Plasma immune signatures can predict rejection-free survival in the first year after pediatric liver transplantation.

BACKGROUND & AIMS: After pediatric liver transplantation (pLT), children undergo life-long immunosuppression since reliable biomarkers for the assessment of rejection probability are scarce. In the multicentre (n=7) prospective clinical cohort "ChilSFree" study, we aimed to characterize longitudinal dynamics of soluble and cellular immune mediators during the first year after pLT and identify early biomarkers associated with outcome. METHODS: Using paired Luminex-based multiplex technique and flow cytometry, we characterized longitudinal dynamics of soluble immune mediators (SIM, n=50) and immune cells in the blood of 244 patients at 8 visits over one year: before, 7/14/21/28 days, 3/6/12 months after pLT. RESULTS: The unsupervised clustering of patients based on SIM profiles revealed 6 unique SIM signatures associated with clinical outcome. From 3 signatures linked to improved outcome, one was associated with one-year-long rejection-free survival and stable graft function and was characterized by low levels of pro-inflammatory (CXCL8/9/10/12, CCL7, SCGF-ß, sICAM-1), high levels of regenerative (SCF, TNF-ß), and pro-apoptotic (TRAIL) SIM (all, p<0.001, fold change >100). Of note, this SIM signature appeared two weeks after pLT and remained stable over the entire year, pointing towards its potential as a novel early biomarker for minimizing or weaning immunosuppression. In the blood of these patients, a higher frequency of CD56bright NK cells (p<0.01), a known hallmark also associated with operationally tolerant pLT patients, was detected. The concordance of the model for prediction of rejection based on identified SIM signatures was 0.715, and 0.795, in combination with living-related transplantation as co-variate, respectively. CONCLUSIONS: SIM blood signatures may enable the non-invasive and early assessment of rejection risks in the first year after pLT, paving the way to improved therapeutic options.

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.

Early steroids after pediatric liver transplantation protect against T-cell-mediated rejection: Results from the ChilSFree study.

Steroid-free immunosuppression protocols gained popularity in pediatric liver transplantation (pLT) after the introduction of IL-2-receptor blockade for induction therapy. We analyzed the clinical and immunologic outcome data of the multicenter prospective observational ChilSFree study to compare the impact of steroid-free versus steroid-containing immunosuppressive therapy following pLT in a real-life scenario. Two hundred forty-six children [55.3% male, age at pLT median: 2.4 (range: 0.2-17.9) y] transplanted for biliary atresia (43%), metabolic liver disease (9%), acute liver failure (4%), hepatoblastoma (9%), and other chronic end-stage liver diseases (39%) underwent immune monitoring and clinical data documentation over the first year after pLT. Patient and graft survival at 1 year was 98.0% and 92.7%, respectively. Primary immunosuppression was basiliximab induction followed by tacrolimus (Tac) monotherapy (55%), Tac plus steroid tapering over 3 months (29%), or cyclosporine and steroid tapering (7%). One center used intraoperative steroids instead of basiliximab followed by Tac plus mycophenolate mofetil (7% of patients). N = 124 biopsy-proven T-cell-mediated rejections were documented in n = 82 (33.3%) patients. T-cell-mediated rejection occurred early (median: 41 d, range: 3-366 d) after pLT. Patients initially treated with Tac plus steroids experienced significantly fewer episodes of rejection than patients treated with Tac alone (chi-square p <0.01). The use of steroids was associated with earlier downregulation of proinflammatory cytokines interferon (IFN)-γ, Interleukin (IL)-6, CX motif chemokin ligand (CXCL)8, IL-7, and IL-12p70. Both primary immunosuppression with Tac plus steroids and living donor liver transplantation were independent predictors of rejection-free survival 1 year after pLT on logistic regression analysis. Adjunctive steroid therapy after pLT leads to earlier suppression of the post-pLT proinflammatory response and significantly reduced rejection rates during the first year after pLT (15.9%). Fifty-one percent of patients initially treated without steroids remain steroid-free over the first 12 months without rejection.

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.

Long-term clinical and socioeconomic outcomes of children with biliary atresia.

Background: Biliary atresia (BA) is rare liver disease of unknown etiology, and is a major indication for liver transplant (LT). Previous data indicate improved outcomes with early referral for Kasai portoenterostomy (KPE). Objective: Evaluate the long-term outcomes in BA, with particular focus on those transitioned to adult care with native livers. Subjects and Methods: Patients with BA treated between1980 and 2012 were identified. Data were collected from the time of referral, transition to adult care, and the most recent clinic notes, from which patient and native liver survival were calculated. Results: Four hundred and fifty-four patients with BA were identified, who were followed up for median of 16.4 years from birth; 74 died (41 of whom had a LT), giving a 20-year survival rate of 83.6%. Two hundred and seventy-two patients received an LT, with the median native liver survival being 35 months. Of patients who transitioned to adult care, 54 of 180 (30.0%) retained their native liver. Of these, 72% (39 of 54) had evidence of chronic liver disease at transition, of whom 8 were subsequently lost to follow-up, 9 were transplanted, and 22 remained stable with compensated liver disease. Of the 15 of 54 patients (28%) with no evidence of chronic disease in their native liver disease at transition, 3 were subsequently lost to follow-up; none received transplants, although 3 patients developed new-onset liver disease. All patients transitioned to adult care completed secondary school education (N = 180), with 49% having attended college/university and 87% being in employment or education at the last follow-up. Of female patients, 34% had at least one pregnancy (27 children in 21 women), while 22% of males had fathered a child. Conclusion: Long-term outcomes in BA are good, with patients surviving into adult life. Progression of chronic liver disease and associated morbidity is common in those who retained their native livers, suggesting that these patients require monitoring of liver disease throughout adult life, and early recognition of the need for LT.

Long-term outcomes of pediatric liver transplantation using organ donation after circulatory death: Comparison between full and reduced grafts.

BACKGROUND: The shortage of donors' livers for pediatric recipients inspired the search for alternatives including donation after cardiac death (DCD). METHODS: Retrospective review of pediatric liver transplant (PLT) using DCD grafts. Patients were divided into either FLG or RLG recipients. Pre-transplant recipient parameters, donor parameters, operative parameters, post-transplant recipient parameters, and outcomes were compared. RESULTS: Overall, 14 PLTs from DCD donors between 2005 and 2018 were identified; 9 FLG and 5 RLG. All donors were Maastricht category III. Cold ischemia time was significantly longer in RLG (8.2 h vs. 6.2 h; p = .038). Recipients of FLG were significantly older (180 months vs. 7 months; p = .012) and waited significantly longer (168 days vs. 22 days; p = .012). Recipients of RLG tended to be sicker in the immediate pre-transplant period and this was reflected by the need for respiratory or renal support. There was no significant difference between groups regarding long-term complications. Three patients in each group survived more than 5 year post-transplant. One child was re-transplanted in the RLG due to portal vein thrombosis but failed to survive after re-transplant. One child from FLG also died from a non-graft-related cause. CONCLUSIONS: Selected DCD grafts are an untapped source to widen the donor pool, especially for sick recipients. In absence of agreed criteria, graft and recipient selection for DCD grafts should be undertaken with caution.

Improving the odds together: a framework for breast cancer research scientists to include patient advocates in their research.

Including patient advocates in basic cancer research ensures that breast cancer research is intentional, supports effective communication with broader audiences, and directly connects researchers with those who they are striving to help. Despite this utility, many cancer research scientists do not work with patient advocates. To understand barriers to engagement and build a framework for enhanced interactions in the future, we hosted a workshop with patient advocates and researchers who do engage, then discussed findings at an international metastatic breast cancer conference to solicit additional feedback and suggestions. Findings demonstrate that researchers are uncertain about how to initiate and maintain relationships with advocates. We offer actionable steps to support researchers working with patient advocates to improve cancer research and accomplish our collective goal of improving lives of those who have been diagnosed with breast cancer. We hope that this initiative will facilitate such collaborative efforts.

The Genetics of Inherited Cholestatic Disorders in Neonates and Infants: Evolving Challenges.

Many inherited conditions cause cholestasis in the neonate or infant. Next-generation sequencing methods can facilitate a prompt diagnosis in some of these cases; application of these methods in patients with liver diseases of unknown cause has also uncovered novel gene-disease associations and improved our understanding of physiological bile secretion and flow. By helping to define the molecular basis of certain cholestatic disorders, these methods have also identified new targets for therapy as well patient subgroups more likely to benefit from specific therapies. At the same time, sequencing methods have presented new diagnostic challenges, such as the interpretation of single heterozygous genetic variants. This article discusses those challenges in the context of neonatal and infantile cholestasis, focusing on difficulties in predicting variant pathogenicity, the possibility of other causal variants not identified by the genetic screen used, and phenotypic variability among patients with variants in the same genes. A prospective, observational study performed between 2010-2013, which sequenced six important genes (ATP8B1, ABCB11, ABCB4, NPC1, NPC2 and SLC25A13) in an international cohort of 222 patients with infantile liver disease, is given as an example of potential benefits and challenges that clinicians could face having received a complex genetic result. Further studies including large cohorts of patients with paediatric liver disease are needed to clarify the spectrum of phenotypes associated with, as well as appropriate clinical response to, single heterozygous variants in cholestasis-associated genes.

Long-term Follow-up of a Randomized Trial of Tacrolimus or Cyclosporine A Microemulsion in Children Post Liver Transplantation.

The aim of this study was to determine the long-term efficacy and safety of tacrolimus (Tac) and cyclosporine immunosuppression in pediatric liver transplantation (LTx). METHODS: One hundred fifty-six patients who had taken part in a multicenter, randomized, open, parallel study of Tac and corticosteroids versus cyclosporine A microemulsion (CyA-ME), corticosteroids, and azathioprine. Patients were assessed at regular intervals up to 14 y after LTx. Analysis was conducted descriptively. RESULTS: In a long-term follow-up, there was a similar incidence of acute rejection (Tac versus CyA-ME, 5 versus 8) and graft loss (5 versus 10). There were 11 deaths in the cohort, which were from infectious complications/malignancy in the Tac group (n = 2/5) and from chronic rejection/liver failure in the CyA-ME group (n = 3/6). A similar incidence of Epstein-Barr virus and posttransplant lymphoproliferative disease was observed (8 versus 8, 3 versus 3). However, there was a greater incidence of cosmetic adverse events in the CyA-ME cohort, with higher incidences of hypertrichosis (8 versus 27) and gum hyperplasia (20 versus 6). Growth improved equally in both groups. Overall, 81% of patients randomized to Tac remained on Tac therapy at study end, compared with 31% of patients randomized to CyA-ME. Common reasons for switching from CyA-ME included steroid-resistant/acute rejection (n = 12/8) and cosmetic changes (n = 8). CONCLUSIONS: This study is the first prospective, observational follow-up study of pediatric patients randomized to Tac and CyA-ME to evaluate long-term outcomes. Our analysis was limited by the degree of switchover between the cohorts; however, there were fewer deaths from chronic rejection/liver failure and reduced adverse events with Tac. Long-term use of Tac and Tac combination therapy appears to be safe and effective immunosuppression for pediatric LTx recipients.

What is the long-term outlook for young people following liver transplant? A single-centre retrospective analysis of physical and psychosocial outcomes.

LT is a successful treatment for end-stage liver disease. The long-term outcome of patients transplanted in childhood has not previously been widely reported. This project assessed the long-term impact of transplantation in patients surviving >15 years. Retrospective data on growth, end-organ damage and psychosocial development were collected in young people transplanted from 1985 to 2000 in a single centre. Clinical notes were reviewed, and patients interviewed at clinic follow-up. 224 patients were transplanted between 1985 and 2000. 143 recipients (63.8%) survived >15 years with a median survival of 19.52 years. The majority were well, and only 10% had abnormal graft function (biochemical/synthetic), the main cause of which was chronic hepatitis (6%). Renal dysfunction and the necessity for renal transplant were identified in 32.8%, of whom 16.7% of patients had a cGFR <70 mL/min/1.73 m2 and 6% of patients had either undergone or awaiting renal transplant. This cohort was healthier than the average age-matched UK population in terms of body mass index (9% obese), smoking and alcohol consumption. 92% of patients had completed or were in education (93/123 had completed education and 20/123 remained in school). 63.7% of patients had been transitioned into adult services, and 46.3% of these patients were employed. 67.5% were in a relationship, one patient was divorced, and 10.6% of patients had one or more children. 11 patients had symptoms that corresponded to a DSM IV diagnosis of depression. Four patients had anorexia nervosa. Developmental delay was identified in 9 out of 99 patients. The development of malignancy, including PTLD, occurred in 10/143 (7%) patients at a median time post-transplant of 2.76 years (range 0.76-9.06 years). Epstein-Barr infection was implicated in 75% of these malignancies. We conclude the long-term outcome of LT in childhood is good with 63.8% surviving into adulthood and over 60% transferring into adult services. Graft dysfunction and end organ damage are minimal. Our cohort is healthier than the general population, and the majority have completed education, sought employment and formed relationships with peers, contributing well to society.

Epidemiology and natural history of hepatitis C virus infection among children and young people.

BACKGROUND & AIMS: Chronic hepatitis C virus (HCV) infection is a global health burden. Although HCV infection rarely contributes to morbidity during childhood, most HCV-infected children develop chronic HCV with a lifetime risk of liver disease. Little is known about the development of long-term liver disease and the effect of treatment in patients infected with HCV in childhood. METHOD: This study was a retrospective review of patients infected with HCV in childhood enrolled in HCV Research UK. A total of 1,049 patients were identified and included. RESULTS: The main routes of infection were intravenous drug use (53%), blood product exposure (24%) and perinatal infection (11%). Liver disease developed in 32% of patients, a median of 33 years after infection, irrespective of the mode of infection. Therefore, patients with perinatal exposure developed cirrhosis at an earlier age than the rest of the risk groups. The incidence of hepatocellular carcinoma (HCC) was 5%, liver transplant 4% and death occurred in 3%. Overall, 663 patients were treated (55% with interferon/pegylated interferon and 40% with direct-acting antivirals). Sustained virological response (SVR) was achieved in 406 (75%). There was a higher mortality rate among patients without SVR vs. those with SVR (5% vs. 1%, p = 0.003). Treatment was more effective in patients without cirrhosis and disease progression was less frequent (13%) than in patients with cirrhosis at the time of therapy (28%) p < 0.001. Patients with cirrhosis were more likely to develop HCC, require liver transplantation, or die. CONCLUSION: HCV infection in young people causes significant liver disease, which can now be prevented with antiviral therapy. Early treatment, especially before development of cirrhosis is essential. Detection of HCV should be aimed at relevant risk groups and antiviral therapy should be made available in childhood to prevent long-term liver disease and spread of HCV. LAY SUMMARY: Chronic hepatitis C virus (HCV) infection is a global health problem, which can now be treated with potent direct-acting antiviral drugs. This study demonstrates that HCV infection in childhood causes serious liver disease in 32% of patients, a median of 33 years after infection, irrespective of age, mode and route of infection. Disease outcomes were better in patients treated before the development of advanced liver disease. Antiviral therapy should be made available in childhood to prevent long-term liver disease and the spread of HCV.

Sonographic Evaluation for Endometrial Polyps: The Interrupted Mucosa Sign.

OBJECTIVES: To evaluate the interrupted mucosa sign for identification of endometrial polyps, using pathologic confirmation as the reference standard, compared to other accepted sonographic findings. METHODS: We reviewed 195 patients referred for pelvic sonographic evaluations for suspected endometrial polyps in this retrospective Institutional Review Board-approved study. Of these, 82 had tissue sampling of the endometrium and constituted the final study group. Patient data, including age, menopausal status, last menstrual period, and final pathologic diagnosis, were recorded. Sonograms were reviewed by 2 blinded board-certified radiologists for endometrial features, including thickness, echogenicity, vascularity, presence of a mass, and the interrupted mucosa sign. Descriptive statistics and multivariate logistic regression analysis were performed. RESULTS: The mean age of the patients was 44.99 (SD, 9.88) years, 79.1% of whom were premenopausal. Pathologic diagnosis confirmed polyps in 58 (70.73%). A single feeding vessel was visualized in 36 patients with polyps (62.07%), whereas the interrupted mucosa sign was visualized in 34 (58.62%). The presence of a feeding vessel, the interrupted mucosa sign, or both detected 48 (82.76%) of the polyps. In the multivariate analysis, only the interrupted mucosa sign was a statistically significant predictor of pathologic diagnosis of a polyp (P= .035), with an odds ratio of 3.83 (95% confidence interval, 1.10-13.29). Other sonographic findings were not independent predictors of a polyp: mass (P = .35), single feeding vessel (P = .31), endometrial thickness (P = .88), and endometrial echogenicity (P = .45). The sensitivity, specificity, and positive predictive value of the interrupted mucosa sign were 59%, 75%, and 85%, respectively. CONCLUSIONS: The interrupted mucosa sign is a promising sonographic sign for identification of endometrial polyps, with greater predictive power than previously described signs. It has the potential to improve the diagnostic performance of sonography, especially when used in combination with other described signs.

Combined liver and kidney transplantation in children: analysis of renal graft outcome.

BACKGROUND: Combined liver-kidney transplantation (CLKT) is the accepted treatment for patients with both liver failure and progressive renal insufficiency. Long-term outcome data for CLKT in children is sparse and controversy exists as to whether simultaneous CLKT with organs from the same donor confers immunologic and survival benefit to the kidney allograft. We report the long-term renal graft outcomes of 40 patients who had simultaneous CLKT. METHODS: A retrospective analysis of kidney graft survival (time from transplantation to death, return to dialysis or last follow-up event) in all pediatric patients (age < 18 years old) who underwent CLKT from March 1994 to January 2015. A 1:1 ratio of controls (deceased donor kidney recipients from our centre matched for age (±2 years) at transplant, time from transplant (±1 year) and treated with the same immunosuppressive regime) to cases was used to compare outcome. Estimated glomerular filtration rate (e-GFR) was calculated using the Schwartz formula. Survival curves were determined using Kaplan-Meier analysis. RESULTS: The kidney graft survival for CLKT patients was 87.4, 82, and 82 % at 1, 5, and 10 years; kidney graft survival for isolated KT patients were 97.2, 93, and 93 % at 1, 5, and 10 years (p = NS). There were two acute rejection episodes (5 %) in the CLKT group compared to five (12.5 %) episodes in the isolated KT group. There was no statistically significant difference in e-GFR at 1, 5, and 10 years in the two groups but there was a statistically significantly greater decline in e-GFR in the KT group compared to CLKT group from 5-10 years following transplant. CONCLUSIONS: There are fewer acute rejection episodes following CLKT compared to isolated KT, and we noted a higher mean e-GFR at 1, 5, and 10 years with significantly lesser decline in e-GFR from 5 to 10 years in the CLKT group.

Early nitisinone treatment reduces the need for liver transplantation in children with tyrosinaemia type 1 and improves post-transplant renal function.

BACKGROUND: Tyrosinaemia type 1 (HT1) is a rare disorder of tyrosine metabolism leading to liver failure and hepatocellular carcinoma. Treatment previously consisted of dietary restriction and orthotopic liver transplantation (OLT) but was transformed by the introduction of nitisinone in 1992. We describe the impact of nitisinone on the outcome and need for OLT in a single centre. METHODS: A retrospective analysis was performed of patients treated for HT1 at Birmingham Children's Hospital from 1989-2009. RESULTS: Thirty eight patients were treated during the study period. Prior to 1992 6/7 (85.7 %) underwent OLT compared to 7/31 (22.6 %) after 1992 (p = 0.004) when nitisinone treatment was available. Furthermore, nitisinone-treated patients proceeding to OLT started treatment at a median age of 428 (86-821) days compared to 52 (2-990) days in those who did not (p = 0.004). Pre-OLT calculated glomerular filtration rate (cGFR) was similar in both groups but nitisinone prevented early decline after OLT (pre-nitisinone median 99.8 to 45.8 ml/min/1.73 m2, p = 0.02 versus nitisinone-treated group median 104.3 to 89.9 ml/min/1.73 m2, p = 0.5). Urinary protein:creatinine ratio (PCR) fell post-OLT to within the normal range for those treated with nitisinone but remained elevated in those not treated with nitisinone. Tubular reabsorption of phosphate (TRP) was normal or near normal in both groups pre-OLT and post-OLT. Hypertension was commoner and more severe in those not treated with nitisinone. CONCLUSIONS: Nitisinone reduces the need for OLT particularly when started early. For those progressing to OLT the use of prior nitisinone therapy results in a preservation of their subsequent renal function.

A comparison of two validated scores for estimating risk of mortality of children with intestinal failure associated liver disease and those with liver disease awaiting transplantation.

BACKGROUND AND AIMS: To evaluate risk of mortality in children with intestinal failure associated liver disease (IFALD) compared with other liver disease using two validated scores. METHODS: Sixty-seven children listed for transplant were studied: cholestatic liver disease (CLDn23); liver disease secondary to other processes (LDsec n11); (IFALDn22), acute liver failure (ALFn11). Paediatric Hepatology Score (PHD) score and Pediatric end-stage liver disease score (PELD) were evaluated by Receiver Operating Curves (ROC), proportional hazards regression. RESULTS: The highest PHD and PELD scores were found in ALF; the lowest in LDsec. Both scores correlated well in identifying waiting list (WL) mortality in patients with CLD and ALF, but not in those with IFALD where PELD scores were lower. Cox proportional hazard regression of time spent on the waiting list prior to death or transplant/delisting showed significant associations with PHD (P=0.006) and PELD (P=0.008). WL mortality was strongly predicted by disease group (6/8 deaths in IFALD). ROC analysis of all data showed that a PHD score greater than 15.5 had sensitivity of 87.5% and specificity of 81% for waiting list mortality (P<0.001); PELD greater than 8 had a sensitivity of 87.5% and specificity of 40%. Neither PHD nor PELD scores correlated with post-transplant mortality. CONCLUSION: PHD and PELD scores had the same sensitivity for identifying risk of WL mortality in all patients, but PELD failed to identify the sickest children with IFALD, lowering its specificity. The PHD score has the added advantage for European centres of being in SI units, not requiring a computer application to calculate and was simpler to use at bedside.

Relative exchangeable copper: a promising tool for family screening in Wilson disease.

BACKGROUND: Family screening is a main step for the diagnosis in Wilson disease. This study was undertaken to evaluate the value of relative exchangeable copper for family screening. METHODS: Data from family screening were collected from the French National Center of Reference for Wilson disease. Subjects who were first- or second-degree relatives of the index case underwent clinical examination and biological parameters. RESULTS: Of 127 subjects examined, copper abnormalities or low ceruloplasminemia were detected in 21 subjects, corresponding to 5 patients with Wilson disease, 14 heterozygous ATP7B carriers and 2 subjects with no ATP7B mutations. Relative exchangeable copper determination significantly discriminates heterozygous ATP7B carriers and subjects with no ATP7B mutations from WD patients with a cutoff of 15%. CONCLUSIONS: Exchangeable copper appears to be a promising tool for family screening in Wilson disease.

Vitamin D deficiency and insufficiency after pediatric liver transplantation.

Vitamin D deficiency and insufficiency are increasingly recognized in the general population, including healthy children. There is also an increasing emphasis on the importance of vitamin D status following pediatric liver transplantation and specifically its relationship to metabolic bone disease and growth retardation. Vitamin D insufficiency has also been associated with multiple immunological and metabolic disorders in adults. To our knowledge, this has not been systematically evaluated in children undergoing liver transplantation to date. Between October 2004 and August 2008, serum 25-(OH)-vitamin D levels were measured in 199 children who had undergone liver transplantation at Birmingham Children's Hospital. Potential factors contributing to vitamin D levels were evaluated. Additionally, we evaluated a possible relationship between vitamin D levels and immunological phenomena and metabolic complications. Median 25-(OH)-vitamin D level was 19.5 ng/mL (range: 4.4-71.4 ng/mL). A total of 105 children (53%) had insufficient vitamin D levels and 28 children (14%) showed vitamin D deficiency. The only factors found to be associated with vitamin D deficiency were season of sample, ethnicity, and PTH levels. Vitamin D deficiency was more prevalent during the first year after transplantation. We did not find a significant relationship between vitamin D levels and graft function or any other immunological and metabolic complications. Vitamin D insufficiency and deficiency are common in children after liver transplantation, especially in winter and spring and in non-white patients. Initial post-transplant period and high PTH are significantly associated with vitamin D deficiency. Vitamin D status should be monitored following pediatric liver transplantation and vitamin D supplementation provided as required.

Phenotypic variation and long-term outcome in children with congenital hepatic fibrosis.

BACKGROUND AND OBJECTIVE: Congenital hepatic fibrosis (CHF) and Caroli syndrome are frequently associated with renal cystic diseases. They have a variable clinical course, and the natural history is not well defined despite molecular advances. Our study describes the clinical manifestations and long-term outcome in children with this disorder. METHODS: A retrospective case review of children with CHF at a single centre diagnosed on the basis of clinical features, radiological and endoscopic evidence of portal hypertension (PHT), and compatible histopathological findings. Children were categorised based on hepatic phenotype-group 1 (Caroli syndrome) and group 2 (CHF). Hepatobiliary as well as renal manifestations were recorded at presentation, and their evolution followed up until transplant or last follow-up. RESULTS: There were 40 children (22 boys) with a median age of 1.3 years at clinical presentation. Fourteen of 40 (35%) children presented in the neonatal period with primarily renal disease, of whom 11 (78%) had Caroli syndrome (P = 0.02). Significant PHT with oesophageal varices was seen in 86%, with no difference in the incidence of gastrointestinal bleeding and varices between Caroli syndrome and CHF. Cholangitis developed in 10 of 40 (25%) and was more common in the Caroli syndrome group (P = 0.009). A higher proportion of children with Caroli syndrome developed chronic kidney disease (CKD) stage 3 and above as compared with CHF (85% vs 42%; P = 0.007). Twelve of 21 (57%) and 8 of 19 (42%) children in the Caroli syndrome and CHF groups required either combined liver-kidney or isolated liver transplant, with the most common indication for renal transplantation being end-stage renal disease (CKD5d) with or without advanced PHT or cholangitis. All 14 (100%) children with neonatal presentation developed CKD5d and required combined liver-kidney transplant before 14 years of age, whereas 77% of children presenting beyond the neonatal period survived without liver-kidney transplant (P < 0.001). Neonatal presentation was the best predictor of the need for transplant. CONCLUSIONS: Caroli syndrome is more likely to present in the neonatal period and these patients are more likely to develop CKD5d. CKD stage 3 or above with recurrent cholangitis is more common in Caroli syndrome presenting beyond the neonatal period and adds to the significant morbidity in these patients. Children presenting in the neonatal period have a more severe phenotype and should be considered early for combined liver-kidney transplant.

Plasma succinylacetone is persistently raised after liver transplantation in tyrosinaemia type 1.

BACKGROUND: Tyrosinaemia type 1 (HT1) is a rare disorder leading to accumulation of toxic metabolites such as succinylacetone (SA) and a high risk of hepatocellular carcinoma. Children with HT1 traditionally required liver transplantation (OLT) and while the need for this has been reduced by the introduction of nitisinone some still require OLT. SA inhibits the enzyme porphobilinogen (PBG) synthase and its activity can be used as a marker of active SA. Elevated urinary SA post OLT has been reported previously. This study describes a novel finding of elevated plasma SA following OLT for HT1. METHODS: A retrospective analysis was performed of patients treated for HT1 at our institution from 1989-2010. RESULTS: Thirteen patients had an OLT for HT1. In patients who received nitisinone prior to OLT, mean urinary and plasma SA were elevated prior to treatment but normalised by the time of OLT (p ≤ 0.01). Mean PBG synthase activity increased from 0.032 to 0.99 nkat/gHb (ref range 0.58-1.25) at the time of OLT (p < 0.01). Mean urinary SA in patients not treated with nitisinone was also elevated prior to OLT; plasma levels and PBG synthase activity were not available prior to OLT for this group. Following OLT, mean urinary and plasma SA were elevated in all for the duration of follow-up and associated with low-normal PBG synthase activity. CONCLUSION: Urinary and plasma SA levels are elevated following OLT for HT1. Low-normal PBG synthase activity suggests the plasma SA may be active. The clinical significance of this is unclear.