Human Menstrual Blood-derived Stem Cell Transplantation Suppresses Liver Injury in DDC-induced Chronic Cholestasis

Background: Cholestasis liver injury can lead to serious symptoms and prognoses in the clinic. Currently, an effective medical treatment is not available for cholestasis liver injury. Human menstrual blood-derived stem cells (MenSCs) have been considered an emerging treatment in various diseases. However, efficiency of MenSCs in cholestasis liver injury has been less investigated. Methods: C57/BL6 mice were fed with 3,5-diethoxycarbonyl-1,4- dihydroxychollidine (DDC) to induce chronic cholestasis liver injury model. DDC mice were injected with either phosphate buffer saline (PBS) or MenSCs at 2 and 4 weeks. Mice were sacrificed at 5 weeks. Serum and liver tissues were collected to test liver function and pathological changes. Proteomics and western blot were used to explore the related molecular mechanisms. Adeno-associated virus (AAV)9 infected mice were used for verifications of MenSC treatment target and related molecular mechanism. Results: We found that MenSCs could protect mice against DDC-induced cholestasis by improving impaired liver function and tissue damage. MenSCs markedly prolonged survival rate of mice, decreased the mice serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), direct bilirubin (DBIL) and total bilirubin (TBIL) levels as well as intrahepatic cholestasis, bile duct dilation and fibrosis. The results further indicated that MenSCs repaired DDC-induced tight junction (TJ) and bile transport function damage and inhibited COL1A1, α-SMA and TGF-β1 activation by upregulating liver β-catenin expression. MenSC transplantation could be an effective treatment method for cholestasis liver injury.

Drug-Induced Vanishing Bile Duct Syndrome: From Pathogenesis to Diagnosis and Therapeutics

The most concerned issue in the context of drug/herb-induced chronic cholestasis is vanishing bile duct syndrome. The progressive destruction of intrahepatic bile ducts leading to ductopenia is usually not dose dependent, and has a delayed onset that should be suspected when abnormal serum cholestasis enzyme levels persist despite drug withdrawal. Immune-mediated cholangiocyte injury, direct cholangiocyte damage by drugs or their metabolites once in bile, and sustained exposure to toxic bile salts when biliary epithelium protective defenses are impaired are the main mechanisms of cholangiolar damage. Current therapeutic alternatives are scarce and have not shown consistent beneficial effects so far. This review will summarize the current literature on the main diagnostic tools of ductopenia and its histological features, and the differential diagnostic with other ductopenic diseases. In addition, pathomechanisms will be addressed, as well as the connection between them and the supportive and curative strategies for ductopenia management.

A ZFYVE19 gene mutation associated with neonatal cholestasis and cilia dysfunction: case report with a novel pathogenic variant

Background ZFYVE19 (Zinc Finger FYVE-Type Containing 19) mutations have most recently been associated to a novel type of high gamma-glutamyl transpeptidase (GGT), non-syndromic, neonatal-onset intrahepatic chronic cholestasis possibly associated to cilia dysfunction. Herein, we report a new case with further studies of whole exome sequencing (WES) and immunofluorescence in primary cilia of her cultured fibroblasts which confirm the observation. Results A now 5-year-old girl born to clinically healthy consanguineous Moroccan parents was assessed at 59 days of life due to severe cholestatic jaundice with increased serum bile acids and GGT, and preserved hepatocellular synthetic function. Despite fibrosis/cirrhosis and biliary ducts proliferation on liver biopsy suggested an extrahepatic biliary obstacle, normal intra-operatory cholangiography excluded biliary atresia. Under choleretic treatment, she maintained a clinically stable anicteric cholestasis but developped hyperlipidemia. After exclusion of the main causes of cholestasis by multiple tests, abnormal concentrations of sterols and WES led to a diagnosis of hereditary sitosterolemia (OMIM #618666), likely unrelated to her cholestasis. Further sequencing investigation revealed a homozygous non-sense mutation (p.Arg223Ter) in ZFYVE19 leading to a 222 aa truncated protein and present in both heterozygous parents. Immunofluorescence analysis of primary cilia on cultured skin fibroblasts showed a ciliary phenotype mainly defined by fragmented cilia and centrioles abnormalities. Conclusions Our findings are consistent with and expands the recent evidence linking ZFYVE19 to a novel, likely non-syndromic, high GGT-PFIC phenotype with neonatal onset. Due to the possible role of ZFYVE19 in cilia function and the unprecedented coexistence of a coincidental hereditary sterol disorder in our case, continuous monitoring will be necessary to substantiate type of liver disease progression and/or possible emergence of a multisystemic involvement. What mentioned above confirms that the application of WES in children with undiagnosed cholestasis may lead to the identification of new causative genes, widening the knowledge on the pathophysiology.

Alagille Syndrome: Features and Outcome among Filipino Children

We report 13 children fulfilling criteria of Alagille syndrome. All had chronic cholestasis secondary to paucity ofintrahepatic bile ducts and triangular facies. Eight children had associated congenital heart disease (six pulmonicstenosis, one each tetralogy of Fallot and patent ductus arteriosus), seven with butterfly vertebrae and onewith posterior embryotoxon. Seven of the 13 children are alive and jaundice-free but three with concomitanthypercholesterolemia; the six other children died of liver-related complications.

PREVENTION OF BLEEDING ASSOCIATED WITH LATE VITAMIN K DEFICIENCY IN INFANTS OF THE FIRST THREE MONTHS OF LIFE - TACTICS OF REDUCTION OF DEATHS AND DISABILITY

The article, intended for neonatologists, general practitioners, family medicine, pediatricians, presents the main causes of disorders in the hemostasis system, which lead to the development of hemorrhagic syndrome in newborns and infants. Emphasis is placed on various forms of neonatal hemorrhagic disease (NHD), which is based on a deficiency of fat-soluble vitamin K. The main risk group for bleeding associated with late vitamin K deficiency is formed by children who are exclusively breastfed. The article presents modern approaches to the prevention of late bleeding associated with vitamin K deficiency, which is based on chronic problems of the digestive system – chronic cholestasis, cystic fibrosis and others. Describes and interprets current guidelines for the prophylactic use of vitamin K in infants in the first three months of life in European countries of high economic development, the United States, which reflects various effective schemes for the prevention of bleeding associated with vitamin K deficiency in infants, differing in single dose application of a preventive course and a way of administration of vitamin K (phytomenadione). The role of parents in the prevention of vitamin K deficiency in infants who are breastfed is emphasized.