{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T11:36:29Z","timestamp":1786534589034,"version":"build-2736575974"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>This review provides a comprehensive synthesis of hepatobiliary involvement in Kawasaki disease (KD), with emphasis on cholestatic hepatitis as a clinical sentinel of hyperinflammation. We critically evaluate current evidence, propose an integrated pathogenic framework\u2014the hepatic vascular-biliary unit injury hypothesis\u2014and identify priority research areas.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Data sources<\/jats:title>\n                    <jats:p>Narrative review of high-quality literature (2015\u20132025) with inclusion of seminal historical studies, using Oxford Centre for Evidence-Based Medicine (OCEBM) evidence-level grading.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Cholestatic hepatitis occurs in 5.2%\u201317.8% of acute KD cases, rising to 22%\u201335% among intravenous immunoglobulin (IVIG)-resistant patients. Large retrospective cohort studies (OCEBM Level 3b) have identified a clinical \u201crisk triangle\u201d comprising IVIG resistance, coronary artery lesions (CALs), and cholestasis as interdependent factors. We propose the hepatic vascular-biliary unit injury hypothesis as an integrated pathogenic framework, supported by correlative pathological and molecular evidence (OCEBM Level 3\u20134), though causality remains unproven and requires validation in conditional endothelial-specific animal models. Current therapeutic evidence for moderate-to-severe cholestasis derives exclusively from retrospective cohorts and case series (OCEBM Level 3\u20134). Emerging evidence from Phase I\/IIa trials supports the use of interleukin-1 blockade (anakinra) in refractory cases, predominantly derived from studies of coronary artery aneurysms rather than cholestasis-specific populations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>KD-associated cholestatic hepatitis is a critical marker of disease severity with prognostic significance. The hepatic vascular-biliary unit hypothesis provides a mechanistic framework linking systemic vasculitis to cholestasis, pending experimental validation. Definitive evidence for optimal therapeutic strategies is lacking; well-designed randomized controlled trials specifically targeting the cholestasis subpopulation are urgently needed. Given the highest incidence in East Asian populations, clinicians in this region should maintain a particularly high index of suspicion for KD-associated cholestasis, particularly in infants presenting with unexplained jaundice.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1852636","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T11:02:44Z","timestamp":1786532564000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Hepatobiliary involvement in Kawasaki disease: from cholestatic hepatitis to the hepatic vascular-biliary unit hypothesis\u2014a state-of-the-art review"],"prefix":"10.3389","volume":"17","author":[{"given":"Yong-Xing","family":"Zhong","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Shaoxing Maternity and Child Health Care Hospital","place":["Shaoxing, Zhejiang, China"]},{"name":"Maternity and Child Health Care Affiliated Hospital, Shaoxing University","place":["Shaoxing, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Zheng","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital, Zhejiang University School of Medicine","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang-Yan","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Shaoxing Maternity and Child Health Care Hospital","place":["Shaoxing, Zhejiang, China"]},{"name":"Maternity and Child Health Care Affiliated Hospital, Shaoxing University","place":["Shaoxing, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000000484","article-title":"Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association","volume":"135","author":"McCrindle","year":"2017","journal-title":"Circulation"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1007\/s10238-023-01265-0","article-title":"The systemic immune-inflammation index (SII) and coronary artery lesions in Kawasaki disease","volume":"24","author":"Huang","year":"2024","journal-title":"Clin Exp Med"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1025","DOI":"10.1186\/s40001-025-03254-3","article-title":"Cholestasis as a complication in Kawasaki disease: an atypical clinical presentation","volume":"30","author":"Hong","year":"2025","journal-title":"Eur J Med Res"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1017\/S104795112500191X","article-title":"Global incidence of Kawasaki disease: a systematic review","volume":"35","author":"Kang","year":"2025","journal-title":"Cardiol Young"},{"key":"B5","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1186\/s12887-024-05278-w","article-title":"Analysis of the clinical characteristics of patients with Kawasaki disease complicated with cholestasis","volume":"24","author":"Yang","year":"2024","journal-title":"BMC Pediatr"},{"key":"B6","article-title":"Clinical characteristics of Kawasaki disease with cholestatic jaundice as the initial symptom","volume":"30","author":"Zhang","year":"2025","journal-title":"Chin Hepatol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2431-14-51","article-title":"Hepatobiliary risk factors for clinical outcome of Kawasaki disease in children","volume":"14","author":"Yi","year":"2014","journal-title":"BMC Pediatr"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1097\/MPG.0b013e31825513de","article-title":"Acute febrile cholestatic jaundice in children: keep in mind Kawasaki disease","volume":"55","author":"Taddio","year":"2012","journal-title":"J Pediatr Gastroenterol Nutr"},{"key":"B9","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1007\/s12098-022-04131-1","article-title":"Cholestatic jaundice as atypical initial feature of Kawasaki disease","volume":"89","author":"Zhu","year":"2022","journal-title":"Indian J Pediatr"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.5409\/wjcp.v14.i3.106693","article-title":"Recent advances in research on gene polymorphisms in Kawasaki disease","volume":"14","author":"Yang","year":"2025","journal-title":"World J Clin Pediatr"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2021680","article-title":"Multisystem inflammatory syndrome in U.S. children and adolescents","volume":"383","author":"Feldstein","year":"2020","journal-title":"N Engl J Med"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1002\/hep.31526","article-title":"Acute hepatitis is a prominent presentation of the multisystem inflammatory syndrome in children: a single-center report","volume":"72","author":"Cantor","year":"2020","journal-title":"Hepatology"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2017.03.025","article-title":"High risk of coronary artery aneurysms in infants younger than 6 months of age with Kawasaki disease","volume":"185","author":"Salgado","year":"2017","journal-title":"J Pediatr"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2022.103240","article-title":"Immune and non-immune mechanisms that determine vasculitis and coronary artery aneurysm topography in Kawasaki disease and MIS-C","volume":"22","author":"Giryes","year":"2023","journal-title":"Autoimmun Rev"},{"key":"B15","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1186\/s12876-020-01461-2","article-title":"Hepatic predominant presentation of Kawasaki disease in adolescence case report and review of literature","volume":"20","author":"Pratap","year":"2020","journal-title":"BMC Gastroenterol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.105.592865","article-title":"Prediction of intravenous immunoglobulin unresponsiveness in patients with Kawasaki disease","volume":"113","author":"Kobayashi","year":"2006","journal-title":"Circulation"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0176957","article-title":"A comparison of the predictive validity of the combination of the neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio and other risk scoring systems for intravenous immunoglobulin (IVIG)-resistance in Kawasaki disease","volume":"12","author":"Takeshita","year":"2017","journal-title":"PLoS One"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.5863\/1551-6776-27.7.669","article-title":"Predicting intravenous immunoglobulin resistance among North American children hospitalized with Kawasaki disease","volume":"27","author":"Singh","year":"2022","journal-title":"J Pediatr Pharmacol Ther"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2024.112194","article-title":"Development of an immunoinflammatory indicator-related dynamic nomogram based on machine learning for the prediction of intravenous immunoglobulin-resistant Kawasaki disease patients","volume":"134","author":"Wang","year":"2024","journal-title":"Int Immunopharmacol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1186\/s12969-024-01015-w","article-title":"A novel scoring system based on sIL-2R for predicting IVIG resistance in Chinese children with KD","volume":"22","author":"Zeng","year":"2024","journal-title":"Pediatr Rheumatol Online J"},{"key":"B21","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1186\/s12969-021-00582-6","article-title":"Predictive model based on gene and laboratory data for intravenous immunoglobulin resistance in Kawasaki disease in a Chinese population","volume":"19","author":"Meng","year":"2021","journal-title":"Pediatr Rheumatol Online J"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2025.1549900","article-title":"Alterations in bile acid metabolites associated with pathogenicity and IVIG resistance in Kawasaki disease","volume":"12","author":"Wang","year":"2025","journal-title":"Front Cardiovasc Med"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.18176\/jiaci.0300","article-title":"Autoimmune aspects of Kawasaki disease","volume":"29","author":"Sakurai","year":"2019","journal-title":"J Investig Allergol Clin Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3400\/avd.sasvp01003","article-title":"Kawasaki disease as a systemic vasculitis in childhood","volume":"3","author":"Takahashi","year":"2010","journal-title":"Ann Vasc Dis"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3390\/medicina58121833","article-title":"Kawasaki disease with hepatobiliary manifestations","volume":"58","author":"Suhaini","year":"2022","journal-title":"Medicina (Kaunas)"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-020-0426-0","article-title":"Kawasaki disease: pathophysiology and insights from mouse models","volume":"16","author":"Noval Rivas","year":"2020","journal-title":"Nat Rev Rheumatol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3760\/cma.j.issn.0253-3758.2016.03.012","article-title":"Phosphatase and tensin homolog deleted on chromosome ten\/phosphatidyl inositol 3-kinase\/vascular endothelial growth factor signaling pathway changes in the rabbit Kawasaki disease model","volume":"44","author":"Niu","year":"2016","journal-title":"Zhonghua Xin Xue Guan Bing Za Zhi"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1002\/art.33316","article-title":"Disruption of vascular homeostasis in patients with Kawasaki disease: involvement of vascular endothelial growth factor and angiopoietins","volume":"64","author":"Breunis","year":"2012","journal-title":"Arthritis Rheum"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.96767","article-title":"Successful resolution of coronary thrombus in a child with Kawasaki disease and giant coronary artery aneurysms using anticoagulation therapy","volume":"17","author":"Almasaeid","year":"2025","journal-title":"Cureus"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3390\/children9050672","article-title":"Efficacy of anakinra on multiple coronary arteries aneurysms in an infant with recurrent Kawasaki disease, complicated by macrophage activation syndrome","volume":"9","author":"Bossi","year":"2022","journal-title":"Children (Basel)"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.124.321201","article-title":"Gut microbiota alterations in patients with Kawasaki disease","volume":"45","author":"Jena","year":"2025","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1541939","article-title":"Identification of novel metabolism-related biomarkers of Kawasaki disease by integrating single-cell RNA sequencing analysis and machine learning algorithms","volume":"16","author":"Feng","year":"2025","journal-title":"Front Immunol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2021.738215","article-title":"Kawasaki disease with combined cholestatic hepatitis and Mycoplasma pneumoniae infection: a case report and literature review","volume":"9","author":"Huang","year":"2022","journal-title":"Front Pediatr"},{"key":"B34","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1186\/s12876-020-01495-6","article-title":"Acute cholestasis as uncommon onset of Kawasaki disease: a case report","volume":"20","author":"Gallerani","year":"2020","journal-title":"BMC Gastroenterol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1111\/1756-185X.14208","article-title":"Kawasaki disease with dilatation of the common bile duct: a case report and review of literature","volume":"24","author":"Morita","year":"2021","journal-title":"Int J Rheum Dis"},{"key":"B36","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1186\/s13052-016-0238-7","article-title":"Kawasaki disease and hepatobiliary involvement: report of two cases","volume":"42","author":"Keeling","year":"2016","journal-title":"Ital J Pediatr"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1097\/MPG.0000000000001334","article-title":"Guideline for the evaluation of cholestatic jaundice in infants: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition","volume":"64","author":"Fawaz","year":"2017","journal-title":"J Pediatr Gastroenterol Nutr"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1111\/ped.15543","article-title":"Clinical implications of gallbladder enlargement in Kawasaki disease","volume":"65","author":"Miyazawa","year":"2023","journal-title":"Pediatr Int"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.4070\/kcj.2010.40.3.137","article-title":"Relationship between gallbladder distension and lipid profiles in Kawasaki disease","volume":"40","author":"Kim","year":"2010","journal-title":"Korean Circ J"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1007\/s00431-024-05689-y","article-title":"Methylprednisolone pulse and prednisolone for intensification of primary treatment in Kawasaki disease patients at high risk of treatment resistance: a multicenter prospective cohort study","volume":"183","author":"Miura","year":"2024","journal-title":"Eur J Pediatr"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(11)61930-2","article-title":"Efficacy of immunoglobulin plus prednisolone for prevention of coronary artery abnormalities in severe Kawasaki disease (RAISE study): a randomised, open-label, blinded-endpoints trial","volume":"379","author":"Kobayashi","year":"2012","journal-title":"Lancet"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1002\/art.41481","article-title":"Phase II open label study of anakinra in intravenous immunoglobulin-resistant Kawasaki disease","volume":"73","author":"Kon\u00e9-Paut","year":"2021","journal-title":"Arthritis Rheumatol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2021.12.035","article-title":"Anakinra treatment in patients with acute Kawasaki disease with coronary artery aneurysms: a phase I\/IIa trial","volume":"243","author":"Yang","year":"2022","journal-title":"J Pediatr"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2021.12.035","article-title":"Anakinra treatment in patients with acute Kawasaki disease with coronary artery aneurysms: a phase I\/IIa trial","volume":"243","author":"Yang","year":"2022","journal-title":"J Pediatr"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1007\/s40272-020-00421-3","article-title":"Anakinra for treatment-resistant Kawasaki disease: evidence from a literature review","volume":"22","author":"Ferrara","year":"2020","journal-title":"Paediatr Drugs"},{"key":"B46","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1186\/s12969-025-01143-x","article-title":"Anakinra for infants under six months with Kawasaki disease and coronary artery lesions: a multicenter case series and literature review","volume":"23","author":"Inguscio","year":"2025","journal-title":"Pediatr Rheumatol Online J"},{"key":"B47","unstructured":"A trial comparing the efficacy and safety of anakinra versus intravenous immunoglobulin (IVIG) retreatment, in patients with kawasaki disease who failed to respond to initial standard IVIG treatment (ANACOMP)\n          \n          \n          Bethesda, MD\n          National Library of Medicine (NLM)\n          ClinicalTrials.gov\n          \n          2020"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.94.6.1379","article-title":"Long-term consequences of Kawasaki disease. A 10- to 21-year follow-up study of 594 patients","volume":"94","author":"Kato","year":"1996","journal-title":"Circulation"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.4103\/aam.aam_27_25","article-title":"Atypical Kawasaki disease in a 5-month-old infant","volume":"24","author":"Rahiman","year":"2025","journal-title":"Ann Afr Med"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1852636\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T11:02:48Z","timestamp":1786532568000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1852636\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,12]]},"references-count":49,"alternative-id":["10.3389\/fimmu.2026.1852636"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1852636","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,12]]},"article-number":"1852636"}}