Elsevier

The Lancet

Volume 396, Issue 10266, 12 December 2020, Pages 1915-1926
The Lancet

Seminar
Primary biliary cholangitis

https://doi.org/10.1016/S0140-6736(20)31607-XGet rights and content

Abstract

Primary biliary cholangitis is an autoimmune liver disease that predominantly affects women. It is characterised by a chronic and destructive, small bile duct, granulomatous lymphocytic cholangitis, with typical seroreactivity for antimitochondrial antibodies. Patients have variable risks of progressive ductopenia, cholestasis, and biliary fibrosis. Considerations for the cause of this disease emphasise an interaction of chronic immune damage with biliary epithelial cell responses and encompass complex, poorly understood genetic risks and environmental triggers. Licensed disease-modifying treatment focuses on amelioration of cholestasis, with weight-dosed oral ursodeoxycholic acid. For patients who do not respond sufficiently, or patients with ursodeoxycholic acid intolerance, conditionally licensed add-on therapy is with the FXR (NR1H4) agonist, obeticholic acid. Off-label therapy is recognised as an alternative, notably with the pan-PPAR agonist bezafibrate; clinical trial agents are also under development. Baseline characteristics, such as young age, male sex, and advanced disease, and serum markers of liver injury, particularly bilirubin and ALP, are used to stratify risk and assess treatment responsiveness. Parallel attention to the burden of patient symptoms is paramount, including pruritus and fatigue.

Introduction

Primary biliary cholangitis (formerly known as primary biliary cirrhosis) is the most common autoimmune liver disease;1 as a lifelong illness, it is reflected histopathologically by a chronic immune-driven injury to the small bile duct (figure 1).2 Understanding autoimmune diseases such as primary biliary cholangitis includes an appreciation of the burden of disease to patients,3 alongside the science explaining the role of genetics, lymphoid subsets as regulators, effector pathways of immune damage, and tissue responses to injury. Primary biliary cholangitis is usually identified (table 1) at an early stage in a patient with a cholestatic pattern of serum liver tests—elevated serum activities of ALP, GGT, or both—and the presence of circulating antimitochondrial antibodies. Symptom burden, although variable, can be marked regardless of underlying disease severity, and sicca complex, abdominal discomfort, pruritus, fatigue, and bone pain are frequently reported by patients. Disease-modifying therapy has a substantial effect when tackling the inflammatory and profibrotic consequences of cholestasis, and the two licensed agents, ursodeoxycholic acid4 and obeticholic acid,5 are bile acid-based therapies ameliorating the consequences of cholestasis; alternative anticholestatic therapies include off-label bezafibrate6 and other emerging clinical trial agents that also target the PPAR pathway.

Patient care focuses on confirming a clear diagnosis; appreciating the severity of liver disease at presentation and over the course of follow-up; identifying the patients at greatest risk for disease progression on the basis of baseline presenting features and on-treatment disease markers; and addressing accompanying symptom burden to mitigate against reduced patient quality of life.

Section snippets

Primary biliary cholangitis: a global perspective

Every year, at least 100 000 individuals worldwide receive a diagnosis of primary biliary cholangitis, with studies suggesting that at least one in 1000 women over the age of 40 years have primary biliary cholangitis.7 The first descriptions of primary biliary cholangitis were of women with dermatological features of end-stage icteric liver disease, with profound xanthelasma or xanthoma (figure 1A). As non-invasive immune serology became commonplace and was validated for primary biliary

Pathogenesis

Primary biliary cholangitis predominantly affects women and rarely affects children.20 The disease is characterised by an HLA-DR-associated loss of immune tolerance to a crucial enzyme of oxidative phosphorylation, the E2 component of the pyruvate dehydrogenase complex (PDC-E2).21, 22 An interleukin-12 (IL-12) and IFNγ driven immune-mediated lymphocytic cholangitis with consequent destructive chronic injury to the biliary epithelial cells (BECs), senescence, and apoptosis define disease,

Reaching a diagnosis

Immunoserology, which must always be interpreted in the context of a patient's overall clinical presentation, is key to diagnosing a patient with primary biliary cholangitis. Over 90% of patients will be positive for antimitochondrial antibodies. This result is most often accompanied by a non-specific rise in serum IgM concentration. When a patient is negative for antimitochondrial antibodies, immunofluorescence patterns of ANAs might help to diagnose patients; notably multinuclear dot,

Disease and risk stratification

Transplant rates for primary biliary cholangitis have fallen over time, consistent with the concept that improving the cholestatic consequence of disease through therapy is effective. Nevertheless, the development of progressive biliary disease is associated with portal hypertension, liver failure, and risk for hepatocellular carcinoma. Survival in primary biliary cholangitis is associated with identifiable baseline and on-treatment risk factors.

To stage liver disease in primary biliary

Managing the patient

Inflammation, cholestasis, and fibrosis define the persistent cycle of injury in patients. Targeting immune injury with biologically based therapies has been unhelpful to date,48, 49, 50, 51 and treatment is focused on bile acid-based drugs, which modify cholestasis, associated inflammation, and subsequent fibrogenesis (table 2). In managing patients, care usually spans primary-care and secondary-care settings, with tertiary programmes focusing on patients at the greatest risk of complications

Managing the complications of primary biliary cholangitis

The management of cirrhosis in patients with primary biliary cholangitis includes a priority to diagnose hepatocellular carcinoma early, preventing variceal haemorrhage, and reducing the risk of osteoporotic fracture. Nuances include a rare potential for non-cirrhotic portal hypertension in patients with primary biliary cholangitis and a recognition that the risk of hepatocellular carcinoma is skewed in patients with primary biliary cholangitis to those with advanced liver disease, patients who

Conclusion

Primary biliary cholangitis is an autoimmune liver disease with therapeutic options and treatment goals that are increasingly ambitious and aimed at full disease control.79 Registry studies, alongside clinical trial data, have helped to inform patient care and focus attention on opportunities for patients with primary biliary cholangitis to prolong their life and improve their quality of life. Future therapeutic approaches might ultimately transition from a present model of escalating therapy

Search strategy and selection criteria

Data for this Seminar were identified by searches of MEDLINE, Current Contents, PubMed, and references from relevant articles by use of search terms, including “primary biliary cholangitis”, “autoimmune liver diseases”, and “cholangiocyte biology”. Only articles published in English were included. We largely selected publications that were published between Jan 1, 2010, and Jan 1, 2020, but we did not exclude commonly referenced and highly regarded older publications.

Acknowledgments

We acknowledge the ongoing support of patients with primary biliary cholangitis for the conduct of multiple observational and interventional studies that have informed the content of this Seminar. GMH is the recipient of the Lily and Terry Horner Chair in Autoimmune Liver Disease Research.

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