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

Disclosures

January 13, 2016

In This Article

An Increase in Nonalcoholic Fatty Liver Disease

NAFLD has rapidly become the most common cause of chronic hepatopathies in children and adolescents in industrialized countries. The growing incidence of NAFLD reflects the worldwide annual increase in the number of obese and overweight individuals observed in recent decades.[3] Indeed, NAFLD is typically associated with metabolic disarray, which increases the risk of developing type 2 diabetes mellitus, the metabolic syndrome, and cardiovascular diseases, even in children.[4]

Today, it is widely accepted that NAFLD represents a spectrum of liver pathology, characterized by accumulation of triglycerides in the hepatocytes, that ranges from simple steatosis (accumulation of fats in > 5% of hepatocytes) to evolutive forms of liver damage with different degrees of inflammation, ballooning, and fibrosis (eg, nonalcoholic steatohepatitis [NASH]), which may progress to advanced liver diseases, cirrhosis, and hepatocellular carcinoma.[5] Therefore, NAFLD should be considered a metabolic condition that includes several diseases that differ widely in presentation, natural history, and outcomes. This necessitates a personalized approach to diagnosis and treatment.

NAFLD in Children

The prevalence of pediatric NAFLD is estimated at 3%-10% of the general population; as expected, this percentage increases to 70%-80% in obese children and adolescents.[6] This large range in prevalence is influenced by the characteristics of the studied population and by the diagnostic methods used to detect fatty liver.[7]

Hits to the Gut/Liver Axis

The pathogenesis of NAFLD remains unclear. The initial accepted theory, the "two-hit model," postulated that the first "hit" involves hepatic lipid accumulation and insulin resistance leading to steatosis. Oxidative stress and proinflammatory markers were the second "hit," heralding progression. However, this theory has been abandoned.

The parallel "multi-hits theory" has been adopted to explain the spectrum of NAFLD onset and progression.[8] Insulin resistance and hepatic triglyceride accumulation remain central factors that render the liver prone to other hits, including oxidative stress, cytokine imbalance, mitochondrial dysfunction, and immune system response, all of which result in the liver damage typical of NAFLD or NASH.[8] It is noteworthy that continuous organ cross-talk sustains all processes implied in NAFLD pathogenesis, and in recent years, a crucial role of the gut has been suggested.[9] In fact, growing animal and human evidence demonstrates that severe liver damage in NAFLD is associated with gut dysbiosis, release of both pathogen- and damage-associated molecules, and increased intestinal permeability.[10]

Recently, it has been demonstrated in both adults[11] and children[12] that biopsy-proven NAFLD is associated with increased intestinal permeability, with disrupted intercellular tight junctions in the intestinal epithelium. A positive correlation exists between intestinal permeability and the severity of liver damage. Moreover, recent studies have demonstrated an important role of changes in gut microbiota composition (small intestinal bacterial overgrowth) in promoting NAFLD, influencing intrahepatic fat accumulation and inflammatory cascade in the liver, principally by gut-derived lipopolysaccharides and production of tumor necrosis factor alpha.[13,14]

Thus, it seems that bacterial overgrowth (a common condition in obese individuals, mainly promoted by slowing of the oro-cecal transit time) increases production of lipopolysaccharide by gram-negative bacteria and impairs intestinal barrier integrity, leading to increased endotoxin absorption by the portal circulation in the liver and enabling progression of liver damage.[13,14]

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