Reply to: “C-reactive protein levels in non-alcoholic fatty liver disease”
Authors: Tine Jess, Esther Zimmermann, Rodolphe Anty, Joan Tordjman, An Verrijken, Philippe Gual, Albert Tran, Antonio Iannelli, Jean Gugenheim, Pierre Bedosa, Sven Francque, Yannick Le Marchand-Brustel, Karine Clement, Luc Van Gaal, Thorkild I.A. Sørensen
Journal: Journal of Hepatology (2011)

C-reactive protein levels in relation to various features of non-alcoholic fatty liver disease among obese patientsJournal of HepatologyVol. 55Issue 3PreviewNon-alcoholic fatty liver disease (NAFLD) is a major hepatic consequence of obesity. It has been suggested that the high sensitivity C-reactive protein (hs-CRP) is an obesity-independent surrogate marker of severity of NAFLD, especially development of non-alcoholic steato-hepatitis (NASH), but this remains controversial. We aimed to investigate whether associations between various features of NAFLD and hs-CRP are independent of body mass index (BMI) in its broad range among obese patients. Full-Text PDF C reactive protein levels in non-alcoholic fatty liver diseaseJournal of HepatologyVol. 56Issue 2PreviewNon-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world. It represents a wide spectrum of conditions ranging from fatty liver, which in general follows a benign, non-progressive clinical course, to nonalcoholic steatohepatitis (NASH), a more serious form of NAFLD that may progress to cirrhosis and end-stage liver disease. Accurate evaluation of liver fibrosis in patients with NAFLD is important to identify patients who may develop complications. Over time, several biological markers have been studied for evaluating the extent of steatosis, the presence of necroinflammation, and the development of fibrosis to avoid performing liver biopsy, an invasive procedure that still represents the gold standard of diagnosis. Full-Text PDF Open Access We thank Dr. Dogru et al. for their comments on our paper on C-reactive protein (CRP) levels in relation to various features of non-alcoholic fatty liver disease (NAFLD) among obese patients [[1]Zimmermann E. Anty R. Tordjman J. Verrijken A. Gual P. Tran A. et al.C-reactive protein levels in relation to various features of non-alcoholic fatty liver disease among obese patients.J Hepatol. 2011; 55: 660-665Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar]. In our study of 627 obese adults with liver histology and measures of body mass index (BMI, kg/m2), and high sensitivity (hs)-CRP, we confirmed a strong association between BMI and hs-CRP, with a 20% increase in hs-CRP level per 10% increase in BMI. Also, we observed a positive association between hs-CRP and liver steatosis, but no BMI independent association between hs-CRP and non-alcoholic steato-hepatitis (NASH), hence questioning whether CRP can be used as a marker of severity of NAFLD [[1]Zimmermann E. Anty R. Tordjman J. Verrijken A. Gual P. Tran A. et al.C-reactive protein levels in relation to various features of non-alcoholic fatty liver disease among obese patients.J Hepatol. 2011; 55: 660-665Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar]. We fully acknowledge that circulating hs-CRP levels may not only associate with obesity, but also with pre-diabetes and diabetes [2Sabanayagam C. Shankar A. Lim S.C. Lee J. Tai E.S. Wong T.Y. Serum C-reactive protein level and prediabetes in two Asian populations.Diabetologia. 2011; 54: 767-775Crossref PubMed Scopus (35) Google Scholar, 3Garcia C. Feve B. Ferre P. Halimi S. Baizri H. Bordier L. et al.Diabetes and inflammation: fundamental aspects and clinical implications.Diabetes Metab. 2010; 36: 327-338Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar], which in turn may associate with NAFLD [[4]Yun J.W. Cho Y.K. Park J.H. Kim H.J. Park D.I. Sohn C.I. et al.Abnormal glucose tolerance in young male patients with nonalcoholic fatty liver disease.Liver Int. 2009; 29: 525-529Crossref PubMed Scopus (44) Google Scholar]. However, obesity (which was adjusted for by use of BMI) is also strongly associated with both diabetes and NAFLD [[5]Boppidi H. Daram S.R. Nonalcoholic fatty liver disease: hepatic manifestation of obesity and the metabolic syndrome.Postgrad Med. 2008; 120: E01-E07Crossref Scopus (67) Google Scholar]. Therefore, further adjustment for diabetes or glucose tolerance abnormalities would not be expected to change our results notably. The same argument holds for the effect of further adjustment for hypertension and lipid profiles. Still, to meet the concern of Dr. Dogru et al., we have reassessed the mentioned metabolic factors in two of the study cohorts. We can now report that in the OBBO cohort, hs-CRP was associated with triglycerides (p= 0.02), but not with glucose tolerance status (test across categories of normal glucose tolerance, impaired fasting glucose [IFG], impaired glucose tolerance [IGT], combined IFG-IGT, and diabetes), systolic or diastolic blood pressure, total cholesterol, HDL-cholesterol, or LDL-cholesterol. In the Nice Obese Subjects cohort, we observed a negative association between CRP and high blood pressure (p = 0.002), but no association between CRP and, respectively, diabetes, glucose intolerance, triglyceride levels, HDL-cholesterol, or the metabolic syndrome. Hence, adjustment for triglycerides and blood pressure could be considered, but would, due to the association with BMI, not be expected to change conclusions. An additional concern raised by Dr. Dogru et al. was the effect of medications on the observed associations. A reduction in hs-CRP caused by medications given primarily to patients with severe metabolic disturbances and related severe NAFLD, could hypothetically explain our finding of no association between hs-CRP levels and severity of NAFLD. Our reassessment of the OBBO cohort revealed that hs-CRP was not associated with medications for diabetes (used by 2%) or medications for blood pressure (used by 35%), whereas a negative association between hs-CRP and medication for lipid disturbances, which was used by 14%, was observed (p = 0.04). It must be carefully considered, if additional adjustment for medications for lipid disturbances would be justifiable in light of the aim of the study, and how they would affect the interpretation of our results. Our primary aim was to test whether hs-CRP could be used as a BMI independent biomarker for severity of NAFLD as an alternative to an invasive procedure, namely the liver biopsy. Adjustment for the medications for lipid disturbances (had they been available for all three sub-cohorts) would potentially have changed the observed association between hs-CRP and NAFLD, but it would not be expected to change the fact, that this association between hs-CRP and NAFLD is not BMI independent. To summarize, we believe that additional adjustments would not add to the interpretation of our results and may potentially cause over-adjustment. As a parallel example, the influence of adjusting or not adjusting for weight, when assessing the association between birth weight and blood pressure, has been examined [[6]Tu Y.K. West R. Ellison G.T. Gilthorpe M.S. Why evidence for the fetal origins of adult disease might be a statistical artifact: the “reversal paradox” for the relation between birth weight and blood pressure in later life.Am J Epidemiol. 2005; 161: 27-32Crossref PubMed Scopus (214) Google Scholar]. This mathematical example illustrated how a genuine inverse relation between birth weight and blood pressure would be exaggerated by adjusting for current weight, whereas a positive relation between birth weight and blood pressure was reversed by adjusting for current weight [[6]Tu Y.K. West R. Ellison G.T. Gilthorpe M.S. Why evidence for the fetal origins of adult disease might be a statistical artifact: the “reversal paradox” for the relation between birth weight and blood pressure in later life.Am J Epidemiol. 2005; 161: 27-32Crossref PubMed Scopus (214) Google Scholar]. In consequence, by adjusting further for the suggested metabolic factors in the present study, we might end up with an over-adjustment leading to an even stronger rejection of the hypothesis of CRP being a marker of NAFLD. In conclusion, we thank Dr. Dogru et al. for bringing these important issues up for discussion, and we adhere to the conclusion, that hs-CRP is a marker of liver steatosis, but not a BMI independent marker of level of NAFLD. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.