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?

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.

Dynamics of Liver Stiffness Measurement and Clinical Course of Primary Biliary Cholangitis.

BACKGROUND & AIMS: In primary biliary cholangitis (PBC), static liver stiffness measurement (LSM) has proven prognostic value. However, the added prognostic value of LSM time course in this disease remains uncertain. METHODS: We conducted an international retrospective cohort study among patients with PBC treated with ursodeoxycholic acid and followed by vibration-controlled transient elastography between 2003 and 2022. Using joint modeling, the association of LSM trajectory and the incidence of serious clinical events (SCE), defined as cirrhosis complications, liver transplantation, or death, was quantified using the hazard ratio and its confidence interval. RESULTS: A total of 6362 LSMs were performed in 3078 patients (2007 on ursodeoxycholic acid alone; 13% with cirrhosis), in whom 316 SCE occurred over 14,445 person-years (median follow-up, 4.2 years; incidence rate, 21.9 per 1000 person-years). LSM progressed in 59% of patients (mean, 0.39 kPa/year). After adjusting for prognostic factors at baseline, including LSM, any relative change in LSM was associated with a significant variation in SCE risk (P < .001). For example, the adjusted hazard ratios (95% confidence interval) associated with a 20% annual variation in LSM were 2.13 (1.89-2.45) for the increase and 0.40 (0.33-0.46) for the decrease. The association between LSM trajectory and SCE risk persisted regardless of treatment response or duration, when patients with cirrhosis were excluded, and when only death or liver transplantation was considered. CONCLUSIONS: Tracking longitudinal changes in LSM using vibration-controlled transient elastography provides valuable insights into PBC prognosis, offering a robust predictive measure for the risk of SCE. LSM could be used as a clinically relevant surrogate end point in PBC clinical trials.

Liver stiffness measurement by vibration-controlled transient elastography improves outcome prediction in primary biliary cholangitis.

BACKGROUND & AIMS: Liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) has been shown to predict outcomes of patients with primary biliary cholangitis (PBC) in small-size studies. We aimed to validate the prognostic value of LSM in a large cohort study. METHODS: We performed an international, multicentre, retrospective follow-up study of 3,985 patients with PBC seen at 23 centres in 12 countries. Eligibility criteria included at least 1 reliable LSM by VCTE and a follow-up ≥ 1 year. Independent derivation (n = 2,740) and validation (n = 568) cohorts were built. The primary endpoint was time to poor clinical outcomes defined as liver-related complications, liver transplantation, or death. Hazard ratios (HRs) with CIs were determined using a time-dependent multivariable Cox regression analysis. RESULTS: LSM was independently associated with poor clinical outcomes in the derivation (5,324 LSMs, mean follow-up 5.0 ± 3.1 years) and validation (1,470 LSMs, mean follow-up 5.0 ± 2.8 years) cohorts: adjusted HRs (95% CI) per additional kPa were 1.040 (1.026-1.054) and 1.042 (1.029-1.056), respectively (p <0.0001 for both). Adjusted C-statistics (95% CI) at baseline were 0.83 (0.79-0.87) and 0.92 (0.89-0.95), respectively. Between 5 and 30 kPa, the log-HR increased as a monotonic function of LSM. The predictive value of LSM was stable in time. LSM improved the prognostic ability of biochemical response criteria, fibrosis scores, and prognostic scores. The 8 kPa and 15 kPa cut-offs optimally separated low-, medium-, and high-risk groups. Forty percent of patients were at medium to high risk according to LSM. CONCLUSIONS: LSM by VCTE is a major, independent, validated predictor of PBC outcome. Its value as a surrogate endpoint for clinical benefit in PBC should be considered. LAY SUMMARY: Primary biliary cholangitis (PBC) is a chronic autoimmune disease, wherein the body's immune system mistakenly attacks the bile ducts. PBC progresses gradually, so surrogate markers (markers that predict clinically relevant outcomes like the need for a transplant or death long before the event occurs) are often needed to expedite the drug development and approval process. Herein, we show that liver stiffness measurement is a strong predictor of clinical outcomes and could be a useful surrogate endpoint in PBC trials.

Real-World Management of Patients with Primary Biliary Cholangitis-A Retrospective Study from a Tertiary Medical Center in Israel.

BACKGROUND: Primary biliary cholangitis (PBC) is a rare autoimmune liver disease with variation in prevalence, phenotype and prognosis across different geographical regions. Little is known about PBC in Israel. Our aim was to characterize the demography, clinical presentation, treatment patterns and prognosis in a cohort of PBC patients followed in a referral center in central Israel. METHODS: Clinical, demographic and laboratory data were collected from the medical records of PBC patients followed at Tel Aviv Medical Center in the years 2003-2020. RESULTS: We have identified 189 patients with a confirmed diagnosis of PBC; 92.6% were female and the mean age at diagnosis was 54.7 years. Thirty-nine percent were diagnosed with another autoimmune disease and 5.9% were diagnosed with a PBC-AIH (autoimmune hepatitis) variant syndrome. Ninety-six percent were treated with ursodeoxycholic acid (UDCA) at a mean dose of 13.3 mg/kg. A total of 28.1% were found with inadequate response to UDCA according to the Toronto criteria, and 53% of the UDCA non-responders were treated with bezafibrate. Younger age at diagnosis, higher baseline levels of alkaline phosphatase (ALP) and gamma-glutamyltransferase (GGT), AIH-PBC variant and positive anti-smooth muscle antibodies (ASMA) were associated with an inadequate UDCA response. In a multivariable analysis, higher ALP at diagnosis (OR = 1.92 CI 1.11-3.20 per 50-unit change, p = 0.018) and ASMA (OR = 27.6 CI 2.58-295, p = 0.006) independently predicted inadequate UDCA response. Higher alanine transaminase (ALT), ALP and GGT, lower albumin, younger age at diagnosis and pruritus conferred an increased risk for disease progression. CONCLUSIONS: Disease characteristics, treatment patterns, response to therapy and prognosis of a PBC patient cohort in a tertiary center in central Israel were revealed. The results highlight the importance of risk stratification in PBC, specifically in younger patients, those presenting with a high level of liver enzymes and in ASMA-positive patients with an assumed diagnosis of the AIH-PBC variant.

Non-coronary cardiac calcifications and outcomes in patients with heart failure.

BACKGROUND: Calcium deposits on heart valves are considered a local manifestation of atherosclerosis and are associated with poor cardiovascular outcomes. The clinical significance of cardiac calcifications among heart failure (HF) patients, as assessed by echocardiography, is unknown. This study evaluated associations of cardiac calcifications with mortality and hospital admissions in this specific population. METHODS: Medical records of all patients who initiated ambulatory surveillance at our HF clinic during 2011-2018 were reviewed. Calcifications in the aortic valve, aortic root, or the mitral valve were evaluated. Patients with moderate to severe regurgitation or stenosis of the aortic or mitral valves were excluded. The primary endpoint was the composite of long-term all-cause mortality and HF hospitalizations. Secondary endpoints were long-term all-cause mortality and more than one hospitalization due to HF. RESULTS: This retrospective study included 814 patients (mean age 70.9 ± 13 years, 63.2% male). Of the total cohort, 350 (43%) had no cardiac calcifications and 464 (57%) had at least 1 calcified site. Considering the patients with no calcification as the reference group yielded a higher adjusted odds ratios for the composite endpoint, all-cause death, and recurrent HF hospitalizations, among patients with any cardiac calcification (OR = 1.68, 95%CI = 1.1-2.5, p = 0.01, OR=1.61, 95%CI = 1.1-2.3, p < 0.01, and OR = 1.50, 95%CI = 1.1-2.2, p < 0.01, respectively). CONCLUSIONS: We found an independent association between cardiac calcifications and the risk of death and HF hospitalizations among ambulatory HF patients. Cardiac calcifications evaluated during routine echocardiography may contribute to the risk stratification of patients with HF.