Association of Plantar Fasciitis with Lipid Prole and Glucose Level: A Case-Control Study

Hyperlipidemia is associated with tendon disorders and biomechanical changes through tissue deposition. In the present study, we seek the relation of plantar fasciitis (PF) with lipid prole parameters and fasting blood sugar (FBS) levels. In a case-control study, we enrolled 68 patients with a clinical diagnosis of PF in the case group and 136 individuals without PF in the control group. Patients’ height, weight, body mass index (BMI), FBS, lipid prole including low-density lipoprotein (LDL), high-density lipoprotein (HDL), total cholesterol, and triglyceride (TG) laboratory tests were also checked as the main study variables to be compared between the two groups. The mean difference of each variable between the two case and control groups was tested using an independent t-test. Correlation coecient analyses were used to calculate the correlation of patients’ BMI with lipid prole and FBS levels to evaluate the BMI variable as a confounder. and (P=0.02). (P=0.13) and (P=0.24) not between two ratio that patients with serum levels LDL mg/dl and > mg/dl were no association between lipid prole parameters and BMI in either of the two groups. plantar fasting blood sugar (FBS), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglyceride (TG), body mass index (BMI), complete blood count (CBC), c-reactive protein (CRP), erythrocyte sedimentation rate (ESR), odds ratio (OR)


Introduction
Plantar heel pain is a common condition, which affects 10% of the population in their lifetime (1,2). More than one million patients are reportedly treated for plantar fasciitis (PF) in the US (3). The condition is more frequently observed among athletes and middle-aged people (4,5). The leading theory regarding PF etiology is the biomechanical overuse (6), resulting from prolonged standing or running with a chronic degenerative process (7). Some non-modi able factors associated with PF, are plantar fascia thickness and calcaneal spur (8). However, given the widespread prevalence and the considerable economic burden (9) of PF, identifying more modi able risk conditions other than higher body mass index, or activity level, that previously determined (10) is worthy of investigation. Hyperlipidemia was associated with tendon disorders like Achilles, lateral epicondylitis, and rotator cuff tendinopathies (11)(12)(13), and thus, it may have a role in the pathophysiology of PF as well. A systematic review with 17 studies and 2612 patients showed a relationship between an individual's lipid pro le and tendon health (14).
As deposition of cholesterol in tendon leads to persistent and mild in ammation, it can result in chronic tendon degeneration and biomechanical changes and attenuation of healing capacity (15,16) which might similarly affect the fascia. Diabetes is also associated with tendinopathies due to a poor healing process (17). One recent study reported the positive role of total cholesterol in PF development (18).
Taking together, we were curious whether other lipid pro le parameters and blood glucose levels are associated with PF. Thus, we could consider the strategy of improving body healing capacity through the modi cation of these factors.
In the present study, we, therefore, aimed to compare the 1) total cholesterol, 2) LDL cholesterol, 3) HDL cholesterol, 4) Triglyceride, and 5) fasting blood glucose (FBS) level between two groups of patients with and without PF in a case-control study. Our primary null hypothesis was no difference in the lipid pro le and blood sugar levels between patients with plantar fasciitis and healthy individuals.

Study Setting and Design
This case-control study was performed in Imam Reza hospital, Mashhad city, Iran, between 2017 and 2019.

Patients
We enrolled 68 patients with the clinical diagnosis of plantar fasciitis in the case group and matched 136 individuals with a ratio of 2:1 in the control group. Inclusion criteria were the age range between 18-60 years, PF clinical diagnosis including: start-up pain (pain during rst steps after getting up in the morning or after longtime sitting and reduce in pain with ambulation) with tenderness at the medial insertion of the plantar fascia to the calcaneus, and symptom duration of less than three months. In addition, the patients with a history of trauma to the heel, injection, or surgery due to prior heel pain, systemic arthritic problems (e.g., rheumatoid arthritis, systemic lupus erythematosus), ESR >20, and a positive CRP were excluded from the study. The criteria for matching were age (+/-3 years) and gender. The control group was recruited from an orthopedic outpatient clinic, and they have reported no history of heel pain and diagnosis of plantar fasciitis in their lifetime.

Descriptive Data
The mean age of the participants was 47±11 and 49±12 in the case and control groups, respectively.
(P=0.32). The female-male ratio was 2.6:1, which was equal in two groups. 64.9% and 35.1% of the patients had unilateral and bilateral involvement, respectively. The obtained results showed no difference in the lipid pro le parameters level between males and females in either of the groups.

Variables
First, all patients in case or control groups were asked to sign the consent form. After being enrolled, Demographic data of age, sex, unilateral or bilateral involvement, and CBC, ESR, CRP lab tests were recorded. Patients' height, weight, body mass index, fasting blood sugar (FBS), lipid pro le including lowdensity lipoprotein (LDL), high-density lipoprotein (HDL), total cholesterol, and Triglyceride laboratory tests were checked at the rst visit and saved in a coded excel le. Blood samples were obtained from control and case groups within seven days of examination.

Statistical analysis
To nd a meaningful difference between two independent groups using a t-test with a medium effect size of 0.5, alpha error=0.05, power=90%, and allocation ratio=2/1, the sample size was 64 for the case and 136 for the control group. Data were entered and analyzed using the SPSS software version. 22 For statistical calculations, the normality of variables was investigated for the interval variable. Mean difference of each variable between the two groups of case and control will be tested using independent t-test. As a case-control study, we will calculate the odds ratio to quantify the strength of association between plantar fasciitis and elevated lipid pro le. The odds ratio is the ratio of these two: odds of developing the disease given exposure is De/He and developing the disease given non-exposure is Dn/Hn. Two events are independent if and only if the OR equals 1.
Spearman's and Pearson's rank correlation coe cients were used to calculate the correlation between the variables. A P-value less than 0.05 was considered statistically signi cant.

Ethical Approval
The Ethics Committee approved the study protocol of Mashhad University of Medical Sciences, Mashhad, Iran (approval code: IR.MUMS.fm.REC.1394.93). In line with the research ethics principles, informed consent was obtained from all the participants, and all of them were assured that their information would remain con dential. Furthermore, the subjects were ensured that they could withdraw from the study at any time.

Results
Correlation Between Cholesterol Level and PF: Patients with PF had a higher total cholesterol level with a mean of 193 mg/dl (range 134-275) than the control group with total cholesterol of 172 mg/dl (range 117-221) (P=0.001). Hypercholesterolemia (TC> 240 mg/dl) was detected in 23% of patients (16 cases) and 13% (18 cases) of our control group. LDL level was signi cantly higher in patients with plantar fasciitis than in the control group (P= 0.004). The HDL level was not different between the two groups (P=0.13) [ Table 1]. Patients with serum levels of LDL >130 mg/dl and total cholesterol > 200 mg/dl are 3.7 and 1.8 times more likely to accompany PF, respectively [ Table 2].
Association Between Triglyceride Level and PF: TG level was signi cantly higher in patients with plantar fasciitis than in the control group (P=0.02) [ Table 1]. Patients with serum levels of TG > 100 mg/dl are 1.3 times more likely to accompany PF [ Table  2].
Association Between Glucose Level and PF: FBS level was not different between patients with plantar fasciitis compared to the control group (P = 0.24) [ Table 1]. Patients with serum levels of FBS > 150 mg/dl are 1.2 times more likely to accompany PF [ Table 2].

Association Between BMI and Lipid Pro le Parameters:
We found no association between lipid pro le parameters and body mass index in either of the two groups [ Table 3].

Discussion
The etiology of plantar fasciitis (PF) is not clearly understood, and many factors may have contributed to the pathophysiology of this disorder. A relationship between hyperlipidemia and tendon disorders has been reported in several studies, which we speculate to have a role in the pathophysiology of PF. This study investigated whether patients with PF were more likely to have a higher lipid pro le than healthy controls.
Limitations: The systematic bias of blood lipid analysis as a standardized laboratory procedure is low. However, the blood collection process may introduce bias. Blood samples were taken from the patients at various times the following fasciitis. In addition, we might have a selection bias, since the control group was selected from patients referred to an orthopedic clinic with a musculoskeletal problem, and they may not be a true representative of the general population. Future studies with sampling from the general population would eliminate this bias.
Discussion of Key Findings: We found that patients with plantar fasciitis would be more likely to have higher TC, LDL, and TG levels than patients with musculoskeletal problems other than PF. On the other hand, there was no correlation between lipid pro le parameters and BMI among patients, indicating the observed association between PF and lipid pro le parameters was not confounded by their BMI. This combination of ndings supports the modi cation of LDL, TC, TG, and glucose levels when managing PF.
A systematic review showed higher rates of TC, LDL-C, and TG and lower HDL-C in people with altered tendon structure compared to those reported for healthy people (14). Ozgurtas et al. identi ed hypercholesterolemia in 74% of patients with Achilles tendon rupture (12). Abboud et al. reported signi cantly higher TC, LDL-C, and TG in patients with rotator cuff tears than normal rotator cuff tendons (11). The deleterious role of a cholesterol-rich environment in embryonic animal broblasts, tail tendon, and skin, as well as tendon biomechanics, is con rmed by animal studies (19). It seems that deposition of cholesterol in tendons leads to persistent and mild in ammation, and it may also change the extracellular matrix of tendons and fascia (20). This can result in chronic tendon degeneration and biomechanical changes. Metabolic parameters might rapidly worsen due to the limitation of physical activity resulting from plantar fasciitis, especially in those who have complete bed rest (21, 22). This phenomenon may have suggested the reverse causality between these two variables (i.e., lipid pro le and tendon disorder). However, the strong association of LDL-C and TG with recent-onset pain provides strong evidence against reverse causation.

Conclusion
A higher level of serum lipid pro le parameters was seen in patients with PF, which may be a risk factor for developing PF. Further studies should be designed to certify the cause and effect between hyperlipidemia and PF and the possible effect of lipid-lowering medicine on resolving the symptoms of this disorder.
The present study was a case-control study, and causation cannot be established based on such data. Therefore, it could not be claimed that there is a de nitive relationship between plantar fasciitis and cholesterol levels. Long-term studies are required to determine stronger relationship between the level of lipid pro le and fasciopathy.