Impact of the COVID-19 pandemic on the treatment of acute cholangitis caused by choledocholithiasis: A single-center retrospective study in Japan.

Objectives: This study aimed to determine the impact of the coronavirus disease 2019 (COVID-19) pandemic on the treatment of acute cholangitis caused by choledocholithiasis. Methods: The Japanese government declared a state of emergency in April 2020 due to the COVID-19 pandemic. We retrospectively reviewed the medical records of 309 patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) for acute cholangitis caused by choledocholithiasis between April 2017 and December 2022. Results: Patients were categorized into a pregroup (n = 134) and a postgroup (n = 175), depending on whether they were diagnosed before or after the state of emergency declaration. The total number of ERCP cases and the number of ERCP cases with endoscopic stone removals increased after the state of emergency declaration. Compared with the pregroup, the numbers of patients with performance status of 0-1 and surgically altered anatomy increased, whereas the numbers of patients taking oral antiplatelets or anticoagulants and those with cerebrovascular disease decreased in the postgroup. The number of single-stage endoscopic stone removals increased and hospital stays were significantly shorter in the postgroup. No differences in adverse event rates were detected between the two groups. Conclusions: Although our hospital provides tertiary care, the number of patients with cholangitis in good general condition and no underlying disease increased after the state of emergency declaration. The COVID-19 pandemic resulted in an increase in the number of single-stage endoscopic treatments and shortened hospital stays for patients with acute cholangitis caused by choledocholithiasis. No safety issues with ERCP were detected, even during the pandemic.

Effects of elafibranor on liver fibrosis and gut barrier function in a mouse model of alcohol-associated liver disease.

BACKGROUND: Alcohol-associated liver disease (ALD) is a leading cause of liver-related morbidity and mortality, but there are no therapeutic targets and modalities to prevent ALD-related liver fibrosis. Peroxisome proliferator activated receptor (PPAR) α and δ play a key role in lipid metabolism and intestinal barrier homeostasis, which are major contributors to the pathological progression of ALD. Meanwhile, elafibranor (EFN), which is a dual PPARα and PPARδ agonist, has reached a phase III clinical trial for the treatment of metabolic dysfunction-associated steatotic liver disease and primary biliary cholangitis. However, the benefits of EFN for ALD treatment is unknown. AIM: To evaluate the inhibitory effects of EFN on liver fibrosis and gut-intestinal barrier dysfunction in an ALD mouse model. METHODS: ALD-related liver fibrosis was induced in female C57BL/6J mice by feeding a 2.5% ethanol (EtOH)-containing Lieber-DeCarli liquid diet and intraperitoneally injecting carbon tetrachloride thrice weekly (1 mL/kg) for 8 weeks. EFN (3 and 10 mg/kg/day) was orally administered during the experimental period. Histological and molecular analyses were performed to assess the effect of EFN on steatohepatitis, fibrosis, and intestinal barrier integrity. The EFN effects on HepG2 lipotoxicity and Caco-2 barrier function were evaluated by cell-based assays. RESULTS: The hepatic steatosis, apoptosis, and fibrosis in the ALD mice model were significantly attenuated by EFN treatment. EFN promoted lipolysis and ß-oxidation and enhanced autophagic and antioxidant capacities in EtOH-stimulated HepG2 cells, primarily through PPARα activation. Moreover, EFN inhibited the Kupffer cell-mediated inflammatory response, with blunted hepatic exposure to lipopolysaccharide (LPS) and toll like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling. EFN improved intestinal hyperpermeability by restoring tight junction proteins and autophagy and by inhibiting apoptosis and proinflammatory responses. The protective effect on intestinal barrier function in the EtOH-stimulated Caco-2 cells was predominantly mediated by PPARδ activation. CONCLUSION: EFN reduced ALD-related fibrosis by inhibiting lipid accumulation and apoptosis, enhancing hepatocyte autophagic and antioxidant capacities, and suppressing LPS/TLR4/NF-κB-mediated inflammatory responses by restoring intestinal barrier function.

Tofogliflozin Delays Portal Hypertension and Hepatic Fibrosis by Inhibiting Sinusoidal Capillarization in Cirrhotic Rats.

BACKGROUND: Liver cirrhosis leads to portal hypertension (PH) with capillarization of liver sinusoidal endothelial cells (LSECs), although drug treatment options for PH are currently limited. Sodium glucose transporter 2 inhibitors, which are antidiabetic agents, have been shown to improve endothelial dysfunction. We aimed to elucidate the effect of tofogliflozin on PH and liver fibrosis in a rat cirrhosis model. METHODS: Male-F344/NSlc rats repeatedly received carbon tetrachloride (CCl4) intraperitoneally to induce PH and liver cirrhosis alongside tofogliflozin (10 or 20 mg/kg). Portal hemodynamics and hepatic phenotypes were assessed after 14 weeks. An in vitro study investigated the effects of tofogliflozin on the crosstalk between LSEC and activated hepatic stellate cells (Ac-HSC), which are relevant to PH development. RESULTS: Tofogliflozin prevented PH with attenuated intrahepatic vasoconstriction, sinusoidal capillarization, and remodeling independent of glycemic status in CCl4-treated rats. Hepatic macrophage infiltration, proinflammatory response, and fibrogenesis were suppressed by treatment with tofogliflozin. In vitro assays showed that tofogliflozin suppressed Ac-HSC-stimulated capillarization and vasoconstriction in LSECs by enhancing the antioxidant capacity, as well as inhibited the capilliarized LSEC-stimulated contractive, profibrogenic, and proliferative activities of Ac-HSCs. CONCLUSIONS: Our study provides strong support for tofogliflozin in the prevention of liver cirrhosis-related PH.

ADAMTS-13: A Prognostic Biomarker for Portal Vein Thrombosis in Japanese Patients with Liver Cirrhosis.

Portal vein thrombosis (PVT), one of the most prevalent hepatic vascular conditions in patients with liver cirrhosis (LC), is associated with high mortality rates. An imbalance between a disintegrin-like metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS-13) enzyme and von Willebrand factor (VWF) is responsible for hypercoagulability, including spontaneous thrombus formation in blood vessels. Herein, we aimed to identify potential prognostic and diagnostic biomarkers in Japanese patients with LC and PVT. In total, 345 patients were divided into two groups: 40 patients who developed PVT (PVT group) and 305 who did not develop PVT (NPVT group). Among the 345 patients with LC, 81% (279/345) were deemed ineligible due to the presence of preventive comorbidities, active or recent malignancies, and organ dysfunction. The remaining 66 patients were divided into two groups: the PVT group (n = 33) and the NPVT group (n = 33). Plasma ADAMTS-13 activity (ADAMTS-13:AC) and the vWF antigen (VWF:Ag) were measured using enzyme-linked immunosorbent assays. Contrast-enhanced, three-dimensional helical computed tomography (CT) was used to detect and characterize PVT. ADAMTS-13:AC was significantly lower in the PVT group than in the NPVT group. No significant differences in plasma vWF:Ag or liver stiffness were observed between the two groups. ADAMTS-13:AC of <18.8 was an independent risk factor for PVT on multivariate analyses (odds ratio: 1.67, 95% confidence interval: 1.21-3.00, p < 0.002). The receiver operating characteristic analysis of ADAMTS-13:AC revealed an area under the curve of 0.913 in PVT detection. Patients with PVT having ADAMTS-13:AC ≥18.8 (n = 17) had higher albumin levels and better prognoses than those with ADAMTS-13:AC <18.8 (n = 16). No significant correlations of ADAMTS-13:AC levels with either fibrin degradation product or D-dimer levels were observed. ADAMTS-13:AC levels could be potential diagnostic and prognostic biomarkers for PVT in Japanese patients with LC.

Improvement of liver histology in hepatic sarcoidosis due to treatment with corticosteroids and ursodeoxycholic acid: a case report.

We report the case of a 48-year-old male with a history of pulmonary and ocular sarcoidosis. Non-caseating granulomas, identified histologically, are the most characteristic manifestation of sarcoidosis. Hepatic sarcoidosis is difficult to diagnose using radiological imaging. In the patient reported in this study, ultrasound and contrast-enhanced computed tomography scans identified multiple intra-abdominal lymphadenopathies, with evidence of liver and splenic infiltrations. The first liver biopsy revealed non-caseating granulomatous hepatitis consistent with hepatic sarcoidosis. The patient was treated with ursodeoxycholic acid (UDCA), but his laboratory parameters did not improve. Prednisone was initiated at a dose of 30 mg daily and slowly tapered. At a dose of 12.5 mg daily, marked improvements in the fibrotic and sarcoid-like lesions were noted at the second biopsy. A third biopsy was performed, with the patient on a prednisone taper of 5 mg/day showed mild fibrous expansion in the portal tracts and mild parenchymal necro-inflammatory lesions. However, overall, fibrosis marker levels remained stable over the course of treatment. A fourth biopsy was performed after a 5-year course of 5 mg/day prednisone. This revealed minimal lobular inflammation without fibrosis. Thus, treatment of this patient with corticosteroids and UDCA resulted in marked improvements in his biochemical and histological parameters.

Effects of entecavir and tenofovir alafenamide fumarate treatment on renal function in Japanese elderly patients with chronic hepatitis B.

AIM: Entecavir (ETV) and tenofovir alafenamide fumarate (TAF) are considered safe nucleoside/nucleotide analogs (NA) for the kidney. This study aimed to investigate the long-term effects of ETV or TAF on renal function in elderly patients with chronic hepatitis B (CHB) in Japan. METHODS: The study included 246 CHB patients treated with ETV (184 patients) or TAF (62 patients) for at least 2 years. These patients were divided into two groups: those <65 years of age (130 patients) and those ≥65 years of age (116 patients). The effects of the NAs on renal functions were examined by comparing the estimated glomerular filtration rates (eGFR) from baseline to 2 years between the two groups. RESULTS: The change in eGFR from baseline to 1 or 2 years after treatment was significantly decreased in both groups. However, the amount of change at 1 and 2 years was significantly greater in the group aged ≥65 years than in the group aged <65 years. The amount of change in eGFR from baseline to 1 and 2 years after treatment was significantly greater in the group aged ≥65 years than in the group aged <65 years, regardless of the type of NA, the prior treatment history, cirrhosis/chronic hepatitis, hypertension, dyslipidemia, and diabetes. Additionally, logistic regression analysis showed that age ≥65 years was independently associated with a decreased eGFR after 2 years of NA treatment. CONCLUSIONS: Long-term administration of NA to CHB patients over 65 years of age should be carefully monitored for renal impairment.

Blockade of angiotensin II modulates insulin-like growth factor 1-mediated skeletal muscle homeostasis in experimental steatohepatitis.

Sarcopenia is associated with mortality in patients with nonalcoholic steatohepatitis (NASH). Angiotensin II receptor blocker (ARB) has been suggested to prevent sarcopenia, but reports on its effect on NASH-derived skeletal muscle atrophy in conjunction with insulin-like growth factor 1 (IGF-1)-mediated muscle homeostasis are few. Our aim was to examine the combined effect of the ARB losartan and IGF-1 replacement on skeletal muscle atrophy in a methionine-choline deficient (MCD) diet-fed murine steatohepatitis model. The MCD-fed mice developed steatohepatitis and skeletal muscle atrophy, as indicated by the reduction of psoas muscle mass and attenuation of forelimb and hindlimb grip strength. Significantly suppressed steatohepatitis and skeletal muscle atrophy was observed after single treatment with ARB or IGF-1, and these effects were augmented after combination treatment. Treatment with ARB and IGF-1 effectively inhibited ubiquitin proteasome-mediated protein degradation by reducing forkhead box protein O1 (FOXO1) and FOXO3a transcriptional activity in the skeletal muscle. Combined ARB and IGF-1 decreased the intramuscular expression of proinflammatory cytokines (i.e., TNFα, IL6, and IL1ß) and increased the Trolox equivalent antioxidant capacity and antioxidant enzymes (CAT, GPX1, SOD2, and CYTB). This antioxidant effect was based on downregulation of NADPH oxidase (NOX) 2, normalization of mitochondrial biogenesis and dynamics. Moreover, ARB increased the hepatic and plasma IGF-1 levels and improved steatohepatitis, leading to enhanced skeletal muscle protein synthesis mediated by IGF-1/ AKT/ mechanistic target of rapamycin signaling. Collectively, combined ARB and IGF-1 replacement could be a promising new therapeutic target for NASH-derived skeletal muscle wasting.

Hemoglobin and Endotoxin Levels Predict Sarcopenia Occurrence in Patients with Alcoholic Cirrhosis.

Alcohol is a major risk factor of liver cirrhosis (LC). This study aimed to elucidate a surrogate marker of sarcopenia in patients with LC of different etiology. Out of 775 patients with LC, 451 were assessed for handgrip strength and skeletal muscle mass (by computed tomography). They were then divided into two groups: alcoholic cirrhosis (AC; n = 149) and nonalcoholic cirrhosis (NAC; n = 302). Endotoxin activity (EA) levels were measured with an EA assay. Group AC showed significantly higher platelet counts (p = 0.027) and lower blood urea nitrogen levels and fibrosis-4 index than group NAC (p = 0.0020 and p = 0.038, respectively). The risk factors of sarcopenia were age ≥ 65 years, female sex, CP-C LC, Hb levels < 12 g/dL, and EA level > 0.4 in all patients with LC; hemoglobin (Hb) levels < 12 g/dL and EA level > 0.4 in group AC; and age ≥ 65 years, CP-C LC, and Hb levels < 12 g/dL in group NAC. The prediction accuracy of Hb for sarcopenia in group AC, group NAC, and all patients was 83.6%, 75.9%, and 78.1% (sensitivity: 92.0%, 69.0%, and 80.2%; specificity: 66.4%, 71.0%, and 64.0%), respectively. Although not significant, the predictive performance was better when using the combination of Hb and EA measurements than when using Hb alone in group AC but was comparable in all patients. Hb levels can predict sarcopenia in patients with LC, but in those with AC, the combination of Hb and EA improves the prediction performance.

Diagnostic yield of liquid-based cytology in serial pancreatic juice aspiration cytological examination.

Objectives: Serial pancreatic juice aspiration cytological examination (SPACE) via endoscopic retrograde cholangiopancreatography is a useful diagnostic method for early-stage pancreatic cancer, such as carcinoma in situ that are difficult to diagnose by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). However, the diagnostic accuracy of SPACE is low, which is attributed to problems regarding specimen treatment. Hence, we evaluated the diagnostic efficacy of liquid-based cytology (LBC) in pancreatic juice cytology for pancreatic cancer. Methods: We retrospectively analyzed 24 patients with suspected pancreatic cancer that was difficult to diagnose by endoscopic ultrasound-guided fine needle aspiration who underwent SPACE using LBC between April 2017 and April 2021. Results: The most common reason for performing SPACE was localized stenosis of the main pancreatic duct without a mass. Eleven patients were diagnosed with malignancy after surgical resection, nine of whom had pancreatic ductal adenocarcinoma. Ten patients were diagnosed as benign after a follow-up of more than 1 year. The nine cases of malignancy were diagnosed before surgical resection by SPACE using LBC, with a sensitivity of 81.8% and specificity of 100%. The overall diagnostic accuracy was 91.7%. A total of 152 LBC examinations were performed via SPACE, with an adequate sample collection rate of 88.9%. No adverse events, including acute pancreatitis, occurred after endoscopic retrograde cholangiopancreatography. Conclusion: SPACE with LBC offers good diagnostic efficacy in patients with pancreatic cancer that is difficult to diagnose by endoscopic ultrasound-guided fine needle aspiration.

Clinical Significance of Serum Zinc Levels on the Development of Sarcopenia in Cirrhotic Patients.

Background/Aim: Sarcopenia increases the mortality in patients with cirrhosis. Approximately 60% of zinc is accumulated in skeletal muscle. We aimed to determine the role of subclinical zinc deficiency on sarcopenia development in patients with cirrhosis. Patients and Methods: We enrolled 151 patients with cirrhosis and divided them into the group with normal serum zinc levels (Group N: 80-130 µg/dl; n=38) and group with subclinical zinc deficiency (Group D: <80 µg/dl; n=113). The risk factors for sarcopenia were then investigated. Results: Group D had more sarcopenia cases than Group N (31.0% vs. 13.2%). In group D, HGS exhibited a weakly positive but significant correlation with serum zinc levels (R=0.287, p=0.00212), serum zinc levels negatively correlated with both ammonia and myostatin levels (R=-0.254, p=0.0078; R=-0.33, p<0.01), and low zinc levels were independently associated with sarcopenia development. Conclusion: Patients with cirrhosis showing subclinical zinc deficiency have a significantly higher risk of developing sarcopenia.

Liver Biopsy-confirmed Primary Hepatic Amyloidosis with Only Jaundice As the Initial Symptom: An Autopsy Case Report.

Amyloidosis causes various symptoms in many organs of the body, but amyloidosis that presents with liver damage alone has never been reported. We treated an 83-year-old man with amyloidosis who presented with liver damage alone. The liver damage in this patient was histologically proven to be liver amyloidosis. The administration of bortezomib and dexamethasone was not effective, so he rapidly died of liver failure. An aggressive liver biopsy should be considered when unexplained jaundice is observed.

Protein-losing gastroenteropathy complicated with asymptomatic primary biliary cholangitis, refractory to immunosuppressant, and improved by Helicobacter pylori eradication: a case report.

BACKGROUND: Protein-losing gastroenteropathy (PLGE) is a syndrome with a chief complaint of hypoalbuminemia, which occurs due to plasma protein leakage in the gastrointestinal tract, leading to general edema, ascites, and pleural effusions. CASE PRESENTATION: A 71-year-old woman visited another hospital for evaluation of hypoalbuminemia and systemic edema. She was hospitalized for a close inspection of hypoalbuminemia and was diagnosed with PLGE. Steroid and azathioprine therapy was prescribed; however, hypoalbuminemia did not improve, and the patient's condition worsened due to anasarca. As hospitalization was prolonged, the patient was transferred to our hospital. She was infected with Helicobacter pylori, and we performed H. pylori eradication. Following H. pylori eradication, her edema improved remarkably. CONCLUSION: We present the first case wherein H. pylori eradication successfully improved protein leakage in the lower gastrointestinal tract in a patient diagnosed with PLGE complicated with refractory to immunosuppressant treatment. H. pylori eradication should be considered in patients with PLGE complicated with H. pylori infection, without specific endoscopic finding or refractory to immunosuppressants.

Severe Aplastic Anemia following Parvovirus B19-Associated Acute Hepatitis.

Human parvovirus (HPV) B19 is linked to a variety of clinical manifestations, such as erythema infectiosum, nonimmune hydrops fetalis, and transient aplastic anemia. Although a few cases have shown HPVB19 infection as a possible causative agent for hepatitis-associated aplastic anemia (HAAA) in immunocompetent patients, most reported cases of HAAA following transient hepatitis did not have delayed remission. Here we report a rare case of severe aplastic anemia following acute hepatitis with prolonged jaundice due to HPVB19 infection in a previously healthy young male. Clinical laboratory examination assessed marked liver injury and jaundice as well as peripheral pancytopenia, and bone marrow biopsy revealed severe hypoplasia and fatty replacement. HPVB19 infection was diagnosed by enzyme immunoassay with high titer of anti-HPVB19 immunoglobulin M antibodies. Immunosuppressive therapy was initiated 2 months after the onset of acute hepatitis when liver injury and jaundice were improved. Cyclosporine provided partial remission after 2 months of medication without bone marrow transplantation. Our case suggests that HPVB19 should be considered as a hepatotropic virus and a cause of acquired aplastic anemia, including HAAA.