INTRAHEPATIC CHOLESTASIS OF PREGNANCY Genetic background, epidemiology and hepatobiliary consequences

................................................................................................... 8 INTRODUCTION ......................................................................................... 9 REVIEW OF THE LITERATURE ................................................................. 10 1. Physiology of bile acids ............................................................................. 10 1.2. Enterohepatic circulation .................................................................. 11 1.3. Transporter mechanisms ................................................................... 13 1.3.1. Basolateral membranes of hepatocytes .................................. 13 1.3.2. Canalicular membranes of hepatocytes ................................. 15 1.3.3. Intestinal transport ................................................................. 15 1.3.4. Regulation ............................................................................... 16 2. Intrahepatic cholestasis ............................................................................. 16 2.1. Intrahepatic cholestatic diseases ....................................................... 17 2.2. Familial cholestatic diseases .............................................................. 17 3. Liver during pregnancy ............................................................................. 21 3.1. Intrahepatic cholestasis of pregnancy .............................................. 21 3.1.1. Epidemiology .......................................................................... 22 3.1.2. Pathogenesis ............................................................................ 22 3.1.3. Genetics ................................................................................... 22 3.1.4. Clinical picture and treatment ............................................... 23 3.1.5. Associated hepatobiliary disorders ......................................... 24 3.2. Other liver diseases and pregnancy .................................................. 25 4. Postmenopausal hormone therapy and liver proteins ............................ 26 4.1. Sex hormone-binding globulin ........................................................ 26 4.2. C-reactive protein .............................................................................. 27 AIMS OF THE STUDY .................................................................................. 29 SUBJECTS AND METHODS ....................................................................... 30 1. Subjects ...................................................................................................... 30 2. Methods ..................................................................................................... 32 2.1.1. Linkage analysis ................................................................................... 32 2.1.2. Polymerase chain reaction .................................................................. 33 2.2. Hormone therapy protocol .................................................................... 33 2.3. Assays ...................................................................................................... 34 3. Statistical analyses ..................................................................................... 34 RESULTS ........................................................................................................ 36 1. Genetics ..................................................................................................... 36 2. Incidence and risk factors ......................................................................... 37 3. The effect of hormone therapy on sex hormone-binding globulin ....... 38 4. The effect of hormone therapy on C-reactive protein ............................ 40 5. Associated liver and biliary diseases ......................................................... 40 DISCUSSION ................................................................................................ 41 CONCLUSIONS ............................................................................................ 46 ACKNOWLEDGEMENTS ............................................................................ 47 REFERENCES ................................................................................................ 49 ORIGINAL PUBLICATIONS ....................................................................... 59