Rodrigo Zapata MD, FAASLD Associate Professor of Medicine Gastroenterology Department & Liver Unit University of Chile School of Medicine, Eastern Campus, Hospital Del Salvador. Clínica Alemana de Santiago, Universidad del Desarrollo, Santiago, Chile. Member WGO Global Guidelines Committee 2015-2017

Introduction

Intrahepatic cholestasis of pregnancy (ICP) is a cholestatic liver disease unique to pregnancy ^1-4 with a variable worldwide prevalence ranging approximately between 0.3 and 5.6% of pregnancies ^{3, 5, 6}. Its prevalence varies greatly according to country and ethnic group, being more common in countries like Chile and Bolivia ⁷.  

It is considered the most common pregnancy-related liver disorder ^{2, 6}. It usually presents during the second and third trimester of pregnancy and is clinically defined by an annoying persistent pruritus (specially involving the palms and soles) and biochemically by elevated serum total bile acid levels and/or abnormal serum liver tests, in the absence of primary skin lesions, which resolves completely in the following few days after delivery.

The cause of ICP is unknown, but genetic, hormonal, and environmental factors are likely involved ^{8, 9}. The importance of its timely recognition is related to an increased risk of stillbirth and preterm delivery with its associated mortality and morbidity for the newborn ^{2, 3}.  Therefore, early recognition, treatment, and timely delivery are imperative. The major clinical features, diagnosis, and treatment of intrahepatic cholestasis of pregnancy will be reviewed here.

Twenty year ago, after ending my GI fellowship at the Catholic University of Chile, I moved to the University of Chile, where I started my academic carrier. At that time I joined the clinical research team of Dr. Humberto Reyes, a Chilean world recognized expert in the field of ICP and who later became one of my mentors. At that time he wrote a very nice review paper titled “Intrahepatic cholestasis: A puzzling disorder of pregnancy” ¹, where he described the state of the art of ICP at that moment, emphasizing its unknown cause and the possible mechanistic interplay between a genetic metabolic predisposition of affected patients and “some” environmental factor(s). He also described how mysteriously the ICP incidence significantly decreased in Chile from 1975 (14% of deliveries) to 1995 (only 4% of deliveries). Twenty years later, ICP remains a “puzzling disease of pregnancy,” even though many significant advances have been made in the pathogenesis and understanding of this intriguing disease.

Epidemiology

The incidence of ICP varies greatly throughout the world. Evidence of family clustering and the different prevalence in certain ethnic groups may partially explain the geographic variation in its incidence. ICP is more common in South America (especially Chile), South Asia, and in Scandinavian countries ^{3, 10, 11}. Recent studies have shown that in the United States the incidence varies widely (between 0.32 to 5.6%), because of its heterogeneous population ⁵. 

Table 1. Studies showing the incidence of intrahepatic cholestasis of pregnancy in different countries.

Author	Year	Country	Period	Number of ICP patients/ total pregnancies	Incidence of ICP
Castaño G, et al	2006	Argentina	2004-2005	41 / 2,596	1.04%
Reyes H,  et al	1978	Chile	1974-1975	132 / 869	13.2%
Ribalta J, et al	1991	Chile	1989-1990	894 /  22,340	4%
Lo TK, et al	2007	China	2003-2005	8 / 16,911	0.047%
Xiao-Lin L, et al	2015	China	2011	1,276/112,441	1.14%
Heinonen S, et al	1999	Finland	1990-1996	91 / 16,909	0.54%
Savander M, et al	2003	Finland	1992-1993	69 / 5,304	1.3%
Alokananda R, et al	2005	India	2003-2004	32 / 2,668	1.2%
Rathi U, et al	2007	India	2002-2004	10 / 12,061	0.082%
Roncaglia L, et al	2002	Italy	1989-1997	206 / 20,815	1%
Glantz A, et al	2004	Sweden	1999-2002	693 / 45,485	1.5%
Laifer SA, et al	2001	USA	1997-1999	20 / 6,250	0.32%
Lee RH, et al	2006	USA (Latinos)	1997-1998	19 / 340	5.6%

Adapted, updated and modified by permission from Zapata R, Glasinovic JC. Intrahepatic cholestasis of pregnancy. In Perez-Sanchez, Donoso E (Eds): Clinical Obstetrics. Chile, Mediterraneo limitada, 2011, p 921. ¹¹
Abbreviations: ICP: intrahepatic cholestasis of pregnancy.

ICP has also been shown to be more frequent in pregnant women with more advanced age, multiparous women, and in those with a personal history of cholestasis due to oral contraceptive use ^{1, 3}. In addition, the prevalence of ICP has been shown to be five times greater in twin pregnancies than in singleton pregnancies ¹². ICP also shows seasonal variation, occurring more frequently in the cold winter months.

Etiology

The cause of ICP is currently unknown, but genetic, hormonal, and environmental factors are involved, as suggested by the higher prevalence seen in certain ethnic groups (Swedish, Chilean, and Araucanian Indians); an increased incidence in late pregnancy and multiple pregnancies with precipitation by exogenous progestogens; and the possible association with low selenium levels. ICP usually appears in the third trimester of pregnancy when estrogen production reaches its maximum levels ^{1, 11}.

Genetic influences play a role, with a strong family tendency (between 10-16% of mothers, sisters, or daughters of previous ICP patients had had liver dysfunction during pregnancy) and the more recent discovery of some specific gene mutations in some ICP cases ^13-16. Genetic defects in at least six canalicular transporters have been found, which may lead to an increased sensitivity to estrogen which has a known role in causing cholestasis ³. The recurrence rate of 40–60% of ICP in the future pregnancies of affected mothers, also reinforces its genetic influences ¹. For this reason, all pregnant women should be asked about their family history regarding liver dysfunction during pregnancy.

Seasonal variations of the disease have been attributed to dietary factors related with high maternal levels of copper and low levels of selenium and zinc ¹⁶.

Recently our group from Chile has also shown an increased intestinal permeability in ICP patients during and after pregnancy ¹⁷. This "leaky gut condition" may participate in the pathogenesis of ICP by enhancing the absorption of bacterial endotoxins and the enterohepatic circulation of cholestatic metabolites of sex hormones and bile salts.

Figure 1. Mechanisms involved in the multifactorial pathogenesis of intrahepatic cholestasis of pregnancy.

Adapted and modified by permission from Zapata R, Glasinovic JC. Intrahepatic cholestasis of pregnancy. In Perez-Sanchez, Donoso E (Eds): Clinical Obstetrics. Chile, Mediterraneo limitada, 2011, p 923). ¹¹
Abbreviations: ICP: intrahepatic cholestasis of pregnancy.

Clinical Presentation and Diagnosis

ICP is clinically characterized by skin pruritus (often of the palms of the hands and soles of the feet), presenting in the late second or early third trimester of pregnancy. Laboratory findings show increased fasting total serum bile salts (>10 μmol/L) and mild abnormalities of aminotransaminases, with alanine aminotransferase (ALT) and aspartate aminotransferase (AST) usually around 2-10 times the upper limit of normal ^1-3. The traditional markers of cholestasis are difficult to interpret due to physiologic elevations in alkaline phosphatase secondary to pregnancy. Gamma-glutamyl transferase (GGT) is usually normal (85-90% cases). In only 10-20% of cases, conjugated mild hyperbilirubinemia may be found, and in some severe cases jaundice. Imaging with ultrasound may be useful in excluding other causes of pruritus and jaundice, including cholelithiasis and biliary tract disease. The diagnosis of ICP is based on clinical history, physical examination, and laboratory findings, but it may need the exclusion of other causes. All these abnormalities disappear in the following few days after delivery.

The serum bile acid level is considered the most sensitive and specific marker for the diagnosis of ICP (fasting serum bile acid concentrations greater than 10 μmol/L). Higher bile acid levels (>40 μmol/L) have been found recently to be associated with a significant higher rate of fetal complications ¹⁸.  A higher level of bile acids may increase the sensitivity and expression of oxytocin receptors in the human myometrium inducing preterm labor as a complication of ICP.

Maternal and Fetal Prognosis

ICP has no significant consequences for the mother; but in contrast, it is associated with an increased risk of fetal distress ^1-3. Potential complications associated with ICP include an increased risk of preterm delivery, meconium-stained amniotic fluid, and fetal distress, which may result in perinatal mortality (stillbirth). Older studies reported a perinatal mortality as high as 5-10%; however, with current active management this appears now to be <1-2% ³.  Glantz et al. ¹⁸ described outcomes in 693 Swedish ICP patients, showing that perinatal mortality rates were slightly increased, but stillbirth was limited only to severe ICP patients characterized by total bile acid levels ≥ 40 μmol/L. Serum total bile acid levels >40 umol/L have been associated with increased risk of meconium staining, low Apgar scores, and preterm delivery, and in cases with bile acid levels of more than 100 umol/L it was associated with an increased risk of stillbirth ¹⁹.

Due to this risk, optimal timing of delivery by 36-37 weeks is considered by most obstetricians, with earlier delivery when jaundice and total bile acid levels are >40 μmol/L ^{3, 6}. The risk of stillbirth has been demonstrated to increase beyond 36 weeks. The intriguing physiopathologic explanation for stillbirth associated with higher levels of bile acids, points to fetal cardiac arrest associated with bile acids entrance to cardiomyocytes in abnormal amounts, resulting in prolonged PR interval and fetal cardiac arrest. A role for bile acids entering the fetal lungs and depleting surfactant is also a possible explanation for neonatal respiratory distress syndrome of newborn of mothers with ICP ³.

Table 2. Spontaneous perinatal complication rate in patients with intrahepatic cholestasis of pregnancy.

Author	Year	Country	Pregnancies with ICP	Spontaneous premature birth	Fetal distress	Stillbirth (perinatal death)	Meconium-stained amniotic fluid
Castaño G, et al	2006	Argentina	41	29%	2.4%	0%	9.7%
Rioseco A, et al	1994	Chile	320	12.1%	2%	1.8%	25%
Wang XD, et al	2006	China	1,210	24%	7.1%	2.25%	23.2%
Alsulyman O, et al.	1996	USA	79	14%	7.6%	2.5%	44.3%
Heinonen S, et al	1999	Finland	91	14.3	7.7%	0%	15.2%
Roncaglia L, et al	2002	Italy	206	27.2%	5.3%	0%	16%
Glantz A, et al.	2004	Sweden	693	4.5%	7.1%	0.4%	24.8%

Adapted by permission from Zapata R, Glasinovic JC. Intrahepatic cholestasis of pregnancy. In Perez-Sanchez, Donoso E (Eds): Clinical Obstetrics. Chile, Mediterraneo limitada, 2011, p 925. ¹¹
Abbreviations: ICP: intrahepatic cholestasis of pregnancy.

Once the diagnosis is made, management should be oriented to reduce the maternal symptoms and offering adequate obstetric care to avoid fetal distress and stillbirth.

Maternal outcomes are excellent, with no long-term sequelae. Malabsorption due to persistent cholestasis has been described due to vitamin K deficiency, leading to intrapartum and postpartum hemorrhage ¹. Pruritus and abnormal liver tests usually disappear within 1-3 weeks after delivery. If liver tests abnormalities persists after a few weeks of delivery, other chronic liver disease should be ruled out. Nevertheless, recent data has shown that ICP patients at long term follow-up may have an increased risk of gallstone disease, pancreatitis, cirrhosis, hepatobiliary cancer, and autoimmune mediated and cardiovascular diseases when compared to women without ICP ^{20, 21}. Pregnancies complicated by ICP are also associated with a higher risk of preeclampsia and gestational diabetes.

Management of ICP Patients

For maternal pruritus, antihistamines and topical therapy with emollients may provide some relief ^{2, 3, 6}. Although cholestyramine may be effective, it may decrease the absorption of fat-soluble vitamins, leading to vitamin K deficiency and fetal coagulopathy.

Considering the previous beneficial experience in primary biliary cirrhosis with the use of Ursodeoxycholic acid (UDCA), an oral hydrophilic tertiary bile acid, our Chilean group was the first one to publish an open clinical trial showing the beneficial effects of UDCA in ICP ²². In this trial, nine patients with severe ICP received oral UDCA 15mg/kg/day (divided twice a day) obtaining relief of pruritus in most mothers and improvement of liver tests without any adverse effect. After discontinuing UDCA, pruritus and biochemical abnormalities reappeared, but they improved again after re-challenge with oral UDCA. Since then, other clinical series and then controlled studies have shown that UDCA administration provides a significant improvement in maternal pruritus, biochemical abnormalities and the fetal prognosis, with no adverse effects for the mother or child ^{3, 8, 16}.

In a recent meta-analysis reviewing nine published, randomized controlled trials comparing UDCA to other drugs, and analyzing the data on 454 patients with ICP ²³, UDCA was demonstrated to be effective in reducing pruritus, improving liver test results, and reducing serum levels of total bile salts (P< 0,0001 for all these variables)

UDCA was also associated with fewer premature births (P < 0.01), less fetal distress (P < 0.01), less frequent respiratory distress syndrome (P < 0.01), and fewer neonates in the intensive care unit (P = 0.046). Since only two cases of intrauterine fetal death were observed (both in the placebo groups) this small number precluded specific analysis on this issue but strongly suggested that UDCA improves fetal outcome. Finally, the systematic review confirmed that UDCA (10–15 mg/kg maternal body weight) was well tolerated by the mother, with rare and mild side effects (diarrhea), and was very safe for the fetus.  UDCA therapy normalized serum bile acid patterns in babies with minimal accumulation in amniotic fluid and cord blood. Our long-term study of 26 children born to mothers with ICP and treated with UDCA, and followed for up to 12 years, showed a normal development ²⁴.

In summary, much has been learned in the last two decades about this initially considered rare disease. Its etiology is likely multifactorial, with the influence of many environmental factors over a genetically predisposed subject. ICP patients with a significant increase in serum total bile acids (>40 umol/L and especially >100 umol/L), are the ones with a higher risk of fetal morbimortality, and should be identified to define an active maternal management. UDCA is currently the main medication in the management of ICP, due to its safety (both for the mother and fetus), with beneficial effects on maternal pruritus, liver function tests, and fetal morbidity. “Significant advances had been made in the last two decades in the study of this disease, but ICP is still, and will continue to be for a long time, a puzzling disease of pregnancy.”

References

1. Reyes H: Review: intrahepatic cholestasis. A puzzling disorder of pregnancy. J Gastroenterol Hepatol 1997; 12: 211-216.
2. Tran TT, Ahn J, Reau NS. ACG Clinical Guideline: Liver Disease and Pregnancy. Am J Gastroenterol. 2016 ;111:176-194.
3. Floreani A, Gervasi MT. New Insights on Intrahepatic Cholestasis of Pregnancy. Clin Liver Dis. 2016; 20:177-189. 
4. Pathak B, Sheibani L, Lee RH. Cholestasis of pregnancy. Obstet Gynecol Clin North Am. 2010;37:269-282.
5. Lee RH, Goodwin TM, Greenspoon J, Incerpi M. The prevalence of intrahepatic cholestasis of pregnancy in a primarily Latina Los Angeles population. J Perinatol. 2006; 26:527-532.
6. Riely CA, Bacq Y. Intrahepatic cholestasis of pregnancy. Clin Liver Dis 2004; 8:167-176.
7. Reyes H. The enigma of intrahepatic cholestasis of pregnancy: lessons from Chile. Hepatology 1982; 2: 87-96.
8. Arrese M, Reyes H. Intrahepatic cholestasis of pregnancy. A past and present riddle. Ann Hepatol 2006; 5: 202-205.
9. Arrese M, Macias RI, Briz O, Perez MJ, Marin JJ. Molecular pathogenesis of intrahepatic cholestasis of pregnancy. Expert Rev Mol Med 2008;10: e9.
10.  Williamson C, Geenes V. Intrahepatic cholestasis of pregnancy. Obstet Gynecol. 2014; 124:120-33
11. Zapata R, Glasinovic. .  “Intrahepatic cholestasis of pregnancy”. Chapter of the book: “Textbook of Clinical Obstetrics”. Editors Drs. Alfredo Pérez Sánchez y Enrique Donoso Silva. Editorial Mediterráneo Limited. 4th Edition. 2011. Santiago,Chile. Chapter 44. Pp. 920-929.
12. Gonzalez MC, Reyes H, Arrese M, Figueroa D, Lorca B, Andresen M, et al. Intrahepatic cholestasis of pregnancy in twin pregnancies. J Hepatol 1989; 9:84-90.
13. Mullenbach R, Bennet A, Tetlow N, et al. ATP8B1 mutations in British cases with intrahepatic cholestasis of pregnancy. Gut 2005;54:829–34.
14. Dixon PH, Wadsworth A, Chambers J, et al. A comprehensive analysis of common genetic variation around six candidate loci for intrahepatic cholestasis of pregnancy. Am J Gastroenterol 2014;109:76–84.
15. Floreani A, Carderi I, Paternoster D, et al. Hepatobiliary phospholipid transporter ABCB4, MDR3 variants in a large cohort of Italian women with intrahepatic cholestasis of pregnancy. Dig Liver Dis 2008;40:366–70.
16. Reyes H. What have we learned about intrahepatic cholestasis of pregnancy? Hepatology. 2016 Jan;63:4-8.
17. Reyes H, Zapata R, Hernández I, Gotteland M, Sandoval L, Jirón MI, Palma J, Almuna R, Silva JJ. Is a leaky gut involved in the pathogenesis of intrahepatic cholestasis of pregnancy? Hepatology. 2006; 43: 715-722.
18. Glantz A, Marschall HU, Mattson LA. Intrahepatic cholestasis of pregnancy:relationships observed bile acid levels and fetal complication rates. Hepatology 2004;40:467–474.
19. Kawakita T, Parikh LI, Ramsey PS, Huang CC, Zeymo A, Fernandez M, et al.  Predictors of adverse neonatal outcomes in Intrahepatic cholestasis of pregnancy. Am J Obstet Gynecol  2015;213:570.e1-8.
20. Marschall HU, Wikström Shemer E, Ludvigsson JF, Stephansson O. Intrahepatic cholestasis of pregnancy and associated hepatobiliary disease: a population-based cohort study. Hepatology. 2013t; 58:1385-91
21. Wilkstromer Shemer EA, Stephansson O, Thuresson M, et al. Intrahepatic cholestasis of pregnancy and cancer, immune-mediated and cardiovascular diseases: a population-based cohort study. J Hepatol 2015;63:456–61.
22. Palma J. Reyes H, Ribalta J, et al. Effects of ursodeoxycholic acid in patients with intrahepatic cholestasis of pregnancy. Hepatology 1992; 15: 1043-7.
23. Bacq Y, Sentilhes L, Reyes H, Glantz A, Kondrackiene J, Binder T, et al. Efficacy of ursodeoxycholic acid in treating intrahepatic cholestasis of pregnancy: a meta-analysis. Gastroenterology 2012;143:1492–1501.
24. Zapata R, Sandoval L, Palma J, Hernández I, Ribalta J, Reyes H, et al.  Ursodeoxycholic acid in the treatment of intrahepatic cholestasis of pregnancy. A 12-year experience. Liver Int 2005;25:548—54.