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.
Hepatic accumulation of bile acids is central to the pathogenesis of cholestatic liver diseases. Endocrine hormone fibroblast growth factor 19 (FGF19) may reduce hepatic bile acid levels through ...modulation of bile acid synthesis and prevent subsequent liver damage. However, FGF19 has also been implicated in hepatocellular carcinogenesis, and consequently, the potential risk from prolonged exposure to supraphysiological levels of the hormone represents a major hurdle for developing an FGF19-based therapy. We describe a nontumorigenic FGF19 variant, M70, which regulates bile acid metabolism and, through inhibition of bile acid synthesis and reduction of excess hepatic bile acid accumulation, protects mice from liver injury induced by either extrahepatic or intrahepatic cholestasis. Administration of M70 in healthy human volunteers potently reduces serum levels of 7α-hydroxy-4-cholesten-3-one, a surrogate marker for the hepatic activity of cholesterol 7α-hydroxylase (CYP7A1), the enzyme responsible for catalyzing the first and rate-limiting step in the classical bile acid synthetic pathway. This study provides direct evidence for the regulation of bile acid metabolism by FGF19 pathway in humans. On the basis of these results, the development of nontumorigenic FGF19 variants capable of modulating CYP7A1 expression represents an effective approach for the prevention and treatment of cholestatic liver diseases as well as potentially for other disorders associated with bile acid dysregulation.
ABSTRACTCholestatic jaundice in infancy affects approximately 1 in every 2500 term infants and is infrequently recognized by primary providers in the setting of physiologic jaundice. Cholestatic ...jaundice is always pathologic and indicates hepatobiliary dysfunction. Early detection by the primary care physician and timely referrals to the pediatric gastroenterologist/hepatologist are important contributors to optimal treatment and prognosis. The most common causes of cholestatic jaundice in the first months of life are biliary atresia (BA, 25–40%) followed by an expanding list of monogenic disorders (25%), plus many unknown or multifactorial (e.g., parenteral nutrition related) causes, each of which may have time-sensitive and distinct treatment plans. Thus, these Guidelines can have an essential role for the evaluation of neonatal cholestasis to optimize care. The recommendations from this clinical practice guideline are based upon review and analysis of published literature as well as the combined experience of the authors. The Committee recommends that any infant noted to be jaundiced after 2 weeks of age be evaluated for cholestasis with measurement of total and direct serum bilirubin, and that an elevated serum direct bilirubin level (direct bilirubin levels >1.0 mg/dl or >17 μmol/L) warrants timely consideration for evaluation and referral to a pediatric gastroenterologist or hepatologist. Of note, current differential diagnostic plans now incorporate consideration of modern broad-based next generation DNA sequencing technologies in the proper clinical context. These recommendations are a general guideline and are not intended as a substitute for clinical judgment or as a protocol for the care of all infants with cholestasis. Broad implementation of these recommendations is expected to reduce the time to the diagnosis of pediatric liver diseases, including BA, leading to improved outcomes.
To evaluate the performance of a diagnostic protocol for neonatal/infantile cholestasis in which the main clinical patterns steered the early use of different genetic testing strategies.
An ...observational study was conducted between 2012 and 2017 in a tertiary care setting on a prospective cohort of children with cholestasis occurring at ≤1 year of age and persisting ≥6 weeks, to measure the detection rate of underlying monogenic diseases. After the exclusion of biliary atresia, a clinically driven genetic testing was performed, entailing 3 different approaches with different wideness: confirmatory single-gene testing; focused virtual panels; and wide search through trio whole-exome sequencing.
We enrolled 125 children (66 female, median age 2 months); 96 (77%) patients had hypocholic stools and were evaluated rapidly to exclude biliary atresia, which was the final diagnosis in 74 (59%). Overall, 50 patients underwent genetic testing, 6 with single confirmatory gene testing, 38 through panels, and 6 with trio whole-exome sequencing because of complex phenotype. The genetic testing detection rate was 60%: the final diagnosis was Alagille syndrome in 11, progressive familial intrahepatic cholestasis type 2 in 6, alpha-1-antitrypsin deficiency in 3, and progressive familial intrahepatic cholestasis type 3 in 2; a further 7 genetic conditions were identified in 1 child each. Overall, only 18 of 125 (14%) remained with an indeterminate etiology.
This protocol combining clinical and genetic assessment proved to be an effective diagnostic tool for neonatal/infantile cholestasis, identifying inherited disorders with a high detection rate. It also could allow a noninvasive diagnosis in children presenting with colored stools.
Intrahepatic cholestasis of pregnancy (ICP) is a poorly understood disease of the late second or third trimester of pregnancy, typically associated with rapid resolution following delivery. It is ...characterized by pruritis, elevated serum bile acids, and abnormal liver function tests and has been linked to stillbirth, meconium passage, respiratory distress syndrome and fetal asphyxial events. The incidence is highly variable, dependent both on the ethnic makeup of the population as well as the diagnostic criteria being used. Management is challenging for clinicians, as laboratory abnormalities often lag behind clinical symptoms making diagnosis difficult. The American Congress of Gastroenterology, Government of Western Australia Department of Health, the Royal College of Obstetricians and Gynaecologists, Society for Maternal Fetal Medicine, European Association for the Study of the Liver, and South Australia Maternal and Neonatal Community of Practice have all released guidelines to address the risks, diagnosis and management of ICP. We performed a descriptive review of these guidelines along with a literature search to address conflicting recommendations and highlight new evidence. The variations in the guidelines reflect the heterogeneity of the literature and the challenges of diagnosing and managing ICP.
Inhibition of microRNA-21 (miR-21) prevents necroptosis in the mouse pancreas. Necroptosis contributes to hepatic necro-inflammation in the common bile duct ligation (BDL) murine model. We aimed to ...evaluate the role of miR-21 in mediating deleterious processes associated with cholestasis. Mechanistic studies established a functional link between miR-21 and necroptosis through cyclin-dependent kinase 2-associated protein 1 (CDK2AP1). miR-21 expression increased in the liver of primary biliary cholangitis (PBC) patients and BDL wild-type (WT) mice at both 3 and 14 days. Notably, under BDL, miR-21
mice displayed decreased liver injury markers in serum compared with WT mice, accompanied by reduced hepatocellular degeneration, oxidative stress and fibrosis. Hallmarks of necroptosis were decreased in the liver of BDL miR-21
mice, via relieved repression of CDK2AP1. Further, miR-21
mice displayed improved adaptive response of bile acid homeostasis. In conclusion, miR-21 ablation ameliorates liver damage and necroptosis in BDL mice. Inhibition of miR-21 should arise as a promising approach to treat cholestasis.
Intrahepatic Cholestasis of Pregnancy Williamson, Catherine; Geenes, Victoria
Obstetrics and gynecology (New York. 1953),
2014-July, Letnik:
124, Številka:
1
Journal Article
Recenzirano
Intrahepatic cholestasis of pregnancy is the most common pregnancy-specific liver disease that typically presents in the third trimester. The clinical features are maternal pruritus in the absence of ...a rash and deranged liver function tests, including raised serum bile acids. Intrahepatic cholestasis of pregnancy is associated with an increased risk of adverse perinatal outcomes, including spontaneous preterm delivery, meconium staining of the amniotic fluid, and stillbirth. It is commonly treated with ursodeoxycholic acid. There is accumulating evidence to suggest that intrahepatic cholestasis of pregnancy has a lasting influence on both maternal and fetal health. We review the etiology, diagnosis, and management of this intriguing condition.
Citrin deficiency is an autosomal recessive metabolic liver disease caused by mutations in the SLC25A13 gene. The disease typically presents with cholestasis, elevated liver enzymes, hyperammonemia, ...hypercitrullinemia, and fatty liver in young infants, resulting in a phenotype known as “neonatal intrahepatic cholestasis caused by citrin deficiency” (NICCD). The diagnosis relies on clinical manifestation, biochemical evidence of hypercitrullinemia, and identifying mutations in the SLC25A13 gene. Several common mutations have been found in patients of East Asian background. The mainstay treatment is nutritional therapy in early infancy utilizing a lactose‐free and medium‐chain triglyceride formula. This approach leads to the majority of patients recovering liver function by 1 year of age. Some patients may remain asymptomatic or undiagnosed, but a small proportion of cases can progress to cirrhosis and liver failure, necessitating liver transplantation. Recently, advancements in newborn screening methods have improved the age of diagnosis. Early diagnosis and timely management improve patient outcomes. Further studies are needed to elucidate the long‐term follow‐up of NICCD patients into adolescence and adulthood.
Citrin deficiency: a metabolic disorder causing neonatal cholestasis and steatosis.
What is Known
Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is an autosomal recessive disorder caused by SLC25A13 gene mutations that may recover or progress to liver cirrhosis.
SLC25A13 gene mutations may have a late‐onset phenotype causing neuropsychiatric symptoms in adulthood.
What is New
Citrin deficiency has been described in several countries beyond Asia and should be considered in the differential diagnosis of all infants with cholestasis and growth failure.
A genetic diagnosis, which is now widely available, is the most reliable tool to confirm citrin deficiency, given the significant variability in both clinical manifestations and genetic mutations.
Early diagnosis and treatment results in improved growth and better patient outcomes.
PDF
