Colestasis intrahepática drepanocítica a propósito de un casoy revisión de la literatura / Sickle cell intrahepatic cholestasis regarding a case and reviewof the literature

La enfermedad de células falciformes (ECF) o anemia drepanocítica, es el trastorno hereditario más frecuente en los glóbulos rojos, y la enfermedad con más complicaciones en diferentes órganos, lo que provoca múltiples presentaciones de una misma enfermedad., se hace revisión literatura sobre ECF y colestasis intrahepática drepanocítica, y se describe un caso presentado en el Hospital General y de Especialidades Nuestra Señora de la Altagracia de Higüey Republica Dominicana en el año 2022. Es un varón de 24 años, con diagnóstico de ECF, que se complicó con una colestasis intrahepática drepanocítica muy severa que se manejó con hemodiálisis. El objetivo de publicar este caso es revisar la información respecto a la incidencia y la morbimortalidad de esta complicación, teniendo en cuenta que fue tratado por un equipo multidisciplinario usando la hemodiálisis como alternativa terapéutica(AU)

Sickle cell disease (SCD) or sickle cell anemia is the most common hereditary disorder in red blood cells, and the disease with the most complications in different organs, which causes multiple presentations of the same disease. Literature review on SCD is made and sickle cell intrahepatic cholestasis,and a case presented at the Hospital General y de Especialidades Nuestra Señora de la Altagracia de Higüey in the Dominican Republic in 2022 is described. Very severe sickle cell intrahepatic disease that was managed with hemodialysis. The purpose of publishing this case is to review the information regarding the incidence and morbidity and mortality of this complication,taking into account that it was treated by a multidisciplinary team using hemodialysis as a therapeutic alternative(AU)

Hiperbilirrubinemia: visión del patólogo / Hyperbilirubinemia: pathologist's view

Los niveles de bilirrubina sérica normal en el adulto varían entre 0,3 mg/dL y 1,2 mg/dL, y su valor está determinado por la tasa de captación hepática, conjugación y excreción. La ictericia se hace evidente cuando los niveles de bilirrubina sérica se elevan por encima de 2,5 mg/dL a 3 mg/dL, siendo un indicador de enfermedad subyacente. La bilis es producida por los hepatocitos y fluye desde los canalículos, canales de Hering, conductos biliares intrahepáticos, conductos hepáticos derechos e izquierdos hasta llegar al duodeno. A nivel histopatológico, cualquier entidad que lleve a la acumulación intrahepática de bilis por disfunción hepatocelular u obstrucción biliar genera colestasis, que se observa en la biopsia hepática como la acumulación de tapones de color marrón verdoso de pigmento biliar en los hepatocitos, y secundariamente se observan los canalículos dilatados. Las causas de colestasis intrahepática son diversas e incluyen enfermedades como colangitis biliar primaria, colangitis esclerosante primaria, hepatitis autoinmune, hepatitis virales y toxicidad medicamentosa. Esta revisión tiene como objetivo analizar algunos tipos de hiperbilirrubinemia, resaltando sus características histopatológicas.

Normal serum bilirubin levels in adults range from 0.3 mg/dL to 1.2 mg/dL, and its value is determined by the rate of hepatic uptake, conjugation, and excretion. Jaundice becomes apparent when serum bilirubin levels rise above 2.5 mg/dL to 3.5 mg/dL and is an indicator of underlying disease. Bile is produced by hepatocytes and flows from the canaliculi, Hering's canals, intrahepatic bile ducts, and right and left hepatic ducts to the duodenum. Pathologically, any condition that leadsto intrahepatic accumulation of bile due to hepatocellular dysfunction or biliary obstruction, generates cholestasis, which is observed in liver biopsy as the accumulation of greenish-brown deposits of bile pigment in hepatocytes, with dilated canaliculi. The causes of intrahepatic cholestasis are diverse and include diseases such as primary biliary cholangitis and primary sclerosing cholangitis, autoimmune hepatitis, viral hepatitis, and drug toxicity. This review aims to analyze some types of hyperbilirubinemia, highlighting their histopathological characteristics.

Expert consensus on the diagnosis and treatment of intrahepatic cholestasis (2021 edition) / 中华肝脏病杂志

Intrahepatic cholestasis is a clinical syndrome due to the defect of bile acid synthesis, abnormal bile excretion, and mechanical or functional disturbance of intrahepatic bile flows caused by hepatic parenchymal cell and/or intrahepatic bile duct diseases. It commonly occurs as cholestatic liver diseases, intrahepatic cholestasis of pregnancy, and genetic/metabolic-related cholestatic diseases. In recent years, new information and progress in diagnosis and treatment of intrahepatic cholestatic diseases have been achieved. In order to provide updated clinical reference and guidance for clinicians, we organized experts to compile the Expert Consensus on the Diagnosis and Treatment of Intrahepatic Cholestasis (2021), on the basis of the 2015 edition.

Analysis of SLC25A13 gene variants in 16 infants with intrahepatic cholestasis caused by citrin protein deficiency / 中华医学遗传学杂志

OBJECTIVE@#To explore the characteristics of SLC25A13 gene variants in 16 infants with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD).@*METHODS@#The infants were subjected to high-throughput DNA sequencing for coding exons and flanking regions of the target genes. Suspected variants were verified by Sanger sequencing and bioinformatic analysis.@*RESULTS@#Among the 16 NICCD cases, 15 were found to harbor pathogenic variants. Among these, IVS14-9A>G, c.1640G>A, c.762T>A, c.736delG, c.1098Tdel and c.851G>A were previously unreported.@*CONCLUSION@#Six novel SLC25A13 variants were found by high-throughput sequencing, which has enriched the spectrum of SLC25A13 gene variants and provided a basis for genetic counseling and prenatal diagnosis.

Colestasis intrahepática del embarazo: forma de presentación temprana y relación con la infección por el virus de la hepatitis C: reporte de casos / Intrahepatic cholestasis of pregnancy: early presentation and relationship with infection by the hepatitis C virus: case reports / Colestase intra-hepática da gravidez: forma de apresentação precoce e sua relação com a infecção por vírus da hepatite C: relato de casos

Se describe los casos de tres pacientes a quien se les realiza diagnóstico de colestasis intrahepática del embarazo (CIE) de aparición temprana. En dos de ellos el diagnóstico se relacionó con infección por el virus de la hepatitis C (VHC). Reconocer que esta enfermedad puede presentarse de manera temprana en el embarazo y su relación con la infección por el VHC es fundamental para hacer un diagnóstico oportuno de ambas enfermedades y tomar las conductas terapéuticas adecuadas, mejorando así el pronóstico materno y fetal.

It is of great importance to acknowledge that this disease can occur early in pregnancy and that its relationship with HCV infection is a key point for a prompt diagnosis, allowing taking timely appropriate therapeutic decisions, aimed at improving the fetal prognosis.

Descrevemos os casos de três pacientes com diagnóstico de colestase intra-hepática da gravidez de início precoce. Em dois deles o diagnóstico estava relacionado à infecção pelo vírus da hepatite C (VHC). Reconhecer que esta doença pode se manifestar precocemente na gravidez e sua relação com a infecção pelo VHC é fundamental para fazer um diagnóstico oportuno de ambas as doenças e assumir condutas terapêuticas adequadas, melhorando assim o prognóstico materno e fetal.

Experiencia inicial con derivación biliar mediante coledocoduodenostomía guiada por ultrasonido endoscópico en la obstrucción biliar maligna en un hospital de referencia en Colombia / Initial experience with endoscopic ultrasound-guided biliary drainage via choledochoduodenostomy (EUS-CDS) in malignant biliary obstruction in a reference hospital in Colombia

Resumen Introducción: en pacientes con obstrucción biliar distal maligna en quienes la derivación biliar mediante colangiopancreatografía retrógrada endoscópica (CPRE) no sea factible o sea fallida, el drenaje biliar guiado por ultrasonido endoscópico mediante coledocoduodenostomía es una opción terapéutica viable, de la que se describen altas tasas de éxito técnico y clínico con una baja morbimortalidad. Adicionalmente, este método podría ser superior en la mejora de la calidad de vida en comparación con el manejo percutáneo o quirúrgico. Objetivo: describir la experiencia inicial con el drenaje biliar guiado por ultrasonido endoscópico en pacientes con obstrucción biliar maligna en un centro de referencia. Métodos: es una serie de casos retrospectiva de 6 pacientes con obstrucción biliar maligna a quienes se les realizó inicialmente una CPRE que fue fallida, por lo cual se procedió a realizar coledocoduodenostomía guiada por ultrasonografía endoscópica. Se describieron las tasas de éxito técnico, éxito clínico, eventos adversos, tasas de disfunción y tiempo de supervivencia de los pacientes. Resultados: se analizaron 6 casos, predominó el sexo femenino, con un promedio de edad de 71,8 ± 19,8 años; las indicaciones fueron adenocarcinoma de páncreas, tumor periampular y colangiocarcinoma distal. Se observó un éxito técnico en el 100 % de los casos y éxito clínico en 83,3 % de los casos. No se registraron eventos adversos graves. En el seguimiento de los casos se observó una supervivencia del 66,7 % a los 30 días. Conclusión: la coledocoduodenostomía es una alternativa terapéutica viable, segura y efectiva en pacientes con obstrucción biliar maligna en quienes la CPRE fue fallida, con una alta tasa de éxito técnico y clínico.

Abstract Introduction: Patients with malignant biliary distal obstruction who cannot be treated with endoscopic retrograde cholangiopancreatography (ERCP) or who had a failed ERCP, can find alternative treatment in endoscopic ultrasound-guided biliary drainage via choledochoduodenostomy. EUS-CDS performs with high rates of technical and clinical success and with low rates of morbimortality. Moreover, this method could have the potential to improve the patient's quality of life, compared with percutaneous or surgical means. Objective: This study aims to describe the initial experience with endoscopic ultrasound-guided biliary drainage in patients with malignant biliary distal obstruction in a reference center. Methods: Retrospective case review of six patients with malignant biliary obstruction and prior ERCP-placed and failed. Endoscopic ultrasound-guided biliary drainage via choledochoduodenostomy was performed as an alternative method. Technical and clinical success rates, adverse event rates, dysfunction rates, and patient survival time were described. Results: 6 cases were analyzed with a higher proportion of female patients, with a mean age of 71,8 ± 19,8 years. The symptoms were related to pancreas adenocarcinoma, periampullary tumor, and distal cholangiocarcinoma. The procedure was technically successful in 100% of cases and clinically successful in 83% of cases. Serious adverse events were nor reported. After 30 days, a survival rate of 66,7 % was observed. Conclusion: Choledochoduodenostomy is a viable, safe, and effective method in patients with malignant biliary obstruction who had a failed ERCP, and it has high rates of technical and clinical success.

Dermatosis específicas de la embarazada (DEE). Propuesta de nueva clasificación / Pregnant specific dermatoses (DEE). Proposal for a new classification

En el presente trabajo se realiza una breve descripción de las dermatosis específicas de la embarazada (DEE). Se considera que la afección específica más frecuente son las pápulas y placas urticarianas pruriginosas del embarazo (PPUPE), y en segundo lugar los prurigos vinculados del embarazo (PVE). Se aporta una propuesta de nueva clasificación de las dermatosis específicas de la embarazada (DEE). En la clasificación se consideran dos grupos de afecciones. Grupo A: dermatosis específicas de la embarazada (DEE), y dentro de él: a) como enfermedad más frecuente las pápulas y placas urticarianas pruriginosas del embarazo (PPUPE); b) seguidas de los prurigos, tanto sea el precoz como el tardío, a los cuales se los une bajo el término de prurigos vinculados del embarazo (PVE) como entidad también frecuente c) la foliculitis pruriginosa del embarazo (FPE). Como afecciones menos frecuentes dentro de este grupo: a) dermatitis papulosa de Spangler (DPS); b) erupción toxémica del embarazo (ETE); c) herpes gestationis (HG); d) impétigo herpetiforme (IH). Grupo B: afección específica de la embarazada sin lesiones en piel: colestasis intrahepática del embarazo (CIE). (AU)

In the present work, a brief description of the specific dermatoses of the pregnant woman (DEE) is made. The most common specific condition is considered to be pruritic urticarial papules and plaques of pregnancy (PPUPE), and secondly, prurigos associated with pregnancy (PVE). A proposal for a new classification of pregnant-specific dermatoses (DEE) is provided. Two groups of conditions are considered in the classification. Group A: pregnant-specific dermatosis (EED), and within it: a) as the most frequent disease, pruritic urticarial papules and plaques of pregnancy (PPUPE); b) followed by prurigos, both early and late, to which they are associated under the term of linked prurigos of pregnancy (PVE); as also frequent entity; c) the pruritic folliculitis of pregnancy (FPE). As less frequent conditions within this group: a) Spangler's papular dermatitis (DPS); b) toxic eruption of pregnancy (TEE); c) herpes gestationis (HG); d) impetigo herpetiformis (IH). Group B: specific condition of the pregnant woman without skin lesions: intrahepatic cholestasis of pregnancy (ICD). (AU)

Variante "no clásica" o "atípica" del síndrome de Stauffer en paciente con carcinoma renal de células claras: reporte de caso / "Non-classical" or "atypical" variant of Stauffer syndrome in a patient with clear cell renal carcinoma: a case report

La manifestación paraneoplásica conocida como síndrome de Stauffer tiene una presentación atípica, caracterizada por ictericia y colestasis intrahepática. Presentamos el caso de un paciente de 53 años de edad, con antecedente de una masa renal derecha en plan de resección quirúrgica programada, con cuadro de evolución de dolor abdominal en hipocondrio derecho e ictericia. A su ingreso se documentó hepatoesplenomegalia, elevación de bilirrubinas a expensas de la directa, y de fosfatasa alcalina junto con elevación de transaminasas. Se descartaron causas obstructivas a nivel de vía biliar intra y extrahepática. No se documentaron metástasis o lesiones focales a nivel de parénquima, ni lesiones de etiología vascular que explicaran el cuadro. También se descartó hepatitis B, C e infección por VIH, por lo cual se consideró un probable síndrome de Stauffer. Fue llevado a nefrectomía intrahospitalaria, con posterior diagnóstico patológico compatible con carcinoma de células claras. Luego del procedimiento se normalizó la bioquímica hepática y se corrigió la ictericia. Es importante reconocer que la afectación hepática en el contexto de neoplasias, no es solo atribuida a metástasis a distancia, sino también a la existencia de síndromes paraneoplásicos como condicionantes.

The paraneoplastic manifestation known as Stauffer syndrome has an atypical presentation, characterized by jaundice and intrahepatic cholestasis. We present the case of a 53-year-old patient, with a history of a right renal mass with a planned surgical resection, who developed abdominal pain in the right upper quadrant and jaundice. Upon admission, hepatosplenomegaly, elevated bilirubin, at the expense of direct bilirubin, alkaline phosphatase and elevated transaminases were documented. Intra- and extrahepatic bile ducts obstruction were ruled out. There were no documented metastases or focal lesions at the level of the parenchyma, or lesions of vascular etiology that could explain the condition. Hepatitis B, C and HIV infection were also ruled out, and a probable Stauffer syndrome was considered. In-hospital nephrectomy was performed, with subsequent pathology compatible with clear cell carcinoma. After the procedure, liver biochemistry was normalized and jaundice was corrected. It is important to recognize that liver involvement in the context of neoplasms is not only attributed to distant metastases but to the existence of paraneoplastic syndromes as determining factors.

Dengue fever as a potential cause of sickle cell intrahepatic cholestasis: A report of two cases

Abstract Sickle cell intrahepatic cholestasis is a potentially fatal syndrome characterized by jaundice, painful hepatomegaly, and organ dysfunction. Two cases of sickle cell intrahepatic cholestasis associated with dengue fever were described. Endothelial damage/dysfunction is a mechanism involved in severe hepatobiliary complications related to sickle cell diseases. However, the reasons for the lack of increase in the admission of patients with sickle cell disease having severe acute hepatobiliary complications triggered by endothelial damage/dysfunction due to dengue fever remain unknown. This study describes the first association between sickle cell intrahepatic cholestasis and dengue fever.

Clinical characteristics and gene variants of patients with infantile intrahepatic cholestasis / 中国当代儿科杂志

OBJECTIVE@#To explore the clinical characteristics and genetic findings of patients with infantile intrahepatic cholestasis.@*METHODS@#The clinical data were collected in children who were admitted to the Department of Gastroenterology in Children's Hospital, Capital Institute of Pediatrics from June 2017 to June 2019 and were suspected of inherited metabolic diseases. Next generation sequencing based on target gene panel was used for gene analysis in these children. Sanger sequencing technology was used to verify the genes of the members in this family.@*RESULTS@#Forty patients were enrolled. Pathogenic gene variants were identified in 13 patients (32%), including @*CONCLUSIONS@#The etiology of infantile intrahepatic cholestasis is complex. Next generation sequencing is helpful in the diagnosis of infantile intrahepatic cholestasis.

Hepatotoxicidade induzida por azatioprina em portadora da síndrome de Vogt-Koyanagi-Harada / Azathioprine-induced hepatotoxicity in a Vogt-Koyanagi-Harada syndrome patient

Este relato teve como objetivo apresentar um caso de hepatotoxicidade colestática induzida por azatioprina em portadora da síndrome de Vogt-Koyanagi-Harada. À admissão, apresentava icterícia +3/+4, acolia fecal e colúria, além de aumento de marcadores hepáticos, sendo compatível com síndrome colestática, cuja etiologia foi confirmada após exclusão de outras causas possíveis e retirada da azatioprina. A paciente evoluiu, após 1 semana de retirada do fármaco, com diurese livre de coloração menos escura e evacuação presente, sem acolia. Além disso, houve melhora nos exames que precederam a alta hospitalar

This report aimed at presenting a case of azathioprine-induced cholestatic hepatotoxicity in a patient with Vogt-Koyanagi-Harada syndrome. On admission, she presented with jaundice +3/+4, acholic feces, and choluria, as well as increased hepatic markers, all consistent with cholestatic syndrome, the etiology of which was confirmed after other possible causes were ruled out and azathioprine was discontinued. After 1 week of the drug discontinuation, the patient progressed with free diuresis of lighter color and defecation, with no acholia. In addition, tests performed before discharge were improved.

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.

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.

Successful Treatment with Rituximab and Immunoadsorption for an Auto-Antibody Induced Bile Salt Export Pump Deficiency in a Liver Transplanted Patient / 대한소아소화기영양학회지

We present an 8 years old girl who was diagnosed at 6 months of age of Progressive Familial Intrahepatic Cholestasis type 2. Although liver transplantation (LT) was classically considered curative for these patients, cholestasis recurrence with normal gamma-glutamyl transpeptidase (GGT), mediated by anti-bile salt export pump (BSEP) antibodies after LT (auto-antibody Induced BSEP Deficiency, AIBD) has been recently reported. Our patient underwent LT at 14 months. During her evolution, patient presented three episodes of acute rejection. Seven years after the LT, the patient presented pruritus with cholestasis and elevation of liver enzymes with persistent normal GGT. Liver biopsy showed intrahepatic cholestasis and giant-cell transformation with very low BSEP activity. Auto-antibodies against BSEP were detected therefore an AIBD was diagnosed. She was treated with Rituximab and immunoadsorption with resolution of the AIBD. As a complication of the treatment she developed a pneumocystis infection successfully treated with corticoids, cotrimoxazol and anidulafungin.

Severe cholestatic syndrome secondary to Graves' disease

This paper reports a case of severe cholestasis as an atypical manifestation of Graves' disease. It discusses the pathophysiology, the diagnosis and the investigation of this complication of hyperthyroidism as well as the impact of this finding on the therapeutic options for managing the disease. (AU)

Relations of neuropeptide Y and heme oxygenase-1 expressions with fetal brain injury in rats with intrahepatic cholestasis of pregnancy

Abstract Purpose: To investigate the relations of neuropeptide Y (NPY) and heme oxygenase-1 (HO-1) expressions with fetal brain injury in rats with intrahepatic cholestasis of pregnancy (ICP). Methods: Sixty rats pregnant for 15 days were randomly divided into experimental and control groups. The ICP model was established in experimental group. On the 21st day, the blood biochemical test, histopathological examination of pregnant rat liver and fetal brain tissues and immunohistochemical analysis of fetal rat brain tissues were performed. Results: On the 21st day, the alanineaminotransferase, aspartate aminotransferase and total bile acid levels in experimental group were significantly higher than control group (P<0.01). Compared with control group, there was obvious vacuolar degeneration in pregnant rat liver tissue and fetal brain tissue in experimental group. NPY expression in fetal brain tissue was negative in control group and positive in experimental group. HO-1 expression in fetal brain tissue was strongly positive in control group and positive in experimental group. There was significant difference of immunohistochemical staining optical density between two groups (P<0.01). Conclusion: In fetal brain of ICP rats, the NPY expression is increased, and the HO-1 expression is decreased, which may be related to the fetal brain injury.

Protective effects and action mechanism of extract from Tibetan medicine Yajima(Chrysosplenium nudicaule) on mice with intrahepatic cholestasis induced by ANIT / 中国中药杂志

Chrysosplenium nudicaule,Tibetan name " Yajima",is recorded as an effective medicine for the treatment of liver and gallbladder diseases by Tibetan Pharmacopoeia published in the past dynasties,but its traditional efficacy has not yet been investigated by means of modern pharmacological research methods. In this paper,the protective effect of extract of C. nudicaule(ECN) on liver injury in mice was observed by using the mice model of intrahepatic cholestasis(IC) induced by α-naphthyl isothiocyanate(ANIT) and the possible mechanism by which ECN work as the therapeutic agent was discussed. The results showed that the serum levels of AST,ALT,ALP,DBIL,TBIL and TBA of the model mice were notably reduced in dose-dependent manner(P<0. 01,P<0. 05). The activity of SOD and GSH-Px in the liver homogenate of mice was increased,while the content of MDA was decreased(P<0. 01,P<0. 05).Pathological examination of liver in mice showed that ECN could improve the pathological changes of liver tissue in mice. The mRNA expression level of genes related to bile acid metabolism were detected by RT-PCR and the results suggested that ECN could significantly increase the expression of genes such as BSEP,FXR and MRP2(P<0. 01,P<0. 05),meanwhile significantly reduce the expression of CYP7 A1(P<0. 01,P<0. 05). These results confirmed the protective effect of ECN on intrahepatic cholestasis-induced liver injury in mice,and indicated that the mechanism may be related to activating FXR and its target genes,reducing bile acid synthesis and increasing bile acid excretion. This study provides a modern pharmacological basis for the clinical application of Yajima in Tibetan medicine.

Mechanism of Cinnamomi Ramulus improving rat model of intrahepatic cholestasis induced by ANIT by regulating FXR pathway / 中国中药杂志

To study the mechanism and action of Cinnamomi Ramulus in ameliorating intrahepatic cholestasis induced by α-isothiocyanate( ANIT) in rats by regulating FXR pathway. Forty SD rats were randomly divided into normal group,model group,positive control( ursodeoxycholic acid) group( 60 mg·kg~(-1)),Cinnamomi Ramulus treatment( 60 mg·kg~(-1)·d~(-1)) group,and Cinnamomi Ramulus treatment( 20 mg·kg~(-1)·d~(-1)) group,with 8 rats in each group. Except for the normal control group,the other groups were intragastrically administered with the corresponding concentrations of continuous aqueous solution( 0. 005 m L·g~(-1)),once a day,for 7 days.Except for the normal group,the other groups were treated with ANIT( 100 mg·kg~(-1)),once a day,for 3 days. Blood was taken from the abdominal aorta 24 hours after the last administration,and serum alanine aminotransferase( ALT),aspartate aminotransferase( AST),total bilirubin( TBi L),and total bile acid( TBA) were measured. 1. 5-2 cm of rat liver tissue was taken. After fixation with10% formaldehyde,paraffin-embedded sections were taken,HE staining was performed,and immunohistochemistry( IHC) was used to analyze the expression of FXR. RNA and protein were extracted from rat liver tissue to detect FXR mRNA expression,as well as bile acid synthesis and detoxification,transport related SHP,UGT2 B4,BSEP protein expressions at downstream of FXR. Compared with the normal group,serum ALT,AST,TBi L,and TBA levels were elevated in the model group( P<0. 01),liver damage was severe,FXR protein's optical density decreased,FXR mRNA expression decreased,and SHP,UGT2 B4,BSEP protein expressions were decreased( P<0. 05,P<0. 01). Compared with the model group,the drug group could reduce serum ALT,AST,TB,TBA levels to different degrees( P<0. 05,P<0. 01),alleviate liver tissue damage,increase the optical density of FXR protein,and promote the expressions of FXR mRNA and FXR,SHP,BSEP and UGT2 B4 proteins( P<0. 05,P<0. 01). Cinnamomi Ramulus can alleviate ANIT-induced intrahepatic cholestasis,and reduce hepatocyte injury and serum ALT,AST,TBi L and TBA levels. The mechanism may be through FXR-SHP,FXR-UGT2 B4,FXR-BSEP signaling pathways. Therefore,in the pathogenesis of intrahepatic cholestasis,we can try to further explore in alleviating intrahepatic cholestasis with Cinnamomi Ramulus,so as to provide effective drugs for clinical treatment of intrahepatic cholestasis.

Progressive Familial Intrahepatic Cholestasis in Korea: A Clinicopathological Study of Five Patients

BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomal recessive liver diseases that present as neonatal cholestasis. Little is known of this disease in Korea. METHODS: The records of five patients histologically diagnosed with PFIC, one with PFIC1 and four with PFIC2, by liver biopsy or transplant were reviewed, and ATP8B1 and ABCB11 mutation status was analyzed by direct DNA sequencing. Clinicopathological characteristics were correlated with genetic mutations. RESULTS: The first symptom in all patients was jaundice. Histologically, lobular cholestasis with bile plugs was the main finding in all patients, whereas diffuse or periportal cholestasis was identified only in patients with PFIC2. Giant cells and ballooning of hepatocytes were observed in three and three patients with PFIC2, respectively, but not in the patient with PFIC1. Immunostaining showed total loss of bile salt export pump in two patients with PFIC2 and focal loss in two. Lobular and portal based fibrosis were more advanced in PFIC2 than in PFIC1. ATP8B1 and ABCB11 mutations were identified in one PFIC1 and two PFIC2 patients, respectively. One PFIC1 and three PFIC2 patients underwent liver transplantation (LT). At age 7 months, one PFIC2 patient was diagnosed with concurrent hepatocellular carcinoma and infantile hemangioma in an explanted liver. The patient with PFIC1 developed steatohepatitis after LT. One patient showed recurrence of PFIC2 after 10 years and underwent LT. CONCLUSIONS: PFIC is not rare in patients with neonatal cholestasis of unknown origin. Proper clinicopathologic correlation and genetic testing can enable early detection and management.