Intrahepatic cholestasis of pregnancy

Intrahepatic cholestasis of pregnancy (ICP), also known as obstetric cholestasis, cholestasis of pregnancy, jaundice of pregnancy, and prurigo gravidarum,[1] is a medical condition in which cholestasis occurs during pregnancy. It typically presents with itching[2] and can lead to complications for both mother and baby.

Intrahepatic cholestasis of pregnancy
SpecialtyObstetrics 

Pruritus (itching) is a common symptom of pregnancy, affecting around 20% of women.[3] The majority of times, itching is a minor annoyance caused by changes to the skin, especially that of the abdomen. However, there are instances when itching may be a symptom of ICP. Although typically noticed on the palms of the hands and the soles of the feet, the itching can occur anywhere on the body.

ICP occurs most commonly in the third trimester, but can begin at any time during the pregnancy.

Signs and symptoms

Most women with this condition present in the third trimester (although it can present as early as seven weeks) with itching without a rash. Typically, the itching is localized to the palms of the hands and soles of the feet, but can be anywhere on the body.

Hallmarks of ICP include the following symptoms:

Most common:

  • Itching, in particular but not limited to that of the palms of the hands and soles of the feet, without presence of a rash
  • Itching that is more noticeable in the evening
  • Darker urine

Less common:

  • Lighter stools
  • Increased clotting time (due to possibly associated vitamin K deficiency)
  • Fatigue
  • Increased nausea
  • Decrease in appetite
  • Jaundice (less than 10% of women)
  • Upper right quadrant pain

Not all ICP sufferers have all of the above symptoms.

Mechanism

The causes of intrahepatic cholestasis of pregnancy are still not fully understood.[4] Hormones, environmental and genetic factors are all thought to contribute to the condition.[5]

Estrogens

Estrogens, and particularly glucuronides such as estradiol-17β-D-glucuronide, have been shown to cause cholestasis in animal studies, by reducing bile acid uptake by hepatocytes.[7]

Progesterone

Treatment with progesterone in the third trimester of pregnancy has been shown to be associated with the development of ICP, and levels of metabolites of progesterone, particularly sulfated progesterone,[8] are higher in patients with ICP than unaffected women, suggesting that progesterone also has a role in ICP.[5]

Genetic factors

Clustering of cases of ICP in families, geographic variation in rates of ICP, and recurrence of ICP in 45-70% of subsequent pregnancies all suggest a genetic component to the disease.[5] Genetic mutations in the hepatocellular transport protein ABCB4 (MDR3), which controls secretion of phosphatidylcholine into bile, have been found in cases of ICP.[9]

Genetic mutations affecting hepatic bile salt transport molecules have also been found in patients with progressive familial intrahepatic cholestasis. It has been found that mothers of patients with this disease have a higher incidence of ICP, suggesting that heterozygote carriers of these mutations are also predisposed to ICP.[5]

In addition to genetic changes to bile salt transport molecules, high levels of estrogen glucuronides have been shown to inhibit the bile salt export pump (BSEP) ABCB11,[10] and high levels of progesterone to inhibit the ABCB4 (MDR3) phospholipid transporter.[11]

Consequently, both genetic mutations in hepatocyte proteins involved in bile secretion together with inhibition of those proteins by high levels of hormone metabolites in pregnancy may have roles in the pathogenesis of ICP.[4]

Environmental factors

A number of features of ICP suggest that environmental factors also have a role in the disease:

  • It has been reported that the incidence of ICP is higher in winter than summer.[12]
  • The incidence of ICP in Chile has dropped from 14% of pregnancies before 1975 to 4% in 2016.[13]
  • ICP recurs in between 60% and 90% of subsequent pregnancies.
  • Low serum selenium levels have been linked to ICP,[14] although the role of selenium in bile secretion is not known.

Diagnosis

ICP is diagnosed by blood tests including a serum bile acid test and liver function test. While most pregnant women experience some itch from time to time, itching on the palms and soles without a visible rash, or persisting severe or extensive itch symptoms should be reported to the midwife or obstetrician.

To obtain a diagnosis of ICP, there are two LFT (liver function tests) and Serum bile acid test. The liver function tests (LFTs) is a simple blood test, the results of which should be available by the next day. If the ALT level is elevated, this, plus pruritus of palms and soles, could be considered as potentially diagnostic of ICP but only with elevated bile acid levels (however LFTs are not always elevated in ICP patients). The serum bile acid blood test for ICP is a quantitative measurement of bile acids.

Other problems with the liver that occur in pregnancy should be considered by the treating clinician. These include preeclampsia, the HELLP syndrome, and acute fatty liver of pregnancy. Furthermore, other causes of hepatitis, like hepatitis viruses, cancer and certain medications, should also be considered.

Treatment

Upon diagnosis, many providers will prescribe Ursodeoxycholic Acid. While there is no cure for ICP, and no way to guarantee a successful outcome, studies have shown a slightly better fetal and maternal outcome from administration of Ursodeoxycholic Acid, whereas Cholestyramine appears to only relieve itching.[7]

If additional blood tests to check clotting function identify a problem, giving Vitamin K may help avoid the risk of hemorrhage at delivery.

Delivery by 35–37 completed weeks may be important to fetal outcome as a recent study demonstrated that in severe ICP (defined as bile acids greater than 40 umol/L) the risk of stillbirth was 1.5% compared to 0.5% of uncomplicated pregnancies. This risk rose further if bile acids doubled.[15] The most recent research, published in The Lancet, suggests that around 90% of women with ICP could wait until 39 weeks of pregnancy to be induced. However, this relies on regular bile acid testing with rapid return of results.[16]

Risks if untreated

Maternal consequences include the following:

  • Itching, which can become intense and debilitating
  • Premature labor
  • Deranged clotting, which requires Vitamin K

Fetal consequences include:

In most cases induction is recommended at 36–38 weeks depending upon the severity of the disease as most stillbirths cluster between 37–39 weeks gestation.[17][18][19][20][21]

The risk of infant and fetal death is lower with delivery beginning at 36 weeks and the risk of expectant management continues to rise each week following 36 weeks gestation.[22]

See also

References
  1. Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1.
  2. Tunzi M, Gray GR (January 2007). "Common skin conditions during pregnancy". American Family Physician. 75 (2): 211–8. PMID 17263216.
  3. Bergman, H.; Melamed, N.; Koren, G. (2013). "Pruritus in pregnancy: Treatment of dermatoses unique to pregnancy". Canadian Family Physician. 59 (12): 1290–1294. PMC 3860924. PMID 24336540.
  4. Pusl T, Beuers U (2007). "Intrahepatic cholestasis of pregnancy". Orphanet Journal of Rare Diseases. 2: 26. doi:10.1186/1750-1172-2-26. PMC 1891276. PMID 17535422.
  5. Lammert F, Marschall HU, Glantz A, Matern S (December 2000). "Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management". J. Hepatol. 33 (6): 1012–21. doi:10.1016/S0168-8278(00)80139-7. PMID 11131439.
  6. Gonzalez MC, Reyes H, Arrese M, et al. (July 1989). "Intrahepatic cholestasis of pregnancy in twin pregnancies". Journal of Hepatology. 9 (1): 84–90. doi:10.1016/0168-8278(89)90079-2. PMID 2768798.
  7. Reyes H, Sjövall J (March 2000). "Bile acids and progesterone metabolites in intrahepatic cholestasis of pregnancy". Annals of Medicine. 32 (2): 94–106. doi:10.3109/07853890009011758. PMID 10766400.
  8. Abu-Hayyeh, S (2015). "Prognostic and mechanistic potential of progesterone sulfates in intrahepatic cholestasis of pregnancy and pruritus gravidarum". Hepatology. 63 (4): 1287–1298. doi:10.1002/hep.28265. PMC 4869673. PMID 26426865.
  9. Dixon, PH (2017). "An expanded role for heterozygous mutations of ABCB4, ABCB11, ATP8B1, ABCC2 and TJP2 in intrahepatic cholestasis of pregnancy". Scientific Reports. 7 (1): 11823. doi:10.1038/s41598-017-11626-x. PMC 5603585. PMID 28924228.
  10. Stieger B, Fattinger K, Madon J, Kullak-Ublick GA, Meier PJ (2000). "Drug- and estrogen-induced cholestasis through inhibition of the hepatocellular bile salt export pump (Bsep) of rat liver". Gastroenterology. 118 (2): 422–30. doi:10.1016/S0016-5085(00)70224-1. PMID 10648470.
  11. Debry P, Nash EA, Neklason DW, Metherall JE (January 1997). "Role of multidrug resistance P-glycoproteins in cholesterol esterification". Journal of Biological Chemistry. 272 (2): 1026–31. doi:10.1074/jbc.272.2.1026. PMID 8995398.
  12. Williamson, Catherine; Geenes, Victoria (2014). "Intrahepatic cholestasis of pregnancy". Obstetrics and Gynecology. 124 (1): 120–33. doi:10.1097/AOG.0000000000000346. PMID 24901263.
  13. Ovadia, Caroline; Williamson, Catherine (2016). "Intrahepatic cholestasis of pregnancy: recent advances". Clinics in Dermatology. 34 (3): 327–34. doi:10.1016/j.clindermatol.2016.02.004. PMID 27265070.
  14. Kauppila A, Korpela H, Mäkilä UM, Yrjänheikki E (January 1987). "Low serum selenium concentration and glutathione peroxidase activity in intrahepatic cholestasis of pregnancy". British Medical Journal (Clinical Research Edition). 294 (6565): 150–2. doi:10.1136/bmj.294.6565.150. PMC 1245162. PMID 3109544.
  15. Geenes, V.; Chappell, L.C.; Seed, P.T.; Steer, P.J.; Knight, M.; Williamson, C. (April 2014). "Association of severe intrahepatic cholestasis of pregnancy with adverse pregnancy outcomes: a prospective population-based case-control study". Hepatology. 59 (4): 1482–91. doi:10.1002/hep.26617. PMC 4296226. PMID 23857305.
  16. Ovadia, Caroline (2019). "Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses". Lancet.
  17. Geenes V, Williamson C: Intrahepatic Cholestasis of pregnancy. World J Gastro 2009;15:2049- 2066.
  18. Fisk NM, Storey GN: Fetal outcome in obstetric cholestasis. Br J Obstet Gynaec 1988;95:1137- 1143.
  19. Zecca E, Costa S, Lauriola V, et al: Bile acid pneumonia: A “new” form of neonatal respiratory distress syndrome? Pediatrics 2003;114:269-272.
  20. Shaw D, Frohlich J, Wittmann BA, Willms M: A prospective study of 18 patients with cholestasis of pregnancy. Am J Obstet Gynecol 1982;142:621-625.
  21. Davies MH, Silva RCMA, Jones SR et al: Fetal mortality associated with cholestasis of pregnancy and the potential benefit of therapy with ursodeoxycholic acid. Gut 1995;37:580-584.
  22. Puljic A, Kim E, Page J, et al: The risk of infant and fetal death by each additional week of expectant management in intrahepatic choelstasis of pregnancy by gestational age. Am J Obstet Gynecol 2015;212(5):667.e1-5.

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