Abstract

Aim

Lustrombopag has been approved for the treatment of thrombocytopenia in patients with chronic liver diseases who are scheduled to undergo an invasive procedure. Here, we report the final results of a post-marketing surveillance assessing the safety and effectiveness of lusutrombopag in Japan.

Methods

This multicenter, prospective, real-world surveillance collected data from case report forms between October 2016 and May 2021. The observation period was 2 months after the first day of lusutrombopag treatment. Safety and effectiveness (proportion of patients avoiding preoperative platelet transfusion and responders who achieved platelet count increase from baseline) were assessed.

Results

The safety analysis set included 1033 (100.0%), 130 (12.6%), and 14 (1.4%) patients who received one or more, two or more, and three or more treatment cycle(s), and 482 (48.9%), 457 (46.3%), and 43 (4.4%) patients who were Child–Pugh class A, B, and C, respectively. The most common serious adverse drug reactions were portal vein thrombosis, pancytopenia, and white blood cell count decrease, reported in 14 (1.36%), three (0.29%), and two (0.19%) patients, respectively. The incidence of adverse drug reactions was not higher in patients with Child–Pugh class C or those undergoing retreatment cycles compared with other Child–Pugh classes or the first treatment cycle, respectively. During the observation period of the first treatment cycle, 94.7% (889/939) of patients avoided preoperative platelet transfusion and 82.8% (741/895) of the patients met the responder criteria.

Conclusions

This surveillance study further supports the safety and effectiveness of lusutrombopag in a broad range of patients with chronic liver diseases undergoing planned invasive procedures.

Clinical Trial Registration

JapicCTI-163432.

Abstract

Aims

Infants with biliary atresia (BA) are treated with Kasai portoenterostomy (KPE) surgery, but many BA patients need subsequent salvage liver transplants. The aim of this study is to develop a comprehensive gene-clinical model based on two-dimensional shear wave elastography (2DSWE), liver gene expression, and other clinical parameters to predict response to KPE for BA patients.

Methods

Differentially expressed gene patterns between liver samples of BA (n = 102) and non-BA control (n = 14) were identified using RNA sequencing analysis. Biliary atresia patients were then randomly assigned to training and validation cohorts. Gene classifier based on the differentially expressed genes was built in the training cohort. Nomogram models with and without gene classifier were further constructed and validated for predicting native liver survival of BA patients. The utility of the nomograms was compared by C-index.

Results

Using the least absolute shrinkage and selection operator model, we generated a nine-gene prognostic classifier. The nomogram based on the nine-gene classifier, age, preoperative 2DSWE, and albumin had the better C-index compared to gene classifier alone in the training cohort (0.83 [0.76–0.90] vs. 0.69 [0.61–0.77], p = 0.003) and the validation cohort (0.74 [0.67–0.82] vs. 0.62 [0.55–0.70], p = 0.001). Using risk scores developed from the nomogram, the 12-month survival rates of BA patients with native liver were 35.7% (95% confidence interval [CI], 22.7–56.3) in the high-risk group and 80.8% (95% CI, 63.4–100.0) in the low-risk group in the validation cohort.

Conclusions

The comprehensive genetic-clinical nomogram based on preoperative 2DSWE, liver gene expression, and other clinical parameters can accurately predict response to KPE.

Genetic analysis based on the DBS system is a feasible strategy for getting a deeper understanding of HBV epidemiology, especially in countries with inadequate infrastructure. Based on the DBS system, we successfully clarified the associations of HLA-DPB1 alleles with chronic HBV infection in the Cambodian population for the first time.

Abstract

Aim

Reports of patients with hepatitis B have highlighted associations between polymorphisms in the human leukocyte antigen (HLA)-DPB1, CXCL13, and CXCR5 genes and disease pathology. Owing to its potential to contribute to the development of new diagnostic and therapeutic methods, we aimed to establish a reliable host genome analysis technique that can be used in countries with inadequate infrastructure.

Method

We compared multiple commercially available kits for dried blood spot (DBS)-based sample collection to develop a basic DBS-based host genome analysis technique. We then collected blood samples from Cambodian patients with hepatitis  B and performed single-nucleotide polymorphism genotyping and HLA allele typing by the DBS system.

Result

We were able to perform single-nucleotide polymorphism genotyping and HLA allele typing with host DNA samples obtained using a combination of a HemaSpot™ filter paper-based device and a SMITEST^® EX-R&D DNA extraction kit. The accuracy of genotyping using samples obtained by this method was not inferior to one using samples obtained by venipuncture. In the Cambodian population, significant associations of HLA-DPB1*04:01 with protection against chronic hepatitis B virus (HBV) infection, and HLA-DPB1*05:01 and HLA-DPB1*13:01 with susceptibility to chronic HBV infection were identified.

Conclusion

Based on the DBS system, we clarified the associations of HLA-DPB1 alleles with chronic HBV infection in the Cambodian population for the first time. Because the DBS is a low-cost, durable, transportable, and easy-to-handle modality, genetic analysis based on the DBS system is a feasible strategy for obtaining a deeper understanding of HBV epidemiology, especially in middle- or low-income countries.

Abstract

Aim

Radiofrequency ablation (RFA) is regarded as a first-line treatment for hepatocellular carcinoma (HCC) at an early stage. When treated with RFA, tumor biopsy may not be performed due to the risk of neoplastic seeding. We previously revealed that the risk of neoplastic seeding is significantly reduced by performing biopsies after RFA. In this study, we investigated the possibility of pathological evaluation and gene mutation analysis of post-RFA tumor specimens.

Methods

Radiofrequency ablation was undertaken on diethylnitrosamine-induced mouse liver tumor, and tumor samples with or without RFA were subjected to whole exome sequencing. Post-RFA human liver tumor specimens were used for detection of TERT promoter mutations and pathological assessment.

Results

The average somatic mutation rate, sites of mutation, and small indels and base transition patterns were comparable between the nontreated and post-RFA tumors. We identified 684 sites of nonsynonymous somatic substitutions in the nontreated tumor and 704 sites of nonsynonymous somatic substitutions in the post-RFA tumor, with approximately 85% in common. In the human post-RFA samples, the TERT promoter mutations were successfully detected in 40% of the cases. Pathological evaluation was possible with post-RFA specimens, and in one case, the diagnosis of adenocarcinoma was made.

Conclusion

Our findings suggest that post-RFA liver tumor biopsy is a useful and safe method for obtaining tumor samples that can be used for gene mutation analysis and for pathological assessment.

Patients with nonalcoholic fatty liver disease are reported to have greater COVID-19 severity than those without nonalcoholic fatty liver disease. The aspartate aminotransferase to platelet ratio index consists of two parameters, aspartate aminotransferase and platelet count, and is much simpler than other liver fibrosis scores. The aspartate aminotransferase to platelet ratio index was independently associated with COVID-19 severity and hospitalization duration for COVID-19 in patients with nonalcoholic fatty liver disease.

Abstract

Aim

Patients with nonalcoholic fatty liver disease (NAFLD) are reported to have greater coronavirus disease 2019 (COVID-19) severity compared with patients without NAFLD. Previous studies have reported that noninvasive liver fibrosis scores, including the Fibrosis-4 index, NAFLD fibrosis score, and aspartate aminotransferase to platelet ratio index (APRI), have utility in predicting COVID-19 mortality and disease severity in patients without NAFLD. However, the utility of liver fibrosis scores in predicting COVID-19 mortality and disease severity among patients with NAFLD infected with SARS-CoV-2 has yet to be evaluated.

Methods

This retrospective observational study comprised 126 patients with NAFLD and active SARS-CoV-2 infection. Patients were classified into low COVID-19 severity (mild or moderate I disease) and high COVID-19 severity (moderate II or severe disease) groups based on the therapeutic guideline implemented by the Ministry of Health, Labor, and Welfare of Japan.

Results

Of the 126 patients, only one had been diagnosed with NAFLD before admission. Age; levels of serum aspartate aminotransferase, γ-glutamyl transpeptidase, lactate dehydrogenase, blood urea nitrogen, and serum C-reactive protein; Fibrosis-4 index; NAFLD fibrosis score; and APRI levels on admission were higher in the high COVID-19 severity group compared with the low COVID-19 severity group. Serum albumin levels, platelet counts, and lymphocyte counts on admission were lower in the high COVID-19 severity group compared with the low COVID-19 severity group. Univariate and multivariate analysis revealed that APRI values were significantly associated with COVID-19 severity and hospitalization duration for COVID-19.

Conclusions

APRI was independently associated with COVID-19 severity and hospitalization duration for COVID-19 in patients with NAFLD.

PVT was diminished under anticoagulation, along with improved liver function and reduced risks for cirrhosis-related complications. The incidence of bleeding events was not increased by the treatment. As a consequence, mortality was reduced in PVT patients by anticoagulation therapy.

Abstract

Aim

Portal vein thrombosis (PVT) is one of the common complications of liver cirrhosis. Although anticoagulation contributes to thrombus resolution and is considered the first-choice treatment, its impact on patients' prognosis is still controversial. This study aimed to clarify the benefit of anticoagulation on mortality, liver function, and the incidence of liver cirrhosis-related complications in cirrhotic PVT patients.

Methods

We conducted a multicenter retrospective review in which we included 78 eligible patients with PVT out of 439. After propensity score matching, 21 cirrhotic PVT patients were included in each one of the untreated control and anticoagulation groups.

Results

Overall survival was significantly improved in the anticoagulation group compared with the control group (p = 0.041), along with PVT size reduction (53.3% vs. 108.2%, p = 0.009). At the time of CT follow-up, the anticoagulation group showed a lower ALBI score (p = 0.037) and its prevalence of massive ascites was significantly lower (p = 0.043) compared with the control group. The incidence of overt encephalopathy was also lower in the anticoagulation group (p = 0.041). The cumulative incidence of bleeding events did not differ significantly between the two groups.

Conclusions

Anticoagulation improves the survival of patients with cirrhotic PVT. Preserved liver function and reduced risks of cirrhosis-related complications under the treatment may have contributed to a better prognosis. Given its efficacy and safety, anticoagulation is worth initiating in patients with PVT.

Our study confirmed that the correlation between the wedged hepatic venous pressure (WHVP) and portal venous pressure groups and between the hepatic venous pressure gradient (HVPG) and portal pressure gradient groups was better in both triphasic shunting and portal vein visualization by innovative angiography, with the best agreement in the portal vein visualization group. Hepatic vein collateral branches were an important factor in underestimating WHVP and HVPG; the earlier the appearance of collateral branches, the more pronounced the underestimation. The absence of hepatic vein collateral veins is a crucial factor in the overestimation of the WHVP and HVPG.

Abstract

Aim

To assess the correlation and agreement between hepatic venous pressure gradient (HVPG) and portal pressure gradient (PPG) in patients with autoimmune liver diseases (ALD) and portal hypertension, and to investigate the extent to which hepatic vein collateralization affects the accuracy of this assessment.

Methods

Ninety-eight patients with ALD between 2017 and 2021 who underwent transjugular intrahepatic portosystemic shunt with conventional and innovative 15 mL pressurized contrast were selected to measure wedged hepatic venous pressure (WHVP) and portal venous pressure and to calculate the HVPG and PPG. Pearson's correlation was used for correlation analysis between the two groups. Bland–Altman plots were plotted to estimate the agreement between paired pressures.

Results

The r values of PPG and HVPG in the early, middle, late, and portal venous visualization were 0.404, 0.789, 0.807, and 0.830, respectively, and the R ² values were 0.163, 0.622, 0.651, and 0.690, respectively. The p value for the r and R ² values in the early group was 0.015, and the p values in the remaining groups were less than 0.001. Bland–Altman plots showed that patients in the portal venous visualization group had the narrowest 95% limits of agreement. The mean value of the difference was close to the zero-scale line.

Conclusions

In patients with ALD, the correlation between the HVPG and PPG was good, and the later the collateral development, the better the correlation. Hepatic vein collateral was an essential factor in underestimating WHVP and HVPG, and the earlier the collateral appeared, the more obvious the underestimation.

Among the 405 patients who received pulse steroid therapy, five patients (1.2%) developed drug-induced autoimmune-like hepatitis (DI-ALH). Prednisolone was effective for DI-ALH due to pulse steroid therapy and could be safely withdrawn once remission was achieved.

Abstract

Aim

Pulse steroid therapy occasionally causes drug-induced autoimmune-like hepatitis (DI-ALH), but the long-term outcome of treated patients is not well known. In this study, we investigated the long-term outcomes of DI-ALH due to pulse steroid therapy.

Methods

We retrospectively reviewed the medical records of 405 patients treated with pulse high-dose methylprednisolone in Kurashiki Central Hospital. The frequency and clinicopathological characteristics of acute liver injury that occurred within 3 months after the therapy were analyzed. The diagnosis of DI-ALH was made according to the revised international autoimmune hepatitis group criteria.

Results

Among the 405 patients treated with methylprednisolone, 61 (15.1%) had acute liver injury after the pulse steroid therapy, and DI-ALH was diagnosed in five patients (1.2%). Absence of oral prednisolone tapering after the pulse steroid therapy was a significant risk factor for the subsequent development of DI-ALH (odds ratio 11.9; p = 0.017). One patient was treated with 3 days of intravenous methylprednisolone followed by oral prednisolone. Two patients were treated with glycyrrhizin followed by oral prednisolone due to ineffectiveness of glycyrrhizin. Remission was achieved with glycyrrhizin alone, and spontaneous remission without drug therapy occurred in one patient each. During the median follow-up period of 34 months, no relapse was evident in all the patients without maintenance therapy.

Conclusions

Pulse steroid therapy can cause DI-ALH, especially when subsequent prednisolone is not tapered. Prednisolone is effective for DI-ALH due to pulse steroid therapy, and can be safely withdrawn once remission is achieved.