Non-alcoholic fatty liver disease (NAFLD) comprises a whole spectrum of diseases, including simple steatosis and steatohepatitis (NASH) which can progress to liver fibrosis, cirrhosis, and hepatocellular carcinoma. NAFLD is highly associated with obesity, insulin resistance, and metabolic syndrome, and it is estimated to affect about 20–40% of the general population in developed countries [24].
Vitamin D has long been regarded as a regulatory factor for phospho-calcium metabolism and bone homeostasis. However, many studies have shown more properties, namely immunomodulatory role [25], involvement in cellular differentiation and proliferation [26], hormone secretion [27], and anti-inflammatory and antifibrotic effects [28]. All these roles support the importance of maintaining optimal vitamin D levels.
Vitamin D deficiency constitutes a largely unrecognized epidemic in many populations worldwide and has been reported in all age groups including healthy children, young adults, middle-aged, and elderly adults [29].
In this study, we measured different demographic, laboratory, and metabolic parameters in forty patients with NASH and compared them with those of age- and sex-matched forty healthy individuals as the control group. Then, vitamin D (4000 IU/day) was given to the NASH group for 12 weeks. All demographic, laboratory, and metabolic parameters including serum leptin level were repeated after the end of treatment. Then, we demonstrated the association of vitamin D supplementation with serum leptin and metabolic parameters in patients with NASH.
In this study, we found that patients with NASH had higher body weight and BMI than the control. Many former studies concluded that obesity is a condition most often associated with NASH as 69 to 100% of patients with NASH were also obese. Obesity is associated with increased FFA delivery to the liver, increased FFA synthesis within the liver, insufficient beta-oxidation of FFA, and insufficient very low-density lipoprotein synthesis or secretion [30].
This study concluded that insulin resistance and dyslipidemia were more common in NASH with higher levels of HbA1c, fasting blood glucose, fasting insulin level, HOMA-IR, cholesterol, LDL, and lower levels of HDL compared to the control. Insulin resistance is associated with various metabolic abnormalities especially hyperglycemia, hypertriglyceridemia, low HDL cholesterol, and high levels of LDL leading to the concept of “metabolic syndrome” [30]. When resistance to antilipolytic action of insulin is present, fatty acids are mobilized more rapidly from visceral (central) than from subcutaneous (peripheral) fat and drained directly to the liver via the portal vein. Excessive intracellular concentrations of fatty acids may be toxic and lead to oxidative stress and thus contribute to NASH [31].
In this study, patients with NASH have significantly low vitamin D levels. This agrees with previous studies that noted high prevalence of hypovitaminosis D in patients with NAFLD [19]. This may be explained by the increased amount of adipose tissue in which the vitamin D is distributed in obese patients with NASH; this will decrease the circulating serum of vitamin D level [32]. Another explanation could be related to sedentary lifestyle, poor micro-nutrient nutrition, and lack of exposure to sunlight [33]. Moreover, in view of the bile acid-dependent uptake of vitamin D, it is reasonable to expect an association between vitamin D status and both cholestatic and noncholestatic chronic liver diseases [19].
The study noted that serum leptin levels were raised in both men and women with NASH compared with age- and sex-matched controls. Several factors could contribute to increased serum leptin levels in NASH. Hyperleptinemia occurs in inflammatory disorders and has been attributed to cytokines such as tumor necrosis factor-α (TNF-α), which is also increased in NASH as TNF-α gene is overexpressed in adipose tissue of obese NASH subjects. Chronic hyperinsulinemia, which is especially relevant in the setting of NASH, is associated with persistent hyperleptinemia. Moreover, leptin also correlates with serum c-peptide. In patients with NASH, c-peptide is not significantly cleared by the liver [9].
Following vitamin D supplementation in a dose of 4000 IU/day for 12 weeks, there was significant improvement of NASH. There was significant decrease in ALT, AST, ALP, GGT, and NAFLD fibrosis score. Previous studies noticed significant improvement in serum levels of ALT in NASH patients who took standard medical treatment (SMT) together with vitamin D when compared with others who took SMT alone [20]. Vitamin D was effective in liver enzyme reduction in another study [34]. Vitamin D-mediated improvement in insulin secretion results in decreased adipose tissue inflammation with decreased hepatic inflammation and fibrosis via the regulation of the vitamin D receptor and several cytokines such as interleukin 6, TNF-α, and adiponectin [18]. New evidence revealed that vitamin D can prevent hepatic stellate cell (HSC) activation which increases cellular transformation and proliferation [35].
In this study, vitamin D treatment significantly decreased insulin resistance in NASH patients. Values of fasting blood sugar, fasting insulin level, and HOMA-IR were significantly decreased after treatment. Vitamin D, through its effect on peroxisome proliferator-activated receptor, can modulate FFA metabolism and reduce FFA-induced insulin resistance in bloodstream [34]. Other studies reported significant reduction in FBS, insulin, and HOMA-IR following vitamin D supplementation in NASH [36]. The decreased production of TNF-α and increasing adiponectin during therapy with vitamin D is expected to improve the underlying IR in patients with NASH [19].
Serum triglycerides (TGs) decreased after treatment with vitamin D while there were no significant change in levels of cholesterol, LDL, and HDL. Foroughi et al. [37] assessed vitamin D effect on TGs in patients with NASH. They stated that, after 10 weeks of vitamin D treatment (50,000 IU/week), a significant decrease in serum TGs was seen when compared with baseline values. Hariri and Zohdi [36] also found that vitamin D supplementation might improve lipid profile and inflammatory mediators (like C-reactive protein) in NASH patients when compared with placebo.
One of the main physiological roles of leptin is to prevent lipid accumulation in nonadipose sites, such as the myocardium, skeletal muscle, pancreas, and liver, a concept referred to as “lipotoxicity” [38]. In this study, treatment with vitamin D has led to significant decrease in serum leptin level. This agreed with previous studies which confirmed that vitamin D level was negatively correlated with leptin in patients with NASH [39]. Other studies also reported vitamin D-mediated inhibition of serum leptin [40].