High Risk For Advanced Fibrosis Research Articles

Prevalence and outcome of sarcopenia in non-alcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) includes a spectrum of conditions, progressing from mild steatosis to advanced fibrosis. Sarcopenia, characterized by decreased muscle strength and mass, shares common pathophysiological traits with NAFLD. An association exists between sarcopenia and increased NAFLD prevalence. However, data on the prevalence of sarcopenia in NAFLD and its impact on the outcomes of NAFLD remain inconsistent. To analyze the prevalence and outcomes of sarcopenia in patients with NAFLD. We conducted a comprehensive search for relevant studies in MEDLINE, Embase, and Scopus from their inception to June 2023. We included studies that focused on patients with NAFLD, reported the prevalence of sarcopenia as the primary outcome, and examined secondary outcomes, such as liver fibrosis and other adverse events. We also used the Newcastle-Ottawa scale for quality assessment. Of the 29 studies included, the prevalence of sarcopenia in NAFLD varied widely (1.6% to 63.0%), with 20 studies reporting a prevalence of more than 10.0%. Substantial heterogeneity was noted in the measurement modalities for sarcopenia. Sarcopenia was associated with a higher risk of advanced fibrosis (odd ratio: 1.97, 95% confidence interval: 1.44-2.70). Increased odds were consistently observed in fibrosis assessment through biopsy, NAFLD fibrosis score/body mass index, aspartate aminotransferase to alanine aminotransferase ratio, diabetes (BARD) score, and transient elastography, whereas the fibrosis-4 score showed no such association. Sarcopenia in NAFLD was associated with a higher risk of steatohepatitis, insulin resistance, cardiovascular risks, and mortality. This systematic review highlights the critical need for standardized diagnostic criteria and measurement methods for sarcopenia in NAFLD patients. The variability in study designs and assessment methods for sarcopenia and liver fibrosis may account for the inconsistent findings. This review demonstrates the multidimensional impact of sarcopenia on NAFLD, indicating its importance beyond liver-related events to include cardiovascular risks, mortality, and metabolic complications.

Development of Clinical Algorithm Utilizing Vibration-Controlled Transient Elastography to Detect Advanced Hepatic Fibrosis in Liver Transplant Recipients

IntroductionVibration-controlled transient elastography (VCTE) based liver stiffness measurement (LSM) is an excellent ‘rule-out’ test for advanced hepatic fibrosis in liver transplant (LT) recipients, however, its ability to ‘rule-in’ the disease is suboptimal. The study aimed to improve diagnostic performance of LSM in LT recipients.MethodsAdult LT recipients with a liver biopsy and VCTE were included (N = 150). Sequential covering analysis was performed to create rules to identify patients at low or high risk for advanced fibrosis (stage 3–4).ResultsAdvanced hepatic fibrosis was excluded in patients with either LSM < 7.45 kPa (n = 72) or 7.45 ≤ LSM < 12.1 kPa and time from LT < 5.6 years (n = 25). Conversely, likelihood of advanced fibrosis was 95% if patients had LSM > 14.1 and controlled attenuation parameter > 279 dB/m (n = 21). Thus, 118 (79%) were correctly identified and 32 (21%) would have required a biopsy to establish the diagnosis. Compared to previously established LSM based cutoff values of 10.5 kPa (Youden index) and 13.3 kPa (maximized specificity), the false positive rates of sequential covering analysis was 1% compared to 16.5% with LSM ≥ 10.5 kPa and 8.3% with LSM ≥ 13.3 kPa. The true positive rates were comparable at 87% for sequential covering analysis, 93% for LSM ≥ 10.5 kPa and 83% for LSM ≥ 13.3 kPa.ConclusionThe proposed clinical sequential covering analysis allows for better risk stratification when evaluating for advanced fibrosis in LT recipients compared to LSM alone. Additional efforts are necessary to further reduce the number of patients with indeterminate results in whom a liver biopsy may be required.

Steatotic liver disease predicts cardiovascular disease and advanced liver fibrosis: A community-dwelling cohort study with 20-year follow-up

BackgroundSteatotic liver disease (SLD) has emerged as new nomenclature to increase awareness and reflect the pathophysiology of the disease better. We investigated the risk of advanced fibrosis and cardiovascular disease (CVD) in SLD using data derived from a Korean prospective cohort. MethodsWe defined SLD using the fatty liver index (FLI) and identified advanced fibrosis with the age-adjusted Fibrosis-4 Index. SLD was further subcategorized into metabolic dysfunction-associated SLD (MASLD), MASLD with increased alcohol intake (MetALD), and alcohol-associated liver disease (ALD). FindingsThe Ansung–Ansan cohort of the Korean Genome and Epidemiology study, following 9497 participants from 2002 to 2020, included 3642 (38.3%) with MASLD, 424 (4.5%) with MetALD, and 207 (2.1%) with ALD. During the median follow-up of 17.5 years, CVD risk was higher in those with MASLD (hazard ratio [HR], 1.27; 95% confidence interval [CI], 1.12–1.45; P < 0.001), MetALD (HR, 1.88; 95% CI, 1.33–2.65; P < 0.001), and ALD (HR, 1.95; 95% CI, 1.01–3.77; P < 0.001) than in those without SLD, after adjusting for conventional risk factors. Notably, CVD risk was higher in the MetALD than in the MASLD group (P = 0.027). In the MASLD group, the number of cardiometabolic risk factors (CMRFs) correlated positively with CVD risk (HR, 1.34; 95% CI, 1.24–1.45; P < 0.001 for trend). Among the CMRFs, hypertension (HR, 1.94; 95% CI, 1.63–2.31; P < 0.001) was the predominant contributor to CVD. The MASLD (HR, 1.39; 95% CI, 1.25–1.55; P < 0.001), MetALD (HR, 1.75; 95% CI, 1.38–2.23; P < 0.001), and ALD (HR, 2.00; 95% CI, 1.30–3.07; P = 0.002) groups had a higher risk of advanced fibrosis than did the non-SLD group (P < 0.001 for trend). InterpretationOur study provides new insight into hepatic and cardiovascular outcomes related to SLD subtypes. The risk of CVD increased in the order of no SLD, MASLD, and MetALD. The SLD subcategories, considering CMRFs and alcohol intake, outperformed traditional fatty liver categorizations in predicting CVD risk. The proposed SLD terminology could impact clinical practice, warranting further exploration of the heterogeneity of clinical outcomes among SLD subtypes.

Exploring factors related to clinically advanced fibrosis in patients with nonalcoholic fatty liver disease or nonalcoholic steatohepatitis

ABSTRACT Objectives To describe the clinical profile of nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH) patients in a Texas integrated delivery network (IDN) and elucidate the local relationship between patient factors and the risk of advanced fibrosis. Methods This observational, retrospective, cross-sectional study utilized existing data from the electronic health record at a large Texas IDN. Data was collected during the study period from 1 January 2019, to 1 March 2023. Patient characteristics, comorbidities, labs, and medication orders were collected from the most recent encounter in which a Fibrosis-4 (FIB-4) score could be calculated. Chi square tests and analysis of variance (ANOVA) tests were conducted to evaluate differences among the three fibrosis risk categories. Ordinal logistic regression was utilized to assess associations between select variables and a higher risk of advanced fibrosis. Results A total of 56,253 patients were included in the study. 34,839 (61.9%) were Low-Risk 15,578 (27.7%) were Intermediate-Risk, and 5,836 (10.4%) were High-Risk of advanced fibrosis. Results showed that up to 70.4% of patients within a risk group were obese. Only 49.5% of patients in the High-Risk group had at least one gastroenterologist or hepatologist visit. Males, Medicare patients, former smokers, and those with hypertension, type 2 diabetes, and chronic kidney disease were associated with a higher risk of advanced fibrosis. Conclusion This study highlights the need for early screening and proactive management of metabolic risk factors for patients with NAFLD/NASH. The findings indicate a notable prevalence of obesity in the study population, a need for specialist referral for those at High-Risk of advanced fibrosis, and the importance of routine labs to evaluate metabolic factors. Primary care providers may be ideal providers to target these interventions and address this care need.

Identifying High-Risk Patients With Nonalcoholic Fatty Liver Disease: An Opportunity for Intervention Within the Primary Care Setting.

Patients with metabolic syndrome (MetS) are likely to have nonalcoholic fatty liver disease (NAFLD), which can progress to advanced fibrosis. Early recognition of those at highest risk may ameliorate outcomes. Noninvasive liver fibrosis assessment through validated scoring systems such as the fibrosis-4 (FIB-4) index is helpful to identify these high-risk patients, with the process ideally beginning in the primary care setting. The primary objective of this study was to determine rates of disease recognition and initial management of patients with NAFLD and advanced fibrosis in a diverse primary care setting. The secondary objective was to define demographic and clinical predictors of NAFLD identification and management in this population. Medical charts from patients seen at three university-based primary care practices in New York City from January 2016 to December 2019 were reviewed. Inclusion criteria consisted of: age 18 years and above, persistent alanine transaminase (ALT) elevation (2 values ≥40IU/mL ≥6mo apart), and body mass index ≥30kg/m 2 . Patients with viral hepatitis or alcohol misuse were excluded. Patients were defined as likely having NAFLD if they met 2 of the following criteria indicating MetS: systolic blood pressure >135mmHg or diastolic blood pressure >85mmHg or active treatment for hypertension; high-density lipoprotein <40g/dL; triglycerides >150mg/dL or active treatment for hyperlipidemia; or hemoglobin A1c ≥5.7% or active treatment for insulin resistance. The primary study endpoints were the frequency of providers' recognition of NAFLD and referral to specialist and/or for imaging based on visit diagnosis codes or chart documentation. The secondary endpoints were frequency of detecting those with NAFLD and advanced fibrosis utilizing previously defined FIB-4 index cutoffs as well as predictors of disease recognition and management. Analysis was completed using descriptive statistics and logistical regression modeling. A total of 295 patients were identified as having persistently elevated ALT, a body mass index ≥30kg/m 2 , and MetS consistent with likely NAFLD diagnosis. In patients meeting these criteria, ALT elevation was documented by primary care providers in 129 patients (43.7%), NAFLD was noted in chart documentation in 76 patients (25.8%), and a NAFLD ICD-10 diagnosis was assigned to 7 patients (2.4%). 50 patients (16.9%) were referred for ultrasound. Among 51 patients (17.2%) at high risk for advanced fibrosis based on FIB-4 >3.25, 23 patients (45.1%) had NAFLD recognized by their provider and 3 (5.9%) were referred to a specialist. On logistic regression, female gender, dyslipidemia, and private insurance were predictors of disease identification by the primary care physician. ALT elevation and NAFLD are under recognized among patients with MetS in the primary care setting. Importantly, while 17.2% of patients with likely NAFLD in our cohort were high risk for advanced fibrosis, less than half of this group had a NAFLD diagnosis recognized by their primary care provider and only three were referred to a liver specialist. Further investigation of disease recognition and management algorithms in the primary care setting are necessary to enhance NAFLD detection, implement clinical care pathways, and reduce disease progression and complications.

FIB 4 Score (Liver Fibrosis) and Attending Level of Vitamin D in Chronic Hepatitis C Patients

Millions of people around the world are affected by chronic hepatitis C (HCV), which is a global health issue. It is a major contributor to chronic liver conditions such as cirrhosis, hepatocellular carcinoma, and liver fibrosis. For optimal therapy and intervention, prompt identification of liver fibrosis is essential. The rate of hepatic fibrosis progression in HCV-infected patients varies substantially. Objective: To evaluate the vitamin D level and liver fibrosis degree by non-invasive Fib 4 score among chronic hepatitis patients. Methods: This Cross-sectional study was conducted at a tertiary care hospital in Karachi, Pakistan, from August 2020 to September 2022. 65 participants were recruited through a non-probability sampling technique. Results: Study findings show that 21.9% of the patients have low risk for advanced fibrosis, whereas 9.2% have an Intermediate risk for advanced fibrosis, and 69.2% have a high risk for advanced fibrosis. Moreover, findings also revealed that among 65 patients, 66.2% have a deficient amount of Vitamin D, whereas 16.9% have an insufficient amount of Vitamin D level and 16.9% have a sufficient amount of vitamin D. Furthermore, the findings also showed significant association based on p-value (0.001) between Age and Fib4 score of the participant. Conclusions: In conclusion, the study revealed that a significant proportion of chronic hepatitis C patients were at high risk for advanced fibrosis, while vitamin D deficiency/ insufficiency were prevalent among the majority of the patients.

Noninvasive disease severity assessment in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease affecting one-fourth population globally. It is also anticipated to be the major cause of liver-related morbidity and transplantation worldwide in the future decades.1 Of note the Asia-Pacific has a tremendous burden because of the rapid Westernization of the region and the racial characteristics.2-4 Currently, NAFLD represents a clinical field possessing several unmet needs. The major one is currently no reliable biomarker for disease severity, disease course, or outcome measurement. Therefore, a reliable and confident biomarker for the purposes deserves exploration. The effort is no doubt more challenging than for viral hepatitis infection. Cheng et al. presented the study results of the correlation of Mac-2 binding protein glycosylation isomer (M2BPGi) serum level with the other documented noninvasive biomarkers or panels in a single-center retrospective NAFLD database.5 M2BPGi has been vigorously studied as a marker for fibrosis in chronic hepatitis B virus infection, chronic hepatitis C virus infection, nonalcoholic steatohepatitis, and even hepatocellular carcinoma.6-9 The cross-sectional study measured the serum levels of the recently-identified glycosylation isoform of Mac-2 binding protein in both NAFLD and healthy controls. The results showed that the serum levels of M2BPGi were significantly correlated with the levels of AST to platelet ratio index, fibrosis 4 score (FIB-4), and NAFLD fibrosis score, respectively. The M2BPGi levels were significantly higher in females and had an incremental increase with age in both NAFLD patients and the healthy controls. In addition, the M2BPGi level was significantly higher in those intermediate or high risk for advanced fibrosis (defined as FIB-4 level ≥ 1.45) than their low-risk counterparts (FIB-4 level < 1.45). The results thus provided a piece of work addressing the noninvasive fibrosis assessment for the complex metabolic liver disorder. Generally, the degree of liver fibrosis is the major determinant and the significant predictor of long-term outcomes in patients with NAFLD. There is a higher risk of mortality associated with a higher stage of fibrosis in NAFLD.10, 11 Moreover, the risk of liver-related mortality increased on an exponential rather than linear scale with an increase in fibrosis stage.12 Liver biopsy remains an expensive and invasive procedure associated with potential complications, sampling error, and interobserver variability. Besides imaging- and elastography-based methods, several serum-based panels have been developed for the noninvasive approach to disease severity. Recently, the easy-to-access FIB-4 method has been validated in providing an accurate prediction of liver fibrosis and liver-related events. The algorithm has been adapted by major societies as a clinically useful tool for advanced fibrosis assessment.13-15 Nonetheless, further validation efforts across disease etiology, ethnicities, and other clinical factors are mandatory. In this direction, the current study provided a real-world validation approach for the performance of the serum biomarker in a clinical setting. Some issues remain under investigation despite the achievements of the study. The transition between fibrosis stages in the disease spectrum of NAFLD remains elusive, which mainly depends on histopathological interpretation. The lack of histopathological data could partly undermine the results and clinical implications. Second, although FIB-4 is widely used to predict the presence of advanced fibrosis, it is a tool for excluding advanced fibrosis rather than diagnosis per se. The cut-off values for FIB-4 in determining different risk levels have been extensively validated in the past decade. The results of the current study could be affected by using different values. In addition, the performance of a single biomarker could be significantly increased by combination with other biomarkers.7 Last but not least, results from a longitudinal follow-up study, preferably with other noninvasive methods, will provide more sufficient and convincing evidence in this regard. In conclusion, M2BPGi is a useful noninvasive biomarker for liver fibrosis assessment in NAFLD patients. Future validation of the performance for outcome prediction in a longitudinal manner will be a promising perspective. The author thanks secretary help from Taiwan Liver Research Foundation (TLRF) and Fatty Liver Special Interest Group of Taiwan Association for the Study of the Liver (TASL). The Foundation and the Association did not influence how the study was conducted or the approval of the manuscript. Jee-Fu Huang: Consultant of Roche, BMS, Gilead, Merck, Sysmex, Pharmaessential, Polaris, Aligos, and Instylla. Speaker for Abbvie, BMS, Gilead, Merck, Sysmex, and Roche.

Development and validation of non-invasive models in predicting advanced fibrosis of choledochal cyst

Patients with choledochal cyst (CDC) develop liver fibrosis, especially advanced fibrosis without prompt surgery. This study validated the aspartate aminotransferase (AST)-to-platelet ratio index (APRI) and Fibrosis-4 index (FIB-4) and constructed a model for predicting advanced fibrosis in pediatric CDCs. Between January 2020 and March 2022, 330 CDCs (advanced fibrosis: 34, Ludwig staging 3-4; non-advanced fibrosis: 296, Ludwig staging 0-2) were reviewed. APRI and FIB-4 were validated. The area under the receiver operating characteristic (AUROC) curve was used to assess discrimination. Relevant variables were analyzed by backward stepwise logistic regression. Enhanced bootstrap method was used for internal verification with 1000 samples. The AUROCs of APRI and FIB-4 were 0.761 (0.673-0.850) and 0.561 (0.455-0.667). AST to prealbumin ratio (APAR), was constructed with an AUROC of 0.776 (0.693-0.860). The AUROCs of APAR + APRI and APAR + FIB-4 were 0.791 (0.713-0.869) and 0.782 (0.699-0.865). No significant differences were noted in the AUROCs of the indices or their combinations. APAR and APRI could be used together to reduce missed diagnosis rate. The risk of advanced fibrosis varied from different APAR and APRI scores. Both APAR and APRI were indispensable to identify CDC patients at high risk of advanced fibrosis.

Clinical characteristics of patients with non-alcoholic fatty liver disease (NAFLD) in Germany - First data from the German NAFLD-Registry.

Non-alcoholic fatty liver disease (NAFLD) affects more than 18 million individuals in Germany. Real-world data help to better characterize the natural history of disease and standard of care. The German NAFLD-Registry is a prospective non-interventional study initiated by the German Liver Foundation and aims to describe clinical characteristics and observe outcomes in patients with NAFLD recruited in secondary and tertiary care. From this ongoing study, baseline data of the first 501 patients (mean age 54 years, 48% women) were analysed. 13 % of the study population had a high risk for advanced fibrosis (FIB-4 ≥2.67), approximately one-third had a liver stiffness value ≥9.6kPa measured by transient elastography, and the clinical diagnosis of liver cirrhosis was present in 10%. Typical comorbidities were more prevalent in high risk as compared to low risk patients (FIB-4 <1.3) including arterial hypertension (85 vs. 42%), hypercholesterolemia (39 vs. 16%), and type 2 diabetes mellitus (T2DM) (69 vs. 26%). Patients with T2DM (192/501) had a higher NAFLD disease burden as shown by liver stiffness values ≥9.6 kPa (51%) and clinical diagnosis of cirrhosis (20%). Statins were used in 22% of the main population, while in diabetic patients, metformin, GLP-1 agonists, and SGLT2 inhibitors were used in 65, 17, and 17%, respectively. Uptake of life-style interventions such as physical exercise or nutritional counselling was generally low. First data of the German NAFLD registry show that approximately every 10th patient has advanced NAFLD, highlights T2DM patients as a high-risk group and gives insights in the use of comedication and life-style interventions in secondary and tertiary care.

Risk of advanced fibrosis in first-degree relatives of patients with nonalcoholic fatty liver disease.

BACKGROUNDA pilot, single-center study showed that first-degree relatives of probands with nonalcoholic fatty liver disease (NAFLD) cirrhosis have a high risk of advanced fibrosis. We aimed to validate these findings using 2 independent cohorts from the US and Europe.METHODSThis prospective study included probands with NAFLD with advanced fibrosis, NAFLD without advanced fibrosis, and non-NAFLD, with at least 1 first-degree relative. A total of 396 first-degree relatives - 220 in a derivation cohort and 176 in a validation cohort - were enrolled in the study, and liver fibrosis was evaluated using magnetic resonance elastography and other noninvasive imaging modalities. The primary outcome was prevalence of advanced fibrosis in first-degree relatives.RESULTSPrevalence of advanced fibrosis in first-degree relatives of probands with NAFLD with advanced fibrosis, NAFLD without advanced fibrosis, and non-NAFLD was 15.6%, 5.9%, and 1.3%, respectively (P = 0.002), in the derivation cohort, and 14.0%, 2.6%, and 1.3%, respectively (P = 0.004), in the validation cohort. In multivariable-adjusted logistic regression models, age of ≥50 years (adjusted OR [aOR]: 2.63, 95% CI 1.0-6.7), male sex (aOR: 3.79, 95% CI 1.6-9.2), diabetes mellitus (aOR: 3.37, 95% CI 1.3-9), and a first-degree relative with NAFLD with advanced fibrosis (aOR: 11.8, 95% CI 2.5-57) were significant predictors of presence of advanced fibrosis (all P &lt; 0.05).CONCLUSIONFirst-degree relatives of probands with NAFLD with advanced fibrosis have significantly increased risk of advanced fibrosis. Routine screening should be done in the first-degree relatives of patients with advanced fibrosis.FUNDINGSupported by NCATS (5UL1TR001442), NIDDK (U01DK061734, U01DK130190, R01DK106419, R01DK121378, R01DK124318, P30DK120515, K23DK119460), NHLBI (P01HL147835), and NIAAA (U01AA029019); Academy of Finland grant 309263; the Novo Nordisk, EVO, and Sigrid Jusélius Foundations; and the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement 777377. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation program and the EFPIA.

Clinical and Metabolic Characteristics of Hyperuricemia with Risk of Liver Fibrosis: A Cross-Sectional Study.

The role of serum uric acid (SUA) in the role of advanced fibrosis is not fully explored. The study assesses the risk of advanced fibrosis according to SUA in an Asian population with a total of 3612 subjects enrolled in one health management center between 2006 and 2008. The fibrosis-4 score was used for the prediction of the high risk of advanced fibrosis. SUA scores higher than 7.6 mg/dL in men and 6.6 mg/dL in women were defined as hyperuricemia. A proportional odds model was used to assess cumulative risks of advanced fibrosis. The prevalence of high risk of advanced fibrosis was 2.5% in the hyperuricemia group and 0.6% in the normal SUA group (p < 0.001). After adjustment for confounding factors, the odds ratios (OR) for more severe advanced fibrosis were 1.37 (95% confidence interval [CI]: 1.07–1.78) in the hyperuricemia group. Hyperuricemia only increased the risk of advanced fibrosis in the non-T2DM group (OR, 1.29; 95% CI, 1.04 to 1.74) instead of T2DM group (OR, 1.85; 95% CI, 0.97 to 3.53). SUA is a risk factor for a higher risk of advanced fibrosis, with the disease likely progressing from a steatotic to a fibrotic picture. The focus should be more emphasized in non-T2DM groups.

Association between liver fibrosis and incident dementia in the UK Biobank study.

There is growing recognition that chronic liver conditions influence brain health. The impact of liver fibrosis on dementia risk was unclear. We evaluated the association between liver fibrosis and incident dementia in a cohort study. We performed a cohort analysis using data from the UK Biobank study, which prospectively enrolled adults starting in 2007, and continues to follow them. People with a Fibrosis-4 (FIB-4) liver fibrosis score &gt;2.67 were categorized as at high risk of advanced fibrosis. The primary outcome was incident dementia, ascertained using a validated approach. We excluded participants with prevalent dementia at baseline. We used Cox proportional hazards models to evaluate the association between liver fibrosis and dementia while adjusting for potential confounders. Among 455,226 participants included in this analysis, the mean age was 56.5 years and 54% were women. Approximately 2.17% (95% confidence interval [CI] 2.13%-2.22%) had liver fibrosis. The rate of dementia per 1000 person-years was 1.76 (95% CI 1.50-2.07) in participants with liver fibrosis and 0.52 (95% CI 0.50-0.54) in those without. After adjusting for demographics, socioeconomic deprivation, educational attainment, metabolic syndrome, hypertension, diabetes, dyslipidemia, and tobacco and alcohol use, liver fibrosis was associated with an increased risk of dementia (hazard ratio 1.52, 95% CI 1.22-1.90). Results were robust to sensitivity analyses. Effect modification by sex, metabolic syndrome, and apolipoprotein E4 carrier status was not observed. Liver fibrosis in middle age was associated with an increased risk of incident dementia, independent of shared risk factors. Liver fibrosis may be an underrecognized risk factor for dementia.

Effects of empagliflozin on markers of liver steatosis and fibrosis and their relationship to cardiorenal outcomes.

Empagliflozin treatment reduced liver fat in small type 2 diabetes cohorts. This post-hoc study evaluated effects of empagliflozin on risk for non-alcoholic fatty liver disease-related steatosis and fibrosis, as well as the relationship between risk categories and cardiorenal outcomes in the randomized, placebo-controlled EMPA-REG OUTCOME trial. EMPA-REG OUTCOME treated 7020 people with type 2 diabetes and cardiovascular disease with 10/25 mg/day empagliflozin or placebo. For this analysis, the Dallas steatosis index, hepatic steatosis index, non-alcoholic fatty liver disease fibrosis score and Fibrosis-4 score were calculated to assess steatosis and fibrosis risk. Changes from baseline in scores were examined by mixed model repeated measures and their associations with cardiorenal outcomes and mortality by Cox regression. At baseline, 73% and 84% of participants had high steatosis risk by Dallas steatosis index and hepatic steatosis index, whereas 23% and 4% had a high risk of advanced fibrosis by non-alcoholic fatty liver disease fibrosis score and Fibrosis-4 score. Percentages of people at high steatosis risk slightly decreased with empagliflozin only, whereas empagliflozin did not improve percentages of individuals at high fibrosis risk over time compared with placebo. The high risk of advanced fibrosis at baseline related to higher risk for cardiovascular events. Effects of empagliflozin on cardiorenal and all-cause mortality outcomes were consistent across all risk groups. Empagliflozin may reduce steatosis but not fibrosis risk in individuals with type 2 diabetes and cardiovascular disease. The improvements in cardiorenal outcomes and mortality associated with empagliflozin therapy appear to be independent of steatosis and fibrosis risk.

Prevalence and characteristics of MAFLD in Chinese adults aged 40 years or older: A community-based study

BackgroundNonalcoholic fatty liver disease (NAFLD) was recently proposed to be renamed metabolic dysfunction-associated fatty liver disease (MAFLD) with the diagnostic criteria revised. We investigated the similarities and differences in the prevalence and clinical characteristics of MAFLD and NAFLD in Chinese adults. MethodsA cross-sectional study of 9980 Chinese individuals aged 40 years or older was performed between 2011 and 2012 using randomized, stratified cluster sampling in Shanghai, China. A detailed questionnaire and the results of abdominal ultrasonography, a standardized 2-h 75-g oral glucose tolerance test and blood biochemical examinations were collected. ResultsA total of 9927 subjects were included in this study. The prevalence of MAFLD (40.3%) was significantly higher than that of NAFLD (36.9%) (P < 0.05). MAFLD was highly prevalent in type 2 diabetes mellitus (T2DM) (53.8%), impaired fasting glucose (35.7%) and impaired glucose tolerance (40.9%). High risk of advanced fibrosis based on fibrosis-4 was highly prevalent (14.7%) in lean MAFLD with T2DM. Among 9927 subjects, 3481 (35.1%) fulfilled the diagnostic criteria for MAFLD and NAFLD (MAFLD+NAFLD+), 521 (5.2%) MAFLD+NAFLD-, and 181 (1.8%) MAFLD-NAFLD+. The MAFLD+NAFLD- group had more significant metabolic disorders than those in the MAFLD+NAFLD+ group (all P < 0.05). Among MAFLD-NAFLD+ subjects, 82.9% had metabolic disorders. ConclusionsThe new definition of MAFLD may better reflect the pathogenesis related to metabolism. Future research should focus on studying the natural history, pathogenesis and treatment effectivity of the overlap and non-overlap of NAFLD and MAFLD subjects.

Abstract #1087690: Are We Missing NAFLD Fibrosis in Our Patients? One Endocrinologist's Clinic Experience

Patients with multiple metabolic risk factors and diabetes are at high risk for Nonalcoholic Fatty Liver Disease (NAFLD). Timely diagnosis of steatohepatitis and advanced fibrosis is crucial to reverse the disease process. Our goal was to estimate the proportion of patients at risk of advanced fibrosis among those seen by an endocrinologist for diabetes and dyslipidemia and to assess the real-world utility of proposed screening algorithms for these patients. This is a cross-sectional, descriptive study. All patients seen at the University of Washington Diabetes Institute and Lipid Clinic from 02/01/2021 to 05/15/2021 by a single endocrinologist were evaluated. We excluded patients with recent excessive alcohol intake, known history of viral hepatitis and those without updated laboratory data. Fibrosis-4 score (FIB-4) and NAFLD fibrosis score (NFS) were calculated on patients who met any of the following criteria: (1) ≥50 years old with diabetes (2) ≥2 metabolic risk factors (hyperlipidemia, hypertension, obesity, impaired glucose tolerance) (3) 1st degree relative with NAFLD fibrosis (4) steatosis on any imaging modality. Patients with a FIB-4 score ≥1.3 or NFS ≥-1.455 (consistent with indeterminate to high risk of advanced fibrosis) were recommended to have elastography. Out of 172 evaluated patients, 148 (86%) met screening criteria for NAFLD. 28 patients (19%) warranted elastography based on either FIB-4 score or NFS, with exclusion of those in whom elastography by Fibroscan is contraindicated, had established diagnosis of steatohepatitis, or elected not to address NAFLD. Among patients who met criteria for elastography, median liver enzymes, albumin and platelet counts were within the normal reference range. 18 patients completed elastography (16 by Fibroscan, 2 by ultrasound-based elastography) thus far. 5/18 (28%) patients had advanced fibrosis (≥F2; liver stiffness ≥7.5 kPa). 88% (14/16) had steatosis on Fibroscan. Incidentally, 7 patients (5% of the 148) had undergone Fibroscan without meeting criteria with FIB-4 or NFS, 100% of them had steatosis and 43% had advanced fibrosis. Majority of patients seen at the diabetes and lipid clinic by one endocrinologist met screening criteria for NAFLD and 19% of them warranted further evaluation with elastography. Approximately a third of patients evaluated by elastography had advanced fibrosis. Furthermore, 5% of patients (who did not even meet criteria for elastography) also had NAFLD and half of those patients had advanced fibrosis. This reveals that screening and risk assessment of patients seen by endocrinologists routinely can help detect most patients with NAFLD fibrosis in a timely manner.

Low awareness of non-alcoholic fatty liver disease in patients with type 2 diabetes in Swedish Primary Health Care

Objectives Non-alcoholic fatty liver disease (NAFLD) is more common in patients with type 2 diabetes mellitus (T2DM) compared to individuals without. Recent guidelines recommend screening for NAFLD in patients with T2DM. Our aim was to investigate the prevalence of NAFLD in patients with T2DM in a Swedish primary health care setting, how they are cared for and assess the risk of biochemical signs of advanced fibrosis. Material and methods In this cohort study, patients with T2DM from five primary health care centers were included. Medical records were retrospectively reviewed and living habits, medical history, results of diagnostic imaging and anthropometric and biochemical features were noted in a standardized form. The risk of steatosis and advanced fibrosis was assessed using commonly used algorithms (FLI, HSI, NAFLD-LFS, NAFLD ridge score, FIB-4 and NFS). Results In total 350 patients were included. Diagnostic imaging had been performed in 132 patients and of these, 34 (26%) had steatosis, which was not noted in the medical records in 16 (47%) patients. One patient with steatosis had been referred to a hepatologist. Of assessable patients, 71–97% had a high to intermediate risk of steatosis and 29–65% had an intermediate to high risk of advanced fibrosis according to the algorithms used. Conclusion This study indicates a high prevalence of NAFLD among T2DM patients in Swedish primary care. Patients with known NAFLD were followed up to a very low extent. Using fibrosis algorithms in primary health care would result in many patients needing further assessment in secondary care.

Type 2 diabetes mellitus increases the risk of hepatic fibrosis in individuals with obesity and nonalcoholic fatty liver disease.

ObjectiveThis study assessed the impact of diabetes mellitus (DM) on nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) with advanced fibrosis prevalence in adults with overweight or obesity in the United States.MethodsParticipants (National Health and Nutrition Examination Survey [NHANES] 2015‐2016 database) included 834 middle‐aged patients with DM (21.7%) and 3,007 without DM (78.3%). NAFLD was defined by Fatty Liver Index (FLI) ≥ 60 or United States FLI (USFLI) ≥ 30. Moderate‐to‐high and high risk of advanced fibrosis was defined by fibrosis‐4 index (FIB‐4) ≥ 1.67 and ≥ 2.67, respectively, and NAFLD fibrosis scores > 0.676 also indicated a high risk.ResultsNAFLD prevalence increased with BMI. Steatosis was higher in individuals with overweight with DM versus without DM (USFLI ≥ 30: 48.3% vs. 17.4%; p < 0.01) and in individuals with obesity with DM versus without DM (USFLI ≥ 30: 79.9% vs. 57.6%; p < 0.01). DM significantly increased the proportion of individuals at moderate‐to‐high risk of fibrosis (FIB‐4 ≥ 1.67: 31.8% vs. 20.1%; p < 0.05). In the high risk of advanced fibrosis group (FIB‐4 ≥ 2.67), the risk almost doubled (3.8% vs. 7.1%). Among individuals with obesity, DM increased the proportion of adults with moderate and high risk of fibrosis by 1.8‐ and 2.5‐fold, respectively (p < 0.01 and p = 0.39, respectively, vs. without DM).ConclusionsIn this US cohort, DM modestly impacted steatosis, which was primarily obesity‐driven. DM added a significant risk of fibrosis to individuals with overweight or obesity, suggesting that screening is imperative in adults with DM.

Changes in markers of hepatic steatosis and fibrosis in patients with type 2 diabetes during treatment with glucagon-like peptide-1 receptor agonists. A multicenter retrospective longitudinal study

AimsMetabolic dysfunction-associated fatty liver disease (MAFLD) is common in people with type 2 diabetes (T2D) and can progress to advanced fibrosis and cirrhosis. In this retrospective study, we explored the longitudinal changes in markers of hepatic steatosis and fibrosis during T2D treatment with glucagon-like peptide-1 receptor agonists (GLP-1RAs). MethodsWe analysed observational data from six diabetes outpatient clinics. In the whole T2D population, we calculated the hepatic steatosis index (HSI), which we previously validated against liver ultrasonography, and the Fibrosis (Fib)-4 index. We then identified patients who initiated a GLP-1RA from 2010 to 2018 and for whom data were available to evaluate changes in both HSI and Fib-4 scores over 24 months. ResultsFrom 83,116 outpatients with T2D, 41,302 (49.7%) had complete data for calculating HSI and Fib-4. Most of these T2D patients (∼70%) had MAFLD (defined as HSI>36), 9.7% of whom had advanced fibrosis based on Fib-4 thresholds. Patients with low compared to high risk of advanced fibrosis were 5-times more likely to be treated with GLP-1RA. In 535 patients who initiated a GLP-1RA, the prevalence of MAFLD based on HSI declined significantly at 6 and 24 months, but Fib-4 categories did not. HSI improved significantly only in patients receiving human-based but not exendin-based GLP-1RA, while patients concomitantly receiving metformin had less worsening in Fib-4 categories. ConclusionsMAFLD is very common among outpatients with T2D (∼70%) and the estimated prevalence of advanced fibrosis was ∼10%. Treatment with GLP-1RAs significantly improved MAFLD, but not MAFLD-associated advanced fibrosis.

Prospective screening of liver fibrosis in a primary care cohort using systematic calculation of fib-4 in routine results.

Background & aimLiver fibrosis screening in primary care population is a major public health issue. The FIB-4 index is a simple non-invasive fibrosis test combining age, transaminases, platelets count, developed for the diagnosis of advanced fibrosis. The aim of our study was to evaluate the interest of liver fibrosis screening using systematic calculation of FIB-4 in routine blood analysis.MethodsBetween December 2018 and May 2019, we conducted a prospective screening of liver fibrosis in 134 158 patients during a medical check-up including routine blood analysis. Among these patients, 29 707 had transaminases and platelets counts available and benefited from an automatic calculation of FIB-4. Results were obtained from 21 French clinical laboratories in the Bouches du Rhône region.ResultsAmong the 29 707 patients, 2161 (7.3%) had a high risk of advanced fibrosis (FIB-4>2.67). Individual investigation of patients with FIB-4>2.67 allowed to screen 1268 (1268/2161: 58.7%) patients who were not managed for any liver disease.ConclusionsThis work demonstrates the interest of FIB-4 for the screening of liver fibrosis in primary care population. Although additional clinical validation study is required to determine the utility and applicability of Fib-4 to daily practice, our study strongly supports this easy-to-implement strategy using a simple Fib-4 measure resulting from the use of available routine test results.

319-OR: Effects of Empagliflozin on Markers of Liver Steatosis and Fibrosis and Their Relation to Cardiorenal Outcomes in the EMPA-REG OUTCOME Trial

Treatment with empagliflozin (EMPA) improves cardiorenal outcomes, but also reduces liver fat content in individuals with both type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD). Thus, we evaluated the effects of EMPA vs. placebo (PLAC) on NAFLD-related steatosis and fibrosis risks and the relation of fibrosis risk to cardiorenal outcomes in individuals with T2D in the randomized controlled trial EMPA-REG OUTCOME. The trial enrolled 7020 people with T2D and cardiovascular disease for treatment with 10 or 25 mg daily EMPA or PLAC. Post-hoc, we derived the Dallas Steatosis Index (DSI) and NAFLD fibrosis score (NFS) to assess the risks of steatosis and fibrosis from baseline to week 164 of treatment, respectively. Changes from baseline in DSI and NFS were examined by mixed model repeated measures analysis, and effects on cardiovascular and all-cause death, hospitalization for heart failure and nephropathy by Cox regression across fibrosis risk categories. At baseline, 72% of participants had high risk of steatosis (DSI probability of &amp;gt;50%; mean, 0.74±0.00 and 23% had high risk of advanced fibrosis (NFS &amp;gt;0.675; mean, 1.26±0.01. Overall DSI (logit) decreased with EMPA compared to PLAC at all timepoints (p&amp;lt;0.001; placebo-corrected change -0.13±0.03 at 164 weeks) and also in the subgroup at high steatosis risk. Despite comparable overall NFS over time in EMPA and PLAC groups, NFS was lower in the EMPA-treated advanced fibrosis subgroup at weeks 12, 28 and 108 (placebo-corrected changes -0.08±0.03, -0.11±0.03 and -0.11±0.04, all timepoints p&amp;lt;0.01 vs. PLAC). Of note, effects of EMPA on cardiorenal and mortality outcomes were consistent across high and low fibrosis risk groups. In conclusion, EMPA may attenuate NAFLD-related steatosis as well as fibrosis progression specifically in individuals at risk of advanced fibrosis, and improves cardiorenal outcomes as well as all-cause mortality independent of fibrosis risk category. Disclosure S. Kahl: None. A. Ofstad: Employee; Self; Boehringer Ingelheim International GmbH. B. Zinman: Advisory Panel; Self; Abbott Diabetes, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk, Sanofi. C. Wanner: Advisory Panel; Self; AstraZeneca, Merck Sharp &amp; Dohme Corp., Consultant; Self; Bayer AG, Boehringer Ingelheim International GmbH, Speaker’s Bureau; Self; Eli Lilly and Company. E. Schueler: None. S. E. Inzucchi: Consultant; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Esperion, Merck &amp; Co., Inc., Novo Nordisk. M. Roden: Advisory Panel; Self; Allergan plc, Bristol-Myers Squibb Company, Novo Nordisk A/S, Research Support; Self; Boehringer Ingelheim International GmbH, Danone Nutricia, Sanofi-Aventis Deutschland GmbH.