-
NeoReviews Dec 2021Cholestatic jaundice is a common presenting feature of hepatobiliary and/or metabolic dysfunction in the newborn and young infant. Timely detection of cholestasis,... (Review)
Review
Cholestatic jaundice is a common presenting feature of hepatobiliary and/or metabolic dysfunction in the newborn and young infant. Timely detection of cholestasis, followed by rapid step-wise evaluation to determine the etiology, is crucial to identify those causes that are amenable to medical or surgical intervention and to optimize outcomes for all infants. In the past 2 decades, genetic etiologies have been elucidated for many cholestatic diseases, and next-generation sequencing, whole-exome sequencing, and whole-genome sequencing now allow for relatively rapid and cost-effective diagnosis of conditions not previously identifiable via standard blood tests and/or liver biopsy. Advances have also been made in our understanding of risk factors for parenteral nutrition-associated cholestasis/liver disease. New lipid emulsion formulations, coupled with preventive measures to decrease central line-associated bloodstream infections, have resulted in lower rates of cholestasis and liver disease in infants and children receiving long-term parental nutrition. Unfortunately, little progress has been made in determining the exact cause of biliary atresia. The median age at the time of the hepatoportoenterostomy procedure is still greater than 60 days; consequently, biliary atresia remains the primary indication for pediatric liver transplantation. Several emerging therapies may reduce the bile acid load to the liver and improve outcomes in some neonatal cholestatic disorders. The goal of this article is to review the etiologies, diagnostic algorithms, and current and future management strategies for infants with cholestasis.
Topics: Biliary Atresia; Child; Cholestasis; Humans; Infant; Infant, Newborn; Infant, Newborn, Diseases; Liver Diseases
PubMed: 34850148
DOI: 10.1542/neo.22-12-e819 -
American Family Physician Feb 2017Jaundice in adults can be an indicator of significant underlying disease. It is caused by elevated serum bilirubin levels in the unconjugated or conjugated form. The... (Review)
Review
Jaundice in adults can be an indicator of significant underlying disease. It is caused by elevated serum bilirubin levels in the unconjugated or conjugated form. The evaluation of jaundice relies on the history and physical examination. The initial laboratory evaluation should include fractionated bilirubin, a complete blood count, alanine transaminase, aspartate transaminase, alkaline phosphatase, ?-glutamyltransferase, prothrombin time and/or international normalized ratio, albumin, and protein. Imaging with ultrasonography or computed tomography can differentiate between extrahepatic obstructive and intrahepatic parenchymal disorders. Ultrasonography is the least invasive and least expensive imaging method. A more extensive evaluation may include additional cancer screening, biliary imaging, autoimmune antibody assays, and liver biopsy. Unconjugated hyperbilirubinemia occurs with increased bilirubin production caused by red blood cell destruction, such as hemolytic disorders, and disorders of impaired bilirubin conjugation, such as Gilbert syndrome. Conjugated hyperbilirubinemia occurs in disorders of hepatocellular damage, such as viral and alcoholic hepatitis, and cholestatic disorders, such as choledocholithiasis and neoplastic obstruction of the biliary tree.
Topics: Cholestasis; Diagnosis, Differential; Humans; Hyperbilirubinemia; Jaundice; Liver Diseases
PubMed: 28145671
DOI: No ID Found -
Seminars in Pediatric Surgery Aug 2020Neonatal cholestasis is characterized by conjugated hyperbilirubinemia in the newborn and young infant and is a sign common to over 100 hepatobiliary and/or metabolic... (Review)
Review
Neonatal cholestasis is characterized by conjugated hyperbilirubinemia in the newborn and young infant and is a sign common to over 100 hepatobiliary and/or metabolic disorders. A timely evaluation for its etiology is critical in order to quickly identify treatable causes such as biliary atresia, many of which benefit from early therapy. An expanding group of molecularly defined disorders involving bile formation, canalicular transporters, tight junction proteins and inborn errors of metabolism are being continuously discovered because of advances in genetic testing and bioinformatics. The advent of next generation sequencing has transformed our ability to test for multiple genes and whole exome or whole genome sequencing within days to weeks, enabling rapid and affordable molecular diagnosis for disorders that cannot be directly diagnosed from standard blood tests or liver biopsy. Thus, our diagnostic algorithms for neonatal cholestasis are undergoing transformation, moving genetic sequencing to earlier in the evaluation pathway once biliary atresia, "red flag" disorders and treatable disorders are excluded. Current therapies focus on promoting bile flow, reducing pruritus, ensuring optimal nutrition, and monitoring for complications, without addressing the underlying cause of cholestasis in most instances. Our improved understanding of bile formation and the enterohepatic circulation of bile acids has led to emerging therapies for cholestasis which require appropriate pediatric clinical trials. Despite these advances, the cause and optimal therapy for biliary atresia remain elusive. The goals of this review are to outline the etiologies, diagnostic pathways and current and emerging management strategies for neonatal cholestasis.
Topics: Cholestasis; Humans; Infant; Infant, Newborn; Infant, Newborn, Diseases
PubMed: 32861449
DOI: 10.1016/j.sempedsurg.2020.150945 -
Radiology Dec 2018Biliary strictures can be broadly classified as benign or malignant. Benign biliary strictures are most commonly iatrogenic in nature and are a consequence of... (Review)
Review
Biliary strictures can be broadly classified as benign or malignant. Benign biliary strictures are most commonly iatrogenic in nature and are a consequence of hepatobiliary surgery. Cholangiocarcinoma and adenocarcinoma of the pancreas are the most common causes of malignant biliary obstruction. This article reviews state-of-the-art minimally invasive techniques used to manage these strictures. In addition, the roles of (a) recently introduced biodegradable biliary stents in the management of benign biliary strictures and (b) intraprocedural imaging and navigation tools, such as cone-beam CT, in percutaneous reconstruction of the biliary-enteric anastomosis are discussed.
Topics: Bile Ducts; Cholestasis; Cone-Beam Computed Tomography; Constriction, Pathologic; Humans; Minimally Invasive Surgical Procedures; Stents
PubMed: 30351249
DOI: 10.1148/radiol.2018172424 -
Clinics and Research in Hepatology and... Feb 2019Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of rare genetic disorders associated with bile acid secretion or transport defects. This is...
BACKGROUND AND AIMS
Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of rare genetic disorders associated with bile acid secretion or transport defects. This is the first systematic review of the epidemiology, natural history and burden of PFIC.
METHODS
MEDLINE and Embase were searched for publications on PFIC prevalence, incidence or natural history, and the economic burden or health-related quality of life (HRQoL) of patients with PFIC. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed.
RESULTS
Of 1269 records screened, 20 were eligible (epidemiology, 17; humanistic burden, 5; both, 2). Incidence of intrahepatic cholestasis, including but not limited to PFIC, was 1/18 000 live births in one study that did not use genetic testing. In two studies of infants and children (2-18 years) with cholestasis, 12-13% had genetically diagnosed PFIC. Of the three main PFIC subtypes, PFIC2 was the most common (21-91% of patients). Common symptoms (e.g. pruritus, jaundice, hepatomegaly, splenomegaly) generally appeared at about 3 months of age and tended to emerge earliest in patients with PFIC2. Patients reported that pruritus was often severe and led to dermal damage and reduced HRQoL. Disease progression led to complications including liver failure and hepatocellular carcinoma, with 20-83% of patients requiring liver transplantation. Mortality was 0-87% across 10 studies (treatment varied among studies), with a median age at death of ~4 years in one study.
CONCLUSIONS
Patients with PFIC face debilitating symptoms and poor prognosis. Further research is needed to inform patient management and clinical trial design. Published data on the epidemiology and socioeconomic burden of PFIC is limited.
Topics: Cholestasis, Intrahepatic; Humans
PubMed: 30236549
DOI: 10.1016/j.clinre.2018.07.010 -
Hepatology (Baltimore, Md.) Apr 2011Recent progress in understanding the molecular mechanisms of bile formation and cholestasis have led to new insights into the pathogenesis of drug-induced cholestasis.... (Review)
Review
Recent progress in understanding the molecular mechanisms of bile formation and cholestasis have led to new insights into the pathogenesis of drug-induced cholestasis. This review summarizes their variable clinical presentations, examines the role of transport proteins in hepatic drug clearance and toxicity, and addresses the increasing importance of genetic determinants, as well as practical aspects of diagnosis and management.
Topics: Carrier Proteins; Chemical and Drug Induced Liver Injury; Cholestasis; Drug-Related Side Effects and Adverse Reactions; Humans; Liver Diseases
PubMed: 21480339
DOI: 10.1002/hep.24229 -
Molecular and Clinical Links between Drug-Induced Cholestasis and Familial Intrahepatic Cholestasis.International Journal of Molecular... Mar 2023Idiosyncratic Drug-Induced Liver Injury (iDILI) represents an actual health challenge, accounting for more than 40% of hepatitis cases in adults over 50 years and more... (Review)
Review
Idiosyncratic Drug-Induced Liver Injury (iDILI) represents an actual health challenge, accounting for more than 40% of hepatitis cases in adults over 50 years and more than 50% of acute fulminant hepatic failure cases. In addition, approximately 30% of iDILI are cholestatic (drug-induced cholestasis (DIC)). The liver's metabolism and clearance of lipophilic drugs depend on their emission into the bile. Therefore, many medications cause cholestasis through their interaction with hepatic transporters. The main canalicular efflux transport proteins include: 1. the bile salt export pump (BSEP) protein (); 2. the multidrug resistance protein-2 (MRP2, ) regulating the bile salts' independent flow by excretion of glutathione; 3. the multidrug resistance-1 protein (MDR1, ) that transports organic cations; 4. the multidrug resistance-3 protein (MDR3, ). Two of the most known proteins involved in bile acids' (BAs) metabolism and transport are BSEP and MDR3. BSEP inhibition by drugs leads to reduced BAs' secretion and their retention within hepatocytes, exiting in cholestasis, while mutations in the gene expose the biliary epithelium to the injurious detergent actions of BAs, thus increasing susceptibility to DIC. Herein, we review the leading molecular pathways behind the DIC, the links with the other clinical forms of familial intrahepatic cholestasis, and, finally, the main cholestasis-inducing drugs.
Topics: Adult; Humans; Cholestasis; Hepatocytes; Bile; Bile Acids and Salts; Cholestasis, Intrahepatic
PubMed: 36982896
DOI: 10.3390/ijms24065823 -
Annals of Hepatology Nov 2017Bile acids (BA) are key molecules in generating bile flow, which is an essential function of the liver. In the last decades there have been great advances in the... (Review)
Review
Bile acids (BA) are key molecules in generating bile flow, which is an essential function of the liver. In the last decades there have been great advances in the understanding of the role of a number of specific transport proteins present at the sinusoidal and canalicular membrane domains of hepatocytes and cholangiocytes in generating and maintaining bile flow. Also, a clearer understanding on how BA regulate their own synthesis and the expression and/or function of transporters has been reached. This new knowledge has helped to better delineate the pathophysiology of cholestasis and the adaptive responses of hepatocytes to cholestatic liver injury as well as of the mechanisms of injury of biliary epithelia. In this context, therapeutic approaches including new hydrophilic BA such as the conjugation-resistant nor- ursodeoxycholic acid, nuclear receptors (FXR, PPAR-alpha) agonists, FGF19 analogues, inhibitors of the apical sodium-dependent bile acid transporter [ASBT] and modulators of the inflammatory cascade triggered by BAs are being studied as novel treatments of cholestasis. In the present review we summarize recent experimental and clinical data on the role of BAs in cholestasis and its treatment.
Topics: Animals; Bile Acids and Salts; Bile Ducts; Cholestasis; Gastrointestinal Agents; Humans; Immunity, Innate; Liver; Signal Transduction
PubMed: 29080340
DOI: 10.5604/01.3001.0010.5497 -
World Journal of Gastroenterology Jul 2014Cholestatic liver disease consists of a variety of disorders. Primary sclerosing cholangitis and primary biliary cirrhosis are the most commonly recognized cholestatic... (Review)
Review
Cholestatic liver disease consists of a variety of disorders. Primary sclerosing cholangitis and primary biliary cirrhosis are the most commonly recognized cholestatic liver disease in the adult population, while biliary atresia and Alagille syndrome are commonly recognized in the pediatric population. In infants, the causes are usually congenital or inherited. Even though jaundice is a hallmark of cholestasis, it is not always seen in adult patients with chronic liver disease. Patients can have "silent" progressive cholestatic liver disease for years prior to development of symptoms such as jaundice and pruritus. In this review, we will discuss some of the atypical causes of cholestatic liver disease such as benign recurrent intrahepatic cholestasis, progressive familial intrahepatic cholestasis, Alagille Syndrome, biliary atresia, total parenteral nutrition induced cholestasis and cholestasis secondary to drug induced liver injury.
Topics: Alagille Syndrome; Biliary Atresia; Chemical and Drug Induced Liver Injury; Cholestasis; Cholestasis, Intrahepatic; Female; Genetic Predisposition to Disease; Heredity; Humans; Male; Parenteral Nutrition, Total; Pedigree; Phenotype; Pregnancy; Pregnancy Complications; Prognosis; Recurrence; Risk Factors; Sepsis
PubMed: 25071336
DOI: 10.3748/wjg.v20.i28.9418 -
Expert Opinion on Therapeutic Targets 2016Cholestasis is a reduction in bile flow that occurs during numerous pathologies. Blockage of the biliary tracts results in hepatic accumulation of bile acids or their... (Review)
Review
INTRODUCTION
Cholestasis is a reduction in bile flow that occurs during numerous pathologies. Blockage of the biliary tracts results in hepatic accumulation of bile acids or their conjugate bile salts. The molecular mechanisms behind liver injury associated with cholestasis are extensively studied, but not well understood. Multiple models of obstructive cholestasis result in a significant inflammatory infiltrate at the sites of necrosis that characterize the injury.
AREAS COVERED
This review will focus on direct bile acid toxicity during cholestasis, bile acid signaling processes and on the development and continuation of inflammation during cholestasis, with a focus on novel proposed molecular mediators of neutrophil recruitment. While significant progress has been made on these molecular mechanisms, a continued focus on how cholestasis and the innate immune system interact is necessary to discover targetable therapeutics that might protect the liver while leaving global immunity intact.
EXPERT OPINION
While bile acid toxicity likely occurs in humans and other mammals when toxic bile acids accumulate, persistent inflammation is likely responsible for continued liver injury during obstructive cholestasis. Targeting molecular mediators of inflammation may help prevent liver injury during acute cholestasis both in murine models and human patients.
Topics: Animals; Bile Acids and Salts; Cholestasis; Disease Models, Animal; Drug Design; Humans; Immunity, Innate; Inflammation; Liver Diseases; Mice; Molecular Targeted Therapy; Neutrophil Infiltration
PubMed: 26479335
DOI: 10.1517/14728222.2016.1103735