Twenty-five percent of the United States population has nonalcoholic fatty liver disease (NAFLD), a disease that includes hepatic fatty infiltration alone (simple steatosis) or steatosis plus inflammation, liver cell injury and death [nonalcoholic steatohepatitis (NASH), which develops in 25% of patients with NAFLD]. NAFLD spectrum disorders are the hepatic manifestation of obesity, insulin resistance, and type 2 diabetes. NASH leads to liver fibrosis, an elevated risk of cirrhosis and hepatocellular carcinoma, and will soon be the leading cause of liver transplantation in the U.S. In the U.S., the cost of management of NASH and its complications is $32 billion annually. Durable therapies are lacking for the NASH spectrum and an acceptable pharmaceutical intervention is not approved. The vertical sleeve gastrectomy(VSG) is a bariatric surgical procedure that dramatically reduces liver injury and favors NASH remission. Importantly, not all patients with NASH demonstrate histologic improvements (as assessedby NAFLD activity score, NAS) following bariatric surgery, and in a small percentage of patients the disease may progress. Furthermore, there are no known antecedent biomarkers that predict histologic changes of NAFLD/NASH following bariatric surgery. In these proposed studies, formal quantifications of liver oxidative and gluconeogenic fluxes (?hepatic energy fluxes?) will be performed at baseline in obese patients who have all received preoperative liver biopsies for histopathological determination, liver MRI-derived proton density fat fraction and elastography assessment of fibrosis, and intravenous glucose tolerance tests, all prior to VSG. The interdisciplinary team will then determine how these preoperative metabolic flux indices correlate with pre- and postoperative histopathological, radiographic, and clinical indices. Thus, the premise of this study is that deranged hepatic mitochondrial metabolism is a key biomarker and mediator of the NAFLD/NASH continuum, and the central hypothesis to be tested is that preoperative hepatic fat oxidation and glucose production flux parameters differ between NAFLD versus NASH (diminished in NASH), and response of the liver to bariatric surgery can be predicted by preoperative fluxes.
In Aim 1, hepatic metabolic fluxes will be quantified in humans with non-NASH NAFLD (NAS <3) versus NASH (NAS ? 4 with at least a score of ?1? for ballooning degeneration), testing the hypothesis that hepatic energy fluxes are decreased in human NASH compared to uncomplicated NAFLD. A secondary hypothesis is that oxidative fluxes do not directly correlate with any specific index component of NAS.
In Aim 2, post-VSG histopathological, radiographic, and clinical outcomes will be compared to preoperative hepatic energy fluxes, testing the hypothesis that preoperative hepatic energy fluxes will predict these outcomes similarly to standard histopathological, radiographic, and metabolic parameters. These proof-of-concept datasets are expected to support future R01 funding that determines the role of hepatic oxidative flux metabolism in human NASH evolution and response to bariatric surgery.
Diseases along the nonalcoholic fatty liver disease spectrum, which are tightly coupled to the obesity epidemic, are soon to become the commonest indication for liver transplantation in the United States. Bariatric surgery shows great promise in the treatment of these diseases. The studies proposed herein will be the first to measure in humans the relationships among (i) the liver?s ability to burn fat and make glucose, two of its primary functions; (ii) the severity of nonalcoholic fatty liver disease; and (iii) the responses to bariatric surgery.
