Claudia Della Corte

Nonalcoholic Fatty Liver Disease: A Challenge for Pediatricians

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and is considered the most common form of chronic liver disease in children. Several factors contribute to NAFLD development, including race/ethnicity, genetic factors, environmental exposures, and alterations in the gut microbiome. The histologic spectrum of NAFLD ranges from simple steatosis to the more aggressive nonalcoholic steatohepatitis (NASH). Fibrosis and eventually cirrhosis can develop from NAFLD during childhood. Diagnosing advanced disease is challenging and may require a liver biopsy, highlighting the urgent need for reliable, noninvasive markers of disease severity. The mainstay of treatment for NAFLD remains lifestyle modifications and weight loss. Probiotics and ω-3 fatty acids may ameliorate disease progression. Recent data have suggested that vitamin E may be considered as a NASH-specific therapy in children, and there are several ongoing human studies evaluating different therapeutic targets for NAFLD. We provide an up-to-date review of the risk factors, diagnosis, and treatment to manage this common disease in children.

Nonalcoholic Fatty Liver in Children and Adolescents: An Overview

Nonalcoholic fatty liver disease is rapidly becoming one of the most common liver diseases in the pediatric population in industrialized countries because of the growing prevalence of obesity and overweight. For this reason, there is a keen and broad interest among researchers to identify new diagnostic noninvasive tools and novel treatment modalities for this condition. Unfortunately, to date, liver biopsy remains the imperfect gold standard for diagnosis. In addition, available noninvasive markers are not fully satisfactory for the diagnosis of fatty liver. Although in recent years many pharmacological agents, on the basis of pathogenetic mechanism of the disease, have been attempted, to date, the guidelines for the management of fatty liver are still lacking. Establishing effective therapeutic strategies to treat the disease represents the challenge for pediatric hepatologists in the near future. In this article, we briefly review the current knowledge and ideas concerning pediatric nonalcoholic fatty liver disease, and discuss the new perspective therapies.

Docosahexanoic acid plus Vitamin D treatment improves features of NAFLD in children with serum Vitamin D deficiency: Results from a single centre trial

Background There are no licensed treatments for non alcoholic fatty liver disease (NAFLD) in adults or children. In NAFLD, several studies have shown a benefit of omega-3 fatty acid treatment on lipid profile, insulin-sensitivity and hepatic steatosis and it has also been suggested that Vitamin D treatment has potential antifibrotic properties in liver disease. Trial Design To date, however, there are no studies that have tested the combination of Docosahexanoic acid (DHA) and vitamin D treatment which may benefit the whole spectrum of disease in NAFLD. Our aim therefore, was to test the effect of daily DHA (500 mg) plus vitamin D (800 IU) treatment, in obese children with biopsy-proven NAFLD and vitamin D deficiency, in a randomized, double-blind placebo-controlled trial. Methods The 41/43 patients completed the study (18-treatment, 23-placebo). At 12 months: i) the main outcome was liver histology improvement, defined by NAS; ii) the secondary outcome was amelioration of metabolic parameters. Results DHA plus vitamin D treatment reduced the NAFLD Activity Score (NAS), in the treatment group (5.4 v1.92; p<0.001 for baseline versus end of study). There was no change in fibrosis score, but a reduction of the activation of hepatic stellate cells (HSC) and fibrillar collagen content was noted (3.51±1.66 v. 1.59±1.37; p = 0.003) in treatment group. Moreover, the triglycerides (174.5 vs. 102.15 mg/dl), ALT (40.25 vs. 24.5 UI/l) and HOMA-IR (4.59 vs. 3.42) were all decreased with treatment. Conclusion DHA plus vitamin D treatment improved insulin-resistance, lipid profile, ALT and NAS. There was also decreased HSC activation and collagen content with treatment.

Autoimmune hepatitis type 2 following anti-papillomavirus vaccination in a 11-year-old girl

In the last years numerous reports describing a possible association between administration of vaccines and development of autoimmune phenomena and overt autoimmune disease were published. Possible mechanisms of induction of autoimmune phenomena by vaccines and their excipients are probably similar to those implicated in induction by infectious agents. Here we report the case of an 11-year-old girl who developed autoimmune hepatitis type II after four weeks from vaccination against human papillomavirus. The possible relationships between the use of adjuvated vaccine against papillomavirus and autoimmune hepatitis are discussed. Although we do not provide evidence for a causal link, we suggest that the occurrence of the autoimmune hepatitis may be related to the stimulation of immune system by adjuvated-vaccine, that could have triggered the disease in a genetically predisposed individual. Therefore a monitoring of liver function test following administration of vaccine against papillomavirus may be useful in adolescent girl with signs of hepatopathy, as jaundice, dark urine or hepatomegaly, to early identify and to promptly treat autoimmune liver disorders.

Management of chronic hepatitis B in children: An unresolved issue

Although a rather benign course of chronic hepatitis B virus (HBV) infection during childhood has been described, 3–5% and 0.01–0.03% of chronic carriers develop cirrhosis or hepatocellular carcinoma before adulthood. Considering the whole lifetime, the risk of hepatocellular carcinoma rises to 9–24% and the incidence of cirrhosis to 2–3% per year. The aim of this article is to review the current knowledge regarding the natural history and treatment of chronic hepatitis B in children and to focus on critical aspects and unresolved questions in the management of childhood HBV infection. A literature search was carried out on MEDLINE, EMBASE, and Web of Science for articles published in English in peer‐reviewed journals from January 1980 to February 2013. The search terms used included “Hepatitis B virus infection,” “children,” “HBV,” “interferon,” “lamivudine,” “adefovir,” “entecavir,” and “tenofovir.” Articles resulting from these searches and relevant references cited in the articles retrieved were reviewed. The current goals of therapy are to suppress viral replication, reduce liver inflammation, and reverse liver fibrosis. Therapeutic options for children are currently limited, and the risk for viral resistance to current and future therapies is a particular concern. Based on the data available at this time, it is the consensus of the panel that it is not appropriate to treat children in the immune‐tolerant phase or in the inactive carrier state. For children in the immune‐active or reactivation phases, liver histology can help guide treatment decisions. Outside of clinical trials, interferon is the agent of choice in most cases; currently, available nucleoside analogs are secondary therapies.

Serum bilirubin level is inversely associated with nonalcoholic steatohepatitis in children.

Objectives: Oxidative stress has been implicated in the development of nonalcoholic fatty liver disease (NAFLD) and progression to the more severe form, nonalcoholic steatohepatitis (NASH), in children. We aimed to study the clinical correlation between bilirubin, a potent endogenous antioxidant with cytoprotective properties, and histopathological findings in pediatric patients with NAFLD. Methods: We included consecutive children with biopsy-proven NAFLD and obtained demographic, clinical, and histopathological data. We performed logistic regression analysis to assess the clinical factors associated with the histological features of NASH or fibrosis. Results: From a total of 302 biopsies, 67% (203) had evidence of NASH, whereas 64.2% had some degree of fibrosis (stage 1 in 51%, stage 2 in 6.3%, and stage 3 in 6.6%). Mean total bilirubin was significantly lower in the NASH group compared with the non-NASH group (0.65 ± 0.24 vs 0.73 ± 0.22 mg/dL, P = 0.007). Higher total bilirubin levels were negatively correlated with the presence of steatosis and the NAFLD activity score (P < 0.05), whereas a trend in that direction was observed for presence of fibrosis and inflammation (P = 0.051). On multivariable analysis, higher bilirubin levels were significantly associated with a decreased likelihood of a histological diagnosis of NASH on biopsy (odds ratio 0.29, 95% CI 0.10–0.85, P = 0.024). Conclusions: In children with NAFLD, there is an inverse relation between serum bilirubin levels and the presence of NASH on biopsy. This may be secondary to the antioxidant effect of bilirubin.

Good adherence to the Mediterranean diet reduces the risk for NASH and diabetes in pediatric patients with obesity: The results of an Italian Study

OBJECTIVE In the last decade, it was demonstrated that the Mediterranean diet (MD) represents an ideal diet for all age groups and has an important role in the prevention of metabolic and cardiovascular diseases, as well as nonalcoholic fatty liver disease (NAFLD). The aim of the present study was to analyze the association between adherence to the MD and NAFLD, with laboratory and histologic evaluation, in a group of children and adolescents with obesity. METHODS We enrolled 243 patients with obesity referred to our department from March 2014 to November 2015. In all patients, we performed abdominal ultrasound and laboratory assays. In selected cases (100 patients) liver biopsy was performed. Level of adherence to the MD was evaluated by a clinical questionnaire, the Mediterranean Diet Quality Index for children and adolescents (KIDMED). RESULTS The prevalence of low KIDMED score was significantly higher in patients with nonalcoholic steatohepatitis compared with other groups; poor adherence to the MD correlated with liver damage, the NAFLD activity score >5, and grade 2 fibrosis. Moreover, in patients with poor adherence to the MD, higher values of C-reactive protein, fasting insulin, homeostatic model assessment of insulin resistance, and homeostatic model assessment of β cell function were observed. CONCLUSION The MD could be a safe and inexpensive therapeutic option for children with obesity and NAFLD.

Fatty liver and insulin resistance in children with hypobetalipoproteinemia: the importance of aetiology.

Hepatic steatosis is strongly associated with insulin resistance, but causative mechanisms that link these conditions are still largely unknown. Nowadays, it is difficult to establish whether fatty liver is the cause of insulin resistance or instead the complex metabolic derangements of insulin resistance determine hepatic steatosis and its progression to fibrosis. In patients with familial hypobetalipoproteinemia (FHBL), hepatic steatosis is because of the genetically determined defective form of apolipoprotein B, independently of metabolic derangements. Therefore patients with FHBL represent a good in vivo model to evaluate the relationships between fatty liver and insulin sensitivity.

Autoimmune hepatitis in children: an overview of the disease focusing on current therapies.

Autoimmune hepatitis (AIH) is an immune-mediated necroinflammatory disease of the liver characterized by elevation of IgG, presence of characteristic autoantibodies, and histological features of interface hepatitis. Two types of juvenile AIH have been recognized according to seropositivity for smooth muscle and/or antinuclear antibody (AIH type 1) or liver kidney microsomal antibody (AIH type 2). The exact pathogenesis of AIH is still unclear, but it is known that unidentified environmental factors, and occasionally drugs, might trigger disease in genetically susceptible individuals. The clinical spectrum of this disease is very wide, ranging from asymptomatic individuals with abnormal liver function to those with fulminant liver failure. The diagnosis is based on a combination of biochemical and histological parameters and on exclusion of other liver diseases. It is a relatively rare but devastating disease, which progresses rapidly unless immunosuppressive treatment is started promptly. Standard therapy consists of a combination of corticosteroids and azathioprine, which is efficacious in 80% of patients. Alternative therapies are increasingly being explored in patients who do not respond to standard treatment and/or have intolerable side-effects. The purpose of this paper is to review our current knowledge about AIH in children, evaluating mainly the therapeutic options for its treatment, considering also the newer immunosuppressant agents used in difficult-to-treat cases.

Obalon intragastric balloon in the treatment of paediatric obesity: a pilot study

Lifestyle interventions are often ineffective in the treatment of pediatric obesity. Weight loss devices have been introduced for the temporary nonsurgical treatment of morbid obesity.