Boston, Massachusetts; Tuesday, November 7, 2007 -- Research efforts in the field of pediatric hepatology have been stimulated by multicenter collaborative studies which have addressed specific liver diseases that affect children. The results of these studies, as well as other innovative research in pediatric liver disease, were reported during the 2007 annual meeting of the American Association for the Study of Liver Diseases (AASLD).


Acute Liver Failure

Can We Improve the Diagnostic Evaluation of the Child With Acute Liver Failure?

In 40% to 50% of children who present with acute liver failure (ALF), the cause is undefined and coded as "indeterminate ALF." Narkewicz and colleagues[1] hypothesized that this may be due, in part, to significant variability in the diagnostic evaluation process. They analyzed the frequency of specific diagnostic evaluations for 611 children enrolled in the Pediatric ALF Study Group Database to clarify current practice. Of the 296 (48%) subjects categorized as indeterminate, only 2% had a complete evaluation for the most common etiologies. Screening methods were not standardized for drug, metabolic, infectious, or autoimmune causes in patients ultimately given a diagnosis of indeterminate ALF. Liver biopsy has been perceived to be a useful tool in the differential diagnosis of indeterminate ALF, although the associated risks increase with multisystem disease and coagulopathy. Hind and colleagues[2] reported that histology did not contribute to diagnosis in 46 of 53 (87%) children who presented with ALF. Although a histologic diagnosis was suggested in 11 of these 46 patients, it differed from the final clinical diagnosis. In the 7 in whom histology was definitive, the clinical diagnosis was made and management decided before biopsy was performed. The study authors examined an additional 58 biopsies obtained from the explanted livers; here again, histology did not contribute to diagnosis in 44 (76%) cases. Of the 14 cases in which histology was confirmative, the clinical diagnosis was made and treatment instituted before transplantation. Thus, the risk of liver biopsy does not seem to justify the minimal benefit. This reinforces the need for a standardized diagnostic approach to children with "indeterminate ALF" to identify potential treatment options.

Is it Possible to Identify Those Patients Likely to Recover Spontaneously From Acute Liver Failure?

Lu and colleagues[3] assessed the predictive value of a scoring system in a test group of 53 pediatric patients with ALF. The score was derived using total bilirubin, prothrombin time/international normalized ratio, and ammonia concentration, through multivariate analysis that identified these parameters as significant predictors. Survival without transplantation at 4 weeks for each previously defined quartile, using the peak score, was as follows: 92%, 78%, 60%, and 25%. The peak and the presentation scores were both predictive of survival without liver transplantation; thus, the score may be useful for establishing transplant priority in children with ALF and as a research tool for stratifying patients into risk groups. Molecular markers, such as indicators of liver regeneration, may also permit identification of patients likely to recover from ALF spontaneously. Indeed, clinical experience suggests that recovery from ALF is related to the ability of the liver to regenerate. Rudnick and colleagues[4] noted that alpha-NH2-butyrate (AAB) levels were elevated in plasma from mice subjected to hepatectomy. Serum AAB levels (characteristic of regeneration) were also greater in children who survived ALF without the need for transplantation. The AAB:leucine (LEU) ratio was also higher in spontaneously surviving patients: 80% with an AAB:LEU ratio > 0.2 survived without transplantation vs only 32% of those with a ratio < 0.2 (P = .008). Additional large-scale, prospective studies are needed to assess the utility of both of these novel candidate diagnostic tools in the management of ALF.


Neonatal Cholestasis

How Can We Differentiate Biliary Atresia From Other Causes of Cholestasis?

Shneider and colleagues[5] assessed the reliability of patterns of presenting features in differentiating biliary atresia from other causes of neonatal cholestasis in 222 children (106 with biliary atresia) enrolled in a prospective multicenter database. Findings that were significantly different between biliary atresia and other liver disorders were: female sex (49% vs 35%), liver size, normal facial features, palpable spleen (56% vs 38%), acholic stools (80% vs 31%), and elevated serum gamma-glutamyl transferase. By multivariate analysis, the independent predictors of biliary atresia were acholic stools, female sex, and elevated serum gamma-glutamyl transferase. The discovery of genetic defects in children with intrahepatic cholestasis may allow a precise diagnosis to be made despite the large overlap in clinical phenotypes. Because of the lack of predominant mutations in target genes, a resequencing chip was developed that reads all exons and intron boundaries of 5 genes known to cause cholestasis: SERPINA1 (for alpha-1-antitrypsin), JAG1 (Alagille syndrome), ATP8B1 (FIC1 [familial cholestasis type 1] deficiency), ABCB11 (BSEP [bile salt export pump] deficiency), and ABCB4 (MDR3 [multidrug resistance P-glycoprotein] deficiency).[6] The chip accurately identified at least 1 candidate mutation in 38 of 48 patients. These mutations correlated with the previously assigned clinical or molecular diagnosis in greater than 90% of patients for individual diseases. Mutations were detected in 7 of 15 subjects with Alagille syndrome. Because of the known high frequency of insertion/deletion mutations in Alagille syndrome, a complementary capillary sequencing approach was used to identify potentially disease-causing mutations in 7 of the remaining 8 subjects. These validation studies showed that the resequencing chip detected candidate mutations in 79% of children with intrahepatic cholestasis and requires complementary capillary sequencing to detect insertions or deletions in JAG1.

What Is the Mechanism of Parenteral Nutrition-Associated Cholestasis?

Cholestatic liver disease is a serious complication of parenteral nutrition therapy in infants with intestinal failure. Novel therapeutic strategies based on the mechanisms involved in this serious liver injury are much needed. A clue is provided by the presence of lipid peroxide products (lipofuscin) in Kupffer cells in children with parenteral nutrition-associated cholestasis. Sokol and colleagues[7] applied comparative proteomics and detected a subset of 4 proteins that were significantly overabundant in the liver of children with parenteral nutrition-associated cholestasis: peroxiredoxin-4, serotransferrin, glutathione S-transferase P, and Mn-superoxide dismutase. Each of these proteins is involved in redox regulation and cellular protection against oxidative stress, a proposed mechanism involved in parenteral nutrition-associated cholestasis. These findings raise the possibility that novel therapeutic approaches for this disease could be targeted at this pathway.

Can Liver Injury Be Avoided in Alpha-1-Antitrypsin Deficiency?

Alpha-1 antitrypsin deficiency may be associated with liver disease and hepatocellular carcinoma in children and adults. The a1AT Z gene encodes a mutant Z protein, which forms insoluble intracellular aggregates injurious to the cell; these aggregates accumulate within hepatocytes, leading to hepatocellular death and a low-grade hepatic regenerative response. Several proteolytic mechanisms are activated within hepatocytes to cope with the intracellular burden of the accumulated mutant protein, including autophagy, which leads to disposal of the polymerized Z protein. Rapamycin causes a cyclical induction of autophagy through specific molecular binding mechanisms. Teckman and colleagues[8] evaluated the effect of rapamycin administration on PiZ mice, a well-characterized animal model that recapitulates many features of human a1AT deficiency liver disease. Weekly dosing of rapamycin increased autophagic activity, as shown by increased numbers of autophagic vacuoles, with a reduction in the intrahepatic accumulation of Z protein. Markers of hepatocellular injury were also decreased. Rapamycin may be therapeutic in patients with a1AT deficiency by reducing the intracellular burden of the polymerized mutant Z protein and by reducing the progression of liver injury.

How Can We Assess Liver Fibrosis in Children?

Liver stiffness measurement correlates with liver fibrosis in adults with chronic liver disease. Children (n = 93) with chronic liver diseases underwent assessment of liver fibrosis using the METAVIR scoring system. Liver stiffness was also assessed using FibroScan (Echosens, France), a noninvasive tool, equipped with a probe for evaluation of children. Ultrasonographic signs of portal hypertension were significantly associated with higher liver stiffness measurement. Reliable liver stiffness measurement was feasible using the dedicated probe in children as young as 1 month of age. Moreover, liver stiffness measurement was strongly correlated with liver fibrosis assessed by histology, biological parameters, and the presence of portal hypertension.


Treatment of Viral Hepatitis: Adults vs Children

In hepatitis C virus (HCV)-infected adults, obesity has been associated with poor response to interferon-based therapy. However, these data are confounded by the use of a single adult dose rather than weight-based dosing, and thus, overweight patients most often receive lower doses relative to their body mass. In children, dosages of medications are determined on the basis of body weight. Delgado-Borrego and colleagues[10] determined the effect of overweight on response to antiviral therapy in 45 HCV-infected children. A multiple logistic regression model controlling for changes in body mass index (BMI) z-score demonstrated a significant association between baseline BMI z-score and response to antiviral therapy. In the same model, children overweight at onset of therapy had 85% lower odds of response to interferon-based therapy (response defined as HCV RNA levels below the limit of detection at the end of therapy). Thus, overweight has an intrinsically adverse effect on treatment and is independently associated with poor response to antiviral therapy against HCV in children.

Another variable that confounds response to therapy in hepatitis C is the presence of autoantibodies. Antithyroid antibodies (in 14%) and autoimmune hepatitis antibodies (up to 90%) are frequently present in adults with chronic hepatitis C.[11] These antibodies have prevented some adults from completing treatment with interferon-based therapy. Although children with HCV infection generally tolerate treatment better than adults and have a higher response rate, little is known about the frequency with which autoantibodies are present. Haber and colleagues[12] assessed the incidence and described the correlates of positive antibodies, thyroid peroxidase (TPO), anti-nuclear antibody (ANA), anti-smooth muscle antibody (ASMA), and anti-liver kidney microsomal antibody (LKM) in 128 treatment-naive children with chronic hepatitis C at entry to the multicenter Peds-C Network clinical trial, funded by the National Institutes of Health. Overall, 14% had measurable autoantibodies: 44% were ASMA positive, 33% ANA positive, 17% LKM positive, and 6% TPO positive. Although autoantibody positivity was less frequent in children with chronic hepatitis C compared with adults, these autoantibodies may be important in the side-effect profile and treatment response.



Is it Possible to Avoid Corticosteroids?

It was postulated by Mazariegos and colleagues[13] that low-dose induction therapy with rATG (rabbit, anti-human thymocyte globulin) would safely reduce maintenance steroid use without significantly altering rejection risk, and thus maintenance immunosuppression monotherapy could be achieved. Therefore, the outcomes of 112 consecutive pediatric patients treated with a steroid-free immunosuppression protocol using an rATG preconditioning regimen and tacrolimus monotherapy were reviewed. Overall patient and graft survival were 97% and 94%, respectively, at a mean follow-up time of 34 months; 78% are free of maintenance steroids and the remainder are being weaned off steroids instituted during treatment rejection. The incidence of drug-associated complications (hypertension, renal insufficiency) and infection was favorable compared with historical controls.

What Is the Quality of Life After Liver Transplantation?

A multicenter study was conducted to examine health-related quality of life (HRQOL) in 675 pediatric liver transplant recipients.[14] The mean age of subjects was 8.0 ± 4.4 years and the mean interval from transplant was 4.1 +/ 2.5 years. Parents and patients 8 years and older) completed the age-appropriate version of the Pediatric Quality of Life Inventory assessment. Pediatric Quality of Life Inventory total scores and all subscale scores for the transplant sample were lower than for the healthy sample, with the highest effect size observed in school function. The transplant sample scored significantly higher than pediatric cancer survivors with respect to total score and physical health (for the child and parent report) and psychosocial health and emotional functioning (for parent report). Transplant recipients and their parents reported lower HRQOL than did healthy controls, with some domains similar to those of children receiving cancer therapy.

A cross-sectional analysis of responses to a structured questionnaire further defined the prevalence of special education requirements and identified learning-related problems in 636 children post liver transplant.[15] Across all age groups, 96% were attending school and only 1% were medically unable to attend. Older children (40%; P = .001) and those less than 18 months from transplant (59%; P < .0001) were more likely to have missed more than 10 days of school in the previous year. Across all age and interval groups, 40% of children had or were receiving special education. Learning disability was reported in 18% and mental retardation was present in 5%, both twice the rate expected for a normative population. Univariate analysis found that male sex and international normalized ratio prior to transplant were predictive of the requirement for special education. Despite excellence in medical outcomes, children post transplant have significant issues with learning regardless of age or interval from transplant. Further determination of the risk factors associated with learning problems will enhance the long-term management and success of children in the posttransplant setting. This and other issues will continue to be best addressed by multicenter collaborative studies

Supported by an independent educational grant from Bristol-Myers Squibb


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