Nonalcoholic Fatty Liver Disease (NAFLD)

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are related, yet distinct, terms. NAFLD refers to a spectrum of liver diseases characterized by excess fat stored in the liver without excessive alcohol consumption or other secondary causes of fatty liver disease. Clinically, NAFLD is categorized as either simple fatty liver (NAFL) in which excess fat accumulation has occurred, but there is no evidence of cellular damage, or NASH, in which, in addition to the excess fat accumulation, inflammation of the liver (hepatitis), cellular damage (i.e., hepatocyte ballooning), and perhaps structural changes such as fibrosis are present. NASH occurs in about 20%^[13] of people with NAFLD and is often thought of as the progressive form of NAFLD. We summarize how a healthy liver progresses through these steps in Figure 3.

In 2020, it was proposed in an international expert consensus statement to rename NAFLD to metabolic dysfunction-associated fatty liver disease (MAFLD).^[14] This term has since been adopted by many, but not all, researchers and practitioners.

The diagnosis of NAFLD is based on the presence of fat in >5% of liver cells in the absence of excess alcohol consumption and other known causes of liver disease. In MAFLD, a “positive criteria” is used to diagnose the disease, rather than relying on the exclusion of certain features.

The diagnosis of MAFLD requires evidence of fat accumulation in the liver in addition to one of the following: overweight or obesity (defined as a BMI ≥ 25 kg/m2 or ≥ 23 kg/m2 in Asians), type 2 diabetes, or metabolic dysregulation as indicated by the presence of at least two metabolic risk abnormalities (i.e., high blood pressure, low HDL-cholesterol, elevated triglycerides, increased waist circumference, prediabetes, insulin resistance, or elevated levels of C-reactive protein (CRP; a marker of inflammation).^[14]

In addition, it’s suggested that MAFLD be used as a single overarching term, with disease severity described by the grade of activity and the stage of fibrosis, rather than the current system which categorizes cases as either NAFL or NASH.

Evidence suggests that about 35–40% of people with early stage NAFLD experience fibrosis progression,^[15][16] which can eventually lead to advanced liver cirrhosis and further complications such as liver cancer and failure, resulting in the need for liver transplantation. Therefore, it’s important to identify risk factors associated with the progression of NAFLD.

Meta-analyses of observational studies report that the strongest predictor of the progression of NAFLD to severe liver disease is the presence of type 2 diabetes.^[17][18] Obesity is also associated with an increased risk of developing severe liver disease.^[17][18]

No, the occurrence of NAFLD in people with a normal BMI (18.5–24.9 kg/m2 or 18.5–22.9 kg/m2 in Asians), otherwise known as lean NAFLD, is more common than one might think. A meta-analysis of 93 studies published in 2020 reported that the prevalence of lean NAFLD in the global NAFLD population was about 19%.^[19]. Notably, the long-term prognosis does not seem to differ much between people with lean NAFLD and nonlean NAFLD.^[20]

Yes, there may be. Silymarin, an extract from milk thistle that has antioxidant and anti-inflammatory properties, has been shown to improve both AST and ALT^[10] in people with NAFLD. Furthermore, it has been shown to reduce fasting blood glucose^[11] in people with type 2 diabetes. Berberine may also benefit people with NAFLD. A randomized-controlled trial showed that berberine was beneficial for reducing hepatic fat content^[12] on top of lifestyle modifications, with a similar efficacy as a thiazolidinedione. There are a handful of other nutraceuticals currently being investigated (e.g., curcumin, CoQ10) but do not currently have substantial enough evidence to indicate they are beneficial.

In people with prediabetes or type 2 diabetes, a diet enriched in monounsaturated fat (22–28% of energy intake; primarily from olive oil) has been shown to reduce liver fat compared to a diet enriched in fiber and slightly higher in carbohydrates, independent of changes in body weight.^[21][22] In addition, saturated fats have been shown to increase liver fat compared to polyunsaturated fats.^{[23][24][25][26]}

Collectively, these findings indicate that unsaturated fat may have a positive effect on liver fat, especially compared to saturated fat. However, in each of these studies, body weight either did not change (the studies on monounsaturated fat) or increased (the studies on polyunsaturated fat).

A randomized controlled trial in participants with abdominal obesity found that a hypocaloric diet enriched in monounsaturated and polyunsaturated fat (13.4% and 7.7% of energy intake) and reduced in saturated fat (8.3% of energy intake) produced similar reductions in liver fat as a hypocaloric diet that was lower in monounsaturated and polyunsaturated fat (9.3% and 4.1% of energy intake) and higher in saturated fat (14.9% of energy intake).^[27] Although it’s possible that the difference in unsaturated fat intake wasn’t large enough to produce significant differences in liver fat between groups, these findings suggest that the potent effects of energy restriction on liver fat far outweigh the effects of the type of fat consumed.

Two randomized controlled trials have demonstrated that a hypocaloric high-protein diet (30% of energy intake) induces greater reductions in liver fat than a hypocaloric lower-protein diet (10–17% of energy intake), despite similar weight loss between groups.^[28][29] However, carbohydrate intake was reduced to accommodate the increase in protein intake in both studies, so it’s unclear how much of the results are attributable to carbohydrate restriction.

Increasing protein intake (whether through high-protein foods or supplementation with essential amino acids) has also been shown to attenuate the increase in liver fat from a hypercaloric diet.^[30][31] In addition, a study that had women with obesity supplement with whey protein for 4 weeks observed a significant decrease in liver fat without changes in body weight,^[32] but a major limitation of this trial was that it lacked a control group.

Multiple lines of evidence suggest that increasing protein intake could help to reduce liver fat, but further randomized controlled trials are needed to increase confidence in these findings.

Relative to other carbohydrate sources, beverages rich in simple sugars (i.e., glucose, fructose, sucrose) can significantly increase liver fat,^[33][34] potentially even without changes in body weight.^[35][36] Moreover, restricting simple sugar intake effectively decreases liver fat.^[37][38] It’s currently unclear whether restricting simple sugar intake reduces liver fat independent of changes in body weight, but there is some evidence to suggest that it might.^[39][40]

Glycemic index is another factor that may influence the effect of carbohydrates on liver fat,^[41] but there is very little research on this topic. In an exploratory 7-day randomized crossover trial, a eucaloric high-glycemic index diet increased liver fat compared to a eucaloric low-glycemic index diet in healthy young men.^[42]

Concerns are often raised about the potential of fruit to increase liver fat due to its high sugar — particularly fructose — content.

A randomized controlled trial found that a fruit-rich diet (9.58 grams of fruit per kilogram of body weight per day) did not affect body weight or liver fat in healthy participants.^[43]

In contrast, another randomized controlled trial found that a fruit-rich diet (about 7 servings of fruit per day) increased liver fat in participants with NAFLD. However, the participants also gained 7 kilograms of body weight, on average,^[44] so all this study indicates is that a hypercaloric diet increases liver fat; it says nothing about whether a high intake of fruit is detrimental for people with NAFLD.

As it stands, there is an absence of evidence to indicate that a fruit-rich diet has adverse effects on liver health. In contrast, fruit can be an important component of a healthy diet: it’s rich in vitamins, minerals, polyphenols, and fiber, and the consumption of multiple servings of fruit per day is consistently associated with a reduced risk of several diseases.^[45]

As alluded to above, the best diet for people with NAFLD is virtually any hypocaloric diet that suits the individual’s preferences and facilitates a weight loss of at least 5%, preferably ≥10%, as more weight loss is associated with improved outcomes.^[46] However, significant weight loss is difficult to achieve, which begs the question of whether dietary adjustments can improve liver health independent of changes in body weight.

Several societies recommend the Mediterranean diet for people with NAFLD.^[1][47][48] A Mediterranean diet has been consistently shown to improve cardiovascular health.^[49] In addition, evidence from mechanistic studies and a couple of randomized controlled trials in humans suggests that a Mediterranean diet may reduce liver fat independent of changes in body weight.^[50][51][52]

Other evidence suggests that under eucaloric conditions, a low-fat, low-saturated fat diet (16–25% of energy from fat; 5–7% of energy from saturated fat) may reduce liver fat compared to a high-fat, high-saturated fat diet (45–56% of energy from fat; 25–28% of energy from saturated fat).^[53][54]