Our study revealed unique characteristics of carnitine in patients with KD. An elevation of FC levels was observed in some patients with KD before IVIG, whereas FC levels were low in the majority of patients with KD. Additionally, FC levels before IVIG were higher in non-responders than in responders. The high FC level correlated with unresponsiveness to IVIG; however, its predictive value was considered to be insufficient. Moreover, FC levels correlated with AST and ALT levels.
Our preliminary study showed that low serum FC levels were very common in hospitalized children with febrile illness . An elevated level of FC represents an exceptional pathological state, such as acute renal failure  and liver cirrhosis . In contrast, various congenital and acquired conditions are known to cause carnitine deficiency . Thus, it is remarkable that high FC was seen in some children with KD. Currently, the pathogenesis resulting in the elevation of FC levels in children with KD remains elusive. Carnitine is primarily stored in skeletal muscle, liver, myocardium, and brain. As such, injuries to these organs could lead to carnitine leakage into the bloodstream. We hypothesize that liver injury is likely to result in an elevation of FC levels in children with KD, because FC levels in our study closely correlated with AST and ALT levels, which are well known markers associated with liver injury. High FC levels were exclusively observed in patients with elevated AST/ALT. This hypothesis should be evaluated by further clinical and experimental studies.
It is interesting that FC levels in children with KD were related to IVIG unresponsiveness, although its predictive value may be insufficient. In this study, not only FC levels but also T-Bil, AST, and ALT level were associated with unresponsiveness to IVIG. Previous studies have shown that these values were higher in non-responders than in responders [20, 21, 22]. It is remarkable that all these factors have also been incorporated into the existing refractory prediction scores, such as Osaka, Kurume, and Gumma scores [7, 8, 9]. As mentioned above, FC levels closely correlated with AST and ALT levels. Thus, the correlation between FC and IVIG unresponsiveness indicates that an elevation of FC levels in children with KD could be a reflection of pathogenesis that could lead to IVIG unresponsiveness. IVIG unresponsiveness in children with KD has been presumed to correlate with the severity of inflammation [23, 24]. Proinflammatory cytokines such as interleukin (IL)-1 and IL-6 have been known to be related to IVIG unresponsiveness. Fury et al. reported transcript abundance of IL-1 pathway genes and MMP-8 in patients with IVIG resistant KD patients . This suggests that IL-1 pathway activation could be related to IVIG unresponsiveness. IL-6 is also associated with various biological functions, such as an increase in acute-phase proteins, T cell activation, procoagulant effects and thrombocytosis, which could lead to resulting in IVIG unresponsiveness [26, 27, 28]. An elevation of FC levels as well as AST, ALT, and T-Bil levels could be attributable to tissue damage that resulted from inflammation induced by proinflammatory cytokines. Regarding the predictive value of FC levels, the sensitivity and specificity were 0.794 and 0.583, respectively, and the AUC was 0.69. While FC levels alone were not accurate enough to predict unresponsiveness to IVIG, these levels in combination with other variables such as AST, ALT, and T-Bil, could become as useful as the Gunma, Kurume, and Osaka scores.
It is noteworthy that FC levels were below the normal range in the majority of responders in this study. This could be attributable to an increased carnitine requirement caused by systemic inflammation in children with KD. It is well known that secondary carnitine deficiency could result from decreased body storage and increased requirements in patients with sepsis [29, 30]. This suggests that patients with systemic inflammation, including KD, will be at a risk of secondary carnitine deficiency. In this study, the magnitude of lower FC levels was not severe in children with KD. There were no patients with carnitine deficiency (FC levels below 20 µmol/L), or symptoms related to low FC levels such as hypoglycemia. We consider that carnitine supplementation is unnecessary in patients with KD.
Serum FC levels were not different according to sampling days of illness, which is presumed to reflect the intensity of systemic inflammation. It is reported that, in the acute febrile stage of KD, the intensity of systemic inflammation may gradually increase and reach the peak (mean at 6th febrile day) . AST and ALT are mainly elevated before peak of the inflammation . The results of our study suggests that serum FC levels may not be directly associated with systemic inflammation. Carnitine deficiency can be observed in patients with sepsis, which causes serious systemic inflammation.
This study has some limitations. First, this is a single center retrospective study with a small number of patients. Therefore, the results of this study should further be verified in other cohorts of patients. Second, serum FC levels were not measured in all children with KD during the study period. As such, prospective studies are necessary to identify carnitine properties in patients with KD more accurately. Finally, we did not examine other clinical data such as triglyceride and ammonia, which could be affected by FC levels. Thus, further studies on these clinical variables are necessary to elucidate the impact of FC levels in children with KD.