Fluctuating biomarkers in primary sclerosing cholangitis: A longitudinal comparison of alkaline phosphatase, liver stiffness, and ELF.

Primary sclerosing cholangitis (PSC) is a progressive liver disease characterised by fluctuating liver biochemistries and highly variable disease progression. The Enhanced Liver Fibrosis (ELF®) test and liver stiffness measurements (LSMs) reflect fibrosis and predict clinical outcomes in PSC; however, longitudinal assessments are missing. We aimed to characterise the systematic change in ELF and LSM over time in a prospective cohort of patients with PSC, along with their longitudinal relationship to alkaline phosphatase (ALP) and bilirubin. We included 113 non-transplant PSC patients (86 males [76.1%]; mean age 43.3 ± 15.7 years) with annual study visits between 2013 and 2019 at 2 Norwegian centres. ELF test, LSM, clinical data, liver biochemistries, and revised Mayo risk score were measured. We used linear mixed-effects models to estimate change over time, intraclass correlations (ICCs), and their relationship with ALP and bilirubin. At baseline, the median (range) ELF test was 9.3 (7.5-12.9) and median LSM 1.26 m/s (0.66-3.04 m/s). ELF and LSM increased over time (0.09 point/year, 95% CI [0.03, 0.15], p = 0.005, vs. 0.12 point/year, 95% CI [0.03, 0.21], p = 0.009). Between-patient effects explained 78% of ELF variation (ICC 0.78) and 56% of LSM variation (ICC 0.56). ALP also increased and showed the highest ICC (0.86). ELF and LSM increased over a 5-year period. Longitudinal analyses demonstrated differences regarding within- and between-patient effects, suggesting that the ELF test may have superior reliability for risk stratification compared with LSM in PSC. Primary sclerosing cholangitis (PSC) is characterised by substantial disease variability between patients and fluctuating liver biochemistries. Hence, new biomarkers are needed to identify individuals with an increased risk of developing end-stage liver disease. We explore the change over time of 2 putative prognostic biomarkers in PSC, the serum Enhanced Liver Fibrosis (ELF®) test and LSMs by ultrasound, demonstrating differences that may reflect differing abilities to discriminate risk.

Fossdal G ，Mjelle AB ，Wiencke K ，Bjørk I ，Gilja OH ，Folseraas T ，Karlsen TH ，Rosenberg W ，Giil LM ，Vesterhus M ... -  《-》

Comprehensive assessment of ECM turnover using serum biomarkers establishes PBC as a high-turnover autoimmune liver disease.

Primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) are phenotypically distinct autoimmune liver diseases that progress to cirrhosis and liver failure; however, their histological fibrosis distribution differs. We investigated the extracellular matrix (ECM) profiles of patients with PSC, PBC, and AIH to establish whether the diseases display differential patterns of ECM turnover. Serum samples were retrospectively collected from the UK (test cohort; PSC n = 78; PBC n = 74; AIH n = 58) and Norway (validation cohort; PSC n = 138; PBC n = 28; AIH n = 27). Patients with ulcerative colitis without liver disease (n = 194) served as controls. We assessed specific serological biomarkers of ECM turnover: type III and V collagen formation (PRO-C3, PRO-C5), degradation of type III and IV collagen (C3M, C4M), biglycan (BGM) and citrullinated vimentin (VICM). Most of the ECM markers showed elevated serum levels in PBC compared with PSC or AIH (p <0.01). PRO-C3 correlated well with liver stiffness and showed the most striking differences between advanced and non-advanced liver disease; several of the other ECM markers were also associated with stage. PRO-C3 and other ECM markers were inversely associated with ursodeoxycholic acid treatment response in PBC and remission in AIH. All ECM remodelling markers were significantly elevated (p <0.05) in patients with PSC, PBC, or AIH compared with ulcerative colitis. In this first study comparing ECM turnover in autoimmune liver diseases, we found increased ECM turnover in PBC compared with either PSC or AIH. The study indicates that ECM remodelling is different in PSC, PBC, and AIH, suggesting differing opportunities for therapeutic intervention. The level of scarring is linked to prognosis in autoimmune liver diseases such as primary sclerosing cholangitis, primary biliary cholangitis, and autoimmune hepatitis; hence, the scarring process is a possible target for novel therapy. Investigating the scarring process using highly specific technology, we show that the scarring process is different between the 3 autoimmune liver diseases, and this may have important implications for the development of medical treatment.

Vesterhus M ，Nielsen MJ ，Hov JR ，Saffioti F ，Manon-Jensen T ，Leeming DJ ，Moum B ，Boberg KM ，Pinzani M ，Karlsen TH ，Karsdal MA ，Thorburn D ... -  《-》

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.

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). 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). 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. 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.

Corpechot C ，Gaouar F ，El Naggar A ，Kemgang A ，Wendum D ，Poupon R ，Carrat F ，Chazouillères O ... -  《-》

Efficacy and safety of curcumin in primary sclerosing cholangitis: an open label pilot study.

Eaton JE ，Nelson KM ，Gossard AA ，Carey EJ ，Tabibian JH ，Lindor KD ，LaRusso NF ... -  《-》

Utility of ElastPQ point-shear wave elastography in the work-up of patients with primary sclerosing cholangitis.

Liver stiffness measurement (LSM) and spleen stiffness measurement (SSM) have been shown to be useful tools for assessing the risk of fibrosis and portal hypertension, respectively. However, data on the accuracy of LSM and SSM measured by point-shear wave elastography (pSWE) in patients affected by primary sclerosing cholangitis (PSC) are still lacking. Thus, we aimed to prospectively assess their performance in a cohort of patients with PSC. We determined the correlation between LSM assessed by a pSWE technique (ElastPQ) and by FibroScan-transient elastography (F-TE). Furthermore, we used receiver-operating characteristic curves and area under the curves (AUROC) to evaluate the performance of LSM by ElastPQ for the staging of fibrosis, using F-TE as a reference standard, and the performance of LSM and SSM by ElastPQ in predicting the presence of oesophageal varices (OVs). One hundred and fifty-two patients with PSC (93 males [61.2%], mean age 46 ± 16 years) were prospectively recruited. ElastPQ and F-TE LSMs were available for all patients, while ElastPQ SSM was available in 109 (72%) patients of whom 35 underwent upper gastrointestinal endoscopy within 1 year of the ultrasound assessment. ElastPQ LSM showed an excellent correlation with F-TE (p <0.001, Spearman's 0.93; Lin's 0.86) and a good diagnostic accuracy for fibrosis staging along all stages of liver fibrosis (AUROCs 0.96, 0.97, 0.97 and 0.99 for fibrosis stages F≥1, F≥2, F≥3 and F=4, respectively), using F-TE as a surrogate of histological fibrosis. ElastPQ SSM showed a good diagnostic performance in predicting the presence of OVs at endoscopy. LSM and SSM by ElastPQ can be used as accurate tools for liver fibrosis risk assessment and fibrosis staging, as well as for predicting the presence of OVs in the work-up of patients with PSC. Liver and spleen stiffness measurement (LSM and SSM, respectively) by ElastPQ point-shear wave elastography in patients with primary sclerosing cholangitis represent reliable and reproducible tools for non-invasively staging the severity of liver disease and stratifying patients according to their risk of developing liver-related outcomes. In particular, LSM shows good accuracy for staging liver fibrosis and therefore detecting those patients at high risk of having compensated advanced chronic liver disease who require close monitoring. SSM seems to be promising to detect the risk of portal hypertension and therefore of oesophageal varices, enabling the triaging of patients who really need to undergo a screening endoscopy.

Roccarina D ，Saffioti F ，Rosselli M ，Marshall A ，Pinzani M ，Thorburn D ... -  《-》