Intrahepatic cholestasis of pregnancy

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Intrahepatic cholestasis of pregnancy
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High magnification micrograph showing liver cholestasis.
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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 fetus.

Contents

Pruritus (itching) is a common symptom of pregnancy, affecting around 23% 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: [4]

Most common:

Less common:

Not all ICP sufferers have all of the above symptoms.

Mechanism

The causes of intrahepatic cholestasis of pregnancy are still not fully understood, but are thought to be caused through a combination of genetics, [5] [6] hormones and environment. [7] Hormones, environmental and genetic factors are all thought to contribute to the condition. [8]

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. [10]

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, [11] are higher in patients with ICP than unaffected women, suggesting that progesterone may have a bigger role than estrogen in ICP. [12]

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. [8] Genetic mutations in the hepatocellular transport protein ABCB4 (MDR3), which controls secretion of phosphatidylcholine into bile, have been found in cases of ICP. [13]

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. [8]

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, [14] and high levels of progesterone to inhibit the ABCB4 (MDR3) phospholipid transporter. [15]

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. [7]

Environmental factors

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

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 without a visible rash, or persistent or extensive itch symptoms should be reported to the midwife or obstetrician. It is important to note that as the level of itch does not correlate with bile acid levels (shown to be the most likely cause of stillbirth in ICP), the itch in ICP can range from being mild to severe.[ citation needed ]

To obtain a diagnosis of ICP, a liver function test and a serum bile acid test should be requested. Although the ALT level may be raised, 20% of women with ICP will always have a normal LFT test result. [19] 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

Many providers will prescribe ursodeoxycholic acid. The most recent trial, PITCHES, [20] did not show an overall beneficial effect, but some researchers believe that it may still be useful to offer ursodeoxycholic acid to women whose bile acids are > 40 μmol/litre. 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. [10] [21]

There is no evidence that giving oral water-soluble Vitamin K may help to avoid the risk of hemorrhage at delivery. However, experts in ICP will prescribe this if the woman reports pale stools, has very severe ICP (bile acids > 100 μmol/litre) or has a known clotting problem.

Delivery from 34 weeks may be important to reduce the risk of stillbirth, as a recent study identified the level of bile acids at which stillbirth risk rises. This research, published in The Lancet, also 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. [22]

Risks if untreated

Maternal consequences include the following:

Fetal consequences include:

In most cases induction is typically recommended anywhere from 34 to 39 weeks. [22] [24] [25] [26] [27] [28]

In the United States, some researchers have suggested that the risk of stillbirth is lower if induction occurs at 36 weeks. Whilst Ovadia's research [22] suggests differently, it is important to note that in the United States bile acid tests can take up to seven days to be processed, and this means that it may be more prudent to base delivery on the US research. [29]

See also

Related Research Articles

<span class="mw-page-title-main">Estrogen</span> Primary female sex hormones

Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal activity: estrone (E1), estradiol (E2), and estriol (E3). Estradiol, an estrane, is the most potent and prevalent. Another estrogen called estetrol (E4) is produced only during pregnancy.

<span class="mw-page-title-main">Progesterone</span> Sex hormone

Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the major progestogen in the body. Progesterone has a variety of important functions in the body. It is also a crucial metabolic intermediate in the production of other endogenous steroids, including the sex hormones and the corticosteroids, and plays an important role in brain function as a neurosteroid.

<span class="mw-page-title-main">Itch</span> Sensation that causes desire or reflex to scratch

Itch is a sensation that causes the desire or reflex to scratch. Itches have resisted many attempts to be classified as any one type of sensory experience. Itches have many similarities to pain, and while both are unpleasant sensory experiences, their behavioral response patterns are different. Pain creates a withdrawal reflex, whereas itches leads to a scratch reflex.

<span class="mw-page-title-main">Primary biliary cholangitis</span> Autoimmune disease of the liver

Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is an autoimmune disease of the liver. It results from a slow, progressive destruction of the small bile ducts of the liver, causing bile and other toxins to build up in the liver, a condition called cholestasis. Further slow damage to the liver tissue can lead to scarring, fibrosis, and eventually cirrhosis.

<span class="mw-page-title-main">Lipoid congenital adrenal hyperplasia</span> Medical condition

Lipoid congenital adrenal hyperplasia is an endocrine disorder that is an uncommon and potentially lethal form of congenital adrenal hyperplasia (CAH). It arises from defects in the earliest stages of steroid hormone synthesis: the transport of cholesterol into the mitochondria and the conversion of cholesterol to pregnenolone—the first step in the synthesis of all steroid hormones. Lipoid CAH causes mineralocorticoid deficiency in affected infants and children. Male infants are severely undervirilized causing their external genitalia to look feminine. The adrenals are large and filled with lipid globules derived from cholesterol.

<span class="mw-page-title-main">Aagenaes syndrome</span> Medical condition

Aagenaes syndrome is a syndrome characterised by congenital hypoplasia of lymph vessels, which causes lymphedema of the legs and recurrent cholestasis in infancy, and slow progress to hepatic cirrhosis and giant cell hepatitis with fibrosis of the portal tracts.

<span class="mw-page-title-main">Ursodeoxycholic acid</span> Metabolite of cholesterol

Ursodeoxycholic acid (UDCA), also known as ursodiol, is a secondary bile acid, produced in humans and most other species from metabolism by intestinal bacteria. It is synthesized in the liver in some species, and was first identified in bile of bears of genus Ursus, from which its name derived. In purified form, it has been used to treat or prevent several diseases of the liver or bile ducts.

<span class="mw-page-title-main">Alagille syndrome</span> Medical condition

Alagille syndrome (ALGS) is a genetic disorder that affects primarily the liver and the heart. Problems associated with the disorder generally become evident in infancy or early childhood. The disorder is inherited in an autosomal dominant pattern, and the estimated prevalence of Alagille syndrome is 1 in every 30,000 to 1 in every 40,000 live births. It is named after the French pediatrician Daniel Alagille, who first described the condition in 1969.

<span class="mw-page-title-main">Hypothalamic–pituitary–gonadal axis</span> Concept of regarding the hypothalamus, pituitary gland and gonadal glands as a single entity

The hypothalamic–pituitary–gonadal axis refers to the hypothalamus, pituitary gland, and gonadal glands as if these individual endocrine glands were a single entity. Because these glands often act in concert, physiologists and endocrinologists find it convenient and descriptive to speak of them as a single system.

<span class="mw-page-title-main">Cholestasis</span> Medical condition

Cholestasis is a condition where bile cannot flow from the liver to the duodenum. The two basic distinctions are an obstructive type of cholestasis where there is a mechanical blockage in the duct system that can occur from a gallstone or malignancy, and metabolic types of cholestasis which are disturbances in bile formation that can occur because of genetic defects or acquired as a side effect of many medications. Classification is further divided into acute or chronic and extrahepatic or intrahepatic.

<span class="mw-page-title-main">Bile acid</span> Steroid acid found predominantly in the bile of mammals and other vertebrates

Bile acids are steroid acids found predominantly in the bile of mammals and other vertebrates. Diverse bile acids are synthesized in the liver. Bile acids are conjugated with taurine or glycine residues to give anions called bile salts.

Progressive familial intrahepatic cholestasis (PFIC) is a group of familial cholestatic conditions caused by defects in biliary epithelial transporters. The clinical presentation usually occurs first in childhood with progressive cholestasis. This usually leads to failure to thrive, cirrhosis, and the need for liver transplantation.

<span class="mw-page-title-main">Pruritic urticarial papules and plaques of pregnancy</span> Chronic rash that occurs during pregnancy

Pruritic urticarial papules and plaques of pregnancy (PUPPP), known in United Kingdom as polymorphic eruption of pregnancy (PEP), is a chronic hives-like rash that strikes some women during pregnancy. Some skin changes are known to occur in people who are pregnant while other skin conditions, or dermatoses, that people have prior to getting pregnant will become altered or symptoms will increase. Pruritic urticarial papules and plaques of pregnancy (PUPPP) is one of many skin conditions that is specific to pregnancy and occurs in about 1 in every 160 (0.625%) of pregnancies.

<span class="mw-page-title-main">ABCB11</span> Protein-coding gene in the species Homo sapiens

ATP-binding cassette, sub-family B member 11 also known as ABCB11 is a protein which in humans is encoded by the ABCB11 gene.

<span class="mw-page-title-main">ABCB4</span> Protein-coding gene in the species Homo sapiens

The ATP-binding cassette 4 gene encodes the Multidrug resistance protein 3. ABCB4 is associated with progressive familial intrahepatic cholestasis type 3 and intrahepatic cholestasis of pregnancy.

Pruritic folliculitis of pregnancy is a skin condition that occurs in one in 3000 people, about 0.2% of cases, who are in their second to third trimester of pregnancy where the hair follicle becomes inflamed or infected, resulting in a pus filled bump. Some dermatologic conditions aside from pruritic folliculitis during pregnancy include "pruritic urticarial papules and plaques of pregnancy, atopic eruption of pregnancy, pemphigoid gestationis, intrahepatic cholestasis of pregnancy, and pustular psoriasis of pregnancy". This pruritic folliculitis of pregnancy differs from typical pruritic folliculitis; in pregnancy, it is characterized by sterile hair follicles becoming inflamed mainly involving the trunk, contrasting how typical pruritic folliculitis is mainly localized on "the upper back, shoulders, and chest." This condition was first observed after some pregnant individuals showed signs of folliculitis that were different than seen before. The inflammation was thought to be caused by hormonal imbalance, infection from bacteria, fungi, viruses or even an ingrown hair. However, there is no known definitive cause as of yet. These bumps usually begin on the belly and then spread to upper regions of the body as well as the thighs.

<span class="mw-page-title-main">Epomediol</span> Synthetic terpenoid

Epomediol is a synthetic terpenoid with choleretic effects. It has been used in the symptomatic treatment of itching due to intrahepatic cholestasis of pregnancy.

Cholestatic pruritus is the sensation of itch due to nearly any liver disease, but the most commonly associated entities are primary biliary cholangitis, primary sclerosing cholangitis, obstructive choledocholithiasis, carcinoma of the bile duct, cholestasis, and chronic hepatitis C viral infection and other forms of viral hepatitis.

<span class="mw-page-title-main">Obeticholic acid</span> Chemical compound

Obeticholic acid (OCA), sold under the brand name Ocaliva, is a semi-synthetic bile acid analogue which has the chemical structure 6α-ethyl-chenodeoxycholic acid. It is used as a medication used to treat primary biliary cholangitis. Intercept Pharmaceuticals Inc. hold the worldwide rights to develop OCA outside Japan and China, where it is licensed to Dainippon Sumitomo Pharma.

<span class="mw-page-title-main">Odevixibat</span> Medication

Odevixibat, sold under the brand name Bylvay, is a medication for the treatment of progressive familial intrahepatic cholestasis. It is taken by mouth. Odevixibat is a reversible, potent, selective inhibitor of the ileal bile acid transporter (IBAT). It was developed by Albireo Pharma.

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. ↑ Kenyon, AP; Tribe, RM; Nelson-Piercy, C; Girling, JC; Williamson, C; Seed, PT; Vaughn-Jones, S; Shennan, AH (2010). "Pruritus in pregnancy: A study of anatomical distribution and prevalence in relation to the development of obstetric cholestasis". Obstetric Medicine. 3 (1): 25–29. doi:10.1258/om.2010.090055. PMC   4989767 . PMID   27582836.
  4. ↑ "Intrahepatic cholestasis of pregnancy". www.marchofdimes.org. Retrieved 2022-04-27.
  5. ↑ Dixon, PH; Wadsworth, CA; Chambers, J; Donnelly, J; Cooley, S; Buckley, R; Mannino, R; Jarvis, S; Syngelaki, A; Geenes, V; Paul, P; Sothinathan, M; Kubitz, R; Lammert, F; Tribe, RM; Ch'ng, CL; Marschall, HU; Glantz, A; Khan, SA; Nicolaides, K; Whittaker, J; Geary, M; Williamson, C (2014). "A comprehensive analysis of common genetic variation around six candidate loci for intrahepatic cholestasis of pregnancy". American Journal of Gastroenterology. 109 (1): 76–84. doi:10.1038/ajg.2013.406. PMC   3887577 . PMID   24366234.
  6. ↑ Dixon, PH; Sambrotta, M; Chambers, J; Taylor-Harris, P; Syngelaki, A; Nicolaides, K; Knisely, AS; Thompson, RJ; Williamson, C (2017). "An expanded role for heterozygous mutations of ABCB4, ABCB11, ATP8B1, ABCC2 and TJP2 in intrahepatic cholestasis of pregnancy". Scientific Reports. 7 (1): 11823. Bibcode:2017NatSR...711823D. doi:10.1038/s41598-017-11626-x. PMC   5603585 . PMID   28924228.
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  9. ↑ 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.
  10. 1 2 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. S2CID   25925651.
  11. ↑ 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.
  12. ↑ Abu-Hayyeh, S; Ovadia, C; Lieu, T; Jensen, DD; Chambers, J; Dixon, PH; Lovgren-Sandblom, A; Bolier, R; Tolenaars, D; Kremer, AE; Syngelaki, A; Noori, M; Williams, D; Marin, JJG; Monte, MJ; Nicolaides, KH; Beuers, U; Oude-Elferink, R; Seed, PT; Chappell, L; Marschall, H-U; Bunnett, NW; Williamson, C (2016). "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. S2CID   20203783.
  13. ↑ 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. Bibcode:2017NatSR...711823D. doi:10.1038/s41598-017-11626-x. PMC   5603585 . PMID   28924228.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ Williamson, Catherine; Geenes, Victoria (2014). "Intrahepatic cholestasis of pregnancy". Obstetrics and Gynecology. 124 (1): 120–33. doi:10.1097/AOG.0000000000000346. PMID   24901263. S2CID   9986882.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ Conti-Ramsden, F; McEwan, M; Hill, R; Wade, J; Abraham, G; Buckeldee, O; Williamson, C; Knight, CL; Girling, J; Chappell, LC (2019). "Detection of additional abnormalities or co-morbidities in women with suspected intrahepatic cholestasis of pregnancy". Obstetric Medicine. 13 (4): 185–191. doi:10.1177/1753495X19868873. PMC   7726172 . PMID   33343695.
  20. ↑ Chappell, LC; Chambers, J; Dixon, PH; Dorling, J; Hunter, R; Bell, JL; Bowler, U; Hardy, P; Juszczak, E; Linsell, L; Rounding, C; Smith, C; Williamson, C; Thornton, JG (2019). "Ursodeoxycholic acid versus placebo in the treatment of women with intrahepatic cholestasis of pregnancy (ICP) to improve perinatal outcomes: protocol for a randomised controlled trial (PITCHES)". Lancet. 394 (10201): 849–860. doi:10.1016/S0140-6736(19)31270-X. PMC   6739598 . PMID   31378395.
  21. ↑ Walker, Kate F.; Chappell, Lucy C.; Hague, William M.; Middleton, Philippa; Thornton, Jim G. (27 July 2020). "Pharmacological interventions for treating intrahepatic cholestasis of pregnancy". The Cochrane Database of Systematic Reviews. 2020 (7): CD000493. doi:10.1002/14651858.CD000493.pub3. ISSN   1469-493X. PMC   7389072 . PMID   32716060.
  22. 1 2 3 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. 393 (10174): 899–909. doi: 10.1016/S0140-6736(18)31877-4 . PMC   6396441 . PMID   30773280. S2CID   72333644.
  23. ↑ Glantz, A; Marschall, HU; Mattsson, LA (2004). "Intrahepatic cholestasis of pregnancy: Relationships between bile acid levels and fetal complication rates". Hepatology. 40 (2): 467–474. doi: 10.1002/hep.20336 . PMID   15368452. S2CID   44954417.
  24. ↑ Geenes V, Williamson C (2009). "Intrahepatic Cholestasis of pregnancy". World Journal of Gastroenterology. 15 (17): 2049–2066. doi: 10.3748/wjg.15.2049 . PMC   2678574 . PMID   19418576.
  25. ↑ Fisk NM, Storey GN: "Fetal outcome in obstetric cholestasis. Br J Obstet Gynaec 1988;95:1137- 1143.
  26. ↑ Zecca E, Costa S, Lauriola V; et al. (2003). "Bile acid pneumonia: A "new" form of neonatal respiratory distress syndrome?". Pediatrics. 114 (1): 269–272. doi:10.1542/peds.114.1.269. PMID   15231944.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  27. ↑ Shaw D, Frohlich J, Wittmann BA, Willms M (1982). "A prospective study of 18 patients with cholestasis of pregnancy". Am J Obstet Gynecol. 142 (6): 621–625. doi:10.1016/s0002-9378(16)32430-9. PMID   7065033.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  28. ↑ Davies MH, Silva RC, Jones SR; et al. (1995). "Fetal mortality associated with cholestasis of pregnancy and the potential benefit of therapy with ursodeoxycholic acid". Gut. 37 (4): 580–584. doi:10.1136/gut.37.4.580. PMC   1382915 . PMID   7489950.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  29. ↑ Puljic A, Kim E, Page J; et al. (2015). "The risk of infant and fetal death by each additional week of expectant management in intrahepatic cholestasis of pregnancy by gestational age". Am J Obstet Gynecol. 212 (5): 667.e1–5. doi:10.1016/j.ajog.2015.02.012. PMID   25687562.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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