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Interleukin-10 (IL-10) signaling genes are attractive inflammatory bowel disease (IBD) candidate genes as IL-10 restricts intestinal inflammation, IL-10 polymorphisms have been associated with IBD in genome-wide association studies, and mutations in IL-10 and IL-10 receptor (IL-10R) genes have been reported in immunodeficient children with severe infantile-onset IBD. Our objective was to determine if IL-10R polymorphisms were associated with early-onset IBD (EO-IBD) and very-early-onset IBD (VEO-IBD).Candidate-gene analysis of IL10RA and IL10RB was performed after initial sequencing of an infantile onset-IBD patient identified a novel homozygous mutation. The discovery cohort included 188 EO-IBD subjects and 188 healthy subjects. Polymorphisms associated with IBD in the discovery cohort were genotyped in an independent validation cohort of 422 EO-IBD subjects and 480 healthy subjects.We identified a homozygous, splice-site point mutation in IL10RA in an infantile-onset IBD patient causing a premature stop codon (P206X) and IL-10 insensitivity. IL10RA and IL10RB sequencing in the discovery cohort identified five IL10RA polymorphisms associated with ulcerative colitis (UC) and two IL10RB polymorphisms associated with Crohn's disease (CD). Of these polymorphisms, two IL10RA single nucleotide polymorphisms, rs2228054 and rs2228055, were associated with VEO-UC in the discovery cohort and replicated in an independent validation cohort (odds ratio [OR] 3.08, combined P = 2 x 10(-4); and OR 2.93, P = 6 x 10(-4), respectively).We identified IL10RA polymorphisms that confer risk for developing VEO-UC. Additionally, we identified the first splice site mutation in IL10RA resulting in infantile-onset IBD. This study expands the phenotype of IL10RA polymorphisms to include both severe arthritis and VEO-UC.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease in adults and children and is currently the third most common indication for liver transplantation in North America. Its pathogenesis is thought to be secondary to multiple "hits" derived from the dietary components, adipose tissue, immune system, and intestinal microbiota. Lack of physical activity may contribute as well. Nutrients may exert their effect directly or through alteration of the intestinal microbiota. Research focusing on specific dietary components predisposing to NAFLD has shown conflicting results. Total energy intake, and macronutrients, has been linked to the development of NAFLD. Fructose not only contributes to hepatic steatosis but may trigger inflammatory signals as well. Polyunsaturated fatty acids are thought to exert anti-inflammatory effects. The role of vitamins as well as minerals in this field is actively being investigated. In this review, we discuss the evidence-linking macronutrients (such as carbohydrates and fat in general and fructose, fiber, short chain fatty acids, polyunsaturated fatty, and choline specifically) and micronutrients (such as vitamin E and C and minerals) with the development and treatment of NAFLD. We also discuss the literature on physical activity and NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. Nonalcoholic steatohepatitis (NASH) reflects severe liver disease within the NAFLD spectrum and can progress to end-stage liver disease. Within this manuscript we review the available evidence for the treatment of NASH as well as the newer therapeutic agents that are currently being investigated.

Alagille syndrome is an autosomal dominant condition with incomplete penetrance that is associated mostly with hepatic, cardiac, and skeletal abnormalities. In addition, the association of Alagille syndrome with ocular abnormalities is well known and is considered one of the characteristic features of this condition. Most commonly, posterior embryotoxon, glaucoma, or retinopathy has been identified in these children. The authors present 2 patients with Alagille syndrome who, before the age of 3 years old, developed idiopathic intracranial hypertension with documented increased intracranial pressure by lumbar puncture and papilledema, which was responsive to acetazolamide.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide.1 The prognosis of HCC depends on the cancer stages at the time of diagnosis. Although surgical therapies have led to an improvement in the 5-year survival of select patients, most patients with HCC gain no significant benefit from traditional chemotherapy.2 Recently, a number of studies have demonstrated that solid tumors such as colon,3 pancreatic,4 brain,5 and prostate cancers6 are initiated from cancer stem cells (CSCs). CSCs are resistant to injury and may account for the relative failure of traditional chemotherapy.7 Several studies have linked CD133 expression to liver CSCs, demonstrating that CD133+ cells from established HCC cell lines displayed significant tumorigenic capacity.8,9 In patients with HCC, a hepatoblast phenotype correlates with a significantly worse prognosis.10 In a previous study, we defined a CD133+ CSC population isolated from methionine adenosyltransferase 1a (Mat1a)-deficient mice during premalignant liver injury.11 Methionine adenosyltransferase (MAT) is an essential enzyme responsible for the synthesis of S-adenosylmethionine, the principal methyl donor required for glutathione biosynthesis.12 The relationship between hepatic MAT activity and chronic liver disease in human patients is well established.12–14 Mat1a knockout mice demonstrated hepatosteatosis, oxidative liver injury, and spontaneous development of HCC by 18 months.14 What was unknown from our initial research was a specific mechanism of survival of the CD133+ cell population. Resistance to transforming growth factor β (TGF-β) has been postulated to be an early event in HCC development. 15,16 TGF-β is the prototype of a large family of structurally related growth and differentiation factors that initiates its signals from a receptor complex,17 and intermediary activated Smads translocate into the nucleus, where they induce or suppress transcription of defined genes.18 In hepatocytes, TGF-β acts as a principle growth inhibitor,19 mediated by inducing expression of the CDK inhibitors p21 and p15, and down-regulating c-myc, cyclin D, and cyclin E.20 In addition, TGF-β induces apoptosis in several established human liver cell lines, including HepG2 hepatoma and HepG3 HCC cells.21 However, the precise role of TGF-β in HCC progression remains complex and depends on the stage of the tumor.15 In order to understand the role of TGF-β in the homeostasis of CD133+ liver CSCs, we tested both the cell growth inhibitory and apoptotic effects of TGF-β on CD133+ CSCs with Mat1a deficiency. Although there is no significant difference in the cell growth inhibition in CD133+ and CD133− cells in response to TGF-β, CD133+ cells did exhibit relative resistance to the apoptotic effects of TGF-β as compared with CD133− cells. Our results indicate that one mechanism for the resistance to TGF-β–induced apoptosis in CD133+ CSCs is an activated mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (Erk) pathway.

Commentary on: MacGillivray S, Fahey T, McGuire W. Lactose avoidance for young children with acute diarrhoea. Cochrane Database Syst Rev 2013;10:CD005433. Acute gastroenteritis in young children is a global health problem accounting for 9% of emergency department visits and 4% of hospitalisations in the Western world.1 ,2 Secondary lactase deficiency may contribute to osmotic diarrhoea in the setting of infectious gastroenteritis; however, the scientific community has not yet reached a consensus regarding lactose avoidance in this setting. The aim of this systematic review is to assess the effects on mortality and symptom duration of minimising lactose in young children with acute diarrhoea. This review included randomised and quasi-randomised controlled studies performed in children over 5 years with acute …