Kawasaki disease with dilatation of the common bile duct: A case report and review of literature

Kawasaki disease (KD) is a syndrome that results in acute systemic vasculitis and is a major cause of acquired heart disease in developed countries. KD is diagnosed based on certain characteristic symptoms and echocardiogram results. It has been reported that abdominal ultrasound is of value in supporting the diagnosis of KD. Nevertheless, abdominal ultrasound is not a routine procedure in KD. Moreover, dilatation of the common bile duct (CBD) has been rarely reported in previous cases.

gallbladder, 7 thickening of gallbladder wall, 8 and segmental bowelwall thickening 9 support the diagnosis of KD. Nevertheless, abdominal ultrasound is not a routine procedure in KD. Moreover, dilatation of the common bile duct (CBD) has been rarely reported.
Herein, we report the case of a 4-year-old boy with KD, and with various ultrasound findings including dilatation of the CBD during the acute phase of the disease.

| C A S E PRE S ENTATI ON
A 4-year-old boy was admitted to our hospital because of markedly high levels of transaminase. The patient had been well until 3 days before admission, when a runny nose and fever were noted. On the day of symptom onset, the patient was evaluated by his primary-care pediatrician and was diagnosed as having bronchitis. After which, the patient experienced nausea and vomiting and was taken to the emergency department at another hospital. At the other hospital, the patient did not appear ill but had redness in the pharynx and cervical lymphadenopathy. The blood test results showed high transaminase levels, after which he was transferred to our hospital.
On arrival, the patient appeared ill and was febrile, with a body temperature of 40.4°C. His blood pressure was 97/48 mm Hg, pulse rate was 148 beats per minute, respiratory rate was 28 breaths per minute, with oxygen saturation of 96% while breathing ambient air.
Physical examination revealed bilateral conjunctival congestion, erythema around the navel, reddening and indurative edema of palms, and cervical lymphadenopathy. There was no evidence of reddening of the lips, strawberry tongue, and redness at the site of bacille Calmette-Guèrin inoculation. The blood test results showed markedly high level of transaminase with acute inflammatory response (white blood cell count, 16 400/µL; erythrocyte sedimentation rate, 50 mm/h; C-reactive protein, 157 mg/L; aspartate aminotransferase, 5323 U/L; alanine aminotransferase, 1554 U/L; total bilirubin, 1.5 mg/dL; γ-glutamyl transpeptidase, 149 U/L; and total bile acid, 381.1 µmol/L). There was no evidence of viral hepatitis (negative results of hepatitis A virus antibody, hepatitis B surface antigen, hepatitis C virus antibody, and polymerase chain reaction for Epstein-Barr virus, cytomegalovirus, herpes simplex viruses 1 and 2, and human herpes virus 6) or autoimmune hepatitis. No bacterial growth was detected in any of the cultures. Some cytokines were measured using cytokine bead assay (BD™ CBA kit, Becton Dickinson, Franklin Lakes, NJ, USA); interleukin-6 (IL-6) level increased to 87.7 pg/mL (reference value <7.0 pg/mL), IL-10 increased to 32.0 pg/mL (reference value <5.0 pg/mL), whereas IL-1β and tumor necrosis factorα levels were normal. Although the echocardiogram showed normal cardiac function with no evidence of valve regurgitation, slight dilatation of the left main trunk was observed (Figure 1). Ultrasonographic evaluation of cervical lymph nodes revealed multiple hypoechoicenlarged nodes, which resembled a cluster of grapes ( Figure 2A).
An abdominal ultrasound showed thickening of the gallbladder wall, increased periportal echogenicity throughout the liver parenchyma, and dilatation of the CBD with a maximum diameter of 6.6 mm at the intrapancreatic region (4-year-old standard value, 2.3 mm, upper limit, 3.7 mm) 10  After admission, intravenous administration of cefotaxime was initiated; however, it was ineffective. On the next day of hospitalization (day 4 of fever), reddening of lips was observed and the patient was diagnosed with KD based on the presence of five principal symptoms. 5 Intravenous immunoglobulin (2 g/kg) was administered as initial therapy. Oral aspirin was not administered because of the high transaminase level. A Kobayashi score of 8 suggested that the patient was at high risk of intravenous immunoglobulin resistance. 11 Viral hepatitis could not be completely ruled out at this point; therefore, steroid administration was avoided. The patient's fever rapidly decreased with the initiation of treatment, and transaminase level gradually improved. However, the patient's fever relapsed on day 6, so intravenous immunoglobulin (2 g/kg) and intravenous prednisolone (2 mg/kg/day) were administered as second-line therapy.
Flurbiprofen, which is used as an alternative to oral aspirin in Japan when high transaminase levels are observed, 12

| D ISCUSS I ON
Our patient was diagnosed with acute KD and showed dilatation of the CBD. Very few reports are available on biliary dilatation in KD patients (Table 1). To the best of our knowledge, only one Japanese study has previously reported on a case of acute-phase KD (only available in the Japanese literature), 13 and our case is the first of its kind to be reported in an international journal.
A Japanese report evaluated the hepatobiliary system using abdominal ultrasound in 68 patients with KD every 3 or 4 days. 13 Of the 68 patients, 20 had dilatation of the gallbladder, and among them, four patients had thickening of the gallbladder wall and three had dilatation of the CBD in acute phase. All three patients with dilatation of the CBD had high transaminase level and cholestasis. Dilatation of the CBD regressed spontaneously in 2 weeks to 1 month (Table 1, cases A1-A3). In the present case, the peak value of alanine aminotransferase and the maximum diameter of the CBD were most severe, and took longer to normalize.
In the subacute phase, which is also rare, a total of three cases of biliary dilatation have been reported. 14 (Table 1, case S3). 15 One of the three cases underwent CBD stent placement, the others spontaneously improved. These findings indicate that KD may lead to cholecystitis and intrahepatic/extrahepatic cholangitis. The relationship between these pathological conditions and ultrasound findings remains unclear. However, it is presumed that inflammation of the cystic duct results in obstruction, causing hydrops of the gallbladder. 13 In addition, our case suggests that thickening of the gallbladder wall, increased periportal echogenicity throughout the liver parenchyma, and dilatation of the CBD also relate to inflammation and subsequent edema and obstruction at each location ( Figure 3).
Our patient demonstrated IL-6 elevation detected using a cytokine bead assay (BD™ CBA kit). Interleukin-6 was discovered as a hepatocyte-stimulating factor 2 induced in acute liver inflammation. 19 It reduces gene expression of excretory transporters such as the bile salt export pump ABCB11 and multidrug-resistanceassociated protein 2 in primary human hepatocyte cell lines, 20 which impair the secretion of bile acids into the bile ducts. Bile acids were also elevated in our patient. Elevated IL-6 may have contributed to cholestasis and led to hepatobiliary abnormalities in KD.

| CON CLUS ION
This case of a 4-year-old with dilatation of the CBD in acute KD highlights the usefulness of abdominal ultrasound and the importance of considering dilatation of the CBD as one of the complications of KD.
Abdominal ultrasound is not a routine procedure in KD, so it is possible that CBD dilatation in KD may remain latent if not investigated thoroughly. Further prospective studies to support these findings are warranted.

ACK N OWLED G EM ENTS
We would like to thank Editage (https://www.edita ge.com/) for editing and reviewing this manuscript for English language.

CO N FLI C T O F I NTE R E S T
None of the authors have any financial or non-financial competing interests to declare in relation to this manuscript.

AUTH O R CO NTR I B UTI O N S
AM and KI made substantial contributions to the conception or design of the work. AM and TI contributed to the acquisition, analysis, or interpretation of ultrasound findings for the work.KI and MT contributed to the acquisition, analysis, or interpretation of comprehensive data for the work. AM and KI drafted the work and HT revised the work critically for important intellectual content. Final approval of the version to be published was provided by AM, KI, TI, MT, and HT.

E TH I C S A PPROVA L A N D CO N S E NT TO PA RTI CI PATE
This study was approved by the ethics committee of the University of Tsukuba Hospital. Written informed consent was obtained from the patient's parents.

CO N S E NT FO R PU B LI C ATI O N
Written informed consent was obtained from the patient's parents.