Variant etiologies of neonatal cholestasis and their outcome: a Middle East single-center experience.

AIM OF THE STUDY: Neonatal cholestasis (NC) constitutes a large proportion of pediatric liver disorders. Nevertheless, awareness of the variant etiologies and how to manage them appropriately are lacking. So, out of a few specialized centers, many cases pass without appropriate management. This study aimed to present our tertiary level center's experience in NC that could increase the pediatrician's awareness of handling this problematic and common medical morbidity efficiently. MATERIAL AND METHODS: It is a retrospective study in which we analyzed the NC cases admitted to the inpatient department within three years. For all recruited patients, the available data were retrieved and recorded. RESULTS: A total of 412 patients were reviewed with 20 different etiologies diagnosed. The most common cause was biliary atresia (n = 151, 37%), followed by progressive familial intrahepatic cholestasis (n = 51, 12%), neonatal sepsis (n = 39, 9%), and cytomegalovirus (n = 33, 8%). Of the 412 patients, 394 (81%) had follow-up ranging from 1 to 36 months. A total of 173 patients improved with supportive and/or specific therapy, while 108 patients died at a median age of 6 months. The commonest cause of death was liver failure (40.7%), followed by pneumonia (28.7%), sudden death (13%), septicemia (6.5%), and hepatorenal syndrome (5.5%). CONCLUSIONS: NC constitutes more than one-third of the inpatient admissions of all pediatric liver disorders and has a high rate of mortality. Awareness of the variety of etiologies and a rapid stepwise approach to diagnosis could have an impact on the outcome of this devastating disease.

Differentiating Biliary Atresia From Idiopathic Neonatal Hepatitis: A Novel Keratin 7 Based Mathematical Approach on Liver Biopsies.

BACKGROUND AND AIMS: Differentiating biliary atresia (BA) from idiopathic neonatal hepatitis (INH) is vital in routine pediatric practice. However, on liver biopsy, few cases offer a diagnostic challenge to discriminate these entities with certainty. Bile ductular reaction (DR), intermediate hepatobiliary cells (IHBC) and extra-portal ductules (EPD) indicate progenitor cell activation, as a response to various hepatic insults. The present study aims to quantify DR, IHBC and EPD by Keratin 7 (CK7) immunohistochemistry (IHC) in BA and INH and to devise a mathematical approach to better differentiate the two, especially in histologically equivocal cases. METHODS: A total of 98 cases were categorized on biopsy as BA, INH or equivocal histology, favoring BA or INH. CK7 DR mean, IHBC mean and EPD mean values were compared between BA and INH. A formula was derived to help distinguish these two entities, the cut-off value, sensitivity and specificity of which were determined by receiver operating characteristic (ROC) curve. This formula was applied and validated on histologically equivocal cases. RESULTS: Univariate logistic regression revealed significant difference between BA and INH with respect to CK7 DR and CK7 EPD mean (p < 0.001 in both); however, CK7 IHBC mean was not significant (p = 0.08). On multivariate logistic regression, only CK7 DR had significant impact on diagnosis (p < 0.001). A formula: (CK7 DR)2 + (CK7 EPD)/(CK7 IHBC) was derived to help distinguish BA from INH. Cut off value of 10.5 and above, determined by ROC curve, favored a diagnosis of BA (sensitivity= 93.4%, specificity= 94.6%). Histologically equivocal and discrepant cases could be correctly categorized using this formula. CONCLUSIONS: Formula using CK7 IHC parameters may aid pathologists better distinguish BA from INH, especially in histologically equivocal cases.

A quantitative image analysis using MRI for diagnosis of biliary atresia.

PURPOSE: Biliary atresia is a life-threatening disease that needs early diagnosis and management. Recently, MRI images have been used for the diagnosis of biliary atresia with improved accuracy of diagnosis when other imaging modalities such as ultrasonography are equivocal. This study aimed to evaluate the juxta-hilar extrahepatic biliary tree using MRI images to determine a quantitative value for diagnosing biliary atresia. MATERIALS AND METHODS: This retrospective study was approved by the Ethical Committee at Mackey Memorial Hospital (IRB Number: 15MMHIS149e). Between January 2010 and December 2015, twenty-five patients with surgically confirmed biliary atresia were enrolled (age 18-65 days). Another 25 patients with clinically or surgically diagnosed idiopathic neonatal hepatitis (age 6-64 days) and 20 patients with non-hepatobiliary disease (age 6-65 days) were considered control group and normal subjects, respectively. The diameter of the enlarged, T2-hyperintense structure was measured using MRI images by two radiologists both blinded. The cut-off value for a biliary atresia diagnosis was obtained by area under the curve analysis. RESULTS: The diameter of the T2-hyperintense structure at porta hepatis in biliary atresia (4.79 ±â€¯1.14 mm) is larger than in idiopathic neonatal hepatitis (1.72 ±â€¯0.42 mm) or in non-hepatobiliary disease (1.72 ±â€¯0.35 mm) (p < 0.05). The optimum cut-off value for diagnosing biliary atresia was 3.1 mm with 98% sensitivity and 98% specificity. CONCLUSION: The value of the enlarged, T2-hyperintense structure measured on MRI images was significantly increased in biliary atresia and may be useful in diagnosing biliary atresia.

Ocular findings in patients with cholestatic disorders of infancy: A single-centre experience.

BACKGROUND AND STUDY AIMS: Neonatal cholestasis can be associated with ocular findings that might aid in its diagnosis, e.g., Alagille syndrome (AGS) and Niemann Pick disease (NPD). We aimed to investigate the frequency of ocular manifestations in infants with cholestasis. PATIENTS AND METHODS: This cross-sectional study included cholestatic infants presenting to the Paediatric Hepatology Unit, Cairo University Paediatric Hospital, Cairo, Egypt. All infants underwent examination of lid, ocular motility, anterior and posterior segments and measurement of intraocular pressure, cycloplegic refraction, ocular ultrasonography and vision. RESULTS: The study included 112 infants with various cholestasis; 73 (65.2%) were males. The median age was 2months. Diagnosis was reached in 39 cases: 14 had AGS, 14 had biliary atresia (BA), 4 had NPD, 4 had post-haemolytic cholestasis, 2 had cytomegalovirus neonatal hepatitis, and one case had hepatorenal tyrosinaemia. Thirteen cases were probably having progressive familiar intrahepatic cholestasis (PFIC) type 1 or 2 considering their persistent cholestasis in the presence of normal gamma-glutamyl transpeptidase; 28 were left with a diagnosis of "idiopathic neonatal hepatitis" (INH), and 32 (28.6%) had no definite diagnosis. Ophthalmologic abnormalities were found in 39 cases (34.8%). The commonest finding was unilateral/bilateral optic nerve drusen in 12 (10.7%), followed by posterior embryotoxon in 11 (9.8%). Ocular findings were observed in 64.3% patients with AGS, 50% patients with NPD, 30.8% cases with suspected PFIC type 1or 2, 28.6% infants with INH, and 14.3% patients with BA. CONCLUSION: Ophthalmologic findings are not uncommon among cholestatic infants. Ophthalmologic examination should be routinely performed, including assessment of anterior segment, fundus examination, and ocular ultrasound.

CD14/-159 and TNFα/-308 promoter polymorphisms are not associated with Development of Idiopathic Neonatal Hepatitis among Filipinos

Objective@# To determine if the CD14/-159 and the TNFα/-308 single nucleotide polymorphisms (SNPs) are associated with the development of Idiopathic Neonatal Hepatitis (INH) in Filipino children. @*Methods@#Genomic DNA from 33 patients diagnosed with INH and 33 age- and sex-matched controls, children without any liver disease, were recruited. Baseline serum total bilirubin (TB), direct bilirubin (DB), and alkaline phosphatase (ALP) of the patients were obtained from their medical records. Genotypes for CD14/159 and TNFα/-308 were determined via PCR and direct sequencing. @*Results@#No significant difference was seen between the frequency of the CD14/-159 T allele (p=0.86) nor the TNFα/-308 A allele (p=0.62) between INH patients and controls. There was also no significant difference between the genotypic distribution of the INH and control populations for both CD14/-159 (p=0.54) and TNFα/-308 (p=0.62). There were also no significant differences noted between the different genotypes of CD14/159 and TNFα/-308 and levels of alkaline phosphatase (p=0.65, p=0.91), total bilirubin (p=0.89, p=0.75), and direct bilirubin (p=0.93, p=0.68). @*Conclusion@#In this preliminary study, CD14/-159 and TNFα/-308 showed no association with the development of INH among Filipinos.

Idiopathic neonatal hepatitis or extrahepatic biliary atresia? The role of liver biopsy.

Cholestasis in early infancy represents a diagnostic dilemma and most of these infants suffer either from extrahepatic biliary atresia or idiopathic neonatal hepatitis. Differentiation between the two conditions may be extremely difficult both clinically and biochemically, and a diagnostic liver biopsy is usually required. We report on a Sudanese infant who presented at the age of 4 weeks with prolonged cholestatic jaundice, abdominal ultrasound was inconclusive, HIDA scan was suggestive of extrahepatic biliary atresia and the diagnosis of idiopathic neonatal hepatitis was only reached by liver biopsy. The infant made full recovery on supportive treatment during a one year follow up period.

Effects of 4-phenylbutyrate therapy in a preterm infant with cholestasis and liver fibrosis.

The bile salt export pump is expressed at the canalicular membrane of hepatocytes and mediates biliary excretion of bile salts. 4-Phenylbutyrate (4 PB), a drug used to treat ornithine transcarbamylase deficiency, has been found to increase the hepatocanalicular expression of bile salt export pump. The beneficial effects of 4-phenylbutyrate therapy have been reported for patients with progressive familial intrahepatic cholestasis, an inherited autosomal recessive liver disease. This is the first study to show the therapeutic effect of 4 PB in a preterm infant with cholestasis and liver fibrosis. The preterm infant had severe cholestasis with jaundice and failure to thrive refractory to ursodeoxycholic acid. Histology indicated giant cell hepatitis, cholestasis, and severe fibrosis. Bile salt export pump immunostaining showed lower expression than in a control. Oral 4 PB was started at a daily dose of 200 mg/kg/day. After the start of 4 PB therapy, cholestasis improved.

Hepatic involvement in congenital cytomegalovirus infection - infrequent yet significant.

Congenital cytomegalovirus (cCMV) infection can reside in many organ systems; however, the virus has a particular predilection towards inhabiting the reticuloendothelial system, especially the liver. Specific studies focusing only on hepatic involvement in infants with cCMV are lacking. We report our experience with a large cohort of infants treated in our hospital clinic due to cCMV and hepatic involvement. Hepatic involvement was defined either as hepatitis (elevated alanine transaminases (ALT) >80 units/L without cholestatic disease) or cholestatic disease (elevated ALT >80 units/L combined with direct bilirubin >2 mg/dL). During the study period, 198 infants were diagnosed with symptomatic cCMV in our clinic. Hepatic involvement was observed in 13 infants (6.6%); 7 (3.5%) with hepatitis and 6 (3%) with cholestatic disease. Maternal primary infection with cytomegalovirus during pregnancy was diagnosed in 7 (53.8%) of the 13 infants, nonprimary in 3 (23.1%) and unknown in 3 (23.1%). Among these 13 infants, central nervous system (CNS) involvement was observed in 11 (84.6%) and hearing impairment in 7 (53.8%). Treatment with an antiviral agent was initiated in all cases. Gradual improvement of hepatic enzymes and cholestasis was observed over a prolonged period. We found that the incidence of hepatic involvement in infants with cCMV is much less frequent than previously reported. The hepatic involvement in these infants may manifest in two different ways, and thus, a high index of suspicion and a stepwise approach will help in correctly diagnosing these infants. Antiviral treatment due to CNS involvement is warranted and prognosis is excellent.