We report the spectrum of liver panel abnormalities in a consecutive series of 259 children with KD presented at a single institution. At least 1 abnormal LFT was detected in almost half of our patients. Of patients in this study, 37% presented with elevation of one or both liver transaminases (ALT, AST) and 41% had elevation of GGT. The prevalence of elevated transaminases and GGT in this study is similar to previous reports.3,7,8
However, in each of these reports, only a single LFT was the main focus of the paper. In the current study, we reported and analyzed a more comprehensive set of liver panel tests in a large population of patients with KD.
Hepatic disease is not a significant cause of morbidity or mortality in patients with KD, but subclinical liver involvement is common. Liver involvement ranges from mild asymptomatic increase in liver enzymes to a severe cholestatic hepatitis and/or hydrops of the gallbladder.3–10
In this study, most patients with elevated transaminases had only mild elevation, less than twice the upper limit of normal. Two patients, however, had transaminase elevations more than 10 times the upper limit of normal, and both of these patients presented with a picture of clinical hepatitis with jaundice. This presentation resulted in initial diagnostic confusion and delayed the diagnosis of KD and initiation of IVIG treatment. Both patients had complete resolution of their liver dysfunction shortly after receiving IVIG, and neither developed coronary artery abnormalities.
As the mechanism of hypoalbuminemia in KD is incompletely understood and likely multifactorial, we elected not to include it as an element in our definition of abnormal LFTs. This is supported by the observation that the median serum albumin was low but not significantly different between the LFT groups. Hypoalbuminemia is commonly observed in patients with KD, and several mechanisms to explain why it occurs have been proposed.11–13
Inflammatory processes have been associated with hypoalbuminemia and appear to be mediated, at least in part, by inflammatory cytokines directing protein synthesis toward increased production of acute phase proteins (ie, CRP), with a subsequent decrease in production of other proteins such as albumin.11
Also, during acute inflammation, there may be increased albumin escape across inflamed vessels, often referred to as capillary leak. Increased capillary permeability may occur as a result of hormonal-mediated, nerve-mediated, or cytokine-mediated (especially IL-2, interferon-α
, and IL-6) increases in the movement of albumin from the intravascular compartment into interstitial fluid.12
Finally, alterations in the interstitial gel matrix associated with an acute phase response may allow for additional interstitial space.13
The mechanism of abnormalities of LFTs in KD has not been established. Hypotheses include generalized inflammation, vasculitis of small and medium sized vessels, congestive heart failure secondary to myocarditis, nonsteroidal anti-inflammatory antipyretics, toxin-mediated effects, or a combination of these events.8,14 –17
Hydrops of the gallbladder has traditionally been thought to be secondary to a vasculitic process in the gallbladder wall, although enlarged lymph nodes surrounding and potentially obstructing the cystic duct have also been reported.18
In support of vasculitis as a potential cause of liver function abnormalities in KD, vasculitis was demonstrated in the liver of 6 of 37 KD patients autopsied.2
Other pathologic findings described in KD patients with hepatic presentation or in autopsies are inflammatory cell infiltration (predominantly polymorphonuclear leukocytes and eosinophils) in sinusoids and portal areas (usually localizing in the lumen of bile ducts), proliferation and/or swelling of Kupffer cells, fatty degeneration, and severe congestion.19–21
Giant mitochondria were seen by electron microscopy of a liver biopsy in a patient with KD who presented with cholestasis.20
As giant mitochondria possibly result from impaired fission because of oxidative damage to mitochondrial DNA, membranes, and proteins, it is possible that oxidant stress that is reported in acute KD may play a role in the pathogenesis of liver function abnormalities.22,23
An acute rise in serum concentration of total bile acids during the acute phase of KD that gradually normalized after IVIG treatment has also been reported. These investigators postulated that the rise in total bile acids may be explained by increased bile acid synthesis from cholesterol or damage to the bile duct cells of the biliary system by cytokine activation.24
In this study, IVIG resistant disease was significantly more common in the abnormal LFT group. Multivariate analysis identified high CRP and high bilirubin at presentation to be significant predictors for IVIG resistant disease. Two previous reports have also identified CRP and bilirubin as predictors for IVIG resistance, however, these 2 studies also identified transaminase elevation as a risk factor.17,25
One of these studies was performed in a Korean population and the other in a Japanese population. In addition, a US study identified GGT >60 IU/L as a predictor for IVIG resistance.26
In our study, looking at GGT as a continuous variable, we did not find it to be a significant risk factor for IVIG resistance.
Although the association between IVIG resistant disease and coronary artery abnormalities has been reported previously, there was no difference in our study in the prevalence of coronary artery abnormalities between patients with and without LFT abnormalities.27,28
However, in the subset of the 163 patients who had complete LFTs obtained, there was a trend toward patients with abnormal LFTs to have a higher percentage of coronary artery abnormalities (31% vs. 19%, P
There are a few limitations to our study. First, not all of the patients included in our study had a complete set of LFTs performed. In particular, several patients did not have a GGT obtained. To control for this potential bias, we conducted a separate analysis of the 163 patients who had complete LFTs. The results from this analysis did not change any of the study conclusions (data not shown). A second possible limitation to our study is that our sample size may have been too small to detect significant differences in coronary artery abnormalities between groups.
The present study demonstrates that abnormal liver panel tests are frequently found in patients with acute KD and are associated with IVIG resistant disease. In particular, elevated bilirubin or CRP is an independent risk factor for IVIG resistant disease.