Predictors of Serious Adverse Events and Non-response in Cirrhotic Patients With Primary Biliary Cholangitis Treated With Obeticholic Acid

Antonio De Vincentis; Daphne D'Amato; Laura Cristoferi; Alessio Gerussi; Federica Malinverno; Ana Lleo; Francesca Colapietro; Fabio Marra; Andrea Galli; Cecilia Fiorini; Barbara Coco; Maurizia Brunetto; Grazia Anna Niro; Rosa Cotugno; Carlo Saitta; Raffaele Cozzolongo; Francesco Losito; Edoardo Giovanni Giannini; Sara Labanca; Marco Marzioni; Giulia Marconi; Anna Morgando; Rinaldo Pellicano; Ester Vanni; Nora Cazzagon; Annarosa Floreani; Luchino Chessa; Olivia Morelli; Luigi Muratori; Adriano Pellicelli; Maurizio Pompili; Francesca Ponziani; Annalisa Tortora; Floriano Rosina; Maurizio Russello; Mariarita Cannavò; Loredana Simone; Silvia Storato; Mauro Viganò; Ludovico Abenavoli; Maria D'Antò; Elisabetta De Gasperi; Marco Distefano; Gaetano Scifo; Teresa Zolfino; Vincenza Calvaruso; Giuseppe Cuccorese; Valeria Pace Palitti; Rodolfo Sacco; Gaetano Bertino; Evelise Frazzetto; Domenico Alvaro; Giacomo Mulinacci; Andrea Palermo; Miki Scaravaglio; Francesca Terracciani; Giovanni Galati; Vincenzo Ronca; Massimo Zuin; Ernesto Claar; Antonio Izzi; Antonio Picardi; Pietro Invernizzi; Umberto Vespasiani-Gentilucci; Marco Carbone


Liver International. 2022;42(11):2453-2465. 

In This Article

Abstract and Introduction


Background & Aims: Obeticholic acid (OCA) has recently been restricted in patients with primary biliary cholangitis (PBC) with "advanced cirrhosis" because of its narrow therapeutic index. We aimed to better define the predicting factors of hepatic serious adverse events (SAEs) and non-response in cirrhotic patients undergoing OCA therapy.

Methods: Safety and efficacy of treatment were evaluated in a cohort of consecutive PBC cirrhotic patients started with OCA. OCA response was evaluated according to the Poise criteria. Risk factors for hepatic SAEs and non-response were reported as risk ratios (RR) with 95% confidence intervals (CIs).

Results: One hundred PBC cirrhotics were included, 97 Child-Pugh class A and 3 class B. Thirty-one had oesophageal varices and 5 had a history of ascites. Thirty-three per cent and 32% of patients achieved a biochemical response at 6 and 12 months respectively. Male sex (adjusted-RR 1.75, 95%CI 1.42–2.12), INR (1.37, 1.00–1.87), Child-Pugh score (1.79, 1.28–2.50), MELD (1.17, 1.04–1.30) and bilirubin (1.83, 1.11–3.01) were independently associated with non-response to OCA. Twenty-two patients discontinued OCA within 12 months: 10 for pruritus, 9 for hepatic SAEs (5 for jaundice and/or ascitic decompensation; 4 for upper digestive bleeding). INR (adjusted-RR 1.91, 95%CI 1.10–3.36), lower albumin levels (0.18, 0.06–0.51), Child-Pugh score (2.43, 1.50–4.04), history of ascites (3.5, 1.85–6.5) and bilirubin (1.30, 1.05–1.56), were associated with hepatic SAEs. A total bilirubin≥1.4 mg/dl at baseline was the most accurate biochemical predictor of hepatic SAEs under OCA.

Conclusions: An accurate baseline assessment is crucial to select cirrhotic patients who can benefit from OCA. Although OCA is effective in one third of cirrhotics, bilirubin level ≥1.4 mg/dl should discourage from its use.


Primary biliary cholangitis (PBC) is an autoimmune disease of the small- and medium-size bile ducts causing chronic cholestasis, which, if untreated or undertreated, can slowly progress to liver fibrosis and cirrhosis.[1] Ursodeoxycholic acid (UDCA) is the first-line treatment and is effective in ~60% of patients, depending on the definition of treatment response applied.[2–4] Obeticholic acid (OCA) is the registered second-line treatment which is offered to patients who do not achieve a satisfactory response, or are intolerant, to UDCA.[1] The addition of OCA can rescue to response ~40% of UDCA non-responders.[5,6] Several real-world experiences have shown that OCA is however less effective in cirrhotic patients, in whom it is associated with a higher drop-out rate from treatment because of higher occurrence of adverse events.[7–9]

Recently, the Food and Drug Administration (FDA) has restricted the use of OCA in PBC patients having "advanced cirrhosis"[10] based on the report of 25 PBC cirrhotic patients, with either compensated and decompensated cirrhosis before starting OCA, who developed serious liver injury leading to liver decompensation or liver failure under OCA treatment. Notably, this restriction has been quickly incorporated into the PBC guidelines of the American Association for the Study of Liver Diseases (AASLD).[11] The FDA, therefore, recommends that, before starting OCA, health care professionals should determine whether a patient with PBC has "advanced cirrhosis", generically defined as cirrhosis with current or prior evidence of hepatic decompensation or portal hypertension.[10]

However, an accurate definition of predicting factors for decompensation under OCA for PBC cirrhotic patients is lacking. This may expose some to a possibly harmful treatment and, on the other hand, deprive some others of effective therapy in a stage of disease where it is highly needed.

In this study using data from the Italian PBC Registry, we aimed to verify the efficacy and safety profile of OCA therapy in a large cohort of PBC cirrhotic patients, and to identify biochemical predictors of hepatic severe adverse events (SAEs) and non-response enabling a more accurate selection for OCA therapy in this at-risk category of PBC patients.