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Abstract
Nonalcoholic fatty liver disease (NAFLD) is increasingly recognized as an important cardiovascular risk (CVR) factor. This is a narrative clinical review aimed at answering how diagnosis and management of CVR should be conducted in the individual patient with NAFLD. To this end, the authors performed an extensive search of the existing literature on PubMed (1993–2014) using pertinent keywords. To date, CVR among patients with NAFLD might be assessed with the Framingham risk score equation or other risk calculators, to be adapted to the true CVR in the specific population being assessed; however, the use of these CVR calculators needs to be validated by future studies in larger cohorts of NAFLD patients of various ethnic backgrounds in order to substantiate their clinical relevance as a foundation for the primary prevention of cardiovascular diseases in this group of patients. Early and aggressive drug treatment of CVR should be started in NAFLD patients with a history of cardiovascular events, established diabetes or who are at high (calculated) CVR. Whether such an aggressive pharmacological approach is also justified in patients with NAFLD, who are at intermediate or low CVR, remains debatable. Currently, there are no clinical trials showing that the treatment of NAFLD per se (either associated or unassociated with traditional CVR factors) will result in decreased risk of cardiovascular events. Accordingly, drug treatment should be better individualized, aiming at correcting all the coexisting cardio-metabolic risk factors of the individual patient with NAFLD. To this end, an overview of the lifestyle interventions and the available drugs is offered, emphasis being conveyed to statins and metformin, which promise to cover worrying complications of NAFLD such as the risk of developing hepatocellular carcinoma.
Acknowledgement
This article is devoted to the memory of Professor Paola Loria. The authors are indebted to J Mole for her editing of English.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.
From a paradigm of non-steatotic liver disease being spared from cardiovascular disease (CVD), we have moved to the recognition of steatotic liver disease as being particularly exposed to increased cardiovascular risk. Nonalcoholic fatty liver disease (NAFLD), not a mere marker of CVD, but a key player in the pathogenesis of CVD, is associated with an increased risk of CVD independent of traditional risk factors. CVD risk does not wane even at the more advanced stages of liver disease and CVD is the primary cause of mortality in NAFLD patients.
Liver biopsy is not necessary in assessing cardiovascular risk (CVR) in the individual NAFLD patient. Framingham Risk Score is accurate in predicting CVR in NAFLD patients from the USA, Australia and New Zealand but it is likely to overestimate this risk in European populations.
Moreover, it is likely that Framingham Risk Score and other CVR scoring systems may underestimate the cardiovascular risk in NAFLD patients given that the subclinical inflamatory, insulin resistant and hypertriglycridemic states of NAFLD are not considered in any of these cardiovascular risk scoring systems. Data suggest that NAFLD patients may benefit from more intensive surveillance and early treatment interventions to decrease their risk of CVD.
The frequency of re-measuring cardiovascular risk should be tailored according to baseline risk. Repeat risk estimation before 8-10 years is not warranted for most people initially not requiring treatment. However, re-measurement within a year seems warrantated in those with an initial 15-<20% risk.
Lifestyle changes, through diet and physical exercise, are universally recommended as the first-line approach to the management of NAFLD. Pharmacological and surgical treatment of NAFLD includes a wide array of options such as antioxidant and vitamins, insulin sensitizers, lipid lowering agents, anti-hypertensives and endoscopic and surgical interventions against obesity.
Metformin, widely used as a first-line treatment for patients with type 2 diabetes reduces body weight and insulin resistance. Although it does not improve NAFLD liver histology, it significantly reduces the conversion of pre-diabetes to diabetes, may exert a cardioprotective effect and has been consistently reported to reduce the risk of developing hepatocellular carcinoma in patients with type 2 diabetes.
Statins effectively reduce various cardiovascular outcomes and NAFLD patients are probably those who benefit most from such a reduction of cardiovascular events. Although not associated with improved NAFLD liver histology, statin use reduces the risk of developing hepatocellular carcinoma in published studies confirming that the action of this class of drugs goes further to their lipid-lowering effect and may be attributable to their anti-inflammatory, antioxidant and antithrombotic activity.
Uncertainty remains about the prognostic value of NAFLD in CVR stratification. Large, long-term, well designed prospective studies should be conducted in patients of various ethnic backgrounds to assess whether adding NAFLD to the currently used prediction algorithms will improve the prediction of cardiovascular outcomes in the specific population being assessed.
Research seems appropriate on cardiovascular and hepatic outcomes of innovative drug agents such as mipomersen, obeticholic acid, 11-hydoxysteroid dehydrogenase type 1 inhibitors and of already available antiplatelet/anticoagulation treatment in NAFLD patients.