Predictive Utility of DASIMAR as a Prognostic Biomarker in Acute-on-chronic Liver Failure (ACLF) (DASIMAR)

The Predictive Utility of the Dimethylarginines and Ischemia Modified Albumin as Prognostic Biomarkers in Patients With Acute-on-chronic Liver Failure

Patients with acute on chronic liver failure have a risk of developing multiorgan failure and a high mortality. The current scoring systems defining the outcome of patients with acute decompensation of cirrhosis fail to identify patients that progress to Acute-on-chronic liver failure (ACLF).

The aim of the study is to evaluate if one can identify these patients early on with the proposed biomarkers: dimethylarginines and ischemia modified albumin.

Study Overview

• Status: Unknown
• Conditions: Liver Cirrhosis

Detailed Description

Patients with acute-on-chronic liver failure (ACLF) are at risk of multiorgan failure and high mortality. Recent data suggest that patients with decompensated liver cirrhosis have higher ADMA (asymmetrical dimethylarginine) levels compared to compensated cirrhosis and plasma ADMA levels correlate with severity of liver dysfunction and inflammation. There is also an increase in symmetric dimethylarginine (SDMA), a stereo-isomer of ADMA, which is largely excreted by the kidney. Plasma SDMA levels have been shown to be associated with patients

progressing to renal failure. In a pilot study by our group involving 52 patients with acute decompensation of chronic liver disease, we showed an increase in the summed product of ADMA and SDMA, which we termed dimethylarginine score ('DAS'): This was shown to have a good predictive utility for outcome in this small group of patients (AUROC=0.89).

Furthermore, we and others have shown that albumin of patients with advanced liver disease has widespread abnormalities. The amount of albumin that is found to have reduced metal binding capacity as a consequence of oxidative damage is termed Ischemia Modified Albumin (IMA).

Our data shows that patients with ACLF who die have a significantly increased IMA/serum albumin ratio (IMAR). The summation of these two pathologically relevant biomarkers (DAS+IMAR) we termed DASIMAR and found this score to have a better predictive utility than DAS alone (AUROC:0.91).

Primary objective : To identify the patients early on that progress to ACLF which would facilitate a goal directed therapeutic approach.

Secondary objective : Generation of this dataset will further define and enable prognostication of ACLF. If this study reveals a role for these biomarkers in patients with ACLF, commercial development of simple kits may be possible.

• Study Type: Observational
• Enrollment (Anticipated): 700

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, WC1E 6HX
    • Recruiting
    • University College London Hospital
    • Contact: Rajeshwar P Mookerjee, BScMRCPPhD; Phone Number: 02076796516
    • Contact: Naina Shah, MBBSMRCP; Phone Number: 02076796516

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Inpatients with acute clinical deterioration of cirrhosis.

Description

Inclusion Criteria:

• All patients with an acute clinical decompensation of presumed cirrhosis (elevated bilirubin >85 µmol/L, or/and increasing ascites or/and hepatic encephalopathy < grade 2) related to a clear precipitating event (e.g. infection, bleeding, alcoholic hepatitis, exposure to hepatotoxin)

Exclusion Criteria:

• Admission for reasons other than decompensation of cirrhosis (other co-morbid diseases, especially established cardiovascular or renal disease (U/S).
• Malignancy (extra-hepatic or a hepatocellular carcinoma).
• Patients who have undergone major surgery or have unsolved surgical problems.
• Pregnancy

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Acute decompensation of cirrhosis; acute decompensation of liver function occuring secondary to precipitating events such as sepsis, GI bleed.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Progress to ACLF	hours, days

Secondary Outcome Measures

Outcome Measure	Time Frame
Prognosticate ACLF	Days

Collaborators and Investigators

• Sponsor: University College London Hospitals
• Collaborators: Medical Research Council
• Investigators: Principal Investigator: Rajeshwar P Mookerjee, BScMRCPPhD, University College London Hospital

Study record dates

Study Major Dates

• Study Start: September 1, 2008
• Primary Completion (Anticipated): November 1, 2010
• Study Completion (Anticipated): November 1, 2010

Study Registration Dates

• First Submitted: February 18, 2010
• First Submitted That Met QC Criteria: February 18, 2010
• First Posted (Estimate): February 19, 2010

Study Record Updates

• Last Update Posted (Estimate): February 19, 2010
• Last Update Submitted That Met QC Criteria: February 18, 2010
• Last Verified: April 1, 2008

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Hepatic Insufficiency; Pathologic Processes; Liver Diseases; Liver Failure, Acute; Fibrosis; End Stage Liver Disease; Liver Failure; Acute-On-Chronic Liver Failure; Liver Cirrhosis
• Other Study ID Numbers: 08/HO714/8