Journal of Exposure Science and Environmental Epidemiology (2014), 1–3 © 2014 Nature America, Inc. All rights reserved 1559-0631/14

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ORIGINAL ARTICLE

Ultrasonographic measurement of the femoral cartilage thickness in patients with occupational lead exposure Mustafa T. Yıldızgören1, Ali E. Baki1, Murat Kara2, Timur Ekiz2, Tülay Tiftik2, Engin Tutkun1, Hınç Yılmaz1 and Levent Özçakar3 The objective of the present study is to compare distal femoral cartilage thicknesses of patients with occupational lead exposure with those of healthy subjects by using ultrasonography. A total of 48 male workers (a mean age of 34.8 ± 6.8 years and mean body mass index (BMI) of 25.8 ± 3.1 kg/m2) with a likely history of occupational lead exposure and age- and BMI-matched healthy male subjects were enrolled. Demographic and clinical characteristics of the patients, that is, age, weight, height, occupation, estimated duration of lead exposure, and smoking habits were recorded. Femoral cartilage thickness was assessed from the midpoints of right medial condyle (RMC), right lateral condyle (RLC), right intercondylar area (RIA), left medial condyle (LMC), left lateral condyle (LLC), and left intercondylar area (LIA) by using ultrasonography. Although the workers had higher femoral cartilage thickness values at all measurement sites when compared with those of the control subjects, the difference reached statistical significance at RLC (P = 0.010), LMC (P = 0.001), and LIA (P = 0.039). There were no correlations between clinical parameters and cartilage-thickness values of the workers. Subjects with a history of lead exposure had higher femoral cartilage thickness as compared with the healthy subjects. Further studies, including histological evaluations, are awaited to clarify the clinical relevance of this increase in cartilage thickness and to explore the long-term follow-up especially with respect to osteoarthritis development. Journal of Exposure Science and Environmental Epidemiology advance online publication, 24 September 2014; doi:10.1038/jes.2014.64 Keywords: lead; knee; cartilage; osteoarthritis; ultrasound; occupational disease

INTRODUCTION Chronic lead toxicity is a common health problem which can cause cognitive decline, renal diseases, and degenerative disorders in various organ systems, that is, musculoskeletal, ophthalmologic, hematopoietic, cardiovascular, reproductive, and so on.1–3 Skeletal involvement pertains to that of increased bone turnover, decreased bone mineral density, and osteoporosis. On the other hand, chondrocytes are also important target cells of lead toxicity.4–7 Inhibition of growth plate development in rats,5 increased cartilage-lead levels in ducks (higher than that of bone),6 and increased cartilage formation with delayed maturation and calcification and increased formation of fibrous tissue during bone repair in mouse7 would be the relevant examples in the literature. However, to our best observation, the possible effects of lead on knee cartilage measurements have not been investigated in subjects with occupational chronic lead exposure. Accordingly, in this study, we aimed to determine whether the distal femoral cartilage thicknesses of healthy subjects and of those with occupational lead exposure would be any different. In this regard, we used ultrasonographic assessment which has been previously shown to be a valid and reliable method. 8–10 METHODS A total of 48 male workers (aged 20–45 years) who were admitted to our clinic with a likely history of occupational lead exposure (working in accumulator manufacturing (N = 23) and in lead melting (N = 25)) and 48 age- and body mass index (BMI)-matched healthy male subjects

were consecutively enrolled. Subjects who had concomitant systemic (osteoarthritis (OA), inflammatory arthritis, or any other heavy metal exposure) and/or local (knee trauma and surgery) disorders that may affect femoral cartilage thickness were excluded. All the subjects were informed about the study procedure and they consented to participate. The study protocol was approved by the local Ethics Committee. Demographic and clinical characteristics of the patients, that is, age, weight, height, BMI, occupation, estimated duration of lead exposure, and smoking habits were recorded. Serum lead levels were determined according to venous blood specimens. EDTA containing tubes were used for testing. Inductively coupled plasma-mass spectrometry was used to detect blood- and hair-lead concentrations.

Ultrasonographic Cartilage Measurements Femoral cartilage-thickness measurements were performed using a linear probe (5–10 MHz, Mindray Bio-Medical Electronics Company, Shenzhen, China) while the patients were in supine position with their knees in maximum flexion. The probe was placed in an axial position on the suprapatellar region. The distal femoral cartilage was visualized as an anechoic structure (between the femur and suprapatellar fat). Femoral cartilage thicknesses were assessed from the midpoints of right medial condyle (RMC), right lateral condyle (RLC), right intercondylar area (RIA), left medial condyle (LMC), left lateral condyle (LLC), and left intercondylar area (LIA) by using ultrasonography (Figure 1).

Statistical Analysis Statistical analysis was performed by using SPSS version 16.0 (SPSS, Chicago, IL, USA). Data were expressed as mean ± standard deviation. After having checked the normal distribution with Kolmogrov–Smirnov test,

1 Ankara Occupational Diseases Hospital, Ankara, Turkey; 2Ankara Physical Medicine and Rehabilitation Training and Research Hospital, Ankara, Turkey and 3Hacettepe University Medical School Department of Physical and Rehabilitation Medicine, Ankara, Turkey. Correspondence: Dr. MT Yıldızgören, Ankara Meslek Hastalıkları Hastanesi, Keçiören, Ankara, Turkey. Tel.: +90 312 580 83 95. Fax: +90 312 580 84 04. E-mail: [email protected] Received 6 May 2014; revised 9 June 2014; accepted 13 July 2014

Ultrasonographic measurement of the femoral cartilage thickness Yıldızgören et al

2 Table 2. Femoral cartilage thickness measurements (mm) of the subjects (mean ± SD).

RLC RIA RMC LMC LIA LLC

Patients (N = 48)

Controls (N = 48)

P

2.40 ± 0.37 2.26 ± 0.39 2.25 ± 0.35 2.36 ± 0.39 2.31 ± 0.46 2.32 ± 0.39

2.25 ± 0.32 2.15 ± 0.47 2.18 ± 0.35 2.12 ± 0.36 2.16 ± 0.39 2.23 ± 0.39

0.010 0.126 0.251 0.001 0.039 0.179

Abbreviations: LIA, left intercondylar area; LLC, left lateral condyle; LMC, left medial condyle; RIA, right intercondylar area; RLC, right lateral condyle; RMC, right medial condyle.

Figure 1. Image illustrating ultrasonographic measurements (suprapatellar axial view) of the distal femoral cartilage. F, Femur; LIA, left intercondylar area; LLC, left lateral condyle; LMC, left medial condyle; RIA, right intercondylar area; RLC, right lateral condyle; RMC, right medial condyle.

Table 1.

Demographic and clinical characteristics of the subjects. Patients (N = 48) Controls (N = 48)

Age (years) BMI (kg/m2) Smokers (%) Duration of lead exposure (years) Serum lead level (μg/dl) Hair lead level (μg/g)

P

34.8 ± 6.8 25.8 ± 3.1 24 (50.0) 7.5 ± 5.7

34.5 ± 6.7 25.5 ± 3.0 21 (43.8) —

0.823 0.573 0.539 —

39.4 ± 10.7 18.9 ± 17.4

— —

— —

Abbreviation: BMI, body mass index. The values are shown in mean ± SD or N (%).

paired t-test or χ2-test was used for comparisons between groups, where appropriate. Pearson coefficients were used for correlation analyses. Statistical significance was set at Po 0.05.

RESULTS Demographic and clinical characteristics of the subjects are shown in Table 1. Patients and control groups were similar concerning the mean age, weight, height, BMI, and the number of smokers (all P40.05). Comparison of the femoral cartilage-thickness measurements are given in Table 2. Although the workers had higher femoral cartilage-thickness values at all the measurement sites when compared with those of the control subjects, the difference reached statistical significance at RLC (P = 0.010), LMC (P = 0.001), and LIA (P = 0.039). There were no correlations between clinical parameters and cartilage-thickness values of the workers. DISCUSSION In this study, we have evaluated the femoral cartilage thickness of the patients with chronic occupational lead exposure, to the best of our knowledge, for the first time in the literature. Despite the absence of any correlation with clinical characteristics, femoral cartilage was thicker in those subjects. Lead is seen as an environmental/occupational toxin which is commonly absorbed through the respiratory and gastrointestinal Journal of Exposure Science and Environmental Epidemiology (2014), 1 – 3

tracts in its dust or inhaler form.1,2 It is stored mainly in the bony tissue (more than 90% in adults and 70% in children), nails, and hair.1,2 Lead intoxication can result in abdominal pain, hypertension, arthralgia, elevated intracranial pressure and headache, anemia, and renal dysfunction.11 It also causes osteoporosis with high bone turnover due to impaired calcium absorption and vitamin D metabolism.12–14 Aside from its aforementioned unfavorable musculoskeletal side effects, recent evidence suggests that lead may be a potential/modifiable environmental risk factor for OA.15 Accumulation of lead has been seen in bone, cartilage,16,17 and synovial fluid in patients with OA without known lead exposure.18 Lead affects chondrocytes and collagen maturation adversely.4,5,19–23 Collagen Type II (the main collagen in chondrocytes) and X, glycosaminoglycans in joint surfaces and transforming growth factor-β (suppressor of metalloproteinases) are shown to be the targets of lead toxicity.19–21 Lead inhibits chondrocyte function by altering 1,25-dihydroxyvitamin D3,12–14 parathyroid hormone-related peptide, transforming growth factorβ, and activator protein-1 and nuclear factor-κB signaling in chondrocytes.21 It may also impair the ability of chondrocytes to respond to these hormonal regulations. According to our results, patients with occupational lead exposure had thicker femoral cartilage values when compared with those of healthy subjects. Since the groups were age-, sex-, and BMI-matched, we attribute this difference to lead exposure, speculating the mechanism to be associated with possibly chondrocyte hypertrophy, matrix degradation and mineralization, and reversion of chondrocyte to a more primitive phenotype.24 At first glance, our data suggest that those patients may have less risk of knee OA; however, having thicker cartilage values do not necessarily show better/healthier cartilage but, on the other hand, may also indicate cartilage edema which represents the earliest abnormality in OA.25 Yet, it has been already shown that intraarticular lead caused osteoarthritic changes (arthritis/synovitis) in human knee joints (due to retained lead bullets)26,27 and also in experimental animal models.28,29 Additionally, a study of articular cartilage and subchondral bone samples from subjects without bone disease and known lead exposure30 showed a highly specific deposition of lead in the cartilage tidemark region (the transition zone between calcified and non-calcified articular cartilage where OA develops). Furthermore, a recent population-based study (without non-occupationally exposed patients) has shown a relationship between blood-lead levels and the presence and severity of radiographic and symptomatic knee OA.16 Therefore, our findings seem to be reasonable, necessitating further evaluations. There are a few important limitations of this study. First is our selection bias; we have recruited only asymptomatic workers. Second is the lack of a detailed laboratory investigation with regard to subjects’ vitamin D, thyroid/parathyroid, and sex hormones which may affect the femoral cartilage thickness. Third, our way of cartilage assessment may also be disputed. In the © 2014 Nature America, Inc.

Ultrasonographic measurement of the femoral cartilage thickness Yıldızgören et al

3 literature, there are studies which suggested volumetric cartilage measurements using magnetic resonance imaging.31 Nevertheless, the pertinent literature also shows that ultrasonographic thickness measurements are acceptable as well.8–10 CONCLUSION In the light of our first and preliminary findings, we may conclude that subjects with a history of lead exposure have higher femoral cartilage thickness as compared with healthy subjects. Keeping in mind the fact that femoral cartilage edema is one of the early findings of knee OA, we believe that further studies, including histological evaluations, are awaited to clarify the clinical relevance of this increase in cartilage thickness and to explore the long-term follow-up especially with respect to OA development. CONFLICT OF INTEREST The authors declare no conflict of interest.

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Journal of Exposure Science and Environmental Epidemiology (2014), 1 – 3

Ultrasonographic measurement of the femoral cartilage thickness in patients with occupational lead exposure.

The objective of the present study is to compare distal femoral cartilage thicknesses of patients with occupational lead exposure with those of health...
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