Date Published: May 17, 2018
Author(s): Nikola Hadzi-Petrushev, Katerina Dimovska, Nikola Jankulovski, Dine Mitrov, Mitko Mladenov.
Oxidative stress and inflammation contribute to the pathogenesis and progression of nonalcoholic fatty liver disease (NAFLD), and the control of lipid status by statins may help to stop the progression of NAFLD. We hypothesized that the addition of antioxidant vitamins C and E to atorvastatin therapy is associated with improved serum enzyme antioxidant status. NAFLD-related serum parameters and the activity of antioxidant enzymes, before and after 3 months of treatment, were determined in patients receiving atorvastatin alone or atorvastatin plus antioxidants. Compared to healthy controls, the patients, before receiving therapy, had increased catalase and glutathione reductase, with no significant difference in glutathione peroxidase activity. After the treatment, the levels of all three antioxidant markers were reduced to the same degree in both groups of patients, indicating therapy-induced lower level of reactive oxygen species production and/or improved nonenzymatic antioxidant mechanisms. Both therapies led to the normalization of the serum lipid profile and aminotransferase levels in the patients, but the reduction in CRP, although significant, did not reduce levels to those of the controls. The obtained results favor the notion that therapy with atorvastatin alone is equally efficient during the early stages of NAFLD, regardless of the addition of antioxidant vitamins. This trial is registered with TCTR20180425001.
Nonalcoholic fatty liver disease (NAFLD) refers to the condition of hepatic steatosis in the absence of excessive alcohol consumption. It is the most common chronic, usually asymptomatic, liver disease that may progress to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. The process begins with the liver becoming steatotic due to the accumulation of fat in liver cells resulting from the increased influx of free fatty acids (FFA) and/or de novo lipogenesis caused by abnormalities in energy metabolism . At this point, the interactions between oxidative stress, inflammatory cytokines, and lipid peroxidation are the main contributors to the development of organelle dysfunction and inflammation within the liver tissue and progression of NAFLD and NASH . The hepatocellular damage is indicated by elevated serum aminotransferase levels, and the increase in the C-reactive protein (CRP) could be used as a marker of inflammation and steatosis .
The median and IQR value of BMI was 31.0 (24.4–32.2) for the NAFLD patients (60% were obese) and 28.5 (23.7–30.9) for the controls (50% were obese). BMI remained within the same category for every subject during the study. Liver fat examined by ultrasonography did not change significantly after the treatment. No side effects were reported in this study.
The observed dyslipidaemia in our NAFLD patients could be attributed to insulin resistance that leads to increased free fatty acid flux to the liver. The compensatory accelerated β-oxidation causes excessive electron flux in the electron transport chain and ROS overproduction . When the cell’s antioxidant capacity is exceeded, it leads to oxidative stress and ultimately apoptosis and release of cell contents . We relate to the described processes in the increased AST and ALT levels observed in our NAFLD patients before treatment. The peroxidation products may also prompt immune responses and activate inflammatory pathways . Although we did not measure proinflammatory cytokines, these might explain the elevated CRP levels in both groups of patients at study entry.
In general, the results of this work show that the correction of hyperlipidaemia is also associated with the reduction of antioxidant enzyme activity in the serum of NAFLD patients. Hence, the study provides a potentially valuable insight to clinicians that the therapy with atorvastatin, in parallel to its effects on the dyslipidaemia, when supplemented by antioxidants has no different effects on the enzymatic antioxidant status in NAFLD patients.