Intrahepatic Ducts Research Articles

Regulatory T cells in inflamed liver are dysfunctional in murine primary biliary cholangitis.

Primary biliary cholangitis (PBC) is a chronic autoimmune disease characterized by immune-mediated destruction of intrahepatic small bile ducts. CD8 T cells play a critical role in biliary destruction. However, regulatory T cells (Tregs) have also been identified in the portal tracts of PBC patients. This study tested the hypothesis that hepatic Tregs in PBC were dysfunctional in suppressing immune responses in disease by using our human PBC-like autoimmune cholangitis (AIC) mouse model induced by 2-octynoic acid-conjugated ovalbumin (2-OA-OVA). Our results showed that female and male mice immunized with 2-OA-OVA developed AIC; however, female AIC mice had more severe liver inflammation and fibrosis than male AIC mice. Levels of functional effector CD8 T cells and their chemoattractants, CXCL9 and CXCL10, in the liver were markedly elevated in female AIC mice than in male AIC mice. These results reinforce that CD8 T cells are the primary effector cells in PBC. The number of hepatic Tregs in AIC mice was also higher than in saline-treated mice, but there was no difference between male and female AIC mice. The suppressive function of AIC Tregs was evident despite a discrepancy in the changes in their co-inhibitory receptors and inhibitory cytokines. However, the expansion of hepatic Tregs by low-dose IL-2 treatment did not reduce immune responses to AIC, which may be due to the dysfunction of Tregs in inhibiting T cells. In conclusion, the function of Tregs in the inflamed liver of PBC was insufficient, and low-dose IL-2 treatment could not restore their function to suppress pathological immune responses. Transferring normal Tregs or directly targeting effector CD8 T cells may be beneficial for treating PBC.

PECULIARITIES OF THE STRUCTURE OF THE INTRAHEPATIC BILE DUCTS OF HERBIVOROUS MAMMALS

Pathology of the organs of the hepatobiliary system, which happens in the form of calculous and non-calculous cholecystitis, cholangitis of various etiologies and other diseases of the biliary system, occupies one of the first places among surgical interventions on the organs of the abdominal cavity.
 Among the adult population, about 10% of those able to work suffer from gallstone disease. This disease is spreading in all countries of the world, and the tendency to its increase is growing. Such an increase in the pathology of the biliary tract is also observed in economically developed countries. Observations show that men suffer less often than women.
 The structure of the wall of the intrahepatic ducts is represented by the inner mucous membrane and the outer adventitia membrane. But the structure of their wall in different parts of the liver has its own characteristics. At the beginning of the intraciliary system of the liver, the mucous membrane is represented by epitheliolytic, which have a cubic shape.
 The outer shell is represented by cells of the fibroblastic series. In the average department of the internal biliary system of the liver, there is an increase in the size and number of cells in the inner lining of the ducts. Nuclei in the initial division change shape to a bean-like one. Changes in the inner membrane are observed in the terminal part of the intraciliary system of the sheep’s liver. Cells become prismatic and folds can be observed on their apical surface. Nuclei are localized on the basal surface and have a bean-like shape.

Trendy v predčasných úmrtiach na zhubné nádory tráviacej sústavy na Slovensku v rokoch 2011–2020: 8 dia gnóz počas 10 rokov

Introduction and objectives: Slovakia ranks among the leaders in preventable deaths, but a systematic analysis of the share of digestive system cancers (DSCs) and their trends has been lacking. We analyzed data on mortality from DSCs in Slovakia in the years 2011–2020 with an emphasis on premature deaths, sex differences, and trends for individual locations. Material and methods: Data in the years 2011–2020 by ICD-10 codes C15–C26 aggregated by age subgroups (<50 years, <65 years, <75 years), sex, and individual locations were available. The crude death rate was calculated per 100,000 inhabitants and linear regression was used for the annual percentage change in mortality. Results: We recorded 46,508 deaths; 27,146 were men and 19,362 women with an average age of 70,5 ±11,6. Deaths under the age of 50, 65, and 75 made up 4.1%, 29.8%, and 60.4% of all deaths from DSCs. Among all deaths due to cancer under the age of 65, deaths from DSCs accounted for one-third in men and one-quarter in women. Under the age of 75, colorectal (41%), pancreatic (21%), stomach (12.8%), and liver (10%) cancers dominated the proportions of locations. The average age of death was significantly lower in men and increased over the decade for all locations. In women, the trend was identical, except for the liver, intrahepatic bile ducts (decrease by 1 year), bile ducts, and stomach (no change). Under the age of 65 in all cases, the average annual mortality rate decreased by 1.7%. In men, it decreased for locations in the esophagus, stomach, colorectum (–1.8%/year), liver, and gallbladder. In women, for colorectum (–1.8%/year) and gallbladder (–6%/year). In contrast, in the entire population mortality increased for locations in the pancreas (+2.3 to 2.8%/year) and bile ducts (+4.4 to 7.3%/year). Conclusion: DSCs are significant burden causing preventable deaths. Some favorable trends (stomach, gall bladder) are simultaneously followed by unfavorable ones (biliary tract, pancreas). In the global context of an aging population and increasingly longer exposure to risk factors, we need to introduce effective societal preventive measures as well as flexible adaptation of our healthcare systems.

Biliary sepsis complication with congenital hepatic fibrosis: an unexpected outcome

BackgroundCHF (Congenital hepatic fibrosis) is a rare hereditary disease characterized by periportal fibrosis and ductal plate malformation. Little is known about the clinical presentations and outcome in CHF patients with an extraordinary complication with biliary sepsis.Case summaryOur case described a 23-year-old female diagnosed as CHF combined with biliary sepsis. Her blood culture was positive for KP (Klebsiella pneumoniae), and with a high level of CA19-9 (> 1200.00 U/ml, ref: <37.00 U/ml). Meanwhile, her imaging examinations showed intrahepatic bile duct dilatation, portal hypertension, splenomegaly, and renal cysts. Liver pathology revealed periportal fibrosis and irregularly shaped proliferating bile ducts. Whole-exome sequencing identified two heterozygous missense variants c.3860T > G (p. V1287G) and c.9059T > C (p. L3020P) in PKHD1 gene. After biliary sepsis relieved, her liver function test was normal, and imaging examination results showed no significant difference with the results harvested during her biliary sepsis occurred.ConclusionThe diagnosis of CHF complicated with biliary sepsis in the patient was made. Severely biliary sepsis due to KP infection may not inevitably aggravate congential liver abnormality in young patients. Our case provides a good reference for timely treatment of CHF patients with biliary sepsis.

Rhino-orbital mucormycosis following liver transplantation in a child with COVID-19 (a review of the literature and clinical observation)

The incidence of mucormycosis, an opportunistic infection, has been increasing worldwide in recent years. This is primarily due to the spread of coronavirus disease 2019 and the increase in the number of at-risk populations. Risk groups include patients with conditions or diseases, such as diabetes, neutropenia, organ or stem cell transplantation (on immunosuppressive therapy), trauma and burns, hematological disorders, and steroid therapy. The basis of successful treatment includes early diagnosis based on the detection of the first nonspecific signs of the disease in patients at risk, rapid verification of pathogens, earliest possible start of etiotropic therapy, and prompt and aggressive surgical treatment (necrectomy). This study presents a clinical case of rhino-orbital mucormycosis in a child at risk. The patient had Alagille syndrome and was followed up from the age of 2 years. The syndrome is characterized by an insufficient number or the small diameter of the intrahepatic bile ducts that remove bile from the liver and lead to the development of liver cirrhosis. Liver transplantation is the only radical treatment method for liver cirrhosis in the absence of gross defects. By the age of 8 years, the syndrome led to liver cirrhosis, and in 2020, hepatectomy was performed, including orthotopic transplantation of a liver fragment from a related donor (aunt). The patient subsequently received immunosuppressive therapy. The article also described the changes in the clinic and imaging methods and stages of treatment by day. Clinical manifestations of mucormycosis appeared on day 6 of hospitalization, that is, edema of the left lower eyelid. The severe general condition of the child did not allow for early surgical treatment with the excision of necrotic tissues. Unfortunately, the patient died. Thus, possible errors in diagnosis and treatment were analyzed.

Surgical Strategies for Neonates with Prenatally Diagnosed Congenital Biliary Dilatation

BackgroundThis study aimed to develop a postnatal treatment strategy for infants with prenatally diagnosed congenital biliary dilatation. MethodsWe performed a retrospective study of patients with prenatal diagnosed congenital biliary dilatation (CBD), aged <1 year who underwent surgery at our hospital between 2013 and 2023. We classified the patients into two groups, the “early group,” consisting of patients who could not wait for growth, and required early surgery, and the “scheduled group,” consisting of patients who were asymptomatic and could undergo scheduled surgery, and compared them. The parameters for early surgical prediction were AST, ALT, TB, DB, and CRP levels at birth, 1 week, 2 weeks, 1 month, 2 months, and 3 months after birth, and immediately before surgery, as well as the cyst diameter, presence of intrahepatic bile duct dilation, and presence of debris in the common bile duct. ResultsDuring the study period, 15 patients were diagnosed prenatally. The cyst diameter was significantly larger at all points in the early group. Patients with a cyst diameter of >30 mm at birth, intrahepatic bile duct dilatation at birth, and postnatal enlargement of the common bile duct to >30 mm are more likely to develop symptoms early. Blood biochemistry tests showed no significant differences between the two groups. ConclusionsPatients with a cyst diameter >30 mm in the early postnatal period require careful postnatal management and parents should be counseled regarding the high likelihood of their child needing surgery within the first 3 months of life. Level of evidenceLevel IV.

Bioinformatic analysis identified novel candidate genes with the potentials for diagnostic blood testing of primary biliary cholangitis.

Primary biliary cholangitis (PBC) is an autoimmune disorder characterized by intrahepatic bile duct destruction and cholestatic liver injury. Diagnosis of PBC is generally based on the existence of anti-mitochondrial antibody (AMA) in blood samples; however, some PBC patients are negative for serum AMA tests, and invasive liver histological testing is required in rare PBC cases. The current study seeks novel candidate genes that are associated with PBC status and have potentials for blood diagnostic testing. Human transcriptomic profiling data of liver and blood samples were obtained from Gene Expression Omnibus (GEO). Three GEO data series (GSE79850, GSE159676, and GSE119600) were downloaded, and bioinformatic analyses were performed. Various differentially expressed genes were identified in three data series by comparing PBC patients and control individuals. Twelve candidate genes were identified, which were upregulated in both liver tissues and blood samples of PBC patients in all three data series. The enrichment analysis demonstrated that 8 out of 12 candidate genes were associated with biological functions, which were closely related to autoimmune diseases including PBC. Candidate genes, especially ITGAL showed good potentials to distinguish PBC with other diseases. These candidate genes could be useful for diagnostic blood testing of PBC, although further clinical studies are required to evaluate their potentials as diagnostic biomarkers.

Surgical Management of Choledochal Cyst in Male Adolescent, Case Report

Common bile duct cysts are a rare medical condition, which is characterized by dilation of the intrahepatic and extrahepatic bile ducts. The main clinical presentation is abdominal pain, jaundice and a palpable abdominal mass. They are premalignant lesions, so the treatment of choice is complete surgical resection with long-term follow-up. The following report relates a male adolescent treated surgically with good results

HLA-DPA1*02:01~B1*01:01 is a risk haplotype for primary sclerosing cholangitis mediating activation of NKp44+ NK cells

ObjectivePrimary sclerosing cholangitis (PSC) is characterised by bile duct strictures and progressive liver disease, eventually requiring liver transplantation. Although the pathogenesis of PSC remains incompletely understood, strong associations with HLA-class...

CD24+LCN2+ liver progenitor cells in ductular reaction contributed to macrophage inflammatory responses in chronic liver injury

BackgroundCD24+CK19+/CD24+SOX9+ resident liver cells are activated and expanded after chronic liver injury in a ductular reaction. However, the sources and functions of these cells in liver damage remain disputed.ResultsThe current study combined genetic lineage tracing with in vitro small-molecule-based reprogramming to define liver progenitor cells (LPCs) derived from hepatic parenchymal and non-parenchymal tissues. tdTom+ hepatocytes were isolated from ROSA26tdTomato mice following AAV8-Tbg-Cre-mediated recombination, EpCAM+ biliary epithelial cells (BECs) from wild-type intrahepatic bile ducts and ALB/GFP−EpCAM− cells were isolated from AlbCreERT/R26GFP mice. A cocktail of small molecules was used to convert the isolated cells into LPCs. These in vitro cultured LPCs with CD24 and SOX9 expression regained the ability to proliferate. Transcriptional profiling showed that the in-vitro cultured LPCs derived from the resident LPCs in non-parenchymal tissues expressed Lipocalin-2 (Lcn2) at high levels. Accordingly, endogenous Cd24a+Lcn2+ LPCs were identified by integration of sc-RNA-sequencing and pathological datasets of liver dysfunction which indicates that LPCs produced by ductular reactions might also originate from the resident LPCs. Transplantation of in-vitro cultured Cd24a+Lcn2+ LPCs into CCl4-induced fibrotic livers exacerbated liver damage and dysfunction, possibly due to LCN2-dependent macrophage inflammatory response.ConclusionsCD24+LCN2+ LPCs constituted the expanding ductular reaction and contributed to macrophage-mediated inflammation in chronic liver damage. The current findings highlight the roles of LPCs from distinct origins and expose the possibility of targeting LPCs in the treatment of chronic hepatic diseases.Graphical

Predictors of success of conventional ERCP for bile duct stones and need for single-operator cholangioscopy.

Background and study aims The characteristics of difficult stones requiring cholangioscopy-assisted lithotripsy are poorly defined. We sought to determine clinician perception of these characteristics and decision-making in biliary endoscopy. Methods One hundred twenty-four delegates attending an online course were invited to assess 20 clinical stone cases. Each image was graded on a 4-point Likert for: grading of stone difficulty, confidence of clearance with conventional endoscopic retrograde cholangiopancreatography (ERCP) methods, likelihood of needing cholangioscopy-assisted lithotripsy, and confidence of clearance with one session of lithotripsy. An independent reviewer rated each case on largest stone size, stone number, presence of stricture distal to stone, size of stone relative to distal duct size, and acute common bile duct (CBD) angulation < 135°. Multilevel (mixed) statistical methods with a two-level model were utilized with multilevel ordinal logistic regression. Results Stone size and location, stricture and stone diameter:duct ratio impacted perceived procedural difficulty P < 0.01). Stone:duct ratio (< 50% odds ratio [OR] 0.22, P < 0.001), stricture (OR 7.26, P < 0.001) and stone location impacted confidence of clearance with conventional ERCP. Intrahepatic and cystic duct stones were least likely to engender confidence ( P < 0.01). The same factors plus CBD angulation < 135° predicted cholangioscopy requirement ( P < 0.01). Stone number did not influence procedure difficulty or cholangioscopy requirement. Strictures (OR 0.29, P < 0.001) and location, especially intrahepatic (OR 0.42, P < 0.001) impaired confidence in clearance with one cholangioscopy session. Conclusions Ductal anatomy, the presence of a stricture distal to a stone, cystic and intrahepatic stones and stones larger than the distal duct are considered by endoscopists to be significant predictors of requiring cholangioscopy-assisted lithotripsy.

Mortality due to malignant neoplasms of the liver and intrahepatic biliary tract in the state of Mato Grosso in 2020

Malignant neoplasms of the liver and intrahepatic biliary tract occupy the third place of cancer deaths in the world and the second most deadly in men and the sixth in women. Eating habits characterized by the consumption of food with high caloric and glycemic indexes, associated with a sedentary lifestyle, provide a greater risk of developing hepatic steatosis, as well as obesity, which, together with the increased incidence of chronic viral hepatitis, excessive alcoholism, and age over 50 years, constitute the main risk factors for the development of these types of cancer. In addition, due to the chronicity of liver pathologies, the diagnosis is usually late, a factor that contributes to increase the mortality rate. Thus, the objective of this work is to analyze the epidemiological profile of deaths due to liver cancer and intrahepatic biliary tract that occurred in the state of Mato Grosso in 2020. This is a cross-sectional study based on data from the Mortality Information System (SIM), made available by the Department of Informatics of the Unified Health System (DATASUS), and in the population estimate of the Brazilian Institute of Geography and Statistics (IBGE) for 2020. A study was carried out of the epidemiological profile of deaths related to liver and intrahepatic biliary ducts neoplasms (CID 10 C-22) of the state of Mato Grosso for the year 2020 regarding age group, sex (gender), and race. A total of 120 deaths due to malignant neoplasms of the liver and intrahepatic biliary tract were reported, corresponding to a mortality rate of approximately 3.4 deaths/100,000 inhabitants, with the proportion of deaths between men and women approximately 4:3. For both sexes, there is an abrupt increase in the incidence of deaths after the sixth decade of life, corresponding to 90% of deaths due to this pathology. Regarding the racial evaluation, deaths are more incident in the yellow race, with about 4.97 deaths/100,000 inhabitants, followed by the black race with 4.87 deaths/100,000 inhabitants. Thus, it is evident that deaths from liver and intrahepatic biliary tract malignant neoplasms in the state of Mato Grosso, in 2020, were concentrated from the sixth decade of life, especially in men, with emphasis on the yellow race. It should be noted that the analysis of epidemiological characteristics is essential for the development of screening policies and early diagnosis in patients with modifiable and non-modifiable risk factors.

Disruption of IL-18 signaling via engineered IL-18BP biologics alleviates experimental cholestatic liver disease

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by progressive inflammation and fibrosis around intrahepatic and extrahepatic bile ducts leading to severe hepatic cirrhosis and high mortality. Although there is an urgent clinical unmet need for PSC, no effective medical therapy has been developed to delay the disease progression until today. IL-18 binding protein (IL-18BP) is well-known to be a natural negative feedback regulator for IL-18, and we have developed a recombinant long-acting IL-18BP referred to as APB-R3 as a therapeutic agent to treat IL-18-related inflammatory diseases. Here, we aimed to study whether disrupted IL-18 signaling by APB-R3 treatment can inhibit PSC injuries in the experimental DDC diet-induced PSC rodent model. First, we found that the amounts of free IL-18 are augmented under PSC condition with increased expression of biliary IL-18 receptors. Administration of APB-R3 effectively attenuated key diagnostic parameters of PSC such as plasma ALP and GGT levels as well as bile acids levels. We also observed that blockade of IL-18 suppressed ductular reactive and proliferative phenotypes of cholangiocytes. Additionally, APB-R3 significantly ameliorated DDC diet-induced periductal fibrosis and transcriptional expressions of pro-fibrotic marker genes. Enhanced senescence associated secretory phenotype (SASP) markers in cholestatic liver disease were diminished by APB-R3 treatment. Our findings clearly demonstrate that the administration of IL-18BP biologics, APB-R3, effectively alleviates DDC diet-induced biliary injuries in rodent PSC model, implying APB-R3 can be a promising therapeutic reagent which warrants clinical human trials as new therapeutic options.

Percutaneous transhepatic digital single-operator cholangioscopy-guided laser lithotripsy in treating difficult intrahepatic duct stone in surgically altered anatomy.

Percutaneous transhepatic digital single-operator cholangioscopy-guided laser lithotripsy in treating difficult intrahepatic duct stone in surgically altered anatomy.

Estrogen receptor alpha-mediated mitochondrial damage in intrahepatic bile duct epithelial cells leading to the pathogenesis of primary biliary cholangitis.

This study investigated the effects of estrogen and estrogen receptor alpha (ERα) on the pathogenesis of primary biliary cholangitis (PBC) in human intrahepatic bile duct epithelial cells (HiBECs). The researchers measured serum levels of ERα, oxidative stress indicators, and cytokines in PBC patients and healthy controls. They examined the expression of ERα, pyruvate dehydrogenase complex E2-component (PDC-E2), and apoptosis-related proteins in the small bile ducts. In vitro experiments with HiBECs showed that estrogen had a dual effect on cell viability, increasing it at low concentrations but reducing it at higher concentrations. ERα activation led to mitochondrial damage, apoptosis, and upregulation of ERα and PDC-E2 expression. These findings suggest that the high expression of ERα in the bile ducts contributes to mitochondrial damage, inflammation, and apoptosis in PBC. The study highlights ERα as a potential target for understanding and treating estrogen-mediated PBC pathogenesis.

Post-COVID-19 cholangiopathy: Systematic review.

The coronavirus disease 2019 (COVID-19) pandemic has had a profound impact on global health, primarily characterized by severe respiratory illness. However, emerging evidence suggests that COVID-19 can also lead to secondary sclerosing cholangitis (SC), referred to as post-COVID-19 cholangiopathy. To synthesize currently reported cases to assess the current state of knowledge on post-COVID-19 cholangiopathy. Medical Subject Headings and Health Sciences Descriptors were used to retrieve relevant studies, which were combined using Boolean operators. Searches were conducted on electronic databases including Scopus, Web of Science, and MEDLINE (PubMed). Studies published in English, Spanish, or Portuguese were included, with no restrictions on the publication date. Additionally, the reference lists of retrieved studies were manually searched. Simple descriptive analyses were used to summarize the results. Then the data were extracted and assessed based on Reference Citation Analysis (https://www.referencecitationanalysis.com/). The initial search yielded a total of 192 articles. After screening, 85 articles were excluded due to duplication, leaving 107 articles for further review. Of these, 63 full-length articles met the inclusion criteria and were included in the analyses. Most of the patients were male and exhibited elevated liver function tests (93.8%). Magnetic resonance imaging revealed duct thickening with contrast enhancement (47.7%), as well as beading of the intrahepatic ducts (45.7%) with peribiliary contrast enhancement on diffusion (28.7%). Liver biopsy results confirmed SC in most cases (74.4%). Sixteen patients underwent liver transplantation, with three experiencing successful outcomes. Post-COVID-19 cholangiopathy is a serious condition that is expected to become increasingly concerning in the coming years, particularly considering long COVID syndromes. Although liver transplantation has been proposed as a potential treatment option, more research is necessary to establish its efficacy and explore other potential treatments.

Intrahepatic cholangiocarcinoma with extensive intraductal extension of high-grade biliary intraepithelial neoplasia: a case report

BackgroundIntrahepatic cholangiocarcinoma (ICC) is frequently associated with precursor lesions, and biliary intraepithelial neoplasia (BilIN) may play a significant role in the development of ICC. However, the exact sequence and progression of these lesions remain to be elucidated. We report a rare case of ICC that exhibited extensive longitudinal intraductal extension of high-grade BilIN in the posterior bile ducts and involved the hepatic hilum and the peripheral hepatic parenchyma.Case presentationA 70-year-old female presented with anorexia. Computed tomography (CT) revealed a 15 mm enhancing intrahepatic tumor extending to the right intrahepatic secondary confluence. This was associated with a 7 mm diameter cystic dilatation of the segment 6 bile duct (B6). Endoscopic retrograde cholangiopancreatography (ERCP) revealed stenosis at the bifurcation of the posterior bile duct branch. Bile cytology confirmed the diagnosis of adenocarcinoma cells. Therefore, the patient was diagnosed with an ICC involving the right glissonean pedicle and underwent a right hepatectomy and lymph node dissection. Histologic examination revealed the tumor consisted of moderately differentiated adenocarcinoma. In connection with this lesion, diffuse intraductal atypical epithelial cells, which were diagnosed as high-grade BilIN, was observed not only in the dilated B6 but in the entire posterior bile ducts, which measured approximately 120 mm in diameter. Furthermore, two distinct foci of adenocarcinomas were identified in the peripheral hepatic parenchyma. A lymph node metastasis was also present. The pathological diagnosis was ICC pT4N1M0 stage IVA. The patient underwent adjuvant chemotherapy and has shown no recurrence 5 years after surgery. Imaging modalities were unable to accurately assess the extent of the intraductal neoplastic lesions due to their low papillary or sessile intraductal tubular growth. No risk factors for BilIN development, which has the potential to predispose to cholangiocarcinoma, were identified in the present case.ConclusionsWe present a case of ICC involving the right hepatic hilum, accompanied by extensive longitudinal extensions of high-grade BilIN and multifocal microscopic invasions in peripheral hepatic parenchyma. Notably, the intraductal lesions involved the entire posterior intrahepatic bile ducts. The presence of biliary neoplasia with extensive intraductal extension, in conjunction with ICC, should be considered as a variant of BilIN.

IL-21, not IL-17A, exacerbates murine primary biliary cholangitis.

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease caused by intrahepatic bile duct injuries, resulting in fibrosis, cirrhosis, and eventually liver failure. T helper (Th) 17 cells are proposed to involve in the pathogenesis of PBC. However, how and which Th17 cell-derived cytokines affect PBC remains unclear. In this study, we investigated the effects of Th17 effector cytokines, including interleukin (IL)-17A, IL-17F, and IL-21 in PBC using a xenobiotic-induced mouse model of autoimmune cholangitis (inducible chemical xenobiotic models of PBC) treated with cytokine-expressing adeno-associated virus. Our results showed that administration of IL-17A, the well-known main cytokine produced by Th17 cells, did not augment liver inflammation or fibrosis. In contrast, we noted IL-17A-treated mice had lower hepatic Th1 cell numbers and higher hepatic CD11b+Ly6G+ polymorphonuclear myeloid-derived suppressor cell numbers. IL-17F did not alter liver inflammation or fibrosis. However, the administration of IL-21 exacerbated liver inflammatory responses and portal cell infiltration. IL-21 markedly increased the numbers of activated CD8+ T cells and liver tissue-resident memory CD8+ T cells. Moreover, IL-21 aggravates liver fibrosis in mice with autoimmune cholangitis. These results emphasized that not IL-17A but IL-21 in Th17 cell-derived cytokines affected the pathogenesis of PBC. IL-21 enhanced liver inflammation and progression to fibrosis by enhancing the numbers and effector activities of CD8+ T cells. Delineation of the effects of different Th17 effector cytokines in PBC offers clues for developing new therapeutic approaches.

Role of biochemical markers and autoantibodies in diagnosis of early-stage primary biliary cholangitis.

Primary biliary cholangitis (PBC) is a chronic progressive autoimmune cholestatic disease. The main target organ of PBC is the liver, and nonsuppurative inflammation of the small intrahepatic bile ducts may eventually develop into cirrhosis or liver fibrosis. To explore the clinical characteristics of early-stage PBC, identify PBC in the early clinical stage, and promptly treat and monitor PBC. The data of 82 patients with PBC confirmed by pathology at Tianjin Second People's Hospital from January 2013 to November 2021 were collected, and the patients were divided into stage I, stage II, stage III, and stage IV according to the pathological stage. The general data, serum biochemistry, immunoglobulins, and autoimmune antibodies of patients in each stage were retrospectively analyzed. In early-stage (stages I + II) PBC patients, 50.0% of patients had normal alanine aminotransferase (ALT) levels, and 37.5% had normal aspartate aminotransferase (AST) levels. For the remaining patients, the ALT and AST levels were mildly elevated; all of these patients had levels of < 3 times the upper limit of normal values. The AST levels were significantly different among the three groups (stages I + II vs stage III vs stage IV, P < 0.05). In the early stage, 29.2% of patients had normal alkaline phosphatase (ALP) levels. The remaining patients had different degrees of ALP elevation; 6.3% had ALP levels > 5 times the upper limit of normal value. Moreover, γ-glutamyl transferase (GGT) was more robustly elevated, as 29.2% of patients had GGT levels of > 10 times the upper limit of normal value. The ALP values among the three groups were significantly different (P < 0.05). In early stage, the jaundice index did not increase significantly, but it gradually increased with disease progression. However, the above indicators were significantly different (P < 0.05) between the early-stage group and the stage IV group. With the progression of the disease, the levels of albumin and albumin/globulin ratio tended to decrease, and the difference among the three groups was statistically significant (P < 0.05). In early-stage patients, IgM and IgG levels as well as cholesterol levels were mildly elevated, but there were no significant differences among the three groups. Triglyceride levels were normal in the early-stage group, and the differences among the three groups were statistically significant (P < 0.05). The early detection rates of anti-mitochondria antibody (AMA) and AMA-M2 were 66.7% and 45.8%, respectively. The positive rate of anti-sp100 antibodies was significantly higher in patients with stage IV PBC. When AMA and AMA-M2 were negative, in the early stage, the highest autoantibody was anti-nuclear antibody (ANA) (92.3%), and in all ANA patterns, the highest was ANA centromere (38.5%). In early-stage PBC patients, ALT and AST levels are normal or mildly elevated, GGT and ALP levels are not elevated in parallel, GGT levels are more robustly elevated, and ALP levels are normal in some patients. When AMA and AMA-M2 are negative, ANA especially ANA centromere positivity suggests the possibility of early PBC. Therefore, in the clinic, significantly elevated GGT levels with or without normal ALP levels and with ANA (particularly ANA centromere) positivity (when AMA and AMA-M2 are negative) may indicate the possibility of early PBC.

Hepatobiliary and pancreatic: Tiny pigmented intra-hepatic ducts stones as the cause of jaundice and liver failure.

Hepatobiliary and pancreatic: Tiny pigmented intra-hepatic ducts stones as the cause of jaundice and liver failure.