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We prospectively screened patients treated with direct-acting antivirals (DAA) in order to detect and analyze serum markers that are present prior to the development of drug-induced liver injury (DILI).The levels of various serum markers among DILI, non-DILI and control groups were compared. The DILI group consisted of eight patients whose alanine aminotransferase (ALT) levels exceeded 32 IU/L during the DAA treatment. Eight patients without DILI were selected for the non-DILI group via a matched-group design based on age, sex and disease severity. Additionally, eight healthy volunteers were employed as the controls. Serum measurements of cytokines/chemokines, cytokeratin-18 fragment (CK-18F) and super oxidase dismutase-2 (SOD2) were evaluated on the date at which hepatitis C virus RNA was absent (baseline). For patients with DILI, serum measurements taken before treatment, 1 week before pronounced transaminase elevation (prominence-1 W) and on the date at which pronounced elevation of transaminase occurred (prominence) were also evaluated.All patients treated with DAA had normalized transaminase levels at baseline. In patients with DILI, interferon-inducible protein-10 (IP-10) levels were higher at prominence-1 W than at baseline. Those patients also had significantly higher levels of SOD2 and CK-18F at prominence-1 W than at baseline.Elevated IP-10 may be a preconditioning chemokine for DAA-induced liver injury, and damage markers associated with cell death and mitochondrial dysfunction are potential predictive serum markers for DILI.

The prognosis of acute-on-chronic liver failure (ACLF) is extremely poor in comparison to acute liver failure (ALF). We aimed to establish methods for the early diagnosis of ACLF and its severity to identify the patients with a poor prognosis.The laboratory data at admission of 30 ACLF and 46 ALF patients were compared. Three established prognosis prediction models (Model for End-Stage Liver Disease [MELD]; MELD modified by serum sodium concentration, [MELD-Na]; and the Japan hepatic encephalopathy prediction model [J-HEPM]) were assessed using area under the receiver-operator curve (AUROC) values.No significant difference was found in the laboratory data of the two patient groups. J-HEPM was able to predict the outcome of the ACLF subjects (AUROC = 0.93).Although ACLF could not be differentially diagnosed from ALF at admission from the laboratory data alone, the J-HEPM effectively predicted the prognosis of liver failure in patients with ACLF. These findings indicate that ACLF patients with high J-HEPM scores require earlier and more intensive care than ALF patients.

The optimal conditions for hepatocyte proliferation should be clarified in an attempt to improve the impaired liver regeneration observed in patients with acute liver failure (ALF). In order to evaluate the significance of the serum α-fetoprotein (AFP). level and prothrombin time international normalized ratio (PT-INR) as possible biomarkers of the proliferation of liver stem/progenitor cells (LPC) and mature hepatocytes (MH), respectively, we focused on donors of living donor liver transplantation (LDLT) and patients with acute liver injury (ALI), including ALF.Seventy-three patients with ALI/ALF and 11 donors for LDLT were evaluated. LPC induction was histologically evaluated using cytokeratin (CK)-7 staining in 45 ALI/ALF patients.The AFP level was not apparently elevated during the observation period in any of the LDLT donors, whereas the serum AFP levels were substantially increased in the patients with ALI/ALF and significantly correlated with the number of CK-7 positive LPC in the liver, except for very severe damaged liver. All patients exhibiting an early peak in the AFP level prior to PT-INR elevation died.The serum AFP level may reflect the induction of LPC in ALI/ALF patients. The substantial and persistent induction of LPC until sufficient regeneration of MH may be needed for a recovery from ALF. We herein demonstrate that the serum AFP level may be a serum marker of LPC in patients with ALI/ALF. A comparison of the serial changes in the AFP levels and PT-INR in our study patients showed impaired proliferation of LPC and delayed recovery of MH in the patients who died.

We measured liver stiffness (LS) in patients with acute liver failure (ALF) using acoustic radiation force impulse (ARFI) elastography and investigated the usefulness of measuring LS for predicting the prognosis of ALF patients.From April 2010 to December 2013, we evaluated 63 patients with acute liver disease. The subjects included 41 patients with acute hepatitis (AH), 16 patients with severe AH (SAH), who had no hepatic encephalopathy despite plasma prothrombin time of 40% or less, and six patients with fulminant hepatitis (FH) diagnosed according to the criteria of the Japanese Study Group. The relationships among shear wave velocity (SWV), clinical diagnosis, liver function tests and prognosis were evaluated. Receiver-operator curve (ROC) analysis was performed to investigate whether ARFI elastography exhibits potential usefulness for the prediction of FH.The mean SWV on admission were 1.98 ± 0.55, 2.61 ± 0.58 and 3.66 ± 0.86 m/s in the AH, SAH and FH groups, respectively. The SWV was significantly higher in the FH group than in the other groups (P 0.001), and in the SAH group than in the AH group (P = 0.002). The area under the ROC for predicting FH was 0.924 (sensitivity, 83.3%; specificity, 93.0%). The SWV was significantly increased in non-survivors, while remaining decreased in survivors (P = 0.002).The SWV measured by ARFI elastography reflects severity of liver damage, and serial changes in SWV predict the prognosis of ALF patients. The SWV is an early and precise biomarker of FH.

A 69-year-old male complained of general fatigue and presented with elevation of liver enzymes without any cause of liver injury. We diagnosed him with hepatocellular drug-induced liver injury (DILI). Liver stiffness, which was evaluated according to the shear wave velocity (SWV) using virtual touch tissue quantification, was serially observed during hospitalization. A fast SWV was noted on the date of admission, indicating a "hard" degree of liver stiffness. The SWV gradually decreased until the 20th hospital day. However, the patient's liver enzymes again became elevated on the 20th hospital day, and the SWV simultaneously increased in association with a rise in the total bilirubin level. The laboratory data for the second peak of the SWV indicated mixed-type DILI; therefore, the patient's pathological state transitioned from the hepatocellular type to the mixed type. A liver biopsy performed before discharge revealed a state of recovery from acute inflammation without fibrotic changes. We conclude that the second peak of the SWV may be affected by the presence of intrahepatic cholestasis. We herein report the occurrence of bimodal peaks of liver stiffness in a patient with DILI. In such cases, each peak of liver stiffness may be the result of a different pathological mechanism, namely acute inflammation versus acute intrahepatic cholestasis. Although the detailed mechanisms underlying the development of liver stiffness due to intrahepatic cholestasis remain unclear, this case presented a limitation of virtual touch tissue quantification for evaluation of liver stiffness as fibrosis marker in the liver with intrahepatic cholestasis.

To evaluate changes in liver function parameters and risk factors 1 year after percutaneous radiofrequency ablation (RFA) therapy in patients with hepatocellular carcinoma (HCC).Subjects in this retrospective study comprised 45 patients with HCC who underwent RFA therapy (RFA alone, n = 25; transcatheter arterial embolization therapy before RFA, n = 20) and showed no recurrence of HCC 1 year after RFA. Serial changes in serum total bilirubin, albumin, prothrombin time and Child-Pugh score (CPs) were evaluated before and after RFA. In addition, Cox proportional hazards regression analysis was used to clarify risk factors for aggravation of liver function after RFA therapy.Serum albumin levels showed a significant decrease from before (3.6 +/- 0.4 g/dL) to 12 months after RFA therapy (3.2 +/- 0.4 g/dL; P/= 0.05). CPs was significantly increased from before (6.4 +/- 1.4) to both 6 months (6.8 +/- 1.9; P/= 0.05) and 12 months after RFA (6.9 +/- 2.0; P/= 0.05). Based on stepwise multivariate analysis, CPs of 9 or more before RFA was selected as a significant risk factor for long-term aggravation of liver function after RFA.Liver function parameters, particularly serum albumin level, gradually and dominantly decreased in HCC patients with grade B and C according to the CPs classification over the course of 1 year after RFA therapy. A CPs of 9 or more represents a major risk factor for the aggravation of liver function after RFA therapy.

AIM Prognosis is extremely poor for advanced hepatocellular carcinoma (HCC) in patients with portal invasion. The present study evaluated the efficacy of combined intra-arterial 5-fluorouracil (5-FU) and systemic pegylated interferon (PEG-IFN)alpha-2b in patients with advanced HCC. METHODS The subjects comprised nine HCC patients with portal vein thrombosis treated using subcutaneous administration of PEG-IFNalpha-2b (50-100 microg on day 1 of every week, for 4 weeks) and intra-arterial infusion of 5-FU (250 mg/day for 5 h on days 1-5 of every week, for 4 weeks). For four patients with hepatitis C virus (HCV) infection, oral administration of ribavirin (400-800 mg/day) was added. At the end of every cycle, response to therapy was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. RESULTS Partial response (PR) was observed in seven of nine patients, with stable or progressive disease in the remaining two patients. Tumors were resectable in three patients displaying PR after treatment. Tumor markers decreased significantly after therapy. Serum HCV-RNA titers were markedly decreased and became undetectable in all patients with HCV infection. National Cancer Institute-Common Toxicity Criteria: version 3.0 (NCI-CTC) grade 3 thrombocytopenia was seen in one case at the end of treatment, but was resolved with cessation of treatment. Other adverse effects were manageable. CONCLUSION Combination therapy with intra-arterial 5-FU and systemic PEG-IFNalpha-2b may be useful as a palliative treatment for patients with advanced HCC. A prospective controlled trial using a larger population of patients with advanced HCC is needed to evaluate this new combination therapy.