Clinical Impact of Sexual Dimorphism in Non-alcoholic Fatty Liver Disease (NAFLD) and Non-alcoholic Steatohepatitis (NASH)

Patrizia Burra; Debora Bizzaro; Anna Gonta; Sarah Shalaby; Martina Gambato; Maria Cristina Morelli; Silvia Trapani; Annarosa Floreani; Fabio Marra; Maurizia Rossana Brunetto; Gloria Taliani; Erica Villa


Liver International. 2021;41(8):1713-173. 

In This Article

Lifestyle Intervention in NAFLD/NASH Patients

The main strategy to treat NAFLD focuses on the control of underlying risk factors like diabetes, hyperlipidaemia, obesity and other comorbidities. Since no effective pharmacological treatment for NAFLD/NASH has been approved, the lifestyle changes, consisting of balanced diet and physical activity represent the cornerstone of intervention for NAFLD treatment.[132]

Recent studies have reported that a 6- to 12-month widespread lifestyle modification, based on reduced energy intake and increased physical activity, leads to improvement in liver enzymes and metabolic parameters, and reduced steatosis and necroinflammation, including ballooning and fibrosi.[133–135] The most recent European and American guidelines recommend that lifestyle interventions should be included as part of the clinical care of all NAFLD patients, regardless of the stage of disease.[136,137]

Preclinical studies demonstrated in animal models that males and females react differently to caloric restriction and intermittent fasting,[138] but clinical human data are still deficient. Only few studies have explored whether sex differences affect weight loss after surgical and non-surgical treatments, achieving conflicting results.[139,140] In general, with lifestyle interventions, men lose more weight and present greater metabolic benefits compared to women.[141] This higher metabolic effect could be partly explained by the fact that during weight loss, men lose mainly visceral adiposity compared with women, who principally lose subcutaneous adiposity.[142,143]

Similarly, in NAFLD patients, higher histological improvement was observed in men than women after weight loss. In fact, in male patients, a modest weight loss, between 7% and 10%, produces a significant histological improvement, while in women a more consistent weight loss (>10%) is necessary to obtain the same effect.[144]

It is well known that inadequate physical activities and sedentary lifestyle are risk factors for NAFLD.[145] Considering this aspect, women are generally more sedentary and have a lower tendency to meet physical activity guidelines. However, they showed a stronger beneficial effect of increased physical activity against NAFLD compared to men. Indeed, the physiological response to exercise appears to be different in men and women because of the different composition of the muscle fibres and different lipid metabolism.[66,146] Women's muscle is characterized by a higher number of type I muscle fibres which has higher capabilities of lipid oxidation, a higher content of intramyocellular lipids and are more sensitive to insulin than men's muscle.[147]

Some attention should be paid to post-menopausal women, in whom significant weight reduction achieved through dietary restrictions can induced negative effects on lean muscle and bone mass.[148] To prevent this side effect, an integrated approach consisting of dietary changes along with regular resistance training or aerobic exercises is mandatory.[148,149] However, only few studies have specifically assessed the role of physical activity in NAFLD post-menopausal women. The available data, however, confirm that physical activity and exercises effectively reduce liver enzymes in overweight post-menopausal women, probably because of the reduction in liver fat content and as the same time reduce cardiovascular risk factors.[150,151]

Thus, optimal lifestyle modifications may differ between men and women, or between pre- and post-menopausal women. However, this topic is still largely unexplored, so these important questions should be better addressed in future interventional clinical trials.