The overall goal of this research is to develop and validate noninvasive Na magnetic resonance(MR) techniques to detect and monitor the progression of liver diseases to hepatitis and cirrhosis. Liver diseases are the eighth leading cause of death in the United States. Regardless of cause, the three major pathologic stages in many liver diseases are:1) steatosis (fataccumulation), 2) hepatitis (inflammation and necrosis), and 3) cirrhosis (fibrosis and irreversible damage). 1H MRI provides excellent methods to quantitatively image fat and water in the liver, but steatosis is a """"""""benign"""""""" condition and does not correlate with the severity of liver disease or predict its progression. Currently, there are no reliable noninvasive methods for monitoring the progression of liver diseases. A transmembrane Na+ gradient is essential for cell survival and is disrupted by cellular damage. Because MR signal from both intra- and extracellular sodium (Nai+ and Nae+) is isochronous, either a shift reagent (SR) or the multiple-quantum-filter (MQF) technique is necessaryto discriminate between the two.An MQF Na MR signal is observed when the correlation time of Na+ is slower than its Larmar period. Because of the high macromolecule concentration inside the cells, a majority of MQF signal comes from Naj+, with only small contribution from Nae+. The three main hypotheses of this proposal are that: 1) steatosis alone does not cause any changes in the transmembrane Na+ gradient, cellular energetics, or pH; 2) hepatitis leads to an increase in total MQF23Na signal, due to both an increase in [Nai+] and a change in the intracellular environment, and no change in the MQF Nae+ signal, although an increase in extracellular space may lead to an increase in the single-quantum (SQ) Nae+ signal; and 3) development of cirrhosis/fibrosis leads to an increase in the MQF Nae+ signal due to an increase in the number of extracellular Na+ binding sites resulting from the increase in extracellular matrix components. If these hypotheses are true, then MQF 23Na MR spectroscopy and imaging can provide techniques to monitor progress of hepatitis and cirrhosis noninvasively. The hypotheses will be tested in rodent models of fatty liver, hepatitis, cirrhosis, fibrosis, and cholestasis using an in vivo Na SR, TmDOTP5"""""""". 1H and 31P MR techniques will also be used to examine the correlation between fat accumulation, bioenergetics, and Na+ and pH gradients. The results of MR experiments will be correlated with histology and blood tests for liver function. In addition, SQ and MQF23Na MRI will be implemented and optimized on a 3T clinical scanner, and the feasibility of quantitative 23Na MRI of the liver in humans will be demonstrated. The overwhelming advantage of MQF23Na MR is that it can be readily translated to human studies. Thus, the proposed 23Na MR techniques will be very helpful in both experimental studies and diagnosis of liver diseases. They may also prove useful for monitoring response to therapy, which will help tremendously in designing more effective strategies for treatment of hepatitis and cirrhosis. The proposed research will also enhance our understanding of the interrelationship between energy status and ion physiology in various stages of liver disease.
