Síndrome de Alagille, reporte de un caso y revisión de la literatura / Alagille Syndrome, case study and literature review / Sindrome de Alagille, relato de caso e revisão de literatura

El síndrome de Alagille es una patología poco frecuente, de herencia autosómica dominante. Se caracteriza por la presencia de colestasis crónica progresiva ocasionada por hipoplasia de las vías biliares; anomalías vertebrales, oculares y cardíacas, y fenotipo facial particular. Entre sus diagnósticos diferenciales se incluyen las infecciones, enfermedades endocrinometabólicas, atresia biliar y causas idiopáticas. El pronóstico de este síndrome es variable y depende de la entidad de la afectación hepática y los defectos cardiovasculares. El abordaje terapéutico suele ser interdisciplinario e individualizado, enfocado en el control sintomático, prevención de la malnutrición y el déficit de vitaminas liposolubles. Se presenta el caso de un lactante de 2 meses en el que se estudiaron las causas más frecuentes de colestasis y se llegó al diagnóstico de síndrome de Alagille. Se describe su abordaje terapéutico y seguimiento.

Alagille syndrome is an inherited autosomal dominant rare disease. It is characterized by the presence of progressive chronic cholestasis caused by hypoplasia of the bile ducts; vertebral, ocular and cardiac anomalies, and particular facial phenotype. Its differential diagnoses include infections, endocrine-metabolic diseases, biliary atresia and idiopathic causes. The prognosis of this syndrome is variable and depends on the degree of liver involvement and cardiovascular defects. The therapeutic approach is usually interdisciplinary and customized, focused on symptomatic control, prevention of malnutrition and fat-soluble vitamin deficiency. We present the case of a 2-month-old infant in whom the most frequent causes of cholestasis were studied and to whom Alagille Syndrome was diagnosed. We hereby describe its therapeutic approach and follow-up.

A síndrome de Alagille é uma doença rara, hereditária, autossômica e dominante. Caracteriza-se pela presença de colestase crônica progressiva causada por hipoplasia das vias biliares; anomalias vertebrais, oculares e cardíacas e fenótipo facial particular. Seus diagnósticos diferenciais incluem infecções, doenças endócrino-metabólicas, atresia biliar e causas idiopáticas. O prognóstico desta síndrome é variável e depende do grau de envolvimento hepático e defeitos cardiovasculares. A abordagem terapêutica geralmente é interdisciplinar e personalizada, focada no controle sintomático, prevenção da desnutrição e deficiência de vitaminas lipossolúveis. Apresentamos o caso de uma criança de 2 meses de idade em que foram estudadas as causas mais frequentes de colestase e a quem foi diagnosticada Síndrome de Alagille. Descrevemos a sua abordagem terapêutica e seguimento.

Serum metabolomics of Tibetan medicine Ershiwuwei Songshi Pills against chronic cholestasis in mice / 中国中药杂志

A chronic cholestasis model was induced in mice by feeding a diet containing 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine(DDC). The effects of Ershiwuwei Songshi Pills(ESP) on endogenous metabolites in mice with chronic cholestasis were investigated by metabolomics analysis based on liquid chromatography-mass spectrometry(LC-MS). The results showed that ESP was effective in improving pathological injury and reducing serum levels of alanine aminotransferase(ALT), aspartate aminotransferase(AST), alkaline phosphatase(ALP), and total bile acid in the model mice. Meanwhile, 13 common differential metabolites were revealed in metabolomic screening between the model/control group and the model/ESP group, including uric acid, glycolaldehyde, kynurenine, flavin adenine dinucleotide, L-3-phenyllactic acid, I-urobilin, leukotriene D4(LTD4), taurocholic acid, trioxilin A3, D-inositol-1,4-diphosphate, PC [16:0/20:2(11Z,14Z)], PC[14:0/22:2(13Z,16Z)], and PC[20:4(5Z,8Z,11Z,14Z)/20:4(5Z,8Z,11Z,14Z)]. After ESP intervention, the levels of all 13 differential metabolites were significantly retraced, and pathway analysis showed that ESP achieved its therapeutic effect mainly by affecting arachidonic acid metabolism, glycerophospholipid metabolism, tryptophan metabolism, and primary bile acid biosynthesis. This study elucidated the mechanism of action of ESP against chronic cholestasis based on metabolites.

Consenso de hiperbilirrubinemia del primer trimestre de la vida / Consensus on hyperbilirubinemia of the first trimester of life

La presencia de ictericia en la etapa neonatal puede responder a diversas causas, desde situaciones fisiológicas hasta enfermedades graves. En los neonatos de término que persisten ictéricos más allá de los 14 días de vida, debe determinarse si la hiperbilirrubinemia es no conjugada o conjugada para establecer, a la brevedad, el plan de estudios etiológicos y la terapéutica correspondiente. La hiperbilirrubinemia conjugada (colestasis) refleja una disfunción hepática en la mayoría de los casos, cuyas consecuencias son alteraciones del flujo biliar secundarias a anormalidades estructurales o moleculares del hígado y/o del tracto biliar.Durante la última década, los nuevos estudios moleculares revolucionaron el abordaje de los pacientes colestáticos, lo que permitió el diagnóstico de diversas entidades genéticas. La etiología de la hiperbilirrubinemia del primer trimestre debe determinarse con urgencia, ya que, en muchos casos, el tratamiento instituido de modo precoz puede modificar sustancialmente la evolución de la enfermedad o salvar la vida del paciente.

Neonatal jaundice may be due to different causes, ranging from physiological conditions to severe diseases. In term neonates with persistent jaundice beyond 14 days of life, it should be determined whether hyperbilirubinemia is unconjugated or conjugated, in order to study the etiology and start early treatment. In the majority of cases, conjugated hyperbilirubinemia (cholestasis) is a sign of liver dysfunction possibly associated with alterations in the bile flow secondary to structural or molecular abnormalities of the liver and/or the biliary tract. Over the past decade, new molecular studies have revolutionized the approach of cholestatic patients, leading to the identification of different genetic entities. It is important to determine the etilogy of neonatal hyperbilirubinemia since in many cases early treatment will substantially improve morbidity and mortality.

Nuevas terapias para la colestasis / New therapies in cholestasis

The introduction of ursodeoxycholic acid (UDCA) in the treatment of patients with cholestasis enabled remarkable progress and improvements in hepatic inflammatory activity, progression to cirrhosis and quality of life. However, the benefits of UDCA are particularly evident in patients with primary biliary cirrhosis and also 30 percent of patients have sub optimal response. For this reason, in order to improve the number of people with complete responses to therapy, new pharmacological alternatives have been investigated to add to UDCA treatment. This review aims to show potential new therapies against cholestasis that have been investigated by systematizing them depending on the receptor or target on which they act. Finally, a special reference will be made in relation to the treatment of pruritus associated with cholestasis.

La introducción del ácido ursodeoxicólico (AUDC) en el tratamiento de los pacientes con colestasia permitió notables avances con mejoras en la actividad inflamatoria hepática, progresión hacia la cirrosis y calidad de vida. Sin embargo, los beneficios de AUDC se aprecian especialmente en pacientes con cirrosis biliar primaria y además, 30 por ciento de los pacientes tiene una respuesta sub óptima. Por esta razón, con la finalidad de mejorar el número de personas con respuestas completas a la terapia, se han investigado nuevas alternativas farmacológicas para adicionar al tratamiento con AUDC. La presente revisión pretende mostrar las nuevas posibles terapias contra la colestasia estudiadas sistematizándolas según el tipo de receptor o diana sobre el que actúan. Finalmente se hará referencia especial en relación al tratamiento del prurito asociado a la colestasia.

A Korean patient with Guillain-Barré syndrome following acute hepatitis E whose cholestasis resolved with steroid therapy

Autochthonous hepatitis E virus (HEV) is an emerging pathogen in developed countries, and several cases of acute HEV infection have been reported in South Korea. However, there have been no reports on HEV-associated Guillain-Barré syndrome (GBS) in Korea. We recently experienced the case of a 58-year-old Korean male with acute HEV infection after ingesting raw deer meat. Persistent cholestasis was resolved by the administration of prednisolone. At 2.5 months after the clinical presentation of HEV infection, the patient developed weakness of the lower limbs, and was diagnosed with GBS associated with acute hepatitis E. To our knowledge, this is the second report on supportive steroid therapy for persistent cholestasis due to hepatitis E, and the first report of GBS in a Korean patient with acute HEV infection.

Effects of the administration of pentoxifylline and prednisolone on the evolution of portal fibrogenesis secondary to biliary obstruction in growing animals: immunohistochemical analysis of the expression of TGF-β and VEGF

OBJECTIVE: During the neonatal and infancy periods, some chronic liver diseases may lead to progressive hepatic fibrosis, which is a condition that can ultimately result in the loss of organ function and severe portal hypertension necessitating hepatic transplantation. In a previous report, pharmacological interventions were demonstrated to modulate hepatic fibrosis induced by bile duct ligation in young rats. The administration of pentoxifylline or prednisolone, or the combination of both, resulted in reduced fibrogenesis in portal spaces. The objectives of the present study were to evaluate the expression of transforming growth factor β and vascular endothelial growth factor after bile duct ligation in young rats and to assess the effect of those same drugs on cytokine expression. METHODS: In this experimental study, 80 young rats (21 or 22 days old) were submitted either to laparotomy and common bile duct ligation or to sham surgery. The animals were allocated into four groups according to surgical procedure, and the following treatments were administered: (1) common bile duct ligation + distilled water, (2) sham surgery + distilled water, (3) common bile duct ligation + pentoxifylline, or (4) common bile duct ligation + prednisolone. After 30 days, a hepatic fragment was collected from each animal for immunohistochemical analysis using monoclonal antibodies against transforming growth factor β and vascular endothelial growth factor. Digital morphometric and statistical analyses were performed. RESULTS: The administration of pentoxifylline reduced the transforming growth factor β-marked area and the amount of transforming growth factor β expressed in liver tissue. This effect was not observed after the administration of prednisolone. There was a significant reduction in vascular endothelial growth factor expression after the administration of either drug compared with the non-treatment group. CONCLUSIONS: The administration of pentoxifylline to cholestatic young rats resulted in the diminished expression of transforming growth factor β and vascular endothelial growth factor in liver tissue. The administration of steroids resulted in the diminished expression of vascular endothelial growth factor only. These pathways may be involved in hepatic fibrogenesis in young rats submitted to bile duct ligation and exposed to pentoxifylline or prednisolone.

Clinical courses after administration of oral corticosteroids in patients with severely cholestatic acute hepatitis A; three cases / 대한간학회지

Acute hepatitis A is currently outbreaking in Korea. Although prognosis of acute hepatitis A is generally favorable, a minority of patients are accompanied by fatal complications. Severe cholestasis is one of the important causes of prolonged hospitalization in patients with acute hepatitis A. In such cases, higher chances of additional complications and increased medical costs are inevitable. We report three cases of severely cholestatic hepatitis A, who showed favorable responses to oral corticosteroids. Thirty milligram of prednisolone was initiated and tapered according to the responses. Rapid improvement was observed in all cases without side effects. We suggest that corticosteroid administration can be useful in hepatitis A patients with severe cholestasis who do not show improvement by conservative managements. Clinical trial will be needed to evaluate effectiveness of corticosteroids in these patients.

Suplementação com ácido ascórbico tem efeito citoprotetor na cirrose biliar secundária: estudo experimental em ratos jovens / Ascorbic acid supplementation has a cytoprotective effect on secondary biliary cirrhosis: experimental study in young rats

OBJETIVO: Testar se a suplementação com ácido ascórbico tem algum afeito citoprotetor em um modelo de cirrose biliar secundária em ratos jovens. MÉTODOS: Foram estudados 40 ratos Wistar desmamados no 21º dia pós-natal. Cada grupo de 10 foi submetido a um dos seguintes quatro tratamentos, até o 49º dia pós-natal, quando foram submetidos a eutanásia: 1) LC - ligadura dupla e ressecção do ducto biliar comum e administração diária de ácido ascórbico [100 mg/g de peso corporal (pc)]; 2) LA - ligadura dupla e ressecção do ducto biliar comum e administração diária de veículo aquoso (1 mL/g pc); 3) SC - operação simulada e administração diária de ácido ascórbico (100 mg/g pc); 4) SA - ligadura dupla e ressecção do ducto biliar comum e administração diária de veículo aquoso (1 mL/g pc). Os ratos eram pesados diariamente. No 27º dia pós-operatório, eles receberam injeção intraperitoneal de 1,5 mg/g pc de pentobarbital sódico, e o tempo de sono induzido pelo pentobarbital foi medido. Coletou-se sangue para determinação de atividade sérica de alanina aminotransferase e de aspartato aminotransferase, níveis de albumina e globulina séricas, e o fígado foi analisado quanto à conteúdo de água e gordura. Os dados foram submetidos à ANOVA two-way, e comparações pareadas entre grupos foram testadas com o método de SNK. O nível de significância foi estabelecido em 0,05. RESULTADOS: A suplementação com ácido ascórbico atenuou os efeitos da colestase: reduziu o tempo de anestesia pelo pentobarbital, globulina sérica e o conteúdo de gordura no fígado. CONCLUSÕES: Nossos resultados corroboram a hipótese de que a suplementação com ácido ascórbico tem um efeito citoprotetor na cirrose biliar secundária.

OBJECTIVE: To test whether ascorbic acid supplementation has any cytoprotective effect on a model of secondary biliary cirrhosis in young rats. METHODS: We studied 40 Wistar rats weaned at the 21st postnatal day. Each group of 10 was subjected to one of the following four treatments, until 49th postnatal day, when they suffered euthanasia: 1) LC-double ligature and resection of the common bile duct and daily administration of ascorbic acid [100 mg/g of body weight (bw)]; 2) LA-double ligature and resection of the common bile duct and daily administration of aqueous vehicle (1 mL/g bw); 3) SC-sham operation and daily administration of ascorbic acid (100 mg/g bw); 4) SA-double ligature and resection of the common bile duct and daily administration of aqueous vehicle (1 mL/g bw). The rats were weighed daily. On the 27th day after the operation they received an intra-peritoneal injection of 1.5 mg/g bw of sodium pentobarbital, and the pentobarbital sleeping time was measured. Blood was collected for serum alanine aminotransferase and aspartate aminotransferase activity measurements, serum albumin and globulin concentrations, and the liver was assessed for liver water and fat content. Data were submitted to two-way ANOVA and paired comparisons between groups were tested using the SNK method. Significance level was set at 0.05. RESULTS: Ascorbic acid supplementation attenuated the effects of cholestasis: decreased the pentobarbital sleeping time, serum globulin, and the liver fat content. CONCLUSIONS: Our results corroborate the hypothesis that ascorbic acid supplementation has a cytoprotective effect in secondary biliary cirrhosis.

Effect of oral vitamin E supplementation in children with cholestasis.

OBJECTIVE: Malabsorption and deficiency of vitamin E are common consequences of chronic cholestasis. The objective of this study was to determine vitamin E status by using plasma vitamin E/total lipid ratio (E/L) in children with cholestasis during supplementation with 20 IU/kg/day and 100 IU/kg/day of oral vitamin E capsule, and 50 IU/kg/day of cold water soluble form (CWSIF) of vitamin E. METHOD: Children with cholestasis who were being supplemented with 20 IU/kg/day of oral vitamin E capsule (dl-alpha-tocopherol) were enrolled into this study. After initial evaluation for vitamin E status and liver function, doses of oral vitamin E supplementation were increased to 100 IU/kg/day for 1 month. Then, supplementation was switched to 50 IU/kg/day of CWS/F vitamin E for 1 month. Vitamin E status was assessed by using plasma E/L after each period of supplementation. RESULTS: Eleven children with biliary atresia, aged between 2 and 18 months, were studied. Their median weight standard deviation score (SDS) was -1.35 and median height SDS was -1.26. The medians of serum direct bilirubin and total bilirubin were 6.5 and 12.9 mg/dl, respectively. Only 2 and 3 out of 9 children had plasma E/L above normal cut-off levels during supplementation with 20 and 100 IU/kg/day of vitamin E capsule, respectively. Additionally, 4 of 9 children had plasma E/L above normal cut-off level after one month's supplementation with 50 IU/kg/day of CWS/F vitamin E. All the responders had serum bilirubin levels less than 4 mg/dl while the remainder with serum direct bilirubin level more than 4 mg/dl had their plasma E/L below normal cut-off levels in spite of any vitamin E supplementation. CONCLUSION: Oral vitamin E supplementation with 20 IU/kg/day and 100 IU/kg/day of vitamin E capsule and with 50 IU/kg/day of CWS/F vitamin E were able to normalize vitamin E status in a few cholestatic children who had serum direct bilirubin levels less them 4 mg/dl. In cases of serum direct bilirubin more than 4 mg/dl, neither of vitamin E supplementations was able to correct the vitamin E deficiency status.

Treatment of cholestasis and cholestatic disorders.

The future of therapy of chronic cholestatic disorders is bright given the large number of new drugs that are in the initial phases of study. UDCA is currently the mainstay of therapy.

Síndromes colestásicos / Cholestatic syndromes

La colestasia es un síndrome caracterizado clínicamente por ictericia y prurito y que desde el punto de vista fisiopatológico es provocado por cualquier interferencia a la secreción bibliar desde el hepatocito mismo hasta la papila de Vater y el esfínter de Oddi

Influência dos sais biliares na resposta motora de alças isoladas a acetilcolina, em ratos / Influence of bile salts on the motor response of isolated ileum to acetylcholine, in rats

A ausência de sais biliares na luz intestinal de pacientes com obstruçao biliar tem sido relacionada ao aumento da flora intestinal e maior produçao de endotoxinas, podendo provocar endotoxemia sistêmica. Entretanto, esses sais têm pequena açao sobre a flora aeróbia e facultativa, que pode estar aumentada por alteraçoes motoras intestinais. Objetivo. Avaliar a resposta motora intestinal na obstruçao biliar em presença de sais biliares. Métodos. Estudaram-se in vitro segmentos ileais de 30 ratos Hotzman do sexo feminino divididos em três grupos (n=10): alça lavada; uso de bile intraluminar e uso de sais biliares exógenos por via oral, durante seis dias. Em cada grupo, cinco animais foram submetidos somente a laparotomia, enquanto cinco outros ratos foram submetidos a ligadura do ducto biliar comum. No sétimo dia pós-operatório, retirou-se um segmento ileal de aproximadamente quatro centrímetros, distantes dez centrímetros da papila ileocecal, e que foi estudado por meio de curva dose-resposta a acetilcolina em banho para órgaos isolados. Resultados. Os resultados obtidos mostraram aumento significativo da afinidade pela acetilcolina no grupo com bile intraluminar. Conclusao. A bile intraluminar, aparentemente, exerce efeito modular positivo sobre a motilidade ileal in vitro.