A Pilot Study: No Therapeutic Effect of L-Alanine in Patients with Nonalcoholic Steatohepatitis
- 1
Abstract
Background: Mitochondrial dysfunction plays a pivotal role in the progression of nonalcoholic steatohepatitis (NASH). L-alanine was shown to restore ATP content and protect the liver in various liver injury models. Aim: To assess the safety and therapeutic effects of long-term administration of L-alanine in patients with NASH, we conducted a pilot trial. Methods: Patients with NASH were enrolled and treated with 6 - 18 g/day L-alanine for 12 months and monitored for serum aminotransferases and renal function. Liver histology was obtained at baseline and 12 months. Changes in serum aminotransferase were assessed by differences from entry and rate of change per month using all available measures. Changes in liver histology were assessed by differences in Brunt scores of steatosis, lobular inflammation, and fibrosis. Results: Nine patients were enrolled and six completed the treatment. The reasons of the study withdrawal were nausea (n = 1), planned bariatric surgery (n = 1), and un-specified reason (n = 1). One participant experienced exacerbation of pre-existing renal failure that required hospitalization, although the medication was safely resumed after 2-week cessation and treatment was completed. Serum alanine aminotransferase (ALT) (?24.8 ± 32.1 IU/L vs.0, p = 0.11) and aspartate aminotransferase (AST) (?8 ± 16.2 1IU/L vs. 0, p = 0.28) were improved in 4 and 3 of the 6 completed participants, while rate of ALT and AST change per month showed improvement over time (negative slope) in 5 and 4 of the 6. Liver histology did not change significantly. Conclusion: The 12-month administration of L-alanine seems to be safe, but did not show significant therapeutic effects on serum aminotransferase or liver histology in patients with NASH, along with less than ideal tolerability.
- L. A. Adams and K. D. Lindor, “Nonalcoholic Fatty Liver Disease,” Annals of Epidemiology, Vol. 17, No. 1, 2007, pp. 863-869.
- S. Kojima, et al., “Increase in the Prevalence of Fatty Liver in Japan over the Past 12 Years: Analysis of Clinical Background,” Journal of Gastroenterology, Vol. 38, No. 10, 2003, pp. 954-961.
- L. A. Adams and P. Angulo, “Treatment of Non-Alco- holic Fatty Liver Disease,” Postgraduate Medical Journal, Vol. 82, No. 967, 2006, pp. 315-322.
- A. J. Sanyal, “Mechanisms of Disease: Pathogenesis of Nonalcoholic Fatty Liver Disease,” Nature Reviews Gastroenterology & Hepatology, Vol. 2, No. 1, 2005, pp. 46- 53.
- P. Jezek and L. Hlavata, “Mitochondria in Homeostasis of Reactive Oxygen Species in Cell, Tissues, and Organism,” International Journal of Biochemistry & Cell Biology, Vol. 37, No. 12, pp. 2478-2503.
- H. Kojima, et al., “Mitochondrial Abnormality and Oxidative Stress in Nonalcoholic Steatohepatitis, Alcohol,” Clinical and Experimental Research, Vol. 31, No. (Suppl. 1), 2007, pp. S61-S66.
- E. Santamaria, et al., “Functional Proteomics of Nonalcoholic Steatohepatitis: Mitochondrial Proteins as Targets of S-Adenosylmethionine,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, No. 6, 2003, pp. 3065-3070.
- A. J. Sanyal, et al., “Nonalcoholic Steatohepatitis: Association of Insulin Resistance and Mitochondrial Abnormalities,” Gastroenterology, Vol. 120, No. 5, 2001, pp. 1183-1192.
- H. Cortez-Pinto, et al., “Alterations in Liver ATP Homeostasis in Human Nonalcoholic Steatohepatitis: A Pilot Study,” Jama, Vol. 282, No. 17, 1999, pp. 1659-1664.
- K. Maezono, et al., “Alanine Protects Liver from Injury Caused By F-Galactosamine and CCl4,” Hepatology, Vol. 24, No. 1, 1996, pp. 185-191.
- K. Maezono, et al., “Effect of Alanine on D-Galacto- samine-Induced Acute Liver Failure in Rats,” Hepatology, Vol. 24, No. 5, 1996, pp. 1211-1216.
- H. Suzuki, et al., “Ethanol and Hydrazine Sulfate Induced Chronic Hepatic Injury in Rats: The Curative Effect of Administration of Glucogenic Amino Acids,” Alcohol Alcohol, Suppl, 1993, pp. 111-117.
- S. Ishizaki-Koizumi, et al., “Mechanisms of the Protective Effect of L-Alanine to D-Galactosamine-Induced Hepatocellular Injury: Comparative Studies of L-Alanine and Pyruvate,” Biochemical and Biophysical Research and Communication, Vol. 291, No. 4, 2002, pp. 738-743.