Noninvasive scores are poorly predictive of histological fibrosis in paediatric fatty liver disease.

OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children. Roughly a quarter of paediatric patients with NAFLD develop nonalcoholic steatohepatitis and fibrosis. Here, we evaluated the diagnostic accuracy of previously published noninvasive fibrosis scores to predict liver fibrosis in a large European cohort of paediatric patients with NAFLD. METHODS: The 457 patients with biopsy-proven NAFLD from 10 specialized centers were included. We assessed diagnostic accuracy for the prediction of any (F ≥ 1), moderate (F ≥ 2) or advanced (F ≥ 3) fibrosis for the AST/platelet ratio (APRI), Fibrosis 4 score (FIB-4), paediatric NAFLD fibrosis score (PNFS) and paediatric NAFLD fibrosis index (PNFI). RESULTS: Patients covered the full spectrum of fibrosis (F0: n = 103; F1: n = 230; F2: n = 78; F3: n = 44; F4: n = 2). None of the scores were able to accurately distinguish the presence of any fibrosis from no fibrosis. For the detection of moderate fibrosis, area under the receiver operating characteristic curve (AUROC) were: APRI: 0.697, FIB-4: 0.663, PNFI: 0.515, PNFS: 0.665, while for detection of advanced fibrosis AUROCs were: APRI: 0.759, FIB-4: 0.611, PNFI: 0.521, PNFS: 0.712. Fibrosis scores showed no diagnostic benefit over using ALT ≤ 50/ > 50 IU/L as a cut-off. CONCLUSIONS: Established fibrosis scores lack diagnostic accuracy to replace liver biopsy for staging of fibrosis, giving similar results as compared to using ALT alone. New diagnostic tools are needed for Noninvasive risk-stratification in paediatric NAFLD.

EASL-ERN position paper on liver involvement in patients with Fontan-type circulation.

Fontan-type surgery is the final step in the sequential palliative surgical treatment of infants born with a univentricular heart. The resulting long-term haemodynamic changes promote liver damage, leading to Fontan-associated liver disease (FALD), in virtually all patients with Fontan circulation. Owing to the lack of a uniform definition of FALD and the competitive risk of other complications developed by Fontan patients, the impact of FALD on the prognosis of these patients is currently debatable. However, based on the increasing number of adult Fontan patients and recent research interest, the European Association for The Study of the Liver and the European Reference Network on Rare Liver Diseases thought a position paper timely. The aims of the current paper are: (1) to provide a clear definition and description of FALD, including clinical, analytical, radiological, haemodynamic, and histological features; (2) to facilitate guidance for staging the liver disease; and (3) to provide evidence- and experience-based recommendations for the management of different clinical scenarios.

'A radical operation' - a thematic analysis of newspaper framing of bariatric surgery in adolescents.

BACKGROUND: Obesity in adolescents is a growing public health issue. Bariatric surgery is an effective, yet controversial treatment option for adolescents. The moral acceptability of this procedure by health-care professionals as well as the general public can be influenced by its portrayal in the news media. Our objective was to analyze how newspaper articles portrayed adolescent bariatric surgery, with attention to the language used and moral arguments made. METHODS: Using an inductive thematic analysis approach, we analyzed 26 UK and 12 US newspaper articles (2014-2022) on adolescent bariatric surgery for implicit or explicit moral evaluations and use of normative language. Coding was performed after immersive reading, assisted by NVivo. Themes were identified and refined iteratively through consecutive auditing cycles to enrich the depth and rigor of our analysis. RESULTS: The major themes identified related to (1) defining the burden of adolescent obesity, (2) sparking moral outrage, (3) sensation-seeking, and (4) raising ethical issues. The articles employed moral language, specifically non-neutral and negative discourse regarding surgery. Blame was attributed to adolescents or their parents. Sensationalist wording often reinforced the normative content, drawing the attention of the reader and contributing to stigmatization of adolescents with severe obesity as lacking will power and being lazy. Further moral issues that stood out were the challenges in obtaining an informed consent, and the unequal access to surgery for socially disadvantaged groups. CONCLUSIONS: Our findings provide insights into how adolescent bariatric surgery is represented in the print news media. Despite frequent citing of experts and studies on the efficacy, safety and unmet need for bariatric surgery, obesity and surgery in adolescents are often stigmatized and sensationalized, with (prospective) patients depicted as looking for an easy way out in the form of a solution brought by others (health systems, society, tax payers). This may increase the stigma surrounding adolescent obesity, and therefore limit the acceptability of specific treatments such as bariatric surgery.

Intensive Lifestyle Management Improves Steatosis and Fibrosis in Pediatric Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: Childhood obesity, with associated comorbidities such as nonalcoholic fatty liver disease (NAFLD), is an increasing global health problem. Although lifestyle management is the mainstay of treatment, its efficacy on liver fibrosis has not yet been established. METHODS: Children and adolescents admitted for severe obesity at a tertiary center (Zeepreventorium, De Haan, Belgium) were enrolled in this prospective study. Intensive lifestyle therapy encompassed caloric restriction, physical activity, education on a healthy lifestyle, and psychosocial support. At baseline, 6 months, and 12 months, liver ultrasound and transient elastography with controlled attenuation parameter were performed to assess liver steatosis and fibrosis. RESULTS: A total of 204 patients (median age, 14.0 y; body mass index Z-score, +2.8) were evaluated at admission. NAFLD on ultrasound was present in 71.1%, whereas 68.6% had controlled attenuation parameter values of 248 dB/m or greater. A total of 32.8% of patients had at least F2 fibrosis, including 10.3% with transient elastography of 9 kPa or greater. After 6 months, the median body weight loss was 16.0% in the 167 patients evaluated. Fibrosis improved in 75.0% (P < .001). Baseline severity of liver fibrosis and steatosis were predictors of fibrosis resolution. Seventy-nine patients had reached the 1-year time point. The improvements were sustained because fibrosis regressed at least 1 stage in all patients with baseline fibrosis. Fasting serum alanine aminotransferase and homeostasis model assessment of insulin resistance decreased significantly over the 1-year period (P < .001). CONCLUSIONS: NAFLD and associated fibrosis are highly prevalent in children and adolescents with severe obesity. An intensive multidisciplinary lifestyle management program that causes significant weight loss not only improves liver steatosis, but also fibrosis.

Non-invasive assessment of liver abnormalities in pediatric Fontan patients.

Liver abnormalities are well known among long-term survivors of Fontan palliation, which remains the definite surgery for complex congenital heart disease and single ventricle physiology. Pediatric data however are scarce. We assessed the prevalence and degree of liver abnormalities in pediatric Fontan patients through non-invasive investigations suitable for longitudinal follow-up. Thirty-five patients with a median age of 11.8 years (5.2-16.6) and median time since Fontan of 6 years (1.17-13.83) were studied. Each child underwent a blood test, liver Doppler ultrasound (US), and transient elastography (TE). Healthy children were used as controls for TE measurement. AST, ALT, γGT, and direct bilirubin were abnormal in respectively 12 (34%), 5 (14%), 24 (69%), and 7 (20%) patients, while platelet count was decreased in 7 (20%). Splenomegaly was present in 7 (20%) patients. Portal vein mean flow velocity was < 15 cm/s in 19 (54%) patients indicative of portal hypertension. Twenty-two patients (63%) showed inferior vena cava collapsibility index values below 17%, indicating venous congestion. Hepatic artery and superior mesenteric artery resistance index were inversely correlated with time post Fontan (p < 0.05). TE values in Fontan patients were significantly higher than controls, with a median of 12.6 versus 4.6 kPa (p < 0.001) and were already increased shortly after Fontan completion. Conclusion: Liver abnormalities are frequently observed in pediatric Fontan patients. The non-invasive investigations used were not able to confirm liver fibrosis or differentiate hepatic congestion from fibrosis. Based on our findings, we propose a prospective screening protocol with serial measurements of laboratory, (Doppler) US, and TE parameters. What is Known: • Hepatic dysfunction is a well-known consequence of the Fontan circulation. • The natural history of Fontan-associated liver disease in the pediatric age group remains unclear. What is New: • Liver abnormalities are frequently observed in pediatric Fontan patients; however, differentiating liver fibrosis and hepatic congestion with non-invasive investigations remains challenging. Sonographic Doppler measurements may improve our insight in both Fontan-associated liver disease development and the functioning of the Fontan circulation. • A prospective screening protocol is proposed to improve our ability to detect Fontan-associated liver disease early on and understand its natural history.

Two cases of DCDC2-related neonatal sclerosing cholangitis with developmental delay and literature review.

Ciliopathies are a group of clinical and molecular heterogeneous conditions with pleiotropic manifestations affecting the central nervous system, renal, liver, skeletal, and ocular systems. Biallelic pathogenic variants in DCDC2 cause a ciliopathy primarily presenting with neonatal sclerosing cholangitis (NSC). Pathogenic variants in DCDC2 have further been reported in the context of nephronophthisis and non-syndromic recessive deafness. Polymorphisms in DCDC2 have also been associated with dyslexia and DCDC2 has a role in neuronal development. We report on two unrelated patients with DCDC2-related NSC with additional central nervous system impairment manifesting as microcephaly, global developmental delay, and axial hypotonia. Histological findings of our patients can mimic biliary atresia or congenital hepatic fibrosis. We further show that transmission electron microscopy in patients with NSC does not always show absence of primary cilia. Hence patients with DCDC2 pathogenic variants should also undergo an evaluation of neuromotor development. Review of all reported patients further reveals a risk for supra-aortic arterial aneurysms.

Intra-patient variability in tacrolimus exposure in pediatric liver transplant recipients: Evolution, risk factors, and impact on patient outcomes.

BACKGROUND: This study aims to investigate the evolution and factors associated with TAC IPV and its impact on patient outcomes in pediatric LT recipients. METHODS: This is a retrospective study including 41 children. The TAC IPV was expressed as the coefficient of variation and was calculated for years 1-5 following LT. The number of missed clinic appointments was used as a surrogate marker for therapy adherence. RESULTS: We identified a decrease in the TAC IPV during the first 3 years after LT (P < 0.01). Serum albumin in the first year (P = 0.03), hematocrit (P = 0.02) and total bilirubin (P = 0.04) in the third year, and therapy adherence (P < 0.01) in the fifth year were associated with TAC IPV. High TAC IPV was associated with biopsy-proven acute allograft rejection (P = 0.04) and the need for biopsy during the first year (P = 0.02). There was a borderline association between TAC IPV and donor-specific antibodies (P = 0.08) and CMV viremia (P = 0.07). High TAC IPV was a predictor of need for liver biopsy and AR with an odds ratio of 1.04 (95% CI 1.0-1.1; P = 0.03) and 1.04 (95% CI 1.0-1.1; P = 0.05), respectively. CONCLUSIONS: Our results highlight the impact of biological factors on TAC IPV during the early LT follow-up and later also therapy adherence. High TAC IPV may be associated with adverse patient outcomes.

Benign anastomotic biliary strictures untreatable by ERCP: a novel percutaneous balloon dilatation technique avoiding indwelling catheters.

OBJECTIVE: To evaluate long-term patency rates of a novel percutaneous threefold balloon dilatation protocol in benign anastomotic biliary strictures. METHODS: Patients with a benign biliary stricture after hepatobiliary surgery or liver transplantation, untreatable with endoscopy, underwent a percutaneous treatment cycle consisting of a 20-min balloon dilatation session on day one, repeated on days three and five. No catheters were left behind after the last dilatation session. Technical and clinical success as well as complications were analysed. Mean primary and secondary patency times were assessed. Cumulative primary and secondary patency rates at 6 months and 1, 2 and 3 years were determined. RESULTS: Seventy patients underwent 135 dilatation treatment cycles (mean 1.9) with a technical success rate of 99%. Clinical success was achieved in 87% of the patients. Fifty-eight of 135 (43%) patients had minor and 15/135 (11%) had major complications. Mean primary and secondary patency times were 26 months and 46 months, respectively, with a median follow-up of 69 months. Cumulative primary patency rate at 6 months was 67%, at 1 year 56%, at 2 years 41% and at 3 years 36%. The cumulative secondary patency rate at 6 months was 83%, at 1 year 79%, at 2 years 70% and at 3 years 64%. CONCLUSION: In benign anastomotic biliary strictures, a percutaneous threefold balloon dilatation treatment is effective. As long indwelling catheters are avoided, patient comfort improves. KEY POINTS: • Percutaneous threefold balloon dilatation treatment is effective in benign anastomotic biliary strictures. • As indwelling catheters after dilatation are avoided, patient comfort improves. • The dilatation protocol can be repeated efficiently in case of recurrent stricture.

Longitudinal Transient Elastography Measurements Used in Follow-up for Patients with Cystic Fibrosis.

Cystic fibrosis-related liver disease (CFLD) is diagnosed using a combination of criteria. Transient elastography (TE), an ultrasonographic method to evaluate liver stiffness, can differentiate patients with and without liver disease. This retrospective study (2007-2013) aimed to detect developing CFLD using consequent TE measurements. All cystic fibrosis patients with TE measurements between 2007 and 2013 (n = 150, median age 17 (9-24) y) were included, of which 118 had a median of three (range, 2-4) measurements with an interval of 1 (1-2) y. Twenty (14%) had CFLD at the first TE measurement; five (3%) developed CFLD during follow-up. The median TE value in CFLD was 14 kPa (8.7-32.2) compared with 5.3 (4.9-5.7) in cystic fibrosis patients without liver disease (CFnoLD; p = 0.0001). In CFnoLD, TE was correlated with age (p = 0.031). A TE result >6.8 kPa had a sensitivity of 91.5% and a specificity of 91.7% in predicting CFLD, according to the receiver operating characteristics analysis. It also has a positive predictive value of 88.6% and a negative predictive value of 86.9%, increasing to 91.7% and 98%, respectively, in patients at risk (<14 y) for developing CFLD. Patients with developing CFLD had progressively increasing consecutive TE measurements.

Clinical zinc deficiency as early presentation of Wilson disease.

Wilson disease is a rare autosomal recessive disorder of the copper metabolism caused by homozygous or compound heterozygous mutations in the ATP-ase Cu(2+) transporting polypeptide (ATP7B) gene. The copper accumulation in different organs leads to the suspicion of Wilson disease. We describe a child with clinical zinc deficiency as presenting symptom of Wilson disease, which was confirmed by 2 mutations within the ATP7B gene and an increased copper excretion.

C-ANCA/proteinase 3-positive colitis in children: a distinctive form of inflammatory bowel disease or vasculitis with colitis as initial presentation?

AIM: Anti-neutrophil cytoplasmic antibodies (ANCAs) detected by indirect immunofluorescence have been found in patients with inflammatory bowel disease (IBD). Nevertheless, specific antibodies against proteinase-3 (PR3) are rare in this context. METHODS: Sera from 30 consecutive pediatric patients with IBD were evaluated for ANCA-indirect immunofluorescence and its specific antibodies to investigate whether PR3-ANCA positivity (PR3-ANCA+) identifies a distinct IBD subtype. RESULTS: The 5 PR3-ANCA+ patients (17%) showed significantly more concomitant biliary disease and severe anal blood loss (P < 0.05). None had vasculitis features at diagnosis nor during follow-up. CONCLUSIONS: This pilot study demonstrates significant clinical differences between the PR3-ANCA-positive and -negative IBD subset.

Clinical practice: neonatal cholestasis.

Neonatal cholestasis is a serious condition which requires urgent further investigation. Delayed referral of cholestatic neonates, however, is still a significant problem. Every child presenting with jaundice beyond the age of 2 weeks should be evaluated with a fractionated bilirubin checked. In case of neonatal cholestasis, the first step should be the assessment of coagulation and urgent parenteral vitamin K administration in case of coagulopathy and the exclusion of life-threatening conditions or disorders requiring urgent specific treatment. Any child presenting with acholic stools should be referred to a paediatric hepatology unit in order to confirm or rule out biliary atresia, as prognosis after porto-enterostomy correlates with younger age at the time of surgery. Once these conditions have been excluded, a more individualised approach is used based on anamnestic, clinical and further diagnostic findings. Besides specific medical or surgical therapy for selected diseases, early supportive treatment aiming for optimal growth and development and prevention of complications is of uttermost importance.

Chronic liver disease related to 6-thioguanine in children with acute lymphoblastic leukaemia.

BACKGROUND/AIMS: The United Kingdom (UK) acute lymphoblastic leukaemia (ALL) 97/99 clinical trial compared 6-mercaptopurine (6MP) with 6-thioguanine (6TG) as maintenance therapy for childhood ALL. Review of interim results has led to discontinuation of the 6TG arm. METHODS: We report six children with ALL, who presented with splenomegaly after a median (range) treatment duration of 12 (6-22) months. All these children were treated in the 6TG-arm. RESULTS: The median (range) age at presentation was 6.6 (3.2-11.5) years. There were five boys. The presenting features were splenomegaly in all and hepatomegaly in four. AST was abnormal in one (80 IU/l, normal range 10-50). Abdominal sonography showed an altered texture of the liver parenchyma and confirmed splenomegaly. Microscopy showed findings within the spectrum of occlusive venopathy and nodular regenerative hyperplasia (NRH). After a median (range) follow-up of 23 (4-36) months splenomegaly and thrombocytopenia, suggestive of progressive portal hypertension, continue to worsen in all children. CONCLUSIONS: 6TG is associated with chronic hepatic toxicity and progressive portal hypertension on follow-up. Microscopy showed NRH in all patients with features in keeping with an intrahepatic occlusive venopathy and variable parenchymal atrophy and loss.