Marco Poeta

Pediatric non-alcoholic fatty liver disease: Recent solutions, unresolved issues, and future research directions

Non-alcoholic fatty liver disease (NAFLD) in children is becoming a major health concern. A “multiple-hit” pathogenetic model has been suggested to explain the progressive liver damage that occurs among children with NAFLD. In addition to the accumulation of fat in the liver, insulin resistance (IR) and oxidative stress due to genetic/epigenetic background, unfavorable lifestyles, gut microbiota and gut-liver axis dysfunction, and perturbations of trace element homeostasis have been shown to be critical for disease progression and the development of more severe inflammatory and fibrotic stages [non-alcoholic steatohepatitis (NASH)]. Simple clinical and laboratory parameters, such as age, history, anthropometrical data (BMI and waist circumference percentiles), blood pressure, surrogate clinical markers of IR (acanthosis nigricans), abdominal ultrasounds, and serum transaminases, lipids and glucose/insulin profiles, allow a clinician to identify children with obesity and obesity-related conditions, including NAFLD and cardiovascular and metabolic risks. A liver biopsy (the “imperfect” gold standard) is required for a definitive NAFLD/NASH diagnosis, particularly to exclude other treatable conditions or when advanced liver disease is expected on clinical and laboratory grounds and preferably prior to any controlled trial of pharmacological/surgical treatments. However, a biopsy clearly cannot represent a screening procedure. Advancements in diagnostic serum and imaging tools, especially for the non-invasive differentiation between NAFLD and NASH, have shown promising results, e.g., magnetic resonance elastography. Weight loss and physical activity should be the first option of intervention. Effective pharmacological treatments are still under development; however, drugs targeting IR, oxidative stress, proinflammatory pathways, dyslipidemia, gut microbiota and gut liver axis dysfunction are an option for patients who are unable to comply with the recommended lifestyle changes. When morbid obesity prevails, bariatric surgery should be considered.

Multiple gut–liver axis abnormalities in children with obesity with and without hepatic involvement

Gut–liver axis (GLA) dysfunction appears to play a role in obesity and obesity‐related hepatic complications.

Gut–Liver Axis Derangement in Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is the most frequent type of chronic liver disease in the pediatric age group, paralleling an obesity pandemic. A “multiple-hit” hypothesis has been invoked to explain its pathogenesis. The “first hit” is liver lipid accumulation in obese children with insulin resistance. In the absence of significant lifestyle modifications leading to weight loss and increased physical activity, other factors may act as “second hits” implicated in liver damage progression leading to more severe forms of inflammation and hepatic fibrosis. In this regard, the gut–liver axis (GLA) seems to play a central role. Principal players are the gut microbiota, its bacterial products, and the intestinal barrier. A derangement of GLA (namely, dysbiosis and altered intestinal permeability) may promote bacteria/bacterial product translocation into portal circulation, activation of inflammation via toll-like receptors signaling in hepatocytes, and progression from simple steatosis to non-alcoholic steato-hepatitis (NASH). Among other factors a relevant role has been attributed to the farnesoid X receptor, a nuclear transcriptional factor activated from bile acids chemically modified by gut microbiota (GM) enzymes. The individuation and elucidation of GLA derangement in NAFLD pathomechanisms is of interest at all ages and especially in pediatrics to identify new therapeutic approaches in patients recalcitrant to lifestyle changes. Specific targeting of gut microbiota via pre-/probiotic supplementation, feces transplantation, and farnesoid X receptor modulation appear promising.

Emerging pathomechanisms involved in obesity.

Objective: Overweight/obesity prevalence has increased dramatically worldwide. Recent evidence suggests sleep deprivation/fragmentation, fructose-exceedingly rich diets, and exposure to endocrine disruptors (eg, bisphenol A, BPA) as emerging additional factors involved in pathomechanisms and in the treatment resistance of obesity and its complications. Our study focuses on these factors for further preventive/therapeutic approaches in paediatric obesity. Methods: Fifty-four Italian children (cases: n = 31 overweight/obese; controls: n = 23 normal weight) were clinically/anthropometrically characterised. Parents completed questionnaires on the relation between obesogenic factors and childhood obesity. BPA was measured by gas chromatography/tandem mass spectrometry on early morning urine samples. Correlations between the continuous variables were analysed using Spearman rank correlation. Results: Sleep deprivation/fragmentation, nocturnal breathing problems, and daytime sleepiness increased with increasing body mass index, correlating with the presence of clinical markers of metabolic syndrome (eg, acanthosis nigricans). Frequency of sugar-enriched drink consumption and the amount of fructose per portion and/or per week increased, paralleling the ponderal excess and all the other anthropometric parameters. In the entire sample population, free and total BPA levels increased paralleling the body mass index increase (r > 0.8), whereas the conjugate demonstrated the opposite trend. The re-use of disposable plastic showed a positive correlation with urinary BPA levels. Conclusions: Despite its exploratory nature, the results of our pilot study confirm the close relation between certain factors and paediatric obesity, underscoring their role as emerging targets for prevention and therapy.

Probiotics to Treat Visceral Obesity and Related Liver Disease

Obesity and its related complications have reached epidemic proportions that cannot be completely explained by energy imbalance between dietary calories and physical exercise. Increasing interest is therefore developing in a number of recently identified obesogenic triggering factors (e.g. endocrine disruptors, sleep deprivation, fructose intake, gut-liver axis, and intestinal microbiota). In this chapter, we will focus on recent advances in our knowledge of the gut-liver axis and gut microbiota, which suggest that: (1) age, geographical origin, breastfeeding, diet, and lifestyle may all influence microbiome composition;

Pediatric non alcoholic fatty liver disease: more on novel treatment targets

The mainstay treatment of non alcoholic fatty liver disease (NAFLD) based on weight loss and/or lifestyle changes is most often unsuccessful at all ages, thus requiring the implementation of pharmacological strategies. Targeting insulin resistance and oxidative stress has recently proven unsatisfactory. Among a number of proposed innovative approaches targeting novel pathomechanisms, probiotics appear an interesting and reasonable option acting on gut-liver axis malfunction through the modulation of diet-driven, obesogenic, and inflammatory intestinal microbiota.A combined multiple pharmacological therapy directed simultaneously towards novel and old pathomechanisms (including, e.g., insulin resistance, oxidative stress, gut-liver axis, apoptosis) along with lifestyle interventions however might be necessary both in adult and pediatric NAFLD therapy.

Three unreported cases of TMEM199-CDG, a rare genetic liver disease with abnormal glycosylation

BackgroundTMEM199 deficiency was recently shown in four patients to cause liver disease with steatosis, elevated serum transaminases, cholesterol and alkaline phosphatase and abnormal protein glycosylation. There is no information on the long-term outcome in this disorder.ResultsWe here present three novel patients with TMEM199-CDG. All three patients carried the same set of mutations (c.13-14delTT (p.Ser4Serfs*30) and c.92G > C (p.Arg31Pro), despite only two were related (siblings). One mutation (c.92G > C) was described previously whereas the other was deemed pathogenic due to its early frameshift. Western Blot analysis confirmed a reduced level of TMEM199 protein in patient fibroblasts and all patients showed a similar glycosylation defect. The patients presented with a very similar clinical and biochemical phenotype to the initial publication, confirming that TMEM199-CDG is a non-encephalopathic liver disorder. Two of the patients were clinically assessed over two decades without deterioration.ConclusionA rising number of disorders affecting Golgi homeostasis have been published over the last few years. A hallmark finding is deficiency in protein glycosylation, both in N- and O-linked types. Most of these disorders have signs of both liver and brain involvement. However, the present and the four previously reported patients do not show encephalopathy but a chronic, non-progressive (over decades) liver disease with hypertransaminasemia and steatosis. This information is crucial for the patient/families and clinician at diagnosis, as it distinguishes it from other Golgi homeostasis disorders, in having a much more favorable course.

Relations of gut liver axis components and gut microbiota in obese children with fatty liver: A pilot study

The prevalence of metabolic syndrome and its hepatic component — non-alcoholic fatty liver disease (NAFLD) — has increased alarmingly, paralleling the worldwide obesity epidemics. The pathophysiology of NAFLD is not clearly understood, but it has been proposed to be the result of multiple ‘‘hits’’[1]. A number of studies increasingly supports the pathogenetic role also of the gut microbiota (GM) both in NAFLD onset and progression. In this respect, GM would exert its noxious effects through the dysfunction of the gut-liver axis (GLA), which includes some or all of the following components: increased intestinal permeability (IP), endogenous ethanol (ETOH) and systemic endotoxin (LPS) concentrations [2,3]. As these players have hitherto not been simultaneously investigated in the same patient [reviewed in reference 4], the aim of our study was to explore the possible existence of reciprocal influences of several GLA components and GM composition in the same group of well characterized obese (Ob) children with and without fatty liver compared to normal-weight (NW) control peers. We studied 10 Ob Italian children, consecutively recruited at our center after parental agreement and written informed consent. The inclusion criteria were age 8—13 years, and a body mass index (BMI) > 97th percentile. Six non-Ob and non-overweight (BMI < 85th percentile), healthy normal-weight (NW) controls with normal anthropometric, clinical, laboratory and ultrasonographic (US) hepatic parameters and no other associated diseases were recruited among patients of the Pediatric Surgery Section listed for elective minor surgery. Lifestyle including eventual medications or alcohol exposition and total daily fructose and caloric intake and food preferences were investigated by multiple-choice questionnaires [5]. Weight, height, BMI values and percentiles,