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Fatty Liver Accelerates Liver Disease: Steatosis, Co-factor in other liver diseases
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Hepatology
16 Jun 2005
Elizabeth E. Powell *, Julie R. Jonsson, Andrew D. Clouston
School of Medicine, Southern Division, University of Queensland, Princess Alexandra Hospital, Brisbane, Australia
Abstract
The prevalence of fatty liver is rising in association with the global increase in obesity and type 2 diabetes. In the past, simple steatosis was regarded as benign, but the presence of another liver disease may provide a synergistic combination of steatosis, cellular adaptation, and oxidative damage that aggravates liver injury. In this review, a major focus is on the role of steatosis as a co-factor in chronic hepatitis C (HCV), where the mechanisms promoting fibrosis and the effect of weight reduction in minimizing liver injury have been most widely studied. Steatosis, obesity, and associated metabolic factors may also modulate the response to alcohol- and drug-induced liver disease and may be risk factors for the development of hepatocellular cancer. The pathogenesis of injury in obesity-related fatty liver disease involves a number of pathways, which are currently under investigation. Enhanced oxidative stress, increased susceptibility to apoptosis, and a dysregulated response to cellular injury have been implicated, and other components of the metabolic syndrome such as hyperinsulinemia and hyperglycemia are likely to have a role. Fibrosis also may be increased as a by-product of altered hepatocyte regeneration and activation of bipotential hepatic progenitor cells. In conclusion, active management of obesity and a reduction in steatosis may improve liver injury and decrease the progression of fibrosis.
Article Text
Because of the global epidemic of obesity, the prevalence of fatty liver in the general population may be even higher than previously suspected. In a recent large U.S. urban population study using proton magnetic resonance spectroscopy, hepatic steatosis was present in almost one third of the subjects.[1] It is most commonly associated with obesity, insulin resistance and other components of the metabolic syndrome (reviewed by Neuschwander-Tetri and Caldwell[2]). Not surprisingly, steatosis is a frequent finding in liver biopsies and may co-exist with other chronic liver diseases.
Until recently, simple steatosis was regarded as inconsequential. However, increasing evidence indicates that a fatty liver is more vulnerable to factors that lead to inflammation and fibrosis.[3] When another liver disease is present, co-existent obesity or steatosis may exacerbate the liver injury. This has important therapeutic implications, because active management of obesity and a reduction in steatosis may improve liver injury and decrease the progression of fibrosis.
In this review, the interaction of obesity-related steatosis with several liver disorders is discussed. The major focus is on chronic hepatitis C (HCV), in which the mechanisms promoting fibrosis and the effect of weight reduction in minimizing liver injury have been most widely studied. The role of obesity and steatosis as co-factors for alcohol- and drug-induced liver disease and primary liver cancer also are discussed.
Steatosis Influences the Progression of Fibrosis in Chronic HCV
Hepatic steatosis is commonly found in subjects with chronic HCV, occurring in approximately 50% of liver biopsy samples, with a reported range of 30% to 70% (reviewed by Clouston and Powell[4]).[5-7] This prevalence is approximately 2.5-fold higher than predicted by chance alone, suggesting that HCV has a direct role in the development of steatosis.[8] Alternatively, the coexistence of fatty liver disease may determine the presentation or referral of these patients and their selection for liver biopsy.
Steatosis is important in this viral infection because there is increasing concern about its role in disease progression. Many studies have now demonstrated a significant relationship between steatosis and hepatic fibrosis,[9-19] although most did not adjust for other metabolic risk factors such as obesity, diabetes, or insulin resistance.[18] Adinolfi and colleagues[12] found an increased yearly rate of fibrosis progression in their patients with higher grades of steatosis, and we showed a similar relationship in our patients with chronic HCV. In addition, Westin and colleagues[13] found that progression of fibrosis on follow-up liver biopsy was more prevalent in patients whose initial biopsy showed steatosis, and in a recent study increasing levels of steatosis at second biopsy were associated with more rapid fibrosis progression.[14] Although most patients with chronic HCV have mild degrees of fat accumulation, even minor amounts of steatosis are associated with increased body mass index (BMI) and higher serum triglycerides[16] and may contribute to the natural history of fibrosis in chronic HCV.[19]
As well as an increase in portal fibrosis, many patients with steatosis and chronic HCV have perisinusoidal fibrosis with a chicken-wire appearance similar to that seen in steatohepatitis[20]. Several risk factors for progression of fibrosis are common to both chronic HCV and obesity-related fatty liver disease. These factors include increased BMI, type 2 diabetes, increasing age, and alcohol intake - all of which may increase the severity of steatosis.[8] The development of cirrhosis in patients with HCV may be associated with regression of steatosis,[21] as has previously been documented in non-alcoholic steatohepatitis (NASH).[22][23] The mechanisms leading to a reduction in steatosis in the liver with cirrhosis remain uncertain but may be associated with portal-systemic shunting resulting in decreased hepatic exposure to insulin.[23]
Both host and viral factors contribute to the development of steatosis in chronic HCV. The virus has a direct steatogenic effect, as evidenced by the accumulation of intracellular lipids in some transgenic cell lines and animal models expressing HCV proteins.[24][25] This may be attributable to viral proteins interfering with mitochondrial function and impairing fatty acid oxidation[26] or to interference with pathways of lipid metabolism. The HCV core protein has been shown to reduce the activity of microsomal triglyceride transfer protein, interfering with the assembly and secretion of very-low-density lipoprotein.[27] There is a discrepancy between these in vitro models of steatosis that have predominantly used HCV genotype 1-derived constructs and clinical studies. Steatosis is more prevalent and severe in patients infected with viral genotype 3, but the explanation for this effect remains unclear. In subjects infected with genotype 3 but not in those infected with genotype 1, steatosis correlates with levels of intrahepatic viral replication and largely resolves after successful antiviral treatment.[12][16][17][28] Importantly, alterations in lipid metabolism might affect HCV replication.[29]
In addition to the viral effect, clear evidence exists that host factors, in particular an increased BMI or central adiposity, are important co-factors in the development of steatosis. Overweight patients have significantly more steatosis than lean subjects irrespective of viral genotype (Fig. 3), and insulin resistance appears to be a key pathophysiological mechanism. Although much of the clinical literature has focused on steatosis being a viral effect in genotype 3 infection and a metabolic effect in non-genotype 3-infected patients, it is likely attributable to a combination of host and viral factors, with the relative importance of each varying with genotype. In support of this, a recent large study[16] found that non-genotype 3 patients with a sustained response to antiviral therapy showed reduced steatosis in 46% of cases, and 29% lost steatosis completely. When metabolic features, genotype and response to therapy were considered, the viral and metabolic influences on steatosis were estimated as follows: genotype 3 - 38% of patients belonged to the group of viral steatosis (sustained virological response and disappearance of steatosis); 24% of patients were considered mixed viral-metabolic steatosis (sustained virological response with decrease of initial steatosis without metabolic improvement if any at baseline); 30% of patients belonged to the group of metabolic steatosis (metabolic factor at baseline or at follow-up, without steatosis improvement in sustained responders); and 8% were unclassified steatosis; non-genotype-3: 12% viral, 6% mixed viral/metabolic, 67% metabolic. Marked reduction in steatosis after weight loss has been seen in several patients infected with genotype 3, confirming that viral factors are not the sole cause of fat accumulation.[30]
In the clinical setting, one must consider the role of other insults such as alcohol in the development of steatosis. Studies have provided conflicting data regarding the contribution of alcohol to steatosis in chronic HCV,[10][15][31] perhaps in part because of the difficulty in obtaining a reliable history of alcohol consumption.
Potential Pathogenic Roles of Steatosis and Obesity in Hepatic
The mechanisms by which obesity and steatosis promote fibrosis in chronic HCV may involve a number of pathways, which are currently under investigation. At least some evidence implicates enhanced oxidative stress, activation of subsinusoidal stellate cells, increased susceptibility to apoptosis, and a dysregulated response to this cellular injury. In addition, fibrogenesis may be enhanced by other components of the metabolic syndrome such as hyperinsulinemia and hyperglycemia. It is also possible that fibrosis is increased as a byproduct of altered hepatocyte regeneration and activation of bipotential hepatic progenitor cells.
Oxidative Stress.
Accumulating evidence suggests that fatty livers are more vulnerable to injury induced by factors that increase hepatic oxidant production. In chronic HCV, the antiviral inflammatory response provides an additional source of oxidative stress and may lead to increased lipid peroxidation, production of proinflammatory cytokines, and cell death (reviewed by Lonardo et al.[8]) More pronounced oxidative DNA damage (assessed by the oxidative DNA adduct 8-hydroxydeoxyguanosine) was found in non-genotype 3 infection, suggesting that viral genotype may also have a role.[32][33]
Steatohepatitis.
Although steatosis is common in association with HCV, the other classical features of steatohepatitis such as hepatocyte ballooning and neutrophil infiltration are infrequent. In contrast to steatosis, which was seen in more than 50% of liver biopsy specimens, only 6%[15] and 18%[34] of biopsy specimens from patients with chronic HCV had strictly defined steatohepatitis. When present, superimposed steatohepatitis was independently associated with advanced fibrosis.[34] In primary nonalcoholic steatohepatitis, hepatocyte ballooning may represent a marker of oxidative stress.[35] Because HCV infection itself is a source of oxidative stress, the combination of simple steatosis and HCV is likely to produce the conditions for a similar pathway of injury.[4] In support of this hypothesis, a significant correlation between steatosis and perisinusoidal fibrosis was observed in subjects with chronic HCV, similar to that seen in steatohepatitis.[20] In that study, a highly significant association between steatosis and portal fibrosis was also demonstrated. After weight loss by HCV-infected patients, there was a reduction in steatosis as well as portal fibrosis and stellate cell/myofibroblast activation.[30] The decrease in mean portal myofibroblast numbers was striking and suggests that steatosis may not only enhance fibrosis locally at the stellate cell level within the lobule but also at a distance through an effect on portal myofibroblasts.
Apoptosis.
Hepatocyte apoptosis is a feature of obesity-related fatty liver disease.[36] Feldstein and colleagues[36] observed a positive correlation between hepatocyte apoptosis and both hepatic inflammatory activity and fibrosis, implicating a role for the apoptotic process in the progression of fatty liver disease. In chronic HCV, a similar significant increase in liver cell apoptosis was seen in liver sections with moderate or severe steatosis and this relationship persisted after multivariate analysis.[37] Bcl-2 and Bax are anti- and pro-apoptotic members, respectively, of the Bcl-2 family of proteins that have a critical role in the regulation of apoptosis. In chronic HCV, increasing steatosis was associated with decreased Bcl-2 mRNA levels and an increase in the pro-apoptotic Bax/Bcl-2 ratio. In subjects with steatosis, increasing apoptosis was associated with both increased stage of fibrosis and activation of stellate cells (assessed by -smooth muscle actin staining). This relationship was not seen in the absence of steatosis. In a preliminary study, Farinati and colleagues[33] also found an association between genotype 3 infection, increased steatosis, and upregulation of the Fas/Fas-ligand system. More recently, detection of apoptotic caspase activity in serum has been proposed as a sensitive method of detecting early liver injury in patients with chronic HCV.[38]
Other Metabolic Factors.
It has been argued that steatosis is simply a by-product of metabolic factors, principally insulin resistance, and that the latter may be the principal driver of enhanced fibrosis in HCV.[39-41] Obesity is associated with insulin resistance resulting in hyperinsulinemia, increased free fatty acid concentrations, and hyperglycemia. Viral factors may also cause insulin resistance,[40] particularly in genotype 1- and 2-infected patients, and this may be mediated by increased intrahepatic tumor necrosis factor alpha levels.[42] A number of studies have now demonstrated a higher prevalence of insulin resistance or type 2 diabetes in patients with chronic HCV and an association with increased fibrosis (reviewed by Lonardo et al.[8]). Elevated circulating insulin and glucose may have a direct role in fibrogenesis[18][43] by stimulating the release of connective tissue growth factor from hepatic stellate cells and the production of extracellular matrix.[44][45] In a recent study, overweight patients with chronic HCV had increased circulating insulin levels irrespective of viral genotype.[43] In overweight subjects, there was a significant association between increasing insulin levels and fibrosis. In contrast, fasting insulin levels were similar in lean patients and did not correlate with the stage of fibrosis. A role for obesity-related alterations in serum leptin levels in chronic HCV remains controversial.[43][46][47] Although in NASH, lower levels of the protective adipokine, adiponectin, are associated with higher grades of steatosis and necroinflammatory activity,[48][49] the contribution of adiponectin to disease progression in HCV has not been determined.
Altered Hepatocyte Regeneration.
Hepatocyte proliferation has been shown to be impaired in alcohol-induced liver disease[50] and more recently in rodents[51-53] and humans with fatty liver.[52] The imbalance between enhanced proliferative drive from HCV and impaired primary hepatocyte proliferation from steatosis and other factors may lead to default proliferation of bipotential hepatic progenitor cells (HPC) and a bile ductular reaction.[54] Ductular epithelium has been shown to express proteins, such as transforming growth factor beta, monocyte chemoattractant protein-1, and platelet-derived growth factor, that attract and activate stellate cells, leading to collagen deposition.[55-57]
Recently, the bile ductular reaction was analyzed in biopsy specimens from 115 patients with HCV, and a highly significant correlation was seen between the area of bile ductules positive for cytokeratin 7 (a marker of bile duct and ductular epithelium) and fibrosis stage (rs = 0.56, P < .0001).[58] Increased HPC were located in close proximity to the ductular reaction, and their numbers were strongly correlated with both fibrosis stage and the ductular area. Steatosis was independently associated with increased HPC and the extent of the ductular reaction, providing a potential mechanism whereby steatosis could contribute to the progression of portal fibrosis. A significant independent relationship was also seen between the number of HPC and the number of hepatocytes in replication arrest, supporting the hypothesis that the periportal ductular reaction is a consequence of altered hepatocyte proliferation.
Effect of Reducing Steatosis
Additional support for the role of steatosis and insulin resistance in HCV-related fibrosis has been provided by studies examining the effect of a reduction in steatosis. A marked improvement in hepatic steatosis after weight reduction has been shown in patients with viral genotypes 1 or 3.[30] These benefits were seen with loss of as little as 4% to 5% body weight, without necessarily normalizing BMI. However, the degree of reduction in steatosis was significantly associated with the percentage of weight loss. In subjects with a decrease in steatosis, a significant decrease occurred in the median fibrosis score, along with a striking reduction in stellate cell activation.[30] In addition, maintenance of weight loss and exercise resulted in a sustained improvement in liver enzymes, serum insulin levels, and quality of life.[59] These results have important clinical implications and suggest that obesity should be actively addressed in the management of patients with chronic HCV.
Steatosis and Response to Antiviral Therapy
There is increasing interest in the role of obesity and hepatic steatosis as modifiable risk factors that may impair the response to antiviral therapy. In subjects with non-genotype 3 infection, absence[16] or lesser degrees[17] of pretreatment steatosis were associated with higher sustained virological response. However, in subjects with viral genotype 3, steatosis does not negatively affect the outcome of treatment, suggesting that steatosis per se may not intrinsically impair antiviral efficacy. Other investigators found that obesity is a negative predictor of treatment response,[60] and in an earlier study, interferon blood levels and 25-oligoadenylatesynthetase induction were lower in obese patients after a dose of interferon-.[61] Because obesity and steatosis are inter-related, whether their effects are independent and whether weight-based dosing can improve the treatment response remain unclear. The mechanisms whereby obesity and insulin resistance reduce the biological response to interferon remain to be determined.
Obesity, Steatosis, and Alcoholic Liver Disease
Excess body weight has also been recognized as a risk factor for the development of cirrhosis in alcoholic liver disease (ALD). In subjects with heavy alcohol consumption, excess body weight markedly increases the presence of steatosis[62] and is a risk factor for the development of acute alcoholic hepatitis and cirrhosis.[63][64] Multiple factors are involved in alcohol-induced liver injury, and the mechanisms by which obesity contributes to this process are now being examined.[65]
The up-regulation of microsomal cytochrome P4502E1 (CYP2E1) by ethanol has a key role in the pathogenesis of alcoholic liver injury.[66] Induction of CYP2E1 leads to generation of reactive oxygen species (ROS) that promote lipid peroxidation and inflammation when antioxidant pathways are depleted. Fatty acids and ketones are also substrates for CYP2E1. An increased delivery of free fatty acids to the liver in obesity may result in greater induction of CYP2E1, leading to increased formation of prooxidant species.[67][68]
Abnormal cytokine metabolism and alteration in hepatic macrophage function are additional factors that may contribute to liver injury in obese alcoholics. In ALD, an increase in circulating endotoxin may lead to Kupffer cell activation and associated increases in proinflammatory cytokines, prostaglandins, and other factors. The production of these inflammatory mediators may be augmented by obesity. In a study of 36 alcoholics, a positive correlation was found between production of the proinflammatory cytokine interleukin-1 by stimulated monocytes and BMI, percentage body fat, abdominal circumference, and total histological score (derived from the sum of fat, necrosis, fibrosis, and inflammation).[69] In addition, adipose tissue itself produces a variety of soluble factors, including adipokines, neurotransmitters, and cytokines, that may modulate the response to alcohol-induced liver injury.[65] Further studies are required to determine whether weight reduction and dietary fat restriction have a role in minimizing liver injury in patients with ALD.
Steatosis, Obesity, and Primary Liver Cancer
There is emerging interest and concern regarding associations of obesity and type 2 diabetes with primary liver cancer. In a study of hepatocellular cancer (HCC) in explanted liver specimens from 19,271 subjects undergoing liver transplantation, obesity was an independent risk factor for HCC in ALD and cryptogenic cirrhosis.[70] Obese subjects with cryptogenic cirrhosis are likely to have had prior NASH, and it was speculated that the presence of antecedent steatosis in both ALD and cryptogenic cirrhosis increased the risk of tumorigenesis.[70] Epidemiological studies also demonstrate an increased risk of HCC among diabetics, along with a higher incidence of chronic non-alcoholic liver disease.[71] In a study of patients with hepatic malignancy complicating cirrhosis, Bugianesi et al.[72] found that obesity and diabetes were more frequent in those whose cirrhosis was cryptogenic, supporting the hypothesis of underlying NASH. Ratziu et al.[73] found that cryptogenic cirrhotics with a history of overweight were significantly more likely to develop HCC (8/27, 30%) compared with those who were lean (0/10), and the frequency was similar to HCC in matched controls with HCV cirrhosis (21%, P = not significant).
Steatosis may also be a co-factor for tumorigenesis in subjects with chronic HCV. Ohata et al.[74] recently found that steatosis was independently associated with an increased risk of HCC in chronically infected patients, and some support for this clinical finding is found in animal studies. Transgenic mice expressing HCV viral proteins[75-77] have an increased risk of developing hepatocellular adenomas and carcinomas. Steatosis occurs in only some of the models as a viral effect,[75][77] and these animals develop spontaneous tumors in the absence of inflammation. Conversely, in a model in which steatosis is not found,[76] tumors developed only after a second insult was delivered by using the hepatotoxin carbon tetrachloride.
Moriya et al.[75] explored the mechanisms contributing to tumorigenesis and found that lipid peroxidation increased in the animals and was driven chiefly by core antigen expression in the absence of inflammation. As the animals aged, there was a change in the oxidant-antioxidant balance. Although ROS were generated in young transgenic mice, they were effectively neutralized by anti-oxidant pathways. In contrast, in older animals, these pathways were less efficient, lipid peroxidation increased, and tumors ensued. The authors suggest that ROS-induced genetic damage may be important in HCV. The exact role of steatosis is enigmatic, because steatosis alone is not sufficient to generate ROS, though potentiation of cellular injury as well as altered progenitor cell expansion[53][54][78-80] are possible mechanisms.
If steatosis and obesity are confirmed as risk factors for HCC, this has therapeutic implications. In addition, the utility of screening and surveillance for HCC in cirrhotic subjects with these risk factors needs to be addressed.
Steatosis and Drug-Induced Liver Disease
Obesity and steatosis are accompanied by numerous pathophysiological changes that could potentially influence the hepatotoxic effects of drugs, but this has not been studied systematically. It is possible that impaired energy production and increased oxidative stress in the fatty liver may lead to increased sensitivity to drugs that interfere with mitochondrial function.[81] For example, fatty liver disease has been reported in association with tamoxifen in the treatment of breast cancer. Although the liver injury may be due to drug-induced mitochondrial dysfunction,[82] it occurs more commonly in patients with other risk factors for steatosis.[83] Obesity and diabetes also have been identified as risk factors for fibrosis in methotrexate-induced liver injury. Langman and colleagues found that some patients receiving methotrexate who developed progressive fibrosis had histological NASH as well as risk factors for this disease, such as obesity or diabetes.[84] In these cases, the pathogenesis of fatty liver disease is likely to be multifactorial, and the presence of two exacerbating causes could be a factor in the development of more severe liver injury.
Is Steatosis a Co-factor in Other Liver Diseases?
Brunt and colleagues analyzed 3,581 liver biopsy specimens and found histological evidence of strictly defined steatohepatitis in almost 12% of them.[85] In 22% of the biopsy specimens with NASH, there was evidence of a second liver disease, although this was usually hepatitis C in their population. Only 13 biopsy specimens had features of NASH in association with a second, non-hepatitis C chronic liver disease. Various second pathologies were seen, including chronic hepatitis B, drug-induced hepatitis, hemochromatosis, primary biliary cirrhosis, and -1 antitrypsin deficiency. Because the analysis by Brunt et al. was restricted only to NASH with at least perivenular fibrosis, a far greater number of patients may have co-existing simple steatosis and a second liver disease. As discussed previously, the benign nature of steatosis cannot be assumed in the presence of another liver disorder.
The relationship between iron and fatty liver is complex. Iron is a source of oxidative stress and has been shown to be a cofactor for progression in some chronic liver diseases.[86] The relationship between iron and nonalcoholic fatty liver disease (NAFLD) is unclear. Many patients with insulin resistance have elevated serum ferritin, and some have mild to moderate hepatic siderosis in a mixed distribution.[87] Earlier studies found an increased frequency of HFE mutations in NAFLD,[88][89] and in one there was also an association with increased iron and fibrosis.[88] The association with HFE mutations may be spurious and possibly related to referral patterns, with more recent studies failing to find a significant association between NAFLD, siderosis, and increased fibrosis.[90-92] Furthermore, hyperferritinemia in these patients correlates more closely with features of insulin resistance rather than iron overload[91] and can be reversed with weight loss.[93][94] In several small studies, venesection has been reported to improve insulin sensitivity[95][96] and metabolic indices,[94] but its role remains experimental.
The role of steatosis and obesity as co-factors in the progression of primary hepatic iron storage diseases, particularly hemochromatosis, has not been studied. Recently, hemochromatosis was shown to be more likely to progress to cirrhosis in the presence of a co-factor such as excess alcohol.[97] In view of the role of metabolic factors in promoting fibrosis in chronic HCV, steatosis is also a candidate co-factor to exacerbate fibrogenesis in untreated hemochromatosis.
In a recent preliminary study of adults with alpha-1 antitrypsin deficiency, obesity was a factor predisposing to advanced liver disease and liver transplantation.[98] Information regarding the role of obesity or steatosis in the progression of other chronic liver diseases remains limited.
Conclusions
Although steatosis without steatohepatitis has been regarded as of little consequence, in patients with another chronic liver disease, co-existent obesity or steatosis may exacerbate the liver injury. In particular, steatosis is now well recognized as a factor that accelerates the development of fibrosis in chronic hepatitis C. Similarly, steatosis, obesity, and associated metabolic factors may modulate the response to alcohol- and drug-induced liver disease and may be risk factors for the development of hepatocellular cancer. The pathogenesis of injury in obesity-related fatty liver disease involves a number of pathways, which are currently under investigation. Enhanced oxidative stress, increased susceptibility to apoptosis, and a dysregulated response to cellular injury have been implicated, along with other components of the metabolic syndrome such as hyperinsulinemia and hyperglycemia. Fibrosis may also be increased as a by-product of altered hepatocyte regeneration and activation of bipotential hepatic progenitor cells.
These findings have important therapeutic implications, and indicate that obesity-related steatosis must be taken into account even when it is not the primary cause of liver disease. In patients with chronic hepatitis C, active management of obesity improves steatosis, and in some patients, may reduce fibrosis and stellate cell activation. Future studies will need to determine the key pathogenic pathways that drive the synergistic effect of steatosis on disordered cellular homeostasis and fibrogenesis and to quantify its effects in a variety of liver diseases. The degree to which weight loss and treatment of the insulin resistance syndrome can minimize liver injury in patients with other forms of chronic liver disease remains to be determined.
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