Pietro Vajro

Diagnosis of nonalcoholic fatty liver disease in children and adolescents: position paper of the ESPGHAN Hepatology Committee.

ABSTRACT Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children and adolescents in the United States, and most probably also in the rest of the industrialized world. As the prevalence of NAFLD in childhood increases with the worldwide obesity epidemic, there is an urgent need for diagnostic standards that can be commonly used by pediatricians and hepatologists. To this end, we performed a PubMed search of the adult and pediatric literature on NAFLD diagnosis through May 2011 using Topics and/or relevant Authors as search words. According to the present literature, NAFLD is suspected based on the association of fatty liver combined with risk factors (mainly obesity), after the exclusion of other causes of liver disease. The reference but imperfect standard for confirming NAFLD is liver histology. The following surrogate markers are presently used to estimate degree of steatosis and liver fibrosis and risk of progression to end-stage liver disease: imaging by ultrasonography or magnetic resonance imaging, liver function tests, and serum markers of liver fibrosis. NAFLD should be suspected in all of the overweight or obese children and adolescents older than 3 years with increased waist circumference especially if there is a NAFLD history in relatives. The typical presentation, however, is in children ages 10 years and older. The first diagnostic step in these children should be abdominal ultrasound and liver function tests, followed by exclusion of other liver diseases. Overweight/obese children with normal ultrasonographic imaging and normal liver function tests should still be monitored due to the poor sensitivity of these tests at a single assessment. Indications for liver biopsy include the following: to rule out other treatable diseases, in cases of clinically suspected advanced liver disease, before pharmacological/surgical treatment, and as part of a structured intervention protocol or clinical research trial.

Long-Term Course of Chronic Hepatitis C in Children: From Viral Clearance to End-Stage Liver Disease

BACKGROUND & AIMS The natural course of chronic hepatitis C (CHC) in children is not well understood. The aim of this study was to assess the long-term course of CHC in a large sample of otherwise healthy children. METHODS From 1990 to 2005, 504 consecutive antihepatitis C virus (HCV)-positive children were enrolled at 12 centers of a national observatory and were followed up retrospectively/prospectively. RESULTS Putative exposure was perinatal in 283 (56.2%) cases, parenteral in 158 (31.3%), and unknown in 63 (12.5%). At baseline, 477 (94.6%) cases were HCV RNA seropositive, 118 (24.7%) of which were treated with standard interferon alpha. Ten years after putative exposure, the outcome in 359 HCV RNA-positive, untreated patients was (1) undetectable viremia in 27 (7.5%) (by Cox regression analysis, spontaneous viral clearance was independently predicted by genotype 3 [hazard ratio 6.44; 95% confidence interval: 2.7-15.5]) and (2) persistent viremia in 332 (92%) cases. Six of these 332 cases (1.8%) progressed to decompensated cirrhosis (mean age, 9.6 years). This latter group included 5 Italian children perinatally infected with genotype 1a (4 of the mothers were drug users). Thirty-three (27.9%) treated patients achieved a sustained virologic response. CONCLUSIONS Over the course of a decade, few children with chronic HCV infection cleared viremia spontaneously, and those who did were more likely to have genotype 3. Persistent viral replication led to end-stage liver disease in a small subgroup characterized by perinatal exposure, maternal drug use, and infection with HCV genotype 1a. Children with such features should be considered for early treatment.

Vitamin E treatment in pediatric obesity-related liver disease: a randomized study.

Objective A beneficial role of antioxidants in hepatopathic obese individuals has hitherto been inferred only from uncontrolled pilot studies. The authors compared the effect of vitamin E and weight loss on transaminase values and on ultrasonographic bright liver in a controlled group of children with obesity-related liver dysfunction. Methods Twenty-eight children with obesity-related hypertransaminasemia and bright liver were randomly allocated to two single-blind groups: group 1 (n = 14) treated with a low-calorie diet associated with oral placebo for 5 months, and group 2 (n = 14) treated with a low-calorie diet associated with oral vitamin E (400 mg/d × 2 months, 100 mg/d × 3 months). Transaminase values and ultrasonographic liver brightness along with weight loss and vitamin E levels were monitored. Results Variations in transaminase levels and percentage of patients with normalized transaminase values were comparable in the two groups. The disappearance of bright liver was observed only in patients who lost weight and was twice as common in patients from group 1. Two subgroups of patients with complete normalization of transaminase values emerged as a consequence of controlled adherence to diet alone (n = 6; significant decrease of percent overweight:P = 0.0019 ) and to vitamin E alone (n = 7; unmodified percent overweight and significant increase of vitamin E/cholesterol ratio:P < 0.0001). Changes in treatment-induced alanine aminotransferase levels in these two subgroups were comparable at month 2, whereas values at month 5 were significantly lower in the subgroup adherent to diet alone (P = 0.04). In the subgroup adherent to vitamin E alone, after 2 months washout, transaminase remained stable in 5 patients and increased in 2; bright liver persisted in all. Conclusions Oral vitamin E warrants consideration in obesity-related liver dysfunction for children unable to adhere to low-calorie diets.

Probiotics Reduce the Inflammatory Response Induced by a High-Fat Diet in the Liver of Young Rats

Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in the pediatric population. Preliminary evidence suggests a potential therapeutic utility of probiotics for this condition. Here, we tested the potential effect of the probiotic VSL#3 (a multistrain preparation composed of Streptococcus thermophilus and several species of Lactobacillus and Bifidobacteria) on oxidative and inflammatory damage induced by a high-fat diet in the liver of young rats. At weaning, young male Sprague-Dawley rats were randomly divided into 3 groups (n = 6) fed a standard, nonpurified diet (Std; 5.5% of energy from fat) or a high-fat liquid diet (HFD; 71% of energy from fat). One of the HFD groups received by gavage VSL#3 (13 x 10(9) bacteria x kg(-1) x d(-1)). After 4 wk, the HFD rats had greater body weight gain, fat mass, serum aminotransferase, and liver weight than rats fed the Std diet. The HFD induced liver lipid peroxidation, tumor necrosis factor (TNFalpha) production, protein S-nitrosylation, inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2 expression, and metalloproteinase (MMP) activity. Moreover, in the HFD group, PPARalpha expression was less than in rats fed the Std diet. In rats fed the HFD diet and treated with VSL#3, liver TNFalpha levels, MMP-2 and MMP-9 activities, and expression of iNOS and COX-2 were significantly lower than in the HFD group. In VSL#3-treated rats, PPARalpha expression was greater than in the HFD group. A modulation of the nuclear factor-kappaB pathway by VSL#3 was also demonstrated. Our data suggest that VSL#3 administration could limit oxidative and inflammatory liver damage in patients with NAFLD.

Effects of Lactobacillus rhamnosus Strain GG in Pediatric Obesity-related Liver Disease

Objective:Various lines of evidence suggest that malfunctioning of the gut–liver axis contributes to hepatic damage of rodents and humans with nonalcoholic fatty liver disease. We evaluated the effects of short-term probiotic treatment in children with obesity-related liver disease who were noncompliant with lifestyle interventions. Patients and Methods:Twenty obese children (age 10.7 ± 2.1 years) with persisting hypertransaminasemia and ultrasonographic (US) bright liver were enrolled in this double-blind, placebo-controlled pilot study. At baseline, patients underwent clinical and laboratory anthropometric evaluation, measurement of the US hepatorenal ratio, standard liver function tests, oral glucose tolerance test, serum tumor necrosis factor-alpha, the glucose hydrogen breath test, and evaluation of serum antibodies to antipeptidoglycan-polysaccharide polymers. After exclusion of causes of liver disease other than obesity, patients received either probiotic Lactobacillus rhamnosus strain GG (12 billion CFU/day) or placebo for 8 weeks. Results:Multivariate analysis after probiotic treatment revealed a significant decrease in alanine aminotransferase (average variation vs placebo P = 0.03) and in antipeptidoglycan-polysaccharide antibodies (average variation vs placebo P = 0.03) irrespective of changes in BMI z score and visceral fat. Tumor necrosis factor-alpha, and US bright liver parameters remained fairly stable. Conclusions:Probiotic L rhamnosus strain GG warrants consideration as a therapeutic tool to treat hypertransaminasemia in hepatopathic obese children noncompliant with lifestyle interventions.

Lack of efficacy of ursodeoxycholic acid for the treatment of liver abnormalities in obese children

OBJECTIVE To determine whether ursodeoxycholic acid (UDCA) is effective for treatment of obesity-related liver abnormalities in children. STUDY DESIGN Thirty-one children (21 bboys; mean age, 8.7 years) had obesity-related persistent elevation of aminotransferase levels, which was associated with ultrasonographic images of bright liver in 27. A preliminary interview determined which patients were (n = 18) or were not (n = 13) likely to comply with a balanced low-calorie diet. Four subgroups emerged: patients who followed the diet (n = 11), patients treated with UDCA (10 mg/kg/d) given alone (n = 7) or added to the diet (n = 7), and untreated control patients (n = 6). RESULTS Diet alone determined weight loss and resolved biochemical liver abnormalities in all patients. Addition of UDCA to the diet was no more efficacious than weight loss alone. UDCA alone was ineffective for the treatment of liver abnormalities in all cases, and results did not differ from those observed in the untreated control group. Improvement of ultrasonographic abnormalities was observed in patients who lost weight, irrespective of UDCA administration. CONCLUSIONS UDCA is not effective for the treatment of obesity-related liver abnormalities in children.

Multiple phenotypes in phosphoglucomutase 1 deficiency

BACKGROUND Congenital disorders of glycosylation are genetic syndromes that result in impaired glycoprotein production. We evaluated patients who had a novel recessive disorder of glycosylation, with a range of clinical manifestations that included hepatopathy, bifid uvula, malignant hyperthermia, hypogonadotropic hypogonadism, growth retardation, hypoglycemia, myopathy, dilated cardiomyopathy, and cardiac arrest. METHODS Homozygosity mapping followed by whole-exome sequencing was used to identify a mutation in the gene for phosphoglucomutase 1 (PGM1) in two siblings. Sequencing identified additional mutations in 15 other families. Phosphoglucomutase 1 enzyme activity was assayed on cell extracts. Analyses of glycosylation efficiency and quantitative studies of sugar metabolites were performed. Galactose supplementation in fibroblast cultures and dietary supplementation in the patients were studied to determine the effect on glycosylation. RESULTS Phosphoglucomutase 1 enzyme activity was markedly diminished in all patients. Mass spectrometry of transferrin showed a loss of complete N-glycans and the presence of truncated glycans lacking galactose. Fibroblasts supplemented with galactose showed restoration of protein glycosylation and no evidence of glycogen accumulation. Dietary supplementation with galactose in six patients resulted in changes suggestive of clinical improvement. A new screening test showed good discrimination between patients and controls. CONCLUSIONS Phosphoglucomutase 1 deficiency, previously identified as a glycogenosis, is also a congenital disorder of glycosylation. Supplementation with galactose leads to biochemical improvement in indexes of glycosylation in cells and patients, and supplementation with complex carbohydrates stabilizes blood glucose. A new screening test has been developed but has not yet been validated. (Funded by the Netherlands Organization for Scientific Research and others.).

A 360-degree overview of paediatric NAFLD: Recent insights

Non-alcoholic fatty liver disease (NAFLD) is a multi-faceted disorder, which ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) with/without fibrosis. The effects of specific risk factors, such as obesity and sedentary lifestyle, on predisposing genetic settings eventually lead to the development of NAFLD in children. The complex interplay between genes and environment in NAFLD pathogenesis is sustained by multiple mechanisms that involve liver crosstalk with other organs and tissues, especially gut and adipose tissue. Unfortunately, natural history of paediatric NAFLD is lacking, and the etiopathogenesis is still in the process of being defined. Potential early predictors and suitable non-invasive diagnostic tools can be discovered based on the pathogenetic mechanisms and histological patterns. This will also help design novel treatments and a comprehensive and successful management strategy for patients. In this review, we discuss the recent advances made in genetics, etiopathogenesis, diagnosis, and therapeutic management of NAFLD, focusing especially on the obesity-related steatotic liver condition.

Pharmacological Interventions for Nonalcoholic Fatty Liver Disease in Adults and in Children : A Systematic Review

Background: Uncertainty exists regarding the treatment of patients with nonalcoholic fatty liver disease (NAFLD) who are unable to lose weight and/or change lifestyle. The present study assesses the effectiveness and safety of pharmacological and dietary supplement interventions for NAFLD. Methods: MEDLINE, EMBASE, and the Cochrane Library were searched for randomized controlled trials (RCTs) both in adults and in children. Results: Fifteen (2 pediatric patients and 13 adults) RCTs met the inclusion criteria. A significant effect on normalization of alanine transaminase was found in patients treated with metformin compared with vitamin E, and in those treated with high-dose (3 g) carnitine vs diet. In contrast, there was no difference in patients treated with pioglitazone combined with vitamin E versus vitamin E alone, ursodeoxycholic acid (UDCA) combined with vitamin E or alone versus placebo, or UDCA versus combination of vitamin E and vitamin C, and in patients treated with vitamin E, probucol, N-acetylcysteine, low doses of carnitine, or Yo Jyo Shi Ko compared with placebo. Aspartate aminotransferase normalization was significantly higher in those treated with UDCA combined with vitamin E versus UDCA alone or placebo, and in those treated with metformin. Small number of subjects, high drop-out rates, and numerous interventions in 1 study limit the value of many studies. Only 7 RCTs analyzed biopsy specimens, but most of them have significant methodological limitations. Pioglitazone had reduced liver necrosis and inflammation in 1 large study. Conclusions: Limited data do not allow one to draw firm conclusions on the efficacy of various treatments for NAFLD.

Re‐evaluation of the diagnostic criteria for Wilson disease in children with mild liver disease

The diagnosis of Wilson disease (WD) is challenging, especially in children. Early detection is desirable in order to avoid dramatic disease progression. The aim of our study was to re‐evaluate in WD children with mild liver disease the conventional diagnostic criteria and the WD scoring system proposed by an international consensus in 2001. Forty children with WD (26 boys and 14 girls, age range = 1.1‐20.9 years) and 58 age‐matched and sex‐matched patients with a liver disease other than WD were evaluated. Both groups were symptom‐free and had elevated aminotransferases as predominant signs of liver disease. In all WD patients, the diagnosis was supported by molecular analysis, the liver copper content, or both. A receiver operating characteristic (ROC) analysis of ceruloplasmin at the cutoff value of 20 mg/dL showed a sensitivity of 95% [95% confidence interval (CI) = 83%‐99.4%] and a specificity of 84.5% (95% CI = 72.6%‐92.6%). The optimal basal urinary copper diagnostic cutoff value was found to be 40 μg/24 hours (sensitivity = 78.9%, 95% CI = 62.7%‐90.4%; specificity = 87.9%, 95% CI = 76.7%‐95%). Urinary copper values after penicillamine challenge did not significantly differ between WD patients and control subjects, and the ROC analysis showed a sensitivity of only 12%. The WD scoring system was proved to have positive and negative predictive values of 93% and 91.6%, respectively. Conclusion: Urinary copper excretion greater than 40 μg/24 hours is suggestive of WD in asymptomatic children, whereas the penicillamine challenge test does not have a diagnostic role in this subset of patients. The WD scoring system provides good diagnostic accuracy. (HEPATOLOGY 2010.)