Request for Funding

Medical Student Research Fellowship for Summer 2004

Mentor: William M. Lee, MD/Frank Wians, PhD
Department: Internal Medicine/Pathology
Room number: F4.302
Mail Code: 9151
Phone number: 83323
E-mail: William.lee@utsouthwestern.edu

Three projects

Project I title: False positive acetaminophen levels in acute liver failure

Human subjects IRB approved project number (where applicable): To be added

Animal subjects IRB approved project number (where applicable): N/A

Project Type: Patient based research

Brief Description of Project:
Acetaminophen (APAP) levels are of value in identifying acetaminophen ingestions when the history of acetaminophen use is unclear. The absolute level can provide insight into the dose of toxin ingested. Recently, acetaminophen levels have been reported to be falsely elevated in situations in which serum bilirubin levels are already elevated.1 Although this setting would be uncommon in acetaminophen overdose, the possibility exists that patients admitted with other forms of liver failure might have an acetaminophen level measured and shown to be elevated when indeed a false positive test had occurred. Package inserts provided with kits for acetaminophen assays disclose that values may be false positive in patients with bilirubin levels = 10 mg/dl.
A patient admitted to Baylor University Medical Center and enrolled in the US ALF Study denied any acetaminophen use and was found to have ALF of unknown etiology. Among the tests performed were an acetaminophen level that was elevated and remained in the same range for the first four days of hospitalization. The bilirubin level on each day was ~30 mg/dL. One:one dilution of the serum abolished the positive test, confirming that this represented a false positive reading.
Although one case report currently exists, we believe this is worth a further analysis. We performed acetaminophen levels on 20 ALF patients with proven viral hepatitis A or B for whom levels had not been done at the patient's hospital, to determine whether these patients might also have received APAP prior to admission. Of the 20, 17 were positive for APAP and all but one that were positive had bilirubin levels = 10 mg/dl. It is unlikely that all these patients had received APAP and more likely that at least some of these were also false positives.
We propose to explore this problem in more detail with a systematic study using samples from the ALF study serum bank with high bilirubins to assess the reliability of acetaminophen assays and the occurrence of false positives in this setting. Thirty samples with a range of bilirubins from 5 to 50 will be used for which 2 ml is available. Samples from later hospital days may be used. Five known positives for acetaminophen will also be tested, and again, only if 2 ml are available without depleting the bank. Samples will be from patients with known diagnoses where acetaminophen for practical purposes has been excluded. Confirmatory testing will be performed using GC mass spectroscopy to determine with certainty the acetaminophen content of samples. Five commercially available assays will be tested to determine the reliability of each assay with the known negatives as well as with the five positive samples.
A manuscript describing the Baylor case is already in draft form but the intent is to use the capabilities of our clinical chemistry department to establish once and for all the characteristics of this false positive problem. An additional case has recently been reported to us from Walter Reed Hospital, Washington, DC., and this case may also be included in the paper.

Project II title: Serum troponin levels in acute liver failure

Human subjects IRB approved project number (where applicable): To be added in

Animal subjects IRB approved project number (where applicable): N/A

Project Type: Patient based research

Brief Description of Project:
Acute liver failure (ALF) is a rare and often fatal condition in which severe hepatocyte injury results from viruses, drugs or other causes. The US Acute Liver Failure Study Group is a network on 24 sites, based at UT Southwestern, collecting prospective clinical data, serum samples and DNA on patients with this rare condition since 1998. The most common cause of ALF in the US and United Kingdom is acetaminophen overdose. Kidney injury frequently accompanies acetaminophen related liver damage. Electrocardiographic abnormalities have occasionally been observed, but no direct evidence has been presented thus far that acetaminophen can injure the myocardium. Creatine kinase and troponin are myocardial enzymes that are found to be elevated in plasma or serum of patients with myocardial infarcts.
We hypothesize that myocardial injury may result from acetaminophen. Serum samples from the US ALF Study Group repository, available on more than 80% of patients will be analyzed using the Behring BNII nephelometer to determine if significant myocardial injury is present in this condition. The US ALFSG database will be used to correlate results on serum samples with clinical information on dose of acetaminophen, levels of hepatic enzyme abnormalities, presence or absence of electrocardiographic abnormalities and outcome.
The results of this study should shed light on the multiorgan failure experienced by patients with acetaminophen-related ALF and specifically whether patients who have a fatal outcome have more frequent evidence of cardiac injury than those who survive this lethal dose-related toxin.

Project III title: Clinical and virological characterization of HIV/HBV/HCV triply-infected patients

Human subjects IRB approved project number (where applicable): 1200-578 and 0803-493

Animal subjects IRB approved project number (where applicable): n/a

Project Type: Patient-based

Brief Description of Project:
Hepatitis C (HCV) and B (HBV) infection can lead to progressive liver disease. HCV is the leading cause of transplantation in the US, and HBV is the leading cause of chronic hepatitis in the world today. HIV-infected individuals have a higher prevalence of co-infected with either of these viruses. An estimated 33% of HIV-infected patients are co-infected with HCV. Approximately 8-10% of HIV-infected patients are co-infected with HBV. Many studies have characterized HIV-infected patients who are co-infected with either HBV or HCV. Little is known about patients who have all three viruses HIV, HBV, and HCV. We propose to examine triple-infected patients from a well-described cohort. We will obtain stored serum samples and examine HCV RNA, HCV genotype, HBV DNA, and HBV genotype. Several drugs now available for the treatment of HIV have the dual advantage of activity against HBV. What impact does HIV treatment have on the development of HBV-resistance? We plan to examine the prevalence of resistance among this treated population and compare it to an untreated population. What impact does triple-infection have on liver and immune-related factors?

The responsibilities of the student-researcher would be to review medical records from a standardized data collection form, obtain serum samples from banked serum, help develop a computerized database, and enter results of the virologic assays and clinical data into the database. The student-researcher will be actively involved in analysis and presentation of the data.

Previous Research Activities or Publications with Medical Students:

Eric Suhler, class of 1998, won US Student Medical Association Prize (national competition) in the Basic Research Category, Galveston Texas, and Best Poster Award at Texas Medical Association, Austin Texas. Title: Serum gelsolin levels in acute liver failure and other forms of multi-organ failure.

Dai Park class of 2006, won one of four Poster Awards at UT Southwestern, January 2004. Title: Survival Rates of Chronic Hepatitis C Patients in a US University Referral Practice.

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