This study was conducted to investigate the iron status in patients with KD and to determine the role of inflammation-induced hepcidin and leptin on the clinical outcome and IVIG resistance. In the present study, serum iron levels were significantly lower in acute KD patients compared with the control groups. However, the presence of iron deficiency in the acute phase of KD did not indicate the poor outcomes such as coronary artery abnormalities and IVIG resistance.
Hepcidin is a small, cysteine-rich peptide which can affect both anemia of inflammation and red blood cell kinetics in health and disease [5]. It is an iron-regulatory hormone and well-known biomarker for IDA. However, a recent study showed that the predictive accuracy of serum hepcidin was poor and urinary hepcidin was good diagnostic tool for IDA [14]. They found that urinary hepcidin levels decreased as the severity of anemia increased. In this study, serum hepcidin was not useful for predicting coronary artery complications in patients with KD. Moreover, the initial serum hepcidin levels were significantly lower in patients with KD compared with febrile control groups.
KD is an acute febrile vasculitis of unknown origin. During the acute phase of KD, certain unidentified agents activate monocytes, T cell and B cell, and up-regulate proinflammatory cytokines such as IL–1, IL–2, IL–6, and TNF-α. Intravenous immunoglobulin (IVIG) has been shown to reduce both the duration of fever and the incidence of CAL [15]. Anemia is a frequent finding in patients with KD and is associated with a more prolonged duration of active inflammation. However, the underlying molecular mechanism of development of anemia in patients with KD has not been clearly elucidated up to now.
Anemia of inflammation is a common disease that exhibits normocytic and normochromic anemia, and sometimes presents with microcytic and hypochromic anemia. In KD patients, normochromic, normocytic anemia occurs commonly and resolves with decrease of inflammation in KD [11]. In particular, iron deficiency anemia is the most common cause of anemia in infants aged 9—24 months. A recent study found that IDA significantly impaired cell-mediated immunity in children although it did not influence humoral immunity [16].In this study, IDA was diagnosed in 34% of patients with acute phase of KD. Meanwhile, IDA was diagnosed in 21.1% of febrile controls and 11.1% of afebrile controls. Although IDA did not influence coronary artery complications, iron levels were positively associated with leptin levels in the acute phase of KD.
Hepcidin plays an important role in iron metabolism and the pathogenesis of anemia of acute by inducing ferroportin degradation. It is expressed in the liver and the adipose tissue at both mRNA and the protein levels [17].Pietrangelo et al. found that IL–6 increased hepcidin expression through a complex of the IL–6 receptor and gp130 dependence [18].However, we didn’t find a correlation between hepcidin and IL–6 levels in patients with KD, most likely due to the small sample size.
In animal study, hepcidin inhibits the absorption of iron from the intestine resulting in hypoferremia [19].However, the level of serum ferritin elevates in the presence of infection, chronic inflammation, malignancy, or liver disease, because it is an acute-phase reactant, so simultaneous measurement of CRP is necessary. Hyperferritinemia with decreased transferrin saturation indicates the presence of functional IDA or anemia of inflammation [20].In this study, ferritin levels in patients with acute KD were significantly higher than those of the febrile controls. We cannot exclude the possibility that higher ferritin levels in KD patients were due to a longer fever duration in KD patients compared with the febrile controls. Measurement of serum ferritin with a combination of other disease markers such as CRP and NT-proBNP levels could be useful for differentiating KD with other febrile conditions.
Iron deficiency can occur as absolute or functional deficiency or combined [20]. A previous study found that anemia in KD patients is related to increased hepcidin levels resulting in functional iron deficiency [21].However, above-mentioned study did not check the time-dependent changes in hemoglobin, hepcidin and cytokine levels especially during the convalescent stage of KD. We demonstrated that high hepcidin and low hemoglobin levels are present in subacute phase of KD while high iron, hemoglobin and transferrin saturation in the convalescent phase.
In addition, a recent study showed that anemia in KD occurs in patients exhibiting more severe inflammation [22].Up to now, it is still unknown how long anemia persists in patients with KD. In our patients, hemoglobin levels decreased significantly after IVIG treatment, but increased above baseline in the convalescent phase without an iron supply. This indicates that IDA in the acute phase of KD is the functional IDA as a redistribution of iron from key sites of its utilization to storage sites rather than absolute IDA, a true decrease in the body’s iron content.
Leptin has a dual role as both a hormone and a cytokine. It influences multiple endocrine functions and bone metabolism as a hormone and promotes inflammatory responses as a cytokine. Inflammatory cells produce leptin, and leptin mRNA expression and circulatory leptin levels are increased by a number of inflammatory stimuli, including IL–1, IL–6 and lipopolysaccharide [23].Conversely, reduced levels of leptin in malnourished patients was associated with the increased infection rates and reduced cell-mediated immunity secondary to insufficient immune cell effector activity [24].Our studyfound that the initial serum leptin levels in patients with KD were lower than that of afebrile control groups, although statistical significance was not reached. It is possible that a low concentration of serum leptin might increase susceptibility to KD. Moreover, there is a strong correlation between leptin, weight and BMI in patients with KD. We speculate that leptin could play an important role by stimulating secretion of inflammatory cytokines especially in obese patients with KD. Furthermore, we found a positive correlation of leptin with age in patients with KD.
This study has some limitations. First, the present study was performed in a single center and had the relatively small number of patients. Therefore, we could not determine whether our results are also applicable to different geographic populations. Second, there were no coronary aneurysms as a complication in patients with KD. Third, serum iron is labile and prone to diurnal variations [25].Morning levels of iron generally assumed to be higher than afternoon or evening levels. However, it is hard to control the time of blood sampling in patients with KD and control subjects. Lastly, the cross-sectional nature of the present study hindered assessment of the causal relationship between hepcidin and anemia in KD patients.