The Role of Life Style Modifications in Comprehensive Non‐Alcoholic Fatty Liver Disease Treatment

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Abbreviations

ATL

alanine aminotransferase

DASH

dietary approach to stop hypertension

IF

intermittent fasting

IR

insulin resistance

MRS

magnetic resonance spectroscopy

NAFLD

nonalcoholic fatty liver disease

NASH

nonalcoholic steatohepatitis

TG

triglyceride

US

ultrasound

VLCD

very low‐calorie diet

Nonalcoholic fatty liver disease (NAFLD) is an umbrella term encompassing distinct histological conditions: nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). Discussing the etiology of NAFLD and differences between NAFL and NASH provides a foundation for patient understanding. Given the association with poor health outcomes when compared with the general population and the variable continuum of NAFLD and NASH in each person, long‐term follow‐up of both conditions is essential.

Because there are currently no FDA‐approved medications for NAFLD, the cornerstone of treatment rests on management of the metabolic syndrome, dyslipidemia, type 2 diabetes, and obesity. ¹ Emphasizing the importance of lifestyle changes and assessing readiness for change represent the start of an NAFLD treatment plan. Although NAFLD trials may be limited by the lack of a systematic approach to lifestyle modifications, providers rely on these clinical trials to guide their recommendations. ²

Diet

Several dietary intervention studies, with varied endpoints, have shown benefits in weight loss and NAFLD (Table 1). In one of the largest prospective studies from Cuba, 293 people with NASH underwent calorie reduction of 750 kcal/day for 52 weeks, resulting in an average weight loss of 4.6 kg ± 3.2 kg and either no change (65%) or improvement (19%) of fibrosis. ³ In those losing ≥10% of total body weight, NASH resolved in 90%, and 45% had fibrosis regression. Resolution of NASH was seen in 25% of the group and correlated positively with weight reduction (Fig. 1).

TABLE 1.

Diets and Reported Outcomes in Lifestyle Intervention Trials for NAFLD

Type of Diet	Weight Loss	Lower ALT	Improved IR	Lower Glucose Levels	Improved NAFLD (US)	Improved Hepatic TG (MRS)	Improved NAFLD (biopsy)	Improved NASH (biopsy)
Low calorie (~1200‐1500 kcal/day)	✔	✔			✔	✔	✔	✔
VLCD (450 kcal/day)	✔				✔
VLCD (800 kcal/day)	✔				✔
Low carbohydrates (<20%‐45%)	✔	✔	✔	✔	✔	✔	✔
Low fat (20%‐27%)	✔	✔		✔		✔	✔	✔
DASH diet (fruits, vegetables, whole grains, low‐fat dairy, low in saturated fats, cholesterol, refined grains, and sweets)	✔	✔	✔		✔		✔
Mediterranean diet	✔		✔		✔
IF	✔		✔

References: Hallsworth K, Adams LA. Lifestyle modification in NAFLD/NASH: facts and figures. JHEP Rep 2019;1:468‐479; Kenneally S, Sier JH, Moore JB. Efficacy of dietary and physical activity intervention in non‐alcoholic fatty liver disease: a systematic review. BMJ Open Gastroenterol 2017;4:e000139; Vilar‐Gomez E, Martinez‐Perez Y, Calzadilla‐Bertot L, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology 2015;149:367‐378.e5; Glass O, Filozof C, Noureddin M, et al. Standardization of Diet and Exercise in Clinical Trials of NAFLD‐NASH: Recommendations from the Liver Forum. J Hepatol 2020. Available at: https://doi.org/10.1016/j.jhep.2020.04.030.

Abbreviations: ALT, alanine aminotransferase; DASH, dietary approach to stop hypertension; IF, intermittent fasting; IR, insulin resistance; MRS, magnetic resonance spectroscopy; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; TG, triglyceride; US, ultrasound; VLCD, very low‐calorie diet.

FIG 1.

Histology improvement of NASH with weight loss. ³ .

Although calorie intake is often reported in clinical trials, dietary composition is also an important factor. In a meta‐analysis of 24 trials of lifestyle interventions for NAFLD, six trials tested diet alone and among these were very low‐calorie diets (VLCDs) of 450 or 800 kcal/day, diets with low carbohydrate intake of <20 g/day, and trials using a low‐calorie “dietary approach to stop hypertension”(DASH) diet. ⁴ The VLCD had the highest weight loss, averaging 9%, whereas others averaged 5.4%. Weight loss improved aminotransferase levels. In three trials where NAFLD was measured either by ultrasound (US) features or hepatic triglyceride (TG) content on magnetic resonance spectroscopy (MRS), all three trials showed NAFLD improvement with weight loss (Table 1).

A Mediterranean diet (high in monounsaturated fats), when compared with an isocaloric low‐fat, high‐carbohydrate diet, showed no difference in weight loss between the groups; however, the Mediterranean diet resulted in both improved hepatic steatosis and improved insulin sensitivity. ⁵ Ketosis in obese individuals promotes weight loss and improves insulin sensitivity. ⁶ Studies evaluating low‐calorie ketogenic diets showed improvement in hepatic steatosis based on imaging and aminotransferases, but these studies were of short duration. Intermittent fasting (IF) regimens have gained popularity as a simpler means to reduce daily caloric intake with the added benefit of modifying hormonal components of obesity by improving insulin resistance (IR). ⁶ Different IF regimens include time‐restricted feeding, alternate day fasting, or periodic fasting a few times a week. Controlled trials are needed to establish the role of IF in NAFLD.

Exercise

Exercise helps maintain weight loss, benefits cardiovascular health, and reduces hepatic and visceral adiposity. ⁵ Six of 24 trials in a meta‐analysis combined dietary intervention and exercise. ⁴ In five of the six trials, a range of 4.4% to 8.8% of total weight loss was noted. NAFLD improved on biopsy and by imaging. In the same meta‐analysis, 10 of 24 studies looked at exercise alone. Aerobic exercise led to NAFLD improvement by aminotransferases and MRI. Resistance training is also beneficial in NAFLD. ⁵ Physical activity of more than 150 min/week or increasing activity by more than 60 min/week reduced aminotransferases regardless of weight loss. ¹

Multidisciplinary interventions in one study incorporated diet and exercise education, weekly one‐on‐one meetings to review food and exercise logs, and individualized discussions aimed at realizing weight loss goals. ⁷ Participants had 9% weight loss and improvement in NASH histology, showing that weight loss is achievable in a study environment. Together, moderate dietary restriction with moderate‐intensity exercise is effective in achieving goal weight loss of 5% to improve NAFLD and 7‐10% to improve NASH features ⁴ (Table 2).

TABLE 2.

Exercise and Activity in NAFLD ⁴

Moderate‐intensity exercise:	Moderate effort Noticeable acceleration of heart rate Increased rate of breathing Able to hold a conversation
Examples:	Brisk walking Taking stairs Using a cross trainer Gardening Vigorous housework
High‐intensity exercise:	Large effort Substantial increase in heart rate Rapid breathing Less able to hold a conversation
Examples:	Running Fast cycling
Activity recommendations for NAFLD: 30‐60 minutes of moderate‐intensity exercise 3‐5 days per week

Beverages

High‐calorie, sugar‐sweetened beverages are associated with weight gain. Fructose specifically upregulates de novo hepatic lipogenesis, leading to IR. ⁵ It is recommended to eliminate these beverages in NAFLD. ² Coffee has been studied in NAFLD given it lowers aminotransferases and reduces fibrosis in alcohol‐related liver disease and hepatitis C. ⁸ In a large cross‐sectional study of NAFLD, there was an inverse proportion of coffee consumption and hepatic fibrosis. Heavy alcohol use in the setting of NAFLD and obesity adds to caloric intake and places individuals at higher risk for liver‐related morbidity, including increased risk for hepatocellular carcinoma. Several cross‐sectional studies suggest a possible benefit of light alcohol consumption on NAFLD, but this may be confounded by the lower rates of obesity seen in moderate drinkers. ¹ Longitudinal studies addressing the possible benefit of light drinking on NAFLD and the cardiovascular and cancer risks are needed.

Sleep, Stress, and Smoking

Sleep deprivation is associated with obesity through mechanisms regulating glucose metabolism, energy expenditure, and increased appetite. ⁹ Inadequate sleep promotes a proinflammatory state that negatively impacts insulin regulation. Stress can lead to obesity through increased intake of highly palatable, energy‐rich foods, cortisol production, and subsequent visceral adiposity. ⁹ In a large cohort study, cigarette smokers showed an increased incidence and severity of NAFLD in a dose‐dependent fashion. ¹⁰ The mechanism is not known, however, but may be due to nicotine‐mediated oxidative stress and hepatic lipogenesis. Given the connections with inflammation, IR, and obesity, the impact of sleep, stress, and smoking in NAFLD bears continued study.

Summary

There are many reasons to promote lifestyle modifications for NAFLD as the first and, perhaps, best therapy (Fig. 2). Clinical trials for NAFLD show that adoption of healthy behaviors is possible in a study environment. Standardization of lifestyle interventions in future trials will allow for improved outcome assessment and help clarify which recommendations are most effective. ² Success beyond clinical trials is attainable but may be challenging because of barriers, including provider‐perceived limitations in training, time, and resources to help long‐term behavior change. ⁵ Although lifestyle changes are difficult to initiate and to maintain, several of these interventions are achievable, and their benefits on general health and NAFLD are worth a detailed and sustained discussion (Table 3).

FIG 2.

Lifestyle recommendations for NAFLD. Adapted from JHEP Reports. ⁵

TABLE 3.

Key Points for Talking to Patients With NAFLD

Treatment of obesity, IR, and metabolic syndrome is important because these are associated with NAFLD. Weight loss of 5% in NAFLD and 7%‐10% in NASH is beneficial and improves hepatic steatosis and inflammation in NASH. Moderate dietary restriction with moderate‐intensity exercise for 30‐60 minutes for 3‐5 days/week can lead to the weight loss goals needed for NAFLD. A variety of diets and behavior modifications can lead to improved health and weight loss, which improve NAFLD.