Background & Aims
Diagnostic criteria for metabolic associated fatty liver disease (MAFLD) have been proposed, but not validated. We aimed to compare the diagnostic accuracy of the MAFLD definition ...vs the existing NAFLD criteria to identify patients with significant fibrosis and to characterize the impact of mild alcohol intake.
Methods
We enrolled 765 Japanese patients with fatty liver (median age 54 years). MAFLD and NAFLD were diagnosed in 79.6% and 70.7% of patients respectively. Significant fibrosis was defined by FIB‐4 index ≥1.3 and liver stiffness ≥6.6 kPa using shear wave elastography. Mild alcohol intake was defined as <20 g/day. Factors associated with significant fibrosis were analysed by logistic regression and decision‐tree analyses.
Results
Liver stiffness was higher in MAFLD compared to NAFLD (7.7 vs 6.8 kPa, P = .0010). In logistic regression, MAFLD (OR 4.401; 95% CI 2.144‐10.629; P < .0001), alcohol intake (OR 1.761; 95% CI 1.081‐2.853; P = .0234), and NAFLD (OR 1.721; 95%CI 1.009‐2.951; P = .0463) were independently associated with significant fibrosis. By decision‐tree analysis, MAFLD, but not NAFLD or alcohol consumption was the initial classifier for significant fibrosis. The sensitivity for detecting significant fibrosis was higher for MAFLD than NAFLD (93.9% vs 73.0%). In patients with MAFLD, even mild alcohol intake was associated with an increase in the prevalence of significant fibrosis (25.0% vs 15.5%; P = .0181).
Conclusions
The MAFLD definition better identifies a group with fatty liver and significant fibrosis evaluated by non‐invasive tests. Moreover, in patients with MAFLD, even mild alcohol consumption is associated with worsening of hepatic fibrosis measures.
Non-alcoholic fatty liver disease(NAFLD) in children is becoming a major health concern. A 'multiple-hit' pathogenetic model has been suggested to explain the progressive liver damage that ...occurs among children with NAFLD. In addition to the accumulation of fat in the liver, insulin resistance(IR) and oxidative stress due to genetic/epigenetic background, unfavorable lifestyles, gut microbiota and gut-liver axis dysfunction, and perturbations of trace element homeostasis have been shown to be critical for disease progression and the development of more severe inflammatory and fibrotic stages (non-alcoholic steatohepatitis(NASH))Simple clinical and laboratory parameters, such as age, history, anthropometrical data(BMI and waist circumference percentiles), blood pressure, surrogate clinical markers of IR(acanthosis nigricans), abdominal ultrasounds, and serum transaminases, lipids and glucose/insulin profiles, allow a clinician to identify children with obesity and obesity-related conditions, including NAFLD and cardiovascular and metabolic risks. A liver biopsy(the 'imperfect' gold standard) is required for a definitive NAFLD/NASH diagnosis, particularly to exclude other treatable conditions or when advanced liver disease is expected on clinical and laboratory grounds and preferably prior to any controlled trial of pharmacological/surgical treatments. However, a biopsy clearly cannot represent a screening procedure. Advancements in diagnostic serum and imaging tools, especially for the non-invasive differentiation between NAFLD and NASH, have shown promising results, e.g., magnetic resonance elastography. Weight loss and physical activity should be the first option of intervention.Effective pharmacological treatments are still under development; however, drugs targeting IR, oxidative stress, proinflammatory pathways, dyslipidemia, gut microbiota and gut liver axis dysfunction are an option for patients who are unable to comply with the recommended lifestyle changes. When morbid obesity prevails, bariatric surgery should be considered.
The Baveno VI consensus proposed a dual liver stiffness (LS) by transient elastography threshold of <10 and >15 kPa for excluding and diagnosing compensated advanced chronic liver disease (cACLD) in ...the absence of other clinical signs. Herein, we aimed to validate these criteria in a real-world multicentre study.
We included 5,648 patients (mean age 51 ± 13 years, 53% males) from 10 European liver centres who had a liver biopsy and LS measurement within 6 months. We included patients with chronic hepatitis C (n = 2,913, 52%), non-alcoholic fatty liver disease (NAFLD, n = 1,073, 19%), alcohol-related liver disease (ALD, n = 946, 17%) or chronic hepatitis B (n = 716, 13%). cACLD was defined as fibrosis stage ≥F3.
Overall, 3,606 (66%) and 987 (18%) patients had LS <10 and >15 kPa, respectively, while cACLD was histologically confirmed in 1,772 (31%) patients. The cut-offs of <10 and >15 kPa showed 75% sensitivity and 96% specificity to exclude and diagnose cACLD, respectively. Examining the ROC curve, a more optimal dual cut-off at <7 and >12 kPa, with 91% sensitivity and 92% specificity for excluding and diagnosing cACLD (AUC 0.87; 95% CI 0.86–0.88; p <0.001) was derived. Specifically, for ALD and NAFLD, a low cut-off of 8 kPa can be used (sensitivity=93%). For the unclassified patients, we derived a risk model based on common patient characteristics with better discrimination than LS alone (AUC 0.74 vs. 0.69; p <0.001).
Instead of the Baveno VI proposed <10 and >15 kPa dual cut-offs, we found that the <8 kPa (or <7 kPa for viral hepatitis) and >12 kPa dual cut-offs have better diagnostic accuracy in cACLD.
The term compensated advanced chronic liver disease (cACLD) was introduced in 2015 to describe the spectrum of advanced fibrosis and cirrhosis in asymptomatic patients. It was also suggested that cACLD could be diagnosed or ruled out based on specific liver stiffness values, which can be non-invasively measured by transient elastography. Herein, we assessed the suggested cut-off values and identified alternative values that offered better overall accuracy for diagnosing or ruling out cACLD.
Display omitted
•cACLD is the spectrum of advanced fibrosis and cirrhosis in asymptomatic patients.•The Baveno VI consensus suggested a dual liver stiffness cut-off to diagnose/rule out cACLD.•Proposed liver stiffness cut-offs of 15 kPa had 75%/96% Se/Sp to rule out/in cACLD.•We showed that liver stiffness cut-offs of 12 kPa are optimal (Se/Sp 91%/92%).•In ALD and NAFLD, a cut-off <8 kPa can be used to rule out cACLD (Se=93%).
The 148 Isoleucine to Methionine protein variant (I148M) of patatin-like phospholipase domain-containing 3 (PNPLA3), a protein is expressed in the liver and is involved in lipid metabolism, has ...recently been identified as a major determinant of liver fat content. Several studies confirmed that the I148M variant predisposes towards the full spectrum of liver damage associated with fatty liver: from simple steatosis to steatohepatitis and progressive fibrosis. Furthermore, the I148M variant represents a major determinant of progression of alcohol related steatohepatitis to cirrhosis, and to influence fibrogenesis and related clinical outcomes in chronic hepatitis C virus hepatitis, and possibly chronic hepatitis B virus hepatitis, hereditary hemochromatosis and primary sclerosing cholangitis. All in all, studies suggest that the I148M polymorphism may represent a general modifier of fibrogenesis in liver diseases. Remarkably, the effect of the I148M variant on fibrosis was independent of that on hepatic steatosis and inflammation, suggesting that it may affect both the quantity and quality of hepatic lipids and the biology of non-parenchymal liver cells besides hepatocytes, directly promoting fibrogenesis. Therefore, PNPLA3 is a key player in liver disease progression. Assessment of the I148M polymorphism will possibly inform clinical practice in the future, whereas the determination of the effect of the 148M variant will reveal mechanisms involved in hepatic fibrogenesis.
Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disorders. It is defined by the presence of steatosis in more than 5% of hepatocytes with little or no alcohol consumption. Insulin ...resistance, the metabolic syndrome or type 2 diabetes and genetic variants of PNPLA3 or TM6SF2 seem to play a role in the pathogenesis of NAFLD. The pathological progression of NAFLD follows tentatively a "three-hit" process namely steatosis, lipotoxicity and inflammation. The presence of steatosis, oxidative stress and inflammatory mediators like TNF-α and IL-6 has been implicated in the alterations of nuclear factors such as CAR, PXR, PPAR-α in NAFLD. These factors may result in altered expression and activity of drug metabolizing enzymes (DMEs) or transporters.
Existing evidence suggests that the effect of NAFLD on CYP3A4, CYP2E1 and MRP3 is more consistent across rodent and human studies. CYP3A4 activity is down-regulated in NASH whereas the activity of CYP2E1 and the efflux transporter MRP3 is up-regulated. However, it is not clear how the majority of CYPs, UGTs, SULTs and transporters are influenced by NAFLD either in vivo or in vitro. The alterations associated with NAFLD could be a potential source of drug variability in patients and could have serious implications for the safety and efficacy of xenobiotics. In this review, we summarize the effects of NAFLD on the regulation, expression and activity of major DMEs and transporters. We also discuss the potential mechanisms underlying these alterations.
Due to the rising prevalence of obesity and type II diabetes mellitus, non-alcoholic fatty liver disease is becoming the leading cause of chronic liver disease in the Western world. In some patients, ...simple steatosis can result in non-alcoholic steatohepatitis which over time can lead to liver cirrhosis and its associated sequelae, including hepatocellular carcinoma. Early identification and management of patients at risk with intensive dietary and lifestyle modification are essential to prevent the development of advanced liver disease and its complications. In this review, we will discuss the epidemiology of non-alcoholic fatty liver disease, pathogenesis, diagnosis, management and surveillance strategies to offset the morbidity and mortality of this disease, as well as liver and non-liver-related complications.
Background and Aims
The surge in unhealthy alcohol use during the COVID‐19 pandemic may have detrimental effects on the rising burden of alcohol‐associated liver disease (ALD) on liver ...transplantation (LT) in the USA. We evaluated the effect of the pandemic on temporal trends for LT including ALD.
Approach and Results
Using data from United Network for Organ Sharing, we analyzed wait‐list outcomes in the USA through March 1, 2021. In a short‐period analysis, patients listed or transplanted between June 1, 2019, and February 29, 2020, were defined as the “pre‐COVID” era, and after April 1, 2020, were defined as the “COVID” era. Interrupted time‐series analyses using monthly count data from 2016‐2020 were constructed to evaluate the rate change for listing and LT before and during the COVID‐19 pandemic. Rates for listings (P = 0.19) and LT (P = 0.14) were unchanged during the pandemic despite a significant reduction in the monthly listing rates for HCV (−21.69%, P < 0.001) and NASH (−13.18%; P < 0.001). There was a significant increase in ALD listing (+7.26%; P < 0.001) and LT (10.67%; P < 0.001) during the pandemic. In the COVID era, ALD (40.1%) accounted for more listings than those due to HCV (12.4%) and NASH (23.4%) combined. The greatest increase in ALD occurred in young adults (+33%) and patients with severe alcohol‐associated hepatitis (+50%). Patients with ALD presented with a higher acuity of illness, with 30.8% of listings and 44.8% of LT having a Model for End‐Stage Liver Disease–Sodium score ≥30.
Conclusions
Since the start of COVID‐19 pandemic, ALD has become the most common indication for listing and the fastest increasing cause for LT. Collective efforts are urgently needed to stem the rising tide of ALD on health care resources.
Whether as wine, beer, or spirits, alcohol has had a constant and often controversial role in social life. In his innovative book on the attitudes toward and consumption of alcohol, Rod Phillips ...surveys a 9,000-year cultural and economic history, uncovering the tensions between alcoholic drinks as healthy staples of daily diets and as objects of social, political, and religious anxiety. In the urban centers of Europe and America, where it was seen as healthier than untreated water, alcohol gained a foothold as the drink of choice, but it has been more regulated by governmental and religious authorities more than any other commodity. As a potential source of social disruption, alcohol created volatile boundaries of acceptable and unacceptable consumption and broke through barriers of class, race, and gender.Phillips follows the ever-changing cultural meanings of these potent potables and makes the surprising argument that some societies have entered "post-alcohol" phases. His is the first book to examine and explain the meanings and effects of alcohol in such depth, from global and long-term perspectives.
Display omitted
•Approximately 15% of hazardous drinkers may have normal liver histology.•Progression to cirrhosis is most common in people with steatohepatitis (10% per year).•Liver-related factors ...are the predominant cause of death in people with steatohepatitis or cirrhosis.•Hepatic steatosis is not benign, with an annual mortality rate of ∼6%/year, but deaths are mainly non-liver related.
To date, studies into the natural history of alcohol-related liver disease (ALD) have lacked long-term follow-up, large numbers of participants, or both. We performed a systematic review to summarise studies that describe the natural history of histologically proven ALD.
PubMed and Medline were searched for relevant studies according to pre-specified criteria. Data were extracted to describe the prevalence of ALD, histological progression of disease and mortality. Single-proportion meta-analysis was used to combine data from studies regarding rates of progression or mortality.
Thirty-seven studies were included, reporting data from 7,528 participants. Amongst cohorts of hazardous drinkers, on average 15% had normal histological appearance, 27% had hepatic steatosis, 24% had steatohepatitis and 26% had cirrhosis. The annualised rates of progression of pre-cirrhotic disease to cirrhosis were 1% (0–8%) for patients with normal histology, 3% (2–4%) for hepatic steatosis, 10% (6–17%) for steatohepatitis and 8% (3–19%) for fibrosis. Annualised mortality was 6% (4–7%) in patients with steatosis and 8% (5–13%) in cirrhosis. In patients with steatohepatitis on biopsy a marked difference was seen between inpatient cohorts (annual mortality 15%, 8–26%) and mixed cohorts of inpatients and outpatients (annual mortality 5%, 2–10%). Only in steatosis did non-liver-related mortality exceed liver-specific causes of mortality (5% per year vs. 1% per year).
These data confirm the observation that alcohol-related hepatic steatohepatitis requiring admission to hospital is the most dangerous subtype of ALD. Alcohol-related steatosis is not a benign condition as it is associated with significant risk of mortality.
Knowledge of the natural history of a disease allows clinicians and patients to understand the risks that are associated with a medical condition. In this study we systematically gathered all the published data regarding the natural history of alcohol-related liver disease in people who had a liver biopsy. We used this data to define the prevalence of the disease, the annual risk of progression to cirrhosis and the annual risk of death at each stage of the disease.
To describe associations between alcoholic liver disease (ALD) or nonalcoholic fatty liver disease (NAFLD) hospital admission and cardiovascular disease (CVD), cancer, and mortality in people with ...type 2 diabetes mellitus (T2DM).
We performed a retrospective cohort study by using linked population-based routine data from diabetes registry, hospital, cancer, and death records for people aged 40-89 years diagnosed with T2DM in Scotland between 2004 and 2013 who had one or more hospital admission records. Liver disease and outcomes were identified by using ICD-9 and ICD-10 codes. We estimated hazard ratios (HRs) from Cox proportional hazards regression models, adjusting for key risk factors.
A total of 134,368 people with T2DM (1,707 with ALD and 1,452 with NAFLD) were studied, with a mean follow-up of 4.3 years for CVD and 4.7 years for mortality. Among those with ALD, NAFLD, or without liver disease hospital records 378, 320, and 21,873 CVD events; 268, 176, and 15,101 cancers; and 724, 221, and 16,203 deaths were reported, respectively. For ALD and NAFLD, respectively, adjusted HRs (95% CIs) compared with the group with no record of liver disease were 1.59 (1.43, 1.76) and 1.70 (1.52, 1.90) for CVD, 40.3 (28.8, 56.5) and 19.12 (11.71, 31.2) for hepatocellular carcinoma (HCC), 1.28 (1.12, 1.47) and 1.10 (0.94, 1.29) for non-HCC cancer, and 4.86 (4.50, 5.24) and 1.60 (1.40, 1.83) for all-cause mortality.
Hospital records of ALD or NAFLD are associated to varying degrees with an increased risk of CVD, cancer, and mortality among people with T2DM.