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A Pilot Study

Helena Cortez-Pinto, MD; John Chatham, PhD; V. P. Chacko, PhD; Cheryl Arnold, RTR; Asif Rashid, MD; Anna Mae Diehl, MD

JAMA. 1999;282:1659-1664.

Context  The mechanisms that drive progression from fatty liver to steatohepatitis and cirrhosis are unknown. In animal models, obese mice with fatty livers are vulnerable to liver adenosine triphosphate (ATP) depletion and necrosis, suggesting that altered hepatic energy homeostasis may be involved.

Objective  To determine if patients with fatty liver disease exhibit impaired recovery from hepatic ATP depletion.

Design  Laboratory analysis of liver ATP stores monitored by nuclear magnetic resonance spectroscopy before and after transient hepatic ATP depletion was induced by fructose injection. The study was conducted between July 15 and August 30, 1998.

Setting  University hospital.

Patients  Eight consecutive adults with biopsy-proven nonalcoholic steatohepatitis and 7 healthy age- and sex-matched controls.

Main Outcome Measure  Level of ATP 1 hour after fructose infusion in patients vs controls.

Results  In patients, serum aminotransferase levels were increased (P = .02 vs controls); albumin and bilirubin values were normal and clinical evidence 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 patients weighed significantly more than controls (P = .02). Liver ATP levels were 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 period (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 aminotransferase elevations, neither of the latter 2 parameters nor the histologic severity of fibrosis strongly predicted hepatic ATP recovery.

Conclusions  These data suggest that recovery from hepatic ATP depletion becomes progressively less efficient as body mass increases in healthy controls and is severely impaired in patients with obesity-related nonalcoholic steatohepatitis.

Author Affiliations: Departments of Medicine (Drs Cortez-Pinto and Diehl), Radiology (Drs Chatham and Chacko and Ms Arnold), and Pathology (Dr Rashid), Johns Hopkins University School of Medicine, Baltimore, Md.

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