirrhosis, hepatocellular carcinoma (HCC), and death. NAFLD and NASH are not only found in adults—there is also a high prevalence of these diseases in children and adolescents. Because of the close association of NAFLD with type 2 diabetes (T2DM) and obesity, the latest models predict that the prevalence of NAFLD and NASH will increase, causing a tremendous clinical and economic burden and poor patient‐reported outcomes. Nonetheless, there is no accurate noninvasive method to detect NASH, and treatment of this disease is limited to lifestyle modifications. To examine the state of NAFLD among different regions and understand the global trajectory of this disease, an international group of experts came together during the 2017 American Association for the Study of Liver Diseases Global NAFLD Forum. We provide a summary of this forum and an assessment of the current state of NAFLD and NASH worldwide.
Summary
Background
The American and European liver associations have endorsed new nomenclature of steatotic liver disease (SLD) and definition of metabolic dysfunction‐associated steatotic liver ...disease (MASLD).
Aims
To review the historical development leading to the changes and to discuss the implications of the changes on research and clinical practice
Methods
We performed a literature search using keywords related to MASLD and non‐alcoholic fatty liver disease (NAFLD).
Results
The SLD umbrella allows classification of patients under the key categories of MASLD, alcohol‐associated liver disease and a new entity termed MetALD, which represents MASLD with increased alcohol intake. The diagnosis of MASLD requires the demonstration of hepatic steatosis and at least one metabolic risk factor, whereas MASLD can co‐exist with other liver diseases such as chronic viral hepatitis. Despite the change in definition, over 95% of patients previously known as having NAFLD fulfil diagnostic criteria for MASLD. It is conceivable that future clinical trials and biomarker studies will continue to exclude concomitant liver diseases. As most patients with MASLD are seen at primary care and non‐hepatology settings, communication with other stakeholders is essential to ensure disease awareness and smooth adoption of the changes.
Conclusions
The new nomenclature is both a challenge, given the need for dissemination and education across the spectrum of stakeholders, and an opportunity to bring everyone together and spark new research to better understand epidemiology, natural history, diagnosis, biomarkers and management strategies across the spectrum of SLD.
The American and European liver associations have endorsed new nomenclature of steatotic liver disease and definition of metabolic dysfunction‐associated steatotic liver disease. The definition recognises the spectrum of disease due to metabolic risk factors, alcohol consumption, or both. This review article discusses the historical development leading to the changes and the implications of the changes on research and clinical practice.
Liver fibrosis is the most important predictor of mortality in nonalcoholic fatty liver disease (NAFLD). Quantitative risk of mortality by fibrosis stage has not been systematically evaluated. We ...aimed to quantify the fibrosis stage–specific risk of all‐cause and liver‐related mortality in NAFLD. Through a systematic review and meta‐analysis, we identified five adult NAFLD cohort studies reporting fibrosis stage–specific mortality (0‐4). Using fibrosis stage 0 as a reference population, fibrosis stage–specific mortality rate ratios (MRRs) with 95% confidence intervals (CIs) for all‐cause and liver‐related mortality were estimated. The study is reported according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses statement. Included were 1,495 NAFLD patients with 17,452 patient years of follow‐up. Compared to NAFLD patients with no fibrosis (stage 0), NAFLD patients with fibrosis were at an increased risk for all‐cause mortality, and this risk increased with increases in the stage of fibrosis: stage 1, MRR = 1.58 (95% CI 1.19‐2.11); stage 2, MRR = 2.52 (95% CI 1.85‐3.42); stage 3, MRR = 3.48 (95% CI 2.51‐4.83); and stage 4, MRR = 6.40 (95% CI 4.11‐9.95). The results were more pronounced as the risk of liver‐related mortality increased exponentially with each increase in the stage of fibrosis: stage 1, MRR = 1.41 (95% CI 0.17‐11.95); stage 2, MRR = 9.57 (95% CI 1.67‐54.93); stage 3, MRR = 16.69 (95% CI 2.92‐95.36); and stage 4, MRR = 42.30 (95% CI 3.51‐510.34). Limitations of the study include an inability to adjust for comorbid conditions or demographics known to impact fibrosis progression in NAFLD and the inclusion of patients with simple steatosis and nonalcoholic steatohepatitis without fibrosis in the reference comparison group. Conclusion: The risk of liver‐related mortality increases exponentially with increase in fibrosis stage; these data have important implications in assessing the utility of each stage and benefits of regression of fibrosis from one stage to another. (Hepatology 2017;65:1557‐1565).
Nonalcoholic fatty liver disease (NAFLD) affects 25% of the global adult population and is the most common chronic liver disease worldwide. Nonalcoholic steatohepatitis (NASH) is the active form of ...NAFLD, with hepatic necroinflammation and faster fibrosis progression. With an increasing number of patients developing NASH-related end-stage liver disease and pharmacological treatments on the horizon, there is a pressing need to develop NAFLD and NASH biomarkers for prognostication, selection of patients for treatment and monitoring. This requirement is particularly true as liver biopsy utility is limited by its invasive nature, poor patient acceptability and sampling variability. This article reviews current and potential biomarkers for different features of NAFLD, namely, steatosis, necroinflammation and fibrosis. For each biomarker, we evaluate its accuracy, reproducibility, responsiveness, feasibility and limitations. We cover biochemical, imaging and genetic biomarkers and discuss biomarker discovery in the omics era.
The aim of this study was to evaluate cenicriviroc (CVC), a dual antagonist of CC chemokine receptor types 2 and 5, for treatment of nonalcoholic steatohepatitis (NASH) with liver fibrosis (LF). A ...randomized, double‐blind, multinational phase 2b study enrolled subjects with NASH, a nonalcoholic fatty liver disease activity score (NAS) ≥4, and LF (stages 1‐3, NASH Clinical Research Network) at 81 clinical sites. Subjects (N = 289) were randomly assigned CVC 150 mg or placebo. Primary outcome was ≥2‐point improvement in NAS and no worsening of fibrosis at year 1. Key secondary outcomes were: resolution of steatohepatitis (SH) and no worsening of fibrosis; improvement in fibrosis by ≥1 stage and no worsening of SH. Biomarkers of inflammation and adverse events were assessed. Full study recruitment was achieved. The primary endpoint of NAS improvement in the intent‐to‐treat population and resolution of SH was achieved in a similar proportion of subjects on CVC (N = 145) and placebo (N = 144; 16% vs. 19%, P = 0.52 and 8% vs. 6%, P = 0.49, respectively). However, the fibrosis endpoint was met in significantly more subjects on CVC than placebo (20% vs. 10%; P = 0.02). Treatment benefits were greater in those with higher disease activity and fibrosis stage at baseline. Biomarkers of systemic inflammation were reduced with CVC. Safety and tolerability of CVC were comparable to placebo. Conclusion: After 1 year of CVC treatment, twice as many subjects achieved improvement in fibrosis and no worsening of SH compared with placebo. Given the urgent need to develop antifibrotic therapies in NASH, these findings warrant phase 3 evaluation. (Hepatology 2018;67:1754‐1767).
Background and Aims
We evaluated the safety and efficacy of cilofexor (formerly GS‐9674), a small‐molecule nonsteroidal agonist of farnesoid X receptor, in patients with nonalcoholic steatohepatitis ...(NASH).
Approach and Results
In this double‐blind, placebo‐controlled, phase 2 trial, 140 patients with noncirrhotic NASH, diagnosed by magnetic resonance imaging–proton density fat fraction (MRI‐PDFF) ≥8% and liver stiffness ≥2.5 kPa by magnetic resonance elastography (MRE) or historical liver biopsy, were randomized to receive cilofexor 100 mg (n = 56), 30 mg (n = 56), or placebo (n = 28) orally once daily for 24 weeks. MRI‐PDFF, liver stiffness by MRE and transient elastography, and serum markers of fibrosis were measured at baseline and week 24. At baseline, median MRI‐PDFF was 16.3% and MRE‐stiffness was 3.27 kPa. At week 24, patients receiving cilofexor 100 mg had a median relative decrease in MRI‐PDFF of −22.7%, compared with an increase of 1.9% in those receiving placebo (P = 0.003); the 30‐mg group had a relative decrease of −1.8% (P = 0.17 vs. placebo). Declines in MRI‐PDFF of ≥30% were experienced by 39% of patients receiving cilofexor 100 mg (P = 0.011 vs. placebo), 14% of those receiving cilofexor 30 mg (P = 0.87 vs. placebo), and 13% of those receiving placebo. Serum gamma‐glutamyltransferase, C4, and primary bile acids decreased significantly at week 24 in both cilofexor treatment groups, whereas significant changes in Enhanced Liver Fibrosis scores and liver stiffness were not observed. Cilofexor was generally well‐tolerated. Moderate to severe pruritus was more common in patients receiving cilofexor 100 mg (14%) than in those receiving cilofexor 30 mg (4%) and placebo (4%).
Conclusions
Cilofexor for 24 weeks was well‐tolerated and provided significant reductions in hepatic steatosis, liver biochemistry, and serum bile acids in patients with NASH. ClinicalTrials.gov No. NCT02854605.
Although nonalcoholic fatty liver disease (NAFLD) is closely linked to obesity, around 10%‐20% of nonobese Americans and Asians still develop NAFLD. Data on this special group are limited. We ...therefore studied the severity and clinical outcomes of nonobese NAFLD patients. Consecutive NAFLD patients who underwent liver biopsy were prospectively recruited. We used the NASH Clinical Research Network system to score the histology. The Asian body mass index cutoff of 25 kg/m2 was used to define nonobese NAFLD. Among 307 recruited NAFLD patients, 72 (23.5%) were nonobese. Compared to obese patients, nonobese patients had lower NAFLD activity score (3.3 ± 1.3 vs. 3.8 ± 1.2; P = 0.019), mainly contributed by steatosis (1.7 ± 0.8 vs. 2.0 ± 0.8; P = 0.014) and presence of hepatocyte ballooning (60.9% vs. 73.4%; P = 0.045). Similarly, nonobese patients had lower fibrosis stage (1.3 ± 1.5 vs. 1.7 ± 1.4; P = 0.004), serum cytokeratin‐18 fragments (283 vs. 404 U/L; P < 0.001) and liver stiffness measurement by transient elastography (6.3 vs. 8.6 kilopascals; P < 0.001). By multivariate analysis in nonobese patients, only elevated serum triglyceride level was independently associated with higher NAFLD activity score (adjusted odds ratio OR, 1.644; P = 0.021), whereas elevated creatinine level was the only factor associated with advanced fibrosis (adjusted OR, 1.044; P = 0.025). After a median follow‐up of 49 months, 6 patients died, 2 developed hepatocellular carcinoma, and 1 had liver failure, all of whom were in the obese group. Conclusion: Nonobese NAFLD patients tend to have less‐severe disease and may have a better prognosis than obese patients. Hypertriglyceridemia and higher creatinine are the key factors associated with advanced liver disease in nonobese patients. (Hepatology 2017;65:54‐64)
New Trends on Obesity and NAFLD in Asia Fan, Jian-Gao; Kim, Seung-Up; Wong, Vincent Wai-Sun
Journal of hepatology,
10/2017, Letnik:
67, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Abstract Traditionally, obesity and its related diseases are considered problems in Western countries. However, in the past two decades, urbanization in many Asian countries has led to sedentary ...lifestyle and overnutrition, and has set the stage for the epidemic of obesity. This article reviews the epidemiological trend of obesity in Asia with special emphasis on the emerging condition of non-alcoholic fatty liver disease (NAFLD). Currently, the population prevalence of NAFLD in Asia is around 25%, similar to that in many Western countries. While hepatocellular carcinoma and end-stage liver disease secondary to NAFLD remain uncommon, a rising trend has recently been observed. Around 8-19% of Asians with body mass index less than 25 kg/m2 are also found to have NAFLD, a condition often described as “lean” or “non-obese” NAFLD. Although the condition is generally less severe than that in more obese patients, steatohepatitis and fibrotic disease are well recognized in non-obese patients with NAFLD. Central adiposity, insulin resistance and weight gain are major risk factors, and genetic predisposition such as the PNPLA3 polymorphism appears to be more important in the development of NAFLD in the non-obese population. Lifestyle modification remains the cornerstone for the management of obesity and NAFLD, but few patients can achieve adequate weight reduction and even fewer can maintain the weight in the long run. While a few agents have entered phase 3 development for steatohepatitis, Asian patients are underrepresented in most drug trials. Future studies should define the optimal management of obesity and NAFLD in Asia.
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