RESUMEN
BACKGROUND: Neonatal Intrahepatic Cholestasis (NICCD), as the early-age stage of Citrin deficiency involving liver dysfunction, lacks efficient diagnostic markers. Procalcitonin (PCT) has been identified as a biomarker for infection as well as various organ damage. This study aimed to explore the potential of PCT as a biomarker for NICCD. METHODS: In a single-center retrospective case-control study. Serum PCT concentrations before and after treatment of 120 NICCD patients, as the study group, were compared to the same number of cholestatic hepatitis patients, as the control group. The potential value of PCT to discriminate NICCD from control disease was further explored using Receiver Operating Characteristic (ROC) curve analysis and compared to those of other inflammatory markers. RESULTS: There was a significantly higher level of PCT in NICCD patients than in the control group. PCT concentrations were only weakly correlated with neutrophil counts and CRP levels (p Ë 0.05). At a cut-off value of 0.495 ng/mL, PCT exhibited a significantly higher diagnostic value compared to other inflammatory markers for discriminating NICCD from the control, with a sensitivity of 90.8 % and specificity of 98.3 %. CONCLUSION: PCT might be used as an initial biomarker to discriminate children with NICCD from another hepatitis disease.
Asunto(s)
Biomarcadores , Colestasis Intrahepática , Citrulinemia , Polipéptido alfa Relacionado con Calcitonina , Curva ROC , Humanos , Polipéptido alfa Relacionado con Calcitonina/sangre , Biomarcadores/sangre , Estudios Retrospectivos , Masculino , Femenino , Estudios de Casos y Controles , Colestasis Intrahepática/sangre , Colestasis Intrahepática/diagnóstico , Citrulinemia/sangre , Citrulinemia/complicaciones , Citrulinemia/diagnóstico , Lactante , Recién Nacido , Sensibilidad y Especificidad , Proteína C-Reactiva/análisis , Valores de ReferenciaRESUMEN
INTRODUCTION AND OBJECTIVES: Intrahepatic cholestasis of pregnancy (ICP) is often accompanied by fetal and maternal complications. MATERIALS AND METHODS: Retrospective review of the clinical course of women with ICP and their neonates treated at our medical center over a 10-year period. Special attention was paid to the maternal and neonatal response to 2 different modes of ursodeoxycholic acid (UDCA) administration. RESULTS: Neonates of mothers with high total bile acid levels had a poorer composite neonatal outcome. Twenty-seven women who presented at an advanced stage of their pregnancies did not receive UDCA. UDCA was administered in 2 modes: either a full dose at admission (76 women) or a gradually increasing dose until the desired dosage was reached (25 women). The mean gestational age at delivery for the 94 neonates that were exposed to full UDCA dose was the lowest (36±2.3 weeks for the full dose, 37±1.4 weeks for the 30 neonates from the gradually increasing dose, 38±1.6 weeks for the 29 neonates from the no treatment group, p<0.001). The group of neonates that were exposed to full UDCA dose had the highest rate of unfavorable composite neonatal outcome (53% for full dose, 30% for gradually increasing dose, 24% for the no treatment group, p=0.006). CONCLUSIONS: Compared to the administration of a full UDCA dose, the administration of a gradually increasing dose of UDCA may be associated with a greater gestational age at delivery and fewer events of unfavorable composite neonatal outcomes. These novel findings should be retested prospectively in a large cohort of patients.
Asunto(s)
Colagogos y Coleréticos , Colestasis Intrahepática , Edad Gestacional , Complicaciones del Embarazo , Ácido Ursodesoxicólico , Humanos , Ácido Ursodesoxicólico/administración & dosificación , Ácido Ursodesoxicólico/uso terapéutico , Femenino , Embarazo , Colestasis Intrahepática/tratamiento farmacológico , Colestasis Intrahepática/diagnóstico , Colestasis Intrahepática/sangre , Estudios Retrospectivos , Complicaciones del Embarazo/tratamiento farmacológico , Complicaciones del Embarazo/sangre , Recién Nacido , Colagogos y Coleréticos/administración & dosificación , Colagogos y Coleréticos/efectos adversos , Colagogos y Coleréticos/uso terapéutico , Adulto , Resultado del Tratamiento , Resultado del EmbarazoRESUMEN
La colestasis intrahepática del embarazo es producida por una disfunción de los hepatocitos, propia de la gestación. Las concentraciones elevadas de hormonas sexuales y la predisposición genética parecen ser factores importantes para su desarrollo. La incidencia depende de la composición étnica de la población y de los criterios diagnósticos utilizados. Está caracterizada por prurito creciente y persistente, aumento de las concentraciones de ácidos biliares, generalmente a finales del segundo o tercer trimestre del embarazo. Lleva a la aparición de hipoxia uteroplacentaria que aumenta el riesgo de líquido amniótico meconial, parto pretérmino, preeclampsia, hemorragia posparto, síndrome de dificultad respiratoria del neonato y muerte perinatal. El manejo terapéutico está dirigido a reducir los síntomas clínicos, normalizar los cambios bioquímicos maternos y prevenir complicaciones fetales. El tratamiento farmacológico principal consiste en la administración de ácido ursodesoxicólico. El objetivo de esta investigación es evaluar el diagnóstico y manejo de la colestasis intrahepática del embarazo(AU)
Intrahepatic cholestasis of pregnancy is caused by a dysfunction of the hepatocytes, typical of pregnancy. High concentrations of sex hormones and genetic predisposition appear to be important factors for their development. The incidence depends on the ethnic composition of the population and the diagnostic criteria used. It is characterized by increasing and persistent pruritus, increased concentrations of bile acids, usually in the late second or third trimester of pregnancy. It leads to the occurrence of uteroplacental hypoxia that increases the risk of meconium amniotic fluid, preterm delivery, preeclampsia, postpartum hemorrhage, neonatal respiratory distress syndrome, and perinatal death. Therapeutic management is aimed at reducing clinical symptoms, normalizing maternal biochemical changes, and preventing fetal complications. The main pharmacological treatment consists of the administration of ursodeoxycholic acid. The objective of this research is to evaluate the diagnosis and management of intrahepatic cholestasis of pregnancy(AU)
Asunto(s)
Humanos , Femenino , Embarazo , Prurito , Embarazo , Colestasis Intrahepática/diagnóstico , Colestasis Intrahepática/etiología , Signos y Síntomas , Conductos Biliares , Hepatocitos , Muerte Fetal , Hemorragia Posparto , Líquido AmnióticoRESUMEN
INTRODUCTION AND OBJECTIVES: Intrahepatic cholestasis is a frequent disease during pregnancy. It is unknown if liver function alterations produce specific placental lesions. The aim of this study was to evaluate placental histopathological changes in patients with intrahepatic cholestasis of pregnancy (ICP), and to explore correlations between the placental histopathology and hepatic function alteration or patient comorbidities, and body mass index. PATIENTS AND METHODS: A retrospective cohort study included women with ICP, most of them showing comorbidities such as overweight/obesity, preeclampsia and gestational diabetes. They were attended at the National Institute of Perinatology in Mexico City for three years. Placental histopathological alterations were evaluated according to the Amsterdam Placental Workshop Group Consensus Statement. Data was analyzed using Graph-Pad Prism 5. RESULTS: The results indicated that the placenta of ICP patients showed many histopathological alterations; however, no correlations were observed between the increase in bile acids or liver functional parameters and specific placental lesions. The most frequent comorbidities found in ICP patients were obesity, overweight and preeclampsia. Surprisingly, high percentage of ICP patients did not respond to UDCA treatment independently of the BMI group to which they belonged. CONCLUSION: The data suggest that ICP contribute to placental lesions. In addition, in patients with normal weight, an increase of chorangiosis and a reduced accelerated villous maturation without syncytial knots were observed in comparison with overweight and obese patients. It is necessary to improve the medical strategies in the treatment and liver disfunction surveillance of ICP patients.
Asunto(s)
Colestasis Intrahepática , Preeclampsia , Complicaciones del Embarazo , Embarazo , Femenino , Humanos , Placenta/patología , Índice de Masa Corporal , Sobrepeso/epidemiología , Estudios Retrospectivos , Complicaciones del Embarazo/epidemiología , Colestasis Intrahepática/diagnóstico , Colestasis Intrahepática/epidemiología , Colestasis Intrahepática/patología , Obesidad/diagnóstico , Obesidad/epidemiologíaRESUMEN
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.
Asunto(s)
Humanos , Femenino , Embarazo , Adulto , Complicaciones Infecciosas del Embarazo/diagnóstico , Prurito , Colestasis Intrahepática/diagnóstico , Colestasis Intrahepática/etiología , Hepatitis C/complicaciones , Segundo Trimestre del Embarazo , Primer Trimestre del Embarazo , Ácido Ursodesoxicólico/uso terapéutico , Clorfeniramina/uso terapéutico , Colestasis Intrahepática/tratamiento farmacológico , Hepatitis C/diagnóstico , Diagnóstico PrecozRESUMEN
INTRODUCTION AND OBJECTIVES: Progressive familial intrahepatic cholestasis type 3 (PFIC-3) is a rare autosomal recessive cholestatic liver disorder caused by mutations in the ABCB4 gene. The aim of this study was to present the phenotypic and genotypic spectrum of 4 Polish PFIC-3 patients diagnosed in a one-referral centre. MATERIALS AND METHODS: The study included 4 patients with cholestasis and pathogenic variants in the ABCB4 gene identified by next-generation sequencing (NGS) of a targeted-gene panel or whole exome sequencing (WES). Clinical, laboratory, histological, and molecular data were collected. RESULTS: Four patients (three males) were identified. The age at first noted clinical signs and symptoms was 6, 2.5, 14, and 2 years respectively; the mean age was 6 years. Those signs and symptoms include pruritus (2 out of 4 patients) and hepatomegaly with splenomegaly (4 out of 4 patients). The age at the time of referral to our centre was 9, 3, 15, and 2.5 years respectively, while the mean age was 7 years. Chronic cholestatic liver disease of unknown aetiology was established in all of them. The NGS analysis was performed in all patients at the last follow-up visit. Three novel variants including c.902T>A, p.Met301Lys, c.3279+1G>A, p.?, and c.3524T>A, p.Leu1175His were identified. The time from the first consultation to the final diagnosis was 14, 9, 3, and 1 year respectively; the mean was 6.8 years. A detailed follow-up was presented. CONCLUSIONS: The clinical phenotype of PFIC-3 could be variable. The clinical and biochemical diagnosis of PFIC-3 is difficult, thus the NGS study is very useful in making a proper diagnosis.
Asunto(s)
Subfamilia B de Transportador de Casetes de Unión a ATP/deficiencia , Colestasis Intrahepática/diagnóstico , Colestasis Intrahepática/genética , Mutación/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Adolescente , Niño , Preescolar , Colestasis Intrahepática/terapia , Femenino , Estudios de Seguimiento , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , PoloniaRESUMEN
INTRODUCTION AND OBJECTIVES: Differentiating biliary atresia from other causes of neonatal cholestasis is challenging, particularly when cytomegalovirus (CMV) and biliary atresia occur simultaneously. We aimed to elucidate whether CMV infection would affect the differential diagnosis of biliary atresia and intrahepatic cholestasis. PATIENTS AND METHODS: This retrospective study was conducted among patients with neonatal cholestasis admitted to three tertiary hospitals between January 2010 and August 2019. The clinical characteristics, laboratory, and imaging findings were recorded. On the basis of the CMV serology results, the infants were classified into CMV-IgM (+) and CMV-IgM (-) groups. The clinical differences and diagnostic performances of routine predictors between biliary atresia and intrahepatic cholestasis were analyzed in each group. Finally, we compared the diagnostic performances of various tests in the two groups. RESULTS: A total of 705 patients with neonatal cholestasis were enrolled: 215 (30.5%) patients were positive for CMV-IgM, among whom 97 had biliary atresia and 118 had CMV hepatitis; 490 infants were CMV-IgM (-), among whom 240 had biliary atresia and 250 had intrahepatic cholestasis. The diagnostic performances of stool color, direct bilirubin level, γ-glutamyl transpeptidase level, abnormal gallbladder, triangular cord sign, and hepatobiliary scintigraphy between CMV hepatitis and CMV-IgM (+) biliary atresia were similar to those between CMV-IgM (-) biliary atresia and CMV-IgM (-) intrahepatic cholestasis groups. CONCLUSIONS: Our large-scale study showed a high prevalence of CMV infection in patients with neonatal cholestasis in China. The presence of CMV infection did not affect the routine predictors to discriminate biliary atresia and intrahepatic cholestasis.
Asunto(s)
Atresia Biliar/diagnóstico , Atresia Biliar/microbiología , Colestasis Intrahepática/diagnóstico , Colestasis Intrahepática/microbiología , Infecciones por Citomegalovirus/epidemiología , Atresia Biliar/complicaciones , China , Colestasis Intrahepática/complicaciones , Infecciones por Citomegalovirus/complicaciones , Infecciones por Citomegalovirus/diagnóstico , Diagnóstico Diferencial , Femenino , Humanos , Recién Nacido , Masculino , Prevalencia , Estudios Retrospectivos , Sensibilidad y EspecificidadRESUMEN
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.
Asunto(s)
Humanos , Masculino , Persona de Mediana Edad , Síndromes Paraneoplásicos/etiología , Carcinoma de Células Renales/complicaciones , Síndromes Paraneoplásicos/diagnóstico , Carcinoma de Células Renales/diagnóstico , Colestasis Intrahepática/diagnóstico , Fosfatasa Alcalina/análisis , Transaminasas/análisis , Ictericia/diagnósticoRESUMEN
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.
Asunto(s)
Humanos , Femenino , Persona de Mediana Edad , Azatioprina/toxicidad , Azatioprina/uso terapéutico , Síndrome Uveomeningoencefálico/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/diagnóstico , Inmunosupresores/toxicidad , Inmunosupresores/uso terapéutico , Sinusitis/tratamiento farmacológico , Azatioprina/efectos adversos , Tórax/diagnóstico por imagen , Radiografía , Colestasis Intrahepática/diagnóstico , Colestasis Intrahepática/sangre , Ultrasonografía , Neumonía Bacteriana/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/sangre , Bocio Nodular/diagnóstico por imagen , Inmunosupresores/efectos adversos , Antibacterianos/uso terapéuticoRESUMEN
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.
Asunto(s)
Humanos , Masculino , Femenino , Recién Nacido , Colestasis/diagnóstico , Colestasis/genética , Colestasis/inmunología , Colestasis Intrahepática/genética , Hiperbilirrubinemia Neonatal/diagnóstico , Hiperbilirrubinemia Neonatal/etiología , Colestasis/etiología , Colestasis/tratamiento farmacológico , Colestasis Intrahepática/diagnóstico , Colestasis Intrahepática/tratamiento farmacológicoRESUMEN
OBJECTIVE: To evaluate the performance of a diagnostic protocol for neonatal/infantile cholestasis in which the main clinical patterns steered the early use of different genetic testing strategies. STUDY DESIGN: An observational study was conducted between 2012 and 2017 in a tertiary care setting on a prospective cohort of children with cholestasis occurring at ≤1 year of age and persisting ≥6 weeks, to measure the detection rate of underlying monogenic diseases. After the exclusion of biliary atresia, a clinically driven genetic testing was performed, entailing 3 different approaches with different wideness: confirmatory single-gene testing; focused virtual panels; and wide search through trio whole-exome sequencing. RESULTS: We enrolled 125 children (66 female, median age 2 months); 96 (77%) patients had hypocholic stools and were evaluated rapidly to exclude biliary atresia, which was the final diagnosis in 74 (59%). Overall, 50 patients underwent genetic testing, 6 with single confirmatory gene testing, 38 through panels, and 6 with trio whole-exome sequencing because of complex phenotype. The genetic testing detection rate was 60%: the final diagnosis was Alagille syndrome in 11, progressive familial intrahepatic cholestasis type 2 in 6, alpha-1-antitrypsin deficiency in 3, and progressive familial intrahepatic cholestasis type 3 in 2; a further 7 genetic conditions were identified in 1 child each. Overall, only 18 of 125 (14%) remained with an indeterminate etiology. CONCLUSIONS: This protocol combining clinical and genetic assessment proved to be an effective diagnostic tool for neonatal/infantile cholestasis, identifying inherited disorders with a high detection rate. It also could allow a noninvasive diagnosis in children presenting with colored stools.
Asunto(s)
Colestasis/diagnóstico , Colestasis/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Subfamilia B de Transportador de Casetes de Unión a ATP/deficiencia , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Síndrome de Alagille/diagnóstico , Síndrome de Alagille/genética , Algoritmos , Atresia Biliar/diagnóstico , Atresia Biliar/genética , Niño , Preescolar , Colestasis Intrahepática/diagnóstico , Colestasis Intrahepática/genética , Exoma , Heces , Femenino , Pruebas Genéticas , Humanos , Lactante , Recién Nacido , Masculino , Fenotipo , Estudios Prospectivos , Atención Terciaria de Salud , Deficiencia de alfa 1-Antitripsina/diagnóstico , Deficiencia de alfa 1-Antitripsina/genéticaRESUMEN
INTRODUCTION AND AIM: Matrix metalloproteinase (MMP)-2 and MMP-9 are reported to participate in several pregnancy-related diseases, including intrahepatic cholestasis of pregnancy (ICP), which is a severe liver disorder in pregnant women. Meanwhile, ample evidences have demonstrated that celastrol inhibits the activity and expression of MMPs. The present study aims to examine the effect of celastrol to alleviate symptoms of ICP in rat model. MATERIAL AND METHODS: By inducing ICP with 17 - ethinylestradiol in pregnant female rats, we assessed the impact of celastrol administration on symptoms of ICP, such as the rate of bile flow, the level of total bile acids (TBA), and the activities of MMP-2 and -9. Furthermore, the correlations between the levels of MMPs with the examined ICP symptoms were investigated. RESULTS: In rats with ICP, both MMP-2 and -9 exhibited significantly elevated activities, which were inhibited by the administration of celastrol. Furthermore, ICP symptoms such as bile flow rate and total TBA were restored by celastrol. Lastly, there were strong correlations between levels of the two MMPs and TBA. CONCLUSION: Our findings described for the first time the effects of celastrol to attenuate ICP symptoms through an inhibition of both MMP-2 and -9, providing evidence for a potential role of celastrol as a new drug for the treatment of ICP.
Asunto(s)
Colestasis Intrahepática/tratamiento farmacológico , Metaloproteinasa 2 de la Matriz/efectos de los fármacos , Metaloproteinasa 9 de la Matriz/efectos de los fármacos , Inhibidores de la Metaloproteinasa de la Matriz/uso terapéutico , Complicaciones del Embarazo/tratamiento farmacológico , Preñez , Triterpenos/uso terapéutico , Animales , Colestasis Intrahepática/diagnóstico , Colestasis Intrahepática/enzimología , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Femenino , Metaloproteinasa 2 de la Matriz/sangre , Metaloproteinasa 9 de la Matriz/sangre , Triterpenos Pentacíclicos , Embarazo , Complicaciones del Embarazo/diagnóstico , Complicaciones del Embarazo/enzimología , Ratas , Ratas Sprague-Dawley , TripterygiumRESUMEN
OBJECTIVE: To test the application of a target enrichment next-generation sequencing (NGS) jaundice panel in genetic diagnosis of pediatric liver diseases. STUDY DESIGN: We developed a capture-based target enrichment NGS jaundice panel containing 42 known disease-causing genes associated with jaundice or cholestasis and 10 pathway-related genes. During 2015-2017, 102 pediatric patients with various forms of cholestasis or idiopathic liver diseases were tested, including patients with initial diagnosis of cholestasis in infancy, progressive familial intrahepatic cholestasis, syndromic cholestasis, Wilson disease, and others. RESULTS: Of the 102 patients, 137 mutations/variants in 44 different genes were identified in 84 patients. The genetic disease diagnosis rate was 33 of 102 (32.4%). A total of 79 of 102 (77.5%) of patients had at least 1 heterozygous genetic variation. Those with progressive intrahepatic cholestasis or syndromic cholestasis in infancy had a diagnostic rate of 62.5%. Disease-causing mutations, including ATP8B1, ABCB11, ABCB4, ABCC2, TJP2, NR1H4 (FXR), JAG1, AKR1D1, CYP7B1, PKHD1, ATP7B, and SLC25A13, were identified. Nine patients had unpredicted genetic diagnosis with atypical phenotype or novel mutations in the investigational genes. We propose an NGS diagnosis classification categorizing patients into high (n = 24), moderate (n = 9), or weak (n = 25) levels of genotype-phenotype correlations to facilitate patient management. CONCLUSIONS: This panel enabled high-throughput detection of genetic variants and disease diagnosis in patients with a long list of candidate causative genes. A NGS report with diagnosis classification may aid clinicians in data interpretation and patient management.
Asunto(s)
Miembro 11 de la Subfamilia B de Transportador de Casetes de Unión al ATP/genética , Colestasis Intrahepática/diagnóstico , ADN/genética , Mutación , Receptores Citoplasmáticos y Nucleares/genética , Miembro 11 de la Subfamilia B de Transportador de Casetes de Unión al ATP/metabolismo , Preescolar , Colestasis Intrahepática/genética , Colestasis Intrahepática/metabolismo , Análisis Mutacional de ADN , Femenino , Estudios de Asociación Genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Recién Nacido , Masculino , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Receptores Citoplasmáticos y Nucleares/metabolismo , Estudios RetrospectivosRESUMEN
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)
Asunto(s)
Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Graves/diagnóstico , Enfermedad de Graves/terapia , Enfermedad de Graves/diagnóstico por imagen , Tiroidectomía/métodos , Colestasis Intrahepática/diagnóstico , Diagnóstico DiferencialRESUMEN
OBJECTIVE: To assess whether prolonged neonatal cholestasis, described in congenital hypopituitarism and septo-optic dysplasia (SOD), is associated with altered expression of selected canalicular ectoenzymes and canalicular transport proteins. STUDY DESIGN: Children with congenital hypopituitarism (n = 21), SOD (n = 18), and cholestasis seen in our center over 26 years were reviewed. Histopathologic findings in archival liver biopsy specimens were assessed (n = 10) and in those with low/normal levels of serum γ-glutamyltransferase (GGT) activity despite conjugated hyperbilirubinemia, expression of canalicular ectoenzymes and canalicular transport proteins was evaluated immunohistochemically. RESULTS: Patients presented at a median age of 8 weeks (range 3-20 weeks) with median total bilirubin 116 µmol/L (45-287 µmol/L), GGT 95 IU/L (25-707 UI/L), and serum cortisol 51 nmol/L (17-240 nmol/L). All but 3 had low free thyroxin (median 9.6 pmol/L [6.8-26.9]) with increased thyroid-stimulating hormone levels (median 5.95 mU/L [<0.1-9.24]). Liver histologic features included moderate-to-severe intralobular cholestasis with nonspecific hepatitis, giant-cell transformation of hepatocytes, and fibrosis. In all, immunohistochemical staining for canalicular ectoenzymes and canalicular transport proteins revealed a degree of reduced expression, associated with normal serum GGT values in 6 of the 10 patients, and another 6 nonbiopsied infants with cholestasis also had low/normal serum GGT activity. Sequencing of ABCB11 and ATP8B1 performed in 6 of the biopsied patients did not identify pathogenic mutations. Following replacement therapy, biochemical evidence of hepatobiliary injury resolved in all children within a median period of 6 months. CONCLUSION: Hepatobiliary involvement in congenital hypopituitarism associated with SOD has a good prognosis, but its etiology remains uncertain. Immunohistochemical expression of canalicular transport proteins was reduced in available liver samples.
Asunto(s)
Miembro 11 de la Subfamilia B de Transportador de Casetes de Unión al ATP/biosíntesis , Transportadoras de Casetes de Unión a ATP/biosíntesis , Colestasis Intrahepática/metabolismo , Hepatocitos/metabolismo , Hipopituitarismo/metabolismo , gamma-Glutamiltransferasa/biosíntesis , Biomarcadores/metabolismo , Biopsia , Colestasis Intrahepática/diagnóstico , Femenino , Hepatocitos/patología , Humanos , Hipopituitarismo/congénito , Inmunohistoquímica , Lactante , Recién Nacido , Masculino , Estudios RetrospectivosRESUMEN
BACKGROUND AND AIM: Intrahepatic cholestasis of pregnancy (ICP) is linked with increased risk of fetal complications. An accurate diagnostic test is needed to diagnose this disorder on time. We aimed to assess sensitivity and specificity of laboratory tests used for diagnosis of intrahepatic cholestasis of pregnancy and determine more reliable cut-off values of transaminases. MATERIAL AND METHODS: Sixty one symptomatic patients with ICP and 29 healthy pregnant women were included in the retrospective analysis. RESULTS: ICP patients had higher total bile acids (TBA) levels than healthy women (32 vs. 6; P < 0.0001) due to increase in cholic acid (CA) and chenodeoxycholic acid (CDCA). CA/CDCA ratio was significantly higher in ICP patients compared to healthy pregnant women (1.13 vs. 0.68; P < 0.00002). TBA, CA, CDCA and CA/CDCA ratio demonstrate the following sensitivity (94%, 96%, 89%, 71.9%) and specificity (63%, 63%, 59%, 79.3%, respectively) for ICP diagnosis. Lowering cut-off values for ALT (31 U/L) and AST (30 U/L) resulted only in minimal increase of sensitivity to 92.2% vs. 90.1% for ALT and to 92.2%, vs. 90.6% for AST. CONCLUSION: The present study did not reveal any single specific and sensitive marker for reliable diagnosis of ICP. Establishment of lower cut-off values for transaminases activity might only minimally increase the accuracy of diagnosing ICP.
Asunto(s)
Alanina Transaminasa/sangre , Aspartato Aminotransferasas/sangre , Ácidos y Sales Biliares/sangre , Colestasis Intrahepática/diagnóstico , Pruebas Enzimáticas Clínicas , Pruebas de Función Hepática , Complicaciones del Embarazo/diagnóstico , Adulto , Biomarcadores/sangre , Ácido Quenodesoxicólico/sangre , Colestasis Intrahepática/sangre , Ácido Cólico/sangre , Femenino , Humanos , Valor Predictivo de las Pruebas , Embarazo , Complicaciones del Embarazo/sangre , Reproducibilidad de los Resultados , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP) is the commonest gestational liver disease. The risk of adverse fetal outcome has been associated with the severity of maternal hypercholanemia after diagnosis. OBJECTIVE: To investigate whether there is a relationship between the severity and timing of onset of hypercholanemia and the risk of meconium-stained amniotic fluid (MSAF) and adverse neonatal events. STUDY DESIGN: The study included 382 pregnancies complicated by ICP managed at a referral hospital in Buenos Aires (Argentina) between June 2009 and December 2013. The patients were classified into three groups according to the severity of hypercholanemia at diagnosis; mild (10-19.9 µmol/L), moderate (20-39.9 µmol/L) and severe (≥40 µmol/L). Their clinical characteristics and pregnancy outcomes were investigated in a prospective observational study. RESULTS: Higher risk of MSAF was observed when ICP appeared early in gestation or when hypercholanemia was more severe. Taking both parameters into account an MSAF risk factor (MRF) was defined. Based on a model of positive/negative predictive values, a cut-off point of MRF = 3 was selected, which prioritized sensitivity versus specificity. In ICP patients with MRF>3, the probability of MSAF was enhanced 4-fold. An increase in the frequency of MSAF was also associated with higher serum levels at diagnosis of alanine transaminase, alkaline phosphatase and direct bilirubin. CONCLUSIONS: The risk of MSAF is associated not only with the magnitude of hypercholanemia at diagnosis but also with the early gestational onset of raised maternal serum bile acids.
Asunto(s)
Líquido Amniótico , Colestasis Intrahepática/diagnóstico , Meconio , Complicaciones del Embarazo/diagnóstico , Alanina Transaminasa/sangre , Fosfatasa Alcalina/sangre , Bilirrubina/sangre , Colestasis Intrahepática/sangre , Femenino , Humanos , Recién Nacido , Masculino , Embarazo , Complicaciones del Embarazo/sangre , Factores de Riesgo , Índice de Severidad de la Enfermedad , Factores de Tiempo , Adulto JovenRESUMEN
Progressive Familial Intrahepatic Cholestasis type 2 (PFIC2) is a rare cholestatic disorder diagnosed in infancy or childhood that can lead to severe hepatic fibrosis and liver failure. Mutations in the ABCB11 gene result in a deficiency of the bile salt export protein (BSEP) and accumulation of bile inside the hepatocytes. Hepatocellular carcinoma is another condition associated with severe forms of deletion mutations in the ABCB11 gene. Treatment options including ursodeoxycholic acid biliary diversion have mixed outcomes and some patients require liver transplantation. Here, we describe two siblings with an extremely mild form of PFIC2 inherited from heterozygous parents. The elder sibling had acute liver failure at the age of six months and both siblings had pruritus, cholestasis, coagulopathy and fat-soluble-vitamin deficiencies in infancy but have been asymptomatic past infancy. Genetic testing of the siblings revealed that each were compound heterozygotes for two missense mutations of the ABCB11 gene: p.C68Y and p.R832H. Medical treatment typical for PFIC2 has not been necessary for either patient. This is the first report of these variants following a mild course in two affected patients.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Colestasis Intrahepática/genética , Mutación Missense , Miembro 11 de la Subfamilia B de Transportador de Casetes de Unión al ATP , Biopsia con Aguja Gruesa , Niño , Preescolar , Colestasis Intrahepática/diagnóstico , Análisis Mutacional de ADN , Femenino , Predisposición Genética a la Enfermedad , Herencia , Heterocigoto , Humanos , Inmunohistoquímica , Masculino , Microscopía Electrónica de Transmisión , Linaje , Fenotipo , Índice de Severidad de la EnfermedadRESUMEN
ABSTRACT Intrahepatic cholestasis of pregnancy (ICP) is a severe liver disease uniquely occurring during pregnancy. In this study we aimed to identify novel biomarker for the diagnosis of ICP in Chinese population. 50 healthy pregnant women, 50 mild ICP patients and 48 severe ICP patients were enrolled for this study. Liver function tests, including serum total bilirubin, direct bilirubin, alanine transaminase, aspartate aminotransferase and cholyglycine, were performed in all participants. After an overnight fast serum levels of total bile acids (TBA), matrix metalloproteinase (MMP)-2 and MMP-9 were measured, and their correlation with liver function tests were analyzed. The observed increase in serum TBA in ICP patients was not statistically significant which made it unreliable for diagnosis of ICP in Chinese population. On the other hand, both MMP-2 and MMP-9 serum levels exhibited a progressive and significant elevation in mild and severe ICP patients compared with healthy pregnant women, which also positively correlated with liver function tests. Serum levels of both MMP-2 and MMP-9 could be reliably used as laboratory abnormalities for accurate diagnosis and sensitive grading of ICP in Chinese population.