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.

UK-Wide Multicenter Evaluation of Second-line Therapies in Primary Biliary Cholangitis.

BACKGROUND & AIMS: Thirty-to-forty percent of patients with primary biliary cholangitis inadequately respond to ursodeoxycholic acid. Our aim was to assemble national, real-world data on the effectiveness of obeticholic acid (OCA) as a second-line treatment, alongside non-licensed therapy with fibric acid derivatives (bezafibrate or fenofibrate). METHODS: This was a nationwide observational cohort study conducted from August 2017 until June 2021. RESULTS: We accrued data from 457 patients; 349 treated with OCA and 108 with fibric acid derivatives. At baseline/pre-treatment, individuals in the OCA group manifest higher risk features compared with those taking fibric acid derivatives, evidenced by more elevated alkaline phosphatase values, and a larger proportion of individuals with cirrhosis, abnormal bilirubin, prior non-response to ursodeoxycholic acid, and elastography readings >9.6kPa (P < .05 for all). Overall, 259 patients (OCA) and 80 patients (fibric acid derivatives) completed 12 months of second-line therapy, yielding a dropout rate of 25.7% and 25.9%, respectively. At 12 months, the magnitude of alkaline phosphatase reduction was 29.5% and 56.7% in OCA and fibric acid groups (P < .001). Conversely, 55.9% and 36.4% of patients normalized serum alanine transaminase and bilirubin in the OCA group (P < .001). The proportion with normal alanine transaminase or bilirubin values in the fibric acid group was no different at 12 months compared with baseline. Twelve-month biochemical response rates were 70.6% with OCA and 80% under fibric acid treatment (P = .121). Response rates between treatment groups were no different on propensity-score matching or on sub-analysis of high-risk groups defined at baseline. CONCLUSION: Across the population of patients with primary biliary cholangitis in the United Kingdom, rates of biochemical response and drug discontinuation appear similar under fibric acid and OCA treatment.

Quantification of polyreactive immunoglobulin G facilitates the diagnosis of autoimmune hepatitis.

BACKGROUND AND AIMS: Detection of autoantibodies is a mainstay of diagnosing autoimmune hepatitis (AIH). However, conventional autoantibodies for the workup of AIH lack either sensitivity or specificity, leading to substantial diagnostic uncertainty. We aimed to identify more accurate serological markers of AIH with a protein macroarray. APPROACH AND RESULTS: During the search for more-precise autoantibodies to distinguish AIH from non-AIH liver diseases (non-AIH-LD), IgG antibodies with binding capacities to many human and foreign proteins were identified with a protein macroarray and confirmed with solid-phase ELISAs in AIH patients. Subsequently, polyreactive IgG (pIgG) was exemplarily quantified by reactivity against human huntingtin-interacting protein 1-related protein in bovine serum albumin blocked ELISA (HIP1R/BSA). The diagnostic fidelity of HIP1R/BSA binding pIgG to diagnose AIH was assessed in a retrospective training, a retrospective multicenter validation, and a prospective validation cohort in cryoconserved samples from 1,568 adults from 10 centers from eight countries. Reactivity against HIP1R/BSA had a 25% and 14% higher specificity to diagnose AIH than conventional antinuclear and antismooth muscle antibodies, a significantly higher sensitivity than liver kidney microsomal antibodies and antisoluble liver antigen/liver pancreas antigen, and a 12%-20% higher accuracy than conventional autoantibodies. Importantly, HIP1R/BSA reactivity was present in up to 88% of patients with seronegative AIH and in up to 71% of AIH patients with normal IgG levels. Under therapy, pIgG returns to background levels of non-AIH-LD. CONCLUSIONS: pIgG could be used as a promising marker to improve the diagnostic workup of liver diseases with a higher specificity for AIH compared to conventional autoantibodies and a utility in autoantibody-negative AIH. Likewise, pIgG could be a major source of assay interference in untreated AIH.

Patient Priorities in Autoimmune Hepatitis: The Need for Better Treatments, More Education and Challenging Stigma.

BACKGROUND: Data show that patients with autoimmune hepatitis have significantly reduced quality-of-life and that corticosteroids carry marked side effects. AIMS: This study explored patients' experiences of autoimmune hepatitis and its treatments; key aspects for developing safe and effective new approaches to therapy. METHODS: An anonymised, internet-based survey collected data including patient demographics, treatments, side-effects, impact on day-to-day life, sources of support and attitudes towards autoimmune hepatitis between December 2019-January 2020. Semi-structured interviews were conducted with 13 patients to further explore their support networks, treatment experiences and health priorities. Descriptive and quantitative analyses were undertaken using R and free text responses were subject to thematic analysis. RESULTS: In total, 270 survey responses were received (median age 55 years and 94% female). Perceived medication side-effects were reported by 66% (169/257) and 73% responded negatively about their experience of corticosteroids. The majority (62·3% [(109/175]) would 'definitely' or 'probably' consider clinical trial participation to improve their care. Only 18·7% (31/166) reported access to a specialist liver nurse and nearly half were involved in support groups. Interview and survey data suggested that major issues were stigma, loss of control and fatigue. CONCLUSIONS: This study provides insights into the realities of living with autoimmune hepatitis with clear issues around lack of support networks, need for patient empowerment and stigma surrounding liver disease. Patient priorities are better therapies to slow disease progression, avoiding corticosteroids and minimising side-effects. Patient willingness to participate in trials suggests that they are achievable provided they have the right design and clinical endpoints.

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.

Pregnancy outcomes in women with liver transplants: systematic review and meta-analysis.

BACKGROUND: Despite increasing reports of pregnancy in liver transplant recipients, questions remain about the impact of transplantation in pregnancy. METHODS: This systematic review was performed according to PRISMA guidelines and eligible studies were identified through a search of PubMed, Scopus and Cochrane CENTRAL databases up to 26th December 2019 for studies reporting pregnancy with liver transplant. A meta-analysis was conducted with the use of random-effects modelling and prospectively registered with the PROSPERO database. RESULTS: Of 1239 unique studies, 28 met inclusion criteria, representing 1496 pregnancies in 1073 liver transplant recipients. The live-birth rate was 85.6% (CI95%: 80.5%-90.7%). The rate of other pregnancy outcomes was as follows: induced abortions (5.7%), miscarriages (7.8%) and stillbirths (3.3%). Pooled rates of obstetric complications were hypertension (18.2%), pre-eclampsia (12.8%) and gestational diabetes (7.0%). Pooled rates of delivery outcomes for caesarean section (C-section) and pre-term birth were 42.2% and 27.8%, respectively. CONCLUSION: In conclusion, live birth outcomes are good among liver transplant recipients and this favourable trend is consistent at an international level. However, special attention should be given to obstetric complications such as hypertension, pre-eclampsia, and preterm delivery. The high incidence of these complications supports the high-risk classification of post-liver transplant pregnancies and it is necessary for a multidisciplinary team to be involved in the monitoring and counselling of liver transplant recipients both before and during pregnancy. Whilst majority data originate from institutions from high-income countries, data from low-middle income countries (LMIC) are needed owing to rising rates of liver transplantation in LMIC.

British Society of Gastroenterology and UK-PSC guidelines for the diagnosis and management of primary sclerosing cholangitis.

These guidelines on the management of primary sclerosing cholangitis (PSC) were commissioned by the British Society of Gastroenterology liver section. The guideline writing committee included medical representatives from hepatology and gastroenterology groups as well as patient representatives from PSC Support. The guidelines aim to support general physicians, gastroenterologists and surgeons in managing adults with PSC or those presenting with similar cholangiopathies which may mimic PSC, such as IgG4 sclerosing cholangitis. It also acts as a reference for patients with PSC to help them understand their own management. Quality of evidence is presented using the AGREE II format. Guidance is meant to be used as a reference rather than for rigid protocol-based care as we understand that management of patients often requires individual patient-centred considerations.

Primary sclerosing cholangitis.

Primary sclerosing cholangitis is a rare, chronic cholestatic liver disease characterised by intrahepatic or extrahepatic stricturing, or both, with bile duct fibrosis. Inflammation and fibrosis of bile ducts and the liver are followed by impaired bile formation or flow and progressive liver dysfunction. Patients might be asymptomatic at presentation or might have pruritus, fatigue, right upper quadrant pain, recurrent cholangitis, or sequelae of portal hypertension. The key diagnostic elements are cholestatic liver biochemistry and bile duct stricturing on cholangiography. Genetic and environmental factors are important in the cause of the disease, with the intestinal microbiome increasingly thought to play a pathogenetic role. Approximately 70% of patients have concurrent inflammatory bowel disease and patients require colonoscopic screening and surveillance. Primary sclerosing cholangitis is associated with increased malignancy risk and surveillance strategies for early cholangiocarcinoma detection are limited. No single drug has been proven to improve transplant-free survival. Liver transplantation is effective for advanced disease but at least 25% of patients develop recurrent disease in the graft.

The British Society of Gastroenterology/UK-PBC primary biliary cholangitis treatment and management guidelines.

Primary biliary cholangitis (formerly known as primary biliary cirrhosis, PBC) is an autoimmune liver disease in which a cycle of immune mediated biliary epithelial cell injury, cholestasis and progressive fibrosis can culminate over time in an end-stage biliary cirrhosis. Both genetic and environmental influences are presumed relevant to disease initiation. PBC is most prevalent in women and those over the age of 50, but a spectrum of disease is recognised in adult patients globally; male sex, younger age at onset (<45) and advanced disease at presentation are baseline predictors of poorer outcome. As the disease is increasingly diagnosed through the combination of cholestatic serum liver tests and the presence of antimitochondrial antibodies, most presenting patients are not cirrhotic and the term cholangitis is more accurate. Disease course is frequently accompanied by symptoms that can be burdensome for patients, and management of patients with PBC must address, in a life-long manner, both disease progression and symptom burden. Licensed therapies include ursodeoxycholic acid (UDCA) and obeticholic acid (OCA), alongside experimental new and re-purposed agents. Disease management focuses on initiation of UDCA for all patients and risk stratification based on baseline and on-treatment factors, including in particular the response to treatment. Those intolerant of treatment with UDCA or those with high-risk disease as evidenced by UDCA treatment failure (frequently reflected in trial and clinical practice as an alkaline phosphatase >1.67 × upper limit of normal and/or elevated bilirubin) should be considered for second-line therapy, of which OCA is the only currently licensed National Institute for Health and Care Excellence recommended agent. Follow-up of patients is life-long and must address treatment of the disease and management of associated symptoms.

Liver toxicity associated with sofosbuvir, an NS5A inhibitor and ribavirin use.

Hepatitis C virus (HCV) infection is a major cause of end-stage liver disease and hepatocellular carcinoma. There have been rapid advances in HCV treatment with the development of oral direct-acting antivirals (DAAs). Studies have shown sustained virological response rates above 90% with combinations of DAAs, including patients with compensated cirrhosis. Thus far, significant drug toxicity has not been seen with these agents, but there is limited experience of using DAAs in decompensated HCV cirrhosis. This report describes the first experience of serious drug-induced hepatotoxicity with the new DAAs. The mechanism underlying these drug reactions is currently unknown. Few patients with decompensated cirrhosis have been treated with DAAs, so the exact pharmacokinetics in this population have not been characterised. In both cases presented here, patients were taking or had recently taken other drugs. It is possible that an unknown interaction or reaction to the drug combination caused the hepatotoxicity. Although the association with the DAAs is not proven these cases indicate that patients with advanced liver disease need close monitoring while on DAA therapy and if there is a significant unexplained deterioration in liver function the DAAs should be discontinued.

Long-Term Fenofibrate Treatment in Primary Biliary Cholangitis Improves Biochemistry but Not the UK-PBC Risk Score.

BACKGROUND: Fenofibrate (FF) has been suggested as a second-line agent in primary biliary cholangitis (PBC) patients who do not achieve adequate biochemical response to ursodeoxycholic acid (UDCA) monotherapy. Limited data exist on FF use beyond 12 months, and its long-term effects are unclear. AIM: To study the biochemical outcome of long-term (>12 months) FF treatment in combination with UDCA (FF + UDCA) in PBC patients and to determine the effect on predicted prognosis using the UK-PBC Risk Score. METHODS: This was a retrospective cohort study of all PBC patients treated in a specialist center with FF + UDCA therapy after failure to achieve biochemical response. Liver and renal biochemical indices and the UK-PBC Risk Score at baseline and at 12, 24, 36, 48, and 60 months of FF + UDCA treatment were compared. Biochemical response was assessed using the POISE trial criteria at the end of FF + UDCA treatment. RESULTS: Data from 23 patients treated with FF + UDCA combination were analyzed. The median dose of fenofibrate was 200 mg/day, and median treatment duration was 21 months (range 1-123 months). Six (26 %) patients discontinued FF within 1 year. In patients who completed 12 months (n = 17) and long-term therapy, significant decrease in ALP was seen at 12 (p = 0.0002), 24 (p = 0.002), and 36 (p = 0.03) months. More than 75 % patients met the POISE criteria of ALP response at all study time points. There was no significant improvement in the 5-, 10-, and 15-year UK-PBC Risk Scores after FF + UDCA treatment. No significant renal impairment or adverse events were reported. CONCLUSION: The long-term treatment of PBC patients with fenofibrate as an adjunct to UDCA is safe and effective in improving ALP, but the treatment did not significantly reduce the estimated probability of liver-related death or need for liver transplantation.

Unmet clinical need in autoimmune liver diseases.

Despite recent advances in understanding and treatment, there remain significant areas of unmet clinical need in each of the autoimmune liver diseases (AILDs). The evolving research landscape and emerging large patient cohorts are creating unique opportunities to translate science into new therapies and care pathways, with the potential to significantly improve the lives of AILD patients. However, the areas of unmet need represent real challenges, which need to be addressed, if this vision is to be realised. This review describes the areas of unmet need in AILD in adults relating to diagnostic and prognostic assessment, primary therapy, symptom management, trial design and delivery, and structured care delivery, with the aim of focusing future research prioritisation.

Fatigue in primary sclerosing cholangitis is associated with sympathetic over-activity and increased cardiac output.

BACKGROUND & AIMS: Patients with primary sclerosing cholangitis (PSC) frequently highlight the impact of fatigue on their life quality. The study aims were to evaluate fatigue and its associations in PSC and investigate whether overt autonomic dysfunction contributes to the expression of fatigue. METHODS: All PSC patients under active follow-up at a regional liver centre were sent disease- and symptom-assessment tools. Three control groups were utilized; unselected community controls, patients with inflammatory bowel disease (IBD) without PSC, and cholestatic controls with primary biliary cirrhosis (PBC). A representative subgroup of PSC patients and normal controls underwent formal autonomic assessment. RESULTS: Symptom-assessment tools were returned by 40 non-transplanted patients. PSC patients had significantly worse fatigue than population controls (P = 0.005). Fatigue was significant compared to population controls whether or not patients had accompanying IBD, although was more marked in those with both PSC and IBD. In patients with PSC and IBD, fatigue severity and autonomic symptoms were significantly increased in those with prior significant surgical intervention. Clinically significant autonomic dysfunction was seen in 22.5% of PSC patients, and of those, 78% had significant fatigue. Neurally mediated hypotension was found in 60% of PSC patients compared to 8% in the control group. The PSC group had increased sympathetic activity and reduced parasympathetic activity. CONCLUSION: Fatigue is a significant problem in a minority of PSC patients and appears to be associated with autonomic dysfunction. Fatigued PSC patients should be screened for autonomic dysfunction and targeting such dysfunction represents a potential approach to treatment which warrants further exploration.

The new epidemiology of primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is an autoimmune cholestatic liver disease. Susceptibility to PBC probably arises from a combination of genetic and environmental factors. The prevalence of PBC varies both on an international and a regional level. This can be explained, in part, by differences in clinical practice and case-finding activity. It is likely, however, that substantive geographical differences exist both in terms of genetic susceptibility and environmental factors that potentially trigger the disease in genetically susceptible individuals. The study of the epidemiology of PBC has strongly supported the concept of an environmental triggering factor, but as yet no specific agent has been identified. Ongoing work to discover the environmental agent, as well as the mechanism that causes the disease will answer key questions as to the epidemiology of this complex autoimmune disease as well as providing useful information for other autoimmune conditions.

Prior hysterectomy and discomfort during colonoscopy: a retrospective cohort analysis.

BACKGROUND AND STUDY AIMS: Discomfort during colonoscopy may affect acceptability of the procedure. The study aim was to determine factors, including prior hysterectomy and gender, associated with higher levels of patient discomfort during colonoscopy to help with procedural planning such as choice of instrument and sedation. METHODS: A retrospective cohort study of colonoscopies (n = 1098) performed between February 2007 and March 2012 at the Tees Bowel Cancer Screening Centre within the English Bowel Cancer Screening Programme (BCSP). Determinants of moderate/severe discomfort assessed using the Gloucester Scale were explored, using logistic regression with a range of participant and procedural variables. RESULTS: Rates of moderate/severe discomfort varied significantly among men, women without hysterectomy, and women with hysterectomy (5.8 %, 10.4 %, and 17.8 %, respectively; P < 0.001). In an unadjusted model, women with hysterectomy were significantly more likely to experience moderate/severe discomfort than those without (odds ratio [OR]1.87, 95 % confidence interval [95 %CI] 1.05 - 3.32, P = 0.005). The very strong influence of sedation on discomfort level precluded an adjusted model. In subgroup analysis of participants receiving sedation, adjusted comparison again showed increased odds for moderate/severe discomfort for women with hysterectomy, compared with women without (OR 1.70, 95 %CI 1.03 - 2.80, P = 0.036). CONCLUSIONS: Prior hysterectomy is associated with greater levels of moderate/severe discomfort in women undergoing colonoscopy. Minimizing participant discomfort is desirable in any screening or surveillance program. This should be considered in preprocedural counseling and in selecting equipment, sedation, and analgesia. Further studies should examine methods to minimize discomfort in those with prior hysterectomy.

Network proximity analysis as a theoretical model for identifying potential novel therapies in primary sclerosing cholangitis.

Primary Sclerosing Cholangitis (PSC) is a progressive cholestatic liver disease with no licensed therapies. Previous Genome Wide Association Studies (GWAS) have identified genes that correlate significantly with PSC, and these were identified by systematic review. Here we use novel Network Proximity Analysis (NPA) methods to identify already licensed candidate drugs that may have an effect on the genetically coded aspects of PSC pathophysiology.Over 2000 agents were identified as significantly linked to genes implicated in PSC by this method. The most significant results include previously researched agents such as metronidazole, as well as biological agents such as basiliximab, abatacept and belatacept. This in silico analysis could potentially serve as a basis for developing novel clinical trials in this rare disease.

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.

Bacterial and metabolic phenotypes associated with inadequate response to ursodeoxycholic acid treatment in primary biliary cholangitis.

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease with ursodeoxycholic acid (UDCA) as first-line treatment. Poor response to UDCA is associated with a higher risk of progressing to cirrhosis, but the underlying mechanisms are unclear. UDCA modulates the composition of primary and bacterial-derived bile acids (BAs). We characterized the phenotypic response to UDCA based on BA and bacterial profiles of PBC patients treated with UDCA. Patients from the UK-PBC cohort (n = 419) treated with UDCA for a minimum of 12-months were assessed using the Barcelona dynamic response criteria. BAs from serum, urine, and feces were analyzed using Ultra-High-Performance Liquid Chromatography-Mass Spectrometry and fecal bacterial composition measured using 16S rRNA gene sequencing. We identified 191 non-responders, 212 responders, and a subgroup of responders with persistently elevated liver biomarkers (n = 16). Responders had higher fecal secondary and tertiary BAs than non-responders and lower urinary bile acid abundances, with the exception of 12-dehydrocholic acid, which was higher in responders. The sub-group of responders with poor liver function showed lower alpha-diversity evenness, lower abundance of fecal secondary and tertiary BAs than the other groups and lower levels of phyla with BA-deconjugation capacity (Actinobacteriota/Actinomycetota, Desulfobacterota, Verrucomicrobiota) compared to responders. UDCA dynamic response was associated with an increased capacity to generate oxo-/epimerized secondary BAs. 12-dehydrocholic acid is a potential biomarker of treatment response. Lower alpha-diversity and lower abundance of bacteria with BA deconjugation capacity might be associated with an incomplete response to treatment in some patients.