Alterations in liver ATP homeostasis in human nonalcoholic steatohepatitis- A pilot study

Context The mechanisms that drive progression from fatty liver to steatohep atitis and cirrhosis are unknown. In animal models, obese mice with fatty l ivers are vulnerable to liver adenosine triphosphate (ATP) depletion and ne crosis, suggesting that altered hepatic energy homeostasis may be involved. Objective To determine ii patients with fatty liver disease exhibit impaire d recovery from hepatic ATP depletion. Design Laboratory analysis of liver ATP stores monitored by nuclear magneti c resonance spectroscopy before and after transient hepatic ATP depletion w as induced by fructose injection. The study was conducted between July 15 a nd August 30, 1998. Setting University hospital. Patients Eight consecutive adults with biopsy-proven nonalcoholic steatohep atitis and 7 healthy age- and sex-matched controls. Main Outcome Measure Level of ATP 1 hour after fructose infusion in patient s vs controls. Results In patients, serum aminotransferase levels were increased (P = .02 vs controls); albumin and bilirubin values were normal and clinical evidenc e of portal hypertension was absent in both groups. However, 2 patients had moderate fibrosis and 1 had cirrhosis on liver biopsy. Mean serum glucose, cholesterol, and triglyceride levels were similar between groups but patie nts weighed significantly more than controls (P = .02). Liver ATP levels we re similar in the 2 groups before fructose infusion and decreased similarly in both after fructose infusion (P = .01 vs initial ATP levels). However, controls replenished their hepatic ATP stores during the 1-hour follow-up p eriod (P<.02 vs minimum ATP) but patients did not. Hence, patients' hepatic ATP levels were lower than those of controls at the end of the study (P = .04), Body mass index (BMI) correlated inversely with ATP recovery, even in controls (R = -0.768; P = .07), Although BMI was greater in patients than controls (P = .02) and correlated strongly with fatty liver and serum amino transferase elevations, neither of the latter 2 parameters nor the histolog ic severity of fibrosis strongly predicted hepatic ATP recovery. Conclusions These data suggest that recovery from hepatic ATP depletion bec omes progressively less efficient as body mass increases in healthy control s and is severely impaired in patients with obesity-related nonalcoholic st eatohepatitis.