ABSTRACT
INTRODUCTION: Up to 40% of Primary biliary cholangitis (PBC) patients have a suboptimal response to Ursodeoxycholic acid (UDCA). Close to half of such patients show a remarkable improvement when additionally treated with Obeticholic acid (OCA) but have a dose-dependent increase of pruritus. This relative success of OCA, a first-in-class Farnesoid receptor (FXR) agonist, has positioned FXR as an attractive target for drug development. Novel candidates have since emerged, providing hope for this subgroup of patients who lack effective and safe treatments. AREAS COVERED: We discussed the role of bile acids in PBC pathogenesis and how the FXR agonists provide therapeutic value by affecting bile acid synthesis and transport. Novel FXR agonists undergoing pre-clinical and clinical trials for PBC were enlisted via literature search by including the terms 'FXR agonists,' 'FXR PBC,' 'PBC clinical trials' on PubMed, MEDLINE via Ovid, and Clinicaltrials.gov. EXPERT OPINION: Novel FXR agonists currently under investigation for PBC improve the disease surrogate markers in early trials. However, as with OCA, pruritus remains a concern with the newer drugs despite targeted chemical modifications to increase FXR specificity. Directing future resources toward studying the molecular mechanisms behind pruritus may lead to better drug design and efficacious yet safer drugs.
Subject(s)
Chenodeoxycholic Acid , Liver Cirrhosis, Biliary , Receptors, Cytoplasmic and Nuclear , Animals , Humans , Bile Acids and Salts/metabolism , Chenodeoxycholic Acid/pharmacology , Chenodeoxycholic Acid/analogs & derivatives , Chenodeoxycholic Acid/therapeutic use , Cholagogues and Choleretics/pharmacology , Dose-Response Relationship, Drug , Drug Development , Drugs, Investigational/pharmacology , Liver Cirrhosis, Biliary/drug therapy , Liver Cirrhosis, Biliary/physiopathology , Pruritus/drug therapy , Receptors, Cytoplasmic and Nuclear/agonists , Receptors, Cytoplasmic and Nuclear/metabolism , Ursodeoxycholic Acid/pharmacologyABSTRACT
INTRODUCTION: Pruritus is common and often undertreated in patients with primary biliary cholangitis (PBC). Existing treatments largely have an aging and low-quality evidence base, and studies included only small numbers of patients. More recent data that has added to our understanding of pruritus treatments has often come from clinical trials where itching was a secondary outcome measure in a trial designed primarily to assess disease-modifying agents. This area represents an unmet clinical need in the management of PBC. AREAS COVERED: In this manuscript, we first summarize the proposed mechanisms for PBC-related pruritus and the current treatment paradigm. We then present an appraisal of the existing pre-clinical and clinical evidence for the use of ileal bile acid transporter inhibitors (IBATis) for this indication in PBC patients. EXPERT OPINION: Evidence for the efficacy of IBATis is promising but limited by the currently available volume of data. Furthermore, larger clinical trials with long-term data on efficacy, safety and tolerability are needed to confirm the role of using IBATis in clinical practice and their place on the itch treatment ladder. Additional focus should also be given to exploring the disease-modifying potential of IBATis in PBC.
Subject(s)
Drug Development , Liver Cirrhosis, Biliary , Organic Anion Transporters, Sodium-Dependent , Pruritus , Humans , Pruritus/drug therapy , Animals , Liver Cirrhosis, Biliary/drug therapy , Liver Cirrhosis, Biliary/physiopathology , Organic Anion Transporters, Sodium-Dependent/antagonists & inhibitors , Symporters/antagonists & inhibitorsABSTRACT
The effects of the obliteration of portal venules (OPV) in cirrhotic portal hypertension are poorly understood. To investigate its contribution to portal hypertension in biliary cirrhosis and its underlying mechanism, we evaluated OPV using two-dimensional (2D) histopathology in liver explants from patients with biliary atresia (BA, n = 63), primary biliary cholangitis (PBC, n = 18), and hepatitis B-related cirrhosis (Hep-B-cirrhosis, n = 35). Then, three-dimensional (3D) OPV was measured by X-ray phase-contrast CT in two parallel models in rats following bile duct ligation (BDL) or carbon tetrachloride (CCl4) administration, representing biliary cirrhosis and post-necrotic cirrhosis, respectively. The portal pressure was also measured in the two models. Finally, the effects of proliferative bile ducts on OPV were investigated. We found that OPV was significantly more frequent in patients with biliary cirrhosis, including BA (78.57 ± 16.45%) and PBC (60.00 ± 17.15%), than that in Hep-B-cirrhotic patients (29.43 ± 14.94%, p < 0.001). OPV occurred earlier, evidenced by the paired liver biopsy at a Kasai procedure (KP), and was irreversible even after a successful KP in the patients with BA. OPV was also significantly more frequent in the BDL models than in the CCl4 models, as shown by 2D and 3D quantitative analysis. Portal pressure was significantly higher in the BDL model than that in the CCl4 model. With the proliferation of bile ducts, portal venules were compressed and irreversibly occluded, contributing to the earlier and higher portal pressure in biliary cirrhosis. OPV, as a pre-sinusoidal component, plays a key role in the pathogenesis of portal hypertension in biliary cirrhosis. The proliferated bile ducts and ductules gradually take up the 'territory' originally attributed to portal venules and compress the portal venules, which may lead to OPV in biliary cirrhosis. © 2024 The Pathological Society of Great Britain and Ireland.
Subject(s)
Hypertension, Portal , Liver Cirrhosis, Biliary , Portal Vein , Hypertension, Portal/pathology , Hypertension, Portal/physiopathology , Animals , Liver Cirrhosis, Biliary/pathology , Liver Cirrhosis, Biliary/complications , Liver Cirrhosis, Biliary/physiopathology , Male , Humans , Female , Portal Vein/pathology , Venules/pathology , Rats , Adult , Portal Pressure , Middle Aged , Disease Models, Animal , Liver/pathology , Liver/blood supply , Rats, Sprague-Dawley , Bile Ducts/pathology , Young Adult , AdolescentABSTRACT
BACKGROUND & AIM: Saroglitazar is a novel peroxisome proliferator-activated receptor (PPAR) agonist with dual agonistic properties (α/γ). Due to a strong mechanistic rationale, we aimed to test the safety and efficacy of saroglitazar in patients with primary biliary cholangitis (PBC) who were either ursodeoxycholic acid (UDCA) resistant or intolerant. METHODS: In this double-blind, phase II proof-of-concept trial, 37 patients with PBC were randomized to saroglitazar 4 mg (n = 13), saroglitazar 2 mg (n = 14), or placebo (n = 10) daily for 16 weeks. The primary efficacy endpoint was the reduction in alkaline phosphatase (ALP) level at Week 16. RESULTS: A significant reduction of mean ALP levels was observed at Week 16 relative to baseline in both the saroglitazar 4 mg (least-squares [LS] mean =-163.3 U/L, SE = 25.1, p <0.001) and 2 mg (LS mean =-155.8 U/L, SE = 24.4, p <0.001) groups, compared with placebo (LS mean =-21.1 U/L, SE = 28.9). Treatment with saroglitazar resulted in a rapid reduction of ALP concentration at Week 4 that was sustained through the study duration. At least 1 treatment-emergent adverse event occurred in 11 (84.6%) patients in the saroglitazar 4 mg group, in 12 (85.7%) patients in the 2 mg group and in 8 (80%) patients in the placebo group. Study drug was discontinued in 4 patients (3 patients in the 4 mg group and 1 patient in the 2 mg group) due to aminotransferase increases that promptly returned to baseline values after drug discontinuation. CONCLUSIONS: Saroglitazar at 2 mg and 4 mg daily was tolerated and resulted in rapid and sustained improvements in ALP. Further studies are underway at a daily dose of 2 mg and 1 mg due to the higher incidence of elevated liver enzymes observed with the 4 mg dose. CLINICALTRIALS. GOV IDENTIFIER: NCT03112681 LAY SUMMARY: Saroglitazar resulted in a rapid and sustained improvement in alkaline phosphatase levels in patients with primary biliary cholangitis. The mean percentage reductions in alkaline phosphatase levels were 49% and 51% in the saroglitazar 4 mg and 2 mg groups compared to 3% in the placebo group.
Subject(s)
Liver Cirrhosis, Biliary/drug therapy , Phenylpropionates/pharmacology , Pyrroles/pharmacology , Double-Blind Method , Female , Humans , Liver Cirrhosis, Biliary/physiopathology , Male , Middle Aged , Phenylpropionates/therapeutic use , Placebos , Pyrroles/therapeutic use , Treatment OutcomeABSTRACT
OBJECTIVE: Primary biliary cholangitis (PBC) is a chronic progressive cholestatic liver disease. In recent years, researchers have found that cysteine-rich angiogenic inducer 61 (Cyr61, also known as CCN1) has a potential role in reducing portal inflammation in patients with PBC. This study aimed to explore the relationship between Cyr61 and PBC to provide new ideas and an experimental basis for the clinical treatment of PBC. METHODS: After induction of the overexpression of Cyr61 in a mouse model of PBC using recombinant adenovirus, hematoxylin and eosin staining and pathological scores were used to indicate intrahepatic inflammation and bile duct damage. Real-time PCR was used to detect changes in inflammation-related cytokines in the liver. To further study the mechanism, we assessed whether Cyr61 protects bile duct epithelial cells from cytotoxic effects. RESULTS: Serum and hepatic Cyr61 levels were increased in the murine model of PBC. Overexpression of Cyr61 alleviated hepatic inflammation and bile duct injury in vivo. Cyr61 inhibited the cytotoxic effects of CD8+ T cells by acting on biliary epithelial cells (BECs) in vitro. CONCLUSION: Our results provide novel insight into the pathogenesis of PBC and suggest that Cyr61 plays a dominant role in the cytotoxic effects on BECs in PBC. Consequently, therapeutic strategies targeting Cyr61 could be a potent therapy for PBC.
Subject(s)
Bile Ducts/immunology , Cysteine-Rich Protein 61 , Cytokines/immunology , Epithelial Cells/immunology , Liver Cirrhosis, Biliary/physiopathology , Animals , CD8-Positive T-Lymphocytes/pathology , Cysteine-Rich Protein 61/blood , Disease Models, Animal , Inflammation Mediators/immunology , Liver/pathology , MiceABSTRACT
Background: Increasing data suggests an interaction between bile acids and intestinal microbiota in the pathogenesis of primary biliary cholangitis (PBC). Bile acid sequestrants are widely used to bind bile acids in the intestinal lumen and are therefore posited to impact gut bacteria. Herein we aimed to investigate the effects of cholestyramine on the bile acid profile and gut microbiome in a cohort of icteric PBC patients.Results: Thirty-three PBC patients were treated with cholestyramine, serum and stool samples were collected at baseline, 4 and 16 weeks. Shotgun metagenomic sequencing and targeted metabolomic profiling were performed. Following cholestyramine administration, patients exhibited a high interpersonal variability in remission of cholestasis, and were therefore dichotomized according to the decrease of total bilirubin. Gut microbial co-abundance networks showed distinct taxa interactions between subjects with superior remission (SR) and those with inferior remission (IR) at baseline. After treatment, compositional shifts of the microbiome in the SR group were characterized with enrichment of two Lachnospiraceae species, typically producing short-chain fatty acids (SCFAs). In contrast, Klebsiella pneumonia, a commensal pathobiont, was only increased in the IR group. Correspondingly, metabolome analysis demonstrated that patients with SR, but not IR, were marked by elevations of SCFAs including valeric acid and caproic acid. Finally, integrative analysis identified robust associations between the variations of microbiota, metabolites, and inflammatory cytokines in SR group, indicating potential mechanistic links.Conclusions: Beneficial responses caused by cholestyramine were closely related with compositional and functional alterations in gut commensal, highlighting the possibility of exploring bile acid-microbiota interactions for treating PBC.
Subject(s)
Bacteria/metabolism , Bile Acids and Salts/metabolism , Bile Acids and Salts/pharmacology , Bile Acids and Salts/therapeutic use , Gastrointestinal Microbiome/drug effects , Liver Cirrhosis, Biliary/drug therapy , Liver Cirrhosis, Biliary/physiopathology , Adult , China , Cohort Studies , Female , Gastrointestinal Agents/metabolism , Gastrointestinal Agents/pharmacology , Gastrointestinal Agents/therapeutic use , Humans , Male , Middle AgedABSTRACT
Cholestatic liver disease is a disease that causes liver damage and fibrosis owing to bile stasis. It is represented by primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), but the pathophysiological pathways that cause bile stasis in both diseases are different. The pathogenesis of the disease is still unclear, although autoimmune mechanisms have been postulated and partially elucidated. Although the disease may progress slowly with only mild liver dysfunction, it may progress to liver cirrhosis or liver failure, which require liver transplantation. As a medical treatment, ursodeoxycholic acid is widely used for PBC and has proved to be very effective against disease progression in cases of PBC. On the other hand, its efficacy is limited in cases of PSC, and the research and development of various drugs are underway. Furthermore, the clinical course of both diseases is quite variable, making the design of clinical trials fairly difficult. In this review, we present the general natural history of PBC and PSC, and provide information on the latest drug therapies currently available and those that are under investigation.
Subject(s)
Cholangitis, Sclerosing/drug therapy , Cholangitis, Sclerosing/physiopathology , Liver Cirrhosis, Biliary/drug therapy , Liver Cirrhosis, Biliary/physiopathology , Anti-Bacterial Agents/pharmacology , Bezafibrate/pharmacology , Cholagogues and Choleretics/therapeutic use , Cholangitis, Sclerosing/complications , Cholangitis, Sclerosing/epidemiology , Fibroblast Growth Factors/agonists , Glucocorticoids/pharmacology , Hepatitis, Autoimmune/epidemiology , Humans , Immunosuppressive Agents/pharmacology , Liver Cirrhosis, Biliary/complications , Liver Cirrhosis, Biliary/epidemiology , Peroxisome Proliferator-Activated Receptors/agonists , Probiotics/pharmacology , Receptors, Cytoplasmic and Nuclear/agonists , Tumor Necrosis Factor-alpha/antagonists & inhibitorsABSTRACT
Cl/HCO3 anion exchangers (AEs), which are members of the solute carrier 4 family, contribute to the exchange of one intracellular HCO3 for one extracellular Cl. AE2, a vital subtype of the Cl/HCO3 exchangers, is expressed widely in various cells and tissues in mammals and serves essential roles in the pathophysiological processes of the cardiovascular system and renal tubular reabsorption. Recently, research on the function of AE2 in the digestive system shed new light on its roles in the regulation of cellular and organ physiology. AE2 not only participates in gastric acid secretion, but also mediates bile secretion and digestive cancer development. The aim of the present review was to describe the role of AE2 in the physiology and pathophysiology of the digestive system, with the aim of guiding clinical diagnosis and treatment.
Subject(s)
Bicarbonates/metabolism , Chloride-Bicarbonate Antiporters/physiology , Chlorides/metabolism , Digestive System/metabolism , Digestive System/physiopathology , Animals , Chloride-Bicarbonate Antiporters/chemistry , Humans , Liver Cirrhosis, Biliary/metabolism , Liver Cirrhosis, Biliary/physiopathology , Liver Neoplasms/metabolism , Liver Neoplasms/physiopathologySubject(s)
Antiviral Agents/administration & dosage , COVID-19 , Hashimoto Disease , Immunoglobulins, Intravenous/administration & dosage , Liver Cirrhosis, Biliary , Adult , Aftercare/methods , Anti-Bacterial Agents/administration & dosage , Autoimmunity , Biopsy/methods , COVID-19/complications , COVID-19/immunology , COVID-19/physiopathology , COVID-19/therapy , Female , Guillain-Barre Syndrome/diagnosis , Guillain-Barre Syndrome/etiology , Hashimoto Disease/diagnosis , Hashimoto Disease/immunology , Humans , Liver/pathology , Liver Cirrhosis, Biliary/blood , Liver Cirrhosis, Biliary/etiology , Liver Cirrhosis, Biliary/physiopathology , Liver Cirrhosis, Biliary/therapy , Liver Function Tests/methods , Neurologic Examination/methods , Respiration, Artificial/methods , SARS-CoV-2/isolation & purificationABSTRACT
Introduction: Patients with cholestatic diseases may develop fatigue and cognitive symptoms. The impact of symptom burden may be significant in some patients. To date, there are no effective pharmacological therapies to improve cognitive symptoms or fatigue in cholestasis and we are wholly reliant on supportive approaches. Area covered: This review provides an overview of cognitive symptoms and fatigue in the cholestatic liver disease primary biliary cholangitis (PBC), including pathophysiology and our approach to the management of these symptoms. Expert opinion: The impact of fatigue and cognitive symptoms on the perceived quality of life can be profound for patients with PBC. The pathophysiology of these symptoms is complex and poorly understood, making the development of therapeutic trials of symptom-directed therapies challenging. The current recommended management for fatigue and cognitive symptoms is mainly supportive.
Subject(s)
Cognition Disorders/physiopathology , Fatigue/physiopathology , Liver Cirrhosis, Biliary/physiopathology , Cholestasis/complications , Cholestasis/physiopathology , Cholestasis/therapy , Cognition Disorders/diagnosis , Cognition Disorders/etiology , Cognition Disorders/therapy , Fatigue/etiology , Fatigue/therapy , Humans , Liver Cirrhosis, Biliary/complications , Liver Cirrhosis, Biliary/therapy , Pruritus/etiology , Pruritus/therapy , Quality of LifeABSTRACT
BACKGROUND: Primary biliary cholangitis (PBC), an immune-mediated disease characterised by destruction of intrahepatic bile ducts, results in progressive damage to the biliary tree, cholestasis and ultimately advanced liver disease. In the last decade, advances in practice have improved clinical care, driven novel therapeutic options and improved risk stratification tools. AIMS: To provide an overview of the disease characteristics of PBC and review a patient-centred management approach for the clinical team caring for those with PBC. METHODS: We reviewed the current literature and guidelines on PBC with a focus on management and therapies. RESULTS: A confident diagnosis of PBC is usually made based on serum liver tests and immune serology. Management of PBC should focus on three main 'process' pillars: (a) treat and risk-stratify through use of biochemical and prognostic criteria; (b) manage concurrent symptoms and other associated diseases; and (c) stage disease, monitor progression and prevent complications. With ongoing complexities in management, including a newly licensed therapy (obeticholic acid) and alternative non-licensed treatments and ongoing clinical trials, discussion with PBC expert centres is encouraged. CONCLUSIONS: PBC is a dynamic disease wherein current treatment goals have become appropriately ambitious. Goals of care should prioritise prevention of end-stage liver disease and amelioration of patient symptom burden for all.
Subject(s)
Liver Cirrhosis, Biliary , Fatigue/etiology , Fatigue/therapy , Humans , Liver Cirrhosis, Biliary/complications , Liver Cirrhosis, Biliary/diagnosis , Liver Cirrhosis, Biliary/physiopathology , Liver Cirrhosis, Biliary/therapy , Liver Transplantation , Metabolic Diseases/etiology , Metabolic Diseases/therapy , Pruritus/etiology , Pruritus/therapy , Ursodeoxycholic Acid/therapeutic useABSTRACT
BACKGROUND: Primary biliary cholangitis-autoimmune hepatitis overlap syndrome (PBC-AIH OS), which exhibits features between autoimmune hepatitis and cholestasis, is a common condition and usually shows a progressive course toward cirrhosis and liver failure without adequate treatment. Synthesis of bile acids (BAs) plays an important role in liver injury in cholestasis, and the process is regulated by fibroblast growth factor 19 (FGF19). The overall role of circulating FGF19 in BA synthesis and PBC-AIH OS requires further investigation. METHODS: We analyzed BA synthesis and correlated clinical parameters with serum BAs and FGF19 in 35 patients with PBC-AIH OS. Serum concentrations of 7alpha-hydroxycholest-4-en-3-one (C4) were used to quantify the synthesis of BA directly. RESULTS: Serum FGF19 levels were higher, while C4 levels were substantially lower in PBC-AIH OS patients than those in healthy controls. Circulating FGF19 levels strongly correlated with C4 (r = -0.695, p < 0.0001), direct bilirubin (r = 0.598, p = 0.0001), and total bile acids (r = 0.595, p = 0.002). Moreover, circulating FGF19 levels strongly correlated with the model for end-stage liver disease score (r = 0.574, p = 0.0005) and Mayo risk score (r = 0.578, p = 0.001). CONCLUSIONS: Serum FGF19 is significantly increased in patients with PBC-AIH OS, while BA synthesis is suppressed. Circulating FGF19 primarily controls the regulation of BA synthesis in response to cholestasis and under cholestatic conditions. Therefore, modulation of circulating FGF19 could provide a promising targeted therapy for patients with PBC-AIH OS.
Subject(s)
Bile Acids and Salts/metabolism , Fibroblast Growth Factors , Hepatitis, Autoimmune , Liver Cirrhosis, Biliary , Cohort Studies , Female , Fibroblast Growth Factors/blood , Fibroblast Growth Factors/metabolism , Hepatitis, Autoimmune/epidemiology , Hepatitis, Autoimmune/metabolism , Hepatitis, Autoimmune/physiopathology , Humans , Liver/chemistry , Liver Cirrhosis, Biliary/epidemiology , Liver Cirrhosis, Biliary/metabolism , Liver Cirrhosis, Biliary/physiopathology , Male , Middle Aged , SyndromeABSTRACT
BACKGROUND Kupffer cells and natural killer (NK) cells has been identified as contributing factors in the pathogenesis of hepatitis, but the detailed mechanism of these cell types in the pathogenesis of primary biliary cholangitis (PBC) is poorly understood. MATERIAL AND METHODS In this study, polyinosinic: polycytidylic acid (poly I: C), 2-octynoic acid-bovine serum albumin (2OA-BSA) and Freund's adjuvant (FA) were injected to establish a murine PBC model, from which NK cells and Kupffer cells were extracted and isolated. The cells were then co-cultivated in a designed culture system, and then NK group 2, member D (NKG2D), retinoic acid early inducible-1 (RAE-1), F4/80, and cytokine expression levels were detected. RESULTS The results showed close crosstalk between Kupffer cells and NK cells. PBC mice showed increased surface RAE-1 protein expression and Kupffer cell cytokine secretion, which subsequently activated NK cell-mediated target cell killing via NKG2D/RAE-1 recognition, and increased inflammation. NK cell-derived interferon-γ (IFN-γ) and Kupffer cell-derived tumor necrosis factor alpha (TNF-alpha) were found to synergistically regulate inflammation. Moreover, interleukin (IL)-12 and IL-10 improved the crosstalk between NK cells and Kupffer cells. CONCLUSIONS Our ï¬ndings in mice are the first to suggest the involvement of the NKG2D/RAE-1 interaction and cytokines in the synergistic effects of NK and Kupffer cells in PBC.
Subject(s)
Killer Cells, Natural/metabolism , Kupffer Cells/metabolism , Liver Cirrhosis, Biliary/metabolism , Animals , Cytokines/metabolism , Disease Models, Animal , Female , Interferon-gamma/metabolism , Interleukin-12/metabolism , Killer Cells, Natural/pathology , Kupffer Cells/pathology , Liver Cirrhosis, Biliary/physiopathology , Mice , Mice, Inbred C57BL , NK Cell Lectin-Like Receptor Subfamily K/metabolism , Nuclear Matrix-Associated Proteins/metabolism , Nucleocytoplasmic Transport Proteins/metabolismABSTRACT
OBJECTIVE: To determine both the incidence and the prevalence of primary biliary cholangitis (PBC) in Eastern Slovakia and to describe its clinical course and the response to ursodeoxycholic acid (UDCA). METHODS: We recorded data of patients with PBC, who were followed up in gastroenterology and hepatology centers in Eastern Slovakia during the period from June 30, 1999, through June 30, 2019. RESULTS: The annual incidence of PBC varied from 0.7 to 1.5 cases per 100,000 inhabitants between 2014 and 2018. PBC prevalence steadily increased from initial 10.2 cases per 100,000 inhabitants in 2014 to 14.9 cases per 100,000 inhabitants in June 2019. The mean age at the time of diagnosis was 56.3 ± 10.9 years. 95.7% of patients were females, and female/male gender ratio was 22.3:1. In June 2019, prevalence in the female population was 28 cases per 100,000 women. At the time of diagnosis, three-quarters of patients were symptomatic and 10% of patients had liver cirrhosis. The mean follow-up was 7.3 ± 5.2 years. Response to UDCA was observed in 72.1% of patients. Patients with higher baseline alkaline phosphatase (ALP) levels, liver cirrhosis at entry or at the end of follow-up and women younger than 45 years responded worse to UDCA. One-quarter of patients had liver cirrhosis at the end of follow-up. During follow-up, 1.6% of patients underwent liver transplantation and 5.5% of patients died. Five-year and 10-year liver-related mortalities were 2.7% and 4.3%, respectively. CONCLUSION: PBC prevalence in Eastern Slovakia is increasing, and most of the patients respond to therapy with UDCA.
Subject(s)
Cholagogues and Choleretics/therapeutic use , Liver Cirrhosis, Biliary/drug therapy , Liver Cirrhosis, Biliary/epidemiology , Liver Cirrhosis, Biliary/physiopathology , Ursodeoxycholic Acid/therapeutic use , Aged , Female , Humans , Incidence , Male , Middle Aged , Prevalence , Slovakia/epidemiologyABSTRACT
INTRODUCTION: Primary biliary cholangitis (PBC) is a progressive inflammatory autoimmune cholestatic liver disease. Without treatment, it may result in fibrosis and eventually end stage liver disease. In addition to the disease burden, the symptom impact on the quality of life for PBC patients is significant. Ursodeoxycholic acid, and the second-line therapy, Obeticholic acid, are the only available licensed treatments. Although there has been rapid development of novel therapies in recent years for the treatment of PBC, there are very few symptoms directed therapies. AREA COVERED: This literature review aims to review the current treatment landscape in PBC and to explore how the next few years may unfold in the field. The current guidelines and emerging therapies in phase 2, 3 and 4 clinical trials have been included. EXPERT OPINION: The currently available therapies are effective, but their use has limitations and challenges and there is still significant unmet need. Although there have been promising therapeutic interventions in recent years, further research into personalizing therapeutic strategies with available treatments and new agents is needed.
Subject(s)
Drug Development , Liver Cirrhosis, Biliary/drug therapy , Quality of Life , Animals , Chenodeoxycholic Acid/analogs & derivatives , Chenodeoxycholic Acid/therapeutic use , Cholagogues and Choleretics/therapeutic use , Disease Progression , Humans , Liver Cirrhosis, Biliary/physiopathology , Ursodeoxycholic Acid/therapeutic useABSTRACT
Primary biliary cholangitis is an uncommon cholestatic liver disease predominantly affecting middle-aged women. Left untreated, there is a high risk of progression to end-stage liver disease. Few treatment options exist. To date, ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) are the only medical therapies approved for use, other than symptomatic treatments and liver transplantation, the latter of which is reserved for those developing complications of cirrhosis or with intractable pruritus. UDCA improves outcomes, but many patients do not adequately respond. OCA therapy may improve response, but long-term data are limited. New therapies are desperately needed, but evaluation has been limited by the fact that the disease is heterogeneous, hard end points take years to develop, and there are different criteria in use for determining therapeutic response based on surrogate biomarkers. Fibrates appear to be the most promising new therapy and have beneficially affected surrogate end points and are beginning to show improvement in clinical end points.
Subject(s)
End Stage Liver Disease/etiology , Liver Cirrhosis, Biliary/therapy , Chenodeoxycholic Acid/analogs & derivatives , Chenodeoxycholic Acid/therapeutic use , Disease Progression , Female , Fibric Acids/therapeutic use , Humans , Liver Cirrhosis, Biliary/epidemiology , Liver Cirrhosis, Biliary/physiopathology , Liver Transplantation/methods , Male , Middle Aged , Ursodeoxycholic Acid/therapeutic useABSTRACT
Primary biliary cholangitis (PBC) is an autoimmune disease characterized by chronic destruction of the bile ducts. A major unanswered question regarding the pathogenesis of PBC is the precise mechanisms of small bile duct injury. Emperipolesis is one of cell-in-cell structures that is a potential histological hallmark associated with chronic hepatitis B. This study aimed to clarify the pathogenesis and characteristics of emperipolesis in PBC liver injury. Sixty-six PBC patients, diagnosed by liver biopsy combined with laboratory test, were divided into early-stage PBC (stages I and II, n = 39) and late-stage PBC (stages III and IV, n = 27). Emperipolesis was measured in liver sections stained with haematoxylin-eosin. The expressions of CK19, CD3, CD4, CD8, CD20, Ki67 and apoptosis of BECs were evaluated by immunohistochemistry or immunofluorescence double labelling. Emperipolesis was observed in 62.1% of patients with PBC, and BECs were predominantly host cells. The number of infiltrating CD3+ and CD8+ T cells correlated with the advancement of emperipolesis (R2 = 0.318, P < .001; R2 = 0.060, P < .05). The cell numbers of TUNEL-positive BECs and double staining for CK19 and Ki67 showed a significant positive correlation with emperipolesis degree (R2 = 0.236, P < .001; R2 = 0.267, P < .001). We conclude that emperipolesis mediated by CD8+ T cells appears to be relevant to apoptosis of BEC and thus may aggravate the further injury of interlobular bile ducts.
Subject(s)
Apoptosis , Bile Ducts/pathology , CD8-Positive T-Lymphocytes/immunology , Emperipolesis , Epithelial Cells/pathology , Liver Cirrhosis, Biliary/physiopathology , Bile Ducts/immunology , Bile Ducts/injuries , Case-Control Studies , Cell Proliferation , Epithelial Cells/immunology , Female , Humans , Male , Middle AgedABSTRACT
Up to 40% of patients with primary biliary cholangitis have an incomplete response to first-line treatment with ursodeoxycholic acid. Obeticholic acid was approved by the US Food and Drug Administration in 2016 as a second-line treatment for patients with primary biliary cholangitis who are unresponsive to ursodeoxycholic acid; however, approximately 50% of patients might need additional treatments to reach therapeutic goals. A considerable need exists for effective treatment options to prevent progression to liver transplantation or death in these patients. Drugs that might modulate immunological abnormalities in primary biliary cholangitis have been studied but their effectiveness varies. Budesonide, ciclosporin, and rituximab have shown potential in modifying the disease process. Bezafibrate, a pan-peroxisome proliferator-activated receptor agonist, has been shown to ameliorate deranged bile acid homoeostasis and attenuate raised concentrations of liver enzymes associated with primary biliary cholangitis. As the mechanisms underlying the pathogenesis and progression of primary biliary cholangitis are further clarified, specific targeted therapies are under development with promising early results. Various therapeutic target bile acid homeostasis, immune dysfunction, and fibrogenetic pathways are being studied. A better understanding of the biochemical and clinical effects of the therapies in development bear discussion, both to guide the discovery of new therapies and to inform clinicians so that rational treatment regimens can be tailored to patients once they become available.
Subject(s)
Homeostasis/drug effects , Liver Cirrhosis, Biliary/complications , Liver Cirrhosis, Biliary/drug therapy , Benzothiazoles/pharmacology , Benzothiazoles/therapeutic use , Bezafibrate/pharmacology , Bezafibrate/therapeutic use , Bile Acids and Salts/physiology , Budesonide/pharmacology , Budesonide/therapeutic use , Case-Control Studies , Chenodeoxycholic Acid/analogs & derivatives , Chenodeoxycholic Acid/chemistry , Chenodeoxycholic Acid/pharmacology , Chenodeoxycholic Acid/therapeutic use , Cholagogues and Choleretics/chemistry , Cholagogues and Choleretics/pharmacology , Cholagogues and Choleretics/therapeutic use , Clinical Trials as Topic , Cyclosporine/pharmacology , Cyclosporine/therapeutic use , Disease Progression , Glucocorticoids/pharmacology , Glucocorticoids/therapeutic use , Humans , Immunologic Factors/pharmacology , Immunologic Factors/therapeutic use , Immunosuppressive Agents/pharmacology , Immunosuppressive Agents/therapeutic use , Isoxazoles/pharmacology , Isoxazoles/therapeutic use , Liver Cirrhosis, Biliary/metabolism , Liver Cirrhosis, Biliary/physiopathology , Liver Transplantation/statistics & numerical data , Peroxisome Proliferator-Activated Receptors/agonists , Receptors, Cytoplasmic and Nuclear/agonists , Rituximab/pharmacology , Rituximab/therapeutic use , Treatment Outcome , United States/epidemiology , United States Food and Drug Administration/organization & administration , Ursodeoxycholic Acid/chemistry , Ursodeoxycholic Acid/pharmacology , Ursodeoxycholic Acid/therapeutic useABSTRACT
Though ursodeoxycholic acid (UDCA) remains the baseline treatment for most cholestatic liver diseases, UDCA treatment leaves approximately one-third of patients with primary biliary cholangitis (PBC) and all patients with primary sclerosing cholangitis (PSC) at risk for disease progression. New anticholestatic agents, including nuclear receptor agonists, choleretics, and bile acid synthesis suppressors, will likely increase response rates to therapy in PBC and PSC. Strategies that target early immune-mediated injury have so far been disappointing, hampered by the lack of biomarkers to detect early disease states, which then could profit from immunomodulatory therapy. Future concepts need to personalize treatments according to disease stage, progression, and phase, and to combine multiple drugs to target different pathogenic pathways.