- Email: [email protected]
Inflammatory interactions between nonalcoholic fatty liver disease and the metabolic syndrome
Letters to the Editor / Journal of Hepatology 45 (2006) 879–882
[2]
[3]
[4]
[5]
disease is characterized by elevated levels of CCL2. J Hepatol 2006;44:1167–1174. Targher G, Bertolini L, Padovani R, Rodella S, Zoppini G, Zenari L, et al. Relations between carotid artery wall thickness and liver histology in subjects with nonalcoholic fatty liver disease. Diabetes Care 2006;29:1325–1330. Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol 1999;94:2467–2474. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al. American Heart Association; National Heart, Lung, and Blood Institute: Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005;112:2735–2752. Marchesini G, Marzocchi R, Agostini F, Bugianesi E. Nonalcoholic fatty liver disease and the metabolic syndrome. Curr Opin Lipidol 2005;16:421–427.
881
[6] Targher G, Arcaro G. Non-alcoholic fatty liver disease and increased risk of cardiovascular disease. Atherosclerosis 2006; doi:10.1016/j.atherosclerosis.2006.08.021. [7] Ballantyne CM, Nambi V. Markers of inflammation and their clinical significance. Atheroscler Suppl 2005;6:21–29.
Giovanni Targher Division of Internal Medicine and Diabetes Unit, Ospedale ‘‘Sacro Cuore – don Calabria’’ Hospital, Via Sempreboni, 5, 37024 Negrar (VR), Italy E-mail address: [email protected]
doi:10.1016/j.jhep.2006.09.005
Inflammatory interactions between nonalcoholic fatty liver disease and the metabolic syndrome To the Editor: We appreciate Targher’s comments on our report on systemic inflammation in nonalcoholic fatty liver disease (NAFLD) [1]. In this paper we reported elevated serum levels of several markers of inflammation in NAFLD patients with particularly high levels of monocyte chemoattractant protein 1 (MCP-1) in those with nonalcoholic steatohepatitis (NASH). By presenting a set of cross-sectional data from NAFLD patients in Italy, Tagher shows that NAFLD patients, and especially those with NASH, have markedly raised CRP levels compared with healthy controls. Additionally, levels of CRP correlated significantly with histological features (degree of steatosis, necroinflammation and fibrosis), giving further support to the hypothesis that NAFLD is associated with low-grade systemic inflammation. In our report, we observed elevated levels of CRP in all patients with NAFLD, however, after adjustment for sex, body mass index (BMI) and age, no significant difference between patients and controls was observed. This might be due to a low sample size in our study, since the difference between patients and controls was still significant after adjustment for several confounders in the study by Targher. Elevated levels of CRP and MCP-1 have been found in patients with the metabolic syndrome [2,3], it is therefore, not surprising that a similar pattern is seen in NAFLD patients as these diseases are strongly associated [4]. However, it is interesting that Targher found CRP to be elevated even after adjustment for the presence of metabolic syndrome and insulin resistance, and in our study, MCP-1 predicted NASH independent of its possible role in the metabolic syndrome. These
observations indicate that the liver disease may be partially responsible for the elevated levels of CRP and MCP-1 in patients with NAFLD. Since these inflammatory markers are recognized as predictors and mediators of cardiovascular disease [5,6], one could hypothesize that NAFLD in itself contributes to vascular inflammation and progression of the atherosclerosis in these patients. However, no conclusion about causeand effect can be drawn from cross-sectional studies. We therefore, fully agree that further prospective and mechanistic studies are needed before causality between NAFLD and cardiovascular disease can be established. Nonetheless, although the identification and characterization of the different actors, as well as their relative importance, are not fulfilled, several studies, including the report by Targher, support the notion of NAFLD as a disorder characterized by low-grade systemic inflammation. It is tempting to hypothesize that NAFLD, the metabolic syndrome, and atherosclerosis may be interacting disorders involving inflammatory mechanisms, potentially representing a common pathogenic loop.
References [1] Haukeland JW, Damas JK, Konopski Z, Loberg EM, Haaland T, Goverud I, et al. Systemic inflammation in nonalcoholic fatty liver disease is characterized by elevated levels of CCL2. J Hepatol 2006;44:1167–1174. [2] Ford ES. The metabolic syndrome and C-reactive protein, fibrinogen, and leukocyte count: findings from the Third National Health and Nutrition Examination Survey. Atherosclerosis 2003;168:351–358.
882
Letters to the Editor / Journal of Hepatology 45 (2006) 879–882
[3] Koh KK, Han SH, Quon MJ. Inflammatory markers and the metabolic syndrome: insights from therapeutic interventions. J Am Coll Cardiol 2005;46:1978–1985. [4] Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 2003;37:917–923. [5] Malik S, Wong ND, Franklin S, Pio J, Fairchild C, Chen R. Cardiovascular disease in US patients with metabolic syndrome, diabetes, and elevated C-reactive protein. Diabetes Care 2005;28:690–693. [6] Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005;352:1685–1695.
John Willy Haukeland Faculty Division Aker University Hospital, Oslo, Norway Department of Gastroenterology, Aker University Hospital, Oslo, Norway E-mail address: [email protected] Pa˚l Aukrust Research Institute for Internal Medicine, Oslo, Norway Section of Clinical Immunology and Infectious Diseases, Department of Medicine, Rikshospitalet-Radiumhospitalet Medical Center, University of Oslo, Oslo, Norway doi:10.1016/j.jhep.2006.09.006
[2]
[3]
[4]
[5]
disease is characterized by elevated levels of CCL2. J Hepatol 2006;44:1167–1174. Targher G, Bertolini L, Padovani R, Rodella S, Zoppini G, Zenari L, et al. Relations between carotid artery wall thickness and liver histology in subjects with nonalcoholic fatty liver disease. Diabetes Care 2006;29:1325–1330. Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol 1999;94:2467–2474. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al. American Heart Association; National Heart, Lung, and Blood Institute: Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005;112:2735–2752. Marchesini G, Marzocchi R, Agostini F, Bugianesi E. Nonalcoholic fatty liver disease and the metabolic syndrome. Curr Opin Lipidol 2005;16:421–427.
881
[6] Targher G, Arcaro G. Non-alcoholic fatty liver disease and increased risk of cardiovascular disease. Atherosclerosis 2006; doi:10.1016/j.atherosclerosis.2006.08.021. [7] Ballantyne CM, Nambi V. Markers of inflammation and their clinical significance. Atheroscler Suppl 2005;6:21–29.
Giovanni Targher Division of Internal Medicine and Diabetes Unit, Ospedale ‘‘Sacro Cuore – don Calabria’’ Hospital, Via Sempreboni, 5, 37024 Negrar (VR), Italy E-mail address: [email protected]
doi:10.1016/j.jhep.2006.09.005
Inflammatory interactions between nonalcoholic fatty liver disease and the metabolic syndrome To the Editor: We appreciate Targher’s comments on our report on systemic inflammation in nonalcoholic fatty liver disease (NAFLD) [1]. In this paper we reported elevated serum levels of several markers of inflammation in NAFLD patients with particularly high levels of monocyte chemoattractant protein 1 (MCP-1) in those with nonalcoholic steatohepatitis (NASH). By presenting a set of cross-sectional data from NAFLD patients in Italy, Tagher shows that NAFLD patients, and especially those with NASH, have markedly raised CRP levels compared with healthy controls. Additionally, levels of CRP correlated significantly with histological features (degree of steatosis, necroinflammation and fibrosis), giving further support to the hypothesis that NAFLD is associated with low-grade systemic inflammation. In our report, we observed elevated levels of CRP in all patients with NAFLD, however, after adjustment for sex, body mass index (BMI) and age, no significant difference between patients and controls was observed. This might be due to a low sample size in our study, since the difference between patients and controls was still significant after adjustment for several confounders in the study by Targher. Elevated levels of CRP and MCP-1 have been found in patients with the metabolic syndrome [2,3], it is therefore, not surprising that a similar pattern is seen in NAFLD patients as these diseases are strongly associated [4]. However, it is interesting that Targher found CRP to be elevated even after adjustment for the presence of metabolic syndrome and insulin resistance, and in our study, MCP-1 predicted NASH independent of its possible role in the metabolic syndrome. These
observations indicate that the liver disease may be partially responsible for the elevated levels of CRP and MCP-1 in patients with NAFLD. Since these inflammatory markers are recognized as predictors and mediators of cardiovascular disease [5,6], one could hypothesize that NAFLD in itself contributes to vascular inflammation and progression of the atherosclerosis in these patients. However, no conclusion about causeand effect can be drawn from cross-sectional studies. We therefore, fully agree that further prospective and mechanistic studies are needed before causality between NAFLD and cardiovascular disease can be established. Nonetheless, although the identification and characterization of the different actors, as well as their relative importance, are not fulfilled, several studies, including the report by Targher, support the notion of NAFLD as a disorder characterized by low-grade systemic inflammation. It is tempting to hypothesize that NAFLD, the metabolic syndrome, and atherosclerosis may be interacting disorders involving inflammatory mechanisms, potentially representing a common pathogenic loop.
References [1] Haukeland JW, Damas JK, Konopski Z, Loberg EM, Haaland T, Goverud I, et al. Systemic inflammation in nonalcoholic fatty liver disease is characterized by elevated levels of CCL2. J Hepatol 2006;44:1167–1174. [2] Ford ES. The metabolic syndrome and C-reactive protein, fibrinogen, and leukocyte count: findings from the Third National Health and Nutrition Examination Survey. Atherosclerosis 2003;168:351–358.
882
Letters to the Editor / Journal of Hepatology 45 (2006) 879–882
[3] Koh KK, Han SH, Quon MJ. Inflammatory markers and the metabolic syndrome: insights from therapeutic interventions. J Am Coll Cardiol 2005;46:1978–1985. [4] Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 2003;37:917–923. [5] Malik S, Wong ND, Franklin S, Pio J, Fairchild C, Chen R. Cardiovascular disease in US patients with metabolic syndrome, diabetes, and elevated C-reactive protein. Diabetes Care 2005;28:690–693. [6] Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005;352:1685–1695.
John Willy Haukeland Faculty Division Aker University Hospital, Oslo, Norway Department of Gastroenterology, Aker University Hospital, Oslo, Norway E-mail address: [email protected] Pa˚l Aukrust Research Institute for Internal Medicine, Oslo, Norway Section of Clinical Immunology and Infectious Diseases, Department of Medicine, Rikshospitalet-Radiumhospitalet Medical Center, University of Oslo, Oslo, Norway doi:10.1016/j.jhep.2006.09.006