Giulia Paolella

Microbiota and Gut–liver Axis: Their Influences on Obesity and Obesity-related Liver Disease

ABSTRACT A specific bacterial gut microbiota profile with increased extraction of energy has recently been associated with obesity, which has been shown to be a transmissible phenotype by microbiota transplantation. At the same time, there is now increasing evidence that gut microbiota plays a role in the development of hepatic steatosis and its progression to nonalcoholic steatohepatitis. This review summarizes well known and unexpected interacting factors leading to obesity and its related hepatic diseases, including intestinal mucosal permeability and its regulation, gut microbiota and translocation of its biological products, and gut-associated lymphoid tissue. These intestinal factors dictate also the balance between tolerance and immune response, which are critical for most of the complications in near and far organs or systems. We review novel mechanisms involving the development of gut permeability and adipose tissue plasticity, for example, the cross-talk between the gut microbiota, lipopolysaccharide, high-fat diet, and the endocannabinoid system tone, which have not been fully explored. Interactions between gut microbiota and other factors (eg, inflammasome deficiency) also are reviewed as emerging but far from being completely elucidated mechanisms influencing the onset of obesity and nonalcoholic fatty liver disease.

Pediatric Celiac Disease, Cryptogenic Hypertransaminasemia, and Autoimmune Hepatitis

Objective: The association between celiac disease (CD) and liver disease in pediatrics is widely recognized, but its prevalence is unknown. This study aims to conduct a systematic review and meta-analysis to evaluate the prevalence of CD in children with cryptogenic persistent hypertransaminasemia (HTS) or autoimmune hepatitis (AIH), and vice versa. Methods: We searched MEDLINE/PubMed, the Cochrane Library, Web of Science, and MD Consult from 1977 to May 2012 for studies reporting either CD and HTS or AIH. Pooled prevalences with 95% confidence intervals (CI) and relative risk (RR) were calculated. Results: Nine studies (2046 patients) were identified. Pooled prevalences of CD in children with mild, nonspecific cryptogenic persistent HTS and vice versa were 12.0% (95% CI 4.17–29.96) and 36.0% (95% CI 32.15–40.11), respectively. A gluten-free diet normalized transaminase levels in 77% to 100% of patients with CD within 4 to 8 months. Pooled prevalences of CD in children with AIH and vice versa were 6.3% (95% CI 3.87–11.73) and 1.4% (95% CI 0.84–2.15), respectively. The RR of HTS in children with CD versus the general population, and of CD in children with HTS was 6.55 (95% CI 5.65–7.60) and 11.59 (95% CI 3.80–35.33), respectively. The corresponding RR of AIH in children with CD was 188.54 (95% CI 92.23–385.43). The RR of CD in children with AIH was 6.63 (95% CI 3.86–11.40). Conclusions: CD is associated with elevated transaminase levels in about one-third of newly diagnosed children. Cryptogenic persistent HTS may signal gluten-dependent nonspecific mild hepatitis (12.0% of cases) or more rarely (6.3%) severe CD-related autoimmune hepatopathy. RRs confirm these trends in the considered associations.

Therapeutic options in pediatric non alcoholic fatty liver disease: current status and future directions

The epidemics of overweight and obesity has resulted in a significant increase of non alcoholic fatty liver disease (NAFLD), a potentially progressive condition. Currently, obesity related hepatopathy represents therefore the main cause of pediatric chronic liver disease. The first choice treatment at all ages is weight loss and/or lifestyle changes, however compliance is very poor and a pharmacological approach has become necessary. In the present article we present a systematic literature review focusing on established pediatric NALFD drugs (ursodeoxycholic acid, insulin sensitizers, and antioxidants) and on innovative therapeutic options as well.Regarding the former ones, a pediatric pilot study highlighted that ursodeoxycholic acid is not efficient on transaminases levels and bright liver. Similarly, a recent large scale, multicenter randomized clinical trial (TONIC study) showed that also insulin sensitizers and antioxidant vitamin E have scarce effects on serum transaminase levels. Among a large series of novel therapeutic approaches acting on recently proposed different pathomechanisms, probiotics seem hitherto the most interesting and reasonable option for their safety and tolerability. Toll-like receptors modifiers, Pentoxifylline, and Farnesoid X receptors agonists have been still poorly investigated, and will need further studies before becoming possible promising innovative therapeutic strategies.

Alagille syndrome: an overview.

Alagille syndrome is an embryofoetopathy, due to mutations in the gene JAG1. It is autosomic dominant with variable expressivity, or sporadic. Neonatal cholestasis is a main feature, due to the paucity of intrahepatic bile ducts. It can rarely develop into cirrhosis, but be responsible for a disabling pruritus and xanthomas. The other features are a peculiar facies, cardiac abnormalities, butterfly vertebrae, and ocular embryotoxon. The prognosis depends on the severity of the liver and heart diseases. Hepatocarcinoma has been reported.

Hypertransaminasemia and coeliac disease

dence. Clin Gastroenterol Hepatol 2008; 6: 765–71. 3. Ong DK, Mitchell SB, Barrett JS, et al. Manipulation of dietary short chain carbohydrates alters the pattern of gas production and genesis of symptoms in irritable bowel syndrome. J Gastroenterol Hepatol 2010; 25: 1366–73. 4. Tack JF, Miner PB, Fischer L, Harris MS. Randomised clinical trial: the safety and efficacy of AST-120 in non-constipating irritable bowel syndrome – a double-blind, placebo-controlled study. Aliment Pharmacol Ther 2011; 34: 868–77.

Autoimmune hepatitis: Current knowledge

Autoimmune hepatitis in children is of type 1, with antinuclear or anti-smooth muscle antibodies, more frequent in teenage girls, or of type 2, with anti-liver-kidney microsomes 1 and/or anti-liver cytosol 1 antibodies, in younger children. Other autoimmune diseases may be present in the patient or his relatives. The diagnosis relies on autoantibodies testing and histology. The treatment with steroids and azathioprine is efficient in most cases. Cyclosporine A is also successfully used. Relapses under treatment are frequent. A long-term treatment may be necessary. Liver transplantation is rarely indicated.

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.

Fatty liver disease and hypertransaminasemia hiding the association of clinically silent Duchenne muscular dystrophy and hereditary fructose intolerance

We report a case with the association of well self-compensated hereditary fructose intolerance and still poorly symptomatic Duchenne type muscular dystrophy. This case illustrates the problems of a correct diagnosis in sub-clinical patients presenting with “cryptogenic” hypertransaminasemia.

Characterization and burden of Campania children health migration across Italian regions during years 2006–2010: chance and/or necessity?

BackgroundTo evaluate medical, economical and sociological variables underlying avoidable pediatric migration from Campania region.MethodsAnalysis of years 2006–2010 hospital discharge records, extracted from the archive of Regional Health Agency (ArSan), classified by Major Diagnostic Categories, Aggregate Clinical Codes, Discipline of dismissal, Local Health Authorities of residence, and age group 0–14 years (excluding those of healthy newborns). Sociological variables were evaluated by questionnaires.ResultsA total of 68,316 hospital discharge records were released by extra-regional structures. Major diagnostic categories and Discipline of dismissal indicated that the most implicated diseases (nervous system and mental disorders, hematology-oncology, and bone diseases) were not always of very high complexity. The total cost paid by the Campania Region was 124.700.000 Euros. The need for more specialized hospital pediatric units and/or with more pediatric subspecialties in the native region was pointed out by most of the self-administered questionnaires.ConclusionsPediatric migration is an important phenomenon with evident implications. The identification of the most concerned sub-specialties here reported can give useful information aiming to assist in the improvement of the existing pediatric resources in Campania region in the wider context of the national global child health advancement.