An Obese Child With Fatty Liver and Abdominal Pain: The Gut/Liver Axis

Valerio Nobili, MD; Claudia Della Corte, MD; Laura Stronati, PhD; Salvatore Cucchiara, MD, PhD


January 13, 2016

In This Article

Management of NAFLD

Therapeutic interventions aim to limit the progression from fatty liver to steatohepatitis and reverse histologic features of necroinflammation and fibrosis. Lifestyle intervention involving a hypocaloric diet and regular physical exercise is the pivotal therapeutic approach, but its results are disappointing, especially with low compliance.[18]

Unfortunately, none of the drugs investigated in children to date have proven to be entirely satisfactory, and therefore novel possible targets or pharmacologic associations are being evaluated.[19] On the basis of the main factors involved in the NAFLD pathogenesis, some targeted pharmacologic interventions have been tested in the pediatric setting, such as insulin-sensitizing agents, antioxidants, and cytoprotective drugs, without success.[19]

In recent years, interesting data have been obtained on such supplements as omega-3 long-chain fatty acids and probiotics.[20] Recent studies have shown anti-inflammatory and insulin-sensitizing properties for omega-3 fatty acids,[21] which have an optimal safety profile. Nobili and coworkers[22,23] reported the results of a randomized clinical trial of docosahexaenoic acid (DHA) in which DHA ameliorated BMI, insulin sensitivity index, serum triglyceride and alanine aminotransferase levels, and steatosis at 6 months by ultrasound and at 18 months by liver biopsy.[22,23]

The new findings about the gut/liver axis led to the idea of manipulating enteric flora as a novel therapeutic strategy in NAFLD. Promising results were derived from animal and human studies testing probiotic treatment in NAFLD.[24] These preliminary data demonstrated that the manipulation of gut microbiota by probiotic supplementation ameliorates liver steatosis, serum aminotransferase levels, oxidative stress markers, inflammation, and insulin resistance. The available data showed that probiotic treatment may promote recovery of the intestinal mucosal barrier, through modulation of cytoskeletal and tight junction proteins and through direct inhibition of proinflammatory mediator production.

Recently, Alisi and colleagues[25] reported exciting results of the first randomized trial on the use of VSL#3®, a mixture of eight probiotics, in children with NASH. The treated group showed improvement in fatty liver on abdominal ultrasound and a significant reduction in BMI.[25] A significant reduction in serum aminotransferase levels has been reported in adults and children after probiotic administration (Lactobacillus species); furthermore, positive effects on inflammation and metabolic parameters, such as lipid profile and glucoinsulinemic status, have been reported in adults.[26]

Even if these data seem to support the use of probiotics in the treatment of NAFLD, more larger, randomized studies are still needed, as stated in a Cochrane meta-analysis.[27]

Prognosis of Children With NAFLD

The natural history of pediatric NAFLD is still poorly understood, but in adults, NAFLD is an emerging cause of liver transplantation.[28] Given the relatively recent occurrence of NAFLD in children, long-term follow-up studies are still limited.[29] Existing data suggest that simple steatosis has a benign course, whereas NASH may progress to end-stage liver disease. As in adults, pediatric NAFLD is associated with severe metabolic impairments, such as insulin resistance, hypertension, and visceral adiposity, and increases the risk for type 2 diabetes mellitus, the metabolic syndrome, and cardiovascular disease.

Several recent advances have been made in knowledge of the pathogenetic mechanisms of NAFLD and obesity-related diseases, opening new and interesting therapeutic scenarios.

Case Conclusion

On the basis of clinical, laboratory, and echographic results, NAFLD was suspected in Rick. He was started on lifestyle modification, with a hypocaloric diet and regular physical activity.

After 6 months of behavioral intervention, the child had not lost weight and was still showing hypertransaminasemia and hepatic steatosis associated with insulin resistance and dyslipidemia. Therefore, he underwent screening for other causes of liver damage, which revealed antinuclear antibody positivity at a low titer (1:40). In accordance with the ESPGHAN guidelines, liver biopsy was performed and showed histologic features of NASH, including hepatic macrovesicular steatosis (40% of hepatocytes), ballooning, low-grade portal inflammation, and fibrosis (F2 [perisinusoidal and portal/periportal fibrosis], NAFLD Activity Score 5).

Considering the promising emerging data on the modulation of gut microbiota and the patient's clinical history of recurrent abdominal pain, Rick was treated with probiotics; in addition to the lifestyle measures reported above, and consistent with trial data in children, VSL#3 was prescribed for 4 months. At the end of treatment, an amelioration of the echographic pattern was observed, with reduction of hepatic steatosis, and serum aminotransferase levels normalized. Amelioration of insulin resistance according to homeostatic model assessment was documented, although a state of insulin resistance persists. Moreover, an initial reduction in BMI has been recorded (26.7 kg/m2).

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