Papel del ácido ursodesoxicólico en 40 años de tratamiento para la colangitis biliar primaria / Role of ursodeoxycholic acid in 40 years of treatment for primary biliary cholangitis

La colangitis biliar primaria es una enfermedad hepática autoinmune que conduce a la destrucción progresiva de los conductos biliares intrahepáticos, lo que aumenta el riesgo de desarrollar cirrosis e hipertensión portal. Actualmente, el ácido ursodesoxicólico es el medicamento de primera línea para el tratamiento de esta entidad. Este medicamento desplaza los ácidos biliares hidrofóbicos y aumenta las concentraciones de ácidos biliares hidrofílicos en la bilis, lo cual favorece la integridad de los conductos biliares, adicionalmente, tiene efectos antiinflamatorios y propiedades inmunomo-duladoras y antiapoptóticas. En los últimos 40 años, numerosos ensayos clínicos han respaldado la eficacia clínica del ácido ursodesoxicólico y su seguridad cuando se utiliza en pacientes con colan-gitis biliar primaria. Se realiza una revisión del ácido ursodesoxicólico en el contexto de colangitis biliar primaria, se describe su historia, mecanismos de acción, efectos secundarios y dosificación. Finalmente, se menciona su uso en situaciones especiales como son el embarazo y la lactancia

Primary biliary cholangitis is an autoimmune liver disease that leads to progressive destruction of intrahepatic bile ducts, increasing the risk of developing cirrhosis and portal hypertension. Currently, ursodeoxycholic acid is the first-line drug for the treatment of this condition. This drug displaces hy-drophobic bile acids and increases concentrations of hydrophilic bile acids in the bile, which favors the integrity of the bile ducts, additionally, it has anti-inflammatory effects and immunoprotective and antiapoptotic properties. Over the past 40 years numerous clinical trials have supported the clinical efficacy of ursodeoxycholic acid and its safety when used in patients with primary biliary cholangitis. A review of ursodeoxycholic acid in the context of primary biliary cholangitis is carried out, and its history, mechanisms of action, side effects and dosage are described. Finally, its use in special situations such as pregnancy and lactation are discussed.

Respuesta terapéutica al ácido ursodesoxicólico en pacientes cubanos con colangitis biliar primaria

Introducción: La colangitis biliar primaria es una enfermedad hepática, crónica y progresiva. El tratamiento con ácido ursodesoxicólico ha ampliado la esperanza de vida de estos pacientes. Objetivo: Describir la respuesta terapéutica al ácido ursodesoxicólico en pacientes con colangitis biliar primaria. Métodos: Estudio descriptivo, longitudinal y ambispectivo en pacientes atendidos en el Instituto de Gastroenterología entre septiembre de 2003 y enero de 2020. Se evaluaron variables clínicas, de laboratorio, histológicas y terapéuticas. El análisis de los resultados se realizó con el paquete SPSS. Resultados: Se incluyeron 45 pacientes. Hubo un predominio del sexo femenino (95,6 %) y una mediana de edad de 54 años. Los niveles bajos de aspartato amino transferasa (p=0,009 HR=0,98) y fosfatasa alcalina (p=0,005, HR=0,99), así como la presencia del síndrome de superposición (p=0,046 HR=3,08) se relacionaron con una buena respuesta al ácido ursodesoxicólico. La mayoría de los que no respondieron al tratamiento tenían cirrosis hepática (68 %). No se observaron diferencias en la supervivencia de los pacientes de acuerdo con su respuesta al tratamiento (p =0,585). Conclusiones: La respuesta terapéutica fue efectiva en menos de la mitad de los tratados con ácido ursodesoxicólico. La cirrosis hepática, el síndrome de superposición y los niveles elevados de aspartato amino transferasa y fosfatasa alcalina se asociaron a la mala respuesta terapéutica.

Introduction: Primary biliary cholangitis is a chronic and progressive liver disease. Treatment with ursodeoxycholic acid has extended the life expectancy of these patients. Objective: To describe the therapeutic response to ursodeoxycholic acid in patients with primary biliary cholangitis. Methods: Descriptive, longitudinal and ambispective study in patients treated at the Institute of Gastroenterology between September 2003 and January 2020. Clinical, laboratory, histological and therapeutic variables were evaluated. The analysis of the results was performed with the SPSS package. Results: Forty-five patients were included, with a predominance of female gender (95.6%) and a average age of 54 years. Low levels of aspartate amino transferase (p=0.009 HR=0.98) and alkaline phosphatase (p=0.005, HR=0.99), as well as the presence of overlap syndrome (p=0.046 HR=3.08) were associated with a better response to ursodeoxycholic acid. Less than half of the patients responded to conventional treatment with UDCA (47.7 %), most of the non-responders suffer from liver cirrhosis (68 %). No differences were observed in patient survival according to their response to treatment (p =0.585). Conclusions: Therapeutic response was effective in less than half of those treated with ursodeoxycholic acid. Liver cirrhosis, overlap syndrome, and elevated aspartate amino transferase and alkaline phosphatase levels were associated with poor therapeutic response.

Hepatotoxicidad por talidomida: caso clínico y revisión de la literatura / Hepatotoxicity by thalidomide: case report and literature review

La talidomida fue desarrollada e introducida al mercado por los laboratorios Grünenthal en 1953, siendo usada principalmente como sedante y también para el tratamiento de las náuseas durante el embarazo. Los informes dan cuenta de aproximadamente 10.000 niños que nacieron con focomelia, dando lugar a la denominada "tragedia de la talidomida", que obligó a su retiro del mercado en 1962. Luego de casi 60 años, es nuevamente utilizada en otros campos de la medicina, entre ellos, para el tratamiento de la lepra y del mieloma múltiple, debido a sus propiedades antinflamatorias, inmunomoduladoras y antiangiogénicas, con expresas advertencias sobre su utilización durante el embarazo; no obstante, con su nuevo uso han sido reportados múltiples efectos adversos, entre los que se encuentra la hepatitis aguda o crónica inducida por este fármaco. Se presenta el caso de una paciente de 34 años con lepra, que estaba en tratamiento con talidomida desde hacía 4 años para combatir las lesiones de piel asociadas a esta enfermedad. Presentó malestar general, vómito, pérdida de peso, artralgias, ictericia, edemas de miembros inferiores, ascitis, coluria y acolia. Se sospechó toxicidad por talidomida, por lo que se suspendió su uso, y se trató con ácido ursodesoxicólico y N-acetilcisteína con mejoría sintomática y de laboratorio, desde la primera semana hasta los 41 días de seguimiento. Las entidades clínicas para las cuales se aprobó talidomida en 1998, pueden traer nuevos problemas y desafíos clínicos. Este caso muestra hepatotoxicidad crónica por talidomida, situación que hasta el momento no se había reportado en la literatura.

Thalidomide was developed and introduced to the market by Grünenthal laboratories in 1953, being used mainly as a sedative and also for the treatment of nausea during pregnancy. Reports give account of approximately 10,000 children who were born with phocomelia, giving rise to the so-called "thalidomide tragedy", which forced its withdrawal from the market in 1962. After almost 60 years, it is usedagain in other fields of medicine, including the treatment of leprosy and multiple myeloma, due to its anti-inflammatory, immunomodulatory and anti-angiogenic properties, with clear warnings about its use during pregnancy; however, multiple adverse effects have been reported in patients with leprosy and multiple myeloma, including acute or chronic hepatitis. We present the case of a 34-year-old patient with leprosy, who had been on thalidomide therapy for 4 years to treat skin lesions associated with this disease. She presented general malaise, vomiting, weight loss, arthralgia, jaundice, lower limb edema, ascites, choluria and acholia. Thalidomide toxicity was suspected, so its use was suspended, and treatment with ursodeoxycholic acid and N-acetylcysteine was initiated, with symptomatic and laboratory improvement from the first week up until 41 days of follow-up. The new range of medical conditions for which thalidomide was approved for in 1998 may bring clinical challenges. This case shows chronic hepatotoxicity due to thalidomide, a situation that had not been reported previously in the literature.

Colangitis esclerosante primaria / Primary sclerosing cholangitis

La colangitis esclerosante primaria (CEP) se define por la inflamación, fibrosis y estenosis de los conductos biliares intra o extrahepáticos que no pueden ser explicadas por otras causas. La prevalencia de CEP está estimada entre 0 a 16,2 por 100.000 habitantes, mientras que la incidencia está entre 0 y 1,3 casos por cada 100.000 personas por año. Las causas siguen siendo difíciles de dilucidar y en muchos casos se establece como de origen idiopático. Sin embargo, se han propuesto factores genéticos, ambientales e isquémicos asociados, además de un componente autoinmune. Existe además una fuerte asociación entre la enfermedad inflamatoria intestinal y la CEP. Los síntomas suelen ser inespecíficos, 50% de los pacientes son asintomáticos, presentando únicamente alteración en el perfil hepático de patrón colestásico, con predominio de elevación de la fosfatasa alcalina. La ictericia es un signo de mal pronóstico que con frecuencia se asocia a colangiocarcinoma. La confirmación diagnóstica se hace por colangiopancreatografía retrógrada endoscópica (CPRE) e imágenes por resonancia magnética. Aún no existe un tratamiento establecido, y en la mayoría de los casos coexiste con otras patologías. El tratamiento es multimodal con fármacos, terapia endoscópica y trasplante hepático.

Primary sclerosing cholangitis (PSC) is defined by inflammation, fibrosis, and stenosis of the intra or extrahepatic bile ducts that cannot be explained by other causes. The prevalence of PSC is estimated between 0 to 16.2 per 100,000 inhabitants, while the incidence is between 0 and 1.3 cases per 100,000 persons-year. The causes remain elusive and, in many cases, it is established as idiopathic in origin. However, genetic, environmental and ischemic factors have been proposed in addition to an autoimmune component. There is also a strong association between inflammatory bowel disease and PSC. Symptoms are usually nonspecific, 50% of the patients are asymptomatic, presenting only an alteration in the liver profile with a cholestatic pattern, and predominance of elevated alkaline phosphatase. Jaundice is a poor prognostic sign and is frequently associated with cholangiocarcinoma. Diagnostic confirmation is made by endoscopic retrograde cholangiopancreatography and magnetic resonance imaging. There is still no established treatment, and in most cases, the disease coexists with other pathologies. Treatment is multimodal with drugs, endoscopic therapy and liver transplantation.

Desenlaces perinatales, en un centro de tercer nivel de México de pacientes con colestasis intrahepática del embarazo / Perinatal outcomes of patients with intrahepatic cholestasis of pregnancy in a third level center in Mexico

Resumen OBJETIVO: Describir la atención, tratamiento, desenlaces perinatales y complicaciones asociadas con la colestasis intrahepática del embarazo. MATERIALES Y MÉTODOS: Estudio de serie de casos, retrospectivo y observacional de pacientes embarazadas, con diagnóstico de colestasis intrahepática atendidas en el Instituto Nacional de Perinatología entre los meses de enero de 2016 a diciembre de 2020. Se evaluaron las características obstétricas, los datos demográficos, clínicos, bioquímicos y de tratamiento, la finalización del embarazo y los desenlaces perinatales. RESULTADOS: Se analizaron 67 casos de colestasis intrahepática que arrojaron una incidencia de 0.57%. La edad promedio de las pacientes fue 29.0 ± 6.8 años, 30 de 67 eran primigestas, 12 tuvieron el antecedente de colestasis intrahepática en el embarazo previo y 7 de óbito. El inicio de la enfermedad fue en el tercer trimestre en 41 de 67 pacientes. En los estudios de bioquímica 32 de 67 tuvieron valores de ácidos biliares entre 10 y 39 μM/L; 12 de las 67: 40-99 μM/L y 23 más de 100 (μM/L). Se administró tratamiento con ácido ursodesoxicólico a 63 de 67 y ante la falta de respuesta se agregó rifampicina. El promedio de semanas de gestación fue 35.6 ± 2.0 semanas con peso promedio de 2397 ± 572 g. Se encontró líquido amniótico con meconio en 10 neonatos y restricción del crecimiento en 20 de 67; se registraron 2 óbitos. CONCLUSIONES: Este es el primer estudio efectuado en México que describe la incidencia de la enfermedad y se utiliza la determinación de los ácidos biliares para establecer el diagnóstico. Los desenlaces perinatales coinciden con lo reportado en la bibliografía.

Abstract OBJECTIVE: To describe the care, treatment, perinatal outcomes and complications associated with intrahepatic cholestasis of pregnancy. MATERIALS AND METHODS: A retrospective and observational case series study of pregnant patients with a diagnosis of intrahepatic cholestasis seen at the National Institute of Perinatology between January 2016 and December 2020. Obstetric characteristics, demographic, clinical, biochemical and treatment data, pregnancy termination and perinatal outcomes were evaluated. RESULTS: Sixty-seven cases of intrahepatic cholestasis were analyzed, yielding an incidence of 0.57%. The mean age of the patients was 29.0 ± 6.8 years, 30 of 67 were primigravidases, 12 had a history of intrahepatic cholestasis in the previous pregnancy and 7 had an abortion. The onset of the disease was in the third trimester in 41 of 67 patients. In biochemistry studies 32 of 67 had bile acid values between 10 and 39 μM/L; 12 of 67: 40-99 μM/L and 23 more than 100 (μM/L). Treatment with ursodeoxycholic acid was administered to 63 of 67 and rifampicin to 4 patients. The mean number of weeks of gestation was 35.6 ± 2.0 weeks with a mean weight of 2397 ± 572 g. Amniotic fluid with meconium was found in 10 neonates and growth restriction in 20 of 67; there were 2 recorded abortions. CONCLUSIONS: This is the first study carried out in Mexico in which the incidence of the disease is described, and the determination of bile acids is used to establish the diagnosis. Perinatal outcomes coincide with those reported in the literature.

Protective effect of Echinochrome against intrahepatic cholestasis induced by alpha-naphthylisothiocyanate in rats / Efeito protetor de Echinochrome contra colestase intra-hepática induzida por isotiocianato de alfa-naftilo em ratos

Abstract The present study was designed to evaluate the protective effects of echinochrome (Ech) on intrahepatic cholestasis in rats induced by a single (i.p.) injection of alpha-naphthylisothiocyanate (ANIT) (75 mg/kg body weight). The rats were pre-treated orally for 48hr (one dose / 24hr) with Ech (1, 5 and 10 mg/kg body weight) or ursodeoxycholic acid (UDCA) 80 mg/kg body weight drug then, injected with ANIT. ANIT markedly increased serum activities of alanine amino transaminase (ALT), aspartate amino transaminase (AST) and alkaline phosphatase (ALP), which was accompanied by a massive inflammation of epithelial cells on bile duct at 24h after ANIT injection. ANIT also increased the levels of total protein (TP), total bilirubin (TB), direct bilirubin (DB), indirect bilirubin (IB), however decrease albumin content (ALB). In addition ANIT increased hepatic MDA and NO level and decreased GSH level and GST activity. The Ech exerted hepatoprotective and anticholestatic effects as assessed by a significant decrease in the activities of serum AST, ALT and ALP, and the levels of TP, TB, DB and IB as well as liver MDA level and NO level. In conclusion, Ech was found to possess hepatoprotective effect against intrahepatic cholestasis induced by hepatotoxin such as ANIT.

Resumo O presente estudo destinou-se a avaliar os efeitos protetores do Ech na colestase intra-hepática em ratos induzidos por uma única injeção (i.p.) de alfa-naftilisotiocianato (ANIT) (75 mg / kg de peso corporal). Os ratos foram pré-tratados oralmente durante 48 horas (uma dose / 24 horas) com cada (1, 5 e 10 mg / kg de peso corporal) e ácido ursodeoxicólico (UDCA) 80 mg / kg de peso corporal, em seguida, injetado com ANIT. ANIT atividades de soro marcadamente aumentadas de alanina amino transaminasa (ALT), aspartato de amino transaminases (AST) e fosfatase alcalina (ALP), que foi acompanhada por uma inflamação maciça de células epiteliais no ducto biliar às 24h após a injeção de ANIT. A ANIT também aumentou os níveis de proteína total (TP), bilirrubina total (TB), bilirrubina direta (DB), bilirrubina indireta (IB), no entanto, diminuem o teor de albumina (ALB). Além disso, a ANIT aumentou o nível de MDA hepático e NO e diminuiu o nível de GSH e a atividade de GST. O Ech exerceu efeitos hepatoprotectores e anticolestáticos como avaliado por uma diminuição significativa nas atividades de AST sérica, ALT e ALP e os níveis de TP, TB, DB e IB, bem como o nível de MDA no fígado e o nível de NO. Ech foi encontrado para possuir efeito protetor no fígado contra a colestase intra-hepática induzida por hepatotoxina, como a ANIT.

N-acetilcisteína e/ou ácido ursodeoxicólico associados à metformina na esteato-hepatite não alcoólica: um estudo aberto, multicêntrico, randomizado controlado / N-acetylcysteine and/or ursodeoxycholic acid associated with metformin in non-alcoholic steatohepatitis: an open-label multicenter randomized controlled trial

ABSTRACT BACKGROUND: Nowadays, pharmacological treatment of non-alcoholic fatty liver disease (NAFLD) is still limited and it is based on the treatment of conditions associated comorbities. Oxidative stress and insulin resistance are the mechanisms that seem to be mostly involved in its pathogenesis. OBJECTIVE: To evaluate the efficacy of N-acetylcysteine (NAC) in combination with metformin (MTF) and/or ursodeoxycholic acid (UDCA) for treatment of non-alcoholic steatohepatitis (NASH). METHODS: Open-label multicenter randomized trial was conducted for 48 weeks. It included patients with biopsy-proven NASH. The patients were randomized into three groups: NAC (1.2 g) + UDCA (15 mg/kg) + MTF (850-1500 mg/day) (n=26); UDCA (20 mg/kg) + MTF (850-1500 mg/day) (n=13); NAC (1.2g) + MTF (850-1500 mg/day) (n=14) for 48 weeks. Clinical, laboratory and the second liver biopsies were performed after 48 weeks. RESULTS: A total of 53 patients were evaluated; 17 (32.1%) were males; median age ±54 (IQR=15, 21-71) years. In the baseline, no difference was seen between groups according clinical and histological parameters. The groups differed only in cholesterol, LDL and triglycerides. No significant differences in biochemical and histologic parameters were found between these the three groups after 48 weeks of treatment. In the intragroup analysis (intention-to-treat) comparing histological and biochemical features, there were significant improvements in the steatosis degree (P=0.014), ballooning (0.027) and, consequently, in the NAFLD Activity Score (NAS) (P=0.005), and in the ALT levels at the end of the treatment only in the NAC + MTF group. No significant evidence of modification in the liver fibrosis could be observed in any of the groups. CONCLUSION: This multicenter study suggests that the association of NAC + MTF could reduce the liver disease activity in patients with NASH. These data stimulate further controlled studies with this therapy for these patients.

RESUMO CONTEXTO: Atualmente, o tratamento farmacológico da doença hepática gordurosa não alcoólica (DHGNA) ainda é limitado e baseia-se no tratamento de condições associadas às comorbidades. O estresse oxidativo e a resistência à insulina são os mecanismos que parecem estar mais envolvidos em sua patogênese. OBJETIVO: Avaliar a eficácia da N-acetilcisteína (NAC) em associação à metformina (MTF) e/ou ácido ursodesoxicólico (UDCA) no tratamento da EHNA. MÉTODOS: Estudo randomizado, multicêntrico e aberto, conduzido por 48 semanas. Incluiu pacientes com esteato-hepatite não alcoólica (EHNA) comprovada por biópsia. Os pacientes foram distribuídos aleatoriamente em três grupos: NAC (1,2 g) + UDCA (15 mg/kg) + MTF (850-1500 mg/dia) (n=26); UDCA (20 mg/kg) + MTF (850-1500 mg/dia) (n=13); NAC (1,2 g) + MTF (850-1500 mg/dia) (n=14) durante 48 semanas. Os dados clínicos, laboratoriais e as segundas biópsias hepáticas foram realizados após 48 semanas. RESULTADOS - Um total de 53 pacientes foram avaliados; 17 (32,1%) eram do sexo masculino; idade mediana de ±54 (IQR=15, 21-71) anos. No baseline, nenhuma diferença foi observada entre os grupos de acordo com parâmetros clínicos e histológicos. Os grupos diferiram apenas em colesterol, LDL e triglicerídeos. Não foram encontradas diferenças significativas nos parâmetros bioquímicos e histológicos entre os três grupos após 48 semanas de tratamento. Contudo, na análise intragrupos (intenção de tratar) comparando características histológicas e bioquímicas, houve melhora significativa no grau de esteatose (P=0,014), balonização (P=0,027) e, consequentemente, no NAFLD Activity Score (NAS) (P=0,005), e nos níveis de ALT no final do tratamento apenas no grupo NAC+MTF. Nenhuma evidência significativa de modificaçãona fibrose hepática pôde ser observada em nenhum dos grupos. CONCLUSÃO: - Este estudo multicêntrico sugere que a associação de NAC+MTF poderia reduzir a atividade da doença hepática em pacientes com EHNA. Esses dados estimulam estudos adicionais controlados com essa terapia para esses pacientes.

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

Protective effect of Echinochrome against intrahepatic cholestasis induced by alpha-naphthylisothiocyanate in rats

Abstract The present study was designed to evaluate the protective effects of echinochrome (Ech) on intrahepatic cholestasis in rats induced by a single (i.p.) injection of alpha-naphthylisothiocyanate (ANIT) (75 mg/kg body weight). The rats were pre-treated orally for 48hr (one dose / 24hr) with Ech (1, 5 and 10 mg/kg body weight) or ursodeoxycholic acid (UDCA) 80 mg/kg body weight drug then, injected with ANIT. ANIT markedly increased serum activities of alanine amino transaminase (ALT), aspartate amino transaminase (AST) and alkaline phosphatase (ALP), which was accompanied by a massive inflammation of epithelial cells on bile duct at 24h after ANIT injection. ANIT also increased the levels of total protein (TP), total bilirubin (TB), direct bilirubin (DB), indirect bilirubin (IB), however decrease albumin content (ALB). In addition ANIT increased hepatic MDA and NO level and decreased GSH level and GST activity. The Ech exerted hepatoprotective and anticholestatic effects as assessed by a significant decrease in the activities of serum AST, ALT and ALP, and the levels of TP, TB, DB and IB as well as liver MDA level and NO level. In conclusion, Ech was found to possess hepatoprotective effect against intrahepatic cholestasis induced by hepatotoxin such as ANIT.

Resumo O presente estudo destinou-se a avaliar os efeitos protetores do Ech na colestase intra-hepática em ratos induzidos por uma única injeção (i.p.) de alfa-naftilisotiocianato (ANIT) (75 mg / kg de peso corporal). Os ratos foram pré-tratados oralmente durante 48 horas (uma dose / 24 horas) com cada (1, 5 e 10 mg / kg de peso corporal) e ácido ursodeoxicólico (UDCA) 80 mg / kg de peso corporal, em seguida, injetado com ANIT. ANIT atividades de soro marcadamente aumentadas de alanina amino transaminasa (ALT), aspartato de amino transaminases (AST) e fosfatase alcalina (ALP), que foi acompanhada por uma inflamação maciça de células epiteliais no ducto biliar às 24h após a injeção de ANIT. A ANIT também aumentou os níveis de proteína total (TP), bilirrubina total (TB), bilirrubina direta (DB), bilirrubina indireta (IB), no entanto, diminuem o teor de albumina (ALB). Além disso, a ANIT aumentou o nível de MDA hepático e NO e diminuiu o nível de GSH e a atividade de GST. O Ech exerceu efeitos hepatoprotectores e anticolestáticos como avaliado por uma diminuição significativa nas atividades de AST sérica, ALT e ALP e os níveis de TP, TB, DB e IB, bem como o nível de MDA no fígado e o nível de NO. Ech foi encontrado para possuir efeito protetor no fígado contra a colestase intra-hepática induzida por hepatotoxina, como a ANIT.

Síndrome LPAC: relato de caso / LPAC syndrome: case report

Síndrome LPAC (Low Phospholipid-Associated Cholelithiasis) é uma enfermidade rara, que cursa com manifestações clínicas recorrentes relacionadas à litíase biliar, mesmo após colecistectomia em indivíduos jovens habitualmente com início dos sintomas antes dos 40 anos. Mutações no gene ABCB4 geram baixa concentração de fosfolipídios na secreção biliar, o que favorece a formação de cálculos de colesterol. Seu diagnóstico é estabelecido por critérios clínicos e o tratamento é fundamentado no uso do ácido ursodesoxicólico (UDCA). O objetivo deste artigo é relatar o caso de um paciente com síndrome LPAC.

Achalasia is an uncommon disorder that affects about LPAC syndrome (Low phospholipid-associated cholelithiasis) is a rare illness that leads to recurrent clinical manifestations related to gallstones, even after cholecystectomy in young individuals, usually with onset of symptoms before age 40. Mutations in the gene ABCB4 generate low concentration of phospholipids in bile secretion, which promotes the formation of cholesterol calculations. The diagnosis is established by clinical criteria and treatment is based on the use of ursodeoxycholic acid (UDCA). The objective of this paper is to report the case of a patient with LPAC syndrome.

Reconstrucción de la vía biliar junto al tratamiento adyuvante con ácidoursodesoxicólico en lesiones/estenosisiatrogénicas posterior a colecistectomías. Resultados iniciales / Biliary reconstruction surgery follow by adju-vant therapy with ursodesoxicolcy acid in injury/stenosis after cholecistectomy. Prelimi-nary results

El tratamiento de la estenosis biliar benigna (EBB) constituye unreto médico, más del 70% de los casos son resueltos endoscópica-mente, reservando los más complejos para el abordaje quirúrgico,con una tasa éxito que ronda del 92 % al 60%. Una técnica qui-rúrgica impecable junto a factores favorables del paciente es la prin-cipal garantía de éxito. Objetivo: Mantener un adecuado flujo biliar es uno de los factoresprincipales para evitar inflamación y éstasis biliar, por lo que hemosemprendido el siguiente protocolo de estudio con terapia adyuvantecon ácido ursodesoxicólico posterior a la reconstrucción biliar.Métodos: Ensayo clínico prospectivo no aleatorizado, donde seincluyen pacientes con estenosis biliar benigna desde agosto 2012hasta agosto 2014.Resultados:Se han incluido 13 pacientes con preponderancia delsexo femenino con un 77 %, las estenosis tipo Bismuth 1 y 2 ocu-paron un 23 %, mientras que para Bismuth 4 y 5 un 15,38 % res-pectivamente, las EBB producto en anastomosis biliodigestiva ocu-rrió en un 23 %. El seguimiento promedio fue de 13,3 meses.Posterior al tratamiento, sólo 1 paciente experimentó colangitis enausencia de estenosis. Hasta la fecha de seguimiento ninguno hapresentado re-estenosis.Conclusión: Una técnica quirúrgica impecable junto al tratamientoadyuvante con ácido ursodesoxicólico pareciera ofrecer buenosresultados a fin de evitar la re-estenosis y la colangitis, por lo que suaplicación debe ser estudiada por periodos de tiempo prolongados(AU)

The benign biliary stenosis is a medical challenge; more than 70%of them are resulted endoscopically, leaving the most difficult casesfor surgical treatment, which can reach a success between 92% and60%. Meticulous surgical techniques with better patient prognosticfactors are guarantee of success. Objective:The adequate biliary flow is related with less inflationand less biliary stasis, that's why we decide to use ursodesoxicolicacid as an adjuvant treatment after biliary reconstruction surgery.Methods: Non randomized clinical trial, including patients betweenAugust 2012 to August 2014 with benign biliary stenosis.Results:Were included 13 patients, most of them women 77%.Type 1 and 2 Bismuth 23%, Bismuth 4 -5 15,38 % respectively, and23 % for stenosis of the biliodigestive anastomosis. The medianfollow up was 13,3 months. After surgical reconstruction there wereonly 1 patient who revealed cholangitis, and no restenosis in thefollow up period. Conclusion:A meticulous surgical technique and adjuvant treat-ment with ursobilanic acid seem to show good results avoiding re-stenosis and cholangitis, prolong study period is required(AU)

Eficacia del ácido ursodesoxicólico en el tratamiento de la enfermedad hepática grasa no alcohólica / Efficacy of ursodeoxycholic acid in the treatment of nonalcoholic fatty liver disease

Introducción: La enfermedad hepática grasa no alcohólica (EHGNA), tiene una prevalencia del 10 % al 24 % en la población general, con una historia natural poco conocida para poder establecer sus opciones terapéuticas. El ácido ursodosoxicólico (AUDC) es una droga utilizada en enfermedades hepáticas colestásicas, la cual tiene un efecto citoprotector en la EHGNA, en donde el estrés oxidativo es uno de los mecanismos fisiopatológicos. Objetivos: evaluar la eficacia del AUDC para mejorar los valores de aminotransferasas (ALT) en un tiempo determinado. Pacientes y métodos: se realizó un estudio prospectivo, experimental, incluyendo aquellos sujetos con aumento de ALT que acudieron a la consulta de centro privado entre enero 2009 - diciembre 2011, se les indicó AUDC a 13 mg/Kg/día por 12 semanas. Para el análisis estadístico se utilizó la prueba de Kolmogorov- Smirnov con un nivel de significancia del 99 % y Chi2 con un nivel de significancia del 95 %. Resultados: del total de los casos n=53, 55 % (n=29) perteneció al sexo femenino con una media de edad de 47,1 años (DS ±13,7 años). Al comparar los promedios de ALT antes y después del tratamiento del total de la muestra, se obtuvo una media 122,3 U/L y 64,7 U/L respectivamente, siendo estas diferencias significativas (p<0,001). Al comparar según sexo, hubo diferencias significativas tanto para el femenino en los promedios ALT antes y después del tratamiento: 110,9 U/L y 53,13 U/L, como en el sexo masculino 136 U/L y 78,7 U/L respectivamente, p<0,001. Existe una relación entre las variables y tiempo de tratamiento, observándose diferencias significativas al comparar los valores de ALT a las 4,8 y 12 semanas con 34,8 %, 30 % y 80 % respectivamente, siendo mayor a las 12 semanas, p<0,05. Conclusión: en nuestro estudio se pudo determinar que el AUDC en un tiempo establecido, mostro ser eficaz para la reducción de los niveles de ALT.

The history natural is poorly unknown for focused therapeutic options. Ursodeoxycholic Acid (UDCA) has long been used in the chronic cholestatic liver diseases, in NALFD believed to have cytoprotective properties and may help to reduce oxidative stress. Objetive: to know the efficacy of UDCA for improvement the serum aminotransferase levels (ALT). Patients and Methods: a prospective, experimental study was performed between january 2009 and december 2011 all patients with elevated ALT were included received UDCA 13 mg/kg/daily for 12 weeks. Analyses were conducted using Kolmogorov-Smirnov and chi-squared test with p<0,001 and p<0,05 was considered as the level of significance respectively. Results: a total of 53 patients, 55 % were female with a mean of 47,1 years old (DS±13,7 years). To compare the mean of ALT among the patients underwent starting treatment before and after was 122,3 U/L y 64,7 U/L respectively and statistically significant p<0,001 and the mean of ALT female gender was rate of response showed difference in patients 110,9 U/L y 53,13 U/L and male gender was 136 U/L y 78,7 U/L before and after UDCA was statistically significant p<0,001. Rate of response did differ in patients treated with UDCA 4, 8 and 12 weeks was 34,8 %, 30 % y 80 % respectively being statistically significant p<0,05 % at 12 weeks. Conclusion: at the present study we determined that UDCA was effective, in a given time, for improvement the serum aminotransferase levels.

Efectividad del ácido ursodesoxicólico versus fenobarbital para el tratamiento de la colestasis en prematuros. Ensayo clínico cruzado / Efectiveness of ursodeoxycholic acid versus phenobarbital for the treatment of neonatal cholestasis: a cross-randomizad clinical trial

Introducción. La prevalencia de colestasis neonatal varía del 7-57%. Parte del manejo incluye al ácido ursodesoxicólico (UDCA) y al fenobarbital, ambos con débil sustento en la literatura. El objetivo de este trabajo es comparar la efectividad del UDCA vs fenobarbital en la reducción de las cifras de bilirrubina directa, en recién nacidos prematuros con colestasis, con peso entre 1 000-2 000 g. Métodos. Se realizó un ensayo clínico aleatorizado cruzado en 18 pacientes. Cada individuo recibió al azar una de las dos intervenciones: UDCA (10 mg/kg/día c/12 h) o fenobarbital (a 3 mg/kg/día c/24 h) durante un período inicial de 7 días. Después de 7 días de lavado, se les asignó el tratamiento contrario. En total se realizaron 36 tratamientos. Se midieron bilirrubinas y pruebas de función hepática al inicio y final de cada tratamiento. El análisis se realizó por medio de medidas de tendencia central y de dispersión, de acuerdo al tipo de variable. Para la comprobación de hipótesis se realizó t pareada. Resultados. En el grupo que recibió UDCA a 10 mg/kg/día c/12 h por 7 días, disminuyeron las cifras de bilirrubina directa en 2.7 mg/dL (P<0.01). Conclusiones. Se recomienda el uso de UDCA a dosis de 10 mg/kg/día c/12 h por vía enteral como coadyuvante para el tratamiento de colestasis neonatal.

Background. The prevalence of neonatal cholestasis varies from 7-57%. Part of the treatment includes ursodeoxycholic acid (UDCA) and phenobarbital, both with little supporting evidence in the literature. We undertook this study to compare the effectiveness of phenobarbital vs. UDCA in reducing the direct serum bilirubin levels in patients with cholestasis and weighing from 1 000 to 2 000 g. Methods. Using a cross-randomized clinical trial, 18 patients were included with 36 treatments. Each subject randomly received one of the two interventions: UDCA (10 mg/kg/day) every 12 h or phenobarbital (3 mg/kg/day, every 24 h for 7 days) continuing with 7 days of wash-out to return to their initial state, and to subsequently receive the other treatment. At the beginning and at the end of the administration of each medication, bilirubin concentrations and hepatic test functions were measured. Central tendency and dispersion measurements were applied according to the type of variable. For hypothesis confirmation, paired t-test was carried out. Results. The obtained results indicate that with UDCA at a dose of 10 mg/kg/day every 12 h for 7 days, serum bilirubin levels decreased to 2.7 mg/dL (p <0.01). Phenobarbital had no effect in reducing bilirubin concentration. Conclusion. Use of UDCA is recommended at a dose of 10 mg/kg/dose every 12 h (PO) as a coadjuvant in the treatment of neonatal cholestasis.

Colestase da gravidez: revisão de literatura / Obstetric cholestasis: review of the literature

Colestase da gravidez (CG) é uma doença hepática específica da gravidez que tipicamente ocorre a partir do final do segundo trimestre. É uma doença de etiologia heterogênea (multifatorial) com contribuição de fatores genéticos e hormonais, caracterizada por prurido generalizado intenso e alterações das provas de função hepática, estando associada ao aumento das taxas de morbidade e mortalidade fetal. A revisão de literatura realizada refere-se à epidemiologia, etiologia, manifestações clínicas, achados laboratoriais e o manejo da CG na qual se conclui que o conhecimento por parte dos profissionais sobre a doença é fundamental para que seja realizado um manejo adequado das gestantes, visando principalmente prevenir complicações fetais. Apesar do número significativo de estudos relacionados com a CG, vários aspectos da sua etiologia e patogênese não foram elucidados. O diagnóstico é feito por meio de achados clínicos e das alterações das provas de função hepática e aumento dos níveis de ácidos biliares. O ácido ursodesoxicólico é a droga atualmente utilizada na terapêutica da CG com eficácia no controle do prurido e no restabelecimento de níveis normais dos ácidos biliares. Porém, há necessidade da condução de pesquisas e ensaios clínicos para a melhor condução desta doença.

Obstetric cholestasis (OC) is a specific hepatic pathology of the pregnancy that typically happens in the end of the second trimester. It is a heterogeneous etiology (multifactorial) disease with contribution from genetic and hormonal factors, characterized by intense itch and abnormal liver function tests, being associated to the increase of perinatal morbidity and mortality. The revision of accomplished literature refers to the epidemiology, etiology, clinical manifestations, laboratory findings and of which management OC concludes that knowledge by professionals about the disease is the key to an appropriate management, undertaken by pregnant women, seeking mainly to prevent fetal complications. In spite of the significant number of studies related with OC, several aspects of its etiology and pathogenesis were not elucidated. The diagnosis is made through the clinical discoveries and abnormal liver function tests and increase of the levels of bile acids. The ursodeoxycholic acid is now the drug used in the therapeutics of OC with effectiveness in the control of the itch and in the re-establishment of normal levels of the bile acids. However, new research and clinical trials are required for best conduction of this pathology