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Immunology of hepatic diseases during pregnancy

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Abstract

The mother’s immune system has to adapt to pregnancy accepting the semi-allograft fetus and preventing harmful effects to the developing child. Aberrations in feto-maternal immune adaptation may result in disease of the mother, such as liver injury. Five pregnancy-associated liver disorders have been described so far, however, little is known concerning immune alterations promoting the respective disease. These liver disorders are pre-eclampsia, hemolysis, elevated liver enzymes, low platelet count (HELLP), acute fatty liver, hyperemesis gravidarum, and intrahepatic cholestasis of pregnancy. On the other hand, pre-existing autoimmune liver injury of the mother can be affected by pregnancy. This review intends to summarize current knowledge linking feto-maternal immunology and liver inflammation with a special emphasis on novel potential biomarkers.

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References

  1. Panther E, Blum HE (2008) Liver diseases in pregnancy. Dtsch Med Wochenschr 133:2283–2287. doi:10.1055/s-0028-1091273

    Article  CAS  PubMed  Google Scholar 

  2. Than NN, Neuberger J (2013) Liver abnormalities in pregnancy. Best Pract Res Clin Gastroenterol 27:565–575. doi:10.1016/j.bpg.2013.06.015

    Article  CAS  PubMed  Google Scholar 

  3. Ch’ng CL, Morgan M, Hainsworth I, Kingham JGC (2002) Prospective study of liver dysfunction in pregnancy in Southwest Wales. Gut 51:876–880

    Article  PubMed  PubMed Central  Google Scholar 

  4. Allen AM, Kim WR, Larson JJ et al (2015) The epidemiology of liver diseases unique to pregnancy in a US community—a population-based study. Clin Gastroenterol Hepatol. doi:10.1016/j.cgh.2015.08.022

    Google Scholar 

  5. Minagawa M, Narita J, Tada T et al (1999) Mechanisms underlying immunologic states during pregnancy: possible association of the sympathetic nervous system. Cell Immunol 196:1–13. doi:10.1006/cimm.1999.1541

    Article  CAS  PubMed  Google Scholar 

  6. Cali U, Cavkaytar S, Sirvan L, Danisman N (2013) Placental apoptosis in preeclampsia, intrauterine growth retardation, and HELLP syndrome: an immunohistochemical study with caspase-3 and bcl-2. Clin Exp Obstet Gynecol 40:45–48

    CAS  PubMed  Google Scholar 

  7. Arck PC, Hecher K (2013) Fetomaternal immune cross-talk and its consequences for maternal and offspring’s health. Nat Med 19:548–556. doi:10.1038/nm.3160

    Article  CAS  PubMed  Google Scholar 

  8. Mor G, Cardenas I (2010) The immune system in pregnancy: a unique complexity. Am J Reprod Immunol N Y N 1989 63:425–433. doi:10.1111/j.1600-0897.2010.00836.x

    CAS  Google Scholar 

  9. Mor G, Cardenas I, Abrahams V, Guller S (2011) Inflammation and pregnancy: the role of the immune system at the implantation site. Ann N Y Acad Sci 1221:80–87. doi:10.1111/j.1749-6632.2010.05938.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Blaschitz A, Hutter H, Dohr G (2001) HLA class I protein expression in the human placenta. Early Pregnancy 5:67–69

    CAS  PubMed  Google Scholar 

  11. Hofmeister V, Weiss EH (2003) HLA-G modulates immune responses by diverse receptor interactions. Semin Cancer Biol 13:317–323

    Article  CAS  PubMed  Google Scholar 

  12. Moffett A, Colucci F (2015) Co-evolution of NK receptors and HLA ligands in humans is driven by reproduction. Immunol Rev 267:283–297. doi:10.1111/imr.12323

    Article  CAS  PubMed  Google Scholar 

  13. Tabiasco J, Rabot M, Aguerre-Girr M et al (2006) Human decidual NK cells: unique phenotype and functional properties—a review. Placenta 27(Suppl A):S34–S39. doi:10.1016/j.placenta.2006.01.009

    Article  PubMed  CAS  Google Scholar 

  14. Kahn DA, Baltimore D (2010) Pregnancy induces a fetal antigen-specific maternal T regulatory cell response that contributes to tolerance. Proc Natl Acad Sci U S A 107:9299–9304. doi:10.1073/pnas.1003909107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Munoz-Suano A, Kallikourdis M, Sarris M et al (2012) A regulatory T cells protect from autoimmune arthritis during pregnancy. J Autoimmun 38:2–3. doi:10.1016/j.jaut.2011.09.007

  16. Wafula PO, Teles A, Schumacher A et al (2009) PD-1 but not CTLA-4 blockage abrogates the protective effect of regulatory T cells in a pregnancy murine model. Am J Reprod Immunol N Y N 1989 62:283–292. doi:10.1111/j.1600-0897.2009.00737.x

    CAS  Google Scholar 

  17. Habicht A, Dada S, Jurewicz M et al (2007) A link between PDL1 and T regulatory cells in fetomaternal tolerance. J Immunol Baltim Md 1950 179:5211–5219

    CAS  Google Scholar 

  18. Blois SM, Ilarregui JM, Tometten M et al (2007) A pivotal role for galectin-1 in fetomaternal tolerance. Nat Med 13:1450–1457. doi:10.1038/nm1680

    Article  CAS  PubMed  Google Scholar 

  19. Crispe IN (2009) The liver as a lymphoid organ. Annu Rev Immunol 27:147–163. doi:10.1146/annurev.immunol.021908.132629

    Article  CAS  PubMed  Google Scholar 

  20. Thomson AW, Knolle PA (2010) Antigen-presenting cell function in the tolerogenic liver environment. Nat Rev Immunol 10:753–766. doi:10.1038/nri2858

    Article  CAS  PubMed  Google Scholar 

  21. Tiegs G, Lohse AW (2010) Immune tolerance: what is unique about the liver. J Autoimmun 34:1–6. doi:10.1016/j.jaut.2009.08.008

    Article  CAS  PubMed  Google Scholar 

  22. Horst AK, Neumann K, Diehl L, Tiegs G (2016) Modulation of liver tolerance by conventional and nonconventional antigen-presenting cells and regulatory immune cells. Cell Mol Immunol. doi:10.1038/cmi.2015.112

    PubMed  PubMed Central  Google Scholar 

  23. Calne RY, Sells RA, Pena JR et al (1969) Induction of immunological tolerance by porcine liver allografts. Nature 223:472–476

    Article  CAS  PubMed  Google Scholar 

  24. Burghardt S, Erhardt A, Claass B et al (2013) Hepatocytes contribute to immune regulation in the liver by activation of the Notch signaling pathway in T cells. J Immunol Baltim Md 1950 191:5574–5582. doi:10.4049/jimmunol.1300826

    CAS  Google Scholar 

  25. Burghardt S, Claass B, Erhardt A et al (2014) Hepatocytes induce Foxp3+ regulatory T cells by Notch signaling. J Leukoc Biol 96:571–577. doi:10.1189/jlb.2AB0613-342RR

    Article  PubMed  CAS  Google Scholar 

  26. Warren A, Le Couteur DG, Fraser R et al (2006) T lymphocytes interact with hepatocytes through fenestrations in murine liver sinusoidal endothelial cells. Hepatol Baltim Md 44:1182–1190. doi:10.1002/hep.21378

    Article  CAS  Google Scholar 

  27. Amiot L, Vu N, Samson M (2015) Biology of the immunomodulatory molecule HLA-G in human liver diseases. J Hepatol 62:1430–1437. doi:10.1016/j.jhep.2015.03.007

    Article  CAS  PubMed  Google Scholar 

  28. Wright GJ, Jones M, Puklavec MJ et al (2001) The unusual distribution of the neuronal/lymphoid cell surface CD200 (OX2) glycoprotein is conserved in humans. Immunology 102:173–179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gorczynski RM (2001) Evidence for an immunoregulatory role of OX2 with its counter ligand (OX2L) in the regulation of transplant rejection, fetal loss, autoimmunity and tumor growth. Arch Immunol Ther Exp (Warsz) 49:303–309

    CAS  Google Scholar 

  30. Gorczynski RM, Cohen Z, Fu XM, Lei J (1999) Anti-rat OX-2 blocks increased small intestinal transplant survival after portal vein immunization. Transplant Proc 31:577–578

    Article  CAS  PubMed  Google Scholar 

  31. Gorczynski RM, Chen Z, Hoang Y, Rossi-Bergman B (1996) A subset of gamma delta T-cell receptor-positive cells produce T-helper type-2 cytokines and regulate mouse skin graft rejection following portal venous pretransplant preimmunization. Immunology 87:381–389

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gorczynski RM, Yu K, Clark D (2000) Receptor engagement on cells expressing a ligand for the tolerance-inducing molecule OX2 induces an immunoregulatory population that inhibits alloreactivity in vitro and in vivo. J Immunol Baltim Md 1950 165:4854–4860

    CAS  Google Scholar 

  33. Clark DA, Ding JW, Yu G et al (2001) Fgl2 prothrombinase expression in mouse trophoblast and decidua triggers abortion but may be countered by OX-2. Mol Hum Reprod 7:185–194

    Article  CAS  PubMed  Google Scholar 

  34. Marsden PA, Ning Q, Fung LS et al (2003) The Fgl2/fibroleukin prothrombinase contributes to immunologically mediated thrombosis in experimental and human viral hepatitis. J Clin Invest 112:58–66. doi:10.1172/JCI18114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Karimi K, Keßler T, Thiele K et al (2015) Prenatal acetaminophen induces liver toxicity in dams, reduces fetal liver stem cells, and increases airway inflammation in adult offspring. J Hepatol 62:1085–1091. doi:10.1016/j.jhep.2014.12.020

    Article  CAS  PubMed  Google Scholar 

  36. Thiele K, Solano ME, Huber S et al (2015) Prenatal acetaminophen affects maternal immune and endocrine adaptation to pregnancy, induces placental damage, and impairs fetal development in mice. Am J Pathol. doi:10.1016/j.ajpath.2015.06.019

    PubMed  Google Scholar 

  37. Schramm C, Herkel J, Beuers U et al (2006) Pregnancy in autoimmune hepatitis: outcome and risk factors. Am J Gastroenterol 101:556–560. doi:10.1111/j.1572-0241.2006.00479.x

    Article  CAS  PubMed  Google Scholar 

  38. Jamjute P, Ahmad A, Ghosh T, Banfield P (2009) Liver function test and pregnancy. J Matern Fetal Neonatal Med 22:274–283. doi:10.1080/14767050802211929

    Article  CAS  PubMed  Google Scholar 

  39. Ahlfeld F (1883) Berichte und Arbeiten aus der geburtshilflich-gynaekologischen Klinik zu Giessen 1881-1882. Grunow FW

  40. Kreek MJ (1987) Female sex steroids and cholestasis. Semin Liver Dis 7:8–23. doi:10.1055/s-2008-1040559

    Article  CAS  PubMed  Google Scholar 

  41. Lammert F, Marschall HU, Glantz A, Matern S (2000) Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management. J Hepatol 33:1012–1021

    Article  CAS  PubMed  Google Scholar 

  42. Wasmuth HE, Glantz A, Keppeler H et al (2007) Intrahepatic cholestasis of pregnancy: the severe form is associated with common variants of the hepatobiliary phospholipid transporter ABCB4 gene. Gut 56:265–270. doi:10.1136/gut.2006.092742

    Article  CAS  PubMed  Google Scholar 

  43. Bull LN, Hu D, Shah S et al (2015) Intrahepatic cholestasis of pregnancy (ICP) in U.S. Latinas and Chileans: clinical features, ancestry analysis, and admixture mapping. PLoS One 10:e0131211–e0131211. doi:10.1371/journal.pone.0131211

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Martineau MG, Raker C, Dixon PH et al (2015) The metabolic profile of intrahepatic cholestasis of pregnancy is associated with impaired glucose tolerance, dyslipidemia, and increased fetal growth. Diabetes Care 38:243–248. doi:10.2337/dc14-2143

    Article  PubMed  Google Scholar 

  45. Elferink RO (2003) Cholestasis. Gut 52(Suppl 2):ii42–ii48

    PubMed  PubMed Central  Google Scholar 

  46. Maringhini A, Ciambra M, Baccelliere P et al (1993) Biliary sludge and gallstones in pregnancy: incidence, risk factors, and natural history. Ann Intern Med 119:116–120

    Article  CAS  PubMed  Google Scholar 

  47. Lammert F, Hochrath K (2015) A letter on ABCB4 from Iceland: on the highway to liver disease. Clin Res Hepatol Gastroenterol 39:655–658. doi:10.1016/j.clinre.2015.08.004

    Article  CAS  PubMed  Google Scholar 

  48. Poupon R (2005) Intrahepatic cholestasis of pregnancy: from bedside to bench to bedside. Liver Int 25:467–468. doi:10.1111/j.1478-3231.2005.01000.x

    Article  PubMed  Google Scholar 

  49. Dixon PH, Weerasekera N, Linton KJ et al (2000) Heterozygous MDR3 missense mutation associated with intrahepatic cholestasis of pregnancy: evidence for a defect in protein trafficking. Hum Mol Genet 9:1209–1217

    Article  CAS  PubMed  Google Scholar 

  50. Schneider G, Paus TC, Kullak-Ublick GA et al (2007) Linkage between a new splicing site mutation in the MDR3 alias ABCB4 gene and intrahepatic cholestasis of pregnancy. Hepatology 45:150–158. doi:10.1002/hep.21500

    Article  CAS  PubMed  Google Scholar 

  51. Johnston RC, Stephenson ML, Nageotte MP (2014) Novel heterozygous ABCB4 gene mutation causing recurrent first-trimester intrahepatic cholestasis of pregnancy. J Perinatol 34:711–712. doi:10.1038/jp.2014.86

    Article  CAS  PubMed  Google Scholar 

  52. Estiú MC, Monte MJ, Rivas L et al (2015) Effect of ursodeoxycholic acid treatment on the altered progesterone and bile acid homeostasis in the mother-placenta-foetus trio during cholestasis of pregnancy. Br J Clin Pharmacol 79:316–329. doi:10.1111/bcp.12480

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Arrese M, Macias RIR, Briz O et al (2008) Molecular pathogenesis of intrahepatic cholestasis of pregnancy. Expert Rev Mol Med 10:e9–e9. doi:10.1017/S1462399408000628

    Article  PubMed  Google Scholar 

  54. Du Q, Pan Y, Zhang Y et al (2014) Placental gene-expression profiles of intrahepatic cholestasis of pregnancy reveal involvement of multiple molecular pathways in blood vessel formation and inflammation. BMC Med Genomics 7:42–42. doi:10.1186/1755-8794-7-42

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Dixon PH, Williamson C (2016) The pathophysiology of intrahepatic cholestasis of pregnancy. Clin Res Hepatol Gastroenterol. doi:10.1016/j.clinre.2015.12.008

    PubMed  Google Scholar 

  56. Zhang R, Pan X-H, Xiao L (2015) Expression of vascular endothelial growth factor (VEGF) under hypoxia in placenta with intrahepatic cholestasis of pregnancy and its clinically pathological significance. Int J Clin Exp Pathol 8:11475–11479

    PubMed  PubMed Central  Google Scholar 

  57. Chen Y, Vasilenko A, Song X et al (2015) Estrogen and estrogen receptor-α-mediated transrepression of bile salt export pump. Mol Endocrinol 29:613–626. doi:10.1210/me.2015-1014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Keitel V, Vogt C, Häussinger D, Kubitz R (2006) Combined mutations of canalicular transporter proteins cause severe intrahepatic cholestasis of pregnancy. Gastroenterology 131:624–629. doi:10.1053/j.gastro.2006.05.003

    Article  CAS  PubMed  Google Scholar 

  59. Floreani A, Carderi I, Paternoster D et al (2008) Hepatobiliary phospholipid transporter ABCB4, MDR3 gene variants in a large cohort of Italian women with intrahepatic cholestasis of pregnancy. Dig Liver Dis 40:366–370. doi:10.1016/j.dld.2007.10.016

    Article  CAS  PubMed  Google Scholar 

  60. Hunt JS, Petroff MG, McIntire RH, Ober C (2005) HLA-G and immune tolerance in pregnancy. FASEB J Off Publ Fed Am Soc Exp Biol 19:681–693. doi:10.1096/fj.04-2078rev

    CAS  Google Scholar 

  61. Ober C, Aldrich C, Rosinsky B, Robertson A, Walker MA, Willadsen S, Verp MS, Geraghty DE, Hunt JS (1998) HLA-G1 protein expression is not essential for fetal survival. Placenta 19(2–3):127–132

  62. Zhang X, Yu L, Ding Y (2014) Human leukocyte antigen G and miR-148a are associated with the pathogenesis of intrahepatic cholestasis of pregnancy. Exp Ther Med 8:1701–1706. doi:10.3892/etm.2014.1986

    PubMed  PubMed Central  Google Scholar 

  63. Tang Y, Liu H, Li H et al (2015) Hypermethylation of the HLA-G promoter is associated with preeclampsia. Mol Hum Reprod 21:736–744. doi:10.1093/molehr/gav037

    Article  PubMed  Google Scholar 

  64. Larson SP, Kovilam O, Agrawal DK (2015) Immunological basis in the pathogenesis of intrahepatic cholestasis of pregnancy. Expert Rev Clin Immunol 1–10. doi: 10.1586/1744666X.2016.1101344

  65. Oztas E, Ozler S, Ersoy AO et al (2015) Placental ADAMTS-12 levels in the pathogenesis of preeclampsia and intrahepatic cholestasis of pregnancy. Reprod Sci. doi:10.1177/1933719115604730

    Google Scholar 

  66. Zhang Y, Hu L, Cui Y et al (2014) Roles of PPARγ/NF-kB signaling pathway in the pathogenesis of intrahepatic cholestasis of pregnancy. PLoS One 9:e87343–e87343. doi:10.1371/journal.pone.0087343

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Kirbas A, Biberoglu E, Ersoy AO et al (2015) The role of interleukin-17 in intrahepatic cholestasis of pregnancy. J Matern Fetal Neonatal Med 1–5. doi: 10.3109/14767058.2015.1028354

  68. Yayi H, Danqing W, Shuyun L, Jicheng L (2010) Immunologic abnormality of intrahepatic cholestasis of pregnancy. Am J Reprod Immunol 63:267–273. doi:10.1111/j.1600-0897.2009.00798.x

    Article  PubMed  CAS  Google Scholar 

  69. Kirbas A, Biberoglu E, Daglar K et al (2014) Neutrophil-to-lymphocyte ratio as a diagnostic marker of intrahepatic cholestasis of pregnancy. Eur J Obstet Gynecol Reprod Biol 180:12–15. doi:10.1016/j.ejogrb.2014.05.042

    Article  PubMed  Google Scholar 

  70. Du Q, Zhou L, Hao K et al (2013) Study on the regulation of cell adhesion molecule expression and function in placenta from women with intrahepatic cholestasis of pregnancy. Med Hypotheses 81:374–375. doi:10.1016/j.mehy.2013.05.018

    Article  CAS  PubMed  Google Scholar 

  71. Manolio TA, Burke GL, Savage PJ et al (1992) Sex- and race-related differences in liver-associated serum chemistry tests in young adults in the CARDIA study. Clin Chem 38:1853–1859

    CAS  PubMed  Google Scholar 

  72. Kremer AE, Bolier R, Dixon PH et al (2015) Autotaxin activity has a high accuracy to diagnose intrahepatic cholestasis of pregnancy. J Hepatol 62:897–904. doi:10.1016/j.jhep.2014.10.041

    Article  CAS  PubMed  Google Scholar 

  73. Abu-Hayyeh S, Ovadia C, Lieu T et al (2015) Prognostic and mechanistic potential of progesterone sulfates in intrahepatic cholestasis of pregnancy and pruritus gravidarum. Hepatology. doi:10.1002/hep.28265

    PubMed  PubMed Central  Google Scholar 

  74. Ersoy AO, Kirbas A, Ozler S et al (2015) Maternal and fetal serum levels of caspase-cleaved fragments of cytokeratin-18 in intrahepatic cholestasis of pregnancy. J Matern Fetal Neonatal Med 29(4):562–566. doi:10.3109/14767058.2015.1011116

    Article  PubMed  CAS  Google Scholar 

  75. Lammert F, Marschall H-U, Matern S (2003) Intrahepatic cholestasis of pregnancy. Curr Treat Options Gastroenterol 6:123–132

    Article  PubMed  Google Scholar 

  76. Marschall H-U (2015) Management of intrahepatic cholestasis of pregnancy. Expert Rev Gastroenterol Hepatol 9:1273–1279. doi:10.1586/17474124.2015.1083857

    Article  CAS  PubMed  Google Scholar 

  77. Carey EJ, White P (2013) Ursodeoxycholic acid for intrahepatic cholestasis of pregnancy: good for the mother, not bad for the baby. Evid Based Med 18:e55–e55. doi:10.1136/eb-2013-101298

    Article  PubMed  Google Scholar 

  78. Geenes V, Chambers J, Khurana R et al (2015) Rifampicin in the treatment of severe intrahepatic cholestasis of pregnancy. Eur J Obstet Gynecol Reprod Biol 189:59–63. doi:10.1016/j.ejogrb.2015.03.020

    Article  CAS  PubMed  Google Scholar 

  79. Zhang L, Liu X-H, Qi H-B et al (2015) Ursodeoxycholic acid and S-adenosylmethionine in the treatment of intrahepatic cholestasis of pregnancy: a multi-centered randomized controlled trial. Eur Rev Med Pharmacol Sci 19:3770–3776

    CAS  PubMed  Google Scholar 

  80. Friberg AK, Zingmark V, Lyndrup J (2016) Early induction of labor in high-risk intrahepatic cholestasis of pregnancy: what are the costs? Arch Gynecol Obstet. doi:10.1007/s00404-016-4019-8

    PubMed  Google Scholar 

  81. Bacq Y, Sapey T, Bréchot MC et al (1997) Intrahepatic cholestasis of pregnancy: a French prospective study. Hepatology 26:358–364. doi:10.1002/hep.510260216

    Article  CAS  PubMed  Google Scholar 

  82. Wikström Shemer EA, Stephansson O, Thuresson M et al (2015) Intrahepatic cholestasis of pregnancy and cancer, immune-mediated and cardiovascular diseases: a population-based cohort study. J Hepatol 63:456–461. doi:10.1016/j.jhep.2015.03.010

    Article  PubMed  CAS  Google Scholar 

  83. Tranquilli AL, Dekker G, Magee L et al (2014) The classification, diagnosis and management of the hypertensive disorders of pregnancy: a revised statement from the ISSHP. Pregnancy Hypertens 4:97–104. doi:10.1016/j.preghy.2014.02.001

    CAS  PubMed  Google Scholar 

  84. Purde M-T, Baumann M, Wiedemann U et al (2015) Incidence of preeclampsia in pregnant Swiss women. Swiss Med Wkly 145:w14175–w14175. doi:10.4414/smw.2015.14175

    PubMed  Google Scholar 

  85. Moffett A, Loke C (2006) Immunology of placentation in eutherian mammals. Nat Rev Immunol 6:584–594. doi:10.1038/nri1897

    Article  CAS  PubMed  Google Scholar 

  86. Smith SD, Dunk CE, Aplin JD et al (2009) Evidence for immune cell involvement in decidual spiral arteriole remodeling in early human pregnancy. Am J Pathol 174:1959–1971. doi:10.2353/ajpath.2009.080995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Ashkar AA, Di Santo JP, Croy BA (2000) Interferon gamma contributes to initiation of uterine vascular modification, decidual integrity, and uterine natural killer cell maturation during normal murine pregnancy. J Exp Med 192:259–270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Zhao H, Ozen M, Wong RJ, Stevenson DK (2014) Heme oxygenase-1 in pregnancy and cancer: similarities in cellular invasion, cytoprotection, angiogenesis, and immunomodulation. Front Pharmacol 5:295–295. doi:10.3389/fphar.2014.00295

    Article  PubMed  CAS  Google Scholar 

  89. Bueno-Sánchez JC, Agudelo-Jaramillo B, Escobar-Aguilerae LF et al (2013) Cytokine production by non-stimulated peripheral blood NK cells and lymphocytes in early-onset severe pre-eclampsia without HELLP. J Reprod Immunol 97:223–231. doi:10.1016/j.jri.2012.11.007

    Article  PubMed  CAS  Google Scholar 

  90. Ning F, Liu H, Lash GE (2016) The role of decidual macrophages during normal and pathological pregnancy. Am J Reprod Immunol. doi:10.1111/aji.12477

    PubMed  Google Scholar 

  91. James JL, Whitley GS, Cartwright JE (2010) Pre-eclampsia: fitting together the placental, immune and cardiovascular pieces. J Pathol 221:363–378. doi:10.1002/path.2719

    Article  CAS  PubMed  Google Scholar 

  92. Reister F, Frank HG, Heyl W et al (1999) The distribution of macrophages in spiral arteries of the placental bed in pre-eclampsia differs from that in healthy patients. Placenta 20:229–233. doi:10.1053/plac.1998.0373

    Article  CAS  PubMed  Google Scholar 

  93. Martin E, Ray PD, Smeester L et al (2015) Epigenetics and preeclampsia: defining functional epimutations in the preeclamptic placenta related to the TGF-beta pathway. PLoS One 10:e0141294–e0141294. doi:10.1371/journal.pone.0141294

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Khani M, Amani D, Taheripanah R et al (2015) Transforming growth factor beta-1 (TGF-β1) gene single nucleotide polymorphisms (SNPs) and susceptibility to pre-eclampsia in Iranian women: a case-control study. Pregnancy Hypertens 5:267–272. doi:10.1016/j.preghy.2015.01.002

    PubMed  Google Scholar 

  95. Eda Gökdemir I, Özdeğirmenci Ö, Elmas B et al (2015) Evaluation of ADAMTS12, ADAMTS16, ADAMTS18 and IL-33 serum levels in pre-eclampsia. J Matern Fetal Neonatal Med 29(15):2450–2455. doi:10.3109/14767058.2015.1087497

    Google Scholar 

  96. Cheng S-B, Nakashima A, Sharma S (2015) Understanding pre-eclampsia using Alzheimer’s etiology: an intriguing viewpoint. Am J Reprod Immunol. doi:10.1111/aji.12446

    Google Scholar 

  97. Southcombe JH, Redman CWG, Sargent IL, Granne I (2015) Interleukin-1 family cytokines and their regulatory proteins in normal pregnancy and pre-eclampsia. Clin Exp Immunol 181:480–490. doi:10.1111/cei.12608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Boraschi D, Lucchesi D, Hainzl S et al (2011) IL-37: a new anti-inflammatory cytokine of the IL-1 family. Eur Cytokine Netw 22:127–147. doi:10.1684/ecn.2011.0288

    CAS  PubMed  Google Scholar 

  99. Barnie PA, Lin X, Liu Y et al (2015) IL-17 producing innate lymphoid cells 3 (ILC3) but not Th17 cells might be the potential danger factor for preeclampsia and other pregnancy associated diseases. Int J Clin Exp Pathol 8:11100–11107

    PubMed  PubMed Central  Google Scholar 

  100. Guillemette L, Lacroix M, Allard C et al (2015) Preeclampsia is associated with an increased pro-inflammatory profile in newborns. J Reprod Immunol 112:111–114. doi:10.1016/j.jri.2015.09.003

    Article  CAS  PubMed  Google Scholar 

  101. Zhao J, Zheng D-Y, Yang J-M et al (2015) Maternal serum uric acid concentration is associated with the expression of tumour necrosis factor-α and intercellular adhesion molecule-1 in patients with preeclampsia. J Hum Hypertens. doi:10.1038/jhh.2015.110

    PubMed Central  Google Scholar 

  102. Collins T, Read MA, Neish AS et al (1995) Transcriptional regulation of endothelial cell adhesion molecules: NF-kappa B and cytokine-inducible enhancers. FASEB J Off Publ Fed Am Soc Exp Biol 9:899–909

    CAS  Google Scholar 

  103. Tsukimori K, Tsushima A, Fukushima K et al (2008) Neutrophil-derived reactive oxygen species can modulate neutrophil adhesion to endothelial cells in preeclampsia. Am J Hypertens 21:587–591. doi:10.1038/ajh.2007.87

    Article  CAS  PubMed  Google Scholar 

  104. Estensen M-E, Grindheim G, Remme EW et al (2015) Elevated inflammatory markers in preeclamptic pregnancies, but no relation to systemic arterial stiffness. Pregnancy Hypertens 5:325–329. doi:10.1016/j.preghy.2015.09.003

    PubMed  Google Scholar 

  105. Onuegbu AJ, Olisekodiaka JM, Udo JU et al (2015) Evaluation of high-sensitivity C-reactive protein and serum lipid profile in southeastern Nigerian women with pre-eclampsia. Med Princ Pract 24:276–279. doi:10.1159/000381778

    Article  PubMed  Google Scholar 

  106. Harmon AC, Cornelius DC, Amaral LM et al (2016) The role of inflammation in the pathology of preeclampsia. Clin Sci Lond Engl 1979 130:409–419. doi:10.1042/CS20150702

    Google Scholar 

  107. Rahimzadeh M, Norouzian M, Arabpour F, Naderi N (2016) Regulatory T-cells and preeclampsia: an overview of literature. Expert Rev Clin Immunol 12:209–227. doi:10.1586/1744666X.2016.1105740

    Article  CAS  PubMed  Google Scholar 

  108. Nagayama S, Ohkuchi A, Shirasuna K et al (2015) The frequency of peripheral blood CD4(+)FoxP3(+) regulatory T cells in women with pre-eclampsia and those with high-risk factors for pre-eclampsia. Hypertens Pregnancy 1–13. doi: 10.3109/10641955.2015.1065884

  109. Liu X, Deng Q, Luo X et al (2016) Oxidative stress-induced Gadd45α inhibits trophoblast invasion and increases sFlt1/sEng secretions via p38 MAPK involving in the pathology of pre-eclampsia. J Matern-Fetal Neonatal Med Off J Eur Assoc Perinat Med Fed Asia Ocean Perinat Soc Int Soc Perinat Obstet 3:1–10. doi:10.3109/14767058.2016.1144744

    Google Scholar 

  110. Szalai G, Romero R, Chaiworapongsa T et al (2015) Full-length human placental sFlt-1-e15a isoform induces distinct maternal phenotypes of preeclampsia in mice. PLoS One 10:e0119547. doi:10.1371/journal.pone.0119547

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Turpin CA, Sakyi SA, Owiredu WKBA et al (2015) Association between adverse pregnancy outcome and imbalance in angiogenic regulators and oxidative stress biomarkers in gestational hypertension and preeclampsia. BMC Pregnancy Childbirth 15:189. doi:10.1186/s12884-015-0624-y

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Sandrim VC, Luizon MR, Palei AC et al (2016) Circulating microRNA expression profiles in pre-eclampsia: evidence of increased miR-885-5p levels. BJOG. doi:10.1111/1471-0528.13903

    PubMed  Google Scholar 

  113. Fisher SJ (2015) Why is placentation abnormal in preeclampsia? Am J Obstet Gynecol 213:S115–S122. doi:10.1016/j.ajog.2015.08.042

    Article  PubMed  PubMed Central  Google Scholar 

  114. Honigberg MC, Cantonwine DE, Thomas AM et al (2015) Analysis of changes in maternal circulating angiogenic factors throughout pregnancy for the prediction of preeclampsia. J Perinatol. doi:10.1038/jp.2015.170

    PubMed  Google Scholar 

  115. Tsiakkas A, Cazacu R, Wright A et al (2015) Serum placental growth factor at 12, 22, 32 and 36 weeks’ gestation in screening for preeclampsia. Ultrasound Obstet Gynecol. doi:10.1002/uog.15816

    Google Scholar 

  116. Moore GS, Allshouse AA, Winn VD et al (2015) Baseline placental growth factor levels for the prediction of benefit from early aspirin prophylaxis for preeclampsia prevention. Pregnancy Hypertens 5:280–286. doi:10.1016/j.preghy.2015.06.001

    PubMed  PubMed Central  Google Scholar 

  117. Litwinska E, Litwinska M, Oszukowski P et al (2015) Biochemical markers in screening for preeclampsia and intrauterine growth restriction. Ginekol Pol 86:611–615

    Article  PubMed  Google Scholar 

  118. Zeisler H, Llurba E, Chantraine F et al (2016) Predictive value of the sFlt-1:PlGF ratio in women with suspected preeclampsia. N Engl J Med 374:13–22. doi:10.1056/NEJMoa1414838

    Article  CAS  PubMed  Google Scholar 

  119. Kramer AW, Lamale-Smith LM, Winn VD (2016) Differential expression of human placental PAPP-A2 over gestation and in preeclampsia. Placenta 37:19–25. doi:10.1016/j.placenta.2015.11.004

    Article  CAS  PubMed  Google Scholar 

  120. Nikolic A, Cabarkapa V, Novakov Mikic A et al (2015) Ceruloplasmin and antioxidative enzymes in pre-eclampsia. J Matern Fetal Neonatal Med 1–19. doi: 10.3109/14767058.2015.1111333

  121. Korkmaz V, Kurdoglu Z, Alısık M et al (2016) Impairment of thiol disulphide homeostasis in preeclampsia. J Matern Fetal Neonatal Med 1–18. doi: 10.3109/14767058.2016.1149561

  122. Mei-Dan E, Wiznitzer A, Sergienko R et al (2013) Prediction of preeclampsia: liver function tests during the first 20 gestational weeks. J Matern-Fetal Neonatal Med Off J Eur Assoc Perinat Med Fed Asia Ocean Perinat Soc Int Soc Perinat Obstet 26:250–253. doi:10.3109/14767058.2012.733771

    CAS  Google Scholar 

  123. Redman CWG (2011) Preeclampsia: a multi-stress disorder. Rev Med Interne 32(Suppl 1):S41–S44. doi:10.1016/j.revmed.2011.03.331

    Article  PubMed  Google Scholar 

  124. Lefkou E, Mamopoulos A, Fragakis N et al (2014) Clinical improvement and successful pregnancy in a preeclamptic patient with antiphospholipid syndrome treated with pravastatin. Hypertension 63:e118–e119. doi:10.1161/HYPERTENSIONAHA.114.03115

    Article  CAS  PubMed  Google Scholar 

  125. Pratt JJ, Niedle PS, Vogel JP et al (2015) Alternative regimens of magnesium sulfate for treatment of pre-eclampsia and eclampsia: a systematic review of non-randomized studies. Acta Obstet Gynecol Scand. doi:10.1111/aogs.12807

    PubMed  Google Scholar 

  126. Ueda A, Kondoh E, Kawasaki K et al (2015) Magnesium sulphate can prolong pregnancy in patients with severe early-onset preeclampsia. J Matern Fetal Neonatal Med 1–22. doi: 10.3109/14767058.2015.1114091

  127. Mackillop L (2015) Pre-eclampsia: reducing the risk with calcium supplements. BMJ Clin Evid 2015

  128. Martinussen MP, Bracken MB, Triche EW et al (2015) Folic acid supplementation in early pregnancy and the risk of preeclampsia, small for gestational age offspring and preterm delivery. Eur J Obstet Gynecol Reprod Biol 195:94–99. doi:10.1016/j.ejogrb.2015.09.022

    Article  CAS  PubMed  Google Scholar 

  129. Bakacak M, Serin S, Ercan O et al (2015) Comparison of vitamin D levels in cases with preeclampsia, eclampsia and healthy pregnant women. Int J Clin Exp Med 8:16280–16286

    PubMed  PubMed Central  Google Scholar 

  130. Marseglia L, D’Angelo G, Manti S et al (2015) Potential utility of melatonin in preeclampsia, intrauterine fetal growth retardation, and perinatal asphyxia. Reprod Sci. doi:10.1177/1933719115612132

    PubMed  Google Scholar 

  131. Klockenbusch W, Rath W (2002) Prevention of pre-eclampsia by low-dose acetylsalicylic acid—a critical appraisal. Z Für Geburtshilfe Neonatol 206:125–130. doi:10.1055/s-2002-33667

    Article  CAS  Google Scholar 

  132. Shinar S, Asher-Landsberg J, Schwartz A et al (2015) Isolated proteinuria is a risk factor for pre-eclampsia: a retrospective analysis of the maternal and neonatal outcomes in women presenting with isolated gestational proteinuria. J Perinatol. doi:10.1038/jp.2015.138

    PubMed  Google Scholar 

  133. Hromadnikova I, Kotlabova K, Hympanova L, Krofta L (2015) Gestational hypertension, preeclampsia and intrauterine growth restriction induce dysregulation of cardiovascular and cerebrovascular disease associated microRNAs in maternal whole peripheral blood. Thromb Res. doi:10.1016/j.thromres.2015.11.032

    PubMed  Google Scholar 

  134. Weinstein L (1982) Syndrome of hemolysis, elevated liver enzymes, and low platelet count: a severe consequence of hypertension in pregnancy 1982. Am J Obstet Gynecol 142:159–167. doi:10.1016/j.ajog.2005.02.113

    CAS  PubMed  Google Scholar 

  135. Erkurt MA, Berber I, Berktas HB et al (2015) A life-saving therapy in class I HELLP syndrome: therapeutic plasma exchange. Transfus Apher Sci 52:194–198. doi:10.1016/j.transci.2014.12.026

    Article  PubMed  Google Scholar 

  136. Reddy A, Zhong XY, Rusterholz C et al (2008) The effect of labour and placental separation on the shedding of syncytiotrophoblast microparticles, cell-free DNA and mRNA in normal pregnancy and pre-eclampsia. Placenta 29:942–949. doi:10.1016/j.placenta.2008.08.018

    Article  CAS  PubMed  Google Scholar 

  137. Sibai BM, Ramadan MK, Usta I et al (1993) Maternal morbidity and mortality in 442 pregnancies with hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome). Am J Obstet Gynecol 169:1000–1006

    Article  CAS  PubMed  Google Scholar 

  138. Sibai BM, Ramadan MK, Chari RS, Friedman SA (1995) Pregnancies complicated by HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets): subsequent pregnancy outcome and long-term prognosis. Am J Obstet Gynecol 172:125–129

    Article  CAS  PubMed  Google Scholar 

  139. Mills AT, Davidson ME, Young P (2014) Concealed paracetamol overdose treated as HELLP syndrome in the presence of postpartum liver dysfunction. Int J Obstet Anesth 23:189–193. doi:10.1016/j.ijoa.2014.01.006

    Article  CAS  PubMed  Google Scholar 

  140. van der Post JAM, Lok CAR, Boer K et al (2011) The functions of microparticles in pre-eclampsia. Semin Thromb Hemost 37:146–152. doi:10.1055/s-0030-1270342

    Article  PubMed  CAS  Google Scholar 

  141. Gardiner C, Tannetta DS, Simms CA et al (2011) Syncytiotrophoblast microvesicles released from pre-eclampsia placentae exhibit increased tissue factor activity. PLoS One 6:e26313. doi:10.1371/journal.pone.0026313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Abildgaard U, Heimdal K (2013) Pathogenesis of the syndrome of hemolysis, elevated liver enzymes, and low platelet count (HELLP): a review. Eur J Obstet Gynecol Reprod Biol 166:117–123. doi:10.1016/j.ejogrb.2012.09.026

    Article  CAS  PubMed  Google Scholar 

  143. Fang CJ, Richards A, Liszewski MK et al (2008) Advances in understanding of pathogenesis of aHUS and HELLP. Br J Haematol 143:336–348. doi:10.1111/j.1365-2141.2008.07324.x

    Article  CAS  PubMed  Google Scholar 

  144. Strand S, Strand D, Seufert R et al (2004) Placenta-derived CD95 ligand causes liver damage in hemolysis, elevated liver enzymes, and low platelet count syndrome. Gastroenterology 126:849–858

    Article  CAS  PubMed  Google Scholar 

  145. Prusac IK, Zekic Tomas S, Roje D (2011) Apoptosis, proliferation and Fas ligand expression in placental trophoblast from pregnancies complicated by HELLP syndrome or pre-eclampsia. Acta Obstet Gynecol Scand 90:1157–1163. doi:10.1111/j.1600-0412.2011.01152.x

    Article  CAS  PubMed  Google Scholar 

  146. van Runnard Heimel PJ, Kavelaars A, Heijnen CJ et al (2008) HELLP syndrome is associated with an increased inflammatory response, which may be inhibited by administration of prednisolone. Hypertens Pregnancy 27:253–265. doi:10.1080/10641950802174953

    Article  PubMed  CAS  Google Scholar 

  147. Azzam HAG, Abousamra NK, Goda H et al (2013) The expression and concentration of CD40 ligand in normal pregnancy, preeclampsia, and hemolytic anemia, elevated liver enzymes and low platelet count (HELLP) syndrome. Blood Coagul Fibrinolysis 24:71–75. doi:10.1097/MBC.0b013e32835a8aca

    Article  CAS  PubMed  Google Scholar 

  148. Karakus S, Bozoklu Akkar O, Yildiz C et al (2015) Serum levels of ET-1, M30, and angiopoietins-1 and -2 in HELLP syndrome and preeclampsia compared to controls. Arch Gynecol Obstet. doi:10.1007/s00404-015-3803-1

    PubMed  Google Scholar 

  149. Marusic J, Prusac IK, Tomas SZ et al (2013) Expression of inflammatory cytokines in placentas from pregnancies complicated with preeclampsia and HELLP syndrome. J Matern Fetal Neonatal Med 26:680–685. doi:10.3109/14767058.2012.746301

    Article  CAS  PubMed  Google Scholar 

  150. Cecati M, Sartini D, Pozzi V et al (2013) Clues to apoptosis pathway involvement in hemolysis, elevated liver enzyme, and low platelet (HELLP) syndrome and intrauterine growth restriction (IUGR). J Matern Fetal Neonatal Med 26:26–31. doi:10.3109/14767058.2012.722713

    Article  CAS  PubMed  Google Scholar 

  151. Wagner MI, Jöst M, Spratte J et al (2015) Differentiation of ICOS(+) and ICOS(-) recent thymic emigrant regulatory T cells (RTE-Tregs) during normal pregnancy, preeclampsia and HELLP-syndrome. Clin Exp Immunol. doi:10.1111/cei.12693

    PubMed Central  Google Scholar 

  152. Mao M, Chen C (2015) Corticosteroid therapy for management of hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome: a meta-analysis. Med Sci Monit 21:3777–3783

    Article  PubMed  PubMed Central  Google Scholar 

  153. Araujo ACPF, Leao MD, Nobrega MH et al (2006) Characteristics and treatment of hepatic rupture caused by HELLP syndrome. Am J Obstet Gynecol 195:129–133. doi:10.1016/j.ajog.2006.01.016

    Article  PubMed  Google Scholar 

  154. Pourrat O, Coudroy R, Pierre F (2013) ADAMTS13 deficiency in severe postpartum HELLP syndrome. Br J Haematol 163:409–410. doi:10.1111/bjh.12494

    Article  CAS  PubMed  Google Scholar 

  155. Gadsby R, Barnie-Adshead AM, Jagger C (1993) A prospective study of nausea and vomiting during pregnancy. Br J Gen Pract 43:245–248

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Fairweather DV (1968) Nausea and vomiting in pregnancy. Am J Obstet Gynecol 102:135–175

    Article  CAS  PubMed  Google Scholar 

  157. Jarraya A, Elleuch S, Zouari J et al (2015) Hyperemesis gravidarum with severe electrolyte disorders: report of a case. Pan Afr Med J 20:264–264. doi:10.11604/pamj.2015.20.264.6298

    Article  PubMed  PubMed Central  Google Scholar 

  158. Trogstad L, Stoltenberg C, Magnus P et al (2005) Recurrence risk in hyperemesis gravidarum. BJOG Int J Obstet Gynaecol 112:1641–1645

    Article  Google Scholar 

  159. Koren G, Boskovic R, Hard M et al (2002) Motherisk-PUQE (pregnancy-unique quantification of emesis and nausea) scoring system for nausea and vomiting of pregnancy. Am J Obstet Gynecol 186:S228–S231

    Article  PubMed  Google Scholar 

  160. Birkeland E, Stokke G, Tangvik RJ et al (2015) Norwegian PUQE (pregnancy-unique quantification of emesis and nausea) identifies patients with hyperemesis gravidarum and poor nutritional intake: a prospective cohort validation study. PLoS One 10:e0119962–e0119962. doi:10.1371/journal.pone.0119962

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  161. Helseth R, Ravlo M, Carlsen SM, Vanky EE (2014) Androgens and hyperemesis gravidarum: a case-control study. Eur J Obstet Gynecol Reprod Biol 175:167–171. doi:10.1016/j.ejogrb.2014.01.007

    Article  CAS  PubMed  Google Scholar 

  162. Arck P, Hansen PJ, Mulac Jericevic B et al (2007) Progesterone during pregnancy: endocrine-immune cross talk in mammalian species and the role of stress. Am J Reprod Immunol N Y N 1989 58:268–279. doi:10.1111/j.1600-0897.2007.00512.x

    CAS  Google Scholar 

  163. Yoneyama Y, Suzuki S, Sawa R et al (2002) The T-helper 1/T-helper 2 balance in peripheral blood of women with hyperemesis gravidarum. Am J Obstet Gynecol 187:1631–1635

    Article  CAS  PubMed  Google Scholar 

  164. Yoshimura M, Hershman JM (1995) Thyrotropic action of human chorionic gonadotropin. Thyroid Off J Am Thyroid Assoc 5:425–434

    Article  CAS  Google Scholar 

  165. Sekizawa A, Sugito Y, Iwasaki M et al (2001) Cell-free fetal DNA is increased in plasma of women with hyperemesis gravidarum. Clin Chem 47:2164–2165

    CAS  PubMed  Google Scholar 

  166. Kaplan PB, Gücer F, Sayin NC et al (2003) Maternal serum cytokine levels in women with hyperemesis gravidarum in the first trimester of pregnancy. Fertil Steril 79:498–502

    Article  PubMed  Google Scholar 

  167. Kuscu NK, Yildirim Y, Koyuncu F et al (2003) Interleukin-6 levels in hyperemesis gravidarum. Arch Gynecol Obstet 269:13–15. doi:10.1007/s00404-002-0412-6

    Article  CAS  PubMed  Google Scholar 

  168. Verberg MFG, Gillott DJ, Al-Fardan N, Grudzinskas JG (2005) Hyperemesis gravidarum, a literature review. Hum Reprod Update 11:527–539. doi:10.1093/humupd/dmi021

    Article  CAS  PubMed  Google Scholar 

  169. Leylek OA, Toyaksi M, Erselcan T, Dokmetas S (1999) Immunologic and biochemical factors in hyperemesis gravidarum with or without hyperthyroxinemia. Gynecol Obstet Investig 47:229–234

    Article  CAS  Google Scholar 

  170. Maltepe C (2014) Surviving morning sickness successfully: from patient’s perception to rational management. J Popul Ther Clin Pharmacol 21:e555–e564

    PubMed  Google Scholar 

  171. Giugale LE, Young OM, Streitman DC (2015) Iatrogenic Wernicke encephalopathy in a patient with severe hyperemesis gravidarum. Obstet Gynecol 125:1150–1152. doi:10.1097/AOG.0000000000000557

    Article  PubMed  Google Scholar 

  172. Stokke G, Gjelsvik BL, Flaatten KT et al (2015) Hyperemesis gravidarum, nutritional treatment by nasogastric tube feeding: a 10-year retrospective cohort study. Acta Obstet Gynecol Scand 94:359–367. doi:10.1111/aogs.12578

    Article  PubMed  Google Scholar 

  173. Shigemi D, Nakanishi K, Miyazaki M et al (2015) A case of maternal vitamin K deficiency associated with hyperemesis gravidarum: its potential impact on fetal blood coagulability. J Nippon Med Sch 82:54–58. doi:10.1272/jnms.82.54

    Article  PubMed  Google Scholar 

  174. Kazemzadeh M, Kashanian M, Baha B, Sheikhansari N (2014) Evaluation of the relationship between Helicobacter pylori infection and hyperemesis gravidarum. Med J Islam Repub Iran 28:72–72

    PubMed  PubMed Central  Google Scholar 

  175. Handa O, Naito Y, Yoshikawa T (2010) Helicobacter pylori: a ROS-inducing bacterial species in the stomach. Inflamm Res Off J Eur Histamine Res Soc Al 59:997–1003. doi:10.1007/s00011-010-0245-x

    CAS  Google Scholar 

  176. Ayyavoo A, Derraik JGB, Hofman PL et al (2013) Severe hyperemesis gravidarum is associated with reduced insulin sensitivity in the offspring in childhood. J Clin Endocrinol Metab 98:3263–3268. doi:10.1210/jc.2013-2043

    Article  CAS  PubMed  Google Scholar 

  177. Vandraas KF, Grjibovski AM, Støer NC et al (2015) Hyperemesis gravidarum and maternal cancer risk, a scandinavian nested case-control study. Int J Cancer. doi:10.1002/ijc.29475

    PubMed  Google Scholar 

  178. Fejzo MS, Magtira A, Schoenberg FP et al (2015) Neurodevelopmental delay in children exposed in utero to hyperemesis gravidarum. Eur J Obstet Gynecol Reprod Biol 189:79–84. doi:10.1016/j.ejogrb.2015.03.028

    Article  PubMed  Google Scholar 

  179. Stander H, Cadden B (1934) Acute yellow atrophy of the liver in pregnancy. Am J Obstet Gynecol

  180. Pollitt RJ (1989) Disorders of mitochondrial beta-oxidation: prenatal and early postnatal diagnosis and their relevance to Reye’s syndrome and sudden infant death. J Inherit Metab Dis 12(Suppl 1):215–230

    PubMed  Google Scholar 

  181. Grimbert S, Fromenty B, Fisch C et al (1993) Decreased mitochondrial oxidation of fatty acids in pregnant mice: possible relevance to development of acute fatty liver of pregnancy. Hepatology 17:628–637

    Article  CAS  PubMed  Google Scholar 

  182. Matern D, Hart P, Murtha AP et al (2001) Acute fatty liver of pregnancy associated with short-chain acyl-coenzyme A dehydrogenase deficiency. J Pediatr 138:585–588. doi:10.1067/mpd.2001.111814

    Article  CAS  PubMed  Google Scholar 

  183. Kaplan MM (1985) Acute fatty liver of pregnancy. N Engl J Med 313:367–370. doi:10.1056/NEJM198508083130606

    Article  CAS  PubMed  Google Scholar 

  184. Wand S, Waeschle RM, Von Ahsen N et al (2012) Acute liver failure due to acute fatty liver of pregnancy. Minerva Anestesiol 78:503–506

    CAS  PubMed  Google Scholar 

  185. Kingham JGC (2010) Swansea criteria for diagnosis of acute fatty liver of pregnancy. Gut. doi:10.1136/gut.2010.222240

    PubMed  Google Scholar 

  186. Goel A, Ramakrishna B, Zachariah U et al (2011) How accurate are the Swansea criteria to diagnose acute fatty liver of pregnancy in predicting hepatic microvesicular steatosis? Gut 60:138–139. doi:10.1136/gut.2009.198465, author reply 139–40

    Article  CAS  PubMed  Google Scholar 

  187. Reyes H, Sandoval L, Wainstein A et al (1994) Acute fatty liver of pregnancy: a clinical study of 12 episodes in 11 patients. Gut 35:101–106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Nelson DB, Yost NP, Cunningham FG (2013) Acute fatty liver of pregnancy: clinical outcomes and expected duration of recovery. Am J Obstet Gynecol 209:456. doi:10.1016/j.ajog.2013.07.006, e1–456.e7

    Article  PubMed  Google Scholar 

  189. Vigil-de Gracia P, Montufar-Rueda C (2011) Acute fatty liver of pregnancy: diagnosis, treatment, and outcome based on 35 consecutive cases. J Matern Fetal Neonatal Med 24:1143–1146. doi:10.3109/14767058.2010.531325

    Article  PubMed  Google Scholar 

  190. Schoeman MN, Batey RG, Wilcken B (1991) Recurrent acute fatty liver of pregnancy associated with a fatty-acid oxidation defect in the offspring. Gastroenterology 100:544–548

    Article  CAS  PubMed  Google Scholar 

  191. Lamireau D, Feghali H, Redonnet-Vernhet I et al (2012) Acute fatty liver in pregnancy: revealing fetal fatty acid oxidation disorders. Arch Pediatr 19:277–281. doi:10.1016/j.arcped.2011.12.020

    Article  CAS  PubMed  Google Scholar 

  192. Nelson DB, Yost NP, Cunningham FG (2014) Hemostatic dysfunction with acute fatty liver of pregnancy. Obstet Gynecol 124:40–46. doi:10.1097/AOG.0000000000000296

    Article  PubMed  Google Scholar 

  193. Treem WR, Rinaldo P, Hale DE et al (1994) Acute fatty liver of pregnancy and long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency. Hepatology 19:339–345

    CAS  PubMed  Google Scholar 

  194. Ibdah JA, Bennett MJ, Rinaldo P et al (1999) A fetal fatty-acid oxidation disorder as a cause of liver disease in pregnant women. N Engl J Med 340:1723–1731. doi:10.1056/NEJM199906033402204

    Article  CAS  PubMed  Google Scholar 

  195. Ding J, Han L-P, Lou X-P et al (2015) Effectiveness of combining plasma exchange with plasma perfusion in acute fatty liver of pregnancy: a retrospective analysis. Gynecol Obstet Investig 79:97–100. doi:10.1159/000368752

    Article  CAS  Google Scholar 

  196. Xiong H-F, Liu J-Y, Guo L-M, Li X-W (2015) Acute fatty liver of pregnancy: over six months follow-up study of twenty-five patients. World J Gastroenterol 21:1927–1931. doi:10.3748/wjg.v21.i6.1927

    Article  PubMed  PubMed Central  Google Scholar 

  197. Vigil-De Gracia P, Lavergne JA (2001) Acute fatty liver of pregnancy. Int J Gynaecol Obstet 72:193–195

    Article  CAS  PubMed  Google Scholar 

  198. English N, Rao J (2015) Acute fatty liver of pregnancy with hypoglycaemia, diabetes insipidus and pancreatitis, preceded by intrahepatic cholestasis of pregnancy. BMJ Case Rep. doi:10.1136/bcr-2015-209649

    Google Scholar 

  199. Luzar B, Ferlan-Marolt V, Poljak M et al (2005) Acute fatty liver of pregnancy—an underlying condition for herpes simplex type 2 fulminant hepatitis necessitating liver transplantation. Z Gastroenterol 43:451–454. doi:10.1055/s-2005-857952

    Article  CAS  PubMed  Google Scholar 

  200. EASL (2015) EASL clinical practice guidelines: autoimmune hepatitis. J Hepatol

  201. European Association for the Study of the Liver (2009) EASL clinical practice guidelines: management of cholestatic liver diseases. J Hepatol 51:237–267. doi:10.1016/j.jhep.2009.04.009

    Article  Google Scholar 

  202. Hirschfield GM, Karlsen TH, Lindor KD, Adams DH (2013) Primary sclerosing cholangitis. Lancet Lond Engl 382:1587–1599. doi:10.1016/S0140-6736(13)60096-3

    Article  Google Scholar 

  203. Westbrook RH, Yeoman AD, Kriese S, Heneghan MA (2012) Outcomes of pregnancy in women with autoimmune hepatitis. J Autoimmun 38:J239–J244. doi:10.1016/j.jaut.2011.12.002

    Article  PubMed  Google Scholar 

  204. Danielsson Borssén Å, Wallerstedt S, Nyhlin N et al (2016) Pregnancy and childbirth in women with autoimmune hepatitis is safe, even in compensated cirrhosis. Scand J Gastroenterol 51:479–485. doi:10.3109/00365521.2015.1115893

    Article  PubMed  Google Scholar 

  205. Stokkeland K, Ludvigsson JF, Hultcrantz R et al (2016) Increased risk of preterm birth in women with autoimmune hepatitis—a nationwide cohort study. Liver Int Off J Int Assoc Study Liver 36:76–83. doi:10.1111/liv.12901

    Google Scholar 

  206. Trivedi PJ, Kumagi T, Al-Harthy N et al (2014) Good maternal and fetal outcomes for pregnant women with primary biliary cirrhosis. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc 12:1179–1185. doi:10.1016/j.cgh.2013.11.030, e1

    Google Scholar 

  207. Wellge BE, Sterneck M, Teufel A et al (2011) Pregnancy in primary sclerosing cholangitis. Gut 60:1117–1121. doi:10.1136/gut.2010.228924

    Article  PubMed  Google Scholar 

  208. Ludvigsson JF, Bergquist A, Ajne G et al (2014) A population-based cohort study of pregnancy outcomes among women with primary sclerosing cholangitis. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc 12:95–100. doi:10.1016/j.cgh.2013.07.011, e1

    Google Scholar 

  209. Floreani A, Infantolino C, Franceschet I et al (2015) Pregnancy and primary biliary cirrhosis: a case-control study. Clin Rev Allergy Immunol 48:236–242. doi:10.1007/s12016-014-8433-z

    Article  PubMed  Google Scholar 

  210. Umemura T, Ota M (2015) Genetic factors affect the etiology, clinical characteristics and outcome of autoimmune hepatitis. Clin J Gastroenterol 8:360–366. doi:10.1007/s12328-015-0620-9

    Article  PubMed  Google Scholar 

  211. Sun Y, Zhang W, Evans JF et al (2016) Autotaxin, pruritus and primary biliary cholangitis (PBC). Autoimmun Rev. doi:10.1016/j.autrev.2016.03.019

    PubMed  Google Scholar 

  212. Schwinge D, Carambia A, Quaas A et al (2015) Testosterone suppresses hepatic inflammation by the downregulation of IL-17, CXCL-9, and CXCL-10 in a mouse model of experimental acute cholangitis. J Immunol 194:2522–2530. doi:10.4049/jimmunol.1400076

    Article  CAS  PubMed  Google Scholar 

  213. Ferri S, Longhi MS, De Molo C et al (2010) A multifaceted imbalance of T cells with regulatory function characterizes type 1 autoimmune hepatitis. Hepatology 52:999–1007. doi:10.1002/hep.23792

    Article  CAS  PubMed  Google Scholar 

  214. Bettelli E, Carrier Y, Gao W et al (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441:235–238. doi:10.1038/nature04753

    Article  CAS  PubMed  Google Scholar 

  215. Park H, Li Z, Yang XO et al (2005) A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 6:1133–1141. doi:10.1038/ni1261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Peiseler M, Sebode M, Franke B et al (2012) FOXP3+ regulatory T cells in autoimmune hepatitis are fully functional and not reduced in frequency. J Hepatol 57:125–132. doi:10.1016/j.jhep.2012.02.029

    Article  CAS  PubMed  Google Scholar 

  217. Taubert R, Hardtke-Wolenski M, Noyan F et al (2014) Intrahepatic regulatory T cells in autoimmune hepatitis are associated with treatment response and depleted with current therapies. J Hepatol 61:1106–1114. doi:10.1016/j.jhep.2014.05.034

    Article  CAS  PubMed  Google Scholar 

  218. Melum E, Franke A, Schramm C et al (2011) Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci. Nat Genet 43:17–19. doi:10.1038/ng.728

    Article  CAS  PubMed  Google Scholar 

  219. Sebode M, Peiseler M, Franke B et al (2014) Reduced FOXP3(+) regulatory T cells in patients with primary sclerosing cholangitis are associated with IL2RA gene polymorphisms. J Hepatol 60:1010–1016. doi:10.1016/j.jhep.2013.12.027

    Article  CAS  PubMed  Google Scholar 

  220. Boonstra K, Weersma RK, van Erpecum KJ et al (2013) Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis. Hepatology 58:2045–2055. doi:10.1002/hep.26565

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors would like to thank Detlev Riller, University Medical Center Hamburg-Eppendorf, for his artwork.

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Authors and Affiliations

  1. Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Lars Bremer & Gisa Tiegs

  2. I. Department of Medicine and Martin Zeitz Centre for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Christoph Schramm

  3. Institut für Experimentelle Immunologie und Hepatologie, Universitätsklinikum Hamburg Eppendorf, Martinistrasse 52, N27, 20246, Hamburg, Germany

    Gisa Tiegs

Authors
  1. Lars Bremer
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  2. Christoph Schramm
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  3. Gisa Tiegs
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Correspondence to Gisa Tiegs.

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The authors declare that they have no conflict of interest.

Funding

This work was supported by the Deutsche Forschungsgemeinschaft, grant TI 169/11-1 to GT, as part of the Clinical Research Unit KFO296.

Christoph Schramm is an endowed professor of the Helmut and Hannelore Greve Fund and supported by the Deutsche Forschungsgemeinschaft (KFO306) and the YAEL-foundation.

Additional information

This article is a contribution to the special issue on Fetomaternal Cross Talk and Its Effect on Pregnancy Maintenance, Maternal and Offspring Health - Guest Editor: Petra Arck

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Bremer, L., Schramm, C. & Tiegs, G. Immunology of hepatic diseases during pregnancy. Semin Immunopathol 38, 669–685 (2016). https://doi.org/10.1007/s00281-016-0573-1

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  • DOI: https://doi.org/10.1007/s00281-016-0573-1

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