Diagnostic Efficacy of Serum Mac-2 Binding Protein Glycosylation Isomer and Other Markers for Liver Fibrosis in Non-Alcoholic Fatty Liver Diseases
2021; 41(3): 302-309
Ann Lab Med 2021; 41(3): 318-322
Published online May 1, 2021 https://doi.org/10.3343/alm.2021.41.3.318
Copyright © Korean Society for Laboratory Medicine.
1Department of Pediatrics, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea; 2Department of Pediatrics, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Korea; 3Department of Pharmacology and Medical Research Center for Gene Regulation, Chonnam National University Medical School, Hwasun-gun, Jeollanam-do, Korea; 4Division of Clinical Pharmacology, Chonnam National University Hospital, Gwangju, Korea; 5Department of Pediatrics, College of Medicine Chosun University, Gwangju, Korea
Correspondence to: Young Kuk Cho, M.D.
Department of Pediatrics, Chosun University Hospital, 365 Pilmun-daero, Dong-gu, Gwangju 61453, Korea
*These authors contributed equally to this study.
Diagnosis of Kawasaki disease (KD) is occasionally delayed because it is solely based on clinical symptoms. Previous studies have attempted to identify diagnostic biomarkers for KD. Recently, patients with KD were reported to have elevated serum ferritin levels. We investigated the usefulness of the serum ferritin level as a diagnostic biomarker for distinguishing KD from other acute febrile illnesses. Blood samples were obtained from pediatric patients with KD (N=77) and those with other acute febrile illnesses (N=32) between December 2007 and June 2011 for measuring various laboratory parameters, including serum ferritin levels. In patients with KD, laboratory tests were performed at diagnosis and repeated at 2, 14, and 56 days after intravenous immunoglobulin treatment. At the time of diagnosis, serum ferritin levels in patients with KD (188.8 μg/L) were significantly higher than those in patients with other acute febrile illnesses (106.8 μg/L, P=0.003). The serum ferritin cut-off value of 120.8 μg/L effectively distinguished patients with KD from those with other acute febrile illnesses, with a sensitivity and specificity of 74.5% and 83.3%, respectively. Serum ferritin may be a useful biomarker to distinguish KD from other acute febrile illnesses.
Keywords: Kawasaki disease, Diagnosis, Ferritin, Biomarker
Kawasaki disease (KD) is an acute febrile systemic vasculitis of unknown etiology [1, 2]. Among all patients diagnosed as having KD, 15%–20% showed incomplete presentation . KD diagnosis depends on the use of adjuvant diagnostic markers, such as echocardiographic findings and laboratory biomarkers, including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), white blood cell count (WBC), hemoglobin, platelet count, and pyuria . Although the laboratory findings observed in KD are not specific enough to conclusively establish a diagnosis, they can be useful, particularly in patients with a high suspicion for KD . Tumor necrosis factor alpha (TNF-α), which is released from activated macrophages under certain inflammatory conditions, induces ferritin synthesis. A serum ferritin level ≥ 200 µg/L has been associated with an increased risk of myocardial infarction and, reportedly, plays an important role in inflammation [3-5]. Like in patients with systemic juvenile idiopathic arthritis, elevated serum ferritin levels have been observed in patients with KD [6-8]. Serum ferritin level is being considered a useful predictor of non-responsiveness to initial intravenous immunoglobulin (IVIG) therapy in KD and a useful biomarker to distinguish between KD and systemic juvenile idiopathic arthritis [7, 8]. However, the utility of serum ferritin levels as a diagnostic biomarker to distinguish between KD and other acute febrile illnesses has not been investigated. We investigated this utility by measuring serum ferritin levels in pediatric patients with acuteand/or convalescent-phase KD.
All procedures involving human participants were carried out in accordance with the ethical standards of the Institutional and/ or National research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The Institutional Review Board of Chonnam National University Hospital, Gwangju, Korea, approved this study (protocol number: I-2009-09-103).
We enrolled 77 pediatric patients (age range, 3 months–6.9 years) who were admitted to Chonnam National University Hospital between December 2007 and June 2011 with a diagnosis of KD. Informed written consent was obtained from the parents of all patients. All patients with KD were administered IVIG at a dose of 2 g/kg, concomitantly with medium-dose aspirin (30–50 mg/kg), during the acute phase with fever. Among the 77 patients with KD who received the initial IVIG infusion, 11 (14.3%) received a second dose. At the time of admission, among the 77 patients with KD, 73 (94.8%), 69 (89.6%), 70 (90.9%), 55 (71.4%), and 45 (58.4%) showed bilateral bulbar conjunctival injection, polymorphous rash, oral mucosal changes, cervical adenopathy with lymph nodes measuring > 1.5 cm in diameter, and changes in their extremities, respectively.
In addition, we enrolled 32 patients with other acute febrile diseases presenting with fever lasting more than three days. Exclusion criteria were the presence of hemophagocytic lymphohistiocytosis, systemic juvenile idiopathic arthritis, and viral infections, such as hepatitis C, avian influenza A (H5N1), dengue fever, and
We measured the complete blood cell count, ESR, CRP, total protein, albumin, electrolytes, blood urea nitrogen, creatinine, AST, ALT, creatine kinase (CK), CK-cardiac isoenzyme (CK-MB), myoglobin, troponin-I, N-terminal pro-brain natriuretic peptide (NT-proBNP), and ferritin in patients with KD at the time of diagnosis and in those with other acute febrile illnesses. Blood samples (5-8 mL) was analyzed within two hours after collection . In addition, we measured serum ESR, CRP, NT-proBNP, and ferritin in these patients at 2, 14, and 56 days after IVIG treatment. A microparticle enzyme immunoassay (MEIA; AxSYM System, Abbot Diagnostics, IL, USA) was used to quantitatively assess serum ferritin levels.
Chi-square test was applied to assess the statistical significance of differences between independent variables and Student’s
Table 1 shows the demographic features and the laboratory findings of the patients with KD and those with other acute febrile illnesses at the time of diagnosis. The clinical diagnoses for patients with other acute febrile illnesses (N = 32) were as follows: viral pneumonia (N = 18), acute tonsillitis (N = 3), acute bronchiolitis (N= 2), acute obstructive laryngitis (N= 2), bacteremia (N= 2), cervical lymphadenitis (N = 1), acute gastroenteritis (N = 1), bacterial keratoconjunctivitis (N = 1), acute otitis media (N = 1), and acute gastroenteritis (N = 1) (Table 1). There were no significant sex differences.
Table 2 shows changes in CRP, ESR, NT-proBNP, and ferritin, at the time of diagnosis and at 2, 14, and 56 days after IVIG treatment. In patients with KD, the increased ferritin levels showed a gradual drop after IVIG treatment (Table 2). There was no significant sex-based difference in ferritin levels in patients with KD (male: 196.0±120.7 µg/L, vs. female: 197.0±88.1 µg/L,
Table 3 shows the diagnostic serum ferritin cut-off value in patients with KD and in those with other acute febrile illnesses. We also evaluated the platelet count, ESR, CRP, and NT-proBNP cut off values, which have been identified as potential diagnostic markers in previous reports (Table 3) [15-17]. The serum ferritin cut-off value of 120.8 µg/L effectively distinguished patients with KD from those with other acute febrile illnesses, with a sensitivity and specificity of 74.5% and 83.3%, respectively (AUC = 0.830, 95% confidence interval: 0.704-0.955) (Table 3).
In our study, serum ferritin levels were significantly higher in patients with KD than in those with other acute febrile illnesses, indicating that the serum ferritin level can serve as a useful diagnostic biomarker for KD. We determined the optimal serum ferritin cut-off value to distinguish between KD and other acute febrile illnesses to be 120.8 µg/L.
Ferritin is an acute-phase reactant that is utilized in clinical practice as a serum biomarker . Ferritin synthesis is markedly induced by TNF-α and IL-1α; thus, serum ferritin levels are elevated in patients with certain inflammatory conditions . Elevated serum ferritin levels have also been implicated in the development of diabetic microvascular disease through interaction with vascular endothelial growth factor (VEGF), which is involved in the pathogenesis of vasculitis [7, 18]. VEGF is also associated with the formation of coronary artery lesions (CALs) in patients with KD; however, an association between VEGF and the serum ferritin level in KD has not been established [7, 19].
While the serum ferritin level is elevated in patients with KD, markedly elevated serum ferritin level is not a common feature in KD, although it has been observed in KD patients with concomitant hemophagocytic lymphohistiocytosis and in adult patients with KD [3, 9, 20]. Nasir,
There were some limitations in our study. (i) Some data pertaining to patient follow-up were missing, perhaps because parents refused to permit blood draws as their children began to recover and appear healthy. (ii) The patients with acute febrile illnesses other than KD had heterogeneous febrile illnesses, which may have affected the measurement of serum ferritin levels owing to differences in inflammation severity. (iii) The number of patients with acute febrile illnesses other than KD was significantly smaller than that of patients with KD. Therefore, large prospective investigations are required for obtaining a more accurate cutoff for ferritin as a diagnostic biomarker.
In conclusion, this was the first study to compare serial serum ferritin levels between patients with KD and those with other acute febrile illnesses. The serum ferritin level may be a useful biomarker to distinguish KD from other acute febrile illnesses.
Kim SH, Song ES, Kang G, and Cho YK made substantial contributions to study planning and design and writing of the manuscript; Yoon S and Eom GH performed data collection, statistical analysis, and provided valuable feedback. Kim SH and Song ES contributed equally to all aspects of this paper. All authors approved the final manuscript submitted and agreed to be accountable for all aspects of the work.
The authors declare that they have no conflict of interest.
This study was supported by a grant (NRF-2015R1D1A1A01059017) provided by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Korea.