Clinical outcomes of antithrombin III-based therapy for patients with portal vein thrombosis: A retrospective, multicenter study.

AIM: The association between thrombolytic therapy and the outcome in patients with portal vein thrombosis (PVT) remains controversial. This study aimed to evaluate the outcome in patients with PVT who received antithrombin III-based therapy. METHODS: This study was a retrospective, multicenter study to investigate the liver-related events and the survival rates in 240 patients with PVT who received the therapy. RESULTS: The patients comprised 151 men and 89 women, with a median age of 69 years. The rate of favorable response, defined as maximum area of PVT changed to ≤75%, was 67.5% (162/240). The cumulative rates of liver-related events at 1, 2, and 3 years were 38.2%, 53.9%, and 68.5%, respectively. The multivariate analysis showed that viable hepatocellular carcinoma, absence of maintenance therapy, non-responder, and PVT progression were significantly associated with liver-related events. The PVT progression was observed in 23.3% (56/240). The multivariate analysis identified older age, absence of maintenance therapy, and non-responder as independent factors associated with PVT progression. The multivariate analysis revealed that younger age, no hepatocellular carcinoma, presence of maintenance therapy, and lower Model for End-stage Liver Disease-Sodium score significantly contributed to 3-year survival. Of the 240 patients, 13 (8.9%) prematurely discontinued treatment due to any adverse events. CONCLUSIONS: This study suggests that maintenance therapy, favorable response, and absence of PVT progression may suppress or control liver-related events in antithrombin III-based therapy for patients with PVT. Specifically, maintenance therapy could suppress not only liver-related events, but also PVT progression and improve the prognosis.

The Risk of Cirrhosis and Its Complications Based on PNPLA3 rs738409 G Allele Frequency.

BACKGROUND: Data regarding the influence of patatin-like phospholipase domain-containing 3 (PNPLA3) polymorphism for patients with liver cirrhosis (LC) are scarce. OBJECTIVE: This study assesses the role of the PNPLA3 polymorphism for the development of LC and its complications by the findings of genetic examinations. METHODS: Patients with LC caused by virus (n = 157), alcohol (n = 104), nonalcoholic fatty liver disease (NAFLD) (n = 106), or autoimmune disease (n = 33) and without LC (n = 128) were enrolled. LC was composed of the presence and absence of complications, such as variceal bleeding, hepatic ascites, and hepatic encephalopathy. To assess the role of the PNPLA3 polymorphism, odds ratio (OR) for the rs738409 variant was calculated for the patients between (i) with LC and without LC in the entire cohort and (ii) the presence and absence of complications in the patients with LC. RESULTS: There was a significant difference among the patients without LC and those with alcohol, NAFLD-related LC in the frequency of G alleles (p < 0.001, both). According to complications of LC, the OR for NAFLD-related cirrhosis significantly increased in the presence of the two mutated alleles (OR = 3.165; p = 0.046) when the wild type was used as the reference. However, there were no significant risks for the complications in the virus and alcohol-related cirrhosis unless there was a presence of G alleles. CONCLUSION: The PNPLA3 polymorphism was associated with the risk of NAFLD-related LC and its complications.

Red dichromatic imaging reduces endoscopic treatment time of esophageal varices by increasing bleeding point visibility (with video).

BACKGROUND: Red dichromatic imaging (RDI) is a novel image-enhanced endoscopy released in 2020, which increases the visibility of deeper vessels. In this study, we retrospectively investigated whether RDI can shorten treatment times of endoscopic injection sclerotherapy (EIS), and which operational procedure times are affected compared with white light imaging (WLI). METHODS: A total of 155 patients (RDI, 70; WLI, 85) with risky esophageal varices (EV), who were treated with EIS were analyzed. Treatment times were compared, and predictors associated with treatment time were analyzed by multivariate analysis. For 24 cases (RDI, 12; WLI, 12) in which treatment videos were recorded, the procedure times of each step (observation of EV, needle flush, positioning, puncture, observation of bleeding, hemostasis, observation after hemostasis) were measured. Regarding the seven patients with EV bleeding, color differences were calculated between the bleeding point and the blood pool using the CIE (L*a*b*) color measurement method, and results were compared between using RDI and WLI. RESULTS: Treatment times were shorter in the RDI group (RDI vs. WLI = 35.1 vs. 42.2 min; P < 0.01). 'RDI function' and 'amount of sclerosant' were extracted as independent predictors of treatment time. Times for 'observation of EV' and 'observation of bleeding' were shorter in the RDI group (P = 0.01 and <0.01, respectively). Regarding the color difference, RDI significantly increased bleeding point visibility (RDI vs. WLI = 31.4 ± 11.8 vs. 8.6 ± 6.2, P < 0.001). CONCLUSION: Red dichromatic imaging can shorten the treatment time of EIS by increasing bleeding point visibility.

Prognostic and recurrence factors after endoscopic injection sclerotherapy for esophageal varices: Multivariate analysis with the propensity score matching: Multivariate analysis with propensity score matching.

BACKGROUND: Peri-esophageal collateral veins have been reported to be associated with the recurrence of esophageal varices (EVs). In this study, we retrospectively analyzed whether endoscopic ultrasonography (EUS) findings obtained just before endoscopic injection sclerotherapy (EIS) are associated with the success rate of intravariceal injection, recurrence rate of EVs, and overall survival rate (OS) of patients. Furthermore, we investigated the independent predictors associated with these factors by multivariate analysis. METHODS: A total of 91 patients with risky EVs treated by EIS were analyzed. The primary endpoint was to identify independent predictors associated with the success rate of intravariceal injection, recurrence rate, and OS by multivariate analysis, to confirm the usefulness of EUS examination. The secondary endpoint was to clarify differences in recurrence rate and OS between patients who underwent additional argon plasma coagulation (APC) and those who did not, by the propensity score matching method. RESULTS: Luminal diameter of EVs and F factor were predictors of the success rate of intravariceal injection. APC was predictor of OS and recurrence of EVs. EUS findings were not associated with these factors. Propensity score matching (APC, 23; without APC, 23) showed that recurrence rate was significantly improved in the APC group (P = 0.050) and that OS had the tendency to be higher in the APC group (P = 0.068). CONCLUSION: Endoscopic ultrasonography findings before EIS were associated with successful intravariceal injection but were not associated with recurrence rate or OS. Additional APC could improve OS and reduce the recurrence of EVs.

[A case of endoscopic injection sclerotherapy for duodenal varices].

A 67-year-old man with a history of esophageal and gastric varices that were treated endoscopically was treated for Budd-Chiari syndrome and immunoglobulin G4-related sclerosing cholangitis in our facility. Varices in the second portion of the duodenum were revealed in follow-up upper endoscopy. The draining vein formed a venous plexus that was detected on computed tomography. Treatment with interventional radiology was difficult;therefore, endoscopic injection sclerotherapy (EIS) was performed instead. No recurrence has been observed to date. Thus, in this case, EIS for duodenal varices was effective.

Thrombopoietin receptor agonist is more effective than platelet transfusion for chronic liver disease with thrombocytopenia, shown by propensity score matching.

AIM: The thrombopoietin receptor agonist, lusutrombopag, was recently adapted for treatment of thrombocytopenia in chronic liver disease. However, no studies have compared the effects of lusutorombopag and platelet transfusion. Therefore, we aimed to clarify the efficacy and proportion of responders of lusutrombopag compared with platelet transfusion, by propensity score matching. METHODS: A total of 200 patients (90 lusutrombopag, 110 platelet transfusion) with thrombocytopenia were enrolled, and matched for age, liver function, renal function, platelet count, peripheral blood count, and spleen size, using the propensity score-matching method. Finally, 52 patients (26 lusutrombopag, 26 platelet transfusion) were included. The primary end-point was an increase in platelet count. Secondary end-points were the proportion of responders, duration of the sustained effect, incidence of adverse events, and predictors associated with an increase in platelet count. RESULTS: The median increase in platelets from baseline was 48 × 103 /µL versus 9.5 × 103 /µL (lusutrombopag vs. transfusion, P < 0.0001). The proportion of responders (increase of >10 × 103 /µL) was 100% versus 50.0% (P < 0.0001). Median duration of the sustained effect (increase of >50 × 103 /µL) was 10 versus 2 days (P < 0.0001). The incidence of adverse events was 7.7% versus 50.0% (P = 0.036). Predictors associated with an increase in platelets were hemoglobin and spleen size by multiple regression analysis. CONCLUSION: Lusutrombopag was more effective in chronic liver disease patients than platelet transfusion. The proportion of responders, effect duration, and non-incidence rate of adverse events were higher in the lusutrombopag group.

Japanese periodical nationwide epidemiologic survey of aberrant portal hemodynamics.

AIM: Idiopathic portal hypertension (IPH), extrahepatic portal obstruction (EHO), and Budd-Chiari syndrome (BCS) are characterized by aberrant portal hemodynamics of unknown etiology. The aim of this study was to explore trends in the descriptive epidemiology of these diseases through periodical nationwide surveys. METHODS: Nationwide epidemiologic surveys were undertaken in 1999, 2005, and 2015 using the same protocol. The survey targets were selected from all departments of gastrointestinal medicine, surgery, pediatrics, and pediatric surgery in Japan by stratified random sampling according to the number of beds. We asked each department to complete a mail-back questionnaire on the annual numbers of patients with IPH, EHO, and BCS during the preceding year. RESULTS: The estimated number of BCS patients increased from 280 (95% confidence interval, 200-360) in 1999 survey to 410 (300-530) in 2015 survey, whereas the number of IPH and EHO patients has remained largely unchanged during the 15 years (IPH was approximately 1000; EHO was approximately 770 in 2015 survey). The mean age at symptom onset was approximately 45 years for IPH, 30 years for EHO, and 40 years for BCS over the past 15 years. Those who described disease aggravation from the time of diagnosis accounted for approximately 10% of IPH, 15% of EHO, and 20% of BCS patients in each of the three surveys. CONCLUSIONS: In Japan, the prevalence of BCS is increasing, while those of IPH and EHO appear to be stable. Clinical characteristics, including prognoses, have remained largely unchanged in the past 15 years.

Role of dual red imaging to guide intravariceal sclerotherapy injection of esophageal varices (with videos).

BACKGROUND AND AIMS: Dual red imaging (DRI) is a novel image-enhanced endoscopy technique that can increase the visibility and predict the depth of esophageal varices (EVs). The recurrence rate of EVs after endoscopic injection sclerotherapy (EIS) reportedly decreases by intravariceal injection of a sclerosant. We evaluated prospectively whether the EIS success rate was increased by DRI compared with the white-light imaging (WLI) mode. METHODS: A total of 79 patients with EVs were randomly divided into the DRI (n = 40) and WLI (n = 39) groups. The primary endpoint was the success rate of intravariceal injection on the first EIS puncture. The secondary endpoint was the recurrence rate. A variable puncture needle was used, and the length was adjusted according to the EV visibility change by DRI. In the WLI group, DRI was not used. RESULTS: The success rate of the first puncture was significantly higher in the DRI group than in the WLI group (80.0% vs 46.2%; P = .0018). The cumulative recurrence rate was significantly lower in the DRI group (P = .031). The sum of the depth and luminal diameter of EVs was investigated by EUS. The Pearson correlation coefficient between this value and the needle length was higher in the DRI group than in the WLI group (r = 0.878 vs 0.603). CONCLUSIONS: DRI increased the EIS success rate and decreased the recurrence rate. This resulted from the puncture needle adjustment to the appropriate length via EV depth prediction by DRI.

Restoration of natural killer cell activity by interferon-free direct-acting antiviral combination therapy in chronic hepatitis C patients.

AIM: Interferon-free direct-acting antiviral (DAA) therapy is an effective treatment for chronic hepatitis C (CH(C)) patients. Activity of natural killer (NK) cells was reported to be impaired in patients with hepatitis C virus infection. The aim of this study was to examine whether DAA therapy could restore NK activity in patients with CH(C). METHODS: Direct-acting antiviral therapy was given to 31 CH(C) patients as asunaprevir/daclatasvir (ASV/DCV) (n = 15), ledipasvir/sofosbuvir (n = 7), ombitasvir/paritaprevir/ritonavir (n = 6), or elbasvir/grazoprevir (n = 3). Prior to therapy (0M), at the completion of the therapy (EOT), and at 24 weeks after completion (AFTER), NK activity and the frequency of CD56dim NK and CD56bright NK cells in peripheral blood were estimated by Cr release assay and flow cytometry. Statistical analysis was carried out by anova and the Mann-Whitney U-test. RESULTS: In one of the ASV/DCV-treated patients, treatment was stopped 12 weeks after initiation of therapy because of viral breakthrough. The anova showed that NK activity significantly improved at EOT (vs. 0M, P < 0.01) and at AFTER (vs. 0M, P < 0.001) in 30 patients with sustained virologic response. It also showed that the frequency of CD56dim NK cells was significantly increased at EOT and at AFTER (vs. 0M, P < 0.05). In addition, the NK activity ratio (AFTER/0M) had no significant difference between patient groups with higher and lower Fibrosis-4 scores. CONCLUSION: Direct-acting antiviral therapy in CH(C) patients could improve NK activity by increasing the frequency of CD56dim NK cells. Additionally, our results might imply that DAAs therapy could reduce the risk of hepatocarcinogenesis by restoring innate immune responses.

Branched-chain amino acid-enriched nutrient increases blood platelet count in patients after endoscopic injection sclerotherapy.

AIM: Protein and energy malnutrition is a severe problem for patients with liver cirrhosis (LC) and fasting often induces starvation which is a vitally important outcome. Dietary restriction is essential for endoscopic injection sclerotherapy (EIS) in patients with risky esophageal varices, thereby creating the possible exacerbation of nutritional state and inducing liver dysfunction. Whether EIS induces nutritional deficiency in LC patients and the effects of branched-chain amino acid (BCAA)-enriched nutrient are prospectively investigated. METHODS: A total of 61 LC patients were randomly divided into an EIS monotherapy group (non-BCAA group, n = 31) and an EIS combined with BCAA therapy group (n = 30). Platelet count, blood chemistry and somatometry values were prospectively measured at five time points. RESULTS: The platelet counts before treatment were at the same level in both groups (P = 0.72). Three months after treatment, the counts decreased in the non-BCAA group; however, they increased in the BCAA group (P = 0.019). Body mass index, triceps skin fold thickness and arm muscle circumference significantly decreased in both groups. The BCAA and tyrosine ratio value increased only in the BCAA group (P < 0.01). The skeletal muscle volume measured by InBody720 significantly decreased in the non-BCAA group (P < 0.001). CONCLUSION: EIS induced protein-energy malnutrition, however, skeletal muscle volume was maintained by taking BCAA. Administration of BCAA had some effect in maintaining the nutritional state, and may improve the platelet count. Taking a greater amount of nutrients and shorter dietary restriction period or hospitalization was desirable.

Focal nodular hyperplasia-like lesion of the liver with focal adenoma features associated with idiopathic portal hypertension.

Great progress has been made in the diagnosis of focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA) in the last few years due to the use of molecular criteria. This has allowed us to identify a new type of hepatic nodule. In this case report, we present a male patient with a hepatic nodule associated with idiopathic portal hypertension (IPH) pathologically exhibiting not only the morphological features of FNH, such as ductular reactions, dilated sinusoids, major vascular abnormalities and an immunohistochemical "map-like" pattern of glutamine synthetase (GS), but also the immunohistological features of focal HCA, such as strong expression of serum amyloid A and C-reactive protein and weak expression of GS. As the final diagnosis, the nodule was identified as an FNH-like lesion with focal inflammatory hepatocellular adenoma.

Outcomes and Recurrence Rate of Esophageal Varices after Endoscopic Treatment in Patients with Alcoholic Cirrhosis and Viral Cirrhosis.

BACKGROUND: The incidence of alcoholic liver cirrhosis (ALC) is increasing. However, few reports have focused on ALC-derived esophageal varices (EV). We retrospectively examined differences in overall survival (OS) and EV recurrence rate in patients after endoscopic injection sclerotherapy (EIS) for ALC and hepatic B/C virus liver cirrhosis (B/C-LC). METHODS: We analyzed data from 215 patients (B/C-LC, 147; ALC, 68) who underwent EIS. The primary endpoints were OS and EV recurrence in patients with unsuccessful abstinence ALC and those with uncontrolled B/C-LC, before and after propensity score matching (PSM) to unify the patients' background. The secondary endpoints were predictors associated with these factors, as determined by multivariate analysis. RESULTS: The observation period was 1,430 ± 1,363 days. In the analysis of all patients, OS was significantly higher in the ALC group than in the B/C-LC group (p = 0.039); however, there was no difference in EV recurrence rate (p = 0.502). Ascites and history of hepatocellular carcinoma (HCC) (p = 0.019 and p < 0.001, respectively) predicted OS, whereas age and EV size predicted recurrence (p = 0.011 and 0.024, respectively). In total, 96 patients without an HCC history were matched by PSM, and there was no significant difference in OS or EV recurrence rate (p = 0.508 and 0.246, respectively). CONCLUSION: When limited to patients without a history of HCC, OS and the EV recurrence rate were comparable in patients with ALC who continued to consume alcohol and those with B/C-LC without viral control.

Hepatocellular carcinoma treated with sorafenib: early detection of treatment response and major adverse events by contrast-enhanced US.

BACKGROUND & AIMS: Early prediction of tumour response and major adverse events (AEs), especially liver failure, in patients with hepatocellular carcinoma (HCC) is essential for maximizing the clinical benefits of sorafenib. To evaluate the usefulness of dynamic contrast-enhanced ultrasound (DCE-US) for the early prediction of tumour response and major AEs in HCC patients. METHODS: Thirty-seven HCC patients were started on a reduced dosage of sorafenib, subsequently increased to the standard dosage. Tumour response at 1 month was assessed by CT using the Response Evaluation Criteria in Solid Tumors (RECIST). Major AEs were defined as grade 3 or higher. DCE-US was performed before treatment (day 0) and on days 7, 14 and 28. Changes in perfusion parameters in the tumour and liver parenchyma between day 0 and later time points were compared between treatment responders and nonresponders based on RECIST and between patients who experienced major AEs and those who did not. Tumour results were also compared with progression-free survival (PFS) and overall survival (OS). RESULTS: Tumour perfusion parameters based on the area under the time-intensity curve (AUC) were statistically significant, with AUC during washin on day 14, the most relevant for tumour response (P = 0.0016) and AUC during washin on day 7, the most relevant for both PFS (P = 0.009) and OS (P = 0.037). A decrease in total AUC between days 0 and 7 in the liver parenchyma was strongly correlated with major AEs (P = 0.0002). CONCLUSION: DCE-US may be useful for the early prediction of tumour response and major AEs in patients with HCC.