At present, non-alcoholic fatty liver disease (NAFLD) is assumed to be the most common chronic liver disease. Retinoic acid (RA) is primarily involved in the regulation of lipid metabolism and hepatic steatosis [13].
Although some studies showed that RA supplementation might be a promising therapeutic approach in fatty liver disease, the clinical relevance of RA in the pathogenesis of hepatic steatosis and NAFLD has not been carefully investigated. So, the present study was designed to study the role of retinoic acid in the development and progression of NAFLD from simple steatosis to NASH and to compare the results with the NAFLD fibrosis score. After approval of the institutional review board, this study was conducted at the Internal Medicine Department, Ain Shams University Hospitals. Informed consent was obtained from all subjects enrolled in the study.
Our study obtained samples from 80 patients in group 1 (52 males and 28 females), 80 patients in group 2 (50 males and 30 females), and 20 control patients (14 males and 6 females). There were no significant differences between the studied groups regarding age and sex. Also, Liu et al. (2015) [14] showed that were no significant differences in age or female to male ratio between subjects in control, NAFLD, and NASH groups. On the other hand, Chaves et al. (2008) [15] showed that the mean age was significantly higher within the NAFLD group with and without steatosis.
Also, there was no significant difference in BMI between the studied groups, and this in disagreement with the studies of Liu et al. (2015)(14) and Bottella et al. (2011) [16] who showed significant difference in BMI between studied groups with higher BMI in NAFLD than the control groups; however, in their study, they selected patient group to be obese from the start. The high prevalence of obesity could explain this in Egyptian people; that is why both patients and controls were obese from the start with no significant statistical difference between them.
The present study showed that FBG had the lowest levels among the control group, followed by the steatosis group and had the highest levels in the NASH group, with no significant differences between the studied groups. Liu et al. (2015) [14] stated that the concentration of fasting plasma glucose in subjects with NAFLD and NASH was significantly higher than that in control subjects.
Miyazaki et al. 2012 [17] showed that BMI, ALT, and LDH were significantly higher in NAFLD patients than in the control group. Nutritional parameters, including total cholesterol, triglyceride, and fasting plasma glucose levels, were higher in the NAFLD patients than in the control group, although these differences were not statistically significant.
HbA1C was significantly higher in the patient groups than the control group with no significant difference between the steatosis group and the NASH group, but TG and TC showed no significant difference between studied groups.
Our study showed that serum retinoic acid level was significantly different among the studied groups, was lowest in the NASH group, followed by the steatosis group and highest in the control group and this was in accordance with Mourad et al. 2018 [18] and Pettinelli et al. 2018 [19].
However, other studies displayed no significant differences between control and NAFLD adults as Cengiz et al. 2010 [20] or even higher serum retinol in patients with NAFLD compared with a control group in Alkhouri et al. 2009 [21]. Senno et al. 2010 [11] found a positive correlation between serum retinol values and concentrations of AST and ALT in NAFLD. Serum retinol was the only biochemical variable that could predict AST and ALT concentrations in these patients, pointing to retinol as a potential marker for liver damage.
NAFLD score was higher in the NASH group than the steatosis group, with a high statistically significant difference in the differentiation between NASH group and the steatosis group.
The correlation analysis revealed a negative correlation between retinoic acid and NAFLD score among the steatosis group and the NASH group. The receiver operating characteristics (ROC) curve was used to define the best cutoff value of serum retinoic acid level. Retinoic acid had a significantly high statistical difference in the differentiation between the study groups similar to that of NAFLD fibrosis score.
Some limitations need to be discussed in the present study. First, more randomized controlled clinical trials in human subjects are required to confirm the fundamental role of low RA concentrations in NAFLD and to correlate the results with a liver biopsy; besides, the possible preventive or therapeutic advantage of RA needs to be evaluated to confirm its benefits and safety.
Furthermore, in diagnosing NAFLD in the studied groups, most of the previous studies used ultrasound only, which is limited by its inability to differentiate mild steatosis from fibrosis and to accurately quantify fatty infiltration; besides, it is an operator dependent. Others used a liver biopsy, which is an invasive method with possible serious complications. Nevertheless, in our study, we used, in addition to ultrasound, NAFLD fibrosis score, which is one of the accurate scores in diagnosing and differentiation simple steatosis from NASH and compared its results with RA serum levels.
Magnetic resonance elastography (MRE) is a non-invasive medical imaging technique that measures liver stiffness can also be used; however, the issue of the cost and the availability of the MRI needs to be discussed. This may open new insights on the use of serum retinoic acid in NAFLD as regards the cost per test, and being a single biomarker could be less costly than variable laboratory parameters already used right now or imaging techniques as MRE.