Indian Journal of Dermatology
  Publication of IADVL, WB
  Official organ of AADV
Indexed with Science Citation Index (E) , Web of Science and PubMed
 
Users online: 1961  
Home About  Editorial Board  Current Issue Archives Online Early Coming Soon Guidelines Subscriptions  e-Alerts    Login  
    Small font sizeDefault font sizeIncrease font size Print this page Email this page


 
Table of Contents 
SPECIAL ARTICLE
Year : 2013  |  Volume : 58  |  Issue : 4  |  Page : 327
Intra-hepatic cholestasis of pregnancy: A comprehensive review


1 Department of Skin and VD, PGIMS, Rohtak, Haryana, India
2 Department of Medicine, PGIMS, Rohtak, Haryana, India

Date of Web Publication25-Jun-2013

Correspondence Address:
Sangita Ghosh
42/136, New Ballygunge Road, Kolkata, West Bengal
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-5154.113971

Rights and Permissions

   Abstract 

Intra-hepatic cholestasis of pregnancy is a cholestatic disorder characterized by i) pruritus, with onset in the third trimester of pregnancy, without any primary skin lesions, ii) elevated fasting serum bile acids > 10 μmol / L (and elevated serum transaminases), iii) spontaneous relief of signs and symptoms within two to three weeks after delivery, and iv) absence of other disease that cause pruritus and jaundice. It is believed to be a multi-factorial disease with interplay between genetic, environmental and hormonal factors. Incidence is between 0.02% to 2.4% of all pregnancies; with wide geographical variations. Maternal prognosis is usually good but can result in adverse fetal outcomes like meconium staining of amniotic fluid, fetal bradycardia and even fetal loss. Response to anti-histaminic is poor. Of all the medical therapies that have been described for the treatment for IHCP, ursodeoxycholic acid has the best response in relieving pruritus in mother, and probably has a role in preventing even the perinatal complications. Timely diagnosis and treatment is urged in order to prevent fetal complications and an early delivery between 37 to 38 weeks should be contemplated in severe cases, especially once fetal lung maturity is attained.


Keywords: Intra-hepatic cholestasis, pregnancy dermatosis, pruritus gravidarum


How to cite this article:
Ghosh S, Chaudhuri S. Intra-hepatic cholestasis of pregnancy: A comprehensive review. Indian J Dermatol 2013;58:327

How to cite this URL:
Ghosh S, Chaudhuri S. Intra-hepatic cholestasis of pregnancy: A comprehensive review. Indian J Dermatol [serial online] 2013 [cited 2019 May 23];58:327. Available from: http://www.e-ijd.org/text.asp?2013/58/4/327/113971

What was known?
1. IHCP is a unique pregnancy dermatosis, occurring in 2nd and 3rd trimester of pregnancy, without any primary skin lesions, characterized by pruritus & elevated serum bile acids and transaminases.2. Maternal prognosis is usually good but can result in adverse fetal outcome.



   Introduction Top


Pregnancy dermatosis has claimed its unique position in the dermatological literature due to its characteristic yet varied presentation and its association with significant maternal and fetal morbidity and mortality, complicated further by our inherent hesitation in prescribing medication to a pregnant lady. Therefore, it is imperative to primarily understand the nature of the dermatosis in a pregnant lady and then offer her safe therapeutic options which could save her pregnancy from reaching a complicated outcome. Morphology is a very important clue in diagnosing a particular dermatosis; but a high degree of suspicion is what we have to rely upon when it comes to diagnosing a dermatosis which lurks beneath and is invisible to a dermatologist's eye. One such dreaded dermatosis is intrahepatic cholestasis of pregnancy (IHCP), also known as pruritus gravidarum or idiopathic jaundice of pregnancy. IHCP is a cholestatic disorder characterized by pruritus in the absence of a skin rash, with elevated aminotransferases and bile acid levels, occurring in the second or third trimester of pregnancy, and spontaneous relief of signs and symptoms two to three weeks after delivery. [1],[2] Apart from the distressing pruritus that the mother can experience, maternal prognosis is usually good. But what makes this entity particularly deserving for a timely diagnosis and intervention are the dreaded fetal outcomes like pre-term delivery, meconium staining of amniotic fluid, fetal bradycardia, fetal distress and, the most unfortunate, fetal loss. [3],[4] Back in 1883, Ahlfeld, a German physician, first conceptualized this disease and much has been written and researched about IHCP since then. [5] But it still needs special highlight even today, as increasing awareness is the first step forward in managing this invisible dermatosis. The terms pruritus gravidarum and IHCP have been used interchangeably in the literature but pruritus gravidarum essentially means pruritus without any skin lesion that occurs in the first trimester of pregnancy. [6]

Incidence

The incidence of IHCP varies from 0.02% to 2.4% of pregnancies and about 70% of them present in the third trimester (mean 31 weeks). [7] The incidence varies significantly with geographical location and ethnic background, with rates up to 15% in Chile and Bolivia and less than 1% in Europe. [8],[9] A higher incidence is seen in twin pregnancies, following in-vitro fertilization, women with age more than 35 years, with history of cholestasis in previous pregnancies and in women with history of biliary disease. [8],[9],[10] Overall incidence of IHCP has increased, reflecting rising awareness of the disease.

Etiology and pathogenesis

The etiology of IHCP is not clear but it is believed to be multifactorial with genetic, environmental and hormonal factors being involved. [1] Familial clustering, ethnic and geographic variation and a high rate of recurrence in subsequent pregnancies support a genetic theory. Mutations of the MDR3 gene encoding the canalicular phosphatidylcholine translocase may in some cases predispose to IHCP. [11] Clinical evidence supports an etiological role of estrogen in the initiation of IHCP. Occurrence in third trimester and higher incidence in twin pregnancies with a higher estrogen level than single gestations, speak in favor of estrogen theory. Some estrogens, in particular 17β-D-glucuronide and sulfated progesterone, have been shown to cause cholestasis but the molecular mechanism is still not clear. [12],[13] Impairment of the functions of major hepatocellular ABC transporters like the bile salt export pump (BSEP)- ABCB11, or the phospholipid transporter, ABCB4 (MDR3), by high levels of estrogen glucuronides and progesterone, respectively, at the post-transcriptional level has been demonstrated in-vitro.[14] A higher incidence of IHCP in winter indicates an environmental factor at play as well. [15],[16] Recent studies also link IHCP to low serum selenium levels. [17]

Clinical features

ICHP usually presents in the third trimester in most cases but rarely presentation as early as 6 to 10 weeks have also been described. [18],[19],[20] A variable degree of pruritus without any primary lesions is the presenting clinical symptoms of IHCP. The severity of itching can be mild to severe enough to cause sleep deprivation, psychological suffering and even suicidal thoughts in the mother. Pruritus is most severe in the evenings with a predilection for the palms and soles, although it may be widespread and associated with malaise. Secondary skin lesions like excoriation marks may be observed, narrating a pruritic tale. Malabsorption of fat secondary to cholestasis can lead to steatorrhea, weight loss and vitamin K deficiency with coagulopathy in severe cases. [21] Mild to moderate icterus is seen in about 10-15% of cases. [18] Jaundice typically develops 1 to 4 weeks after the onset of pruritus but occasionally can be the initial symptom. [22],[23] The condition usually resolves within 48 hours of giving birth, with biochemical markers becoming normal about 2-4 weeks postnatal. [8] The risk of recurrence in subsequent pregnancies runs between 40 to 60%. i Incidence of gallstone formation and cholecystitis is higher in women with history of IHCP. [24]

Diagnosis

For a diagnosis of IHCP to be established, there must be no history of exposure to hepatitis viruses or hepatotoxic drugs or past history of liver or gall bladder diseases. [21] Pruritus secondary to any cutaneous disease or other specific gestational dermatosis should also be excluded. Laboratory markers include elevated fasting serum bile acids (SBA) levels measuring more than 10 μmol / L (4.08 μg/mL). [25] Serum level of bile acids correlate with the severity of pruritus. Prospective studies indicate that usually the fetal complications are associated with SBA level more than 40 μmol / L in most cases. [26],[10] Serum transaminases like Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) can be raised by up to 20 times their normal level. [26] Occasionally, there is a mild to moderate bilirubin elevation (34-86 μmol/L) in jaundiced patients. Coagulation studies may reveal prolonged prothrombin time reflecting vitamin K deficiency. [9] Skin biopsy findings are non specific, whereas liver biopsy may reveal changes of mild cholestasis, namely, dilated bile canaliculi, staining of parenchyma with bile pigments and minimal inflammation. [27]

Fetal complications

IHCP has been associated with increased risk of pre-term delivery (up to 19 to 60%), [18],[4] meconium staining of amniotic fluid (up to 27% cases), [3] fetal bradycardia (up to 14%), [3] fetal distress (22%-41%), [4],[28],[16] and fetal loss (0.4 to 4.1%), [3],[4] particularly when SBA level goes beyond 40 μmol / L. The pathogenesis of fetal complications is still poorly understood, although a role of bile acids and toxic metabolites of bile acids which can induce contraction of chorionic veins of placenta have been hypothesized. [29] There is also a theory that says myometrial sensitivity to oxytocin is enhanced in the presence of cholic acid. [30]

Maternal complications

Apart from the distressing pruritus, prolonged and severe IHCP can cause coagulopathies due to vitamin K deficiency, which can result in post-partum hemorrhage in mothers. [31] There has been a high incidence of gallstones in females with history of IHCP. [24] IHCP recurs during subsequent pregnancies in 40-60% cases with varying severity of recurrent episodes. [10] Overall maternal prognosis is good and symptoms resolve rapidly within 48 hours of delivery.

Management

The primary objective of pharmacological treatment of IHCP is to alleviate maternal symptoms and improve fetal outcome. The pruritus associated with mild cholestasis responds to bland anti pruritic emollients, soothing baths, primrose oil and topical anti-pruritics. [31],[32] General measures like use of cool cotton, loose clothing and keeping skin well moisturized should be given special attention to. Increased water intake and a low fat diet can be beneficial. [23] Antihistaminics are usually not effective but can relieve pruritus to some extent through their sedative side effects. The most efficacious, current medical management that improves maternal condition and might prevent perinatal complications of IHCP, is ursodeoxycholic acid (UDCA). The dose required to attain effect on maternal pruritus and SBA is between 10 to 15 mg/Kg/day in two or three divided doses for three or more weeks before delivery. Relief usually occurs within one to two weeks. [10],[26],[33] UDCA seems to be well tolerated by pregnant women and no adverse effects on mothers or newborn have been observed. Although the mechanism of action is not fully understood, it is postulated that UDCA works by displacing hydrophobic endogenous bile salts from the bile acid pool, and protects hepatocytes from their toxic effects and enhances bile acid clearance across placenta from the fetus. [34] It also inhibits intestinal absorption of more cytotoxic bile acids. [35] Other drugs like benzodiazepines, phenobarbital, opioid antagonists, dexamethasone, epomediol, S-adenosyl-L-methionine (SAMe) and cholestyramine have been used but not introduced into clinical practice because of limited efficacy and / or tolerability. [1],[36],[37],[38] In a randomized prospective comparative study, use of UDCA (750 mg/day orally) and SAMe (1000 mg/day intravenous) in 78 patients with IHCP, suggested that both regimens improved pruritus but the combined therapy had no additive effect on pruritus as compared to UDCA monotherapy. [38] Ultra-violet B phototherapy has also been used with variable results. [31],[32] IHCP causes reduction of circulating entero-hepatic bile acids causing reduced absorption of fat-soluble vitamins like vitamin K, which is required for coagulation. Hence, to avoid resultant coagulopathy in IHCP, it is advisable to supplement vitamin K orally 10 mg/day. [34] Multivitamin supplementation to compensate for the nutritional deficiency that can result from steatorrhea and fat malabsorption can also prove to be a wise decision. None of these above mentioned pharmacotherapy has definitive protective role when it comes to preventing adverse fetal outcomes. Hence it is advisable to aim at delivering the fetus between 37 to 38 weeks of gestation or even earlier (as soon as fetal lung maturity is attained) if there is sufficient risk of maternal morbidity or fetal compromise detected. [8],[9],[39]


   Conclusions Top


Intra-hepatic cholestasis of pregnancy is a common pregnancy dermatosis that usually presents in third trimester of pregnancy with pruritus, without any primary skin lesions. Biochemically, the condition is characterized by increased SBA and aminotransferases, with or without increased serum bilirubin. Though it is a benign condition in the mother, in the fetus it can be responsible for adverse outcomes like pre-term delivery, fetal distress to even fetal loss. Various studies have shown ursodeoxycholic acid as the most effective treatment of IHCP, which improves maternal condition and probably even prevents perinatal complications. Apart from timely diagnosis and treatment frequent fetal surveillance is strongly urged, aiming at an early delivery once fetal lung maturity is attained.

 
   References Top

1.Lammert F, Marschall HU, Glantz A, Matern S. Intrahepatic cholestasis of pregnancy: Molecular pathogenesis, diagnosis and management. J Hepatol 2000;33:1012-21.  Back to cited text no. 1
    
2.Beuers U, Pusl T. Intrahepatic cholestasis of pregnancy: A heterogeneous group of pregnancy-related disorders? Hepatol 2006;43:647-9.  Back to cited text no. 2
    
3.Reid R, Ivey KJ, Rencoret RH, Storey B. Fetal complications of obstetric cholestasis. Br Med J 1976;1:870-2.  Back to cited text no. 3
    
4.Fisk NM, Storey GN. Fetal outcome in obstetric cholestasis. Br J Obstet Gynaecol 1988;95:1137-43.  Back to cited text no. 4
    
5.Ahlfeld F. Berichte und Arbeiten aus der geburtshilflich-gynaekologischen Klinik zu Giessen 1881-1882. Leipzig: Grunow FW; 1883. p. 148.  Back to cited text no. 5
    
6.Roger D, Vaillant L, Fignon A, Pierre F, Bacq Y, Brechot JF, et al. Specific pruritis disease of pregnancy: A prospective study of 3192 pregnant women. Arch Dermatol 1994;130:734-9.  Back to cited text no. 6
    
7.Itching in pregnancy [editorial]. Br Med J 1975;3:608.  Back to cited text no. 7
    
8.Greenes V, Williamson C. Intahepatic cholestasis of pregnancy. World J Gastroenterol 2009;15:2049-66.  Back to cited text no. 8
    
9.Kondrackiene J, Kupcinskas L. Intrahepatic cholestasis of pregnancy-current achievements and unsolved problems. World J Gastroenterol 2008;14:5781-8.  Back to cited text no. 9
    
10.Pathak B, Sheibani L, Lee RH. Cholestasis of Pregnancy. Obstet Gynecol Clin North Am 2010;37:269-82.  Back to cited text no. 10
    
11.Jacquemin E, Cresteil D, Manouvrier S, Boute O, Hadchouel M. Heterozygous non-sense mutation of the MDR3 gene in familial intrahepatic cholestasis of pregnancy. Lancet 1999;353:210-11.  Back to cited text no. 11
    
12.Reyes H, Simon FR. Intrahepatic cholestasis of pregnancy: An estrogen-related disease. Semin Liver Dis 1993;13:289-301.  Back to cited text no. 12
    
13.Kreek MJ. Female sex steroids and cholestasis. Semin Liver Dis 1987;7:8-23.  Back to cited text no. 13
    
14.Simon FR, Fortune J, Iwahashi M, Gartung C, Wolkoff A, Sutherland E. Ethinyl estradiol cholestasis involves alterations in expression of liver sinusoidal transporters. Am J Physiol 1996;271 (6 PT 1):G1043-52.  Back to cited text no. 14
    
15.Brites D, Rodrigues CM, van-Zeller H, Brito A, Silva R. Relevance of serum bile acid profile in the diagnosis of intrahepatic cholestasis of pregnancy in a high incidence area: Portugal. Eur J Obstet Gynecol Reprod Biol 1998;80:31-8.  Back to cited text no. 15
    
16.Laatikainen T, Ikonen E. Fetal prognosis in obstetric hepatosis. Ann Chir Gynaecol Fenn 1975;64:155-64.  Back to cited text no. 16
    
17.Kauppila A, Korpela H, Makila UM, Yrjanheikki E. Low serum selenium concentration and glutathione peroxidase activity in intrahepatic cholestasis of pregnancy. Br Med J 1987;294:150-2.  Back to cited text no. 17
    
18.Bacq Y, Sapey T, Brechot MC, Pierre F, Fignon A, Dubois F. Intrahepatic cholestasis of pregnancy: A French prospective study. Hepatology 1997;26:358-64.  Back to cited text no. 18
    
19.Fagan EA. Intrahepatic cholestasis of pregnancy. Clin Liver Dis 1999;3:603-32.  Back to cited text no. 19
    
20.Brites D, Rodrigues CM, Cardoso MC, Graca LM. Unusual case of severe cholestasis of pregnancy with early onset, improved by ursodeoxycholic acid administration. Eur J Obstet Gynecol Reprod Biol 1998;76:165-8.  Back to cited text no. 20
    
21.Sasseville D, Wilkinson RD, Schnader JY. Dermatoses of pregnancy. Int J Dermatol 1981;20:223-41.  Back to cited text no. 21
    
22.Knox TA, Olans LB. Liver disease in pregnancy. N Engl J Med 1996;335:569-76.  Back to cited text no. 22
    
23.Nichols AA. Cholestasis of pregnancy: A review of the evidence. J Perinat Neonatal Nurs 2005;19:217-25.  Back to cited text no. 23
    
24.Ropponen A, Sund R, Riikonen S, Ylikorkala O, Aittomaki K. Intrahepatic cholestasis of pregnancy as an indicator of liver and biliary diseases: A population-based study. Hepatology 2006;43:723-8.  Back to cited text no. 24
    
25.Glantz A, Reilly SJ, Benthin L, Lammert F, Mattsson LA, Marschall HU. Intrahepatic Cholestasis of Pregnancy: Amelioration of Pruritis by UDCA Is Assoiciated with Decreased Progesterone Disulphates in Urine. Hepatology 2008;47:544-51.  Back to cited text no. 25
    
26.Joshi D, James A, Quaglia A, Westbrook RH, Heneghan MA. Liver disease in pregnancy. Lancet 2010;375:594-605.  Back to cited text no. 26
    
27.Reyes H. The spectrum of liver and gastrointestinal disease seen in cholestasis of pregnancy. Gastroenterol Clin North Am 1992;905-21.  Back to cited text no. 27
    
28.Shaw D, Frohlich J, Wittmann BA, Willms M. A prospective study of 18 patients with cholestasis of pregnancy. Am J Obstet Gynecol 1982;142 (6 Pt 1):621-5.  Back to cited text no. 28
    
29.Sepulveda WH, Gonzalez C, Cruz MA, Rudolph MI. Vasoconstrictive effect of bile acids on isolated human placental chorionic veins. Eur J Obstet Gynecol Reprod Biol 1991;42:211-15.  Back to cited text no. 29
    
30.Germain AM, Kato S, Carvajal JA, Valenzuela GJ, Valdes GL, Glasinovic JC. Bile acids increase response and expression of human myometrial oxytocin receptor. Am J Obstet Gynecol 2003;189:577-82.  Back to cited text no. 30
    
31.Shornick JK. Dermatoses of pregnancy. Semin Cutan Med Surg 1998;17:172-81.  Back to cited text no. 31
    
32.Vaughan Jones SA, Black MM. Pregnancy dermatoses. J Am Acad Dermatol 1999;40 (2 PT 1):233-41.  Back to cited text no. 32
    
33.Palma J, Reyes H, Ribalta J, Iglesias J, Gonzalez MC, Hernandez I, et al. Effects of ursodeoxycholic acid in patients with intrahepatic cholestasis of pregnancy. Hepatology 1992;15:1043-7.  Back to cited text no. 33
    
34.rcog.org [Internet]. UK: Royal College of Obstetricians and Gynaecologists. Obstetric cholestasis. Green-Top Guideline No 43. Available from http://www.rcog.org.uk. [Updated May 2006; cited May 2012].  Back to cited text no. 34
    
35.Stiehl A, Raedsch R, Rudolph G. Acute effects of ursodeoxycholic and chenodeoxycholic acid on the small intestinal absorption of bile acids. Gastroenterology 1990;98:424-8.  Back to cited text no. 35
    
36.Glantz A, Marschall HU, Lammert F, Mattsson LA. Intrahepatic cholestasis of pregnancy: A randomized controlled trial comparing dexamethasone and ursodeoxycholic acid. Hepatology 2005;42:1399-405.  Back to cited text no. 36
    
37.Kondrackiene J, Beuers U, Kupcinskas L. Efficacy and safety of ursodeoxycholic acid versus cholestyramine in intrahepatic cholestasis of pregnancy. Gastroenterology 2005;129:894-901.  Back to cited text no. 37
    
38.Binder T, Salaj P, Zima T, Vitek L. Randomized prospective comparative study of ursodeoxycholic acid and S-adenosyl-Lmethionine in the treatment of intrahepatic cholestasis of pregnancy. J Perinat Med 2006;34:383-91.  Back to cited text no. 38
    
39.Mays JK. The active management of intrahepatic cholestasis of pregnancy. Curr Opin Obstet Gynecol 2010;22:100-3.  Back to cited text no. 39
    

What is new?
1. Ursedeoxycholic acid is the most efficacious medical treatment available for IHCP, but has no definitive role in preventing adverse fetal outcome. 2. It is advisable to aim at delivering the fetus between 37-38 weeks of gestation or even earlier (as soon as fetal lung maturity is attained) if there is sufficient risk of maternal morbidity or fetal compromise is detected.



This article has been cited by
1 The incidence of coagulopathy in pregnant patients with intrahepatic cholestasis: should we delay or avoid neuraxial analgesia?
Alexander DeLeon,Gildasio S. De Oliveira,Manoj Kalayil,Shweta Narang,Robert J. McCarthy,Cynthia A. Wong
Journal of Clinical Anesthesia. 2014;
[Pubmed] | [DOI]



 

Top
Print this article  Email this article
 
 
  Search
 
  
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Article in PDF (434 KB)
    Citation Manager
    Access Statistics
    Reader Comments
    Email Alert *
    Add to My List *
* Registration required (free)  


    Abstract
   Introduction
   Conclusions
    References

 Article Access Statistics
    Viewed2943    
    Printed58    
    Emailed0    
    PDF Downloaded148    
    Comments [Add]    
    Cited by others 1    

Recommend this journal