Nonalcoholic Fatty Liver Disease and Atherosclerosis
http://www.100md.com
动脉硬化血栓血管生物学 2005年第7期
Division of Internal Medicine and Diabetes Unit Ospedale "Sacro Cuore – don G. Calabria", Negrar (VR), Italy
To the Editor:
I read with interest the article by Brea et al1 regarding the strong relationship between nonalcoholic fatty liver disease (NAFLD) and carotid atherosclerosis (as measured by intima-media thickness [IMT] and plaque prevalence) in a sample of predominantly obese and hypertensive subjects.
Notably, they reported substantially similar results to those recently published by our group in a sample of nonobese healthy men,2 thus further supporting the notion that people with NAFLD are at increased risk of CVD.
However, I partly disagree with the authors’ conclusions suggesting that NAFLD is a strong risk factor for carotid atherosclerosis beyond its association with the metabolic syndrome (MetS).
In both studies, patients with NAFLD had, other than several features resembling MetS, a marked increase in carotid IMT values compared with those without NAFLD. However, in the study by Brea et al1 the increase in carotid IMT (but not that in the prevalence of carotid plaques) remained statistically significant after adjustment for the presence of MetS (as defined by ATP-III or WHO criteria). On the contrary, in our study the increase in carotid IMT was largely mediated by the extent of visceral fat accumulation, as measured by computed tomography (CT).2 It is known that WHO and ATP-III definitions of MetS include waist circumference (or waist/hip ratio) among their diagnostic criteria. However, it is also known that waist circumference provides only an indirect and crude estimation of visceral fat,3 so we cannot be certain that the results of the study by Brea et al completely exclude an effect of visceral adipose tissue. This could be done by controlling for a more accurate measure of visceral fat obtained by CT or MRI.3 We have substantiated this showing that carotid IMT remained significantly different between those with and without NAFLD when CT-measured visceral fat was replaced as a covariate by waist circumference.2
Overall, therefore, I think there is now greater published evidence to support the possibility that the relationship between NAFLD and carotid atherosclerosis reflects the overall adverse impact of MetS (particularly insulin resistance and increased visceral fat, possibly through its multiple secreted factors, ie, free fatty acids, tumor necrosis factor-alpha, and other adipocytokines) more rather than a direct impact of NAFLD on carotid atherosclerosis. Accordingly, several studies showed a strong association of carotid IMT with abdominal fat distribution and insulin resistance.3–5 Moreover, interventional studies reported a beneficial impact of weight loss, known to primarily reduce intra-abdominal fat depots, on the progression rate of early carotid atherosclerosis in obese individuals.6,7 Similarly, a gradual weight loss significantly improved liver-biopsy features and liver-test results in most NAFLD patients, and the results of small pilot trials evaluating metformin and thiazolidinediones, drugs that are effective for insulin resistance, have recently suggested that these medications may be of potential benefit for NAFLD patients.8
All of these findings, therefore, strongly support a pivotal role of visceral fat and insulin resistance in the development of atherosclerosis and NAFLD; this further emphasizes the use of aggressive nonpharmacological and pharmacological interventions capable of avoiding abdominal obesity and reducing insulin resistance (ie, lifestyle changes and drugs specifically targeting the MetS phenotype), with the aim of preventing atherosclerotic diseases and improving NAFLD and its potential complications.
Prospective studies are clearly needed to corroborate these cross-sectional findings and better estimate the individual CVD risks associated with the presence of MetS and NAFLD.
References
Brea A, Mosquera D, Martin E, Arizti A, Cordero JL, Ros E. Nonalcoholic fatty liver disease is associated with carotid atherosclerosis: a case-control study. Arterioscler Thromb Vasc Biol. 2005; 25: 1045–1050.
Targher G, Bertolini L, Padovani R, Zenari L, Zoppini G, Falezza G. Relation of nonalcoholic hepatic steatosis to early carotid atherosclerosis in healthy men. Role of visceral fat accumulation. Diabetes Care. 2004; 27: 1498–1500.
Wajchenberg BL. Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev. 2000; 21: 697–738.
Folsom AR, Eckfeldt JH, Weitzman S, Ma J, Chambless LE, Barnes RW, Cram Hutchinson RG. Relation of carotid artery wall thickness to diabetes mellitus, fasting glucose and insulin, body size, and physical activity. Atherosclerosis Risk Communities (ARIC) Study Investigators. Stroke. 1994; 25: 66–73.
De Michele M, Panico S, Iannuzzi A, Celentano E, Ciardullo AV, Galasso R, Sacchetti L, Zarrilli F, Bond MG, Rubba P. Association of obesity and central fat distribution with carotid artery wall thickening in middle-aged women. Stroke. 33: 2923–2928.
Karason K, Wikstrand J, Sjostrom L, Wendelhag I. Weight loss and progression of early atherosclerosis in the carotid artery: a four-year controlled study of obese subjects. Int J Obes Relat Metab Disord. 1999; 23: 948–956.
Mavri A, Stegnar M, Sentocnik JT, Videcnik V. Impact of weight reduction on early carotid atherosclerosis in obese premenopausal women. Obes Res. 2001; 9: 511–516.
Harrison SA, Neuschwander-Tetri BA. Pharmacologic management of nonalcoholic fatty liver disease. Clin Liver Dis. 2004; 8: 715–728.
In Response:
Angel Brea
Lipid Clinic, Internal Medicine Service Hospital San Millán-San Pedro Logro?o, Spain
Emilio Ros
Lipid Clinic, Endocrinology and Nutrition Service Institut d’Investigacions Biomediques August Pi Sunyer Hospital Clínico Barcelona, Spain
We appreciate the interest of Dr Targher in our recent publication on the association between nonalcoholic fatty liver disease (NAFLD) and carotid atherosclerosis.1 Dr Targher and associates recently published the results of a study showing a similar relation of NAFLD to increased carotid intima-media thickness (IMT), and this association was explained on multivariate analysis by the extent of visceral fat accumulation, as measured by CT.2 Because we did not perform abdominal CT but instead used waist circumference (WC) as a surrogate measure of visceral fat, Dr Targher contends that our finding of an independent association of NAFLD with increased carotid IMT beyond the presence of the metabolic syndrome (MetS) and all its individual traits might be spurious, and that a more sophisticated measurement of visceral fat would have shown it to be the culprit.
Although we grant that CT precisely determines the proportion of abdominal adipose tissue, the results of this technique strongly correlate with WC measurements.3 In addition to being a simple and highly reproducible measurement,4 WC is considered as a reliable indicator for the syndrome of central fat accumulation and associated disease risks,5,6 including NAFLD.7 Thus, we feel that WC provided a valid estimate of abdominal adiposity in our study.
The discrepant associations with IMT observed in the 2 studies might be explained in part by different populations and carotid ultrasound methods. Targher et al studied relatively young nonobese men, whereas we studied men and women with wide age and body mass index ranges, a population that is more representative of NAFLD patients.7 Although it is not specified whether they measured mean or maximum IMT, the values provided by Targher et al are much higher than those measured in our participants, suggesting important differences in the carotid scanning protocol. At any rate, besides the results of multivariate analyses, data from our study provide additional evidence for an independent association of NAFLD with increased carotid IMT. As shown in Figure 2 of our article,1 sex- and age-adjusted IMT increased in the sequence: control without MetS
References
Brea A, Mosquera D, Martin E, Arizti A, Cordero JL, Ros E. Nonalcoholic fatty liver disease is associated with carotid atherosclerosis: a case-control study. Arterioscler Thromb Vasc Biol. 2005; 25: 1045–1050.
Targher G, Bertolini L, Padovani R, Zenari L, Zoppini G, Falezza G. Relation of nonalcoholic hepatic steatosis to early carotid atherosclerosis in healthy men. Diabetes Care. 2004; 27: 2498–2500.
Pouliot MC, Després JP, Lemieux S, Moorjani S, Bouchard C, Tremblay A, Nadeau A, Lupien PJ. Waist circumference and abdominal sagittal diameter: best simple anthropometric indexes of abdominal visceral adipose tissue accumulation and related cardiovascular risk in men and women. Am J Cardiol. 1994; 74: 460–468.
Wang J, Thornton JC, Bari S, Williamson B, Gallagher D, Heymsfield SB, Horlick M, Kotler D, Laferrère B, Mayer L, Pi-Sunyer FX, Pierson RN Jr. Comparison of waist circumference measured at 4 sites. Am J Clin Nutr. 2003; 77: 379–384.
Després JP, Lemieux I, Prud’homme D. Treatment of obesity: need to focus on high risk abdominally obese patients. BMJ. 2001; 322: 716–720.
Pi-Sunyer FX. The epidemiology of central fat distribution in relation to disease. Nutr Rev. 2004; 62: S120–S126.
Angulo P. Non alcoholic fatty liver disease. N Engl J Med. 2002; 346: 1221–1231.
Kerner A, Avizohar O, Bartha P, Zinder O, Markiewicz W, Levy Y, Brook GJ, Aronson D. Association between elevated liver enzymes and C-reactive protein: possible hepatic contribution to systemic inflammation in the metabolic syndrome. Arterioscler Thromb Vasc Biol. 2005; 25: 193–197.
Lee DH, Jacobs DR Jr. Association between serum gamma-glutamyltransferase and C-reactive protein. Atherosclerosis. 2005; 178: 327–330.
Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14 719 initially healthy Am women. Circulation. 2003; 107: 391–397.(Giovanni Targher)
To the Editor:
I read with interest the article by Brea et al1 regarding the strong relationship between nonalcoholic fatty liver disease (NAFLD) and carotid atherosclerosis (as measured by intima-media thickness [IMT] and plaque prevalence) in a sample of predominantly obese and hypertensive subjects.
Notably, they reported substantially similar results to those recently published by our group in a sample of nonobese healthy men,2 thus further supporting the notion that people with NAFLD are at increased risk of CVD.
However, I partly disagree with the authors’ conclusions suggesting that NAFLD is a strong risk factor for carotid atherosclerosis beyond its association with the metabolic syndrome (MetS).
In both studies, patients with NAFLD had, other than several features resembling MetS, a marked increase in carotid IMT values compared with those without NAFLD. However, in the study by Brea et al1 the increase in carotid IMT (but not that in the prevalence of carotid plaques) remained statistically significant after adjustment for the presence of MetS (as defined by ATP-III or WHO criteria). On the contrary, in our study the increase in carotid IMT was largely mediated by the extent of visceral fat accumulation, as measured by computed tomography (CT).2 It is known that WHO and ATP-III definitions of MetS include waist circumference (or waist/hip ratio) among their diagnostic criteria. However, it is also known that waist circumference provides only an indirect and crude estimation of visceral fat,3 so we cannot be certain that the results of the study by Brea et al completely exclude an effect of visceral adipose tissue. This could be done by controlling for a more accurate measure of visceral fat obtained by CT or MRI.3 We have substantiated this showing that carotid IMT remained significantly different between those with and without NAFLD when CT-measured visceral fat was replaced as a covariate by waist circumference.2
Overall, therefore, I think there is now greater published evidence to support the possibility that the relationship between NAFLD and carotid atherosclerosis reflects the overall adverse impact of MetS (particularly insulin resistance and increased visceral fat, possibly through its multiple secreted factors, ie, free fatty acids, tumor necrosis factor-alpha, and other adipocytokines) more rather than a direct impact of NAFLD on carotid atherosclerosis. Accordingly, several studies showed a strong association of carotid IMT with abdominal fat distribution and insulin resistance.3–5 Moreover, interventional studies reported a beneficial impact of weight loss, known to primarily reduce intra-abdominal fat depots, on the progression rate of early carotid atherosclerosis in obese individuals.6,7 Similarly, a gradual weight loss significantly improved liver-biopsy features and liver-test results in most NAFLD patients, and the results of small pilot trials evaluating metformin and thiazolidinediones, drugs that are effective for insulin resistance, have recently suggested that these medications may be of potential benefit for NAFLD patients.8
All of these findings, therefore, strongly support a pivotal role of visceral fat and insulin resistance in the development of atherosclerosis and NAFLD; this further emphasizes the use of aggressive nonpharmacological and pharmacological interventions capable of avoiding abdominal obesity and reducing insulin resistance (ie, lifestyle changes and drugs specifically targeting the MetS phenotype), with the aim of preventing atherosclerotic diseases and improving NAFLD and its potential complications.
Prospective studies are clearly needed to corroborate these cross-sectional findings and better estimate the individual CVD risks associated with the presence of MetS and NAFLD.
References
Brea A, Mosquera D, Martin E, Arizti A, Cordero JL, Ros E. Nonalcoholic fatty liver disease is associated with carotid atherosclerosis: a case-control study. Arterioscler Thromb Vasc Biol. 2005; 25: 1045–1050.
Targher G, Bertolini L, Padovani R, Zenari L, Zoppini G, Falezza G. Relation of nonalcoholic hepatic steatosis to early carotid atherosclerosis in healthy men. Role of visceral fat accumulation. Diabetes Care. 2004; 27: 1498–1500.
Wajchenberg BL. Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev. 2000; 21: 697–738.
Folsom AR, Eckfeldt JH, Weitzman S, Ma J, Chambless LE, Barnes RW, Cram Hutchinson RG. Relation of carotid artery wall thickness to diabetes mellitus, fasting glucose and insulin, body size, and physical activity. Atherosclerosis Risk Communities (ARIC) Study Investigators. Stroke. 1994; 25: 66–73.
De Michele M, Panico S, Iannuzzi A, Celentano E, Ciardullo AV, Galasso R, Sacchetti L, Zarrilli F, Bond MG, Rubba P. Association of obesity and central fat distribution with carotid artery wall thickening in middle-aged women. Stroke. 33: 2923–2928.
Karason K, Wikstrand J, Sjostrom L, Wendelhag I. Weight loss and progression of early atherosclerosis in the carotid artery: a four-year controlled study of obese subjects. Int J Obes Relat Metab Disord. 1999; 23: 948–956.
Mavri A, Stegnar M, Sentocnik JT, Videcnik V. Impact of weight reduction on early carotid atherosclerosis in obese premenopausal women. Obes Res. 2001; 9: 511–516.
Harrison SA, Neuschwander-Tetri BA. Pharmacologic management of nonalcoholic fatty liver disease. Clin Liver Dis. 2004; 8: 715–728.
In Response:
Angel Brea
Lipid Clinic, Internal Medicine Service Hospital San Millán-San Pedro Logro?o, Spain
Emilio Ros
Lipid Clinic, Endocrinology and Nutrition Service Institut d’Investigacions Biomediques August Pi Sunyer Hospital Clínico Barcelona, Spain
We appreciate the interest of Dr Targher in our recent publication on the association between nonalcoholic fatty liver disease (NAFLD) and carotid atherosclerosis.1 Dr Targher and associates recently published the results of a study showing a similar relation of NAFLD to increased carotid intima-media thickness (IMT), and this association was explained on multivariate analysis by the extent of visceral fat accumulation, as measured by CT.2 Because we did not perform abdominal CT but instead used waist circumference (WC) as a surrogate measure of visceral fat, Dr Targher contends that our finding of an independent association of NAFLD with increased carotid IMT beyond the presence of the metabolic syndrome (MetS) and all its individual traits might be spurious, and that a more sophisticated measurement of visceral fat would have shown it to be the culprit.
Although we grant that CT precisely determines the proportion of abdominal adipose tissue, the results of this technique strongly correlate with WC measurements.3 In addition to being a simple and highly reproducible measurement,4 WC is considered as a reliable indicator for the syndrome of central fat accumulation and associated disease risks,5,6 including NAFLD.7 Thus, we feel that WC provided a valid estimate of abdominal adiposity in our study.
The discrepant associations with IMT observed in the 2 studies might be explained in part by different populations and carotid ultrasound methods. Targher et al studied relatively young nonobese men, whereas we studied men and women with wide age and body mass index ranges, a population that is more representative of NAFLD patients.7 Although it is not specified whether they measured mean or maximum IMT, the values provided by Targher et al are much higher than those measured in our participants, suggesting important differences in the carotid scanning protocol. At any rate, besides the results of multivariate analyses, data from our study provide additional evidence for an independent association of NAFLD with increased carotid IMT. As shown in Figure 2 of our article,1 sex- and age-adjusted IMT increased in the sequence: control without MetS
References
Brea A, Mosquera D, Martin E, Arizti A, Cordero JL, Ros E. Nonalcoholic fatty liver disease is associated with carotid atherosclerosis: a case-control study. Arterioscler Thromb Vasc Biol. 2005; 25: 1045–1050.
Targher G, Bertolini L, Padovani R, Zenari L, Zoppini G, Falezza G. Relation of nonalcoholic hepatic steatosis to early carotid atherosclerosis in healthy men. Diabetes Care. 2004; 27: 2498–2500.
Pouliot MC, Després JP, Lemieux S, Moorjani S, Bouchard C, Tremblay A, Nadeau A, Lupien PJ. Waist circumference and abdominal sagittal diameter: best simple anthropometric indexes of abdominal visceral adipose tissue accumulation and related cardiovascular risk in men and women. Am J Cardiol. 1994; 74: 460–468.
Wang J, Thornton JC, Bari S, Williamson B, Gallagher D, Heymsfield SB, Horlick M, Kotler D, Laferrère B, Mayer L, Pi-Sunyer FX, Pierson RN Jr. Comparison of waist circumference measured at 4 sites. Am J Clin Nutr. 2003; 77: 379–384.
Després JP, Lemieux I, Prud’homme D. Treatment of obesity: need to focus on high risk abdominally obese patients. BMJ. 2001; 322: 716–720.
Pi-Sunyer FX. The epidemiology of central fat distribution in relation to disease. Nutr Rev. 2004; 62: S120–S126.
Angulo P. Non alcoholic fatty liver disease. N Engl J Med. 2002; 346: 1221–1231.
Kerner A, Avizohar O, Bartha P, Zinder O, Markiewicz W, Levy Y, Brook GJ, Aronson D. Association between elevated liver enzymes and C-reactive protein: possible hepatic contribution to systemic inflammation in the metabolic syndrome. Arterioscler Thromb Vasc Biol. 2005; 25: 193–197.
Lee DH, Jacobs DR Jr. Association between serum gamma-glutamyltransferase and C-reactive protein. Atherosclerosis. 2005; 178: 327–330.
Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14 719 initially healthy Am women. Circulation. 2003; 107: 391–397.(Giovanni Targher)