Diagnosis Of Pediatric Liver Disease Research Articles

Panel-Based Next-Generation Sequencing for the Diagnosis of Cholestatic Genetic Liver Diseases: Clinical Utility and Challenges

To test the application of a target enrichment next-generation sequencing (NGS) jaundice panel in genetic diagnosis of pediatric liver diseases. 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. 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. 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.

Percutaneous Liver Biopsy in the Diagnosis of Pediatric Liver Diseases

Background: Liver is prone to different diseases including congenital, infections, metabolic and malignancies. Liver biopsy is an aggressive but definitive way to diagnose liver diseases.Objective: To diagnose different types of liver diseases and to determine the safety of percutaneous liver biopsy by disposable Tru-Cut needle.Materials & Methods: A descriptive study was done in the department of Pediatric Gastroenterology, Hepatology & Nutrition, Dhaka Shishu (Children) Hospital, Dhaka, Bangladesh from January 2014 to January 2016. After getting history, physical examination and ultrasonogram, the biopsy was done with the help of Tru-Cut needle of different sizes under local anesthetics (2% lidocaine) with 3 hours fasting. The biopsy specimens were immediately fixed in 10% formal-saline and alcohol. The tissues were processed in automatic tissue processor under standard condition.Results: Age of the children was 1 month to 12 years with mean age of 3.1 years (3.1±0.763) with a range from 1 month to 12 years and male:female ratio was 1.1:1. The most common histological diagnosis was neonatal hepatitis (23.3%) followed by biliary atresia (16.7%). There were chronic hepatitis (10.0%), glycogen storage disease (10.0%), cirrhosis (6.7%) and hepatoblastoma (6.7%) in moderate frequency. Other cases of least frequency (3.3%) were fatty change, lipid storage disease, intra-hepatic bile duct paucity, congenital hepatic fibrosis and Von Meyenburg complex. Neonatal hepatitis & biliary atresia were common among ?1 year age group and glycogen storage disease, hepatoblastoma & non-specific changes in 1-5 year age group. In the older children (>5 years), chronic hepatitis (10.0%) & cirrhosis (6.6%) were the common causes. Consanguinity was present in storage disease, neonatal hepatitis, congenital hepatic fibrosis, von meyenburg complex and intra-hepatic bile duct paucity. After biopsy, mild pain and discomfort was present in 23 (38.3%) children, while diffuse pain which required analgesics in 11 (18.3%) children without any major complications.Conclusion: Liver biopsy is a useful and practical tool for the diagnosis of pediatric liver diseases. Neonatal hepatitis, biliary atresia, storage disorders and chronic hepatitis were common entities in our set up. Consanguinity was more common in hereditary and metabolic liver diseases. Liver biopsy is safe having minimal complications.Bangladesh J Child Health 2016; VOL 40 (2) :72-78

Guideline for the Evaluation of Cholestatic Jaundice in Infants: Joint Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition.

Cholestatic jaundice in infancy affects approximately 1 in every 2500 term infants and is infrequently recognized by primary providers in the setting of physiologic jaundice. Cholestatic jaundice is always pathologic and indicates hepatobiliary dysfunction. Early detection by the primary care physician and timely referrals to the pediatric gastroenterologist/hepatologist are important contributors to optimal treatment and prognosis. The most common causes of cholestatic jaundice in the first months of life are biliary atresia (25%-40%) followed by an expanding list of monogenic disorders (25%), along with many unknown or multifactorial (eg, parenteral nutrition-related) causes, each of which may have time-sensitive and distinct treatment plans. Thus, these guidelines can have an essential role for the evaluation of neonatal cholestasis to optimize care. The recommendations from this clinical practice guideline are based upon review and analysis of published literature and the combined experience of the authors. The committee recommends that any infant noted to be jaundiced after 2 weeks of age be evaluated for cholestasis with measurement of total and direct serum bilirubin, and that an elevated serum direct bilirubin level (direct bilirubin levels >1.0 mg/dL or >17 μmol/L) warrants timely consideration for evaluation and referral to a pediatric gastroenterologist or hepatologist. Of note, current differential diagnostic plans now incorporate consideration of modern broad-based next-generation DNA sequencing technologies in the proper clinical context. These recommendations are a general guideline and are not intended as a substitute for clinical judgment or as a protocol for the care of all infants with cholestasis. Broad implementation of these recommendations is expected to reduce the time to the diagnosis of pediatric liver diseases, including biliary atresia, leading to improved outcomes.

La biopsia hepática en niños, experiencia de 5 años en un hospital pediátrico colombiano

Objetivo: evaluar la distribución por frecuencia de las enfermedades hepáticas que justificaron el estudio por biopsia en pacientes pediátricos colombianos. Metodología: se evaluaron las biopsias de hígado realizadas durante 5 años en un hospital pediátrico y se agruparon las enfermedades hepáticas por diagnóstico y edad. Resultados: se encontraron 182 estudios histopatológicos de 168 pacientes, 14 de ellos contaban con 2 procedimientos; 53,6% fueron niños y 46,4%, niñas. El grupo de edad con más biopsias fue el de los lactantes menores y la colestasis fue en ellos la indicación más frecuente del estudio. Los grupos de enfermedades más diagnosticadas fueron los procesos inflamatorios (30,2%), las anormalidades de la vía biliar (26,4%), las enfermedades tumorales (14,9%) y los trastornos metabólicos/de depósito (9,3%). Los porcentajes restantes correspondieron a entidades infrecuentes y biopsias normales. Conclusión: la biopsia hepática es una herramienta útil y práctica en el diagnóstico de la enfermedad hepática pediátrica cuando se combina con datos clínicos y de laboratorio. En nuestro estudio, los procesos inflamatorios, las anormalidades de la vía biliar y las enfermedades tumorales fueron las categorías más diagnosticadas.

Elastographic assessment of liver fibrosis in children: A prospective single center experience

BackgroundThe assessment of liver damage in various disease states relies on a combination of clinical findings, biochemical parameters and invasive tests such as liver biopsy. The ultrasound elastography has emerged as a potential alternative test, providing quantifiable information on the elasticity/stiffness of the examined-tissues. We assessed the performance of ultrasound elastography using real-time Acoustic Radiation Force Imaging (ARFI) technology in evaluating the degree of liver fibrosis in children with and without liver disease. MethodsChildren aged 0–18 years, hospitalized in the Emergency Clinical County Hospital Tg. Mures, Romania, between September 15, 2010 and January 15, 2011, were eligible for the study. Four groups were recruited as follow: patients with liver disease in the setting of various malignant disorders, children with non-malignant liver disease, overweight and obese children and healthy controls. The liver tissue elasticity was assessed in each individual using Shear Wave Velocity (SWV). Biochemical tests included transaminase levels. 19 children with chronic liver disease underwent biopsies. SWV was measured globally and separately for the liver-segments 1 and 8. Correlations between the SWV and laboratory test were established using non-parametric Spearman correlation test. ResultsA total of 103 children underwent liver ultrasound elastographic assessments. Of these, 39 had malignancies, 19 had various chronic liver diseases, 13 had nonalcoholic fatty liver disease (NAFLD), and 32 were healthy controls. The transaminase values differed significantly between children with liver diseases and controls. In normal controls SWV values in the 1st segment were significantly lower compared to those in the in 8th segment of the liver (p=0.0216). In the group with hepatic steatosis, the SWV values were statistically higher compared to those in healthy controls. Positive statistical correlations have been established between AST and SWV in the group of children with NAFLD and those with malignancies (p=0.0032, p=0.0045). ConclusionsQuantification of liver fibrosis by ARFI method correlates with the histological fibrosis stage in children with chronic liver disease and NAFLD. Clinical applications of this method in the diagnosis of pediatric liver disease deserve further study.

Novel Heterozygous Mutations in TALDO1 Gene Causing Transaldolase Deficiency and Early Infantile Liver Failure

JPGN Volume 52, N T ransaldolase (TALDO) deficiency (OMIM #606003), a recently recognized new inborn error of the pentose phosphate pathway (PPP), has been reported to date in only 10 patients from 6 families, presenting primarily with liver disease and variable clinical course (1–6). The PPP is a multifunctional pathway that plays a pivotal role in supplying ribose-5-phosphate for nucleic acid biosynthesis and for generation of reducing equivalents, which regulate the cellular redox potential via maintenance of the reduced glutathione (GSH) pool and neutralization of reactive oxygen intermediates (ROIs). TALDO is one of the key enzymes responsible for this neutralization. TALDO deficiency was first described in 2001 (1) and has a broad phenotypic heterogeneity, ranging from fetal hydrops (3) to slowly progressive liver cirrhosis (1). The leading symptoms in the neonatal period in all 10 patients reported were bleeding tendencies with thrombocytopenia, abnormal liver function tests, hepatosplenomegaly, hemolytic anemia, and dysmorphic features (antimongoloid slant, low-set ears, and cutis laxa). Interestingly, mental development and motor development were normal in the majority who were assessed (3 patients died before 6 months of age). The biochemical profile of all of the affected patients is similar: elevated urine erythritol, arabitol, ribitol, sedoheptitol, perseitol, sedoheptulose, mannoheptulose, and sedoheptulose-7P (1,2,7). Measurement of TALDO activity in fibroblasts, lymphoblasts or liver tissue, and sequence analysis of the TALDO1 gene confirm the diagnosis. We report an additional patient with TALDO deficiency with the hope of increasing awareness of this rare disorder that should be rential diagnosis of pediatric liver diseases. We also review the literature on TALDO deficiency.

Liver needle biopsy in Iraninan pediatric patients: Diagnostic significance and pattern of liver diseases

We aimed at determining the pattern of liver disease in the Iranian children referred to the Medical Center of Children affiliated with the Tehran University of Medical Sciences. In a cross-sectional study conducted over 2 years, 425 liver needle biopsies were sent to the pathology laboratory of our center. Slides were prepared from paraffin-embedded blocks, stained by routine H & E and special stains and were then reviewed. The frequency of each disorder, separately and in combination with the age group or gender of the patients was calculated and compared with other similar studies. The male to female ratio was 1.42:1. The age range was between 1 month and 18 years old and 41.4% were less than 2 years old. The most common histological diagnosis was iron overload due to major thalassemia (17.5%) followed by biliary atresia (9.7%), no significant pathologic change (8.7%), neonatal hepatitis (8.7%), chronic hepatitis (8.5%), cirrhosis (6.5%), metabolic disease (5.5%) and progressive familial intrahepatic cholestasis (5%). RESULTS of the hemosiderosis grading in patients with thalassemia revealed no or minimal, mild, medium, or marked increase in 10%, 27.1%, 10%, 21.4% and 31.5% of the cases, respectively and the degree of iron deposition rose in parallel with age and also the stage of fibrosis (p< 0.05). A liver biopsy is a useful and practical tool for the appropriate diagnosis of pediatric liver diseases. Also, we found that in non thalassemic children, biliary atresia, chronic hepatitis and neonatal hepatitis, in the stated order, are the most prevalent histologic diagnoses in Iranian pediatrics.

The role of subfractionation of alpha-fetoprotein in the treatment of pediatric surgical patients

Subfractionation of serum alpha-fetoprotein (AFP) is a useful method to discriminate between yolk sac tumors, hepatic malignancies, and benign liver diseases in adults but has not been validated in infants and children. AFP subfractionation was performed on AFP-positive sera from 73 infants and children. AFP subfraction profiles were classified into three common types: (1) yolk sac type, (2) hepatoblastoma type, and (3) benign hepatic type, according to the reactivity of individual AFP samples to lectins. In 68 of 73 samples (93.2%), AFP subfraction profiles were accurately classified into these three types, and an atypical AFP subfraction profile resembling the hepatoblastoma type was found in sera from five infants (6.8%). Differentiation between hepatoblastoma and hepatitis when patients are very young can be difficult. Subfractionation is more accurate when patients are older. This technique was found to be useful in the diagnosis of neonatal ovarian tumors, in recurrent hepatoblastoma/yolk sac tumor with low serum AFP, and in the differential diagnosis of hepatic mass (malignancy versus hyperplastic nodule) in the liver with long-standing cholestasis. Estimation of serum AFP subfraction profiles facilitates the differential diagnosis of various AFP-positive pediatric diseases, such as hepatoblastoma, hepatoma, hepatitis or germ cell tumors. This test is inexpensive, can be carried out within 48 hours, and should be performed for the differnetial diagnosis of pediatric liver disease.

Serum Amino Acid Analysis may be Worthwhile for the Differential Diagnosis of Pediatric Liver Diseases and for Getting Some Clues of their Pathogenesis

Serum Amino Acid Analysis may be Worthwhile for the Differential Diagnosis of Pediatric Liver Diseases and for Getting Some Clues of their Pathogenesis