Medical Student Research Fellowship for Summer 2007

Mentor: William M. Lee, MD
Department: Internal Medicine
Room number: POB1, Suite 420
Mail Code: 8887
Phone number: 214 645 6111
E-mail: William.lee@utsouthwestern.edu
Project title: Possible role of phosphatonins in the hypophosphatemia of acute liver failure
Human subjects IRB approved project number (where applicable): IRB No. 0798 317
Animal subjects IRB approved project number (where applicable): N/A
Project Type: Patient based research

Brief Description of Project: Introduction: Very low serum phosphate levels characterize acute liver failure patients and may affect outcome. The reasons for these low levels are unclear; is it massive excretion of phosphate in the urine or some other mechanism such as intra-cellular uptake of phosphate? Phosphatonins are newly described mediators of phosphate excretion that are active in tumor related hypophosphatemia

Hypothesis We postulate that mRNA levels of phosphatonins are elevated in hepatocytes during hypophosphatemic Acute Liver Failure (ALF) patients. High levels of phosphatonins result in hypophosphatemia in ALF patients by increasing phosphaturia. Aims To elucidate the cause and mechanisms of hypophosphatemia observed in patients with ALF. Is there a relationship between measured serum phosphate and phosphatonin levels? Can either of these values be correlated to outcome in this severely ill patient group? To propose a connection between hypophosphatemia related to ALF and hypophosphatemia found in other conditions involving hepatic injury such as liver resection. Are they both mediated by elevated phosphatonin levels? Methods To determine whether ALF patients are experiencing hyperphophaturia, urine samples collected from 7-10 ALF patients with documented hypophosphatemia will be tested for phosphate levels in the Charles Pak Center for Mineral Metabolism at UT Southwestern Medical Center at Dallas (Dr. Clarita Odvina).
If the test confirms that these patients are indeed hyperphosphaturic, mRNA in frozen liver tissue samples from hypophosphatemic patients (n=5-10) will be analyzed by Northern Blotting. These results will be compared with the sequences of known phosphatonins such as PTH, FGF-23 and sFRP-4 in an mRNA database. Patients with different etiologies of ALF will be selected that have demonstrated low levels of PO4 for this initial proof of principle. No control group is necessary because mRNA sequences found in normal hepatocytes have been established.
If results from these pilot studies are promising, specifically, if marked abnormalities in phosphatonin mRNA levels are observed, in a second phase of the study we will test for serum phosphatonin levels in a cohort of 150 consecutive patients with ALF of all etiologies to characterize further the levels of phosphatonins observed, and their correlation with phosphate levels in urine and serum as well as outcome. Assays for FGF-23 and for sFRP-4 are available in the laboratories of the Pak Center.

Previous Research Activities or Publications with Medical Students: Project with Blake Gregory, Student Summer Research Program, 2006. Abstract and oral presentation: Reliability of Acetaminophen (ACM) Dosing Information in ACM-Induced Acute Liver Failure Project with Veeral Ajmeera: Molecular aspects of HAV Acute Liver Failure. Manuscript submitted for publication to Hepatology. Accepted for oral presentation at Digestive Disease Week in Washington DC, May 20, 2007

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