Daniel H. Leung

Primary Prophylaxis of Variceal Bleeding in Children and the Role of MesoRex Bypass–Summary of the Baveno VI Pediatric Satellite Symposium

Approaches to the management of portal hypertension and variceal hemorrhage in pediatrics remain controversial, in large part because they are not well informed by rigorous clinical studies. Fundamental biological and clinical differences preclude automatic application of approaches used for adults to children. On April 11‐12, 2015, experts in the field convened at the first Baveno Pediatric Satellite Meeting to discuss and explore current available evidence regarding indications for MesoRex bypass (MRB) in extrahepatic portal vein obstruction and the role of primary prophylaxis of variceal hemorrhage in children. Consensus was reached regarding MRB. The vast majority of children with extrahepatic portal vein obstruction will experience complications that can be prevented by successful MRB surgery. Therefore, children with extrahepatic portal vein obstruction should be offered MRB for primary and secondary prophylaxis of variceal bleeding and other complications, if appropriate surgical expertise is available, if preoperative and intraoperative evaluation demonstrates favorable anatomy, and if appropriate multidisciplinary care is available for postoperative evaluation and management of shunt thrombosis or stenosis. In contrast, consensus was not achieved regarding primary prophylaxis of varices. Although variceal hemorrhage is a concerning complication of portal hypertension in children, the first bleed appears to be only rarely fatal and the associated morbidity has not been well characterized. Conclusion: There are few pediatric data to indicate the efficacy and safety of pharmacologic or endoscopic therapies as primary prophylaxis or that prevention of a sentinel variceal bleed will ultimately improve survival; therefore, no recommendation for primary prophylaxis with endoscopic variceal ligation, sclerotherapy, or nonspecific beta‐blockade in children was proposed. (Hepatology 2016;63:1368–1380)

Aspartate aminotransferase to platelet ratio and fibrosis-4 as biomarkers in biopsy-validated pediatric cystic fibrosis liver disease

Up to 10% of cystic fibrosis (CF) children develop cirrhosis by the first decade. We evaluated the utility of two simple biomarkers, aspartate aminotransferase to platelet ratio index (APRI) and FIB‐4, in predicting degree of fibrosis in pediatric CF liver disease (CFLD) validated by liver biopsy. In this retrospective, cross‐sectional study, 67 children with CFLD had dual‐pass liver biopsies and 104 age‐ and sex‐matched CF children without liver disease (CFnoLD) had serum to calculate APRI and FIB‐4 collected at enrollment. CFLD was defined as having two of the following: (1) hepatomegaly ± splenomegaly; (2) >6 months elevation of ALT (>1.5× upper limit of normal ULN); or (3) abnormal liver ultrasound findings. Biopsies were staged according to Metavir classification by two blinded pathologists. Receiver operating characteristic (ROC) analysis and continuation ratio logistic regression were performed to assess the predictability of these biomarkers to distinguish CFLD from CFnoLD and determine fibrosis stage‐specific cut‐off values. The AUC for APRI was better than FIB‐4 (0.75 vs. 0.60; P = 0.005) for predicting CFLD and severe CFLD (F3‐F4) (0.81). An APRI score >0.264 demonstrated a sensitivity (95% confidence interval [CI]) of 73.1% (60.9, 83.2) and specificity of 70.2% (60.4, 78.8) in predicting CFLD. A 50% increase in APRI was associated with a 2.4‐fold (95% CI: 1.7, 3.3) increased odds of having CFLD. APRI demonstrated full agreement with histology staging 37% of the time, but was within one stage 73% of the time. Only FIB‐4 predicted portal hypertension at diagnosis (area under the receiver operator characteristic curve [AUC] = 0.91; P < 0.001). Conclusion: This is the first liver biopsy‐validated study of APRI and FIB‐4 in pediatric CFLD. APRI appears superior to FIB‐4 in differentiating CFLD versus CFnoLD. APRI also exhibited a high AUC in predicting severe liver fibrosis with specific cutoffs for lower stages. (Hepatology 2015;62:1576–1583)

Age- and Ethnic-Specific Elevation of ALT Among Obese Children at Risk for Nonalcoholic Steatohepatitis (NASH): Implications for Screening

The objectives are to: (1) characterize ethnic-specific differences in alanine aminotransferase (ALT) elevation among obese children, (2) investigate the earliest ages at which significant ALT elevation occurs, and (3) determine associations between ALT and biochemical parameters. A cohort of 134 multiethnic obese children and adolescents was analyzed retrospectively. ALT levels ≥45 U/L or <45 U/L, denoting high or normal risk, were used to categorize obese childrens risk for developing nonalcoholic steatohepatitis. In all, 60% of Hispanics had high-risk ALT levels compared with 12% of whites and 8% of blacks. A significantly higher proportion of boys had ALT ≥ 45 U/L (49.4%, vs 37.9% for girls, P = .002); 17.5% were Hispanic boys less than 7 years old. Obese Hispanic children, particularly boys, not only have higher ALT levels but present alarmingly young with high-risk levels. This study highlights a discrete subgroup of children who may present with fatty liver at a younger age and should be screened earlier.

Baseline Ultrasound and Clinical Correlates in Children with Cystic Fibrosis

OBJECTIVE To investigate the relationship between abdominal ultrasound findings and demographic, historical, and clinical features in children with cystic fibrosis (CF). STUDY DESIGN Children age 3-12 years with CF without known cirrhosis, were enrolled in a prospective, multicenter study of ultrasound to predict hepatic fibrosis. Consensus ultrasound patterns were assigned by 3 radiologists as normal, heterogeneous, homogeneous, or cirrhosis. Data were derived from direct collection and US or Toronto CF registries. χ(2) or ANOVA were used to compare variables among ultrasound groups and between normal and abnormal. Logistic regression was used to study risk factors for having abnormal ultrasound. RESULTS Findings in 719 subjects were normal (n = 590, 82.1%), heterogeneous (64, 8.9%), homogeneous (41, 5.7%), and cirrhosis (24, 3.3%). Cirrhosis (P = .0004), homogeneous (P < .0001), and heterogeneous (P = .03) were older than normal. More males were heterogeneous (P = .001). More heterogeneous (15.0%, P = .009) and cirrhosis (25.0%, P = .005) had CF-related diabetes or impaired glucose tolerance vs normal (5.4%). Early infection with Pseudomonas aeruginosa (<2 years old) was associated with a lower risk (OR 0.42, P = .0007) of abnormal. Ursodeoxycholic acid use (OR 3.69, P < .0001) and CF-related diabetes (OR 2.21, P = .019) were associated with increased risk of abnormal. CONCLUSIONS Unsuspected cirrhosis is seen in 3.3% of young patients with CF, heterogeneous in 8.9%. Abnormal ultrasound is associated with CF-related diabetes, and early P aeruginosa is associated with normal ultrasound. Prospective assessment of these risk factors may identify potential interventional targets. TRIAL REGISTRATION ClinicalTrials.gov: NCT01144507.

Angiosarcoma successfully treated with liver transplantation and sirolimus

Malignant liver tumors represent approximately 1% of malignancies in children. HA is a high‐grade tumor of endothelial cells that is even more rare in the pediatric population. HA has a limited response to chemotherapy, radiation and resection with universal tumor recurrence with LT and nearly 100% mortality by 18 months. This is the first reported successful case of hepatic angiosarcoma in a child who was treated by LT in combination with sirolimus. Sirolimus antagonizes the mTOR pathway, which regulates cell proliferation, differentiation, and migration, and is being studied as an anti‐neoplastic agent for solid tumors.

Use of allopurinol in children with acute lymphoblastic leukemia to reduce skewed thiopurine metabolism

Mercaptopurine (6‐MP), a critical component of acute lymphoblastic leukemia (ALL) therapy, is metabolized to 6‐thioguanine (6‐TGN) which is responsible for its anti‐leukemic effect, and to 6‐methylmercaptopurine nucleotides (6‐MMPN/6‐MMP) which can be hepatotoxic. Some patients preferentially metabolize 6‐MP to 6‐MMPN which may increase the risk of liver injury, reduce serum levels of 6‐TGN and potentially increase the risk of relapse. The addition of allopurinol to oral 6‐MP has been shown to optimize metabolism towards 6‐TGN in patients with inflammatory bowel disease (IBD); however, this use has not been reported in patients undergoing treatment for ALL. Pediatr Blood Cancer 2014;61:1114–1117.

A 10-Year united network for organ sharing review of mortality and risk factors in young children awaiting liver transplantation.

Young children < 2 years of age with chronic end‐stage liver disease (YC2) are a uniquely vulnerable group listed for liver transplantation, characterized by a predominance of biliary atresia (BA). To investigate wait‐list mortality, associated risk factors, and outcomes of YC2, we evaluated United Network for Organ Sharing registry data from April 2003 to March 2013 for YC2 listed for deceased donor transplant (BA = 994; other chronic liver disease [CLD] = 221). Overall, wait‐list mortality among YC2 was 12.4% and posttransplant mortality was 8%, accounting for an overall postlisting mortality of 19.6%. YC2 demonstrated 12.2%, 18.7%, and 20.6% wait‐list mortality by 90, 180, and 270 days, respectively. YC2 with CLD demonstrated significantly higher wait‐list mortality compared with BA among YC2 (23.9% versus 9.8%; P < 0.05). Multivariate analyses revealed that listing Pediatric End‐Stage Liver Disease [PELD] > 21 (hazard ratio [HR], 3.2; 95% confidence interval [CI], 1.6‐6.5), lack of exception (HR, 5.8; 95% CI, 2.8‐11.8), listing height < 60.6 cm (HR, 2.1; 95% CI, 1.4‐3.1), listing weight  > 10 kg (HR, 3.8; 95% CI, 1.5‐9.2), and initial creatinine > 0.5 (HR, 6.8; 95% CI, 3.4‐13.5) were independent risk factors for YC2 wait‐list mortality (P < 0.005 for all). Adjusting for all variables, the risk of death among CLD patients was 2 (95% CI, 1.3‐3.1) times greater than patients with BA + surgery (presumed Kasai). Furthermore, the risk of death in BA surgery was 1.9 (95% CI, 1‐3.4) times greater than BA with presumed Kasai. Our data highlight unacceptably high wait‐list and early post–liver transplant mortality in YC2 not predicted by PELD and suggest key risk factors deserving of further study in this age group. Liver Transplantation 22 1584–1592 2016 AASLD.

Hepatitis C in the pediatric population: transmission, natural history, treatment and liver transplantation.

The number of children affected by the hepatitis C virus (HCV) in the United States is estimated to be between 23000 to 46000. The projected medical cost for children with HCV in the United States is

Cystic Fibrosis-related cirrhosis

199-366 million over the next decade. The implementation of routine screening of blood supply has virtually eliminated transmission via transfusion and vertical transmission is now the most common mode of infection in children. Infections acquired during infancy are more likely to spontaneously resolve and fibrosis of the liver tends to increase with age suggesting slow progressive histologic injury. Anti-viral treatment may be warranted in children with persistently elevated liver enzymes or with significant fibrosis on liver biopsy. Current standard of care includes weekly pegylated interferon and ribavirin twice daily. Predictors of high sustained viral response include genotype 2 and 3 and low viral load in children with genotype 1 (< 600000 IU/mL). Phase 1 and 2 trials with triple therapy (interferon, ribavirin, and a protease inhibitor) are ongoing. Triple therapy is associated with a significantly higher rate of sustained virologic response (> 90%). Only 34 pediatric patients were transplanted with hepatitis C between January 2008 and April 2013. The majority of pediatric patients were born prior to universal screening of blood products and, as of June 2013, there are only two pediatric patients awaiting liver transplantation for end-stage liver disease secondary to hepatitis C. Pediatric survival rates post-transplant are excellent but graft survivals are noticeably reduced compared to adults (73.73% for pediatric patients at one year compared to 87.69% in adult patients). New safe and effective antiviral therapies for recurrent HCV should help increase graft survival.

Early attained weight and length predict growth faltering better than velocity measures in infants with CF

While liver involvement is common in cystic fibrosis, the major liver disorder with impact on the clinical outcome of individuals with CF is the development of multilobular cirrhosis with progression to portal hypertension. Interestingly, this is a disorder primarily of children and adolescents. We review the proposed pathogenesis, clinical presentation, diagnostic work-up, medical and surgical management, and complications of CF cirrhosis.