The Intestinal Tract Brush Border in Young Children Uniformly Expresses Guanylate Cyclase C.

The present study examined staining of guanylate cyclase C (GCC/GUCY2C) in the small and large intestines of children younger than age 7 years. Normal intestinal tissue from children aged 0 to 7 years was stained using GCC, uroguanylin, and villin antibodies and scored for staining intensity. A subset underwent quantitative real-time polymerase chain reaction. Data were analyzed using t test of independent means, descriptive statistics, and logistic regression. Four hundred sixty-four specimens underwent immunohistochemistry; 291 specimens underwent real-time polymerase chain reaction. GCC, villin, and uroguanylin were detected across age groups and anatomic sites. No significant differences were identifiable across age groups. GUCY2C and uroguanylin mRNA was detected in all samples, with no variability of statistical significance of either target-to-villin normalization between any age cohorts. A gradient of expression of GCC across age groups does not seem to exist.

Biliary Excretion Noted on Hepatobiliary Iminodiacetic Acid Scan Does Not Exclude Diagnosis of Biliary Atresia.

A hepatobiliary iminodiacetic acid (HIDA) scan is frequently used in an attempt to exclude biliary atresia in infants who are cholestatic. We present 6 cases of confirmed biliary atresia in infants who had biliary patency reported on HIDA scan. We demonstrate that misinterpreted HIDA scans led to delayed diagnosis and surgical intervention for biliary atresia.

Immunohistochemical Staining for Uroguanylin, a Satiety Hormone, is Decreased in Intestinal Tissue Specimens From Female Adolescents With Obesity.

Gastrointestinal tract-secreted satiety hormones play a significant role in one of the largest health-care challenges for children and adults, obesity. Recent studies in mice identified a novel role for uroguanylin, the endogenous intestinal hormone that binds guanylyl cyclase C (GUCY2C), in regulating satiety via a gut-brain signaling pathway. Mice bred without GUCY2C receptors over-ate and developed obesity. We hypothesized that intestinal uroguanylin expression in pediatric patients with obesity would be lower than patients without obesity, and we attempted to examine the difference with immunohistochemistry. Retrospective chart review of gastrointestinal endoscopic procedures at an academic children's hospital identified patients with normal pathology findings on biopsy. Children aged 8-17 were included in the review; we analyzed biopsy samples from 20 matched pairs that differed only by body mass index (BMI)-for-age (average: 25%-75% vs. high: >95%). Biopsies of the duodenum, terminal ileum, ascending colon, and descending colon were subjected to immunohistochemistry for GUCY2C, uroguanylin, and the endogenous colonic hormone, guanylin. Intensity staining of all specimens was scored by a blinded pathologist. The overall staining intensity for females with high BMI-for-age was less for uroguanylin and guanylin as compared to average BMI-for-age females while GUCY2C staining was equal. Males did not exhibit different staining intensities for uroguanylin or guanylin. More matched female pairs had greater uroguanylin and guanylin staining in the average BMI-for-age cohort. The intestinal expression of uroguanylin, a key satiety hormone, appears to be diminished in female pediatric patients in the setting of obesity.

Pilot Study Measuring the Novel Satiety Hormone, Pro-Uroguanylin, in Adolescents With and Without Obesity.

OBJECTIVE: Disruption of satiety signaling may lead to increased caloric intake and obesity. Uroguanylin, the intestinal hormone, travels as a precursor to the central nervous system where it activates guanylyl cyclase C and stimulates pro-satiety neurons. Rodent studies have demonstrated that guanylyl cyclase C-knockout mice overeat and have increased weight gain versus wild-type mice and hyper-caloric obesity diminishes uroguanylin expression. We measured circulating plasma pro-uroguanylin, along with other gastrointestinal peptides and inflammatory markers, in human adolescents with and without obesity, as a pilot study. We hypothesized that adolescents with obesity would have less circulating pro-uroguanylin than adolescents without obesity have. METHODS: We recruited 24 adolescents (age 14-17 years) with and without obesity (body mass index >95% or body mass index <95%) and measured plasma pro-uroguanylin at fasting and successive time points after a meal. We measured 3 other satiety hormones and 2 inflammatory markers to characterize overall satiety signaling and highlight any link between uroguanylin and inflammation. RESULTS: Female adolescents with obesity had lower circulating pro-uroguanylin levels than female adolescents without obesity; we observed no difference in males. Other measured gastrointestinal peptides varied in their differences between cohorts. Inflammatory markers were higher in female participants with obesity. CONCLUSIONS: In adolescents with and without obesity, we can measure circulating pro-uroguanylin levels. In female adolescents without obesity, levels are particularly higher. Pro-uroguanylin secretion patterns differ from other circulating gastrointestinal peptides. In female adolescents with obesity, inflammation correlates with decreased pro-uroguanylin levels.

Opposite roles of cannabinoid receptors 1 and 2 in hepatocarcinogenesis.

OBJECTIVE: The endocannabinoid system (ECS) exerts key roles in the development of liver fibrosis and fatty liver, two diseases that promote the development of hepatocellular carcinoma (HCC). Although cannabinoids exert potent antitumour effects in vitro, the contribution of the ECS to carcinogenesis in vivo remains elusive. DESIGN: Expression of key components of the ECS, including endocannanabinoids, endocannabinoid-degrading enzymes and endocannabinoid receptors, was determined in healthy liver and tumours. Diethylnitrosamine-induced hepatocarcinogenesis was determined in mice deficient in fatty acid amide hydrolase (FAAH), the main anandamide (AEA)-degrading enzyme, in cannabinoid receptor (CB)1, CB2, or transient receptor potential cation channel subfamily V member 1 (TRPV1)-deficient mice. RESULTS: Murine and human HCCs displayed activation of the ECS with strongly elevated expression of CB1 and CB2 but only moderately altered endocannabinoid levels. Contrary to the antitumour effects of cannabinoids in vitro, we observed increased hepatocarcinogenesis in FAAH-deficient mice, a mouse model with increased AEA levels. Accordingly, inactivation of CB1, the main receptor for AEA, in wild-type or FAAH-deficient mice suppressed hepatocarcinogenesis. In contrast, inactivation of CB2 increased hepatocarcinogenesis. CB1 was strongly expressed within HCC lesions and its inactivation suppressed proliferation and liver fibrosis. CB2 was predominantly expressed in macrophages. CB2 inactivation decreased the expression of T-cell-recruiting chemokines and inhibited hepatic T-cell recruitment including particular CD4+ T cells, a population with known antitumour effects in HCC. TRPV1 deletion did not alter HCC development. CONCLUSIONS: Similar to their role in fibrogenesis, CB1 and CB2 exert opposite effects on hepatocarcinogenesis and may provide novel therapeutic targets.

Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4.

Increased translocation of intestinal bacteria is a hallmark of chronic liver disease and contributes to hepatic inflammation and fibrosis. Here we tested the hypothesis that the intestinal microbiota and Toll-like receptors (TLRs) promote hepatocellular carcinoma (HCC), a long-term consequence of chronic liver injury, inflammation, and fibrosis. Hepatocarcinogenesis in chronically injured livers depended on the intestinal microbiota and TLR4 activation in non-bone-marrow-derived resident liver cells. TLR4 and the intestinal microbiota were not required for HCC initiation but for HCC promotion, mediating increased proliferation, expression of the hepatomitogen epiregulin, and prevention of apoptosis. Gut sterilization restricted to late stages of hepatocarcinogenesis reduced HCC, suggesting that the intestinal microbiota and TLR4 represent therapeutic targets for HCC prevention in advanced liver disease.