Special articleHistological grading and staging of chronic hepatitis
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Cited by (4411)
Quantitative digital pathology enables automated and quantitative assessment of inflammatory activity in patients with autoimmune hepatitis
2024, Journal of Pathology InformaticsChronic liver disease diagnoses depend on liver biopsy histopathological assessment. However, due to the limitations associated with biopsy, there is growing interest in the use of quantitative digital pathology to support pathologists. We evaluated the performance of computational algorithms in the assessment of hepatic inflammation in an autoimmune hepatitis in which inflammation is a major component.
Whole-slide digital image analysis was used to quantitatively characterize the area of tissue covered by inflammation [Inflammation Density (ID)] and number of inflammatory foci per unit area [Focal Density (FD)] on tissue obtained from 50 patients with autoimmune hepatitis undergoing routine liver biopsy. Correlations between digital pathology outputs and traditional categorical histology scores, biochemical, and imaging markers were assessed. The ability of ID and FD to stratify between low-moderate (both portal and lobular inflammation ≤1) and moderate-severe disease activity was estimated using the area under the receiver operating characteristic curve (AUC).
ID and FD scores increased significantly and linearly with both portal and lobular inflammation grading. Both ID and FD correlated moderately-to-strongly and significantly with histology (portal and lobular inflammation; 0.36≤R≤0.69) and biochemical markers (ALT, AST, GGT, IgG, and gamma globulins; 0.43≤R≤0.57). ID (AUC: 0.85) and FD (AUC: 0.79) had good performance for stratifying between low-moderate and moderate-severe inflammation.
Quantitative assessment of liver biopsy using quantitative digital pathology metrics correlates well with traditional pathology scores and key biochemical markers. Whole-slide quantification of disease can support stratification and identification of patients with more advanced inflammatory disease activity.
Integration of network pharmacology and serum medicinal chemistry to investigate the pharmacological mechanisms of QiZhuYangGan Decoction in the treatment of hepatic fibrosis
2024, Journal of EthnopharmacologyQizhuyanggan Decoction (QZD), a traditional Chinese medicine formula, is frequently utilized in clinical practice for managing hepatic fibrosis. However, the specific target and mechanism of action of QZD for hepatic fibrosis treatment remain unknown.
By combining network pharmacology, serum medicinal chemistry, and experimental validation methods, our study aimed to investigate the therapeutic effects of QZD on hepatic fibrosis, the anti-hepatic fibrosis active ingredients, and the possible mechanism of anti-hepatic fibrosis action.
The study aimed to investigate the therapeutic effect of QZD on hepatic fibrosis induced by CCl4 in SD rats, as well as its mechanism of action. The rats were anesthetized intraperitoneally using 3% pentobarbital and were executed after asphyxiation with high concentrations of carbon dioxide. Several techniques were employed to evaluate the efficacy of QZD, including ELISA, Western blot, HYP reagent assay, and various pathological examinations such as HE, Masson, Sirius Red staining, and immunohistochemistry (IHC). Additionally, serum biochemical assays were conducted to assess the effect of QZD on liver injury. Network pharmacology, UPLC, molecular docking, and molecular dynamics simulation were utilized to explore the mechanism of QZD in treating hepatic fibrosis. Finally, experimental validation was performed through ELISA, IHC, RT-qPCR, and Western blot analysis.
Liver histopathology showed that QZD reduced inflammation and inhibited collagen production, and QZD significantly reduced HA and LN content to treat hepatic fibrosis. Serum biochemical analysis showed that QZD improved liver injury. Network pharmacology combined with UPLC screened six active ingredients and obtained 87 targets for the intersection of active ingredients and diseases. The enrichment analysis results indicated that the PI3K/AKT pathway might be the mechanism of action of QZD in the treatment of hepatic fibrosis, and counteracting the inflammatory response might be one of the pathways of action of QZD. Molecular docking and molecular dynamics simulations showed that the active ingredient had good binding properties with PI3K, AKT, and mTOR proteins. Western blot, ELISA, PCR, and IHC results indicated that QZD may treat hepatic fibrosis by inhibiting the PI3K/AKT/mTOR pathway and suppressing M1 macrophage polarization, while also promoting M2 macrophage polarization.
QZD may be effective in the treatment of hepatic fibrosis by inhibiting the PI3K/AKT/mTOR signaling pathway and M1 macrophage polarization, while promoting M2 macrophage polarization. This provides a strong basis for the clinical application of QZD.
Effectiveness of metformin for the reversal of cold-ischemia-induced damage in hepatosteatosis
2024, Clinics and Research in Hepatology and GastroenterologyPrimary dysfunction and rejection are more common in donor liver tissues with steatosis. AMP-activated protein kinase (AMPK) assumes organ-protective functions during ischemia. Metformin was used for the activation of AMPK in hepatocytes. The aim of this study is to investigate the effectiveness of metformin administration for the reversal of cold-ischemia-induced damage in hepatosteatosis.
Seven-week-old C7BL56 male-mice (n = 109) were separated into four groups depending on diet type and metformin use. A specific diet model was followed for 10 weeks to induce hepatosteatosis. A group of the animals was administered with metformin for the last four weeks via oral gavage. After resection, the liver tissues were perfused and kept for 0–6–12–24 h in the UW solution. Histopathological examinations were performed, and Western blot was utilized to analyze p-AMPK and AMPK expression levels.
Hepatosteatosis decreased significantly with metformin. The steatotic liver group had more prominent pericentral inflammation, necrosis as well as showing a decreased and more delayed AMPK response than the non-fat group. All these alterations could be corrected using metformin.
Metformin can increase the resistance of livers with hepatosteatosis to cold-ischemia-induced damage, which in turn may pave the way for successful transplantation of fatty living-donor livers.
Regression of Liver Fibrosis in Patients on Hepatitis B Therapy Is Associated With Decreased Liver-Related Events
2024, Clinical Gastroenterology and HepatologyLiver fibrosis in patients with chronic hepatitis B can regress with successful antiviral therapy. However, the long-term clinical benefits of fibrosis regression have not been fully elucidated. This study investigated the association between biopsy-proven fibrosis regression by predominantly progressive, indeterminate, and predominantly regressive (P-I-R) score and liver-related events (LREs) in chronic hepatitis B patients.
Patients with on-treatment liver biopsy and significant fibrosis/cirrhosis (Ishak stage ≥3) were included in this analysis. Fibrosis regression was evaluated according to the P-I-R score of the Beijing Classification. LREs were defined as decompensations, hepatocellular carcinoma, liver transplantation, or death. The Cox proportional hazards model was used to determine associations of fibrosis regression with LREs.
A total of 733 patients with Ishak stages 3/4 (n = 456; 62.2%) and cirrhosis (Ishak stages 5/6; n = 277; 37.8%) by on-treatment liver biopsy were enrolled. According to the P-I-R score, fibrosis regression, indeterminate, and progression were observed in 314 (42.8%), 230 (31.4%), and 189 (25.8%) patients, respectively. The 7-year cumulative incidence of LREs was 4.1%, 8.7%, and 18.1% in regression, indeterminate, and progression, respectively (log-rank, P < .001). Compared with patients with fibrosis progression, those with fibrosis regression had a lower risk of LREs (adjusted hazard ratio, 0.40; 95% CI, 0.16–0.99; P = .047), followed by the indeterminate group (adjusted hazard ratio, 0.86; 95% CI, 0.40–1.85; P = .691). Notably, this favorable association also was observed in patients with cirrhosis or low platelet counts (<150 × 109/L).
Antiviral therapy–induced liver fibrosis regression assessed by P-I-R score is associated with reduced LREs. This shows the utility of histologic fibrosis regression assessed by on-treatment P-I-R score as a surrogate endpoint for clinical events in patients with hepatitis B virus–related fibrosis or early cirrhosis.
Morphology of immune-mediated hepatitis: A comparison between immune checkpoint inhibitor therapy and combined immune checkpoint inhibitor/anti-angiogenic therapy
2024, Annals of Diagnostic PathologyThe combination of immune checkpoint inhibitors (ICIs) with anti-angiogenic drugs has shown promising anticancer effects. However, ICIs can trigger immune-mediated hepatitis (IMH). We aimed to clarify whether the combined use of anti-angiogenic drugs and ICIs would increase the severity of IMH.
One hundred IMH patients (ICI monotherapy vs. ICI plus anti-angiogenic therapy 30 vs. 70) were retrospectively enrolled. Clinicopathological parameters were compared between the two groups.
IMH mainly showed variable degrees of panlobular hepatitis (84 %), while some cases presented mixed cholangio-hepatitic (14 %) or cholangitic (2 %) pattern. The incidence of moderate-severe injury was not significantly different between the two groups (combination vs. monotherapy 38.6 % vs. 20.0 %, p = 0.109). Specifically, the rates of marked lobular injury and portal inflammation were higher in the combination group than in the monotherapy cohort (p < 0.005), while the frequencies of interface hepatitis, bile duct injury, histiocytosis aggregates, and endothelialitis were comparable between the two groups (p > 0.05). Compared to mild IMH cases, severe IMH cases showed higher immunostaining expression levels of PD-L1 (60.7 % vs. 19.4 %, p < 0.0001). Treatments and outcomes of IMH were not significantly different between the two groups (p > 0.05).
Compared to ICI monotherapy, the administration of anti-angiogenic drugs in combination with ICIs was not associated with increased hepatotoxicity.
Relationship Between Spleen Pathologic Changes and Spleen Stiffness in Portal Hypertension Rat Model
2024, Ultrasound in Medicine and BiologyThe aim of the study described here was to explore the influence of splenic pathology and hemodynamic parameters on spleen stiffness in portal hypertension (PH).
A Sprague‒Dawley rat model of PH (n = 34) induced by CCl4 was established, and 9 normal rats were used as controls. All animals underwent a routine ultrasound examination, spleen stiffness measurement (SSM), liver stiffness measurement (LSM), portal vein pressure (PVP) measurement and histopathologic assessment. The diagnostic performance of SSM and LSM in PH was evaluated. SSMs were compared among the groups at different pathologic and hemodynamic levels. Multiple linear regression was used to analyze the factors affecting SSM.
SSM had excellent diagnostic efficacy for PH (area under the receiver operating characteristic curve [AUC] = 0.900) and was superior to LSM (AUC = 0.794). In a rat model of PH, pathologic changes such as splenic sinus widening, thickening of the splenic capsule and an increase in collagen fibers were observed in the spleen. There were significant differences in SSM at different splenic capsule thicknesses and splenic sinus widths (all p values <0.05), but there were no significant differences in the SSM at different levels of the splenic collagen fiber area and red pulp area (all p values >0.05). In addition, there were significant differences in SSM at different levels of portal vein diameter, blood flow and congestion index (all p values <0.05). Multiple linear regression analysis revealed that PVP, portal vein congestion index and splenic capsule thickness were significantly associated with SSM.
SSM is a good non-invasive way to assess PH. PVP, splenic capsule thickness and portal vein congestion index are responsible for spleen stiffness but not the proliferation of splenic fibrous tissue.