Biliary disease progression in childhood onset autoimmune liver disease: A 30-year follow-up into adulthood.

Background & Aims: Long-term follow-up studies of paediatric onset autoimmune liver disease (AILD) are invaluable in helping better understand the clinical course of disease. In day-to-day practice clinicians struggle with disease definitions whilst patients and parents lack clear prognostic information. Methods: The clinical progression of 159 patients with childhood onset AILD between June 1990 and December 2013 was reviewed, capturing data up to adulthood (ending May 2021). Results: Presentation with autoimmune hepatitis (AIH) was dominant (n = 119); biliary presentations accounted for 25%. During follow up, biliary disease progression confirmed by cholangiography and/or liver histology was observed frequently: 19.8% (20/101) patients with childhood onset AIH type 1 (AIH-1) developed biliary features by adulthood and of these 50% phenotypically transitioned to primary sclerosing cholangitis (PSC); the remaining transitioned to an overlap disease phenotype. No patients with AIH type 2 developed biliary progression. Two-thirds of patients with overlap features (14/21) in childhood had phenotypically progressed to PSC by adulthood. Approximately 43% (6/14) of AIH-1 patients requiring a liver transplant in adulthood had explant evidence of biliary disease compared with 11% (1/9) in childhood, whereas 35.7% (5/14) of patients had histology diagnostic of PSC in their explant liver and 7.1% (1/14) had overlap features. All patients with biliary phenotypes (PSC, autoimmune sclerosing cholangitis, overlap) who required a transplant (n = 18) were found to have explant histology consistent with PSC. Twelve of 14 patients with biliary progression developed ulcerative colitis during follow-up with 92% progressing to PSC. Conclusions: Three decades of follow-up demonstrated how children presenting with AILD had a significant risk of clinical transformation to PSC. Biliary progression was significantly associated with the development of inflammatory bowel disease. Impact and implications: Childhood onset autoimmune liver disease remains very impactful for patients and families. Disease nomenclature can however be confusing. Long-term follow up studies as children become adults is important to help understand how and why disease behaves over time. Understanding more about the long-term course of childhood autoimmune liver disease will help patients, families and doctors striving to improve care and reduce poor clinical outcomes. We followed over 150 patients with childhood onset autoimmune liver diseases into adulthood. We found that amongst patients with classical autoimmune hepatitis, 1 in 5 developed biliary disease over time, mostly consisting of primary sclerosing cholangitis. This was associated with developing inflammatory bowel disease. Our study design was retrospective and has relevant limitations. Defining phenotypes of autoimmune liver diseases is difficult and there is insufficient consensus, especially between adult and childhood physicians. Our data confirms the critical importance of careful long-term follow-up of patients, including safe transition to adult care, as well as robustly demonstrates, using real-world data, how disease nature can change over time. Our study affirms the need for investment in prospective cohort studies.

Long-term Outcome of Asymptomatic Patients With Graft Fibrosis in Protocol Biopsies After Pediatric Liver Transplantation.

BACKGROUND: The histological prevalence of allograft fibrosis in asymptomatic children after liver transplantation (LT) is well documented. However, long-term graft and patient survival remain unclear. This retrospective multicenter study aims to determine the prevalence of allograft fibrosis and analyze the long-term outcome for patients transplanted in childhood. METHODS: We reviewed clinical data of children who had undergone 10-y protocol liver biopsies. We excluded patients with autoimmune hepatitis, primary sclerosing cholangitis, hepatitis B or C, and retransplantation. In total, 494 patients transplanted in childhood across 12 international transplant centers were included. We evaluated the development of fibrosis by comparing the results with biopsies obtained 5 and 15 y post-LT. Histological findings were correlated with graft and patient survival up to 20 y post-LT. RESULTS: In the 10-y biopsies, periportal or pericentral fibrosis was observed in 253 patients (51%), 87 (18%) had bridging fibrosis, 30 (6%) had cirrhosis, and 124 (25%) had no fibrosis. The prevalence and stage of graft fibrosis significantly progressed from 5 to 10 y. At 10 y, the severity of fibrosis correlated significantly with inflammation. Patients with graft cirrhosis in the 10-y biopsy were more likely to die or require retransplantation subsequently ( P = 0.027). CONCLUSIONS: At 10 y post-LT, most patients transplanted in childhood developed fibrosis, based on the protocol liver biopsies. Although mild-to-moderate graft fibrosis did not largely affect patient or graft survival up to 20 y post-LT, this progressive fibrosis finding has substantial implications for developing cirrhosis and portal hypertension in adult care.

Impact of ulcerative colitis on liver-related outcomes of children with primary sclerosing cholangitis.

AIM: Primary sclerosing cholangitis (PSC) is a chronic progressive cholestatic disorder associated with ulcerative colitis (UC). Although the inflammatory bowel disease phenotype has been characterised in patients with PSC, the impact of UC on the course and progression of PSC-UC is less clear. We aimed to evaluate the effects of UC on liver-related outcomes in children with PSC. METHODS: Retrospective analysis of children aged ≤18 years diagnosed with PSC with/without UC at a single tertiary paediatric liver unit between January 1998 and May 2016. Patients were followed up until transition to an adult service. Outcomes studied included biliary complications, clinically significant portal hypertension, need for liver transplantation and post-transplantation recurrence. RESULTS: Fifty-one children (31 female) were diagnosed with PSC (median age - 11.3 years (interquartile range 7)), follow-up median duration 54 months (interquartile range 56). Thirty-seven (73%) patients had concurrent UC, of which 26 had their diagnosis confirmed prior to or within 6 months of PSC diagnosis (early-onset). PSC complications were more common in children with PSC-UC compared with PSC alone (24/37 (65%) vs. 2/14 (14%); P = 0.001). Furthermore, children with endoscopically mild or moderate UC at diagnosis showed a greater propensity for liver-related complications compared with children with severe UC (24/32 vs. 0/5; P = 0.003). Children with late-onset UC had higher rates of clinically significant portal hypertension (5/11 (45%) vs. 3/26 (12%); P = 0.007) and liver transplantation (5/11(45%) vs. 2/26 (8%); P = 0.02). Children with PSC-UC had significantly higher rates of pancolitis, rectal sparing and milder colitis than those with UC alone. CONCLUSION: The presence and a later-onset of UC are associated with more significant progression to end-stage liver disease. There is an inverse trend between UC severity and PSC severity in children with concurrent PSC-UC.

Impact of Changing Treatment Strategies on Outcomes in Pediatric Ulcerative Colitis.

BACKGROUND: In recent years, treatment strategies for ulcerative colitis have evolved with an early step-up approach, the availability of biologicals, and therapeutic drug monitoring.We carried out this study to evaluate the effect of these changes on disease outcomes. METHODS: In this retrospective review, 2 time periods were defined: Group 1 (2005-2010) and Group 2 (2011-2016). Baseline demographic, endoscopic parameters, and medication use were compared. Overall colectomy rate, number of disease flares per year, and number of hospital admissions per year were compared between the 2 groups. RESULTS: Group 1 had 71 children, and in children in Group 2. The use of 5-ASA increased in Group 2 (Group 2, 99.2% vs. Group 1, 84.5%, P = 0.0007). In addition, infliximab and thiopurines were introduced earlier in the disease course.The 2-year cumulative probability of colectomy decreased from 14% to 3% (P = 0.02) between the 2 periods. No change in median number of flares per year [Group 1, 0.41 (IQR 0.6) vs. Group 2, 0.62 (IQR 0.91), P = 0.28] or median number of hospital admissions per year [Group 1, 0.30 (IQR 0.77) vs. Group 2, 0.21 (IQR 0.75), P = 0.52] was seen.Thereafter, we proceeded to identify the changes in treatment strategies that were responsible for the reduction in colectomy and we found that the use of infliximab OR 3.7 (95% CI 1.1-11.7), P = 0.02, was independently associated with it. CONCLUSIONS: A reduction in 2-year colectomy rates has been observed in patients with pediatric ulcerative colitis since biologics have become available for its treatment. The numbers of disease-flares rates and hospital admissions remain unchanged.

Report of the 24th Annual Congress of the International Liver Transplantation Society.

The 24th Joint Annual Congress of the International Liver Transplantation Society in association with European Liver and Intestine Transplant Association and Liver Intensive Care Group of Europe was held in Lisbon, Portugal from May 23 to 26, 2018. More than 1200 participants from over 60 countries including surgeons, hepatologists, anesthesiologists and critical care intensivists, radiologists, pathologists, organ procurement personnel, and research scientists came together with the common aim of improving care and outcomes for liver transplant recipients. Over 600 scientific abstracts were presented. The principal themes were living donation, use of marginal liver donors, machine preservation, disease-specific immunosuppressive regimen, malignancies, and advances in pediatric liver transplantation and liver transplant anesthesia. This report presents excerpts from invited lectures and select abstracts from scientific sessions, which add to current knowledge, and will drive clinical practice and future research.

Lower 6-MMP/6-TG Ratio May Be a Therapeutic Target in Pediatric Autoimmune Hepatitis.

BACKGROUND: Azathioprine (AZA) is the mainstay of maintenance therapy in pediatric autoimmune hepatitis (AIH). The use of thiopurines metabolites to individualize therapy and avoid toxicity has not, however, been clearly defined. METHODS: Retrospective analysis of children ≤18 years diagnosed with AIH between January 2001 and 2016. Standard definitions were used for treatment response and disease flare. Thiopurine metabolite levels were correlated with the corresponding liver function test. RESULTS: A total of 56 children (32 girls) were diagnosed with AIH at a median age of 11 years (interquartile range [IQR] 9). No difference in 6-thioguanine-nucleotide (6-TG) levels (271[IQR 251] pmol/8 × 10 red blood cell vs 224 [IQR 147] pmol/8 × 10 red blood cell, P = 0.06) was observed in children in remission when compared with those who were not in remission. No correlation was observed between the 6-TG and alanine aminotransferase levels (r = -0.179, P = 0.109) or between 6-methyl-mercaptopurine (6-MMP) and alanine aminotransferase levels (r = 0.139, P = 0.213). The 6-MMP/6-TG ratio was significantly lower in patients who were in remission (2[7] vs 5 (10), P = 0.04). Using a quartile analysis, we found that having a ratio of <4 was significantly associated with being in remission with OR 2.50 (95% confidence interval 1.02-6.10), P = 0.047. Use of allopurinol with low-dose AZA in 6 children with preferential 6-MMP production brought about remission in 5/6 (83.3%). CONCLUSIONS: Thiopurine metabolite levels should be measured in patients with AIH who have experienced a loss of remission. A 6-MMP/6-TG ratio of <4 with the addition of allopurinol could be considered in these patients.

Side effects and efficacy of renal sparing immunosuppression in pediatric liver transplantation-A single center matched cohort study.

Immunosuppressive combination therapy with MMF can reduce CNI associated nephrotoxicity. We investigated effectiveness and safety of de novo MMF-tacrolimus based immunosuppression after pLTx. Patients after pLTx receiving immunosuppression with MMF/tacrolimus (MMF/TAC) were compared to retrospectively selected age- and diagnosis-matched patients with tacrolimus monotherapy (TAC) and cyclosporine/prednisolone therapy (CSA) (19 patients each, n = 57). Effectiveness, renal function and side effects were analyzed for 1 year after pLTx. Tacrolimus reduction in combination therapy (0.7 µg/L over the year) was lower than aspired (2 µg/L). Acute BPAR occurred equally in MMF/TAC and TAC groups (31.6% each), being slightly higher in CSA group (42.1%; OR = 1.5; 95% CI = 0.42-5.44; P = .5). GFR deteriorated comparably in all 3 groups (P < .01 each) without significant differences between the groups. Septicemia was detected significantly more often in MMF/TAC (73.6%) than in TAC (31.6%) (OR 4.17; 1.07-16.27; P = .04). EBV reactivation occurred more often in CSA patients (84.2%) than in MMF/TAC (47.4%; OR 5.16; 0.98-27.19; P = .05) and TAC patients (52.6%; OR 8.16; 1.48-44.89; P = .02) the same was true for other viral infections (47.4% (CSA) vs 15.8% (TAC); OR 4.21; 0.95-18.55; P = .05). Our study does not provide additional evidence for a benefit of initial use of MMF/TAC over TAC regarding renal function, but raises concerns regarding a potentially increased risk of serious infections under MMF/TAC compared to TAC monotherapy at equivalent renal outcome; our study is, however, limited by the minor CNI reduction in combination therapy.

Late graft hepatitis and fibrosis in pediatric liver allograft recipients: Current concepts and future developments.

Liver transplantation (LT) in children now has a 20-year survival of >80%, but the longterm outcome of these grafts remains uncertain. Serial protocol liver biopsies after transplantation from several pediatric centres have demonstrated the gradual development of unexplained graft inflammation ("idiopathic" posttransplant hepatitis; IPTH) and graft fibrosis in biopsies obtained >12 months post-LT in children with good graft function and (near) normal liver biochemistry. Although the clinical significance of these findings is uncertain, there is evidence to suggest that IPTH may be a form of rejection or chronic antibody-mediated rejection as it is associated with the presence of auto/alloantibodies; de novo Class II donor-specific HLA antibodies (DSA); previous episodes of rejection, and may improve or be prevented with increased immunosuppression. Currently, the only method of diagnosing either hepatitis or fibrosis has been by serial protocol biopsies as neither serum markers of fibrosis nor noninvasive methods to detect fibrosis such as transient elastography (TE) are sufficiently validated in children. This review will focus on the diagnosis and management of idiopathic posttransplant hepatitis and graft fibrosis, discuss current methods for detecting graft injury, and potential mechanisms for their development. Liver Transplantation 22 1593-1602 2016 AASLD.

Biliary epithelium and liver B cells exposed to bacteria activate intrahepatic MAIT cells through MR1.

BACKGROUND & AIMS: Mucosal-Associated Invariant T (MAIT) cells are innate-like T cells characterised by the invariant TCR-chain, Vα7.2-Jα33, and are restricted by MR1, which presents bacterial vitamin B metabolites. They are important for antibacterial immunity at mucosal sites; however, detailed characteristics of liver-infiltrating MAIT (LI-MAIT) and their role in biliary immune surveillance remain unexplored. METHODS: The phenotype and intrahepatic localisation of human LI-MAIT cells was examined in diseased and normal livers. MAIT cell activation in response to E. coli-exposed macrophages, biliary epithelial cells (BEC) and liver B cells was assessed with/without anti-MR1. RESULTS: Intrahepatic MAIT cells predominantly localised to bile ducts in the portal tracts. Consistent with this distribution, they expressed biliary tropic chemokine receptors CCR6, CXCR6, and integrin αEß7. LI-MAIT cells were also present in the hepatic sinusoids and possessed tissue-homing chemokine receptor CXCR3 and integrins LFA-1 and VLA-4, suggesting their recruitment via hepatic sinusoids. LI-MAIT cells were enriched in the parenchyma of acute liver failure livers compared to chronic diseased livers. LI-MAIT cells had an activated, effector memory phenotype, expressed α4ß7 and receptors for IL-12, IL-18, and IL-23. Importantly, in response to E. coli-exposed macrophages, liver B cells and BEC, MAIT cells upregulated IFN-γ and CD40 Ligand and degranulated in an MR1-dependent, cytokine-independent manner. In addition, diseased liver MAIT cells expressed T-bet and RORγt and the cytokines IFN-γ, TNF-α, and IL-17. CONCLUSIONS: Our findings provide the first evidence of an immune surveillance effector response for MAIT cells towards BEC in human liver; thus they could be manipulated for treatment of biliary disease in the future.

Chronic Hepatitis C Infection in Children: Current Treatment and New Therapies.

Viral hepatitis C is responsible for a large burden of disease worldwide. Treatment of hepatitis C infection is currently undergoing a revolution with the development of new direct acting antivirals that offer higher cure rates and fewer side effects than other medications currently available. Treatment options for children, although well-defined and evidence-based, are limited relative to adults as there are few trials regarding the use of these newly developed agents in children. With so much optimism in the development of novel therapeutic options for hepatitis C, it is timely to review and summarize the current standard of care treatment and indications for treatment of chronic hepatitis C in children. We provide here an overview of recent drug developments and their potential for use in children.

Pediatric acute liver failure: etiology, outcomes, and the role of serial pediatric end-stage liver disease scores.

To describe etiology, short-term outcomes and prognostic accuracy of serial PELD scores in PALF. Retrospective analysis of children aged ≤16 yr, admitted with PALF under the QLTS, Brisbane, Australia, between 1991 and 2011. PELD-MELD scores were ascertained at three time points (i) admission (ii), meeting PALF criteria, and (iii) peak value. Fifty-four children met criteria for PALF, median age 17 months (1 day-15.6 yr) and median weight 10.2 kg (1.9-57 kg). Etiology was known in 69%: 26% metabolic, 15% infective, 13% drug-induced, 6% autoimmune, and 9% hemophagocytic lymphohistiocytosis. Age <3 months and weight <4.7 kg predicted poor survival in non-transplanted children. Significant independent predictors of poor outcome (death or LT) were peak bilirubin > 220 µm/L and peak INR > 4. Serial PELD-MELD scores were higher in the 17 (32%) transplant recipients (mean: [i] 26.8, [ii] 31.8, [iii] 42.6); highest in the 12 (22%) non-transplanted non-survivors (mean: [i] 31.6, [ii] 37.2, [iii] 45.7) compared with the 25 (46%) transplant-free survivors (mean: [i] 25.3, [ii] 26.0, [iii] 30.3). PELD-MELD thresholds of ≥27 and ≥42 at (ii) meeting PALF criteria and (iii) peak predicted poor outcome (p < 0.001). High peak bilirubin and peak INR predict poor outcome and serial PELD-MELD is superior to single admission PELD-MELD score for predicting poor outcome.