Towards an individual screening strategy for first-degree relatives of celiac patients.

Celiac disease (CD) is known to be more prevalent in first-degree relatives of patients. In this retrospective cohort study of 609 relatives between 1994 and 2016, we investigated the effect of sex, HLA type, and age at time of index celiac diagnosis. Pearson's chi-square test and Kaplan-Meier survival analysis were used as statistical analyses. CD screening was carried out for 427 relatives (70%), resulting in a prevalence of 15%. HLA typing in 335 relatives showed HLA-DQ2/DQ8 positivity in 87.5%. In 63% of children and all parents, celiac disease was diagnosed at first screening. It was diagnosed significantly more often in females, HLA-DQ2 homozygosity, and children (all p < 0.05). In children aged 0-1 year at time of index diagnosis, celiac disease was diagnosed after consecutive screening in 58%, after 3.9 ± 2.5 (max 10) years (p < 0.001).Conclusion: Future screening policies for relatives of celiac patients should include retesting, especially in HLA-positive relatives younger than 10 years of age. In addition, one-time celiac-specific antibody testing alone could be sufficient to rule out the disease in adolescent siblings and parents of newly diagnosed celiac patients. What is Known: • Celiac disease is more prevalent in first-degree relatives of celiac patients (risk 3-12%). • HLA-DQ2 homozygous sisters/daughters are at highest risk (25%). What is New: • If younger than 10 years of age, repeated testing is necessary in HLA-DQ2/DQ8-positive first-degree relatives when celiac disease is diagnosed in a family. • One-time celiac-specific antibody testing alone could be sufficient to rule out the disease in adolescent siblings and parents of newly diagnosed celiac patients.

Achievement of developmental milestones in young adults after liver transplantation in childhood.

Little is known about the achievement of developmental milestones (i.e., COL) after pediatric liver transplantation. The aim of this study was to examine the COL of young adults who underwent a liver transplantation during childhood and to compare it to healthy peers. Furthermore, we studied factors possibly related to their COL. COL was assessed using the CLQ, which assesses the achievement of developmental milestones (autonomy, psychosexual, social, and antisocial development) and risk behavior (substance abuse and gambling). Sociodemographic characteristics and clinical data were collected using the prospective institutional liver transplantation database. A total of 39 young adults who underwent a liver transplantation at the UMCG in their childhood completed the CLQ. They achieved fewer milestones with regard to autonomy, psychosexual, and social development compared to healthy peers, and they reported less risk behavior. Neither age at the time of study nor age at the time of transplantation was significantly correlated with any of the COL subscales. Young adults show delay in reaching developmental milestones in every dimension after a liver transplantation during their childhood.

Biliary atresia in the Netherlands: outcome of patients diagnosed between 1987 and 2008.

OBJECTIVE: To examine the outcome of biliary atresia (BA) and to identify prognostic factors using a national database. STUDY DESIGN: All children born between January 1987 and December 2008 who underwent the Kasai surgical procedure for BA were retrieved from the Netherlands Study Group on Biliary Atresia Registry database. Outcomes were measured in terms of clearance of jaundice (bilirubin <1.17 g/dL, or 20 µmol/L, within 6 months after surgery) and 4-year transplant-free survival. Two cohorts, one from 1987-1997 and the other from 1998-2008, were compared. Survival rates were determined using Kaplan-Meier analysis, and prognostic factors were tested with univariate and multivariate analyses. RESULTS: Between January 1987 and December 2008, 214 patients underwent Kasai surgery for BA. In this series, the 4-year transplant-free survival was 46%±4%, and 4-year overall survival was 73%±3%. Clearance of jaundice, surgery within 60 days, and postoperative antibiotic prophylaxis use were independently associated with increased transplant-free survival. The yearly caseload per center (range, 0.5-2.1) was not correlated with transplant-free survival (r=0.024; P=.73). CONCLUSION: During the past 2 decades, outcome parameters have remained constant and are comparable with those reported from other Western countries, despite a relatively low annual caseload per center. Timely surgical correction and postoperative antibiotic therapy were associated with a higher transplant-free survival rate.

Twenty-year transplant-free survival rate among patients with biliary atresia.

BACKGROUND & AIMS: Surgical treatment with Kasai portoenterostomy has improved the prognosis for patients with biliary atresia, although most patients ultimately require liver transplantation. Well-described patients with long-term, transplant-free survival are scarce; we assessed liver status and health perception among Dutch patients who survived 20 years after therapy and investigated whether the rate of transplant-free survival increases with time. METHODS: By using the Dutch national database for biliary atresia, we identified 104 patients, born between 1977 and 1988. We collected data on clinical characteristics, liver biochemistry, and ultrasonography from all transplant-free patients who were alive at age 20 years (n = 28; 27% of the patients). General health perception data (RAND-36) were collected at the last examination. RESULTS: The 20-year transplant-free survival rate increased from 20% (10 of 49) in the 1977 to 1982 cohort to 32% (18 of 55) in the 1983 to 1988 cohort (P = .03). Twenty-one percent of the long-term survivors (6 of 28) had normal liver biochemistry test results and no clinical or ultrasonographic signs of cirrhosis. The general health perception of female, but not male, patients, was lower, compared with controls (RAND-36 score, 54 ± 14 vs 74 ± 18; P = .005). CONCLUSIONS: More than 25% of patients with biliary atresia survive at least 20 years without liver transplantation in The Netherlands. Women with biliary atresia have a reduced perception of their health, compared with control patients. Twenty percent of long-term survivors are symptom-free, without clinical or ultrasonographic signs of cirrhosis or portal hypertension.

Mortality of biliary atresia in children not undergoing liver transplantation in the Netherlands.

In order to further improve the outcome of BA, we characterized the mortality of BA patients who did not undergo OLT in the Netherlands, and compared our results with international data. For this purpose, we analyzed the causes of mortality of non-transplanted BA patients before the age of five yr, using the NeSBAR database. To evaluate trends in mortality, we compared the cohort 1987-1996 (n=99) with 1997-2008 (n=111). We compared clinical condition at OLT assessment with available international data, using the PELD-score. Mortality of non-transplanted BA children was 26% (26/99) in 1987-1996 and 16% (18/111) in 1997-2008 (p=0.09). Sepsis was the prevailing direct cause of death (30%; 13/44). PELD-scores at the time of assessment were higher in non-transplanted BA patients (median 20.5; range 13-40) compared with international data (mean/median between 11.7 and 13.3). Based on our national data, we conclude that pretransplant mortality of BA patients is still considerable, and that sepsis is a predominant contributor. Our results strongly indicate that the prognosis of patients with BA in the Netherlands can be improved by earlier listing of patients for OLT and by improving pretransplant care.

Overall Quality of Life in Adult Biliary Atresia Survivors with or without Liver Transplantation: Results from a National Cohort.

Background Biliary atresia (BA) is a rare cholestatic disease of infancy. Kasai portoenterostomy and liver transplantation (LT) are the two sequential treatment options. An increasing number of patients survive into adulthood. Little is known about their health-related quality of life (HRQOL). This study aims to compare HRQOL of transplanted and nontransplanted patients in a cohort of young adult BA survivors. Patients and Methods RAND-36 and Liver Disease Index Score (LDSI) questionnaires were sent to eligible adult patients with BA. Clinical characteristics were obtained from the NeSBAR (Netherlands Study group on Biliary Atresia Registry) and the national pediatric LT database. RAND-36 domain and summary scores were compared with those of an age-matched Dutch reference group. The correlations between several clinical variables and HRQOL were analyzed. Results Mean RAND-36 domain and summary scores of transplanted (n = 15) and nontransplanted (n = 25) patients with BA (response 74%) were similar to the reference scores, with the exception of a decreased general health perception in nontransplanted patients (63 ± 21 vs. 75 ± 17; [p < 0.001], particularly in females. RAND-36 domain and summary scores were not significantly correlated to age at LT, time since LT, serum bilirubin, aspartate amino transferase or albumin levels, but were moderately to strongly correlated to LDSI total scores (r values 0.35-0.77). Conclusions Overall, young adult patients with BA have a HRQOL similar to an age-matched reference group. However, general health perception of nontransplanted patients, particularly of females, was decreased. HRQOL is correlated to liver disease symptoms but not to liver biochemistry parameters. Nontransplanted females and patients suffering from liver disease-associated symptoms may be a target for tailored supportive interventions.

Cholic acid induces a Cftr dependent biliary secretion and liver growth response in mice.

The cause of Cystic fibrosis liver disease (CFLD), is unknown. It is well recognized that hepatic exposure to hydrophobic bile salts is associated with the development of liver disease. For this reason, we hypothesize that, CFTR dependent variations, in the hepatic handling of hydrophobic bile salts, are related to the development CFLD. To test our hypothesis we studied, in Cftr-/- and control mice, bile production, bile composition and liver pathology, in normal feeding condition and during cholate exposure, either acute (intravenous) or chronic (three weeks via the diet). In Cftr-/- and control mice the basal bile production was comparable. Intravenous taurocholate increased bile production to the same extent in Cftr-/- and control mice. However, chronic cholate exposure increased the bile flow significantly less in Cftr-/- mice than in controls, together with significantly higher biliary bile salt concentration in Cftr-/- mice. Prolonged cholate exposure, however, did not induce CFLD like pathology in Cftr-/- mice. Chronic cholate exposure did induce a significant increase in liver mass in controls that was absent in Cftr-/- mice. Chronic cholate administration induces a cystic fibrosis-specific hepatobiliary phenotype, including changes in bile composition. These changes could not be associated with CFLD like pathological changes in CF mouse livers. However, chronic cholate administration induces liver growth in controls that is absent in Cftr-/- mice. Our findings point to an impaired adaptive homeotrophic liver response to prolonged hydrophobic bile salt exposure in CF conditions.

Health status and quality of life in adult biliary atresia patients surviving with their native livers.

INTRODUCTION: Gaining an insight into the quality of life (QOL) in long-term biliary atresia (BA) survivors is becoming more important. Identifying patients with limitations might make tailor made interventions possible. This is the first study investigating the health status (HS) and QOL in adults surviving BA with their native livers, and comparing them with healthy peers. METHODS: BA patients surviving with their native liver were identified in the Netherlands Study Group on Biliary Atresia Registry database. The RAND-36 and the World Health Organization Quality of Life assessment instrument-100 (WHOQOL-100) were used to measure HS and QOL, respectively. Correlation between the RAND-36 and WHOQOL-100 was also assessed. Hospital Anxiety and Depression Scale (HADS) and the Impact Event Scale (IES) were also completed. RESULTS: In total, 25 (83%) of the 30 eligible patients after Kasai portoenterostomy completed the questionnaires (median age 23.2 years). A lower perceived level of general health in HS was found as compared with the reference group and a higher score on the social domain was reported in QOL. Correlations between HS and QOL questionnaires were moderate to good. For the group, overall HADS and IES scores were good, though individual patients did score above the cutoff of both the questionnaires. CONCLUSION: Adult BA patients surviving with their native liver have similar HS and QOL as compared with their healthy peers. RAND-36 and WHOQOL-100 questionnaires are not interchangeable, but complementary to assess the patients' outcomes. The overall scores did not point to increased levels of anxiety and depression. However, on an individual level, three and six patients had a score above the cutoff of the HADS subscales demonstrating clinically relevant levels of anxiety and depression, respectively.

Course of life into adulthood of patients with biliary atresia: the achievement of developmental milestones in a nationwide cohort.

PURPOSE: To investigate the course of life of young adults diagnosed with biliary atresia (BA) in infancy by comparing patients who did and did not underwent transplantation with an age-matched Dutch reference group. METHODS: All patients from the Dutch BA registry, aged >18 years, were invited to complete the course of life questionnaire. RESULTS: Forty patients participated (response = 74%). Twenty-five had not undergone transplantation; 15 had undergone orthotopic liver transplantation. One significant between-group difference was found, namely in substance use and gambling. BA patients who underwent transplantation reported less use than the reference group (p = .01, moderate effect size). Additional moderate effect sizes were found for differences in psychosexual and social development and antisocial behavior. Patients who underwent transplantation had lower scores than one or both other groups. CONCLUSIONS: Development of BA survivors who did not undergo transplantation seems not delayed, whereas that of transplanted patients does seem somewhat delayed. However, patients who underwent transplantation display less risk behavior. Larger samples are necessary to confirm these findings.

Pulmonary medium vessel vasculitis in an 11 year old boy: Hughes Stovin syndrome as a variant of polyarteritis nodosa?

We present the case of an 11-year-old boy presenting with haemoptysis, dyspnoea and weight loss as a manifestation of isolated pulmonary vasculitis, leading to pulmonary hypertension. He also appeared to have a longstanding dural venous sinus thrombosis. This rare presentation, especially in childhood, might represent a case of the seldomly reported Hughes-Stovin syndrome. The patient achieved remission after therapy with cyclophosphamide pulses and high-dose steroids. Based on the presented case and review of the literature, we propose that this syndrome might be a variant of polyarteritis nodosa. This report highlights diagnostic issues and describes a successful treatment regimen.