Carey, Elizabeth J.

Introduction: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease without approved medical therapies. We examined the efficacy and safety of oral vancomycin (OV) in those with PSC. Methods: In this phase 3, 18-month, double-blind, placebo-controlled trial, we randomly assigned adults with PSC and a serum alkaline phosphatase (SAP) greater than 1.5 times the upper limit of normal to placebo or oral vancomycin (OV) with dosages ranging from 125-375 mg four times daily pending biochemical response. The primary endpoint was normalization of SAP. Results: Of the 82 patients who underwent randomization, 73 individuals had at least one outcome assessment. Individuals who withdrew early were less likely to rate their baseline health as excellent or very good (23.4% vs 54.5%, p<0.01) despite having similar PSC prognostic features to those who completed the study. SAP normalization rates were similar (5% placebo, 6.7% OV, p=1.00) after 18 months. Those who received OV had greater reduction in SAP (+1.2% placebo, -21.9% OV, p=0.03). There were no differences in the changes in either the Mayo PSC risk score (-0.1 placebo, -0.1 OV, p=0.88) or liver stiffness values (+0.1 kPa placebo, -4.0 kPa OV, p=0.15). Discoloration of the teeth and tongue was the most common side effect of OV (17.5%). Conclusions: OV was not associated with clinically significant reductions in markers of PSC disease severity. Impairments in quality of life may influence patient retention in clinical trials.

ABSTRACT Background and Aims Primary sclerosing cholangitis (PSC) is a progressive cholestatic liver disease with a high risk of malignancy and limited therapeutic options. Both the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) recommend structured baseline evaluation, fibrosis staging and longitudinal surveillance. However, real‐world adherence to these practices in North America remains unclear. Methods We conducted a retrospective cohort study of 1300 patients with PSC enrolled in the Consortium for Autoimmune Liver Diseases (CALiD) registry between 2018 and 2024 across 19 centres in North America. Guideline adherence was assessed for diagnostic measures at baseline (colonoscopy to establish IBD status and noninvasive fibrosis staging) and longitudinal surveillance (colonoscopy in PSC‐IBD, abdominal imaging for hepatobiliary cancer surveillance and CA 19‐9 testing). Prescribing patterns for ursodeoxycholic acid (UDCA) were also characterised. Multivariable logistic regression was used to evaluate demographic, clinical and socioeconomic predictors of adherence. Results At diagnosis, 78.8% of eligible patients with available data underwent colonoscopy to establish IBD status, and 45% underwent noninvasive fibrosis staging. During follow‐up, only 30%–35% of patients with PSC‐IBD underwent colonoscopy annually, while abdominal imaging for hepatobiliary cancer surveillance declined from 74% at Year 1 to 51% by Year 4. CA 19‐9 testing was documented in 47% over 5‐year period. UDCA was prescribed in 51% at baseline, with median dose of 12.5 mg/kg/day. Socioeconomic factors, including lower education and household income, were associated with reduced adherence, while cirrhosis strongly predicted completion of surveillance imaging. Conclusions Adherence to guideline‐based care in PSC remains suboptimal in North America Suboptimal adherence was observed for strongly recommended practices with longstanding guideline support (colonoscopy to establish IBD status; annual CRC surveillance in PSC‐IBD) as well as practices where guideline consensus has evolved more recently or where societies differ (baseline fibrosis assessment; hepatobiliary cancer imaging). Efforts to standardise care and address socioeconomic barriers are urgently needed to improve outcomes.

INTRODUCTION: Despite the widespread use of ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC), many patients remain at risk of progression. Emerging data suggest that normalization of alkaline phosphatase (ALP) and total bilirubin (TB)—particularly when TB < 0.6 times the upper limit of normal (× ULN)—is associated with improved outcomes compared with ALP reduction to < 1.5 × ULN. This study investigated the association between ALP normalization in response to UDCA and long-term clinical outcomes in a real-world cohort of patients with PBC. METHODS: We compared complication-free survival in patients achieving an ALP > ULN and < 1.5 × ULN (adequate response) with those with an ALP ≤ ULN on UDCA monotherapy. Complication-free survival was defined as the absence of serious liver-related clinical events. Restricted mean survival time was used to quantify survival time gained. RESULTS: Patients achieving normal ALP and/or TB ≤ 0.6 × ULN demonstrated significantly improved complication-free survival compared with those with an adequate ALP response. Event-free survival was extended by 1.34 years (95% CI: 0.56, 2.11; P = 0.001) for ALP normalization alone, 3.7 years (95% CI: 3.11, 4.29; P < 0.001) for TB ≤ 0.6 × ULN, and 4.51 years (95% CI: 4.13, 4.88; P < 0.001) for those meeting both criteria. The risk of severe clinical events was reduced in patients achieving ALP normalization (hazard ratio [HR] 0.34; 95% CI: 0.15, 0.80; P = 0.01), TB ≤ 0.6 × ULN (HR 0.23; 95% CI: 0.09, 0.55; P = 0.001), or both (HR 0.14; 95% CI: 0.05, 0.38; P < 0.001). High-risk patients, defined by liver stiffness measurement ≥ 10 kPa or clinical, histological, or laboratory evidence of cirrhosis or portal hypertension, derived the greatest benefit. DISCUSSION: Achieving normal ALP and TB ≤ 0.6 × ULN is associated with significantly improved complication-free survival, particularly in high-risk patients. These findings highlight the potential of biochemical thresholds as a meaningful therapeutic goal in PBC management.

ABSTRACT Hepatopulmonary syndrome (HPS) affects up to one‐third of patients with advanced chronic liver disease (ACLD) and is an independent risk factor for increased mortality. While HPS often improves following liver transplantation, patients with severe or very severe HPS—classified by partial pressure of arterial oxygen (PaO 2 ) <60 mmHg—face higher post‐transplant complications and mortality. However, evidence suggests that even patients with severe HPS may benefit from liver transplantation when performed at high‐volume centers. To assess post‐transplant outcomes in this population, we conducted a retrospective chart review of 20 patients diagnosed with severe or very severe HPS who underwent liver transplantation at Mayo Clinic Hospital in Arizona between 2014 and 2024. The most common post‐transplant complication was persistent hypoxemia, managed on a case‐by‐case basis with various treatments, though no single approach proved consistently superior. All patients who received transplants demonstrated improvement; 84% of patients ultimately discontinued supplemental oxygen, with a mean time of 250 days (range: 0–1113 days). Time was the key factor in recovery. Notably, no deaths in our cohort were directly attributed to HPS. These findings support liver transplantation as a viable treatment option for HPS, even in severe cases, and underscore the importance of experienced transplant centers in optimizing patient outcomes.

ABSTRACTThe incidence of ischemic cholangiopathy (IC) is expected to remain significant due to rising rates of transplants performed with livers donated after circulatory death (DCD), despite the use of machine perfusion. Absent established pharmacologic interventions against this progressive etiology of allograft dysfunction and failure, we describe the use of fenofibrate—a cheap and widely‐accessible peroxisome proliferator‐activated receptor agonist that downregulates bile acid production—to impede IC progression in 15 DCD liver recipients who were not responding to reactive, standard‐of‐care management. All patients were undergoing serial endoscopic retrograde cholangiopathy (ERC) to maintain biliary patency but demonstrated progressive cholestasis, with serum alkaline phosphatase (ALP) rising 70.3% over the 90 days preceding fenofibrate. Cholestasis improved in all patients after fenofibrate initiation, with a 63.9% reduction in mean ALP at 90 days, maintained at 270 days (p = 0.02) and 360 days (p = 0.06). ALP improvement was associated with reduced ERC frequency during and after fenofibrate treatment, and this improvement was independent of concurrent ERC or ursodeoxycholic acid use during fenofibrate treatment. In patients who stopped treatment, ALP increased. No fenofibrate‐associated adverse events were seen. These preliminary data support the further study of agents that downregulate bile acid production as a means of impeding IC in DCD livers.

Background. Cardiovascular disease and physical decline are prevalent and associated with morbidity/mortality in liver transplant (LT) patients. Cardiopulmonary exercise testing (CPX) provides comprehensive cardiopulmonary and exercise response assessments. We investigated cardiorespiratory fitness (CRF) and cardiac stress generated during CPX in LT candidates. Methods. LT candidates at 2 centers underwent CPX. Standard-of-care cardiac stress testing (dobutamine stress echocardiography, DSE) results were recorded. Physical function was assessed with liver frailty index and 6-min walk test. CPX/DSE double products were calculated to quantify cardiac stress. To better study the association of CPX-derived metrics with physical function, the cohort was divided into 2 groups based on 6-min walk test median (372 m). Results. Fifty-four participants (62 ± 8 y; 65% men, Model for End-Stage Liver Disease-Na 14 [10–18]) underwent CPX. Peak oxygen consumption was 14.1 mL/kg/min for an anerobic threshold of 10.2 mL/kg/min, with further CRF decline in the lower 6MWT cohort despite lack of liver frailty index-frailty in 90%. DSE was nondiagnostic in 18% versus 4% of CPX (P = 0.058). All CPX were negative for ischemia. A double product of ≥25 000 was observed in 32% of CPX and 11% of DSE (P = 0.020). Respiratory function testing was normal. No patient presented major cardiovascular events at 30 d post-LT. Conclusions. CPX provided efficient and effective combined cardiopulmonary risk and frailty assessments of LT candidates in a 1-stop test. The CRF was found to be very low despite preserved physical function or lack of frailty.

Background and Aims: Sarcopenia is highly prevalent in patients with liver cirrhosis and is associated with adverse clinical outcomes, including HE. Androgen receptor agonists, androgen receptor agonists, can address these conditions through multimodal mechanisms of action; however, their safety and efficacy in patients with cirrhosis have not been well established. Approach and Results: In this multicenter, double-blind, phase 2 trial, men with sarcopenia and cirrhosis awaiting liver transplant were randomized 1:1 to receive either oral Androgen Receptor Agonist LPCN 1148 or placebo for 24 weeks (NCT04874350). The primary end point was the change from baseline to 24 weeks in skeletal muscle index measured by a CT scan of the L3 region, analyzed with a prespecified modified intent-to-treat population. The secondary end point was the number of overt HE events. Twenty-nine participants (mean age=59 y, MELD=17) received at least 1 dose of LPCN 1148 (n=15) or placebo (n=14). Baseline characteristics were similar between groups. Primary end point analysis demonstrated an increase in L3-skeletal muscle index measured by a CT scan of the L3 region in the LPCN 1148 group (n=15) compared to placebo (n=10), with a mean group difference of 4.4 cm2/m2 (95% CI: 1.3–7.4 cm2/m2, p=0.007). Participants in LPCN 1148 experienced fewer episodes of overt HE (Common Terminology Criteria for Adverse Events grade ≥2; p=0.02) than placebo. The number and severity of treatment-emergent adverse events were similar between arms. Conclusions: LPCN 1148 treatment improved sarcopenia and reduced the number of overt HE episodes in men with cirrhosis and sarcopenia awaiting liver transplant. These findings support additional research on the efficacy of LPCN 1148 in treating sarcopenia and preventing HE recurrence.

Background: The natural history of primary sclerosing cholangitis (PSC) among African Americans (AA) is not well understood. Methods: Transplant-free survival and hepatic decompensation–free survival were assessed using a retrospective research registry from 16 centers throughout North America. Patients with PSC alive without liver transplantation after 2008 were included. Diagnostic delay was defined from the first abnormal liver test to the first abnormal cholangiogram/liver biopsy. Socioeconomic status was imputed by the Zip code. Results: Among 850 patients, 661 (77.8%) were non-Hispanic Whites (NHWs), and 85 (10.0%) were AA. There were no significant differences by race in age at diagnosis, sex, or PSC type. Inflammatory bowel disease was more common in NHWs (75.8% vs. 51.8% p =0.0001). The baseline (median, IQR) Amsterdam-Oxford Model score was lower in NHWs (14.3, 13.4–15.2 vs. 15.1, 14.1–15.7, p =0.002), but Mayo risk score (0.03, −0.8 to 1.1 vs. 0.02, −0.7 to 1.0, p =0.83), Model for End-stage Liver Disease (5.9, 2.8–10.7 vs. 6.4, 2.6–10.4, p =0.95), and cirrhosis (27.4% vs. 27.1%, p =0.95) did not differ. Race was not associated with hepatic decompensation, and after adjusting for clinical variables, neither race nor socioeconomic status was associated with transplant-free survival. Variables independently associated with death/liver transplant (HR, 95% CI) included age at diagnosis (1.04, 1.02–1.06, p <0.0001), total bilirubin (1.06, 1.04–1.08, p <0.0001), and albumin (0.44, 0.33–0.61, p <0.0001). AA race did not affect the performance of prognostic models. Conclusions: AA patients with PSC have a lower rate of inflammatory bowel disease but similar progression to hepatic decompensation and liver transplant/death compared to NHWs.