Diagnostic Performance of Noninvasive Tests for Advanced Hepatic Fibrosis in Young Age Population.

BACKGROUND & AIMS: Most noninvasive tests (NITs) for hepatic fibrosis are designed for middle-aged patients with chronic liver disease. We compared the diagnostic performance of major NITs (aspartate aminotransferase-to-platelet ratio index [APRI], Fibrosis-4 index, and nonalcoholic fatty liver disease fibrosis score) for a community-based cohort. METHODS: This cross-sectional study analyzed 8775 participants who underwent magnetic resonance elastography at community health check-up centers. Advanced hepatic fibrosis (≥F3) was defined by magnetic resonance elastography thresholds of 3.6 kPa. The diagnostic performance of 3 NITs was evaluated according to the etiology of liver disease, sex, metabolic syndrome, obesity, and increased aminotransferase levels in 4 age groups. RESULTS: The APRI generally showed the best area under the receiver operating characteristic curve in patients aged 45 years or younger, and it was statistically significant in patients with chronic viral hepatitis and alcoholic fatty liver disease (P < .043). The best APRI cut-off value for detecting advanced hepatic fibrosis was 0.4, with a sensitivity and specificity of 75.8% and 73.5%, respectively, in the community-based cohort. The APRI showed balanced sensitivity and specificity across all age groups, whereas the other metrics showed low sensitivity in those aged <45 and low specificity in those >65 years. CONCLUSIONS: The APRI showed better sensitivity and negative predictive value than the Fibrosis-4 index and the nonalcoholic fatty liver disease fibrosis score in community-based populations with mixed etiology, and, thus, can be performed as the primary test in young adults (age, ≤45 y).

Clinical features and evolution of bacterial infection-related acute-on-chronic liver failure.

BACKGROUND & AIMS: Bacterial infections can trigger the development of organ failure(s) and acute-on-chronic liver failure (ACLF). Geographic variations in bacteriology and clinical practice could lead to worldwide differences in ACLF epidemiology, phenotypes and associated outcomes. Herein, we aimed to evaluate regional differences in bacterial infection-related ACLF in patients with cirrhosis admitted to hospital. METHODS: This post hoc analysis included 1,175 patients with decompensated cirrhosis (with bacterial infection on admission or nosocomial infection) from 6 geographic regions worldwide. Clinical, laboratory and microbiological data were collected from the diagnosis of infection. Patients were followed-up for organ failure(s) and ACLF development according to the EASL-CLIF criteria from enrolment to discharge/death. RESULTS: A total of 333 patients (28%) had ACLF at diagnosis of infection, while 230 patients developed ACLF after diagnosis of infection, resulting in an overall rate of bacterial infection related-ACLF of 48%, with rates differing amongst different geographic regions (38% in Southern Europe vs. 75% in the Indian subcontinent). Bacterial infection related-ACLF more frequently developed in younger patients (55 ± 13 vs. 58 ± 14 years), males (73% vs. 62%), patients with alcohol-related cirrhosis (59% vs. 45%) and those with a higher baseline MELD score (25 ± 11 vs. 16 ± 5) (all p <0.001). Spontaneous bacterial peritonitis, pneumonia or infections caused by extensively drug resistant (XDR) bacteria were more frequently associated with ACLF development. More patients with ACLF had a positive quick sequential organ failure assessment score and septic shock, resulting in a lower infection resolution rate (all p <0.001). CONCLUSIONS: Bacterial infections, especially with XDR organisms, are associated with the highest risk of ACLF development, accounting for almost half of cases globally. Geographic differences result in variable epidemiology and clinical outcomes. LAY SUMMARY: Bacterial infections can trigger a sudden deterioration in an otherwise stable cirrhotic patient, a condition known as acute-on-chronic liver failure or ACLF. This study has found that the development of ACLF following bacterial infection occurs most commonly in the Indian subcontinent and less so in Southern Europe. The common infections that can trigger ACLF include infection of the abdominal fluid, known as spontaneous bacterial peritonitis, pneumonia and by bacteria that are resistant to multiple antibiotics. Patients who develop ACLF following a bacterial infection have high death rates and are frequently unable to clear the infection.

Barriers to care linkage and educational impact on unnecessary MASLD referrals.

Background: The importance of primary care physicians (PCPs) in managing metabolic dysfunction-associated steatotic liver disease (MASLD) has increased. This study aimed to assess the effectiveness of an online educational program on MASLD among physicians. Methods: In total, 869 physicians (72 physicians at referral centers and 797 PCPs) participated in this study. They completed an initial survey regarding their clinical practices for patients with MASLD, followed by a second online survey 8 weeks after receiving a series of seven weekly sets of educational materials on MASLD. Results: In the baseline survey, most PCPs did not routinely evaluate the stage of hepatic fibrosis in MASLD; they typically initiated assessments based on elevated liver enzyme levels. Only a limited number of PCPs used vibration-controlled transient elastography. The main hurdles in managing MASLD were "the absence of a fee for patient education" for PCPs and "short consultation time" for referral-center physicians. In the follow-up survey, the percentage of liver fibrosis assessments using noninvasive tests increased from 7.0 to 11.2%. Additionally, evaluations for cardiovascular disease increased from 3.9 to 8.2%, and the risk of ischemic stroke increased from 13.7 to 16.9%. The percentage of immediate referrals of patients to specialists after an MASLD diagnosis decreased from 15.4 to 12.3%. Conclusion: The discrepancies in management strategies and viewpoints regarding MASLD between PCPs and referral-center physicians can hinder efforts to mitigate the disease burden. Increasing awareness among PCPs regarding MASLD through a 7-week education program led to a reduction in unnecessary referral rates and an increase in cardiovascular evaluations.

A survey on the awareness, current management, and barriers for non-alcoholic fatty liver disease among the general Korean population.

Non-alcoholic fatty liver disease (NAFLD) is often diagnosed incidentally during medical evaluation for diseases other than liver disease or during health checkups. This study aimed to investigate the awareness, current status, and barriers to the management of NAFLD in the general population. This cross-sectional study used an online survey, which consisted of 3-domain and 18-item questionnaires. The content validity index for each item of the questionnaire was rated above 0.80. Most respondents (72.8%) reported having heard of the term 'NAFLD', and a large proportion of the general population (85.7%) recognized the possibility of developing fatty liver without consuming alcohol. Awareness of the terminology of NAFLD and that NAFLD is a disease that needs to be managed is relatively high. However, the knowledge that NAFLD can progress to end-stage liver disease and new cardiovascular diseases is lacking. Only 25.7% of the general population is aware that NAFLD increases the incidence of heart and cerebrovascular diseases. Only 44.7% of those who were incidentally diagnosed during a health check-up were provided with any specific guidance on NAFLD, and more than half (55.3%) were not provided with education or guidance on NAFLD or did not remember it. Only 40.2% of people diagnosed with NAFLD incidentally visited a clinic. The reason for not visiting a clinic for the evaluation of NAFLD varied greatly depending on sex and age group. Only 40.2% of patients visited the clinic after being diagnosed with NAFLD. The reasons for not visiting the clinic after NAFLD diagnosis differed significantly according to sex and age.

Discovery biomarker to optimize obeticholic acid treatment for non-alcoholic fatty liver disease.

The response rate to obeticholic acid (OCA), a potential therapeutic agent for non-alcoholic fatty liver disease, is limited. This study demonstrated that upregulation of the alternative bile acid synthesis pathway increases the OCA treatment response rate. The hepatic transcriptome and bile acid metabolite profile analyses revealed that the alternative bile acid synthesis pathway (Cyp7b1 and muricholic acid) in the OCA-responder group were upregulated compared with those in the OCA-non-responder group. Intestinal microbiome analysis also revealed that the abundances of Bacteroidaceae, Parabacteroides, and Bacteroides, which were positively correlated with the alternative bile acid synthesis pathway, were higher in the OCA-responder group than in the non-responder group. Pre-study hepatic mRNA levels of Cyp8b1 (classic pathway) were downregulated in the OCA-responder group. The OCA response rate increased up to 80% in cases with a hepatic Cyp7b1/Cyp8b1 ratio ≥ 5.0. Therefore, the OCA therapeutic response can be evaluated based on the Cyp7b1/Cyp8b1 ratio or the alternative/classic bile acid synthesis pathway activity.

ALS-L1023 from Melissa officinalis Alleviates Liver Fibrosis in a Non-Alcoholic Fatty Liver Disease Model.

ALS-L1023 is an ingredient extracted from Melissa officinalis L. (Labiatae; lemon balm), which is known as a natural medicine that suppresses angiogenesis. Herein, we aimed to determine whether ALS-L1023 could alleviate liver fibrosis in the non-alcoholic fatty liver disease (NAFLD) model. C57BL/6 wild-type male mice (age, 6 weeks old) were fed a choline-deficient high-fat diet (CDHFD) for 10 weeks to induce NAFLD. For the next 10 weeks, two groups of mice received the test drug along with CDHFD. Two doses (a low dose, 800 mg/kg/day; and a high dose, 1200 mg/kg/day) of ALS-L1023 were selected and mixed with feed for administration. Obeticholic acid (OCA; 10 mg/kg/day) was used as the positive control. Biochemical analysis revealed that the ALS-L1023 low-dose group had significantly decreased alanine transaminase and aspartate transaminase. The area of fibrosis significantly decreased due to the administration of ALS-L1023, and the anti-fibrotic effect of ALS-L1023 was greater than that of OCA. RNA sequencing revealed that the responder group had lower expression of genes related to the hedgehog-signaling pathway than the non-responder group. ALS-L1023 may exert anti-fibrotic effects in the NAFLD model, suggesting that it may provide potential benefits for the treatment of liver fibrosis.

Regulation of Hepatocyte Nuclear Factor 4α Attenuated Lipotoxicity but Increased Bile Acid Toxicity in Non-Alcoholic Fatty Liver Disease.

Hepatocyte nuclear factor 4 alpha (HNF4α) is a key master transcriptional factor for hepatic fat and bile acid metabolic pathways. We aimed to investigate the role of HNF4α in non-alcoholic fatty liver disease (NAFLD). The role of HNF4α was evaluated in free fatty acid-induced lipotoxicity and chenodeoxycholic acid (CDCA)-induced bile acid toxicity. Furthermore, the role of HNF4α was evaluated in a methionine choline deficiency (MCD)-diet-induced NAFLD model. The overexpression of HNF4α reduced intracellular lipid contents and attenuated palmitic acid (PA)-induced lipotoxicity. However, the protective effects of HNF4α were reversed when CDCA was used in a co-treatment with PA. HNF4α knockdown recovered cell death from bile acid toxicity. The inhibition of HNF4α decreased intrahepatic inflammation and the NAFLD activity score in the MCD model. Hepatic HNF4α inhibition can attenuate bile acid toxicity and be more effective as a therapeutic strategy in NAFLD patients; however, it is necessary to study the optimal timing of HNF4α inhibition.