Infantile Intrahepatic Cholestasis Research Articles

Clinical characteristics and gene variants of patients with infantile intrahepatic cholestasis

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 SLC25A13 gene variation in 3 patients who were diagnosed with citrin deficiency, JAG1 gene variation in 3 patients who were diagnosed with Alagille syndrome, ABCB11 gene variation in 3 patients who were diagnosed with progressive familial intrahepatic cholestasis type 2, HSD3B7 gene variation in 1 patient who was diagnosed with congenital bile acid synthesis defect type 1, AKR1D1 gene variation in 1 patient who was diagnosed with congenital bile acid synthesis defect type 1, NPC1 gene variation in 1 patient who was diagnosed with Niemann-Pick disease, and CFTR gene variation in 1 patient who was diagnosed with cystic fibrosis. Conclusions The etiology of infantile intrahepatic cholestasis is complex. Next generation sequencing is helpful in the diagnosis of infantile intrahepatic cholestasis.

AKR1D1 and CYP7B1 mutations in patients with inborn errors of bile acid metabolism: Possibly underdiagnosed diseases

Inborn errors of bile acid metabolism (IEBAM) cause rare but treatable genetic disorders that can present as neonatal cholestasis or neurological diseases. Without timely primary bile acid treatment, patients may develop liver failure early in life. This study aimed to analyze the types and treatment outcomes of IEBAM in Taiwanese infants and document the allele frequency of CYP7B1 hot spot mutations in the population. Urine samples from patients with infantile intrahepatic cholestasis and suspected IEBAM were subjected to urinary bile acid analysis by gas chromatography-mass spectrometry (GC/MS). Genetic diagnoses were made using direct sequencing or next-generation sequencing. We also tested healthy control subjects for a probable hot spot point mutation of CYP7B1. Among the 75 patients with infantile intrahepatic cholestasis tested during 2000 -2016, three had ∆4-3-oxosteroid 5β-reductase deficiency with AKR1D1 mutations, and three had oxysterol-7α-hydroxylase deficiency with CYP7B1 mutation. Two patients with ∆4-3-oxosteroid 5β-reductase deficiency were successfully treated with cholic acid. The three unrelated infants with oxysterol 7α-hydroxylase deficiencies had the same p.R112X homozygous CYP7B1 mutation. Two had mild renal or neurological involvement. Among 608 healthy control subjects, the allele frequency of the heterozygous mutation for p.R112X was 2/1216 (0.16%). The only surviving patient with oxysterol 7α-hydroxylase deficiency recovered from liver failure after chenodeoxycholic acid (CDCA) treatment beginning at 3 months of age. Distinct types of IEBAM disease were found in the Taiwanese population. Patients with early diagnosis and early treatment had a favorable outcome. IEBAM prevalence rates may be higher than expected due to the presence of heterozygous mutations in the general population.

Prognostic roles of tetrahydroxy bile acids in infantile intrahepatic cholestasis

Tetrahydroxy bile acids (THBAs) are hydrophilic and are present at minimal or undetectable levels in healthy human adults, but are present at high levels in bile salt export pump (abcb11)-knockout mice. The roles of THBAs in human cholestatic diseases are unclear. We aimed to investigate the presence of THBAs in patients with infantile intrahepatic cholestasis and its correlation with outcome. Urinary bile acids (BAs) were analyzed by GC-MS. Data were compared between good (n = 21) (disease-free before 1 year old) and poor prognosis groups (n = 19). Good prognosis patients had a higher urinary THBA proportion than poor prognosis patients [25.89% (3.45-76.73%) vs. 1.93% (0.05-48.90%)]. A urinary THBA proportion >7.23% predicted good prognosis with high sensitivity (95.24%), specificity (84.21%), and area under the curve (0.91) (P < 0.0001). A THBA proportion 7.23% was an independent factor for decreased transplant-free survival (hazard ratio = 7.16, confidence interval: 1.24-41.31, P = 0.028). Patients with a confirmed ABCB11 or tight junction protein 2 gene mutation (n = 7) had a minimally detectable THBA proportion (0.23-2.99% of total BAs). Three patients with an ATP8B1 mutation had an elevated THBA proportion (7.51-37.26%). In conclusion, in addition to disease entity as a major determinant of outcome, a high THBA level was associated with good outcome in the infantile intrahepatic cholestasis patients.

γ-Glutamyl transpeptidase level as a screening marker among diverse etiologies of infantile intrahepatic cholestasis.

Low γ-glutamyl transpeptidase (GGT) level is an important marker for progressive familial intrahepatic cholestasis, yet the cutoff level and clinical application is not well defined. This study aimed to evaluate the role of GGT as a screening marker among diverse etiologies of infantile cholestasis. This retrospective study analyzed 256 cholestatic infants admitted to a tertiary referral center between 2000 and 2012. After excluding 121 infants of extrahepatic cholestasis, advanced investigations for 135 infants with intrahepatic cholestasis were performed. The etiologies, outcomes, and correlations with GGT levels were analyzed. Good prognosis was defined as clinical recovery before 1 year of age; poor prognosis as persistent disease, liver transplantation, or death before 1 year. Among 135 patients of intrahepatic cholestasis, >12 different etiologies were found. Neonatal hepatitis (49.6%), progressive familial intrahepatic cholestasis (21.5%), and neonatal cholestasis caused by citrin deficiency (10.4%) were the leading causes. Patients with initial GGT between 75 and 300 U/L had a higher chance of good prognosis (61/74, 82.4%) than those with GGT <75 U/L or >300 U/L (25/61, 41%, P < 0.0001). In the low-GGT group (≤ 100 U/L), 52.6% (30/57) of the patients have good prognosis; and GGT level ≤ 75 U/L has a sensitivity, specificity, and positive predictive value of 100%, 43.3%, and 61.4% in predicting poor prognosis. Patients with GGT levels ≤ 75 or ≥ 300 U/L should receive advanced investigations such as genetic/metabolic assays early; otherwise, the amount of diagnostic workup may be limited if no signs of progressive disease.

Study on Short Term Outcome of intrahepatic Infantile Cholestasis

Background: Outcome of infantile intrahepatic cholestasis is highly variable. Aim to investigate various factors affecting outcome of infantile cholestasis. Methods: Retrospective study was conducted through data collection of 70 infant’s files who presented with intrahepatic cholestasis. They were divided into two groups according to the fate of jaundice at the end of the first year follow up. Group I: cases with persistent jaundice and group II: cases that were jaundice free by the end of the year. A comparison was done at presentation, 3 and 12 months between the two groups. Results: Group I had a higher mortality and morbidity. Both groups were significantly different regards etiology, onset of jaundice, presentation to medical care, prevalence of consanguinity and pruritus. After 3 month, group I showed significant bigger and firm liver, higher ALT, AST, S.bilirubin. At 1 year, differences in weight, splenic size and S.albumin were found. Conclusion: The predictive parameters of a high risk group of intrahepatic cholestasis at presentation included etiology, age of onset, positive consanguinity and itching, where at 3rd month of follow-up included big firm liver, persistently pale stool, high ALT and AST and at one year included splenomegaly and lower albumin. Abbreviations: IHCintrahepatic cholestasis, BAbile acids, INHidiopathic neonatal hepatitis, CMVcytomegalovirus, IHBDintrahepatic biliary ducts, PFIC-progressive familial intrahepatic cholestasis. Key Wards: Alagille syndrome, infantile cholestasis, PFIC,

The mutation spectrum of the SLC25A13 gene in Chinese infants with intrahepatic cholestasis and aminoacidemia

SLC25A13 gene mutations cause citrin deficiency, which leads to neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). Information on the mutation spectrum of SLC25A13 in the Chinese population is limited. The aim of this study was to explore the mutation spectrum of the SLC25A13 gene in Chinese infants with intrahepatic cholestasis and various forms of aminoacidemia. Sequence analyses were performed on 39 infants with intrahepatic cholestasis and various forms of aminoacidemia. Novel mutations were subjected to homology and structural analyses. Western blots were performed when liver specimens available. Genetic testing revealed the presence of SLC25A13 gene mutations (9 heterozygotes, 6 homozygotes and 13 compound heterozygotes) in 28 infants. Subsequent Western blot analysis revealed 22 cases of citrin deficiency, accounting for 56.4% of the 39 patients. Twelve types of mutations, including nine known mutations and three novel mutations, were found. Of the 49 mutated alleles, known ones include 851del4 (26 alleles, 53.1%), 1638ins23 (6 alleles, 12.2%), IVSl6ins3kb (3 alleles, 6.1%), IVS6+5G>A (2 alleles, 4.1%), E601K (2 alleles, 4.1%) and IVS11+1G>A, R184X, R360X and R585H (1 allele each, 2.0%). The three novel mutations were a splice site change (IVS6+1G>A), a deletion mutation (1092_1095delT) and a missense mutation (L85P), each in one allele. The mutation spectrum of the SLC25A13 gene in a Chinese population of infants with intrahepatic cholestasis with various forms of aminoacidemia was found to be different from that of other population groups in East Asia. The SLC25A13 gene mutation is the most important cause of infantile intrahepatic cholestasis with various forms of aminoacidemia.

Technical innovation for noninvasive and early diagnosis of biliary atresia: the ultrasonographic "triangular cord" sign.

In this article, we introduce our experience regarding a new and noninvasive diagnostic tool, using ultrasonography, for the early and definite diagnosis of biliary atresia. We have focussed on the ultrasonographic image of the cone-shaped periportal fibrous mass in infants with biliary atresia since 1992, and have finally identified a triangular or band-like periportal echogenicity ("triangular cord" sign), mainly cranial to the portal vein. Based on our experience and other reports from Japan and Singapore, the ultrasonographic triangular cord sign is a simple, time-saving, highly reliable, and definite tool in the diagnosis of biliary atresia from infantile intrahepatic cholestasis, representing a positive predictive value greater than 95%. We have proposed a new diagnostic strategy in the evaluation of infantile cholestasis, with emphasis on the ultrasonographic triangular cord sign.

The ultrasonographic ‘triangular cord’ coupled with gallbladder images in the diagnostic prediction of biliary atresia from infantile intrahepatic cholestasis

Purpose : The aim of this study was to evaluate the importance of the ultrasonographic “triangular cord” (TC) coupled with gallbladder images in the diagnostic prediction of biliary atresia (BA) from infantile intrahepatic cholestasis. Methods : Seventy-nine infants with cholestatic jaundice underwent ultrasound examinations, focusing on the TC and gallbladder images. The TC was defined as visualization of a triangular or bandlike periportal echogenicity (3 mm or greater in thickness), which represents a cone-shaped fibrotic mass cranial to the portal vein in infants with BA. An abnormal gallbladder (nonvisualized or small) was thought to be more suggestive of BA than infantile intrahepatic cholestasis. Results : Among 25 infants with BA, 21 showed TC, whereas 4 had no TC. Fifty-three of 54 infants with infantile intrahepatic cholestasis had no TC, showing a diagnostic accuracy of 94% with 84% sensitivity and 98% specificity. As for positive predictive value in the diagnosis of BA by the TC coupled with gallbladder images, it was 100% when a positive TC was coupled with an abnormal gallbladder and 88% when a positive TC was coupled with a normal gallbladder. It decreased to 25% when a negative TC was coupled with an abnormal gallbladder. Conclusions : The TC appears to be a very specific and definite ultrasonographic finding in the early diagnosis of BA. Positive TC regardless of gallbladder images is highly suggestive of BA, showing a 95% positive predictive value, but BA cannot be ruled out when negative TC is coupled with an abnormal gallbladder, requiring further diagnostic modalities such as liver needle biopsy or hepatobiliary scintigraphy.