Elsevier

Journal of Hepatology

Volume 33, Issue 6, December 2000, Pages 1012-1021
Journal of Hepatology

Review
Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management

https://doi.org/10.1016/S0168-8278(00)80139-7Get rights and content

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Hormonal factors: estrogens

Genetic predisposition and hormonal factors play key roles in the pathogenesis of ICP. Evidence for a primary role of hormonal factors in ICP was provided by the following observations (2):

  • The disease starts in the last trimester which is the period of the highest hormone concentrations.

  • Twin pregnancies display both a higher incidence of ICP and more pronounced rises in hormone levels.

  • ICP resolves promptly after delivery, when levels of placental hormones return to normal.

  • In further

Symptoms

In the past, icterus was believed to be the major clinical finding in ICP. However, the most common symptom is severe pruritus, which most typically appears in the third trimester and starts in palms and soles. In 10% of the patients, pruritus develops in the first trimester and 25% of the patients present with pruritus in the second trimester (70). The pruritus is generally more severe at night and can lead to considerable discomfort for the patients. Only 10% of the patients with pruritus

Diagnosis

Liver function tests are to be performed in every pregnant woman who experiences pruritus. The increase of serum bile acids in combination with typical pruritus is highly suggestive of the diagnosis of ICP.

Among standard liver tests, alanine transaminase (ALT) is a very sensitive parameter for ICP (3). Serum transaminase levels are normal until delivery in healthy pregnancies and therefore, any rise should alert and lead to further tests. ALT is released into the blood in increasing amounts

Differential Diagnosis

The main differential diagnoses of pruritus of ICP without icterus are skin diseases, allergic reactions and pruritus related to abdominal striae. Only 0.07% of all pregnant woman develop visible icterus (95). The clinician distinguishes icterus in graviditate, the coincidence of icterus and pregnancy, from icterus e graviditate as a specific complication of pregnancy (Table 3). The acute fatty liver of pregnancy presents with transaminases up to 12 μkat/l (500 U/l), severe hypoglycemia,

Management

ICP is a fairly common disease with a high impact on fetal morbidity and mortality, and it is also a condition of great discomfort for the patients. Obstetric management of patients with ICP varies widely over the world. In spite of numerous reports of increased fetal risk 4., 5., 96. many obstetric clinics still choose to manage ICP pregnancies expectantly. Many different protocols for intensified surveillance have been proposed. It has been shown that a regimen including weekly fetal

Pharmacological Treatment

Antihistamines, anion exchange resins and phenobarbital are given to remove putative peripheral pruritogens or to reverse their effects on empiric grounds (97). These therapeutic options have not received wide acceptance for treatment of ICP patients because of their ambiguous efficacy or side effects. Anion exchange resins such as colestipol or colestyramine bind bile acids and interrupt their enterohepatic circulation. They should therefore be given separately from ursodeoxycholic acid (UDCA,

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References (135)

  • LJ Meng et al.

    Profiles of bile acids and progesterone metabolites in the urine and serum of women with intrahepatic cholestasis of pregnancy

    J Hepatol

    (1997)
  • T Laatikainen et al.

    Exertion of progesterone metabolites in urine and bile of pregnant women with intrahepatic cholestasis

    J Steroid Biochem

    (1973)
  • LJ Meng et al.

    The identification of novel steroid N-acetylglucosaminides in the urine of pregnant women

    J Steroid Biochem Mol Biol

    (1996)
  • RT Holzbach et al.

    Familial recurrent intrahepatic cholestasis of pregnancy: a genetic study providing evidence for transmission of a sex-limited, dominant trait

    Gastroenterology

    (1983)
  • RP Oude Elferink et al.

    Cracking the genetic code for benign recurrent and progressive familial intrahepatic cholestasis

    J Hepatol

    (1998)
  • AG De Pagter et al.

    Familial benign recurrent intrahepatic cholestasis. Interrelation with intrahepatic cholestasis of pregnancy and from oral contraceptives?

    Gastroenterology

    (1976)
  • E Jacquemin et al.

    Heterozygous non-sense mutation of the MDR3 gene in familial intrahepatic cholestasis of pregnancy

    Lancet

    (1999)
  • P Debry et al.

    Role of multidrug resistance P-glycoproteins in cholesterol esterification

    J Biol Chem

    (1997)
  • D Brites et al.

    Unusual case of severe cholestasis of pregnancy with early onset, improved by ursodeoxycholic acid administration

    Eur J Obstet Gynecol Reprod Biol

    (1998)
  • TJ Laatikainen

    Fetal bile acid levels in pregnancies complicated by maternal intrahepatic cholestasis

    Am J Obstet Gynecol

    (1975)
  • WH Sepulveda et al.

    Vasoconstrictive effect of bile acids on isolated human placental chorionic veins

    Eur J Obstet Gynecol Reprod Biol

    (1991)
  • MA Serrano et al.

    Beneficial effect of ursodeoxycholic acid on alterations induced by cholestasis of pregnancy in bile acid transport across the human placenta

    J Hepatol

    (1998)
  • R Olsson et al.

    Prolonged postpartum course of intrahepatic cholestasis of pregnancy

    Gastroenterology

    (1993)
  • CB Leevy et al.

    Recurrent familial prolonged intrahepatic cholestasis of pregnancy associated with chronic liver disease

    Gastroenterology

    (1997)
  • P Kirkinen et al.

    Gallbladder function and maternal bile acids in intrahepatic cholestasis of pregnancy

    Eur J Obstet Gynecol Reprod Biol

    (1984)
  • M Lunzer et al.

    Serum bile acid concentrations during pregnancy and their relationship to obstetric cholestasis

    Gastroenterology

    (1986)
  • T Laatikainen et al.

    Determination of serum bile acids by glass capillary gas-liquid chromatography

    Clin Chim Acta

    (1975)
  • D Brites et al.

    Correction of maternal serum bile acid profile during ursodeoxy-cholic acid therapy in cholestasis of pregnancy

    J Hepatol

    (1998)
  • K Sjövall et al.

    Serum bile acid levels in pregnancy with pruritus (bile acids and steroids 158)

    Clin Chim Acta

    (1966)
  • Y Bacq et al.

    Serum conjugated bile acid profile during intrahepatic cholestasis of pregnancy

    J Hepatol

    (1995)
  • T Laatikainen et al.

    Biliary bile acids in uncomplicated pregnancy and in cholestasis of pregnancy

    Clin Chem Acta

    (1978)
  • JL Wolf

    Liver disease in pregnancy

    Med Clin North Am

    (1996)
  • H Adlercreutz et al.

    Recurrent jaundice in pregnancy. I. A clinical and ultrastructural study

    Am J Med

    (1967)
  • F Ahlfeld

    Berichte und Arbeiten aus der Geburtshilflich-Gynäkologischen Klinik zu Gießen 1881-1882

    (1883)
  • MJ Kreek

    Female sex steroids and cholestasis

    Semin Liver Dis

    (1987)
  • Y Bacq et al.

    Intrahepatic cholestasis of pregnancy: a French prospective study

    Hepatology

    (1997)
  • NM Fisk et al.

    Fetal outcome in obstetric cholestasis

    Br J Obstet Gynaecol

    (1988)
  • NM Fisk et al.

    Maternal features of obstetric cholestasis: 20 years experience at King George V Hospital

    Aust N Z J Obstet Gynaecol

    (1988)
  • B Berg et al.

    Cholestasis of pregnancy. Clinical and laboratory studies

    Acta Obstet Gynecol Scand

    (1986)
  • EL Forker

    The effect of estrogen on bile formation in the rat

    J Clin Invest

    (1969)
  • RA Davis et al.

    Alterations of hepatic Na+,K+-ATPase and bile flow by estrogen: effects on liver surface membrane lipid structure and function

    Proc Natl Acad Sci USA

    (1978)
  • FR Simon

    The role of sex hormones and hepatic plasma membranes in the pathogenesis of cholestasis

  • UA Boelsterli et al.

    Modulation by S-adenosyl-L-methionine of hepatic Na+,K+-ATPase, membrane fluidity, and bile flow in rats with ethinyl estradiol-induced cholestasis

    Hepatology

    (1983)
  • FR Simon et al.

    Ethinyl estradiol cholestasis involves alterations in expression of liver sinusoidal transporters

    Am J Physiol

    (1996)
  • M Meyers et al.

    Steroid D-ring glucuronides: characterization of a new class of cholestatic agents in the rat

    J Pharmacol Exp Ther

    (1981)
  • H Adlercreutz et al.

    Recurrent jaundice in pregnancy. IV. Quantitative determination of urinary and biliary estrogens, including studies in pruritus gravidarum

    J Clin Endocrinol Metab

    (1974)
  • J Sjövall et al.

    Bile acids and progesterone metabolites in intrahepatic cholestasis of pregnancy

    Ann Med

    (2000)
  • EE Lutz et al.

    Obstetric hepatosis: treatment with cholestyramine and interim response to steroids

    Obstet Gynecol

    (1969)
  • J Sjövall et al.

    Steroid sulphates in plasma from pregnant women with pruritus and elevated plasma bile acid levels

    Ann Clin Res

    (1970)
  • TJ Laatikainen et al.

    Effect of maternal intrahepatic cholestasis on fetal steroid metabolism

    J Clin Invest

    (1974)
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