Relationship of sarcopenia with steatohepatitis and advanced liver fibrosis in non-alcoholic fatty liver disease: a meta-analysis

Non-alcoholic fatty liver disease (NAFLD) has become the predominant cause for chronic liver disease in the Western countries and is estimated to impact more than 30% of Americans [1] and Chinese [2], with the prevalence continuously rising. Globally, the prevalence of NAFLD is rising as a result of increasingly sedentary lifestyle, globalization of Western diet and increasing frequency of obesity [3]. NAFLD comprises of a wide spectrum of disease including simple steatosis, non-alcoholic steatohepatitis (NASH), from liver fibrosis to cirrhosis, liver failure and hepatocellular carcinoma. It is generally recognised that the presence of histologic NASH is associated with worse outcomes compared to no-NASH NAFLD and the general population [4, 5]. Several studies have shown that NAFLD with advanced fibrosis is a significant predictor of mortality from cardiovascular diseases [6] as well as of liver-related events [7]. Thus, early assessment and intervention of this high-risk subjects may reduce the burden associated with these diseases.

Sarcopenia is characterised by generalised and progressive loss of skeletal muscle mass and strength, frequently associated with poor quality of life, physical disability and death [8]. Previously, it was regarded as consequence of ageing; but recently, studies identified it as a progressive disease frequently associated with multisystem disorders [9]. As both diseases - sarcopenia and NAFLD – share similar mediator such as insulin resistance, increased inflammation and physical inactivity, many studies have emerged over the past few years examining the relationship of sarcopenia with the presence of NAFLD [10, 11] and its severity [12‐15]. In our study, we aimed to systematically review and quantify the association between sacropenia and the histological severity of NAFLD. We hypothesised that sacropenia was associated with steatohepatitis and advanced liver fibrosis in non-alcoholic fatty liver disease.

A significant direct association was found between sarcopenia and NASH (OR = 2.35, 95%CI 1.45, 3.81) or ALF (OR = 2.41, 95%CI 1.94, 2.98) in this systematic review and meta-analysis including more than 3000 NAFLD patiens. Several hypotheses could be put forward to further explain the complex inter-relationships between sarcopenia and NAFLD.

Skeletal muscle plays a key role in insulin resistance as a primary tissue contributing to whole body insulin-mediated glucose uptake [18], muscle depletion reduces the predominant cellular target for insulin action, inducing glucose intolerance and accelerating gluconeogenesis, which conversely, will promote proteolysis and muscle wasting. Moreover, insulin resistance results in lipolysis and accordingly generation of free fatty acids, which can easily be taken by both muscle and liver [19, 20]. The insulin resistance-mediated muscle depletion mass and thus the less uptake of free fatty acids by muscle will further result in exposure to and increased uptake in free fatty acids by liver [21].

Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) is another potential link between sarcopenia and NAFLD. GH and IGF-I play important roles in linear growth in childhood, and continue to have essential metabolic fuctions throughout whole life. GH and IGF-1 are key effectors of changes in muscle mass. It has been well-described that abdominal and visceral obesity have strong influence on the suppression of GH secretion, and obese patients with the lowest GH secretion presenting the most severe metabolic complications; reduced GH and IGF-1 levels seen in patients with obesity, may be detrimental to both skeletal muscle and liver, contributing to ectopic fat storage [22]. Growing evidence has revealed that GH as well as IGF-I also play important roles in the liver, GH/IGF-1 axis impairment seems to be associated to the risk of both developing to sarcopenic obesity and ectopic fat storage in the liver [23‐25].

Chronic inflammation and oxidative stress have been shown to prompt muscle wasting [26]. The interaction of several intracellular signaling pathways may affect the balance between protein synthesis and breakdown, inducing apoptosis, which cause the primary pathology of muscle wasting [27]. Oxidative stress and chronic inflammation also can result in a stress response of hepatocytes, leading to the development of NASH and progression of fibrosis [28].

Additionally, the link between sarcopenia and NAFLD severity may partially owing to the vitamin D deficiency frequently found in patients with liver diseases. Growing evidence has established a close association between vitamin D status and sarcopenia. Some data suggest that vitamin D deficiency may impair muscle function and is associated with sarcopenia, furthermore, low vitamin D status is associated with lower muscle mass, poorer muscle function, and predicts more severe muscle loss and disability development [29]. As well, the association between vitamin D levels and NAFLD has been increasingly recognized. A meta-analysis with seventeen studies demonstrated that NAFLD patients had significant lower vitamin D levels and higher probability of vitamin D deficiency, compared to controls [30]. In vitro study, vitamin D supplementation was shown to ameliorate NASH progression in choline-deficient and iron-supplemented l-amino acid-defined diet-induced NASH model [31], suggesting a potential role of vitamin D in the development of NAFLD.

Overall, the overlap in the pathophysiology of sarcopenia and NAFLD make it challenging to determine whether sarcopenia is a risk factor for NASH, or it is a complication of NASH. The two entities are so intricately intermeshed that the presence of either one may increases the risk for the other. Clinicians should have an increased awareness of sarcopenia to diagnose it in patients with NAFLD, and should intervene early in these high-risk patients. Further studies are needed to assess intervention in sarcopenia and the development of pharmacologic intervention that addresses both conditions.

To our knowledge, this is the first meta-analysis to investigate sarcopenia with steatohepatitis and advanced liver fibrosis in NAFLD. Another strength of this study was that only high quality articles based on NOS quality assessment were included. The limitations of the study need to be considered: (a) all studies included are of cross-section nature, thus a cause-effect relationship between sarcopenia and NAFLD severity cannot be drawn. (b) Two of the studies used liver biopsy-the gold standard, while another study used noninvasive markers to identify NAFLD cases and advanced histology, the different method for NAFLD diagnosis may result in increased risk of publication bias. (c) some of the original studies did not provide ORs adjusted for potentially important confounders, such as BMI, age, and presence of diabetes.

In summary, this meta-analysis demonstrated that sarcopenia was associated with the severity of NAFLD. The possible causal relationship between sarcopenia and the severity of NAFLD, which needs to be proven by future prospective studies, may offer attractive therapeutic opportunities for treatment of NAFLD.