Chronic Hepatitis Is Common and Often Untreated Among Children with Hepatitis B Infection in the United States and Canada.

OBJECTIVE: To determine the outcomes of chronic hepatitis B virus (HBV) infection in a large, prospectively studied cohort of children in the US and Canada. STUDY DESIGN: This was a prospective, observational study of children with chronic HBV enrolled in 7 clinical centers and evaluated at baseline, weeks 24 and 48, and annually thereafter, with analysis of demographic, clinical, physical examination, and blood test data. RESULTS: Among 362 children followed for a median of 4.2 years, elevated alanine aminotransferase (ALT) levels (>1 upper limit of normal) were present in 72% at last evaluation, including in 60% of children with loss of hepatitis B e antigen during follow-up and 70% of those who were hepatitis B e antigen negative at baseline. Significant ALT flares (male patients ≥400 U/L, female patients ≥350 U/L) occurred in 13 children. Of 129 children who fulfilled the American Association for the Study of Liver Diseases treatment criteria during follow-up, anti-HBV treatment was initiated in only 25. One child died (unrelated to liver disease), 1 developed cirrhosis, but no episodes of cirrhotic decompensation or hepatocellular carcinoma were observed. Decline in platelet count was inversely associated with ALT elevations. CONCLUSIONS: In a cohort of children with chronic HBV infection in the US and Canada, many children remained at risk of progressive liver disease due to active hepatitis, but major clinical outcomes such as cirrhosis, cancer, and death were rare. Many children who met criteria for treatment remained untreated.

Treatment of Chronic Hepatitis C in Young Children Reduces Adverse Outcomes and Is Cost-Effective Compared with Deferring Treatment to Adulthood.

OBJECTIVE: To evaluate the cost-effectiveness of treating young children with chronic hepatitis C virus (HCV) with new direct-acting antivirals. STUDY DESIGN: A state-transition model of chronic HCV was developed to conduct a cost-effectiveness analysis comparing treatment at age 6 years vs delaying treatment until age 18 years. Model inputs were derived from recently conducted systematic reviews, published literature, and government statistics. Medical care costs were obtained from linked population level laboratory and administrative data (Ontario, Canada). Outcomes are expressed in expected quality-adjusted life-years and costs (CAD$). Analysis included a base-case to estimate the expected value and one-way and probabilistic sensitivity analyses to evaluate the impact of uncertainty of the model inputs. RESULTS: After 20 years, treating 10 000 children early would prevent 330 cases of cirrhosis, 18 cases of hepatocellular carcinoma, and 48 liver-related deaths. The incremental cost-effectiveness ratio of early treatment compared to delayed treatment was approximately $12 690/quality-adjusted life-years gained and considered cost-effective. Model results were robust to variation in fibrosis progression rates, disease state-based costs, treatment costs, and utilities. CONCLUSIONS: Delaying treatment until age 18 years results in an increased lifetime risk of late-stage liver complications. Early treatment in children is cost effective. Our work supports clinical and health policies that broaden HCV treatment access to young children.

Heterogeneous Liver on Research Ultrasound Identifies Children with Cystic Fibrosis at High Risk of Advanced Liver Disease: Interim Results of a Prospective Observational Case-Controlled Study.

OBJECTIVE: To assess if a heterogeneous pattern on research liver ultrasound examination can identify children at risk for advanced cystic fibrosis (CF) liver disease. STUDY DESIGN: Planned 4-year interim analysis of a 9-year multicenter, case-controlled cohort study (Prospective Study of Ultrasound to Predict Hepatic Cirrhosis in CF). Children with pancreatic insufficient CF aged 3-12 years without known cirrhosis, Burkholderia species infection, or short bowel syndrome underwent a screening research ultrasound examination. Participants with a heterogeneous liver ultrasound pattern were matched (by age, Pseudomonas infection status, and center) 1:2 with participants with a normal pattern. Clinical status and laboratory data were obtained annually and research ultrasound examinations biannually. The primary end point was the development of a nodular research ultrasound pattern, a surrogate for advanced CF liver disease. RESULTS: There were 722 participants who underwent screening research ultrasound examination, of which 65 were heterogeneous liver ultrasound pattern and 592 normal liver ultrasound pattern. The final cohort included 55 participants with a heterogeneous liver ultrasound pattern and 116 participants with a normal liver ultrasound pattern. All participants with at least 1 follow-up research ultrasound were included. There were no differences in age or sex between groups at entry. Alanine aminotransferase (42 ± 22 U/L vs 32 ± 19 U/L; P = .0033), gamma glutamyl transpeptidase (36 ± 34 U/L vs 15 ± 8 U/L; P < .001), and aspartate aminotransferase to platelet ratio index (0.7 ± 0.5 vs 0.4 ± 0.2; P < .0001) were higher in participants with a heterogeneous liver ultrasound pattern compared with participants with a normal liver ultrasound pattern. Participants with a heterogeneous liver ultrasound pattern had a 9.1-fold increased incidence (95% CI, 2.7-30.8; P = .0004) of nodular pattern vs a normal liver ultrasound pattern (23% in heterogeneous liver ultrasound pattern vs 2.6% in normal liver ultrasound pattern). CONCLUSIONS: Research liver ultrasound examinations can identify children with CF at increased risk for developing advanced CF liver disease.

Portal Angiogenesis in Chronic Liver Disease Patients Correlates with Portal Pressure and Collateral Formation.

BACKGROUND/AIMS: One hallmark of chronic liver disease in patients with portal hypertension is the formation of portal-systemic collaterals in which angiogenesis has a fundamental role. We studied patients with chronic liver disease undergoing liver transplantation to correlate levels of circulating angiogenic factors in portal and peripheral circulation with portal pressure and portal-systemic collaterals. METHODS: Sixteen patients who underwent liver transplantation were enrolled. During transplant surgery, we determined portal venous pressure and portal-systemic collateral formation. We determined angiogenics mediator levels in systemic and portal plasma. Peripheral plasma from healthy donors was measured as controls. RESULTS: Vascular endothelial growth factor (VEGF)-R1 and 2, Ang-1 and 2, Tie2, FGF- 1 and 2, CD163, PDGFR-ß, PDGFsRα, PDGF-AB and BB, CD163, TGF-ß VASH-1 levels were significantly different in the controls in comparison to cases. Significantly decreased portal venous levels of Ang-1, FGF-1, PDGF-AB/BB, and CC were observed in patients with higher portal pressure. Peripheral VEGF, Ang-1, pPDGF-AB, BB, and CC were significantly decreased in patients with more severe collateral formation. While peripheral VEGF-R1 was higher in patients with severe collateral formation. For portal circulation, VEGF, Ang-1, -pPDGF-AB, BB, and CC were significantly decreased in patients with more severe collateral formation Conclusions: Angiogenesis factors correlated with portal pressure and collateral formation and different patterns of circulating angiogenesis mediators were found in peripheral and portal blood of patients with chronic liver disease. These results support the importance of angiogenic pathways in cirrhosis and portal hypertension and highlight areas for further study to identify clinically useful noninvasive markers of portal pressure and collateral formation.

New Onset Autoimmune Hepatitis during Anti-Tumor Necrosis Factor-Alpha Treatment in Children.

OBJECTIVES: To evaluate a large anti-tumor necrosis factor (TNF)-treated pediatric inflammatory bowel disease cohort for drug-induced liver injury (DILI) following presentation of an index case with suspected DILI with autoimmune features after infliximab exposure. To characterize the incidence, natural history, and risk factors for liver enzyme elevation with anti-TNF use. STUDY DESIGN: We reviewed the index case and performed a retrospective cohort study of 659 children receiving anti-TNF therapy between 2000 and 2015 at a tertiary pediatric inflammatory bowel disease center. Patients with alanine aminotransferase (ALT) ≥×2 the upper limit of normal were included. The incidence, evolution, and risk factors for liver injury were examined with univariate and multivariable proportional hazards regression. Causality was assessed using the Roussel-Uclaf Causality Assessment Method. RESULTS: The index case, a teenage girl with Crohn's disease, developed elevated liver enzymes and features of autoimmune hepatitis on liver biopsy 23 weeks after starting infliximab. The injury resolved entirely within 4 months of withdrawing infliximab without additional therapy. Overall, 7.7% of our cohort developed new ALT elevations while on anti-TNF. Most ALT elevations were mild and transient and attributable to alternate etiologies. No additional clear cases of autoimmune hepatitis were identified. CONCLUSIONS: Transient liver enzyme abnormalities are relatively common among anti-TNF-treated children. Anti-TNF-related DILI with autoimmune features is rare but must be recognized so that therapy can be stopped.

Angiogenesis and portal-systemic collaterals in portal hypertension.

In patients with advanced liver disease with portal hypertension, portal-systemic collaterals contribute to circulatory disturbance, gastrointestinal hemorrhage, hepatic encephalopathy, ascites, hepatopulmonary syndrome and portopulmonary hypertension. Angiogenesis has a pivotal role in the formation of portal-systemic shunts. Recent research has defined many of the mediators and mechanisms involved in this angiogenic process, linking the central roles of hepatic stellate cells and endothelial cells. Studies of animal models have demonstrated the potential therapeutic impact of drugs to inhibit angiogenesis in cirrhosis. For example, inhibition of VEGF reduces portal pressure, hyperdynamic splanchnic circulation, portosystemic collateralization and liver fibrosis. An improved understanding of the role of other angiogenic factors provides hope for a novel targeted therapy for portal hypertension with a tolerable adverse effect profile.

Children with Chronic Hepatitis B in the United States and Canada.

OBJECTIVES: To test the hypothesis that children with chronic hepatitis B living in the US and Canada would have international origins and characteristic hepatitis B virus (HBV) genotypes and laboratory profiles. STUDY DESIGN: Clinical characteristics of children enrolled in the Hepatitis B Research Network were collected from 7 US and Canadian centers. RESULTS: Children (n = 343) with an age range of 1.0-17.8 years were enrolled; 78% of the children were Asian, 55% were adopted, and 97% had international origins with either the child or a parent born in 1 of 31 countries. The majority had HBV genotype B (43%) or C (32%), and the remainder had genotype A (5%), D (16%), E (4%), or multiple (<1%). Children with genotype B or C were more likely to be Asian (98% and 96%), more consistently hepatitis B envelope antigen positive (95% and 82%), had higher median HBV DNA levels (8.2 and 8.3 log10 IU/mL), and less frequently had elevated alanine aminotransferase values (43% and 57%) compared with children with other genotypes. The percentage of hepatitis B envelope antigen positivity and of those with HBV DNA ≥6 log10 IU/mL declined with age. CONCLUSIONS: The majority of children in the Hepatitis B Research Network have HBV genotypes that reflect their international origins. Clinical and laboratory data differ substantially by patient age and HBV genotype. Use of these data can help drive the development of optimal strategies to manage and treat children with chronic hepatitis B.

A clinical prediction rule and platelet count predict esophageal varices in children.

BACKGROUND & AIMS: The validation of noninvasive tests to diagnose esophageal varices is a priority in children because repeated endoscopic evaluations are too invasive. We measured the ability of a previously developed noninvasive clinical prediction rule (CPR) to predict the presence of esophageal varices in children. METHODS: We analyzed data from 108 children, younger than age 18, who received endoscopies at 8 centers, to assess portal hypertension from chronic liver disease or portal vein obstruction. Blood test and abdominal ultrasound scan results were obtained within 4 months of endoscopy. Grading of varices identified by endoscopy was confirmed by independent blinded review. Spleen size, based on data from the ultrasound scan, was expressed as a standard deviation score relative to normal values for age. RESULTS: Of the children studied, 74 had esophageal varices (69%), including 35 with large varices (32%). The best noninvasive predictors of esophageal varices of any size were as follows: platelet:spleen size z-score ratio (area under the receiver operating characteristic curve [AUROC], 0.84; 95% confidence interval [CI] 0.75-0.93), CPR (AUROC, 0.80; 95% CI, 0.70-0.91), and platelet count (AUROC, 0.79; 95% CI, 0.69-0.90). The positive predictive values for the CPR and platelet count were 0.87 and 0.86, the negative predictive values were 0.64 and 0.63, the positive likelihood ratios were 3.06 and 2.76, and the negative likelihood ratios were 0.64 and 0.63, respectively. Based on positive and negative predictive values, the most accurate noninvasive tests were the CPR and platelet counts. CONCLUSIONS: Noninvasive tests such as CPR and platelet count can assist in triaging children for endoscopy to identify esophageal varices.

Variation in care for children with esophageal varices: a study of physicians', patients', and families' approaches and attitudes.

BACKGROUND AND AIMS: Inadequate evidence to guide the management of children with esophageal varices may lead to variation in care and the provision of poor-quality care to some children. The aims of the study were to describe approaches taken by pediatric gastroenterologists for the management of esophageal varices in children, and to determine the attitudes of children, parents, and physicians toward screening endoscopy for identification of varices. METHODS: Canadian pediatric gastroenterologists and hepatologists were questioned about their approaches to screening for esophageal varices and therapy to prevent or treat variceal hemorrhage. Consecutive children with portal hypertension and their parents were surveyed about attitudes to screening endoscopy. RESULTS: Forty-seven of 72 (65%) physicians responded. Seventy percent of respondents screen for esophageal varices in selected children, most using endoscopy (77%). Fifty-eight percent of respondents who screen for varices would provide primary prophylactic treatment. Most would treat an acute variceal bleed with antibiotics, acid suppression, octreotide, and endoscopy within 24 hours (76%) and then secondary prophylaxis with endoscopic variceal ligation (96%) or ß-blockers (28%). Among 29 families surveyed, 63% of parents and 50% of patients would agree to screening endoscopy to understand their risk of variceal bleeding and 67% if prophylactic therapy were available. Families were more concerned about the risk of endoscopic adverse events than were gastroenterologists. CONCLUSIONS: Pediatric gastroenterologists vary in the care they provide for children at risk for esophageal varices and their attitudes toward the role of screening endoscopy differ from that of their patients. Further evidence is required to support practice guidelines that may reduce variation in care and thus improve its quality.

Derivation of a clinical prediction rule for the noninvasive diagnosis of varices in children.

BACKGROUND AND OBJECTIVES: Identification of children who are at high risk for having varices using noninvasive tests would enable the selection of children for future studies of primary prophylaxis of variceal hemorrhage, but this has been inadequately studied. The objective of the study was to derive a noninvasive clinical prediction rule that is able to identify children with esophageal varices. METHODS: Fifty-one consecutive children with liver disease or portal hypertension who underwent endoscopy were included in the present retrospective study. At endoscopy, variceal size was graded on a 4-point Likert scale. Results of physical examination, blood tests, and abdominal ultrasound scan (USS) were recorded. Spleen length on USS was expressed as a standard deviation score (z score). A descriptive univariate analysis was performed on variables that were potentially associated with esophageal varices and multivariate logistic regression was then modeled to derive a clinical prediction rule. RESULTS: Esophageal varices were found in 17 of the 51 children (33%). Variables found to differ significantly between children with and without varices included platelet/spleen-length z score ratio (P < 0.001), platelet count (P < 0.001), international normalized ratio (P = 0.001), aspartate aminotransferase/alanine aminotransferase ratio (P = 0.002), and albumin (P = 0.003). Using multivariate logistic regression, a model with platelet count, spleen length z score, and albumin as the independent variables had the best fit. Area under the receiver operating characteristic curve for this clinical prediction rule was 0.93 (95% confidence interval 0.85-0.99), sensitivity 94%, specificity 81%, positive predictive value 0.83, negative predictive value 0.94, positive likelihood ratio 5, and negative likelihood ratio 0.06. CONCLUSIONS: This clinical prediction rule is a simple noninvasive measure that may identify children at high risk for esophageal varices. A prospective validation study is in progress.