Pharmacotherapy for primary biliary cholangitis: an assessment of medication candidacy and rates of treatment.

BACKGROUND: Ursodeoxycholic acid is the preferred first-line therapy for primary biliary cholangitis. Alternative therapies, such as obeticholic acid, are recommended for patients who cannot tolerate ursodeoxycholic acid or who have an inadequate response to ursodeoxycholic acid monotherapy. Prior investigations have suggested that as many as 30% of patients with primary biliary cholangitis may have never received treatment with ursodeoxycholic acid. No prior investigations have examined usage rates of obeticholic acid in the treatment of primary biliary cholangitis. METHODS: All patients with an ICD-10 diagnosis of primary biliary cholangitis who had any records within the health system were included. A review of medical records was performed to confirm the diagnosis of primary biliary cholangitis and determine which medications had been prescribed for treatment, as well as candidacy for second-line therapies. RESULTS: A total of 495 patients met inclusion criteria. Notably, 95% of patients were taking ursodeoxycholic acid for treatment of their primary biliary cholangitis, with 67% of patients having disease that was well-controlled on ursodeoxycholic acid monotherapy. In total, 8% of patients were taking obeticholic acid (either as combination or monotherapy). Only 3% would benefit from the addition of a second line therapy but had not yet been offered medication. Only 3% of patients were not on any medication for management of their primary biliary cholangitis. CONCLUSIONS: Ursodeoxycholic acid is a readily available and generally well-tolerated medication that should be offered to all patients with primary biliary cholangitis as first-line therapy. While prior investigations have suggested that up to 30% of patients with primary biliary cholangitis may never have received treatment for the disorder, the present study suggests that patients are generally being managed according to guidelines. Moreover, a significant proportion of patients with primary biliary cholangitis will qualify for second line therapies and prescribers should be aware of the indications to use these medications.

Machine-Learning-Guided Engineering of an NADH-Dependent 7ß-Hydroxysteroid Dehydrogenase for Economic Synthesis of Ursodeoxycholic Acid.

Enzymatic synthesis of ursodeoxycholic acid (UDCA) catalyzed by an NADH-dependent 7ß-hydroxysteroid dehydrogenase (7ß-HSDH) is more economic compared with an NADPH-dependent 7ß-HSDH when considering the much higher cost of NADP+/NADPH than that of NAD+/NADH. However, the poor catalytic performance of NADH-dependent 7ß-HSDH significantly limits its practical applications. Herein, machine-learning-guided protein engineering was performed on an NADH-dependent Rt7ß-HSDHM0 from Ruminococcus torques. We combined random forest, Gaussian Naïve Bayes classifier, and Gaussian process regression with limited experimental data, resulting in the best variant Rt7ß-HSDHM3 (R40I/R41K/F94Y/S196A/Y253F) with improvements in specific activity and half-life (40 °C) by 4.1-fold and 8.3-fold, respectively. The preparative biotransformation using a "two stage in one pot" sequential process coupled with Rt7ß-HSDHM3 exhibited a space-time yield (STY) of 192 g L-1 d-1, which is so far the highest productivity for the biosynthesis of UDCA from chenodeoxycholic acid (CDCA) with NAD+ as a cofactor. More importantly, the cost of raw materials for the enzymatic production of UDCA employing Rt7ß-HSDHM3 decreased by 22% in contrast to that of Rt7ß-HSDHM0, indicating the tremendous potential of the variant Rt7ß-HSDHM3 for more efficient and economic production of UDCA.

Clostridium butyricum Strain CCFM1299 Reduces Obesity via Increasing Energy Expenditure and Modulating Host Bile Acid Metabolism.

Clostridium butyricum is a butyrate-producing microorganism which has beneficial effects on various diseases, including obesity. In our previous study, the anti-obesity Clostridium butyricum strain CCFM1299 (C20_1_1) was selected, but its anti-obesity mechanism was not clarified. Herein, CCFM1299 was orally administrated to high-fat-diet-treated C57BL/6J mice for 12 weeks to uncover the way the strain alleviates obesity. The results indicated that CCFM1299 alleviated obesity through increasing the energy expenditure and increasing the expression of genes related to thermogenesis in brown adipose tissue (BAT). Moreover, strain CCFM1299 could also affect the expression of immune-related genes in epididymal white adipose tissue (eWAT). This immunomodulatory effect might be achieved through its influence on the complement system, as the expression of the complement factor D (CFD) gene decreased significantly. From the view of metabolites, CCFM1299 administration increased the levels of ursodeoxycholic acid (UDCA) in feces and taurohyodeoxycholic acid (THDCA) in serum. Together, the anti-obesity potential of CCFM1299 might be attributed to the increase in energy consumption, the regulation of immune-related gene expression in eWAT, and the alteration of bile acid metabolism in the host. These provided new insights into the potential application of anti-obesity microbial preparations and postbiotics.

Cost-effectiveness of ursodeoxycholic acid in preventing new-onset symptomatic gallstone disease after Roux-en-Y gastric bypass surgery.

BACKGROUND: The aim was to evaluate the cost-effectiveness and cost-utility of ursodeoxycholic acid (UDCA) prophylaxis for the prevention of symptomatic gallstone disease after Roux-en-Y gastric bypass (RYGB) in patients without gallstones before surgery. METHODS: Data from a multicentre, double-blind, randomized placebo-controlled superiority trial were used. Patients scheduled for laparoscopic RYGB or sleeve gastrectomy were randomized to receive 900 mg UDCA or placebo for 6 months. Indicated by the clinical report, prophylactic prescription of UDCA was evaluated economically against placebo from a healthcare and societal perspective for the subgroup of patients without gallstones before surgery who underwent RYGB. Volumes and costs of in-hospital care, out-of-hospital care, out-of-pocket expenses, and productivity loss were assessed. Main outcomes were the costs per patient free from symptomatic gallstone disease and the costs per quality-adjusted life-year (QALY). RESULTS: Patients receiving UDCA prophylaxis were more likely to remain free from symptomatic gallstone disease (relative risk 1.06, 95 per cent c.i. 1.02 to 1.11; P = 0.002) compared with patients in the placebo group. The gain in QALYs, corrected for a baseline difference in health utility, was 0.047 (95 per cent bias-corrected and accelerated (Bca) c.i. 0.007 to 0.088) higher (P = 0.022). Differences in costs were -€356 (95 per cent Bca c.i. €-1573 to 761) from a healthcare perspective and -€1392 (-3807 to 917) from a societal perspective including out-of-pocket expenses and productivity loss, both statistically non-significant, in favour of UDCA prophylaxis. The probability of UDCA prophylaxis being cost-effective was at least 0.872. CONCLUSION: UDCA prophylaxis after RYGB in patients without gallstones before surgery was cost-effective.

Simplified care-pathway selection for nonspecialist practice: the GLOBAL Primary Biliary Cholangitis Study Group Age, Bilirubin, Alkaline phosphatase risk assessment tool.

BACKGROUND: Opportunity to redefine the care journeys for those living with primary biliary cholangitis (PBC) includes facilitating access to enhanced (PBC-dedicated) programmes by nonspecialist risk 'flagging' of patients. OBJECTIVE: To develop a nonexpert PBC stratification tool to help care pathway choices (standard vs. enhanced) choices in PBC. METHODS: We included ursodeoxycholic acid-treated patients with PBC from the Global PBC Study Group. The performance of baseline and 1-year clinical markers with transplant-free survival was assessed to develop the 'ABA' tool using Age (A), Bilirubin (B), and Alkaline phosphatase (A). Added value of fibrosis estimation was assessed. RESULTS: 'ABA' classification mapped three risk groups (n = 2226): low [Age > 50 years, bilirubin ≤ 1 × ULN, alkaline phosphatase (ALP) ≤ 3 × ULN], high (Age ≤ 50 years, bilirubin > 1 × ULN, ALP > 3 × ULN), and intermediate (other). Transplant-free survival at 10 years in the low-, intermediate-, and high-risk groups were 89, 77, and 59% at baseline and 86, 76, and 40% at 1 year, respectively. We propose that high-risk patients at baseline be directly triaged to enhanced (PBC-dedicated) care and the remaining be reassessed at 1 year. Modelling showed after 1 year 46% patients were proposed to enhanced care and 54% to standard care. The 'ABA' mapped pathways facilitated identification of patients at risk based on a young age, as compared to traditional liver biochemical stratification. In patients proposed to standard care, estimated fibrosis stage had ongoing prognostic value. CONCLUSION: Nonspecialist use of the 'ABA' risk tool could prioritize care journey choices for patients with PBC.

Veno-occlusive Disease in HSCT Patients: Consensus-based Recommendations for Risk Assessment, Diagnosis, and Management by the GITMO Group.

Variation in clinical practice affects veno-occlusive disease management, mainly in patients who undergo allogeneic hematopoietic stem cell transplantation. Disputes about diagnostic criteria, treatment, and prophylaxis, due to the lack of high-quality data, are at the base of this variability. With the aim of limiting inconsistency in clinical care, thus improving both patient outcomes and data collection reliability, the Italian Society of Stem cell transplant (Gruppo Italiano Trapianto Midollo Osseo e Terapia Cellulare) launched a collaborative effort to formulate recommendations based on integration of available evidence and expert's consensus. A systematic method, according to US National Institute of Health guidelines and Italian National System for Guidelines, was used. Twenty-nine recommendations were approved with a strong (20) or weak (9) level of agreement, while 26 were rejected. In particular, the panel pointed out the need to achieve an early diagnosis, encouraging the adoption of European Society for Blood and Marrow Transplantation criteria and the prompt use of ultrasonography. Moreover, our experts strongly recommended in favor of prophylactic use of ursodeoxycholic acid. As soon as a veno-occlusive disease diagnosis is established, treatment with defibrotide should be started for at least 21 days. A number of areas of uncertainty, particularly concerning risk stratification and use of diagnostic tools such as elastography has been identified and discussed.

A randomized crossover trial to assess therapeutic efficacy and cost reduction of acid ursodeoxycholic manufactured by the university hospital for the treatment of primary biliary cholangitis.

BACKGROUND: Health care costs are growing faster than the rest of the global economy, according to the World Health Organization (WHO). Countries' health expenditures include paying for general medicine, diagnostic procedures, hospitalizations and surgeries, as well as medications and prescribed treatment. Primary biliary cholangitis (PBC) is a rare autoimmune liver disease and the first line available treatment is ursodeoxycholic acid (UDCA), however, direct and indirect treatment costs are expensive. Main aim of this trial was to assess if the therapeutic efficacy of UDCA manufactured by the university hospital is equivalent to that of standard UDCA and treatment cost reduction in patients with PBC. METHODS: It is a prospective, interventional, randomized, and crossover study in patients diagnosed with PBC. UDCA 300 mg tablets and capsules were developed and manufactured by the university hospital. Thirty patients under treatment with standard UDCA, in stable doses were randomized in sequence A and B, 15 patients in each arm. The groups were treated for 12 weeks and after, the UDCA formulation was changed, following for another 12 weeks of continuous therapy (tablets and capsules / capsules and tablets). Laboratory tests were performed at time T0 (beginning of treatment), T1 (at the 12 week-therapy, before the crossing-over) and T2 (end of treatment). The evaluation was done by comparing the hepatic parameters ALP, GGT, ALT, AST and total bilirubin, also considering the adverse events. The comparison of costs was based on price of the manufactured UDCA and standard UDCA price of the hospital. RESULTS: Hospital reduced 66.1% the PBC treatment costs using manufactured UDCA. There were no differences in the biochemical parameters between sequence (A and B) and tablets or capsules of UDCA formulations applied in the treatment of PBC. CONCLUSIONS: The study showed that there was no significant difference between manufactured UDCA (capsule and tablet) and standard UDCA. Hospital reduced the PBC treatment costs using the manufactured UDCA by the university hospital. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03489889 retrospectively registered on January 12th, 2018; Ethics Committee approved the study (ID: 1.790.088) on October 25th, 2016.

Informe diário de evidências COVID-19: busca realizada em 11 de agosto de 2020 / COVID-19 daily evidence report: search conducted on August 11, 2020

O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referentes ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 14 artigos e 5 protocolos.

The value of routine laboratory screening in the neonatal intensive care unit.

BACKGROUND: Healthcare spending is expected to grow faster than the economy over the next decade, and the cost of prematurity increases annually. The aim of this study was to investigate the frequency of intervention after routine laboratory testing in preterm infants. METHODS: This was a retrospective study of preterm infants (≤34 weeks) admitted to the NYU Langone Health NICU from June 2013 to December 2014. Data collected included demographics, results of laboratory tests, and resulting interventions. Intervention after a hemogram was defined as a blood transfusion. Intervention after a hepatic panel was defined as initiation or termination of ursodiol or change in dose of vitamin D. Subjects were stratified into 3 groups based on gestation (<28 weeks, 28-31 6/7 weeks, 32-34 weeks). Chi-square analysis was used to compare the frequency of intervention between the groups. RESULTS: A total of 135 subjects were included in the study. The frequency of intervention after a hemogram was 8.4% in infants <28 weeks, 4.6% in infants 28-31 6/7 weeks, and 0% in infants 32-34 weeks; this difference was found to be statistically significant (p = 0.02). The frequency of intervention after a hepatic panel was 4.2% in infants <28 weeks, 5.7% in infants 28-31 6/7 weeks, and 0% in infants 32-34 weeks, which was not found to be a statistically significant different. CONCLUSION: No interventions were undertaken post-routine laboratory testing in any infant 32-34 weeks and routine testing in this population may be unnecessary. Further studies are needed to elucidate if routine testing affects neonatal outcomes.

Ácido ursodeoxicolico para la profilaxis de síndrome de obstrucción sinusoidal en pacientes post trasplante de células progenitoras hematopoyéticas / Ursodeoxycholic acid for the prophylaxis of sinusoidal obstruction syndrome in post-hematopoietic progenitor cell transplant patients

INTRODUCCIÓN: El síndrome de obstrucción sinusoidal (SOS) es una complicación potencialmente fatal que clásicamente se asocia al trasplante de células progenitoras hematopoyéticos (TPH). Otras causas identificadas son: Irradiación, administración de alcaloides de pirrolizidina presentes en plantas tipo crotalaria y senecio (tés de arbustos medicinales) y otras hierbas (p. ej., consuelda), otras hepatotoxinas (p. ej., dimetilnitrosamina, aflatoxina, azatioprina, algunos antineoplásicos). A. Cuadro clínico: Debido a la elevada morbilidad y mortalidad del SOS, y a los malos resultados obtenidos con la mayoría de las medidas terapéuticas empleadas, la prevención debe tener carácter prioritario. Las medidas preventivas deben dirigirse, en primer lugar, a reducir al máximo el impacto de los factores de riesgo modificables conocidos, siendo uno de éstos el ácido ursodesoxicólico (ursodeoxycholic acid, UDCA por sus siglas en inglés), entre otros. B. Tecnología sanitaria: El Ácido Ursodesoxicolico (UDCA) es un ácido biliar secundario endógeno altamente hidrofilico que interfiere en la suspensión de cristales de colesterol, bloqueando parcialmente su precipitación. Este acido biliar, no tóxico, presenta multiples actividades hepatoprotectoras, de las que destacan las propiedades citoprotectoras, antiapoptoticas e inmunomoduladoras, así como su efecto colerético. OBJETIVO: Evaluar la eficacia y seguridad, así como documentos relacionados a la decisión de cobertura del ácido ursodeoxicolico en la profilaxis de síndrome de obstrucción sinusoidal. METODOLOGÍA: Se realizó una búsqueda en las principales bases de datos bibliográficas: MEDLINE, LILACS, COCHRANE, así como en buscadores genéricos de Internet incluyendo Google Scholar y TRIPDATABASE. Adicionalmente, se hizo una búsqueda dentro de la información generada por las principales instituciones internacionales de enfermería y agencias de tecnologías sanitarias que realizan revisiones sistemáticas (RS), evaluación de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC). RESULTADOS: Se selecciono una RS y cuatro GPC, no se identificaron evaluaciones de tecnología sanitaria ni evaluaciones económicas de la región. CONCLUSIONES: La evidencia con respecto al ácido ursodeoxicolico en la profilaxis de síndrome de obstrucción sinusoidal es escasa. Basada en una revisión sistemática de ensayos clínicos aleatorizados de alta calidad metodológica, se muestra que UDCA podría prevenir la incidencia de SOS comparado con placebo, no profilaxis o heparina. Además, se encontraron resultados superiores para UDCA con respecto a la mortalidad post-transplante después de 100 días y la mortalidad asociada a SOS. No se encontraron diferencias en la sobrevida global a largo plazo con los mismos comparadores. Tres GPC recomiendan el uso de UDCA en profilaxis de SOS mientras que una GPC no lo recomienda. En general, las GPC que recomiendan UDCA lo hacen mostrando defibrótido como otra opción no preferente para la misma indicación en la profilaxis de SOS. No existen estudios de comparaciones directas o indirectas entre UDCA y defibrotido.

Assessment of selected parameters of placental microstructure in patients with intrahepatic cholestasis of pregnancy.

OBJECTIVES: Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disorder during pregnancy. Cholestasisis associated with increased risk of fetal complications: prematurity, perinatal hypoxia and meconium stained amnioticfluid, and sudden intrauterine fetal death. The exact mechanisms associated with cholestasis fetal sequelae are not fullyunderstood. The aim of the study was the histopathological evaluation of placentas from patients with cholestasis andhealthy pregnant women to establish whether cholestasis is accompanied by changes in placental microstructure. MATERIAL AND METHODS: The effect of cholestasis on placental microstructure was investigated using placental tissue frompatients with cholestatsis treated with ursodeoxycholic acid (UDCA) and from uncomplicated pregnancies. Five placentalhistopathological features were analyzed: number of syncytial knots, number of capillaries per villous, structure of stroma,presence of Hofbauer cells, and villitis of unknown etiology. RESULTS: There were no statistically significant differences in any of the studied parameters between cholestasis-affectedand healthy control groups. CONCLUSIONS: There are no diffrences in placental microstructure in cholestasis patients treated with UDCA and in patientswith uncomplicated pregnancy.

A facile synthesis of ursodeoxycholic acid and obeticholic acid from cholic acid.

A novel synthetic route of producing ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) was developed through multiple reactions from cheap and readily-available cholic acid. The reaction conditions of the key elimination reaction of mesylate ester group were also investigated and optimized, including solvent, base and reaction temperature. In the straightforward synthetic route for preparation of UDCA and OCA, most of the reaction steps have high conversions with average yields of 94% and 92%, and overall yield up to 65% (7 steps) and 36% (11 steps) from cholic acid, respectively. This promising route offers economical and efficient strategies for potential large-scale production of UDCA and OCA.

Ácido ursodesoxicólico para colangite biliar primária / Ursodeoxycholic acid for primary biliary cholangitis

INTRODUÇÃO: A colangite biliar primária (CBP) é uma doença hepática autoimune colestática rara, caracterizada por inflamação e destruição progressiva dos ductos interlobulares de pequeno e médio calibre, colestase que provoca fadiga e prurido debilitantes, podendo evoluir para fibrose, cirrose, doença hepática terminal e morte. Estudos epidemiológicos de base populacional de diversos países mostrou taxas de incidência que variam de 0,33 a 5,8 por 100 mil habitantes por ano e taxas de prevalência 1,91 a 40,2 por 100 mil habitantes por ano. Atualmente, o SUS oferece apenas alternativas para o tratamento dos sintomas da doença hepática terminal (cirrose), e não possui nenhuma alternativa terapêutica com idicação para CBP. TECNOLOGIA: Ácido Ursodesoxicólico (Ursacol®). PERGUNTA: O uso de ácido ursodesoxicólico (AUDC) é eficaz e seguro em pacientes com colangite biliar primária quando comparado às opções disponíveis atualmente no SUS? EVIDÊNCIAS CIENTÍFICAS: Com base nos critérios de inclusão, na estratégia de busca e nas referências dos artigos selecionados, foram incluídos 13 estudos, 10 já incluídos pelo demandante e três pela Secretaria-Executiva da CONITEC. Mortalidade foi avaliada por seis estudos, três observaram que não houve diferença estatisticamente significante entre AUDC e placebo, em outros três estudos os resultados foram variados. A sobrevida global foi avaliada por três estudos que concluíram que a sobrevida observada foi significativamente (P< 0.001) maior no grupo tratado com AUDC quando comparado ao previsto pelo modelo de Mayo ou grupo não tratado. Os resultados de sobrevida livre de transplante (SLT) de quatro estudos puderam ser meta-analisados, e o tratamento com AUDC apresentou aumento do tempo de SLT no acompanhamento de longo prazo a partir do quinto ano de tratamento, com resultados estatisticamente significantes para os anos 5, 8 e 10 (p< 0,01). Não houve diferença estatisticamente significantes nas meta-análises para proporção de eventos adversos graves quando se comparou AUDC com placebo/não tratamento. AVALIAÇÃO ECONÔMICA: O demandante delineou em sua proposta um estudo de custo-efetividade do AUDC como opção de tratamento em pacientes com CBP sintomáticos. O estudo demonstrou uma RCEI de R$ 9,32 mil por ano livre de transplante salvo e R$ 13,26 mil por ano de vida salvo, quando comparado ao placebo. O modelo possui limitações na fonte de dados de eficácia, no levantamento dos custos e no horizonte temporal usado no modelo que limitam a interpretação do resultado. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: A partir das premissas adotadas pelo demandante, o impacto orçamentário incremental com a incorporação do AUDC no SUS seria de R$11,77 milhões no primeiro ano e de R$98,52 milhões no acumulado de cinco anos. Entretanto, análise possui limitações quanto à estimativa da população e a previsão de custos. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: As buscas apontaram haver quatro potenciais medicamentos nas fases 3 ou 4 de desenvolvimento clínico para a indicação terapêutica considerada. Destes, o ácido obeticólico e selaldelpar lisina parecem estar num horizonte mais próximo, dado que obtiveram registro sanitário no FDA e/ou EMA nos últimos dois anos. RECOMENDAÇÃO DA CONITEC: Os membros presentes em sua 68º reunião ordinária, no dia 05 de julho de 2018, deliberaram que o tema fosse submetido à consulta pública com recomendação preliminar desfavorável à incorporação do AUDC para tratamento de pacientes com CBP. CONSULTA PÚBLICA: Foram recebidas 25 contribuições técnico-científicas e 140 contribuições de experiência e opinião durante o período de consulta pública, entre 04 de agosto a 23 de agosto de 2018. Dentre as contribuições, a maioria foram contrárias à recomendação da CONITEC. Os principais argumentos enviados pela empresa fabricante foram: alto custo do medicamento, única opção terapêutica para CBP, melhroa dos parâmetros hepáticos, recomendação de agências internacionais, mudança da história natural da doença e redução dos eventos adversos. O plenário da CONITEC entendeu a necessidade de modificar sua recomendação inicial e deliberaram, por unanimidade, por recomendar a incorporação no SUS do AUDC para CBP. DELIBERAÇÃO FINAL: Os membros da CONITEC presentes na 68ª reunião ordinária, no dia 04 de julho de 2018, deliberaram, por unanimidade, por recomendar a incorporação do AUDC para tratamento de pacientes com Colangite Biliar Primária. Foi assinado o Registro de Deliberação nº 355/2018. DECISÃO: A Portaria nº 47, de 16 de outubro de 2017, tornou pública a decisão de incorporar o ácido ursodesoxicólico para colangite biliar, no âmbito do Sistema Único deSaúde - SUS. Publicada no Diário Oficial da União nº 200, seção 1, página 44.

Cost effectiveness of using ursodeoxycholic acid to treat primary biliary cholangitis.

Primary biliary cholangitis is a chronic inflammatory, autoimmune cholestatic liver disease, which untreated will usually progress to end-stage biliary cirrhosis. The aims of treatment and management of primary biliary cholangitis are the amelioration of associated symptoms, particularly pruritis and fatigue, and the prevention of end-stage liver disease. The presentation, natural history and clinical course are variable. Recent published European and UK clinical guidelines have emphasized the need for risk stratification and an individualized approach to patient management in primary biliary cholangitis. The bile acid, ursodeoxycholic acid, is established as the first-line treatment of primary biliary cholangitis. Assessment of clinical response to treatment is based on specified improvements in serum liver tests including near normalization of the serum alkaline phosphatase level at 1 year. At least two thirds of patients with primary biliary cholangitis should respond to ursodeoxycholic acid after 1 year's treatment. The correct dosage of ursodeoxycholic acid is determined by body weight viz 13-15 mg/kg/day. A significant number of patients with primary biliary cholangitis in the UK are being underdosed. Over a third of ursodeoxycholic acid partial responders become responders within 2 years after increasing the ursodeoxycholic acid doses to recommended levels. While transplant rates for primary biliary cholangitis have halved over the last 20 years, it is clear that optimizing the dose of ursodeoxycholic acid in partial responders would further decrease morbidity, mortality and the need for liver transplantation.

O tratamento contínuo superior a cinco anos com ácido ursodesoxicólico gera benefícios na taxa de mortalidade e na taxa de transplantes em colangite biliar primária: revisão sistemática da literatura e metanálise / Continuous treatment with ursodeoxycholic acid over five years generates benefits in mortality rate and transplantation rate in primary biliary cholangitis: systematic review of the literature and meta-analysis

Objetivos: A colangite biliar primária (CBP) é uma doença hepática colestática, autoimune, inflamatória e crônica que, quando não tratada, evolui para cirrose e eventualmente insuficiência hepática em um período de 10 a 20 anos. Este estudo teve como objetivo avaliar o impacto em longo prazo do tratamento com ácido ursodesoxicólico (AUDC) em pacientes com CBP. Métodos: Uma revisão sistemática da literatura foi conduzida até maio de 2017. Os desfechos incluíram sobrevida livre de transplante (SLT) ou morte, sobrevida global (SG), taxa de mortalidade, taxa de transplantes e a taxa combinada de mortes e transplantes. A análise dos dados foi realizada por meio de um modelo de efeitos aleatórios, utilizando-se o método de DerSimonian e Laird. Resultados: Doze estudos foram incluídos na metanálise. O tratamento com AUDC apresentou aumento do tempo de SLT no acompanhamento em longo prazo a partir do quinto ano de tratamento, com resultados estatisticamente significativos para os anos de 5 e 10 (p < 0,01). Os resultados da metanálise das taxas de mortalidade, transplante e taxa combinada de mortalidade e transplante mostraram-se não significativos para os três desfechos apresentados. A inclusão dos estudos de braço comparador teórico alterou de maneira significativa os resultados da análise principal, tornando os resultados estatisticamente significativos a partir do terceiro ano de acompanhamento. Conclusões: AUDC é eficaz no aumento da SLT ou morte, com resultados estatisticamente significativos em 5 e 10 anos, quando os pacientes são tratados de maneira crônica.

Objectives: Primary biliary cholangitis (PBC) is an inflammatory and chronic autoimmune cholestatic liver disease that, when left untreated, progresses to cirrhosis and eventually liver failure in a period of 10 to 20 years. This study aimed to evaluate the long-term impact of treatment with ursodeoxycholic acid (UDCA) in patients with PBC. Methods: A systematic literature review was conducted until May 2017. The endpoints included transplant-free survival (TFS) or death, overall survival (OS), mortality rate, transplantation rates and the combined rate of deaths and transplants. Data analysis was performed using a random effects model with the DerSimonian and Laird method. Results: Twelve studies were included in the meta-analysis. Treatment with UDCA showed an increase in TFS time in the long-term follow up from the fifth year of treatment, with statistically significant results for the years 5 and 10 (p < 0.01). Meta-analysis results for mortality rates, transplantation and combined mortality and transplantation rates were not significant for the three outcomes presented. The inclusion of the theoretical comparator arm studies significantly altered the results of the main analysis, making the results statistically significant from the third year of follow-up. Conclusions: UDCA is effective in increasing TFS or death, with statistically significant results at 5 and 10 years, when patients are treated chronically

Ursodeoxycholic acid for the prevention of symptomatic gallstone disease after bariatric surgery: study protocol for a randomized controlled trial (UPGRADE trial).

BACKGROUND: The number of bariatric interventions for morbid obesity is increasing worldwide. Rapid weight loss is a major risk factor for gallstone development. Approximately 11 % of patients who underwent Roux-en-Y gastric bypass develop symptomatic gallstone disease. Gallstone disease can lead to severe complications and often requires hospitalization and surgery. Ursodeoxycholic acid (UDCA) prevents the formation of gallstones after bariatric surgery. However, randomized controlled trials with symptomatic gallstone disease as primary endpoint have not been conducted. Currently, major guidelines make no definite statement about postoperative UDCA prophylaxis and most bariatric centers do not prescribe UDCA. METHODS: A randomized, placebo-controlled, double-blind multicenter trial will be performed for which 980 patients will be included. The study population consists of consecutive patients scheduled to undergo Roux-en-Y gastric bypass or sleeve gastrectomy in three bariatric centers in the Netherlands. Patients will undergo a preoperative ultrasound and randomization will be stratified for pre-existing gallstones and for type of surgery. The intervention group will receive UDCA 900 mg once daily for six months. The placebo group will receive similar-looking placebo tablets. The primary endpoint is symptomatic gallstone disease after 24 months, defined as admission or hospital visit for symptomatic gallstone disease. Secondary endpoints consist of the development of gallstones on ultrasound at 24 months, number of cholecystectomies, side-effects of UDCA and quality of life. Furthermore, cost-effectiveness, cost-utility and budget impact analyses will be performed. DISCUSSION: The UPGRADE trial will answer the question whether UDCA reduces the incidence of symptomatic gallstone disease after Roux-en-Y gastric bypass or sleeve gastrectomy. Furthermore it will determine if treatment with UDCA is cost-effective. TRIAL REGISTRATION: Netherlands Trial Register (trialregister.nl) 6135 . Date registered: 21-Nov-2016.

Zebrafish larva as a reliable model for in vivo assessment of membrane remodeling involvement in the hepatotoxicity of chemical agents.

The easy-to-use in vivo model, zebrafish larva, is being increasingly used to screen chemical-induced hepatotoxicity, with a good predictivity for various mechanisms of liver injury. However, nothing is known about its applicability in exploring the mechanism called membrane remodeling, depicted as changes in membrane fluidity or lipid raft properties. The aim of this study was, therefore, to substantiate the zebrafish larva as a suitable in vivo model in this context. Ethanol was chosen as a prototype toxicant because it is largely described, both in hepatocyte cultures and in rodents, as capable of inducing a membrane remodeling leading to hepatocyte death and liver injury. The zebrafish larva model was demonstrated to be fully relevant as membrane remodeling was maintained even after a 1-week exposure without any adaptation as usually reported in rodents and hepatocyte cultures. It was also proven to exhibit a high sensitivity as it discriminated various levels of cytotoxicity depending on the extent of changes in membrane remodeling. In this context, its sensitivity appeared higher than that of WIF-B9 hepatic cells, which is suited for analyzing this kind of hepatotoxicity. Finally, the protection afforded by a membrane stabilizer, ursodeoxycholic acid (UDCA), or by a lipid raft disrupter, pravastatin, definitely validated zebrafish larva as a reliable model to quickly assess membrane remodeling involvement in chemical-induced hepatotoxicity. In conclusion, this model, compatible with a high throughput screening, might be adapted to seek hepatotoxicants via membrane remodeling, and also drugs targeting membrane features to propose new preventive or therapeutic strategies in chemical-induced liver diseases. Copyright © 2016 John Wiley & Sons, Ltd.

Primary Biliary Cholangitis: Medical and Specialty Pharmacy Management Update.

BACKGROUND: Chronic liver disease and cirrhosis are a leading cause of morbidity and mortality in the United States. Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis and which has been designated an orphan condition, is a chronic autoimmune disease resulting in the destruction of the small bile ducts in the liver. Without effective treatment, disease progression frequently leads to liver failure and death. Until May 2016, the only FDA-approved treatment for PBC was ursodiol (UDCA), an oral hydrophilic bile acid, which can slow progression of liver damage due to PBC. However, 1 out of 3 patients taking UDCA has an inadequate biochemical response, leading to increased risk of disease progression, liver transplantation, and mortality. Given this unmet clinical need, new therapies are in development for the treatment of PBC. To provide pharmacists with an overview of the latest research on the pathophysiology of PBC and potential new treatment options and to highlight medical and specialty pharmacy approaches to managing access to drugs to treat orphan diseases such as PBC, a 2-hour satellite symposium was presented in conjunction with the 2015 Academy of Managed Care Pharmacy (AMCP) Nexus meeting. Although obeticholic acid was approved by the FDA for the treatment of PBC in May 2016, this development occurred after the symposium presentation. The symposium was supported by an independent educational grant from Intercept Pharmaceuticals and was managed by Analysis Group. Robert Navarro, PharmD, moderated the CPE-accredited symposium titled "Medical and Specialty Pharmacy Management Update on Primary Biliary Cirrhosis." Expert panelists included Christopher L. Bowlus, MD; James T. Kenney, RPh, MBA; and Gary Rice, RPh, MS, MBA, CSP. OBJECTIVE: To summarize the educational satellite symposium presentations and discussions. SUMMARY: Autoimmune liver diseases, including PBC, are responsible for 15% of all liver transplants performed and an equal percentage of deaths related to liver disease. UDCA is the only FDA-approved therapy for treatment of PBC and is considered the standard of care. Nevertheless, many patients do not respond to UDCA, creating the need for new therapeutic options to improve clinical outcomes for PBC patients with inadequate response to treatment. While several agents are being studied in combination with UDCA, monotherapy with the novel agent obeticholic acid, a farnesoid X receptor agonist, has also shown promising results. Health plans are anticipated to assign any newly introduced therapy for the treatment of PBC to specialty pharmacy given its orphan disease status. This assignment enables the health plan to receive disease education, which is particularly important when new drugs are indicated for orphan diseases, and assistance with designing appropriate prior authorization criteria. The clinical value of any new therapeutic options that will inform formulary decisions and prior authorization criteria will be assessed based on evidence of efficacy, safety, and tolerability, among other factors, such as the potential to reduce or delay medical resource utilization (e.g., liver transplant). Key considerations for prior authorization of a new therapy will be determining which PBC patients are appropriate candidates for the new therapy and developing criteria for that determination. These are likely to include clinical diagnostic criteria and degree of response to prior treatment with UDCA. Initially, any new therapy would likely be positioned as noncovered until appropriate prior authorization criteria are established. CONCLUSIONS: PBC is a chronic liver disease with significant morbidity and mortality, as well as a significant burden on the health care system if the disease progresses to the point at which a liver transplant is needed. Although UDCA, the current standard of care, has improved outcomes for many patients, others have an inadequate response to this treatment. This symposium discussed these issues and also addressed the overall treatment paradigm for orphan drug therapies, key implications for patient management, and the role of specialty pharmacy management and any associated needs both in general and specifically for new therapeutic options for PBC.

Ácido ursodesoxicólico para o tratamento da hepatopatia crônica criptogênica / Ursodeoxycholic acid for the treatment of chronic cryptogenic liver disease

CONTEXTO: A hepatopatia é um termo empregado para designar um conjunto de doenças que acometem o fígado. Segundo a Classificação Internacional de Doenças 10a versão (CID-10), compreende as doenças de CID-10 K70 a K77. A hepatopatia crônica criptogênica refere-se a doença hepática sem etiologia conhecida (K73.9) (1). Além dessas, existem as doenças hepáticas de origem viral (CID-10 B15-B19) (2). As principais doenças hepáticas crônicas (DHC) são: hepatite viral (B15-B19), alcoólica (K70) ou autoimune (K75.4), doença hepática gordurosa não alcoólica (DHGNA) (K76.0), cirrose hepática (K74) e carcinoma hepatocelular (C22.0). A cirrose, doença difusa do fígado, é considerada estágio próprio da evolução de diversas doenças hepáticas crônicas e pode evoluir para insuficiência hepática e carcinoma hepatocelular. TECNOLOGIA: Ácido ursodesoxicólico (Ursacol®). PERGUNTA: Ácido ursodesoxicólico é eficaz e seguro para o tratamento da hepatopatia crônica criptogênica? EVIDENCIAS: Não foram encontrados estudos que avaliassem o ácido ursodesoxicólico para o tratamento de doenças hepáticas crônicas de etiologia desconhecida. Foi incluída uma revisão sistemática que avaliou o uso de ácido ursodesoxicólico para o tratamento da cirrose biliar primária, sua indicação em bula no FDA. Os resultados mostraram não haver diferença significativa no efeito entre o ácido ursodesoxicólico e placebo ou "não intervenção" para mortalidade por todas as causas; mortalidade por todas as causas ou transplante de fígado; eventos adversos graves ou eventos adversos não graves. O ácido ursodesoxicólico não influenciou o número de pacientes com prurido ou com fadiga. A pressão portal, varizes, varizes hemorrágicas, ascite e encefalopatia hepática não foram significativamente afetadas pelo ácido ursodesoxicólico. O ácido ursodesoxicólico diminuiu significativamente a concentração sérica de bilirrubina e a atividade da fosfatase alcalina sérica em comparação com placebo ou nenhuma intervenção. Ácido ursodeoxicólico também pareceu melhorar os níveis séricos de gama-glutamil transferase, aminotransferases, colesterol total e concentração de imunoglobulina M plasmática. O ácido rsodesoxicólico pareceu ter um efeito benéfico sobre a agravamento do estágio histológico. Os autores concluíram que os resultados da revisão sistemática não demonstraram quaisquer benefícios significativos de ácido rsodesoxicólico na mortalidade por todas as causas, transplante de fígado, prurido, ou fadiga em pacientes com cirrose biliar primária. O ácido ursodesoxicólico demonstra ter um efeito benéfico sobre as medidas bioquímicas do fígado e na progressão histológica em comparação com o grupo controle. CONCLUSÕES: Não existem evidencias diretas para o uso de ácido ursodesoxicólico para o tratamento de hepatopatia crônica criptogênica. Nos casos de hepatopatias que apresentam comprometimento colestático crônico, o ácido ursodesoxicólico melhora os parâmetros bioquímicos e histológico sem, entretanto, trazer benefícios nos desfechos de mortalidade por todas as causas, mortalidade por todas as causas ou transplante hepático, fadiga e prurido.