Serum autotaxin is a prognostic indicator of liver-related events in patients with non-alcoholic fatty liver disease.

BACKGROUND: Circulating autotaxin (ATX) levels have been reported to correlate with liver inflammation activity and liver fibrosis severity in patients with non-alcoholic fatty liver disease (NAFLD). The objective of this study is to investigate whether serum ATX could predict liver-related events (LRE) in NAFLD patients. METHODS: This retrospective investigation includes 309 biopsy-proven NAFLD patients registered at Shinshu University Hospital. All patients are followed for at least 1 year, during which time the prevalence of LRE, including newly developing hepatocellular carcinoma, hepatic encephalopathy, ascites, and esophagogastric varices, is investigated in relation to ATX levels at the time of liver biopsy. RESULTS: During the median follow-up period of 7.0 years, LRE are observed in 20 patients (6.5%). The area under the receiver operating characteristic curve and cut-off value of serum ATX for predicting LRE are 0.81 and 1.227 mg/l, respectively. Multivariate Cox proportional hazards models for LRE determine ATX and advanced fibrosis as independently associated factors. Furthermore, in a competing risk analysis that considered non-liver-related death as a competing event, ATX (HR 2.29, 95% CI 1.22-4.30, p = 0.010) is identified as an independent factor associated with LRE, along with advanced fibrosis (HR 8.01, 95% CI 2.10-30.60, p = 0.002). The predictive utility of ATX for LRE is validated in an independent cohort. CONCLUSIONS: Serum ATX may serve as a predictive marker for LRE in patients with NAFLD.

In non-alcoholic fatty liver disease (NAFLD), fat accumulates and can cause damage within the liver. The disease is becoming increasingly common worldwide. It is therefore important to identify individuals with NAFLD who are at higher risk of developing severe liver complications. In this study, we found that NAFLD patients with elevated levels of a substance called autotaxin (ATX) in their blood were more prone to liver-related issues. Thus, it is crucial for doctors to give special attention to NAFLD patients exhibiting high ATX levels. Through close ATX monitoring and appropriate treatment, doctors can potentially enhance their health outcomes and prevent the onset of more severe liver complications.

Serum aryl hydrocarbon receptor activity is associated with survival in patients with alcohol-associated hepatitis.

BACKGROUND AND AIMS: Patients with alcohol-associated hepatitis (AH) have an altered fecal metabolome, including reduced microbiota-derived tryptophan metabolites, which function as ligands for aryl hydrocarbon receptor (AhR). The aim of this study was to assess serum AhR ligand activity in patients with AH. APPROACH AND RESULTS: The study included 74 controls without AUD, 97 patients with AUD, and 330 patients with AH from 2 different multicenter cohorts (InTeam: 134, AlcHepNet: 196). Serum AhR activity was evaluated using an AhR reporter assay with HepG2-Lucia cells incubated with serum for 24 hours. Serum AhR activity was significantly higher in patients with AH compared with both controls (1.59 vs. 0.96-fold change, p < 0.001) and patients with AUD (1.59 vs. 0.93, p < 0.001). In both AH cohorts, patients with AhR activity ≥ 2.09 had significantly lower cumulative survival rates at 30, 60, 90, and 180 days compared to those with AhR activity < 2.09. When serum AhR activity was used to further stratify patients with severe AH, the cumulative 30, 60, 90, and 180-day survival rates for patients with severe AH and the AhR activity ≥ 2.09 group were all significantly lower than those with an AhR activity < 2.09 group. CONCLUSIONS: Serum AhR activity was significantly higher in patients with AH compared with controls and individuals with AUD, and this increased activity was associated with higher mortality. Consequently, serum AhR activity holds potential as a prognostic marker.

Thrombospondin 2 is a key determinant of fibrogenesis in non-alcoholic fatty liver disease.

OBJECTIVE: Hepatic overexpression of the thrombospondin 2 gene (THBS2) and elevated levels of circulating thrombospondin 2 (TSP2) have been observed in patients with chronic liver disease. This study aimed to identify the specific cells expressing THBS2/TSP2 in non-alcoholic fatty liver disease (NAFLD) and investigate the underlying mechanism behind THBS2/TSP2 upregulation. DESIGN: Comprehensive NAFLD liver gene datasets, including single-cell RNA sequencing (scRNA-seq), in-house NAFLD liver tissue, and LX-2 cells derived from human hepatic stellate cells (HSCs), were analysed using a combination of computational biology, genetic, immunological, and pharmacological approaches. RESULTS: Analysis of the genetic dataset revealed the presence of 1433 variable genes in patients with advanced fibrosis NAFLD, with THBS2 ranked among the top 2 genes. Quantitative polymerase chain reaction (qPCR) examination of NAFLD livers showed a significant correlation between THBS2 expression and fibrosis stage (r = .349, p < .001). In support of this, scRNA-seq data and in situ hybridization demonstrated that the THBS2 gene was highly expressed in HSCs of NAFLD patients with advanced fibrosis. Pathway analysis of the gene dataset revealed THBS2 expression to be associated with the transforming growth factor beta (TGFß) pathway and collagen gene activation. Moreover, the activation of LX-2 cells with TGFß increased THBS2/TSP2 and collagen expression independently of the TGFß-SMAD2/3 pathway. THBS2 gene knockdown significantly decreased collagen expression in LX-2 cells. CONCLUSIONS: THBS2/TSP2 is highly expressed in HSCs and plays a role in regulating fibrogenesis in NAFLD patients. THBS2/TSP2 may therefore represent a potential target for anti-fibrotic therapy in NAFLD.

Symptom-based portopulmonary hypertension screening questionnaire in Japanese patients with chronic liver disease.

Background and Aim: As the exact prevalence of portopulmonary hypertension (PoPH) and the etiology of chronic liver disease (CLD) remain unknown, the present study aimed to clarify these points in Japanese patients with CLD using symptom-based questionnaire screening. Methods: Patients with CLD were asked to complete an eight-item written questionnaire on pulmonary hypertension (PH) symptoms. If at least one item response was "yes," the patient was offered ultrasonic echocardiography (UCG). Patients identified as having an intermediate or high risk of PH by UCG were referred to a cardiologist for further evaluation, whereby a definitive diagnosis of PoPH was made using right heart catheterization (RHC) findings. Results: A total of 1111 patients with CLD completed the survey. Of the 566 symptomatic patients with at least one question answered as "yes," approximately half agreed to undergo UCG (n = 267). Compared with asymptomatic patients, symptomatic patients were significantly older, predominantly female, and more frequently exhibited cirrhosis. Based on UCG findings, 228, 12, and 8 patients had a low, intermediate, or high risk for PH, respectively. Intermediate-/high-risk patients showed significantly more advanced disease progression status than low-risk patients. The frequencies of answer to the eight questions were comparable. Ultimately, three patients were diagnosed as having PoPH (1.1% of UCG cases), one with underlying hepatitis C virus (HCV) infection and two with primary biliary cholangitis (PBC). Conclusion: This symptom-based PoPH screening study clarified the prevalence of PoPH in CLD patients according to a PH symptom questionnaire, UCG, and RHC. Patients with HCV and PBC may have a higher risk of PoPH.

HLA-G susceptibility to hepatitis B infection and related hepatocellular carcinoma in the Japanese population.

AIMS: Human leukocyte antigen (HLA)-G plays a role in various physiological immunomodulatory functions. Aberrant HLA-G expression is observed in various disease states, including tumors, autoimmune disorders, and viral infections. The present study investigated the association between HLA-G functional gene polymorphisms (rs1736933 [-486 C > A], rs1049033 [+2018 C > T], 14 bp Insertion [Ins]/Deletion [Del] [+2961 Del > Ins], and rs1063320 [+3142 C > G]) and disease susceptibility, hepatocellular carcinoma (HCC) development, and hepatitis B surface antigen (HBsAg) clearance. METHODS: Allele discrimination of the 3 SNPs (-486 C > A, +2018 C > T, +3142 C > G) was determined by a TaqMan 5' exonuclease assay, while the 14 bp Ins/Del polymorphism was typed by fragment analysis using Genetic Analyzer and GeneMapper software. The above polymorphisms were analyzed for 325 Japanese hepatitis B virus (HBV) patients, 355 Japanese healthy subjects (Controls) as healthy controls, and 799 Japanese hepatitis C virus (HCV) patients as disease controls, respectively. RESULTS: The 14 bp Insertion allele was significantly more frequent in HBV patients than Controls (27.1 % vs 20.6 %, odds ratio [OR] 1.43, P = 0.005) but did not differ between HCV patients and Controls. Similar results were found for the rs1063320 G allele (38.9 % vs 26.3 %, OR 1.78, P < 0.001) and the rs1736933 T allele (32.2 % vs 26.9 %, OR 1.29, P = 0.034) between HBV and Controls. The rs1049033 T allele showed a weak but significant association with HCC development in the dominant model (OR 1.95, P = 0.04). Regarding HBsAg clearance, the A allele at rs1736933 was significantly correlated in the recessive model (OR 3.23, P = 0.003). CONCLUSIONS: This study revealed significant associations of HLA-G gene polymorphisms with disease susceptibility, HCC development, and HBsAg clearance in HBV patients.

Acute alcohol-associated hepatitis: Latest findings in non-invasive biomarkers and treatment.

Acute alcohol-associated hepatitis (AH) is a syndrome that occurs in heavy and long-term drinkers and results in severe jaundice and liver failure. The mortality rate in severe cases is 20%-50% at 28 days, and in cases that do not improve despite appropriately timed corticosteroid therapy, the mortality rate reaches 70% at 6 months. The only curative treatment is early liver transplantation, but less than 2% of patients with severe AH are eligible. In order to improve the prognosis, diagnostic tools are needed to detect appropriate cases at risk of severe conditions, and new therapies need to be developed that can replace corticosteroids. Recent research has revealed that the pathogenesis of AH involves a complex of factors, including changes in the gut microbiota, inflammatory and cytokine signalling, oxidative stress and mitochondrial dysfunction, and abnormalities in the hepatic regenerative capacity. Non-invasive diagnostic tools focusing on these specific pathologies have been reported in recent years. In addition, several novel agents targeting specific pathways are currently being developed and tested in clinical trials. This review will provide an overview of alcohol-associated hepatitis and focus on the latest diagnostic tools, particularly non-invasive biomarkers, and novel therapies.

A Diagnostic Impact of Serum Autotaxin Levels in Patients with Bone Marrow Fibrosis.

BACKGROUND: Bone marrow (BM) fibrosis is a condition characterized by deposition of reticulin and collagen fibers in BM. It may confer a poor prognosis in some of hematological malignancies. However, the relationship between fibrosis and the disease pathology is not fully understood and no biomarkers for BM fibrosis are available in clinical practice. Autotaxin (ATX) is a secreted enzyme that is associated with various pathophysiological responses, including fibrosis. We conducted a pilot study to investigate the serum ATX levels in various hematological disorders in patients with or without BM fibrosis. PATIENTS AND METHODS: The serum levels of ATX in a total of 198 patients with hematological disorders and 160 healthy subjects were analyzed. Because of sexual difference in ATX level, the ATX ratio-determined by dividing the ATX level by the mean value of ATX of control subjects of the same sex-was calculated for further comparative analysis. A trephine biopsy samples from 53 patients were also evaluated to determine the Reticulin Fibrosis Index and Collagen Fibrosis Index of each sample. RESULTS: In comparison to the control group, the ATX ratio was significantly higher in patients, especially those with malignant lymphoma. The ATX ratio in lymphoma patients with BM fibrosis was significantly higher than that in patients without BM fibrosis. The Collagen Fibrosis Index showed statistically significant negative correlation with the ATX ratio. CONCLUSION: Our results suggest that the ATX ratio may be a candidate diagnostic biomarker for BM fibrosis in selected patients, including those with malignant lymphoma.

Circulating thrombospondin 2 levels reflect fibrosis severity and disease activity in HCV-infected patients.

Among several secreted glycoproteins belonging to the thrombospondin family, thrombospondin 2 (TSP2) is involved in various functions, including collagen/fibrin formation. Liver/serum TSP2 levels have been correlated to liver fibrosis stage and disease activity in nonalcoholic fatty liver disease. This study investigated whether serum TSP2 was associated with clinicopathological features in hepatitis C virus (HCV)-infected patients as well. A total of 350 patients with HCV who had undergone liver biopsy were retrospectively enrolled and divided into a discovery cohort (n = 270) and a validation cohort (n = 80). In the discovery cohort, serum TSP2 levels were moderately correlated with both liver fibrosis stage (r = 0.426, P < 0.0001) and activity grade (r = 0.435, P < 0.0001). The area under the receiver operating characteristic curve of TSP2 for predicting severe fibrosis (≥ F3) was 0.78 and comparable to or better than those of autotaxin (0.78), FIB-4 index (0.78), and APRI (0.76). The discovery cohort findings were closely replicated in the validation cohort. Moreover, comprehensive liver genetic analysis of HCV-infected patients confirmed that the expression of the THBS2 gene encoding TSP2 was significantly higher in severely fibrotic F4 than in F1 patients. Circulating TSP2 levels may reflect the severity of hepatic fibrosis/inflammation in HCV-infected patients.

Higher Responsiveness for Women, High Transaminase Levels, and Fat Percentage to Pemafibrate Treatment for NAFLD.

Aim: Pemafibrate (PEM) is a novel selective peroxisome proliferator-activated receptor alpha modulator that is effective for hypertriglyceridemia accompanying non-alcoholic fatty liver disease (HTG-NAFLD). This study aimed to identify the predictors of PEM efficacy for HTG-NAFLD in clinical practice. Methods: We retrospectively enrolled 88 HTG-NAFLD patients treated with PEM for 6 months for the analysis of routine blood and body composition testing. A PEM response was defined as a decrease in serum alanine aminotransferase (ALT) of >30% compared with pre-treatment level. The clinical features related to PEM responsiveness were statistically tested between responders and non-responders. Results: All 88 patients completed the 6 month drug regimen without any adverse effects. PEM treatment significantly decreased liver enzymes, triglycerides, and total cholesterol levels, without any detectable impact on body weight or body composition. Comparisons of baseline clinical features revealed female and greater aspartate aminotransferase (AST), ALT, and fat mass % levels to be significantly associated with a PEM response. The optimal cut-off values to predict responders as determined by receiver operating characteristic analysis were AST 45 U/L, ALT 60 U/L, and fat mass 37%. Conclusions: Female HTG-NAFLD patients with higher transaminase and fat mass % levels may be preferentially indicated for PEM treatment. Additional large-scale prospective studies are warranted to verify our results.

2-Step PLT16-AST44 method: Simplified liver fibrosis detection system in patients with non-alcoholic fatty liver disease.

AIM: Accurate detection of the hepatic fibrosis stage is essential to estimate the outcome of patients with non-alcoholic fatty liver disease (NAFLD). Many formulas, biomarkers, and imaging tests are being developed to predict advanced liver fibrosis without performing a liver biopsy. However, these tests do not have high efficiency in detecting early-stage hepatic fibrosis. Therefore, we aimed to detect the presence of hepatic fibrosis (≥F1) merely by using only standard clinical markers. METHODS: A total of 436 patients with NAFLD who underwent liver biopsy were retrospectively enrolled as the discovery cohort (316 patients) and the validation cohort (120 patients). Liver biopsy and laboratory data were matched to extract simple parameters for identifying ≥F1. RESULTS: We developed a novel simplified ≥F1 detecting system, designated as 2-Step PLT16-AST44 method, where (1) PLT of 16 × 104 /µl or less, or (2) PLT greater than 16 × 104 /µl and AST greater than 44 U/L is determined as having ≥F1 fibrosis. The 2-Step PLT16-AST44 method had a sensitivity of 68%, a specificity of 90%, a positive predictive value (PPV) of 97%, a negative predictive value (NPV) of 40%, and an accuracy of 72% to detect ≥F1 fibrosis in the discovery cohort. Validation studies further supported these results. Despite its simplicity, the 2-Step PLT16-AST44 method's power to detect ≥F1 fibrosis in total NAFLD patients was comparable to hyaluronic acid, type 4 collagen 7S, FIB-4, and APRI. CONCLUSIONS: We propose the 2-Step PLT16-AST44 method as a simple and beneficial early-stage hepatic fibrosis detection system.

Association analysis of KIR/HLA genotype with liver cirrhosis, hepatocellular carcinoma, and NUC freedom in chronic hepatitis B patients.

Natural killer cells are modulated through the binding of killer cell immunoglobulin-like receptors (KIRs) with human leukocyte antigen (HLA) class I ligands. This study investigated the association of KIR/HLA pairs with progression to liver cirrhosis, hepatocellular carcinoma (HCC) development, and nucleot(s)ide (NUC) treatment freedom in hepatitis B virus (HBV) infection. KIR, HLA-Bw, and HLA-C were genotyped in 280 Japanese HBV patients for clinical comparisons. No significant associations of KIR/HLA pairs were detected in terms of liver cirrhosis development. The KIR2DS3 positive rate was significantly higher in patients with HCC (n = 39) than in those without (n = 241) [30.8% vs. 14.9%, odds ratio (OR) 2.53, P = 0.015]. The KIR3DL1/HLA-Bw4 pair rate was significantly lower in the NUC freedom group (n = 20) than in the NUC continue group (n = 114) (25.0% vs. 52.6%, OR 0.30, P = 0.042). In conclusion, this study indicated remarkable associations of KIR/HLA with HCC development (KIR2DS3) and freedom from NUC therapy (KIR3DL1/HLA-Bw4) in HBV patients, although the number of cases was insufficient for statistical purposes. Additional multi-center analyses of larger groups are needed to clarify whether KIR/HLA pairs play a role in HBV patient status.

Successful treatment by glecaprevir/pibrentasvir followed by hepatoprotective therapy of acute chronic hepatitis exacerbation caused by daratumumab-based regimen for multiple myeloma: Case report and review of the literature.

Hepatitis C virus (HCV) exacerbation is relatively rare as compared with hepatitis B virus reactivation in patients treated with immunosuppressive or anticancer drugs. We herein present the first reported case of acute exacerbation of chronic hepatitis in a patient with HCV persistent infection caused by combination treatment with daratumumab (DARA), bortezomib, and dexamethasone (DVd therapy). A 79-year-old woman diagnosed as having chronic HCV infection 11 years prior without successful viral elimination was referred to our hospital for the treatment of acute liver injury. Multiple myeloma (MM; IgG-κ type) was diagnosed two years before referral and subjected to several treatments. She had commenced DVd therapy four months prior to admission. Since her liver enzymes did not normalize with drug discontinuation and hepatoprotective therapy, we suspected HCV exacerbation and began direct-acting antiviral (DAA) treatment with glecaprevir/pibrentasvir (GLE/PIB). Soon afterwards, her liver enzymes normalized, and she achieved a sustained virological response after 8 weeks of treatment. Clinicians should bear in mind HCV exacerbation when encountering chronic HCV with acute liver injury under MM treatment including a DARA-based regimen. In such cases, DAA therapy is an option when other urgent treatments are needed.

Protocol: Prospective observational study aiming for micro-elimination of hepatitis C virus in Nagawa town: The Nagawa Project.

BACKGROUND: The World Health Organization has set a goal of hepatitis C virus (HCV) elimination by the year 2030. However, no regions in Japan have succeeded in eradicating HCV. Micro-elimination is an approach to attain hepatitis C eradication in which national eradication goals are applied to specific populations so that viral treatment and control efforts can move forward quickly and efficiently. In order to eradicate HCV from Japan, this study aims to achieve HCV micro-elimination in the town of Nagawa. METHODS AND DESIGN: The Nagawa Project is an ongoing, prospective, multiple-institution, observational study running from April 1, 2021, to March 31, 2024. All residents of Nagawa town, excluding those under 20 years of age, not consenting to the study, or unable to undergo health check-ups due to nursing care needs, will be included. If found to be HCV antibody-positive, the participant will be recommended to see a doctor in consideration of MAC-2 binding protein glycosylation isomer values. Then, the participant will undergo serum HCV RNA measurement with the real-time polymerase chain reaction by an attending physician. If the participant is HCV RNA-positive, he or she will be referred to a hepatologist for further evaluation. In the case of a definitive diagnosis of chronic hepatitis C, direct acting antiviral treatment will be initiated. Through this process, HCV will be systematically micro-eliminated from the region. DISCUSSION: The Nagawa Project will reveal the prevalence of chronic HCV in addition to the HCV eradication rate in Nagawa town towards achieving HCV micro-elimination. TRIAL REGISTRATION: This study is performed by Shinshu University School of Medicine and was registered as UMIN 000044114 on May 6, 2021.

aMAP score prediction of hepatocellular carcinoma occurrence and incidence-free rate after a sustained virologic response in chronic hepatitis C.

AIMS: Hepatocellular carcinoma (HCC) can still occur in hepatitis C virus (HCV) patients who have achieved a sustained virologic response (SVR), which remains an important clinical issue in the direct-acting antivirals era. The current study investigated the clinical utility of the aMAP score (consisting of age, male, albumin-bilirubin, and platelets) for predicting HCC occurrence in HCV patients achieving an SVR by direct-acting antivirals. METHODS: A total of 1113 HCV patients without HCC history, all of whom achieved an SVR, were enrolled for clinical comparisons. RESULTS: Hepatocellular carcinoma was recorded in 50 patients during a median follow-up period of 3.7 years. The aMAP score was significantly higher in the HCC occurrence group than in the HCC-free group (53 vs. 47, p < 0.001). According to risk stratification based on aMAP score, the cumulative incidence of HCC occurrence for the low-, medium-, and high-risk groups was 0.14%, 4.49%, and 9.89%, respectively, at 1 year and 1.56%, 6.87%, and 16.17%, respectively, at 3 years (low vs. medium, low vs. high, and medium vs. high: all p < 0.01). Cox proportional hazard analysis confirmed aMAP ≥ 50 (hazard ratio [HR]: 2.78, p = 0.014), age≥ 70 years (HR: 2.41, p = 0.028), ALT ≥ 17 U/L (HR: 2.14, p < 0.001), and AFP ≥ 10 ng/mL (HR: 2.89, p = 0.005) as independent risk factors of HCC occurrence. Interestingly, all but one patient (99.5%) with aMAP less than 40 was HCC-free following an SVR. CONCLUSION: The aMAP score could have clinical utility for predicting HCC occurrence in HCV patients achieving an SVR.

Investigation of the Effect of KIR-HLA Pairs on Hepatocellular Carcinoma in Hepatitis C Virus Cirrhotic Patients.

Natural killer cells are partially mediated through the binding of killer cell immunoglobulin-like receptors (KIR) with human leukocyte antigen (HLA) class I ligands. This investigation examined the risk of hepatocellular carcinoma (HCC) in relation to KIR-HLA pairs in patients with compensated hepatitis C virus (HCV)-associated cirrhosis. A total of 211 Japanese compensated HCV cirrhotic cases were retrospectively enrolled. After KIR, HLA-A, HLA-Bw, and HLA-C typing, associations between HLA, KIR, and KIR-HLA combinations and HCC development were evaluated using the Cox proportional hazards model with the stepwise method. During a median follow-up period of 6.6 years, 69.7% of patients exhibited HCC. The proportions of HLA-Bw4 and the KIR3DL1 + HLA-Bw4 pair were significantly higher in patients with HCC than in those without (78.9% vs. 64.1%; odds ratio (OR)-2.10, 95% confidence interval (CI)-1.10-4.01; p = 0.023 and 76.2% vs. 60.9%, odds ratio-2.05, p = 0.024, respectively). Multivariate analysis revealed the factors of male gender (hazard ratio (HR)-1.56, 95% CI-1.12-2.17; p = 0.009), α-fetoprotein > 5.6 ng/mL (HR-1.56, 95% CI-1.10-2.10; p = 0.011), and KIR3DL1 + HLA-Bw4 (HR-1.69, 95% CI-1.15-2.48; p = 0.007) as independent risk factors for developing HCC. Furthermore, the cumulative incidence of HCC was significantly higher in patients with KIR3DL1 + HLA-Bw4 than in those without (log-rank test; p = 0.013). The above findings suggest KIR3DL1 + HLA-Bw4, in addition to HLA-Bw4, as a novel KIR-HLA pair possibly associated with HCC development in HCV cirrhosis. HCV-associated cirrhotic patients with the risk factors of male gender, α-fetoprotein > 5.6 ng/mL, and KIR3DL1 + HLA-Bw4 may require careful surveillance for HCC onset.

Quantitative and qualitative lipid improvement with chronic hepatitis C virus eradication using direct-acting antivirals.

AIM: Direct-acting antivirals have revolutionized hepatitis C virus (HCV) therapy by providing a high sustained virological response (SVR) rate and subsequent favorable lipid increases. Proprotein convertase subtilisin-kexin like-9 (PCSK9) plays an important role in regulating quantitative lipid levels. This study examined the interactions between quantitative PCSK9 and lipid changes, as well as qualitative lipid changes in terms of lectin-like oxidized low-density lipoprotein (LDL) receptor-1 ligand containing apolipoprotein B (LAB) and high-density lipoprotein (HDL) cholesterol uptake capacity (HDL-CUC). METHODS: Patients with chronic HCV infection (N = 231) who achieved an SVR by direct-acting antivirals without lipid-lowering therapy were included for comparisons of PCSK9, LAB, HDL-CUC, and other clinical indices between pretreatment and SVR12 time points. RESULTS: LDL (LDL) cholesterol and HDL cholesterol levels were quantitatively increased at SVR12, along with higher PCSK9 (all p < 0.0001). PCSK9 was significantly correlated with LDL cholesterol (r = 0.244, p = 0.0003) and apolipoprotein B (r = 0.222, p = 0.0009) at SVR12. Regarding qualitative LDL changes, LAB was significantly decreased and LAB/LDL cholesterol and LAB/apolipoprotein B proportions were improved at SVR12 (all p < 0.0001). In terms of qualitative HDL changes, HDL-CUC was significantly ameliorated, along with HDL-CUC/HDL cholesterol, HDL-CUC/ apolipoprotein A1, and HDL-CUC/ apolipoprotein A2 at SVR12 (all p < 0.0001). CONCLUSIONS: HCV eradication by direct-acting antivirals may produce quantitative lipid profile changes, along with PCSK9 production recovery in addition to qualitative lipid improvement, which possibly confers the additional secondary benefits of atherosclerosis improvement and cardiovascular disease event reduction.

Primary Hepatic Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue in a Patient with Chronic Hepatitis B Virus Infection: Case Report and Summary of the Literature.

BACKGROUND: The incidence of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is low, at 7-8% of all non-Hodgkin lymphoma cases. The most common site of MALT lymphoma occurrence is the stomach. Primary hepatic extranodal marginal zone lymphoma of MALT is classified as a type of non-gastric MALT lymphoma and is considered extremely rare, with no consensus on imaging study findings or treatment due to a limited number of reports. We herein describe a rare case of primary hepatic extranodal marginal zone lymphoma of MALT with underlying hepatitis B infection (HBV) and present useful diagnostic findings of various imaging modalities, including contrast-enhanced ultrasonography (CEUS) with Sonazoid. CASE PRESENTATION: A 66-year-old woman was diagnosed as being a non-active carrier of HBV at 51 years of age at the time of total hysterectomy and bilateral adnexectomy for uterine cervical cancer. She was admitted to our hospital following the incidental detection of two focal liver lesions on computed tomography. The lesions were considered malignant based on clinical and other radiologic imaging findings. Her CEUS results of hypo-enhancement in the portal and late phases were consistent with those of previously reported cases of hepatic extranodal marginal zone lymphoma of MALT, and histological liver biopsy findings were compatible with the diagnosis. CONCLUSIONS: Primary hepatic extranodal marginal zone lymphoma of MALT is a rare condition that can appear in HBV carriers. Characteristic CEUS findings may help in disease diagnosis. Clinicians should bear primary hepatic extranodal marginal zone lymphoma of MALT in mind when encountering patients with focal liver lesions which exhibit image findings different from those of typical hepatocellular carcinoma.

Protocol: Prospective observational study investigating the prevalence and clinical outcome of portopulmonary hypertension in Japanese patients with chronic liver disease.

BACKGROUND: Portopulmonary hypertension (PoPH) is a subtype of the pulmonary arterial hypertension (PAH) associated with portal hypertension. There is a dissociation between the proportion of PoPH in PAH and that of PoPH in patients with liver cirrhosis, suggesting PoPH underdiagnosis and an incomplete understanding of this entity in the clinical setting. Specifically, real-world data in Japan is largely unknown as compared with in Europe and the United States. The present study aims to elucidate the prevalence and etiology of PoPH in Japanese patients with chronic liver disease. METHODS AND DESIGN: In this prospective, single-center, observational investigation of PoPH patients with chronic liver disease, a targeted 2,500 Japanese adult patients regularly visiting Shinshu University Hospital in Matsumoto, Japan, for chronic liver disease will complete a standardized questionnaire on the presence of PoPH symptoms. If the respondent has signs of possible PoPH, ultrasound echocardiography (UCG) will be performed as a primary screening. In the case that UCG findings indicate pulmonary hypertension, the patient will be referred to a cardiologist for further evaluation, whereby a definitive diagnosis PoPH can be made. PoPH prevalence and etiology will be investigated at the time of diagnosis. Afterwards, patients with PoPH will be followed for five years for determination of survival rate. DISCUSSION: This study will reveal the prevalence, etiology, and 5-year survival rate of PoPH in Japanese patients with chronic liver disease. TRIAL REGISTRATION: This study is being performed at Shinshu University following registration as UMIN 000042287 on October 29, 2020.

An Autopsy Case of Primary Biliary Cholangitis with Histological Submassive Hepatic Necrosis Caused by Acute Hepatitis E Virus Infection.

A 59-year-old woman who had been diagnosed with cirrhotic primary biliary cholangitis (PBC) 5 years earlier was admitted for severe jaundice (total bilirubin: 30.1 mg/dL). We suspected that her cirrhotic PBC had deteriorated acutely for some reason. Her general condition deteriorated quickly, and she passed away on day 18 of admission. Hepatitis E virus (HEV)-IgA antibodies were positive, and Genotype 3b HEV involvement was confirmed from a blood sample taken on admission. Histopathological findings revealed cirrhosis and submassive loss and necrosis of hepatocytes. Clinicians should consider the possibility of acute HEV infection as a trigger for acute PBC exacerbation.