Liver diseases: rethinking food and exercise for a healthy liver

Western countries are experiencing liver diseases at an unprecedented rate, could adopting the Mediterranean diet be the best tool to combat this?

Non-alcoholic fatty liver disease (NAFLD) has quietly reached epidemic levels. A meta-analytic assessment of the global epidemiology of NAFLD estimates that the worldwide prevalence of NAFLD is 25%, with the highest prevalence in the Middle East and South America and the lowest in Africa. NAFLD is currently the most common of liver diseases in Western countries, affecting 17-46% of adults, with differences in prevalence stemming from variables such as the diagnostic method, age, sex and ethnicity. A new report from United European Gastroenterology (UEG), ‘Nutrition and Chronic Digestive Diseases: An Action Plan for Europe’, states that about 75% of obese individuals have a fatty liver, one of the leading causes of NAFLD.

NAFLD is characterised by excessive accumulation of fat in the liver, primarily affecting overweight and obese sectors of society. The disease encompasses two pathologically distinct conditions with different prognoses: non-alcoholic fatty liver (NAFL), which is pure steatosis with or without inflammation, and non-alcoholic steatohepatitis (NASH) that can progress to liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC).

Approximately 20% of NAFL patients may progress to NASH. Liver fibrosis is the most clinically significant feature of NASH and is related with increased risk for mortality. The progression of fibrosis is highly variable and strongly influenced by metabolic risk factors, especially type-2 diabetes. The association of NAFLD with a range of additional diseases and risk factors such as type-2 diabetes, cardiovascular disease (CVD) and its link with significant cardiovascular and liver-related morbidity and mortality, create significant challenges for primary care physicians with regards to the diagnosis and treatment of NAFLD and its comorbidities.

A variety of lifestyle interventions could be useful across the spectrum of NAFLD patients. To improve the success of lifestyle interventions we need to explore beyond total calories to the type of diet, the role of micro and macronutrients and evidence-based benefits of physical activity and exercise. Proven behaviour change models and techniques must also support these modifications.

Added sugar

Added sugars refers to refined sugars (sucrose, fructose and high fructose corn syrup- HFCS) added to sugar sweetened beverages (SSB) and incorporated into food, fruit drinks and other beverages. There is convincing evidence regarding the association between added sugars and NAFLD and this link becomes more prominent with SSB. In the Framingham Heart study cohort, composed of 5908 participants, a dose-response association was observed between soft drinks and fatty liver disease. Daily consumers of SSB had a 61% increased risk of fatty liver disease compared to non-consumers. In contrast, there was no significant association between diet soda intake and liver fat or ALT levels. These findings imply that, like alcohol, questions regarding soft-drink consumption should be part of a patient’s medical history.

A sucrose or fructose rich diet has a variety of other adverse health effects. For example, high consumption of fructose or sucrose can increase the hepatic synthesis of triglycerides, raising the risk of heart disease or stroke. Animal studies have also revealed a link between fructose and an alteration in the gut microbiota, increased gut permeability and hepatic steatosis amongst other conditions. Fructose also promotes uric acid production, which may cause oxidative stress and insulin resistance, increasing the risk of type 2 diabetes. Indeed, epidemiological studies demonstrated that serum uric acid was associated with the development of cirrhosis and NAFLD.

Mediterranean diet tackling liver diseases

The Mediterranean diet includes a high intake of olive oil, vegetables, fruits, nuts, legumes, whole grains, fish and seafood, and a low intake of red or processed meat. Interestingly, recent studies indicate a possible association between high meat intake and NAFLD, with an increasing level of specificity starting from high animal protein intake and pointing to meat, to meat in general, to specifically red and processed meat intake. The Mediterranean diet has been recommended for the treatment of NAFLD by The European Association for the Study of the Liver (EASL)-European Association for the Study of Diabetes (EASD)-European Association for the Study of Obesity (EASO) Clinical Practice Guidelines due to its established superiority in long-term weight reduction over low fat diets. It also improves metabolic status and steatosis without weight reduction.

New large prospective observational studies support the association of NALFD with healthy eating patterns, which includes the Mediterranean diet. In a multi-ethnic cohort that contained almost 2,000 participants, adherence to healthy eating patterns (Mediterranean diet, Healthy Eating Index etc.) was related to a lower amount of liver fat. Specifically, those in the upper tertile of healthy eating pattern scores had only half the risk of NAFLD compared with the participants in the lower tertile.

Similarly, among 1,521 participants of the Framingham cohort, increased adherence over time to two healthy eating patterns, the Mediterranean diet and the Alternative Healthy Eating Index, was associated with a reduced amount of liver fat and a reduction in the incidence of NAFLD by 21-26% for each standard deviation increase in the diet indexes during follow-up. Findings also suggested a gene-diet interaction; higher genetic risk for NAFLD was not associated with increased liver fat accumulation in those who had stable or improved healthy eating patterns. These results emphasise that a healthy diet may be important in those with a genetic predisposition for NAFLD.

The beneficial effect of the Mediterranean diet in NAFLD, even with minimal or no weight loss, and its superiority over other diets, has also been supported by randomised control trials (RCTs). An eighteen-month RCT among 278 adults demonstrated the superiority of a low carbohydrate version of the Mediterranean diet over low-fat diets in decreasing intra-hepatic fat, despite a similar degree of weight loss in the two groups. Studies have also shown that adherence to the Mediterranean diet is higher in comparison to low-fat diets.

Role of dietary composition in the risk for transition from NASH to HCC

The increasing incidence of NAFLD/NASH has subsequently led to a dramatic rise in NASH-related HCC incidence. Despite this concerning trend, little is currently known about the association between dietary composition and HCC in humans, which could be a crucial mechanism in the reduction of HCC risk. Evidence for a potential association between dietary composition and HCC has been provided by several large prospective studies.

In a population-based prospective cohort study of 90,296 Japanese subjects, consumption of n-3 PUFA-rich fish and individual types of n-3 PUFAs was inversely associated with HCC. In another prospective cohort of 9,221 American participants of the first National Health and Nutrition Examination Survey, high cholesterol intake but not total fat consumption was associated with a higher risk of cirrhosis or liver cancer. In agreement with that, high consumption of red and processed meats and specifically saturated fat was also demonstrated to increase the risk for HCC. Additionally, amongst 477,206 participants of the European Prospective Investigation into Cancer and Nutrition cohort, the risk for liver cancer was increased by 43% per 50g/day of total sugar and was reduced by 30% 10g/day of total dietary fibre.

Accordingly, in a meta-analysis of observational studies, the intake of vegetables, but not fruit, was associated with a lower risk of hepatocellular carcinoma, which decreased by 8% for every 100g/day increase in vegetable intake. These findings confirm the beneficial aspects of the Mediterranean diet, which is based on the high consumption of fish, low consumption of red and processed meats, high consumption of vegetables and fibre, with a low consumption of sugar. Indeed, adherence with the Mediterranean diet has been demonstrated to have a protective association with HCC in a large case-control study.

An additional way to reduce HCC risk is by drinking coffee. According to animal studies, coffee exerts reduction in hepatic fat accumulation, systematic and liver oxidative stress and liver inflammation. Caffeinated and decaffeinated coffee is also associated with reduced diabetes risk in a dose-response manner. Epidemiological studies in NAFLD patients repeatedly suggested an inverse association between coffee consumption and liver fibrosis and HCC. A recent prospective cohort study also supports the protective role of coffee in HCC prevention.

A US multi-ethnic cohort that included 162,022 participants, demonstrated that compared with non-coffee drinkers, those who drank 2-3 cups per day had a 38% reduction in risk for HCC and those who drank ≥4 cups per day had a 71% reduction. The inverse associations were significant regardless of the participants’ ethnicity, sex, body mass index, smoking status, alcohol intake, or diabetes status.

Although the association between diet and liver cancer appears to be of importance, the results of these observational studies should be confirmed in additional prospective studies specific for NAFLD patients, carefully controlling other dietary and lifestyle-related potential confounders.

Liver diseases: summary and conclusions

Lifestyle change, including dietary habits and physical activity are the first line treatment in NAFLD and NASH. Weight reduction is the most established treatment for both NAFLD and NASH, with a clear dose-response association. Any generally healthy diet (low-fat, low carbohydrate or Mediterranean diet, all low in sugar and saturated fat), which will lead to caloric reduction and is acceptable by the patient, should be encouraged.

For those who find caloric restriction challenging, changing dietary composition without necessarily reducing caloric intake may offer a more feasible alternative, although the benefit to liver health is not as marked as weight reduction. The importance of weight loss is highlighted in people with NASH where weight loss of >7% is associated with a clinically meaningful regression of disease status. Exercise produces significant changes in liver fat. However, given the strong cardiovascular benefits of exercise, the optimal placement for exercise is likely as an adjunct to dietary manipulation, whether in NAFLD or NASH.

Combined, this evidence strongly supports the role of lifestyle as a primary therapy for the management of NAFLD and NASH. The question is no longer whether lifestyle is an effective clinical therapy; the question is now how do we implement lifestyle as a therapy in everyday clinical care. It is integral that we start thinking differently about nutrition and fitness. Instead of counting calories, we should focus on the ingredients going into the preparation of the foods we eat. Cutting back on our intake of heavily processed foods, sweetened beverages, alongside an active lifestyle, are key to a healthy liver.

Professor Shira Zelber-Sagi, BSc, RD, PhD
Head of Nutrition, Health and Behavior Program
School of Public Health
University of Haifa
Department of Gastroenterology and Hepatology
Tel-Aviv Medical Center
UEG Public Affairs Committee

Please note, this article will appear in issue 10 of Health Europa Quarterly, which will be available to read in July 2019.