Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common chronic liver disease globally and is independently associated with an increased risk of Type 2 Diabetes (T2DM) and cardiovascular diseases. Approximately one-third of the global population is currently facing the health threat posed by NAFLD, yet it appears that healthcare systems are not giving it enough attention. On the first day of the 58th Annual Meeting of the European Association for the Study of the Liver (EASL 2023) and the EASL Congress 2023, Doctor Elisabetta Bugianesi from the Department of Digestive Internal Medicine at the University of Turin, Italy, urged the public to take NAFLD seriously. She provided a detailed overview of lifestyle interventions as a key means of preventing and treating NAFLD, sharing the latest research evidence, guideline recommendations, and future strategies. Hepatology Digest has compiled this report for the benefit of its readers.
Non-Alcoholic Fatty Liver Disease (NAFLD) encompasses a spectrum of liver conditions, ranging from Non-Alcoholic Fatty Liver (NAFL) to Non-Alcoholic Steatohepatitis (NASH) and liver fibrosis, with liver fibrosis being the primary cause of progression to cirrhosis and hepatocellular carcinoma (HCC). NAFLD patients often have comorbidities like obesity and/or diabetes. Obesity and Type 2 diabetes can influence the progression of NAFLD, making patient stratification essential for identifying and implementing new therapeutic interventions to improve liver health. Currently, there are no approved drug treatments, making lifestyle improvements a necessary step for both adults and children.
1. Raising Awareness and Enhancing Preventive Measures
The clinical burden of NAFLD extends beyond liver-related morbidity and mortality. It also includes a range of other prevalent non-communicable diseases that can increase the incidence of NAFLD. NAFLD is a well-established predictor of metabolic syndrome, T2DM, cardiovascular diseases, and certain extraneous liver tumours.
The global prevalence of NAFLD has increased by 50%, from 25% between 1990 and 2006 to 38% between 2016 and 2019. The regions with the highest NAFLD prevalence are Latin America (44%), followed by the Middle East and North Africa (36%), South Asia (33%), Southeast Asia (33%), North America (31%), East Asia (29%), the Asia-Pacific region (28%), and Western Europe (25%). Moreover, approximately one-fifth of NAFLD patients progress to NASH. Despite its high prevalence and close association with obesity and metabolic syndrome, NAFLD still appears to lack the global health attention it deserves.
All complications related to NAFLD impose significant health, economic, and experiential burdens on patients, their families, and society as a whole. Additionally, there is no global strategy for NAFLD and NASH treatment that calls for increased allocation of medical resources to address the disease. Therefore, it is essential to establish multidisciplinary teams that focus on health plans, including improving patient awareness and compliance, as most NAFLD patients do not perceive themselves as being in a diseased state.
2. Starting with Children: Promoting Healthy Lifestyles to Prevent NAFLD
NAFLD is an early-onset disease, and with the increasing prevalence of overweight and obesity, it is becoming more prevalent in children and adolescents. Research suggests that obese children have an increased risk of liver-related mortality in their later lives. Therefore, the first step in preventing NAFLD is to combat obesity by promoting physically active and healthier dietary lifestyles.
Monitoring childhood obesity throughout the lifecycle is crucial. Currently, children tend to adopt unhealthy dietary patterns, characterized by increased consumption of high-sugar, ultra-processed foods, and reduced intake of fiber-rich foods such as fruits, vegetables, and whole grains. Marketing plays a significant role in promoting the consumption of energy-dense foods rich in saturated fat, trans fat, added sugars, and salt, while offering little nutritional value.
There is limited evidence from randomized controlled trials regarding the effect of lifestyle interventions for pediatric NAFLD treatment. However, there is evidence to suggest that a combination of diet and increased physical activity yields beneficial results. In a systematic review and meta-analysis of 19 studies involving 923 participants aged 6 to 18, where NAFLD was primarily diagnosed through ultrasound, interventions included aerobic exercise and dietary changes. Lifestyle modifications did not significantly impact BMI (combined RR = -0.82; 95% CI: -1.26 to -0.37), but they significantly reduced liver fat by 61% (combined RR = 0.039; 95% CI: 0.27 to 0.56). Therefore, even in patients who did not experience significant weight loss, lifestyle adjustments resulted in improvements in NAFLD markers.
It is crucial to raise public awareness about the preventable and treatable nature of many liver diseases, especially during childhood. Initiatives aimed at addressing unhealthy diets, lack of physical activity, and alcohol consumption are essential for achieving positive outcomes. Similarly, focusing on schools, providing healthy school lunches, and necessary physical activities, increasing community involvement, and developing well-equipped and safe communities will help prevent these diseases.
3. Improving Lifestyle Leads to Histological Benefits
Histologically, NAFLD is typically divided into two categories: 1) NAFL, also known as simple steatosis, and 2) NASH, where the presence of liver fat is accompanied by liver cell damage and inflammation with or without fibrosis. In this sense, weight reduction has also shown benefits in reducing histological activity and fibrosis. A study of 293 confirmed NAFLD patients from a tertiary medical center in Havana, Cuba, revealed that a 52-week lifestyle intervention resulted in weight loss of more than 5% and 10%, improving NASH by 58% and 90%, respectively. Among those who achieved a weight loss of over 10%, 45% experienced fibrosis reversal.
Indeed, a meta-analysis of 43 studies, including 2809 participants, showed that weight loss of 1 kg was associated with a reduction in liver fat by 0.03 percentage points (95% CI: 0.02% to 0.04%, P < 0.0001, I2 = 77%, n = 12). For each 1 kg of weight loss, alanine aminotransferase (ALT) decreased by 0.83 U/L (95% CI: 0.53 to 1.14, P < 0.0001, I2 = 92%, n = 18), and aspartate aminotransferase (AST) decreased by 0.56 U/L (95% CI: 0.32 to 0.79, P < 0.0001, I2 = 68%, n = 11). A decrease of 0.77 percentage points (95% CI: 0.51 to 1.03, P < 0.0001, I2 = 72%, n = 11) was observed in radiological or histological assessment of liver fat with each 1 kg of weight loss. Furthermore, there was a dose-response relationship between weight loss and liver inflammation, steatosis, and ballooning. Histologically, NASH resolution occurred in 66% of participants with >10% weight loss, 25% with 5-10% weight loss, and 10% with <5% weight loss.
Moreover, exercise has a positive effect on NAFLD outcomes. A systematic review and meta-analysis of 31 randomized controlled trials involving 1,405 NAFLD patients found that exercise significantly reduced liver fat (-2.06%, 95% CI: -3.32 to -0.80, P = 0.001, I2 = 89%) and ALT (-7.21 U/L, 95% CI: -12.59 to -1.83, P = 0.009, I2 = 94%). Subgroup analyses demonstrated that resistance training and combined training (aerobic and resistance) showed the greatest effect on liver fat reduction.
4. Nutrition: A Key Component in Preventing and Treating NAFLD
Nutrition is a crucial factor in NAFLD prevention and treatment. Research has shown that a balanced diet can help reduce liver fat, inflammation, and fibrosis, and even lead to NASH resolution. A study of 293 confirmed NAFLD patients from Havana, Cuba, reported that a 52-week lifestyle intervention, including a balanced diet, led to NASH resolution in 58% of participants and fibrosis reversal in 45% of those who achieved a weight loss of over 10%. Dietary strategies should aim to lower energy intake, especially from sugar, and focus on reducing saturated and trans fats while increasing the consumption of unsaturated fats, fruits, vegetables, whole grains, and legumes.
There is a growing body of evidence supporting the beneficial effects of certain diets in NAFLD. These include the Mediterranean diet, the Dietary Approaches to Stop Hypertension (DASH) diet, and the Ketogenic diet. In a randomized controlled trial of 100 NAFLD patients, the Mediterranean diet demonstrated significant improvements in liver enzymes, weight loss, and histological resolution of NASH compared to a standard low-fat diet. The DASH diet, which emphasizes whole grains, fruits, vegetables, and lean protein, has also shown positive effects on liver health. A study of 24 NAFLD patients on the DASH diet for eight weeks found significant reductions in liver fat content and ALT levels compared to a control group on a typical American diet. Additionally, the Ketogenic diet, which restricts carbohydrate intake and promotes fat consumption, has demonstrated improvements in liver fat, ALT levels, and weight loss in various studies.
It is essential to note that while diet plays a crucial role in NAFLD management, there is no one-size-fits-all approach. Personalized dietary plans, tailored to individual patients’ preferences and metabolic needs, can lead to better adherence and outcomes. Furthermore, nutrition education is a key component of NAFLD management, as it empowers patients to make informed choices about their dietary habits.
5. Physical Activity: An Effective Intervention for NAFLD
Physical activity is a cornerstone of lifestyle interventions for NAFLD. Regular exercise can help reduce liver fat, inflammation, and fibrosis while improving insulin sensitivity and cardiovascular health. Both aerobic exercise and resistance training have been shown to benefit NAFLD patients, and a combination of the two appears to be particularly effective.
Aerobic exercise, such as brisk walking, jogging, cycling, and swimming, can help burn calories and improve insulin sensitivity. A systematic review and meta-analysis of 31 randomized controlled trials involving 1,405 NAFLD patients found that exercise significantly reduced liver fat (-2.06%, 95% CI: -3.32 to -0.80) and ALT levels (-7.21 U/L, 95% CI: -12.59 to -1.83). Subgroup analyses revealed that both aerobic exercise and combined training (aerobic and resistance) were effective in reducing liver fat and ALT levels, with combined training showing a slightly greater effect.
Resistance training, which involves activities like weightlifting and bodyweight exercises, can help build lean muscle mass and improve insulin sensitivity. A meta-analysis of 14 randomized controlled trials involving 744 NAFLD patients found that resistance training significantly reduced liver fat (-2.49%, 95% CI: -3.91 to -1.07) and ALT levels (-6.36 U/L, 95% CI: -10.11 to -2.61).
The combined approach, which includes both aerobic and resistance training, appears to offer the most comprehensive benefits for NAFLD patients. A systematic review and meta-analysis of 10 randomized controlled trials involving 471 NAFLD patients found that combined training resulted in significant reductions in liver fat (-3.84%, 95% CI: -6.20 to -1.47) and ALT levels (-9.27 U/L, 95% CI: -15.07 to -3.46).
In summary, physical activity is a critical component of lifestyle interventions for NAFLD. Both aerobic exercise and resistance training can lead to improvements in liver health, and a combination of the two may be the most effective approach. Healthcare providers should work with NAFLD patients to develop personalized exercise plans that take into account their individual preferences and fitness levels.
6. Beyond Diet and Exercise: Emerging Therapies for NAFLD
While lifestyle modifications are currently the cornerstone of NAFLD management, researchers are actively exploring pharmacological and non-pharmacological interventions to complement these approaches. Some emerging therapies for NAFLD and NASH include:
a. Pharmacological Therapies: Several drugs are being investigated for the treatment of NAFLD and NASH. These include:
– Obeticholic acid (OCA): A farnesoid X receptor (FXR) agonist that has shown promise in improving liver histology in NASH patients.
– Elafibranor: A dual peroxisome proliferator-activated receptor (PPAR) alpha and delta agonist that has demonstrated potential in reducing liver fat and inflammation in NASH.
– Semaglutide: A glucagon-like peptide-1 (GLP-1) receptor agonist that has shown benefits in reducing liver fat and fibrosis in NAFLD/NASH patients with or without diabetes.
b. Bariatric Surgery: Weight loss surgeries, such as gastric bypass and sleeve gastrectomy, have been shown to lead to significant improvements in NAFLD and NASH. These procedures can result in substantial weight loss and metabolic changes that positively impact liver health.
c. Fecal Microbiota Transplantation (FMT): The gut microbiome plays a role in NAFLD development, and FMT is being explored as a potential treatment. Early studies have shown promising results in improving liver enzymes and reducing liver fat.
d. Anti-fibrotic Agents: Fibrosis is a critical factor in NAFLD progression. Various anti-fibrotic agents are under investigation, including cenicriviroc, an inhibitor of chemokine receptor type 2 and 5 (CCR2/CCR5), and selonsertib, a selective inhibitor of apoptosis signal-regulating kinase 1 (ASK1).
It’s important to note that many of these emerging therapies are still in the investigational stage, and their long-term safety and efficacy are being evaluated in clinical trials. Additionally, the management of NAFLD and NASH may require a combination of lifestyle modifications and pharmacological interventions, tailored to individual patient needs.
7. Conclusion
Non-alcoholic fatty liver disease (NAFLD) is a significant public health concern, with a growing global prevalence. It encompasses a spectrum of liver conditions, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) and advanced fibrosis. NAFLD is strongly associated with obesity, insulin resistance, type 2 diabetes, and metabolic syndrome.
Lifestyle modifications are the primary approach to managing NAFLD. These interventions include weight loss through diet and exercise, which can lead to improvements in liver fat, inflammation, and fibrosis. Nutrition plays a pivotal role, with diets such as the Mediterranean diet, DASH diet, and Ketogenic diet showing promise in reducing liver fat and improving liver enzymes. Physical activity, including both aerobic exercise and resistance training, is essential for enhancing insulin sensitivity and reducing liver fat.
Emerging therapies, such as pharmacological agents and bariatric surgery, are being investigated to complement lifestyle interventions. While these therapies hold promise, they are not yet widely adopted as first-line treatments.
Overall, the prevention and management of NAFLD require a multidisciplinary approach, involving healthcare providers, dietitians, and exercise specialists. Patients should receive individualized care, with treatment plans tailored to their specific needs and risk factors. Additionally, ongoing research is crucial to further our understanding of NAFLD and develop more effective interventions for this complex condition.
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