Diet
Although it seems intuitive that certain elements of diet and weight control would predispose specific populations to NAFLD, the literature that explores these factors is more recent. Overall, increased intake of saturated fats, fructose, and cholesterol-rich sources predisposes individuals to NAFLD.85 Although evidence currently is limited, sedentary behavior has been increasingly accepted as an independent risk factor for NAFLD.86 As an example to the beneficial effect of physical activity, aerobic exercise that contributes to progressive increase in fat-free, lean mass can provide protection against NAFLD. Dietary elements typical of the Western Diet in addition to Western eating habits, such as snacking, have been shown to independently contribute to hepatic steatosis.87 Soft-drink consumption, rampant in the West, has been shown to increase liver fat by 140% over a period of 6 months in otherwise healthy individuals.88 Relatedly, it was found that a diet of 3 g fructose/kg increases the amount of hepatic fat in adult men.89
Limiting consumption of carbohydrates has generally been noted to improve NAFLD;90 however, if carbohydrates are examined overall, a focus on ethnic diet variations presents a more complicated picture. For example, the traditional Chinese diet is high in carbohydrates but is also vegetable-rich and has proven to be low-risk for NAFLD. Consistent with earlier mentioned data, a more recent study noted that “Westernization” of South Korean food, via refined grains, processed meats, fried foods, etc., correlated with increased incidence of NAFLD diagnosed by ultrasound.91 Such regions have also noted that weight gain in general, irrespective of diet, seems to predispose people to NAFLD in certain regional studies. Korean studies have noted that weight gain as low as 2 kg can contribute to NAFLD development.92 More specifically, data from Hong Kong reported that the presence of central obesity predisposes patients to NAFLD.93
Variations and similarities in the standard diet within a geographic region or amongst individuals of a particular ethnic background has allowed researchers to investigate the different nutritional patterns that promote hepatic steatosis and the progression of NAFLD, as well as whether a specific diet affects disease progression differently in patients of various backgrounds. Ultimately, this informs healthcare providers when counseling patients with NAFLD on ideal eating habits, and whether recommendations can be generalizable to individuals of various ethnicities.
The Western dietary pattern, containing large amounts of red meat, processed meat, and fried foods, has a well-established link to the development of MS.94 Unfortunately, this diet has established itself and its associated adverse health consequences globally. A study of 170 Iranians with NAFLD evaluated the effects of an Iranian, Western and “healthy dietary patterns” on liver fibrosis. The Western dietary pattern was strongly associated with fibrosis, with an odds ratio of 4.21. The investigators noted that higher consumption of red meat, hydrogenated fats, and soda drinks increased the odds of fibrosis measured by elastography, while a diet rich in low-fat diary, nuts, fruit, and coffee or tea was protective.95 Interestingly, the positive association between a Western diet and NAFLD was not replicated in a prospective cross-sectional study of 1,190 Korean patients with and without NAFLD. Four dietary patterns and their association with a diagnosis of hepatic steatosis were analyzed, including a traditional Korean diet, Western and high-carbohydrate diets, and a simple meal pattern diet. As previously mentioned, this study revealed no association between a Western or carbohydrate-rich diet and the presence of NAFLD, while a traditional Korean diet was positively correlated with presence of the disease.96 While the absence of an association between increased carbohydrate intake and NAFLD is somewhat surprising, data from other studies have been inconsistent with regards to the effect of carbohydrate intake. Patients who were on a 2-week carbohydrate-restricted diet had similar weight loss but more hepatic fat reduction than patients who were on a reduced calorie-only diet.90 However, another study demonstrated similar improvements in hepatic steatosis between patients on a high-carbohydrate diet and low-carbohydrate diet when weight loss was comparable,97 suggesting that the true benefit of carbohydrate restriction on NAFLD arises primarily when it is linked to weight reduction. However, a low carbohydrate diet in patients with NAFLD has been associated with a decrease in alanine aminotransferase, although the diet was primarily soy-based.98
In contrast to the Korean dietary study and similar to findings of the Iranian investigators, a study out of Greece confirmed the increased odds of NAFLD with a fast-food type dietary pattern, while also confirming that when unsaturated fatty acid intake was divide into quartiles, those in the second quartile had an over 50% reduced odds of NAFLD compared to individuals within the first quartile of dietary intake.99 With respect to fats, a potential therapeutic strategy includes increased consumption of both mono-unsaturated fatty acids and poly-unsaturated fatty acids. Increased intake of poly-unsaturated fatty acids results in greater reduction in hepatic steatosis when used in combination with a heart healthy diet compared to dieting alone.100 In fact, a meta-analysis has found that omega-3 fatty acids derived from seafood sources have a positive effect on hepatic steatosis.101
Given the increased popularity and presence globally of the Western style diet, the above data generally seem to suggest a benefit to avoiding this type of nutritional behavior. In fact, a study assessing patients (Framingham Heart Study), consisting primarily of Caucasian patients in the USA reinforced the benefits of focusing on alternative diets for liver fat accumulation. The study investigated how changes in the Mediterranean-style diet score and Alternative Healthy Eating Index affected liver fat and new-onset fatty liver. An increase in either dietary score was inversely associated with liver fat accumulation and incident NAFLD, with a reduction in the odds of fatty liver by 26% for every 1-standard deviation increase in Mediterranean-style diet score. Moreover, individuals with a higher genetic predisposition to NAFLD as determined by single nucleotide polymorphisms and decreased Mediterranean-style diet score or Alternative Healthy Eating Index scores had higher liver fat compared to patients with improved or stable scores.102 Thus, adopting the Mediterranean diet, typically characterized by high intake of olive oil, nuts, fruits, vegetables, legumes, and fish, with wine in moderation, can be suggested to patients with NAFLD, especially given the broad health benefits related to a variety of different health conditions related to MS. Despite heterogeneity in the way the Mediterranean Diet is defined in different studies, it has consistently shown favorable health outcomes.103 Studies from multiple regions of the world have reported a marked regression of NAFLD when patients switched to the Mediterranean Diet,104 reinforcing its broad appeal regardless of patient ethnicity. A large randomized control trial to evaluate the benefit of this diet, independent of weight loss, is currently underway in Australia.105
With respect to protein intake, it seems that a diet consisting of a larger proportion of protein does not necessarily aid in improvement of NAFLD. However, a moderate protein diet encompassing 25% of total caloric intake has been shown to be optimal, and higher percentages do not necessarily reduce body fat content any better.106
Ultimately, the guidance provided by a patient’s healthcare provider is key to successful changes in dietary habits that can ultimately improve or reverse hepatic steatosis. Studies show that patients will make better nutritional choices after having expressed better understanding of what NAFLD is, reinforcing the importance of patient education. Moreover, as a preventative measure, recommending dietary patterns that reflect an adherence to a healthy diet can reduce NAFLD risk in the general population. An analysis of the multiethnic cohort consisting of patients of African American, Japanese American, Latino, Native Hawaiian, and Caucasian descent revealed that high Healthy Eating Index and Dietary Approaches to Stop Hypertension scores were associated with lower risk of fatty liver, with no observed differences by race or ethnicity.107 However, a more recent analysis of the same cohort focused on the specific components of enrollees’ diets at baseline and association with NAFLD. Overall, when comparing 2,974 patients with NAFLD and 29,474 matched controls, intake of poultry, cholesterol, processed red meat and red meat in general was associated with NAFLD. When stratified by race and ethnicity, poultry intake and cholesterol intake was only significantly associated with NAFLD in Whites and Native Hawaiians. Processed red meat correlated significantly with NAFLD in Latinos and Whites, and increased fiber intake was protective in these two ethnic groups.108 The damaging effects of red meat consumption and the associated risk of NAFLD was further demonstrated in a cross-sectional study of 789 adults. After controlling for BMI, smoking, alcohol intake, physical activity, energy and saturated fat and cholesterol intake, the consumption of meat in general and red or processed meat was associated with increased odds for insulin resistance and NAFLD.109 Thus, while an overall healthy diet is recommended for all patients, with the ultimate goal of achieving meaningful weight loss, a specific list of foods to avoid may be tailored to a patient based on race and ethnicity.
Intermittent fasting has recently gained popularity as an alternative to more traditional diets, aimed at reducing weight and improving obesity-related comorbidities. It includes diets that focus on a particular eating pattern where caloric intake is eliminated during a predefined period of time, and has consistently proven beneficial for both weight loss and reduction in obesity-related comorbidities.110 A randomized controlled trial assessing a modified alternative-day calorie restriction diet, another form of intermittent fasting, found that adherence to this diet amongst patients with NAFLD was excellent (75–83%) with a significant reduction in liver steatosis and fibrosis (measured by shear wave elastography) amongst individuals randomized to 8 weeks of the intervention diet arm.111
Physical activity
Exercise as an intervention in NAFLD has also been studied, although the data concerning its benefits independent of the weight loss requires further clarification. Studies have noted a 20–30% decrease in hepatic lipid content with general exercise. Interestingly, even when these patients regain lost weight, there seems to be a persistent long lasting beneficial effect on liver fat and insulin resistance.112 Aerobic exercise has been shown to reduce hepatic triglycerides in sedentary and obese patients.113 Weight resistance exercise has also been linked to a reduction in hepatic steatosis without weight loss.114 Although evidence on aerobic vs. resistance training is mixed, combination therapy seems to be superior to either. However, weight loss was a confounder when comparing aerobic with resistance exercise and a combination of the two,115 and thus these recommendations require further investigation prior to unlinking their benefits to weight loss alone.
Non-obese patients with underlying NAFLD or NASH can be more challenging to manage in the absence of approved pharmacotherapy. As mentioned previously, the strongest evidence for the management of NAFLD and NASH comes from studies focused on interventions that achieve weight loss and increased physical activity. While implementing these interventions intuitively makes sense in obese individuals or those with other components of MS, it is less obvious for those considered within normal BMI range, which has been more commonly seen in patients of east Asian background.116 However, a study examining the effect of diet modification and exercise on hepatic steatosis in 1,365 potential living donors with NAFLD on initial biopsy revealed that although only 5% of patients were obese at the start of the study, histological improvement on repeat biopsy was observed in 85.8% of participants.117 Some of these findings may, in part, be related to the response to weight loss seen with variants of the PNPLA3 alleles. More specifically, the GG genotype that is more commonly observed in Asian patients with “lean NAFLD” has been linked to a favorable histologic response to diet modification leading to weight loss. Thus, despite the challenges associated with recommending weight loss to patients with a normal BMI, interventions that reduce weight are likely to be beneficial in this patient population. Moreover, although “lean NAFLD” is well recognized in patients of Asian background, with prevalence as high as 19% in Asia compared to 7% in the USA, this phenotype is now increasingly recognized in other races. In fact, a large Swedish cohort with 646 patients with biopsy-proven NAFLD, the “lean NAFLD” prevalence was reported as 19%,118 identical to estimates from Asia, making these recommendations more generalizable than previously thought.
Studies assessing the efficacy of caffeinated beverages have shown consistent results. Overall, while the majority of studies do not show any significant improvement in steatosis with increased caffeine intake, coffee and other caffeinated beverages may have a protective effect against the development or presence of fibrosis.119 An analysis of the multiethnic cohort evaluating the association between coffee intake and chronic liver disease and HCC revealed an inverse association between increased coffee consumption and the incidence of HCC or chronic liver disease. In fact, consuming ≥4 cups of coffee a day was associated with a 41% reduction in HCC and a 71% reduction in chronic liver disease, when compared to non-coffee drinkers. This association did not differ based on patient race or ethnicity. Given the risk of HCC associated with NAFLD, including in the absence of cirrhosis, a balanced increase in coffee intake may be beneficial regardless of race.120