Association of autoimmune hepatobiliary pathology with inflammatory bowel diseases in children

Introduction. Hepatobiliary pathology (HBP) occurs in approximately 30% of patients with inflammatory bowel disease (IBD). However, the features of its course in the pediatric cohort of patients remain insufficiently studied. Purpose: to study the features of the course of autoimmune forms of HBD in children with IBD. Materials and methods. A comprehensive clinical, laboratory and instrumental examination was carried out in 84 children with autoimmune forms of HBP in combination with IBD (HBP+IBD), which made up the main group, and 79 patients with isolated forms of IBD included in the comparison group. Results. The prevalence of autoimmune HBP in IBD children was 10.2%. Primary sclerosing cholangitis (PSC) was diagnosed in 64.3% of cases, which was mainly associated with ulcerative colitis. The incidence of autoimmune hepatitis (AIH) was 8.3%. In the structure of the overlap syndrome, the most frequent combination was AIH+PSC (15.5%). The debut of the disease was manifested by diarrhea, abdominal pain syndrome, cytolysis and cholestasis syndromes, haemicolitis. With HBP+IBD, there was an increase in serum concentrations of alanine (ALT) and aspartate aminotransferases (AST), total protein, γ-glutamyl transferase (GGT), alkaline phosphatase, direct bilirubin and IgG. Approximately with the same frequency in PSC, antibodies to saccharomycetes (ASCA) - 80% and antibodies to the cytoplasm of neutrophils (ANCA) - 75% were detected. In AIH, antinuclear antibodies (ANA) and antibodies to liver and kidney microsomes (anti-LKM1) were detected in 100%. HBP-IBD equally (28.6%) revealed moderate fibrosis and cirrhosis, no fibrosis in 20.6%, moderate fibrosis in 15.9% of cases, mild fibrosis in 6,3%. Cirrhosis of the liver in 55.6% of cases was the outcome of the course of PSC, in 16.7% - AIH, in 27.8% was associated with the course of the overlap syndrome. Conclusion. Various forms of autoimmune HBP occur in 10.2% of cases, are more often associated with UC, are represented by PSC and AIH, occur in males, at the onset signs are clinically presented by diarrhea, abdominal pain syndrome, cytolysis and cholestasis syndromes, and haemicolitis.

Guan Q. A comprehensive review and update on the pathogenesis of inflammatory bowel disease. J. Immunol. Res. 2019; 2019: 7247238. https://doi.org/10.1155/2019/7247238

Marotto D., Atzeni F., Ardizzone S., Monteleone G., Giorgi V., Sarzi-Puttini P. Extra-intestinal manifestations of inflammatory bowel diseases. Pharmacol. Res. 2020; 161: 105206. https://doi.org/10.1016/j.phrs.2020.105206

DeFilippis E.M., Kumar S. Clinical presentation and outcomes of autoimmune hepatitis in inflammatory bowel disease. Dig. Dis. Sci. 2015; 60(10): 2873–80. https://doi.org/10.1007/s10620-015-3699-4

Palmela C., Peerani F., Castaneda D., Torres J., Itzkowitz S.H. Inflammatory bowel disease and primary sclerosing cholangitis: a review of the phenotype and associated specific features. Gut. Liver. 2018; 12(1): 17–29. https://doi.org/10.5009/gnl16510

Núñez F.P., Quera P.R., Gomollón F. Primary sclerosing cholangitis and inflammatory bowel disease: Intestine-liver interrelation. Colangitis esclerosante primaria y enfermedad inflamatoria intestinal: interrelación intestino-hígado. Gastroenterol. Hepatol. 2019; 42(5): 316–25. https://doi.org/10.1016/j.gastrohep.2019.02.004

de Vries A.B., Janse M., Blokzijl H., Weersma R.K. Distinctive inflammatory bowel disease phenotype in primary sclerosing cho­langitis. World J. Gastroenterol. 2015; 21(6): 1956–71. https://doi.org/10.3748/wjg.v21.i6.1956

de Krijger M., Wildenberg M.E., de Jonge W.J., Ponsioen C.Y. Return to sender: Lymphocyte trafficking mechanisms as contributors to primary sclerosing cholangitis. J. Hepatol. 2019; 71(3): 603–15. https://doi.org/10.1016/j.jhep.2019.05.006

Halling M.L., Kjeldsen J., Knudsen T., Nielsen J., Hansen L.K. Patients with inflammatory bowel disease have increased risk of autoimmune and inflammatory diseases. World J. Gastroenterol. 2017; 23(33): 6137–46. https://doi.org/10.3748/wjg.v23.i33.6137

Gulamhusein A.F., Juran B.D., Lazaridis K.N. Genome-wide association studies in primary biliary cirrhosis. Semin. Liver. Dis. 2015; 35(4): 392–401. https://doi.org/10.1055/s-0035-1567831

Shi T., Zhang T., Zhang L., Yang Y., Zhang H., Zhang F. The distribution and the fibrotic role of elevated inflammatory Th17 cells in patients with primary biliary cirrhosis. Medicine (Baltimore). 2015; 94(44): e1888. https://doi.org/0.1097/MD.0000000000001888

Keskin O., Idilman R. Sequential development of acute autoimmune hepatitis may lead to a serious clinical picture in primary biliary cirrhosis. Eur. J. Gastroenterol. Hepatol. 2015; 27(10): 1228–9. https://doi.org/0.1097/MEG.0000000000000417

Pinto C., Lagos I., Brahm J. Sequential overlap syndrome: Clinical characteristics of 10 patients. Ann. Hepatol. 2018; 17: 1123–4.

Lunder A.K., Hov J.R., Borthne A., Gleditsch J., Johannesen G., Tveit K., et al. Prevalence of sclerosing cholangitis detected by magnetic resonance cholangiography in patients with long-term inflammatory bowel disease. Gastroenterology. 2016; 151(4): 660–9.e4. https://doi.org/10.1053/j.gastro.2016.06.021

Belle A., Laurent V., Pouillon L., Baumann C., Orry X., Lopez A., et al. Systematic screening for primary sclerosing cholangitis with magnetic resonance cholangiography in inflammatory bowel disease. Dig. Liver. Dis. 2018; 50(10): 1012–8. https://doi.org/10.1016/j.dld.2018.06.024

Eksteen B., Heatherington J., Oshiomogo J., Panaccione R., Kaplan G., Ghosh S. Efficacy and safety of induction dosing of vedolizumab for reducing biliary inflammation in primary sclerosing cholangitis (PSC) in individuals with inflammatory bowel disease. J. Hepatol. 2016; 64(2S): S199. https://doi.org/10.1016/S0168-8278(16)01707-4

Caron B., Peyrin-Biroulet L., Pariente B., Bouhnik Y., Seksik P., Bouguen G., et al. Vedolizumab therapy is ineffective for primary sclerosing cholangitis in patients with inflammatory bowel disease: a GETAID multicentre cohort study. J. Crohns. Colitis. 2019; 13(10): 1239–47. https://doi.org/10.1093/ecco-jcc/jjz088

Lynch K.D., Chapman R.W., Keshav S., Montano-Loza A.J., Mason A.L., Kremer A.E., et al. Effects of Vedolizumab in patients with primary sclerosing cholangitis and inflammatory bowel diseases. Clin. Gastroenterol. Hepatol. 2020; 18(1): 179–87.e6. https://doi.org/10.1016/j.cgh.2019.05.013

Christensen B., Micic D., Gibson P.R., Yarur A., Bellaguarda E., Corsello P., et al. Vedolizumab in patients with concurrent primary sclerosing cholangitis and inflammatory bowel disease does not improve liver biochemistry but is safe and effective for the bowel disease. Aliment. Pharmacol. Ther. 2018; 47(6): 753–62. https://doi.org/10.1111/apt.14525

Honap S., Sticova E., Theocharidou E., Berry P., Irving P.M., Samaanet M.A., et al. Vedolizumab-associated drug-induced liver injury: a case series. Inflamm. Bowel. Dis. 2021; 27(3): 32–4. https://doi.org/10.1093/ibd/izaa286

Maaser C., Sturm A., Vavricka S.R., Kucharzik T., Fiorino G., Annese V., et al. ECCO-ESGAR guideline for diagnostic assessment in IBD Part 1: Initial diagnosis, monitoring of known IBD, detection of complications. J. Crohns. Colitis. 2019; 13(2): 144–64. https://doi.org/10.1093/ecco-jcc/jjy113

Turner D., Hyams J., Markowitz J., Lerer T., Mack D.R., Evans J., et al. Appraisal of the pediatric ulcerative colitis activity index (PUCAI). Inflamm. Bowel Dis. 2009; 15(8): 1218–23. https://doi.org/10.1002/IBD.20867

Turner D., Levine A., Walters T.D., Focht G., Otley A., López V.N., et al. Which PCDAI version best reflects intestinal inflammation in pediatric Crohn disease? J. Pediatr. Gastroenterol. Nutr. 2017; 64(2): 254–60. https://doi.org/10.1097/MPG.0000000000001227

Dvoryakovskiy I.V., ed. Ultrasound Anatomy of a Healthy Child [Ul’trazvukovaya anatomiya zdorovogo rebenka]. Moscow: Firma STROM; 2009. (in Russian)

Jang H.J., Kang B., Choe B.H. The difference in extraintestinal manifestations of inflammatory bowel disease for children and adults. Transl. Pediatr. 2019; 8(1): 4–15. https://doi.org/10.21037/tp.2019.01.06

Faubion W.A. Jr., Loftus E.V., Sandborn W.J., Freese D.K., Perrault J. Pediatric “PSC-IBD”: a descriptive report of associated inflammatory bowel disease among pediatric patients with PSC. J. Pediatr. Gastroenterol. Nutr. 2001; 33(3): 296–300. https://doi.org/10.1097/00005176-200109000-00013

Yoon J., Oh S.H., Kim H.J., Park S.H., Ye B.D., Yang S.K., et al. Primary sclerosing cholangitis with inflammatory bowel disease in Korean children. Pediatr. Gastroenterol. Hepatol. Nutr. 2015; 18(4): 268–75. https://doi.org/10.5223/pghn.2015.18.4.268

Kucharska M., Daniluk U., Kwiatek-Średzińska K.A., Wasilewska N., Filimoniuk A., Jakimiec P., et al. Hepatobiliary manifestations of inflammatory bowel disease in children. Clin. Exp. Hepatol. 2019; 5(3): 203–9. https://doi.org/10.5114/ceh.2019.87632

Gregorio G.V., Portmann B., Karani J., Harrison P., Donaldson P.T., Vergani D., et al. Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study. Hepatology. 2001; 33(3): 544–53. https://doi.org/10.1053/jhep.2001.22131

Agrawal M., Kim E.S., Colombel J.F. JAK inhibitors safety in ulcerative colitis: practical implications. J. Crohns Colitis. 2020; 14(Suppl. 2): 755–60. https://doi.org/10.1093/ecco-jcc/jjaa017

Greuter T., Bertoldo F., Rechner R., Straumann A., Biedermann L., Zeitz J., et al. Extraintestinal manifestations of pediatric inflammatory bowel disease: prevalence, presentation, and anti-TNF treatment. J. Pediatr. Gastroenterol. Nutr. 2017; 65(2): 200–6. https://doi.org/10.1097/MPG.0000000000001455

Daniluk U., Kwiatek-Sredzinska K., Jakimiec P., Daniluk J., Czajkowska A., Lebensztejn D.M. Liver pathology in children with diagnosed inflammatory bowel disease-a single center experience. J. Clin. Med. 2021; 10(22): 5359. https://doi.org/10.3390/jcm10225359

Valentino P.L., Feldman B.M., Walters T.D., Griffiths A.M., Ling S.C., Pullenayegum E.M., et al. Abnormal liver biochemistry is common in pediatric inflammatory bowel disease: prevalence and associations. Inflamm. Bowel Dis. 2015; 21(12): 2848–56. https://doi.org/10.1097/MIB.0000000000000558

Pluskota C.A., Subhan A., Korkor S., Landsman M., Wolfe M.M. Disseminated intravascular coagulopathy and newly diagnosed ulcerative colitis, a rare but serious complication: a case report. Am. J. Gastroenterol. 2017; 112(1): 1092.

European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Autoimmune hepatitis. J. Hepatol. 2015; 63(4): 971–1004. https://doi.org/10.1016/j.jhep.2015.06.030

European Association for the Study of the Liver. EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis. J. Hepatol. 2017; 67(1): 145–72. https://doi.org/10.1016/j.jhep.2017.03.022

Nikitin A.V., Volynets G.V. Sclerosing cholangitis and inflammatory bowel disease: which comes first? Rossiyskiy vestnik perinatologii i pediatrii. 2021; 66(1): 39–46. https://doi.org/10.21508/1027-4065-2021-66-1-39-46 (in Russian)

Nikitin A.V., Volynets G.V., Smirnov I.E., Skvortsova T.A., Potapov A.S., Komarova N.L., et al. Differential diagnosis of various types of intrahepatic cholestasis in children with chronic liver diseases. Rossiyskiy pediatricheskiy zhurnal. 2016; 19(3): 144–50. https://doi.org/10.18821/1560-9561-2016-19-3-144-150 (in Russian)

Sebode M., Weiler-Normann C., Liwinski T., Schramm C. Autoantibodies in autoimmune liver disease-clinical and diagnostic relevance. Front. Immunol. 2018; 9: 609. https://doi.org/10.3389/fimmu.2018.00609

Malik N., Venkatesh S.K. Imaging of autoimmune hepatitis and overlap syndromes. Abdom. Radiol. (NY). 2017; 42(1): 19–27. https://doi.org/10.1007/s00261-016-1019-x

Liberal R., Grant C.R., Longhi M.S., Mieli-Vergani G., Vergani D. Diagnostic criteria of autoimmune hepatitis. Autoimmun. Rev. 2014; 13(4-5): 435–40. https://doi.org/10.1016/j.autrev.2013.11.009

Ivleva S.A., Dvoryakovskiy I.V., Smirnov I.E. Modern non-invasive methods of diagnostics of liver fibrosis in children. Rossiyskiy pediatricheskiy zhurnal. 2017; 20(5): 300–6. https://doi.org/10.18821/1560-9561-2017-20-5-300-306 (in Russian)

Fisenko A.P., Smirnov I.E. Molecular diagnosis of fibrosis in diffuse liver diseases. Rossiyskiy pediatricheskiy zhurnal. 2019; 22(2): 106–15. https://doi.org/10.18821/1560-9561-2019-22-2-106-115 (in Russian)

Singh S., Venkatesh S.K., Wang Z., Miller F.H., Motosugi U., Low R.N., et al. Diagnostic performance of magnetic resonance elastography in staging liver fibrosis: a systematic review and meta-analysis of individual participant data. Clin. Gastroenterol. Hepatol. 2015; 13(3): 440–51.e6. https://doi.org/10.1016/j.cgh.2014.09.046