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.

A Placebo-Controlled Trial of Bezafibrate in Primary Biliary Cholangitis.

BACKGROUND: Patients with primary biliary cholangitis who have an inadequate response to therapy with ursodeoxycholic acid are at high risk for disease progression. Fibrates, which are agonists of peroxisome proliferator-activated receptors, in combination with ursodeoxycholic acid, have shown potential benefit in patients with this condition. METHODS: In this 24-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 100 patients who had had an inadequate response to ursodeoxycholic acid according to the Paris 2 criteria to receive bezafibrate at a daily dose of 400 mg (50 patients), or placebo (50 patients), in addition to continued treatment with ursodeoxycholic acid. The primary outcome was a complete biochemical response, which was defined as normal levels of total bilirubin, alkaline phosphatase, aminotransferases, and albumin, as well as a normal prothrombin index (a derived measure of prothrombin time), at 24 months. RESULTS: The primary outcome occurred in 31% of the patients assigned to bezafibrate and in 0% assigned to placebo (difference, 31 percentage points; 95% confidence interval, 10 to 50; P<0.001). Normal levels of alkaline phosphatase were observed in 67% of the patients in the bezafibrate group and in 2% in the placebo group. Results regarding changes in pruritus, fatigue, and noninvasive measures of liver fibrosis, including liver stiffness and Enhanced Liver Fibrosis score, were consistent with the results of the primary outcome. Two patients in each group had complications from end-stage liver disease. The creatinine level increased 5% from baseline in the bezafibrate group and decreased 3% in the placebo group. Myalgia occurred in 20% of the patients in the bezafibrate group and in 10% in the placebo group. CONCLUSIONS: Among patients with primary biliary cholangitis who had had an inadequate response to ursodeoxycholic acid alone, treatment with bezafibrate in addition to ursodeoxycholic acid resulted in a rate of complete biochemical response that was significantly higher than the rate with placebo and ursodeoxycholic acid therapy. (Funded by Programme Hospitalier de Recherche Clinique and Arrow Génériques; BEZURSO ClinicalTrials.gov number, NCT01654731 .).

The Complementary Value of Magnetic Resonance Imaging and Vibration-Controlled Transient Elastography for Risk Stratification in Primary Sclerosing Cholangitis.

OBJECTIVES: Magnetic resonance (MR) risk scores and liver stiffness (LS) have individually been shown to predict clinical outcomes in primary sclerosing cholangitis (PSC). The aim of this study was to assess their complementary prognostic value. METHODS: Patients with PSC from 3 European centers with a 3-dimensional MR cholangiography available for central reviewing and a valid LS measurement assessed by vibration-controlled transient elastography by FibroScan performed within a 6-month interval were included in a longitudinal retrospective study. The MR score (Anali) without gadolinium (Gd) was calculated according to the formula: (1 × dilatation of intrahepatic bile ducts) + (2 × dysmorphy) + (1 × portal hypertension). The primary end point was survival without liver transplantation or cirrhosis decompensation. The prognostic values of LS and Anali score without Gd were assessed using Cox proportional hazard models. RESULTS: One hundred sixty-two patients were included. Over a total follow-up of 753 patient-years, 40 patients experienced an adverse outcome (4 liver transplantations, 6 liver-related deaths, and 30 cirrhosis decompensations). LS and Anali score without Gd were significantly correlated (ρ = 0.51, P < 0.001) and were independently associated with the occurrence of an adverse outcome. Optimal prognostic thresholds were 10.5 kPa for LS and 2 for the Anali score without Gd. Hazard ratios (95% confidence interval) were 2.07 (1.06-4.06) and 3.78 (1.67-8.59), respectively. The use in combination of these 2 thresholds allowed us to separate patients into low-, medium-, and high-risk groups for developing adverse outcomes. The 5-year cumulative rates of adverse outcome in these 3 groups were 8%, 16%, and 38% (P < 0.001), respectively. DISCUSSION: The combined use of MRI and vibration-controlled transient elastography permits easy risk stratification of patients with PSC.

Large-scale characterization study of patients with antimitochondrial antibodies but nonestablished primary biliary cholangitis.

The prevalence, clinical characteristics, and outcomes of patients with antimitochondrial antibodies (AMAs), but no clinical evidence of primary biliary cholangitis (PBC), are largely unknown. A prospective study of AMA incidence was conducted through a nation-wide network of 63 French immunology laboratories. Clinical data from 720 of 1,318 AMA-positive patients identified in 1 year were collected. Patients were categorized as either newly diagnosed with PBC (n = 275), previously diagnosed with PBC (n = 216), or with nonestablished diagnosis of PBC (n = 229). The latter group was specifically evaluated. Follow-up data were collected for up to 7 years after detection of AMAs. Prevalence of AMA-positive patients without evidence of PBC was 16.1 per 100,000. These patients had the following characteristics: 78% female; median age 58 years; median AMA titer 1:160; extrahepatic autoimmune disorders 46%; normal serum alkaline phosphatases (ALP) 74%; ALP above 1.5 times the upper limit of normal 13%; and cirrhosis 6%. Compared to those newly diagnosed with PBC, the patients were slightly younger, had lower AMA titers, and lower sex-ratio imbalance. Among the patients with normal ALP and no evidence of cirrhosis, the 5-year incidence rate of PBC was 16%. Whereas no patients died from PBC, the 5-year survival rate was 75%, as compared to 90% in a control, standardized population matched for age and sex (P < 0.05). CONCLUSION: Nearly half of the newly detected AMAs in clinical practice does not lead to a diagnosis of PBC. PBC is unrecognized in 13% of those cases. Only 1 in 6 patients with AMAs and normal ALP will develop PBC after 5 years. The mortality of AMA-positive patients without PBC is increased irrespective of the risk of PBC development. (Hepatology 2017;65:152-163).

Baseline values and changes in liver stiffness measured by transient elastography are associated with severity of fibrosis and outcomes of patients with primary sclerosing cholangitis.

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease that leads to extensive liver fibrosis and cirrhosis, which are associated with poor outcome. However, there are no validated noninvasive markers of liver fibrosis in patients with PSC. We assessed the diagnostic performance, reproducibility, longitudinal changes, and prognostic value of liver stiffness measurement (LSM) using vibration-controlled transient elastography (VCTE). METHODS: In a prospective study, we analyzed percutaneous liver biopsy specimens from 73 consecutive patients with PSC from January 2005 to December 2010. Patients underwent VCTE no more than 6 months after the biopsy specimens were collected. The biopsy specimens were analyzed by a pathologist blinded to the results of VCTE for the stage of fibrosis, and LSM was associated with the stage of fibrosis and other variables using the Kruskal-Wallis and Spearman correlation tests. The cutoff values of LSM were selected based on the accuracy with which they identified the stage of fibrosis on receiver-operating characteristic analysis. The rates of LSM progression were assessed using a linear mixed model, and the association between LSM values and clinical outcomes were evaluated using Cox regression analysis in 168 patients with PSC treated with ursodeoxycholic acid and followed up from November 2004 to July 2013 (mean follow-up period, 4 years). RESULTS: LSM was independently linked to the stage of fibrosis. Cutoff values for fibrosis stages ≥F1, ≥F2, ≥F3, and F4 were 7.4 kPa, 8.6 kPa, 9.6 kPa, and 14.4 kPa, respectively. The adjusted diagnostic accuracy values for severe fibrosis and cirrhosis were 0.83 and 0.88, respectively. The diagnostic performance of LSM was comparable to that of hyaluronic acid measurement but superior to the aspartate aminotransferase/platelet ratio index, FIB-4 score, and Mayo risk score in differentiating patients with significant or severe fibrosis from those without. LSM had a high level of reproducibility between operators for the same measurement site and for the same operator between 2 adjacent sites. LSM increased significantly and exponentially over time. Baseline measurements and rate of LSM progression were strongly and independently linked with patients' outcomes. CONCLUSIONS: VCTE is able to differentiate severe from nonsevere liver fibrosis with high levels of confidence in patients with PSC. Baseline measurements of LSM and longitudinal changes are prognostic factors for PSC.

Noninvasive elastography-based assessment of liver fibrosis progression and prognosis in primary biliary cirrhosis.

UNLABELLED: The development of liver fibrosis markers in primary biliary cirrhosis (PBC) is needed to facilitate the assessment of its progression and the effectiveness of new therapies. Here, we investigated the potential usefulness of transient elastography (TE) in the noninvasive evaluation of liver fibrosis stage and disease progression in PBC. We performed, first, a prospective performance analysis of TE for the diagnosis of METAVIR fibrosis stages in a diagnostic cohort of 103 patients and, second, a retrospective longitudinal analysis of repeated examinations in a monitoring cohort of 150 patients followed-up for up to 5 years. All patients were treated with ursodeoxycholic acid. Diagnostic thresholds of liver stiffness in discriminating fibrosis stages ≥ F1, ≥ F2, ≥ F3, and =F4 were 7.1, 8.8, 10.7, and 16.9 kPa, respectively. TE showed high performance and was significantly superior to biochemical markers (e.g., aspartate aminotransferase [AST]/platelet ratio, FIB-4, hyaluronic acid, AST/alanine aminotransferase ratio, and Mayo score) in diagnosing significant fibrosis, severe fibrosis, or cirrhosis. Analysis of the monitoring cohort data set using generalized linear models showed the following: (1) an overall progression rate of 0.48 ± 0.21 kPa/year (P = 0.02) and (2) no significant progression in patients with F0-F1, F2, or F3 stages, but a significant increase (4.06 ± 0.72 kPa/year; P < 0.0001) in cirrhotic patients. A cut-off value of 2.1 kPa/year was associated with an 8.4-fold increased risk of liver decompensations, liver transplantations, or deaths (P < 0.0001, Cox regression analysis). CONCLUSION: TE is one of the best current surrogate markers of liver fibrosis in PBC. Over a 5-year period, on-treatment liver stiffness appears stable in most noncirrhotic PBC patients, whereas it significantly increases in patients with cirrhosis. Progression of liver stiffness in PBC is predictive of poor outcome.

Smoking as an independent risk factor of liver fibrosis in primary biliary cirrhosis.

BACKGROUND & AIMS: Smoking has been identified as a potential predisposition factor for primary biliary cirrhosis (PBC). However, it remains unclear whether it is associated with more active and severe disease. Our aim was to assess the relationships between smoking and the severity of the elementary histological lesions, as well as the biochemical and immunological features of PBC. METHODS: Smoking history data were collected from 223 PBC patients using a standardized questionnaire. Histological data were available in 164 patients at presentation. Liver fibrosis and histological inflammatory activity were semi-quantified according to a METAVIR-based classification system. Odds ratios (OR) were assessed using a logistic regression analysis. RESULTS: Smoking history prior to diagnosis was reported in 58 patients (26%). Twenty-five patients (11%) were active smokers at diagnosis. Male gender (OR, 4.5), alcohol intake >20 g/d (OR, 4.2), and F3-F4 fibrosis stage (OR, 2.7), but not inflammatory grade, bile duct changes, biochemical or immunological features, were associated with smoking history. Smoking intensity was significantly higher in patients with F3-F4 stage (8.1±14.2 pack-years vs. 3.0±7.0 pack-years; p=0.01). Adjusted logistic regression identified smoking history and smoking intensity as independent risk factors of advanced fibrosis. Each pack-year of increase in smoking intensity was associated with a 5.0% (95% CI, 1.3-8.7%) increased likelihood of advanced fibrosis. CONCLUSIONS: Smoking increases, in a dose-dependent fashion, the risk of liver fibrosis in PBC without apparent increase in the histological inflammatory activity, bile duct lesions, biochemical, and immunological features of the disease. PBC patients should be strongly encouraged not to smoke.

Low-phospholipid-associated cholelithiasis syndrome: Prevalence, clinical features, and comorbidities.

BACKGROUND & AIMS: Low-phospholipid-associated cholelithiasis (LPAC) syndrome, a rare genetic form of intrahepatic cholelithiasis in adults, is still poorly understood. We report the results of the largest-ever case-control study of patients with LPAC syndrome aiming to assess the prevalence, clinical features, and comorbidities of the disease. METHODS: We included all LPAC cases diagnosed between 2001 and 2016 in 11 French centres. Controls consisted of all patients who underwent a cholecystectomy for common gallstone disease in a single non-academic centre over 1 year. A logistic regression analysis was used to identify the clinical features associated with LPAC syndrome across several patient strata with increasing levels of diagnostic confidence. The ratio between the incident cases of LPAC syndrome and the total number of cholecystectomies for gallstones was used to assess the relative prevalence of the disease. RESULTS: In this study, 308 cases and 206 controls were included. LPAC syndrome accounted for 0.5-1.9% of all patients admitted with symptomatic gallstone disease. Age at first symptoms <40 years, absence of overweight, persistence of symptoms after cholecystectomy, intrahepatic micro- or macrolithiasis, common bile duct (CBD) lithiasis, and no history of cholecystitis were independently associated with LPAC diagnosis. ATP-binding cassette subfamily B member 4 (ABCB4) variants, present in 46% of cases, were associated with CBD lithiasis, chronic elevation of gamma-glutamyltransferase (GGT), and personal or family history of hepato-biliary cancer. CONCLUSIONS: In this case-control study, LPAC syndrome accounted for approximately 1% of symptomatic cholelithiasis in adults. In addition to pre-established diagnostic criteria, normal weight, CBD lithiasis, and no history of cholecystitis were significantly associated with the syndrome. ABCB4 gene variations in patients with LPAC were associated with CBD lithiasis, chronic cholestasis, and a personal or family history of hepato-biliary cancer. LAY SUMMARY: In the largest case-control study ever conducted in patients with LPAC syndrome, a rare genetic form of intrahepatic cholelithiasis in young adults, LPAC syndrome was found in approximately 1% of all patients admitted to the hospital for symptomatic gallstones and, in addition to the pre-established characteristics of the syndrome (age at first symptoms <40 years, recurrence of symptoms after cholecystectomy, and/or imaging evidence of intrahepatic microlithiasis), was associated with lower BMI, higher prevalence of common bile duct stones, and lower incidence of acute cholecystitis. ABCB4 gene variants, which were detected in about half of cases, were associated with common bile duct stones and a personal or family history of hepato-biliary cancer.

Primary sclerosing cholangitis response to the combination of fibrates with ursodeoxycholic acid: French-Spanish experience.

BACKGROUND & AIMS: In patients with primary sclerosing cholangitis (PSC), ursodeoxycholic acid (UDCA) treatment improves serum liver tests and surrogate markers of prognosis but has no proven effect on survival. Additional therapies are obviously needed. Fibrates, PPAR agonists with anti-cholestatic properties, have a beneficial effect in primary biliary cholangitis. The aim of this study was to evaluate the safety and efficacy of fibrates in PSC patients. METHODS: Retrospectively, we investigated PSC patients treated with fibrates (fenofibrate 200mg/day or bezafibrate 400mg/day) for at least 6 months in addition to UDCA, after an incomplete biochemical response (alkaline phosphatase [ALP] ≥1.5×upper limit of normal) to UDCA. Changes in biochemical parameters and clinical features were assessed. RESULTS: Twenty patients were included (fourteen from Paris and six from Barcelona): median age 43.8 years, median liver stiffness 11kPa (≥F3). Upon treatment with fibrates (median duration of 1.56 years), liver tests significantly improved, including a reduction of ALP levels by 41% and pruritus significantly decreased. No serious adverse event attributable to fibrates occurred. Discontinuation of fibrates was followed by a clear rebound of ALP. Despite biochemical improvement, liver stiffness significantly increased. CONCLUSIONS: Combining UDCA with fibrates results in a significant biochemical improvement and pruritus decrease in PSC patients with incomplete response to UDCA. These results provide a rationale for larger and prospectively designed studies to establish the efficacy and safety of fibrates in PSC.

Liver Steatosis Assessed by Controlled Attenuation Parameter (CAP) Measured with the XL Probe of the FibroScan: A Pilot Study Assessing Diagnostic Accuracy.

To assess liver steatosis, the controlled attenuation parameter (CAP; giving an estimate of ultrasound attenuation ∼3.5 MHz) is available with the M probe of the FibroScan. We report on the adaptation of the CAP for the FibroScan XL probe (center frequency 2.5 MHz) without modifying the range of values (100-400 dB/m). CAP validation was successfully performed on Field II simulations and on tissue-mimicking phantoms. In vivo performance was assessed in a cohort of 59 patients spanning the range of steatosis. In vivo reproducibility was good and similar with both probes. The area under receiver operative characteristic curve was equal to 0.83/0.84 and 0.92/0.91 for the M/XL probes to detect >2% and >16% liver fat, respectively, as assessed by magnetic resonance imaging. Patients can now be assessed simultaneously for steatosis and fibrosis using the FibroScan, regardless of their morphology.