Predictive formula of coma onset and prothrombin time to distinguish patients who recover from acute liver injury.

BACKGROUND AND AIM: Acute liver failure (ALF) is defined as acute liver injury (ALI) associated with coagulopathy. A follow-up strategy for ALI and characterization of ALI patients with a risk of progressing to ALF have never been established. To establish predictive markers for progression from ALI to ALF, this study compared the clinical characteristics and laboratory data on the day of registration to data from a regional referral system of patients with ALI. METHODS: This prospective, observational study enrolled 365 consecutive patients with ALI/ALF between 2007 and 2016. We evaluated 109 ALI patients, 27 of whom satisfied the ALF criteria during observation and another 82 patients who recovered without progression to ALF. RESULTS: Four patients died; all were in the ALF group. The variables of age, incidence of autoimmune hepatitis, model of end-stage liver disease score, values for total bilirubin and prothrombin time (PT)-international ratio, and Japan Hepatic Encephalopathy Prediction Model (JHEPM) probability at registration were significantly higher in ALF patients than in ALI patients. In multivariate analysis, PT and JHEPM were identified as risk factors for progression to ALF. The cut-off values of 13%, 4.9%, 65%, and 1.32% for the model of end-stage liver disease score, JHEPM probability, PT, and PT-international ratio values, respectively, had high negative predictive values. Furthermore, among patients whose JHEPM was underestimated, none died due to ALF. CONCLUSION: The JHEPM probability is a predictive parameter that can be used to decide a follow-up treatment strategy for ALI patients.

Appropriate timing to start and optimal response evaluation of high-dose corticosteroid therapy for patients with acute liver failure.

BACKGROUND: Corticosteroid therapy has been commonly administered to patients with acute liver injury (ALI)/acute liver failure (ALF) in Japan to prevent the development of hepatic encephalopathy, but the appropriate timing to start corticosteroid therapy has not been determined and optimal response evaluation of the therapy has not been conducted. We prospectively investigated the optimal timing to start therapy on the established severity indication: the Japan Hepatic Encephalopathy Prediction Model (JHEPM) and prothrombin time (PT). METHODS: This prospective observational study enrolled 469 patients with ALI/ALF from 2004 to 2015. We evaluated 44 patients with ALF on high-dose corticosteroid therapy before hepatic coma development. The predictive performance for coma development was assessed using the receiver operator curve method in both PT and JHEPM probability the day before administering high-dose corticosteroid therapy. RESULTS: Among these patients, nine developed hepatic coma after the therapy. Selection bias was adjusted using propensity score method. High-dose corticosteroid therapy tended to decrease the risk of coma development although there was no statistical significance. The cut-off value of 53%, 1.95, and 39% in JHEPM probability, PT-international normalized ratio (PT-INR), and PT activity, respectively, showed high sensitivity and specificity. CONCLUSIONS: We propose the appropriate timing to start high-dose corticosteroid therapy in patients with ALI/ALF; 40% of JHEPM probability, 1.53 of PT-INR, and 52% of PT because these values were theoretically discriminated at 98% coverage to the patients with coma. Because the study contained selection bias, the appropriate timing for therapy should be confirmed in a future prospective study.

Necrotic cell death and suppression of T-cell immunity characterized acute liver failure due to drug-induced liver injury.

BACKGROUND & AIMS: The aim of this study was to investigate the clinical characteristics and pathophysiology of drug-induced liver injury (DILI) - acute liver failure (ALF). METHODS: The patients with acute liver injury (ALI) including ALF from 2009 to 2014 were analyzed. The hepatic encephalopathy (HE) development rate was compared with the findings from a national survey in Japan. The serum cytokines levels and the findings of a liver function test were evaluated in the DILI patients. RESULTS: The HE development rate substantially decreased for autoimmune hepatitis (AIH) - and undetermined cause-induced ALI owing to the early prediction system, but not in DILI-ALI. Among the DILI-ALF and AIH-ALF cases, the CK-18 fragment (1480.1U/L, 3945.4U/L), IL-8 (82.9pg/mL, 207.5pg/mL), IP-10 (1379.6pg/mL, 3731.2pg/mL) and MIP-1ß (1017.7pg/mL, 2273.3pg/mL) levels were lower in the DILI-ALF cases. Among the DILI-ALI and DILI-ALF cases, IL-4 (19.8pg/mL, 25.4pg/mL) and RANTES (14028.0pg/mL, 17804.7pg/mL) were higher in DILI-ALI, and HMGB-1 (397.1pg/µL, 326.2pg/µL) and HGF (2.41ng/mL, 0.55ng/mL) were higher in DILI-ALF. We observed that HGF independently associated with DLI-ALF development. CONCLUSIONS: Despite the low grade apoptosis and inflammation, DILI patients progressed to ALF comparable with that of the AIH patients.

Reversible sclerosing cholangitis with ulcerative colitis.

Sclerosing cholangitis (SC) with granulocytic epithelial lesion (GEL) responds well to immunosuppression therapy. We treated a 42-year-old Japanese female with ulcerative colitis, who was admitted for further evaluation of both an elevated alkaline phosphatase level and dilated intrahepatic bile ducts. A liver biopsy on the fourth hospital day revealed the infiltration of neutrophils into the bile duct epithelium, which was diagnosed as GEL. Because her ulcerative colitis was in an active stage, prednisolone (PSL) therapy was started. After the administration of PSL, laboratory data dramatically decreased. A liver biopsy was performed on the 66th hospital day to confirm the lesion around bile ducts in the portal tract. The infiltration of neutrophils into the bile duct epithelium disappeared after PSL administration, and IgG4-positive plasma cells were not found in the liver. Herein, we report a rare case of GEL-positive SC. The present case provides early evidence of treatment-induced histological changes as well as serial changes in biochemical data during the course of immunosuppression therapy.

Hepatic Hemodynamics and Elevation of Liver Stiffness as Possible Predictive Markers of Late-onset Hepatic Failure.

A 52-year-old Japanese woman admitted to our hospital for the treatment of liver dysfunction due to an undetermined cause developed disorientation on the 58th hospital day and was diagnosed with late-onset liver failure. Abdominal ultrasound examinations were performed several times from the admission. Before the disorientation appeared, the results of the examinations revealed that the portal flow decreased, after which the hepatic arterial flow increased and the degree of liver stiffness became elevated. Although the pathophysiology of these changes remains unclear, hemodynamic changes and elevation of liver stiffness might be predictive markers of severe liver tissue damage.

Predictive formula for acute liver failure is useful for predicting the prognosis of patients with acute-on-chronic liver failure.

AIM: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Alpha-fetoprotein: A biomarker for the recruitment of progenitor cells in the liver in patients with acute liver injury or failure.

AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Clinical and molecular analyses of sporadic acute hepatitis A and E and the specific viral genotypes isolated in Iwate and three neighboring prefectures in the northern part of Honshu, Japan, between 2004 and 2013.

AIM: To examine the prevalence and characteristics of hepatitis A virus (HAV) and hepatitis E virus (HEV) infections in the northern part of Honshu, Japan, during the last decade. METHODS: Using the registration system of a prospective cohort study for acute liver injury (ALI) in Iwate and three neighboring prefectures, we examined the prevalence of sporadic acute hepatitis (AH) with HAV (AH-A) and HEV (AH-E) and the distribution of viral genotypes in 487 patients diagnosed with ALI between 2004 and 2013. RESULTS: Among all 487 patients, 135 (28%) had ALI with viral infection. In the cases with viral ALI, the prevalence of hepatitis B virus-related AH was highest (55.6%). AH-E was seen in 23 patients (17.0%) and its prevalence was higher than that of AH-A (10 patients, 7.4%). There were no appreciable differences in the prevalence of AH-A and AH-E between 2004-2008 and 2009-2013. However, subgenotype IIIA HAV homologous to Korean strains has recently emerged, and the number of AH-E cases seems to be increasing. HEV genotype 3 was predominant throughout the observation period, but HEV genotype 4 was found in three patients after 2010. The transmission routes of HAV and HEV infections were unknown in approximately 60% of the patients. CONCLUSION: In the northern part of Honshu, Japan, HEV has been more frequently implicated in the development of AH than HAV, and HEV genotype 4 has been recently increasing. To provide an effective prophylactic management for HAV and HEV infections, further clarification of the transmission routes is needed.

Prostaglandin E2 receptor EP4 agonist induces Bcl-xL and independently activates proliferation signals in mouse primary hepatocytes.

BACKGROUND: To improve the survival rate of fulminant hepatic failure (FHF), we examined the mechanism of the antiapoptotic effect, and the possible proliferative effect, of a specific agonist of prostaglandin E2 receptor EP4 (PGEP4-A) on mouse primary hepatocytes, as a candidate for a new therapeutic agent. METHODS: The expression of four PGE2 receptor subtypes was detected by a reverse transcriptase polymerase chain reaction (PCR) method. Hepatocytes were stimulated with PGEP4-A, ONO-AE1-437, and changes in the expression levels of Bcl-xL and cyclin D1 and in the phosphorylation of epidermal growth factor receptor (EGF-R) and extracellular-signal related kinase (ERK) were examined by Western blot analysis. RESULTS: Mouse primary hepatocytes constitutively expressed the mRNAs of all four PGE2 receptor subtypes, including that of PGEP4. PGEP4-A induced not only Bcl-xL protein expression (as we had previously demonstrated in HepG2 cells) but also induced cyclin D1 protein expression in mouse primary hepatocytes as well as the phosphorylation of EGF-R and ERK. The inhibition of ERK phosphorylation by a specific inhibitor, PD98059, did not affect the increase in Bcl-xL expression level. CONCLUSIONS: PGEP4-A may be a therapeutic agent for FHF because of its antiapoptotic and regenerative effects on hepatocytes.