Hepatic dysfunction secondary to Kawasaki disease: characteristics, etiology and predictive role in coronary artery abnormalities

  • Goshgar Mammadov
  • Hui Hui Liu
  • Wei Xia Chen
  • Guo Zhen Fan
  • Rui Xue Li
  • Fei Fei Liu
  • Sama Samadli
  • Jing Jing Wang
  • Yang Fang Wu
  • Huang Huang Luo
  • Dong Dong Zhang
  • Wei Wei
  • Peng HuEmail author
Original Article


Coronary artery abnormalities (CAAs) are prominent during the acute Kawasaki disease (KD) episode and represent the major contributors to the long-term prognosis. Several meta-analysis and published scoring systems have identified hepatic dysfunction as an independent predictor of CAA risks. The medical records of 210 KD children were reviewed. Blood samples were collected from all subjects at 24 h pre-therapy and 48 h post-therapy, respectively. Liver function test (LFT) and inflammatory mediators were detected. Multivariate logistic regression analysis was conducted to identify the reliable biomarkers predicting whether CAAs existed or not in KD patients. 90.95% of KD patients had at least 1 abnormal LFT. Hypoalbuminemia was the most prevalent type of hepatic dysfunction, followed by elevated aspartate aminotransferase, low TP, low A/G and hyperbilirubinemia, respectively. The elevated inflammatory mediators (procalcitonin and C-reactive protein) and moderate dose of aspirin played a synthetic role in hepatic dysfunction secondary to KD. However, LFT presented no significant differences between infectious and noninfectious conditions. By a multivariate analysis, a lower albumin/globulin ratio (A/G, OR 13.50, 95% CI 3.944–46.23) served as an independent predictor of CAAs and had a sensitivity of 56.25%, and a specificity of 61.11% at a cutoff value of < 1.48. In conclusion, hepatic dysfunction is a common complication during the acute KD episode, characterized by elevated serum liver enzymes, hypoalbuminemia and hyperbilirubinemia. Systemic inflammation and aspirin, rather than infectious agents, are both the major contributors of hepatic dysfunction secondary to KD. A lower A/G serves as an independent predictor of CAAs.


Coronary artery abnormalities Hepatic dysfunction Hypoalbuminemia Kawasaki disease Multivariate analysis 


Author’s contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by GM, HHL and WXC. The first draft of the manuscript was written by GM, HHL and WXC and all authors commented on previous versions of the manuscript. All authors contributed to the data interpretation and manuscript revision. All authors read and approved the final manuscript.


This study was supported by the New Technology Project of the First Affiliated Hospital, Anhui Medical University (2014-01).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The research was in compliance with the Declaration of Helsinki. Approval for this research was acquired from the Medical Ethic Committee of the First Affiliated Hospital of Anhui Medical University (Code number; LLSC/20150009).

Informed consent

Informed consent was obtained from all individual participants included in the study.


  1. 1.
    Wu MH, Lin MT, Chen HC, Kao FY, Huang SK. Postnatal risk of acquiring Kawasaki disease: a nationwide birth cohort database study. J Pediatr. 2017;180:80–6.PubMedCrossRefGoogle Scholar
  2. 2.
    Makino N, Nakamura Y, Yashiro M, et al. Descriptive epidemiology of Kawasaki disease in Japan, 2011–2012: from the results of the 22nd nationwide survey. J Epidemiol. 2015;25:239–45.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    McCrindle BW, Rowley AH, Newburger JW, et al. American heart association rheumatic fever, endocarditis, and kawasaki disease committee of the council on cardiovascular disease in the young; council on cardiovascular and stroke nursing; council on cardiovascular surgery and anesthesia; and council on epidemiology and prevention. Diagnosis, treatment, and long-term management of kawasaki disease: a scientific statement for health professionals from the american heart association. Circulation. 2017;135:e927–99.PubMedCrossRefGoogle Scholar
  4. 4.
    Hu P, Jiang GM, Wu Y, et al. TNF-α is superior to conventional inflammatory mediators in forecasting IVIG nonresponse and coronary arteritis in Chinese children with Kawasaki disease. Clin Chim Acta. 2017;471:76–80.PubMedCrossRefGoogle Scholar
  5. 5.
    Kato H, Sugimura T, Akagi T, et al. Long-term consequences of Kawasaki disease. A 10-to 21-year follow-up study of 594 patients. Circulation. 1996;94:1379–85.PubMedCrossRefGoogle Scholar
  6. 6.
    Kobayashi T, Inoue Y, Takeuchi K, et al. Prediction of intravenous immunoglobulin unresponsiveness in patients with Kawasaki disease. Circulation. 2006;113:2606–12.PubMedCrossRefGoogle Scholar
  7. 7.
    Egami K, Muta H, Ishii M, et al. Prediction of resistance to intravenous immunoglobulin treatment in patients with Kawasaki disease. J Pediatr. 2006;149:237–40.PubMedCrossRefGoogle Scholar
  8. 8.
    Bai L, Feng T, Yang L, et al. Retrospective analysis of risk factors associated with Kawasaki disease in China. Oncotarget. 2017;8:54357–63.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Eladawy M, Dominguez SR, Anderson MS, Glodé MP. Abnormal liver panel in acute kawasaki disease. Pediatr Infect Dis J. 2011;30:141–4.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Kobayashi T, Fuse S, Sakamoto N, et al. Z Score Project Investigators. A new Z score curve of the coronary arterial internal diameter using the lambda-mu-sigma method in a pediatric population. J Am Soc Echocardiogr. 2016;29:794–801.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Wu Y, Liu FF, Xu Y, et al. Interleukin-6 is prone to be a candidate biomarker for predicting incomplete and IVIG nonresponsive Kawasaki disease rather than coronary artery aneurysm. Clin Exp Med. 2019;19:173–81.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Burns JC, Glodé MP. Kawasaki syndrome. Lancet. 2004;364:533–44.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Tizard E. Complications of Kawasaki disease. Curr. Paediatr. 2005;15:62–8.Google Scholar
  14. 14.
    Ohshio G, Furukawa F, Fujiwara H, Hamashima Y. Hepatomegaly and splenomegaly in Kawasaki disease. Pediatr Pathol. 1985;4:257–64.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Bader-Meunier B, Hadchouel M, Fabre M, Arnoud MD, Dommergues JP. Intrahepatic bile duct damage in children with Kawasaki disease. J Pediatr. 1992;120:750–2.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Tremoulet AH, Jain S, Chandrasekar D, Sun X, Sato Y, Burns JC. Evolution of laboratory values in patients with Kawasaki disease. Pediatr Infect Dis J. 2011;30:1022–6.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Okada Y, Minakami H, Tomomasa T, et al. Serum procalcitonin concentration in patients with Kawasaki disease. J Infect. 2004;48:199–205.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Samadli S, Liu FF, Mammadov G, et al. The time option of IVIG treatment is associated with therapeutic responsiveness and coronary artery abnormalities but not with clinical classification in the acute episode of Kawasaki disease. Pediatr Rheumatol Online J. 2019;17:53.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Si F, Wu Y, Gao F, Feng S, Liu R, Yi Q. Relationship between IL-27 and coronary arterial lesions in children with Kawasaki disease. Clin Exp Med. 2017;17:451–7.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Su Y, Feng S, Luo L, Liu R, Yi Q. Association between IL-35 and coronary arterial lesions in children with Kawasaki disease. Clin Exp Med. 2019;19:87–92.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Amano S, Hazama F, Hamashima Y. Pathology of Kawasaki disease: II. Distribution and incidence of the vascular lesions. Jpn Circ J. 1979;43:741-8.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Seki S, Habu Y, Kawamura T, et al. The liver as a crucial organ in the first line of host defense: the roles of Kupffer cells, natural killer (NK) cells and NK1.1 Ag + T cells in T helper 1 immune responses. Immunol Rev. 2000;174:35–46.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Ishihara K, Miyazaki A, Nabe T, et al. Group IVA phospholipase A2 participates in the progression of hepatic fibrosis. FASEB J. 2012;26:4111–21.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Zalewski A, Macphee C. Role of lipoprotein-associated phospholipase A2 in atherosclerosis: biology, epidemiology, and possible therapeutic target. Arterioscler Thromb Vasc Biol. 2005;25:923–31.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Tanaseanu C, Tudor S, Tamsulea I, Marta D, Manea G, Moldoveanu E. Vascular endothelial growth factor, lipoporotein-associated phospholipase A2, sP-selectin and antiphospholipid antibodies, biological markers with prognostic value in pulmonary hypertension associated with chronic obstructive pulmonary disease and systemic lupus erithematosus. Eur J Med Res. 2007;12:145–51.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Prete M, Fatone MC, Vacca A, Racanelli V, Perosa F. Severe pulmonary hypertension as the initial manifestation of systemic lupus erythematosus: a case report and review of the literature. Clin Exp Rheumatol. 2014;32:267–74.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Sauer M, Doß S, Ehler J, Mencke T, Wagner NM. Procalcitonin impairs liver cell viability and function in vitro: a potential new mechanism of liver dysfunction and failure during sepsis? Biomed Res Int. 2017;2017:6130725.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Principi N, Rigante D, Esposito S. The role of infection in Kawasaki syndrome. J Infect. 2013;67:1–10.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Hall M, Hoyt L, Ferrieri P, Schlievert PM, Jenson HB. Kawasaki syndrome-like illness associated with infection caused by enterotoxin B-secreting Staphylococcus aureus. Clin Infect Dis. 1999;29:586–9.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Matsubara K, Fukaya T, Miwa K, et al. Development of serum IgM antibodies against superantigens of Staphylococcus aureus and Streptococcus pyogenes in Kawasaki disease. Clin Exp Immunol. 2006;143:427–34.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Kanegane H, Tsuji T, Seki H, et al. Kawasaki disease with a concomitant primary Epstein-Barr virus infection. Acta Paediatr Jpn. 1994;36:713–6.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Embil JA, McFarlane ES, Murphy DM, Krause VW, Stewart HB. Adenovirus type 2 isolated from a patient with fatal Kawasaki disease. Can Med Assoc J. 1985;132:1400.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Hagiwara K, Komura H, Kishi F, Kaji T, Yoshida T. Isolation of human herpesvirus-6 from an infant with Kawasaki disease. Eur J Pediatr. 1992;151:867–8.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Johnson D, Azimi P. Kawasaki disease associated with Klebsiella pneumoniae bacteremia and parainfluenza type 3 virus infection. Pediatr Infect Dis. 1985;4:100.PubMedCrossRefGoogle Scholar
  35. 35.
    Matsuno S, Utagawa E, Sugiura A. Association of rotavirus infection with Kawasaki syndrome. J Infect Dis. 1983;148:177.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Hu P, Wang J, Fan XC, Hu B, Lu L. Hypertension triggers the rupture of coronary artery aneurysm in an 8-year-old boy with Kawasaki disease. J Clin Hypertens (Greenwich). 2014;16:766–7.CrossRefGoogle Scholar
  37. 37.
    Hu P, Guan Y, Fan XC, Lu FY, Song LM. Incomplete Kawasaki disease induced by measles in a 6-month-old male infant. Int J Dermatol. 2016;55:e34–6.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Peng Y, Liu X, Duan Z, et al. Prevalence and characteristics of arthritis in Kawasaki disease: a Chinese cohort study. Clin Exp Med. 2019;19:167–72.PubMedCrossRefGoogle Scholar
  39. 39.
    Jordan-Villegas A, Chang ML, Ramilo O, Mejías A. Concomitant respiratory viral infections in children with Kawasaki disease. Pediatr Infect Dis J. 2010;29:770–2.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Ramphul K, Mejias SG. Kawasaki disease: a comprehensive review. Arch Med Sci Atheroscler Dis. 2018;3:e41–5.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Onouchi Z, Kawasaki T. Overview of pharmacological treatment of Kawasaki disease. Drugs. 1999;58:813–22.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Baumer JH, Love SJ, Gupta A, Haines LC, Maconochie I, Dua JS. Salicylate for the treatment of Kawasaki disease in children. Cochrane Database Syst Rev. 2006;4:CD004175.Google Scholar
  43. 43.
    Matsubara T, Mason W, Kashani IA, Kligerman M, Burns JC. Gastrointestinal hemorrhage complicating aspirin therapy in acute Kawasaki disease. J Pediatr. 1996;128:701–3.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Lee JH, Hung HY, Huang FY. Kawasaki disease with Reye syndrome: report of one case. Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi. 1992;33:67–71.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Aithal GP, Day CP. Nonsteroidal anti-inflammatory drug-induced hepatotoxicity. Clin Liver Dis. 2007;11:563–75.PubMedCrossRefGoogle Scholar
  46. 46.
    Chen J, Liu Y, Liu W, Wu Z. A meta-analysis of the biomarkers associated with coronary artery lesions secondary to Kawasaki disease in Chinese children. J Huazhong Univ Sci Technolog Med Sci. 2011;31:705.PubMedCrossRefGoogle Scholar
  47. 47.
    Lin MT, Chang CH, Sun LC, et al. Risk factors and derived formosa score for intravenous immunoglobulin unresponsiveness in Taiwanese children with Kawasaki disease. J Formos Med Assoc. 2016;115:350–5.PubMedCrossRefGoogle Scholar
  48. 48.
    Tang Y, Yan W, Sun L, et al. Prediction of intravenous immunoglobulin resistance in Kawasaki disease in an East China population. Clin Rheumatol. 2016;35:2771–6.PubMedCrossRefGoogle Scholar
  49. 49.
    Hua W, Ma F, Wang Y, et al. A new scoring system to predict Kawasaki disease with coronary artery lesions. Clin Rheumatol. 2019;38:1099–107.PubMedCrossRefGoogle Scholar
  50. 50.
    Kuwabara M, Yashiro M, Kotani K, et al. Cardiac lesions and initial laboratory data in Kawasaki disease: a nationwide survey in Japan. J Epidemiol. 2015;25:189–93.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Nicholson JP, Wolmarans MR, Park GR. The role of albumin in critical illness. Br J Anaesth. 2000;85:599–610.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Ballmer PE. Causes and mechanisms of hypoalbuminaemia. Clin Nutr. 2001;20:271–3.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Goshgar Mammadov
    • 1
  • Hui Hui Liu
    • 1
  • Wei Xia Chen
    • 1
  • Guo Zhen Fan
    • 1
  • Rui Xue Li
    • 1
  • Fei Fei Liu
    • 1
  • Sama Samadli
    • 1
  • Jing Jing Wang
    • 1
  • Yang Fang Wu
    • 1
  • Huang Huang Luo
    • 1
  • Dong Dong Zhang
    • 1
  • Wei Wei
    • 1
  • Peng Hu
    • 1
    Email author
  1. 1.Department of PediatricsThe First Affiliated Hospital of Anhui Medical UniversityHefeiPeople’s Republic of China

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