Novel labeling approaches for the assessment of human hepatic metabolism by in vivo magnetic resonance spectroscopy

T he metabolism of carbohydrates, lipids, and protein and the detoxification of an organism are the primary roles of the liver. These processes are crucial for the well-being of the human body and a precise knowledge of these mechanisms is essential for understanding the reactions of the liver tissue to chronic or acute pathologic conditions. Biochemical or histopathological analysis of a liver tissue biopsy can supply ultimate answers to many of the diagnostic questions, but its invasive nature inhibits its application in cross-sectional investigations of a broad population, the frequent follow-ups required to monitor therapy. Further on, fast degradation of many metabolites in invasively sampled tissue prevents human studies directly assessing the metabolic fluxes in healthy and diseased states. However, for this purpose in vivo magnetic resonance spectroscopy (MRS), as shown by Skamarauskas et al. in this issue of HEPATOLOGY, can serve as a unique tool for direct assessment of metabolic fluxes or measuring metabolite concentration in the hepatic tissue. No other analytic method provides a noninvasive access to such broad biochemical information. One of the most straightforward applications, currently available on the majority of clinical MR systems, is the measurement of hepatocellular lipid (HCL) content by single voxel localized proton (H) MRS. The method is sensitive enough to measure HCL levels below 1% (volume fat fraction) and it has already been validated against gold-standard histological and biochemical analysis of tissue biopsy. The application of this noninvasive method enabled studies on larger populations, showing that almost a third of the Dallas County, Texas, population presented with hepatic steatosis. Improvements in the hardware and optimization of the measurement protocol also allow for absolute quantification of the total amount of choline-containing compounds, which can further be studied by phosphorus (P) MRS. Excellent P MRS signal separation can be achieved at magnetic fields 3T and changes in the pattern of P MR spectra have already been shown to accompany nonalcoholic steatosis and steatohepatitis. An advanced dynamic method of P MRS, called saturation transfer, can even assess the chemical exchange between the cphosphorus of adenosine triphosphate (ATP) and the inorganic phosphate enabling insight into the kinetics of ATP synthesis adjacent to oxidative and glycolytic hepatic metabolism. The spatial resolution of P and C MR experiments is hampered by low intrinsic sensitivity and, in the case of carbon, by a low natural abundance of the isotope (1.1%) as well. To overcome these problems, a volume of interest of up to 100 cm is chosen, frequently by applying localization based on the sensitive volumes of radiofrequency (RF) surface coil probes and volume-selective schemes. Using this approach, the detection limit is about 0.1 mmol/L of tissue for P and about 20-50 mmol/L of tissue for C MRS. Healthy liver presents with a glycogen concentration in a range between 200 and 400 mmol/L of tissue. A large homogenous liver volume close to the body surface can be well covered by the appropriate MR surface coil. Thus, net glycogen accumulation and glycogenolysis can be monitored under various conditions. Advanced approaches for increasing the signal-tonoise ratio of nonproton (X-nuclei) spectra include: 1) the use of so-called proton decoupling, special hardand software experimental set-ups eliminating signal splitting of X nuclei due to magnetic interaction with surrounding protons; 2) selective suppression of unwanted signals; and 3) increasing the abundance of isotope of interest by systemic infusion of substrate Abbreviations: ATP, adenosine triphosphate; HCL, hepatocellular lipid; MRS, magnetic resonance spectroscopy; TCA, tricarboxylic acid. Address reprint requests to: Martin Kr s s ak, Ph.D., Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna, W€ ahringer G€ urtel 18-20, A-1090 Wien, Austria. E-mail: martin.krssak@ meduniwien.ac. at; fax: 143-1-40400 7631. Received January 10, 2014; accepted February 19, 2014. Copyright VC 2014 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27091 Potential conflict of interest: Nothing to report.