Overlap syndrome and primary sclerosing cholangitis in childhood and adolescence: Response to antibiotics and related changes in gut microflora and bile acids profile

Details

Supervisors

Sokal, Etienne

Faculty

Faculté de médecine et médecine dentaire

Degree label

Master [180] en médecine

Abstract

RETROSPECTIVE PART: Introduction: Concomitant presence of autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC) is labelled as AIH-SC overlap syndrome or autoimmune sclerosing cholangitis (ASC). Treatment of the AIH component with corticosteroids and azathioprine; and of the PSC component with ursodeoxycholic acid (UDCA) is the standard practice. Antibiotics are increasingly being shown to have benefit in PSC but their role in pediatric ASC is not well evaluated. We retrospectively investigated the response to oral antibiotics as initial or rescue therapy in children with ASC. A historical control-group included ASC patients treated without oral antibiotics but with recommended therapies including corticosteroids. Methods: Patients diagnosed with ASC on basis of biochemical, liver biopsy and radiology findings were included. They received metronidazole (MTZ) or vancomycin for 14 days either at diagnosis (initial therapy) or during their maintenance period (rescue therapy). When antibiotics were administered as initial therapy, corticosteroids-free induction regime was adopted. During the maintenance phase antibiotics were administered if patients had not achieved biochemical remission with their standard treatment of corticosteroids, azathioprine and UDCA. The outcome parameters to assess the efficacy of antibiotics were achievement of biochemical remission and additionally corticosteroids avoidance when given in the initial therapy. Results: Eleven children with ASC were included, of which 7 received oral antibiotics (4 MTZ, 3 vancomycin) at diagnosis and 4 received MTZ during the maintenance period. All patients showed a significant decrease in their AST (-56%, p=0,006), ALT (-83%, p=0,004) and GGT (-54%, p=0,004), without significant difference across the two groups. All 7 children in the initial therapy group did not need corticosteroids and continue to be in remission until last follow up duration of 351 days [216-888]. Among the 4 children receiving antibiotics in the maintenance phase, two did not show any benefit and relapsed after stopping antibiotics while two remaining patients showed biochemical remission and corticosteroids could be tapered in one and stopped in the second. Compared to the historical control-group treated with corticosteroids, patients who received antibiotics significantly showed a higher proportion of long-term biochemical remission (p=0.034) and long-term corticosteroids-free maintenance therapy (p=0.019) as well as a reduced proportion of relapse (p=0.025), with a shorter therapy duration (p=0.0003). Conclusion: We demonstrate the benefit of antibiotics in ASC by achieving biochemical remission and corticosteroids-free treatment when given at diagnosis as induction regime. When given in the maintenance phase they assist in achieving long-term biochemical remission in an otherwise uncontrolled ASC. PROSPECTIVE PART: Introduction: Based upon our retrospective use of oral antibiotics, we prospectively analysed the gut microflora and serum bile acids (BAs) pool before and after antibiotic therapy in children with ASC or PSC alone, and evaluated whether changes in gut microflora and/or BAs correlated with response to treatment. Methods: Patients diagnosed with ASC or PSC on basis of biochemical, liver biopsy and radiology findings were included. They prospectively received metronidazole (MTZ) for 14 days as induction or rescue therapy. MTZ were administrated in addition to the standard treatment of UDCA for PSC patients and azathioprine, and UDCA and/or corticosteroids for ASC patients. Stool and serum samples were collected before and after MTZ therapy. DNA isolation, amplification and Illumina sequencing to profile the microbiota composition were performed using the bacterial 16s rRNA while serum BAs were assessed by ultraperformance liquid chromatography coupled to mass spectrometry. The beta-diversity measured the dissimilarity between each paired stool samples. The outcome parameters to assess the efficacy of antibiotics were reduction liver enzymes and subsequently achievement of sustained biochemical remission. Results: Seven children (4 ASC, 3 PSC) were included, of which 5 have a concomitant ulcerative colitis (UC). All patients showed a significant decrease in their AST (-55%, p<0.025), ALT (-56%, p<0.025) and GGT (-41%, p<0.025) under MTZ. Three children relapsed after stopping MTZ while the four other children showed a sustained biochemical remission (liver enzymes below 1.5 times upper limit of normal) after a median follow-up of 375 days [119-502]. Among these four patients, three exhibited a wide different microbial composition before and after MTZ as expressed by the beta-diversity variation. They also expanded their total serum BAs size (from 1542.96 to 2620.99 pmol/100µl, +69.87%), primarily due to the large increment of UDCA and its glycine- and taurine-conjugates which finally represented nearly 40% of the total serum BAs. On the contrary, the microbiota of patients who relapsed remained unchanged pre- and post-MTZ and total BAs pool decreased. Conclusion: Our study suggests that short-term oral antibiotics therapy could be an effective treatment of ASC and PSC, especially when administrated at diagnosis, and that intestinal microflora and BAs play a major role in these diseases as sustained biochemical remission is associated with wide changes in gut microbiota communities and BAs profile after taking antibiotics.

Citations

• APA

Sambon, P. (2018). Overlap syndrome and primary sclerosing cholangitis in childhood and adolescence: Response to antibiotics and related changes in gut microflora and bile acids profile.