This is the first study to examine the effect of abdominal adiposity and other environmental risk factors on the inflammatory response to injury as indicated by serum CRP. We primarily defined CRP response to surgery as the logarithm of postoperative peak CRP adjusted for preoperative CRP level. We also used a secondary definition of the logarithm of the additive change in CRP pre and post surgery. These two measures gave similar results. CRP response was higher with higher waist:hip ratio, increasing age and longer duration of surgery. The relation to waist:hip ratio was continuous with no apparent threshold effect.
Although some of the established risk factors for atherosclerosis and other chronic diseases such as cigarette smoking, ethnic group and social class exhibited associations with baseline CRP (for exercise there was a trend in the expected direction) in univariate analysis, there were no important effects on response after adjustment for other factors. The study was not designed to explore these effects and may have been too small to detect them or alternatively they may not have been present. The reduction in the magnitude of the effects supports the latter.
This is a relatively small study, but the magnitude of the effects we observed for waist:hip ratio leave little doubt as to the fact that they are true findings. We chose hernia repair as it is easily standardised, easy to grade the insult, and is associated with a demonstrable inflammatory response. It is unlikely that the exaggerated response in subjects with a high waist:hip ratio and increased age were due to differences in surgical technique, as the association was independent of duration of surgery or wound length even although the latter was associated with waist:hip ratio. We cannot entirely discount the possibility that the increased response with waist:hip ratio was due to increased damage to subcutaneous adipose tissue due to a greater depth of incision. However if this were the case, it would be expected that wound length would be independently associated with inflammatory response and that it would confound the association with waist:hip ratio which it did not. It seems unlikely that wound depth which we did not measure would vary inversely with wound length. Importantly, there was no association of the duration of surgery with waist:hip ratio. Furthermore, the association of waist:hip ratios with CRP response was continuous throughout the range of ages and waist:hip ratios with no evidence of a threshold for the effect. Likewise it seems unlikely that differences in CRP response could be explained by post-operative infection being more common as waist:hip ratio rises. We did not find any instances of post-operative infection and if lung infection caused by atelectasis related to the anaesthetic were responsible, a higher post-operative response in smokers would have been expected. It seems most likely therefore that waist:hip ratio is associated with an increased CRP responsiveness to injury through mechanisms independent of the degree of tissue damage or procedure related infection.
The C-reactive protein response to inguinal hernia repair has been described on numerous occasions, but with the goal of comparing operative technique rather than studying host characteristics which determine the inflammatory response
. Future studies in this area should take account of age and waist:hip ratio. They should also take account of the length of incision and more importantly the duration of surgery. One other study has explored the relationship of obesity to the post operative inflammatory response following laparoscopic cholycystectomy and like the current study found it to be exagerated with impaired anti-inflammatory cytokine production. This study however was small with only 34 subjects, only compared obese and normal BMI subjects and did not study other host characteristics which could influence the inflammatory response
We chose peak CRP adjusted for baseline CRP as the measure of response. Similar findings were obtained when the additive change in CRP was used. However the better model fit was with the former. Whilst baseline CRP was strongly associated with peak CRP, there was no association with the additive change, suggesting that regression to the mean is not an explanation for association of waist:hip ratio with the latter. For logistic and resource reasons we did not measure CRP beyond 48 hrs and it is possible that we would have obtained some higher peak values had we done so. However, values beyond 48 hrs would have been more likely to be influenced by factors other than the initial surgical insult which it was our goal to measure the effect of.
The measure of adiposity most strongly related to CRP response was waist:hip ratio, which is the best measure of visceral adipose tissue, followed by waist circumference with only a weak association with BMI. Had we measured visceral adipose tissue more directly using CT scanning, it is likely that we would have found an even stronger association. The stronger association of waist:hip ratio is in line with other studies assessing the association of adiposity with circulating inflammatory markers and the metabolic syndrome
[6, 8]. Studies of the association of adiposity with disease end points however suggest that BMI may be the better marker
, but that waist:hip ratio has an additional effect independent of BMI. BMI is the more imperfect measure of abdominal adiposity but possibly a better measure of total adiposity. It is also easier to measure than waist:hip ratio in large field studies.
It can be speculated that the finding that waist:hip ratio and age influence baseline and post-injury CRP levels with a very similar size of effect supports the contention that baseline CRP is a measure of inflammatory responsiveness to casual stimuli and that obesity and higher age modulate the generic excitability of the inflammatory system leading to both higher baseline CRP and higher CRP response to surgery through similar mechanisms. The mechanism for the association of baseline CRP and waist:hip ratio to cardiovascular disease and other disease outcomes could be through this increase in inflammatory system excitability leading to exaggerated local inflammatory responses to environmental exposures, specifically hypertension at the blood vessel wall in the case of atherosclerosis, and various organ specific locations in cancer.
There are other possible explanations for the association of basal CRP with risk of atherosclerosis rather than as an indicator of immune responsiveness. The elevated CRP could be the result of inflammation in response to sub-clinical disease. This however is unlikely, as the relationship of baseline CRP with many adverse outcomes does not diminish with time from when it was measured
. Another interpretation is that the environmental factors which cause disease through other mechanisms also activate inflammation. We cannot discount this possibility. Finally it is possible that the inflammatory responses of which CRP is a marker induce changes in conventional risk factors such as lipids, insulin and blood sugar which are related to insulin resistance as part of the metabolic syndrome and that it is these which result in the adverse consequences. Only one other study has addressed this issue, the Rancho Bernado Study
. In this study, adjustment for CRP attenuated the effect of the metabolic syndrome by 35%, whereas adjustment of the effect of CRP for the metabolic syndrome did not reduce the size of effect. This suggests that the association between features of the metabolic syndrome and atherosclerosis may at least to an important degree be explained by its association with underlying inflammatory mechanisms.
As well as the relevance of our findings to the study of the inflammatory response to surgery, atherosclerosis, cancer and other chronic diseases, these findings would explain the rather puzzling observation that obesity, increased waist:hip ratio and CRP are related to risk of death from external causes and the higher rates of morbidity in the obese from trauma, surgery and acute pancreatitis
[16, 17]. Furthermore it would explain the higher rates of osteoarthritis in non weight bearing joints in obese subjects
. Exaggerated inflammatory responses could be damaging through a number of mechanisms and could delay healing and resolution of inflammation.