The combination of the enhanced liver fibrosis and FIB-4 scores to determine significant fibrosis in patients with nonalcoholic fatty liver disease.

BACKGROUND: The presence of fibrosis in NAFLD is the most significant risk factor for adverse outcomes. We determined the cutoff scores of two non-invasive te sts (NITs) to rule in and rule out significant fibrosis among NAFLD patients. METHODS: Clinical data and liver biopsies were used for NAFLD patients included in this analysis (2001-2020). The enhanced liver fibrosis (ELF) and FIB-4 NITs were calculated. Liver biopsies were read by a single hematopathologist and scored by the NASH CRN criteria. Significant fibrosis was defined as stage F2-F4. RESULTS: There were 463 NAFLD patients included: 48 ± 13 years old, 31% male, 35% type 2 diabetes; 39% had significant fibrosis; mean ELF score was 9.0 ± 1.2, mean FIB-4 score was 1.22 ± 1.05. Patients with significant fibrosis were older, more commonly male, had lower BMI but more components of metabolic syndrome, higher ELF and FIB-4 (p < 0.0001). The performance of the two NITs in identifying significant fibrosis was: AUC (95% CI) = 0.78 (0.74-0.82) for ELF, 0.79 (0.75-0.83) for FIB-4. The combination of ELF score ≥9.8 and FIB-4 ≥ 1.96 returned a positive predictive value of 95% which can reliably rule in significant fibrosis (sensitivity 22%, specificity >99%), while an ELF score ≤7.7 or FIB-4 ≤ 0.30 had a negative predictive value of 95% ruling out significant fibrosis (sensitivity 98%, specificity 22%). CONCLUSIONS: The combination of ELF and FIB-4 may provide practitioners with easily obtained information to risk stratify patients with NAFLD who could be referred to specialists or for enrollment in clinical trials.

The impact of variants and vaccination on the mortality and resource utilization of hospitalized patients with COVID-19.

BACKGROUND: COVID-19 outcomes among hospitalized patients may have changed due to new variants, therapies and vaccine availability. We assessed outcomes of adults hospitalized with COVID-19 from March 2020-February 2022. METHODS: Data were retrieved from electronic health medical records of adult COVID-19 patients hospitalized in a large community health system. Duration was split into March 2020-June 2021 (pre-Delta period), July-November 2021 (Delta period), and December 2021-February 2022 (Omicron period). RESULTS: Of included patients (n = 9582), 75% were admitted during pre-Delta, 9% during Delta, 16% during Omicron period. The COVID-positive inpatients were oldest during Omicron period but had lowest rates of COVID pneumonia and resource utilization (p < 0.0001); 46% were vaccinated during Delta and 61% during Omicron period (p < 0.0001). After adjustment for demographics and comorbidities, vaccination was associated with lower inpatient mortality (OR = 0.47 (0.34-0.65), p < 0.0001). The Omicron period was independently associated with lower risk of inpatient mortality (OR = 0.61 (0.45-0.82), p = 0.0010). Vaccination and Omicron period admission were also independently associated with lower healthcare resource utilization (p < 0.05). Magnitudes of associations varied between age groups with strongest protective effects seen in younger patients. CONCLUSION: Outcomes of COVID-19 inpatients were evolving throughout the pandemic and were affected by changing demographics, virus variants, and vaccination. KEY POINT: In this observational study of almost 10,000 patients hospitalized from March 2020-February 2022 with COVID-19, age and having multiple comorbidities remained consistent risk factors for mortality regardless of the variant. Vaccination was high in our hospitalized patients. Vaccination conveyed less severe illness and was associated with lower inpatient mortality.

The impact of the COVID-19 pandemic on patients with chronic liver disease: Results from the Global Liver Registry.

Patients with preexisting chronic liver disease (CLD) may experience a substantial burden from both coronavirus 2019 (COVID-19) infection and pandemic-related life disruption. We assessed the impact of the COVID-19 pandemic on patients with CLD. Patients enrolled in our Global Liver Registry were invited to complete a COVID-19 survey. As of June 2021, 2500 patients (mean age ± SD, 49 ± 13 years; 53% men) from seven countries completed the survey. Of all survey completers, 9.3% had COVID-19. Of these patients, 19% were hospitalized, 13% needed oxygen support, but none required mechanical ventilation. Of all patients including those not infected with COVID-19, 11.3% reported that the pandemic had an impact on their liver disease, with 73% of those reporting delays in follow-up care. The Life Disruption Event Perception questionnaire confirmed worsening in at least one area (food/nutrition, exercise, social life, vocation/education, financial situation, housing, or health care) in 81% and 69% of patients with and without a history of COVID-19, respectively (p = 0.0001). On a self-assessed Likert health score scale (range, 1-10; 10 indicates perfect health), patients with a COVID-19 history scored lower (mean ± SD, 6.7 ± 2.2 vs. 7.4 ± 2.2, respectively; p < 0.0001) despite reporting similar health scores if there was no pandemic (mean ± SD, 8.5 ± 1.4 vs. 8.4 ± 1.6, respectively; p = 0.59). After adjustment for country of enrollment, liver disease etiology and severity, age, sex, body mass index, diabetes, and history of psychiatric comorbidities, COVID-19 was found to be independently associated with lower self-assessed health scores (beta = -0.71 ± 0.14; p < 0.0001). The COVID-19 pandemic resulted in a substantial burden on the daily life of patients with CLD.

Serum Biomarkers are Associated With Atherosclerotic Cardiovascular Disease Among Patients With Nonalcoholic Fatty Liver Disease Undergoing Elective Angiography.

BACKGROUND & AIMS: Cardiovascular disease is the most common cause of death among patients with nonalcoholic fatty liver disease (NAFLD). We assessed select cardiac biomarker associations for existing or future coronary artery disease (CAD) risk in patients with NAFLD. METHODS: Patients with/without NAFLD undergoing elective cardiac angiography were prospectively enrolled. Severe CAD was defined as presence of at least 1 proximal artery >70% stenosis; risk of severe CAD as either existing severe CAD or atherosclerotic cardiovascular disease score ≥20; NAFLD was defined as hepatic fat in the absence of other liver diseases. Cardiac biomarkers (high-sensitivity C-reactive protein, N-terminal pro-brain natriuretic peptide, and high-sensitivity cardiac troponin I [hs-cTnI]) were measured using Atellica Solution assays (Siemens Healthineers). RESULTS: A total of 619 patients were enrolled (mean age, 63 ± 10 years; 80% male; 31% type 2 diabetes; 65% NAFLD); 42% had severe CAD, and 57% had risk of severe CAD. NAFLD prevalence was similar between patients with and without severe CAD (68% vs 62%; P > .05). Patients with NAFLD with severe CAD (44%) or with risk of severe CAD (58%) had higher levels of hs-cTnI than NAFLD controls (both P < .001). Presence of severe CAD or risk of severe CAD in all patients was associated with older age, male, aspects of metabolic syndrome, and elevated hs-cTnI: odds ratio 2.0 (95% confidence interval [CI],1.4-2.9) and 1.8 (95% CI, 1.1-3.0), respectively; 2.3 (95% CI, 1.4-3.8) and 2.2 (95% CI, 1.2-4.2), respectively, in patients with NAFLD (all P < .02). CONCLUSION: CAD is common in patients with NAFLD. High hs-cTnI was associated with an increased risk of CAD. Pending validation, hs-cTnI may be a useful marker for CAD risk prediction in patients with NAFLD.

Independent Predictors of Mortality Among Patients With NAFLD Hospitalized With COVID-19 Infection.

The impact of the coronavirus disease 2019 (COVID-19) pandemic among patients with chronic liver disease is unknown. Given the high prevalence of nonalcoholic fatty liver disease (NAFLD), we determined the predictors of mortality and hospital resource use among patients with NAFLD admitted with COVID-19 by using electronic medical records data for adult patients with COVID-19 hospitalized in a multihospital health system who were discharged between March and December 2020. NAFLD was diagnosed by imaging or liver biopsy without other liver diseases. Charlson's comorbidity index (CCI) and Elixhauser comorbidity index (ECI) scores were calculated. In the study sample, among the 4,835 patients hospitalized for COVID-19, 553 had NAFLD (age: 55 ± 16 years, 51% male, 17% White, 11% Black, 58% Hispanic, 8% Asian, 5% from congregated living, 58% obese, 15% morbid obesity [body mass index ≥ 40], 51% type 2 diabetes, 63% hypertension, mean [SD] baseline CCI of 3.9 [3.2], and baseline ECI of 13.4 [11.3]). On admission, patients with NAFLD had more respiratory symptoms, higher body temperature and heart rate, higher alanine aminotransferase and aspartate aminotransferase than non-NAFLD controls (n = 2,736; P < 0.05). Of the patients with NAFLD infected with COVID-19, 3.9% experienced acute liver injury. The NAFLD group had significantly longer length of stay, intensive care unit use, and mechanical ventilation, with a crude inpatient mortality rate of 11%. In multivariate analysis, independent predictors of inpatient mortality among patients with NAFLD infected with COVID-19 were older age, morbid obesity, ECI score ≥ 11, higher Fibrosis-4 Index (FIB-4) score, and oxygen saturation <90% (all P < 0.05), but not sex, race/ethnicity, or any individual comorbidity (all P > 0.05). Conclusion: Patients with NAFLD infected with COVID-19 tend to be sicker on admission and require more hospital resource use. Independent predictors of mortality included higher FIB-4 and multimorbidity scores, morbid obesity, older age, and hypoxemia on admission.

Performance of the Enhanced Liver Fibrosis Test to Estimate Advanced Fibrosis Among Patients With Nonalcoholic Fatty Liver Disease.

Importance: The most important surrogate for increased risk of adverse clinical outcomes among patients with nonalcoholic fatty liver disease (NAFLD) is the patient's stage of liver fibrosis. There is a significant barrier to risk-stratifying patients in clinical practice owing to the need for liver biopsy. Objective: To determine the performance of the enhanced liver fibrosis (ELF) test as a noninvasive test for assessment of liver fibrosis among patients with NAFLD. Design, Setting, and Participants: This retrospective cross-sectional study was conducted among patients recruited from a large, community-based hospital system's outpatient liver clinic from 2001 to 2020. Patients with NAFLD defined as steatosis greater than 5% without evidence of other liver disease or excessive alcohol use were included. Data were analyzed from August 2020 through February 2021. Intervention: Enhanced liver fibrosis score was calculated. Main Outcomes and Measures: Advanced fibrosis was identified by liver biopsy or transient elastography. Results: Among 829 patients with NAFLD, the mean (SD) age was 53.1 (14.0) years, there were 363 (43.8%) men, 294 patients (35.5%) had type 2 diabetes, and the mean (SD) fibrosis-4 (fib-4) score was 1.34 (0.97). There were 463 patients with liver biopsy, among whom 113 individuals (24.4%) had bridging fibrosis or cirrhosis; among 462 patients with transient elastography data, 79 individuals (17.1%) had liver stiffness results of 9.6 kPa or more (ie, advanced fibrosis). Patients with advanced fibrosis had statistically significantly increased mean (SD) ELF scores compared with patients without advanced fibrosis as determined by biopsy (10.1 [1.3] vs 8.6 [1.0]; P < .001) or transient elastography (10.0 [1.1] vs 9.0 [0.8]; P < .001). Among all patients with NAFLD, the area under the receiver operating characteristic curve (AUROC) for ELF in identifying patients with advanced fibrosis was 0.81 (95% CI, 0.77-0.85) for patients diagnosed by biopsy and 0.79 (95% CI, 0.75-0.82) for those diagnosed by transient elastography. Performance of the ELF score was similar among patients with NAFLD who were aged 65 years or older (AUROC, 0.74; 95% CI, 0.58-0.87) or had type 2 diabetes (AUROC, 0.78; 95% CI, 0.71-0.84). The combination of an ELF score of 7.2 or greater with a fib-4 score of 0.74 or greater was associated with a negative predictive value of 95.1% (95% CI, 91.8%-98.4%) and a sensitivity of 92.5% (95% CI, 87.4%-97.5%), which can reliably rule out advanced fibrosis. An ELF score of 9.8 or greater with a fib-4 score of 2.9 or greater was associated with a positive predictive value of 95.0% (95% CI, 85.5%-100%) and a specificity of 99.7% (95% CI, 99.1%-100%), which can be used to rule in advanced fibrosis. Conclusions and Relevance: These findings suggest that the ELF test performs well in identifying patients with NAFLD who are at increased risk of advanced fibrosis and that this test combined with fib-4 score may be reliably used in clinical practice to assess the presence or absence of advanced fibrosis among patients with NAFLD.

Identification of High-Risk Patients With Nonalcoholic Fatty Liver Disease Using Noninvasive Tests From Primary Care and Endocrinology Real-World Practices.

INTRODUCTION: We aimed to identify high-risk nonalcoholic fatty liver disease (NAFLD) patients seen at the primary care and endocrinology practices and link them to gastrohepatology care. METHODS: Using the electronic health record, patients who either had the diagnosis of type 2 diabetes or had 2 of 3 other metabolic risk factors met criteria for inclusion in the study. Using noninvasive fibrosis tests (NITs) to identify high risk of fibrosis, patients who met the NIT prespecified criteria were referred to gastrohepatology for clinical assessment and transient elastography. RESULTS: From 7,555 patients initially screened, 1707 (22.6%) met the inclusion criteria, 716 (42%) agreed to enroll, and 184 (25.7%) met the prespecified NIT criteria and eligibility for linkage to GE-HEP where 103 patients (68 ± 9 years of age, 50% men, 56% white) agreed to undergo linkage assessments. Their NIT scores were APRI of 0.38 ± 0.24, FIB-4 of 1.98 ± 0.87, and NAFLD Fibrosis Score of 0.36 ± 1.03; 68 (66%) linked patients had controlled attenuation parameter >248 dB/m, 62 (60%) had liver stiffness <6 kPa, and 8 (8%) had liver stiffness >12 kPa. Liver stiffness for the overall group was 6.7 ± 4.2 kPa, controlled attenuation parameter 282 ± 64 dB/m, and FAST score 0.22 ± 0.22. Linked patients with presumed advanced fibrosis had significantly higher body mass index (36.4 ± 6.6 vs 31.2 ± 6.4 kg/m2, P = 0.025) and higher NIT scores (APRI 0.89 ± 0.52 vs 0.33 ± 0.14, FIB-4 3.21 ± 2.06 vs 1.88 ± 0.60, and NAFLD Fibrosis Score 1.58 ± 1.33 vs 0.25 ± 0.94). DISCUSSION: By applying a simple prespecified multistep algorithm using electronic health record with clinical risk factors and NITs followed by transient elastography, patients with nonalcoholic fatty liver disease seen in PCP and ENDO practices can be easily identified.

Major Histocompatibility Complex Class I-Related Chain A Alleles and Histology of Nonalcoholic Fatty Liver Disease.

Major histocompatibility complex class I-related chain A (MICA) is a highly polymorphic gene that modulates immune surveillance by binding to its receptor on natural killer cells, and its genetic polymorphisms have been associated with chronic immune-mediated diseases. The progressive form of nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), is characterized by accumulation of fat and inflammatory cells in the hepatic parenchyma, potentially leading to liver cell injury and fibrosis. To date, there are no data describing the potential role of MICA in the pathogenesis of NAFLD. Therefore, our aim was to assess the association between MICA polymorphism and NASH and its histologic features. A total of 134 subjects were included. DNA from patients with biopsy-proven NAFLD were genotyped using polymerase chain reaction-sequence-specific oligonucleotide for MICA alleles. Liver biopsies were assessed for histologic diagnosis of NASH and specific pathologic features, including stage of fibrosis and grade of inflammation. Multivariate analysis was performed to draw associations between MICA alleles and the different variables; P ≤ 0.05 was considered significant. Univariate analysis showed that MICA*011 (odds ratio [OR], 7.14; 95% confidence interval [CI], 1.24-41.0; P = 0.04) was associated with a higher risk for histologic NASH. Multivariate analysis showed that MICA*002 was independently associated with a lower risk for focal hepatocyte necrosis (OR, 0.24; 95% CI, 0.08-0.74; P = 0.013) and advanced fibrosis (OR, 0.11; 95% CI, 0.02-0.70; P = 0.019). MICA*017 was independently associated with a higher risk for lymphocyte-mediated inflammation (OR, 5.12; 95% CI, 1.12-23.5; P = 0.035). Conclusion: MICA alleles may be associated with NASH and its histologic features of inflammation and fibrosis. Additional research is required to investigate the potential role of MICA in increased risk or protection against NAFLD.

Burden of Primary Biliary Cholangitis Among Inpatient Population in the United States.

Primary biliary cholangitis (PBC) is an autoimmune liver disease that can lead to cirrhosis and liver failure. Our aim was to assess the recent trends in the mortality rates and health care utilization of patients with PBC seen in the inpatient setting in the United States. We used the National (Nationwide) Inpatient Sample data (2005-2014). The study population included adults with PBC, using International Classification of Diseases, Ninth Revision codes. Trends in PBC-related discharges, total charges, length of stay (LoS), and in-hospital mortality were evaluated. Hierarchical generalized linear models were performed for determining predictors of mortality and total hospital charges. Between the study years of 2005 and 2014, a total of 22,665 hospitalized cases with PBC were identified (mean age 63 years; 84% female, 76% white). The number of PBC-related discharges increased from 3.24 per 100,000 in 2005 to 3.68 per 100,000 in 2014, with an average annual increase of 1.4% (95% confidence interval [CI]: 0.4%-2.4%). Fifty-seven percent had Medicare as their primary payer, 37% had cirrhosis, and 1.3% had hepatocellular carcinoma. Between 2005 and 2014, the average total charges for PBC increased from $53,901 to $57,613 (annual percent change [APC], 1.7%; 95% CI: -0.2%-3.5%), LoS decreased from 6.9 days to 5.4 days (APC, -2.2%; 95% CI: -3.2% to -1.1%), and mortality rate decreased from 3.8% to 2.8% (APC, -5.4%; 95% CI: -8.4% to -2.4%). Multivariable analysis revealed that ascites were independently associated with increased risk of in-hospital mortality (odds ratio: 1.77; 95% CI: 1.50-2.08), increased charge (percent change: 22.5%; 95% CI: 18.6%-26.7%), and increased LoS (percent change: 29.7%; 95% CI: 25.7%-33.9%). Conclusion: The number of PBC cases has increased in recent years. Mortality and LoS have decreased, and the total charges have remained the same.

An exploratory study examining how nano-liquid chromatography-mass spectrometry and phosphoproteomics can differentiate patients with advanced fibrosis and higher percentage collagen in non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is among the leading causes of liver disease worldwide. It is increasingly recognized that the phenotype of NASH may involve a number of different pathways, of which each could become important therapeutic targets. The aim of this study is to use high resolution mass spectrometry (MS) and phosphoproteomics techniques to assess the serum proteome and hepatic phosphoproteome in subjects with NASH-related fibrosis. METHODS: Sixty-seven biopsy-proven NAFLD subjects with frozen sera and liver tissue were included. Reverse phase protein microarray was used to quantify the phosphorylation of key signaling proteins in liver and nano-liquid chromatography (LC)-MS was used to sequence target biomarkers in the serum. An image analysis algorithm was used to quantify the percentage of collagen (% collagen) using computer-assisted morphometry. Using multiple regression models, serum proteomes and phosphorylated hepatic proteins that were independently (p ≤ 0.05) associated with advanced fibrosis (stage ≥ 2) and higher % collagen were assessed. RESULTS: Phosphorylated signaling pathways in the liver revealed that apoptosis signal-regulating kinase 1, mitogen-activated protein kinase (ASK1-MAPK pathway involving ASK1 S38 (p < 0.02) and p38 MAPK (p = 0.0002)) activated by the inflammatory cytokine interleukin (IL-10) (p < 0.001), were independently associated with higher % collagen. LC-MS data revealed that serum alpha-2 macroglobulin (α2M) (p = 0.0004) and coagulation factor V (p = 0.0127) were independently associated with higher % hepatic collagen. CONCLUSIONS: Simultaneous profiling of serum proteome and hepatic phosphoproteome reveals that the activation of ASK1 S38, p38 MAPK in the liver, and serum α2M and coagulation factor V are independently associated with hepatic collagen deposition in patients with NASH. These data suggest the role of these pathways in the pathogenesis of NASH-related fibrosis as a potential therapeutic target.

Polymorphisms in the receptor for advanced glycation end-products (RAGE) gene and circulating RAGE levels as a susceptibility factor for non-alcoholic steatohepatitis (NASH).

Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome and major cause of chronic liver disease in developed countries. Its prevalence is increasing in parallel with the prevalence of obesity and other components of the metabolic syndrome. As the liver is central to the clearance and catabolism of circulating advanced glycosylation end-products (AGEs), AGEs and their cognate receptors-RAGE (receptor for AGEs) system might be involved in NAFLD in obese patients. To examine this, we investigated four common polymorphisms of RAGE gene: 1704G/T (rs184003), G82S (rs2070600), -374T/A (rs1800624) and -429T/C (rs1800625) in 340 obese patients with metabolic syndrome. and protein levels of AGE and RAGE. This is the first study to describe association of 4 common polymorphisms with non-alcoholic steatohepatitis (NASH) as well as to examine protein levels of RAGE and AGE. Univariate analysis showed patients carrying the rs1800624 heterozygote genotype (AT) exhibited 2.36-fold increased risk of NASH (odds ratio (OR) = 2.36; 95% confidence interval (95% CI): 1.35-4.19) after adjusting for confounders. The minor allele -374 A has been shown to suppress the expression of RAGE protein. The protein levels of esRAGE, total sRAGE and AGE protein levels did not correlate with each other in obese patients with no liver disease, indicative of RAGE signaling playing an independent role in liver injury. In obese patients with non-NASH NAFLD and NASH respectively, esRAGE protein showed strong positive correlation with total sRAGE protein. Further, haplotype analysis of the 4 SNPs, indicated that haplotype G-A-T-G was significantly associated with 2-fold increased risk for NASH (OR = 2.08; 95% CI: 1.21-3.5; P = 0.006) after adjusting for confounders. In conclusion, the presented data indicate that the G-A-T-G haplotype containing minor allele at position -374 A and major allele at position -429T, 1704G, and G82S G could be regarded as a marker for NASH.

Vaccination against hepatitis A and B in patients with chronic liver disease and type 2 diabetes: has anything changed?

BACKGROUND & AIMS: Given the severity of acute hepatitis in patients with chronic liver diseases (CLD) and patients with type 2 diabetes (DM), most of these patients are recommended to be vaccinated. The aim is to assess the recent changes in HAV and HBV vaccination rates in patients with CLD and DM in the U.S. using the most recent population data. METHODS: We used the National Health and Nutrition Examination Surveys (NHANES) cycles 2009-2012 and 2013-2014, and compared those to previous cycles (1999-2004 and 2005-2008). RESULTS: In general U.S. population, the rates of quality measure (QM, serologic immunity or history of vaccination) for HBV increased from 31.9% in 1999-2004 to 49.5% in 2013-2014 (P < 0.0001), synchronously with an increase in self-reported HBV vaccination: from 24.4% to 41.3% (P < 0.0001). A similar increase was noted for HAV: 12.0% in 1999-2004 to 33.4% in 2013-2014 in vaccination, 44.0% to 52.4% in HAV QM (all P < 0.0001). Greater recent increases in HBV QM were noted in non-HBV CLD patients: 34.7% to 56.8% in HBV QM and 22.7% to 51.1% in HBV vaccination (all P < 0.0001), while the changes in patients with diabetes were similar to those in general U.S. population despite the recent CDC recommendation (for the age 19-59): 31.0% to 45.1% (P = 0.007) in HBV QM, and 22.3% to 39.0% (P = 0.0004) in HBV vaccination. CONCLUSIONS: Despite recommendations, HAV and HBV vaccination rates in patients with CLD and DM remain relatively low. Better vaccination strategies for these high risk patients should be undertaken.

Non-alcoholic Fatty Liver Disease (NAFLD) is associated with impairment of Health Related Quality of Life (HRQOL).

BACKGROUND: NAFLD impacts patient reported outcomes (PROs). Our aim was to assess the impact of NAFLD on patients' HRQOL. METHODS: National Health and Nutrition Examination Survey (NHANES) 2001-2011 data were used to identify adult patients with NAFLD [Fatty Liver Index (FLI) > 60 in absence of other liver disease and excessive alcohol >20 g/day for men, >10 g/day for women]. Patients with other chronic diseases (ex. HIV, cancer, end-stage kidney disease) were excluded. Subjects without any of these conditions were healthy controls. HCV RNA (+) patients were HCV-controls. All patients completed NHANES HRQOL-4 questionnaire. Linear regression determined the association between NAFLD and HRQOL components adjusting for age, gender, race, and BMI. RESULTS: Participants with complete data were included (n = 9661); 3333 NAFLD (age 51 years and BMI 34 kg/m(2)); 346 HCV+ (age 49 years; BMI 27 kg/m(2)) and 5982 healthy controls (age 48 years and BMI 26 kg/m(2)). The proportion of subjects rating their health as "fair" or "poor" in descending order were HCV controls (30 %) NAFLD (20 %) and healthy controls (10 %) (p < 0.001). HRQOL-4 components scores 2-4 were lowest for HCV, followed by NAFLD and then healthy controls (p-values p = 0.011 to < .0001). After adjustment for age, gender, race, and BMI, NAFLD patients were 18-20 % more likely to report days when their physical health wasn't good or were unable to perform daily activities as a result (p < .0001). CONCLUSIONS: NAFLD causes impairment of HRQOL. As NAFLD is becoming the most important cause of CLD, its clinical and PRO impact must be assessed.