The British Society of Gastroenterology/UK-PBC primary biliary cholangitis treatment and management guidelines

Abstract

Primary biliary cholangitis (formerly known as primary biliary cirrhosis, PBC) is an autoimmune liver disease in which a cycle of immune mediated biliary epithelial cell injury, cholestasis and progressive fibrosis can culminate over time in an end-stage biliary cirrhosis. Both genetic and environmental influences are presumed relevant to disease initiation. PBC is most prevalent in women and those over the age of 50, but a spectrum of disease is recognised in adult patients globally; male sex, younger age at onset (<45) and advanced disease at presentation are baseline predictors of poorer outcome. As the disease is increasingly diagnosed through the combination of cholestatic serum liver tests and the presence of antimitochondrial antibodies, most presenting patients are not cirrhotic and the term cholangitis is more accurate. Disease course is frequently accompanied by symptoms that can be burdensome for patients, and management of patients with PBC must address, in a life-long manner, both disease progression and symptom burden. Licensed therapies include ursodeoxycholic acid (UDCA) and obeticholic acid (OCA), alongside experimental new and re-purposed agents. Disease management focuses on initiation of UDCA for all patients and risk stratification based on baseline and on-treatment factors, including in particular the response to treatment. Those intolerant of treatment with UDCA or those with high-risk disease as evidenced by UDCA treatment failure (frequently reflected in trial and clinical practice as an alkaline phosphatase >1.67 × upper limit of normal and/or elevated bilirubin) should be considered for second-line therapy, of which OCA is the only currently licensed National Institute for Health and Care Excellence recommended agent. Follow-up of patients is life-long and must address treatment of the disease and management of associated symptoms.

Keywords: autoimmune liver disease; care pathway; guidelines; obeticholic acid; ursodeoxycholic acid.

Figure 1

The BSG/UK-PBC consensus care pathway for patients with primary biliary cholangitis (PBC). While care needs always to be personalised to the patient, there are consensus pathways that are important for patients with PBC, which encompass the important ‘pillars’ of care that are believed to provide optimal management of disease and its complications.

Figure 2

The histopathology of PBC classical staging systems for PBC divide the histological injury of PBC into four stages: florid duct lesions and portal inflammation without interface activity (stage 1), interface hepatitis, ductular proliferation and periportal fibrosis (stage 2), bridging necrosis or bridging fibrosis (stage 3), and cirrhosis (stage 4). These systems are easy to apply and are quite reproducible. However, their practical utility is limited because of the uneven distribution of diagnostic histological lesions of PBC and different disease stages co-existing at any time. Furthermore, they incorporate features such as inflammation, which are more appropriately regarded as a manifestation of disease activity (histological ‘grade’) rather than disease progression (histological ‘stage’). A more recent scoring system described by Nakanuma and colleagues sums up individual scores for fibrosis, bile duct loss and severity of chronic cholestasis based on copper-associated protein deposition to assess disease stage and provides a separate system for grading necroinflammatory activity based on cholangitic and hepatitic features. Similar to the classical staging systems, the Nakanuma staging system correlates well with clinical and laboratory features. Subsequent studies have suggested that the Nakanuma system is more useful than previously described staging systems in predicting adverse outcomes in patients with PBC and may also be helpful in predicting treatment responses. Another recently described histological scoring system for PBC based on prognostically significant lesions (ie, fibrosis, bile duct loss and lymphocytic interface hepatitis) showed better interobserver agreement and correlation with biochemical abnormalities than traditional scoring systems, but predictive value for adverse outcomes could not be assessed. Problems with sampling variability apply to all of the histological staging systems that have been described for patients with PBC, which limits the utility of liver biopsy to assess disease severity in routine clinical practice, but they may still have a role in the context of clinical trials where liver biopsies have been used for risk stratification and as a surrogate marker of treatment outcomes. (A) Early PBC is characterised mainly by portal lesions and mild necroinflammatory changes in the acini. Portal tracts may show cholangiocentric granulomatous inflammation composed of lymphocytes, occasionally numerous plasmacytes, and polymorphs including eosinophils. Lymphoid follicles with germinal centres may form. The lymphoid inflammatory infiltrate extends to the biliary epithelium (cholangitis) (arrow), disrupting the basement membrane sometimes leading to bile duct destruction (florid duct lesion). Granulomas, ranging from small collections of histiocytes to easily discerned non-caseating epithelioid granulomas, may be present in portal tracts near damaged bile ducts and less often in the acini. In the progressive lesion of PBC, lymphocytic interface hepatitis may predominate blurring the portal tract boundary and extending into the acinus (arrowheads). Ductular proliferation at the portal-parenchymal interface may be prominent with associated stromal oedema and neutrophilic inflammation. Parenchymal necroinflammatory activity and hepatocellular injury are usually mild. Small and large cell change and hepatocellular regeneration may be seen (H&E, x20). (B) Keratin 7 immunostaining highlights loss of bile ducts (arrowhead indicates a keratin 7-positive bile duct epithelial remnant) leading to chronic cholestasis with features of feathery degeneration, Mallory-Denk bodies, copper-associated protein deposition in periportal/periseptal hepatocytes (cholate stasis), cholestatic rosettes and biliary metaplasia of hepatocytes (arrow) (keratin 7 immunostain, DAB chromagen, x10). (C) Loss of canals of Hering in acinar zone 1 (arrowheads) detected by keratin 19 immunostaining has recently been proposed as an early feature of PBC in the absence of the classic destructive biliary lesions. Focal intraepithelial inflammation (cholangitis) is noted in the K19-positive interlobular bile duct (arrow) (keratin 19 immunostain, DAB chromagen, x20).