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Correspondence to: Claudio Chiesa, MD, Institute of Translational Pharmacology, National Research Council, Via del Fosso del Cavaliere, 100, I-00133 Rome, Italy. firstname.lastname@example.org
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Nonalcoholic fatty liver disease (NAFLD) encompasses a range of liver histology severity and outcomes in the absence of chronic alcohol use. The mildest form is simple steatosis in which triglycerides accumulate within hepatocytes. A more advanced form of NAFLD, non-alcoholic steatohepatitis, includes inflammation and liver cell injury, progressive to cryptogenic cirrhosis. NAFLD has become the most common cause of chronic liver disease in children and adolescents. The recent rise in the prevalence rates of overweight and obesity likely explains the NAFLD epidemic worldwide. NAFLD is strongly associated with abdominal obesity, type 2 diabetes, and dyslipidemia, and most patients have evidence of insulin resistance. Thus, NAFLD shares many features of the metabolic syndrome (MetS), a highly atherogenic condition, and this has stimulated interest in the possible role of NAFLD in the development of atherosclerosis. Accumulating evidence suggests that NAFLD is associated with a significantly greater overall mortality than in the general population, as well as with increased prevalence of cardiovascular disease (CVD), independently of classical atherosclerotic risk factors. Yet, several studies including the pediatric population have reported independent associations between NAFLD and impaired flow-mediated vasodilatation and increased carotid artery intimal medial thickness-two reliable markers of subclinical atherosclerosis-after adjusting for cardiovascular risk factors and MetS. Therefore, the rising prevalence of obesity-related MetS and NAFLD in childhood may lead to a parallel increase in adverse cardiovascular outcomes. In children, the cardiovascular system remains plastic and damage-reversible if early and appropriate interventions are established effectively. Therapeutic goals for NAFLD should address nutrition, physical activity, and avoidance of smoking to prevent not only end-stage liver disease but also CVD.
Over the last two decades, the rise in the prevalence rates of overweight and obesity may explain the emergence of nonalcoholic fatty liver disease (NAFLD) as the leading cause of liver disease in pediatric populations worldwide. NAFLD comprises a disease spectrum ranging from simple steatosis to steatohepatitis (NASH), with varying degrees of inflammation and fibrosis, progressing to end-stage liver disease with cirrhosis and hepatocellular carcinoma[2,3]. NAFLD affects from 2.6% to 9.8% of children and adolescents, and this figure increases up to 74% among obese individuals[4-8]. NAFLD is strongly associated with obesity, insulin resistance, hypertension, and dyslipidemia, and is now regarded as the liver manifestation of the metabolic syndrome (MetS), a highly atherogenic condition. When compared to control subjects who do not have steatosis, patients with NAFLD have a higher prevalence of atherosclerosis, as shown by increased carotid wall intimal thickness, increased numbers of atherosclerotic plaques, and increased plasma markers of endothelial dysfunction, that are independent of obesity and other established risk factors[10-13]. Consistent with these observations natural history studies have reported that the increased age-related mortality observed in patients with NAFLD is attributable to cardiovascular as well as liver-related deaths[14-17].
Pathologic studies have shown that atherosclerosis is an early process beginning in childhood, with fatty streaks observed in the aorta and the coronary and carotid arteries in children and adolescents[18,19]. There is a positive correlation between the extent of early atherosclerotic lesions in the aorta and the coronary and carotid arteries and cardiovascular risk factors, including obesity, dyslipidemia, hypertension, and diabetes[20-22]. Yet the exposure to cardiovascular risk factors of children and adolescents is independently associated with an increased carotid atherosclerosis in early to middle adulthood[23,24]. Thus, the possible impact of NAFLD on cardiovascular disease (CVD) deserves particular attention in view of the implications for screening/surveillance strategies in the growing number of children and adolescents with NAFLD. In the present review, we examine the current evidence on the association between NAFLD and atherosclerosis in the pediatric population, discuss briefly the possible biological mechanisms linking NAFLD and early vascular changes, and address the approach to treatment of NAFLD to prevent not only end-stage liver disease but also CVD.
NAFLD is closely associated with abdominal obesity, atherogenic dyslipidemia, hypertension, insulin resistance and impaired glucose tolerance, which are all features of the MetS. Approximately 90% of patients with NAFLD have at least one of the features of MetS, and about 33% meet the complete diagnosis, placing NAFLD as the hepatic representation of MetS. The relationship of NAFLD with MetS features has been confirmed in adults in several studies[9,26-29]. Evidence for a relationship between MetS and NAFLD in children is also emerging[30-32]. The Korean National and Nutrition Examination Survey found that participants aged 10-19 years who presented with three or more risk factors for MetS, had an odds ratio (OR) of 6.2 (95% CI, 2.3-16.8) for an elevated serum alanine aminotransferase (ALT), which they used as an indicator of fatty liver. A single center study from Italy reported MetS to be present in 65.8% of children (3-18 years) with biopsy-proven NAFLD and found grade of fibrosis to be the only histological feature significantly associated with MetS on univariate analysis. A case-control study comparing 150 overweight children with biopsy-proven NAFLD to 150 age-, sex-, and obesity-matched children without evidence of NAFLD, found that, after adjustment for age, sex, race, ethnicity, and hyperinsulinemia, children with MetS had an OR of 5.0 (95% CI, 2.6-9.7) for NAFLD compared with children without MetS. This is the most compelling data to support a significant relationship between NAFLD and MetS, not explicable merely by the coexistence of overweight or obesity in these two conditions, and lend support to the hypothesis that fat accumulation in the liver has an important role in the pathogenesis of other obesity-related comorbidities.
Increases in morbidity and mortality from CVD are probably among the most important clinical features associated with NAFLD. Published studies have shown that mortality among patients with NAFLD is higher than that in the general population, mainly due to concomitant CVD and liver dysfunction[14-17]. Using the resources of the Rochester Epidemiology Project, Adams et al conducted a population-based cohort study to examine the natural history of patients diagnosed with NAFLD on the basis of imaging studies (83%) or liver biopsy (17%). Mean (SD) follow-up was 7.6 (4.0) years culminating in 3192 persons/years follow-up. Death occurred in 12.6% of patients and was most commonly due to malignancy and ischemic heart disease, which were also the two most common causes of death in the Minnesota general population of the same age and sex. Liver disease was also an important contributor of death among patients with NAFLD, being the third most common cause and accounting for 13% of all deaths. In contrast, “chronic liver disease and cirrhosis” was the 13th leading cause of death among the Minnesota general population, accounting for less than 1% of all deaths. This implies that the increased overall mortality rate among NAFLD patients compared with the general population was at least in part due to complications of NAFLD. In a cohort study involving 129 consecutively enrolled patients diagnosed with biopsy-proven NAFLD, Ekstedt et al compared survival and causes of death with a matched reference population. Mean follow-up (SD) was 13.7 (1.3) years. Mortality was not increased in patients with steatosis. In contrast, survival of patients with NASH was significantly reduced. A comparison of the causes of death of patients with NASH with those of the corresponding reference population showed it was significantly more common for patients with NASH to die from liver-related causes (2.8% vs 0.2%) and from cardiovascular disease (15.5% vs 7.5%). No significant differences in causes of death were found between non-NASH patients and the corresponding reference population. In a cohort study involving 173 patients retrospectively identified as having a diagnosis of biopsy-proven NAFLD, Rafiq et al showed that after a median follow-up of 18.5 years, patients with histologic NASH had significantly higher liver-related mortality than the non-NASH NAFLD cohort (17.5% vs 2.7%). The most common causes of death were coronary artery disease, malignancy, and liver-related death. In a very recent study involving a cohort of 118 subjects with NAFLD who underwent liver biopsy because of elevated liver enzymes, Söderberg et al confirmed that, after a 28-year follow-up, overall survival was reduced in subjects with NASH, whereas bland steatosis with or without severe fibrosis was not associated with any increase in mortality risk in comparison with the general population. The main causes of death among patients with NAFLD were CVD, followed by extrahepatic cancers and hepatic diseases. All these data provide evidence of an increased risk for cardiovascular mortality in patients with NASH. However, most studies which examined the natural history of NAFLD were retrospective cohort studies with relatively small numbers of patients with histologically proven NAFLD who were seen at tertiary referral centers - features that limit the generalizability of the findings to a community-based practice where patients may have a milder disease. Indeed, among people with NAFLD, those who are referred to hepatologists may have a more advanced liver disease than those detected in the community or population based screening but are not referred. Therefore, the magnitude of mortality risk in NAFLD depends on the setting and method of ascertainment. Future longitudinal studies with larger and less selected cohorts of patients are needed to identify through reliable, noninvasive means the true impact of the wide spectrum of NAFLD in the general population on the long-term overall and cardiovascular mortality.
Data on the prognosis and clinical complications of NAFLD in children remain scant. Although coronary artery disease and stroke usually occur in middle and late age, autopsy studies have shown that the atherosclerotic process in the vascular wall begins in childhood and is accelerated in the presence of risk factors[18-24]. Given the large number of children affected, it is imperative that we establish a better understanding of the natural history of pediatric NAFLD in terms of the progression of liver disease as well as its complications (including long-term cardiovascular risk profile). Feldstein et al recently reported the first longitudinal study describing the long-term survival of children with NAFLD who underwent a follow-up of up to 20 years. That study demonstrated that NAFLD in children is a disease of progressive potential. Some children presented with cirrhosis, others progressed to advanced fibrosis or cirrhosis during follow-up, and some developed end-stage liver disease with the consequent need for liver transplantation. Feldstein et al also showed that NAFLD in children is associated with significantly shorter long-term survival than the expected survival in the general population of the same age and sex. Children with NAFLD had a 13.8-fold higher risk of dying or requiring liver transplantation than the general population of the same age and sex. The recorded deaths were not liver-related.
Recent epidemiological studies in adult subjects have also demonstrated that NAFLD is associated with an increased risk of incident CVD that is independent of the risk conferred by traditional risk factors and components of the MetS[35-42]. Yet, several studies (including the pediatric population) have reported independent associations between NAFLD and impaired flow-mediated vasodilatation (FMD) and increased carotid-artery intimal medial thickness (cIMT) - two reliable markers of subclinical atherosclerosis - after adjusting for cardiovascular risk factors and MetS[10,12,43-47].
The relation between obesity and atherosclerosis development has been evaluated in many pediatric studies, but few studies focused on the relation between NAFLD and atherosclerosis (Table (Table11)[32,47,49-56]. In an autopsy study involving 817 children (aged 2 to 19 years) who died of external causes (accident, homicide, suicide) from 1993 to 2003, Schwimmer et al showed that the prevalence of atherosclerosis was increased by a factor of 2 among those with NAFLD. Atherosclerosis was assessed as absent, mild (aorta only), moderate (coronary artery streaks/plaques), or severe (coronary artery narrowing). Fatty liver was present in 15% of the children. For the entire cohort, mild atherosclerosis was present in 21% and moderate to severe atherosclerosis in 2%. Atherosclerosis was significantly more common in children with fatty liver than those without the disease (30% vs 19%, P < 0.001). Body mass index (BMI) was not independently correlated to the presence of atherosclerosis, but fatty liver status and BMI did interact significantly (P < 0.01). Consequently, for obese subjects the odds of having atherosclerosis was more than 6 times higher in children with fatty liver than those without.
Despite this, there are currently few data regarding the possible association between liver histopathologic changes and atherogenic risk in children[32,52,56]. In the Bogalusa heart study in children, investigators found that the extent to which the intimal surface was covered with atherosclerotic lesions was significantly associated with elevation of concentrations of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), triglycerides (TG), and lower concentration of high-density lipoprotein cholesterol (HDL-c). Ratios of cholesterol ester-rich lipoprotein level (TC/HDL-c and LDL-c/HDL-c) are well-established predictors of C VD. More recently, the TG/HDL-c ratio has been shown to be a strong predictor of MetS and CVD[58,59]. In a case-control study, Schwimmer et al showed that children with a biopsy-proven NAFLD had a significantly higher fasting glucose, insulin, TC, LDL-c, TG, systolic and diastolic blood pressure than age-, sex-, and BMI-matched peers without NAFLD. These data confirm that fat accumulation in the liver may play a more important role than obesity itself in determining the risk for “weight-related” metabolic comorbidities. Thus, the authors concluded that NAFLD may serve as a marker to stratify the cardiovascular risk of overweight and obese children and adolescents. Furthermore, in a study involving 118 consecutive children with biopsy-proven NAFLD undergoing extensive metabolic profiling, Nobili and colleagues found that the NAFLD activity and fibrosis scores had a significant positive correlation with TG/HDL-c, TC/HDL-c, and LDL-c/HDL-c ratios. After adjusting for potential confounders including BMI, homeostatic model assessment index, impaired glucose tolerance, and presence of MetS, both NAFLD activity score and stage of fibrosis remained independent predictors of an atherogenic lipid profile. The lipid ratios were found to be markedly higher in children with established NASH compared with those patients with simple steatosis or borderline disease, indicating that severity of liver injury in children with NAFLD is strongly associated with increased atherogenic risk.
Recent improvements in imaging technology have identified early vascular changes that can be assessed by the use of ultrasonography. These early changes include impairment of FMD, arterial stiffness, and increased cIMT. The measurement of FMD and cIMT by high-resolution ultrasound is increasingly used for cardiovascular risk evaluation in young individuals with obesity, MetS or its components, and pre-diabetes[23,60,61]. Pacifico et al first showed that the severity of ultrasonographically diagnosed NAFLD in obese children was significantly associated with carotid atherosclerosis, independently of anthropometric and metabolic features. Demircioglu et al, in a subsequent study, also found an association between ultrasonographically detected NAFLD and cIMT measured at sites of the common carotid artery, carotid bulb and internal carotid artery. In addition, there was an increase in the mean of cIMT of each segment with the increase in hepatosteatosis grade. Kelishadi et al also demonstrated that cIMT was significantly associated with insulin resistance and NAFLD, suggesting that the liver and the vessels share common mediators. This is in contrast to the case-control study by Manco et al including a mixed population of overweight and mildly obese children of whom 31 had biopsy-proven NAFLD, whereas 49 had no ultrasound evidence of NAFLD and no abnormal levels of aminotransferases. Although cIMT was statistically significantly higher on the left side in NAFLD cases, the authors concluded that this difference was unlikely to be clinically relevant because of the substantial overlap of cIMT values between cases and controls. Also, there were no differences in the frequency of MetS components between the groups. Finally, there was no association between histologic severity of NAFLD and cIMT. However, a recent study by Patton et al  showed the potential power of MetS as a prognostic indicator of disease severity in NAFLD. Of the MetS features, central obesity and insulin resistance were most consistently associated with NAFLD histology.
The association between NAFLD and carotid atherosclerosis has also been determined in a large, randomly selected adolescent population from Reggio Calabria, a town in southern Italy. The authors found that NAFLD, BMI, waist circumference, and systolic blood pressure were independent markers of increased cIMT. Likewise, in a very recent study with a large sample size it has been shown that obese children with NAFLD have a significantly lower FMD response and increased cIMT compared to obese children without NAFLD independently of other cardiovascular risk factors and MetS, and that obese children exhibit more functional and morphologic vascular changes than healthy lean controls, regardless of liver involvement. The larger number of subjects in that study may in part account for the associations the authors were able to identify between NAFLD and functional vascular changes, in contrast to the study by Weghuber et al. in which a very small sample of obese children with and without NAFLD had a similar FMD response.
Although longitudinal studies are needed to clarify the extent to which pediatric NAFLD and its severity influence long-term cardiovascular outcomes in the general population, overall the above cross-sectional findings suggest that childhood NAFLD is associated with early atherosclerosis.
The biologic mechanisms by which NAFLD contributes to accelerated atherosclerosis, independently of other risk factors, are still poorly understood. Increased visceral adipose tissue and insulin resistance are the undisputed major contributors to NAFLD, MetS, and atherosclerosis[9,62,63]. The adipose tissue inflammation with consequent release of multiple proinflammatory molecules is one of the earliest steps in the chain of events involved in the development of insulin resistance and atherosclerosis, in particular in obese and overweight persons[64-66]. While insulin resistance promotes fatty acid accumulation in the liver, the latter causes hepatic insulin resistance characterized by a lack of suppression of endogenous liver glucose production. Therefore, NAFLD might act as a stimulus for further increased whole-body insulin resistance and dyslipidemia (with a characteristic overproduction of triglyceride- and cholesterol-rich remnant particles), leading to accelerated atherosclerosis. It is also conceivable that other atherogenic mechanisms could be involved in patients with NAFLD including enhanced oxidative stress and chronic, subclinical inflammation, which are thought to be causal factors in the progression from simple steatosis to more advanced forms of NAFLD[27-29,62]. Indeed, patients with NAFLD frequently have higher plasma markers of oxidative stress and inflammation, at least partially derived from the diseased liver, as well as decreased adiponectin concentrations, an adipose-secreted cytokine with antiatherogenic properties[11,67-69].
Recent research has suggested a role for increased fructose consumption as a risk factor for NAFLD[70,71]. Strong evidence exists that fructose consumption may promote hepatic de novo lipogenesis and intrahepatic lipids, inhibition of mitochondrial β-oxidation of long-chain fatty acids, triglyceride formation and steatosis. In addition, compared to glucose consumption, sustained dietary fructose has been reported to significantly increase plasma concentrations of fasting small dense LDL-c, oxidized LDL-c, and postprandial remnant-like-particle-triglyceride and -cholesterol in overweight and obese subjects. These changes may be associated with increased risk of CVD[74,75].
Finally, NAFLD could be linked to accelerated atherogenesis through the presence of abnormal lipoprotein metabolism, especially during the post-prandial phase[76,77]. Apolipoprotein (APO) B is a large protein involved in the transport of triglycerides and cholesterol from the liver to peripheral tissues. Diminished synthesis of APO B, a rate-determining step in the very low density lipoproteins (VLDL) assembly, would impair the ability of the hepatocyte to export triglycerides and cholesterol esters. Impaired VLDL secretion would also result in increased levels of atherogenic triglyceride- and cholesterol-rich remnant particles. Recent studies have suggested a genetic basis for abnormal lipoprotein metabolism in patients with NAFLD. Two single-nucleotide polymorphisms in the gene encoding APOC3 may be associated with hypertriglyceridemia[78-80]. APOC3 variants C-482T and T-455C lead to increased plasma concentrations of APOC3, which in turn inhibit lipoprotein lipase and triglyceride clearance, thus conferring a predisposition to both fasting and postprandial hypertriglyceridemia due to an increase in chylomicron-remnant particles.
The only accepted therapy for pediatric NAFLD is lifestyle modification with diet and physical exercise. The close association of NAFLD with MetS and obesity in children provides the rationale for the therapeutic role of weight reduction in the treatment of fatty liver disease. Fortunately, this approach may also be beneficial in improving cardiovascular risk profile.
Weight-loss oriented lifestyle interventions in the overweight pediatric population have been shown to increase glucose tolerance and improve the MetS risk factors. In children with presumed NAFLD, several studies demonstrate a normalization of serum ALT associated with weight loss[5,83,84]. However, the relative efficacy of weight loss and degree of weight loss needed to induce histologic improvement in pediatric NAFLD is unknown. Studies in adults with NAFLD suggest that weight loss also leads to significant improvement in liver histology. In particular, a weight loss greater than 5% has been associated with significant improvement in liver histology. There is only one clinical trial using liver histology as the primary end point in children and adolescents with NAFLD. The study demonstrated that 2 years of lifestyle intervention with a diet tailored on individual caloric requirement and increased physical activity was associated with a mean weight loss of approximately 5 kg, resulting in a significant improvement in liver histology as well as in insulin resistance, serum levels of aminotransferases, and lipid levels. No information exists on recommending any type of diet. A low-carbohydrate diet has been shown to lead to a reduction in serum ALT and fatty liver content in adult patients. A randomized controlled study in obese adolescents has demonstrated that a diet based on a reduced glycemic load is more effective than a low fat diet in achieving weight loss, but similar data are not available in children with NAFLD. Current data on the role of a low fructose diet in children with NAFLD are inconclusive. A 6-month pilot study in children with NAFLD showed that a low fructose diet was associated with a significant decrease in oxidized LDL-c. However, no effect on serum ALT concentrations was found. N-3 long-chain polyunsaturated fatty acids (LCPUFA) including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been reported to control some of the metabolic stigmata of obesity. Dietary N-3 LCPUFA lower blood triglycerides and have anti-inflammatory as well as insulin-sensitizing effects. A recent randomised clinical trial has shown that the supplementation of DHA improves liver steatosis and insulin sensitivity in children with NAFLD. Their role in prevention of CVD is also emerging. At this time, however, the available information is insufficient to derive dietary intake recommendations for EPA and DHA. Finally, diet duration and amount of weight loss have not been definitively assessed in children[83,93,94].
A general consensus exists about the key role of physical activity and its synergic effect when combined to diet modifications. Increasing energy expenditure is an additional way to reducing daily calories. Liver biopsy has shown improvement of histologic features in children with NAFLD who were engaged in a moderate daily exercise program (45 min/d aerobic physical exercise) associated to dietary changes.
Owing to the likely role of insulin resistance and oxidative stress in the development and progression of NAFLD, most studies on pharmacological treatment have focused on the use of metformin or antioxidants. These drugs have been found to be effective in pilot studies. Recently, in a multicenter, randomized, placebo-controlled clinical trial of treatment with metformin, vitamin E, or placebo for 96 wk in 173 nondiabetic children with histologically confirmed NAFLD, the Nonalcoholic Steatohepatitis Clinical Research Network found that compared with placebo, neither vitamin E nor metformin was associated with a sustained reduction in serum ALT[95,96]. Compared to placebo, vitamin E significantly improved hepatocellular ballooning and NAFLD activity score and, in the subset of children with NASH at baseline, significantly increased resolution of NASH. Metformin had no significant effect on any secondary histologic outcome. Neither vitamin E nor metformin had significant effects on fibrosis, lobular inflammation, or portal inflammation scores. No significant differences in safety were reported between groups. However, the likelihood that vitamin E would need to be taken indefinitely underlines the importance of long-term prospective studies involving patients with NASH to assess the effect of vitamin E on liver-related and cardiovascular mortality.
Given the role of obesity in the pathogenesis of NAFLD, bariatric surgery has been proposed as a potential treatment strategy. In obese adult patients, bariatric surgery has been shown to induce weight loss, ameliorate cardiovascular risk factors, resolve hepatic steatosis and, in most studies, inflammation[99-101]. NASH was improved in the majority of affected patients and was intimately associated with insulin resistance over both the short and long term. The issue of NAFLD and bariatric surgery in children is complex. Though adolescents are increasingly undergoing surgical treatment of obesity, the guidelines for eligibility are not standardized. In addition, children with a clinical diagnosis of NAFLD are different from those typically undergoing bariatric surgery. Children with a clinical diagnosis of NAFLD tend to be younger and less obese than adolescents undergoing surgical treatment of obesity. Although several studies report resolution or improvement of comorbidities after bariatric surgery in adolescents[104,105], liver outcome data are needed. In a series of 41 adolescents, Nadler et al reported improvement in liver function enzymes 1 to 2 years after surgery.
The current body of evidence suggests that NAFLD is associated with a significantly greater overall mortality than in the general population, as well as with increased CVD prevalence, independently of classical atherosclerotic risk factors. These observations raise the possibility that NAFLD may be not only a marker but also an early mediator of atherosclerosis.
Children with NAFLD may also be at a higher risk for atherosclerosis. Therefore, the rising prevalence of obesity-related MetS and NAFLD in childhood may lead to a parallel increase in adverse cardiovascular outcomes. In children, the cardiovascular system remains plastic and damage-reversible if early and appropriate interventions are established effectively. Therapeutic goals for NAFLD should address nutrition, physical activity and avoidance of smoking to prevent not only end-stage liver disease but also CVD.
Peer reviewers: Eyvind J Paulssen, MD, PhD, Department of Gastroenterology, University Hospital of North Norway, PO Box 83, Tromsø, N-9038, Norway; Yoshihisa Takahashi, MD, Department of Pathology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan
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