Low-to-moderate alcohol consumption is associated with increased fibrosis in individuals with metabolic dysfunction-associated steatotic liver disease.

BACKGROUND & AIMS: Both metabolic dysfunction and alcohol consumption cause steatotic liver disease (SLD). New nomenclature and distinction of metabolic dysfunction-associated SLD (MASLD) and MetALD categories is based on arbitrary thresholds of alcohol intake. We assessed the impact of different levels of alcohol consumption on SLD severity and its interaction with metabolic comorbidities. METHODS: Population-based study with transient elastography (FibroScan®) data from participants in Spain (derivation) and U.S. (validation) cohorts. Controlled attenuation parameter (CAP≥275 dB/m) identified SLD. At least one cardiometabolic risk factor was required to define MASLD. Among MASLD patients, low alcohol consumption was defined as an average of 5-9 drinks/week, moderate consumption as 10-13 drinks/week for females and 10-20 drinks/week for males, and increased alcohol intake (MetALD) as 14-35 drinks/week for females and 21-42 drinks/week for males. Significant fibrosis was defined as LSM≥8 kPa and at-risk MASH as FAST score≥0.35. RESULTS: The derivation cohort included 2,227 subjects with MASLD (9% reported low, 14% moderate alcohol consumption), and 76 cases with MetALD. Overall prevalence of significant fibrosis and at-risk MASH were 7.6% and 14.8%, respectively. In the multivariable analysis, alcohol consumption was independently associated with significant fibrosis and at-risk MASH. A dose-dependent increase in the prevalence of significant fibrosis and at-risk MASH was observed between the number of drinks/week and the number of cardiometabolic factors. The validation cohort included 1,732 participants with MASLD, of whom 17% had significant fibrosis and 13% at-risk MASH. This cohort validated the association between moderate intake and MASLD at risk of progression (OR=1.69 [95%CI 1.06-2.71]). CONCLUSIONS: Moderate alcohol intake is commonly seen in MASLD and increases the risk of advanced disease, in a similar magnitude to MetALD spectrum. IMPACT AND IMPLICATIONS: Metabolic risk factors such as overweight, diabetes or dyslipidemia, and alcohol consumption can cause liver disease. These factors frequently co-exist, but their joint effects on liver fibrosis remain uncertain. This study analyzes subjects form the general population with metabolic dysfunction-associated steatotic liver disease (MASLD) enrolled in Spain and U.S. We show that moderate alcohol consumption has a supra-additive effect with metabolic risk factors, exponentially increasing the risk of liver fibrosis. These results suggest that patients with unhealthy metabolic status and MASLD have no safe limits of daily alcohol intake.

Increases and decreases in liver stiffness measurement are independently associated with the risk of liver-related events in NAFLD.

BACKGROUND & AIMS: The clinical significance of change in liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) in patients with non-alcoholic fatty liver disease (NAFLD) is not well-understood. We prospectively defined rates of progression to and regression from LSM-defined compensated advanced chronic liver disease (cACLD) and their associations with liver-related events (LREs). METHODS: Participants in the NASH Clinical Research Network-led NAFLD Database 2 and 3 studies were included. Progression to cACLD was defined as reaching LSM ≥10 kPa in participants with LSM <10 kPa on initial VCTE; regression from cACLD was defined as reaching LSM <10 kPa in participants with baseline LSM ≥10 kPa. LREs were defined as liver-related death, liver transplant, hepatocellular carcinoma, MELD >15, development of varices, or hepatic decompensation. Univariate and multivariable interval-censored Cox regression analyses were used to compare the cumulative LRE probability by LSM progression and regression status. RESULTS: In 1,403 participants, 89 LREs developed over a mean follow-up of 4.4 years, with an annual incidence rate for LREs of 1.5 (95% CI 1.2-1.8). In participants at risk, progression to LSM ≥10 or ≥15 kPa occurred in 29% and 17%, respectively, whereas regression to LSM <10 or <15 kPa occurred in 44% and 49%, respectively. Progressors to cACLD (≥10 kPa) experienced a higher cumulative LRE rate vs. non-progressors (16% vs. 4%, adjusted hazard ratio 4.0; 95% (1.8-8.9); p <0.01). Regressors from cACLD (to LSM <10 kPa) experienced a lower LRE rate than non-regressors (7% vs. 32%, adjusted hazard ratio 0.25; 95% CI 0.10-0.61; p <0.01). CONCLUSIONS: Change in LSM over time is independently and bi-directionally associated with risk of LRE and is a non-invasive surrogate for clinical outcomes in patients with NAFLD. IMPACT AND IMPLICATIONS: The prognostic value of change in LSM in patients with NAFLD is not well understood. In this large prospective study of patients with NAFLD and serial vibration-controlled transient elastography exams, baseline and dynamic changes in LSM were associated with the risk of developing liver-related events. LSM is a useful non-invasive surrogate of clinical outcomes in patients with NAFLD.

Effects of Food Insecurity on Hepatic Steatosis and Fibrosis in People With HIV.

BACKGROUND & AIMS: Food insecurity (FI) is a risk factor for nonalcoholic fatty liver disease (NAFLD) and advanced fibrosis in the general population, but its impact on liver disease in people with HIV (PWH) is unknown. METHODS: We examined the association of FI with prevalence of NAFLD and fibrosis in a diverse cohort of PWH. PWH aged ≥ 18 years on antiretroviral therapy, HIV RNA <200 copies/mL, and without other known liver diseases were screened for NAFLD (controlled attenuated parameter ≥263 decibels/meter) and advanced fibrosis (liver stiffness measurement ≥11 kilopascals) by vibration controlled transient elastography at 8 U.S. CENTERS: Participants were categorized as food insecure using the Six-Item Short Form Household Food Security Survey. We used multivariable logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of NAFLD and advanced fibrosis by FI status. RESULTS: Among 654 PWH, NAFLD was present in 348 (53%) and advanced fibrosis in 41 (6%). FI was present in 203 of participants (31%), including 97/348 with NAFLD (28%) and 18/41 with advanced fibrosis (44%). In multivariable analysis, FI was associated with lower odds of NAFLD (OR, 0.57; 95% CI, 0.37-0.88) and a greater, but nonsignificant, odds of advanced fibrosis (OR, 1.38; 95% CI, 0.65-2.90). We identified a significant interaction between FI and diabetes (P = .02) on fibrosis risk, with greater odds of fibrosis among food insecure PWH and diabetes (OR, 3.83; 95% CI, 1.15-12.73) but not among food insecure nondiabetics (OR, 1.12; 95% CI, 0.47-2.98). CONCLUSIONS: FI is highly prevalent among PWH and associated with lower odds of NAFLD, and among PWH with diabetes, there is greater odds of advanced fibrosis. FI may contribute to hepatic fibrosis through mechanisms other than steatosis in PWH.

PNPLA3 rs738409, age, diabetes, sex, and advanced fibrosis jointly contribute to the risk of major adverse liver outcomes in metabolic dysfunction-associated steatotic liver disease.

BACKGROUND AND AIMS: The patatin-like phospholipase domain-containing protein 3 ( PNPLA3 ) rs738409 variant is associated with steatotic liver disease and its progression. We examined the association between PNPLA3 and the development of major adverse liver outcomes (MALOs) and how nonmodifiable and modifiable conditions modify this relationship. APPROACH AND RESULTS: A total of 2075 adults with biopsy-confirmed metabolic dysfunction-associated steatotic liver disease (MASLD) were enrolled in the metabolic dysfunction-associated steatohepatitis Clinical Research Network (MASH CRN) studies and followed prospectively until death, transplant, or withdrawal of consent. One hundred four MALOs were recorded during an average of 4.3 years. PNPLA3 G-allele (Adj. sub-hazard ratio (sHR): 1.4, 95% CI: 1.07-1.8), advanced fibrosis (AF) (Adj. sHR: 7.8, 95% CI: 4.4-13.8), age >60 years (Adj. sHR: 2.9, 95% CI: 1.3-6.8), and type 2 diabetes mellitus (Adj. sHR: 2.8, 95% CI: 1.8-4.2) were associated with MALO. Among participants with AF, those carrying the G-allele displayed the highest cumulative incidence of MALO (85%) versus noncarriers (53%), p =0.03, and p -value for interaction <0.01. The strength of the association between PNPLA3 and MALO was statistically significantly greater among older than 60 years (sHR: 2.1, 95% CI: 1.5-2.8), women (sHR: 1.4, 95% CI: 1.1-1.9), and those with AF (sHR: 1.9, 95% CI: 1.5-2.4) or type 2 diabetes mellitus (sHR: 2.1, 95% CI: 1.5-2.8) as compared with their counterparts, p -value for interaction between PNPLA3 and each factor<0.01. CONCLUSIONS: The deleterious effects of PNPLA3 rs738409 on the risk of MALO are significantly worsened by AF, age, type 2 diabetes mellitus, and sex.

Role of Spleen Stiffness Measurement in the Evaluation of Metabolic Dysfunction-Associated Steatotic Liver Disease.

BACKGROUND: Spleen stiffness measurement (SSM) correlates with the severity of portal hypertension. AIMS: We investigated the utility of SSM in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) for detecting cirrhosis, esophageal varices (EV), and high-risk EV. METHODS: 154 study participants with MASLD underwent simultaneous liver stiffness measurement (LSM) and SSM. 96 (62%) participants had an upper endoscopy (73 participants, i.e., 47% undergoing within a year). The diagnostic performance of SSM, as well as the BAVENO VII proposed SSM cutoffs (≥ 21 kPa, > 40 kPa, and > 50 kPa), was examined. RESULTS: The failure rate for SSM was 19% compared to 5% for LSM. An invalid SSM was statistically significantly associated with a higher body mass index, a larger waist circumference, and a lower fibrosis stage. The area under the receiver operating characteristics for SSM to diagnose cirrhosis, EV, and high-risk EV was 0.78 (95% CI 0.70-0.85), 0.74 (95% CI 0.61-0.84), and 0.82 (95% CI 0.75-0.98), respectively. SSM ≥ 21 kPa cutoff had a sensitivity > 96% for all three outcomes, with a positive predictive value (PPV) of 88% for cirrhosis. In contrast, SSM > 40 kPa and SSM > 50 kPa cutoffs had better diagnostic abilities for identifying EV, particularly high-risk EV (sensitivity of 100% and 93% with NPV of 100% and 96%, respectively). CONCLUSION: SSM has a higher failure rate in individuals who are non-cirrhotic or have a higher BMI, or larger waist circumference. Although useful for diagnosing NASH cirrhosis, SSM is most reliable in excluding EV and high-risk EV.

Primary Sclerosing Cholangitis Limited to Intrahepatic Bile Ducts Has Distinctly Better Prognosis.

BACKGROUND: There are two sub-phenotypes of large-duct primary sclerosing cholangitis (PSC): isolated intrahepatic PSC (IIPSC) and extrahepatic disease with or without intrahepatic (extra/intrahepatic). AIMS: This study examined the differences in outcomes in patients with IIPSC compared to extra/intrahepatic and small-duct PSC. METHODS: Patients with PSC treated at our institution from 1998 to 2019 were investigated. Biochemistries, clinical events, and survival were assessed by chart review and National Death Index. Cox-proportional hazards were used to determine the risk of clinical outcomes based on biliary tract involvement. RESULTS: Our cohort comprised 442 patients with large-duct PSC (57 had IIPSC, 385 had extra/intrahepatic PSC) and 23 with small-duct PSC. Median follow-up in the IIPSC group was not significantly different from the extra/intrahepatic group [7 vs. 6 years, P = 0.06]. Except for lower age (mean 37.9 vs. 43.0 years, P = 0.045), the IIPSC group was not different from the extra/intrahepatic. The IIPSC group had longer transplant-free survival (log-rank P = 0.001) with a significantly lower risk for liver transplantation (12% vs. 34%, P < 0.001). The IIPSC group had a lower risk of death or transplantation than the extra/intrahepatic PSC group [HR: 0.34, 95% CI: 0.17-0.67, P < 0.001]. No bile duct or gallbladder cancers developed in patients with IIPSC, compared to 24 in the extra/intrahepatic group. The clinical characteristics and outcomes of IIPSC were similar to 23 individuals with small-duct PSC. CONCLUSIONS: Patients with IIPSC have a favorable prognosis similar to small-duct PSC. These data are important for counseling patients and designing therapeutic trials for PSC.

Diagnostic Ability of Simple Noninvasive Blood Tests to Predict Increased Liver Stiffness in People Living With HIV and Steatotic Liver Disease.

INTRODUCTION: Steatotic liver disease is common in people with HIV (PWH). Identifying those with advanced fibrosis (AF, bridging fibrosis or cirrhosis), F3-4, is important. We aimed to examine the performance of FIB-4 and nonalcoholic fatty liver disease (NAFLD) fibrosis score (NFS) in PWH to identify those with AF assessed by liver stiffness measurement (LSM). METHODS: We prospectively collected data on adults participating in 2 National Institute of Health-sponsored HIV NAFLD networks. All had HIV on antiretroviral therapy (ART) ≥6 months with HIV RNA <200 copies/mL. Those with viral hepatitis, other liver disease, excessive alcohol use, or hepatic decompensation were excluded. Vibration-controlled transient elastrography for LSM was performed, and AF defined as ≥11 kPa was compared with FIB-4 and NFS at predefined thresholds (<1.3 and >2.67 for FIB-4 and <-1.455 and >0.675 for NFS). RESULTS: A total of 1,065 participants were analyzed: mean age 51.6 years, 74% male, 28% White, 46% Black, 22% Hispanic, with 34% overweight (body mass index 25-29 kg/m 2 ) and 43% obese (body mass index ≥30 kg/m 2 ). Features of the metabolic syndrome were common: hyperlipidemia 35%, type 2 diabetes 17%, and hypertension 48%. The median CD4 + T-cell count was 666 cells/mm 3 , 74% had undetectable HIV RNA, and duration of HIV-1 was 17 years with most taking a nucleoside reverse transcriptase inhibitor (92%) and an integrase inhibitor (83%). The mean LSM was 6.3 kPa, and 6.3% had AF. The area under the receiver characteristic curve for FIB-4 and NFS to identify AF were 0.70 and 0.75, respectively. While both had high negative predictive values (97%-98%), the sensitivity at low thresholds and specificity at high thresholds were 64% and 97% for FIB-4 and 80% and 96% for NFS, respectively. Neither FIB-4 nor NFS at either threshold had good positive predictive value to detect AF. DISCUSSION: FIB-4 and NFS have excellent specificity and negative predictive value for detecting AF, and thus can be used as screening tools in PWH to exclude those with AF who do not need further testing (LSM) or referral to hepatologist.

Thirty-Day Readmissions Are Largely Not Preventable in Patients With Cirrhosis.

INTRODUCTION: Hospital readmissions are common in patients with cirrhosis, but there are few studies describing readmission preventability. We aimed to describe the incidence, causes, and risk factors for preventable readmission in this population. METHODS: We performed a prospective cohort study of patients with cirrhosis hospitalized at a single center between June 2014 and March 2020 and followed up for 30 days postdischarge. Demographic, clinical, and socioeconomic data, functional status, and quality of life were collected. Readmission preventability was independently and systematically adjudicated by 3 reviewers. Multinomial logistic regression was used to compare those with (i) preventable readmission, (ii) nonpreventable readmission/death, and (iii) no readmission. RESULTS: Of 654 patients, 246 (38%) were readmitted, and 29 (12%) were preventable readmissions. Reviewers agreed on preventability for 70% of readmissions. Twenty-two (including 2 with preventable readmission) died. The most common reasons for readmission were hepatic encephalopathy (22%), gastrointestinal bleeding (13%), acute kidney injury (13%), and ascites (6%), and these reasons were similar between preventable and nonpreventable readmissions. Preventable readmission was often related to paracentesis timeliness, diuretic adjustment monitoring, and hepatic encephalopathy treatment. Compared with nonreadmitted patients, preventable readmission was independently associated with racial and ethnic minoritized individuals (odds ratio [OR] 5.80; 95% CI, 1.96-17.13), nonmarried marital status (OR 2.88; 95% CI, 1.18-7.05), and admission in the prior 30 days (OR 3.45; 95% CI, 1.48-8.04). DISCUSSION: For patients with cirrhosis, readmission is common, but most are not preventable. Preventable readmissions are often related to ascites and hepatic encephalopathy and are associated with racial and ethnic minorities, nonmarried status, and prior admissions.

Clinical characteristics and prognosis of hospitalized patients with moderate alcohol-associated hepatitis.

BACKGROUND AND AIMS: Little is known about the clinical characteristics and prognosis of hospitalized patients with moderate alcohol-associated hepatitis (mAH) as compared to severe alcohol-associated hepatitis (sAH). Therefore, we aimed to describe the clinical characteristics and risk factors associated with mortality in hospitalized mAH patients. METHODS: Patients hospitalized with alcohol-associated hepatitis (AH) from 1 January 2010 to 31 December 2020 at a large US healthcare system [11 hospitals, one liver transplant centre] were retrospectively analysed for outcomes. Primary outcome was 90-day mortality. AH and mAH were defined according to NIAAA Alcoholic Hepatitis Consortia and Model for End-stage Liver Disease Score ≤ 20 respectively. Multivariable Cox regression analysis was performed to identify independent risk factors associated with 90-day mortality. RESULTS: 1504 AH patients were hospitalized during the study period, of whom 39% (n = 590) had mAH. Compared to sAH patients, mAH patients were older (50 vs. 48 years, p < 0.001) and less likely to have underlying cirrhosis (74% vs. 83%, p < 0.001). There were no differences between the two groups for median alcohol intake g/day (mAH 140.0 vs. sAH 112.0, p = 0.071). The cumulative proportion surviving at 90 days was 88% in mAH versus 62% in sAH (p < 0.001). On multivariable analysis, older age [HR 1.03 (95% CI 1.00-1.06), p = 0.020], corticosteroid use [HR 1.80 (95% CI 1.06-3.06), p = 0.030] and acute kidney injury (AKI) [HR 2.43 (95% CI 1.33-4.47), p = 0.004] were independently associated with 90-day mortality. CONCLUSIONS: mAH carries a 12% mortality rate at 90 days. Age, AKI and corticosteroid use were associated with an increased risk for 90-day mortality. Avoidance of corticosteroids and strategies to reduce the risk of AKI could improve outcomes in mAH patients.

Age, BMI, and Type 2 Diabetes Modify the Relationship Between PNPLA3 and Advanced Fibrosis in Children and Adults With NAFLD.

BACKGROUND & AIMS: PNPLA3 G-allele is an important determinant of disease severity in nonalcoholic fatty liver disease (NAFLD). Here, we investigated the effect of age, body mass index (BMI), and type 2 diabetes mellitus (T2DM) on the relationship between PNPLA3 G-allele and advanced fibrosis in adults and children with histologically characterized NAFLD. METHODS: A total of 1047 children and 2057 adults were included. DNA was genotyped for rs738409 in duplicate. Primary outcome of interest was advanced fibrosis (fibrosis stage ≥3). Regression analyses were performed after controlling for relevant covariates. An additive model was used to assess the effect of PNPLA3 G-allele (CC vs CG vs GG). RESULTS: PNPLA3 G-allele was significantly associated with advanced fibrosis in children (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.16-2.09) and adults (OR, 1.55; 95% CI, 1.16-1.54). Across the cohort, older age significantly increased the risk for advanced fibrosis for PNPLA3 CC (OR, 1.019; 95% CI, 1.013-1.026), CG (OR, 1.024; 95% CI, 1.018-1.030), and GG (OR, 1.03; 95% CI, 1.023-1.037) genotypes. BMI significantly increased the relationship between PNPLA3 genotypes and advanced fibrosis in children and adults. A BMI of 30 kg/m2 was the cutoff beyond which PNPLA3 G-allele had exponential effect on the risk for advanced fibrosis in children and adults. T2DM significantly worsened the relationship between PNPLA3 G-allele and advanced fibrosis in children and adults (interaction P < .01 for both). CONCLUSIONS: Age, BMI, and T2DM modify the risk of advanced fibrosis associated with PNPLA3 G-allele. Preventing or reversing T2DM and obesity in persons carrying PNPLA3 G-allele may lower the risk for advanced fibrosis in NAFLD.

Prevalence of steatotic liver disease, MASLD, MetALD and significant fibrosis in people with HIV in the United States.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) has recently been proposed as a replacement term for NAFLD. AIMS: To assess the effects of this new nomenclature on the prevalence and distribution of different SLD categories in people with HIV (PWH) and identified factors associated with MASLD and clinically significant fibrosis (CSF). METHODS: PWH were prospectively enrolled from 9 US centres and underwent clinical evaluation and vibration-controlled transient elastography for controlled attenuation parameter (CAP) and liver stiffness measurement (LSM). SLD was defined as CAP ≥ 263 dB/m, CSF as LSM of ≥8 kPa, and advanced fibrosis (AF) as LSM ≥ 12 kPa. The prevalence of SLD, MASLD, metabolic dysfunction and alcohol-associated liver disease (MetALD), ALD, cryptogenic (cSLD), CSF and AF were determined. Uni- and multivariate logistic regression models were used to assess factors associated with MASLD and CSF risk. RESULTS: Of 1065 participants, 74% were male, mean (SD) age 51.6 ± 11.9 years, 46% non-Hispanic Black and 74% with undetectable HIV RNA. The prevalence of SLD was 52%, MASLD 39%, MetALD 10%, ALD 3%, CSF 15% and AF 4%. Only 0.6% had cSLD. Black race was protective whereas obesity, ALT and AST levels were associated with increased risk of MASLD and CSF in MASLD. HIV or antiretroviral therapy did not affect MASLD risk. CONCLUSIONS: MASLD and MetALD are the dominant causes of SLD in PWH, affecting almost half. Application of the new nomenclature resulted in minimal change in the proportion of patients with MASLD who would have been diagnosed previously with NAFLD.

Incidence, clinical characteristics, and risk factors associated with recurrent alcohol-associated hepatitis.

BACKGROUND: Alcohol relapse occurs frequently in alcohol-associated hepatitis (AH) survivors, but data on the frequency and course of recurrent alcohol-associated hepatitis (rAH) are sparse. We investigated the incidence, risk factors, and outcomes of rAH. METHODS: Hospitalized patients with AH from 2010 to 2020 at a large health care system were followed until death/liver transplant, last follow-up, or end of study (December 31, 2021). AH was defined by NIAAA Alcoholic Hepatitis Consortium criteria; rAH was defined a priori as a discrete AH episode >6 months from index AH hospitalization with interim >50% improvement or normalization of total bilirubin. Multivariable competing risk analysis was performed to identify factors associated with rAH. Landmark Kaplan-Meier analysis was performed to compare survival between patients who did versus those who did not develop rAH. RESULTS: Of 1504 hospitalized patients with AH, 1317 (87.6%) survived and were analyzed. During a 3055 person-year follow-up, 116 (8.8%) developed rAH at an annual incidence rate of 3.8% (95% CI: 2.8-4.8). On multivariable competing risk analysis, marital status [sub-HR 0.54 (95% CI: 0.34, 0.92), p=0.01] and medications for alcohol use disorder [sub-HR 0.56 (95% CI: 0.34, 0.91), p=0.02] were associated with a lower risk for rAH. On landmark Kaplan-Meier analysis, the cumulative proportion surviving at 1 year (75% vs. 90%) and 3 years (50% vs. 78%) was significantly lower in patients who developed rAH compared to those who did not develop rAH (log-rank p<0.001). CONCLUSIONS: rAH develops in ~1 in 10 AH survivors and is associated with lower long-term survival. Medications for alcohol use disorder lower the risk for rAH and, therefore, could be a key preventative strategy to improve outcomes.

Physical Activity and Nonalcoholic Fatty Liver Disease: A Roundtable Statement from the American College of Sports Medicine.

ABSTRACT: Although physical activity (PA) is crucial in the prevention and clinical management of nonalcoholic fatty liver disease, most individuals with this chronic disease are inactive and do not achieve recommended amounts of PA. There is a robust and consistent body of evidence highlighting the benefit of participating in regular PA, including a reduction in liver fat and improvement in body composition, cardiorespiratory fitness, vascular biology, and health-related quality of life. Importantly, the benefits of regular PA can be seen without clinically significant weight loss. At least 150 min of moderate or 75 min of vigorous intensity PA are recommended weekly for all patients with nonalcoholic fatty liver disease, including those with compensated cirrhosis. If a formal exercise training program is prescribed, aerobic exercise with the addition of resistance training is preferred. In this roundtable document, the benefits of PA are discussed, along with recommendations for 1) PA assessment and screening; 2) how best to advise, counsel, and prescribe regular PA; and 3) when to refer to an exercise specialist.

American College of Sports Medicine (ACSM) International Multidisciplinary Roundtable report on physical activity and nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: We present findings from the inaugural American College of Sports Medicine (ACSM) International Multidisciplinary Roundtable, which was convened to evaluate the evidence for physical activity as a means of preventing or modifying the course of NAFLD. APPROACH AND RESULTS: A scoping review was conducted to map the scientific literature and identify key concepts, research gaps, and evidence available to inform clinical practice, policymaking, and research. The scientific evidence demonstrated regular physical activity is associated with decreased risk of NAFLD development. Low physical activity is associated with a greater risk for disease progression and extrahepatic cancer. During routine health care visits, all patients with NAFLD should be screened for and counseled about physical activity benefits, including reduction in liver fat and improvement in body composition, fitness, and quality of life. While most physical activity benefits occur without clinically significant weight loss, evidence remains limited regarding the association between physical activity and liver fibrosis. At least 150 min/wk of moderate or 75 min/wk of vigorous-intensity physical activity are recommended for all patients with NAFLD. If a formal exercise training program is prescribed, aerobic exercise with the addition of resistance training is preferred. CONCLUSIONS: The panel found consistent and compelling evidence that regular physical activity plays an important role in preventing NAFLD and improving intermediate clinical outcomes. Health care, fitness, and public health professionals are strongly encouraged to disseminate the information in this report. Future research should prioritize determining optimal strategies for promoting physical activity among individuals at risk and in those already diagnosed with NAFLD.

Significant Dose-Response Association of Physical Activity and Diet Quality With Mortality in Adults With Suspected NAFLD in a Population Study.

INTRODUCTION: We aimed to determine whether higher levels (volume and intensity) of physical activity (PA) and diet quality (DQ) are associated with better survival rates in nonalcoholic fatty liver disease (NAFLD). METHODS: Using data from the 2011-2014 National Health and Nutrition Examination Survey, 3,548 participants with a Fatty Liver Index ≥60 were included. PA was collected using a wrist-worn triaxial accelerometer and expressed as 2 metrics using Monitor-Independent Movement Summary (MIMS) units: the average of daily MIMS, which represents volume, and peak 30-minute MIMS, which is the average of the highest 30 MIMS min/d and represents intensity. DQ was assessed by the Healthy Eating Index-2015. Mortality follow-up was recorded using the National Death Index linkage through December 31, 2019. RESULTS: Our analyses revealed a dose-dependent, nonlinear association of PA (volume and intensity) with all-cause mortality and a dose-dependent, linear association of DQ with all-cause mortality. The maximum protective dose of PA volume was observed at 14,300 MIMS/min (adj. HR: 0.20, 95% CI: 0.11-0.38). The maximum protective dose of PA intensity was observed at 54.25 MIMS/min (adj. HR: 0.10, 95% CI: 0.05-0.23), beyond which mortality risks flattened. The Healthy Eating Index-2015 showed its maximum protective effect at 66.17 (adj. HR: 0.54, 95% CI: 0.40-0.74). Higher PA (volume and intensity) levels were associated with a lower risk of cardiovascular-related but not cancer-related mortality. A healthier diet was linked to a reduced risk of cardiovascular-specific and cancer-specific mortality. Sensitivity analyses showed that the beneficial effects of PA and DQ on survival rates remained significant across sex, racial/ethnic, and age groups as well as in participants without NAFLD. DISCUSSION: Our findings suggest that higher daily accumulated and peak effort PA and DQ are associated with lower all-cause and cardiovascular mortality in US adults with NAFLD.

CAP and LSM as determined by VCTE are independent predictors of all-cause mortality in the US adult population.

BACKGROUND AND AIM: Data retrospective cohort studies have shown that liver stiffness measurement (LSM) by transient elastography (TE, FibroScan) can predict mortality in patients with NAFLD, however, its ability to predict mortality at a population level is unknown. We investigated the ability of LSM and controlled-attenuation parameter (CAP) by TE to predict mortality in a prospective US cohort. APPROACH AND RESULTS: A total of 4192 US adults aged ≥18 years enrolled in the National Health, and Nutrition Examination Survey (NHANES) (2017-2018) with reliable information on CAP and LSM by TE were included in this analysis. All-specific and cause-specific mortality were ascertained by linkage to National Death Index records through December 31, 2019. Cox models were used to estimate HR and 95% CI. During a mean follow-up of 24.4 months, there were 68 deaths (1.6%). CAP (adjusted HR: 1.01, 95% CI: 1.0-1.05), and LSM (adjusted HR: 1.06, 95% CI: 1.02-1.11) were independently associated with overall mortality. NAFLD by CAP ≥285 had a 2.2-fold (95% CI: 1.0-4.7) increased odds of mortality compared with non-NAFLD. Cumulative mortality rates were significantly higher in participants with LSM of 9.7-13.5 (advanced fibrosis) and LSM ≥13.6 (cirrhosis) as compared with LSM <9.7; p value for trend across groups <0.01. LSM ≥13.6 displayed the highest mortality risk (adjusted HR: 3.2, 95% CI: 1.3-7.8). Compared with LSM <10 [absence of advanced chronic liver disease (ACLD)], LSM 10-19.9 (likely ACLD), and ≥20 kPa (likely ACLD with clinically significant portal hypertension) conferred a 3.4-fold (95% CI: 1.0-13.8) and 5.2-fold (95% CI: 1.2-22.3) increase in hazards of mortality. CONCLUSIONS: Our study findings highlight the importance of liver health as a predictor of overall mortality at a population level.