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Investigation and management of recurrent cholestasis of pregnancy
Published in Minakshi Rohilla, Recurrent Pregnancy Loss and Adverse Natal Outcomes, 2020
Intrahepatic cholestasis of pregnancy (ICP) has long been implicated as a rare cause of antepartum stillbirths, now being categorized under the Antepartum hypoxia category (A3) for the fetus and Maternal medical condition (M4) in the World Health Organization (WHO) application of the International Classification of Diseases, 10th Revision, to deaths during the perinatal period (ICD–Perinatal Mortality, ICD-PM) classification of stillbirths [1]. Intrahepatic cholestasis of pregnancy is a pregnancy-related liver disorder [2]. It usually presents in the second and third trimesters, though cases in the first trimester have also reported [3]. It is characterized by pruritis without a rash, especially on the palms and soles, that manifests itself more at night. A rise in bile acids is noted. This entity is characterized by a resolution of the symptoms and biochemical indicators after pregnancy. Cholestasis of pregnancy is associated with adverse fetal outcome, and so it is significant in women with previously unfavorable obstetric history. A history of recurrent cholestasis with jaundice and neonatal death should also be evaluated for genetic diseases, such as progressive familial intrahepatic cholestasis (PFIC) [4]. These women are also predisposed to develop various hepatobiliary, cardiovascular, and immune-mediated diseases in later life. The defining criteria and recommendations for management and delivery timing vary in the literature.
ABC Transporters, Organic Solute Carriers and Drug Metabolising Enzymes in Bile Duct Epithelial Cells
Published in Gianfranco Alpini, Domenico Alvaro, Marco Marzioni, Gene LeSage, Nicholas LaRusso, The Pathophysiology of Biliary Epithelia, 2020
ABC transporters are primary active transporters. Their function depends on the hydrolysis of ATP. ABC transporters can mediate steep uphill transport. In transport from hepatocyte to bile, ABC transporters have to overcome up to thousand fold substrate concentration-gradients. BSEP, the bile salt export pump, mediates bile salt transport from hepatocyte to bile.7 Its genetic deficiency, as occurs in progressive familial intrahepatic cholestasis type 2, leads to a severe form of congenital cholestatic liver disease. Thus, for the hepatobiliary secretion of monovalent bile salts there appears to be no other canalicular transporter that can take over its function. Bile salt glucuronides and sulphates, with two or more negative charges, are transported byMRP2/mrp2.15,16
Biliary Atresia
Published in John F. Pohl, Christopher Jolley, Daniel Gelfond, Pediatric Gastroenterology, 2014
Medical: – Neonatal hepatitis.– Giant cell hepatitis.– Alpha-1 antitrypsin deficiency.– Alagille syndrome (due to bile duct paucity).– Progressive familial intrahepatic cholestasis (Type 1, 2, and 3).
Phenotype-Genotype Correlation of North Indian Progressive Familial Intrahepatic Cholestasis type2 Children Shows p.Val444Ala and p.Asn591Ser Variants and Retained BSEP Expression
Published in Fetal and Pediatric Pathology, 2020
Suvradeep Mitra, Ashim Das, Baburam Thapa, Rakesh Kumar Vasishta
Progressive familial intrahepatic cholestasis (PFIC) constitutes a hereditary cause of infantile and childhood cholestasis, transmitted in an autosomal recessive fashion and is characterized by defective bile secretion [1]. This disease can cause significant morbidity in infancy and childhood presenting as jaundice or intractable pruritus, sometimes spaced out in time and complicated by its progression to cirrhosis and end-stage liver failure. Three different types of familial intrahepatic cholestasis syndromes occur as a result of 3 mutant genes, namely ATP8B1, ABCB11, and ABCB4. Their genetic products are FIC1, BSEP and MDR3 proteins giving rise to PFIC1, PFIC2, and PFIC3, respectively that are genetically, morphologically and prognostically different from each other [2–9]. In addition, PFIC4 is a recently described entity caused by mutation in TJP2 (tight junction protein) gene producing zona occludens 2 (ZO-2) [10,11]. PFIC2 is a low/normal-GGT variant of PFIC with ABCB11 mutation and deficient/defective expression of BSEP. PFIC2 patients usually present in infancy or early childhood and relentlessly progress with the requirement of liver transplant by late childhood. There are multiple studies in the Western population highlighting the clinical, histopathological and genetic features of PFIC2 along with genotype–phenotype correlation [3,6,12–18]. There is only one previous Indian study that has depicted the Indian scenario of PFIC [19]. However, the genetic background and genotype–phenotype correlation of PFIC2 children in India are hitherto unknown. Our study is the first study assessing the genetic background and genotype–phenotype correlation of PFIC2 in Indian children.
Farnesoid X receptor modulators 2014-present: a patent review
Published in Expert Opinion on Therapeutic Patents, 2018
Valentina Sepe, Eleonora Distrutti, Stefano Fiorucci, Angela Zampella
Cholestasis could result from several acquired liver diseases, such as progressive familial intrahepatic cholestasis (PFIC), hepatitis, drug-induced liver injury, pregnancy and primary biliary cirrhosis (PBC), and from two rare autosomal recessive disorders, PFIC, and benign recurrent intrahepatic cholestasis.
Odevixibat: a promising new treatment for progressive familial intrahepatic cholestasis
Published in Expert Opinion on Pharmacotherapy, 2022
Sarah M. Bedoyan, Olya T. Lovell, Simon P. Horslen, James E. Squires
Bile is a complex biochemical mixture with a broad range of functions that is continuously made by the liver. While mostly water, bile also contains a complex composition of inorganic and organic solutes [1]. Organic solutes include bile acids (BAs), phospholipids, cholesterol, proteins, and bilirubin, while inorganic solutes are composed mostly of electrolytes [1,2]. An estimated 700–800 mL/day of bile traverses the bile ducts and drain into the small intestine. The two primary BAs (cholic acid and chenodeoxycholic acid) are synthesized by the liver from cholesterol through a series of complex chemical reactions catalyzed by specific hepatic enzymes [3]. The primary BAs are then transported into bile by the action of specific canalicular membrane transporters. Once in the canalicular space, BAs are transported with other bile products along the extensive network of intrahepatic ducts and into the intestine where they enable fat emulsification and absorption from the small intestine. BAs reaching the terminal ileum will undergo enterohepatic circulation, a process whereby they are re-absorbed, returned to the liver, and re-secreted into bile (Figure 1). Intestinal re-absorption of BAs occurs via the ileal sodium/bile acid cotransporter, also known as the apical sodium-bile acid transporter (ASBT) or the ileal bile acid transporter (IBAT) encoded by the SLC10A2 gene. In addition to its main role in determining the BA pool, ASBT is also important in the regulation lipid and cholesterol homeostasis and has been proposed as a promising target for several disease processes [4]. The efficiency of the enterohepatic circulation system is remarkable, and BAs may undergo 6–10 cycles/day of enterohepatic circulation. From the total BA pool excreted into the intestine (approximately 20–40 g), only 0.2–0.6 g/day of BAs are lost in the feces [5]. Recent advances have enabled a greater understanding of how BAs, and their disrupted homeostasis, may contribute to a broad range of gastrointestinal and hepatic disease [6], including the family of conditions broadly referred to as progressive familial intrahepatic cholestasis (PFIC).