Transcriptomic profiling reveals a pronociceptive role for angiotensin II in inflammatory bowel disease.

ABSTRACT: Visceral pain is a leading cause of morbidity in inflammatory bowel disease (IBD), contributing significantly to reduced quality of life. Currently available analgesics often lack efficacy or have intolerable side effects, driving the need for a more complete understanding of the mechanisms causing pain. Whole transcriptome gene expression analysis was performed by bulk RNA sequencing of colonic biopsies from patients with ulcerative colitis (UC) and Crohn's disease (CD) reporting abdominal pain and compared with noninflamed control biopsies. Potential pronociceptive mediators were identified based on gene upregulation in IBD biopsy tissue and cognate receptor expression in murine colonic sensory neurons. Pronociceptive activity of identified mediators was assessed in assays of sensory neuron and colonic afferent activity. RNA sequencing analysis highlighted a 7.6-fold increase in the expression of angiotensinogen transcripts, Agt , which encode the precursor to angiotensin II (Ang II), in samples from UC patients ( P = 3.2 × 10 -8 ). Consistent with the marked expression of the angiotensin AT 1 receptor in colonic sensory neurons, Ang II elicited an increase in intracellular Ca 2+ in capsaicin-sensitive, voltage-gated sodium channel subtype Na V 1.8-positive sensory neurons. Ang II also evoked action potential discharge in high-threshold colonic nociceptors. These effects were inhibited by the AT 1 receptor antagonist valsartan. Findings from our study identify AT 1 receptor-mediated colonic nociceptor activation as a novel pathway of visceral nociception in patients with UC. This work highlights the potential utility of angiotensin receptor blockers, such as valsartan, as treatments for pain in IBD.

Primary Budd-Chiari Syndrome in Children: King's College Hospital Experience.

Primary Budd-Chiari syndrome is a rare cause of liver disease in children in the western world. Here we present a retrospective review of children with Primary Budd-Chiari syndrome presenting from January 2001 to November 2015 to our hospital. Seven children were identified. Their presentation was mostly chronic. All had predisposing factors for thrombosis and were started on anticoagulation. Radiological interventions (2 transjugular intrahepatic portosystemic shunts and 1 hepatic vein stenting), liver transplant and mesocaval shunt were done in 3, 2, and 1 patients, respectively; 1 child underwent bone marrow transplantation following transjugular intrahepatic portosystemic shunts and 1 child was managed only medically. After liver transplantation, one child died 3 years later as a result of subarachnoid haemorrhage, whereas others remain well at a median follow-up of 6 years. Despite high morbidity, the disease can have a good long-term outcome with a multidisciplinary approach.

A longitudinal study to identify laboratory predictors of liver disease outcome in Alagille syndrome.

OBJECTIVES: Liver disease in Alagille syndrome (AGS) is highly variable, ranging from biochemical abnormalities only to end-stage disease. It is not possible to predict whether a child with cholestasis will have improvement or progression of liver disease. This poses a challenge to the clinician in terms of timing therapies. The study aim was to identify laboratory markers present in children younger than 5 years that could predict the ultimate outcome of liver disease in AGS. METHODS: A retrospective review of laboratory data from 33 subjects with AGS was performed. Patients older than 10 years of age were stratified into mild (22) and severe (11) hepatic outcome groups. Nonparametric analysis was performed on longitudinal data from birth to 5 years to determine association with hepatic outcome. JAGGED1 mutational analysis was performed on available samples. RESULTS: The following variables were statistically different between severe and mild outcome groups: total bilirubin (TB, P = 0.0001), conjugated bilirubin (CB, P = 0.0066), and cholesterol (P = 0.0022). Further analysis revealed cutoff values that differentiated between severe and mild outcomes; TB 6.5 mg/dL (111 micromol/L), CB 4.5 mg/dL (77 micromol/L), and cholesterol 520 mg/dL (13.5 mmol/L). Genetic analysis of JAGGED1 mutations did not reveal genotype-phenotype correlation. CONCLUSIONS: TB >6.5 mg/dL, CB >4.5 mg/dL, and cholesterol >520 mg/dL in children younger than 5 years of age are likely to be associated with severe liver disease in later life. These data represent cutoff values below which a child is likely to have a benign outcome and above which more aggressive therapy may be warranted, and can thus be used to guide management.