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  1. Robin Spiller, editor,
  2. Magnus Simren, deputy editor

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NEW GENETIC MARKERS OF SUSCEPTIBILITY TO EARLY GASTRIC CANCER

Genetic polymorphisms increasing the production of the pro-inflammatory cytokine interleukin1β are known to increase the risk of gastric carcinoma (GC). This large study, which included 393 Portuguese patients with GC, examined the impact of polymorphisms in the promoter region of another pro-inflammatory gene interferon-γ receptor 1 (IFNGR1). Although there was no association overall, restricting analysis to those aged <40 years showed that having the TT variant of the IFNGR1 –56*C/*T polymorphism conferred a 4.1-fold increased risk. When the age distribution of GC was plotted for the different genotypes, TT developed GC at a significantly earlier age than CC. Confidence in this effect was considerably strengthened by its replication in an independent Italian cohort of patients with GC under the age of 55. Here, the TT geneotype gave a 2.7-fold increased risk (see table). Importantly, the authors also showed that the T variant of the polymorphic gene significantly increased the transcription of the IFNGR1 promoter in two cell lines. The authors conclude that this polymorphism could be one of a panel of markers which, in the future, would identify patients at greatest risk of developing GC.

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INFGR1 –56 genotype frequencies and odd’s ratio (OR) in the confirmatory Italian cohort of patients aged ⩽55 years with gastric carcinoma compared with controls

C-REACTIVE PROTEIN AS A PREDICTIVE FACTOR AND MARKER OF INFLAMMATION IN INFLAMMATORY BOWEL DISEASE

In the clinical setting, measurement of serum levels of C-reactive protein (CRP) is used as part of the disease activity assessment in patients with inflammatory bowel disease (IBD). However, its use as a predictive factor for outcome is not well established. In this issue of Gut, Henriksen and colleagues present data supporting the use of CRP as a predictive factor and marker of inflammation in patients with IBD. In this 5-year follow-up study, CRP levels at diagnosis were related to the extent of disease in patients with ulcerative colitis but not to the phenotype in patients with Crohn’s disease. It was also a predictor of surgery in subgroups of patients with IBD, namely in patients with ulcerative colitis and extensive colitis (see fig) and in patients with Crohn’s disease and terminal ileitis. However, CRP levels at diagnosis were found to perform poorly in differentiating between patients with IBD and functional disorders because many patients with IBD had levels within the normal range.

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ROLE OF THE ADIPOCYTOKINE, ADIPONECTIN, IN MEDIATING THE LINK BETWEEN HIGH-FAT DIET AND COLORECTAL CANCER

Obesity and/or type II diabetes mellitus, both conditions that increase the risk of colon cancer, reduce adiponectin levels in humans. The study by Fujisawa and co-authors used mice in whom either the gene for adiponectin or one of its two receptors had been genetically deleted and found that the adiponectin-deficient mice (KO) had an increased risk of colonic polyp formation on a high-fat diet. They also had a decreased survival, an increase in aberrant crypt foci (ACF) (see fig) and in cell proliferation. Recombinant adiponectin normalised both proliferation and ACF formation in KO mice. The authors showed that the adiponectin receptor 1 (adipoR1) but not adipoR2 was expressed within the colon and that adipoR1 -/- mice had significantly greater numbers of ACFs on the high-fat diet, an effect not seen in the adipoR2 -/- mice. mTOR, a key factor governing mRNA translation and controlling cell proliferation, was shown to be activated in the KO mice, a process reversed by recombinant adiponectin. The authors conclude that enzymes within the mTOR pathway might be a therapeutic target for colorectal cancer prevention in an obese population.

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POOR DIAGNOSTIC UTILITY OF ALARM FEATURES FOR COLORECTAL CANCER

Alarm features—such as rectal bleeding, a change of bowel habit, anaemia or the presence of a palpable right-sided abdominal or rectal mass—have been proposed to have diagnostic utility to identify patients with colorectal cancer. In order to validate these recommendations, Ford and co-workers performed a systematic review of the literature to assess the diagnostic accuracy of alarm features in predicting colorectal cancer. Fifteen studies with 19 443 patients were included in the review. Unfortunately, the pooled sensitivity of the different alarm features was very poor, ranging from 5 to 64% (see table). However, the specificity of two of the alarm features, dark red rectal bleeding and abdominal mass, was >95%. Based on this systematic review, the usefulness of the recently published National Institute for Health and Clinical Excellence (NICE) guidelines can be questioned. Future studies should be optimised regarding patient selection, collection of symptom data, use of combinations of alarm features, uniformity of bowel preparation and the type of colon investigation. Furthermore, they should probably concentrate on maximising specificity and not sensitivity to be able to prioritise urgent referral more effectively.

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Sensitivity, specificity and positive and negative likelihood ratios of individual symptom items and statistical models in predicting colorectal cancer

ANTIPLATELET DRUGS FOR THE TREATMENT OF NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD)

Non-alcoholic fatty liver disease (NAFLD) is now the commonest form of chronic liver disease. Although diet and exercise can help, in many patients such endeavours are ineffective. Anecdotal clinical evidence suggests benefit of antiplatelet drugs, which led to this study in a rat model. NAFLD was induced using a choline-deficient l-amino acid-defined diet or by a high-fat, high-calorie diet. The effects of aspirin 150 mg/day or ticlodipine or cilostazol 100 mg/kg/day were examined for their effect on histology and biochemical markers. All three drugs significantly reduced serum alanine aminotransferase and triglyceride while reducing liver weight. In addition, liver collagen content was reduced (see fig). Cilostazol was the most effective in suppressing liver steatosis and this was confirmed in the high-fat, high-calorie diet model. Further studies showed that cilostazol upregulated genes that encoded angiogenic factors including vascular endothelial growth factor, hepatocyte growth factor and endothelial nitric oxide synthase and decreased the platelet-derived growth factor C mRNA. This was associated with an inhibition of the phosphorylation of MAPK proteins. This would be predicted to inhibit cAMP response element binding protein, a key regulator of hepatic cholesterol synthesis and glucose metabolism. This novel concept is now right for testing in clinical trials.

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HOST AND ENVIRONMENTAL FACTORS PREDICT HEALTH-RELATED QUALITY OF LIFE IN HEPATITIS C

Several studies have demonstrated reduced health-related quality of life (HRQoL) in patients with hepatitis C virus (HCV). Helbling and colleagues performed a cross-sectional study evaluating factors of importance for HRQoL in anti-HCV-positive patients (n = 833). The study confirmed the reduced HRQoL in patients with hepatitis C relative to the general population. Low income was independently associated with both reduced mental and physical HRQoOL—whereas a low physical HRQoL was also associated with age and diabetes—and reduced mental HRQoL with intravenous drug use (see table). On the other hand, the level of HCV RNA was not associated with HRQoL measures. Contrary to some previous studies, this cross-sectional study provides evidence that host and environmental, rather than viral factors, seem to impact on HRQoL in patients with hepatitis C. This finding questions the recommendation that a low HRQoL alone may establish an indication for antiviral treatment, even in the presence of minimal or no HCV-related liver pathology.

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Factors independently associated with physical and mental health-related quality of life in patients with hepatitis C
Kaplan–Meier plot showing risk for surgery in patients with ulcerative colitis and extensive colitis with C-reactive protein (CRP) levels above (dotted line) or below (solid line) 23 mg/l at diagnosis.
Increased number of aberrant crypts (ACs) in adiponectin-deficient mice (KO) given a high-fat diet. *p<0.05. WT, wild-type mice.
Effect of antiplatelet drugs on liver collagen content in rats given a choline-deficient l-amino acid- (CDAA) defined diet. Control diet was choline-sufficient l-amino acid- (CSAA) defined.
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