Nestel, Paul J.a; Mensink, Ronald P.b
aBaker IDI Heart and Diabetes Institute, Melbourne, Australia
bDepartment of Human Biology, School for Nutrition, Toxicology and Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands
Correspondence to Professor Paul J. Nestel, Baker IDI Heart and Diabetes Institute, PO Box 6492, St Kilda rd Central, Melbourne 8008, Australia. Tel: +61 3 8532 1383; e-mail: firstname.lastname@example.org
Nonalcoholic fatty liver disease (NAFLD) has emerged as a clear risk factor for cardiovascular risk. Through its association with metabolic syndrome including insulin resistance and type 2 diabetes, NAFLD certainly has strong indirect associations with cardiovascular risk. Recent population studies have strengthened the association with prevalent coronary heart disease. Investigative cardiology has shown that NAFLD is also associated with markers of subclinical atherosclerosis, such as diminished endothelial function and carotid artery intima-media thickening. Though causality between NAFLD and cardiovascular disease can only be tested in a clinical trial, these recent findings do emphasize the need to develop strategies including nutritional that may prevent NAFLD.
Nonalcoholic fatty liver disease (NAFLD) is a disorder that is part of and possibly the cause of a wide spectrum of metabolic and chronic diseases. Fat accumulation in the liver defined as exceeding 5–10% by wet weight is one of several sites of ‘ectopic’ fat storage that is equal in its adverse outcomes to excess visceral obesity. It was most recently reviewed by one of us (R.P.M.) in this Journal in 2008 . Although strongly associated with the metabolic syndrome and elevated BMI, with most obese patients showing a degree of liver fat accumulations, it can also occur in people of normal weight. It needs to be distinguished from the more severe manifestation of steatohepatitits (NASH), which is complicated by hepatic inflammation and may proceed to cirrhosis and cancer of the liver.
The prevalence of NAFLD is said to involve about one-third of adults  resembling recent global estimates including a report from China in 2012 . The independent association of NAFLD with two of the most prevalent chronic diseases, type 2 diabetes and coronary heart disease has focused increasing attention on the central role of the liver. However since liver enzymes are generally not elevated in earlier stages of NAFLD and ultrasound and more advanced imaging techniques detect the disorder only when a third or so of the liver is involved, it is difficult to quantify the risk for cardiovascular disease (CVD) posed by NAFLD. The elevation of plasma γ-glutamyltransferase (GGT), which is a common finding in patients with insulin resistance and dyslipidaemia may herald risk for future CVD .
A recent comprehensive review of NAFLD as a determinant of CVD appeared in 2012 from the University of Southampton, UK . Fifteen studies were reviewed in which NAFLD was diagnosed through elevated liver enzymes including GGT, or by ultrasound or liver biopsy. These epidemiologic studies were of variable strength, many depending on liver enzyme levels or having small populations and liver biopsies were mostly carried out for liver-related clinical indications. Nevertheless, the risk estimates did suggest significantly raised risk for future CVD that was independent of other risk factors including diabetes. The differentiation between NAFLD and NASH (which carried a worse prognosis) could mostly not be made with certainty. Not surprisingly the HRs and ORs predicted increments for adverse CVD outcomes that varied widely being as high as 4.12 in one of the larger (1637 patients) and longer (follow-up 5.8 years) studies based on ultrasonography in Japan . A larger study among type 2 diabetics also defined by ultrasound carried an HR of 1.87 that was independent of risk factors other than well controlled diabetes . Mostly the risk predictions were of a lower order.
The association between NAFLD and subclinical atherosclerosis has been investigated in the carotid artery (intima-media thickening and/or plaque burden). A systematic analysis of seven published studies concluded that a significant association existed between CIMT and NAFLD although when compared with a non-NAFLD group the difference was only 13% lesser CIMT . The Southampton group's review also advised caution in interpreting the claimed associations between severity of coronary disease and NAFLD . An association in Asian Indians between NAFLD, endothelial dysfunction and carotid intima-media thickness has been reported independently of obesity and metabolic syndrome . Further, the recent report from China where 30% of a population of 8632 was found to have NAFLD, demonstrated a significantly higher CIMT among those affected compared with patients without NAFLD . There was also an association between NAFLD and arterial stiffness measured by pulse wave velocity .
Cardiometabolic surrogate biomarkers are more readily measured and have been validated to be associated with NAFLD. Each of the key components of the metabolic syndrome, and insulin resistance in particular has been shown to be strongly linked to NAFLD . These links between NAFLD, visceral adiposity, hypertension, type 2 diabetes, dyslipidaemia and high C-reactive protein concentration apply globally. A large multiethnic study involving 4504 patients from 29 countries found no differences in this constellation of abnormalities among patients with differing ethnic backgrounds . Increased oxidative stress and evidence of inflammation through raised levels of inflammatory cytokines raise the question of when do these biomarkers define the progression of NAFLD to NASH.
An intriguing point is the bidirectional relationship between insulin resistance and NAFLD with each predicting the future development of the other . This is partly based on the finding that higher circulating hepatic enzymes, such as alanine aminotransferase (ALT) predict decline in hepatic insulin sensitivity . Raised levels of GGT also appear to predict deteriorating glucose tolerance leading to type 2 diabetes . The link between liver enzymes and cardiometabolic parameters, and the responses of both to lifestyle changes that are advocated for treating NAFLD has been recently reported by Straznicky et al.. Predicated on their earlier findings of increased sympathetic activation in the insulin-resistant state they examined the relationships of muscle sympathetic nerve activity (microneurography) and norepinephrine kinetics (an index of global sympathetic activity) with the concentrations of plasma liver enzymes. The effects of weight loss and exercise on these parameters were then investigated in obese patients with metabolic syndrome. Among their participants 22% had raised ALT and/or raised GGT concentrations. ALT correlated strongly with body mass, fasting insulin and inversely with insulin sensitivity. ALT but not GGT was positively correlated with energy and fat intake, especially that of saturated fat. In women, GGT was associated with hsCRP and HOMA-IR an index of insulin resistance. Both ALT and GGT declined significantly by between 20 and 30% with weight loss of 8–9% or by aerobic exercise plus weight loss together with a decline in sympathetic nervous system activity . ALT decline correlated also with reduced saturated fat intake. These improvements were interpreted as reflecting diminishing fat storage in the liver. The improvement in liver enzymes with weight loss has also been shown to relate to improved hepatic histology . The relationship between NAFLD and increased sympathetic activity, which drives many cardiovascular functions that may become pathological through excess sympathetic activity provide a further link between NAFLD and CVD.
Information on dietary determinants of NAFLD is still limited and nutritional advice to reduce excess fat storage in the liver has changed little since the 2008 review . Experimentally in overweight people, a hypercaloric diet, more than 1000 extra kilocalories daily provided from simple carbohydrates, led to a remarkable 27% increase in liver fat within 3 weeks , probably reflecting de-novo lipogenesis. Equally interesting was the restoration of hepatic fat to normal through subsequent weight loss. Increased physical activity, which is generally recommended, can lead to reduced liver fat even without weight loss . On the contrary, high intakes of fat, and in particular of saturated fat, and of fructose may increase intrahepatic lipid content, whereas polyunsaturated fatty acids, short-chain fatty acid production from fibres in the colon, choline, antioxidants and high-protein diets rich in isoflavones may have a protective effect [17–19]. Interestingly, already in children relations between dietary intake and NAFLD have been found . Results, however, are conflicting and only a limited number of intervention studies have been carried out so far. The optimal dietary advice for NAFLD treatment remains therefore open-ended. However, it is clear that a recommended diet, weight loss and physical exercise are the cornerstone for the prevention of NAFLD.
Conflicts of interest
There are no conflicts of interest.
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