Non-Alcoholic Fatty Liver Disease and Cardiovascular Risk

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a very common cause of chronic liver disease in United States. A large proportion of patients with NAFLD have co-existing metabolic syndrome which is a major risk factor for cardiovascular disease. A strong association between NAFLD and cardiovascular disease has been long suspected and recent studies have confirmed that cardiovascular disease is the single most important cause of mortality in these patient population. There is a suggestion that NAFLD may pose cardiovascular risk above and beyond that is conferred by traditional cardiovascular risk factors (e.g., dyslipidemia, diabetes and smoking). Health care providers managing patients with NAFLD should recognize this increased cardiovascular risk and should undertake early aggressive risk factor modification.

Introduction

More than 65% of Americans are either overweight or obese. [1] Excess body weight predisposes individuals to chronic diseases such as coronary artery disease, diabetes and nonalcoholic fatty liver disease (NAFLD). The NAFLD is one of the most common causes of chronic liver disease in the United States. It is histologically characterized by the presence of macrovesicular steatosis but occurs in the absence of excessive alcohol consumption. Its histological spectrum includes simple steatosis and steatohepatitis (NASH). The latter presentation can progress to cirrhosis in 15–20% of subjects over the course of ensuing 10–15 years. [2] As patients with NAFLD are enriched with risk factors known to cause and exacerbate atherosclerosis, it has been suspected that individuals with NAFLD are at heightened risk for cardiovascular disease.[3]

Cardiovascular risk factors in patients with NAFLD

Conventional risk factor increasing CVD include age, hypertension, diabetes, physical inactivity, smoking, hyperlipidemia, metabolic syndrome and diet. New and novel risk factors for cardiovascular disease include markers for inflammation (e.g., hsCRP, lipoprotein(a), homocysteine), markers of fibrinolytic and hemostatic function (e.g., fibrinogen, tissue plasminogen activator (t-PA), and plasminogen activator inhibitor 1 (PAI-1) antigens), and more recently NAFLD itself. [4–7] Recent data suggest that many of these newer and novel risk factors are also associated with NAFLD (vide infra). The common denominator for both diseases i.e. NAFLD and cardiovascular disease is obesity related metabolic syndrome and it is increasing virtually in all age groups in the United States. [8–10]

Several studies have shown that patients with NAFLD are heavily enriched with many components of the metabolic syndrome (Table 1). In a cross-sectional study of 876 Taiwanese subjects, 74% of subjects with the metabolic syndrome had ultrasound evidence of NAFLD confirmed by ultrasound, and hypertriglyceridemia, hyperglycemia, and increased waist circumference were independently associated with the presence of NAFLD.[11] A group from Italy reported increased prevalence of coronary (23 % vs. 15.5%), cerebrovascular (17.2% vs. 10.2%) and peripheral vascular disease (12.8% vs. 7%) in people with type2 diabetes and NAFLD as compared to diabetic patients without NAFLD.[12] It has recently been suggested that NAFLD might be an independent risk factor for cardiovascular disease. [6]

Table 1.

Cardiovascular disease risk factors and nonalcoholic fatty liver disease

Higher prevalence of traditional cardiovascular risk factors
Obesity Type2 diabetes Ox-LDL Metabolic Syndrome	Marchesini et al. 2003[51] Tsai et al. 2008[11] Schwimmer et al. 2008[5]
Higher prevalence of surrogate markers of CVD
Increased pericardial fat pad	Perseghin et al. 2008[52]
Endothelial dysfunction	Senturk et al. 2008[53]
Framingham Risk Score	Ioannou et al. 2006[13]
Carotid intima media thickness	Targher et al. 2004[17] Brea et al. 2005[16] Volzke et al. 2005[19] Pacifico et al. 2008[15]
hsCRP	Yoneda et al. 2007[54]

NAFLD and surrogate markers of cardiovascular disease

Several recent studies have shown that adults and children with NAFLD are enriched with risk factors that are generally accepted as surrogates for the risk of cardiovascular disease. Various surrogates used in clinical studies include Framingham Risk Score (consisting age, gender, hypertension, smoking, and hyperlipidemia), carotid artery intima-media thickness, hsCRP, atheroma formation, mediastinal fat pad, endothelial dysfunction and coronary calcium scores (Table 1).

In a cross-sectional population-based study (NHAHES 3), Ioannou et al., compared the 10-year risk of cardiovascular events based on the Framingham risk score (FRS) in individuals with normal and elevated ALT activity (> 43 IU/L).[13] After excluding viral hepatitis and excessive alcohol consumption, individuals with elevated ALT had significantly higher FRS than those with normal ALT.[13] A Turkish study in 92 consecutive patients who underwent coronary angiogram for acute coronary syndrome found that NAFLD independently increased the risk for significant coronary artery disease, as documented by coronary angiogram; this was despite controlling for other risk factors .[14] An Italian pediatric study showed that obese children with NAFLD diagnosed by ultrasound had significantly increased carotid artery intima-media thickness (IMT) compared to obese children without NAFLD and lean children.[15] This was confirmed in a subsequent case-control study that showed that biopsy-proven NAFLD (n=150) had significantly higher prevalence of cardiovascular risk factors than age, gender and BMI-matched children without NAFLD (n=150).[5] Other cross-sectional studies have also documented that patients with NAFLD have significantly greater carotid artery wall thickness than those without NAFLD. [16–18] A large population-based study also suggest premature atherosclerosis in patients with NAFLD.[19]

Cardiovascular morbidity and mortality in NAFLD: Longitudinal studies

In addition to increased prevalence of cardiovascular risk factors and surrogate markers of atherosclerosis and cardiac events, several recent longitudinal studies have actually shown that cardiovascular disease is one of the most important causes of morbidity and mortality in patients with NAFLD. In a study consisting of 132 patients with biopsy proven NAFLD followed for 18 years, cardiovascular disease was the second most common cause of deaths after all of the cancers combined.[20] In a population-based Olmsted county study, the overall mortality of 420 NAFLD patients was significantly increased over a mean follow-up of 7.6 years compared to general population and cardiovascular disease was among the most common causes of death.[21] Another Swedish study consisting of 129 patients with NAFLD showed that patients with NASH had higher incidence of cardiovascular mortality compared to reference population.[22] A population-based study of 980 NAFLD patients and 6,594 controls followed long term (mean:8.7 yrs [range 0.05–11.7 yrs]) showed that NAFLD patients had significantly increased all-cause mortality and cardiovascular mortality, especially in the 45–54 years age group.[24] More recently, another study that linked NHANES III participants to follow-up mortality data showed that cardiovascular disease was the leading cause of death in patients with NAFLD.[25]

NAFLD, inflammatory markers, thrombogenic factors, adipocytokines and cardiovascular risk

Besides the traditional risk factors such as diabetes and hypertension, it is now recognized that cardiovascular disease and metabolic syndrome involve a chronic inflammatory process and impairment in the hemostatic or prothrombotic mechanisms.[3] Recent studies showed high sensitivity of the C-reactive protein (CRP) to predict cardiovascular events.[3] Hemostatic factors associated with increased cardiovascularc risk include plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA), von Willebrand factor, and fibrinogen. The Edinburg Artery Study showed that patients with metabolic syndrome (n=264) had significantly higher levels of fibrinogen, tPA, e-Selectin, CRP, ICAM, and IL-6 compared to patients without metabolic syndrome (n=498).[26] More importantly, in a recent study of healthy non-smoking volunteers, plasma CRP, fibrinogen, v-WF and plasminogen activator inhibitor- 1 (PAI-1) activity levels were markedly higher in subjects with hepatic steatosis than in those without, even after controlling for other confounders such as age, BMI, blood pressure, insulin resistance and triglyceride levels.[27] Recently, IL-6 and CRP have been shown to correlate with higher degrees of fibrosis and inflammation (i.e. NASH) in patients with NAFLD.[28] Therefore, NAFLD/NASH should be considered a chronic inflammatory condition which could add further atherogenic stimuli to the already proinflammatory status conferred by the metabolic syndrome.[29, 30] In both humans and rodents, adipose tissue macrophages accumulate in adipose tissue with increasing body weight and their quantity correlates with measures of insulin resistance.[31] In obese subjects, adipose tissues macrophages content is higher in visceral than subcutaneous adipose tissue, consistent with the hypothesis that visceral fat plays a more prominent role in insulin resistance.[31] These macrophages are a prominent source of proinflammatory cytokines such as TNF-α. This inflammatory cytokine causes a decrease in the level of adiponectin in obesity. [32] Decreased plasma levels of adiponectin, an adipose-secreted adipocytokine with antiatherogenic properties may represent another possible mechanism linking NAFLD and vascular disease.[33]

Therapeutic approach to reducing cardiovascular risk

Some of the treatments aimed at improving NAFLD are also beneficial in improving cardiovascular risk profile (weight reduction, better control of diabetes, insulin sensitizers), whereas management of co-morbidities such as hypertension and dyslipidemia are not expected to liver condition but are critical to reducing cardiovascular morbidity and mortality.

Weight reduction

It is generally recommended that initial weight loss target for improving liver histology is ~ 10% of baseline body weight and it should proceed at a rate of 1–2 pounds per week.[3] Rapid weight fluctuations should be avoided and patients should explicitly be instructed to minimize sudden gain of significant body weight as it may worsen hepatic histology. A recent Swedish study found that 10% increase in body weight achieved by indulging in two fast food meals per day increased ALT levels from an average of 22 to 97 U/L, and hepatic triglyceride content from 1.1 to 2.8%., measured by nuclear magnetic resonance spectroscopy.[35]

Among pharmacological agents for weight loss, Rimonabant, a selective CB1 endocannabinoid receptor antagonist, is effective in promoting weight loss and improving metabolic syndrome in obese patients.[36] A study showed that Rimonabant 20 mg, combined with a hypocaloric diet over 1 year, promoted significant decrease in body weight and waist circumference, and cardiovascular risk factors.[37] This medication is not yet approved by the United States FDA. Two multicenter trials have been begun to evaluate Rimonabant but it will be several years before their results become available. It is noteworthy that CB1 receptors are receiving significant attention as a therapeutic target due to their ubiquitous presence in various organs and due to the availability of its antagonists.[38] Exenatide used to treat type2 diabetes leads to weight loss in addition to glycemic control. Its utility in NAFLD is unknown and recent reports of rare but serious episodes of acute pancreatitis argue against empiric use of this compound to treat NASH. [39] Orlistat, a reversible inhibitor of gastric and pancreatic lipase, may promote weight loss in selected patients but it does not seem to offer any therapeutic benefit beyond that is conferred by the weight loss. [40].

Over the last several years, various forms of laparoscopic weight-loss surgery have become popular. The commonly performed foregut bariatric surgical procedures include roux-en-Y gastric bypass, adjustable gastric banding, gastroplasty and sleeve gastrectomy. Liver histology improves following foregut bariatric surgery in most patients with a very minimal risk of worsening.[41, 42] In a recent meta-analysis consisting of 15 studies and 766 paired liver biopsies, Mummadi et al., showed that all components of NAFLD showed significant improvement following foregut bariatric surgery.[42] The impact of bariatric surgery on metabolic syndrome was assessed in a retrospective study in Olmsted County which showed that the number of patients with metabolic syndrome during the follow-up was significantly lower in the surgical group compared to the nonsurgical group (29% vs 75%). A relative risk reduction of 0.59 (95% CI, 0.48–0.67; P<.001) was observed in terms of metabolic syndrome in patients who underwent bariatric surgery.[43] Another study which was prospective but with shorter follow up showed that bariatric surgery reduced 10-year cardiovascular risk reduced from 6.7% at baseline to 5.2% at 12 months following the surgery. [44] Although no specific studies were conducted to show if sustained and significant weight reduction would improve cardiovascular outcome in addition to liver histology in patients with NAFLD, there are no reasons to believe why it would not be the case.

Lipid lowering agents

For cardiovascular risk reduction, ATP III guidelines recommend that LDL cholesterol should be maintained below 100 mg/dL in subjects with known coronary artery disease or those who are at high risk for coronary artery disease (e.g., type2 diabetics).[3] As patients with NAFLD are heavily enriched with cardiac risk factors and cardiovascular morbidity and mortality is such a dominant issue, their dyslipidemia should be aggressively managed. However, the package inserts for various statins discourage their use in individuals with active liver disease. Over the last 5 years, many studies have consistently shown that statins are very safe in patients with different types of chronic liver disease including nonalcoholic fatty liver.[45–47] Lewis and colleagues have recently reported the results of their double-blind, placebo-controlled, multicenter study of high-dose pravastatin (80 mg/day) to treat dyslipidemia in patients with chronic liver disease. Compared to placebo, patients receiving high-dose pravastatin over the course of 36 weeks not only did not have increased frequency of adverse events but there was a significant reduction in the mean ALT value.[48] Additionally, statins have known anti-inflammatory effects and there are several small studies showing that they may actually improve hepatic histology in patients with NASH.[49, 50] Based on these emerging data, it is safe to conclude that statins are exceptionally safe in patients with NAFLD and should be prescribed to treat dyslipidemia in eligible patients with NAFLD.

Conclusion

Patients with NAFLD have very high prevalence of cardiac risk factors and several recent studies have shown that cardiovascular morbidity and mortality are in fact more important than hepatic adverse events in patient population. Healthcare providers should recognize this heightened cardiovascular risk. Patients should be educated as it is our experience that they become singularly focused on liver enzymes and ignore more important cardiovascular health. Weight loss and optimal management of diabetes and dyslipidemia would improve hepatic histology and also improve cardiovascular morbidity. Many recent studies have shown that statins are safe in patients with chronic liver disease and thus they should not be avoided in NAFLD patients with dyslipidemia.

Table 2.

Longitudinal studies assessing cardiovascular mortality in nonalcoholic fatty liver disease

Author	N	NAFLD diagnosis	F/U (years)	Comments
Matteoni et al.[20]	132	Liver biopsy	18	Cardiovascular disease and liver disease are the two most common causes of death (~11%)
Adams et al.[21]	420	Clinical + imaging ± biopsy	8	Cardiovascular disease was the most common cause of death
Ekstedt et al.[22]	129	Liver biopsy	13.7	Cardiovascular disease caused significantly more deaths than liver disease (15.5% vs. 2.8%)
Dunn et al.[24]	980 NAFLD and 6594 normal subjects	Unexplained elevation in ALT	8.7	Suspected NAFLD had significantly higher all-cause (4.40 95% CI 1.27–13.23) and cardiovascular mortality (8.15, 95% CI 2.00–33.20) after adjusting for conventional cardiovascular risk factors.
Ong et al.[25]	80 NAFLD and 1453 controls	Unexplained elevation in ALT	8.7	Cardiovascular disease is the most common cause of death in NAFLD