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Biomarkers of hepatic injury and function in neonatal hypoxic ischemic encephalopathy and with therapeutic hypothermia

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European Journal of Pediatrics Aims and scope Submit manuscript

An Erratum to this article was published on 07 August 2017

This article has been updated

Abstract

Therapeutic hypothermia (TH) is now provided as standard care to infants with moderate-severe hypoxic ischemic encephalopathy (HIE). The role of TH in limiting neuronal injury is well recognized, but its effect on hepatic injury which occurs frequently in neonatal HIE is not known. Our objective was to characterize biomarkers of liver injury and function in the setting of neonatal HIE and to describe whether HIE severity and provision of TH influence these hepatic biomarkers. We performed a multicenter retrospective study and compared hepatic biomarkers obtained during the first postnatal week, according to the severity of HIE and whether treated with TH. Of a total of 361 infants with HIE, 223 (62%) received TH and 138 (38%) were managed at normal temperature. Most hepatic biomarkers and C-reactive protein (CRP) were significantly associated with the severity of HIE (p < 0.001). Infants treated with TH had lower peak alanine aminotransferase (ALT) concentrations (p = 0.025) and a delay in reaching peak CRP concentration (p < 0.001).

Conclusion: We observed a significant association between the clinical grade of HIE and biomarkers of liver metabolism and function. Therapeutic hypothermia was associated with delayed CRP responses and with lower ALT concentrations and so may have the potential to modulate hepatic injury.

What is Known:

• Ischemic hepatic injury occurs frequently as a part of multiorgan dysfunction in infants with hypoxic ischemic encephalopathy (HIE).

• The neuroprotective role of therapeutic hypothermia in management of infants with HIE is well recognized, but the potential hepato-protective effects of hypothermia are unclear.

What is New/What this study adds:

• Therapeutic hypothermia was associated with lower alanine aminotransferase and albumin concentrations and a delayed C-reactive protein (CRP) response and so may have the potential to modulate hepatic injury.

• An elevated CRP concentration during the first postnatal week may be regarded as an expected finding in moderate and severe HIE and, in the overwhelming majority of cases, occurs secondary to hepatic hypoxia-ischemia in the absence of blood culture-positive sepsis.

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Change history

  • 07 August 2017

    An erratum to this article has been published.

Abbreviations

ALB:

Albumin

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

CB:

Conjugated bilirubin

CRP:

C-reactive protein

GGT:

Gamma glutaryl transpeptidase

HIE:

Hypoxic ischemic encephalopathy

NE:

Neonatal encephalopathy

PTT:

Partial thromboplastin time

PT:

Prothrombin time

TH:

Therapeutic hypothermia.

References

  1. Azzopardi DV, Strohm B, Edwards AD, Dyet L, Halliday HL, Juszczak E, TOBY Study Group et al (2009) Moderate hypothermia to treat perinatal asphyxia encephalopathy. N Engl J Med 361:1349–1358. doi:10.1056/NEJMoa0900854

    Article  CAS  PubMed  Google Scholar 

  2. Azzopardi D, Strohm B, Marlow N, Brocklehurst P, Deierl A, Eddama O, TOBY Study Group et al (2014) Effects of hypothermia for perinatal asphyxia on childhood outcomes. N Engl J Med 371:140–149. doi:10.1056/NEJMoa1315788

    Article  CAS  PubMed  Google Scholar 

  3. Barnett CP, Perlman M, Ekert PG (1997) Clinicopathological correlations in postasphyxial organ damage: a donor organ perspective. Pediatrics 99:797–799

    Article  CAS  PubMed  Google Scholar 

  4. Chakkarapani E, Davis J, Thoresen M (2014) Therapeutic hypothermia delays the C-reactive protein response and suppresses white blood cell and platelet count in infants with neonatal encephalopathy. Arch Dis Child Fetal Neonatal Ed 99:F458–F463. doi:10.1136/archdischild-2013-305763

    Article  PubMed  Google Scholar 

  5. Chhavi N, Zutshi K, Singh NK, Awasthi A, Goel A (2014) Serum liver enzyme pattern in birth asphyxia associated liver injury. Pediatr Gastroenterol Hepatol Nutr 17:162–169. doi:10.5223/pghn.2014.17.3.162

    Article  PubMed  PubMed Central  Google Scholar 

  6. Choudhary M, Sharma D, Dabi D, Lamba M, Pandita A, Shastri S (2015) Hepatic dysfunction in asphyxiated neonates: prospective case-controlled study. Clin Med Insights Pediatr 12:1–6. doi:10.4137/CMPed.S21426

    Google Scholar 

  7. Clarke P, Muniraman H, Gardner D, Venkatesh V, Curley A, Victor S et al (2015) Investigation of neonatal encephalopathy: the oft-lost placental “black box” [letter]. Pediatr Dev Pathol 18:343–344. doi:10.2350/15-02-1611-LET.1

    Article  PubMed  Google Scholar 

  8. Edwards AD, Yue X, Squier MV, Thoresen M, Cady EB, Penrice J et al (1995) Specific inhibition of apoptosis after cerebral hypoxia-ischaemia by moderate post-insult hypothermia. Biochem Biophys Res Commun 217:1193–1199

    Article  CAS  PubMed  Google Scholar 

  9. Eklund CM (2009) Proinflammatory cytokines in CRP baseline regulation. Adv Clin Chem 48:111–136

    Article  CAS  PubMed  Google Scholar 

  10. Fanaroff and Martin’s Neonatal-Perinatal Medicine (2015) Diseases of the fetus and infant. 10th Edition. Appendix B tables of normal values, Table B-10. Tests of Liver Function. Philadelphia: Elsevier Saunders

  11. Garland JS et al (1988) Ischemic hepatitis in children: diagnosis and clinical course. Crit Care Med 16:1209–1212

    Article  CAS  PubMed  Google Scholar 

  12. Giannini EG, Testa R, Savarino V (2005) Liver enzyme alteration: a guide for clinicians. CMAJ 172:367–379

    Article  PubMed  PubMed Central  Google Scholar 

  13. Gibson PR, Dudley FJ (1984) Ischemic hepatitis: clinical features, diagnosis and prognosis. Aust NZ J Med 14:822–825

    Article  CAS  Google Scholar 

  14. Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM et al (2005) Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomized trial. Lancet 365(9460):663–670

    Article  PubMed  Google Scholar 

  15. Hankins GD, Koen S, Gei AF, Lopez SM, Van Hook JW, Anderson GD (2002) Neonatal organ system injury in acute birth asphyxia sufficient to result in neonatal encephalopathy. Obstet Gynecol 99:688–691

    PubMed  Google Scholar 

  16. Hofer N, Müller W, Resch B (2011) Non-infectious conditions and gestational age influence C-reactive protein values in newborns during the first 3 days of life. Clin Chem Lab Med 49:297–302. doi:10.1515/CCLM.2011.048

    Article  CAS  PubMed  Google Scholar 

  17. Islam MT, Islam MN, Mollah AH, Hoque MA, Hossain MA, Nazir F et al (2011) Status of liver enzymes in babies with perinatal asphyxia. Mymensingh Med J 20:446–449

    CAS  PubMed  Google Scholar 

  18. Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG (2013) Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev (1):CD003311. doi:10.1002/14651858.CD003311.pub3

  19. Jenkins DD, Lee T, Chiuzan C, Perkel JK, Rollins LG, Wagner CL et al (2013) Altered circulating leukocytes and their chemokines in a clinical trial of therapeutic hypothermia for neonatal hypoxic ischemic encephalopathy. Pediatric Crit Care Med 14:786–795. doi:10.1097/PCC.0b013e3182975cc9

    Article  Google Scholar 

  20. Karlsson M, Blennow M, Nemeth A, Winbladh B (2006) Dynamics of hepatic enzyme activity following birth asphyxia. Acta Paediatr 95:1405–1411

    Article  PubMed  Google Scholar 

  21. Lackmann GM, Tollner U, Mader R (1993) Serum enzyme activities in full-term asphyxiated and healthy newborns: enzyme kinetics during the first 144 hours of life. Enzyme Protein 47:160–172

    Article  CAS  PubMed  Google Scholar 

  22. Okumuş N, Beken S, Aydın B, Erol S, Dursun A, Fettah N et al (2015) Effect of therapeutic hypothermia on C-reactive protein levels in patients with perinatal asphyxia. Am J Perinatol 32:667–674

    PubMed  Google Scholar 

  23. Perrone S, Szabó M, Bellieni CV, Longini M, Bangó M, Kelen D et al (2010) Whole body hypothermia and oxidative stress in babies with hypoxic-ischemic brain injury. Pediatr Neurol 43:236–240. doi:10.1016/j.pediatrneurol.2010.05.009

    Article  PubMed  Google Scholar 

  24. Shah P, Riphagen S, Beyene J, Perlman M (2004) Multiorgan dysfunction in infants with post-asphyxial hypoxic-ischaemic encephalopathy. Arch Dis Child Fetal Neonatal Ed 89:F152–F155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Shang Y, Mu L, Guo X, Li Y, Wang L, Yang W et al (2014) Clinical significance of interleukin-6, tumor necrosis factor-α and high-sensitivity C-reactive protein in neonates with hypoxic-ischemic encephalopathy. Exp Ther Med 8:1259–1262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, National Institute of Child Health and Human Development Neonatal Research Network et al (2005) Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 353:1574–1584

    Article  CAS  PubMed  Google Scholar 

  27. Tarcan A, Tiker F, Güvenir H, Gürakan B (2007) Hepatic involvement in perinatal asphyxia. J Matern Fetal Neonatal Med 20:407–410

    Article  PubMed  Google Scholar 

  28. Thoresen M, Penrice J, Lorek A, Cady EB, Wylezinska M, Kirkbride V et al (1995) Mild hypothermia after severe transient hypoxia-ischemia ameliorates delayed cerebral energy failure in the newborn piglet. Pediatr Res 37:667–670

    Article  CAS  PubMed  Google Scholar 

  29. Vejchapipat P, Williams SR, Proctor E, Lauro V, Spitz L, Pierro A (2001) Moderate hypothermia ameliorates liver energy failure after intestinal ischaemia-reperfusion in anaesthetised rats. J Pediatr Surg 36:269-275

  30. Xanthou M, Fotopoulos S, Mouchtouri A, Lipsou N, Zika I, Sarafidou J (2002) Inflammatory mediators in perinatal asphyxia and infection. Acta Paediatr Suppl 91:92–97

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors sincerely thank the anonymous referees for their helpful constructive comments on an earlier version of the manuscript.

Author information

Authors and Affiliations

  1. Neonatal Unit, Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK

    Hemananda Muniraman, Sunil Sanka & Paul Clarke

  2. Division of Neonatology, Department of Pediatrics, Keck School of Medicine, Los Angeles County Medical Center, University of Southern California, Los Angeles, USA

    Hemananda Muniraman

  3. Neonatal Unit, Liverpool Women’s Hospital NHS Foundation Trust, Liverpool, UK

    Danielle Gardner, Anna Paweletz & Mark A. Turner

  4. Norwich Medical School, University of East Anglia, Norwich, UK

    Jane Skinner & Paul Clarke

  5. Neonatal Unit, Central Manchester NHS Foundation Trust (St Mary’s Hospital), Manchester, UK

    Anitha Vayalakkad, Clare Clifford & Suresh Victor

  6. Neonatal Unit, Cambridge University NHS Foundation Trust (Addenbrooke’s Hospital), Cambridge, UK

    Ying Hui Chee, Vidheya Venkatesh & Anna Curley

  7. Neonatal Unit, National Maternity Hospital, Dublin, Ireland

    Anna Curley

  8. Centre for Developing Brain, Division of Imaging Sciences and Biomedical Engineering, King’s College London, King’s Health Partners, St. Thomas’ Hospital, London, UK

    Suresh Victor

  9. Department of Women’s and Children’s Health, Institute of Translational Medicine, University of Liverpool, Liverpool, UK

    Mark A. Turner

Authors
  1. Hemananda Muniraman
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  2. Danielle Gardner
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Contributions

HM co-designed the study protocol, co-drafted the data collection form, and helped obtain the ethics approval; also collected the local data, co-wrote the first manuscript draft, led on manuscript re-drafting, provided intellectual input, finalized the revised manuscript version, and approved the final submitted manuscript version.

DG collected the data from her center, contributed to manuscript drafting and approved the final submitted manuscript version.

JS provided expert statistical input, performed all the main data analyses, contributed to manuscript drafting and approved of the final submitted manuscript version.

AP collected the data from her center, contributed to manuscript drafting and approved the final submitted manuscript version.

AV collected the data from her center, contributed to manuscript drafting and approved the final submitted manuscript version.

YHC collected the data from her center, contributed to manuscript drafting and approved the final submitted manuscript version.

CC collected the data from her center, contributed to manuscript drafting and approved the final submitted manuscript version.

SS helped collect the data from his center, contributed to manuscript drafting and approved the final submitted manuscript version.

VV collected the data from his center, contributed to manuscript drafting and approved the final submitted manuscript version.

AC obtained local governance approvals and helped collect the data from her center, verified data queries, provided intellectual input, contributed to manuscript drafting, and approved the final manuscript version.

SV obtained local governance approvals and helped collect the data, verified data queries, provided intellectual input, contributed to manuscript drafting, and approved the final submitted manuscript version.

MAT obtained local governance approvals, provided intellectual input, contributed to manuscript drafting, and approved the final submitted manuscript version.

PC conceived the idea for this study. He co-designed the study protocol, co-drafted the data collection form, obtained the ethics approval and also local governance approvals for his center, undertook local data collection, assisted with data analysis, verified data queries, provided intellectual input, and co-wrote the first and final submitted manuscript drafts. PC is the guarantor for this work.

Corresponding author

Correspondence to Paul Clarke.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Funding

No specific funding was received for this study.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors, and informed consent was not required for the purpose of the study. This study was done with the approval of the National Research Ethics Service Committee East of England—Cambridge Central (REC reference: 11/EE/0349).

Additional information

Communicated by Patrick Van Reempts

The original version of this article was revised: in this article, the previously misaligned p value columns in Tables 2 and 3 have been corrected so that p values do now properly correspond to their correct respective rows of variables as were present in the authors’ final submitted manuscript version.

An erratum to this article is available at https://doi.org/10.1007/s00431-017-2980-2.

Electronic supplementary material

Table S1

(DOCX 25.1 kb).

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Muniraman, H., Gardner, D., Skinner, J. et al. Biomarkers of hepatic injury and function in neonatal hypoxic ischemic encephalopathy and with therapeutic hypothermia. Eur J Pediatr 176, 1295–1303 (2017). https://doi.org/10.1007/s00431-017-2956-2

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