Exploring the impact of the PNPLA3 I148M variant on primary human hepatic stellate cells using 3D extracellular matrix models.

BACKGROUND & AIMS: The PNPLA3 rs738409 C>G (encoding for I148M) variant is a risk locus for the fibrogenic progression of chronic liver diseases, a process driven by hepatic stellate cells (HSCs). We investigated how the PNPLA3 I148M variant affects HSC biology using transcriptomic data and validated findings in 3D-culture models. METHODS: RNA sequencing was performed on 2D-cultured primary human HSCs and liver biopsies of individuals with obesity, genotyped for the PNPLA3 I148M variant. Data were validated in wild-type (WT) or PNPLA3 I148M variant-carrying HSCs cultured on 3D extracellular matrix (ECM) scaffolds from human healthy and cirrhotic livers, with/without TGFB1 or cytosporone B (Csn-B) treatment. RESULTS: Transcriptomic analyses of liver biopsies and HSCs highlighted shared PNPLA3 I148M-driven dysregulated pathways related to mitochondrial function, antioxidant response, ECM remodelling and TGFB1 signalling. Analogous pathways were dysregulated in WT/PNPLA3-I148M HSCs cultured in 3D liver scaffolds. Mitochondrial dysfunction in PNPLA3-I148M cells was linked to respiratory chain complex IV insufficiency. Antioxidant capacity was lower in PNPLA3-I148M HSCs, while reactive oxygen species secretion was increased in PNPLA3-I148M HSCs and higher in bioengineered cirrhotic vs. healthy scaffolds. TGFB1 signalling followed the same trend. In PNPLA3-I148M cells, expression and activation of the endogenous TGFB1 inhibitor NR4A1 were decreased: treatment with the Csn-B agonist increased total NR4A1 in HSCs cultured in healthy but not in cirrhotic 3D scaffolds. NR4A1 regulation by TGFB1/Csn-B was linked to Akt signalling in PNPLA3-WT HSCs and to Erk signalling in PNPLA3-I148M HSCs. CONCLUSION: HSCs carrying the PNPLA3 I148M variant have impaired mitochondrial function, antioxidant responses, and increased TGFB1 signalling, which dampens antifibrotic NR4A1 activity. These features are exacerbated by cirrhotic ECM, highlighting the dual impact of the PNPLA3 I148M variant and the fibrotic microenvironment in progressive chronic liver diseases. IMPACT AND IMPLICATIONS: Hepatic stellate cells (HSCs) play a key role in the fibrogenic process associated with chronic liver disease. The PNPLA3 genetic mutation has been linked with increased risk of fibrogenesis, but its role in HSCs requires further investigation. Here, by using comparative transcriptomics and a novel 3D in vitro model, we demonstrate the impact of the PNPLA3 genetic mutation on primary human HSCs' behaviour, and we show that it affects the cell's mitochondrial function and antioxidant response, as well as the antifibrotic gene NR4A1. Our publicly available transcriptomic data, 3D platform and our findings on NR4A1 could facilitate the discovery of targets to develop more effective treatments for chronic liver diseases.

Impact of Diabetes, Drug-Induced Liver Injury, and Sepsis on Outcomes in MAFLD-Related Acute-on-Chronic Liver Failure.

BACKGROUND: The prevalence of Metabolic dysfunction associated fatty liver disease (MAFLD) and its complication, MAFLD-related acute on chronic liver failure (MAFLD-ACLF), is rising. Yet, factors determining patient outcomes in MAFLD-ACLF remain understudied. METHODS: Patients with MAFLD-ACLF were recruited from the AARC registry. The diagnosis of MAFLD-ACLF was made when the treating unit had identified the etiology of chronic liver disease (CLD) as MAFLD (or previous nomenclature such as NAFLD, NASH, or NASH-cirrhosis). Patients with coexisting other etiologies of CLD (such as alcohol, HBV, HCV, etc.) were excluded. Data was randomly split into derivation (n=258) and validation (n=111) cohorts at a 70:30 ratio. The primary outcome was 90-day mortality. Only the baseline clinical, laboratory features and severity scores were considered. RESULTS: The derivation group had 258 patients; 60% were male, with a mean age of 53. Diabetes was noted in 27%, and hypertension in 29%. The dominant precipitants included viral hepatitis (HAV and HEV, 32%), drug-induced injury (DILI, 29%) and sepsis (23%). MELD-Na and AARC scores upon admission averaged 32±6 and 10.4±1.9. At 90 days, 51% survived. Non-viral precipitant, diabetes, bilirubin, INR, and encephalopathy were independent factors influencing mortality. Adding diabetes and precipitant to MELD-Na and AARC scores, the novel MAFLD-MELD-Na score (+12 for diabetes, +12 for non-viral precipitant) and MAFLD-AARC score (+5 for each) were formed. These outperformed the standard scores in both cohorts. CONCLUSION: Almost half of MAFLD-ACLF patients die within 90 days. Diabetes and non-viral precipitants such as DILI and sepsis lead to adverse outcomes. The new MAFLD-MELD-Na and MAFLD-AARC scores provide reliable 90-day mortality predictions for MAFLD-ACLF patients.

Systematic Review and Meta-analysis: The Role of Diet in the Development of Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: The association of nonalcoholic fatty liver disease (NAFLD) with dietary factors is well established but not thoroughly investigated. This systematic review and meta-analysis synthesizes available evidence regarding the effect of nutrition on the presence and severity of NAFLD. METHODS: A literature search was conducted identifying studies published between January 1985 and May 2021. We included studies with a dietary assessment and anthropometry based on validated tools, performed by a qualified dietitian or a trained health professional. We examined differences between patients with NAFLD and healthy controls as well as patients with NAFLD and nonalcoholic steatohepatitis (NASH). Risk of bias was assessed with the Risk Of Bias In Non-randomised Studies of Interventions (ROBINS-I) tool. RESULTS: There were 60 eligible studies with 100,621 patients. The risk of bias was moderate for the majority of studies (41/60; 68%). According to meta-analyses, total caloric intake was higher in patients with NAFLD compared with controls (mean difference, 78.08; 95% confidence interval, 41.03-115.13). Macronutrient (protein, fat, and carbohydrate) consumption as proportion of total caloric intake and daily intake of fiber, caffeine and vitamins E, A, and C did not significantly differ between patients with NAFLD and controls. Soft drink consumption had a trend towards association with the presence of NAFLD. However, the odds ratio was 4.4 and the confidence intervals very wide. Finally, there was no significant difference in any comparison between patients with NAFLD and NASH, although the number of patients was relatively small. All meta-analyses had significant heterogeneity. CONCLUSIONS: Overall, despite high heterogeneity among studies, this meta-analysis demonstrated that higher caloric intake is positively associated with NAFLD, whereas diet composition in macronutrients was not associated with the presence or severity of the disease.

Validation and prognostic value of EZ-ALBI score in patients with intermediate-stage hepatocellular carcinoma treated with trans-arterial chemoembolization.

BACKGROUND: Heterogeneity of liver function and tumor burden in intermediate-stage hepatocellular carcinoma (HCC) results in different outcomes after transarterial chemoembolization (TACE). Easy albumin-bilirubin (EZ-ALBI), a simplified albumin-bilirubin (ALBI) score, has recently been proposed as a new prognostic score for HCC. This study aimed to validate the EZ-ALBI score and evaluate the impact of dynamic changes in patients with intermediate-stage HCC undergoing TACE. METHODS: All patients with HCC treated with TACE at King Chulalongkorn Memorial Hospital, Bangkok, Thailand, between January 2015 and December 2019 were prospectively enrolled. Intermediate-stage HCC was defined as Barcelona Clinic Liver Cancer (BCLC) stage B or unresectable single HCC with size > 5 cm in BCLC stage A. EZ-ALBI and ALBI scores were calculated and stratified into three different grades. Overall survival (OS) and prognostic factors were assessed using the Kaplan-Meier curve and Cox proportional hazard model. Decision analysis curves were used to evaluate the clinical utility of the predictive scores. RESULTS: Among 672 patients with HCC treated with TACE, 166 patients with intermediate-stage HCC who met the eligibility criteria were enrolled. The median OS of all patients in the cohort was 21 months. A good correlation between the EZ-ALBI and ALBI scores was observed (correlation coefficient 1.000, p < 0.001). The baseline EZ-ALBI grades 1, 2, and 3 were 24.5%, 70%, and 5.5%, respectively. EZ-ALBI grade can stratify patients with significantly different prognoses (p = 0.002). Baseline EZ-ALBI grade 2, 3, and serum alpha-fetoprotein > 20 ng/ml were significantly associated with OS [hazard ratio (HR) 2.20 (95% confidence interval [CI] 1.24-3.88, p = 0.007), 3.26 (95% CI 1.24-8.57, p = 0.016), and 1.77 (95% CI 1.10-2.84, p = 0.018), respectively]. Following TACE, 42 (29.6%) patients had a worsening EZ-ALBI grade. However, the EZ-ALBI grade migration was not significantly correlated with OS. EZ-ALBI and ALBI score provided improved discriminatory ability (Harrell's concordance index 0.599 and 0.602, respectively) and better net benefit compared with Child-Turcotte-Pugh and Model for End-stage Liver Disease scores. CONCLUSIONS: The baseline EZ-ALBI score demonstrated good predictive performance for survival and a strong correlation with conventional ALBI scores. Both the EZ-ALBI and ALBI scores outperformed other prognostic models in patients with intermediate-stage HCC receiving TACE. However, the dynamic change in the EZ-ALBI grade after TACE was not associated with postprocedural survival.

Changes in hepatic fibrosis and vitamin D levels after viral hepatitis C eradication using direct-acting antiviral therapy.

BACKGROUND: Vitamin D (VD) is important in hepatic fibrogenesis in animal models and human studies. VD deficiency is associated with liver fibrosis progression. Metabolic dysfunction of the liver, as an intermediate organ for VD metabolism, contributes partly to this deficiency. We hypothesized that improving hepatic fibrosis and inflammation in chronic hepatitis C (CHC) patients after eradication with direct-acting antivirals (DAA) would increase 25-hydroxyVD [25(OH)VD] levels. METHODS: Eighty CHC patients (17 chronic hepatitis, and 63 cirrhosis) were enrolled. Baseline characteristics, hepatitis C viral load (VL), genotypes, liver enzymes and liver stiffness measurements (LSM) were assessed at baseline. Blood samples for 25(OH)VD and the procollagen type III N-terminal peptide (P3NP) were collected at baseline, 24 and 48 weeks. LSMs were re-evaluated at 48 weeks. Serum 25(OH)VD levels < 30 ng/mL were defined as VD insufficiency/deficiency. Paired t-tests were used for statistical analyses. RESULTS: Among 80 patients, the mean age was 57.7 ± 10.5 years, and 52.5% were men. The mean VL was 6.1 ± 0.7 logIU/mL with genotype 1 predominance (55%). All patients achieved sustained virological response. The alanine aminotransferase levels decreased from 79.9 ± 53.3 U/L at baseline to 25.7 ± 17.2 and 22.3 ± 11.0 U/L at 24 and 48 weeks, respectively (p < 0.001). The mean LSM decreased from 19.2 ± 15.3 to 11.7 ± 8.0 kPa at 48 weeks (p < 0.001). The P3NP levels decreased from 43.6 ± 22.0 ng/mL before treatment to 35.7 ± 21.1 and 29.4 ± 15.0 ng/mL at 24 and 48 weeks, respectively (p < 0.001). The proportions of VD insufficiency/deficiency were 72.5%, 91.3%, and 86.5% at baseline, 24 and 48 weeks, respectively. The 25(OH)VD levels decreased from 26.3 ± 10.7 ng/mL at baseline to 20.8 ± 8.1 and 20.8 ± 8.5 ng/mL at 24 and 48 weeks, respectively (p < 0.001). CONCLUSIONS: Curative treatment with DAA attenuated the liver stiffness and inflammation but did not improve VD levels. Over 80% of patients remained VD insufficient/deficient. Whether VD replacement during and after DAA therapy can improve hepatic fibrosis remains unclear. Trial registration The Thai Clinical Trial Registry as TCTR20161025001 (31 October 2016). http://www.clinicaltrials.in.th/index.php?tp=regtrials&menu=trialsearch&smenu=fulltext&task=search&task2=view1&id=2136 .

The incidence, etiologies, outcomes, and predictors of mortality of acute liver failure in Thailand: a population-base study.

BACKGROUND: Acute liver failure (ALF) is uncommon but progresses rapidly with high mortality. We investigated the incidence, etiologies, outcomes, and predictive factors for 30-day mortality in patients with ALF. METHODS: We conducted a population-based study of ALF patients hospitalized between 2009 and 2013 from the Thai Nationwide Hospital Admission database, which comprises 76% of all admissions from 858 hospitals across 77 provinces in Thailand. ALF was diagnosed using ICD-10 codes K72.0 and K71.11. Patients with liver cirrhosis were excluded. RESULTS: There were 20,589 patients diagnosed with ALF during the study period with 12,277 (59.6%) males and mean age of 46.6 ± 20.7 years. The incidence of ALF was 62.9 per million population per year. The most frequent causes of ALF were indeterminate (69.4%), non-acetaminophen drug-induced (26.1%), and viral hepatitis (2.5%). Acetaminophen was the presumptive cause in 1.7% of patients. There were 5502 patients (26.7%) who died within 30 days after admission. One patient (0.005%) underwent liver transplantation. The average hospital stay was 8.7 ± 13.9 days, and the total cost of management was 1075.2 ± 2718.9 USD per admission. The most prevalent complications were acute renal failure (ARF)(24.2%), septicemia (18.2%), and pneumonia (12.3%). The most influential predictive factors for 30-day mortality were ARF (HR = 3.64, 95% CI: 3.43-3.87, p < 0.001), malignant infiltration of the liver (HR = 3.37, 95% CI: 2.94-3.85, p < 0.001), and septicemia (HR = 1.96, 95%CI: 1.84-2.08, p < 0.001). CONCLUSIONS: ALF patients have poor outcomes with 30-day mortality of 26.7% and high economic burden. Indeterminate etiology is the most frequent cause. ARF, malignant infiltration of the liver, and septicemia are main predictors of 30-day mortality.

Vitamin D-related gene polymorphism predict treatment response to pegylated interferon-based therapy in Thai chronic hepatitis C patients.

BACKGROUND: Patients with chronic hepatitis C (HCV) infection have high prevalence of vitamin D deficiency. Genome-wide association study data has showed that several genetic variants within vitamin D cascade affect vitamin D function. This study aimed to determine whether genetic polymorphisms of genes in the vitamin D pathway are associated with treatment responses to pegylated interferon (PEG-IFN)-based therapy in patients with chronic HCV infection. METHODS: The study included 623 Thai patients from 2 university hospitals diagnosed with chronic HCV infection who were treated with a PEG-IFN and ribavirin. Patients were genotyped for functional variants on vitamin D synthetic pathway including GC (rs4588, rs7041, rs22020, rs2282679), CYP2R1 (rs2060793, rs12794714), CYP27B1 (rs10877012), and DHCR7 (rs12785878). Pre-treatment predictors of sustained virologic response (SVR) at 24 weeks following discontinuation of therapy were identified using a logistic regression analysis. RESULTS: SVR was achieved by 60.5% of patients (52.9% with HCV genotype 1; 66.7% with HCV non-genotype 1). In 44.6% of HCV genotype 1-infected patients, only the variant rs12785878 in the DHCR7 locus was significantly associated with an SVR. HCV genotype 1 patients who had DHCR7 rs12785878 GT/TT had a higher rate of SVR than those with the GG allele (59.7% vs. 43.4%, P = 0.03), but in HCV non-genotype 1-infected patients, the SVR rate did not differ between the two groups (63.3% and 59.1% for GT/TT and GG allele, P = 0.54). By multivariate analysis, liver fibrosis stage 0-1 (OR = 5.00; 95% CI, 2.02-12.37; P < 0.001), and DHCR7 rs12785878 GT/TT allele (OR = 2.69; 95% CI, 1.03-7.05; P = 0.04) were independent pre-treatment predictors of SVR following PEG-IFN-based therapy in HCV genotype 1 patients. Baseline HCV RNA < 400,000 IU/ml (OR = 1.96; 95% CI, 1.13-3.39; P = 0.02) was the only independent predictor of SVR in HCV non-genotype 1 patients. The polymorphisms of GC, CYP2R1 and CYP27B1 were not associated with treatment outcome even in genotype 1 or non-genotype 1 HCV infection. CONCLUSION: The DHCR7 polymorphism may be a pre-treatment predictive marker for response to PEG-IFN-based therapy in chronic HCV genotype 1 infection.

A significant cancer burden and high mortality of intrahepatic cholangiocarcinoma in Thailand: a nationwide database study.

BACKGROUND: We aimed to examine the burden of intrahepatic cholangiocarcinoma (ICC) in Thailand and identify the prognostic factors for all-causes of death. METHODS: We conducted a population-based study of ICC patients admitted during 2009-2013 using the Nationwide Hospital Admission Database, the National Health Security Office (NHSO). There was an average of 1,051,146 patients/year with diagnosis of gastrointestinal diseases (GI). All patients with a diagnosis of ICC (ICD10- C221) were included from a total of 72,479 admissions from 858 hospitals. The surgical resection procedures such as the radical pancreaticoduodenectomy, subtotal and partial hepatectomy were analyzed. Data for all patients were censored 1 year post-study or death, whichever came first. RESULTS: A total of 34,325 patients with ICC during a 5-year study period (on average, 6865 patients/year, with the incidence rate of 14.6 per 100,000 population, per year. The ICC patients had a mean age of 63.8+/-11.6 years and 63% were males. The mean length of hospital stay was 6.4+/-7.3 days with a mean+/-SD cost of hospitalization of $595+/-$1160 USD per admission. There were 659 patients (1.9%) underwent surgical resection. The overall survival of ICC patients with surgery was significantly better than those patients without surgery. Hazard ratio of death for patients without surgery was 2.5 (95% CI of 2.3-2.7). Approximately 14% of the ICC patients died during hospitalization. The median overall survival of all patients after the first admission was 53 +/-0.6 days. From the multivariate analysis, factors related to all-causes of death were: patients' age >60 years (OR = 1.2, 95% CI; 1.1-1.3), length of hospital stay of >7 days (OR = 1.1, 95% CI; 1.02-1.2), male (OR = 1.3, 95% CI; 1.2-1.4), living in the northern part of Thailand (OR = 1.5, 95% CI; 1.3-1.8) and presence of complications during admission (OR = 1.3, 95% CI; 1.1-1.5). CONCLUSION: The disease burden of patients with ICC in Thailand is significant with the incidence rate of 14.6 per 100,000 population, per year during 2009-2013 and showed high mortality rate of 14%.

Prospective comparison of three risk scoring systems in non-variceal and variceal upper gastrointestinal bleeding.

BACKGROUND AND AIM: Data regarding the efficacy of the Glasgow Blatchford score (GBS), full Rockall score (FRS) and pre-endoscopic Rockall scores (PRS) in comparing non-variceal and variceal upper gastrointestinal bleeding (UGIB) are limited. Our aim was to determine the performance of these three risk scores in predicting the need for treatment, mortality, and re-bleeding among patients with non-variceal and variceal UGIB. METHODS: During January, 2010 and September, 2011, patients with UGIB from 11 hospitals were prospectively enrolled. The GBS, FRS, and PRS were calculated. Discriminative ability for each score was assessed using the receiver operated characteristics curve (ROC) analysis. RESULTS: A total of 981 patients presented with acute UGIB, 225 patients (22.9%) had variceal UGIB. The areas under the ROC (AUC) of the GBS, FRS, and PRS for predicting the need for treatment were 0.77, 0.69, and 0.61 in non-variceal versus 0.66, 0.66, and 0.59 in variceal UGIB. The AUC for predicting mortality and re-bleeding during admission were 0.66, 0.80, and 0.76 in non-variceal versus 0.63, 0.57, and 0.63 in variceal UGIB. AUC score was not statistically significant for predicting need for therapy and clinical outcome in variceal UGIB. The GBS ≤ 2 and FRS ≤ 1 identified low-risk non-variceal UGIB patients for death and re-bleeding during hospitalization. CONCLUSION: In contrast to non-variceal UGIB, the GBS, FRS, and PRS were not precise scores for assessing the need for therapy, mortality, and re-bleeding during admission in variceal UGIB.

Aloe vera attenuated liver injury in mice with acetaminophen-induced hepatitis.

BACKGROUND: An overdose of the acetaminophen causes liver injury. This study aims to examine the anti-oxidative, anti-inflammatory effects of Aloe vera in mice with acetaminophen induced hepatitis. METHODS: Male mice were randomly divided into three groups (n = 8 each). Control group were given orally distilled water (DW). APAP group were given orally N-acetyl-P-aminophenol (APAP) 400 mg/kg suspended in DW. Aloe vera-treated group were given orally APAP and Aloe vera (150 mg/kg) suspended in DW. Twenty-four hours later, the liver was removed to determine hepatic malondialdehyde (MDA), hepatic glutathione (GSH), the number of interleukin (IL)-12 and IL-18 positive stained cells (%) by immunohistochemistry method, and histopathological examination. Then, the serum was collected to determine transaminase (ALT). RESULTS: In APAP group, ALT, hepatic MDA and the number of IL-12 and IL-18 positive stained cells were significantly increased when compared to control group (1210.50 ± 533.86 vs 85.28 ± 28.27 U/L, 3.60 ± 1.50 vs 1.38 ± 0.15 nmol/mg protein, 12.18 ± 1.10 vs 1.84 ± 1.29%, and 13.26 ± 0.90 vs 2.54 ± 1.29%, P = 0.000, respectively), whereas hepatic GSH was significantly decreased when compared to control group (5.98 ± 0.30 vs 11.65 ± 0.43 nmol/mg protein, P = 0.000). The mean level of ALT, hepatic MDA, the number of IL-12 and IL-18 positive stained cells, and hepatic GSH in Aloe vera-treated group were improved as compared with APAP group (606.38 ± 495.45 vs 1210.50 ± 533.86 U/L, P = 0.024; 1.49 ± 0.64 vs 3.60 ± 1.50 nmol/mg protein, P = 0.001; 5.56 ± 1.25 vs 12.18 ± 1.10%, P = 0.000; 6.23 ± 0.94 vs 13.26 ± 0.90%, P = 0.000; and 10.02 ± 0.20 vs 5.98 ± 0.30 nmol/mg protein, P = 0.000, respectively). Moreover, in the APAP group, the liver showed extensive hemorrhagic hepatic necrosis at all zones while in Aloe vera-treated group, the liver architecture was improved histopathology. CONCLUSIONS: APAP overdose can cause liver injury. Our result indicate that Aloe vera attenuate APAP-induced hepatitis through the improvement of liver histopathology by decreased oxidative stress, reduced liver injury, and restored hepatic GSH.

The safety of propofol infusion compared to midazolam and meperidine intravenous bolus for patients undergoing double balloon enteroscopy.

OBJECTIVE: The double balloon enteroscopy (DBE) procedure is long and requires moderate sedation. We aim to determine whether the administration of propofol infusion is safe by comparing it to intravenous midazolam/meperidine in patients undergoing DBE. MATERIAL AND METHOD: A prospective study with 48 patients was conducted at King Chulalongkorn Hospital randomizing (block of four) patients into two groups. In group 1, 28 patients were enrolled for intravenous midazolam/meperidine, and one patient was dropped out before underwent DBE due to hemodynamic instability. Therefore, 27 (n = 27) participants were included in Group 1. In group 2, 28 patients were enrolled for propofol infusion, and seven patients were dropped out before underwent DBE, five due to hemodynamic instability (n = 5), and two refused treatment (n = 2). Therefore, 1 (n = 21) participants were included in Group 2. Vital signs and oxygen saturation were regularly monitored. RESULTS: Mean +/- SD age of patients was 56.8 +/- 9.2 years, and 41.7% of patients were male. There was no difference in demographic data between the groups. For the safety profile, 25.9% of the midazolam/meperidine group and 33.3% of the propofol group developed hypotension and/or desaturation (p = 0.45). The patients' satisfaction of group 1 and group 2 were 86.7 +/- 6.5% and 86.3 +/- 8.1%, respectively, and presented no significant difference (p = 0.89). CONCLUSION: Propofol infusion is safe and shows no difference in outcome from the midazolam and meperidine sedation for the DBE procedure.

Correction: The association between vitamin D receptor polymorphism and phases of chronic hepatitis B infection in HBV carriers in Thailand.

[This corrects the article DOI: 10.1371/journal.pone.0277907.].

Bacterial DNA Translocation Is Associated With Overt Hepatic Encephalopathy and Mortality in Patients With Cirrhosis.

INTRODUCTION: Data on the relationship between bacterial translocation, hepatic encephalopathy (HE), and mortality are scarce. This study aimed to assess the association between bacterial DNA (bactDNA) translocation, inflammatory response, ammonia levels, and severity of HE in patients with cirrhosis, as well as the role of bactDNA translocation in predicting mortality. METHODS: Cirrhotic patients without bacterial infection were prospectively enrolled between June 2022 and January 2023. Grading of HE was classified by the West Haven Criteria and Psychometric Hepatic Encephalopathy Score ≤ -5. RESULTS: Overall, 294 cirrhotic patients were enrolled, with 92 (31.3%) and 58 (19.7%) having covert and overt HE, respectively. BactDNA translocation was detected in 36.1% of patients (n = 106). Patients with overt HE had more bactDNA translocation and higher serum lipopolysaccharide-binding protein (LBP), tumor necrosis factor-α, interleukin-6 (IL-6), and ammonia levels than those without HE. Patients with detectable bactDNA had higher white cell counts and serum LBP and IL-6 levels than those without. By contrast, bactDNA, serum LBP, and soluble CD14 levels were comparable between patients with covert HE and those without HE. The multivariate Cox regression analysis revealed that bactDNA translocation (hazard ratio [HR] = 2.49, 95% confidence interval [CI]: 1.22-5.11), Model for End-Stage Liver Disease score (HR = 1.12, 95% CI: 1.09-1.16), age (HR = 1.05, 95% CI: 1.000-1.002), and baseline IL-6 (HR = 1.001, 95% CI: 1.000-1.002) were independent factors associated with 6-month mortality. DISCUSSION: Apart from hyperammonemia, bactDNA translocation is a possible factor associated with overt HE in cirrhotic patients. BactDNA translocation and IL-6 are independent factors associated with 6-month mortality.

Ammonia is associated with liver-related complications and predicts mortality in acute-on-chronic liver failure patients.

The relationship between ammonia and liver-related complications (LRCs) in acute-on-chronic liver failure (ACLF) patients is not clearly established. This study aimed to evaluate the association between ammonia levels and LRCs in patients with ACLF. The study also evaluated the ability of ammonia in predicting mortality and progression of LRCs. The study prospectively recruited ACLF patients based on the APASL definition from the ACLF Research Consortium (AARC) from 2009 to 2019. LRCs were a composite endpoint of bacterial infection, overt hepatic encephalopathy (HE), and ascites. A total of 3871 cases were screened. Of these, 701 ACLF patients were enrolled. Patients with LRCs had significantly higher ammonia levels than those without. Ammonia was significantly higher in patients with overt HE and ascites, but not in those with bacterial infection. Multivariate analysis found that ammonia was associated with LRCs. Additionally, baseline arterial ammonia was an independent predictor of 30-day mortality, but it was not associated with the development of new LRCs within 30 days. In summary, baseline arterial ammonia levels are associated with 30-day mortality and LRCs, mainly overt HE and ascites in ACLF patients.

Comparison of long-term outcome of patients with Wilson's disease presenting with acute liver failure versus acute-on-chronic liver failure.

OBJECTIVE: Wilson's disease (WD) is an inherited disorder of copper metabolism, leading to hepatic and neuropsychiatric manifestations. The long-term outcome of patients with Wilson's disease presenting with acute liver failure (ALF) versus those with acute-on-chronic liver failure (ACLF) has not been well documented. The authors' aimed to compare the clinical presentations and long-term outcome after standard treatments between patients with ALF versus those with ACLF. MATERIAL AND METHOD: The authors performed a retrospective review of 39 patients with Wilson's disease, at the King Chulalongkorn Memorial Hospital between January 2003 and December 2011. Primary outcome of the present study was liver complications or deaths from any cause. ACLF was defined as an acute hepatic insult in patients with previously diagnosed or undiagnosed chronic liver disease, whereas ALF was defined as an occurrence in the absence of any preexisting liver disease. RESULTS: Twenty-two of 39 patients (56.4%) presented predominantly with hepatic symptoms with the mean duration of follow-up of 7.7 +/- 8.5 years. Ten of them (45%) presented with ALF, whereas 12 patients (55%) presented with ACLF. Patients with ALF showed a significantly earlier age of onset of presenting symptoms than those with ACLF (15.4 +/- 4.5 vs. 28.1 +/- 13.0 years; p < 0.05). The mean baseline of 24-hour urinary copper in patients with ALF was higher than those found in ACLF (1,645 +/- 1,406 vs. 441 +/- 434 mg/day; p < 0.05, respectively). Fourteen patients (63.6%) improved with supportive care and chelating agents. No significant difference of clinical improvement was found between patients presented with ALF and ACLF (80% vs. 50%; p = 0.19). By using the survival analysis, the mean duration time to liver complications or all cause of death in patients with ALF was significantly longer than those with ACLF (16.2 +/- 2.3 years vs. 8.5 +/- 3.2 years; p = 0.012) as well as higher cumulative percent of free a period from liver complication or death during a 9-year period (80% vs. 21%, p = 0.012). CONCLUSION: Patients with Wilson's disease presenting with acute-on-chronic liver failure manifested symptoms later and had more liver complications than patients with acute liver failure, as well as a lower cumulative free period from liver complication or death.

Psychometric Hepatic Encephalopathy Score for the Diagnosis of Minimal Hepatic Encephalopathy in Thai Cirrhotic Patients.

The psychometric hepatic encephalopathy score (PHES) is the gold standard for diagnosing minimal hepatic encephalopathy (MHE). Screening for MHE is frequently overlooked in clinical practice due to time constraints. Furthermore, the simplified animal naming test (S-ANT1) is a new simple tool for evaluating MHE in cirrhotic patients. The purpose of this study was to standardize the PHES in a healthy Thai population, assess the prevalence of MHE, and validate the S-ANT1 in detecting MHE in patients with cirrhosis. The study included 194 healthy controls and 203 cirrhotic patients without overt HE. Psychometric tests and the S-ANT1 were administered to all participants. Multiple linear regression was used to analyze factors related to PHES results, and formulas were developed to predict the results for each PHES subtest. In healthy controls, age and education were predictors of all five subtests. The PHES of the control group was −0.26 ± 2.28 points, and the threshold for detecting MHE was set at ≤ −5 points. The cirrhotic group had PHES values of −2.6 ± 3.1 points. Moreover, MHE was found to be present in 26.6% of cirrhotic patients. S-ANT1 had a moderate positive correlation with PHES (r = 0.44, p < 0.001). S-ANT1 < 22 named animals detected MHE with a sensitivity of 71.2%, specificity of 65%, and area under the receiver operating curve of 0.68 (p < 0.001). In conclusion, Thai PHES normative data have been developed to detect MHE in cirrhotic patients who do not have overt HE. The optimal cutoff for detecting MHE in Thai cirrhotic patients was PHES ≤ −5 points and S-ANT1 < 22 named.

Validation of the albumin-bilirubin score for identifying decompensation risk in patients with compensated cirrhosis.

BACKGROUND: The albumin-bilirubin (ALBI) score is an index of liver function recently developed to assess prognosis in patients with hepatocellular carcinoma (HCC). It can detect small changes in liver dysfunction and has been successfully applied to the prediction of survival in patients with non-malignant liver diseases of various etiologies. AIM: To investigate the ALBI score for identifying decompensation risk at the 3-year follow-up in patients with compensated cirrhosis. METHODS: One-hundred and twenty-three patients with compensated cirrhosis without HCC in King Chulalongkorn Memorial Hospital diagnosed by imaging were retrospectively enrolled from January 2016 to December 2020. A total of 113 patients (91.9%) had Child A cirrhosis with a median model for end-stage liver disease (MELD) score of less than 9. Baseline clinical and laboratory variables and decompensation events were collected. The ALBI score was calculated and validated to classify decompensation risk into low-, middle-, and high-risk groups using three ALBI grade ranges (ALBI grade 1: ≤ -2.60; grade 2: > -2.60 but ≤ -1.39; grade 3: > -1.39). Decompensation events were defined as ascites development, variceal bleeding, or grade 3 or 4 hepatic encephalopathy. RESULTS: Among 123 cirrhotic patients enrolled, 13.8% (n = 17) developed decompensating events at a median time of 25 [95% confidence interval (CI): 17-31] mo. Median baseline ALBI score in compensated cirrhosis was significantly lower than that of patients who developed decompensation events [-2.768 (-2.956 to -2.453) vs -2.007 (-2.533 to -1.537); P = 0.01]. Analysis of decompensation risk at 3 years showed that ALBI score had a time-dependent area under the curve (tAUC) of 0.86 (95%CI: 0.78-0.92), which was significantly better than that of ALBI-Fibrosis-4 (ALBI-FIB4) score (tAUC = 0.77), MELD score (tAUC = 0.66), Child-Pugh score (tAUC = 0.65), and FIB-4 score (tAUC = 0.48) (P < 0.05 for all). The 3-year cumulative incidence of decompensation was 3.1%, 22.6%, and 50% in the low-, middle-, and high-risk groups, respectively (P < 0.001). The odds ratio for decompensation in patients of the high-risk group was 23.33 (95%CI: 3.88-140.12, P = 0.001). CONCLUSION: The ALBI score accurately identifies decompensation risk at the 3-year follow-up in patients with compensated cirrhosis. Those cirrhotic patients with a high-risk grade of ALBI score showed a 23 times greater odds of decompensation.

Prevalence of hepatitis D virus infection among patients with chronic hepatitis B infection in a tertiary care centre in Thailand.

Knowledge about the epidemiology of hepatitis D virus (HDV) is essential for effective screening and management. Our study aimed to update the prevalence of HDV infection among patients with hepatitis B virus (HBV) infection at hepatology clinics in Thailand. We enrolled HBV-infected patients from hepatology clinics at King Chulalongkorn Memorial Hospital, Bangkok, Thailand, between June 2022 and November 2023. Demographic, biochemical characteristics, and liver-related complications (LRC), including cirrhosis and hepatocellular carcinoma, were reviewed. The competitive enzyme and chemiluminescence immunoassays were used to detect anti-HDV antibodies. Real-time polymerase chain reaction (RT-PCR) was used to test for HDV RNA in anti-HDV-positive patients. The HDV genotype was identified in detectable HDV RNA samples. Of the 702 enrolled patients, four (0.6%) had positive and equivocal for both anti-HDV tests. Two (50.0%) of the four patients tested positive for HDV RNA and genotype 1 was identified; one had multiple risk factors. Anti-HDV seroprevalence was not significantly different between patients with and without LRC. In conclusion, HDV co-infection is less common in Thailand than globally. Additionally, our study identified genotype 1, the predominant HDV genotype worldwide, and observed co-infection even without LRC.

Modified albumin-bilirubin predicted survival of unresectable hepatocellular carcinoma patients treated with immunotherapy.

BACKGROUND: Modified albumin-bilirubin (mALBI) grade has been established as a survival determinant in hepatocellular carcinoma (HCC) patients who receive locoregional and targeted therapies. AIM: To investigate whether mALBI could predict survival in unresectable HCC (uHCC) patients who were treated with atezolizumab plus bevacizumab (AB). METHODS: A single-center, retrospective cohort study enrolled uHCC patients who received AB treatment between September 2020 and April 2023 and were followed up until June 2023. An association between mALBI and patient survival was determined using Cox proportional hazards analysis. RESULTS: Of the 83 patients, 67 patients (80.7%) were male with the mean age of 60.6 years. Among them, 22 patients (26.5%) were classified as Barcelona Clinic Liver Cancer B, and 61 patients (73.5%) were classified as Barcelona Clinic Liver Cancer C. Cirrhosis was present in 76 patients (91.6%), with 58 patients classified as Child-Turcotte-Pugh (CTP) A and 18 as CTP B. The median overall survival (OS) and progression-free survival were 13.0 mo [95% confidence interval (CI): 5.2-20.8] and 9.0 mo (95%CI: 5.0-13.0), respectively. The patients were divided into two groups based on mALBI grades: 42 patients (50.6%) in the mALBI 1 + 2a group; and 41 patients (49.4%) in the mALBI 2b + 3 group. During the median follow-up period of 7.0 mo, the mALBI 1 + 2a group exhibited significantly better survival compared to the mALBI 2b + 3 group, with a median OS that was not reached vs 3.0 mo (95%CI: 0.1-6.0, P < 0.001). In a subgroup of patients with CTP A, the mALBI 1 + 2a group also showed significantly longer survival compared to the mALBI 2b + 3 group, with a median OS that was not reached vs 6.0 mo (95%CI: 3.4-8.6, P < 0.001). In the multivariate analysis, both CTP class and mALBI grade were independently associated with survival, with adjusted hazard ratios (95%CI) of 2.63 (1.19-5.78, P = 0.020) and 3.90 (1.71-8.90, P = 0.001), respectively. CONCLUSION: mALBI grades can determine survival of uHCC patients receiving AB treatment, particularly those who have mildly impaired liver function. This highlights the importance of assessing mALBI before initiating AB treatment to optimize therapeutic efficacy in clinical practice.

Awareness of colorectal cancer screening in primary care physicians.

OBJECTIVE: Colorectal cancer is one of the leading causes of cancer related death worldwide. Primary care physicians play an important role in colorectal cancer screening. However the awareness and knowledge on the methods for colorectal cancer screening are still lacking. The authors aimed to assess Thai primary care physicians' knowledge and practice regarding colorectal cancer screening. MATERIAL AND METHOD: Between October and December 2010, questionnaires were distributed to 447 Thai physicians. The questionnaires included demographic data, self-responded knowledge, and practice. Their responses were analyzed. RESULTS: Three hundred eighty seven physicians completed the questionnaires (86.5% response rate). Of these, 44.7% were internists, 27.4% general practitioners (GPs), 11.9% surgeons, and 16.0% other specialists. Two hundred forty of physicians (62%) routinely recommended colorectal cancer screening to asymptomatic, average-risk patients. Only 43% gave the correct recommendation for the correct starting age. Colonoscopy (47.5%) and fecal occult blood test (40.0%) were preferred by the majority of physicians, whereas flexible sigmoidoscopy, double contrast barium enema, and CT colonoscopy were chosen by 5.7%, 4.4%, and 1.8% of physicians respectively. Surgeons had more knowledge of test efficacy and frequency. They also were more aware of colorectal cancer screening than internists. Patient ignorance (66.1%), unavailability of the test (64.6%), unawareness of physicians (57.9%), and financial problems (41.1%) were determinedas barriers for colorectal cancer screening. CONCLUSION: Although the majority of physicians are aware of colorectal cancer screening, the correct knowledge is lacking. Colonoscopy and FOBT are their most preferred tests. Patient ignorance, unavailability of the test, unawareness of physician, and financial problems are the main barriers for colorectal cancer screening. Improvement in academic support services and standard clinical practice guideline are needed to improve overall morbidity and mortality of colorectal cancer.