Impact of Pretransplant Diabetes on Outcomes After Liver Transplantation: An Updated Meta-analysis With Systematic Review.

BACKGROUND: Preliver transplant diabetes mellitus (pre-LT DM) is a common comorbidity in LT recipients associated with poorer post-transplant survival. However, its relationship with other important outcomes, including cardiovascular and renal outcomes, remains unclear. This meta-analysis aims to provide an updated analysis of the impact of pre-LT DM on key post-LT outcomes. METHODS: A search was conducted in Medline and Embase databases for articles comparing the post-transplant outcomes between patients with and without pre-LT DM. Pairwise analysis using random effects with hazard ratios (HRs) was used to assess the longitudinal post-LT impacts of pre-LT DM. In the absence of HR, pooled odds ratios analysis was conducted for secondary outcomes. RESULTS: Forty-two studies involving 77,615 LT recipients were included in this analysis. The pooled prevalence of pre-LT DM amongst LT recipients was 24.79%. Pre-LT DM was associated with significantly lower overall survival (HR, 0.65; 95% confidence interval, 0.52-0.81; P<0.01) and significantly increased cardiovascular disease-related mortality (HR, 1.78; 95% confidence interval, 1.11-2.85; P=0.03). Meta-regression of other patient characteristics identified Asian ethnicity and hypertension to be significant predictors of worse overall survival, whereas African-American ethnicity was associated with significantly improved overall survival in patients with pre-LT DM. Further analysis of secondary outcomes revealed pre-LT DM to be a significant predictor of post-LT cardiovascular events and end-stage renal disease. CONCLUSIONS: The present study illustrates the impact of pre-LT DM on post-LT survival, and cardiovascular and renal outcomes and provides a sound basis for revision of preoperative management of pre-LT DM.

Clinical Course, Immunogenicity, and Efficacy of BNT162b2 mRNA Vaccination Against SARS-CoV-2 Infection in Liver Transplant Recipients.

Background: Immunocompromised individuals have been excluded from landmark studies of messenger RNA vaccinations for severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). In such patients, the response to vaccination may be blunted and may wane more quickly compared with immunocompetent patients. We studied the factors associated with decreased antibody response to SARS-CoV-2 vaccination and risk factors for subsequent breakthrough infections in liver transplant (LT) patients undergoing coronavirus disease 2019 vaccination with at least 2 doses of messenger RNA vaccine from April 28, 2021, to April 28, 2022. Methods: All LT recipients received at least 2 doses of the BNT162b2 (Pfizer BioNTech) vaccine 21 d apart. We measured the antibody response against the SARS-CoV-2 spike protein using the Roche Elecsys immunoassay to the receptor-binding domain of the SARS-CoV-2 spike protein, and the presence of neutralizing antibodies was measured by the surrogate virus neutralization test (cPass) before first and second doses of vaccination and also between 2 and 3 mo after the second dose of vaccination. Results: Ninety-three LT recipients who received 2 doses of BNT162b2 were included in the analysis. The mean time from LT was 110 ± 154 mo. After 2-dose vaccination, 38.7% of LT recipients (36/93) were vaccine nonresponders on the cPass assay compared with 20.4% (19/93) on the Roche S assay. On multivariable analysis, increased age and increased tacrolimus trough were found to be associated with poor neutralizing antibody response (P = 0.038 and 0.022, respectively). The use of antimetabolite therapy in conjunction with tacrolimus approached statistical significance (odds ratio 0.21; 95% confidence interval, 0.180-3.72; P = 0.062). Breakthrough infection occurred in 18 of 88 LT recipients (20.4%). Female gender was independently associated with breakthrough infections (P < 0.001). Conclusions: Among LT recipients, older age and higher tacrolimus trough levels were associated with poorer immune response to 2-dose SARS-CoV-2 vaccination. Further studies are needed to assess variables associated with breakthrough infections and, hence, who should be prioritized for booster vaccination.

Meta-analysis: Prevalence of significant or advanced fibrosis in adults with alpha-1-antitrypsin deficiency.

BACKGROUND: The prevalence of liver fibrosis detected by non-invasive imaging in alpha-1-antitrypsin (AAT) deficiency has not been systematically assessed. AIMS: We conducted a systematic review and meta-analysis to determine the prevalence of significant fibrosis and advanced fibrosis in AAT deficiency based on non-invasive imaging. METHODS: Medline and Embase electronic databases were searched for studies from inception to 13 November 2022 that provided data for the prevalence of fibrosis in adults with AAT deficiency. A generalised linear mixed model with Clopper-Pearson intervals was used to pool single-arm outcomes. RESULTS: Of the 214 records identified, 8 studies were included. Five studies assessed fibrosis using vibration-controlled transient elastography. The prevalence of significant fibrosis (defined as ≥7.1 kPA) in Z homozygosity, Z heterozygosity and non-carrier status was 22.10% (five studies, 95% CI: 17.07-28.12), 9.24% (three studies, 95% CI: 4.68-17.45) and 5.38% (one study, 95% CI: 3.27-8.73), respectively, p < 0.0001, and the prevalence of advanced fibrosis (defined as ≥9.5 kPa) was 8.13% (five studies, 95% CI: 4.60-13.96), 2.96% (three studies, 95% CI: 1.49-5.81) and 1.08% (one study, 95% CI: 0.35-3.28), respectively, p = 0.003. There were limited data regarding the use of magnetic resonance elastography or acoustic radiation force impulse to assess for fibrosis. CONCLUSION: More than one in five adult individuals with AAT deficiency and Z homozygosity harbour significant fibrosis, and nearly 1 in 10 harbours advanced fibrosis. The risk of fibrosis increases incrementally with the frequency of Pi*Z mutations.

De novo metabolic syndrome after liver transplantation: a meta-analysis on cumulative incidence, risk factors, and outcomes.

Post-transplant metabolic syndrome (PTMS) has been associated with increased cardiovascular risk which significantly impacts the morbidity and mortality rates of liver transplant (LT) recipients. This study sought to conduct a meta-analysis and systematic review on the cumulative incidence, risk factors, and cardiovascular outcomes associated with de novo PTMS.Medline and Embase were searched for articles describing the incidence, risk factors, and cardiovascular outcomes of de novo PTMS. Meta-analysis of proportions was conducted to calculate incidence. Conventional pairwise analysis using random effects model was used to tabulate OR and hazard ratio for risk factors and cardiovascular outcomes, respectively. Fifteen studies involving 2683 LT recipients were included. Overall rate of de novo PTMS was 24.7% (CI: 18.0%-32.9%) over a mean follow-up period of 15.3 months and was highest in patients with NAFLD (60.0%, CI: 52.0%-67.5%) compared with other liver diseases. Older age (OR: 1.05, CI: 1.01-1.09, p = 0.02) and pre-LT type II diabetes mellitus (OR: 5.00, CI: 4.17-5.99, p < 0.01) were predictive factors of de novo PTMS. Patients with de novo PTMS had significantly higher likelihood of cardiovascular disease events compared with those who did not (hazard ratio: 2.42, CI: 1.54-3.81, p < 0.01). De novo PTMS is a common complication and is significantly associated with increased cardiovascular disease morbidity. High-risk patients such as elderly recipients, those with pre-LT type II diabetes mellitus, or NASH-related cirrhosis should undergo routine screening to allow timely intervention.

Safety and tolerability of obeticholic acid in chronic liver disease: a pooled analysis of 1878 individuals.

BACKGROUND AND AIMS: Obeticholic acid (OCA) is a farnesoid X receptor agonist used in primary biliary cholangitis (PBC) treatment. Recent studies have expanded OCA use for NASH treatment and results from phase 3 clinical trial have shown beneficial reduction of ≥1 stage of fibrosis with no NASH worsening. However, safety concerns still preside, thus we systematically examine the safety profile of OCA in chronic liver disease. MATERIALS AND METHODS: A search was conducted in Medline and Embase databases for OCA randomized controlled trials in chronic liver disease. Binary events were pooled with Paule-Mandel random effects model and proportional events were examined in a generalized linear mixed model with Clopper-Pearson intervals. RESULTS: A total of 8 studies and 1878 patients were analyzed. There was a 75% [risk ratio (RR): 1.75, 95% CI: 1.43-2.15, p < 0.01] increased pruritis risk. OCA increased constipation incidence (RR: 1.88, 95% CI: 1.45-2.43, p < 0.01), decreased diarrhea (RR: 0.62, 95% CI: 0.50-0.77, p < 0.01), and increased development of hyperlipidemia (RR: 2.69, 95% CI: 1.85-3.92, p < 0.01) relative to placebo. Sensitivity analysis in NASH-only studies found a dose-dependent effect with pruritis which increases to RR: 3.07 (95% CI: 1.74-5.41) at 25 mg. However, up to 9.98% (95% CI: 5.01%-18.89%) of NAFLD patients with placebo similarly experience pruritis events. Overall, 16.55% (95% CI: 6.47%-36.24%) of patients with NAFLD on OCA experienced pruritis. There was no significant increase in cardiovascular events. CONCLUSIONS: OCA may represent the first pharmacological treatment approved for NASH. However, pruritis, constipation, diarrhea, and hyperlipidemia were major events with evident dose-dependent effect that affect tolerability in NASH. Future long-term studies for longitudinal safety events are required.

Examining the interim proposal for name change to steatotic liver disease in the US population.

BACKGROUND AND AIMS: Fatty liver is the commonest liver condition globally and traditionally associated with NAFLD. A consensus meeting was held in Chicago to explore various terminologies. Herein, we explore the proposed changes in nomenclature in a population data set from the US. APPROACH AND RESULTS: Statistical analysis was conducted using survey-weighted analysis. Assessment of fatty liver was conducted with vibration-controlled transient elastography. A controlled attenuation parameter of 288 dB/m was used to identify hepatic steatosis. Patients were classified into nonalcoholic steatotic liver disease, alcohol-associated steatotic liver disease, and viral hepatitis steatotic liver disease. Liver stiffness measures at ≥8.8, ≥11.7, and ≥14 kPa were used to identify clinically significant fibrosis, advanced fibrosis, and cirrhosis, respectively. A total of 5102 individuals were included in the analysis. Using a survey-weighted analysis, a total of 25.43%, 6.95%, and 0.73% of the population were classified as nonalcoholic steatotic liver disease, alcohol-associated steatotic liver disease, and viral hepatitis steatotic liver disease, respectively. A sensitivity analysis at controlled attenuation parameter of 248 dB/m and fatty liver index found similar distribution. In a comparison between nonalcoholic steatotic liver disease, alcohol-associated steatotic liver disease, and viral hepatitis steatotic liver disease, there was no significant difference between the odds of advanced fibrosis and cirrhosis between groups. However, viral hepatitis steatotic liver disease individuals were found to have a significantly higher odds of clinically significant fibrosis (OR: 3.76, 95% CI, 1.27-11.14, p =0.02) compared with nonalcoholic steatotic liver disease. CONCLUSIONS: The current analysis assessed the proposed changes based on discussions from the consensus meeting. Although the definitions are an interim analysis of discussions, steatotic liver disease respects the underlying liver etiology and reduces stigma while increasing awareness of FL among viral and alcohol-associated steatosis/steatohepatitis.

Meta-analysis: Chemoprevention of hepatocellular carcinoma with statins, aspirin and metformin.

BACKGROUND: Emerging data suggest that statins, aspirin and metformin may protect against hepatocellular carcinoma (HCC) development. However, prior meta-analyses were limited by heterogeneity and inclusion of studies without adequate adjustment for baseline risks. AIM: To examine by an updated meta-analysis the association between these medications and HCC risk. METHODS: Medline and Embase databases were searched from inception to March 2022 for studies that balanced baseline risks between study groups via propensity score matching or inverse probability of treatment weighting, that reported the impact of statins, aspirin or metformin on HCC risk. Multivariable-adjusted hazard ratios (HRs) for HCC were pooled using a random effects model. RESULTS: Statin use was associated with reduced HCC risk overall (HR: 0.52; 95% CI: 0.37-0.72) (10 studies, 1,774,476), and in subgroup analyses for cirrhosis, hepatitis B/C, non-alcoholic fatty liver disease, studies accounting for concurrent aspirin and metformin consumption and lipophilic statins. Aspirin use was associated with reduced HCC risk overall (HR: 0.48; 95% CI: 0.27-0.87) (11 studies, 2,190,285 patients) but not in studies accounting for concurrent statin and metformin use. Metformin use was not associated with reduced HCC risk overall (HR: 0.57; 95% CI: 0.31-1.06) (3 studies, 125,458 patients). Most analyses had moderate/substantial heterogeneity, except in follow-up <60 months for aspirin (I2  = 0%). CONCLUSION: Although statin and aspirin use were associated with reduced HCC risk, only statin use was significant in subgroup analyses accounting for concurrent medications. Metformin use was not associated with reduced HCC risk. These data have implications for future clinical trial design.

Global prevalence of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in the overweight and obese population: a systematic review and meta-analysis.

BACKGROUND: The global burden of non-alcoholic fatty liver disease (NAFLD) parallels the increase in obesity rates across the world. Although overweight and obesity status are thought to be an effective indicator for NAFLD screening, the exact prevalence of NAFLD in this population remains unknown. We aimed to report the prevalence of NAFLD, non-alcoholic fatty liver (NAFL), and non-alcoholic steatohepatitis (NASH) in the overweight and obese population. METHODS: In this systematic review and meta-analysis, we searched Medline and Embase from database inception until March 6, 2022, using search terms including but not limited to "non-alcoholic fatty liver disease", "overweight", "obesity", and "prevalence". Cross-sectional and longitudinal observational studies published after Jan 1, 2000, written in or translated into English were eligible for inclusion; paediatric studies were excluded. Articles were included if the number of NAFLD, NAFL, or NASH events in an overweight and obese population could be extracted. Summary data were extracted from published reports. The primary outcomes were the prevalence of NAFLD, NAFL, and NASH in an overweight and obese population and the prevalence of fibrosis in individuals who were overweight or obese and who had NAFLD. A meta-analysis of proportions was done with the generalised linear mixed model. This study is registered with PROSPERO (CRD42022344526). FINDINGS: The search identified 7389 articles. 151 studies met the inclusion criteria and were included in the meta-analysis. In the pooled analysis comprising 101 028 individuals, the prevalence of NAFLD in the overweight population was 69·99% (95% CI 65·40-74·21 I2=99·10%), the prevalence of NAFL was 42·49% (32·55-53·08, I2=96·40%), and the prevalence of NASH was 33·50% (28·38-39·04, I2=95·60%). Similar prevalence estimates were reported in the obese population for NAFLD (75·27% [95% CI 70·90-79·18]; I2=98·50%), NAFL (43·05% [32·78-53·97]; I2=96·30%) and NASH (33·67% [28·45-39·31]; I2=95·60%). The prevalence of NAFLD in the overweight population was the highest in the region of the Americas (75·34% [95% CI: 67·31-81·93]; I2=99·00%). Clinically significant fibrosis (stages F2-4) was present in 20·27% (95% CI 11·32-33·62; I2= 93·00%) of overweight individuals with NAFLD and in 21·60% (11·47-36·92; I2=95·00%) of obese patients with NAFLD while 6·65% (4·35-10·01; I2=58·00%) of overweight individuals with NAFLD and 6·85% (3·85-11·90; I2=90·00%) of obese individuals with NAFLD had advanced fibrosis (stages F3-4). INTERPRETATION: This study summarises the estimated global prevalence of NAFLD, NAFL, and NASH in overweight and obese individuals; these findings are important for improving the understanding of the global NAFLD burden and supporting disease management in the at-risk overweight and obese population. FUNDING: None.

Complete alcohol abstinence increases the risk of NAFLD but not severity. A population analysis with transient elastography.

BACKGROUND & AIMS: As the global prevalence of non-alcoholic fatty liver disease (NAFLD) continues to rise, ubiquity of alcohol use has also prompted discussion regarding the potential interactions between the two. This study aims to examine the effects of modest alcohol consumption on the prevalence and complications of NAFLD in a multi-ethnic population. METHODS: This study analyses the 2017-2018 cycles of NHANES that examined liver fibrosis and steatosis with vibration controlled transient elastography. A coarsened exact matching was conducted to reduce confounding. Logistic regression was done with a multivariate model to assess the relationship between alcohol consumption (modest drinkers and non-drinkers) and risk of NAFLD and its complications. RESULTS: 2,067 individuals were found to have NAFLD and 284 NAFLD patients had a total history of alcohol abstinence. After coarsened exact matching, the prevalence of NAFLD was 49% (CI: 0.41 - 0.58) in non-drinkers and 33% (CI: 0.26 - 0.41) in modest drinkers. Non-drinkers had twice the odds of NAFLD compared to modest drinkers (OR: 1.99, CI: 1.22 - 3.22, p<.01) after adjustment for confounders. There were no significant differences in the odds of significant fibrosis, advance fibrosis, cirrhosis, cardiovascular disease and stroke between non-drinkers and modest drinkers. The odds of malignancy in non-drinkers were almost significantly less than modest drinkers (OR: 0.28, CI:0.08 - 1.02, p=.053). CONCLUSION: Interestingly, modest alcohol consumption is associated with decreased odds of NAFLD. Further investigations are required to examine the relationship between alcohol consumption and NAFLD and subsequently the potential impact on NAFLD management.

Global prevalence of depression and anxiety in patients with hepatocellular carcinoma: Systematic review and meta-analysis.

BACKGROUND/AIMS: Depression and anxiety are associated with poorer outcomes in patients with hepatocellular carcinoma (HCC). However, the prevalence of depression and anxiety in HCC are unclear. We aimed to establish the prevalence of depression and anxiety in patients with HCC. METHODS: MEDLINE and Embase were searched and original articles reporting prevalence of anxiety or depression in patients with HCC were included. A generalized linear mixed model with Clopper-Pearson intervals was used to obtain the pooled prevalence of depression and anxiety in patients with HCC. Risk factors were analyzed via a fractional-logistic regression model. RESULTS: Seventeen articles involving 64,247 patients with HCC were included. The pooled prevalence of depression and anxiety in patients with HCC was 24.04% (95% confidence interval [CI], 13.99-38.11%) and 22.20% (95% CI, 10.07-42.09%) respectively. Subgroup analysis determined that the prevalence of depression was lowest in studies where depression was diagnosed via clinician-administered scales (16.07%;95% CI, 4.42-44.20%) and highest in self-reported scales (30.03%; 95% CI, 17.19-47.01%). Depression in patients with HCC was lowest in the Americas (16.44%; 95% CI, 6.37-36.27%) and highest in South-East Asia (66.67%; 95% CI, 56.68-75.35%). Alcohol consumption, cirrhosis, and college education significantly increased risk of depression in patients with HCC. CONCLUSION: One in four patients with HCC have depression, while one in five have anxiety. Further studies are required to validate these findings, as seen from the wide CIs in certain subgroup analyses. Screening strategies for depression and anxiety should also be developed for patients with HCC.

DEXA Scan Body Fat Mass Distribution in Obese and Non-Obese Individuals and Risk of NAFLD-Analysis of 10,865 Individuals.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide yet predicting non-obese NAFLD is challenging. Thus, this study investigates the potential of regional fat percentages obtained by dual-energy X-ray absorptiometry (DXA) in accurately assessing NAFLD risk. Using the United States National Health and Nutrition Examination Survey (NHANES) 2011−2018, multivariate logistic regression and marginal analysis were conducted according to quartiles of regional fat percentages, stratified by gender. A total of 23,752 individuals were analysed. Males generally showed a larger increase in marginal probabilities of NAFLD development than females, except in head fat, which had the highest predictive probabilities of non-obese NAFLD in females (13.81%, 95%CI: 10.82−16.79) but the lowest in males (21.89%, 95%CI: 20.12−23.60). Increased percent of trunk fat was the strongest predictor of both non-obese (OR: 46.61, 95%CI: 33.55−64.76, p < 0.001) and obese NAFLD (OR: 2.93, 95%CI: 2.07−4.15, p < 0.001), whereas raised percent gynoid and leg fat were the weakest predictors. Ectopic fat deposits are increased in patients with non-obese NAFLD, with greater increases in truncal fat over gynoid fat. As increased fat deposits in all body regions can increase odds of NAFLD, therapeutic intervention to decrease ectopic fat, particularly truncal fat, may decrease NAFLD risk.

A poor perspective of self weight significantly increases adverse outcomes in non-alcoholic fatty liver disease (NAFLD).

Background: Non-alcoholic fatty liver disease (NAFLD) is prevalent amongst overweight and obese individuals, and weight loss remains the main mode of treatment for NAFLD patients. Weight perception plays a key role in the efficacy of such treatment. The current study aims to investigate the prevalence, associating factors and implications of poor weight perception amongst such individuals. Methods: An analysis was done on data collected from NHANES between 1999 and 2018. Comparison was made between NAFLD individuals with and without poor weight perception in terms of prevalence, associated characteristics, and clinical outcomes. Multivariate analysis was used to compare effect size of adverse events associated with NAFLD individuals with poor weight perception. Results: Of the 12,170 NAFLD patients, 19.2% (CI: 18.5 to 19.9%) had poor weight perception. Poor weight perception was significantly associated with lower education levels, reduced levels of exercise and unhealthier lipid profiles. There was an increased risk in all-cause mortality (HR: 1.18, CI: 1.00 to 1.38, p = 0.047), cardiovascular disease mortality (SHR: 1.33, CI: 1.03 to 1.71, p = 0.026), major adverse cardiovascular events (OR: 1.21 CI: 1.10 to 1.32, p < 0.001), and advanced fibrosis (OR: 1.30, CI: 1.03 to 1.64, p = 0.025) for individuals with poor weight perception. Conclusion: This study highlights the positive association between appropriate weight perception and better outcomes in individuals with NAFLD. Poor weight perception increased the risk of adverse events and decreased inclination toward seeking weight loss treatment. Greater emphasis should be placed on dealing with weight perception in individuals with NAFLD for better treatment outcomes.

Depression in non-alcoholic fatty liver disease is associated with an increased risk of complications and mortality.

Background and aims: The global prevalence of non-alcoholic fatty liver disease (NAFLD) is expected to rise continuously. Furthermore, emerging evidence has also shown the potential for concomitant depression in NAFLD. This study aims to examine the prevalence, risk factors, and adverse events of depression in NAFLD and evaluate whether treated depression can reverse the increased risks of adverse outcomes. Materials and methods: This study analyses the 2000-2018 cycles of NHANES that examined liver steatosis with fatty liver index (FLI). The relationship between NAFLD and depression was assessed with a generalized linear mix model and a sensitivity analysis was conducted in the no depression, treated depression, and untreated depression groups. Survival analysis was conducted with cox regression and fine gray sub-distribution model. Results: A total of 21,414 patients were included and 6,726 were diagnosed with NAFLD. The risk of depression in NAFLD was 12% higher compared to non-NAFLD individuals (RR: 1.12, CI: 1.00-1.26, p = 0.04). NAFLD individuals with depression were more likely to be older, females, Hispanics or Caucasians, diabetic, and have higher BMI. Individuals with depression have high risk for cardiovascular diseases (CVD) (RR: 1.40, CI: 1.25-1.58, p < 0.01), stroke (RR: 1.71, CI: 1.27-2.23, p < 0.01), all-cause mortality (HR: 1.50, CI: 1.25-1.81, p < 0.01), and cancer-related mortality (SHR: 1.43, CI: 1.14-1.80, p = 0.002) compared to NAFLD individuals without depression. The risk of CVD, stroke, all-cause mortality, and cancer-related mortality in NAFLD individuals with treated depression and depression with untreated treatment was higher compared to individuals without depression. Conclusion: This study shows that concomitant depression in NAFLD patients can increase the risk of adverse outcomes. Early screening of depression in high-risk individuals should be encouraged to improve the wellbeing of NAFLD patients.

Historical Changes in Weight Classes and the Influence of NAFLD Prevalence: A Population Analysis of 34,486 Individuals.

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease globally in tandem with the growing obesity epidemic. However, there is a lack of data on the relationship between historical weight changes 10 years ago and at present on NAFLD prevalence at the population level. Therefore, we sought to evaluate the relationship between weight classes and the prevalence of NAFLD. Methods: Data were used from the United States National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018. Univariate and multivariate general linear model analyses were used to obtain risk ratio (RR) estimations of NAFLD events. Results: In total, 34,486 individuals were analysed, with those who were lean at both time points as the control group. Overweight (RR: 14.73, 95%CI: 11.94 to 18.18, p < 0.01) or obese (RR: 31.51, 95%CI: 25.30 to 39.25, p < 0.01) individuals at both timepoints were more likely to develop NAFLD. Residual risk exists where previously obese individuals became overweight (RR: 14.72, 95%CI: 12.36 to 17.52, p < 0.01) or lean (RR: 2.46, 95%CI: 1.40 to 4.31, p = 0.02), and previously overweight individuals who became lean (RR 2.24, 95%CI 1.42 to 3.54, p = 0.01) had persistent elevated risk of developing NAFLD despite weight regression. Sensitivity analysis identified that a higher proportion of individuals with regression in weight class were diabetics and Mexican Americans, while fewer African Americans saw weight-class regression. Conclusions: Residual risk exists in patients who lost weight despite the smaller magnitude of effect, and targeted weight reductions should still be used to mitigate the risk of NAFLD at the population level.