Materiały źródłowe

• #1 Primary Biliary Cholangitis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK459209/

  Primary biliary cholangitis (PBC), formerly termed primary biliary cirrhosis, is an autoimmune disorder that gradually destroys intrahepatic bile ducts, resulting in periportal inflammation and cholestasis. Prolonged hepatic cholestasis subsequently causes cirrhosis and portal hypertension. […] The pathogenesis of primary biliary cholangitis is thought to be related to the interaction between genetic predisposition and environmental triggers. The genetic predisposition is suggested by a strong prevalence of the disease in first-degree relatives, with an odds ratio of 11. There is also a high degree of concordance in monozygotic twins. Daughters of index women have the highest relative risk for the development of primary biliary cholangitis. Several human leukocyte antigen (HLA) allele associations have been reported with primary biliary cirrhosis, which includes DRB1, DR3, DPB1, DQA1, and DQB1. HLA-DRB1*08 is common in European and Asian descent, whereas HLA-DRB1*11 is protective.

• #1 Primary Biliary Cholangitis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK459209/

  The environmental triggers include toxic waste, cigarette smoking, nail polish, hair dye, and various xenobiotics (eg, Escherichia coli, Mycobacterium gordonae, Novosphingobium aromaticivorans). These environmental triggers induce the autoimmune reaction in genetically susceptible patients, which is evident by the presence of a humoral and cellular response to an intracytoplasmic antigen, the presence of anti-mitochondrial antibody (highly specific), and the involvement of T lymphocytes in the destruction of bile ducts. In addition, bacteria containing lipoylated proteins lead to immune response targeting their lipoylated proteins via molecular mimicry. When apoptosis occurs in somatic cells, the exposed epitope is blocked by the attachment of a glutathione residue. […] The development of primary biliary cholangitis results from the interaction between genetic predisposition and an environmental trigger. Once the genetically susceptible patient is exposed to the environmental toxins or bacteria, humoral (B-cell-mediated) and cellular (T-cell-mediated) responses occur. B cells and T cells target antigens that infiltrate the liver and start attacking bile ductular cells, destroying small interlobular bile duct cells. The destruction of bile duct cells leads to the obstruction of bile drainage from canaliculi, which results in cholestasis and the destruction of hepatocytes. This cholestatic hepatitis subsequently leads to progressive fibrosis and cirrhosis.

• #1 Primary biliary cholangitis – Wikipedia

  https://en.wikipedia.org/wiki/Primary_biliary_cholangitis

  Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is an autoimmune disease of the liver. It results from a slow, progressive destruction of the small bile ducts of the liver, causing bile and other toxins to build up in the liver, a condition called cholestasis. Further slow damage to the liver tissue can lead to scarring, fibrosis, and eventually cirrhosis. […] PBC has an immunological basis, and is classified as an autoimmune disorder. It results from a slow, progressive destruction of the small bile ducts of the liver, with the intralobular ducts and the canals of Hering (intrahepatic ductules) being affected early in the disease. […] A failure of immune tolerance against the mitochondrial pyruvate dehydrogenase complex (PDC-E2) is a primary cause, with shedding of the antigen into apoptotic bodies or „apotopes” leading to the anatomic localization. Such autoreactivity may also be the case with other proteins, including the gp210 and p62 nuclear pore proteins. Gp210 has increased expression in the bile duct of anti-gp210 positive patients, and these proteins may be associated with prognosis. […] The mechanism appears to be a cross-reaction between the proteins of the bacterium and the mitochondrial proteins of the liver cells.

• #1 Pathogenesis of Primary Biliary Cirrhosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2095651/

  PBC is characterised immunologically by the breakdown of immune self-tolerance to highly conserved mitochondrial and nuclear antigens. The first autoreactive responses to be characterised in PBC were the serum antibody responses directed at antigens present on the inner mitochondrial membrane (antimitochondrial antibodies; AMA). AMA, which are present, often at very high titre, in over 95% of patients, are directed at the members of the 2-oxoacid dehydrogenase complex family of multienzyme complexes. […] Despite the importance of serum AMA in the history of PBC (and its ongoing importance in the serological diagnosis of the disease), the actual role it plays in disease pathogenesis appears to be limited (although a number of potential mechanisms, such as antibody-directed cell cytotoxicity remain to be fully explored).

• #1 Pathogenesis of Primary Biliary Cirrhosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2095651/

  The potential for T-cell autoreactive immune responses to contribute to bile duct injury in PBC is suggested by a number of observations, not least the almost universal presence of activated T cells in the portal tract infiltrates surrounding affected bile ducts. Both CD4 and CD8 autoreactive T-cell responses directed at self-PDCE2 have now been extensively characterised in PBC patients. […] In a separate strand of work, animal modelling studies have suggested that the breakdown of tolerance to PDC at the T-cell level is associated with the development of portal tract inflammation and bile duct changes with features redolent of early human PBC. […] The balance of evidence in PBC remains strongly in favour of an autoimmune process in which autoreactive effector mechanisms are directed at epitopes within self-PDCE2 expressed normally or aberrantly by BEC. There is a strong evidence base to support both altered-self and molecular mimicry mechanisms for the breakdown of tolerance to self-PDC, with cross-reactivity between the lipoic acid cofactor and environmental xenobiotics, between bacterial and self-PDC and between self-PDC and viral protein all potentially playing important roles.

• #1 Primary Biliary Cholangitis (Primary Biliary Cirrhosis): Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/171117-overview

  A continuous destruction of small and medium bile ducts occurs, which is mediated by activated CD4 and CD8 lymphocytes. As a result, chronic cholestasis is the prominent clinical and laboratory finding. Once destroyed, it is well established that regeneration of bile ducts is either not possible or inefficient. […] Subsequent to the loss of the intrahepatic bile ducts, a disruption of the normal bile flow occurs with retention and deposition of toxic substances, which are normally excreted into bile. The retention of toxic substances, such as bile acids and copper, can cause a further secondary destruction of the bile ducts and the hepatocytes. […] An association has been suggested between primary biliary cholangitis and haplotype HLA-DR8 and HLA-DPB1. […] In a controlled, interview-based study of 1032 patients, Selmi et al noted that in genetically susceptible persons, environmental factors may induce primary biliary cholangitis.

• #1

  https://journals.lww.com/co-gastroenterology/fulltext/2021/03000/primary_biliary_cholangitis__pathogenic_mechanisms.5.aspx

  Primary biliary cholangitis (PBC) is characterized by autoimmune damage of intrahepatic bile ducts associated with a loss of tolerance to mitochondrial antigens. PBC etiopathogenesis is intriguing because of different perplexing features, namely: a) although mitochondria are present in all cell types and tissues, the damage is mainly restricted to biliary epithelial cells (BECs); b) despite being an autoimmune disorder, it does not respond to immunosuppressive drugs but rather to ursodeoxycholic acid, a bile salt that induces HCO3 rich choleresis; c) the overwhelming female preponderance of the disease remains unexplained. […] PBC develops in patients with genetic predisposition to autoimmunity in whom epigenetic mechanisms silence the Cl/HCO3 exchanger AE2 in both cholangiocytes and lymphoid cells. Defective AE2 function can produce BECs damage as a result of decreased biliary HCO3 secretion with disruption of the protective alkaline umbrella that normally prevents the penetration of toxic apolar bile salts into cholangiocytes. AE2 dysfunction also causes increased intracellular pH (pHi) in cholangiocytes, leading to the activation of soluble adenylyl cyclase, which sensitizes BECs to bile salt-induced apoptosis.

• #1

  https://journals.lww.com/co-gastroenterology/fulltext/2021/03000/primary_biliary_cholangitis__pathogenic_mechanisms.5.aspx

  The immune-mediated cholangiocellular injury appears to be secondary to the failure of BEC to secrete HCO3 to bile due to AE2 deficiency. This defect is likely because of epigenetic factors involving miR-506 upregulation and AE2 promoter methylation. Impaired biliary HCO3 secretion disrupts the defensive bicarbonate umbrella allowing the penetration of hydrophobic bile acids into BECs resulting in senescence and apoptosis of these cells. In addition, AE2 deficiency alters cholangiolar pHi leading to sAC activation and increased sensitivity to bile salt-induced apoptosis. Increased pHi likely disturbs mitophagy, with resulting accumulation of faulty mitochondria, and this would trigger oxidative stress while promoting the presentation of mitochondrial antigens to the immune system. […] In summary, PBC could be considered as a disease that occurs in patients with genetic predisposition to autoimmunity in which AE2 is epigenetically downregulated both in liver and lymphoid cells.

• #1 An Integrated Pathogenetic Model of Primary Biliary Cholangitis

  https://www.mdpi.com/2673-4389/5/2/15

  Data supporting molecular mimicry and the viral etiology of PBC are analyzed. […] Finally, an integrated model is proposed based on interactions of the factors that may participate in PBC pathogenesis. […] An interplay of genetic and environmental factors is implicated as the driving force for the breach of tolerance and autoimmune-mediated cellular death that follows. […] However, many gaps in PBC pathogenesis require explanation. […] In addition, AMAs have diagnostic but not prognostic value. […] The co-localization of the mitochondrial protein PDC-E2 with the autophagy protein LC3B indicated that in addition to the mainstream autophagy, mitophagy is also implicated. […] Importantly, autophagy is also involved in the intracellular antigen processing required for the association of the antigen with the MHC I and II molecules and subsequent presentation to APC cells.

• #1 An Integrated Pathogenetic Model of Primary Biliary Cholangitis

  https://www.mdpi.com/2673-4389/5/2/15

  Dysregulated autophagy may be implicated in the abnormal expression of mitochondrial antigens and also in BECs’ senescence in PBC. […] The significance of apoptosis in cholangiopathies was recently shown in studies on ductular reactive cells. […] Apoptosis may explain the presence of AMAs in the serum of PBC patients. […] The loss of recognition of this epitope in other cells under normal conditions is due to a modification of a PDC-E2 sulfhydryl group by glutathione. […] The degree of senescent BECs in small bile ducts and bile ductules is positively correlated with the stage and activity of PBC, while the increased expression of the senescent marker p16 INK4a in bile ductules was associated with a reduced response to UDCA. […] The other fundamental point is the reduction in AE2 and the resultant decrease in the bicarbonate umbrella, which is associated with dysregulated autophagy.

• #1 Primary biliary cholangitis | Iljinsky | Russian Journal of Transplantology and Artificial Organs

  https://journal.transpl.ru/vtio/article/view/1319?locale=en_US

  Primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis, is an organ-specific autoimmune disease predominantly affecting middle-aged women. […] Over the past 30 years, there has been an increased incidence of PBC, while significant progress has been made in understanding the pathogenesis of PBC due to the development of innovative technologies in molecular biology, immunology and genetics. […] Small- and medium-sized bile ducts are the targets of PBC. […] In the first stage of the disease, granulomatous destruction of the bile ducts occurs; in the second stage, loss of bile ducts, their proliferation, increased size of the portal tracts with chronic inflammation; in the third stage – fibrosis with septal formation, loss of bile ducts and cholestasis; in the fourth stage – liver cirrhosis.

• #1 Mechanism of formation and significance of antimitochondrial autoantibodies in the pathogenesis of primary biliary cholangitis

  https://www.explorationpub.com/Journals/ei/Article/1003163

  The presence of AMAs and ANAs served as the basis for considering PBC as a prototype of autoimmune disease and for describing it as a paradigmatic model of autoimmune disease. […] PBC is described as a chronic cholestatic liver disease that is characterized by immune-mediated destruction of BECs of small and medium intrahepatic bile ducts. […] The antigen for AMA production in PBC is the dihydrolipoyl transacetylase (E2) of the pyruvate dehydrogenase complex (PDC, E2 PDC), which localizes to the inner mitochondrial membrane. […] The question of the factors that trigger the mechanism of AMA formation and their significance in the development of the pathological process in PBC remains open. […] The loss of immune tolerance to E2 PDC in PBC is believed to be the initial event in the mechanism of AMA formation and plays an important role as a triggering factor for cholangiocyte damage.

• #1 Mechanism of formation and significance of antimitochondrial autoantibodies in the pathogenesis of primary biliary cholangitis

  https://www.explorationpub.com/Journals/ei/Article/1003163

  The view of immune-mediated destruction of small and medium intrahepatic bile ducts is discussed by many researchers. […] The defective biliary HCO3 umbrella theory is based on a number of clinical and experimental studies demonstrating inadequate synthesis and delivery of HCO3 to the bile ducts in PBC. […] The mechanisms of protonation-deprotonation of bile acids and their subsequent entry into the BECs are discussed in detail in the reviews. […] The persistent and constant destabilization of the biliary HCO3 umbrella in PBC contributes to the continuous accumulation and detergent action of bile acids on small BECs. This process is characterized by the continuous destruction of BECs, which line the intralobular, interlobular, and septal bile ducts. This destruction results in the continuous production of AMAs.

• #1 Primary Biliary Cholangitis and Primary Sclerosing Cholangitis: Current Knowledge of Pathogenesis and Therapeutics

  https://www.mdpi.com/2227-9059/10/6/1288

  The biliary epithelium expresses toll-like receptors (TLRs). Once various ligands, including microbial products such as lipopolysaccharide (LPS), bind to TLRs, cellular injury occurs through the proinflammatory nuclear factor-κB pathway and IL-8 and CX3C-chemokine ligand 1 (CX3CL1) release, which facilitates the recruitment of effector lymphoid cells into portal tracts in the livers of PBC patients. […] The toxic effects of bile acids are explained by cholestasis, changes in the bile composition of disease progression in the bile ducts and colon, or impaired protective mechanisms. […] The protective mechanism of hepatocytes against harmful bile acid accumulation is explained by FGF19, which is a negative feedback regulator of bile synthesis produced in the ileum after FXR activation by bile acids.

• #1 Concept on the pathogenesis and treatment of primary biliary cirrhosis

  https://www.wjgnet.com/1007-9327/full/v12/i45/7250.htm

  The epithelium of the bile ducts whose cell surface expresses antigens of the histocompatibility complex is considered to be the major target for AMA. […] The generation of immune responsiveness to self-antigen can result in pathogenic autoimmune damage of the intrahepatic biliary epithelial cells mediated by both humoral and cellular immune responses. […] PBC is characterized by chronic destructive cholangitis with a Th1-predominant cytokine milieu. […] Toll-like receptor-3 and type I interferon signaling pathways are active in both the portal tract and liver parenchyma of early-stage PBC, and form the basis for hypothesis that these signaling pathways are involved in the pathophysiology of PBC. […] Oxidative stress- and nitric oxide-mediated cellular senescence may be involved in bile duct lesions, which are followed by progressive bile duct loss in primary biliary cirrhosis.

• #1 Primary Biliary Cholangitis and Primary Sclerosing Cholangitis: Current Knowledge of Pathogenesis and Therapeutics

  https://www.mdpi.com/2227-9059/10/6/1288

  Chronic injury can lead to cholangiocyte senescence and differentiation of matrix-depositing HSCs from myofibroblasts and portal fibroblasts, resulting in tissue scarring and bile duct strictures. […] The PSC is considered a part of the hepatobiliary manifestation of IBD, and gut-derived adaptive and innate immune responses contribute to chronic and progressive biliary inflammation.

• #1 Concept on the pathogenesis and treatment of primary biliary cirrhosis

  https://www.wjgnet.com/1007-9327/full/v12/i45/7250.htm

  The canals of Hering (CoH) are destroyed in PBC in concert with the destruction of small bile ducts. […] The increased number of desolating bile ductules gradually result in impairment of bile excretion and in deficient entry of bile acids into the duodenum. […] The altered composition of bile acids secreted into bile in patients with PBC leads to the impaired ratio of cholesterol, bile acids, and lecithin (in favor of cholesterol), which changes bile viscosity, and increases the bile lithogenicity index. […] Thus, an autoimmune pathological process occurring for unknown reasons triggers the development of intrahepatic cholestasis in PBC.

• #1 Pathophysiology of biochemical signs of primary biliary cholangitis

  https://www.explorationpub.com/Journals/edd/Article/100524

  The enhanced activity of ALP and 5-NT in PBC is associated with an increase in the synthesis of these enzymes. […] The elevated serum level of -GT in combination with the enhanced activity of ALP and 5-NT in PBC reflects damage to the biliary tract to a greater extent than damage to hepatocytes. […] The secretion of bicarbonate ions protects cholangiocytes from uncontrolled transmembrane current of glycochenodeoxycholic acid, which can induce apoptosis of biliary epithelial cells. […] The entrance of bile acids into the blood plasma of patients with PBC is one of the causes of the development of pruritus already in the asymptomatic stage of the disease and lipid metabolism disorders. […] The formation of LP-X can be considered as a protective mechanism in response to developing cholestasis.

• #1 Precirrhotic Primary Biliary Cholangitis with Portal Hypertension: Bile Duct Injury Correlate

  https://www.gutnliver.org/journal/view.html?pn=ahead&uid=2179&vmd=Full

  Precirrhotic PBC with PH was significantly positively correlated with bile duct loss, degree of cytokeratin 7 positivity, and degree of fibrosis in the portal area, but significantly negatively correlated with lymphoid follicular aggregation. Compared to the non-PH group, patients in the PH group showed a higher prevalence of obliterative portal venopathy, incomplete septal fibrosis, portal tract abnormalities and non-zonal sinusoidal dilatation. Approximately 24.2% of precirrhotic PBC patients have PH, which is histologically related to the injury of bile ducts. High alkaline phosphatase levels, low white blood cell counts, high Mayo scores, and high FIB-4 index values are associated with increased risk of precirrhotic PBC with PH. […] The existing studies have primarily focused on histological staging, and the histopathological mechanisms underlying precirrhotic PBC with PH remain unclear. Our study is the first to comprehensively investigate the details of bile duct injury or loss in precirrhotic PBC patients with PH. The study revealed that 24.2% of patients with precirrhotic PBC may experience PH. According to Nakanuma’s pathologic staging, there were 5.2% (1/19) of patients with PH in the histologic stage I of our study, 17.3% (17/98) of the patients in stage II had PH, and 45.8% (22/48) of the patients in stage III had comorbid PH. The occurrence of combined PH increases as the histology progresses.

• #1 Primary biliary cirrhosis | Nature Reviews Gastroenterology & Hepatology

  https://www.nature.com/subjects/primary-biliary-cirrhosis/nrgastro

  In 2016, obeticholic acid became the first new licensed therapy for primary biliary cholangitis in 20 years. This therapeutic came at a time of improved disease understanding from biliary and immunological mechanistic insights. […] Evolution in our understanding of disease mechanisms in PBC is rapidly leading to the advent of new and re-purposed therapeutic agents targeting key processes. […] Fatigue is a common symptom of primary biliary cirrhosis (PBC) yet little is understood about the pathogenesis of this condition and there is no specific treatment. The central and the peripheral mechanisms that have been suggested for the pathogenesis of fatigue in PBC are also described and treatment options are outlined.

• #1 Primary biliary cirrhosis: Pathophysiology, clinical presentation and therapy

  https://www.wjgnet.com/1948-5182/full/v7/i7/926.htm

  UDCA has three mechanisms of action: (1) protection of cholangiocytes from cytotoxicity of hydrophobic bile acids by modulating the composition of mixed phospholipid-rich micelles, reduced bile acid cytotoxicity, and, possibly, reduced concentration of hydrophobic bile acids in cholangiocytes; (2) stimulation of biliary secretion of bile acids; and (3) protection of hepatocytes against bile acid-induced apoptosis, by inhibiting mitochondrial membrane permeability transition. […] The future of PBC promises to be exciting. Genetic, immunologic, and epidemiologic data should further elucidate the pathogenesis of PBC, especially in the era of genome-wide association studies and epigenetics.

• #1

  https://journals.lww.com/hepcomm/fulltext/2023/06010/primary_biliary_cholangitis__epidemiology,.27.aspx

  […] […] OCA is a synthetically modified hydrophobic BA derived from chenodeoxycholic acid that has a high affinity for Farsenoid X receptors (FXRs). FXRs are transcription factors belonging to the superfamily of nuclear receptors with high expression in the liver and intestines. FXR regulates BA synthesis, conjugation, and transport, as well as various aspects of lipids and glucose metabolism. For instance, its activation upregulates the synthesis of short heterodimeric partner, a suppressive protein that inhibits the expression of cholesterol 7-hydroxylase. This is a rate-limiting enzyme necessary for the synthesis of BA. FXR also suppresses BA synthesis through FGF-19 and FGF-4 activation, and directly enhances the expression of several BA transporters and uptake proteins. The net effect from FXR activation is, therefore, a reduction in the total BA pool by limiting their synthesis and uptake and promoting choleresis.

• #1

  https://journals.lww.com/hepcomm/fulltext/2023/06010/primary_biliary_cholangitis__epidemiology,.27.aspx

  […] […] Fibrates are strong peroxisome proliferator-activated receptor (PPAR) agonists. PPAR are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. They exist in 3 isoforms: PPAR-, PPAR-, and PPAR-, with the former predominantly expressed in hepatocytes. When activated, PPAR- induces the expression of numerous genes with a number of them involved in lipid pathways that regulate fatty acid oxidation, triglyceride degradation and BA synthesis, metabolism, and transport, reducing BA concentration inside hepatocytes, augmenting phospholipid excretion into the biliary canaliculi, and inhibiting proinflammatory agents within the liver and biliary tree.

• #1

  https://www.xiahepublishing.com/1555-3884/GE-2023-00015

  Primary biliary cholangitis (PBC) is a chronic, progressive autoimmune disease whose natural course leads to hepatic cirrhosis and failure, with an eventual need for liver transplantation. […] In PBC, T-cell activation against mitochondrial and nuclear antigens in biliary epithelial cells leads to the destruction of small- and medium-sized intralobular bile ducts. This results in progressive ductopenia, cholestasis, and fibrosis, with the potential to advance to cirrhosis and liver failure. […] The mechanism by which fibrates alter physiology in patients with PBC is incompletely understood. Studies on fenofibrate suggest that activation of PPAR- causes simultaneous upregulation of genes that are involved in bile excretion and detoxification and downregulation of genes involved in bile acid synthesis. These effects are overall anti-cholestatic and anti-inflammatory.

• #1 GLISTEN phase III trial results show linerixibat significantly improves cholestatic pruritus (relentless itch) in primary biliary cholangitis (PBC) | GSK

  https://www.gsk.com/en-gb/media/press-releases/glisten-phase-iii-trial-results-show-linerixibat-significantly-improves-cholestatic-pruritus/

  GSK plc (LSE/NYSE: GSK) today announced positive results from the GLISTEN phase III trial evaluating linerixibat, an investigational targeted inhibitor of the ileal bile acid transporter (IBAT), in adults with cholestatic pruritus and PBC, a rare autoimmune liver disease. […] In PBC, a cholestatic liver disease, bile flow from the liver is disrupted. The resulting excess bile acids in circulation are thought to play a causal role in cholestatic pruritus, an internal itch that cannot be relieved by scratching. […] Linerixibat is an IBAT inhibitor, a targeted oral agent with potential to treat cholestatic pruritus (itch) associated with the rare autoimmune liver disease known as PBC. By inhibiting bile acid re-uptake, linerixibat reduces multiple mediators of pruritus in circulation.

• #1 Primary Biliary Cholangitis: New treatment goals and novel salvage therapy | World Gastroenterology Organisation

  https://www.worldgastroenterology.org/publications/e-wgn/e-wgn-expert-point-of-view-articles-collection/primary-biliary-cholangitis-new-treatment-goals-and-novel-salvage-therapy

  […] Recent studies point towards normal ALP levels as the desired biochemical goal for effective PBC therapy. […] Additionally, an analysis made with data extracted from the GLOBAL PBC Study Group, compared ten-year survival rates of a cohort of PBC patients and found an association between normal ALP levels and lower risk for OLT or death in these patients. […] […] Given that, as discussed above, none of the existing criteria really prioritize normalization of ALP or TB levels to qualify a successful treatment, it is easy to see how findings like this could have very important implications on the future management of PBC patients, particularly when deciding to start any treatment beyond first line therapy. […] […] Seladelpar is a PPAR- agonist, a receptor found in hepatocytes, cholangiocytes and various immune cells known to play a role in the pathogenesis of PBC. […] Its mechanism is thought to consist in a reduction of bile acid synthesis as well as an increase in lipid degradation. […] […] The treatment and management of PBC patients is evolving. […] These findings carry even more weight when we look at the high number of promising therapeutic options, with many different mechanisms of action, currently being investigated.

• #1 Current concepts in the pathogenesis of primary biliary cirrhosis | Annals of Hepatology

  https://www.elsevier.es/en-revista-annals-hepatology-16-articulo-current-concepts-in-pathogenesis-primary-S1665268119320617

  Current concepts in the pathogenesis of primary biliary cirrhosis favor the hypothesis that the disease develops as a result of an inappropriate immune response following stimulation by an environmental or infectious agent. […] The pathogenetic mechanism is believed to be caused by a defect in immunologic tolerance, resulting in the activation and expansion of self-antigen specific T and B lymphocyte clones and the production of circulating autoantibodies in addition to a myriad of cytokines and other inflammatory mediators. […] The breakdown of immunologic tolerance results in the activation and expansion of self-antigen specific T and B lymphocyte clones and the production of circulating autoantibodies in addition to a myriad of cytokines and other inflammatory mediators. […] The induction of an antibody response reactive with self-antigen may result from a number of different priming events including exposure to bacterial PDC or retroviral proteins or xenobiotics or microchimerism or apoptotic cell express PDC that induce an antibody response cross-reactive with self-PDC.

• #1 Primary Biliary Cholangitis: New treatment goals and novel salvage therapy | World Gastroenterology Organisation

  https://www.worldgastroenterology.org/publications/e-wgn/e-wgn-expert-point-of-view-articles-collection/primary-biliary-cholangitis-new-treatment-goals-and-novel-salvage-therapy

  […] Clinical trials have demonstrated a 25% to 53.9% drop in alkaline phosphatase (ALP) levels in patients started on treatment with OCA in comparison to placebo groups. […] Additionally, data suggests that the combination of UDCA and OCA could lead to a decrease in the 15-year cumulative incidence of cirrhosis, HCC, OLT need, and death due to liver related complications. […] […] The first line of treatment for PBC is a trial of weight-based (13 mg/kg/day in divided doses) UDCA therapy. […] Response is usually evaluated after one year of treatment with UDCA, using any of the response criteria described in Table 1. […] In those with the above indications, guidelines currently recommend the addition of 5 mg OCA with titration to 10 mg if the patient had adequate toleration but suboptimal response to OCA.

• #2 Pathogenesis of primary biliary cholangitis (primary biliary cirrhosis) – UpToDate

  https://www.uptodate.com/contents/pathogenesis-of-primary-biliary-cholangitis-primary-biliary-cirrhosis

  Pathogenesis of primary biliary cholangitis (primary biliary cirrhosis) is characterized by a T-lymphocyte-mediated attack on small intralobular bile ducts. A continuous assault on the bile duct epithelial cells leads to their gradual destruction and eventual disappearance. The sustained loss of intralobular bile ducts causes the signs and symptoms of cholestasis, and eventually results in cirrhosis and liver failure. […] The precise cause of PBC is unknown but, as with other autoimmune diseases, is related to genetic susceptibility and environmental factors. A number of environmental causes have been implicated, including several bacteria, viruses, toxins, and drugs. Some of the most compelling evidence for an environmental factor has been derived from epidemiologic studies, which have demonstrated geographic clustering, clustering of cases across time, and seasonal variation in the diagnosis of PBC.

• #2

  https://link.springer.com/article/10.1007/s12328-017-0799-z

  Primary biliary cholangitis (PBC) is a chronic, slowly progressive cholestatic autoimmune liver disease predominantly afflicting women. PBC is characterized by the presence of disease-specific antimitochondrial antibodies and the histological destruction of intrahepatic bile ducts, which eventually lead to cirrhosis and hepatic failure. […] The precise cause of PBC is unclear, but as with other autoimmune diseases, is likely related to both genetic susceptibility and environmental factors. Genetic factors are considered to play a prominent role in disease onset as higher concordance rates in monozygotic twins than in dizygotic twins and familial clustering of patients with PBC have been demonstrated in numerous family and population studies. PBC is therefore presumed to be a multifactorial polygenic condition caused by allelic triggers and environmental influences in genetically susceptible individuals along with other epigenetic mechanisms.

• #2 Primary Biliary Cholangitis (Primary Biliary Cirrhosis): Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/171117-overview

  Environmental triggers include toxic waste, chemicals found in cigarette smoke, and infectious agents introduced through urinary tract infections; these agents trigger an autoimmune reaction in this population that ultimately results in the destruction of bile ducts. […] Additionally, Selmi et al noted stated that exogenous estrogens may also contribute to the disease’s development and that this may help to explain why the disease occurs more frequently in females than in males.

• #2 Current concepts in the pathogenesis of primary biliary cirrhosis | Annals of Hepatology

  https://www.elsevier.es/en-revista-annals-hepatology-16-articulo-current-concepts-in-pathogenesis-primary-S1665268119320617

  Current concepts in the pathogenesis of primary biliary cirrhosis favor the hypothesis that the disease develops as a result of an inappropriate immune response following stimulation by an environmental or infectious agent. […] The pathogenetic mechanism is believed to be caused by a defect in immunologic tolerance, resulting in the activation and expansion of self-antigen specific T and B lymphocyte clones and the production of circulating autoantibodies in addition to a myriad of cytokines and other inflammatory mediators. […] The breakdown of immunologic tolerance results in the activation and expansion of self-antigen specific T and B lymphocyte clones and the production of circulating autoantibodies in addition to a myriad of cytokines and other inflammatory mediators. […] The induction of an antibody response reactive with self-antigen may result from a number of different priming events including exposure to bacterial PDC or retroviral proteins or xenobiotics or microchimerism or apoptotic cell express PDC that induce an antibody response cross-reactive with self-PDC.

• #2 Primary Biliary Cholangitis (PBC) – Hepatic and Biliary Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/hepatic-and-biliary-disorders/fibrosis-and-cirrhosis/primary-biliary-cholangitis-pbc

  Primary biliary cholangitis (PBC; formerly known as primary biliary cirrhosis) is an autoimmune liver disorder characterized by the progressive destruction of intrahepatic bile ducts, leading to cholestasis, cirrhosis, and liver failure. […] An autoimmune mechanism has been implicated; antibodies to antigens located on the inner mitochondrial membranes occur in 95% of cases. These antimitochondrial antibody (AMA), the serologic hallmarks of PBC, are not cytotoxic and are not involved in bile duct damage. […] T cells attack the small bile ducts. CD4 and CD8 T lymphocytes directly target biliary epithelial cells. The trigger for the immunologic attack on bile ducts is unknown. Exposure to foreign antigens, such as an infectious (bacterial or viral) or toxic agent, may be the instigating event. These foreign antigens might be structurally similar to endogenous proteins (molecular mimicry); then the subsequent immunologic reaction would be autoimmune and self-perpetuating. Destruction and loss of bile ducts lead to impaired bile formation and secretion (cholestasis). Retained toxic materials such as bile acids then cause further damage, particularly to hepatocytes. Chronic cholestasis thus leads to liver cell inflammation and scarring in the periportal areas. Eventually, hepatic inflammation decreases as hepatic fibrosis progresses to cirrhosis. […] AMA -negative PBC is characterized by autoantibodies, such as antinuclear antibodies (ANAs), antismooth muscle antibodies, or both and has a clinical course and response to treatment that are similar to those of PBC. However, AMA is absent.

• #2 Primary Biliary Cholangitis and Primary Sclerosing Cholangitis: Current Knowledge of Pathogenesis and Therapeutics

  https://www.mdpi.com/2227-9059/10/6/1288

  Both PBC and PSC are considered immune-mediated cholangiopathies and have features of portal inflammation, biliary tract injury, and sequential fibrosis and cirrhosis development, leading to end-stage liver failure. […] Thus, in this review, we address the mechanism of functional loss of cholangiocytes in the initiation and progression of PBC and PSC, together with the treatments based on currently ongoing studies. […] The immune system plays a central role in PBC pathogenesis, and various immune cells have been shown to infiltrate the portal tract areas of PBC patients. The primary cause of PBC relates to the loss of immune tolerance to PDC-E2. […] Aberrant modification of mitochondrial PDC-E2 occurs within apoptotic BECs, and characteristic apoptotic blebs containing immunologically intact PDC-E2 are released.

• #2 Animal models of primary biliary cholangitis: status and challenges | Cell & Bioscience | Full Text

  https://cellandbioscience.biomedcentral.com/articles/10.1186/s13578-023-01170-9

  Primary biliary cholangitis (PBC) is an autoimmune liver disease. The aetiology of PBC remains unclear, and its pathogenesis is complex. Animal models are essential to clarify the pathogenesis of PBC and explore the occurrence of early events. […] Genetic susceptibility and environmental factors result in the loss of tolerance to self-antigens and multilineage immune dysregulation, inducing targeted damage in bile duct epithelial cells (BECs). Multiple immune cells are involved in the pathogenesis of PBC. CD8+T cells target and destroy BECs, while CD4+T cells induce an inflammatory microenvironment around BECs by producing multiple cytokines, which recruit CD8+T cells. Further, in the early phase of the disease, Th1 cells are predominantly pro-inflammatory, and Th1 responses have been shown to predominate over Th2 responses in PBC. Th1 cytokines, such as interleukin(IL)-12, tumour necrosis factor(TNF)-, and interferon (IFN)-, play an important role in the initiation and development of the disease.

• #2 Mechanism of formation and significance of antimitochondrial autoantibodies in the pathogenesis of primary biliary cholangitis

  https://www.explorationpub.com/Journals/ei/Article/1003163

  The view of immune-mediated destruction of small and medium intrahepatic bile ducts is discussed by many researchers. […] The defective biliary HCO3 umbrella theory is based on a number of clinical and experimental studies demonstrating inadequate synthesis and delivery of HCO3 to the bile ducts in PBC. […] The mechanisms of protonation-deprotonation of bile acids and their subsequent entry into the BECs are discussed in detail in the reviews. […] The persistent and constant destabilization of the biliary HCO3 umbrella in PBC contributes to the continuous accumulation and detergent action of bile acids on small BECs. This process is characterized by the continuous destruction of BECs, which line the intralobular, interlobular, and septal bile ducts. This destruction results in the continuous production of AMAs.

• #2 A Practical Review of Primary Biliary Cholangitis for the Gastroenterologist – Gastroenterology & Hepatology

  https://www.gastroenterologyandhepatology.net/archives/march-2019/a-practical-review-of-primary-biliary-cholangitis-for-the-gastroenterologist/

  Despite the ubiquitous nature of the mitochondrial autoantigen, targeted biliary injury may be related to aberrant modification of PDC-E2 within apoptotic biliary epithelia, leaving the antigenic epitope immunologically preserved within an apoptotic bleb, and, thereby, recognizable by circulating AMAs. […] The interface between immunologic and cholestatic injury may exist at the surface of BECs through disruption of the biliary bicarbonate umbrella, critical in maintaining integrity of BECs. […] Disruption of this protective layer via dysfunctional AE2 allows invasion of hydrophobic bile acid monomers. […] Cholangiocytes insulted by hydrophobic bile acids are sensitized to apoptosis, and hydrophobic bile acids induce reactive oxygen species and BEC senescence, further propagating bile duct injury.

• #2 An Integrated Pathogenetic Model of Primary Biliary Cholangitis

  https://www.mdpi.com/2673-4389/5/2/15

  Dysregulated autophagy may be implicated in the abnormal expression of mitochondrial antigens and also in BECs’ senescence in PBC. […] The significance of apoptosis in cholangiopathies was recently shown in studies on ductular reactive cells. […] Apoptosis may explain the presence of AMAs in the serum of PBC patients. […] The loss of recognition of this epitope in other cells under normal conditions is due to a modification of a PDC-E2 sulfhydryl group by glutathione. […] The degree of senescent BECs in small bile ducts and bile ductules is positively correlated with the stage and activity of PBC, while the increased expression of the senescent marker p16 INK4a in bile ductules was associated with a reduced response to UDCA. […] The other fundamental point is the reduction in AE2 and the resultant decrease in the bicarbonate umbrella, which is associated with dysregulated autophagy.

• #2 Concept on the pathogenesis and treatment of primary biliary cirrhosis

  https://www.wjgnet.com/1007-9327/full/v12/i45/7250.htm

  The epithelium of the bile ducts whose cell surface expresses antigens of the histocompatibility complex is considered to be the major target for AMA. […] The generation of immune responsiveness to self-antigen can result in pathogenic autoimmune damage of the intrahepatic biliary epithelial cells mediated by both humoral and cellular immune responses. […] PBC is characterized by chronic destructive cholangitis with a Th1-predominant cytokine milieu. […] Toll-like receptor-3 and type I interferon signaling pathways are active in both the portal tract and liver parenchyma of early-stage PBC, and form the basis for hypothesis that these signaling pathways are involved in the pathophysiology of PBC. […] Oxidative stress- and nitric oxide-mediated cellular senescence may be involved in bile duct lesions, which are followed by progressive bile duct loss in primary biliary cirrhosis.

• #2 Concept on the pathogenesis and treatment of primary biliary cirrhosis

  https://www.wjgnet.com/1007-9327/full/v12/i45/7250.htm

  The canals of Hering (CoH) are destroyed in PBC in concert with the destruction of small bile ducts. […] The increased number of desolating bile ductules gradually result in impairment of bile excretion and in deficient entry of bile acids into the duodenum. […] The altered composition of bile acids secreted into bile in patients with PBC leads to the impaired ratio of cholesterol, bile acids, and lecithin (in favor of cholesterol), which changes bile viscosity, and increases the bile lithogenicity index. […] Thus, an autoimmune pathological process occurring for unknown reasons triggers the development of intrahepatic cholestasis in PBC.

• #2 Precirrhotic Primary Biliary Cholangitis with Portal Hypertension: Bile Duct Injury Correlate

  https://www.gutnliver.org/journal/view.html?pn=ahead&uid=2179&vmd=Full

  Primary biliary cholangitis (PBC) is a relatively common autoimmune liver disease. Histologically, PBC manifests as chronic cholestasis which is characterized by non-suppurative progressive injury to the small intrahepatic bile ducts. It is generally divided into four phases: phase I, cholangitis; phase II, peri-congestive cholangitis; phase III, progressive fibrosis; and phase IV, cirrhosis. Portal hypertension (PH) refers to is an elevated pressure in the portal vein due to various causes, and it is associated with clinical manifestations such as splenomegaly, hypersplenism, esophagogastric fundal varices and ascites, etc. As PBC progresses, it can eventually lead to biliary cirrhosis, resulting in a variety of complications, including PH. However, there exists a subset of patients with PBC who have not yet developed cirrhosis histologically but with PH and may experience with severe complications, including splenomegaly, hypersplenism, and even gastrointestinal hemorrhage. Related studies have shown that 5% to 10% of patients with precirrhotic PBC develop esophageal varices under endoscopy. Their results suggest that low platelets (PLT), low albumin (ALB), and high total bilirubin (TBIL) are independent predictors for the development of esophageal varices in early PBC. Furthermore studies have shown that PH in early PBC is considered to be presinusoidal PH, which may be associated with nodular regenerative hyperplasia. A study of hepatic venous pressure gradient (HVPG) measurements in PBC patients shows that about 34% of precirrhotic PBC patients have high-risk PH, which is associated with portal vein and hepatic sinusoid lesions.

• #2 Primary Biliary Cholangitis: What It Is, Symptoms, Treatment

  https://my.clevelandclinic.org/health/diseases/17715-primary-biliary-cholangitis-pbc

  Primary biliary cholangitis is a chronic and progressive condition that causes inflammation and, eventually, the destruction of the bile ducts that run through your liver. […] Primary biliary cholangitis (PBC) is a liver disease that affects the bile ducts that run through your liver. It slowly degrades those bile ducts, making it harder for bile to flow through. […] In PBC, it appears that your own immune system attacks the cells lining your intrahepatic bile ducts, causing inflammation. […] Chronic inflammation leads to scarring.

• #2 Primary Biliary Cholangitis (PBC) – Calliditas Therapeutics AB

  https://www.calliditas.se/en/our-science/primary-biliary-cholangitis-pbc/

  The pathogenesis of PBC is a cycle of inflammation and fibrosis enabled by ros-driven cell injury. […] PBC patients undergo immune injury to their biliary epithelial cells, which results in an inter-dependent chronic cycle of cholestasis and fibrosis in the bile ducts and surrounding tissue. […] This results in the generation of excess ROS, resulting in cell death and a further cascade of inflammatory signaling which sets up the cycle of damage to the integrity of the bile ducts. […] Inflammation is the primer of fibrosis, which is the cellular reparative response to cell injury. […] The persistent biliary inflammation fuels the stimulation of fibrosis as a reparative response to the tissue, and as a result, there is excessive deposition of fibrotic tissue in the portal space.

• #2 Precirrhotic Primary Biliary Cholangitis with Portal Hypertension: Bile Duct Injury Correlate

  https://www.gutnliver.org/journal/view.html?pn=ahead&uid=2179&vmd=Full

  Precirrhotic PBC with PH was significantly positively correlated with bile duct loss, degree of cytokeratin 7 positivity, and degree of fibrosis in the portal area, but significantly negatively correlated with lymphoid follicular aggregation. Compared to the non-PH group, patients in the PH group showed a higher prevalence of obliterative portal venopathy, incomplete septal fibrosis, portal tract abnormalities and non-zonal sinusoidal dilatation. Approximately 24.2% of precirrhotic PBC patients have PH, which is histologically related to the injury of bile ducts. High alkaline phosphatase levels, low white blood cell counts, high Mayo scores, and high FIB-4 index values are associated with increased risk of precirrhotic PBC with PH. […] The existing studies have primarily focused on histological staging, and the histopathological mechanisms underlying precirrhotic PBC with PH remain unclear. Our study is the first to comprehensively investigate the details of bile duct injury or loss in precirrhotic PBC patients with PH. The study revealed that 24.2% of patients with precirrhotic PBC may experience PH. According to Nakanuma’s pathologic staging, there were 5.2% (1/19) of patients with PH in the histologic stage I of our study, 17.3% (17/98) of the patients in stage II had PH, and 45.8% (22/48) of the patients in stage III had comorbid PH. The occurrence of combined PH increases as the histology progresses.

• #2 Pathophysiology of biochemical signs of primary biliary cholangitis

  https://www.explorationpub.com/Journals/edd/Article/100524

  Hypercholesterolemia in PBC is not accompanied by an increase in the frequency of cardiovascular events. […] The development of liver cirrhosis at a late stage of PBC is accompanied by a disturbance of the protein-synthesizing function of liver cells. […] The imbalance associated with the lower concentration of the vitamin K-dependent glycoproteins C and S than that of the decreased level of blood clotting factors may contribute to increased thrombosis.

• #2 Precirrhotic Primary Biliary Cholangitis with Portal Hypertension: Bile Duct Injury Correlate

  https://www.gutnliver.org/journal/view.html?pn=ahead&uid=2179&vmd=Full

  In summary, the percentage of precirrhotic PBC patients with PH at the time of diagnosis was 24.2%. High ALP decreased PLT count, high Mayo score, and high FIB-4 index at the time of diagnosis were effective predictors of the presence of PH in precirrhotic PBC patients, and tests related to PH should be reviewed regularly in such patients. The presence of combined PH in precirrhotic of PBC is associated with cholestasis. Cholestasis due to bile duct defects may affect the function of endothelial cells in portal vein vessels, which in turn may lead to venous hypertension.

• #2

  https://link.springer.com/article/10.1007/s11901-019-00455-3

  Primary biliary cholangitis (previously known as primary biliary cirrhosis, PBC) is a progressive cholestatic liver disease that, if untreated, ultimately leads towards cirrhosis, liver failure, and premature death. […] Inflammation and cholestasis, a defect in biliary secretion leading to the accumulation of toxic bile acids within the liver, are the main driving factors of the disease. […] Fibrates in PBC probably act through different mechanisms commonly shared across all members of the PPAR- agonists class. […] Three main mechanisms have been suggested to account for the beneficial effects of fibrates in PBC, including the reduction of bile acid overload in liver cells, the increase of phospholipid excretion into the bile, and the inhibition of pro-inflammatory agents within the liver and biliary tree.

• #2 Primary Biliary Cholangitis: New treatment goals and novel salvage therapy | World Gastroenterology Organisation

  https://www.worldgastroenterology.org/publications/e-wgn/e-wgn-expert-point-of-view-articles-collection/primary-biliary-cholangitis-new-treatment-goals-and-novel-salvage-therapy

  […] UDCA is currently the standard first line therapy for PBC patients and has been demonstrated to significantly impact the course of disease. […] It has additionally been shown to protect cholangiocytes from cholestatic injury by toxic bile acids, like chenodeoxycholic acid (CDCA). […] Benefits include a reduction in progression to cirrhosis, as well as a decrease in the need for orthotopic liver transplantation (OLT) in PBC patients. […] […] OCA was approved by the FDA in May 2016, as a second line drug to be used in combination with UDCA non-responders (UDCA-NR), or as an alternative monotherapy for those who are intolerant to UDCA. […] Other mechanisms include anti-inflammatory and anti-fibrotic properties, as well as decreased absorption, secretion, and metabolism of bile acids.

• #2

  https://link.springer.com/article/10.1007/s11901-019-00455-3

  Fibrates, indeed, repress by approximately 60% the activity of cholesterol 7-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid biosynthesis, thus reducing the production of bile acids in hepatocytes. […] PPAR- agonists also enhance the biliary output of phospholipids through transcriptional induction of the phospholipid-flippase multidrug resistance protein 3 (MDR3), the consequence of which is a better protection of the hepatocytes and cholangiocytes from membrane damage caused by accumulation of toxic bile acids. […] Fibrates have inherent anti-inflammatory effects. […] Fibrates are therefore able to inhibit pro-inflammatory genes, and experimental models have shown that they can prevent liver inflammation.

• #2

  https://www.xiahepublishing.com/1555-3884/GE-2023-00015

  Fibrates such as fenofibrate and bezafibrate improve biochemical markers of disease in patients with PBC when added to UDCA therapy, with additional evidence of symptomatic benefit. […] Despite a strong safety profile and evidence of biochemical and symptomatic benefits, the FDA specifically contraindicates fibrates for cholestatic diseases such as PBC.

• #2 GSK’s Linerixibat Offers Breakthrough Relief for PBC-Related Itch, Fueling Regulatory and Market Momentum

  https://www.ainvest.com/news/gsk-linerixibat-offers-breakthrough-relief-pbc-related-itch-fueling-regulatory-market-momentum-2505/

  Linerixibat’s mechanism is central to its promise. As an oral inhibitor of the ileal bile acid transporter (IBAT), it blocks bile acid reabsorption in the ileum, reducing circulating bile acids—a known driver of itching. […] Unlike existing therapies such as ursodeoxycholic acid (UDCA) or obeticholic acid (OCA), which primarily manage liver disease but inadequately address pruritus, linerixibat directly targets the root cause of itching. This specificity is critical, as current anti-itch treatments like rifampin or sertraline often lack efficacy or tolerability. […] The safety profile, coupled with the drug’s mechanism, suggests it could become a cornerstone therapy for PBC-related pruritus.

• #2

  https://journals.lww.com/hepcomm/fulltext/2023/06010/primary_biliary_cholangitis__epidemiology,.27.aspx

  […] […] The introduction of UDCA has helped reshape the progression and prognosis of PBC. The transplant-free survival rate for untreated patients has been estimated at 79%, 59%, and 32% at 5, 10, and 15 years, respectively. In contrast, those treated with UDCA experience significantly higher survival rates of 90%, 78%, and 66% at 5, 10, and 15 years, respectively. Similar results were obtained after pooling a large cohort of patients from the Global PBC Study Group database in which treated individuals had a 20% higher transplant-free survival rate at 10 years (79.7% among UDCA-treated patients vs. 60.7% among untreated patients) and a statistically significant reduced risk of liver transplant (LT) or death at all histological stages of the disease. Treatment with UDCA has additionally been shown to significantly delay the development of esophageal varices.

• #2 Pathogenesis of Primary Biliary Cirrhosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2095651/

  The potential for T-cell autoreactive immune responses to contribute to bile duct injury in PBC is suggested by a number of observations, not least the almost universal presence of activated T cells in the portal tract infiltrates surrounding affected bile ducts. Both CD4 and CD8 autoreactive T-cell responses directed at self-PDCE2 have now been extensively characterised in PBC patients. […] In a separate strand of work, animal modelling studies have suggested that the breakdown of tolerance to PDC at the T-cell level is associated with the development of portal tract inflammation and bile duct changes with features redolent of early human PBC. […] The balance of evidence in PBC remains strongly in favour of an autoimmune process in which autoreactive effector mechanisms are directed at epitopes within self-PDCE2 expressed normally or aberrantly by BEC. There is a strong evidence base to support both altered-self and molecular mimicry mechanisms for the breakdown of tolerance to self-PDC, with cross-reactivity between the lipoic acid cofactor and environmental xenobiotics, between bacterial and self-PDC and between self-PDC and viral protein all potentially playing important roles.

• #2

  https://journals.lww.com/hepcomm/fulltext/2023/06010/primary_biliary_cholangitis__epidemiology,.27.aspx

  […] […] OCA is a synthetically modified hydrophobic BA derived from chenodeoxycholic acid that has a high affinity for Farsenoid X receptors (FXRs). FXRs are transcription factors belonging to the superfamily of nuclear receptors with high expression in the liver and intestines. FXR regulates BA synthesis, conjugation, and transport, as well as various aspects of lipids and glucose metabolism. For instance, its activation upregulates the synthesis of short heterodimeric partner, a suppressive protein that inhibits the expression of cholesterol 7-hydroxylase. This is a rate-limiting enzyme necessary for the synthesis of BA. FXR also suppresses BA synthesis through FGF-19 and FGF-4 activation, and directly enhances the expression of several BA transporters and uptake proteins. The net effect from FXR activation is, therefore, a reduction in the total BA pool by limiting their synthesis and uptake and promoting choleresis.

• #3 A Practical Review of Primary Biliary Cholangitis for the Gastroenterologist – Gastroenterology & Hepatology

  https://www.gastroenterologyandhepatology.net/archives/march-2019/a-practical-review-of-primary-biliary-cholangitis-for-the-gastroenterologist/

  Primary biliary cholangitis (PBC) is an autoimmune chronic cholestatic liver disease characterized by biliary destruction and progressive intrahepatic cholestasis. […] The etiology of PBC is thought to be related to interactions between underlying genetic predisposition and microbial and xenobiotic environmental triggers. […] Disease is thought to arise in the background of genetic predisposition after exposure to an as-of-yet undefined environmental trigger. […] Several large-scale epidemiologic studies have been performed that support an association with urinary tract infections (caused by Escherichia coli, Mycobacterium gordonae, or Novosphingobium aromaticivorans), reproductive hormone replacement, nail polish, hair dyes, past cigarette smoking, and toxic waste sites as environmental triggers associated with disease onset.

• #3 Primary Biliary Cholangitis: New treatment goals and novel salvage therapy | World Gastroenterology Organisation

  https://www.worldgastroenterology.org/publications/e-wgn/e-wgn-expert-point-of-view-articles-collection/primary-biliary-cholangitis-new-treatment-goals-and-novel-salvage-therapy

  […] Recent studies point towards normal ALP levels as the desired biochemical goal for effective PBC therapy. […] Additionally, an analysis made with data extracted from the GLOBAL PBC Study Group, compared ten-year survival rates of a cohort of PBC patients and found an association between normal ALP levels and lower risk for OLT or death in these patients. […] […] Given that, as discussed above, none of the existing criteria really prioritize normalization of ALP or TB levels to qualify a successful treatment, it is easy to see how findings like this could have very important implications on the future management of PBC patients, particularly when deciding to start any treatment beyond first line therapy. […] […] Seladelpar is a PPAR- agonist, a receptor found in hepatocytes, cholangiocytes and various immune cells known to play a role in the pathogenesis of PBC. […] Its mechanism is thought to consist in a reduction of bile acid synthesis as well as an increase in lipid degradation. […] […] The treatment and management of PBC patients is evolving. […] These findings carry even more weight when we look at the high number of promising therapeutic options, with many different mechanisms of action, currently being investigated.

• #3

  https://journals.lww.com/hepcomm/fulltext/2023/06010/primary_biliary_cholangitis__epidemiology,.27.aspx

  […] […] Fibrates are strong peroxisome proliferator-activated receptor (PPAR) agonists. PPAR are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. They exist in 3 isoforms: PPAR-, PPAR-, and PPAR-, with the former predominantly expressed in hepatocytes. When activated, PPAR- induces the expression of numerous genes with a number of them involved in lipid pathways that regulate fatty acid oxidation, triglyceride degradation and BA synthesis, metabolism, and transport, reducing BA concentration inside hepatocytes, augmenting phospholipid excretion into the biliary canaliculi, and inhibiting proinflammatory agents within the liver and biliary tree.

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