Douglas Thorburn

BACKGROUND & AIMS: The development of non-invasive liver fibrosis tests may enable earlier identification of patients with non-alcoholic fatty liver disease (NAFLD) requiring referral to secondary care. We developed and evaluated a pathway for the management of patients with NAFLD, aimed at improving the detection of cases of advanced fibrosis and cirrhosis, and avoiding unnecessary referrals. METHODS: This was a prospective longitudinal cohort study, with analyses performed before and after introduction of the pathway, and comparisons made to unexposed controls. We used a 2-step algorithm combining the use of Fibrosis-4 score followed by the ELF™ test if required. RESULTS: In total, 3,012 patients were analysed. Use of the pathway detected 5 times more cases of advanced fibrosis (Kleiner F3) and cirrhosis (odds ratio [OR]5.18;95%CI2.97-9.04; p <0.0001), while reducing unnecessary referrals from primary care to secondary care by 81% (OR0.193; 95%CI 0.111-0.337; p <0.0001). Although it was used for only 48% of referrals, significant benefits were observed in practices exposed to the pathway compared to those which were not, with unnecessary referrals falling by 77% (OR0.23; 95% CI0.658-0.082; p = 0.006) and a 4-fold improvement in detection of cases of advanced fibrosis and cirrhosis (OR4.32; 95% CI1.52-12.25; p = 0.006). Compared to referrals made before the introduction of the pathway, unnecessary referrals fell from 79/83 referrals (95.2%) to 107/152 (70.4%), representing an 88% reduction in unnecessary referrals when the pathway was followed (OR0.12; 95%CI0.042-0.349; p <0.0001). CONCLUSIONS: The use of non-invasive blood tests for liver fibrosis improves the detection of advanced fibrosis and cirrhosis, while reducing unnecessary referrals in patients with NAFLD. This strategy improves resource use and benefits patients. LAY SUMMARY: Non-alcoholic fatty liver disease effects up to 30% of the population but only a minority of cases develop liver disease. Our study has shown that established blood tests can be used in primary care to stratify patients with fatty liver disease, leading to a reduction in unnecessary referrals by 80% and greatly improving the detection of cases of advanced fibrosis and cirrhosis.

UNLABELLED: The biochemical response to ursodeoxycholic acid (UDCA)--so-called "treatment response"--strongly predicts long-term outcome in primary biliary cholangitis (PBC). Several long-term prognostic models based solely on the treatment response have been developed that are widely used to risk stratify PBC patients and guide their management. However, they do not take other prognostic variables into account, such as the stage of the liver disease. We sought to improve existing long-term prognostic models of PBC using data from the UK-PBC Research Cohort. We performed Cox's proportional hazards regression analysis of diverse explanatory variables in a derivation cohort of 1,916 UDCA-treated participants. We used nonautomatic backward selection to derive the best-fitting Cox model, from which we derived a multivariable fractional polynomial model. We combined linear predictors and baseline survivor functions in equations to score the risk of a liver transplant or liver-related death occurring within 5, 10, or 15 years. We validated these risk scores in an independent cohort of 1,249 UDCA-treated participants. The best-fitting model consisted of the baseline albumin and platelet count, as well as the bilirubin, transaminases, and alkaline phosphatase, after 12 months of UDCA. In the validation cohort, the 5-, 10-, and 15-year risk scores were highly accurate (areas under the curve: >0.90). CONCLUSIONS: The prognosis of PBC patients can be accurately evaluated using the UK-PBC risk scores. They may be used to identify high-risk patients for closer monitoring and second-line therapies, as well as low-risk patients who could potentially be followed up in primary care.

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.