Intrahepatic cholestasis of pregnancy

Intrahepatic cholestasis of pregnancy
Intrahepatic Cholestasis of Pregnancy
Classification and external resources
ICD-10 O26.6
ICD-9 646.73
DiseasesDB 6884

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

Itching has long been considered to be a common symptom of pregnancy. The vast majority of times, itching, or pruritus, is a minor annoyance caused by changes to the skin, especially that of the abdomen. However, there are instances when itching is a symptom of ICP. This is usually most intense on the palms of the hands, and the soles of the feet, but can be wide spread.

ICP occurs most commonly in the third trimester, but can begin at any time during the pregnancy. It is also the second most common cause of jaundice in pregnancy.


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:

Delivery has been recommended in the 38th week when lung maturity has been established. [3]

Signs and symptoms

Most women with this condition present in third trimester with intense itching without a rash. Generally, the itching is localized to the abdomen, legs, palms, and soles, but can be generalized.

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 increases in the evening
  • Itching that does not respond favorably to anti-histamines or other anti-itch remedies
  • Often, elevated LFT results as well as serum bile acid counts

Less common:

  • Darker urine
  • Lighter stools
  • Increased clotting time (due to possibly associated vitamin K deficiency)
  • Fatigue
  • Increased nausea
  • Decrease in appetite
  • Jaundice
  • Upper right quadrant pain

It is important to note that not all ICP sufferers have all of the above symptoms. For example, Jaundice only occurs in relatively small subset of cases, and in some cases abnormal lab results were not seen until 15 weeks or more after the onset of symptoms.


The causes of intrahepatic cholestasis of pregnancy are still not fully understood.[3] Hormones and genetic factors are likely to be important in the pathogenesis of the disease.[4] A number of features of the disease suggest a link to hormones:[5]


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]


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, are higher in patients with ICP than unaffected women, suggesting that progesterone also has a role in ICP.[4]

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.[4] Genetic mutations in the hepatocellular transport protein ABCB4 (MDR3), which controls secretion of phosphatidylcholine into bile, have been found in 15% of cases of ICP.[8]

Genetic mutations affecting hepatic bile salt transport molecules have also been found in patients with progressive familial intrahepatic cholestasis (PFIC). It has been found that mothers of patients with PFIC have a higher incidence of ICP, suggesting that heterozygote carriers of these mutations are also predisposed to ICP.[4]

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,[9] and high levels of progesterone to inhibit the ABCB4 (MDR3) phospholipid transporter.[10]

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.[3]

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 in Sweden, Finland and Chile.
  • The incidence of ICP in Chile has dropped from 14% of pregnancies before 1975 to less than 2% in 1997.[3]
  • ICP recurs in between 45% and 70% of subsequent pregnancies.
  • Low serum selenium levels have been linked to ICP,[11] although the role of selenium in bile secretion is not known.


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 obstetrican.

To obtain a diagnosis of ICP, there are two LFT 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, should be treated as diagnostic of ICP (however LFT's are not always elevated in ICP patients). The serum bile acid blood test for ICP is a quantitative measurement of bile salts. The results of this test often take longer to return, but the test is more specific for ICP.

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 and certain medications, should also be considered.


Upon diagnosis, most 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 37 completed weeks is considered crucial to fetal outcome [12], though it does not completely eliminate the risks associated with the condition.

See also


  1. ^ a b c d Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 1-4160-2999-0. 
  2. ^ Tunzi M, Gray GR (January 2007). "Common skin conditions during pregnancy". Am Fam Physician 75 (2): 211–8. PMID 17263216. 
  3. ^ a b c d Pusl T, Beuers U (2007). "Intrahepatic cholestasis of pregnancy". Orphanet J Rare Dis 2: 26. doi:10.1186/1750-1172-2-26. PMC 1891276. PMID 17535422. Retrieved 2009-10-22. 
  4. ^ a b c d 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. Retrieved 2009-10-22. 
  5. ^ Kreek MJ (February 1987). "Female sex steroids and cholestasis". Semin. Liver Dis. 7 (1): 8–23. doi:10.1055/s-2008-1040559. PMID 3296217. 
  6. ^ Gonzalez MC, Reyes H, Arrese M, et al. (July 1989). "Intrahepatic cholestasis of pregnancy in twin pregnancies". J. Hepatol. 9 (1): 84–90. doi:10.1016/0168-8278(89)90079-2. PMID 2768798. 
  7. ^ a b Reyes H, Sjövall J (March 2000). "Bile acids and progesterone metabolites in intrahepatic cholestasis of pregnancy". Ann. Med. 32 (2): 94–106. doi:10.3109/07853890009011758. PMID 10766400. 
  8. ^ Jacquemin E, Cresteil D, Manouvrier S, Boute O, Hadchouel M (January 1999). "Heterozygous non-sense mutation of the MDR3 gene in familial intrahepatic cholestasis of pregnancy". Lancet 353 (9148): 210–1. doi:10.1016/S0140-6736(05)77221-4. PMID 9923886. Retrieved 2009-10-23. 
  9. ^ 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. Retrieved 2009-10-23. 
  10. ^ Debry P, Nash EA, Neklason DW, Metherall JE (January 1997). "Role of multidrug resistance P-glycoproteins in cholesterol esterification". J. Biol. Chem. 272 (2): 1026–31. doi:10.1074/jbc.272.2.1026. PMID 8995398. Retrieved 2009-10-23. 
  11. ^ Kauppila A, Korpela H, Mäkilä UM, Yrjänheikki E (January 1987). "Low serum selenium concentration and glutathione peroxidase activity in intrahepatic cholestasis of pregnancy". Br Med J (Clin Res Ed) 294 (6565): 150–2. doi:10.1136/bmj.294.6565.150. PMC 1245162. PMID 3109544. Retrieved 2009-10-23. 
  12. ^ Fagen EA, "Intrahepatic cholestasis of pregnancy," BMJ 1994;309:1243-1244 (12 November)

External links

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