cytellin and Cholestasis--Intrahepatic

Bile is a complex mixture that includes bile salts, the membrane phospholipid phosphatidylcholine (PC), cholesterol and various endobiotic and xenobiotic toxins, each of which is secreted across the canalicular membrane of the hepatocyte by different ATP-binding cassette (ABC) transporters. The bile salts are essential for the emulsification of dietary fat and lipophilic vitamins. They are synthesized from cholesterol in the hepatocyte and their secretion by the bile salt export pump (BSEP or ABCB11) drives bile flow and is the starting point for the enterohepatic cycle. The detergent nature of bile salts that is key to their physiological role also means that they are inherently cytotoxic, and failure to secrete bile (intraheptic cholestasis) can precipitate severe liver disease and mortality. Such progressive familial intrahepatic cholestasis (PFIC) comes in three types of autosomal recessive disease. PFIC2 is caused by mutation to ABCB11. PFIC3 is caused by mutation of a closely related ABC transporter, ABCB4, which flops PC into the outerleaflet of the canalicular membrane. The flopped PC is extracted by the bile salts in the canaliculus to form a mixed micelle that reduces bile salt detergent activity. The third protein that is essential for bile flow from the hepatocyte is a member of a different class of transporter protein, a P-type ATPase, ATP8B1. Mutation of ATP8B1 causes PFIC1, but ATP8B1 does not transport a component of bile into the canaliculus. Data from different laboratories, published this year, suggests two different roles for ATP8B1 in the hepatocyte: a lipid flippase, that counterbalances the deleterious effects of ABCB4 on barrier function of the canalicular membrane; and an anchor of the actin cytoskeleton necessary to form the microvilli of the brush border. These latest discoveries are described, along with a spectrum of cholestatic disorders whose aetiologies lie in these and other transporters of the canalicular membrane.

Topics: Animals; ATP-Binding Cassette Transporters; Bile Acids and Salts; Bile Canaliculi; Biological Transport, Active; Cholestasis, Intrahepatic; Disease Models, Animal; Hepatocytes; Homeostasis; Humans; Intestinal Absorption; Microvilli; Mutation; Phospholipid Transfer Proteins; Sitosterols

Cholestatic syndromes are inborn or acquired disorders of bile formation. In recent years, several inherited cholestatic syndromes were characterized at the molecular level: progressive familial intrahepatic cholestasis (PFIC) and benign recurrent intrahepatic cholestasis (BRIC). Both PFIC and BRIC were divided phenotypically in distinct subtypes; however, at the genotype level, these clinical entities overlap. PFIC starts in early childhood and progresses toward liver cirrhosis, which often requires liver transplantation within the first decade of life. The diagnosis of PFIC is usually made on the basis of clinical and laboratory findings but needs to be confirmed by genetic and histological analysis. Only recently was it recognized that BRIC, which was estimated as a milder form of PFIC-1, may be caused by more than one gene.

Topics: ATP Binding Cassette Transporter, Subfamily B; ATP-Binding Cassette Transporters; Bile Canaliculi; Biological Transport; Carrier Proteins; Cholestasis, Intrahepatic; Cholesterol; Humans; Jaundice, Chronic Idiopathic; Mutation; Sitosterols

Topics: Bile Ducts; Carrier Proteins; Cholestasis, Intrahepatic; Cholesterol; Cystic Fibrosis; Female; Humans; Jaundice, Chronic Idiopathic; Lithiasis; Liver; Multidrug Resistance-Associated Proteins; Pregnancy; Pregnancy Complications; Receptors, Cytoplasmic and Nuclear; Sitosterols

Our aim was to investigate whether intestinal binding of bile acids by guar gum, a dietary fibre, relieves cholestasis and pruritus in intrahepatic cholestasis of pregnancy.. Forty-eight pregnant women with cholestasis and pruritus were randomized double-blind to guar gum and placebo until the time of delivery, and 20 healthy pregnant women were used as control subjects. The pruritus score and serum bile acids, lipids and non-cholesterol sterols were measured at baseline, at least 2 weeks after treatment, just before delivery and up to 4 weeks after delivery.. The increase in serum bile acids and worsening of pruritus were prevented by guar gum in relation to placebo (P < 0.05). Serum cholesterol was unchanged, but increased cholesterol precursor sterol values suggested that cholesterol synthesis was increased by guar gum. Serum cholestanol proportion, an indicator of cholestasis, was related to pruritus but was unaffected by guar gum.. We conclude that in intrahepatic cholestasis of pregnancy and pruritus, guar gum treatment is beneficial in relieving pruritus, even although indicators of cholestasis are only partially reduced.

Topics: Administration, Oral; Adult; Cholestanol; Cholestasis, Intrahepatic; Cholesterol; Desmosterol; Dietary Fiber; Double-Blind Method; Female; Galactans; Humans; Mannans; Phytosterols; Plant Gums; Pregnancy; Pregnancy Complications; Pruritus; Random Allocation; Sitosterols