Adequate versus deep response to ursodeoxycholic acid in primary biliary cholangitis: To what extent and under what conditions is normal alkaline phosphatase level associated with complication-free survival gain?

Abstract

Background and Aims: Normal alkaline phosphatase (ALP) levels in ursodeoxycholic acid (UDCA)-treated patients with primary biliary cholangitis (PBC) are associated with better long-term outcome. However, second-line therapies are currently recommended only when ALP levels remain above 1.5 times the upper limit of normal (×ULN) after 12-month UDCA. We assessed whether, in patients considered good responders to UDCA, normal ALP levels were associated with significant survival gains. Approach and Results: We performed a retrospective cohort study of 1047 patients with PBC who attained an adequate response to UDCA according to Paris-2 criteria. Time to liver-related complications, liver transplantation, or death was assessed using adjusted restricted mean survival time (RMST) analysis. The overall incidence rate of events was 17.0 (95% CI: 13.7–21.1) per 1000 out of 4763.2 patient-years. On the whole population, normal serum ALP values (but not normal gamma-glutamyl transpeptidase (GGT), alanine aminotransferase (ALT), or aspartate aminotransferase (AST); or total bilirubin < 0.6 ×ULN) were associated with a significant absolute complication-free survival gain at 10 years (mean 7.6 months, 95% CI: 2.7 - 12.6 mo.; p = 0.003). In subgroup analysis, this association was significant in patients with a liver stiffness measurement ≥ 10 kPa and/or age ≤ 62 years, with a 10-year absolute complication-free survival gain of 52.8 months (95% CI: 45.7–59.9, p < 0.001) when these 2 conditions were met. Conclusions: PBC patients with an adequate response to UDCA and persistent ALP elevation between 1.1 and 1.5 ×ULN, particularly those with advanced fibrosis and/or who are sufficiently young, remain at risk of poor outcome. Further therapeutic efforts should be considered for these patients.

A new and simple score to predict adequate and deep response to ursodeoxycholic acid in patients with primary biliary cholangitis: the ALP-A score

“…Several studies have identified prognostic factors that might influence UDCA response and PBC natural history, such as baseline levels of ALP, gamma-glutamyl transferase and bilirubin, age at diagnosis, ethnicity, gender, presence of advanced fibrosis, pattern of auto-antibodies positivity and overlapping with autoimmune hepatitis [7,16,17,21–27] It would be most interesting if the prediction of UDCA response could be based only on simple pretreatment parameters, such as ALP and age. High baseline ALP level seems to be the strongest predictor of response to UDCA therapy in untreated PBC patients, suggesting that the severity of biliary injury or advanced stages of disease are key determinants of whether choleretic therapy will be effective [7,16].…”

“…Furthermore, Corpechot et al . demonstrated that adequate response to UDCA by Paris-2 criteria may be not enough for some patients and that additional complication-free survival benefit is obtained after normalization of ALP and bilirubin [17]. As treatment options for PBC continue to increase, it is possible to aspire for normal liver biochemistry for high-risk patients.…”

Optimizing treatment of primary biliary cholangitis: Is good, good enough?

“…In the current issue of H epatology , Corpechot et al quantified the theoretical benefit in terms of complication-free survival gains within a group of patients with PBC who met the binary Paris-II response criteria of an ALP < 1.5 × ULN, AST < 1.5 × ULN, and total bilirubin < ULN 7 . Patients were also required to have had an LSM and, importantly, complications included not only death or LT but also hepatocellular cancer and hepatic decompensation.…”

“…In the current issue of HEPATOLOGY, Corpechot et al quantified the theoretical benefit in terms of complication-free survival gains within a group of patients with PBC who met the binary Paris-II response criteria of an ALP < 1.5 × ULN, AST < 1.5 × ULN, and total bilirubin < ULN. [7] Patients were also required to have had an LSM and, importantly, complications included not only death or LT but also hepatocellular cancer and hepatic decompensation. Among 1047 patients included with a mean UDCA treatment duration of 7.8 years, there were 15 hepatic decompensation events, 3 HCCs, 5 transplants, and 58 total deaths, but only 16 liver-related deaths.…”

Letter to the Editor: Improving access to transient elastography data for real-world prognostic applications in primary biliary cholangitis

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To the editor, With great interest, we read the article of Corpechot et al, [1] who identify levels of alkaline phosphatase <1.0 × upper limit of normal during therapy with ursodeoxycholic acid as the ideal biochemical response. This is especially true for patients with liver stiffness measurement ≥ 10 kPa and/or age ≤ 62 years with a 10-year complication-free survival gain of more than four years.

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