Ignite Creation Date:
2024-05-06 @ 6:32 PM
Last Modification Date:
2024-10-26 @ 2:49 PM
Study NCT ID:
NCT05691036
Status:
RECRUITING
Last Update Posted:
2023-01-19
First Post:
2022-08-01
Brief Title:
Bile Acids Metabolism and Genetic Mutation Profile in the ICP in the Indian Population
Sponsor:
Post Graduate Institute of Medical Education and Research Chandigarh
Organization:
PGIMER
Study Overview
Official Title:
Bile Acids Metabolism and Genetic Mutation Profile in the Etiopathogenesis of Intrahepatic Cholestasis of Pregnancy in the Indian Population- A Prospective Study
Status:
RECRUITING
Status Verified Date:
2023-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
ICP
Brief Summary:
Intrahepatic cholestasis of pregnancy ICP is a disorder characterized by itching elevated fasting serum bile acids 10μmolL and elevated serum transaminases with increased risks of perinatal complications including spontaneous preterm labor fetal distress infant respiratory distress syndrome meconium-stained liquor MSL and sudden intrauterine death IUD The Incidence of ICP varies from 01 to 156 of all pregnancies with the highest cases in Chile South Asia America and Scandinavia The burden of ICP in India according to various states is as follows Punjab 31 Chandigarh 48 Delhi 079 West Bengal 33 and Lucknow Uttar Pradesh 28
Detailed Description:
Many physiological anatomical and hormonal changes occur in the body during pregnancy to facilitate the best possible growth of the fetus A functional liver and bile acids BA milieu are critical for the development of the fetus and adverse pregnancy outcomes are possible in women who have primary liver disease Some pre-existing hepatobiliary diseases may be diagnosed incidentally during pregnancy such as chronic viral hepatitis Some common pregnancy-related liver diseases are Intrahepatic Cholestasis of pregnancy ICP hemolysis elevated liver enzymes and low platelets HELLP syndrome and acute fatty liver of pregnancy AFLP ICP is a cholestatic disorder characterized by i pruritus with onset in the second and third trimester of pregnancy without any primary skin lesions ii elevated fasting serum bile acids 10μmolL and elevated serum transaminases iii spontaneous relief of signs and symptoms within two to three weeks after delivery and iv absence of other diseases that cause pruritus and jaundice Many studies have attempted to associate maternal serum bile acids total bile acids with adverse fetal outcomes ICP is associated with increased risks of perinatal complications including spontaneous preterm labor fetal distress infant respiratory distress syndrome meconium-stained amniotic fluid and sudden intrauterine death IUD Recent data suggest that women with jaundice had higher rates of prenatal abnormalities than women with just pruritus in ICP Pruritus can appear as early as seven weeks without causing a rash Itching is usually noticed early on the palms of the hands and the soles of the feet although it can occur everywhere on the body Other symptoms of ICP include dark urine increased clotting time fatigue nausea loss of appetite jaundice and discomfort in the upper right quadrant of the abdomen It may be mild and tolerable for some patients but may also be very severe and disabling Women with ICP develop mild jaundice and subclinical steatorrhea Jaundice typically develops 1 to 4 weeks after the onset of pruritus Subclinical steatorrhea with fat malabsorption leads to vitamin K deficiency resulting in prolonged prothrombin time and postpartum hemorrhage
The incidence and prevalence of ICP vary with ethnicity and geography Ethnic distribution of ICP as Caucasian 536 South Asian 226 African 06 Asian 84 and Australian 38 were noted 8 Among the Asians Asian of Indian origin 124 Pakistan origin of 146 and whites of 062 were found to show Indians and Pakistan origin of Asian have a higher prevalence than whites Concerning the geographic distribution of ICP the Incidence of ICP varies from 01 to 156 of all pregnancies with the highest cases in Chile South Asia America and Scandinavia In the case of individual countries such as Chile 9 Canada 007 China 032 and North California 19 incidence were reported It is more common in South America as compared to other northern European continents The incidence of ICP was reported as 05-15 of pregnancies in Finland As this study will be done among the Indian population the burden of ICP in India is reported as Punjab at 31 Chandigarh at 48 Delhi at 079 Nepal at 115 West Bengal at 33 Lucknow 28 indicating an urgent need to focus and find out cost-effective and early prognosis and diagnosis of ICP
ICP is a multifactorial disease interplay between genetic environmental and hormonal factors Common risk factors are the history of oral contraceptive pill OCP use twins selenium deficiency genetic transporters defects and recurrence in the subsequent pregnancy Patients are usually diagnosed in the second and third trimesters with increased incidence in winter Genetic factors contribute as risk factors for ICP including mutation in ATP binding cassette family as ATP binding cassette subfamily B member 4ABCB4 ATP-binding cassette sub-family B member 11ABCB11 ATPase Phospholipid Transporting 8B1ATP8B1 ATP Binding Cassette Subfamily C Member 2ABCC2 and tight junction protein 2TJP2 genes Bile mainly consists of bile salt organic anions electrolytes phosphatidylcholine and cholesterol These components are transported by active process against the concentration gradient by specific transporters such as bile salt export pump BSEP Sodium taurocholate co-transporting polypeptide NTCP major transporter for the secretion of bile acids from hepatocytes into bile in humans A study on deoxyribonucleic acid DNA of the Italian population with the help of polymerase chain reaction PCR and automated sequencing They found five novel variants of mutation in ABCB4 and ABCB11 and confirmed the statistically significant susceptibility to ICP Environmental factors associated with ICP include seasonal variation selenium deficiency and vitamin D deficiency Hormonal factors such as estrogen level sulfated progesterone intake of oral contraceptive pills and second-trimester hormonal changes in pregnant women can be attributed as risk factors for ICP In the urine of pregnant women with ICP sulfated progesterone correlates with the severity of ICP Apart from these other risk factors are responsible for ICP and they found a statically significant association between pregestational diabetes tobacco use history of cholecystectomy history of ICP in a previous pregnancy and pregnancy-induced hypertension PIH
Placental expression of genes due to placental hypoxia and proteins related to apoptosis oxidative stress lipid metabolism cell proliferation and immunological response are associated with ICP Increased total serum BAs and changes in BAs profile reverse the transplacental BAbile acids gradient and increased inflammatory cytokines like interleukin 4IL4 interleukin 6IL6 interleukin 12 IL12 and tumor necrosis factorTNF cause respiratory distress in infants and preterm delivery Immune response vascular endothelial growth factorVGEFsignaling pathway and G-protein-coupled receptor signaling were the most common regulatory genes responsible for inflammatory response vasculogenesis and angiogenesis all essential in ICP pathogenesis Autotaxin ATX is lysophosphatidic acid LPA essential for angiogenesis and neuronal development during embryogenesis cellular motility proliferation and lymphocyte homing ATX levels are reported to be increased during pregnancy and correlate positively with gestational age LPA and ATX levels were significantly higher in ICP A large prospective study in Sweden revealed severe perinatal outcomes of ICP as spontaneous preterm labor asphyxia events meconium staining of amniotic fluid and placental and membrane changes did not occur until the level of serum bile acid reached40umolL ICP is a pregnancy-related disorder that is expected to resolve after delivery However population-based cohort studies revealed that ICP acts as a risk factor for hepatobiliary disease even after the completion of pregnancy A significant association between hepatitis C virus HCV non-alcoholic liver disease gallstone and cholelithiasis with increased risk of non-alcoholic pancreatitis in women was observed in women with ICP A population-based cohort study with an of 032-058 of ICP in Sweden gives a significant risk association of ICP with gestational diabetes pre-eclampsia and a nonsignificant association with postpartum hemorrhage Total serum bile acids 40mmoll as severe ICP and associated with increased risk of gestational diabetes mellitusGDM pregnancy-induced hypertensionPIH was reported and managed with ursodeoxycholic acid UDCA
Some therapeutic agents such as ursodeoxycholic acidUDCA rifampicin antihistaminic drugs vitamin K and some topical emollients have been used to alleviate nocturnal pruritus pruritus in ICP Some trials related to reducing the adverse perinatal outcome of ICP were done with the administration of UDCA dexamethasone cholestyramine S-adenosyl methionineSAMe plasmapheresis and fish supplements UDCA is currently the most effective therapeutic agent used in clinical practice to manage ICP Several meta-analyses with observational studies or randomized trials have been done on the effectiveness of UDCA but the results are equivocal Dexamethasone rifampicin SAMe and cholestyramine also have some roles in the management of ICP However reducing pruritus and other adverse perinatal outcomes in pregnancy is unclear UDCA was effective in improving clinical presentation normalization of serum profile and a significant reduction in meconium staining spontaneous birth or fetal distress compared to the control placebo group Maternal total serum BAs are significantly associated with reduced infant size and are small for gestational age Since ICP is the most typical pregnancy-related liver disorder has multifactorial risk factors has unclear etiopathogenesis and results in adverse perinatal outcomes Pruritus may considerably impair the patients quality of life as a pregnant woman causing sleep deprivation and psychological suffering Only a few studies have been done in India concerning ICP most of which are related to the reference range of total BAs and the prevalence of ICP There is no Indian data on how ICP affects the quality of life of a pregnant woman or prospective assessment of genetic risk and bile acid metabolism So the aim is to determine the bile acid profile and related metabolites in serum identify prognostic markers of ICP and assess related risk factors including the effect of medication and the quality of life of patients with ICP This research will prospectively evaluate perinatal outcomes and genetic risk factors which have a bearing on neonatal health Keeping in mind the symptoms and severity of pruritus the factors affecting the disease course of pregnant women suffering from ICP will also be evaluated
The incidence and prevalence of ICP vary with ethnicity and geography Ethnic distribution of ICP as Caucasian 536 South Asian 226 African 06 Asian 84 and Australian 38 were noted 8 Among the Asians Asian of Indian origin 124 Pakistan origin of 146 and whites of 062 were found to show Indians and Pakistan origin of Asian have a higher prevalence than whites Concerning the geographic distribution of ICP the Incidence of ICP varies from 01 to 156 of all pregnancies with the highest cases in Chile South Asia America and Scandinavia In the case of individual countries such as Chile 9 Canada 007 China 032 and North California 19 incidence were reported It is more common in South America as compared to other northern European continents The incidence of ICP was reported as 05-15 of pregnancies in Finland As this study will be done among the Indian population the burden of ICP in India is reported as Punjab at 31 Chandigarh at 48 Delhi at 079 Nepal at 115 West Bengal at 33 Lucknow 28 indicating an urgent need to focus and find out cost-effective and early prognosis and diagnosis of ICP
ICP is a multifactorial disease interplay between genetic environmental and hormonal factors Common risk factors are the history of oral contraceptive pill OCP use twins selenium deficiency genetic transporters defects and recurrence in the subsequent pregnancy Patients are usually diagnosed in the second and third trimesters with increased incidence in winter Genetic factors contribute as risk factors for ICP including mutation in ATP binding cassette family as ATP binding cassette subfamily B member 4ABCB4 ATP-binding cassette sub-family B member 11ABCB11 ATPase Phospholipid Transporting 8B1ATP8B1 ATP Binding Cassette Subfamily C Member 2ABCC2 and tight junction protein 2TJP2 genes Bile mainly consists of bile salt organic anions electrolytes phosphatidylcholine and cholesterol These components are transported by active process against the concentration gradient by specific transporters such as bile salt export pump BSEP Sodium taurocholate co-transporting polypeptide NTCP major transporter for the secretion of bile acids from hepatocytes into bile in humans A study on deoxyribonucleic acid DNA of the Italian population with the help of polymerase chain reaction PCR and automated sequencing They found five novel variants of mutation in ABCB4 and ABCB11 and confirmed the statistically significant susceptibility to ICP Environmental factors associated with ICP include seasonal variation selenium deficiency and vitamin D deficiency Hormonal factors such as estrogen level sulfated progesterone intake of oral contraceptive pills and second-trimester hormonal changes in pregnant women can be attributed as risk factors for ICP In the urine of pregnant women with ICP sulfated progesterone correlates with the severity of ICP Apart from these other risk factors are responsible for ICP and they found a statically significant association between pregestational diabetes tobacco use history of cholecystectomy history of ICP in a previous pregnancy and pregnancy-induced hypertension PIH
Placental expression of genes due to placental hypoxia and proteins related to apoptosis oxidative stress lipid metabolism cell proliferation and immunological response are associated with ICP Increased total serum BAs and changes in BAs profile reverse the transplacental BAbile acids gradient and increased inflammatory cytokines like interleukin 4IL4 interleukin 6IL6 interleukin 12 IL12 and tumor necrosis factorTNF cause respiratory distress in infants and preterm delivery Immune response vascular endothelial growth factorVGEFsignaling pathway and G-protein-coupled receptor signaling were the most common regulatory genes responsible for inflammatory response vasculogenesis and angiogenesis all essential in ICP pathogenesis Autotaxin ATX is lysophosphatidic acid LPA essential for angiogenesis and neuronal development during embryogenesis cellular motility proliferation and lymphocyte homing ATX levels are reported to be increased during pregnancy and correlate positively with gestational age LPA and ATX levels were significantly higher in ICP A large prospective study in Sweden revealed severe perinatal outcomes of ICP as spontaneous preterm labor asphyxia events meconium staining of amniotic fluid and placental and membrane changes did not occur until the level of serum bile acid reached40umolL ICP is a pregnancy-related disorder that is expected to resolve after delivery However population-based cohort studies revealed that ICP acts as a risk factor for hepatobiliary disease even after the completion of pregnancy A significant association between hepatitis C virus HCV non-alcoholic liver disease gallstone and cholelithiasis with increased risk of non-alcoholic pancreatitis in women was observed in women with ICP A population-based cohort study with an of 032-058 of ICP in Sweden gives a significant risk association of ICP with gestational diabetes pre-eclampsia and a nonsignificant association with postpartum hemorrhage Total serum bile acids 40mmoll as severe ICP and associated with increased risk of gestational diabetes mellitusGDM pregnancy-induced hypertensionPIH was reported and managed with ursodeoxycholic acid UDCA
Some therapeutic agents such as ursodeoxycholic acidUDCA rifampicin antihistaminic drugs vitamin K and some topical emollients have been used to alleviate nocturnal pruritus pruritus in ICP Some trials related to reducing the adverse perinatal outcome of ICP were done with the administration of UDCA dexamethasone cholestyramine S-adenosyl methionineSAMe plasmapheresis and fish supplements UDCA is currently the most effective therapeutic agent used in clinical practice to manage ICP Several meta-analyses with observational studies or randomized trials have been done on the effectiveness of UDCA but the results are equivocal Dexamethasone rifampicin SAMe and cholestyramine also have some roles in the management of ICP However reducing pruritus and other adverse perinatal outcomes in pregnancy is unclear UDCA was effective in improving clinical presentation normalization of serum profile and a significant reduction in meconium staining spontaneous birth or fetal distress compared to the control placebo group Maternal total serum BAs are significantly associated with reduced infant size and are small for gestational age Since ICP is the most typical pregnancy-related liver disorder has multifactorial risk factors has unclear etiopathogenesis and results in adverse perinatal outcomes Pruritus may considerably impair the patients quality of life as a pregnant woman causing sleep deprivation and psychological suffering Only a few studies have been done in India concerning ICP most of which are related to the reference range of total BAs and the prevalence of ICP There is no Indian data on how ICP affects the quality of life of a pregnant woman or prospective assessment of genetic risk and bile acid metabolism So the aim is to determine the bile acid profile and related metabolites in serum identify prognostic markers of ICP and assess related risk factors including the effect of medication and the quality of life of patients with ICP This research will prospectively evaluate perinatal outcomes and genetic risk factors which have a bearing on neonatal health Keeping in mind the symptoms and severity of pruritus the factors affecting the disease course of pregnant women suffering from ICP will also be evaluated
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None