BACKGROUND: ABCB4 gene-related cholestatic liver diseases have a wide spectrum of clinical and genetic variations. The correlation between genotype and clinical phenotype still unclear. This study retrospectively analyzed the clinical and pathological characteristics of 23 patients with ABCB4 gene-related cholestatic liver diseases. Next-generation sequencing was used to identify the genetic causes.
RESULTS: The 23 included patients (15 children and 8 adults) were diagnosed as progressive familial intrahepatic cholestasis type 3 (PFIC3), drug-induced liver injury (DILI), cirrhosis cholestasis, cirrhosis, and mild liver fibrosis. Nineteen patients underwent liver pathological examination of the liver, exhibiting fibrosis, small bile duct hyperplasia, CK7(+), Cu(+), bile duct deletion, and cirrhosis. Thirty ABCB4 variants were identified, including 18 novel variants.
CONCLUSIONS: ABCB4 gene-related cholestatic liver diseases have a wide spectrum of clinical and genetic variations. Biallelic ABCB4 mutation carriers tended to severe PFIC3, which mostly occurs in children; while ABCB4 non-biallelic variants can lead to milder ICP, LACP, DILI or overlapping, mostly in adults. Thus, the ABCB4 genotype has a specific correlation with the phenotype, but there are exceptions. Non-biallelic null mutations can cause severe diseases. The mechanisms underlying this genetic phenotype require further investigation.

The effects of the obliteration of portal venules (OPV) in cirrhotic portal hypertension are poorly understood. To investigate its contribution to portal hypertension in biliary cirrhosis and its underlying mechanism, we evaluated OPV using two-dimensional (2D) histopathology in liver explants from patients with biliary atresia (BA, n = 63), primary biliary cholangitis (PBC, n = 18), and hepatitis B-related cirrhosis (Hep-B-cirrhosis, n = 35). Then, three-dimensional (3D) OPV was measured by X-ray phase-contrast CT in two parallel models in rats following bile duct ligation (BDL) or carbon tetrachloride (CCl4) administration, representing biliary cirrhosis and post-necrotic cirrhosis, respectively. The portal pressure was also measured in the two models. Finally, the effects of proliferative bile ducts on OPV were investigated. We found that OPV was significantly more frequent in patients with biliary cirrhosis, including BA (78.57 ± 16.45%) and PBC (60.00 ± 17.15%), than that in Hep-B-cirrhotic patients (29.43 ± 14.94%, p < 0.001). OPV occurred earlier, evidenced by the paired liver biopsy at a Kasai procedure (KP), and was irreversible even after a successful KP in the patients with BA. OPV was also significantly more frequent in the BDL models than in the CCl4 models, as shown by 2D and 3D quantitative analysis. Portal pressure was significantly higher in the BDL model than that in the CCl4 model. With the proliferation of bile ducts, portal venules were compressed and irreversibly occluded, contributing to the earlier and higher portal pressure in biliary cirrhosis. OPV, as a pre-sinusoidal component, plays a key role in the pathogenesis of portal hypertension in biliary cirrhosis. The proliferated bile ducts and ductules gradually take up the \'territory\' originally attributed to portal venules and compress the portal venules, which may lead to OPV in biliary cirrhosis. © 2024 The Pathological Society of Great Britain and Ireland.

UNASSIGNED: Schistosoma japonicum-infected IL-33 and ST2 gene deficiency (IL-33 -/- and ST2-/- , respectively) mice were used to explore the role of the IL-33/ST2 axis in liver pathology targeting regulatory T cells (Treg)/T helper 17 cells (Th17).
UNASSIGNED: Each mouse was infected percutaneously with 20 S. japonicum cercariae. Hepatic mass index (HMI), liver egg granulomas, hepatic fibrosis biomarkers and serum levels of alanine aminotransferase (ALT) were investigated. Treg and Th17 frequency was determined by flow cytometry. Expressions of Foxp3, ST2, TGF-β1, IL-10, RORγt, and IL-17A were measured via quantitative real-time polymerase chain reaction (qRT-PCR). Concentrations of TGF-β1, IL-10 and IL-17A were tested with ELISA. In vitro experiments, mRNA expressions of Foxp3, TGF-β1, IL-10, Atg5, Beclin-1 and p62 associated with polarization of Treg by recombinant mouse IL-33 (rmIL-33) were detected by qRT-PCR.
UNASSIGNED: An increased expression of IL-33/ST2 was shown in S. japonicum-infected mice. Deficiency of IL-33 or ST2 gene led to an aggravated liver pathology, which was evidenced by elevated hepatic granuloma volume, HMI and ALT levels and fibrosis, which was demonstrated by increased hepatic collagen deposition in the infected mice. Injection of rmIL-33 into the infected IL-33-/- mice strongly abrogated the liver pathology and fibrosis, whereas no detectable effect with injecting rmIL-33 into the infected ST2-/- mice. Furthermore, depletion of the IL-33/ST2 axis inhibited Treg, accompanied by increased Th17. rmIL-33 treatment upregulated Treg and downregulated Th17 in the infected IL-33-/- mice, while no effect in the infected ST2-/- mice. rmIL-33 led to elevated expressions of Atg5, Beclin-1 and inhibited expression of p62 in expansion of Treg.
UNASSIGNED: The IL-33/ST2 axis plays a protective role in S. japonicum infected mice, which is closely related to increasing Treg responses as well as suppressing Th17 responses. Expansion of Treg by IL-33 may be associated with its regulation of autophagy.

BACKGROUND: Although Plasmodium parasites and intestinal helminths share common endemic areas, the mechanisms of these co-infections on the host immune response remain not fully understood. Liver involvement in severe Plasmodium falciparum infections is a significant cause of morbidity and mortality. However, the effect of pre-existing Trichinella spiralis infection on the immune response and liver immune-pathogenesis in P. berghei ANKA (PbANKA)-infected mice needs to be elucidated.
METHODS: Outbred Kunming mice were infected with T. spiralis and 9 days later were challenged with P. berghei ANKA (PbANKA), and the investigation occurred at 13 days after co-infection.
RESULTS: Compared with PbANKA-mono-infected mice, T. spiralis + PbANKA-co-infected mice had similar survival rate but lower PbANKA parasitaemia; however, there were more severe hepatosplenomegaly, increased liver and spleen indexes, and increased liver pathology observed by hematoxylin and eosin staining; higher expression levels of galectin (Gal)-1, Gal-3, CD68+ macrophages, and elastase-positive neutrophils measured by immunohistochemical staining; upregulated mRNA expression levels of Gal-1, Gal-3, cytokines (interferon-gamma (IFNγ) and interleukin (IL)-6), and M1 macrophage polarization marker (inducible nitric oxide synthase (iNOS)) in the liver, and increased expression levels of Gal-1, IFNγ, IL-6, eosinophil cationic protein, eosinophil protein X, and M1 (IL-1β and iNOS) and M2 (Ym1) macrophage polarization markers in the spleen of co-infected mice detected by using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). In vitro study showed that compared with PbANKA-mono-infected mice, there were significantly increased expression levels of Gal-1, Gal-3, IL-6, IL-1β, and iNOS in the peritoneal macrophage isolated from co-infected mice detected by using qRT-PCR. Correlation analysis revealed significant positive correlations between Gal-3 and IL-1β in the peritoneal macrophages isolated from PbANKA-mono-infected mice, between Gal-3 and IFNγ in the spleen of co-infected mice, and between Gal-1 and Ym1 in the peritoneal macrophages isolated from co-infected mice.
CONCLUSIONS: Our data indicate that pre-existing infection of T. spiralis may suppress P. berghei parasitaemia and aggravate malaria-induced liver pathology through stimulating Gal-1 and Gal-3 expression, activating macrophages, neutrophils, and eosinophils, and promoting mediator release and cytokine production.

OBJECTIVE: To investigate the effect of gender on hepatic pathology and antibody-mediated immunity in Schistosoma japonicum-infected C57BL/6 mice.
METHODS: Female and male C57BL/6 mice were infected with S. japonicum, and the hepatic pathological changes were observed using HE and picrosirius red staining in mice 8 weeks post-infection. The serum specific IgG antibody levels against the soluble adult worm antigen (SWA) and soluble egg antigen (SEA) were measured in mice using enzyme-linked immunosorbent assay (ELISA), and the percentages of follicular helper T (Tfh) cells and regulatory T (Treg) cells were detected in mouse spleen and lymph nodes using flow cytometry.
RESULTS: HE staining showed no significant difference in the mean area of a single hepatic egg granuloma between female and male mice 8 weeks post-infection with S. japonicum [(28.050 ± 3.576) × 104 μm2 vs. (26.740 ± 4.093) × 104 μm2; t = 0.241, P = 0.821], and picrosirius red staining revealed no statistical differences between female and male mice in terms of the mean proportion of picrosirius red stained hepatic tissues [(7.667 ± 1.856)% vs. (7.667 ± 1.764)%; t = 0, P = 1] or the mean optical density [(0.023 ± 0.003) vs. (0.027 ± 0.007); t = 0.447, P = 0.678]. ELISA detected no significant differences in the serum IgG antibody levels against SWA [(2.098 ± 0.037) vs. (1.970 ± 0.071); t = 1.595, P = 0.162] or SEA [(3.738 ± 0.039) vs. (3.708 ± 0.043); t = 0.512, P = 0.623] between female and male mice 8 weeks post-infection with S. japonicum. Flow cytometry detected significantly greater percentages of Tfh cells in the spleen [female mice, (8.645 ± 1.356)% vs. (1.730 ± 0.181)%, t = 5.055, P = 0.002; male mice, (8.470 ± 1.161)% vs. (1.583 ± 0.218)%, t = 5.829, P = 0.001] and lymph nodes [female mice, (3.218 ± 0.153)% vs. (1.095 ± 0.116)%, t = 11.040, P < 0.001; male mice, (3.673 ± 0.347)% vs. (0.935 ± 0.075)%, t = 8.994, P = 0.001) of both female and male mice 8 weeks post-infection with S. japonicum than in uninfected mice; however, no significant differences were seen between female and male mice 8 weeks post-infection with S. japonicum in terms of the percentages of Tfh cells in the spleen [(8.645 ± 1.356)% vs. (8.470 ± 1.161)%; t = 0.098, P = 0.925] or lymph nodes [(3.218 ± 0.153)% vs. (3.673 ± 0.347)%; t = 1.332, P = 0.241]. There was no significant difference in the proportion of Treg cells in the spleen of male mice between infected and uninfected mice [(10.060 ± 0.361)% vs. (10.130 ± 0.142)%; t = 0.174, P = 0.867], while a higher proportion of Treg cells was seen in the spleen of female mice 8 weeks post-infection with S. japonicum than in uninfected mice [(10.530 ± 0.242)% vs. (9.450 ± 0.263)%; t = 3.021, P = 0.023]. There was no significant difference in the proportion of Treg cells in the spleen between female and male mice infected with S. japonicum [(10.530 ± 0.242)% vs. (10.060 ± 0.361)%; t =1.077, P = 0.323]. In addition, the proportions of Treg cells were significantly greater in the lymph node of S. japonicum -infected female [(17.150 ± 0.805)% vs. (13.100 ± 0.265)%; t = 4.781, P = 0.003] and male mice [(18.550 ± 0.732)% vs. (12.630 ± 0.566)%; t = 6.402, P = 0.001] than in uninfected mice; however, no significant difference was seen between female and male mice 8 weeks post-infection [(17.150 ± 0.805)% vs. (18.550 ± 0.732)%; t = 1.287, P = 0.246].
CONCLUSIONS: There are no gender-specific hepatic pathological changes or antibody-mediated immunity in C57BL/6 mice post-infection with S. japonicum.
［摘要］ 目的 探讨性别因素对日本血吸虫感染所致C57BL/6小鼠肝脏病理及抗体免疫的影响。方法 雌、雄C57BL/6 小鼠分别感染日本血吸虫8周, 应用HE染色、天狼星红染色观察小鼠肝脏病理变化。采用酶联免疫吸附试验 (ELISA) 检测雌、雄C57BL/6小鼠血清抗可溶性成虫抗原 (SWA) 和可溶性虫卵抗原 (SEA) 特异性IgG抗体水平, 采用流式细胞术检测雌、雄C57BL/6小鼠脾脏、淋巴结中滤泡辅助性T (Tfh) 细胞和调节性T (Treg) 细胞水平。结果 感染日本血吸虫 8 周后, 雌 ([ 28.050 ± 3.576) × 104 μm2]、雄小鼠肝组织中平均单个虫卵肉芽肿面积 ([ 26.740 ± 4.093) × 104 μm2] 差异无统计学意义 (t = 0.241, P = 0.821); 天狼星红染色结果显示, 感染日本血吸虫雌、雄小鼠肝纤维化程度差异亦无统计学意义[天狼星红染色阳性区域平均比例： (7.667 ± 1.856) % vs. (7.667 ± 1.764) %; t = 0, P = 1; 平均光密度： (0.023 ± 0.003) vs. (0.027 ± 0.007); t = 0.447, P = 0.678]。ELISA检测结果显示, 雌、雄小鼠感染日本血吸虫 8 周后血清抗 SWA [ (2.098 ± 0.037) vs. (1.970 ± 0.071); t = 1.595, P = 0.162] 和SEA特异性IgG抗体水平 ([ 3.738 ± 0.039) vs. (3.708 ± 0.043); t = 0.512, P = 0.623] 差异均无统计学意义。流式细胞术检测结果表明, 感染日本血吸虫8周后雌、雄小鼠脾脏[雌鼠： (8.645 ± 1.356) % vs. (1.730 ± 0.181) %, t = 5.055, P = 0.002; 雄鼠： (8.470 ± 1.161) % vs. (1.583 ± 0.218) %, t = 5.829, P = 0.001]、淋巴结 [雌鼠： (3.218 ± 0.153) % vs. (1.095 ± 0.116) %, t = 11.040, P < 0.001; 雄鼠： (3.673 ± 0.347) % vs. (0.935 ± 0.075) %, t = 8.994, P < 0.001]中Tfh细胞比例均显著高于未感染小鼠, 但雌、雄小鼠脾脏 ([ 8.645 ± 1.356) % vs (. 8.470 ± 1.161) %; t = 0.098, P = 0.925]和淋巴结 ([ 3.218 ± 0.153) % vs. (3.673 ± 0.347) %; t = 1.332, P = 0.241]中Tfh细胞比例差异均无统计学意义。感染日本血吸虫8周雄鼠脾脏中Treg细胞比例与未感染小鼠无显著差异 ([ 10.060 ± 0.361) % vs. (10.130 ± 0.142) %; t = 0.174, P = 0.867], 而日本血吸虫感染雌鼠脾脏中Treg细胞比例显著高于未感染小鼠 ([10.530 ± 0.242) % vs. (9.450 ± 0.263) %; t = 3.021, P = 0.023], 但感染日本血吸虫雌、雄小鼠脾脏中Treg 细胞比例差异无统计学意义 ([ 10.530 ± 0.242) % vs. (10.060 ± 0.361) %; t =1.077, P = 0.323]; 日本血吸虫感染8周后, 雌 ([ 17.150 ± 0.805) % vs. (13.100 ± 0.265) %; t = 4.781, P = 0.003]、雄鼠淋巴结中Treg细胞比例均较未感染小鼠显著增加 ([ 18.550 ± 0.732) % vs. (12.630 ± 0.566) %; t = 6.402, P < 0.001], 但感染日本血吸虫雌、雄小鼠淋巴结中Treg 细胞比例差异无统计学意义 ([ 17.150 ± 0.805) % vs. (18.550 ± 0.732) %; t = 1.287, P = 0.246]。结论 利用C57BL/6小鼠研究日本血吸虫感染所致肝脏病理及抗体产生机制时, 不需要考虑性别因素。.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, and novel methods for early/rapid diagnosis of HCC are needed. Terahertz (THz) spectroscopy is considered to have the potential to distinguish between normal liver tissue and HCC tissue; however, there are few reports on it. We conduct this observational study to explore the feasibility of THz imaging for the diagnosis of HCC.
OBJECTIVE: To evaluate the feasibility of THz for discriminating between HCC and normal liver tissues using fresh tissue specimens obtained from HCC patients who had undergone surgery.
METHODS: Normal liver tissue and HCC tissue were cryosectioned into 50 μm-thick slices and placed on cover glass. Two adjacent tissue sections were separated subjected to histopathological examination by hematoxylin and eosin staining or THz transmission examination, and THz images were compared with pathologically mapped images. We determined the typical tumor and normal liver tissue regions by pathological examination; the corresponding areas of adjacent sections were examined by THz transmission.
RESULTS: The transmission rate of HCC tissue was 0.15-0.25, and the transmission rate of typical HCC tissue was about 0.2. THz transmittance in normal liver tissue is slightly higher than 0.4, but there were many influencing factors, including the degree of liver cirrhosis, fat components, ice crystals in frozen sections, and apoptosis.
CONCLUSIONS: In conclusion, this study shows that THz imaging can detect HCC tissue. Further research will yield more detailed data of the THz transmission rates of HCC tissue with different degrees of differentiation.

UNASSIGNED: Lysine is used widely in livestock production due to the shortage of feed protein resources. L-lysine·H2SO4 contains L-lysine sulphate as well as fermentation co-products which contain other amino acids and phosphorus. However, there are few articles about L-lysine·H2SO4 product regarding intestinal morphology and liver pathology of broiler chickens. In this article, we focus on the absorption and metabolism of L-lysine·H2SO4 revealed in the variation of intestinal morphology and liver pathology to determine the tolerance of chicks for L-lysine·H2SO4.
UNASSIGNED: To evaluate the tolerance of broilers for L-lysine·H2SO4, 240 one day old broilers were allocated randomly to one of five dietary treatments which included corn-soybean diets containing 0, 1%, 4%, 7% or 10% L-lysine·H2SO4 (L-lysine content = 55%).
UNASSIGNED: Supplementation of 1% L-lysine·H2SO4 in the diet had no negative effects. However, 4%, 7% or 10% L-lysine·H2SO4 supplementation produced negative responses on broiler performance, carcass characteristics, blood biochemistry, and particularly on intestinal morphology and liver pathology compared with broilers fed the control diet.
UNASSIGNED: Our results show that supplementation with 1% L-lysine·H2SO4 had no negative effects on performance, carcass characteristics, blood biochemistry, intestinal morphology and liver pathology in broilers, but supplementation with 4%, 7% or 10% L-lysine·H2SO4 produced a negative response, particularly with respect to intestinal morphology and liver pathology.

Liver-related autoimmune toxicities triggered by agonistic anti-CD137 antibodies have greatly limited their use in clinical applications. Here, we found that anti-CD137 monoclonal antibody (mAb) treatment in mice induced the infiltration of a large number of S100A4+ macrophages into the liver. Depletion of these cells or deficiency of S100A4 decreased inflammatory cytokine profiles and drastically reduced the number of liver pathogenic CD8+ T cells. Mechanistically, soluble S100A4 directly activated the Akt pathway and specifically prolonged CD8+ T cell survival. Interestingly, one S100A4 neutralizing mAb selectively alleviated liver abnormalities but did not affect the antitumor immunity induced by anti-CD137 mAb therapy. Thus, our study presents a novel molecular link to the liver pathology induced by an immune stimulatory antibody and proposes that combinational immunotherapies targeting those pathways could potentially elicit optimal antitumor immunity with minimal side effects.

Liver disease is a primary cause of liver-related morbidity and mortality worldwide. Currently, histological examination is the gold standard for diagnosis and classification of liver disease; however, due to its several drawbacks, including the risk of complications and sampling variability, noninvasive diagnostic options are favorable. Exosomal miRNAs have recently been considered as an important source of medical biomarkers due to being widely distributed in body fluids. This review summarizes existing concepts related to the origin, mode of transportation and possible functions of exosomal miRNAs, and recent findings on the role of exosomal miRNAs in liver diseases and development of exosomal miRNA-based diagnostic biomarkers in the primary forms of liver diseases.

Objective: To investigate the expression of programmed death-1 (PD-1) in liver tissue and its association with liver pathology in patients with autoimmune hepatitis (AIH). Methods: A total of 54 AIH patients (38 in the active stage and 16 in the remission stage) were enrolled, and 9 healthy volunteers were enrolled as control group. Immunohistochemistry combined with quantitative image analysis was used to measure the expression of PD-1 in liver tissue. The t-test, rank sum test, one-way analysis of variance, least significant difference t-test, Mann-Whitney U test, and Pearson relation analysis were used for statistical analysis of different types of data. Results: The AIH group had a significantly higher positive rate of PD-1 in liver tissue than the control group (13.57%±6.84% vs 2.22%±0.66%, P < 0.01), and the patients in the active stage of AIH had a significantly higher positive rate of PD-1 in liver tissue than those in the remission stage (16.53%±7.72% vs 6.56%±3.16%, P < 0.01). The positive rate of PD-1 in liver tissue was 6.56%±3.16% in G0 group, 14.33%±5.08% in G1-2 group, and 19.23%±5.41% in G3-4 group (P < 0.01), but there was no significant difference in the positive rate of PD-1 between S0, S1-2, and S3-4 groups (P > 0.05). In AIH patients, the positive rate of PD-1 in liver tissue was positively correlated with the levels of total bilirubin, alanine aminotransferase, aspartate aminotransferase, and IgG (r = 0.665, 0.721, 0.711, and 0.813, all P < 0.01). Conclusion: AIH patients have regulated PD-1 expression in liver tissue, which is closely associated with liver inflammation and is not associated with fibrosis degree, suggesting that PD-1 is involved in the development and progression of inflammation in AIH patients.
目的： 研究自身免疫性肝炎（AIH）患者肝组织中程序性死亡受体1（PD-1）的表达情况，并探讨其与肝脏病理的相关性。 方法： 收集54例AIH患者（活动期38例和缓解期16例），并选择9例健康者为对照组。采用免疫组织化学方法结合图像定量分析系统检测肝组织中PD-1的表达。据资料不同分别采用t检验、秩和检验、单因素方差分析及LSD-t检验、Mann-Whitney U及Pearson相关分析进行统计学分析。 结果： AIH患者肝组织PD-1阳性表达率高于对照组（13.57%±6.84%对比2.22%±0.66%，P < 0.01）；AIH活动期肝组织PD-1阳性表达率高于缓解期（16.53%±7.72%对比6.56%±3.16%，P < 0.01）。G0组、G1～2组及G3～4组AIH患者肝组织中PD-1阳性表达率逐渐升高，分别为6.56%±3.16%、14.33%±5.08%、19.23%±5.41%（P < 0.01），而S0组、S1～2组及S3～4组AIH患者肝组织中PD-1阳性表达率则无差异（P > 0.05）。AIH患者肝组织PD-1阳性表达率与总胆红素、丙氨酸氨基转移酶、天冬氨酸氨基转移酶及IgG水平均呈正相关（r分别是0.665、0.721、0.711、0.813，P < 0.01)。 结论： AIH患者肝组织PD-1表达上调，与肝组织炎症活动密切相关，但与纤维化分级无相关性，提示PD-1参与了AIH炎症的发生及发展。.