aUniversity of Montreal (St-Luc Hospital), Montreal, QC, CanadabUniversity of Magdeburg (University Hospital), Magdeburg, Germany
Roger F. Butterworth, PhD, DSc
University of Montreal (St-Luc Hospital)
45143 Cabot Trail, Englishtown, Nova Scotia
Montreal, QC B0C 1H0 (Canada)
E-Mail rb
Keywords: L-ornithine L-aspartateNon-alcoholic fatty liver diseaseNon-alcoholic steatohepatitisHepatoprotectionAntioxidantHepatic microcirculationGlutamine
Abstract
Background: Non-alcoholic fatty liver disease (NAFLD) is the leading chronic hepatic condition worldwide and new approaches to management and treatment are limited. Summary: L-ornithine L-aspartate (LOLA) has hepatoprotective properties in patients with fatty liver of diverse etiology and results of a multicenter randomized clinical trial reveal that 12 weeks treatment with oral LOLA (6–9 g/d) results in a dose-related reduction in activities of liver enzymes and triglycerides together with significant improvements of liver/spleen CT ratios. A preliminary report described improvements of hepatic microcirculation in patients with non-alcoholic steatohepatitis (NASH) following treatment with LOLA. Mechanisms responsible for the beneficial effects of LOLA in NAFLD/NASH involve, in addition to its established ammonia-lowering effect, metabolic transformations of the LOLA-constituent amino acids L-ornithine and L-aspartate into L-glutamine, L-arginine, and glutathione. These metabolites have well-established actions implicated in the prevention of lipid peroxidation, improvement of hepatic microcirculation in addition to anti-inflammatory, and anti-oxidant properties. Key Messages: (1) LOLA is effective for the treatment of key indices in NAFLD/NASH. (2) Mechanisms other than LOLA’s ammonia-lowering action have been postulated. (3) Further assessments in the clinical setting are now required.
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Introduction
Non-alcoholic fatty liver disease (NAFLD) has emerged as the leading chronic liver disease worldwide that is strongly associated with obesity and the metabolic syndrome. The pathological spectrum of NAFLD spans simple hepatic steatosis, non-alcoholic steatohepatitis (NASH) to liver fibrosis with subsequent development of cirrhosis leading in many cases to hepatocellular carcinoma <1>.
Given the key role of the liver in the removal of excess ammonia, it is not surprising that patients with NASH are hyperammonemic <2> and hepatic accumulation of ammonia has been confirmed in both patients and animal models of fatty liver disease <3>.
L-ornithine L-aspartate (LOLA) is a mixture of endogenous amino acids with the demonstrated capacity to increase ammonia removal by residual hepatocytes and skeletal muscle of patients with cirrhosis <4>. Recent reports suggest that LOLA has, in addition to its established role as an ammonia scavenger, a direct protective effect on the liver per se. In a groundbreaking report by Grüngreiff and Lambert-Baumann <5>, 463 patients with fatty liver, 29% of whom were non-alcoholic, were treated with a range of doses of oral LOLA for periods of 30–90 days. Increased blood levels of liver enzymes (ASAT, ALT and y-GT) were significantly attenuated (by up to 70%) by LOLA treatment (Table 1) indicative of improving hepatic function and the effect was dose-related. Beneficial treatment outcomes were more pronounced in patients with fatty liver compared to patients with cirrhosis, and subgroup analysis revealed that only patients with clear abstinence from alcohol achieved optimal outcomes with respect to liver enzymes.
LOLA in the Treatment of NAFLD/NASH
LOLA manifests hepato-protective properties in patients with fatty liver of diverse etiology as summarized above. In order to address this issue directly in relation to NAFLD/NASH, a multicenter open label, multi-dose, randomized controlled trial comprising 72 such patients was undertaken in order to assess the efficacy of LOLA administered orally for a 12-week period. Patients were diagnosed with NASH according to the 2010 edition of “The Guidelines for the treatment of NASH”: liver-spleen CT ratio of less than 1 through CT scan, ALT 1.3 times higher than the normal upper limit, aged between 18 and 65 years. After 12 weeks of oral LOLA treatment, a significant dose-related reduction in ALT was observed together with significant decreases in concentration of triglycerides. Liver/spleen CT ratios also improved significantly following LOLA treatment <6>.
In a subsequent trial, 78 patients with NASH all of whom manifested disorders of hepatic microcirculation were studied using the technique of polyhepatography, a modified technique for the noninvasive estimation of intrahepatic blood flow. Changes produced by LOLA consisted of increased resistance and abnormalities of waveform and amplitude (sinusoidal level). Improvements of hepatic microcirculation were observed in all patients even in the presence of 0–1 stage fibrosis <7>.
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Mechanisms Involved in Hepatoprotection by LOLA in NAFLD/NASH
The pathogenesis of NAFLD has not been fully elucidated. However, the “two-hit hypothesis” has gained considerable attention where the initial hit relating to altered lipid metabolism results in fat accumulation. The second hit relates to a series of factors including oxidative stress and inflammation.
The principle mechanism of action of LOLA that underpins its ammonia scavenger properties in chronic liver disease involves the removal of ammonia via 2 distinct mechanisms, namely, the synthesis of urea (L-ornithine is a metabolic intermediate in the urea cycle) by periportal hepatocytes and the synthesis of glutamine via the enzyme glutamine synthetase (GS), an enzyme located in both the perivenous hepatocytes and skeletal muscle. It is well established that flux through the GS pathway is reduced by up to 50% in liver biopsy samples from patients with histologically-proven steatosis and raised serum transaminases and bilirubin <8>. These findings are consistent with the significant loss of the high-affinity ammonia-removing pathway involving GS located in the perivenous hepatocytes.
Studies in recent years have identified a series of mechanisms involving LOLA’s effects on sarcopenia as well as hepatic intermediary metabolism, oxidative stress, and lipid peroxidation that could play a role in the hepatoprotective effects of LOLA in NAFLD/NASH.
Sarcopenia
Defined as a progressive loss of skeletal muscle mass, strength, and function, sarcopenia is a risk factor for the development of NAFLD. Mechanisms relating sarcopenia to NAFLD include proinflammatory factors with the potential to result in liver injury <9>. It has been reported that LOLA treatment in patients with cirrhosis <10, 11> or experimental animals with chronic liver failure <12> results in the restoration of muscle proteostasis and significant improvements of muscle function. It is possible that the apparent hepatoprotective properties of LOLA in patients with NAFLD are mediated, at least in part, via mechanisms involving improvements of skeletal muscle function. Further evaluations of this possibility are ongoing.
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Glutamine
Treatment of experimental chronic liver disease with LOLA results in a significant threefold increase of plasma glutamine resulting from a 2-step reaction involving the transamination of L-ornithine to glutamate, the obligate substrate for GS <13>. Intravenous infusions of LOLA likewise result in significant increases of plasma glutamate and restoration of glutamine in patients with chronic liver disease <14>. Restoration of the synthesis of glutamine in liver may represent an important step implicated in the hepatoprotective properties of LOLA in NAFLD/NASH in view of the observations that administration of glutamine results in improvement of hepatic injury caused by a range of insults including ischemia/reperfusion injury and that resulting from chronic alcohol ingestion <15, 16>. More recently, reports from 2 studies in experimental NAFLD/NASH demonstrate significant hepatoprotective effects of glutamine <17, 18>. In the first of these studies, NAFLD was induced by a high fat diet and oral treatment with glutamine resulted in reduced expression of hepatic markers of oxidative stress and inhibition of NFkB p65 accompanied by improvement in hepatic steatosis. In the second study, the hepato-protective effects of oral glutamine supplements on the development of Western-style diet-induced NASH were associated with protection against lipid peroxidation in the liver. Moreover, glutamine supplements were associated with significantly less proinflammatory activity (Fig. 1).