Combined effect of histological findings and diabetes mellitus on liver-related events in patients with metabolic dysfunction-associated steatotic liver disease.

AIM: Advanced fibrosis has a strong influence on the occurrence of liver-related events in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), while diabetes mellitus (DM), which is often complicated by MASLD, is associated with the progression of MASLD. We stratified patients with MASLD according to the severity of liver pathological findings and the presence of DM, aiming to examine whether these indices could be used to accurately assess the risk of developing liver-related events. METHODS: A total of 282 patients with liver biopsy-proven MASLD were included. Liver-related events were defined as the occurrence of hepatocellular carcinoma (HCC) and complications of liver cirrhosis, such as ascites, hepatic encephalopathy, Child-Pugh class B and C, as well as treatment-eligible esophageal and gastric varices. RESULTS: Multivariate analysis adjusted for age, sex, body mass index, alanine aminotransferase, creatinine, hemoglobin A1c, smoking habits, dyslipidemia, hypertension, nonalcoholic fatty liver disease activity score (NAS), or fibrosis stage showed that advanced fibrosis with or without DM was a risk factor for liver-related events. The combined effect of DM and advanced fibrosis increased the risk of HCC onset. However, DM alone or in combination with NAS did not affect the development of liver-related events, including the occurrence of HCC and complications of liver cirrhosis. CONCLUSIONS: While the assessment of fibrosis in patients with MASLD is important for evaluating the risk of developing liver-related events, combining the assessment of DM may be possible to stratify groups at higher risk of developing HCC.

Impact of fibrosis on liver-related event incidence in nonalcoholic fatty liver disease: A multicenter observational study.

AIM: There are few reports on the prognosis of liver-related events in Japanese patients with nonalcoholic fatty liver disease (NAFLD). We undertook an observational study to compare the prognosis between fibrotic and nonfibrotic groups in Japanese NAFLD patients. METHODS: Prognosis in 393 NAFLD patients who underwent liver biopsy between April 2013 and April 2015 at multiple centers were investigated. The time to onset of liver-related events, cardiovascular events, development of extrahepatic cancers, and death were compared between the pathologically fibrotic nonalcoholic steatohepatitis (NASH) group and nonalcoholic fatty liver (NAFL) + nonfibrotic NASH group. A similar analysis was carried out based on the fibrotic classification diagnosed using four noninvasive fibrosis prediction models. RESULTS: The mean age and body mass index at the time of liver biopsy was 55.7 years old and 28.04 kg/m2 , respectively The cumulative incidence of liver-related events at 1080 days after liver biopsy was 5.79% in the pathologically fibrotic NASH group and 0% in the NAFL + nonfibrotic NASH group, with a significant difference (p = 0.0334). The cumulative incidence of liver-related events was significantly higher in the positive group for the prediction model than in the negative group in all four models (all p values were <0.0001). There was no significant difference between the pathologically fibrotic NASH group and NAFL + nonfibrotic NASH group in terms of cumulative incidence of cardiovascular events, development of extrahepatic cancers, and death. CONCLUSIONS: The incidence of liver-related events was significantly higher in the fibrotic NASH group than that of the NAFL + nonfibrotic NASH group in Japanese NAFLD patients.

Non-invasive tests accurately stratify patients with NAFLD based on their risk of liver-related events.

BACKGROUND & AIMS: Previous studies on the prognostic significance of non-invasive liver fibrosis tests in non-alcoholic fatty liver disease (NAFLD) lack direct comparison to liver biopsy. We aimed to evaluate the prognostic accuracy of fibrosis-4 (FIB4) and vibration-controlled transient elastography (VCTE), compared to liver biopsy, for the prediction of liver-related events (LREs) in NAFLD. METHODS: A total of 1,057 patients with NAFLD and baseline FIB4 and VCTE were included in a multicenter cohort. Of these patients, 594 also had a baseline liver biopsy. The main study outcome during follow-up was occurrence of LREs, a composite endpoint combining cirrhosis complications and/or hepatocellular carcinoma. Discriminative ability was evaluated using Harrell's C-index. RESULTS: FIB4 and VCTE showed good accuracy for the prediction of LREs, with Harrell's C-indexes >0.80 (0.817 [0.768-0.866] vs. 0.878 [0.835-0.921], respectively, p = 0.059). In the biopsy subgroup, Harrell's C-indexes of histological fibrosis staging and VCTE were not significantly different (0.932 [0.910-0.955] vs. 0.881 [0.832-0.931], respectively, p = 0.164), while both significantly outperformed FIB4 for the prediction of LREs. FIB4 and VCTE were independent predictors of LREs in the whole study cohort. The stepwise FIB4-VCTE algorithm accurately stratified the risk of LREs: compared to patients with "FIB4 <1.30", those with "FIB4 ≥1.30 then VCTE <8.0 kPa" had similar risk of LREs (adjusted hazard ratio [aHR] 1.3; 95% CI 0.3-6.8), whereas the risk of LREs significantly increased in patients with "FIB4 ≥1.30 then VCTE 8.0-12.0 kPa" (aHR 3.8; 95% CI 1.3-10.9), and even more for those with "FIB4 ≥1.30 then VCTE >12.0 kPa" (aHR 12.4; 95% CI 5.1-30.2). CONCLUSION: VCTE and FIB4 accurately stratify patients with NAFLD based on their risk of LREs. These non-invasive tests are alternatives to liver biopsy for the identification of patients in need of specialized management. LAY SUMMARY: The amount of fibrosis in the liver is closely associated with the risk of liver-related complications in non-alcoholic fatty liver disease (NAFLD). Liver biopsy currently remains the reference standard for the evaluation of fibrosis, but its application is limited by its invasiveness. Therefore, we evaluated the ability of non-invasive liver fibrosis tests to predict liver-related complications in NAFLD. Our results show that the blood test FIB4 and transient elastography stratify the risk of liver-related complications in NAFLD, and that transient elastography has similar prognostic accuracy as liver biopsy. These results support the use of non-invasive liver fibrosis tests instead of liver biopsy for the management of patients with NAFLD.

Prognostic value of the combined use of transient elastography and fibrotest in patients with chronic hepatitis B.

BACKGROUND & AIMS: Liver stiffness (LS) measurement using transient elastography and the FibroTest (FT) are alternatives to liver biopsy (LB) in assessing liver fibrosis. We investigated the prognostic role of the combined use of LS and FT in predicting liver-related events (LREs) in patients with chronic hepatitis B (CHB). METHODS: Consecutive patients with CHB who underwent LB, along with LS and FT on the same day were recruited. LRE was defined as hepatic decompensation, hepatocellular carcinoma (HCC) or liver-related death. RESULTS: A total of 151 patients (86 male) were analyzed. During follow-up (median 59.9 months), overall 18 (11.9%) patients experienced LREs. The areas under receiver-operating characteristic curves of LS, FT, LS + FT and LS × FT in predicting LRE were 0.701, 0.668, 0.702 and 0.741 respectively. After adjusting for age and histological fibrosis staging, significant variables in univariate analysis (both P < 0.05), LS + FT and LS × FT were independent predictors of LREs with hazard ratios (HRs) of 1.080 and 1.126 (all P < 0.05) respectively. When subjects were divided into three groups according to quartile stratification (low quartile, interquartile and high quartile) using LS + FT and LS × FT, cumulative LRE development rate significantly increased with a corresponding increase in value among three groups respectively (log-rank test, all P < 0.05). CONCLUSION: The combined use of LS and FT significantly predicted forthcoming LRE development, but with only a slight additional benefit compared to LS or FT alone.

Natural history of lean and non-lean metabolic dysfunction-associated steatotic liver disease.

BACKGROUND: Conflicting evidence regarding the prognosis of lean metabolic dysfunction-associated steatotic liver disease (MASLD) has raised substantial questions. AIM: This study aimed to elucidate the prognosis of lean MASLD by conducting a comprehensive analysis of a vast Asian cohort. METHODS: This study used a nationwide, population-based database and analyzed 2.9 million patients. The primary endpoints were liver-related events (LREs) and cardiovascular events (CVEs) in patients with lean MASLD, non-lean MASLD, and normal liver control groups. RESULTS: The median observation period was 4.2 years. The 5-year incidence values of LREs in the lean MASLD, non-lean MASLD, and normal liver control groups were 0.065%, 0.039%, and 0.006%, respectively. The LRE risk of lean MASLD was significantly higher than that of normal liver control (adjusted hazard ratio [aHR]: 5.94, 95% confidence interval [CI]: 3.95-8.92) but comparable to that of non-lean MASLD (aHR: 1.35, 95% CI: 0.87-2.08). By contrast, for CVEs, the non-lean MASLD group exhibited a higher 5-year cumulative incidence rate (0.779%) than the lean MASLD (0.600%) and normal liver control (0.254%) groups. The lean MASLD group had a reduced risk of CVEs compared with the non-lean MASLD group (aHR, 0.73; 95% CI: 0.64-0.84), and comparable risk of CVEs to the normal liver control group (aHR, 0.99; 95% CI: 0.88-1.12). CONCLUSION: Lean MASLD exhibits a similar LRE risk and a lower CVE risk to non-lean MASLD. Therefore, follow-up and treatment strategies should be tailored to the specific MASLD condition.

Effect of metabolic dysfunction on the risk of liver-related events in patients cured of hepatitis C virus.

The impact of metabolic dysfunction or metabolic dysfunction-associated fatty liver disease (MAFLD) on liver-related events (LREs) in patients with chronic hepatitis C (CHC) who had achieved a sustained virologic response (SVR) to direct-acting antiviral agents (DAAs) is unknown. A total of 924 patients with cured CHC and documented body mass index (BMI) were included in the analysis, and the data period was from September 2012 to April 2022. Hepatic steatosis was identified either through ultrasonography or blood biomarkers. Metabolic dysfunction was defined as the presence of overweight or obesity (BMI ≥ 23 kg/m2), type 2 diabetes mellitus (DM), and metabolic dysregulation. Patients may have more than one metabolic dysfunction. Variables at 12 or 24 weeks after DAA therapy (PW12) were used to identify predictors of LREs. The median age of the 924 patients was 58 (49-65) years. Of the participants, 418 (45.2%) were male. The median BMI was 24.01 (21.78-26.73) kg/m2, and 174 (18.8%) patients had DM. A multivariable Cox regression analysis revealed that age, male, albumin, total bilirubin, alpha-fetoprotein (AFP), metabolic dysfunction (hazard ratio: 1.709, 95% confidence interval: 1.128-2.591, P = .011), and FIB-4 > 3.25 were independent predictors of LREs. Type 2 DM and metabolic dysregulation exhibited a larger time-dependent area under the receiver operating characteristic curve for LREs than did overweight or obesity. Moreover, metabolic dysfunction was identified to be an independent predictor of hepatocellular carcinoma. Metabolic dysfunction increased the risk of LREs and HCC in patients with CHC who had achieved an SVR to DAA therapy.

Long-term clinical outcomes of adults with metabolic dysfunction-associated fatty liver disease: a single-centre prospective cohort study with baseline liver biopsy.

BACKGROUND: There are limited data on the long-term adverse clinical outcomes of adults with metabolic dysfunction-associated fatty liver disease (MAFLD). METHODS: This is a single-centre prospective study of a well-characterized cohort of MAFLD patients who underwent liver biopsy and followed every 6-12 months for adverse clinical outcomes. RESULTS: The data for 202 patients were analyzed [median age 55.0 (48.0-61.3) years old; male, 47.5%; obese, 88.6%; diabetes mellitus, 71.3%; steatohepatitis, 76.7%; advanced fibrosis, 27.2%]. The median follow-up interval was 7 (4-8) years. The cumulative incidence of liver-related events, cardiovascular events, malignancy and mortality was 0.43, 2.03, 0.60 and 0.60 per 100 person-years of follow-up, respectively. Liver-related events were only seen in patient with advanced fibrosis at 9.1% vs 0% in patient without advanced liver fibrosis (p < 0.001). The cumulative incidence of liver-related events among patients with advanced fibrosis was 1.67 per 100 person-years of follow-up. When further stratified to bridging fibrosis and cirrhosis, the cumulative incidence of liver-related events was 1.47 and 3.85 per 100 person-years of follow-up, respectively. Advanced fibrosis was not significantly associated with cardiovascular events, malignancy or mortality. The cumulative incidence of liver-related events, cardiovascular events, malignancy and mortality were not significantly different between patients with and without steatohepatitis and between obese and non-obese patients. However, liver-related events were only seen among obese patients. CONCLUSION: Overall, the cumulative incidence of liver-related event is low in patients with MAFLD, but it is much higher among those with advanced fibrosis. However, there is a relatively high cumulative incidence of cardiovascular event among patients with MAFLD.

Prediction of Liver-Related Events With a Combination of Liver Stiffness Measurements and Controlled Attenuation Parameters in Japanese Patients With Biopsy-Proven Non-alcoholic Fatty Liver Disease.

OBJECTIVE: Liver stiffness measurements (LSMs) and controlled attenuation parameters (CAPs) obtained using vibration-controlled transient elastography (VCTE) are recognized non-invasive methods of assessing liver histology. The usefulness of CAP for predicting liver-related events (LREs: hepatocellular carcinoma, decompensation, bleeding varices) is not well understood worldwide. Our aim was to re-evaluate the cutoff values of LSM/CAP in Japan and to examine whether LSM/CAP can predict LRE. METHODS: Japanese NAFLD patients (n = 403) who underwent both liver biopsy and VCTE were enrolled. We determined optimal cutoff values of LSM/CAP diagnoses for fibrosis stage and steatosis grade and investigated their clinical outcome based on LSM/CAP values. RESULTS: The LSM cutoff values for F1 to F4 are 7.1, 7.9, 10.0 and 20.2 kPa, and the CAP cutoff values for S1 to S3 are 230, 282 and 320 dB/m. During a median follow-up of 2.7 y (range: 0.0-12.5 y), 11 patients developed LREs. The incidence of LREs in the LSM Hi (≥8.7) group was significantly higher than that in the LSM Lo (<8.7) group (p = 0.003), and the incidence in the CAP Lo (<295) group was higher than that in CAP Hi (≥295) group (p = 0.018). Considering LSM and CAP together, the risk of LRE was higher in the LSM Hi CAP Lo group than in the LSM Hi CAP Hi group (p = 0.03). CONCLUSION: We set LSM/CAP cutoff values to diagnose liver fibrosis and steatosis in Japan. Our study determined that NAFLD patients with high LSM and low CAP values are at high risk for LREs.

FIB-4 and APRI as Predictive Factors for Short- and Long-Term Survival in Patients with Transjugular Intrahepatic Portosystemic Stent Shunts.

(1) Background: Transjugular intrahepatic portosystemic shunt (TIPS) is a standard therapy for portal hypertension. We aimed to explore the association of established baseline scores with TIPS outcomes. (2) Methods: In total, 136 liver cirrhosis patients underwent TIPS insertion, mainly to treat refractory ascites (86%), between January 2016 and December 2019. An external validation cohort of 187 patients was chosen. (3) Results: The majority of the patients were male (62%); the median follow-up was 715 days. The baseline Child­Turcotte−Pugh stage was A in 14%, B in 75% and C in 11%. The patients' liver-transplant-free (LTF) survival rates after 3, 12 and 24 months were 87%, 72% and 61%, respectively. In the univariate analysis, neither bilirubin, nor the international normalized ratio (INR), nor liver enzymes were associated with survival. However, both the APRI (AST-to-platelet ratio index) and the FIB-4 (fibrosis-4 score) were associated with LTF survival. For patients with FIB-4 > 3.25, the hazard ratio for mortality after 2 years was 3.952 (p < 0.0001). Liver-related clinical events were monitored for 24 months. High FIB-4 scores were predictive of liver-related events (HR = 2.404, p = 0.001). Similarly, in our validation cohort, LTF survival was correlated with the APRI and FIB-4 scores. (4) Conclusions: Well-established scores that reflect portal hypertension and biochemical disease activity predict long-term outcomes after TIPS and support clinical decisions over TIPS insertion.