Materiały źródłowe

• #1 Pregnancy Intrahepatic Cholestasis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK551503/

  Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder in the late second and early third trimester of pregnancy. It is also known as obstetric cholestasis (OC) and is characterized by pruritus with increased serum bile acids and other liver function tests. The pathophysiology of ICP is still not completely understood. […] Genetic susceptibility and reproductive hormones, especially estrogen, are found to be the principal contributing factors to the development of intrahepatic cholestasis of pregnancy (ICP). […] Estrogen reduces the expression of nuclear hepatic bile acid receptors and hepatic biliary canalicular transport proteins in genetically susceptible women causing impairment of hepatic bile acid homeostasis and subsequent increased level of bile acids. […] Downregulation of placental expression of bile acid transporters organic anion transporting polypeptides OATP1A2 and OATP1B3 in ICP placenta in one report also indicates a role in pathophysiology.

• #2 Molecular Pathogenesis of Intrahepatic Cholestasis of Pregnancy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8181114/

  Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disease. The maternal symptoms are characterized by skin pruritus and elevated bile acids, causing several adverse outcomes for fetuses, including an increased risk of preterm birth, meconium-stained amniotic fluid, neonatal depression, respiratory distress syndrome, and stillbirth. Genetic, hormonal, immunological, and environmental factors contribute to the pathogenesis of ICP, and the estrogen-bile acid axis is thought to play a dominant role. […] The pathogenesis of ICP is multifactorial, with an interaction of genetic, hormonal, immunological, and environmental factors. Although the exact molecular mechanism of how ICP occurs is still elusive, the advances in the past 10 years uncover more details. The estrogen-bile acid axis still accounts for the majority of research studies, with more associated genes and signaling pathways found. Moreover, dysregulation of extracellular matrix and oxygen supply, organelle dysfunction, epigenetic changes, and so on are found to cause ICP.

• #3 Intrahepatic Cholestasis of Pregnancy: Practice Essentials, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/1562288-overview

  Intrahepatic cholestasis of pregnancy (ICP) is a reversible type of hormonally influenced cholestasis. It frequently develops in late pregnancy in individuals who are genetically predisposed and is the most common pregnancy-related liver disorder. […] ICP has no clear etiology, and it is believed to be a multifactorial disorder with environmental, hormonal, and genetic contributions. […] Affected individuals have a defect involving the excretion of bile salts, which leads to increased serum bile acids. These are deposited within the skin, causing intense pruritus. The cause of ICP is unknown but is thought to be multifactorial with genetic, hormonal, and environmental involvement. […] Changes induced by these genetic mutations lead to an increased sensitivity to estrogen. Estrogen has a known role in causing cholestasis, and, thus, cholestasis can arise from estrogen-containing OCPs.

• #4

  https://link.springer.com/article/10.1007/s12072-023-10604-y

  Intrahepatic cholestasis of pregnancy (ICP) is the most common pregnancy-specific liver disease. It is characterized by pruritus, abnormal liver function and elevated total bile acid (TBA) levels, increasing the risk of maternal and fetal adverse outcomes. Its etiology remains poorly elucidated. Over the years, various omics techniques, including metabolomics, microbiome, genomics, etc., have emerged with the advancement of bioinformatics, providing a new direction for exploring the pathogenesis, diagnosis and treatment of ICP. […] In this review, we first summarize the role of bile acids and related components in the pathogenesis of ICP and then further illustrate the results of omics studies. […] Potential role of trans-inhibition of the bile salt export pump by progesterone metabolites in the etiopathogenesis of intrahepatic cholestasis of pregnancy.

• #5 Intrahepatic cholestasis of pregnancy | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-2-26

  Intrahepatic cholestasis of pregnancy (ICP) is a cholestatic disorder characterized by (i) pruritus with onset in the second or third trimester of pregnancy, (ii) elevated serum aminotransferases and bile acid levels, and (iii) spontaneous relief of signs and symptoms within two to three weeks after delivery. […] Genetic and hormonal factors, but also environmental factors may contribute to the pathogenesis of ICP. […] The etiology of ICP is not completely understood and is still under discussion. Genetic and hormonal factors, but also environmental factors may contribute to the pathogenesis of ICP. […] Familial clustering, ethnic and geographic variation, and the high rate of reoccurrence in subsequent pregnancies support a genetic predisposition for ICP. […] Mutations in the hepatocellular phospholipid transporter, ABCB4 (MDR3), that mediates secretion of the major human phospholipid, phosphatidylcholine (lecithine) into bile, have been estimated to account for up to 15% of all ICP cases.

• #6 Intrahepatic cholestasis of pregnancy: A past and present riddle | Annals of Hepatology

  https://www.elsevier.es/en-revista-annals-hepatology-16-articulo-intrahepatic-cholestasis-pregnancy-a-past-S1665268119320125

  Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific disorders that occurs mainly in the third trimester of pregnancy and is characterized by pruritus and elevated bile acid levels. […] The pathogenesis of disease is unknown but likely involves a genetic hypersensitivity to estrogen or estrogen metabolites. […] Mutations or polymorphisms of some hepatobiliary transport proteins may contribute to disease pathogenesis or severity. […] Despite intense research in the field the cause of ICP remains unknown although its pathogenesis appears to be related to the effects of sex hormones in the liver of genetically predisposed women. […] Several lines of evidence suggest that estrogens are involved in the pathogenesis of ICP. […] The disease appears in the third trimester when the estrogen production reaches its maximum.

• #7 Intrahepatic cholestasis of pregnancy: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/intrahepatic-cholestasis-of-pregnancy/

  Intrahepatic cholestasis of pregnancy is a complex disorder. It is believed to be caused by a combination of genetic, hormonal, and environmental factors. […] Variants in several different genes are believed to increase the risk of developing intrahepatic cholestasis of pregnancy. Many of these genes provide instructions for making proteins that help with the production (synthesis) or transportation of bile acids. […] The largest genetic contributor is the ABCB4 gene; variants in this gene have been found in up to 25 percent of women with intrahepatic cholestasis of pregnancy. […] Even with these variants, enough protein is still available in most cases to move an adequate amount of phospholipids out of liver cells to bind to bile acids. The added stress on the liver during pregnancy, however, contributes to the buildup of bile acids. Toxic levels of bile acids can impair liver function, including the regulation of bile flow. […] An increased susceptibility to intrahepatic cholestasis of pregnancy typically has an autosomal dominant pattern of inheritance, which means one copy of the altered gene in each cell is sufficient to increase the risk of developing the disorder.

• #8 Molecular Pathogenesis of Intrahepatic Cholestasis of Pregnancy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8181114/

  The bile salt export pump (BSEP) is responsible for the secretion of bile acids. Estrogen was reported to decrease the protein level of bile salt export pump (BSEP) and multidrug resistant-associated protein 2 (MRP2), both of which are involved in bile acid homeostasis. […] The link between estrogen and ICP is obvious. ICP mainly occurs during the last trimester, and twin pregnancy also has a higher risk of ICP. […] The disturbed bile acid homeostasis plays a key role in the pathogenesis of ICP. Research studies from the last 10 years illuminate how increased bile acids cause ICP from physiological, cellular, and molecular levels. […] Bile acids can also affect heart function. […] How increased level of bile acids causes cell senescence and apoptosis is uncovered based on in vitro cell culture data. […] The advancement in our understanding of the molecular pathogenesis of ICP has uncovered more potential drug targets, whose clinical application needs to be further explored.

• #9 Review of a challenging clinical issue: Intrahepatic cholestasis of pregnancy

  https://www.wjgnet.com/1007-9327/full/v21/i23/7134.htm

  The etiology of ICP is multifactorial, and involves genetic, hormonal, and environmental factors. Estrogens and progesterone metabolites have been demonstrated to have role in the pathogenesis of ICP. The disease usually appears in the third trimester of pregnancy when estrogen production reaches its maximum levels. The prevalence of ICP is five times greater in multiple pregnancies, which are associated with higher levels of estrogens in comparison with singleton pregnancies. A high level of estrogen in genetically-predisposed individuals may be inducing intrahepatic cholestasis by impaired sulfation and the transport of bile acids. The role of progesterone with respect to the pathogenesis of ICP seems to be still unclarified. Patients with ICP might have been presenting a selective defect in the secretion of sulfated progesterone metabolites into bile due to the genetic polymorphism of canalicular transporters for steroid sulfates or their regulation. Family clustering, presence of ethnic and geographic variations, and recently demonstrated mutations in gene coding for hepatobiliary transport proteins indicate a genetic predisposition in ICP. Genetic predisposition may lead to altered cell membrane composition of bile ducts and hepatocytes, as well as the subsequent dysfunction of biliary canalicular transporters. Mutations in the hepatic phospholipid transporter (MDR3/ABCB4), aminophospholipid transporter (ATP8B1/FIC1), and bile salt export pump (BSEP/ABCB11) have been found in patients with ICP.

• #10 Molecular pathogenesis of intrahepatic cholestasis of pregnancy | Expert Reviews in Molecular Medicine | Cambridge Core

  https://www.cambridge.org/core/journals/expert-reviews-in-molecular-medicine/article/molecular-pathogenesis-of-intrahepatic-cholestasis-of-pregnancy/843A64A453BE4DF196560F41D2B29801

  Intrahepatic cholestasis of pregnancy (ICP) occurs mainly in the third trimester and is characterised by pruritus and elevated serum bile acid levels. […] Although the pathogenesis of this disease is unknown, a genetic hypersensitivity to female hormones (oestrogen and/or progesterone) or their metabolites is thought to impair bile secretory function. […] Recent data suggest that mutations or polymorphisms of genes expressing hepatobiliary transport proteins or their nuclear regulators may contribute to the development and/or severity of ICP. […] Unidentified environmental factors may also influence pathogenesis of the disease. […] This review summarises current knowledge on the potential mechanisms involved in ICP at the molecular level.

• #11 Intrahepatic cholestasis of pregnancy | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-2-26

  Clinical evidence supports an etiologic role for estrogens in the initiation of ICP. […] Finally, estrogen oral contraceptive use among women with a personal or family history of ICP could result in clinical features of ICP particularly when former high-dose preparations were used. […] Thus, mutations in genes encoding hepatobiliary transport proteins as well as abnormal metabolites impairing hepatobiliary carriers may be involved in the pathogenesis of ICP. […] The seasonal variation, the incomplete recurrence in subsequent pregnancies, as well as the decrease in the prevalence of ICP in high-incidence regions in association with improved nutritional supply suggest that exogenous factors such as nutritional factors like selenium deficiency may contribute to ICP.

• #12 Intrahepatic cholestasis of pregnancy: A past and present riddle | Annals of Hepatology

  https://www.elsevier.es/en-revista-annals-hepatology-16-articulo-intrahepatic-cholestasis-pregnancy-a-past-S1665268119320125

  Moreover, the prevalence of ICP is five times greater in twin pregnancies which are characterized by higher levels of estrogens than single pregnancies. […] Administration of an estrogen derivative to experimental animals is able to induce cholestasis which appears related to impaired expression and/or function of specific transporter proteins such as the Na+/taurocholate cotransporting polypeptide [Ntcp, Slc10a1], the bile salt export pump (Bsep, Abcb11) and the multidrug resistance associated protein-2 (Mrp2, Abcc2). […] Progesterone metabolites may also play a role in the pathogenesis of ICP. […] The importance of a genetic predisposition in the occurrence of ICP is enforced by both familial clustering of the disease, the higher prevalence of ICP in Mapuche Indians, and the exaggerated response to an estrogen challenge that was observed in both nulliparous sisters and brothers of ICP patients.

• #13 Prevalence and risk factors of intrahepatic cholestasis of pregnancy in a Chinese population | Scientific Reports

  https://www.nature.com/articles/s41598-020-73378-5

  Epidemiological studies show that the increased estrogen levels in twin pregnancies are associated with a greater risk of ICP. […] Our current study found a complex association between pre-pregnancy BMI and ICP risks, which may provide an additional explanation to why the incidence of ICP differs among different populations and ethnicities. […] Logistic regression models showed that in this cohort maternal age below 25 or above 35 years, pre-pregnancy underweight, inadequate GWG, lower maternal education, multiparity, and twins/multiple pregnancies were risk factors of ICP.

• #14 Cholestasis – Wikipedia

  https://en.wikipedia.org/wiki/Cholestasis

  Although estrogen’s exact pathomechanism in ICP remains unclear, several explanations have been offered. Estrogen may induce a decrease in the fluidity of the hepatic sinusoidal membrane, leading to a decrease in the activity of basolateral Na+/K+-ATPase. A weaker Na+ gradient results in diminished sodium-dependent uptake of bile acids from venous blood into hepatocytes by the sodium/bile acid cotransporter. More recent evidence suggests that estrogen promotes cholestasis via its metabolite estradiol-17–D-glucuronide (E2). E2 secreted into the canaliculi by MRP2 was found to repress the transcription of bile salt export pump (BSEP), the apical ABC transporter responsible for exporting monoanionic conjugated bile acids from hepatocytes into bile canaliculi. E2 was also found to upregulate miR-148a, which represses expression of the pregnane X receptor (PXR). PXR is a nuclear receptor in hepatocytes that senses intracellular bile acid concentrations and regulates gene expression accordingly to increase bile efflux.

• #15 Intrahepatic Cholestasis of Pregnancy: Practice Essentials, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/1562288-overview

  Environmental factors are also thought to contribute to the development of ICP. Many patients have more mild recurrence in subsequent pregnancies, which suggests that environmental factors play a role in the development and severity of ICP. […] Studies have implemented 2 bile acids, taurocholic and taurodeoxycholic aids, as being the specific ones elevated in ICP. […] A study by Abu-Hayyeh et al found that sulfated progesterone metabolites are a prognostic indicator for ICP and can help predict onset of ICP and distinguish it from benign pruritus gravidarum.

• #16

  https://link.springer.com/article/10.1007/s12072-023-10604-y

  Intrahepatic cholestasis of pregnancy levels of sulfated progesterone metabolites inhibit farnesoid X receptor resulting in a cholestatic phenotype. […] Placental gene-expression profiles of intrahepatic cholestasis of pregnancy reveal involvement of multiple molecular pathways in blood vessel formation and inflammation.

• #17 Intrahepatic cholestasis of pregnancy: insights into pathogenesis and advances in omics studies

  https://ouci.dntb.gov.ua/en/works/4Lw8kZK7/

  Intrahepatic cholestasis of pregnancy: new insights into its pathogenesis. […] Placental gene-expression profiles of intrahepatic cholestasis of pregnancy reveal involvement of multiple molecular pathways in blood vessel formation and inflammation. […] Potential role of trans-inhibition of the bile salt export pump by progesterone metabolites in the etiopathogenesis of intrahepatic cholestasis of pregnancy. […] Intrahepatic cholestasis of pregnancy levels of sulfated progesterone metabolites inhibit farnesoid X receptor resulting in a cholestatic phenotype. […] Intrahepatic cholestasis of pregnancy increases inflammatory susceptibility in neonatal offspring by modulating gut microbiota. […] Gut microbiota alters host bile acid metabolism to contribute to intrahepatic cholestasis of pregnancy.

• #18 Bile Acids in Intrahepatic Cholestasis of Pregnancy

  https://www.mdpi.com/2075-4418/12/11/2746

  Activation of the NF-κB pathway through the G protein-coupled BA receptor 1 (GPBAR1) is induced by BAs, resulting in elevated levels of inflammatory genes in trophoblasts, abnormal leukocyte infiltration, and placental inflammation. […] The accumulation of BAs in the maternal and fetal liver observed in ICP may lead to oxidative stress and hepatocyte apoptosis, significantly affecting the course of pregnancy. […] An altered BA profile is observed in women with ICP. CA remains the major BA and its concentration is significantly higher than that of CDCA, resulting in an increase in the CA/CDCA ratio and a decrease in the percentage of CDCA in the total pool of BAs. […] The level of total serum BAs is currently considered to be the most sensitive and specific biochemical marker used in the diagnosis and monitoring of ICP.

• #19 Intrahepatic cholestasis of pregnancy: Changes in maternal-fetal bile acid balance and improvement by ursodeoxycholic acid | Annals of Hepatology

  https://www.elsevier.es/en-revista-annals-hepatology-16-articulo-intrahepatic-cholestasis-pregnancy-changes-in-S166526811932188X

  Current research indicates that mutations of the MDR3 gene encoding the canalicular phosphatidylcholine translocase may in some cases predispose to ICP, justifying the raised -glutamiltranspeptidase in 20 to 40% of the patients. […] The most serious consequences of ICP are increased fetal distress, premature deliveries and perinatal mortality and morbidity. […] Several treatments, such as cholestyramine, phenobarbital, dexamethasone, S-adenosyl-L-methionine, and epomediol failed to improve pruritus, biochemical abnormalities, or fetal prognosis during ICP. […] The most efficacious current medical management that improves maternal condition and might prevent the perinatal complications of ICP is ursodeoxycholic acid (UDCA) administration. […] During ICP, in addition to the increased levels of bile acids, the efficiency of the ATP-independent transport mechanisms is enhanced.

• #20 Intrahepatic Cholestasis of Pregnancy: Even Today a Puzzling Disease of Pregnancy | World Gastroenterology Organisation

  https://www.worldgastroenterology.org/publications/e-wgn/e-wgn-expert-point-of-view-articles-collection/intrahepatic-cholestasis-of-pregnancy-even-today-a-puzzling-disease-of-pregnancy

  Recently our group from Chile has also shown an increased intestinal permeability in ICP patients during and after pregnancy. […] 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. […] 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. […] Its etiology is likely multifactorial, with the influence of many environmental factors over a genetically predisposed subject.

• #21 Bile Acids in Intrahepatic Cholestasis of Pregnancy

  https://www.mdpi.com/2075-4418/12/11/2746

  Intrahepatic cholestasis of pregnancy (ICP) is the most common, reversible, and closely related to pregnancy condition characterized by elevated levels of bile acids (BAs) in blood serum and an increased risk of adverse perinatal outcomes. […] The pathophysiology of the disease is based on inflammatory mechanisms caused by elevated BA levels. […] One of these mechanisms is undoubtedly the inflammatory mechanism that underlies the pathophysiology of ICP. Elevated levels of BAs induce the production of pro-inflammatory mediators in hepatocytes, attracting immune cells and initiating inflammation in the liver, eventually leading to cholestatic liver damage. […] The NLR family pyrin domain containing 3 (NLRP3) inflammasome in hepatic stellate cells and Kupffer cells is activated by BAs, causing inflammation or fibrosis.

• #22 Researchers Reveal Mechanism of Aberrant Placental Inflammation in Patients with Intrahepatic Cholestasis of Pregnancy—-Chinese Academy of Sciences

  https://english.cas.cn/newsroom/archive/research_archive/rp2016/201608/t20160801_166228.shtml

  Researchers Reveal Mechanism of Aberrant Placental Inflammation in Patients with Intrahepatic Cholestasis of Pregnancy […] Intrahepatic cholestasis of pregnancy (ICP) is the most frequent liver disease arising in the second or third trimester of pregnancy that is characterized by elevated maternal serum bile acids levels. […] Researchers from Prof. CHEN Jianfengs group at Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences (SIBS) of Chinese Academy of Sciences (CAS), revealed that maternal high serum bile acids can induce placental inflammation and then affect fetal outcome. […] They found that high level bile acids induce inflammatory response in trophoblasts by activating NF-kappaB pathway via G-protein-coupled bile acid receptor 1 (Gpbar1). Consequently, leukocytes are recruited and result in an aberrant inflammation in placenta.

• #23 The role of metabolic disorders in the pathogenesis of intrahepatic cholestasis of pregnancy

  https://www.termedia.pl/The-role-of-metabolic-disorders-in-the-pathogenesis-of-intrahepatic-cholestasis-of-pregnancy,80,34314,0,1.html

  Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder which typically commences in the late second or third trimester and resolves within 48 hours after delivery. […] The etiology of ICP is still not completely explicit. Pathogenesis includes a combination of hormonal and environmental factors superimposing on a genetic predisposition. […] During recent years increasingly ICP is recognized to be associated with an abnormal metabolic profile, including glucose intolerance and dyslipidemia, although it is considered to be secondary to maternal aberrant BA homeostasis. […] This article reviews the recent literature data and current concepts for ICP, with emphasis on a possibility of metabolic disorders being primary causative factors in ICP pathogenesis.

• #24 Intrahepatic cholestasis of pregnancy is associated with an increased risk of gestational diabetes and preeclampsia

  https://atm.amegroups.org/article/view/57492/html

  Bile acid as a ligand combined with farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5) can broadly influence glucolipid metabolism. […] The significant increase of GDM among women with ICP may thus be due to the decrease in FXR and TGR5 activities, which could lead to aberrant bile acid homeostasis. […] High bile acid levels have also been shown to cause vasoconstriction of the chorionic plate veins which leads to structural damage of the placenta, causing reduced oxygen. […] Bile acids also contribute to endothelial damage in the kidneys and lungs through the production and release of reactive oxygen species, which can lead to oxidative stress. […] We observed a significant correlation between ICP and adverse perinatal outcomes, and investigators previously reported that ICP was associated with an increased risk of stillbirth. […] Although a strong association was found between ICP and GDM as well as between ICP and preeclampsia, ICP did not increase the risk of stillbirth.

• #25 Intrahepatic cholestasis of pregnancy is associated with an increased risk of gestational diabetes and preeclampsia

  https://atm.amegroups.org/article/view/57492/html

  Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disease that is characterized by pruritus, elevated total bile acids (TBAs), and abnormal liver function tests usually presenting in the second or third trimester. The pathogenesis of ICP remains poorly understood and may be associated with genetic, hormonal, immunologic and/or environmental factors. […] Previous investigators have concluded that ICP is associated with an increased risk for spontaneous and iatrogenic preterm labor, respiratory distress syndrome (RDS), meconium-stained amniotic fluid (MSAF), neonatal intensive care unit (NICU) admission, and stillbirth. […] In this study we showed a higher risk of GDM and preeclampsia among women with ICP compared with those without, which is consistent with previous studies. The mechanism(s) underlying the direct relation of ICP to GDM and preeclampsia remains unclear.

• #26 Cholestasis of pregnancy – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/cholestasis-of-pregnancy/symptoms-causes/syc-20363257

  Intrahepatic cholestasis of pregnancy, commonly known as cholestasis of pregnancy, is a liver condition that can occur in late pregnancy. […] The exact cause of cholestasis of pregnancy is unclear. Cholestasis is reduced or stopped bile flow. Bile is the digestive fluid made in the liver that helps break down fats. Instead of leaving the liver for the small intestine, bile builds up in the liver. As a result, bile acids eventually enter the bloodstream. High levels of bile acids appear to cause the symptoms and complications of cholestasis of pregnancy. […] Pregnancy hormones, genetics and the environment may all play a role. […] Cholestasis of pregnancy increases the risk of complications during pregnancy such as preeclampsia and gestational diabetes. […] Complications from cholestasis of pregnancy appear to be due to high bile acid levels in the blood. Complications may occur in the mom, but the developing baby is especially at risk.

• #27

  https://journals.lww.com/greenjournal/FullText/2009/02001/Sudden_Fetal_Death_in_Intrahepatic_Cholestasis_of.22.aspx?generateEpub=Article%7Cgreenjournal:2009:02001:00022%7C10.1097/aog.0b013e31818db1c9%7C

  Intrahepatic cholestasis of pregnancy is associated with an increased risk of fetal death. The mechanism of death is unknown. […] Fetal death from intrahepatic cholestasis of pregnancy can be abrupt and not reliably predicted by the characteristics of the fetal heart rate tracing.

• #28 Metabolic changes in bile acids with pregnancy progression and their correlation with perinatal complications in intrahepatic cholestasis of pregnant patients | Scientific Reports

  https://www.nature.com/articles/s41598-022-22974-8

  The occurrence of ICP may be due to the hindered transformation of primary to secondary BAs, which results in the accumulation of conjugated CA and CDCA. […] Increased TCA percentages can be used to predict PTB in the LICP group. […] The mechanism of ICP-induced PTB is still uncertain. This effect seems to be related to the accumulation of BAs in the fetal compartment and the increased reaction of the myometrium to BAs. […] The different CA-conjugated BA forms related to different types of ICP may be ascribed to metabolic changes in the BA profile throughout pregnancy. […] In EICP, elevated ALB, TBA, TB and GCA percentages taken together predict the risk of PTB, suggesting that the increased liver load in the second trimester is positively correlated with PTB. […] In conclusion, we found that patients with different types of ICP have distinct serum BA profiles. BA metabolism is not disorganized in ICP. In fact, it is related to gestational age.

• #29 Review of a challenging clinical issue: Intrahepatic cholestasis of pregnancy

  https://wjgnet.com/1007-9327/full/v21/i23/7134.htm

  Intrahepatic cholestasis of pregnancy (ICP) is a unique hepatic disorder in pregnancy characterized by mild to severe pruritus and disturbed liver function tests. ICP is a reversible form of cholestasis (impaired bile flow) appearing mainly in the late second or third trimester of pregnancy, and tends to dissolve rapidly after delivery. Incidence varies geographically between 0.1%-15.6%. It is the second most frequent cause of jaundice in pregnancy following viral hepatitis. Etiology seems to be multifactorial, with a combination of hormonal and environmental factors superimposing on a genetic predisposition. Maternal prognosis is usually good, with intractable pruritus and a higher predisposition to postpartum bleeding being the leading causes of maternal morbidity. On the other hand, ICP is associated with increased fetal morbidity and mortality, particularly with regards to preterm delivery, fetal distress, and sudden intrauterine fetal death. It appears to be of utmost importance to establish a clinical awareness with respect to the potential adverse fetal outcome in ICP and consider it as a high-risk pregnancy disorder. An early and accurate diagnosis with an appropriate medical intervention is mandatory for an improved fetal prognosis. The etiology of ICP is multifactorial, and involves genetic, hormonal, and environmental factors. Estrogens and progesterone metabolites have been demonstrated to have role in the pathogenesis of ICP. The disease usually appears in the third trimester of pregnancy when estrogen production reaches its maximum levels. The prevalence of ICP is five times greater in multiple pregnancies, which are associated with higher levels of estrogens in comparison with singleton pregnancies. A high level of estrogen in genetically-predisposed individuals may be inducing intrahepatic cholestasis by impaired sulfation and the transport of bile acids. The role of progesterone with respect to the pathogenesis of ICP seems to be still unclarified. Family clustering, presence of ethnic and geographic variations, and recently demonstrated mutations in gene coding for hepatobiliary transport proteins indicate a genetic predisposition in ICP. Genetic predisposition may lead to altered cell membrane composition of bile ducts and hepatocytes, as well as the subsequent dysfunction of biliary canalicular transporters. Mutations in the hepatic phospholipid transporter (MDR3/ABCB4), aminophospholipid transporter (ATP8B1/FIC1), and bile salt export pump (BSEP/ABCB11) have been found in patients with ICP. Genetic variation in ATP8B1 which encodes phosphatidylserine flippase FIC1 has been identified in a small number of ICP cases. Environmental factors, such as geographic and seasonal conditions, may induce ICP in genetically-susceptible individuals. ICP is shown to be associated with poor perinatal outcome and increased risk of preterm labor, fetal distress, and sudden intrauterine fetal death. Although the pathophysiology of fetal risk has yet to be clarified, an elevation in maternal-fetal bile acid flow and a reduced fetal capacity to eliminate bile acids through the immature fetal liver, in addition to altered placental function, appear to be responsible for impaired fetal-maternal bile acid transport in ICP. The etiopathogenetic mechanism of premature labor in ICP still remains to be elucidated. Elevated levels of bile acids have been suggested to stimulate myometrial contractions and increase oxytocin bioactivity triggering preterm labor.

• #30 Review of a challenging clinical issue: Intrahepatic cholestasis of pregnancy

  https://www.wjgnet.com/1007-9327/full/v21/i23/7134.htm

  The etiopathogenetic mechanism of premature labor in ICP still remains to be elucidated. Elevated levels of bile acids have been suggested to stimulate myometrial contractions and increase oxytocin bioactivity triggering preterm labor. Hemorrhagic complications due to vitamin K deficiency may contribute to fetal mortality.

• #31 Severe Intrahepatic Cholestasis of Pregnancy—Potential Mechanism by Which Fetuses Are Protected from the Hazardous Effect of Bile Acids

  https://www.mdpi.com/2077-0383/12/2/616

  Severe Intrahepatic Cholestasis of Pregnancy—Potential Mechanism by Which Fetuses Are Protected from the Hazardous Effect of Bile Acids […] Intrahepatic cholestasis of pregnancy (ICP) is characterized by elevated total bile acids (TBA). Although elevated maternal TBA is a major risk factors for fetal morbidity and mortality, it is unclear why some fetuses are more prone to the hazardous effect of bile acids (BA) over the others. […] Importantly, since TBA level remains low even though maternal TBA level is high the fetuses are protected from the hazardous effects of maternal BA. Our findings suggest that there is no effective metabolism of BA in the fetus and the main decrease in TBA in the fetus is related to placental BA uptake. […] The etiology of ICP is multifactorial but a crucial cause is gene mutations in the hepatocellular transporters that are responsible for the transfer of bile acids (BA) to the bile canaliculi which result in accumulation of BA in maternal hepatocytes and consequently in maternal blood. […] Interestingly, although maternal TBA level > 40 μmol/L (and even more so > 100 μmol/L) are a major risk factors for fetal compromise, most of the fetuses who are exposed to high TBA levels are born without major complications. Therefore, it was suggested that these fetuses are protected from the toxic effect of excessive BA by either uptake of BA in the placenta, BA metabolism in fetal liver or the therapeutic effect of UDCA. The underling mechanism of this protective effect is unclear, and data are limited.

• #32 Severe Intrahepatic Cholestasis of Pregnancy—Potential Mechanism by Which Fetuses Are Protected from the Hazardous Effect of Bile Acids

  https://www.mdpi.com/2077-0383/12/2/616

  In this prospective study we have shown that among women with severe ICP at delivery the TBA levels in the umbilical vein was significantly lower as compared to maternal serum TBA. […] Therefore, our finding is highly important, and it suggests that fetal liver metabolism does not play a crucial role in the metabolism of bile acids being transferred from maternal origin. These findings are further supported by studies which reported that during intrauterine life fetal hepatobiliary excretory function is not efficient while the main route for the elimination of BA is their transfer to the mother across the placenta. […] Taken together the data suggest that placental excretion of bile acid during maternal cholestasis plays a major role in the protection of the fetus against the toxic bile acids existing in the maternal side while fetal BA metabolism is of minor importance. This mechanism can be enhanced by UDCA. This has an important implication, because even in situations of high maternal TBA there is only a mild increase in bile acid concentrations in fetal serum.

• #33 Intrahepatic Cholestasis of Pregnancy | MDedge

  https://mdedge.com/cutis/article/176979/mixed-topics/intrahepatic-cholestasis-pregnancy

  Intrahepatic cholestasis of pregnancy is a rare form of reversible cholestasis occurring in the second half of pregnancy. […] The pathogenesis of ICP is not fully understood. During pregnancy, estrogens interfere with bile acid secretion, and progestins inhibit hepatic glucuronyltransferase. Increased IFN-γ, natural killer cells, and natural killer T cells, as well as decreased T cells in decidua parietalis, also have been reported. […] Mutations in the ATP binding cassette subfamily B member 4 gene, ABCB4, which encodes the multidrug resistance protein 3, a canalicular phosphatidylcholine translocase, have been found in several women with ICP. […] Generally, there are no cutaneous signs other than excoriation marks, contrary to primary skin lesions found in other specific dermatoses of pregnancy.

• #34 Pulsenotes | Intrahepatic cholestasis of pregnancy

  https://app.pulsenotes.com/specialities/obstetrics/notes/intrahepatic-cholestasis-of-pregnancy

  Intrahepatic cholestasis of pregnancy is a liver disease unique to pregnancy that is characterised by pruritus and elevated bile acids. […] The exact cause of ICP remains unknown. […] The exact cause is unknown by is likely due to a combination of genetic susceptibility, hormonal and environmental factors. […] Oestrogen is suspected to play a significant role in ICP. Oestrogen is highest during the second half of pregnancy when ICP occurs and oestrogen is known to cause cholestasis. Excess administration of progesterone may also contribute to ICP in pregnancy. […] There is a small association between ICP and underlying liver disease (e.g. NAFLD) that may be revealed during pregnancy and contribute to the development of ICP. […] The principal treatment of ICP is ursodeoxycholic acid (UDCA) although this does not seem to improve fetal outcomes. […] Once initiated, weekly blood can be assessed to determine the level of bile acids. However, UDCA does not seem to affect fetal/neonatal outcomes. […] Importantly, ICP will recur in 60-70% of pregnancies, but the clinical course is highly variable.

• #35 Metabolic changes in bile acids with pregnancy progression and their correlation with perinatal complications in intrahepatic cholestasis of pregnant patients | Scientific Reports

  https://www.nature.com/articles/s41598-022-22974-8

  Intrahepatic cholestasis of pregnancy (ICP) is a rare liver disease occurring during pregnancy that is characterized by disordered bile acid (BA) metabolism. […] The etiology of ICP is still unknown. Genetics, environmental factors and changes in hormone profiles during pregnancy may all lead to ICP. […] ICP, especially early-onset ICP (EICP), is associated with adverse perinatal complications, including preterm birth (PTB), stillbirth and even long-term metabolic disorders, which may be attributable to the accumulation of maternal bile acids (BAs) in the fetus and the long exposure time in utero. […] Maternal serum TBA has diagnostic significance in ICP, and the incidence of poor pregnancy outcomes increases with increasing TBA. […] Studies have suggested maternal TBA as a threshold for predicting the occurrence of fetal complications, with each additional 1-mol/L of TBA increasing the incidence of fetal complications by 12%.

• #36 Intrahepatic cholestasis of pregnancy | RCOG

  https://www.rcog.org.uk/for-the-public/browse-our-patient-information/intrahepatic-cholestasis-of-pregnancy/

  ICP is a condition that affects how your liver works when you are pregnant. It is sometimes called obstetric cholestasis. […] ICP causes a build-up of bile acids in your body. Bile acids are made in your liver and they help you to digest fat and fat soluble vitamins. […] If your bile acid levels are 100 micromol/L or more (Severe ICP), your chance of having a stillbirth is higher than someone who doesn’t have ICP and is around 3%. […] There is no treatment available that helps your baby or that will make your bile acid levels better. Ursodeoxycholic acid may reduce your chance of giving birth prematurely but it does not prevent stillbirth. […] The recommended timing of your baby’s birth will depend on the level of bile acids in your blood and also whether you have any additional risk factors such as multiple pregnancy, gestational diabetes or pre-eclampsia.

• #37 Intrahepatic Cholestasis of Pregnancy Archives – The ObG Project

  https://www.obgproject.com/tag/intrahepatic-cholestasis-of-pregnancy/

  SMFM has released a Consult Series entry on Intrahepatic Cholestasis of Pregnancy (ICP), that typically presents in the second and third trimester of pregnancy. It is characterized by pruritus without rash, as well as elevated bile acids. […] The highest risk if bile acids above 100 micromol/L. […] Underlying mechanism: Possibly due to arrhythmia or placental vessel vasospasm. […] UDCA is first line for the treatment of maternal symptoms but data has not demonstrated impact on adverse neonatal outcomes.

• #38 Intrahepatic cholestasis of pregnancy (ICP) – hjog.org

  https://hjog.org/?p=1887

  The exclusion of other causes is done by a liver ultrasound, viral tests and detection of liver auto-antibodies. […] The risk is reduced by progesterone pills, only if the liver enzymes levels return to normal after delivery. […] The future goals include better comprehension of ICP pathophysiology, an improved understanding of the intrauterine death mechanism, discovering of risk assessment methods, and verification of the accurate role of UDCA in lowering the risk of an intrauterine death and its safe administration.

• #39 The effect of intrahepatic cholestasis of pregnancy and ursodeoxycholic acid treatment on Doppler parameters of fetal and maternal circulation | Vural Yılmaz | Ginekologia Polska

  https://journals.viamedica.pl/ginekologia_polska/article/view/96400

  Ursodeoxycholic acid (UDCA) is a natural bile acid that is found in humans and is usually used to treat hepatobiliary diseases. It is also the most recommended agent in the world for ICP disease. It improves cholestasis by several mechanisms. It increases biliary BA excretion, stimulates hepatocellular secretion, stabilizes plasma membranes and protects cholangiocytes and hepatocytes from cytotoxicity of bile acids. Although UDCA is the most used agent for ICP treatment worldwide, its benefit on fetal outcome is unclear. A Cochrane systematic review of the effectiveness of UDCA for ICP disease concluded that it improves maternal symptoms mildly, however evidence for fetal adverse outcomes was not shown with certainty. […] In this study, we evaluated fetal and maternal circulation with routine Doppler USG parameters in pregnant women with ICP disease and compared the results with pregnant women without disease, and we also aimed to evaluate the effect of UDCA treatment on these parameters. We found that fetomaternal Doppler parameters were similar between pregnant women complicated with ICP and without disease and UDCA had no effect on these parameters.

• #40 Intrahepatic cholestasis of pregnancy: Changes in maternal-fetal bile acid balance and improvement by ursodeoxycholic acid | Annals of Hepatology

  https://www.elsevier.es/en-revista-annals-hepatology-16-articulo-intrahepatic-cholestasis-pregnancy-changes-in-S166526811932188X

  Intrahepatic cholestasis of pregnancy (ICP) is a disease characterized by generalized pruritus and biochemical cholestasis that appears typically during the last trimester of gestation. […] Although essentially benign for the mother, evidence associates ICP with fetal poor prognosis resulting from increased transfer of bile acids from mother to fetus, who showed reduced ability to eliminate bile acids across the placenta. […] Ursodeoxycholic acid (UDCA) treatment was shown to reduce the bile acid content in the fetal compartment, while restoring the ability of the placenta to carry out vectorial transfer of these compounds towards the mother, decreasing bile acid levels in maternal serum and its passage to the fetus. […] Therefore, it is tempting to indicate UDCA as a first choice therapy for ICP as much as relevant aspects of fetal outcome may also be improved.

• #41 A multi-centre, open label, randomised, parallel-group, superiority Trial to compare the efficacy of URsodeoxycholic acid with RIFampicin in the management of women with severe early onset Intrahepatic Cholestasis of pregnancy: the TURRIFIC randomised tri

  https://bmcpregnancychildbirth.biomedcentral.com/articles/10.1186/s12884-020-03481-y

  Since the publication of the previous Cochrane review in 2013, there has been increasing interest in the use of rifampicin in treating women with ICP. Rifampicin is a semisynthetic antibiotic with a wide range of antimicrobial activity and is a first-line agent for treatment of tuberculosis, including for treatment of pregnant women. […] Rifampicin has also been shown to have the capacity to reduce serum BA in the management of cholestasis outside of pregnancy. It is a pregnane X-receptor (PXR) agonist and a potent inducer of key enzymes in the hepatic and intestinal detoxification machinery (such as CYP3A4, CYP2D, UGT1A1, SULT2A1) and export pump MRP2. […] Data from The Netherlands suggest that rifampicin may be a more appropriate therapy for individuals with ABCB11 mutations associated with clinical BSEP deficiency and Benign Recurrent Intrahepatic Cholestasis (BRIC) outside of pregnancy. […] Our study will be the first to examine the outcomes of treatment specifically in the severe early onset form of ICP, comparing standard UDCA therapy with rifampicin, and so be able to provide for the first-time high-quality evidence for use of rifampicin in severe ICP.

• #42 Intrahepatic cholestasis of pregnancy linked to poor outcomes | 2 Minute Medicine

  https://www.2minutemedicine.com/intrahepatic-cholestasis-of-pregnancy-linked-to-poor-outcomes/

  These findings suggest that maternal bile acid levels may be useful in predicting risk for adverse fetal outcomes for infants being born to mothers suffering from ICP. […] Severe ICP was associated with lower birthweight (p=0.009), preterm birth (p=0.03), meconium-stained fluid (p=0.003), postpartum hemorrhage (p=0.019) and perinatal death (p=0.009). […] Furthermore, every 10μmol/L was associated with increased likelihood for spontaneous preterm delivery (OR 1.15, CI 1.03-1.28) and meconium-stained fluid (OR 1.15, CI 1.06-1.25). […] The highest measured maternal bile acid level was positively correlated with umbilical cord bile acid levels (p=0.006).

• #43

  https://link.springer.com/article/10.1007/s43032-023-01437-z

  Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disease, which can lead to adverse fetal outcomes, including preterm labor and intrauterine death. The pathogenesis of ICP is still unclear. […] Investigation of these differences in protein expression in parallel profiling is essential to understand the comprehensive pathophysiological mechanism underlying ICP. […] This study has identified up-regulated APOA2 associated with PPAR signaling pathway and PPAR/RXR activation in ICP. Thus, APOA2 may be involved in ICP pathogenesis, serving as a novel biomarker for its diagnosis. […] The etiology of ICP is multifactorial and may be related to elevated estrogen levels and altered hepatobiliary transporter protein expression during pregnancy. […] Although different tentative studies about ICP have been carried out, the precise pathogenesis of ICP still remains unclear.

• #44

  https://link.springer.com/article/10.1007/s43032-023-01437-z

  Given the pivotal role of PPAR in liver lipid homeostasis and the treatment of fenofibrate, severe as a PPAR agonist, against cholestasis-induced hepatic injury, the expression of APOA2 and PPAR was detected by western blotting to verify the relationship between ICP and control groups. […] Thus, highly expressed APOA2 in the placenta could be a sign of PPAR signaling pathway and PPAR/RXR activation; then, the upregulated APOA2 cause severe oxidative damage and trigger a series of inflammatory responses consequently. […] In our study, APOA2 was first reported that could be related to the mechanism of ICP.

• #45 Intrahepatic Cholestasis of Pregnancy: New Insights on an Old Issue – Women’s Healthcare

  https://www.npwomenshealthcare.com/intrahepatic-cholestasis-of-pregnancy-new-insights-on-an-old-issue/

  Intrahepatic cholestasis of pregnancy (ICP) is a hepatic disorder that complicates 0.2% to 2% of pregnancies and poses significant risk to the fetus including preterm delivery and stillbirth. […] Cholestasis occurs when bile acid secretion is impaired leading to the accumulation and circulation of toxic bile salts. Various conditions of the liver, the bile duct, or the pancreas can impair bile acid secretion and result in cholestasis. Hormonal, genetic, and exogenous factors like advanced maternal age, in vitro fertilization, multiple gestations, and hepatitis C infection contribute to the development of ICP. During pregnancy, progressive insulin resistance, increases in progesterone and estrogen and their metabolites, and genetically influenced alterations in the bile acid pathway impact maternal lipid metabolism and liver function impairing hepatic bile acid homeostasis. In a pregnancy complicated by ICP, there is an excessive increase in bile acids in both the pregnant person and the fetus causing damage to liver cells and tissues. […] Although these changes resolve rapidly in the pregnant person postpartum, evidence suggests that fetuses exposed to elevated bile acids may develop metabolic syndrome later in life.

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