C-Reactive Protein, Chronic Low Back Pain and, Diet and Lifestyle

Abstract

C-Reactive Protein (CRP) is best known as an acute phase protein and is typically assessed in most general blood work. High sensitivity CRP (hsCRP) may be a useful clinical marker of chronic inflammatory states in musculoskeletal conditions. It appears that it is raised in inflammatory chronic low back pain (CLBP) and associated with reduced pain thresholds, weakness and reduced function. It is also possible CRP could contribute towards the development and maintenance of CLBP by activating the complement system which increases peripheral nociception. Diet and lifestyle factors can promote raised CRP. A hsCRP level of < 1mg/l appears ideal and the higher the level the more emphasis should be placed on chronic inflammation as a contributor to symptoms. Diet and lifestyle can significantly reduce CRP levels and may be a useful adjunct in treating CLBP patients with elevated CRP. This might make CRP a useful clinical marker of inflammation in CLBP and a therapeutic target for diet and lifestyle interventions.

Introduction

C-Reactive Protein (CRP) is best known as an acute phase protein and is typically assessed in most general blood work. More recently high sensitivity C-reactive protein (hsCRP) has been used in cardiovascular research as a marker of chronic inflammation. As chronic low back pain (CLBP) can have an inflammatory component it would be useful to have a clinical marker to assess in practice. Furthermore it may help us understand a component of how diet and lifestyle can influence CLBP.

C-Reactive Protein and Chronic Low Back Pain

In the 1940s CRP was considered as a possible marker of chronic low level inflammation but the standard assay lacks the sensitivity to determine normal ranges. Since the advent of the hsCRP test large-scale epidemiological studies have identified that CRP is a strong independent risk factor of future myocardial infarction, stroke, peripheral arterial disease, and vascular death among individuals without known cardiovascular disease [1]. In cardiovascular disease hsCRP is a sensitive and specific measure across many populations.  As these conditions are associated with inflammatory processes it is possible hsCRP may be a useful marker of chronic inflammation in musculoskeletal conditions such as chronic low back pain.

More recently CRP has received attention as a marker of chronic inflammation in musculoskeletal conditions. Chronic inflammation has been associated with arthritis [2], and chronic musculoskeletal injuries  [3-5]. Repetitive tissue injury has been theorised to contribute to lower level rises in chronic inflammation [3]. Inflammation and pain are intimately interrelated and pain perception may be higher in those with raised CRP. In a study of 99 pairs of twins, higher levels of CRP were associated with lower pain thresholds and increased pain sensation [6]. Similarly, in cancer patients CRP is significantly correlated with perceived pain [7]. Thus a hsCRP test could provide insight in to the inflammatory contribution chronic pain states.

CRP is also associated with poorer function in symptomatic individuals. Carp et al [4] found asymptomatic subjects averaged 0.8 mg/l, whereas those scoring 50-74 on the upper body musculoskeletal analysis (UMBA) averaged 1.8 mg/l, and those scoring over 75 on the UMBA averaged 5.4 mg/l. Interestingly, CRP was more strongly correlated with symptom levels than IL-1β, TNF-α and IL-6. Suggesting CRP may be the more clinically useful marker. These results are similar to that of Ravaglia et al [8] who found CRP levels were related to functional impairment. Cesari at al [9] found older adults with a CRP >6 mg/l had significant weakness and poorer physical function compared with those with a CRP <6 mg/l, conditions that may lead to chronic pain states. Carp et al explain their results by suggesting that worse disability is caused by worse injury and thus a greater acute phase response. However, injury and disability are not necessarily strongly associated. For example data from the LAIDBACK study has shown that at 3 years there is not a strong correlation between lumbar spine magnetic resonance imaging findings and symptoms [10]. It may be that in some patients it is the systemic inflammatory level that may be influencing the disability.

The association between raised CRP and CLBP is controversial. Studies looking at inflammatory pathologies such as herniated discs [11,12], nerve root inflammation [11], sciatica [13], and Modic changes [14] have shown positive correlations. Whereas those with smaller sample sizes and inclusion of acute and chronic patients in one heterogenous group have failed to show associations [15,16]. Briggs et al [17] conducted a population based study using 15 322 participants examining CRP levels, obesity and low back pain (LBP). They found that those with CRP levels of >30.0 mg/l had nearly twice the odds of reporting LBP. It should be noted they used standard CRP assessment and thus the figures are higher than for the hsCRP. Additionally, those with a body mass index >30 and elevated levels of CRP were 2 to 3 times as likely to report LBP. They found a significant association between LBP and elevated CRP, suggesting CRP could be a valuable marker of chronic inflammation in CLBP patients.

CRP is more than a useful marker and can contribute towards the development of chronic pain. Animal studies have suggested raised CRP plays a role in the chronic inflammation that leads to reduced tissue tolerance, and paves the way for chronic pain states [19]. Further, CRP may contribute to the initiation and continuation of joint pain [20]. In cancer patients elevated CRP can modulate pain [21] and contribute to the amplification and persistence of pain [22]. CRP can be viewed as both a marker for the underlying processes involved in increased pain sensation and a direct contributor to increased pain sensation. CRP activates the compliment system, which in turn sensitises peripheral nociceptors [23]. Effectors of the compliment cascade impact peripheral nociceptive sensitisation through the release of soluble factors and interacting directly with nociceptors. For example C5a and C3a injection can cause behavioural hyperalgesia in rats. In addition effectors of the complement cascade activate mast cells, which can sensitise nociceptors in multiple ways [23]. Thus CRP could feasibly contribute to the progression towards and maintenance of CLBP.

Diet and Lifestyle May Increase C-Reactive Protein Levels

As CRP may contribute to the underlying pathogenesis of CLBP it is prudent to consider some of the contributing factors in this process. Diet and lifestyle are powerful modulators of CRP levels and thus may contribute to the pathogenesis of CLBP through this mechanism. Smoking has been found to be associated with raised CRP [24]. Sleep disorders and poor sleep quality are associated with elevated CRP [25,26]. Psychological stress has been linked with raised CRP when perceived stress is increased [27], and during depression and loneliness [28]. Increased dietary saturated fat increases CRP whereas an equal increase in unsaturated fatty acids did not [29]. Higher carbohydrate intake was associated raised CRP levels in overweight and obese individuals [30]. Of the minerals magnesium has perhaps been most closely associated with CRP. Current recommendations for magnesium intake range from 310-420mg per day. King et al [31] found those who consumed less than the RDI of magnesium were greater than 1.45 times more likely to have a CRP level over 3.0 mg/l. 68% of US adults consumed less than the recommended daily intake (RDI), with 19% consuming less half the RDI. Of the vitamins deficiencies in vitamins B6 and D have received some interest. B6 appears to be utilised as part of the inflammatory process and thus those with elevated CRP level have significantly lower levels [32]. The interest in vitamin D and CRP has come from cardiovascular research. Low plasma vitamin D status is inversely associated with CRP levels [33]. Exercise can have both a positive and negative effect on CRP levels. However, overtraining such as that caused by playing professional soccer has been found to cause elevation in CRP during the season [34]. These results fit with the theme that deviations from a “healthy” lifestyle are associated with elevations in CRP levels.

Clinical Use

Given that there is an association between CLBP and CRP levels it is suggested a hsCRP test may be a useful clinical marker for managing these patients. This needs to be considered within a broader framework of the multitude of bio-psycho-social factors that influence CLBP. The question of what level is significant is unclear. In the literature there is no consensus for its use in musculoskeletal conditions. Levels as low as >1 mg/l have used, whilst the highest used is >6.0 mg/l. Thus in practice the measure can be used non-diagnostically with an appreciation of the cardiovascular research. It needs to be remembered that levels may be spiked during acute infection, trauma and post intense exercise. A level >1 mg/l is likely indicative of increased systemic inflammation, the higher this figure is the more significant a contributor it should be considered.

Pharmacological approaches have been considered for modifying CRP levels, with statins being potentially the most promising but diet and lifestyle changes can significantly improve CRP levels. An 8-week mindfulness programme reduced CRP levels from 2.98 to 2.09 [35]. Similarly, an 8-week programme of exercise decreased CRP levels by 38% and improved function in automotive workers with low back pain [36]. As visceral adipocytes produce CRP reducing body fat levels is another potential therapeutic target, and a carbohydrate restricted has been shown to reduce CRP levels [37]. More broadly going from 2 to 5 or 8 portions of fruit and vegetables per day significantly reduced CRP levels [38]. Furthermore, in a study of 1200 Puerto Rican adults aged 45-75 the variety of fruit and vegetable intake but not the quantity was inversely related with CRP levels [39]. Specifically, vitamin C intake from fruit and plasma vitamin C levels was inversely related to CRP levels in a cross-sectional study of 3258 British men aged 60-79 [40]. Other substances high in antioxidants have been found to favourably alter CRP levels including coffee [41], fruit juice [42,43] and dark chocolate [44]. Thus, diet and lifestyle modification of CRP levels may prove an effective component of CLBP treatment and may help reduce symptoms through other mechanisms as well.

Conclusion

CRP may be a useful clinical marker of chronic inflammation in chronic low back pain. It appears that it is elevated in inflammatory CLBP and associated with reduced tissue tolerance, reduced pain thresholds, weakness and reduced function. It may also contribute to peripheral sensitisation as part of the progression towards and maintenance of chronic pain. Diet and lifestyle factors can promote raised CRP. A hsCRP level of < 1mg/l appears ideal and the higher the level the more emphasis should be placed on chronic inflammation as a contributor to symptoms. Diet and lifestyle can significantly reduce CRP levels and may be a useful adjunct in treating CLBP patients with elevated CRP.

 

References

1. Ridker  PM (2001) High-sensitivity C-reactive protein potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. Circulation 103(13): 1813-1818.

2. Stürmer T, Brenner H, Koenig W, Günther K (2004) Severity and extent of osteoarthritis and low grade systemic inflammation as assessed by high sensitivity C reactive protein. Ann Rheum Dis 63: 200–205.

3. Barbe MF, Barr AE (2006) Inflammation and the pathophysiology of work-related musculoskeletal disorders. Brain Behav Immun 20: 423–429.

4. Carp S, Barbe M, Winter K, Amin M, Barr A (2007) Inflammatory biomarkers increase with severity of upper-extremity overuse disorders. Clin Sci 112: 305–314.

5. Carp SJ, Barr AE, Barbe MF (2008) Serum biomarkers as signals for risk and severity of work-related musculoskeletal injury. Biomark Med 2: 67–79.

6. Afari N, Mostoufi S, Noonan C, Poeschla B, Succop A, et al. (2011) C-reactive protein and pain sensitivity: findings from female twins. Annals of Behavioral Medicine 42(2): 277-283.

7. Oliveira KG, von Zeidler SV, Lamas AZ, de Podestá, JRV, Sena A, et al. (2014) Relationship of inflammatory markers and pain in patients with head and neck cancer prior to anticancer therapy. Brazilian Journal of Medical and Biological Research (epub ahead of print).

 8. Ravaglia, G., Forti, P., Maioli, F. et al. (2004) Peripheral blood markers of inflammation and functional impairment in elderly community-dwellers. Exp. Gerontol. 39,1415–1422

9. Cesari M, Penninx BW, Pahor M, et al. (2004) Inflammatory markers and physical performance in older persons: the InCHIANTI study. J Gerontol A Biol Sci Med Sci 59: 242–248.

10. Suri P, Boyko EJ, Goldberg J, et al. (2014). Longitudinal associations between incident lumbar spine MRI findings and chronic low back pain or radicular symptoms: retrospective analysis of data from the longitudinal assessment of imaging and disability of the back (LAIDBACK). BMC Musculoskeletal Disorders 15(1): 152.

11. Ahn SH, Cho YW, Ahn MW, Jang SH, Sohn YK, et al. (2002) mRNA expression of cytokines and chemokines in herniated lumbar intervertebral discs. Spine (Phila Pa 1976) 27: 911–917.

12. Burke J, Watson R, McCormack D, Dowling F, Walsh M, et al. (2002) Intervertebral discs which cause low back pain secrete high levels of proinflammatory mediators. Br J Bone Joint Surg 84: 196–201.

13. Stürmer T, Raum E, Buchner M, et al. (2005) Pain and high sensitivity C reactive protein in patients with chronic low back pain and acute sciatic pain. Ann Rheum Dis 64: 921–925.

14. Rannou F, Ouanes W, Boutron I, et al. (2007) High-sensitivity C-reactive protein in chronic low back pain with vertebral end-plate modic signal changes. Arthritis Rheum 57: 1311–1315.

15. Park CH, Lee SH (2010) Investigation of high-sensitivity c-reactive protein and erythrocyte sedimentation rate in low back pain patients. Korean J Pain 23: 147–150.

16. Gebhardt K, Brenner H, Sturmer T, et al. (2006) The course of high-sensitive C-reactive protein in correlation with pain and clinical function in patients with acute lumbosciatic pain and chronic low back pain—a 6 months prospective longitudinal study. Eur J Pain 10: 711–719.

17. Briggs MS, Givens DL, Schmitt LC, Taylor CA (2013) Relations of C-reactive protein and obesity to the prevalence and the odds of reporting low back pain. Archives of physical medicine and rehabilitation 94(4): 745-752.

18. Peyrin-Biroulet L, Gonzalez F, Dubuquoy L, Rousseaux C, Dubuquoy C, et al. (2012) Mesenteric fat as a source of C reactive protein and as a target for bacterial translocation in Crohn’s disease. Gut 61(1): 78-85.

19. Barr AE, Barbe MF (2004) Inflammation reduces physiological tissue tolerance in the development of work-related musculoskeletal disorders. J Electromyogr Kinesiol 14: 77–8.

20. Schaible H, von Banchet GS, Boettger M, et al. (2010) The role of proinflammatory cytokines in the generation and maintenance of joint pain. Ann N Y Acad Sci 1193: 60–69.

21. Watkins LR, Maier SF (2002) Beyond neurons: evidence that immune and glial cells contribute to pathological pain states. Physiol Rev 82: 981-1011.

22. Laird BJ, Scott AC, Colvin LA, McKeon AL, Murray GD, Fearon KC, et al. (2011) Cancer pain and its relationship to systemic inflammation: an exploratory study. Pain 152: 460-463.

23. Ren K, Dubner R, (2010) Interactions between the immune and nervous systems in pain. Nature medicine 16(11): 1267-1276.

24. Le-Ha C, Beilin LJ, Burrows S, Oddy WH, Hands B, et al. (2014) Gender and the active smoking and high-sensitivity C-reactive protein relation in late adolescence. Journal of lipid research 55(4): 758-764.

25. Larkin EK, Rosen CL, Kirchner HL, Storfer-Isser A, Emancipator JL, et al (2005) Variation of C-reactive protein levels in adolescents association with sleep-disordered breathing and sleep duration. Circulation 111(15): 1978-1984.

26. Liu R, Liu X, Zee PC, Hou L, Zheng Z, et al. (2014) Association between Sleep Quality and C-Reactive Protein: Results from National Health and Nutrition Examination Survey, 2005-2008. PloS one 9(3): e92607.

27. Gouin JP, Glaser R, Malarkey WB, Beversdorf D, Kiecolt-Glaser J (2012) Chronic stress, daily stressors, and circulating inflammatory markers. Health Psychology 31(2): 264.

28. Copeland WE, Shanahan L, Worthman C, Angold A, Costello EJ (2012) Cumulative depression episodes predict later C-reactive protein levels: a prospective analysis. Biological psychiatry 71(1): 15-21.

29. Koopmans SJ, Dekker R, Ackermans MT, et al. (2011) Dietary saturated fat/cholesterol, but not unsaturated fat or starch, induces C-reactive protein associated early atherosclerosis and ectopic fat deposition in diabetic pigs. Cardiovasc Diabetol 10: 64.

30. Neuhouser ML, Schwarz Y, Wang C, et al. (2012) A low-glycemic load diet reduces serum C-reactive protein and modestly increases adiponectin in overweight and obese adults. The Journal of nutrition 142(2): 369-374.

31. King DE, Mainous III AG, Geesey ME, Woolson RF (2005) Dietary magnesium and C-reactive protein levels. Journal of the American College of Nutrition 24(3): 166-171.

32. Friso S, Jacques PF, Wilson PW, Rosenberg IH, Selhub J (2001) Low circulating vitamin B6 is associated with elevation of the inflammation marker C-reactive protein independently of plasma homocysteine levels. Circulation 103(23): 2788-2791.

33. Silva JR, Rebelo A, Marques F, Pereira L, Seabra A, et al. (2013) Biochemical impact of soccer: an analysis of hormonal, muscle damage, and redox markers during the season. Applied Physiology, Nutrition, and Metabolism 39(4): 432-438.

34. Faraj J, Ronnenberg A, (2014) Inflammation, vitamin D, and depression symptoms among reproductive-aged women from the National Health and Nutrition Examination Survey 2005-2006 (1034.20). The FASEB Journal 28(1 Supplement): 1034-20.

35. Creswell JD, Irwin MR, Burklund LJ, Lieberman MD, Arevalo JM, et al. (2012) Mindfulness-based stress reduction training reduces loneliness and pro-inflammatory gene expression in older adults: a small randomized controlled trial. Brain, behavior, and immunity 26(7): 1095-1101.

36. Kim SK, Jung I, Kim JH (2008) Exercise reduces C-reactive protein and improves physical function in automotive workers with low back pain. J Occup Rehabil 18: 218–222.

37. Wood RJ, Volek JS, Davis SR, Dell’Ova C, Fernandez ML (2006) Effects of a carbohydrate-restricted diet on emerging plasma markers for cardiovascular disease. Nutr Metab (Lond), 3(1): 19.

38. Watzl B, Kulling SE, Möseneder J, Barth SW, Bub A (2005) A 4-wk intervention with high intake of carotenoid-rich vegetables and fruit reduces plasma C-reactive protein in healthy, nonsmoking men. The American journal of clinical nutrition 82(5): 1052-1058.

39. Bhupathiraju SN, Tucker KL (2011) Greater variety in fruit and vegetable intake is associated with lower inflammation in Puerto Rican adults. The American journal of clinical nutrition 93(1): 37-46.

40. Wannamethee SG, Lowe GD, Rumley A, Bruckdorfer KR, Whincup PH (2006) Associations of vitamin C status, fruit and vegetable intakes, and markers of inflammation and hemostasis. The American journal of clinical nutrition 83(3): 567-574.

41. Kotani K, Tsuzaki K, Sano Y, Maekawa M, Fujiwara S, et al. (2008) The relationship between usual coffee consumption and serum C-reactive protein level in a Japanese female population. Clinical Chemistry and Laboratory Medicine 46(10): 1434-1437.

42. Devaraj S, Autret BC, Jialal I (2006) Reduced-calorie orange juice beverage with plant sterols lowers C-reactive protein concentrations and improves the lipid profile in human volunteers. The American journal of clinical nutrition 84(4): 756-761.

43. Howatson G, McHugh MP, Hill JA, Brouner J, Jewell AP, et al. (2010) Influence of tart cherry juice on indices of recovery following marathon running. Scandinavian journal of medicine & science in sports 20(6): 843-852.

44. Di Giuseppe R, Di Castelnuovo A, Centritto F, Zito F, De Curtis A, et al. (2008) Regular consumption of dark chocolate is associated with low serum concentrations of C-reactive protein in a healthy Italian population. The Journal of nutrition 138(10): 1939-1945.