L-Carnitine Supplementation to Diet: A New Tool in Treatment of Nonalcoholic Steatohepatitis—A Randomized and Controlled Clinical Trial

Mariano Malaguarnera AP; Maria Pia Gargante MD; Cristina Russo MD; Tijana Antic MD; Marco Vacante MD; Michele Malaguarnera MD; Teresio Avitabile; Giovanni Li Volti AP; Fabio Galvano AP

Disclosures

Am J Gastroenterol 

In This Article

Discussion

In this study, we found that the patients with NASH who were treated with L-carnitine compared with patients who were treated with placebo have an improvement in histological findings of the liver.

We registered a decrease in hepatic inflammation and fibrosis supported by reduction of some inflammatory indexes such as CRP and TNF-α Probably, TNF-α might have a pivotal role given that mitochondrial dysfunction was associated with increased serum TNF-α levels. Naturally, an improvement in lipid profile and also a better insulin sensitivity and lower values of fasting plasma glucose have a close relationship with a reduction of steatosis such as many studies reported.[20,21]

The study of pathophysiologic process and molecular mechanisms of NASH is limited by the lack of appropriate animal models, but we can focus our attention on mitochondrial β-oxidation (causing steatosis) and respiration (causing increased formation of ROS and adenosine triphosphate depletion) through inhibition of carnitine palmitoyl transferase I and acyl-coenzyme A, respectively.[22]

L-carnitine is an essential factor in the production of acetyl-CoA. It regulates the turnover of the fatty acids into phospholipids membranes, a process known as the deacylation–reacylation cycle of phospholipids membranes. L-carnitine is suggested to act as CoA buffer, maintaining the acyl Co A/CoA ratio in cells and exerts a function in several metabolic processes. The transport of acyl-CoA across the inner mitochondrial membrane to the matrix determine a reduced availability of CoA in the matrix and a decrease of CoA-SH. It determines a parallel increase in the acil coA/CoASH ratio, which inhibits the mitochondrial dehydrogenases; consequently, not only the oxidation of fatty acids but also the utilization of carbohydrates becomes impaired.[23]

Various studies have indicated that the risk factors implicated in the development of NASH include insulin resistance, oxidative stress, stellate cell activation, apoptosis, cytokine, and adipokine pathways.[4]

L-carnitine could also have beneficial effects on the mitochondrial respiratory chain. Several studies on aging showed that L-carnitine increases the mitochondrial content of cardiolipin reducing the mitochondrial impairment of electron transfer in liver.[24] In addition, L-carnitine has some antioxidant and antiapoptotic properties.[25] The mechanisms whereby L-carnitine could mediate its antioxidant action is still unclear, but several studies pointed to increased levels of different antioxidant enzymes (e.g., SOD, catalase, glutathione peroxidase) and vitamins (e.g., vitamins C and E).[26] Finally, L-carnitine could exert its antiapoptotic effects by decreasing ROS production, removing toxic fatty acid derivatives, and reducing generation of ceramides.[25]

In our study, L-carnitine decreases plasma glucose level and insulin resistance. Insulin resistance is one of the characteristics of the NASH and the metabolic syndrome. However, few studies investigated the effects of carnitine therapy on insulin resistance.[27,28]L-carnitine is reported to control hyperglycaemia and improve insulin sensitivity[29] and also increase the peripheral glucose utilization[30] in the insulin resistance patients.[31] Deficiency of L-carnitine has been reported in type 2 diabetic women with complication[32] in children with type 1 diabetes,[33] in experimental diabetic neuropathy[34] and in streptozotocin-diabetic rats.[35]

Moreover, it is well known that amplification of fatty acid esterification pathway and triglycerides formation could be implicated in hepatic insulin resistance.[36]

Stored free fatty acid (FFA) can be mobilized from adipose tissue through lipolysis. This process is headed by glucagon, insulin resistance, sudden weight loss or starvation, glucocorticosteroids, leptin, and TNF-α.[37] In the patients treated with L-carnitine, we observed a decrease in total and LDL cholesterol and in triglycerides. L-carnitine binds to fatty acyl-CoA and regulates their transport into the mitochondrial matrix for β-oxidation. L-carnitine deficiency causes reduced oxidation of FFA and accumulation of long-chain fatty acyl-CoA and diabetic complications.[33] Metabolism of FFA would be diverted toward esterification pathway rather than oxidation leading to accumulation of diacyl glycerol, and triglyceride. FFA has diabetogenic effects in the liver by having an influence on hepatic glycogenolysis, breakdown of hepatic autoregulation to glycogen deposition, and insulin resistance. FFA also decreases insulin biosynthesis, alters bioinsulin processing, and decreases insulin gene transcription.[38,39]

L-carnitine administration in rodents decreases liver triglycerides and hepatic steatosis after administration of a high fat diet, after total parenteral nutrition, or after alcohol intoxication.[40,41,42,43] Interestingly, in one study dealing with ethanol-induced liver damage, L-carnitine even reduced hepatic inflammation and plasma levels of ALT and TNF-α.[23]

One study showed no improvement in transaminase levels, plasma FFA levels, plasma triglyceride levels, or the grade of hepatic steatosis by histological examination.[44] Previous studies carried out in chronic hepatitis patients treated with α interferon and ribavirin, L-carnitine treatment showed a reduction of steatosis, fibrosis, and hepatic inflammation.[14]

In our study, L-carnitine reduces CRP and TNF-α levels with a huge benefit for patients. Previous data regarding the effect of carnitine in patients with elevated CRP levels showed big benefits too.

Although L-carnitine supplementation improves liver biochemistry, metabolic studies in humans did not show any beneficial effect with the use of L-carnitine supplementation during total parenteral nutrition or on the rates of fatty acid oxidation.[45,46]

We highlighted that oxidation of FFAs is the most important cellular source of ROS; on the other hand, FFA are a normal and important compound of our body synthesized in the liver when necessary. Nevertheless, when the liver is overloaded with FFA, it becomes weak to adequately secrete them into circulation; it determines an overload system with synthesis and accumulation of triglycerides in the liver resulting in steatosis.[47] Given the potential role of oxidative stress in the pathogenesis of NASH, investigators have focused on the use of antioxidants to protect cellular structures against damage from oxygen free radicals and from reactive products of lipid peroxidation.

In our study, we noted that L-carnitine supplementation induces regression of NASH even if both plasma and hepatic carnitine levels have been shown to be normal in subjects with NASH. Moreover, we noted a decrease of TNF-α, CRP, glucose plasma levels, and improvement of lipid profile. The real mechanism underlying this is not clear, but we can assume that L-carnitine can interfere with processes involved in β-oxidation and accumulation of lipotoxic metabolites that might contribute to mitochondrial dysfunction and insulin resistance. L-carnitine could act through mechanisms that are independent of the putative detoxifying role.

In future studies, it will be important to examine the relationship between circulating and intrahepatic fatty acid composition, liver damage and antioxidant therapy in patients with NASH.

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