ReviewIntrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management
Section snippets
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,
References (135)
- et al.
Intrahepatic cholestasis of pregnancy: a retrospective case-control study of perinatal outcome
Am J Obstet Gynecol
(1994) - et al.
A prospective study of 18 patients with cholestasis of pregnancy
Am J Obstet Gynecol
(1982) - et al.
Intrahepatic cholestasis of pregnancy: perinatal outcome associated with expectant management
Am J Obstet Gynecol
(1996) - et al.
Maternal serum bile acid levels and fetal distress in cholestasis of pregnancy
Int J Gynaecol Obstet
(1984) - et al.
Drug- and estrogen-induced cholestasis through inhibition of the hepatocellular bile salt export pump (Bsep) of rat liver
Gastroenterology
(2000) - et al.
The rat canalicular conjugate export pump (Mrp2) is down-regulated in intrahepatic and obstructive cholestasis
Gastroenterology
(1997) Estrogen cholestasis. Membranes, metabolites, or receptors?
Gastroenterology
(1987)- et al.
The adverse influence of pregnancy upon sulphation: a clue to the pathogenesis of intrahepatic cholestasis of pregnancy?
J Hepatol
(1994) Intrahepatic cholestasis of pregnancy
Clinics Liver Dis
(1999)- et al.
Progesterone metabolites and bile acids in serum of patients with intrahepatic cholestasis of pregnancy: effect of ursodeoxycholic acid therapy
Hepatology
(1997)
Profiles of bile acids and progesterone metabolites in the urine and serum of women with intrahepatic cholestasis of pregnancy
J Hepatol
Exertion of progesterone metabolites in urine and bile of pregnant women with intrahepatic cholestasis
J Steroid Biochem
The identification of novel steroid N-acetylglucosaminides in the urine of pregnant women
J Steroid Biochem Mol Biol
Familial recurrent intrahepatic cholestasis of pregnancy: a genetic study providing evidence for transmission of a sex-limited, dominant trait
Gastroenterology
Cracking the genetic code for benign recurrent and progressive familial intrahepatic cholestasis
J Hepatol
Familial benign recurrent intrahepatic cholestasis. Interrelation with intrahepatic cholestasis of pregnancy and from oral contraceptives?
Gastroenterology
Heterozygous non-sense mutation of the MDR3 gene in familial intrahepatic cholestasis of pregnancy
Lancet
Role of multidrug resistance P-glycoproteins in cholesterol esterification
J Biol Chem
Unusual case of severe cholestasis of pregnancy with early onset, improved by ursodeoxycholic acid administration
Eur J Obstet Gynecol Reprod Biol
Fetal bile acid levels in pregnancies complicated by maternal intrahepatic cholestasis
Am J Obstet Gynecol
Vasoconstrictive effect of bile acids on isolated human placental chorionic veins
Eur J Obstet Gynecol Reprod Biol
Beneficial effect of ursodeoxycholic acid on alterations induced by cholestasis of pregnancy in bile acid transport across the human placenta
J Hepatol
Prolonged postpartum course of intrahepatic cholestasis of pregnancy
Gastroenterology
Recurrent familial prolonged intrahepatic cholestasis of pregnancy associated with chronic liver disease
Gastroenterology
Gallbladder function and maternal bile acids in intrahepatic cholestasis of pregnancy
Eur J Obstet Gynecol Reprod Biol
Serum bile acid concentrations during pregnancy and their relationship to obstetric cholestasis
Gastroenterology
Determination of serum bile acids by glass capillary gas-liquid chromatography
Clin Chim Acta
Correction of maternal serum bile acid profile during ursodeoxy-cholic acid therapy in cholestasis of pregnancy
J Hepatol
Serum bile acid levels in pregnancy with pruritus (bile acids and steroids 158)
Clin Chim Acta
Serum conjugated bile acid profile during intrahepatic cholestasis of pregnancy
J Hepatol
Biliary bile acids in uncomplicated pregnancy and in cholestasis of pregnancy
Clin Chem Acta
Liver disease in pregnancy
Med Clin North Am
Recurrent jaundice in pregnancy. I. A clinical and ultrastructural study
Am J Med
Berichte und Arbeiten aus der Geburtshilflich-Gynäkologischen Klinik zu Gießen 1881-1882
Female sex steroids and cholestasis
Semin Liver Dis
Intrahepatic cholestasis of pregnancy: a French prospective study
Hepatology
Fetal outcome in obstetric cholestasis
Br J Obstet Gynaecol
Maternal features of obstetric cholestasis: 20 years experience at King George V Hospital
Aust N Z J Obstet Gynaecol
Cholestasis of pregnancy. Clinical and laboratory studies
Acta Obstet Gynecol Scand
The effect of estrogen on bile formation in the rat
J Clin Invest
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
The role of sex hormones and hepatic plasma membranes in the pathogenesis of cholestasis
Modulation by S-adenosyl-L-methionine of hepatic Na+,K+-ATPase, membrane fluidity, and bile flow in rats with ethinyl estradiol-induced cholestasis
Hepatology
Ethinyl estradiol cholestasis involves alterations in expression of liver sinusoidal transporters
Am J Physiol
Steroid D-ring glucuronides: characterization of a new class of cholestatic agents in the rat
J Pharmacol Exp Ther
Recurrent jaundice in pregnancy. IV. Quantitative determination of urinary and biliary estrogens, including studies in pruritus gravidarum
J Clin Endocrinol Metab
Bile acids and progesterone metabolites in intrahepatic cholestasis of pregnancy
Ann Med
Obstetric hepatosis: treatment with cholestyramine and interim response to steroids
Obstet Gynecol
Steroid sulphates in plasma from pregnant women with pruritus and elevated plasma bile acid levels
Ann Clin Res
Effect of maternal intrahepatic cholestasis on fetal steroid metabolism
J Clin Invest
Cited by (376)
Selective feticide reverses intrahepatic cholestasis of pregnancy in twins discordant for growth: A case report
2023, Case Reports in Women's HealthObstetric cholestasis: A case report on rapid bile acid elevation
2023, Case Reports in Women's HealthObstetric Cholestasis: Investigation of a suspected high incidence in the West of Ireland
2022, European Journal of Obstetrics and Gynecology and Reproductive BiologyThe wide phenotypic and genetic spectrum of ABCB4 gene deficiency: A case series
2022, Digestive and Liver DiseaseCitation Excerpt :The range of diseases can be very wide: Low Phospholipid Associated Cholelithiasis syndrome (LPAC), characterized by symptomatic and recurring cholelithiasis in young adults, is a result of cholesterol crystallization promoted by micellar destabilization [3,4]; Intrahepatic Cholestasis of Pregnancy (ICP), usually presents with pruritus and elevated serum bile salt concentration in the third trimester of pregnancy and resolves after birth. The pathogenesis of this condition is still unknown but the effect of heterozygous ABCB4 mutations on hormonal levels have been associated with symptomatic presentation of ICP [5]. Patients with ICP are also susceptible to hormone-induced cholestasis related to oral contraception and other forms of drug-induced liver injury (DILI) have been associated with ABCB4 variants [6–8].
Recognition of asymptomatic hypercholanemia of pregnancy: Different clinical features, fetal outcomes and bile acids metabolism from intrahepatic cholestasis of pregnancy
2022, Biochimica et Biophysica Acta - Molecular Basis of Disease