Role of microRNA biomarkers to predict complications of gallstones
Th'Ng, Francesca Chun Sau
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Gallstones are the most common cause for abdominal pain requiring an emergency hospital admission. About 5.5 million people in the UK have the condition and over 60,000 cholecystectomies are performed every year. At present there are no specific biomarker tests that can predict whether an individual patient with gallstones has severe inflammatory, infective or obstructive complications requiring inpatient management and urgent surgical intervention; or has symptoms without complications that can be managed as an outpatient or day-case basis. Building on evidence that microRNA (miRNA) biomarkers can predict acute cholestatic liver injury, and have been shown to be superior to alanine aminotransferase (ALT), this study hypothesised that miRNA biomarkers might be used to predict gallstone complications in emergency surgical patients and help to inform clinical decision-making. The specific aim of this research is to determine whether microRNA (miR) -122 and miR-210 measured at first presentation to hospital can predict complications of gallstone diseases and differentiate those patients who require acute inpatient admission. Patients admitted to the Royal Infirmary of Edinburgh from 3rd September 2014 to 12th May 2015 with a differential diagnosis of gallstone disease on index presentation were recruited to this study and a blood sample was taken for miRNA analysis in the plasma fraction. A pilot study was carried out after 6 months of patient recruitment with a third of the samples collected. miR-122 and -210 were quantified by PCR. All analyses were performed blinded to the clinical data. Each patient was followed up for a minimum period of one month during which investigation reports, operation notes and pathology results were obtained. A total of 232 patients were recruited to the study. Eight-two random samples were analysed in the pilot study. As the pilot study did not show any significant differences in miR- 210 concentration between different patient groups (P=0.365), the main study only focused on miR-122 analysis. There was a significant difference in plasma miR-122 concentration between patients with gallstone (Median: 0.039 [95% CI: 0.027 , 0.059]) and non-gallstone diseases (Median: 0.011 [95% CI: 0.0079 , 0.015]) (P<0.001); and between uncomplicated (Median: 0.062 [95% CI: 0.039 , 0.11]) and complicated (Median: 0.030 [95% CI: 0.022 , 0.047]) gallstone diseases (P=0.040). Plasma miR-122 was significantly lower in patients with cholecystitis (Median: 0.023 [95% CI: 0.017 , 0.032]) (P=0.006) and significantly higher in patients with choledocholithiasis (Median: 0.099 [95% CI: 0.054 , 0.17]) (P<0.001). The PPV and NPV for plasma miR-122 in detecting (a) gallstone diseases were 78.0% and 41.9% respectively; (b) complicated gallstone diseases were 81.0% and 32.0% respectively; and (c) choledocholithiasis were 63.0% and 75.9% respectively. In conclusion, relative miR-122 concentration in plasma at presentation to hospital is significantly different in patients with complications of gallstone diseases that may require acute in-patient admission. When these tests are developed for rapid analysis or made suitable for a near-patient assay platform, and if these findings are validated in an independent cohort, there exists the potential to substantially reduce emergency hospital admissions by identifying low risk patients suitable for direct discharge from the Emergency Department and further management in an outpatient setting.