Long-Term pemafibrate treatment exhibits limited impact on body fat mass in patients with hypertriglyceridemia accompanying NAFLD.

Aim: Short-term use of pemafibrate (PEM), a selective modulator of peroxisome proliferator-activated receptor alpha, has been reported to improve abnormal liver function in patients with nonalcoholic fatty liver disease with hypertriglyceridemia (HTG-NAFLD). This study aimed to clarify the effects and predictive factors of long-term 72-week PEM administration on body composition, and laboratory tests in HTG-NAFLD patients. Methods: Fifty-three HTG-NAFLD patients receiving a 72-week PEM regimen were retrospectively enrolled. Routine blood and body composition results were analyzed immediately before and at the end of the study period. Results: PEM treatment significantly improved liver enzyme levels such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, and gamma-glutamyl transferase, along with lipid profiles including triglyceride, total cholesterol, and low-density lipoprotein cholesterol. PEM did not have any detectable impact on body composition parameters. The factors of female, higher AST (≥ 46 U/L) and fat mass (≥ 31.9%), as well as lower soft lean mass (< 61.6%), skeletal muscle mass (< 36%), and skeletal muscle mass index (< 6.9 kg/m2) were significantly associated with the treatment response status of a > 30% decrease in ALT. All patients completed the treatment without any adverse effects. Conclusions: Long-term PEM treatment had a positive impact on liver enzymes and lipid profiles, but it did not result in significant changes in body composition among HTG-NAFLD patients. In predicting the response to PEM treatment, the evaluation of AST and body composition may be useful.

Case of severe alcoholic hepatitis following acute pancreatitis.

This report describes the clinical course of a 41 year-old African woman who presented with an episode of acute alcoholic pancreatitis followed next by severe alcoholic hepatitis (SAH). Initially admitted for pancreatitis, the patient responded promptly to comprehensive treatment with strict abstinence from alcohol. However, remarkable elevations in white blood cell count to 44,000/µL and total bilirubin level to 12.4 mg/dL were observed 5-7 weeks later. Contrast-enhanced computed tomography revealed rapidly progressing hepatosplenomegaly. Histological analysis of a liver biopsy detected ballooned hepatocytes with Mallory-Denk bodies and significant neutrophilic infiltration in the hepatic parenchyma, which confirmed the diagnosis of SAH. The patient's hepatosplenomegaly and overall condition improved with supportive care alone. The reported case reveals the unexpected fact that SAH can develop after alcoholic acute pancreatitis.

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.

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.

Pyogenic liver abscess associated with Klebsiella oxytoca: Mimicking invasive liver abscess syndrome.

A pyogenic liver abscess (PLA) is a space-occupying lesion in the liver that is associated with significant morbidity and mortality. We herein present the case of a Japanese 76-year-old man who visited our hospital with fever and back pain lasting 3 weeks after endoscopic treatment for common bile duct stones. He was accompanied by poorly controlled diabetes mellitus (DM) with an HbA1c of 9.7 %. Laboratory tests disclosed elevated C-reactive protein level (22.1 mg/dL) and white cell count (11,910/µL). Abdominal computed tomography (CT) revealed hypodense lesions in the right liver lobe, with abdominal ultrasonography showing an echogenicity-mixed hypoechoic lesion. Percutaneous needle aspiration of a liver lesion was performed under suspicion of a PLA. Subsequent enhanced CT and magnetic resonance imaging confirmed the hepatic lesions in the right lobe as well as a septic pulmonary embolism, right hepatic vein thrombosis, spondylodiscitis, and a retroperitoneal abscess. Gram staining of the abscess drainage revealed gram-negative bacteria. The above findings indicated invasive liver abscess syndrome (ILAS) caused by Klebsiella pneumoniae. However, further examination of blood, urine, and abscess drainage cultures revealed positivity for Klebsiella oxytoca. This case illustrates that K. oxytoca may cause ILAS-like symptoms. Screening for systemic metastatic infection should be considered in patients with PLA due to K. oxytoca in whom therapeutic intervention has been delayed, especially in patients with poorly controlled DM.

Prognostic Significance of C-Reactive Protein in Lenvatinib-Treated Unresectable Hepatocellular Carcinoma: A Multi-Institutional Study.

BACKGROUND: Serum C-reactive protein (CRP) is an established biomarker for acute inflammation and has been identified as a prognostic indicator for hepatocellular carcinoma (HCC). However, the significance of the serum CRP level, specifically in HCC patients treated with lenvatinib, remains unclear. METHODS: We retrospectively analyzed 125 HCC patients who received lenvatinib treatment at six centers. Clinical characteristics were assessed to identify clinical associations between serum CRP and HCC prognosis. RESULTS: The median overall serum CRP level was 0.29 mg/dL. The cohort was divided into two groups: the low-CRP group with a serum CRP < 0.5 mg/dL and the high-CRP group with a serum CRP ≥ 0.5 mg/dL. The low-CRP group exhibited significantly longer overall survival (OS) than the high-CRP group (22.9 vs. 7.8 months, p < 0.001). No significant difference was observed for progression-free survival (PFS) between the high- and low-CRP groups (9.8 vs. 8.4 months, p = 0.411), while time-to-treatment failure (TTF) was significantly longer in the low-CRP group (8.5 vs. 4.4 months, p = 0.007). The discontinuation rate due to poor performance status was significantly higher in the high-CRP group (p < 0.001). CONCLUSION: A baseline serum CRP level exceeding 0.5 mg/dL was identified as an unfavorable prognostic factor in HCC patients receiving lenvatinib treatment.

Establishment of Novel Mouse Model of Dietary NASH Rapidly Progressing into Liver Cirrhosis and Tumors.

Non-alcoholic steatohepatitis (NASH), which is the most severe manifestation of non-alcoholic fatty liver disease (NAFLD), has been recognized as a major hepatocellular carcinoma (HCC) catalyst. However, the molecular mechanism of NASH-liver fibrosis-HCC sequence remains unclear and a specific and effective treatment for NASH has not yet been established. The progress in this field depends on the availability of reliable preclinical models which show the steady progression to NASH, liver cirrhosis, and HCC. However, most of the NASH mouse models that have been described to date develop NASH generally for more than 24 weeks and there is an uncertainty of HCC development. To overcome such shortcomings of experimental NASH studies, we established a novel NASH-HCC mouse model with very high reproducibility, generality, and convenience. We treated male C57BL/6J mice with a newly developed choline-deficient and methionine-restricted high-fat diet, named OYC-NASH2 diet, for 60 weeks. Treatment of OYC-NASH2 diet for 3 weeks revealed marked steatosis, lobular inflammation, and fibrosis, histologically diagnosed as NASH. Liver cirrhosis was observed in all mice with 48-week treatment. Liver nodules emerged at 12 weeks of the treatment, > 2 mm diameter liver tumors developed in all mice at 24 weeks of the treatment and HCC appeared after 36-week treatment. In conclusion, our rapidly progressive and highly reproducible NASH-liver cirrhosis-HCC model is helpful for preclinical development and research on the pathogenesis of human NAFLD-NASH-HCC. Our mouse model would be useful for the development of novel chemicals for NASH-HCC-targeted therapies.

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.

Kinetics of serum O-glycosylated M-hepatitis B surface antigen with hepatocellular carcinoma history and nucleos(t)ide analogue therapy in hepatitis B patients.

A newly developed O-glycosylated M-hepatitis B surface antigen (HBsAgGi) measurement system can detect hepatitis B surface antigen (HBsAg) associated with infectious particles. We investigated the association of HBsAgGi levels with clinical parameters and a history of hepatocellular carcinoma (HCC) development in a cross-sectional cohort analysis (Study 1) as well as the quantitative changes in HBsAgGi during nucleos(t)ide analogue (NA) therapy in a longitudinal cohort analysis (Study 2). A total of 124 patients with genotype C chronic HBV infection were analysed in Study 1 to evaluate correlations of HBsAgGi with conventional HBV markers and HCC history. Among those, 36 patients receiving NA therapy were enrolled in Study 2 for quantitative comparisons between pre-treatment baseline and 48 weeks of NA therapy. In Study 1, serum HBsAgGi was significantly associated with HBsAg (r = .5857, p < .00001) and weakly but significantly correlated with HBV DNA (r = .2936, p = .001). Although HBsAgGi (p = .111) was comparable between HCC history (+) group and HCC history (-) group, the HBsAgGi/HBsAg ratio (p = .011) was significantly higher in HCC history (+) patients. In Study 2, HBsAgGi was significantly decreased after 48 weeks of NA therapy (p < .001). HBsAg findings were similar (p = .005) along with an HBV DNA reduction (p < .001). In the baseline hepatitis B e antigen (HBeAg) (+) subgroup, HBsAgGi decreased significantly between baseline and 48 weeks of NA (p = .005), while HBsAg was comparable (p = .051). Low HBsAg and high HBsAgGi were associated with a history of HCC development. HBsAgGi decreased significantly by 48-week NA therapy.

A case of malignant peritoneal mesothelioma with a Fitz-Hugh-Curtis syndrome-like imaging finding.

Malignant peritoneal mesothelioma (MPeM) is a rare disease with a poor prognosis that develops in the mesothelial cells of the peritoneum. We encountered a 48-year-old man with no prior asbestos exposure who visited our hospital with abdominal pain. Laboratory findings showed elevated C-reactive protein of 15.5 mg/dL. Contrast-enhanced computed tomography (CT) detected a Fitz-Hugh-Curtis syndrome-like contrast effect on the liver surface and thickening of the peritoneum. Blood culture, Mycobacterium tuberculosis-specific IFN-γ release assay, Chlamydia trachomatis and Neisseria gonorrhoeae DNA testing, and antinuclear antibody were all negative. CA125 was high at 124.8 U/mL. The laparoscopy for diagnostic purposes revealed adhesions between the liver surface and peritoneum in addition to numerous small and large white nodules on the peritoneum. Biopsy of the nodules confirmed the diagnosis of epithelial-type MPeM. Treatment was initiated with combined cisplatin and pemetrexed, and CT 6 months later showed a reduced contrast effect on the liver surface and improved peritoneal thickening. A Fitz-Hugh-Curtis syndrome-like contrast effect on the liver surface on contrast-enhanced CT may help identify MPeM.

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.

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.