How effective are experienced hepatologists at staging fibrosis using non-invasive fibrosis tests in patients with metabolic dysfunction-associated steatotic liver disease?

BACKGROUND: Sequential use of non-invasive fibrosis tests (NITs) to identify patients with advanced hepatic fibrosis is recommended. However, it remains unclear how reliable clinicians are staging liver fibrosis using combinations of NITs. AIM: Our aim was to assess concordance between NIT-based 'clinician fibrosis assessment (CFA)' and histology in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and compare this with established algorithmic approaches. METHODS: Six experienced hepatologists independently staged 230 MASLD patients for advanced fibrosis (F0-2 vs F3-4) using FIB-4, FIB-4+ELF, FIB-4+ vibration controlled transient elastography (VCTE; Fibroscan™) and FIB-4+ELF+VTCE. Concordance between histology and CFA or algorithmic approaches were assessed. RESULTS: A total of 230 patients were included (median age 54 [22-78] years; 55% female; median FIB-4 1.21 [IQR: 0.78-1.91]; ELF 9.3 [IQR: 8.6-10.2]; VCTE 9.4 [IQR: 6.3-14.3]; 41% F0-1, 22% F2, 21% F3 and 16% F4). Overall, area under the receiver operator curves for histologic F3-4 for the raw tests were 0.84 for FIB-4, 0.86 for ELF and 0.86 for VCTE. Concordance between the hepatologists was good (FIB4, κ = 0.64; FIB-4+ELF, κ = 0.70; FIB-4+VCTE, κ = 0.69; FIB-4+ELF+VCTE, κ = 0.70). Concordance between individual CFA and histology was variable, which was reflected in variability in sensitivity (44%-84%) and specificity (76%-94%). Concordance with histology was better when clinicians used NIT combinations. Purely algorithmic approaches, particularly sequential use of FIB-4 then VCTE, tended to perform better than the CFA. CONCLUSIONS: Adhering to the recommended algorithmic approaches using NITs to stage fibrosis tended to perform more accurately than less-structured clinician NIT-based assessments conducted by experienced hepatologists.

Anti-Cholestatic Therapy with Obeticholic Acid Improves Short-Term Memory in Bile Duct-Ligated Mice.

Patients with cholestatic liver disease, including those with primary biliary cholangitis, can experience symptoms of impaired cognition or brain fog. This phenomenon remains unexplained and is currently untreatable. Bile duct ligation (BDL) is an established rodent model of cholestasis. In addition to liver changes, BDL animals develop cognitive symptoms early in the disease process (before development of cirrhosis and/or liver failure). The cellular mechanisms underpinning these cognitive symptoms are poorly understood. Herein, the study explored the neurocognitive symptom manifestations, and tested potential therapies, in BDL mice, and used human neuronal cell cultures to explore translatability to humans. BDL animals exhibited short-term memory loss and showed reduced astrocyte coverage of the blood-brain barrier, destabilized hippocampal network activity, and neuronal senescence. Ursodeoxycholic acid (first-line therapy for most human cholestatic diseases) did not reverse symptomatic or mechanistic aspects. In contrast, obeticholic acid (OCA), a farnesoid X receptor agonist and second-line anti-cholestatic agent, normalized memory function, suppressed blood-brain barrier changes, prevented hippocampal network deficits, and reversed neuronal senescence. Co-culture of human neuronal cells with either BDL or human cholestatic patient serum induced cellular senescence and increased mitochondrial respiration, changes that were limited again by OCA. These findings provide new insights into the mechanism of cognitive symptoms in BDL animals, suggesting that OCA therapy or farnesoid X receptor agonism could be used to limit cholestasis-induced neuronal senescence.

Neurosteroid Activation of GABA-A Receptors: A Potential Treatment Target for Symptoms in Primary Biliary Cholangitis?

Background and Aims: A third of patients with primary biliary cholangitis (PBC) experience poorly understood cognitive symptoms, with a significant impact on quality of life (QOL), and no effective medical treatment. Allopregnanolone, a neurosteroid, is a positive allosteric modulator of gamma-aminobutyricacid-A (GABA-A) receptors, associated with disordered mood, cognition, and memory. This study explored associations between allopregnanolone and a disease-specific QOL scoring system (PBC-40) in PBC patients. Method: Serum allopregnanolone levels were measured in 120 phenotyped PBC patients and 40 age and gender-matched healthy controls. PBC subjects completed the PBC-40 at recruitment. Serum allopregnanolone levels were compared across PBC-40 domains for those with none/mild symptoms versus severe symptoms. Results: There were no overall differences in allopregnanolone levels between healthy controls (median = 0.03 ng/ml (IQR = 0.025)) and PBC patients (0.031 (0.42), p = 0.42). Within the PBC cohort, higher allopregnanolone levels were observed in younger patients (r (120) = -0.53, p < 0.001) but not healthy controls (r (39) = -0.21, p = 0.21). Allopregnanolone levels were elevated in the PBC-40 domains, cognition (u = 1034, p = 0.02), emotional (u = 1374, p = 0.004), and itch (u = 795, p = 0.03). Severe cognitive symptoms associated with a younger age: severe (50 (12)) vs. none (60 (13); u = 423 p = 0.001). Conclusion: Elevated serum allopregnanolone is associated with severe cognitive, emotional, and itch symptoms in PBC, in keeping with its known action on GABA-A receptors. Existing novel compounds targeting allopregnanolone could offer new therapies in severely symptomatic PBC, satisfying a significant unmet need.

Improved outcomes following the implementation of a decompensated cirrhosis discharge bundle.

Introduction: Mortality from liver disease is increasing and management of decompensated cirrhosis (DC) is inconsistent across the UK. Patients with DC have complex medical needs when discharged from hospital and early readmissions are common. Our aims were: (1) to develop a Decompensated Cirrhosis Discharge Bundle (DCDB) to optimise ongoing care and (2) evaluate the impact of the DCDB. Methods: A baseline review of the management of patients with DC was conducted in Newcastle in 2017. The DCCB was developed and implemented in 2018. Impact of the DCDB was evaluated in two cycles, first a paper version (November 2018-October 2019) and then an electronic version (November 2020-March 2021). Key clinical data were collected from the time of discharge. Results: Overall, 192 patients (62% male; median age 55; median model for end-stage liver disease 17; 72% alcohol related) were reviewed in three cycles. At baseline, management was suboptimal, particularly ascites/diuretic management and provision of follow-up for alcohol misuse and 12% of patients had a potentially avoidable readmission within 30 days. After DCDB introduction, care improved across most domains, particularly electrolyte monitoring (p=0.012) and provision of community alcohol follow-up (p=0.026). Potentially preventable readmissions fell to 5% (p=0.055). Conclusions: Use of a care bundle for patients with DC can standardise care and improve patient management. If used more widely this could improve outcomes and reduce variability in care for patients with DC.

The relationship between disease activity and UDCA response criteria in primary biliary cholangitis: A cohort study.

BACKGROUND: Uncertainty exists about how best to identify primary biliary cholangitis (PBC) patients who would benefit from second-line therapy. Existing, purely clinical, ursodeoxycholic acid (UDCA) response criteria accept degrees of liver biochemistry abnormality in responding patients, emerging data, however, suggest that any degree of ongoing abnormality may, in fact, be associated with an increased risk of adverse outcomes. This cohort study explores the link between response status, the biology of high-risk disease and its implications for clinical practice. METHODS: Proteomics, exploring 19 markers previously identified as remaining elevated in PBC following UDCA therapy, were performed on 400 serum samples, from participants previously recruited to the UK-PBC Nested Cohort between 2014 and 2019. All participants had an established diagnosis of PBC and were taking therapeutic doses of UDCA for greater than 12 months. UDCA response status was assessed using Paris 1, Paris 2 and the POISE criteria, with additional analyses using normal liver blood tests stratified by bilirubin level. Statistical analysis using parametric t tests and 1-way ANOVA. FINDINGS: Disease markers were statistically significantly higher in UDCA non-responders than in responders for all the UDCA response criteria, suggesting a meaningful link between biochemical disease status and disease mechanism. For each of the criteria, however, marker levels were also statistically significantly higher in responders with ongoing liver function test abnormality compared to those who had normalised their liver biochemistry. IL-4RA, IL-18-R1, CXCL11, 9 and 10, CD163 and ACE2 were consistently elevated across all responder groups with ongoing LFT abnormality. No statistically significant differences occurred between markers in normal LFT groups stratified by bilirubin level. INTERPRETATION: This study provides evidence that any ongoing elevation in alkaline phosphatase levels in PBC after UDCA therapy is associated with some degree of ongoing disease activity. There was no difference in activity between patients with normal LFT when stratified by bilirubin. These findings suggest that if our goal is to completely control disease activity in PBC, then normalisation of alkaline phosphatase and bilirubin should be the treatment target. This would also simplify messaging around goals of therapy in PBC, benefiting both patients and clinicians. FUNDING: Funding by the UK Medical Research Council (Stratified Medicine Programme) and an independent research grant by Pfizer. The study funders played no role in the study design, data collection, data analyses, data interpretation or manuscript writing.

The Serum Proteome and Ursodeoxycholic Acid Response in Primary Biliary Cholangitis.

BACKGROUND AND AIMS: Stratified therapy has entered clinical practice in primary biliary cholangitis (PBC), with routine use of second-line therapy in nonresponders to first-line therapy with ursodeoxycholic acid (UDCA). The mechanism for nonresponse to UDCA remains, however, unclear and we lack mechanistic serum markers. The UK-PBC study was established to explore the biological basis of UDCA nonresponse in PBC and identify markers to enhance treatment. APPROACH AND RESULTS: Discovery serum proteomics (Olink) with targeted multiplex validation were carried out in 526 subjects from the UK-PBC cohort and 97 healthy controls. In the discovery phase, untreated PBC patients (n = 68) exhibited an inflammatory proteome that is typically reduced in scale, but not resolved, with UDCA therapy (n = 416 treated patients). Nineteen proteins remained at a significant expression level (defined using stringent criteria) in UDCA-treated patients, six of them representing a tightly linked profile of chemokines (including CCL20, known to be released by biliary epithelial cells (BECs) undergoing senescence in PBC). All showed significant differential expression between UDCA responders and nonresponders in both the discovery and validation cohorts. A linear discriminant analysis, using serum levels of C-X-C motif chemokine ligand 11 and C-C motif chemokine ligand 20 as markers of responder status, indicated a high level of discrimination with an AUC of 0.91 (CI, 0.83-0.91). CONCLUSIONS: UDCA under-response in PBC is characterized by elevation of serum chemokines potentially related to cellular senescence and was previously shown to be released by BECs in PBC, suggesting a potential role in the pathogenesis of high-risk disease. These also have potential for development as biomarkers for identification of high-risk disease, and their clinical utility as biomarkers should be evaluated further in prospective studies.

Quality of life in patients with primary biliary cholangitis: A cross-geographical comparison.

BACKGROUND & AIMS: Several symptoms impair the quality of life (QoL) of patients with primary biliary cholangitis (PBC). They are reported to vary significantly in different countries. Aim of our study was to explore whether there is a geographical clustering that accounts for symptoms in PBC. METHODS: Data was analysed from four cohorts of PBC patients from the UK, Spain, Japan and Italy using the PBC-27 scale. RESULTS: Overall, 569 patients from four cohorts were identified, including 515 females (90.5%) with a mean age of 61 years. The analysis provided evidence for strict factorial invariance of the scale, a robust indicator of its validity for cross-cultural research. The mean of the fatigue domain of British patients was significantly greater than that of the Japanese (p â€‹< â€‹0.05), Italian (p â€‹< â€‹0.05), and Spanish patients (p â€‹< â€‹0.001). The mean of the cognitive domain after 54 years of age, was significantly greater in the British patients than in the Japanese (p â€‹< â€‹0.05) and Spanish patients (p â€‹< â€‹0.01). However, after 69 years of age, there were not significant differences between countries. The mean of the emotion domain after 54 years of age, was greater in the British that in the Spanish (p â€‹< â€‹0.01) and Italian patients (p â€‹< â€‹0.01). CONCLUSIONS: Differences in the four countries concerning fatigue, cognitive and emotional dysfunction were found. The association of latitude and symptoms might provide new insights into the role of sun exposure, genetics and/or cultural component into disease phenotype in PBC.

Rituximab Is Ineffective for Treatment of Fatigue in Primary Biliary Cholangitis: A Phase 2 Randomized Controlled Trial.

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease. Half of patients experience debilitating fatigue, which is currently untreatable. Previous studies have shown muscle bioenergetic abnormalities in PBC, including increased muscle acidosis with exercise linked to the antimitochondrial antibody (AMA) diagnostic of the disease, and reduced anaerobic threshold. In this study we addressed the hypothesis that fatigue in PBC is driven by muscle bioenergetic abnormality related to AMA, and that AMA reduction with B-cell depletion therapy will improve fatigue. In our single-center phase 2 randomized controlled trial, 57 participants aged 18 years or older with PBC and moderate to severe fatigue were randomized to receive two doses of either rituximab (1000 mg) or saline (placebo). The primary outcome measure was fatigue severity assessed using the PBC-40 fatigue domain at 3 months. Secondary outcome measures included patient-reported outcomes and immunological and bioenergetics disease parameters. Experimental outcomes included biochemical markers of disease severity. Improvement in fatigue score at 3 months was seen in both arms, with no significant difference (adjusted mean difference -0.9 [95% confidence interval -4.6 to 3.1]). Little difference was observed in other patient-reported outcomes or physical activity. Significant anaerobic threshold improvement was seen in the rituximab group, only but this was not associated with fatigue improvement. No treatment-emergent serious adverse events were seen. Conclusions: Rituximab was safe over the 12-month study period but showed no evidence of effectiveness for the treatment of fatigue in PBC. Anaerobic threshold improvement was seen, potentially linking AMA with muscle bioenergetics dysfunction; however, this was not related to improvement in fatigue. Rituximab had some evidence of a beneficial effect on alkaline phosphatase levels in this largely ursodeoxycholic acid (UDCA)-responding, early-disease stage cohort. (Hepatology 2018; 00:000-000).

Are Clinicians Ready for Safe Use of Stratified Therapy in Primary Biliary Cholangitis (PBC)? A Study of Educational Awareness.

BACKGROUND: Primary Biliary Cholangitis (PBC, formerly cirrhosis), is a chronic cholestatic liver disease which until spring 2016 had a single licensed therapy, Ursodeoxycholic acid (UDCA). Approximately 30% of patients do not respond to UDCA, and are high-risk for progressing to end stage liver disease, transplantation or death. A new era of stratified medicine with second-line therapies to treat high-risk disease is emerging, with the first such second-line agent obeticholic acid recently receiving FDA and EMA approval and entering practice. Recent experience in the USA of inappropriate use and associated deaths has highlighted concerns as to whether clinicians have the knowledge to implement second-line therapies appropriately and safely. METHODS: Online survey of knowledge regarding optimal PBC management in Gastroenterologists and Hepatologists in the USA; the first 100 completed responses from each group used for analysis. RESULTS: 80% of Hepatologists felt they were highly competent in their understanding of the importance of early diagnosis and early UDCA therapy in PBC compared with 65% of gastroenterologists. However, only 36% of Hepatologists and 30% of gastroenterologists felt competent at assessing response to UDCA. Competence in knowledge (mode of action, efficacy, and side effects) of second-line therapies and enrollment into trials was low among both groups. CONCLUSION: Significant knowledge gaps in clinicians managing PBC presents a problem in optimizing care. It is perhaps not surprising that knowledge of emerging second-line therapies is low, however more concerning is sub-optimal use of UDCA in real-life practice and the lack of confidence at assessing treatment response which should be a routine part of clinical practice to assess risk of disease progression and will be key in delivering stratified medicine.

Early Molecular Stratification of High-risk Primary Biliary Cholangitis.

High-risk primary biliary cholangitis (PBC), defined by inadequate response at one year to Ursodeoxycholic acid (UDCA), is associated with disease progression and liver transplantation. Stratifying high-risk patients early would facilitate improved approaches to care. Using long-term follow-up data to define risk at presentation, 6 high-risk PBC patients and 8 low-risk patients were identified from biopsy, transplant and biochemical archival records. Formalin-fixed paraffin-embedded (FFPE) liver biopsies taken at presentation were graded (Scheuer and Nakanuma scoring) and gene expression analysed using the NanoString® nCounter PanCancer Immunity 770-gene panel. Principle component analysis (PCA) demonstrated discrete gene expression clustering between controls and high- and low-risk PBC. High-risk PBC was characterised by up-regulation of genes linked to T-cell activation and apoptosis, INF-γ signalling and leukocyte migration and down-regulation of those linked to the complement pathway. CDKN1a, up-regulated in high-risk PBC, correlated with significantly increased expression of its gene product, the senescence marker p21WAF1/Cip, by biliary epithelial cells. Our findings suggest high- and low-risk PBC are biologically different from disease outset and senescence an early feature in high-risk disease. Identification of a high-risk 'signal' early from standard FFPE tissue sections has clear clinical utility allowing for patient stratification and second-line therapeutic intervention.

Exercise therapy in primary biliary cirrhosis: the importance of moving while sitting on a surgical waiting list-a case study.

BACKGROUND: It is being increasingly recognised that reduced cardiorespiratory fitness is associated with poorer outcomes after major surgery. Exercise limitation and reduced aerobic capacity are common in people with end-stage liver disease. There is limited evidence about the role of exercise therapy in the management of primary biliary cirrhosis (PBC) and no studies have looked at the effect of exercise in people with PBC who are awaiting liver transplantation. This case study is the first to report that personalised exercise therapy improves cardiorespiratory fitness in a patient with PBC without worsening symptoms of severe fatigue. METHODS: Cardiopulmonary exercise testing was used to assess cardiorespiratory fitness in a patient with end-stage PBC prior to listing for transplantation. A personalised exercise programme was designed to improve cardiorespiratory fitness while the patient was on the transplant waiting list. RESULTS: Anaerobic threshold, VO2PEAK and maximum workload all improved with regular exercise. Fatigue levels remained unaltered. CONCLUSIONS: This patient tolerated and adhered to a personalised exercise programme for a prolonged period of time while awaiting surgery despite significant fatigue and disease burden. Liver transplantation was successfully completed and this woman remains well over 2 years post-surgery.

Improving testing for hepatitis B before treatment with rituximab.

AIMS/OBJECTIVES/BACKGROUND: Individuals with current or previous infection with the hepatitis B virus (HBV) can experience viral reactivation when treated with immunosuppression. Rituximab, an anti-CD20 antibody used to treat many diseases, has potent immunosuppressant effects with a high risk of causing HBV reactivation. Reactivation can range from elevated liver enzymes to acute severe hepatitis with liver failure and a significant mortality risk. HBV screening and appropriate use of prophylactic antiviral therapy can prevent reactivation. This work describes the introduction of a local policy for HBV testing in patients before rituximab treatment and assesses its impact. METHODS AND RESULTS: A baseline review (before policy introduction) of 90 patients showed that only 21 (23%) had hepatitis B surface antigen (HBsAg) and 17 (19%) had hepatitis B core antibody (anti-HBcAb) tested before receiving rituximab. Following introduction of the policy (on the basis of international guidelines), improved laboratory reporting protocols and targeted education sessions, two further reviews of HBV testing rates among patients being initiated onto rituximab were performed. There was a marked increase in pre-rituximab testing for HBsAg from 23 to 79% and for anti-HBcAb from 19 to 78%. Throughout the study period, a total of one (0.8%) HBsAg-positive and six (4.7%) anti-HBcAb-positive patients were identified. CONCLUSIONS: This work clearly indicates that simple strategies can markedly improve appropriate HBV screening. In our cohort, 6% (of whom only 43% had recognized HBV risk factors) required antiviral prophylaxis, which emphasizes the importance of universal screening before rituximab. Reinforcement of the guidelines and ongoing education is needed to further increase testing rates.

Understanding and Treating Fatigue in Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis.

Fatigue is a significant problem for patients with primary biliary cirrhosis and although experienced less by patients with primary sclerosing cholangitis, a minority still report significant fatigue. Fatigue is the symptom with the greatest impact on quality of life, particularly when associated with social dysfunction. The pathogenesis of fatigue in cholestatic liver disease is complex, poorly understood, and probably has central and peripheral components. Managing fatigue in cholestatic liver disease presents a challenge for clinicians given the complexity and its numerous associations. This article presents a structured approach to managing fatigue in cholestatic liver disease to improve fatigue severity and quality of life.

Fatigue in Primary Biliary Cirrhosis: Prevalence, Pathogenesis and Management.

Fatigue is a significant problem in approximately 50% of primary biliary cirrhosis (PBC) patients, with 20% of all patients experiencing significant or life-altering fatigue. Large-scale population studies show that fatigue has a major impact on quality of life (QoL) in PBC, and that it disproportionately affects younger patients. The presence of social dysfunction that accompanies fatigue appears to be a major factor in determining whether fatigue of a particular severity impacts on QoL. The pathogenesis of fatigue in PBC remains unclear, although it is unrelated to the severity of underlying disease and is unresponsive to ursodeoxycholic acid. Perhaps, unsurprisingly, it appears to be complex in origin, probably multifactorial in the majority of patients and associated with depression, autonomic dysfunction and sleep disturbance. Clinically, fatigue has both central and peripheral components. The central component is associated with cognitive impairment and sleep disturbance and characterised by neurophysiological abnormalities of activation and facilitation, together with CNS changes. Peripheral fatigue is associated with muscle dysfunction and an inability to sustain exercise. One hypothesis is that the central processes result directly from cholestasis, which impacts autonomic centres in the brain; these processes then regulate peripheral muscle perfusion, leading to systemic peripheral effects. At present, there is no specific drug therapy for fatigue in PBC and no significant improvement following transplantation. In managing patients with fatigue, understanding their situation is crucial and advice regarding pacing and maintaining social interactions is critical. Most important of all is an understanding of the impact this symptom has on patients' lives and an empathetic clinical interaction.

RITPBC: B-cell depleting therapy (rituximab) as a treatment for fatigue in primary biliary cirrhosis: study protocol for a randomised controlled trial.

INTRODUCTION: Primary biliary cirrhosis (PBC) is an autoimmune liver disease with approximately 50% of patients experiencing fatigue. This can be a particularly debilitating symptom, affecting quality of life and resulting in social isolation. Fatigue is highlighted by patients as a priority for research and patient support groups were involved in designing this trial. This is the first randomised controlled trial to investigate a treatment for fatigue in PBC. The trial protocol is innovative as it utilises novel magnetic resonance spectroscopy (MRS) techniques as an outcome measure. The protocol will be valuable to research groups planning clinical trials targeting fatigue in PBC and also transferrable to other conditions associated with fatigue. METHODS AND ANALYSIS: RITPBC is a Medical Research Council (MRC) and National Institute for Health Research (NIHR) Efficacy and Mechanism Evaluation Programme (EME)-funded project. It is a phase II, single-centre, randomised controlled, double-blinded trial comparing rituximab with placebo in fatigued PBC patients. 78 patients with PBC and moderate to severe fatigue will be randomised to receive two infusions of rituximab or placebo. The study aims to assess whether rituximab improves fatigue in patients with PBC, the safety, and tolerability of rituximab in PBC and the sustainability of any beneficial actions. The primary outcome will be an improvement in fatigue domain score of the PBC-40, a disease-specific quality of life measure, evaluated at 12-week assessment. Secondary outcome measures include novel MRS techniques assessing muscle bioenergetic function, physical activity, anaerobic threshold and symptom, and quality of life measures. The trial started recruiting in October 2012 and recruitment is ongoing. ETHICS AND DISSEMINATION: The trial has ethical approval from the NRES Committee North East, has Clinical Trial Authorisation from MHRA and local R&D approval. Trial results will be communicated to participants, presented at national and international meetings and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN03978701.