Novel findings from family-based exome sequencing for children with biliary atresia

Biliary atresia (BA) is a progressive inflammation and fibrosis of the biliary tree characterized by the obstruction of bile flow, which results in liver failure, scarring and cirrhosis. This study aimed to explore the elusive aetiology of BA by conducting whole exome sequencing for 41 children with BA and their parents (35 trios, including 1 family with 2 BA-diagnosed children and 5 child-mother cases). We exclusively identified and validated a total of 28 variants (17 X-linked, 6 de novo and 5 homozygous) in 25 candidate genes from our BA cohort. These variants were among the 10% most deleterious and had a low minor allele frequency against the employed databases: Kinh Vietnamese (KHV), GnomAD and 1000 Genome Project. Interestingly, AMER1, INVS and OCRL variants were found in unrelated probands and were first reported in a BA cohort. Liver specimens and blood samples showed identical variants, suggesting that somatic variants were unlikely to occur during morphogenesis. Consistent with earlier attempts, this study implicated genetic heterogeneity and non-Mendelian inheritance of BA.

An Unexpected Hepatic Hydrothorax After a Successful Kasai Portoenterostomy: A Case Report

Hepatic hydrothorax (HH) represents a rare complication of portal hypertension among adult cirrhotic patients. Here, we describe a pediatric case of HH, observed in a biliary atresia infant. The child presented with recurrent right-sided pleural effusion, after a successful Kasai portoenterostomy with restoration of bile flow and without overt signs of hepatic failure. Recurrence of HH led the patient to liver transplant despite a low pediatric end-stage liver disease value. Although rare, HH can also occur in children and should be suspected in patients with portal hypertension and respiratory distress. HH may be an indication for liver transplantation.

Bile Acid Receptors in Cholangiocyte

Bile acids are known to play a role in helping the digestion of lipid and maintenance of the bile flow. However, since the first bile acid receptor was discovered in 1999, it has been found that various bile acid receptors are present. Bile acid receptors are involved in bile acid physiology, energy metabolism, and inflammatory response. G-protein bile acid-activated receptor 1 (GPBAR1) and Sphingosine-1-phosphate receptor 2 (S1PR2) are representative bile acid receptors in cholangiocyte. They are involved in proliferation and secretion of cholangiocyte, which seem to protect cholangiocyte from the toxicity of bile acids. GPBAR1 and S1PR2 are also associated with the progression of cholangiocarcinoma.

Farnesoid X Receptor as Target for Therapies to Treat Cholestasis-Induced Liver Injury

Recent studies on liver disease burden worldwide estimated that cirrhosis is the 11th most common cause of death globally, and there is a great need for new therapies to limit the progression of liver injuries in the early stages. Cholestasis is caused by accumulation of hydrophobic bile acids (BA) in the liver due to dysfunctional BA efflux or bile flow into the gall bladder. Therefore, strategies to increase detoxification of hydrophobic BA and downregulate genes involved in BA production are largely investigated. Farnesoid X receptor (FXR) has a central role in BA homeostasis and recent publications revealed that changes in autophagy due to BA-induced reactive oxygen species and increased anti-oxidant response via nuclear factor E2-related factor 2 (NRF2), result in dysregulation of FXR signaling. Several mechanistic studies have identified new dysfunctions of the cholestatic liver at cellular and molecular level, opening new venues for developing more performant therapies.

Protective effect of Glechoma hederacea extract against gallstone formation in rodent models

Background Our current study aimed to evaluate the effect of an Glechoma hederacea extract (Hitrechol®) in normal rats and gallstone diseased mice to explore its underlying mechanisms. Normal rats and C57BL/6 mice with/without cholesterol gallstone were used in this study. Methods To monitor the effect of Hitrechol® on bile secretion, bile flow rates at 15 min interval until 2 h post-dosing in normal rats treated with vehicle and Hitrechol® were compared using multiple t-test with a p < 0.05 considered as statistically significant different. To further evaluate the effect of Hitrechol® against the development of gallstone in lithogenic diet treated mice, mice were treated with vehicle or Hitrechol® (QD-once daily or TID-three times daily) for 3 weeks followed by comparing the levels of bile composition among the treatment groups. In addition, the anti-oxidative biomarkers in liver and anti-inflammatory biomarkers in serum were detected and compared among all the treatment groups to evaluate the hepato-protective effect of Hitrechol®. The obtained levels of biomarkers and bile composition were compared among different treatment groups using one-way ANOVA tests followed by Tukey’s multiple comparisons with p < 0.05 considered as statistically significant. Results Despite no significant impact on the bile flow rate, Hitrechol® TID treatment dramatically decreased size and amount of gallstone crystals and total cholesterol level (p < 0.05), as well as total bile acid (p < 0.05) and several types of bile acid (p < 0.05) levels in gallstone disease model mice. Hitrechol® TID treatment could significantly decrease the frequencies of hepatocyte necrosis and lipid aggregation notably as well as increase the antioxidant enzyme level (p < 0.05) in the liver. Conclusions Our findings for the first time demonstrated the beneficial effect of Hitrechol® against gallstone via its litholytic, liver-protective and antioxidant activities.

Ultrasonography in diagnosis of the common bile duct pathology and pathology of the major duodenal papilla, complicated by mechanical jaundice

Mechanical jaundice is a clinical syndrome that develops due to the bile flow impairment along the bile ducts to the duodenum, remains one of the urgent problems of medicine. Of great importance among the causes of mechanical jaundice are diseases of the common bile duct and the major duodenal papilla, the diagnosis of which to this day remains a rather difficult task. The use of MRCP, ERСP, endo-ultrasonography and other highly informative bile tract imaging methods, despite great diagnostic capabilities, is associated with a number of limitations. In this regard, an important place, especially in the primary examination of patients, is occupied by transabdominal ultrasound, the advantages of which are non-invasiveness, portability, accessibility, safety, the possibility of multiple reiteration. A review of the literature presents domestic and foreign data of researchers regarding the possibility of ultrasonography in diagnostics of the common bile duct pathology and the pathology of the major duodenal papilla that are complicated by mechanical jaundice, as well as the greatest difficulties in diagnosing this pathology.

Neutrophils’ functional activity in patients with mechanical jaundice and different levels of bilirubin

Introduction: Mechanical jaundice (MJ) or bile duct blockage occurs when the bile ducts' patency is impaired, and the bile flow has stopped. One of the main pathogenetic factors developing complications with MJ is immune system imbalance, particularly its phagocytic link. The purpose of the study was to understand neutrophils' functional activity dependence with different blood bilirubin levels in men with mechanical jaundice. Methods: Forty-seven middle-aged men with mechanical jaundice were divided into three groups depending on the bilirubin levels in their blood: less than 60 μmol/L (n = 10), 60 – 200 μmol/L (n = 20), and more than 200 μmol/L (n = 17). The control group consisted of 50 practically healthy men of the same age. The neutrophils' functional state was assessed using the methods of spontaneous and induced luminol-dependent chemiluminescence of neutrophils. Results: In the group of patients with mechanical jaundice and a bilirubin level of less than 60 μmol/L, there was an increase in the values of T max spontaneous by 96%, I max spontaneous by 44.81%, S spontaneous by 224.6%, T max induced by 19.9%, I max induced by 13.5%, and S induced by 140.3%. In the group with bilirubin levels from 60 – 200 μmol/L, there was an increase in the values of T max spontaneous by 86.8%, I max spontaneous at 47.7%, S spontaneous at 204.6%, I max induced at 28.3%, S induced at 445%, and activation index at 70%. The group with bilirubin levels more than 200 μmol/L showed an increase in the level of T max spontaneous by 85.9%, I max spontaneous by 53.4%, S spontaneous by 927.3%, I max induced by 28.6%, S induced by 1045%, and activation index by 92.3% compared with the control values. The intergroup differences were found in S spontaneous levels, which were higher in the group with more than 200 μmol/L bilirubin levels compared with the 60 – 200 μmol/L group and less than the 60 μmol/L groups by 216.9% and 237.3% respectively. Conclusion: The revealed changes characterize the functional activity of neutrophils' increase with an increase in the bilirubin levels in patients with mechanical jaundice.

Novel Findings From Family-based Exome Sequencing for Children With Biliary Atresia

Biliary atresia (BA) is a progressive inflammation and fibrosis of the biliary tree, characterized by the obstruction of bile flow led to liver failure, scarring and cirrhosis. This study aimed to explore the elusive etiology of BA by conducting whole exome sequencing (WES) for 41 children with BA and their parents (35 trios, including one family with two BA diagnosed children and five child-mother cases). We exclusively identified and validated a total of 28 variants (17 X-linked, six de novo and five homozygous) in 25 candidate genes from our BA cohort. These variants were among the 10% most deleterious and having a low minor allele frequency against three employed databases: Kinh Vietnamese (KHV), gnomad and 1000 Genome project. Interestingly, AMER1, INVS and OCRL variants were repeatedly found in unrelated probands, and were firstly reported in a BA cohort. Liver specimens and blood samples showed identical variants, suggesting that somatic mutations were unlikely to occur during the morphogenesis. In agreement with earlier attempts, this study implicated a genetical heterogeneity and non-Mendelian inheritance of BA.