Elsevier

Metabolism

Volume 65, Issue 8, August 2016, Pages 1109-1123
Metabolism

Nonalcoholic Fatty Liver Disease: From Pathogenesis to Emerging Treatment
Non-alcoholic fatty liver disease and dyslipidemia: An update

https://doi.org/10.1016/j.metabol.2016.05.003Get rights and content

Abstract

Non-alcoholic fatty liver (NAFLD) is the most common liver disease worldwide, progressing from simple steatosis to necroinflammation and fibrosis (leading to non-alcoholic steatohepatitis, NASH), and in some cases to cirrhosis and hepatocellular carcinoma. Inflammation, oxidative stress and insulin resistance are involved in NAFLD development and progression. NAFLD has been associated with several cardiovascular (CV) risk factors including obesity, dyslipidemia, hyperglycemia, hypertension and smoking. NAFLD is also characterized by atherogenic dyslipidemia, postprandial lipemia and high-density lipoprotein (HDL) dysfunction. Most importantly, NAFLD patients have an increased risk for both liver and CV disease (CVD) morbidity and mortality.

In this narrative review, the associations between NAFLD, dyslipidemia and vascular disease in NAFLD patients are discussed. NAFLD treatment is also reviewed with a focus on lipid-lowering drugs. Finally, future perspectives in terms of both NAFLD diagnostic biomarkers and therapeutic targets are considered.

Introduction

Non-alcoholic fatty liver (NAFLD) is the most common chronic liver disease worldwide, representing the hepatic manifestation of the metabolic syndrome (MetS) [1]. NAFLD may progress from simple steatosis (i.e. fat accumulation in ≥ 5% of the hepatocytes) to necroinflammation and fibrosis, leading to non-alcoholic steatohepatitis (NASH), and in some cases to cirrhosis and even to hepatocellular carcinoma [2], [3]. These liver histological alterations occur in the absence of alcohol abuse or other causes of chronic hepatic disease [4].

Excess fat accumulates in the hepatocytes in the form of lipid droplets coated by several structural proteins which may be involved in the pathophysiology of liver diseases [5], [6], [7]. In NAFLD, this intrahepatic lipid accumulation results from lipid metabolism abnormalities such as increased whole body lipolysis, liver free fatty acid (FFA) uptake and very low density lipoprotein (VLDL) synthesis as well as reduced FFA oxidation and triglycerides (TG) export [8], [9]. These alterations in lipid metabolism are linked to an induction of inflammation and oxidative stress as well as to abnormal adipokine (such as leptin, adiponectin, resistin, visfatin and retinol-binding protein-4) production that affect signaling pathways [10], [11], [12], [13], [14]. Several other cytokines including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 and IL-6 and acute phase proteins (e.g. C-reactive protein) are involved in the process as shown in proteomic studies [15], [16], [17]. The pathogenetic interplay between lipid metabolism and NAFLD is summarized in Fig. 1. An imbalance of the hepatic phospholipid and bile acid homeostasis has also been described in the presence of NAFLD [8]. Furthermore, an emerging pathophysiological mechanism of NAFLD involves gut microbiota that can affect inflammatory and immune pathways as well as lipid metabolism, representing the so-called “gut-liver” axis [18], [19].

Obesity and insulin resistance predispose to NAFLD and may contribute to the above mentioned lipid disorders [20]. Of note, liver steatosis has been associated with insulin signaling inhibition, decreased glycogen synthesis and induced gluconeogenesis, thus further impairing glucose metabolism [9], [21]. NAFLD has also been linked to type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) [22], [23], [24].

With regard to cardiovascular (CV) risk factors and apart from obesity, dyslipidemia and hyperglycemia, NAFLD has been associated with hypertension and smoking [25], [26]. Most importantly, NAFLD patients have an increased risk for both liver and CV disease (CVD) morbidity and mortality [22].

In this narrative review, we discuss the associations between NAFLD, dyslipidemia and vascular disease in NAFLD patients. NAFLD treatment is also reviewed with a special focus on lipid-lowering drugs. Finally, future perspectives in terms of both NAFLD diagnostic biomarkers and therapeutic targets are considered.

In NAFLD, similarly to obesity and MetS [27], dyslipidemia is characterized by elevated TG and low-density lipoprotein cholesterol (LDL-C) levels and by decreased high-density lipoprotein cholesterol (HDL-C) concentrations [28], [29]. This atherogenic dyslipidemia may be at least partially responsible for the increased CVD risk in NAFLD patients as these lipid abnormalities have been independently associated with CVD morbidity and/or mortality [30], [31], [32], [33]. Furthermore, NAFLD has been independently related to increased small dense LDL (sdLDL) particles [34], [35], [36]. It should be noted that elevated sdLDL concentrations represent an emerging CVD risk factor frequently present in obese and MetS patients [37]. NASH patients may have even higher sdLDL levels than NAFLD individuals, thus possibly contributing to the higher CVD risk found in NASH compared with NAFLD patients [38], [39].

With regard to HDL-C and despite the evidence for a significant association between low HDL-C levels and CVD risk, several trials failed to demonstrate any significant effect of drug-induced HDL-C rising on CVD prevalence [40], [41]. These findings led to the concept of HDL functionality, supporting an important role of HDL quality (and not only quantity) on atheroprotection [42], [43], [44]. In this context, although HDL exerts beneficial pleiotropic properties [45], in the presence of inflammation, oxidative stress and/or dysglycemia, HDL particles may be transformed to dysfunctional molecules exerting pro-atherogenic effects [46]. In NAFLD patients, circulating levels of HDL2, possibly the strongest antiatherogenic HDL subfraction, were more decreased than total HDL-C concentrations, thus suggesting the presence of dysfunctional HDL particles in such patients [47]. Similarly, NASH patients had significantly lower HDL2 levels compared with controls [48].

Postprandial lipemia has been linked to an increased CVD risk [49], [50], [51]. The definition, evaluation and clinical significance of postprandial lipemia were reviewed by an expert panel [52], [53]. NASH patients were reported to exert a higher magnitude of postprandial lipemia following an oral fat meal compared with controls [54], [55]. Of note, postprandial lipemia is also related to obesity, T2DM and MetS [56], [57], [58].

Lipoprotein (a) [Lp(a)] has been linked to an increased CVD risk independently of other CVD risk factors [59], [60]. Data on Lp(a) levels in NAFLD patients are limited. In 2 studies, the presence of NAFLD was inversely associated with elevated Lp(a) concentrations [61], [62]. Further research is needed to establish the relationship between NAFLD and Lp(a).

Several apolipoproteins (apos) including apoA4, apoA5, apoC3 and apoE may affect lipid metabolism in NAFLD [63], [64], [65], [66]. In this context, gene polymorphisms of apos were also reported in NAFLD patients [67], [68], [69]. It should be noted that some apos have been associated with CVD risk [70], [71], [72], [73], [74].

Lipoprotein lipase (LPL) is the main enzyme removing TG from the circulation [75]. LPL gene variants may predispose to CVD [76]. Both hepatic LPL synthesis and activity are enhanced in obese patients, favoring liver fat accumulation and thus NAFLD development [77]. Hepatic lipase activity is also higher in NAFLD patients compared with controls [78].

NAFLD patients are at a high risk for both coronary heart disease (CHD) and stroke [79], [80], [81], [82], [83]. Furthermore, NAFLD has been linked to both CHD prevalence and severity [84]. Possible mechanisms for this NAFLD-induced vascular risk include oxidative stress, inflammation, insulin resistance, endothelial dysfunction and cytokine abnormalities [85]. Furthermore, several CVD risk factors such as hypertension, dyslipidemia, obesity and T2DM frequently co-exist with NAFLD, thus contributing to the increased CVD risk seen in these patients [25], [28]. Of note, elevated serum liver enzyme activities [e.g. gamma-glutamyltransferase (γGT), alanine aminotransferase (ALT) and alkaline phosphatase)] may independently predict CVD morbidity and/or mortality as well as all-cause death [86], [87], [88], [89].

NAFLD has been associated with subclinical atherosclerosis assessed by increased arterial stiffness (AS), impaired flow-mediated vasodilation (FMD) and increased carotid intima-media thickness (cIMT) as reported in a recent meta-analysis [90]. The independent relationship between NAFLD and carotid artery disease refers to both elevated cIMT and carotid plaque prevalence [91], [92] as also supported in recent meta-analyses [93], [94]. Interestingly, NAFLD improvement may decrease cIMT progression [95]. Apart from NAFLD, increased AS has been linked to other CVD risk factors such as age, hypertension, dyslipidemia, obesity, T2DM, smoking and MetS [96], [97], [98], [99], [100], [101]. Furthermore, AS may independently predict CVD morbidity and mortality [102], [103], [104]. Similarly, impaired FMD and increased cIMT are related to increased CVD risk [105], [106]. Therefore, the measurement of such markers of early atherosclerosis may contribute to vascular risk stratification in NAFLD patients.

Coronary and abdominal aortic calcification, impaired left ventricular function and heart failure (HF) are also linked to NAFLD [83], [107], [108], [109], [110], [111]. Of note, the risk for HF rehospitalization at 1 year was significantly higher in patients hospitalized for HF with NAFLD compared with those without NAFLD [112]. A strong association between NAFLD and other cardiac diseases i.e. heart valve diseases and atrial fibrillation has also been reported [113], [114], [115], [116], [117]. Furthermore, epicardial fat, an emerging CVD risk factor [118], [119], [120], has been linked to NAFLD prevalence and severity [121], [122], [123].

Peripheral artery disease (PAD) is a CHD equivalent as reported in the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) [124]. Data on NAFLD in PAD patients are scarce. In 2 studies, PAD prevalence was significantly higher in NAFLD patients with T2DM compared with those diabetics without NAFLD [125], [126]. Further large studies are required to assess the link between PAD and NAFLD.

CKD grade 3–5 stage 3, defined as estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2), is recognized as a CHD equivalent by several scientific societies including the Canadian Cardiovascular Society [127] and the European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) [128]. NAFLD has been associated with increased CKD incidence and severity [24]. CKD may aggravate NAFLD (and vice versa) through several pathways such as oxidative stress, insulin resistance, inflammation, activation of the renin-angiotensin system and hepatokines [23], [129]. The presence of CKD in NAFLD patients may further increase CVD risk in this patient population [130]. Of note, similar to NAFLD, MetS has been also linked to non-cardiac vascular diseases (i.e. carotid artery disease, peripheral artery disease and CKD) [131].

Hyperuricemia has been related to CKD and CVD risk as well as to NAFLD [132], [133], [134], [135]. Serum uric acid (SUA) lowering therapy (i.e. both xanthine oxidase inhibitors, allopurinol and febuxostat) may suppress CKD progression [136], [137], [138]. Febuxostat was also shown to inhibit NASH development in an animal model [139].

Rheumatoid arthritis, systemic lupus erythematosus and psoriasis are associated with higher CVD risk [140], [141], [142], [143] as recognized by the Canadian Cardiovascular Society [127], the ESC/EAS [128] and the European League Against Rheumatism (EULAR) [144]. These autoimmune diseases have also been linked to NAFLD development [145], [146], [147], [148].

Erectile dysfunction (ED) represents another emerging CVD risk factor [149], [150]; ED patients have a higher risk for CVD morbidity and mortality as well as for total mortality [151], [152], [153]. Although there is a paucity of data, in one study, ED was associated with NAFLD [154]. In another experimental study, NASH was related to ED pathogenesis [155]. Further research is needed to evaluate the association, if any, between ED and NAFLD.

A link between obstructive sleep apnea syndrome (OSAS) and CVD risk has been reported [156], [157], [158], [159]. Of note, continuous positive airway pressure (CPAP) therapy may decrease CVD morbidity and mortality as shown in a recent meta-analysis [160]. Another meta-analysis found that OSAS patients have higher serum liver enzyme activities and an increased risk for NAFLD prevalence compared with controls [161]. OSAS has been also associated with NAFLD severity [162]. Possible pathophysiological mechanisms involve oxidative stress, inflammation, insulin resistance and chronic intermittent hypoxia [163], [164], [165], [166].

Currently there are no established international guidelines for NAFLD treatment. However, the American Association for the Study of Liver Diseases, the American College of Gastroenterology and the American Gastroenterological Association published in 2012 their practical recommendations on NAFLD diagnosis and management supporting the implementation of lifestyle measurements and the use of certain drugs to treat NAFLD patients based on available evidence [167]. In this context, a Mediterranean diet or following the Dietary Approaches to Stop Hypertension (DASH) diet as well as exercise (both aerobic and anaerobic) have been shown to improve insulin resistance and hepatic steatosis in NAFLD patients [168], [169]. These benefits were also seen in NAFLD patients on the Mediterranean diet, even without achieving weight loss [170]. Nutritional therapy including vitamins (E and D), polyphenols, minerals and long-chain n-3 polyunsaturated fatty acids has been also proposed for NAFLD patients [171], [172]. Furthermore, vitamin E therapy and obeticholic acid were reported to significantly improve NASH [173], [174]. Of note, nutraceuticals may exert beneficial cardiometabolic effects (such as lipid-, weight- and glucose-lowering) [172], [175], [176], [177]. However, the use of supplemented antioxidants has been questioned in terms of both long-term efficacy and safety [178], [179], [180], [181], [182], [183]. Therefore, further larger trials are needed to establish the role of nutritional therapy in NAFLD therapy.

Weight reduction represents the first-line therapeutic option for NAFLD [184]. Following intensive lifestyle intervention, weight loss (7–10%) was reported to reduce liver steatosis and fibrosis, leading to NASH remission [185]. The percentage of weight reduction has been independently related to histological improvements in NASH patients [186]; NASH resolution was significantly more frequent in patients with ≥ 5% weight loss compared with those who lost < 5% of their initial weight. Bariatric surgery may be even more effective in improving both biochemical and histological features of NAFLD [187] as also supported in a previous meta-analysis [188].

With regard to drug treatment, metformin may reduce insulin resistance and liver enzyme activities but data on its effects on hepatic histology are controversial [189], [190], [191]. In contrast, pioglitazone was reported to improve both biochemical and histological parameters in NAFLD patients [191], [192]. A previous meta-analysis also supported such beneficial effects of pioglitazone in NASH patients [193]. It should be noted that pioglitazone is a generally safe drug in contrast to rosiglitazone that was linked to an increased CVD risk in T2DM patients [194], [195]; the US Food and Drug Administration (FDA) has recently eliminated the Risk Evaluation and Mitigation Strategy (REMS) for drugs containing rosiglitazone [196]. Pioglitazone was also reported to decrease total cholesterol and TG levels, and to increase HDL-C in a previous meta-analysis [197].

Glucagon-like peptide-1 (GLP-1) agonists were shown to beneficially affect NAFLD by acting both directly on liver lipid metabolism and inflammation and indirectly on glucose metabolism and insulin sensitivity [198], [199]. In this context, lixisenatide was shown to decrease liver transaminases in T2DM patients [200]. Exendin-4 prevented dyslipidemia, liver VLDL overproduction, hepatic steatosis and fibrosis in animal models [201], [202]. Furthermore, exenatide significantly reduced AST, ALT and γGT levels as well as liver steatosis in T2DM patients [203], [204]. Similarly, liraglutide was reported to protect against dyslipidemia, hyperglycemia and liver steatosis in experimental studies [205], [206]. Liraglutide therapy was also associated with NASH resolution in the liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN) study [207], [208]. Interestingly, abnormal baseline transaminases levels and their reduction during treatment with GLP-1 agonists (85% liraglutide) were linked to a better glycemic control in T2DM patients [209]. Dipeptidyl peptidase-4 (DPP-4) inhibitors may improve hepatic steatosis [210]. Of note, DPP-4 expression in the liver is increased in hepatic diseases [210]. Sodium glucose cotransporter 2 (SGLT2) inhibitors (gliflozins) represent a novel antidiabetic drug category that exerts its glucose-lowering effects independently of insulin via decreasing kidney glucose reabsorption [211]. Limited data from animal studies support a beneficial role of these drugs on hepatic steatosis and liver tests [212], [213]. Further research is needed to evaluate SGLT2 inhibitors effects on NAFLD.

Pentoxifylline therapy also exerts beneficial effects on both biochemical and histological parameters in NAFLD patients as reported in previous meta-analyses [214], [215], [216]. The use of renin-angiotensin system (RAS) blockers was negatively associated with advanced hepatic fibrosis in biopsy proven NAFLD patients [217]. These antihypertensive agents were shown to reduce liver inflammation and fibrosis [218].

Statins are both effective (in terms of CVD risk reduction and improvements in biochemical parameters and ultrasound findings) and safe in NAFLD patients, even with high baseline transaminases levels (< 3 × upper limit of normal) [219], [220], [221], [222]. In this context, in a post hoc analysis of the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study (n = 1600), long-term (3 years of follow-up) statin treatment (mean dose 24 mg/day, mainly atorvastatin) was shown to substantially reduce liver tests (p < 0.0001) in patients with possible NAFLD (as represented by liver ultrasound and transaminase activity) [223]. In contrast, liver enzyme activity was further increased and liver ultrasound findings were worsened in those patients not on a statin. Furthermore, CVD relative risk reduction was significantly lower in NAFLD patients on a statin compared with those with NAFLD not taking a statin (68% vs 39%, respectively; p = 0.0074) [223]. Similarly, in a post hoc analysis of the Assessing The Treatment Effect in Metabolic Syndrome Without Perceptible diabeTes (ATTEMPT) study (n = 1123; 42 months duration), multifactorial treatment including atorvastatin was beneficial in primary CVD prevention and safe in patients with MetS and NAFLD/NASH [224]. Furthermore, liver tests and ultrasound findings were normalized in statin treated patients achieving LDL-C levels < 100 mg/dl. Later on, the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) trial (n = 8888; 5 years duration) confirmed the safety and efficacy in CVD risk reduction and liver tests improvement of intensive vs moderate statin treatment (atorvastatin 80 mg/day vs simvastatin 20 mg/day) in patients with increased baseline ALT concentrations [225]. This CVD benefit was greater in these patients compared with those with normal baseline ALT levels.

Statins have been also reported to protect against the development of hepatic steatosis, fibrosis and NASH, or even reverse NASH in studies with liver biopsies [226], [227], [228], [229], [230], [231], [232], [233], [234]. However, further large studies are needed to establish statin effects on liver histology. It should be noted that statins exert beneficial effects on several CVD risk factors related to NAFLD pathophysiology including sdLDL, postprandial lipemia, AS, CKD, hyperuricemia, ED and OSAS [222], [235], [236], [237], [238], [239], [240].

Statins are underused in NAFLD patients possibly due to the fear of statin-related hepatic damage, thus depriving them from benefits on CVD and liver health [241], [242]. Of note, recent recommendations suggest that statins are safe and beneficial in patients with NAFLD [243]. Health-care providers should be properly educated and reinforced in the appropriate use of statins in these patients to achieve maximum benefits.

Apart from statins, ezetimibe was also reported to reduce lipid levels, insulin resistance and CVD risk as well as to improve liver tests and hepatic histology in NAFLD/NASH patients [244], [245], [246], [247], [248], [249], [250]. Statin + ezetimibe combination may prove even more beneficial than each drug alone in NAFLD patients but this remains to be established in future trials [251]. It should be mentioned that the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) showed a significant reduction in first primary endpoint (PEP) in patients (n = 18,144) with an acute coronary syndrome taking ezetimibe + simvastatin compared with placebo + simvastatin [252]. LDL-C levels were significantly lower in the combination group compared with the monotherapy group (53.7 vs 69.5 mg/dl; p < 0.001). These benefits on lipids and CVD risk were seen despite the fact that baseline LDL-C levels were relatively low (i.e. 50–100 mg/dl in patients on lipid-lowering drugs or 50–125 mg/dl in patients not receiving such drugs) [252]. The recently published analysis of IMPROVE-IT considering all PEP events is even more impressive showing more than double reduction in the number of events prevented compared with examining only the first event [253]. These findings highlight the clinical benefit of continuing combination therapy in such high-risk patients [254].

Fibrates are useful in treating the atherogenic dyslipidemia in NAFLD patients and especially in reducing TG and sdLDL levels [255], [256]. Furthermore, fibrates were shown to improve liver tests [257] but not steatosis or fibrosis [258]. Further research is needed to investigate the impact, if any, of fibrates on NAFLD histological features.

Niacin has been reported to prevent or ameliorate hepatic steatosis via reduction in oxidative stress and inflammation in experimental studies [259], [260]. Limited and conflicting data exist with regard to niacin effects on liver fat content in human studies [261], [262]. It should be noted that 2 large clinical trials with niacin i.e. the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) study [263] and the Heart Protection Study 2 – Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) study [264] found no further CVD benefit from adding niacin to simvastatin, one of them even showing an increase in the risk for ischemic stroke in patients on niacin. These findings led to the withdrawal of niacin from the European market as recommended by the European Medicines Agency (EMA) [265]. Only a few studies assessed the impact of bile-acid binding resins (such as colesevelam and probucol) on liver tests and histological parameters in NASH patients, reporting conflicting results [266], [267], [268]. Table 1 summarizes the characteristics and main findings of trials with hypolipidemic drugs on non-alcoholic fatty liver disease.

Overall, a multifactorial intervention including lifestyle measures and drugs targeting dyslipidemia, hypertension and dysglycemia represent the best therapeutic approach to treat NAFLD patients.

MicroRNAs (miRs) are non-coding RNAs controlling gene expression that are involved in the pathophysiology of several cardiometabolic diseases including CVD, MetS and T2DM [269]. Silencing harmful miRs and replacing (by miR mimics) or inducing the expression of beneficial miRs may represent developing treatment strategies [270]. Recently, miRs have been suggested as promising biomarkers for NAFLD diagnosis and monitoring as well as potential therapeutic targets [271], [272]. Targeting nuclear receptors may be another therapeutic approach to treat NAFLD [273]. Furthermore, genetic studies can lead to personalized medicine in NAFLD [88], [274]. Such studies may provide further information with regard to individual variability in pharmacokinetics and treatment response [275]. Modulating epigenetic pathways may affect NAFLD progression, thus representing an emerging treatment option in selected NAFLD patients [276]. Liver transplantation may be also indicated in some cases of NAFLD and/or NASH [277], [278], [279].

LDL receptor-related protein 6 is currently investigated as a possible therapeutic target in NAFLD [280]. Furthermore, ETC-1002 is a novel LDL-C-lowering drug, exerting several cardiometabolic beneficial effects that may be proven beneficial in NAFLD [281], [282]. Leptin replacement therapy [283], and adiponectin receptor agonists [284], [285] may have a role in NAFLD treatment but this remains to be conclusively demonstrated by future studies. Irisin, a newly discovered myokine, has been also associated with NAFLD pathogenesis and progression [286], [287], [288], thus representing another potential target for NAFLD therapy [289].

Finally, gut microbiota are involved in the pathophysiology of several metabolic diseases including NAFLD [290], [291]. The administration of probiotics was shown to improve both the biochemical parameters and the histological features of NAFLD [290], [291].

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is involved in the degradation of the LDL receptor in hepatocytes; PCSK9 inhibition has been investigated as a promising therapeutic option in patients with familial hypercholesterolemia (FH) or statin intolerance in the last few years [292], [293]. Recently, 2 different PCSK9 inhibitors, evolocumab and alirocumab, have been approved from both the US FDA and the European Medicines Agency (EMA) for treating dyslipidemia in patients with FH or CVD in cases where LDL-C targets cannot be achieved with standard therapy [294], [295], [296], [297], [298]. Of note, both these drugs were reported to significantly decrease LDL-C levels by over 60% as well as to reduce total cholesterol, TG and Lp(a) levels, and to increase HDL-C in statin-treated patients [299], [300]. Apart from lipid improvements, both alirocumab and evolocumab were shown to significantly reduce CVD events by approximately 50% in a post hoc analysis of the Long-term Safety and Tolerability of Alirocumab in High Cardiovascular Risk Patients with Hypercholesterolemia Not Adequately Controlled with Their Lipid Modifying Therapy (ODYSSEY LONG TERM) [299] for alirocumab, and in a prespecified but exploratory analysis of the Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) [300] for evolocumab. However, the number of events was small and these trials were not powered to show event rates. Trials evaluating the effects of PCSK9 inhibitors on NAFLD are lacking; one in vitro study recently reported that PCSK9 may be implicated in TG metabolism and accumulation in the liver via CD36 degradation [301]. Further research is needed to explore in depth the association between PCSK9 inhibitors and NAFLD.

Section snippets

Conclusions

NAFLD is the most frequent chronic liver disease and it can progress from simple steatosis to necroinflammation and fibrosis (i.e. NASH), and in some cases to cirrhosis and hepatocellular carcinoma. Several pathophysiological mechanisms are involved in NAFLD development and progression including inflammation, oxidative stress and insulin resistance. NAFLD is characterized by lipid disorders such as atherogenic dyslipidemia, postprandial lipemia and HDL dysfunction. NAFLD patients are at an

Declaration of Interest

This publication was not sponsored. Niki Katsiki has given talks, attended conferences and participated in trials sponsored by MSD, AstraZeneca, Novartis, Amgen, Sanofi, Novo Nordisk and Libytec. Dimitri P Mikhailidis has given talks and attended conferences sponsored by MSD, AstraZeneca and Libytec. Christos S Mantzoros has no conflicts related to NAFLD/NASH or hyperlipidemia.

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