Pathophysiology of non-alcoholic fatty liver disease (NAFLD)

Current knowledge has led to the development of the multiple strike hypothesis in the pathophysiology of NAFLD (1). Insulin resistance constitutes the first strike, increasing the amount of circulating free fatty acids and fat deposition in hepatocytes (1). This process leads to increased lipid peroxidation, hepatocyte apoptosis and cytokine activity (1). The associated production of proinflammatory adipokines, increased oxidative stress and mitochondrial dysfunction, in turn, further contributes to the progression of the disease (1). The gut microbiota, now linked to the development of obesity and chronic disease, may play a role in the development of NAFLD, including alterations in bacterial translocation and lipopolysaccharide (LPS) production, which are associated with increased pro-inflammatory signaling, insulin resistance, hepatic oxidative stress, hepatotoxicity and fibrosis (1). Through its endocrine functions, visceral adipose tissue may also play a role, where its excessive accumulation may increase insulin resistance and the production of proinflammatory cytokines (1). Finally, an increase in hepatic lipogenesis following excessive glucose consumption would lead to increased free fatty acid production and hyperinsulinemia, ultimately resulting in increased de novo lipogenesis, decreased glycogen synthesis, increased hepatic free fatty acid uptake, inhibition of B-oxidation and alterations to triglyceride transport (1). 

Treatment: weight loss as the first line intervention

The first recommendation made by the Canadian NASH Network (CanNASH) (2) and most other groups (3) in the treatment of hepatic steatosis is a weight loss of 5-7% or 10% to reduce fibrosis (4). A maximum weight loss of 1.5 kg/week (5) has been previously recommended, as faster weight loss has been associated with increased inflammation and periportal fibrosis (5). Increased free fatty acid flow to the liver and decreased antioxidant intake have been suggested as a cause of these problems (6). However, some rapid weight loss techniques, such as bariatric surgery, significantly improve NAFLD (7). As such, caution is advised in cases of alcoholic steatohepatitis or cirrhosis (7). 

Type of diet: Mediterranean diet still the winner

CanNASH (2) and several of the other groups (3) suggest the Mediterranean diet as the most widely documented treatment for NALFD (8-9). Several European associations have also suggested a low-carbohydrate/ketogenic diet due to its impact on insulin resistance, as discussed previously (3). A greater decrease in intrahepatic lipid concentration was observed in the low-carbohydrate diet compared to the low-fat diet after 48 hours, but this difference disappeared after 3 months (10). In contrast, a greater decrease in aspartate aminotransferase (AST) was observed in a 16-week low-carbohydrate diet compared to a low-fat diet, without significantly different weight loss (10). Some authors have suggested that the benefit associated with low-carbohydrate diets on NAFLD is observed in the short term (12). A meta-analysis found no difference between low- and high-carbohydrate diets, although few studies were included (13). As such, the impact of a low-carbohydrate diet on NAFLD remains a matter of debate. Other groups have investigated the effect of a ketogenic diet in the treatment of NALFD. However, a lack of a comparative group and small sample sizes make it impossible to determine if the impact of the ketogenic diet on NAFLD is due to the weight loss of the diet itself (14). A potential exacerbation of NAFLD must also be considered in high-fat dietary interventions, as the increased flow of fatty acids to the liver may increase lipid peroxidation and hepatocyte necrosis (6). Further, intermittent fasting has garnered mounting scientific interest, given that increased food intake in the morning, regular meal intake and decreased snacking in the evening are associated with an improved liver profile (12). However, further research is needed to understand the full impact of fasting on NAFLD (12,14). In sum, the Mediterranean diet remains the diet of choice for NALFD with the currently available data. 

Omega-3: an ally in the treatment of NAFLD

According to CanNASH, a reduction in liver enzymes and NAFLD severity is reported with omega-3 consumption, but there is insufficient data to recommend supplementation (2). In one study, supplementation with 2 g of omega-3 per day for 6 months resulted in a decrease in NAFLD severity, plasma ALT, tumor necrosis factor (TNF)-alpha and insulin resistance (15). Similar results have been reported when supplementing 1g of omega-3 for 12 months in 42 participants (16). These results are confirmed by a systematic review, which observed that omega-3 supplementation reduces hepatic fatty acid concentration (17). However, according to this review, the heterogeneity of the studies does not make it possible to establish an optimal dose of omega-3 in the treatment of NAFLD. 

The role of prebiotics and probiotics in NAFLD

Prebiotics and probiotics may improve liver enzyme levels, but data are limited according to CanNASH (2). A small pilot study of 7 people with NAFLD supplemented with 16g oligofructose per day reported a decrease in circulating AST levels after 8 weeks (18). Another study reported a decrease in intrahepatic lipids measured by spectroscopy and plasma AST in patients treated with probiotics (strains of Lactobacillus and Bifidobacterium bifidum) for 6 months, without significant impact on weight and waist circumference (19). In another randomized controlled trial, the addition of 300g of yogurt supplemented with Lactobacillus acidophilus and Bifidobacterium lactis for 8 weeks resulted in a decrease in plasma AST and ALT, again in patients with NAFLD (20). Although promising, translation of these results to the clinic is difficult, given the heterogeneity of the studies and the small samples (1). 

Coffee: a beverage of choice for NAFLD

The consumption of 3 to 4 cups of coffee per day is recommended by CanNASH (2). Consumption of 1 to 4 cups of coffee (caffeinated or decaffeinated) per day is also recommended as a second line supplement to the treatment of NAFLD according to a literature review by Examine (21). According to two meta-analyses, coffee consumption is associated with a 29% decrease in the risk of NAFLD, 27-30% decrease in liver fibrosis, and 39% decrease in the risk of cirrhosis (22-23). This effect can be explained by a reduction in intrahepatic lipid accumulation through an increase in lipid B-oxidation, a decrease in inflammation and oxidative stress, and an increase in the expression of antioxidant proteins such as glutathione (3). 

The role of fructose

High fructose intake from high-fructose corn syrup and soft drinks alters the gut microbiota and increases de novo lipogenesis, thus increasing the risk of advanced fibrosis and NAFLD (2). However, according to a meta-analysis, the relationship between NAFLD and fructose could be confounded by excessive energy intake. As such, the evidence remains insufficient to conclude an effect of fructose on NAFLD (24). However, several mechanisms could explain alterations in NALFD with excessive fructose consumption, including its direct passage to the liver following absorption, its high availability in the liver as a substrate for de novo lipogenesis, and an associated increase in free fatty acid synthesis and insulin resistance due to increases in Srebp1c and Chrebp-β expression (3). However, the strong association between high fructose consumption and both weight gain and excessive energy intake continues to support current recommendations to reduce the consumption of energy-dense foods rich in fructose, such as soft drinks and sugary processed foods (25).  

In sum, further research is required to elucidate the best avenues in the nutritional treatment of NAFLD. In all cases, personalized nutrition is essential in maintaining long term dietary and lifestyle changes (2,7). Our dietitians at TeamNutrition are experts at adapting our practice to the personalized needs of each client. Do not hesitate to contact us to learn more about our services! 

References: 

1. Eslamparast, T., Tendon, P and Raman, M. (2017). Dietary Composition Independent of Weight Loss in the Management of Non-Alcoholic Fatty Liver Disease. Nutrients, 9(8), 800. https://doi.org/10.3390/nu9080800   
2. Sebastiani, G., Patel, K., Ratzium, V., Feld, J.J., Neuschwander-Tetri, B.A., Pinzani, M., Petta, S., Berzigotti, A., Metrakos, P., Shoukry, N., Brunt, E.M., Tang, A., Cobbold, J.F., Ekoe, J-M., Seto, K., Ghali, P., Chevalier, S., Anstee, Q.M., Watson, H., (…) and Ramji, A. (2022) Current considerations for clinical management and care of non-alcoholic fatty liver disease: Insights from the 1st International Workshop of the Canadian NASH Network (CanNASH). Can Liver J, 5(1), 61-90. https://doi.org/10.3138/canlivj-2021-0030
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