Kawasaki disease (KD) is the most common vasculitis in childhood, still representing the leading cause of acquired heart disease among children of developed countries (1). Diagnostic criteria for KD exist, but atypical or incomplete forms can be observed in almost 20% of patients (2), representing a high clinical risk for developing heart disease (3). Several atypical manifestations of KD have been reported (4), and liver involvement with histological evidence of inflammatory bile duct injury and proliferation has already been sporadically related to KD (5).
The purpose of our study was to report the clinical features of acute febrile cholestatic liver injury in children with KD. For this reason, we retrospectively reviewed the records of all patients who presented with febrile cholestatic jaundice from 2003 through 2010 in 2 pediatric clinics in northern Italy. The reports of 5 cases with KD involving liver and biliary tract are the basis of this article.
This is a bicentric retrospective study based on institutional review board–approved record review. Only records of patients who met criteria for febrile cholestatic jaundice, and had disease onset before age 16 years, were reviewed.
Criteria for febrile cholestatic jaundice were considered the following: presence of fever at time of admission (≥38.5°C); presence of clinically apparent jaundice with serum concentration of total bilirubin ≥3 mg/dL; and elevation of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and γ-glutamyl transpeptidase (GGT) activity.
All of the patients were first seen between 2003 and 2010 in the following tertiary care centers: Department of Pediatrics, IRCCS Burlo Garofolo, University of Trieste, Italy; and the Department of Pediatrics, Gastrointestinal and Liver Unit, University Hospital Santa Chiara, Pisa, Italy. The clinical course, physical examination at admission, and laboratory tests were evaluated.
Patients reviewed were 12 boys and 12 girls (median age 7 years 3 months, range 1 year–13 years 6 months). All of the parents were asked if patients were taking some medicaments at time of onset of the disease. All of the children had serologic evaluation to detect underlying viral infection, metabolic diseases, or other autoimmune diseases. KD was finally diagnosed in 5 patients. Thirteen of the remaining 19 patients received serologically confirmed diagnosis of viral cholestatic hepatitis (4 caused by Epstein-Barr virus, 4 by hepatitis A virus, 2 by cytomegalovirus, 2 by adenovirus, 1 by herpes simplex virus), 4 patients received diagnosis of drug-induced cholestatic liver injury (2 patients caused by azathioprine, 1 by amoxicillin and 1 by azithromycin), 1 patient presented with choledocal cyst, and 1 presented with symptomatic cholelithiasis.
The main clinical features of the 5 patients finally diagnosed with KD were fever, rash, and jaundice. All of the patients presented with liver enlargement at physical examination as well as a rise in inflammatory indices (C-reactive protein [CRP]; erythrocyte sedimentation rate, [ESR]). Clinical and laboratory features are summarized in Tables 1 and 2. In all of the patients, concomitant viral infections, autoimmune hepatitis, or metabolic disease was ruled out. All of the patients were treated with intravenous immunoglobulins (IVIG) and oral acetylsalicylic acid (ASA) with resolution of symptoms and no cardiac complication.
A 3-year-old boy presented with a 5-day history of urticarian rash, fever, and jaundice. Physical examination revealed palmar and perineal erythema with monolateral cervical nodes, and hepatosplenomegaly. Laboratory findings showed neutrophilic leukocytosis (13,400 cells/mm3, with 77% neutrophils), hyperbilirubinemia (total/conjugated bilirubin: 4.0/3.1 mg/dL), elevation of ESR (49 mm/hour normal value <20), CRP was 5.4 mg/dL, (normal value <0.5), ALT 7 times the upper limit of normal (N), AST 4 × N, and GGT 6.5 × N. Abdominal ultrasound was unremarkable. The day after, cheilitis and conjunctivitis appeared, suggesting KD. Resolution of symptoms and normalization of liver enzymes occurred after administration of high-dose IVIG (2 g/kg) and ASA (50 mg · kg−1 · day−1), without further cardiac complications.
A 10-year-old girl was admitted for a 20-day history of persistent fever with arthralgia, urticarian rash, and a recent onset of jaundice. Physical examination revealed jaundice, urticarian rash, and hepatosplenomegaly. Laboratory examination showed leukocytosis (15,950 cells/mm3) with elevation of ESR (50 mm/hour), CRP (4.4 mg/dL), bilirubin (total/conjugated bilirubin 5.2/5 mg/dL), and a marked increase of ALT (37 × N), AST (27 × N), and GGT (8 × N). Abdominal ultrasound revealed thickening of gallbladder walls. The day after mucositis, cheilitis and extremities desquamation appeared, suggesting KD. IVIG (2 g/kg), ASA (40 mg/kg), and corticosteroids were administered. A complete clinical and biochemical remission was gained in 24 hours. No cardiac involvement was found.
A 4-year-old girl was admitted for a 10-day history characterized by persistent fever, scarlet fever–like rash, and recent onset of jaundice. Physical examination revealed jaundice, rash, and hepatosplenomegaly. Abdominal ultrasound was negative, and laboratory findings showed hyperbilirubinemia (total/conjugated bilirubin 3.4/2.5 mg/dL), elevation of ESR (77 mm/hour), CRP (3.3 mg/dL), and elevation of liver enzymes (ALT 37 × N, AST 27 × N, GGT 8 × N). Further appearance of mucositis, conjunctivitis, and extremities changes were consistent with KD diagnosis. ASA (35 mg/kg) was started, but a complete resolution of clinical symptoms and laboratory abnormalities was achieved after IVIG administration (2 g/kg), without cardiac complications.
A 1-year-old child with fever and scarlet fever–like rash abruptly developed jaundice. Clinical examination revealed jaundice; mild bilateral conjunctival injection; dry, cracked lips; pharyngitis; and hepatomegaly. Blood test showed leukocytosis (14,100 cells/mm3 with 76% neutrophils) with elevation of ESR (62 mm/hour) and evidence of cholestatic jaundice (total/conjugated bilirubin 6.0/4.9 mg/dL, elevation of AST [5 × N], ALT [20 × N], and GGT [7 × N]). Abdominal ultrasound was negative as well as electrocardiogram and echocardiography. KD was suspected, and IVIG (2 g · kg−1 · day−1) and ASA (30 mg · kg−1 · day−1) were given at fifth day from disease onset. Thereafter, lamellar desquamation of fingers and palms developed. The child recovered completely and a follow-up echocardiography was normal.
An 8-year-old child was admitted for fever lasting for 6 days, abdominal pain, scarlet fever–like rash, and dark urine. Clinical examination showed mild jaundice; a strawberry tongue; mild bilateral conjunctival injection; dry, cracked lips; and liver enlargement with a palpable spleen. Blood examinations showed leukocytosis (12,000 cells/mm3 with 74% neutrophils), total/conjugated bilirubin of 3.1/1.7 mg/dL, and elevation of AST (2.5 × N), ALT (11 × N), and GGT (4 × N). Abdominal ultrasound was normal. IVIG (2 g/kg) were given with ASA (30 mg · kg−1 · day−1) with disappearance of rash and fever in 24 hours. Electrocardiogram and echocardiography were normal. Lamellar desquamation of fingers, palms, and soles developed. Liver test became normal in 4 weeks. A follow-up echocardiography excluded coronary complications.
The classic diagnostic criteria of KD include at least 5 days of fever and 4 of the 5 following conditions: bilateral nonpurulent conjunctival injection, oral mucosal changes (erythema or dryness or fissuring of the lips, strawberry tongue, erythema of the oropharynx), peripheral extremity changes (edema or erythema of palms or soles, desquamation of tips of fingers and toes), rash (polymorphic and nonvesicular, commonly truncal), and cervical unilateral lymphadenopathy (>1.5 cm) (6).
Although gastrointestinal involvement does not belong to the classic diagnostic criteria, symptomatic or asymptomatic gallbladder hydrops has been often associated with KD onset (7–9); on the contrary, jaundice of acute onset has been only occasionally reported (10,11). Acute cholestatic injury in children and adults may arise from many causes such as extrahepatic biliary obstruction, autoimmune disorders, drug-induced liver injury, metabolic disease, and infections (12).
In our study reviewing patients who were admitted for febrile cholestatic jaundice in 2 tertiary pediatric care centers, KD was the second most frequent cause (21%) after viral infections followed by drug-induced liver injury (16% of cases). Febrile cholestatic jaundice may thus represent the main form of gastrointestinal involvement at onset of KD, and gallbladder ultrasound abnormalities such as hydrops or increased gallbladder wall thickness may be absent; in fact, only 1 patient among those we described presented ultrasound evidence of gallbladder involvement with thickening of the gallbladder wall.
At the time of admission, all 5 patients affected by KD presented with atypical and incomplete form of the disease; in fact, the main clinical features of these patients were persistent fever, rash, and jaundice. Only 2 of them showed additional clinical features consistent with KD such as bilateral nonexudative conjunctival injection and changes in lips and oral cavity. All of the patients presented at physical examination liver enlargement and a rise in inflammatory markers, liver enzymes, and cholestatic indices.
After admission, however, the patients developed some other clinical manifestations compatible with KD: conjunctivitis (2 patients), changes in lips or oral cavity (3 patients), extremities changes (2 patients), and cervical lymphoadenopathy (1 patient), which helped physicians make correct clinical diagnoses.
In all of these patients, hepatotropic viral infections (hepatitis A, hepatitis B, hepatitis C, adenovirus, cytomegalovirus, Epstein-Barr virus, herpes simplex virus, parvovirus B), autoimmune hepatitis (absence of serum autoantibodies), and Wilson disease were ruled out by appropriate serological tests. No one was taking drugs.
Diagnosis of the atypical and incomplete form remains a clinical dilemma for patients with KD. Early reports suggested a severe prognosis for children with atypical or incomplete KD, including a sobering mortality rate of 41% among children with coronary artery aneurisms (13). This death rate is at least partially due to inherent bias, in that by definition if there are fewer than the required criteria, coronary abnormalities have traditionally been required to confirm the diagnosis. Moreover, diagnostic delays are more common if the clinical phenotype is not typical; delayed treatment results in poorer outcomes (14). One group requiring particular care is infants. Incomplete features of KD are more common in children younger than 6 months or older than 5 years, and particularly in the younger group, the percentage demonstrating full diagnostic criteria is lower and the incidence of coronary arteritis higher (15).
Organ systems involved in atypical KD are wide and include renal, central nervous system, ocular, and gastrointestinal implication. Abdominal manifestations may sometimes be so acute and severe as to mimic appendicitis or pancreatitis, leading to surgical interventions (16). A report described 10 children, most of whom did not have the required classical criteria, who had disease onset with severe gastrointestinal complaints (acute abdominal pain and distension, vomiting, hepatomegaly, and jaundice) (8).
The pathophysiology of cholestatic liver damage occurring in KD is unknown. The presence of an increase in serum GGT activity (17), a marker of cholangiocyte injury, suggests bile duct damage (18). When a liver biopsy was performed in patients with KD and cholestatic jaundice, the hepatic lobule was relatively intact, whereas portal tracts were expanded by an inflammatory infiltrate of neutrophils and eosinophils around the lumina of bile duct cells with ductular proliferation and evidence of cholangiocyte injury, featuring an acute cholangiolitis (5,19). The association in some patients with acute hydrops of gallbladder suggests that inflammatory injury to cholangiocytes may extend from small to large bile ducts.
The 5 patients with KD we described presented with clinical features that were consistent with febrile cholestatic jaundice, but no one presented with so severe a disease to suggest the need for surgical intervention. To promptly diagnose and consequently treat these patients, we would like to emphasize the importance of detecting rash in a patient with febrile cholestatic jaundice: in our experience, rash was the most greatly suggestive feature of KD.
Patients with KD and acute cholestatic jaundice should be treated without delay; in our series, almost all of the patients were treated with IVIG within the first 10 days from onset except patient 2; however, all of them completely recovered in almost 24 hours and no one needed further infusions. Moreover, among total follow-up time, for all of the patients longer than 12 months, liver function completely normalized in all of the subjects and no patient developed recurrent episodes of intrahepatic cholestasis. We also emphasize that no patient presented cardiac involvement, either in the acute phase or during follow-up.
Despite the absence of coronary abnormalities revealed in our series, prompt diagnosis of KD is crucial because the administration of IVIG within 10 days reduces the rate of coronary abnormalities to <5%. Such atypical clinical pictures of KD may cause delay in treatment.
In conclusion, considering the relative high frequency of this condition, a high index of suspicion of KD should be maintained in patients presenting with febrile cholestatic jaundice.
1. Burns JC, Kushner HI, Bastian JF, et al. Kawasaki disease
: a brief history. Pediatrics
2. Falcini F, Cimaz R, Calabri GB, et al. Kawasaki's disease in northern Italy: a multicenter retrospective study of 250 patients. Clin Exp Rheumatol
3. Baker AL, Newburger JW. Cardiology patient pages. Kawasaki disease
4. Cimaz R, Sundel R. Atypical and incomplete Kawasaki disease
. Best Pract Res Clin Rheumatol
5. Bader-Meunier B, Hadchouel M, Fabre M, et al. Intrahepatic bile duct damage in children
with Kawasaki disease
. J Pediatr
6. Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment, and long-term management of Kawasaki disease
: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease
, Council on Cardiovascular Disease in the Young, American Heart Association. Pediatrics
7. Singh R, Ward C, Walton M, et al. Atypical Kawasaki disease
and gastrointestinal manifestations. Paediatr Child Health
8. Zulian F, Falcini F, Zancan L, et al. Acute surgical abdomen as presenting manifestation of Kawasaki disease
. J Pediatr
9. Magilavy DB, Speert DP, Silver TM, et al. Mucocutaneous lymph node syndrome: report of two cases complicated by gallbladder hydrops and diagnosed by ultrasound. Pediatrics
10. Falcini F, Resti M, Azzari C, et al. Acute febrile cholestasis as an inaugural manifestation of Kawasaki's disease. Clin Exp Rheumatol
11. Valentini P, Ausili E, Schiavino A, et al. Acute cholestasis
: atypical onset of Kawasaki disease
. Dig Liver Dis
12. Bernal W, Auzinger G, Dhawan A, et al. Acute liver failure. Lancet
13. Levy M, Koren G. Atypical Kawasaki disease
: analysis of clinical presentation and diagnostic clues. Pediatr Infect Dis J
14. Anderson MS, Todd JK, Glode MP. Delayed diagnosis of Kawasaki syndrome: an analysis of the problem. Pediatrics
15. Genizi J, Miron D, Spiegel R, et al. Kawasaki disease
in very young infants: high prevalence of atypical presentation and coronary arteritis. Clin Pediatr (Phila)
16. Beiler HA, Schmidt KG, von Herbay A, et al. Ischemic small bowel strictures in a case of incomplete Kawasaki disease
. J Pediatr Surg
17. Ting EC, Capparelli EV, Billman GF, et al. Elevated gamma-glutamyltransferase concentrations in patients with acute Kawasaki disease
. Pediatr Infect Dis J
18. Maggiore G, Bernard O, Hadchouel M, et al. Diagnostic value of serum gamma-glutamyl transpeptidase activity in liver diseases in children
. J Pediatr Gastroenterol Nutr
19. Edwards KM, Glick AD, Greene HL. Intrahepatic cholangitis associated with mucocutaneous lymph node syndrome. J Pediatr Gastroenterol Nutr