Effectiveness of 1-year pemafibrate treatment on steatotic liver disease: the influence of alcohol consumption.

BACKGROUND/AIMS: Pemafibrate is a selective peroxisome proliferator-activated receptor α modulator that improves serum alanine aminotransferase (ALT) in dyslipidemia patients. We previously reported that pemafibrate significantly improves liver function, serum triglyceride (TG) levels and liver stiffness in non-alcoholic fatty liver disease patients, however the influence of alcohol consumption was not considered. Therefore, we explored pemafibrate efficacy in patients with steatotic liver disease (SLD) and alcohol-associated liver disease (ALD). METHODS: We retrospectively evaluated pemafibrate efficacy on liver enzymes and lipids in metabolic dysfunction-associated SLD (MASLD) (n = 93), MASLD plus increased alcohol intake (MetALD; n = 23) and ALD (n = 22) patients who had taken pemafibrate for at least 48 weeks. Liver shear wave velocity (SWV, n = 75) was also evaluated. RESULTS: In MASLD group, ALT, aspartate aminotransferase (AST), γ-glutamyl transpeptidase (γ-GTP) and TG values were significantly decreased from baseline to week 24 and week 48 ( P  < 0.0001). ALT and TG values in MetALD group and ALT and AST values in ALD group were also significantly decreased from baseline to week 24 and week 48. Study participant SWV values decreased from baseline to week 48. We observed no significant difference in changes to ALT, AST, γ-GTP and TG (value at week 24 or week 48 minus value at baseline) among the three groups. CONCLUSION: Pemafibrate improves liver function and liver stiffness thus making it a promising therapeutic agent for SLD, even in patients with excess alcohol consumption (MetALD and ALD groups).

Serum Zinc-α2-glycoprotein Levels Are Associated with the Hepatorenal Function and Predict the Survival in Cases of Chronic Liver Disease.

Objective Zinc-α2-glycoprotein (ZAG) is secreted by various organs, such as liver, kidney and adipose tissue, is involved in lipolysis, and may contribute to the pathogenesis of chronic liver disease (CLD). We therefore assessed whether or not ZAG is a surrogate marker for the hepatorenal function, body composition and all causes of mortality, as well as complications, including ascites, hepatic encephalopathy (HE) and portosystemic shunts (PSS) in CLD. Methods Serum ZAG levels were measured in 180 CLD patients upon hospital admission. The associations of ZAG levels with the liver functional reserve and clinical parameters were investigated using a multiple regression analysis. Kaplan-Meier analyses were performed to evaluate the associations of the ZAG/creatinine ratio (ZAG/Cr) and prognostic factors with mortality. Results High serum ZAG levels were associated with preserving the liver function and renal insufficiency. A multiple regression analysis showed that the estimated glomerular filtration rate (p<0.0001), albumin-bilirubin (ALBI) score (p=0.0018) and subcutaneous fat area (p=0.0023) had a significant independent correlation with serum ZAG levels. Serum ZAG levels were elevated in the absence of HE (p=0.0023) and PSS (p=0.0003). In all patients and those without hepatocellular carcinoma (HCC), the cumulative mortality rate was significantly decreased in patients with a high ZAG/Cr compared with those with a low ZAG/Cr (p=0.0018 and p=0.0002, respectively). The ZAG/Cr, presence of HCC, ALBI score and psoas muscle index were independent predictors of the prognosis in CLD patients. Conclusion Serum ZAG levels are associated with the hepatorenal function and can be used to predict the survival in CLD patients.

Effect of pemafibrate on liver enzymes and shear wave velocity in non-alcoholic fatty liver disease patients.

Background/Aims: Pemafibrate is a selective peroxisome proliferator-activated receptor α modulator that improves serum alanine aminotransferase (ALT) in dyslipidemia patients. Pemafibrate was reported to reduce ALT in non-alcoholic fatty liver disease (NAFLD) patients, but efficacy was not clearly elucidated due to the small size of previous study populations. Therefore, we explored pemafibrate efficacy in NAFLD patients. Methods: We retrospectively evaluated pemafibrate efficacy on liver enzymes (n = 132) and liver shear wave velocity (SWV, n = 51) in NAFLD patients who had taken pemafibrate for at least 24 weeks. Results: Patient ALT levels were decreased from 81.0 IU/L at baseline to 48.0 IU/L at week 24 (P < 0.0001). Serum levels of aspartate aminotransferase (AST), γ-glutamyl transpeptidase (γ-GTP) and triglyceride (TG) were significantly decreased, and high-density lipoprotein cholesterol and platelet count were significantly increased, with no change in body weight being observed. Study participant SWV values decreased from 1.45 m/s at baseline to 1.32 m/s at week 48 (P < 0.001). Older age (P = 0.035) and serum TG levels (P = 0.048) were significantly associated with normalized ALT. Changes in AST, ALT, γ-GTP and body weight were significantly correlated with change in SWV. Conclusion: Pemafibrate significantly improves liver function, serum TG and liver stiffness in NAFLD patients. Pemafibrate is a promising therapeutic agent for NAFLD and may be a candidate for NAFLD patients with elevated TG.

Risk factors for portopulmonary hypertension in patients with cirrhosis: a prospective, multicenter study.

BACKGROUND: Tricuspid regurgitation pressure gradient (TRPG) measurement by echocardiography is recommended as the most objective examination to detect portopulmonary hypertension (PoPH). This study aimed to identify factors associated with a high TRPG in patients with cirrhosis and develop a scoring model for identifying patients who are most likely to benefit from echocardiography investigations. RESULTS: A total of 486 patients who underwent echocardiography were randomly allocated to the derivation and validation sets at a ratio of 2:1. Of the patients, 51 (10.5%) had TRPG ≥ 35 mmHg. The median brain natriuretic peptide (BNP) was 39.5 pg/mL. Shortness of breath (SOB) was reported by 91 (18.7%) patients. In the derivation set, multivariate analysis identified female gender, shortness of breath, and BNP ≥ 48.9 pg/mL as independent factors for TRPG ≥ 35 mmHg. The risk score for predicting TRPG ≥ 35 mmHg was calculated as follows: - 3.596 + 1.250 × gender (female: 1, male: 0) + 1.093 × SOB (presence: 1, absence: 0) + 0.953 × BNP (≥ 48.9 pg/mL: 1, < 48.9 pg/mL: 0). The risk score yielded sensitivity of 66.7%, specificity of 75.3%, positive predictive value of 25.5%, negative predict value of 94.3%, and predictive accuracy of 74.4% for predicting TRPG ≥ 35 mmHg. These results were almost similar in the validation set, indicating the reproducibility and validity of the risk score. CONCLUSIONS: This study clarified the characteristics of patients with suspected PoPH and developed a scoring model for identifying patients at high risk of PoPH, which may be used in selecting patients that may benefit from echocardiography.

Hepatocellular Carcinoma Pseudoprogression Involving the Main Portal Vein, Right Ventricular Invasion, and Exacerbation of Lung Metastases in a Patient on Atezolizumab Plus Bevacizumab.

A 70-year-old man was diagnosed with hepatocellular carcinoma (HCC) with portal vein invasion and lung metastases, for which atezolizumab plus bevacizumab (ATZ/BEV) was initiated. After two months, computed tomography revealed tumor growth accompanied by ascites, right ventricular invasion, exacerbation of the lung metastases, and main portal vein invasion. However, continuation of ATZ/BEV caused remarkable size reductions in all lesions, finally resulting in the disappearance of the vascular invasion and lung metastases after nine cycles of treatment. The tumor growth was considered to reflect pseudoprogression, which is difficult to distinguish from hyperprogression. We herein report a remarkable HCC case of pseudoprogression on ATZ/BEV.

The prognostic role of controlling nutritional status and skeletal muscle mass in patients with hepatocellular carcinoma after curative treatment.

BACKGROUND: Nutritional status and skeletal muscle mass affect the prognosis of hepatocellular carcinoma (HCC). Nutritional status is closely associated with skeletal muscle mass. Here, we investigate the effect of controlling preoperative nutritional status and skeletal muscle mass on the prognosis of HCC after curative treatment. METHODS: This retrospective analysis contained 181 patients who received curative treatment of HCC including liver resection or radiofrequency ablation (RFA) therapy. Nutritional status and skeletal muscle mass were evaluated prior to therapy using the controlling nutritional status (CONUT) score and psoas muscle mass index (PMI), respectively. Associations of predictor variables with overall survival (OS) and progression-free survival (PFS) were determined using Cox proportional hazards regression and CHAID decision tree algorithm analysis. RESULTS: A total of 111 patients (61.3%) were determined to be of poor nutritional status and 100 patients (55.2%) had muscle mass depletion. Patients with PS 0, Barcelona clinic liver cancer (BCLC) stage 0, low CONUT score, and high PMI showed significantly better OS than those with PS 1, BCLC stage A, high CONUT score, and low PMI. Multivariate analysis indicated that a high CONUT score [hazard ratio (HR) 4.130; 95% confidence interval (CI), 1.713-9.958; P < 0.01) and low PMI (HR 4.625; 95% CI, 1.704-12.549; P < 0.01) found to be useful for predicting OS in patients after curative treatment of HCC. Regarding PFS, a significant predictor was only tumor numbers in univariate analysis (HR 2.147; 95% CI, 1.350-3.414; P = 0.001). In decision tree analysis, the mortality rate was 28.8%, 12.5%, and 1.9% in patients with a high CONUT score, with a low CONUT score-low PMI, or with a low CONUT score-high PMI, respectively. CONCLUSION: The combined CONUT score and PMI were found to be independent predictors of OS in HCC patients after liver resection or RFA.

Association of lithocholic acid with skeletal muscle hypertrophy through TGR5-IGF-1 and skeletal muscle mass in cultured mouse myotubes, chronic liver disease rats and humans.

Background: Hepatic sarcopenia is one of many complications associated with chronic liver disease (CLD) and has a high mortality rate; however, the liver-muscle axis is not fully understood. Therefore, few effective treatments exist for hepatic sarcopenia, the best of which being branched-chain amino acid (BCAA) supplementation to help increase muscle mass. Our aim was to investigate the molecular mechanism(s) of hepatic sarcopenia focused on bile acid (BA) composition. Methods: The correlation between serum BA levels and psoas muscle mass index (PMI) was examined in 73 CLD patients. Gastrocnemius muscle phenotype and serum BA levels were assessed in CLD rats treated with BCAA. Mouse skeletal muscle cells (C2C12) were incubated with lithocholic acid (LCA), G-protein-coupled receptor 5 (TGR5) agonist or TGR5 antagonist to assess skeletal muscle hypertrophy. Results: In human CLD, serum LCA levels were the sole factor positively correlated with PMI and were significantly decreased in both the low muscle mass group and the deceased group. Serum LCA levels were also shown to predict patient survival. Gastrocnemius muscle weight significantly increased in CLD rats treated with BCAA via suppression of protein degradation pathways, coupled with a significant increase in serum LCA levels. LCA treated C2C12 hypertrophy occurred in a concentration-dependent manner linked with TGR5-Akt pathways based upon inhibition results via a TGR5 antagonist. Conclusions: Our results indicate LCA-mediated skeletal muscle hypertrophy via activation of TGR5-IGF1-Akt signaling pathways. In addition, serum LCA levels were associated with skeletal muscle mass in cirrhotic rats, as well as CLD patients, and predicted overall patient survival. Funding: This research was supported by JSPS KAKENHI Grant Number 22K08011 and 21H02892, and AMED under Grant Number JP21fk0210090 and JP22fk0210115. Maintaining cirrhotic rats were partially supported by Otsuka Pharmaceutical Company.

The prognostic potential of fragmented CK18 serum levels in HCC patients reflecting disease progression and overall hepatocyte damage.

Background: Fragmented cytokeratin 18 (fCK18) is released from damaged hepatocytes undergoing apoptosis and is recognized as a liver condition biomarker. We have developed a highly sensitive serum fCK18 CLEIA and reported that serum levels of this caspase-derived protein were significantly associated with hepatocyte ballooning, thus assisting in the accurate diagnosis of nonalcoholic steatohepatitis (NASH). We aim to investigate serum fCK18 levels in a variety of chronic liver diseases and to explore its potential as a prognostic marker of survival in hepatocellular carcinoma (HCC) patients. Methods: Serum fCK18 levels were measured using a highly sensitive CLEIA in 497 chronic liver disease patients (297 outpatients and 200 hospitalized with HCC). Results: In 497 chronic liver disease patients, serum fCK18 levels were significantly correlated with overall liver condition, including ALT, FIB-4 index and albumin-bilirubin (ALBI) score and were significantly increased in patients with HCC. In 200 HCC patients, serum fCK18 levels were significantly correlated with alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP), and were significantly associated with HCC stage, whereas FIB-4 index and ALBI score were not changed based on HCC stage. The Survival group had significantly lower levels of serum fCK18, AFP, DCP, FIB-4 index and ALBI score. A ROC analysis yield area under the curve (AUC) value of 0.728 for serum fCK18 is a significantly high value when compared to AUC measurements for other factors. Notably, AUROC values for serum fCK18 levels were constant in the short- and long-term by time-dependent ROC analysis for the prediction of HCC patient survival. HCC patients with serum fCK18 measured at < 1.15 ng/mL, AFP < 7.7 ng/mL, DCP < 133 mAU/mL, ALBI score < -2.97 or FIB-4 index < 6.4 had significantly longer rates of survival when compared to patients with values exceeding these thresholds. Serum fCK18 (HR, 3.5; P < 0.0001), DCP (HR, 3.2; P < 0.0001) and Barcelona Clinic Liver Cancer (BCLC) (HR, 2.4; P = 0.001) values were independent predictors of patient survival. [Conclusion] Serum fCK18 levels reflect overall liver function, the level of liver fibrosis and the progression of HCC, and are a potential predictor of survival in HCC patients.

Elevation of enterococcus-specific antibodies associated with bacterial translocation is predictive of survival rate in chronic liver disease.

Introduction/purpose: The gut-liver axis contributes to disease progression, a rise in infection rate, organ failure and a poor overall outcome in chronic liver diseases (CLD). Monitoring of the gut-liver axis is critical in understanding disease status, but biomarkers have not been elucidated. The aim of this study is to determine the level of serum antibodies against Enterococcus (E.) faecalis in evaluating patients with CLD, including those treated with rifaximin (a minimally absorbed antibiotic), and in patients with alcohol-associated liver disease (ALD). Materials and methods: We enrolled 109 CLD patients (cohort 1), 30 hepatic encephalopathy patients treated with rifaximin (cohort 2), 53 inpatients with ALD undergoing alcohol cessation (cohort 3) and 33 healthy subjects. To assess the consequences of E. faecalis translocation, we developed an assay for the detection of a serum antibody against E. faecalis capsular polysaccharide (E.CPS). Results: Serum E.CPS antibody titer was elevated only in those patients with advanced CLD and ALD. The E.CPS antibody titer was an independent prognostic factor (p < 0.05), while Mac-2 binding protein and albumin-bilirubin score were not independent predictors of survival. The improvement of predictive model in integrated factors was significant [continuous net reclassification index (value 0.699, p < 0.05) and integrated discrimination improvement (value 0.164, p = 0.051)]. Furthermore, rifaximin treatment led to a decrease of serum E.CPS antibody titer resulting in a significantly longer overall rate of survival. Conclusion: The E.CPS antibody titer appears to be a strong predictor of survival in CLD patients. Serum E.CPS levels decrease in CLD patients receiving rifaximin, and may be associated with an overall improvement in rate of survival.

Effects of endoscopic injection sclerotherapy for esophagogastric varices on portal hemodynamics and liver function.

OBJECTIVES: To identify patients suitable for endoscopic injection sclerotherapy (EIS) by evaluating their portal hemodynamics and liver function. METHODS: We selected 58 patients with esophagogastric varices (EGV) and liver cirrhosis (LC) related to either hepatitis C virus (C) (n = 19), hepatitis B virus (n = 2), alcohol (AL) (n = 20), C + AL (n = 6), non-alcoholic steatohepatitis (n = 6), others (n = 3), or non-LC (n = 2). All patients underwent EIS. We measured their portal venous tissue blood flow (PVTBF) and hepatic arterial tissue blood flow (HATBF) using xenon computed tomography before and after EIS. We classified them into increased group and decreased group according to the PVTBF to identify the predictors that contribute to PVTBF increase post-EIS. RESULTS: Low value of indocyanine green retention at 15 min (ICG-R15), the absence of paraesophageal veins, and low baseline PVTBF/HATBF (P/A) ratio predicted increased PVTBF in the multivariate logistic analysis (odds ratio (OR) 10.46, p = 0.0391; OR 12.45, p = 0.0088; OR 13.57, p = 0.0073). The protein synthetic ability improved 1 year post-EIS in increased group. Cox proportional hazards regression identified alcohol drinking (hazard ratio; 3.67, p = 0.0261) as an independent predictor of EGV recurrence. CONCLUSIONS: Patients with low ICG-R15, low P/A ratio, and the absence of paraesophageal veins were probable predictors of PVTBF improvement post-EIS. In addition, the improvement of hepatic hemodynamics likely enhanced liver function following EIS.

Recurrent hepatocellular carcinoma with osteoclast-like giant cells: a case report.

BACKGROUND: Hepatocellular carcinoma with osteoclast-like giant cells is very rare and has an extremely poor prognosis. Here, we report a case of hepatocellular carcinoma with osteoclast-like giant cells that had a relatively better prognosis. CASE PRESENTATION: A 70-year-old Japanese man with hepatitis B virus-related liver cirrhosis was admitted to our hospital for the treatment of recurrent hepatocellular carcinoma. At the age of 60 years, he was first diagnosed as having hepatocellular carcinoma in the right lobe (9 cm in diameter), and liver resection of segment 7/8 was performed. Histological findings showed well-differentiated hepatocellular carcinoma. Since then, imaging studies have been performed every 3 or 4 months. One year later, hepatocellular carcinoma recurred in the lateral segment, and radiofrequency ablation was performed. Nine years after the first presentation, hepatocellular carcinoma recurrences were detected in the caudate lobe and segment 5 by imaging studies. Surgical resection of the caudate lobe was performed, and ultrasonography-guided radiofrequency ablation was subsequently performed for the segment 5 tumor. The resected tumor was simple nodular, well-differentiated HCC; it measured 21 × 21 mm and contained many osteoclast-like giant cells. As neither vascular nor bile duct invasion was found, we believe that radical resection was achieved. Since then, the hepatocellular carcinoma has not recurred for over a year and a half. CONCLUSION: Hepatocellular carcinoma with osteoclast-like giant cells is very rare and the prognosis is extremely poor, but early detection can lead to a better clinical course.

A new detection system for serum fragmented cytokeratin 18 as a biomarker reflecting histologic activities of human nonalcoholic steatohepatitis.

Caspase-generated fragmented cytokeratin 18 (fCK18) is recognized as a useful noninvasive biomarker in the diagnosis of nonalcoholic fatty liver disease (NAFLD), particularly nonalcoholic steatohepatitis (NASH). However, fCK18 measurement is not applied clinically due to widely variable cut-off values under the current enzyme-linked immunosorbent assay platform. Therefore, we developed a highly sensitive chemiluminescent enzyme immunoassay using newly developed monoclonal antibodies against fCK18 and investigated its relevance in NASH diagnosis. Serum fCK18 levels were measured in the derivation and validation cohort. The correlation between serum fCK18 levels and NAFLD activity score (NAS), fibrosis stage, and liver function was examined. Serum fCK18 levels were significantly correlated with alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transpeptidase. Serum fCK18 levels were significantly associated with NAS, Brunt's grade/stage, Matteoni's classification, portal inflammation, and fat accumulation in the liver. Notably, hepatocyte ballooning was the only independent variable significantly associated with serum fCK18 in the multivariate linear regression analysis. Serum fCK18 levels were significantly elevated in patients with NAFLD and nonalcoholic fatty liver (NAFL) compared to healthy individuals. They were also significantly elevated in patients with NAFL compared to NASH defined by NAS or Matteoni's classification, with area under the curve values being 0.961 (NAFLD vs. healthy), 0.913 (NAFL vs. healthy), 0.763 (NASH vs. NAFL), and 0.796 (NASH type 3-4 vs. NAFL type 1-2). These results were confirmed by a validation cohort. Notably, changes over time in serum fCK18 levels were significantly correlated with changes in ALT, AST, and the fibrosis-4 index in 25 patients who underwent lifestyle modification. Serum fCK18 levels were significantly correlated with liver damage associated with NASH pathology. Serum fCK18 levels are accurate in distinguishing patients with NAFL or NASH from healthy individuals and may be useful to monitor NASH over time.

Accuracy of carbohydrate-deficient transferrin as a biomarker of chronic alcohol abuse during treatment for alcoholism.

AIM: Clinical evaluations are generally used to verify the effectiveness of detoxification treatments for alcohol dependence, but new objective biomarkers are essential for accurate diagnosis. We aim to assess the accuracy of carbohydrate-deficient transferrin (%CDT) in a cohort of Japanese patients admitted to a psychiatric hospital specializing in alcohol dependence. In addition, we investigated the kinetics of %CDT during alcohol moderation or cessation. METHODS: The study cohort consisted of 126 alcohol-dependent patients. The levels of serum %CDT were assessed by the N Latex CDT direct immunonephelometric assay. RESULTS: Alcohol consumption was significantly correlated with %CDT. The only independent predictive factor of alcohol consumption was %CDT, with glutamyltranspeptidase (GGT) and albumin-bilirubin score proving insufficient. The cut-off value of %CDT was 1.9% with high sensitivity and specificity in detecting alcohol abstinence beyond 30 days (68.6% sensitivity, 91.8% specificity) and excessive alcohol drinking (77.9% sensitivity, 77.1% specificity). The %CDT levels were significantly decreased at 30 days of abstinence when compared with baseline. Notably, %CDT values were significantly changed even in the light alcohol drinking cohort (p = 0.0009), whereas GGT levels were not significantly changed. CONCLUSIONS: Our results indicate that %CDT is an accurate and specific biomarker of alcohol consumption and is useful in detecting alcohol abstinence even in a low alcohol intake patient cohort. These results suggest that %CDT could be a useful objective biomarker of chronic alcohol abuse during clinical treatment for alcoholism.

Update on blood-based biomarkers for chronic liver diseases prognosis: Literature review and institutional experience.

Liver cirrhosis is the final stage of chronic liver disease (CLD) and is associated with high morbidity and mortality. Various complications such as portal hypertension, ascites retention, hepatic encephalopathy, and hepatorenal syndrome deeply affect patient outcome. The most common tools to predict the outcome of a CLD patient include the following: assessing severity of portal hypertension; scoring systems such as the model of end-stage liver disease and Child-Pugh score and blood biomarkers related to complications and/or survival rate. In this article, we summarize recent studies of noninvasive markers for predicting impending complications related to CLD and discuss the clinical value of currently available blood biomarkers based on evidence from the literature. In addition, noninvasive blood biomarker assays for different prognostic functions were validated on 113 liver cirrhosis patients at our institution using Kaplan-Meier curve analysis to confirm that these markers can satisfactorily predict CLD-related patient death.

Prediction of esophagogastric varices associated with oxaliplatin administration.

BACKGROUND: Oxaliplatin is a key drug for the chemotherapy of colorectal cancer; however, it is also known to cause non-cirrhotic portal hypertension. We aimed to identify the characteristics of patients who developed esophagogastric varices (EGVs) after treatment with oxaliplatin. METHODS: This study retrospectively analyzed patients with colorectal cancer who were treated with chemotherapy including oxaliplatin between 2010 and 2016. All patients were evaluated by contrast-enhanced computed tomography (CE-CT) every 3 months both during and after treatment; and endoscopy was performed when appearance of portal hypertension was suspected. RESULTS: A total of 106 patients were divided into two groups: EGV formation (n = 6) and EGV non-formation (n = 100). In the EGV group, platelet counts decreased and the size of the spleen calculated by CT (CT spleen index; CT-SI) increased markedly. The highest area under the receiver operating characteristic curve (AUC) for the change in platelet counts was 0.81 (80% sensitivity and 83% specificity) at 3 months post treatment, and the maximum AUC for CT-SI was 0.89 (79% sensitivity and 83% specificity) at 6 months post treatment. CONCLUSIONS: EGV formation could be predicted by the assessment of platelet counts and spleen size. If progressive splenomegaly and thrombocytopenia are observed not only during but also after completion of the oxaliplatin-containing chemotherapy, EGVs should be confirmed by endoscopy for avoiding subsequent rupture.

Serum Copeptin and Zinc-α2-glycoprotein Levels Are Novel Biomarkers of Tolvaptan Treatment in Decompensated Cirrhotic Patients with Ascites.

Objective The efficacy of tolvaptan, an orally active vasopressin V2-receptor antagonist, has recently been reported in patients with massive ascites unresponsive to conventional diuretics. However, the effect of tolvaptan varies among patients. Recently, the prognostic role of the tolvaptan response in cases of decompensated liver cirrhosis (LC) has been attracting increasing attention. Using serum copeptin (vasopressin precursor), zinc-α2-glycoprotein (ZAG), cystatin C (renal biomarker), neutrophil gelatinase-associated lipocalin (NGAL) and liver-type fatty acid-binding protein (L-FABP), we explored which factors portend a good response to tolvaptan in LC patients with ascites. Methods We enrolled 113 LC patients and divided them into the tolvaptan treatment group and non-treatment group. Tolvaptan (3.75 or 7.5 mg/day) was administrated to 38 LC patients with ascites, and a follow-up assessment was performed after a 7-day tolvaptan treatment regimen. Results We determined the predictive ability for kidney and/or liver damage of serum copeptin, ZAG, cystatin C, NGAL and L-FABP levels in all patients. After 7-day tolvaptan treatment, 19 patients had lost more than 1.5 kg of body weight (Responders), while 19 showed no marked change in their body weight (Non-responders). Basal blood urea nitrogen (BUN) (p=0.0014), serum copeptin (p=0.0265) and serum ZAG levels (p=0.0142) were significantly higher in the Non-responders than in the Responders. BUN (odds ratio 7.43, p=0.0306), copeptin (odds ratio 9.12, p=0.0136) and ZAG (odds ratio 7.43, p=0.0306) were determined to be predictive factors of drug responsiveness using a multivariate logistic regression analysis. Conclusion Serum BUN, copeptin and ZAG levels predict the patient response to tolvaptan, even when measured prior to treatment.

Rifaximin ameliorates intestinal inflammation in cirrhotic patients with hepatic encephalopathy.

Rifaximin (RFX) treatment can attenuate not only hyperammonemia but also Enterococcus faecalis translocation and 10-7G values, suggesting that RFX treatment may improve intestinal inflammation and result in better overall survival.

Serum copeptin level is a biomarker associated with ascites retention and the formation of a portosystemic shunt in chronic liver disease.

BACKGROUND AND AIM: Copeptin is a stable cleavage product of the arginine vasopressin precursor and is equimolarly secreted with arginine vasopressin. We aimed to assess whether copeptin is the surrogate marker for complications related chronic liver disease (CLD) such as ascites, hepatic encephalopathy (HE), portosystemic shunts (PSSs), and all causes of mortality in CLD. METHODS: Serum copeptin was measured in 170 CLD patients upon hospital admission. The association of copeptin levels with liver enzymes, liver functional reserve, and clinical parameters was investigated. Cox proportional hazard regression, logistic regression, and Kaplan-Meier analyses were performed to evaluate the associations of copeptin and ascites, HE and PSS formation, and prognostic factors with short-term (1 year) and long-term (4 years) mortality. RESULTS: Serum copeptin levels were significantly correlated with liver and renal function, elevated in parallel with liver disease progression, and also associated with HE. Serum copeptin, albumin-bilirubin score and hepatocellular carcinoma were independent predictors of PSS formation and decreased rate of survival. Serum copeptin and albumin-bilirubin scores were independent predictors of ascites retention. The short-term and long-term cumulative mortality rate was significantly decreased in patients with serum copeptin >5.5 or >4.8 pmol/mL compared with patients in whom serum copeptin levels were <5.5 or <4.8 pmol/mL (P < 0.0001; P < 0.0001). CONCLUSIONS: Serum copeptin level is a predictor for ascites retention and HE and PSS formation associated with portal hypertension. Moreover, serum copeptin level may be useful in predicting the rate of survival in patients with CLD.

Serum copper, zinc and metallothionein serve as potential biomarkers for hepatocellular carcinoma.

BACKGROUND: Copper (Cu) and zinc (Zn) are essential nutrients and cofactors of enzymatic reactions with their binding partner. Metallothionein (MT) plays an important role in protecting against heavy metals and oxidative injury, however it may also portend drug resistance and a worse prognosis for hepatocellular carcinoma (HCC) patients. The aim of this study was to determine the amount of Cu, Zn, Cu/Zn and MT in evaluating a group of patients with HCC, including those treated with lenvatinib. METHODS: We enrolled 175 patients with HCC (139 men, 36 women; mean age 71.1 years; hepatitis C virus n = 85, hepatitis B virus n = 19, hepatitis C virus and hepatitis B virus n = 2, non-alcoholic steatohepatitis n = 39, alcohol n = 25, others n = 5; Child-Pugh A n = 141, Child-Pugh B n = 30, Child-Pugh C n = 4; Barcelona clinic liver cancer (BCLC) stage 0 n = 38, stage A n = 56, stage B n = 39, stage C n = 38, stage D n = 4). We evaluated the associations between Cu, Zn and MT. The study outcome was liver cancer-specific survival. Moreover, we treated 12 HCC patients with lenvatinib and investigated the changes in MT during lenvatinib therapy. RESULTS: The serum level of Cu was positively correlated with alanine aminotransferase and the BCLC stage. The serum level of Zn decreased concordant with liver disease progression. Patients with a Cu/Zn ratio≥0.999 had significantly improved rates of survival when compared to patients with a Cu/Zn ratio<0.999 (45.3 vs. 30.1 months, p<0.001). MT was significantly correlated with the Cu/Zn ratio and increased after the administration of lenvatinib. Using multivariate Cox regression analyses, it was determined that the Cu/Zn ratio (hazard ratio [HR]: 1.442, p = 0.008), alpha-fetoprotein (HR: 1.000, p<0.001) and BCLC stage (HR: 2.087, p<0.001) were independent predictors of survival. CONCLUSIONS: The Cu/Zn ratio could serve as a useful predictive marker for survival in cases of HCC. MT levels increased in HCC patients receiving lenvatinib therapy, and maybe a predictor of reduced survival.