Nonalcoholic Fatty Liver Disease Cohort Research Articles

Transient elastography with controlled attenuation parameter versus two-dimensional shear wave elastography with attenuation imaging for the evaluation of hepatic steatosis and fibrosis in NAFLD.

This study compared the controlled attenuation parameter (CAP) to attenuation imaging (ATI) in the diagnosis of steatosis and transient elastography (TE) to two-dimensional shear wave elastography (2D-SWE) for the diagnosis of fibrosis in a prospectively constructed nonalcoholic fatty liver disease (NAFLD) patient cohort. Participants who underwent TE with CAP were included from a previously constructed NAFLD cohort with multiparametric ultrasound data. The degree of hepatic steatosis and stage of liver fibrosis were assessed. Diagnostic performance was evaluated using the area under the receiver operating characteristic curve (AUROC) for the grades of steatosis (S1-3) and fibrosis (F0-F4). There were 105 participants. The distribution of hepatic steatosis grades (S0-S3) and liver fibrosis stages (F0-F4) was as follows: S0, n=34; S1, n=41; S2, n=22; S3, n=8; F0, n=63; F1, n=25; F2, n=5; F3, n=7; and F4, n=5. No significant difference was found between CAP and ATI in detecting ≥S1 (AUROC: 0.93 vs. 0.93, P=0.956) or ≥S2 (0.94 vs. 0.94, P=0.769). However, the AUROC of ATI in detecting ≥S3 was significantly higher than that of CAP (0.94 vs. 0.87, P=0.047). Regarding the detection of liver fibrosis, no significant difference was found between TE and 2D-SWE. The AUROCs of TE and 2D-SWE were as follows: ≥F1, 0.94 vs. 0.89 (P=0.107); ≥F2, 0.89 vs. 0.90 (P=0.644); ≥F3, 0.91 vs. 0.90 (P=0.703); and ≥F4, 0.88 vs. 0.92 (P=0.209). 2D-SWE and TE showed comparable diagnostic performance in assessing liver fibrosis, and ATI provided significantly better performance in detecting ≥S3 steatosis than CAP.

Prevalence of Small Intestinal Bacterial Overgrowth Syndrome in Patients with Non-Alcoholic Fatty Liver Disease/Non-Alcoholic Steatohepatitis: A Cross-Sectional Study.

Non-alcoholic fatty liver disease (NAFLD) is a multifactorial, wide-spectrum liver disorder. Small intestinal bacterial overgrowth (SIBO) is characterized by an increase in the number and/or type of colonic bacteria in the upper gastrointestinal tract. SIBO, through energy salvage and induction of inflammation, may be a pathophysiological factor for NAFLD development and progression. Consecutive patients with histological, biochemical, or radiological diagnosis of any stage of NAFLD (non-alcoholic fatty liver [NAFL], non-alcoholic steatohepatitis [NASH], cirrhosis) underwent upper gastrointestinal endoscopy. Duodenal fluid (2cc) was aspirated from the 3rd-4th part of duodenum into sterile containers. SIBO was defined as ≥103 aerobic colony-forming units (CFU)/mL of duodenal aspirate and/or the presence of colonic-type bacteria. Patients without any liver disease undergoing gastroscopy due to gastroesophageal reflux disease (GERD) comprised the healthy control (HC) group. Concentrations (pg/mL) of tumor necrosis factor alpha (TNFα), interleukin (IL)-1β, and IL-6 were also measured in the duodenal fluid. The primary endpoint was to evaluate the prevalence of SIBO in NAFLD patients, while the comparison of SIBO prevalence among NAFLD patients and healthy controls was a secondary endpoint. We enrolled 125 patients (51 NAFL, 27 NASH, 17 cirrhosis, and 30 HC) aged 54 ± 11.9 years and with a weight of 88.3 ± 19.6 kg (NAFLD vs. HC 90.7 ± 19.1 vs. 80.8 ± 19.6 kg, p = 0.02). Overall, SIBO was diagnosed in 23/125 (18.4%) patients, with Gram-negative bacteria being the predominant species (19/23; 82.6%). SIBO prevalence was higher in the NAFLD cohort compared to HC (22/95; 23.2% vs. 1/30; 3.3%, p = 0.014). Patients with NASH had higher SIBO prevalence (6/27; 22.2%) compared to NAFL individuals (8/51; 15.7%), but this difference did not reach statistical significance (p = 0.11). Patients with NASH-associated cirrhosis had a higher SIBO prevalence compared to patients with NAFL (8/17; 47.1% vs. 8/51; 15.7%, p = 0.02), while SIBO prevalence between patients with NASH-associated cirrhosis and NASH was not statistically different (8/17; 47.1% vs. 6/27; 22.2%, p = 0.11). Mean concentration of TNF-α, IL-1β, and IL-6 did not differ among the different groups. The prevalence of SIBO is significantly higher in a cohort of patients with NAFLD compared to healthy controls. Moreover, SIBO is more prevalent in patients with NASH-associated cirrhosis compared to patients with NAFL.

Risk of Adverse cardiovascular outcomes among persons living with HIV and nonalcoholic fatty liver disease: a multicenter matched cohort study.

To examine and compare the risk of major adverse cardiovascular events (MACE) between persons living with HIV (PLWH) with and without nonalcoholic fatty liver disease (NAFLD). Population-based, multicenter, retrospective cohort study. Data on PLWH between January 1, 2008, and December 31, 2020 were extracted from the TriNetX database. Primary outcomes were defined as the first incidence of myocardial infarction (MI), MACE, new-onset heart failure (HF), and a composite of cerebrovascular disease. Cox models were used to obtain hazard ratios (HR) and 95% confidence intervals (CI). A total of 151,868 patients were identified as having HIV. After exclusions, 4969 patients were identified as having NAFLD. Of them, 4463 (90%) were propensity matched to a non-NAFLD control. Patients with NAFLD were older(42.9 vs. 40.8 years). Among the NAFLD cohort, most participants were male and had a smoking history (12.3% vs. 9.8%) than non-NAFLD. The mean follow-up was 4.8 ± 1.1 years for the NAFLD group and 5.3 ± 1.2 years for the non-NAFLD group. The risk of all outcomes was statistically significantly higher in NAFLD patients compared to those without NAFLD: MI (HR, 1.49, 95% CI, 1.11-2.01) MACE (HR, 1.49, 95% CI, 1.25-1.79), HF (HR, 1.73, 95% CI 1.37 - 2.19) and, cerebrovascular diseases (HR, 1.25, 95% CI, 1.05-1.48) and sensitivity analysis showed similar magnitude to the one generated in the primary analysis. Patients with NAFLD have an elevated risk of cardiovascular events. The results indicate the need for targeted efforts to improve awareness of CVEs risk in PLWH with NAFLD.

Abstract P587: Patients With Diabetes Mellitus and Atrial Fibrillation Affected by Non-Alcoholic Fatty Liver Disease Have Greater Risk of Mortality and Worse Clinical Outcomes

Background: Patients with diabetes mellitus (DM) are increasingly affected by AF. Non-Alcoholic Fatty Liver Disease (NAFLD) is an emerging disease and risk factor of interest that predisposes to adverse outcomes. Nevertheless, there is limited scientific evidence of clinical outcomes of NAFLD in patients with AF&DM. Therefore, we sought to investigate this population. Methods: We queried NIS between 2016-2019 for adult patients who were hospitalized with AF&DM and had NAFLD. The primary outcome was inpatient mortality. The secondary outcomes were cardiogenic shock, cardiac arrest, gastrointestinal bleeding (GIB), invasive mechanical ventilation, length of stay (LOS) and total hospital charge. Multivariable logistic and Poisson regression analyses were used to estimate clinical outcomes. P-value < 0.05 was significant. Results: There were 6,723,293 patients with AF&DM and 253,639 (3.7%) had NAFLD. NAFLD and non-NAFLD cohorts were with mean age of 70.4 vs. 73.8 yrs; males 57.2% vs 55.6%; Caucasians 70.5% vs 73.9%; HTN 20.3% vs 29.2%; HF 61.4% vs 56%; CKD 53.4% vs 45.2%; obese 26.9% vs 27.1%; dyslipidemia 49.8% vs 61.9%; anemia 24.8% vs 19.2%; history of MI 10.9% vs 13.3%; stroke 2.4% vs 4.1%, COPD 28.8% vs 31.1%; alcohol use 5.2% vs 2.2%, respectively. NAFLD cohort had significantly higher mortality and worse clinical outcomes (Table 1). Conclusion: AF&DM patients with NAFLD demonstrated significantly worse clinical outcomes and higher resource utilization. They were younger, with greater comorbid HF, anemia, CKD. Cardiogenic shock, cardiac arrest and GI bleed were all higher in the NAFLD subgroup. NAFLD may therefore raise the risk for ventricular dysfunction and coagulopathy. Awareness of this risk factor is essential in the AF&DM population. Further research is necessary to assess long-term outcomes.

Abstract P325: Adverse Clinical Outcomes in Non-Alcoholic Fatty Liver Disease Patients Admitted With Heart Failure and Chronic Kidney Disease

Background: Patients with heart failure (HF) are increasingly affected by (CKD). There is a growing evidence connecting Non-Alcoholic Fatty Liver Disease (NAFLD) with poor health outcomes. Nevertheless, there is limited scientific evidence of clinical outcomes in NAFLD population with HF and CKD. Therefore, we sought to investigate this population. Methods: We queried NIS between 2016-2019 for adult patients who were hospitalized with HF and CKD and had NAFLD. The primary outcome was inpatient mortality. The secondary outcomes were cardiogenic shock, cardiac arrest, gastrointestinal bleeding (GIB), acute kidney injury (AKI), invasive mechanical ventilation, length of stay (LOS) and total hospital charge. Multivariable logistic and Poisson regression analyses were used to estimate clinical outcomes. P-value < 0.05 was significant. Results: There were 9,221,158 patients with HF and CKD, of which 405,290 (4.3%) had NAFLD. NAFLD and non-NAFLD cohorts were with mean age of 68.4 vs. 72.7 yrs; males 57.2% vs 53.5%; Caucasians 60.1% vs 63.4%; systolic HF 44.2% vs 41.7%; obesity 21.3% vs 23.0%; dyslipidemia 43.3% vs 56.1%; anemia 24.3% vs 22.4%, DM 59.3% vs 57.7%; AF 43.6% vs 43.5%; history of MI 12.6% vs 16.1%; stroke 1.9% vs 2.2%, COPD 30.5% vs 34.3%, respectively. NAFLD cohort had significantly higher mortality and worse clinical outcomes (Table 1). Conclusion: HF patients with co-existent CKD who were affected by NAFLD demonstrated significantly worse clinical outcomes and higher resource utilization. They were younger, male, with prevalent systolic HF, anemia, diabetes, AF. NAFLD is associated with increased GIB and AKI and may raise risk for systolic dysfunction and coagulopathy. Early NAFLD detection and management in HF and CKD population may improve clinical outcomes. Clinicians should be aware of this negative predictor when managing patients with HF&CKD. Further research is needed to describe this population.

TREM2 Regulates the Removal of Apoptotic Cells and Inflammatory Processes during the Progression of NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver pathology worldwide. In mice and humans, NAFLD progression is characterized by the appearance of TREM2-expressing macrophages in the liver. However, their mechanistic contributions to disease progression have not been completely elucidated. Here, we show that TREM2+ macrophages prevent the generation of a pro-inflammatory response elicited by LPS-laden lipoproteins in vitro. Further, Trem2 expression regulates bone-marrow-derived macrophages (BMDMs) and Kupffer cell capacity to phagocyte apoptotic cells in vitro, which is dependent on CD14 activation. In line with this, loss of Trem2 resulted in an increased pro-inflammatory response, which ultimately aggravated liver fibrosis in murine models of NAFLD. Similarly, in a human NAFLD cohort, plasma levels of TREM2 were increased and hepatic TREM2 expression was correlated with higher levels of liver triglycerides and the acquisition of a fibrotic gene signature. Altogether, our results suggest that TREM2+ macrophages have a protective function during the progression of NAFLD, as they are involved in the processing of pro-inflammatory lipoproteins and phagocytosis of apoptotic cells and, thereby, are critical contributors for the re-establishment of liver homeostasis.

Influence of nonalcoholic fatty liver disease on inflammatory bowel disease hospitalizations in the United States.

The reported prevalence of nonalcoholic fatty liver disease (NAFLD) in patients with inflammatory bowel disease (IBD) is 32%. We assessed the influence of NAFLD on IBD hospitalizations in the United States (US). We utilized the National Inpatient Sample database, from 2016-2019, to identify the total IBD hospitalizations in the US and we further subdivided them according to the presence or absence of NAFLD. Hospitalization characteristics, comorbidities and outcomes were compared. Statistical significance was set at P<0.05. There were 1,272,260 IBD hospitalizations in the US, of which 5.04% involved NAFLD. For IBD hospitalizations with NAFLD, the mean age was 50-64 years, and the proportion of males was 46.97%. IBD hospitalizations with NAFLD had a lower proportion of African Americans (8.7% vs. 11.38%, P<0.001). Comorbidities such as hypertension (50.34% vs. 44.04%, P<0.001) and obesity (18.77% vs. 11.81%, P<0.001) were significantly higher in the NAFLD cohort. Overall, based on the Charlson Comorbidity Index, patients with NAFLD had a higher number of comorbidities (52.77% vs. 20.66%, P<0.001). Mortality was higher in the NAFLD compared to the non-NAFLD cohort (3.14% vs. 1.44%, P<0.001). Patients with NAFLD also incurred significantly higher hospital charges ($69,536 vs. $55,467, p<0.001) and had a longer mean length of stay (6.10 vs. 5.27 days, P<0.001) compared to the cohort without NAFLD. Complications and inpatient procedure requirements were also higher in the NAFLD cohort. Our study revealed greater mortality, morbidity, and healthcare resource utilization in patients with IBD who were hospitalized with a concomitant diagnosis of NAFLD.

Interplay Between Fatty Acids, Stearoyl-Co-A Desaturase, Mechanistic Target of Rapamycin, and Yes-Associated Protein/Transcriptional Coactivator With PDZ-Binding Motif in Promoting Hepatocellular Carcinoma

Interplay Between Fatty Acids, Stearoyl-Co-A Desaturase, Mechanistic Target of Rapamycin, and Yes-Associated Protein/Transcriptional Coactivator With PDZ-Binding Motif in Promoting Hepatocellular Carcinoma

Nonalcoholic fatty liver disease is specifically related to the risk of hepatocellular cancer but not extrahepatic malignancies.

We performed a matched cohort study among individuals with and without nonalcoholic fatty liver disease (NAFLD) to determine: 1) the incidence of cancers (extrahepatic and liver) and their spectrum and 2) if NAFLD increases the risk of extrahepatic cancers. The NAFLD and non-NAFLD (control) cohorts were identified from electronic medical records via International Classification of Diseases (ICD) codes from a single center and followed from 2010 to 2019. Cohorts were matched 1:2 for age, sex, race, body mass index (BMI), and type 2 diabetes. A total of 1,412 subjects were included in the analyses. There were 477 individuals with NAFLD and 935 controls (median age, 52 years; women, 54%; white vs. black: 59% vs. 38%; median BMI, 30.4 kg/m2; type 2 diabetes, 34%). The cancer incidence (per 100,000 person-years) was 535 vs. 1,513 (NAFLD vs. control). Liver cancer incidence (per 100,000 person-years) was 89 in the NAFLD group vs. 0 in the control group, whereas the incidence of malignancy was higher across other types of cancer in the control group vs. in the NAFLD group. The overall extrahepatic cancer risk in NAFLD is not increased above and beyond the risk from background risk factors such as age, race, sex, BMI, and type 2 diabetes.

Non-alcoholic fatty liver disease (NAFLD) in lean individuals - Single centre large cohort clinicopathologic and immunophenotypic study.

Non-alcoholic fatty liver disease is one of the most common causes of chronic liver diseases and occurs even in lean individuals having normal or low body mass index (BMI). Crucial issue is understanding the clinical, pathobiologic and metabolic characteristics in comparison to obese patients. Very few studies have compared clinicopathological characteristics between lean and obese. Published literature is generally in a small cohort of patients, rarely included over-weight as separate category, and most often had non-standardized use of BMI criteria with discordant conclusions. There is very sparse published literature on liver biopsy-confirmed cohort and that to from Asia; also, none had explored the role of mediators such as stellate cells, progenitor cells and macrophages. To evaluate the prevalence of NAFLD in lean patients in a large cohort of histology-confirmed NAFLD, and explore clinico-pathological spectrum of lean NAFLD in comparison to over-weight and obese. Also, to investigate role of hepatic stellate cells, macrophage polarization and their relation to hepatic progenitor cells, in particular the relation to fibrosis and to different BMI categories. Prospective analysis of eleven-year retrospective cross-sectional data of all consecutive patients of NAFLD diagnosed in the period between the year 2011 and 2021. All histologically confirmed cases of NAFLD fulfilling inclusion and exclusion criteria were stratified to three groups according to BMI based on Asian criteria. Demographic, lab, metabolic, and histological comparisons between lean and overweight-obese patients were performed. Histological grading and staging of NAFLD components were performed by NAS-CRN score. Immunohistochemical and image analysis-based assessment and quantification of stellate cells, progenitor cells, and macrophage polarization was performed. Appropriate statistical methods were applied, and study was approved by the Institutional ethics committee. Lean patients with biopsy-proven diagnosis constituted 21% (n=267) of total NAFLD (n=1273). Other groups were-over-weight patients (232;18.2%), and the highest were obese patients (774; 60.8%). 13.9% of the lean patients with NAFLD were under-weight with BMI<18.5kg/m2. Lean patients had significantly lower BMI and waist circumference along with lesser fasting glucose levels in comparison to the other groups. Rest of the metabolic parameters were nearly similar. Lean patients showed higher serum ALT levels, and histological characteristics such as ballooning of hepatocytes and steatosis were also more marked in comparison to other groups. Lobular inflammation and advanced fibrosis were significantly less common in lean patients with NASH related cirrhosis found in only 20.9% of them. Immunophenotypic studies revealed the inter-relationship of HPCs, HSCs, and macrophages was influenced by the stage of fibrosis and not by the BMI. Prevalence of NAFLD in lean individuals in a histological-confirmed patient cohort was 21%. (n=267/1273). Major strengths of this study are large cohort of lean individuals from a single center, inclusion of only histology-confirmed cases, Asia specific BMI criteria usage, comparative clinical, metabolic, immune-morphologic and image analysis-based characterization, inclusion of over-weight in addition to obese patients, and investigating cross-talk of principal patho-physiologic markers.

Hypertension is prevalent in non-alcoholic fatty liver disease and increases all-cause and cardiovascular mortality

Background and aimsHypertension (HTN) is a common comorbidity in non-alcoholic fatty liver disease (NAFLD) affecting up to 40% of individuals. However, the impact of HTN and its control on outcomes in NAFLD remains unclear. Therefore, we aimed to examine the impact of HTN on survival outcomes in a longitudinal cohort of NAFLD patients.MethodsThe analysis consisted of adults in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018 with data on socio-demographic characteristics and comorbidities. NAFLD was diagnosed with fatty liver index (FLI) and United States-FLI at a cut-off of 60 and 30, respectively in the substantial absence of alcohol use. A multivariate regression analysis was conducted to adjust for confounders.ResultsA total of 45,302 adults were included, and 27.83% were identified to have NAFLD. Overall, 45.65 and 35.12% of patients with NAFLD had HTN and uncontrolled HTN, respectively. A multivariate analysis with confounders demonstrated that hypertensive NAFLD had a significantly increased risk of all-cause mortality (HR: 1.39, CI: 1.14–1.68, p < 0.01) and cardiovascular disease (CVD) mortality (HR: 1.85, CI: 1.06–3.21, p = 0.03). Untreated HTN remained to have a significantly increased risk in all-cause (HR: 1.59, CI: 1.28–1.96, p < 0.01) and CVD mortality (HR: 2.36, CI: 1.36–4.10, p < 0.01) while treated HTN had a non-significant increased risk of CVD mortality (HR: 1.51, CI: 0.87–2.63, p = 0.14) and a lower magnitude of increase in the risk of all-cause mortality (HR: 1.26, CI: 1.03–1.55, p = 0.03).ConclusionDespite the significant burden of HTN in NAFLD, up to a fifth of patients have adequate control, and the lack thereof significantly increases the mortality risk. With the significant association of HTN in NAFLD, patients with NAFLD should be managed with a multidisciplinary team to improve longitudinal outcomes.

Greater Muscular Strength Is Associated with a Lower Risk of Pulmonary Dysfunction in Individuals with Non-Alcoholic Fatty Liver Disease.

This study investigated the combined effect of handgrip strength (HGS) and non-alcoholic fatty liver disease (NAFLD) on pulmonary function using the Korea National Health and Nutrition Examination Survey (KNHANES) from 2016 to 2018. For the present study, forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), the FEV1/FVC ratio, handgrip strength (HGS) and the hepatic steatosis index (HSI) to estimate NAFLD were obtained from nationwide cross-sectional surveys. For HGS, subjects were divided into higher HGS (upper 50%) and lower HGS (lower 50%). For NAFLD, subjects were divided into the NAFLD cohort (HSI > 36) and the normal cohort (HSI ≤ 36). Of 1651 subjects (men, n = 601), 25.5% of subjects (n = 421) met the HSI > 36. Based on the normal cohort with high HGS, the normal cohort with low HGS showed an increased risk of reduced FVC (OR = 3.062, 95% CI = 2.46–4.83, p < 0.001) and the NAFLD cohort with low HGS showed a further increased risk of reduced FVC (OR = 4.489, 95% CI = 3.43–7.09, p < 0.001). However, the risk of reduced FVC was not significantly increased in NAFLD with high HGS (OR = 1.297, 95% CI = 0.67–2.50, p = 0.436). After adjusted for covariates such as age, sex, smoking, FBG, HDL-C, TG, SBP, DBP, CRP and alcohol consumption, the results remained similar. More importantly, these results were consistent in the obesity-stratified analysis. The current findings of the study suggest that higher muscle strength is associated with a lower risk of reduced pulmonary function in individuals with NAFLD.

Hepatic patatin-like phospholipase domain-containing 3 levels are increased in I148M risk allele carriers and correlate with NAFLD in humans.

In nonalcoholic fatty liver disease (NAFLD) the patatin‐like phospholipase domain‐containing 3 (PNPLA3) rs738409 variant is a contributor. In mice, the Pnpla3 148M variant accumulates on lipid droplets and probably leads to sequestration of a lipase cofactor leading to impaired mobilization of triglycerides. To advance our understanding of the localization and abundance of PNPLA3 protein in humans, we used liver biopsies from patients with NAFLD to investigate the link to NAFLD and the PNPLA3 148M genotype. We experimentally qualified an antibody against human PNPLA3. Hepatic PNPLA3 protein fractional area and localization were determined by immunohistochemistry in biopsies from a well‐characterized NAFLD cohort of 67 patients. Potential differences in hepatic PNPLA3 protein levels among patients related to degree of steatosis, lobular inflammation, ballooning, and fibrosis, and PNPLA3 I148M gene variants were assessed. Immunohistochemistry staining in biopsies from patients with NAFLD showed that hepatic PNPLA3 protein was predominantly localized to the membranes of small and large lipid droplets in hepatocytes. PNPLA3 protein levels correlated strongly with steatosis grade (p = 0.000027) and were also significantly higher in patients with lobular inflammation (p = 0.009), ballooning (p = 0.022), and significant fibrosis (stage 2–4, p = 0.014). In addition, PNPLA3 levels were higher in PNPLA3 rs738409 148M (CG, GG) risk allele carriers compared to 148I (CC) nonrisk allele carriers (p = 0.0029). Conclusion: PNPLA3 protein levels were associated with increased hepatic lipid content and disease severity in patients with NAFLD and were higher in PNPLA3 rs738409 (148M) risk allele carriers. Our hypothesis that increased hepatic levels of PNPLA3 may be part of the pathophysiological mechanism of NAFLD is supported.

Comparison of Mac‐2 binding protein glycosylation isomer (M2BPGi) with AST to platelet ratio index (APRI), fibrosis 4 Score (FIB‐4), and nonalcoholic fatty liver disease (NAFLD) fibrosis score (NFS) for NAFLD patients

AbstractThe serum level of Mac‐2 binding protein glycosylation isomer (M2BPGi) has been found to increase with the severity of liver fibrosis in biopsy‐proved nonalcoholic fatty liver disease (NAFLD). However, the comparison of M2BPGi with noninvasive fibrosis markers such as AST to platelet ratio index (APRI), Fibrosis 4 Score (FIB‐4), and NAFLD fibrosis score (NFS) in NAFLD patients remains unclear. The participants of Tzu Chi NAFLD cohort (TCNC) including health controls or NAFLD patients were enrolled in Taipei Tzu Chi Hospital. NAFLD was defined as fatty liver in imaging without hepatitis B virus (HBV), hepatitis C virus (HCV), drug, alcohol, or other known causes of chronic liver disease. A total of 777 subjects were included for final analysis. The serum levels of M2BPGi correlated with APRI, FIB‐4 score, and NFS, respectively (P &lt; .001). Of them, 376 (48.4%) were NAFLD patients and 401 were healthy controls. In the group of health controls or NAFLD patients, the M2BPGi levels were significantly higher in female subjects than those of male subjects (P = .027 and 0.006, respectively). Categorized by age, the levels of M2BPGi were significantly higher in elder age groups either in healthy controls or NAFLD patients (P &lt; .05). Compared with healthy controls, NAFLD patients had significantly higher levels of BMI, waist circumference, metabolic components, and liver fibrosis markers such as APRI, NFS, and M2BPGi (P &lt; .05), but no difference in FIB‐4 score (P = .685). According to FIB‐4 score, “intermediate‐ or high‐risk group” had higher APRI, NFS, and M2BPGi than low‐risk group. The serum M2BPGi levels correlated with three noninvasive biomarkers of liver fibrosis including APRI, FIB‐4 score, and NFS. They were significantly higher in female or elder population. Furthermore, APRI, NFS, and M2BPGi were different between NAFLD patients and healthy controls, but no FIB‐4 score. According to FIB‐4 score to determine the risk of liver fibrosis, APRI, NFS, and M2BPGi were also different between low risk and “intermediate or high risk” of NAFLD patients, suggesting a surrogate marker for assessing liver fibrosis of NAFLD patients.

Autoimmune Antibodies in Children and Adolescents With Nonalcoholic Fatty Liver Disease

The clinical significance of autoantibody positivity in nonalcoholic fatty liver disease (NAFLD) in the absence of autoimmune hepatitis (AIH) remains uncertain. We aimed to determine the prevalence of autoantibodies in a pediatric cohort with biopsy-proven NAFLD and investigate the association between autoantibodies and NAFLD histologic grade. Single-center, retrospective study of patients ≤21 years with biopsy-proven NAFLD from 2014 to 2019. Clinical and laboratory data were obtained within 90 days of liver biopsy. Autoantibody positivity was defined as serum titer ≥1:80 or units ≥20. Liver biopsies were evaluated for features of AIH, then scored for steatosis, hepatocyte ballooning, lobular inflammation, and NAFLD activity score (NAS) was calculated. Portal inflammation and fibrosis were scored separately. Multivariable logistic regression was used for continuous and binary outcomes. Sixty-seven subjects met inclusion criteria. Positive antinuclear antibody (ANA), antismooth muscle antibody (ASMA), antineutrophil cytoplasmic antibody (ANCA), anti-F-actin antibody (F-actin), anti-liver kidney microsomal (LKM) antibody, or any combination was observed in 43%, 39%, 19%, 13%, 0%, and 66% of subjects, respectively. After controlling for confounders, positive ANA and alanine aminotransferase (ALT) >80 had 4.6 greater odds of having an NAS ≥5 ( P = 0.035; 95% confidence interval [CI], 1.12-19.01). Autoantibody positivity resolution occurred in 10%-50% who underwent serial monitoring. Autoantibodies, except LKM, were frequently encountered in our pediatric NAFLD cohort in the absence of AIH. ANA positivity with ALT may help clinically stratify pediatric patients with suspected NAFLD targeting those at greater risk for nonalcoholic steatohepatitis (NASH).

A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation.

Nonalcoholic fatty liver disease (NAFLD) is a growing cause of chronic liver disease. Using a proxy NAFLD definition of chronic elevation of alanine aminotransferase (cALT) levels without other liver diseases, we performed a multiancestry genome-wide association study (GWAS) in the Million Veteran Program (MVP) including 90,408 cALT cases and 128,187 controls. Seventy-seven loci exceeded genome-wide significance, including 25 without prior NAFLD or alanine aminotransferase associations, with one additional locus identified in European American-only and two in African American-only analyses (P < 5 × 10-8). External replication in histology-defined NAFLD cohorts (7,397 cases and 56,785 controls) or radiologic imaging cohorts (n = 44,289) replicated 17 single-nucleotide polymorphisms (SNPs) (P < 6.5 × 10-4), of which 9 were new (TRIB1, PPARG, MTTP, SERPINA1, FTO, IL1RN, COBLL1, APOH and IFI30). Pleiotropy analysis showed that 61 of 77 multiancestry and all 17 replicated SNPs were jointly associated with metabolic and/or inflammatory traits, revealing a complex model of genetic architecture. Our approach integrating cALT, histology and imaging reveals new insights into genetic liability to NAFLD.

Metabolic Stress Index Including Mitochondrial Biomarker for Noninvasive Diagnosis of Hepatic Steatosis.

BackgroundMitochondrial dysfunction with oxidative stress contributes to nonalcoholic fatty liver disease (NAFLD) progression. We investigated the steatosis predictive efficacy of a novel non-invasive diagnostic panel using metabolic stress biomarkers.MethodsAltogether, 343 subjects who underwent magnetic resonance imaging-based liver examinations from a population-based general cohort, and 41 patients enrolled in a biopsy-evaluated NAFLD cohort, participated in the development and validation groups, respectively. Serologic stress biomarkers were quantitated by enzyme-linked immunosorbent assay.ResultsMultivariate regression showed that waist-to-hip ratio, fibroblast growth factor (FGF) 21, FGF19, adiponectin-to-leptin ratio, insulin, albumin, triglyceride, total-cholesterol, and alanine-aminotransferase were independent predictors of steatosis (rank-ordered by Wald). The area under receiver-operator characteristics curve [AUROC (95%CI)] of the metabolic stress index for steatosis (MSI-S) was 0.886 (0.85−0.92) and 0.825 (0.69−0.96) in development and validation groups, respectively. MSI-S had higher diagnostic accuracy (78.1%−81.1%) than other steatosis indices. MSI-S notably differentiated steatosis severities, while other indices showed less discrimination.ConclusionMSI-S, as a novel non-invasive index, based on mitochondrial stress biomarker FGF21 effectively predicted steatosis. Furthermore, MSI-S may increase the population that could be excluded from further evaluation, reducing unnecessary invasive investigations more effectively than other indices.

Validation model of fibrosis-8 index score to predict significant fibrosis among patients with nonalcoholic fatty liver disease.

BACKGROUNDIdentifying hepatic fibrosis is crucial for nonalcoholic fatty liver disease (NAFLD) management. The fibrosis-8 (FIB-8) score, recently developed by incorporating four additional variables into the fibrosis-4 (FIB-4) score, showed better performance in predicting significant fibrosis in NAFLD.AIMTo validate the FIB-8 score in a biopsy-proven NAFLD cohort and compare the diagnostic performance of the FIB-8 and FIB-4 scores and NAFLD fibrosis score (NFS) for predicting significant fibrosis.METHODSWe collected the data of biopsy-proven NAFLD patients from three Asian centers in three countries. All the patients with available variables for the FIB-4 score (age, platelet count, and aspartate and alanine aminotransferase levels) and FIB-8 score (the FIB-4 variables plus 4 additional parameters: The body mass index (BMI), albumin to globulin ratio, gamma-glutamyl transferase level, and presence of diabetes mellitus) were included. The fibrosis stage was scored using nonalcoholic steatohepatitis CRN criteria, and significant fibrosis was defined as at least fibrosis stage 2.RESULTSA total of 511 patients with biopsy-proven NAFLD and complete data were included for validation. Of these 511 patients, 271 (53.0%) were female, with a median age of 51 (interquartile range: 41, 58) years. The median BMI was 29 (26.3, 32.6) kg/m2, and 268 (52.4%) had diabetes. Among the 511 NAFLD patients, 157 (30.7%) had significant fibrosis (≥ F2). The areas under the receiver operating characteristic curves of the FIB-8 and FIB-4 scores and NFS for predicting significant fibrosis were 0.774, 0.743, and 0.680, respectively. The FIB-8 score demonstrated significantly better performance for predicting significant fibrosis than the NFS (P = 0.001) and was also clinically superior to FIB-4, although statistical significance was not reached (P = 0.073). The low cutoff point of the FIB-8 score for predicting significant fibrosis of 0.88 showed 92.36% sensitivity, and the high cutoff point of the FIB-8 score for predicting significant fibrosis of 1.77 showed 67.51% specificity.CONCLUSIONWe demonstrated that the FIB-8 score had significantly better performance for predicting significant fibrosis in NAFLD patients than the NFS, as well as clinically superior performance vs the FIB-4 score in an Asian population. A novel simple fibrosis score comprising commonly accessible basic laboratories may be beneficial to use for an initial assessment in primary care units, excluding patients with significant liver fibrosis and aiding in patient selection for further hepatologist referral.

Perceptions of weight status and energy balance behaviors among patients with non-alcoholic fatty liver disease

Weight loss through behavioral modification is central to treating non-alcoholic fatty liver disease (NAFLD). To achieve this, patients need to accurately self-perceive their health behaviors. We aimed to identify predictors of concordance between self-perception and objective measures of body weight, physical activity (PA) and dietary behaviors. We used data from the Harris County NAFLD Cohort, an ongoing prospective study in a regional safety-net healthcare system. Patients completed self-administered baseline questionnaires on demographics, diet, PA, and self-perceptions. We assessed concordance between actual and self-perceived body weight and energy-balance behaviors. Multivariable logistic regression identified predictors of concordance. Patients (n = 458; average age 46.5 years) were 90% Hispanic and 76% female. PA and fruit/vegetable intake guidelines were met among 37% and 9%, respectively. Most (89%) overweight/obese patients accurately perceived themselves as such. However, 41% of insufficiently-active and 34% of patients not meeting fruit/vegetable intake guidelines inaccurately self-perceived their behaviors as “just right”. Women were 3 times more likely to accurately self-perceive weight status (adjusted odds ratio [AOR] 3.24; 95% CI 1.68–6.25) but 51% less likely to accurately self-perceive PA levels than men (AOR 0.49; 95% CI 0.29–0.81). Lower acculturation was associated with higher odds of accurate PA self-perception. Patients with prediabetes or diabetes vs normoglycemia were more likely to accurately self-perceive their fruit/vegetable intake. Most NAFLD patients accurately self-perceived their body weight. A third or more of those not meeting fruit/vegetable intake or PA guidelines had inaccurate perceptions about their behaviors. Our findings highlight key areas to target in NAFLD-specific behavioral modification programs.

Transcriptomic profiling of a multiethnic pediatric NAFLD cohort reveals genes and pathways associated with disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common type of chronic liver disease in children. The mechanisms that drive NAFLD disease progression in this specific patient population remain poorly defined. In this study, we obtained liver biopsy samples from a multiethnic cohort of pediatric patients with NAFLD (n = 52, mean age = 13.6 years) and healthy liver controls (n = 5). We analyzed transcriptomic changes associated with NAFLD stages using high‐throughput RNA sequencing. Unsupervised clustering as well as pairwise transcriptome comparison distinguished NAFLD from healthy livers. We identified perturbations in pathways including calcium and insulin/glucose signaling occurring early in NAFLD disease, before the presence of histopathologic evidence of advanced disease. Transcriptomic comparisons identified a 25‐gene signature associated with the degree of liver fibrosis. We also identified expression of the insulin‐like growth factor binding protein (IGFBP) gene family (1/2/3/7) as correlating with disease stages, and it has the potential to be used as a peripheral biomarker in NAFLD. Comparing our data set with publicly available adult and adolescent transcriptomic data, we identified similarities and differences in pathway enrichment and gene‐expression profiles between adult and pediatric patients with NAFLD. Regulation of genes including interleukin‐32, IGFBP1, IGFBP2, and IGFBP7 was consistently found in both NAFLD populations, whereas IGFBP3 was specific to pediatric NAFLD. Conclusion: This paper expands our knowledge on the molecular mechanisms underlying pediatric NAFLD. It identifies potential biomarkers and directs us toward new therapies in this population.