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Prevalence of and risk factors for nonalcoholic fatty liver disease: The Dionysos nutrition and liver study
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Hepatology
July 2005
Giorgio Bedogni 1 2, Lucia Miglioli 2, Flora Masutti 2, Claudio Tiribelli 1 2, Giulio Marchesini 3, Stefano Bellentani 1 2 4
1Centro Studi Fegato, AREA Science Park, Basovizza, and Department of BBCM, University of Trieste, Trieste, Italy
2Fondo Studio Malattie del Fegato-ONLUS, Trieste and Campogalliano, Italy
3Department of Internal Medicine and Gastroenterology, University of Bologna, Bologna, Italy
4Azienda USL Modena, Distretto di Carpi e Campogalliano, Modena, Italy
".....BMI is an independent predictor of NAFLD (nonalcoholic fatty liver disease).......Visceral adiposity (belly fat) is supposed to play a central role in the pathogenesis of fatty liver by increasing the flux of fatty acids to the liver through the portal vein..... Our data show that insulin resistance is a risk factor for NAFLD but also indicate that in the general population, the two components of HOMA are independent and better predictors of NAFLD. HOMA is known to lose accuracy as a marker of insulin resistance in the presence of diabetes mellitus, when insulin production drops......The association of hypertension with NAFLD is well documented, independently of ALT elevation, and is confirmed and expanded by the current study at the population level...... NAFLD is similarly prevalent in individuals with and without suspected liver disease, and is associated with most of the features of the metabolic syndrome, strongly suggesting that NAFLD is the hepatic component of this syndrome....."
ABSTRACT
The prevalence of and the risk factors for fatty liver have not undergone a formal evaluation in a representative sample of the general population. We therefore performed a cross-sectional study in the town of Campogalliano (Modena, Italy), within the context of the Dionysos Project.
Of 5,780 eligible persons aged 18 to 75 years, 3,345 (58%) agreed to participate in the study. Subjects with suspected liver disease (SLD), defined on the basis of elevated serum alanine aminotransferase (ALT) and -glutamyl-transferase (GGT) activity, hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV)-RNA positivity, were matched with randomly selected subjects of the same age and sex without SLD.
A total of 311 subjects with and 287 without SLD underwent a detailed clinical, laboratory, and anthropometrical evaluation. Fatty liver was diagnosed by ultrasonography, and alcohol intake was assessed by using a 7-day diary. Multinomial logistic regression was used to detect risk factors for normal liver versus nonalcoholic fatty liver disease (NAFLD) and for alcoholic fatty liver (AFLD) versus NAFLD.
The prevalence of NAFLD was similar in subjects with and without SLD (25 vs. 20%, P = .203). At multivariable analysis, normal liver was more likely than NAFLD in older subjects and less likely in the presence of obesity, hyperglycemia, hyperinsulinemia, hypertriglyceridemia, and systolic hypertension; AFLD was more likely than NAFLD in older subjects, males, and in the presence of elevated GGT and hypertriglyceridemia, and less likely in the presence of obesity and hyperglycemia.
In conclusion, NAFLD is highly prevalent in the general population, is not associated with SLD, but is associated with many features of the metabolic syndrome.
Multivariable Analysis of Risk Factors for NAFLD:
Table 4 gives the results of the multivariable analysis of risk factors for NAFLD. Normal liver was more likely than NAFLD in individuals aged 66 years and older (OR = 3.10) and less likely than NAFLD in those with obesity (OR = 0.26), hyperglycemia (OR = 0.33), hypertriglyceridemia (OR = 0.54), and systolic hypertension (OR = 0.50). Normal liver was also less likely than NAFLD in individuals with insulin levels in the 2nd, 3rd, and 4th quartiles (OR = 0.19, 0.33, and 0.22, respectively) but the interquartile trend observed at univariable analysis was lost. The odds of normal liver versus NAFLD were similar in males and females, in individuals with or without elevated ALT or GGT, large waist, low HDL, and diastolic hypertension. AFLD was more likely than NAFLD in individuals aged 66 years and older (OR = 3.36), in males (OR = 16.24), in subjects with elevated GGT (OR = 2.61), and in those with hypertriglyceridemia (OR = 1.99). AFLD was less likely than NAFLD in individuals with obesity (OR = 0.43) and hyperglycemia (OR = 0.30). The odds of AFLD versus NAFLD were similar in individuals with insulin levels in the 2nd, 3rd, and 4th quartiles of insulin and in individuals with or without elevated ALT, large waist, low HDL, systolic hypertension, and diastolic hypertension. When HOMA was added to the multivariable model in place of glucose and insulin, it contributed significantly to the outcome of interest (P = .045, likelihood ratio test; model not shown), albeit to a lesser degree than either glucose and insulin.
Article Text
In the last two decades, nonalcoholic fatty liver disease (NAFLD) has been increasingly recognized as the most common liver disease in Western countries. Estimates obtained from clinical series, autopsy studies, and convenience samples of the general population suggest that 20% to 30% of individuals in Western countries have NAFLD.[1][2] These estimates, however, need to be confirmed in representative samples of the general population.[2]
The risk factors for NAFLD have been extensively investigated. The association with sex is controversial: whereas in old studies NAFLD was more frequent in women, the opposite was found in recent series.[3] The prevalence of NAFLD increases with age, type 2 diabetes, obesity, and hypertriglyceridemia.[3][4] Visceral obesity, as operationally defined by a large waist circumference,[5] is also considered a risk factor for NAFLD.[3] After exclusion of other risk factors for liver disease, an elevated serum activity of alanine aminotransferase (ALT) has been suggested as the hallmark of NAFLD in the general population.[3] However, the prevalence of NAFLD is substantially higher than that predicted on the basis of elevated ALT.[3]
In the absence of obesity and diabetes, hyperinsulinemia and insulin resistance are associated with NAFLD and ALT activity.[6][7] The presence of hyperinsulinemia or insulin resistance and the association with some of the features of the metabolic syndrome suggest that NAFLD might be the liver component of the metabolic syndrome.[6] In clinical series,[6] individuals with the metabolic syndrome are at greater risk for NAFLD, but no data are available at the population level, and the relative contribution of each component of the metabolic syndrome to the risk of NAFLD is unknown.
We took advantage of the Dionysos Study on the prevalence, incidence, and natural history of chronic liver disease (CLD) to perform a cross-sectional study aimed to establish the prevalence of and risk factors for NAFLD in a representative sample of the general population.
DISCUSSION
The Dionysos Nutrition and Liver Study is the first study specifically aimed at establishing the prevalence of and the risk factors for NAFLD in the general population. In Campogalliano, a town of Northern Italy, the prevalence of NAFLD was similar in that of individuals with and without SLD (25% vs. 20%, P = .203) and within the range (20%-30%) hypothesized for Western countries on the basis of clinical series, autopsy studies, and convenience samples of the general population.[1][2]
Several risk factors for NAFLD have been identified in previous studies.[3] Although age increases the risk of obesity and of the metabolic syndrome, NAFLD is not systematically associated with age.[21] In our population, an age 66 years was an independent predictor of normal liver and AFLD as compared with NAFLD, suggesting that age may be a protective factor for NAFLD. Although NAFLD was originally described to be more prevalent in females,[3] most recent series report a higher prevalence in males.[22-24] These studies are biased, however, by their selection criteria and especially by the use of an elevated ALT as an entry criterion. We found that male sex was a strong and independent risk factor for AFLD but that the odds of normal liver versus NAFLD were similar in males and females. Thus, our study does not support the hypothesis that any specific gender is a risk factor for NAFLD in the general population. This conclusion applies to Caucasian subjects and might not be valid for individuals of other ethnic background.[25][26]
An elevated ALT did not discriminate NAFLD either from normal liver or from AFLD, indicating that ALT is not an independent predictor of NAFLD. In addition, only 54% of NAFLD cases were observed in subjects with elevated ALT. This finding has relevant clinical implications because, as shown by biopsy studies, liver disease in subjects with NAFLD but without elevated ALT may be severe.[27] The optimum cutoff of ALT for the diagnosis of liver disease has been recently reevaluated, and lower values are probably needed to increase the negative predictive value.[28] Our findings confirm nonetheless that there is a high prevalence of NAFLD in subjects without elevated ALT in the general population and that the use of elevated ALT as a marker of NAFLD has to be discouraged. An elevated GGT was an independent risk factor for AFLD versus NAFLD, in agreement with the specific role of GGT as marker of alcohol abuse,[29] but the odds of normal liver versus NAFLD were the same in subjects with and without elevated GGT.
Both normal liver and AFLD were less likely than NAFLD in obese subjects, confirming that BMI is an independent predictor of NAFLD.[4][30] By contrast, a large waist as identified by the operational definition of the metabolic syndrome,[5] although associated with NAFLD at univariable analysis, was not an independent predictor of NAFLD. Waist circumference is a surrogate marker of visceral adiposity and a risk factor for cardiovascular and metabolic disease.[20][31] Visceral adiposity is supposed to play a central role in the pathogenesis of fatty liver by increasing the flux of fatty acids to the liver through the portal vein.[32] In line with this hypothesis, one can speculate that, at the population level, the contribution of a large waist to fatty liver may be decreased by the inclusion of triglycerides into the model. Ethnic differences,[5] potentially accounting for different visceral fat accumulation, do not play a role in our population because it is of almost uniformly Caucasian origin. Another confounding factor may be the use of thiazolidinediones, which may cause a redistribution of body fat.[33] However, none of our subjects was under therapy with thiazolidinediones at the time the study was performed. Although waist circumference was not an independent predictor of NAFLD at the cutoff adopted by the definition of the metabolic syndrome,[5] this does not imply that waist may not be a predictor of NAFLD at different cutoffs.
Normal liver was less likely and AFLD more likely than NAFLD in subjects with hypertriglyceridemia, in line with previous studies performed in selected groups of patients.[6] Both normal liver and AFLD were less likely than NAFLD in individuals with hyperglycemia, confirming that an altered glucose metabolism is a risk factor for NAFLD.[3] Importantly, hyperglycemia was associated with a greater risk of NAFLD independently from hypertriglyceridemia. On the contrary, insulin was identified as an independent predictor of NAFLD versus normal liver, but it did not discriminate NAFLD from AFLD. HOMA, a measure of insulin resistance, was less associated with NAFLD than its two individual components (glucose and insulin). It should be pointed out that HOMA is only a surrogate marker of insulin resistance, although extensively validated for epidemiological studies,[34] and increasingly used as a marker of insulin resistance in NAFLD studies.[1][6][35][36] The clinical significance of fasting insulin as a marker of insulin resistance is also well documented.[37] Our data show that insulin resistance is a risk factor for NAFLD but also indicate that in the general population, the two components of HOMA are independent and better predictors of NAFLD. HOMA is known to lose accuracy as a marker of insulin resistance in the presence of diabetes mellitus, when insulin production drops.[38][39] An analysis of the data after exclusion of subjects with diabetes (n = 29; 15 with NAFLD, 8 with AFLD and 6 with normal liver, as diagnosed by a value of blood glucose 126 mg/dL or the use of anti-diabetic drugs[5]) showed no change in the predictive power of HOMA both at univariable and multivariable analysis (data not shown).
Lastly, systolic, but not diastolic, hypertension was associated with a greater risk of NAFLD. The association of hypertension with NAFLD is well documented,[40] independently of ALT elevation, and is confirmed and expanded by the current study at the population level.
NAFLD and AFLD were separated by using the currently suggested cutoff of 20 g/day of ethanol intake.[1] Using a cutoff of 30 g/day, the prevalence of NAFLD would be 3% higher in subjects with (28%) and 4% higher (24%) in those without SLD. This difference is not very large, but, having being detected by a 7-day diary of alcohol intake, it points to the importance of an accurate assessment of ethanol consumption,[17] besides the need of common diagnostic criteria for NAFLD.[1] It is of some interest that ethanol intake was lower and less variable in subjects with NAFLD than in those with normal liver. Moreover, the percentage of abstainers was higher among NAFLD (48%) than normal liver (31%) subjects (P = .0015), giving partial support to the hypothesis that moderate alcohol consumption may be associated with a lower risk of NAFLD.[41]
Although performed in the general population, our study is not without limitations. The most important limitation is the suboptimal respondent rate. Only 58% of potential subjects agreed to participate to the study. Nonresponders were younger and more frequently males than responders, a pattern similar to that observed in the first phase of the Dionysos study.[8][11] The second limitation is the use of ultrasonography to diagnose liver steatosis. Even if ultrasonography is reasonably accurate as compared with nuclear magnetic resonance spectroscopy and liver biopsy, it cannot identify fatty infiltration of the liver below a threshold of 30%.[2][14][42] Accordingly, an undefined number of cases of fatty liver is missed in subjects both with and without SLD. Ultrasonography also does not provide any information about the histological features more closely associated with disease progression, such as inflammation and fibrosis.[1] This information can be obtained only by liver biopsy, but histological series are neither feasible nor ethically justified in a condition with low risk of progression and no definite treatment.[3]
In conclusion, our study shows that in the general population of a Northern Italian town, NAFLD is similarly prevalent in individuals with and without SLD and is associated with most of the features of the metabolic syndrome, strongly suggesting that NAFLD is the hepatic component of this syndrome.
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