inflammation is associated with atherosclerosis as well as with fatty liver disease ( fld ) .
both diseases are common in the western world   and several studies indicate that there could be a link between both disorders .
inflammation causes formation of vascular atheromas and thinning of the plaque 's fibrous cap ; unstable plaques can rupture and cause coronary thrombosis resulting in myocardial infarction .
fatty liver disease is considered to be the hepatic manifestation of metabolic diseases , summarized as the metabolic syndrome ( nonalcoholic fatty liver disease ) .
severe forms are characterized by an inflammation of the hepatic tissue , induced by inflammatory cell invasion and cytokine production , leading to hepatocyte necrosis and fibrosis .
nafld and cvd are inflammatory diseases and a number of common cytokines are involved in the inflammatory process of both diseases [ 5 , 6 ] .
a variety of potentially predictive biomarkers have been identified so far   ( see below ) ; some of these might play an active role in the initiation and progression of cvd and might also be linked to nafld , such as adiponectin or interleukin- ( il- ) 6 .
alcohol intake is associated with the risk of all - cause mortality in u- or j - shaped manner , primarily through reduction of the risk for coronary heart disease ( chd ) [ 8 , 9 ] . in several meta - analyses
, the lowest risk has been found among those with light - to - moderate alcohol consumption ( 525  g / day ) [ 10 , 11 ] . some studies could demonstrate that moderate alcohol consumption
is associated with lower concentrations of circulating inflammatory biomarkers compared to nondrinkers and those with high alcohol consumption [ 12 , 13 ] .
thus , it has been suggested that potential beneficial effects of moderate alcohol consumption might be mediated at least in part by lowering the inflammatory burden in different stages of atherosclerotic disease [ 14 , 15 ] . as moderate alcohol consumption seems to have anti - inflammatory effects , one might speculate that it may also reduce the risk of developing nafld .
further , nafld has been shown to be associated with an increased risk for cardiovascular events [ 16 , 17 ] .
there is an ongoing debate whether nafld is an independent risk factor for cardiovascular disease or a concomitant disease [ 5 , 18 ] . given the link between these two inflammatory entities ,
further , it might interact with the effect of alcohol intake on markers of inflammation and thus also on the cardiovascular risk .
lipoprotein oxidation , especially of low - density lipoprotein ( oxldl ) , is a crucial step in the development of early atherosclerotic lesions . in cohort studies ,
low serum levels of adiponectin can be found in patients with type 2 diabetes or coronary artery disease .
c - reactive protein ( crp ) , an acute phase - protein , is produced by the liver . increased serum levels in noninfectious situations , as measured by high sensitivity assays ,
fibrinogen levels have been shown to be inversely correlated with alcohol consumption [ 12 , 13 ] .
elevated serum levels are thought to reflect early stages of atherosclerotic vascular disease [ 7 , 22 ] .
we examined the association between alcohol consumption and prevalence of nafld , their interaction with serum levels of different biomarkers predictive for cardiovascular disease , or its complications in a large cross - sectional population - based study .
a subsample of 515 men and women aged 1849 was randomly selected according to the amount of self - reported alcohol consumption from a population - based cross - sectional survey including 2445 individuals in the area of leutkirch in southern germany .
this survey was primarily designed to estimate the prevalence of echinococcus multilocularis and internal diseases in leutkirch ( emil ) study .
a standardized interview was performed by trained personnel , including sociodemographic data , medical history , and lifestyle habits , including physical activity , drug history , and alcohol consumption . to estimate alcohol consumption , each subject
was interviewed about the amount of beer , wine , and spirits he or she had consumed on the previous workday and over the last weekend .
total alcohol intake was calculated by multiplying weekday consumption by five and adding this figure to weekend consumption .
this recall method had been validated in a subsample of 899 male participants of the first monica augsburg survey in 1984/85 .
body height ( in m ) , body weight ( in kg ) , waist circumference , and hip circumference were measured in a standardized manner .
body mass index ( kg / m ) , waist - to - hip ratio , and daily alcohol intake were calculated .
physical inactivity was defined as being physically active during leisure time neither in summer nor in winter .
collection of data on physical activity was based on standardized and validated questions used in previous large epidemiological studies .
all subjects gave informed , written consent , and all protocols and collection procedures were approved by the relevant institutional committees .
all participants underwent a real - time ultrasonographic examination of the liver for detection of typical signs of fatty liver disease and other pathologies performed by a single investigator ( hdi 5000 , advanced technology laboratories , philips medical systems , bothell , wa , usa ) .
the diagnosis of a fatty liver was based on the finding of a bright liver tissue signal with fine tightly packed echoes , making it significantly more echogenic compared to the adjacent right kidney [ 25 , 26 ] .
fasting blood was collected from the antecubital vein in the supine position with minimal suction and short - term occlusion .
plasma was obtained by centrifugation at 3,000  g for 15  min and was stored at 20c within 90  min and then stored at 70c until analysis .
liver enzymes were measured the same day photometrically from lithium - heparin plasma on a dimension xl ( dade behring , marburg , germany ) .
hdl - cholesterol was measured enzymatically on a dimension rxl ( dade behring , marburg , germany ) .
further measurements were performed using a highly sensitive elisa for il-6 ( r&d systems , wiesbaden , germany ; range 010  pg / ml ; coefficient of variation ( cv ) 17.8% ) , an elisa for e - selectin ( r&d systems , wiesbaden , germany ; range 09.69  ng / ml ; cv 7.92% ) , and also one for oxldl ( mercodia , usa ; range 07.6 
u / l ; cv 7.99% ) . a high - sensitivity assay ( latex - enhanced nephelometry ; cv 4.26% for apolipoprotein control and 5.85% for rheuma control ) was used for crp , also nephelometry for fibrinogen ( dade behring , marburg , germany ; cv 5.73% ) .
adiponectin concentrations were measured using an elisa ( quantikine , r&d systems , wiesbaden , germany ; 0250  ng / ml range ; cv 8,93% ) .
sociodemographic , clinical , and biochemical characteristics were analyzed in a descriptive manner . adjusted geometric mean for crp and adjusted arithmetic
mean for the other inflammatory markers were calculated in categories of daily alcohol intake from multiple linear regression analyses . known or presumed potential confounders including age ( four categories ) ,
sex , smoking status ( current , ex , and never ) , body mass index ( continuous ) , hdl - cholesterol ( continuous ) , formal education , and physical activity ( two categories ) were forced into all models .
all tests performed were two - sided , and a p value < 0.05 was considered statistically significant .
characteristics of the subgroups , divided according to the quantity of alcohol consumption , are shown in table 1 .
this group showed a heterogeneous characteristics pattern , which differed notably from that of nondrinkers ( data not shown ) .
there was no significant difference between groups in terms of age , smoking history , hypertension , bmi , physical inactivity , intake of aspirin or statins , and presence of coronary artery disease .
prevalence of fatty liver disease was far the lowest among participants reporting consumption of 020  g of alcohol per day ( 19.0% ) .
higher or no intake ( abstinence ) was associated with a substantially higher prevalence of nafld ( 35.0% for 0 
g / d , 38.6% for 4060  g / d , and 44.9% for > 60 
serum levels of ggt as well as of alt showed a slight increase with more alcohol consumption ( 12 to 36  u / l for ggt p < 0.0001 , 14 to 19  u / l alt p = 0.0004 ) . in the  moderate drinker 
group ( 020  g / d ) , though , serum levels were comparable to those of nondrinkers ( table 2 ) .
when subgroups were divided by presence or absence of fatty liver disease , serum levels for alt were consistently higher in people with nafld .
next , we analyzed pro- and anti - inflammatory biomarkers with regard to the presence or absence of fld ( table 3 ) . across all subgroups , concentrations of proinflammatory biomarkers
accordingly , concentrations of adiponectin , an anti - inflammatory marker , were lower . of all biomarkers , only il-6 showed an approximately linear association with alcohol consumption , with a slight  notch  at 4060  g  alcohol / d .
we found a clear association between alcohol intake and inflammatory markers neither in males nor among females .
low levels of adiponectin were found in nondrinkers ( 5.04  g / ml with fld , 7.59  g / ml without fld ) , whereas levels at low - moderate alcohol consumption were significantly higher ( 7.74  g / ml with fld , 8.91  g / ml without fld ) . particularly in those with fld , the increased serum level of adiponectin at moderate alcohol consumption was remarkable . with higher alcohol intake ,
the present study analyzed the associations between alcohol consumption and the prevalence of fld and of pro- and anti - inflammatory biomarkers in a cross - sectional sample of a general urban population .
nine out of ten people consuming more than 40  g alcohol per day were men , whereas , in the nondrinkers and moderate drinkers group , men represented less than 50% .
the low prevalence of nafld among subjects with moderate alcohol consumption represents the most intriguing finding in this study .
the prevalence of fld in the group consuming less than 20  g alcohol per day was 19% .
below 20  g per day , alcohol consumption is in general not considered to cause fld . in the total study population , mean bmi ranged from 24.8 to 26.3  kg / m . although the data had been adjusted for potential confounders like bmi , education , physical inactivity , and age , it can not be completely ruled out that subjects with a generally healthier lifestyle and a higher socioeconomic status are overrepresented in the moderate drinker group .
the prevalence of nonalcoholic fatty liver disease found in this study is comparable to that of the dionysos nutrition and liver study with 20 to 25%
. a recent analysis of a large , representative cross - sectional study ( nhanes iii ) , which investigated the association between consumption of different alcoholic beverages up to 10  g daily and unexplained liver enzyme elevation ( alt ) , found the lowest prevalence of alt elevation among wine drinkers . even though the authors reported differences in the prevalence of fld depending on the type of beverage , it was almost the highest in nondrinkers compared to subjects drinking any alcohol .
interestingly , in a cross - sectional population with biopsy proven nafld ( none and moderate drinkers ) , moderate alcohol consumption was associated with lower odds for steatohepatitis and fibrosis compared to nondrinkers . in another study with a sample of 132 severely obese patients , who underwent liver biopsy , however ,
no differences in the prevalence or severity of fatty liver disease were seen in relation to the level of alcohol consumption . however , among these morbid patients with a mean bmi of 43  kg / m , only about 10% showed no fld and the majority ( > 80% ) had severe fld across all categories of alcohol intake .
in these subjects , the underlying metabolic syndrome might have been the driving force of hepatic pathophysiology .
, we found a consistent correlation between ggt serum concentrations and self - reported alcohol intake .
serum levels for nondrinkers and subjects with low - to - moderate alcohol consumption were not different , indicating a low likelihood for liver damage .
it is possible that elevated serum levels of ggt itself contribute to the increased risk for cardiovascular events in heavy drinkers .
recently , ggt has been proposed as an independent cardiovascular risk marker and several mechanisms have been suggested to explain its active role in atherogenesis .
as shown in table 3 , there is an increase in serum levels in subjects with fld of all proinflammatory biomarkers , namely , fibrinogen , ox - ldl , il-6 , crp , and e - selectin .
the presence of fld thus constantly increases the inflammatory burden and thereby might be correlated with an increased cardiovascular risk .
however , most likely fld does not alter the known association between alcohol consumption and cardiovascular risk .
crp , for example , has been described to be associated with alcohol consumption in a j - shaped manner .
yet , we were not able to identify a clear j - shaped association in individuals neither with nor without fld . at present , the crp lowering effect of alcohol is still discussed controversially . a meta - analysis of interventional studies by brien et al .
including 5 studies with a total of only 186 participants was not able to find a significant reduction of crp in moderate drinkers . also , association curves for all other biomarkers did not reflect the known j - shaped association .
therefore , in this study , the effect of alcohol on inflammatory biomarkers is not conclusive , which might be due , at least in part , to the small sample size in each category .
a large number of cardiovascular biomarkers have been suggested to be lowered in subjects with moderate alcohol intake .
all other biomarkers chosen in this study ( il-6 , e - selectin , and oxldl ) reflect different stages of vascular inflammation .
yet , it is not fully understood how moderate amounts of alcohol reduce cardiovascular mortality , although anti - inflammatory mechanisms might play a role . a meta - analysis of prospective studies on alcohol intake and its effects on biomarkers by brien et al
. showed that high levels of hdl - cholesterol and adiponectin and low levels of fibrinogen correlated best with moderate alcohol intake .
these markers might be the key to understand antiatherogenic mechanisms and the role of alcohol in other inflammatory conditions , such as fatty liver disease . finally , the most important limitation of our study is its cross - sectional design not allowing causal inferences .
the present study demonstrates that low - to - moderate alcohol consumption is associated with lower prevalence of fld compared to nondrinkers and heavy drinkers .
however , in our study , alcohol consumption showed no interaction with inflammatory biomarkers . assuming the same drinking habits , subjects with fld had higher levels of inflammatory biomarkers than those without .
 
 background and aims . local and systemic inflammation represent a major feature of atherosclerotic cardiovascular disease ( cvd ) and are also linked to nonalcoholic fatty liver disease ( nafld ) . 
 studies indicate that nafld might be a risk factor for cvd whereas low - to - moderate alcohol consumption is associated with lower cardiovascular morbidity and mortality compared to abstainers and heavy drinkers . 
 we hypothesize that fld interacts with the effect of alcohol intake on markers of inflammation , and thus potentially on cardiovascular risk . 
 methods and results . we evaluated alcohol consumption , markers of inflammation and sonographic criteria of fld in 515 subjects , representing a subsample of a cross - sectional population based study ( echinococcus multilocularis and internal diseases in leutkirch ( emil ) study ) . 
 
 presence of fld was markedly reduced in subjects drinking 020  g alcohol / d ( 19% ) , compared to nondrinkers ( 35% ) and heavy drinkers ( 3444.9% ) . 
 serum concentrations of inflammatory markers were substantially higher in subjects with fld . 
 however , presence of fld showed no effect on the association between alcohol consumption and inflammatory biomarkers . 
 conclusions . based on data from a population - based sample , 
 there is no evidence for a link between fld , alcohol consumption , and inflammatory cardiovascular risk markers . 
 however , larger prospective studies are needed to confirm this . 
1. Introduction
2. Methods
3. Results
4. Discussion
5. Conclusion