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Patholphysiology

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Normal Bile Flow: Primary bile salts are produced in the liver and actively pumped into the bile cannaliculi system. Bile is transported through the biliary tree to the intestine where primary bile acids are converted to secondary bile acids. The majority of these are reabsorbed and travel back to the liver forming the enterohepatic circulation. Bile is important for the disposal of fat soluble waste products and the absorption of fat soluble vitamins. Cholestasis refers to the diminished flow of bile formed by the liver when it reaches a degree of functional insufficiency. As a result bile constituents accumulate in the blood and may cause itching. In addition, fat soluble vitamins (such as vitamin k) are not absorbed resulting in increased maternal risk of post partum haemorrhage (Reference1,Reference3) and fetal intracranial haemorrhage (Reference2).

The primary bile acids, especially cholic acid, are preferentially raised in the serum of those patients with obstetric cholestasis (Reference4). Bile acids are also raised in the fetal serum, amniotic fluid and meconium(Reference5,Reference6).

The pathogenesis is multifactorial and has yet to be fully elucidated. Oestrogen and progesterone have both been implicated in view of the timing of presentation during pregnancy and resolution post delivery. In addition, some women experience a similar condition on the oral contraceptive pill or present with cyclical itching. Oestrogen is known to have cholestatic properties. However the total amount of circulating oestrogen and progesterone in the blood is similar in pregnancies with or without cholestasis, but there are differences in their metabolites (Reference7). Therefore cholestasis may be the result of the action of a metabolite or increased sensitivity to normally raised levels of oestrogen or progesterone during pregnancy.

Genetics

A family history has been demonstrated in 33-50% of patients (Reference8). In addition, obstetric cholestasis has been described in the mothers of children with a subtype of autosomal recessive progressive familial intrahepatic cholestasis (PFIC) (Reference9). The mothers are heterozygous for a mutation in the human multidrug resistance 3 (MDR3) gene, whilst their children are homozygous. This gene codes for a glycoprotein involved in the biliary secretion of phospholipids. Thus the mutation results in alterations in the bile composition. Heterozygosity for this mutation has also been found in a subgroup of women with no family history of PFIC but raised gamma-glutamyl transpeptidase (Reference10). This may represent a further subgroup of women with OC and raised GGT secondary to a genetic mutation.

Proposed Mechanism for Fetal Compromise

Several mechanisms have been proposed including a direct toxic effect on the fetus or a vasospastic effect on the placental circulation (Reference11). A recent study has demonstrated that addition of the primary bile acid taurocholate causes a decrease in the rate of contraction of rat cardiomyocytes in vitro (Reference12). Addition of the bile acid to a network of such cells caused a further decrease in contractility and disruption to the integrity of the network. This could explain the development of fetal dysrrhythmia and sudden intra-uterine death.


References

1.Reid R, Ivey KJ, Rencoret RH, Storey B. Fetal complications of obstetric cholestasis. Br Med Journal 1976;1:870-2, Abstract

2. Fisk NM, Storey GNB. Fetal outcome in obstetric cholestasis. Br J Obstet Gynaecol 1988; 95:1137-43, Abstract

3. Johnston WG, Baskett TF. Obstetric cholestasis. A 14 year review. Am J Obstet Gynaecol 1979;133:299-301, Abstract

4.Bacq Y,Myara A, Brechot MC, Hamon C, Studer E, Trivin F, Metman EH. Serum conjugated bile acid profile during intrahepatic cholestasis of pregnancy. Journal of Hepatology. 1995; 22(1): 66-70, Abstract

5 Laatikainen TJ. Lehtonen PJ. Hesso AE. Fetal sulfated and nonsulfated bile acids in intrahepatic cholestasis of pregnancy. Journal of Laboratory & Clinical Medicine.1978; 92(2):185-93, Abstract

6. Rodrigues CMP, Marin JJG, Brites D. Bile acid patterns in meconium are influenced by cholestasis of pregnancy and not altered by ursodeoxycholic acid.Gut 1999;45(3):446-452, Abstract

7. Reyes H, Sjovall J. Bile acids and progesterone metabolites in intrahepatic cholestasis of pregnancy. Annals of Medicine 2000; 32(2):94-106, Abstract

8. Reyes H. The spectrum of liver and gastrointestinal disease in cholestasis of pregnancy. Gastroenterol Clin North Am 1992; 21:905-21, Abstract

9. de Vree JM. Jacquemin E. Sturm E. Cresteil D. Bosma PJ. Aten J. Deleuze JF. Desrochers M. Burdelski M. Bernard O. Oude Elferink RP. Hadchouel M. Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis. Proceedings of the National Academy of Sciences of the United States of America. 1998;95(1):282-7, Abstract

10.Dixon PH. Weerasekera N. Linton KJ. Donaldson O. Chambers J. Egginton E. Weaver J. Nelson-Piercy C. de Swiet M. Warnes G. Elias E. Higgins CF. Johnston DG. McCarthy MI. Williamson C. Heterozygous MDR3 missense mutation associated with intrahepatic cholestasis of pregnancy: evidence for a defect in protein trafficking. Human Molecular Genetics.2000; 9(8):1209-17, Abstract

11. Sepulveda WH. Gonzalez C. Cruz MA. Rudolph MI. Vasoconstrictive effect of bile acids on isolated human placental chorionic veins. European Journal of Obstetrics, Gynecology, & Reproductive Biology.1991; 42(3):211-5, Abstract

12.Williamson C. Gorelik J. Eaton BM. Lab M. de Swiet M. Korchev Y. The bile acid taurocholate impairs rat cardiomyocyte function: a proposed mechanism for intra-uterine fetal death in obstetric cholestasis. Clinical Science.2001; 100(4): 363-9, Abstract


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