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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.
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Colangitis Esclerosante , Colangitis Esclerosante/tratamiento farmacológico , Colangitis Esclerosante/genética , Humanos , Estudio de Asociación del Genoma Completo , Modelos TeóricosRESUMEN
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.
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Diagnóstico por Imagen de Elasticidad , Cirrosis Hepática , Humanos , Femenino , Masculino , Persona de Mediana Edad , Cirrosis Hepática/patología , Diagnóstico por Imagen de Elasticidad/métodos , Anciano , Adulto , Índice de Severidad de la Enfermedad , Hígado Graso/patología , Adulto Joven , Algoritmos , Biopsia/métodos , Enfermedad del Hígado Graso no Alcohólico/patología , Hígado/patologíaRESUMEN
BACKGROUND & AIMS: Recurrent primary biliary cholangitis (rPBC) develops in approximately 30% of patients and negatively impacts graft and overall patient survival after liver transplantation (LT). There is a lack of data regarding the response rate to ursodeoxycholic acid (UDCA) in rPBC. We evaluated a large, international, multi-center cohort to assess the performance of PBC scores in predicting the risk of graft and overall survival after LT in patients with rPBC. METHODS: A total of 332 patients with rPBC after LT were evaluated from 28 centers across Europe, North and South America. The median age at the time of rPBC was 58.0 years [IQR 53.2-62.6], and 298 patients (90%) were female. The biochemical response was measured with serum levels of alkaline phosphatase (ALP) and bilirubin, and Paris-2, GLOBE and UK-PBC scores at 1 year after UDCA initiation. RESULTS: During a median follow-up of 8.7 years [IQR 4.3-12.9] after rPBC diagnosis, 52 patients (16%) had graft loss and 103 (31%) died. After 1 year of UDCA initiation the histological stage at rPBC (hazard ratio [HR] 3.97, 95% CI 1.36-11.55, p = 0.01), use of prednisone (HR 3.18, 95% CI 1.04-9.73, p = 0.04), ALP xULN (HR 1.59, 95% CI 1.26-2.01, p <0.001), Paris-2 criteria (HR 4.14, 95% CI 1.57-10.92, p = 0.004), GLOBE score (HR 2.82, 95% CI 1.71-4.66, p <0.001), and the UK-PBC score (HR 1.06, 95% CI 1.03-1.09, p <0.001) were associated with graft survival in the multivariate analysis. Similar results were observed for overall survival. CONCLUSION: Patients with rPBC and disease activity, as indicated by standard PBC risk scores, have impaired outcomes, supporting efforts to treat recurrent disease in similar ways to pre-transplant PBC. IMPACT AND IMPLICATIONS: One in three people who undergo liver transplantation for primary biliary cholangitis develop recurrent disease in their new liver. Patients with recurrent primary biliary cholangitis and incomplete response to ursodeoxycholic acid, according to conventional prognostic scores, have worse clinical outcomes, with higher risk of graft loss and mortality in similar ways to the disease before liver transplantation. Our results supportsupport efforts to treat recurrent disease in similar ways to pre-transplant primary biliary cholangitis.
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INTRODUCTION: Pruritus is common and often undertreated in patients with primary biliary cholangitis (PBC). Existing treatments largely have an aging and low-quality evidence base, and studies included only small numbers of patients. More recent data that has added to our understanding of pruritus treatments has often come from clinical trials where itching was a secondary outcome measure in a trial designed primarily to assess disease-modifying agents. This area represents an unmet clinical need in the management of PBC. AREAS COVERED: In this manuscript, we first summarize the proposed mechanisms for PBC-related pruritus and the current treatment paradigm. We then present an appraisal of the existing pre-clinical and clinical evidence for the use of ileal bile acid transporter inhibitors (IBATis) for this indication in PBC patients. EXPERT OPINION: Evidence for the efficacy of IBATis is promising but limited by the currently available volume of data. Furthermore, larger clinical trials with long-term data on efficacy, safety and tolerability are needed to confirm the role of using IBATis in clinical practice and their place on the itch treatment ladder. Additional focus should also be given to exploring the disease-modifying potential of IBATis in PBC.
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Desarrollo de Medicamentos , Cirrosis Hepática Biliar , Transportadores de Anión Orgánico Sodio-Dependiente , Prurito , Humanos , Prurito/tratamiento farmacológico , Animales , Cirrosis Hepática Biliar/tratamiento farmacológico , Cirrosis Hepática Biliar/fisiopatología , Transportadores de Anión Orgánico Sodio-Dependiente/antagonistas & inhibidores , Simportadores/antagonistas & inhibidoresRESUMEN
Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease. The management landscape was transformed 20 years ago with the advent of ursodeoxycholic acid. Up to 40% of patients do not, however, respond adequately to ursodeoxycholic acid and therefore still remain at risk of disease progression to cirrhosis. The introduction of obeticholic acid as a second-line therapy for patients failing ursodeoxycholic acid has improved outcomes for patients with PBC. There remains, however, a need for better treatment for patients at higher risk. The greatest threat facing our efforts to improve treatment in PBC is, paradoxically, the regulatory approval model providing conditional marketing authorization for new drugs based on biochemical markers on the condition that long-term, randomized placebo-controlled outcome trials are performed to confirm efficacy. As demonstrated by the COBALT confirmatory study with obeticholic acid, it is difficult to retain patients in the required follow-on confirmatory placebo-controlled PBC outcome trials when a licensed drug is commercially available. New PBC therapies in development, such as the peroxisome proliferator-activated receptor agonists, face even greater challenges in demonstrating outcome benefit through randomized placebo-controlled studies once following conditional marketing authorization, as there will be even more treatment options available. A recently published EMA Reflection Paper provides some guidance on the regulatory pathway to full approval but fails to recognize the importance of real-world data in providing evidence of outcome benefit in rare diseases. Here we explore the impact of the EMA reflection paper on PBC therapy and offer pragmatic solutions for generating evidence of long-term outcomes through real-world data collection.
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BACKGROUND AND AIMS: Normal alkaline phosphatase (ALP) levels in ursodeoxycholic acid (UDCA)-treated patients with primary biliary cholangitis (PBC) are associated with better long-term outcome. However, second-line therapies are currently recommended only when ALP levels remain above 1.5 times the upper limit of normal (×ULN) after 12-month UDCA. We assessed whether, in patients considered good responders to UDCA, normal ALP levels were associated with significant survival gains. APPROACH AND RESULTS: We performed a retrospective cohort study of 1047 patients with PBC who attained an adequate response to UDCA according to Paris-2 criteria. Time to liver-related complications, liver transplantation, or death was assessed using adjusted restricted mean survival time (RMST) analysis. The overall incidence rate of events was 17.0 (95% CI: 13.7-21.1) per 1000 out of 4763.2 patient-years. On the whole population, normal serum ALP values (but not normal gamma-glutamyl transpeptidase (GGT), alanine aminotransferase (ALT), or aspartate aminotransferase (AST); or total bilirubin < 0.6 ×ULN) were associated with a significant absolute complication-free survival gain at 10 years (mean 7.6 months, 95% CI: 2.7 - 12.6 mo.; p = 0.003). In subgroup analysis, this association was significant in patients with a liver stiffness measurement ≥ 10 kPa and/or age ≤ 62 years, with a 10-year absolute complication-free survival gain of 52.8 months (95% CI: 45.7-59.9, p < 0.001) when these 2 conditions were met. CONCLUSIONS: PBC patients with an adequate response to UDCA and persistent ALP elevation between 1.1 and 1.5 ×ULN, particularly those with advanced fibrosis and/or who are sufficiently young, remain at risk of poor outcome. Further therapeutic efforts should be considered for these patients.
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Cirrosis Hepática Biliar , Ácido Ursodesoxicólico , Humanos , Persona de Mediana Edad , Ácido Ursodesoxicólico/uso terapéutico , Cirrosis Hepática Biliar/complicaciones , Cirrosis Hepática Biliar/tratamiento farmacológico , Fosfatasa Alcalina , Colagogos y Coleréticos/uso terapéutico , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
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.
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Microbioma Gastrointestinal , Cirrosis Hepática Biliar , Humanos , Ácido Ursodesoxicólico/uso terapéutico , Cirrosis Hepática Biliar/tratamiento farmacológico , Ácido Deshidrocólico/uso terapéutico , ARN Ribosómico 16S/genética , Colagogos y Coleréticos/uso terapéutico , Ácidos y Sales Biliares/uso terapéutico , Biomarcadores , Fenotipo , Bacterias/genéticaRESUMEN
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.
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Colangitis , Cirrosis Hepática Biliar , Humanos , Ácido Ursodesoxicólico/uso terapéutico , Cirrosis Hepática Biliar/tratamiento farmacológico , Fosfatasa Alcalina , Alanina Transaminasa , Ácidos Fíbricos/uso terapéutico , Bilirrubina , Colangitis/tratamiento farmacológicoRESUMEN
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.
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Hepatitis Autoinmune , Humanos , Femenino , Persona de Mediana Edad , Masculino , Hepatitis Autoinmune/tratamiento farmacológico , Encuestas y Cuestionarios , Calidad de Vida , Participación del Paciente , Investigación CualitativaRESUMEN
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.
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Colestasis , Memoria a Corto Plazo , Humanos , Ratones , Animales , Colestasis/tratamiento farmacológico , Ácido Quenodesoxicólico/farmacología , Conductos Biliares/cirugía , Hígado , LigaduraRESUMEN
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.
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Cirrosis Hepática Biliar , Neuroesteroides , Receptores de GABA-A , Humanos , Cirrosis Hepática Biliar/complicaciones , Cirrosis Hepática Biliar/tratamiento farmacológico , Neuroesteroides/farmacología , Neuroesteroides/uso terapéutico , Pregnanolona/farmacología , Pregnanolona/uso terapéutico , Calidad de Vida , Receptores de GABA-A/efectos de los fármacosRESUMEN
INTRODUCTION: Generic fibrates are used off-label as add-in therapy for the management of primary biliary cholangitis (PBC) but with unproven long-term liver-related survival benefits. The recently developed fibrate, seladelpar, has shown promising results in clinical trials, but these outcomes have been previously marred by safety concerns. AREAS COVERED: We summarize existing treatment options in PBC and evaluate current trial data for seladelpar in relation to liver biochemistry, symptomology, and safety. EXPERT OPINION: Seladelpar leads to marked improvement in liver biochemistry and may improve symptoms. Safety concerns around liver toxicity appear to have been addressed. With likely increasing evidence compared to existing off-label fibrates, seladelpar has the potential as an attractive future second-line agent in PBC.
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Acetatos , Drogas en Investigación , Cirrosis Hepática Biliar , Humanos , Acetatos/efectos adversos , Drogas en Investigación/efectos adversos , Cirrosis Hepática Biliar/tratamiento farmacológico , Ensayos Clínicos como AsuntoRESUMEN
INTRODUCTION: Symptomatic umbilical hernias are a common cause of morbidity and mortality in patients with cirrhosis and end-stage liver disease (ESLD). This study set out to characterise the factors predicting outcome following repair of symptomatic umbilical hernias in ESLD at a single institution. METHODS: A retrospective review was performed of all patients with ESLD who underwent repair of a symptomatic umbilical hernia between 1998 and 2020. Overall survival was predicted using the Kaplan-Meier method. Logistic regression was used to determine predictors of decompensation and 30-day, 90-day and 1-year mortality. RESULTS: One-hundred-and-eight patients with ESLD underwent umbilical hernia repair (emergency n = 78, 72.2%). Transjugular shunting was performed in 29 patients (26.9%). Decompensation occurred in 44 patients (40.7%) and was predicted by emergency surgery (OR, 13.29; P = 0.001). Length of stay was shorter in elective patients compared to emergency patients (3-days vs. 7-days; P = 0.003). Thirty-day, 90-day and 1-year survival was 95.2, 93.2 and 85.4%, respectively. Model for ESLD score >15 predicted 90-day mortality (OR, 18.48; P = 0.030) and hyponatraemia predicted 1-year mortality (OR, 5.31; P = 0.047). Transjugular shunting predicted survival at 1 year (OR, 0.15; P = 0.038). CONCLUSIONS: Repair of symptomatic umbilical hernias in patients with ESLD can be undertaken with acceptable outcomes in a specialist centre, however, this remains a high-risk intervention. Patients undergoing emergency repair are more likely to decompensate postoperatively, develop wound-related problems and have a longer length of stay. Transjugular shunting may confer a benefit to survival, but further prospective trials are warranted.
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Enfermedad Hepática en Estado Terminal , Hernia Umbilical , Procedimientos Quirúrgicos Electivos/efectos adversos , Procedimientos Quirúrgicos Electivos/métodos , Enfermedad Hepática en Estado Terminal/complicaciones , Enfermedad Hepática en Estado Terminal/diagnóstico , Enfermedad Hepática en Estado Terminal/cirugía , Hernia Umbilical/etiología , Hernia Umbilical/cirugía , Humanos , Estudios Retrospectivos , Factores de RiesgoRESUMEN
A woman in her 50s was referred to nephrology clinic due to progressive chronic kidney disease. She exhibited features of proximal renal tubulopathy, namely Fanconi syndrome, including normoglycaemic glycosuria, normal anion gap metabolic acidosis, and intermittent hypouricaemia and hypophosphataemia. Kidney biopsy showed tubulointerstitial inflammation and focal chronic damage. In addition, antimitochondrial antibodies were present and she had abnormal liver blood tests. A unifying diagnosis of primary biliary cholangitis with an associated renal tubulopathy and interstitial nephritis was made. She was commenced on sodium bicarbonate, ursodeoxycholic acid and oral prednisolone, leading to an improvement in liver biochemistry. Kidney function was stabilised, but a sustained improvement was not seen. This case acts as a reminder of the rare association of tubulointerstitial nephritis and Fanconi syndrome with primary biliary cholangitis, which may be an under-recognised phenotype.
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Síndrome de Fanconi , Cirrosis Hepática Biliar , Nefritis Intersticial , Síndrome de Fanconi/complicaciones , Síndrome de Fanconi/diagnóstico , Síndrome de Fanconi/patología , Femenino , Humanos , Cirrosis Hepática Biliar/complicaciones , Cirrosis Hepática Biliar/diagnóstico , Cirrosis Hepática Biliar/tratamiento farmacológico , Nefritis Intersticial/diagnóstico , Nefritis Intersticial/tratamiento farmacológico , Nefritis Intersticial/etiología , Fenotipo , Ácido Ursodesoxicólico/uso terapéuticoRESUMEN
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.
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Diagnóstico por Imagen de Elasticidad , Cirrosis Hepática Biliar , Humanos , Cirrosis Hepática Biliar/diagnóstico por imagen , Cirrosis Hepática Biliar/patología , Estudios Retrospectivos , Hígado/diagnóstico por imagen , Hígado/patología , Vibración , Estudios de Cohortes , Estudios de Seguimiento , Pronóstico , Cirrosis Hepática/patologíaRESUMEN
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.
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Cirrosis Hepática Biliar , Ácido Ursodesoxicólico , Fosfatasa Alcalina , Bilirrubina , Colagogos y Coleréticos/uso terapéutico , Estudios de Cohortes , Humanos , Cirrosis Hepática Biliar/diagnóstico , Cirrosis Hepática Biliar/tratamiento farmacológico , Resultado del Tratamiento , Ácido Ursodesoxicólico/uso terapéuticoRESUMEN
BACKGROUND: Northern England has been experiencing a persistent rise in the number of primary liver cancers, largely driven by an increasing incidence of hepatocellular carcinoma (HCC) secondary to alcohol-related liver disease and non-alcoholic fatty liver disease. Here we review the effect of the COVID-19 pandemic on primary liver cancer services and patients in our region. OBJECTIVE: To assess the impact of the COVID-19 pandemic on patients with newly diagnosed liver cancer in our region. DESIGN: We prospectively audited our service for the first year of the pandemic (March 2020-February 2021), comparing mode of presentation, disease stage, treatments and outcomes to a retrospective observational consecutive cohort immediately prepandemic (March 2019-February 2020). RESULTS: We observed a marked decrease in HCC referrals compared with previous years, falling from 190 confirmed new cases to 120 (37%). Symptomatic became the the most common mode of presentation, with fewer tumours detected by surveillance or incidentally (% surveillance/incidental/symptomatic; 34/42/24 prepandemic vs 27/33/40 in the pandemic, p=0.013). HCC tumour size was larger in the pandemic year (60±4.6 mm vs 48±2.6 mm, p=0.017), with a higher incidence of spontaneous tumour haemorrhage. The number of new cases of intrahepatic cholangiocarcinoma (ICC) fell only slightly, with symptomatic presentation typical. Patients received treatment appropriate for their cancer stage, with waiting times shorter for patients with HCC and unchanged for patients with ICC. Survival was associated with stage both before and during the pandemic. 9% acquired COVID-19 infection. CONCLUSION: The pandemic-associated reduction in referred patients in our region was attributed to the disruption of routine healthcare. For those referred, treatments and survival were appropriate for their stage at presentation. Non-referred or missing patients are expected to present with more advanced disease, with poorer outcomes. While protective measures are necessary during the pandemic, we recommend routine healthcare services continue, with patients encouraged to engage.
Asunto(s)
COVID-19 , Carcinoma Hepatocelular , Neoplasias Hepáticas , COVID-19/epidemiología , Carcinoma Hepatocelular/epidemiología , Humanos , Neoplasias Hepáticas/epidemiología , Pandemias , Estudios RetrospectivosRESUMEN
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.
Asunto(s)
Autoanticuerpos/sangre , Hepatitis Autoinmune/diagnóstico , Inmunoglobulina G/sangre , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Diagnóstico Diferencial , Femenino , Hepatitis Autoinmune/sangre , Hepatitis Autoinmune/inmunología , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is common and is associated with liver-related and cardiovascular-related morbidity. Our aims were: (1) to review the current management of patients with NAFLD attending hospital clinics in North East England (NEE) and assess the variability in care; (2) develop a NAFLD 'care bundle' to standardise care; (3) to assess the impact of implementation of the NAFLD care bundle. METHODS: A retrospective review was conducted to determine baseline management of patients with NAFLD attending seven hospitals in NEE. A care bundle for the management of NAFLD was developed including important recommendations from international guidelines. Impact of implementation of the bundle was evaluated prospectively in a single centre. RESULTS: Baseline management was assessed in 147 patients attending gastroenterology, hepatology and a specialist NAFLD clinic. Overall, there was significant variability in the lifestyle advice given and management of metabolic risk factors, with patients attending an NAFLD clinic significantly more likely to achieve >10% body weight loss and have metabolic risk factors addressed. Following introduction of the NAFLD bundle 50 patients were evaluated. Use of the bundle was associated with significantly better documentation and implementation of most aspects of patient management including management of metabolic risk factors, documented lifestyle advice and provision of NAFLD-specific patient advice booklets. CONCLUSION: The introduction of an outpatient 'care bundle' led to significant improvements in the assessment and management of patients with NAFLD in the NEE and could help improve and standardise care if used more widely.