Placental exosomal level of alanine aminotransferase is more accurate predictive biomarker of intrahepatic cholestasis of pregnancy than total bile acid

  • Sahaya Ravichandran School of Bio Sciences, Kuvempu University, Shimoga, India
  • Rupa Karunanithi School of Bio Sciences, Kuvempu University, Shimoga, India
Keywords: ICP, exosome, TBA, ALT, biomarker, receiver operating characteristic curve analysis


Aims: As a serious liver abnormality, intrahepatic cholestasis of pregnancy (ICP) uniquely occurs in pregnant women. In the present study, we examined whether placental exosomes and their protein contents could serve as novel indicators to help early diagnosis of ICP.

Methods: The current retrospective stratified study design included a 100 healthy pregnant females and a 100 patients with ICP. Plancental exosomes were isolated to determine the exosomal levels of alanine aminotransferase (ALT) and total bile acid (TBA). The predictive values of placental exosomal TBA and ALT were determined using receiver operating characteristic (ROC) curve analysis.

Results: The placental exosomal TBA level did not exhibit any obvious differences between healthy and ICP pregnancies. Moreover, placental exosomal ALT level was significantly higher in ICP-affected pregnancy than healthy control. Analysis of the ROC curve further demonstrated that placental exosomal level of ALT yields better sensitivity and specificity to distinguish ICP patients from healthy individuals, than that of TBA.

Conclusions: Placental exosomal ALT is a more accurate predictive biomarker of ICP than TBA and, therefore, can be employed with reliability as a characteristic abnormality in diagnosis of ICP.


Download data is not yet available.


Geenes V, Williamson C. Intrahepatic cholestasis of pregnancy. World J Gastroenterol 2009; 15(17): 2049–66. doi: 10.3748/wjg.15.2049

Reyes H. Review: intrahepatic cholestasis. A puzzling disorder of pregnancy. J Gastroenterol Hepatol 1997; 12(3): 211–16. doi: 10.1111/j.1440-1746.1997.tb00410.x

Glantz A, Marschall HU, Mattsson LA. Intrahepatic cholestasis of pregnancy: relationships between bile acid levels and fetal complication rates. Hepatology 2004; 40(2): 467–74. doi: 10.1002/hep.20336

Nichols AA. Cholestasis of pregnancy: a review of the evidence. J Perinat Neonatal Nurs 2005; 19(3): 217–25. doi: 10.1097/00005237-200507000-00007

Pusl T, Beuers U. Intrahepatic cholestasis of pregnancy. Orphanet J Rare Dis 2007; 2: 26. doi: 10.1186/1750-1172-2-26

Reyes H, Radrigan ME, Gonzalez MC, Latorre R, Ribalta J, Segovia N, et al. Steatorrhea in patients with intrahepatic cholestasis of pregnancy. Gastroenterology 1987; 93(3): 584–90. doi: 10.1016/0016-5085(87)90922-X

Mullally BA, Hansen WF. Intrahepatic cholestasis of pregnancy: review of the literature. Obstet Gynecol Surv 2002; 57(1): 47–52. doi: 10.1097/00006254-200201000-00023

Ovadia C, Williamson C. Intrahepatic cholestasis of pregnancy: recent advances. Clin Dermatol 2016; 34(3): 327–34. doi: 10.1016/j.clindermatol.2016.02.004

Riely CA, Bacq Y. Intrahepatic cholestasis of pregnancy. Clin Liver Dis 2004; 8(1): 167–76. doi: 10.1016/S1089-3261(03)00131-4

Pathak B, Sheibani L, Lee RH. Cholestasis of pregnancy. Obstet Gynecol Clin North Am 2010; 37(2): 269–82. doi: 10.1016/j.ogc.2010.02.011

Heikkinen J, Maentausta O, Tuimala R, Ylostalo P, Janne O. Amniotic fluid bile acids in normal and pathologic pregnancy. Obstet Gynecol 1980; 56(1): 60–4.

Laatikainen T, Tulenheimo A. Maternal serum bile acid levels and fetal distress in cholestasis of pregnancy. Int J Gynaecol Obstet 1984; 22(2): 91–4. doi: 10.1016/0020-7292(84)90019-5

Rodrigues CM, Marin JJ, Brites D. Bile acid patterns in meconium are influenced by cholestasis of pregnancy and not altered by ursodeoxycholic acid treatment. Gut 1999; 45(3): 446–52. doi: 10.1136/gut.45.3.446

Meng LJ, Reyes H, Axelson M, Palma J, Hernandez I, Ribalta J, et al. Progesterone metabolites and bile acids in serum of patients with intrahepatic cholestasis of pregnancy: effect of ursodeoxycholic acid therapy. Hepatology 1997; 26(6): 1573–9. doi: 10.1002/hep.510260627

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 an high incidence area: Portugal. Eur J Obstet Gynecol Reprod Biol 1998; 80(1): 31–8. doi: 10.1016/S0301-2115(98)00086-4

Mays JK. The active management of intrahepatic cholestasis of pregnancy. Curr Opin Obstet Gynecol 2010; 22(2): 100–3. doi: 10.1097/GCO.0b013e328337238d

Huang WM, Gowda M, Donnelly JG. Bile acid ratio in diagnosis of intrahepatic cholestasis of pregnancy. Am J Perinatol 2009; 26(4): 291–4. doi: 10.1055/s-0028-1103158

Mitchell MD, Peiris HN, Kobayashi M, Koh YQ, Duncombe G, Illanes SE, et al. Placental exosomes in normal and complicated pregnancy. Am J Obstet Gynecol 2015; 213(4 Suppl): S173–81. doi: 10.1016/j.ajog.2015.07.001

Rabinowits G, Gercel-Taylor C, Day JM, Taylor DD, Kloecker GH. Exosomal microRNA: a diagnostic marker for lung cancer. Clin Lung Cancer 2009; 10(1): 42–6. doi: 10.3816/CLC.2009.n.006

Xiao D, Ohlendorf J, Chen Y, Taylor DD, Rai SN, Waigel S, et al. Identifying mRNA, microRNA and protein profiles of melanoma exosomes. PLoS One 2012; 7(10): e46874. doi: 10.1371/journal.pone.0046874

Tan KH, Tan SS, Sze SK, Lee WK, Ng MJ, Lim SK. Plasma biomarker discovery in preeclampsia using a novel differential isolation technology for circulating extracellular vesicles. Am J Obstet Gynecol 2014; 211(4): 380.e1–13. doi: 10.1016/j.ajog.2014.03.038

Pillay P, Maharaj N, Moodley J, Mackraj I. Placental exosomes and pre-eclampsia: maternal circulating levels in normal pregnancies and, early and late onset pre-eclamptic pregnancies. Placenta 2016; 46: 18–25. doi: 10.1016/j.placenta.2016.08.078

Mashige F, Imai K, Osuga T. A simple and sensitive assay of total serum bile acids. Clin Chim Acta 1976; 70(1): 79–86. doi: 10.1016/0009-8981(76)90007-3

Feldmann D, Fenech C, Cuer JF. Evaluation of a sample-preparation procedure for bile acids in serum and bile. Clin Chem 1983; 29(9): 1694. doi: 10.1093/clinchem/29.9.1694a

Ekiz A, Kaya B, Avci ME, Polat I, Dikmen S, Yildirim G. Alanine aminotransferase as a predictor of adverse perinatal outcomes in women with intrahepatic cholestasis of pregnancy. Pak J Med Sci 2016; 32(2): 418–22. doi: 10.12669/pjms.322.9057

Dann AT, Kenyon AP, Seed PT, Poston L, Shennan AH, Tribe RM. Glutathione S-transferase and liver function in intrahepatic cholestasis of pregnancy and pruritus gravidarum. Hepatology 2004; 40(6): 1406–14. doi: 10.1002/hep.20473

Karmen A, Wroblewski F, Ladue JS. Transaminase activity in human blood. J Clin Invest 1955; 34(1): 126–31. doi: 10.1172/JCI103055

Zhang L, Valencia CA, Dong B, Chen M, Guan PJ, Pan L. Transfer of microRNAs by extracellular membrane microvesicles: a nascent crosstalk model in tumor pathogenesis, especially tumor cell-microenvironment interactions. J Hematol Oncol 2015; 8: 14. doi: 10.1186/s13045-015-0111-y

Sabapatha A, Gercel-Taylor C, Taylor DD. Specific isolation of placenta-derived exosomes from the circulation of pregnant women and their immunoregulatory consequences. Am J Reprod Immunol 2006; 56(5–6): 345–55. doi: 10.1111/j.1600-0897.2006.00435.x

Salomon C, Torres MJ, Kobayashi M, Scholz-Romero K, Sobrevia L, Dobierzewska A, et al. A gestational profile of placental exosomes in maternal plasma and their effects on endothelial cell migration. PLoS One 2014; 9(6): e98667. doi: 10.1371/journal.pone.0098667

Sarker S, Scholz-Romero K, Perez A, Illanes SE, Mitchell MD, Rice GE, et al. Placenta-derived exosomes continuously increase in maternal circulation over the first trimester of pregnancy. J Transl Med 2014; 12: 204. doi: 10.1186/1479-5876-12-204

How to Cite
RavichandranS., & KarunanithiR. (2023). Placental exosomal level of alanine aminotransferase is more accurate predictive biomarker of intrahepatic cholestasis of pregnancy than total bile acid. STEMedicine, 4(1), e157.
Research articles