Circulatory dysfunction in NAFLD — Which is first, which is last, and what do we do in between?
Authors: David D. McPherson
Journal: Hepatology (2005)

In this issue of the journal, Villanova et al.1 describe the evaluation of cardiovascular risk factors in subjects with nonalcoholic fatty liver disease (NAFLD). Flow-mediated vasodilation and cardiovascular risk profiles were examined in subjects with NAFLD and compared to age and gender matched controls. The risk of coronary events was calculated. The main findings were that endothelial dysfunction was present in the majority of subjects with NAFLD, and that these vascular abnormalities were similar to those seen in patients with the metabolic syndrome. Importantly, the 10-year probability of cardiovascular events was increased in subjects with NAFLD. This finding raises the question as to whether cardiovascular events will occur prior to the development of liver failure in patients with NAFLD, and if aggressive treatment of cardiovascular risk factors is an important treatment modality for all patients with NAFLD. NAFLD, nonalcoholic fatty liver disease; EDRF, endothelium-derived relaxation factor. In this editorial, we will first identify what exactly is flow-mediated vasodilation, what this methodology tests, and what pathological abnormalities it identifies. We will also review the implications of altered flow–mediated vasodilation in NAFLD and its effect on the therapeutic approach to patients with NAFLD. The evaluation of arterial beds to determine endothelial dysfunction is a well-developed methodology to examine the presence of early atherosclerosis. It has been found that endothelium-dependent arterial relaxation is impaired in various pathological conditions, including hypercholesterolemia,2 atherosclerosis,3, 4 and systemic hypertension.5 In vitro and in vivo studies have demonstrated the link between endothelial dysfunction and impaired release of substances from the endothelium, such as endothelium-derived relaxation factor (EDRF) and prostacyclin,6 which have anti-atherogenic properties and are responsible for regulation of vascular tone. The development of methods using B-mode ultrasound imaging to assess brachial vascular reactivity allows noninvasive evaluation of endothelial function in various populations. The technique essentially induces reactive hyperemia in the forearm and evaluates the change of the brachial artery diameter. It was first developed and introduced by Celermajer et al.7 This relatively simple test evaluates the brachial artery with ultrasound at the location 3–7 cm above the anticubital crease. The image is recorded using the longitudinal view. Brachial artery vasoreaction is induced due to the initial gross decrease of blood flow and subsequent marked increase in shear stress produced by sudden release of the external mechanical occlusion (i.e., inflation of pressure cuff to suppress arm blood flow for 4.5–5 minutes). Figure 1 demonstrates pictorially the brachial artery before and after external occlusion in a normal subject. The arterial diameter is measured at baseline and during reactive hyperemia and, if there is both endothelial dependent and independent vasodilation, the arterial diameter will increase following release of cuff occlusion. If endothelium dependent or independent vasodilation is abnormal, the arterial diameter will not increase appropriately following release of the blood pressure cuff. Two images from a study subject with normal vascular reactivity. (A) baseline. (B) 60 seconds following occlusion cuff release. Change in arterial diameter 13%. Endothelium dependent vasodilation occurs when the increased shear stress from the reactive hyperemia stimulates the endothelium to release EDRF, that results in arterial dilatation. The first identification of EDRF was by Furchgott and Zawadzki in 1980.6 Its existence was confirmed by others and proved to be mainly nitric oxide or a similar chemically related compound.8, 9 Nitric oxide is released following shear stress of the endothelium. Nitric oxide subsequently diffuses across the extracellular space into smooth muscle cells to stimulate an enhanced form of cyclic GMP,10 an intracellular second messenger. Its elevation activates the cyclic c-GMP dependent kinase in smooth muscle cells, which results in the reduction of activating calcium available for contraction.11 Nitric oxide thus relaxes vascular smooth muscle to modulate systemic vascular resistance, blood pressure, and the basal vascular tone in the coronary, pulmonary, and peripheral circulations. Endothelium independent vasodilation is the direct response of the muscular media to vasodilatory stimuli. This is usually demonstrated using nitroglycerin, which relaxes smooth muscle and its presence demonstrates integrity of vascular smooth muscle cells. In this study,1 the authors demonstrated that endothelial independent vasodilation is not affected in NAFLD. With developing atherosclerosis, both structural and functional changes occur. There is hypertrophy of the vascular media, thickening of the intima, and a core filled with cholesterol esters. The endothelium becomes dysfunctional as well. With developing atherosclerosis there is an anatomical impediment exists for gaseous substances such as nitric oxide to reach the vascular media in order to cause relaxation. In addition, there is also impairment of endothelial nitric oxide production, release, and activity.12, 13 Additionally, there is some suggestion that the half-life of nitric oxide is shortened, potentially due to an insensitive smooth muscle response to nitric oxide. Endothelial dysfunction occurs early in the development of vascular disease and it is a systemic alteration. Nonalcoholic fatty liver disease is associated with features of the metabolic syndrome. The metabolic syndrome is characterized by an excess of abdominal fat, hyperlipidemia, hyperglycemia, hypertension, and abnormal metabolic factors, including elevated levels of proinflammatory cytokines and adhesion molecules.14 The latter are very important in the development of endothelial dysfunction and atheroma. Therefore, the findings of abnormal flow-mediated vasodilation with NAFLD, and in particular nonalcoholic steatohepatitis, are not surprising. However, the finding that the 10-year probability of cardiovascular events was increased and may precede the burden of liver failure, means that NAFLD should be treated on many levels. Not only should the treatment of the liver disease be considered, but aggressive treatment of atherosclerotic risk factors needs to be initiated, as many subjects with NAFLD will have major cardiovascular events and death prior to the development of liver failure. In these patients, especially those with nonalcoholic steatohepatitis, two metabolic aspects must be aggressively addressed. The first is glucose control. Some recent evidence demonstrated that the level of glycemic control is as, if not more, important as lipid levels in improving endothelial vasomotor function in patients with obesity and the metabolic syndrome15 The second is cholesterol control. The latter patients definitely should have LDL cholesterol levels below 100 mg/dL and, given these data, possible consideration of LDL levels below 70 mg/dL should be made. Aggressive lipid lowering is often problematic, although the potential of cholesterol reducing agents to aggravate hepatic disease maybe less pronounced than previously thought.16 Finally, what is the initiating pathophysiological event? Does altered hepatic function stimulate the development of the metabolic syndrome and dyslipidemia, or are dyslipidemia and the metabolic syndrome the precursors that help initiate and promote altered hepatic function? By determining the order of these abnormalities, a treatment approach can be developed that is directed toward resolving the dyslipidemia, the metabolic syndrome, and the hepatic pathology. Importantly, the determination of endothelial function using brachial vascular reactivity can be used as a surrogate to evaluate the effect of treatment approaches to NAFLD. This measure may be as powerful a predictor of future events or lack of events as the determination of the serum liver profile. Future studies are necessary to elucidate the role of brachial vascular reactivity in monitoring NAFLD progression. Abnormal lipid metabolism, abnormal glucose metabolism, abnormal liver disease—which comes first and which follows? More importantly, which ends up as the terminal endpoint? Although it may matter to develop future optimal treatment approaches, the take-home message of these data1 is that we must aggressively treat all three abnormalities in concert.