Predictive utility of the dimethylarginines and ischemia modified albumin as prognostic markers in liver failure

When the liver fails, almost all the organs of the body are affected and they function inadequately. In patients that have existent liver disease, a relatively minor event such as intercurrent infection or bleeding can lead to catastrophic liver failure. This condition is referred to as acute on chronic liver failure. Our studies over the past 5 years have revealed that the current conventional tests that are performed to determine whether a patient with cirrhosis, who develop intercurrent problems, will progress to full blown liver failure are inadequate. A good test that could accurately identify patients at high risk of progressing to liver failure and mortality would allow early aggressive approach to treatment, transfer to specialist centres and listing for liver transplantation. Such a test is urgently needed. During studies determining why several organs fail to function during liver failure, we discovered two blood tests that may predict which ?at risk? patients would proceed to develop advanced liver failure and die. When these two tests were combined into a single scoring system, they were shown to correctly predict the outcome of about 90% of the 52 patients that were studied. We propose to perform a large study involving several important specialist centres in the UK to validate whether the test that we have developed is indeed useful. UCL has patented the test and a company developing an extracorporeal liver support device will co-fund the project. If the data are in keeping with those of the pilot experiments, it is possible that this test could reach the patients quickly and start to make a difference to their outcome.

Acute on chronic liver failure (ACLF) is a newly defined entity that encompasses patients with acute deterioration in liver function on the background of cirrhosis due to the effects of a defined precipitant that culminates in multiorgan dysfunction. ACLF is an important cause of mortality in patients with cirrhosis. If the end-organs and liver can be adequately supported, this condition has the potential for recovery. Evaluation of data from our prospective study over the past 5 years suggested that the currently used prognostic markers such as Child-Pugh, SOFA and MELD scores had poor sensitivity and specificity in predicting the outcome of these patients but pointed to the important role of inflammation from the pathophysiological perspective. Our studies focusing on the pathophysiologic basis of ACLF have suggested that superimposed inflammation on the background of cirrhosis increases the dimethylarginines (asymmetric and symmetric -ADMA/SDMA) by modulating the expression of their regulatory enzymes and further reduces albumin function. We therefore hypothesised that these may also serve as biomarkers to define outcome of patients with acute decompensation of cirrhosis. Pilot data: Following our initial studies in animals models of liver failure we included 52 patients with acute decompensation of cirrhosis and showed that DAS score (sum of ADMA+SDMA) and IMAR (Ischaemia Modified Albumin/Albumin concentration) predicted the risk of mortality (DAS:AUROC, 0.89), (IMAR:AUROC, 0.73) respectively. The combination of DAS score and IMAR (DAS+IMAR: DASIMAR) predicted outcome more accurately (AUROC: 0.92; sensitivity 92% and specificity 80%). The aims of the proposed study are to validate the role of DASIMAR as biomarkers in patients with acute decompensation of cirrhosis. The study has 2 primary endpoints: (a) to determine if the DASIMAR score is able to define which ?at-risk? patients progress to organ failure and (b) to determine the predictive utility of DASIMAR in defining mortality of patients that develop organ failure. Sequential blood samples and clinical data will be collected from 700 consecutive patients from 6 centres over a 2 year period. The data generated will be analysed using classical statistical modeling methods and also using novel mathematical tools. The proposed biomarkers have been patented by UCL and the Industrial partner, Vital Therapies Inc (USA) have committed to providing about 50% of the overall cost of the project.