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Table of Contents
ORIGINAL ARTICLE
Year : 2022  |  Volume : 11  |  Issue : 3  |  Page : 167-174

Vitamin D status in primary hyperparathyroidism in 1990 and thence – Emergence of normocalcaemic presentation and diagnostic challenges – Utility of parathyroid function index


1 Institute of Endocrinology, Diabetes, Thyroid and Osteoporosis Disorders, Sakra World Hospitals, Bengaluru, Karnataka; Department of Medicine and Endocrinology, Saveetha Institute of Medical and Technical Sciences University, Saveetha Medical College, Chennai, Tamil Nadu, India
2 Department of ENT, Head and Neck Surgery, Sakra World Hospitals, Bengaluru, Karnataka, India
3 Department of Endocrinology, Fortis Hospital, Bengaluru, Karnataka, India
4 Formerly Department of Statistics, Sri Venkateswara University, Tirupati, Andhra Pradesh, India
5 Department of Radiology, Sakra World Hospitals, Bengaluru, Karnataka, India
6 Institute of Endocrinology, Diabetes, Thyroid and Osteoporosis Disorders, Sakra World Hospitals, Bengaluru, Karnataka, India

Date of Submission19-Mar-2022
Date of Decision03-May-2022
Date of Acceptance04-May-2022
Date of Web Publication12-Jul-2022

Correspondence Address:
Chittari Venkata Harinarayan
Director, Institute of Endocrinology, Diabetes, Thyroid and Osteoporosis Disorders, Sakra World Hospitals, Sy No 52/2 and 53/3, Deverabeesanahalli (Opp Intel, Outer Ring Road), Varathur Hobili, Marathahalli, Bengaluru 560 103, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcsr.jcsr_44_22

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  Abstract 


Background: 25-hydroxyvitamin D (25OHD) levels much influence parathyroid hormone levels and bone disease in primary hyperparathyroidism (PHPT). With the emergence of the normocalcaemic PHPT (NCPHPT), repletion of the 25OHD level to rule out secondary hyperparathyroidism (SHPT) is essential. This may delay the diagnosis of PHPT, and a diagnostic tool like parathyroid function index (PF index) may help in the early diagnosis.
Methods: The biochemical and hormonal profiles of 52 patients with PHPT were analysed and compared with first description in 1990. Patients were grouped based on symptoms and albumin-corrected serum calcium levels. Those with normocalcaemia were subgrouped into those with and without 25OHD deficiency. Data were extracted from the hospital's electronic medical records to find subjects with SHPT and normal controls and calcium-to-phosphate ratio (C/P ratio) and the PF index were calculated. Receiver operating characteristic curves to decide the cut-off values that help in identifying PF index and C/P ratio between various subgroups.
Results: Sixty-two per cent (32/52) were asymptomatic, 40% (21/52) normocalcaemic, amongst which 48% (10/21) had normal 25OHD levels. Across all categories, the PF index was more sensitive, specific and superior compared to the C/P ratio in the diagnosis of PHPT (P = 0·02), NCPHPT (P = 0·03) or SHPT (P = 0·0001). PF index (>25·8) was more sensitive (90%), specific (96.51%), compared to C/P ratio (>0·211) (P = 0·04) in differentiating NCPHPT from SHPT.
Conclusions: The prevalence of asymptomatic PHPT and NCPHPT is on the rise. PF index helps distinguish NCPHPT from SHPT minimising the time required for confirming the diagnosis post-25OHD repletion.

Keywords: 25-hydroxyvitamin D, asymptomatic primary hyperparathyroidism, calcium-to-phosphate ratio, normocalcaemic primary hyperparathyroidism, parathyroid function index, primary hyperparathyroidism, secondary hyperparathyroidism


How to cite this article:
Harinarayan CV, Ashok H, Munigoti SP, Tandon S, Subbaraya Sarma KV, Tandon AS, Chandy SP, Chandran D. Vitamin D status in primary hyperparathyroidism in 1990 and thence – Emergence of normocalcaemic presentation and diagnostic challenges – Utility of parathyroid function index. J Clin Sci Res 2022;11:167-74

How to cite this URL:
Harinarayan CV, Ashok H, Munigoti SP, Tandon S, Subbaraya Sarma KV, Tandon AS, Chandy SP, Chandran D. Vitamin D status in primary hyperparathyroidism in 1990 and thence – Emergence of normocalcaemic presentation and diagnostic challenges – Utility of parathyroid function index. J Clin Sci Res [serial online] 2022 [cited 2022 Dec 7];11:167-74. Available from: https://www.jcsr.co.in/text.asp?2022/11/3/167/350739




  Introduction Top


Primary hyperparathyroidism (PHPT) is the third most common endocrine disorder with variable clinical presentation in an outpatient setting. Fuller Albert (1948)[1] described the disease, as one with bone, stones, abdominal moans and groans. During the earlier decades from 1930 to 1970, PHPT was an asymptomatic disorder with overt skeletal and renal complications. Since the early 1970s, PHPT was increasingly reported as an asymptomatic disease.[2] In early 1953[3] and later, other workers[4],[5] described a new phenotype of PHPT biochemically characterised by normal calcium levels, the NCPHPT. Widespread testing and improved sensitivity of biochemical tests have led to increasing recognition of PHPT in recent times, both in normocalcaemic and asymptomatic patients. Most of the cases identified while screening for low bone mass and osteoporosis in the early 21st century turned out as NCPHPT.[6] Earlier attempts to define PHPT had not considered the 25OHD levels as part of the definition.

Occurrence of 25OHD deficiency in PHPT was first documented in 1971.[7] In 1990, an observational study from India involving PHPT patients found that nearly half of PHPT patients were normocalcaemic at presentation. The same study also documented low 25OHD levels in both normocalcaemic and hypercalcaemic patients with PHPT.[8] Since then, there is increasing recognition of the role of 25OHD on PTH levels as a potential confounding factor in the diagnosis of PHPT, particularly NCPHPT. This has led to a consensus towards defining the entity (NCPHPT) at the fourth international workshop on the management of asymptomatic PHPT in 2014.[9] Currently, NCPHPT is a diagnosis of exclusion with the following criteria: (a) raised PTH levels with normal albumin-adjusted (corrected) serum calcium (ACSC) and ionised calcium levels; (b) 25OHD levels >30 ng/mL; (c) adequate dietary calcium intake; (d) creatinine clearance >60 mL/Min; (e) ruling out a secondary cause of PTH elevation and (f) not on medications including loop diuretics, thiazides, lithium, bisphosphonates or denosumab.[9],[10]

Published literature on PHPT dating back to years before this recent consensus encompass a spectrum of PHPT ranging from normocalcaemia to hypercalcaemia with coexistent 25OHD deficiency when measured. In such a situation, wherein PHPT may coexist with low Vitamin D status, phosphate values could help in distinguishing 25OHD deficiency and PHPT, particularly the NCPHPT, as both these disorders may present with normocalcaemia and high PTH levels. Whereas PHPT is classically associated with relatively higher serum calcium but lower phosphate concentration, it is not so with 25OHD deficiency. Given this, we explored the calcium-to-phosphorus ratio (C/P ratio) as a tool to find PHPT more reliably.[11] While the C/P ratio remains an attractive and simple tool, PTH levels that define PHPT and NCPHPT are not accounted for in their measurement limiting their potential. Hence, a new index, namely PF index, was developed using calcium, phosphorus and PTH together to magnify the biochemical differences between disorders both characterised by raised PTH, thereby helping in the diagnosis of PHPT, particularly NCPHPT despite coexistent low 25OHD status.[12]


  Material and Methods Top


The study was initiated after obtaining Institutional Ethics Committee approval (SWH_IEC_11/Dr.HCV/Ju 6, l2021, dated July 14, 2021).

We included patients, presenting to the department of endocrinology and metabolism, who underwent surgery after being evaluated for PHPT from 2014 to 2021 in the study. We profiled the biochemical, hormonal, functional, structural imaging and bone mineral density (BMD) of PHPT patients with radiologically proven adenomas who then underwent parathyroidectomy and carefully characterised them as symptomatic versus asymptomatic PHPT and hypercalcaemic versus normocalcaemic variants of PHPT. We developed a new cut-off ratio for parathyroid index (PF index) after including data from a large number of normal patients with and without adequate 25OHD levels as controls and used it to redefine the diagnosis of PHPT and NCPHPT in our cohort. We also compared our first documented biochemical profile levels in patients with PHPT in 1990 with the present data of 2021 to look at the pattern of change in the past three decades with improving the Vitamin D and calcium status of the population.

We estimated serum albumin, creatinine, calcium, phosphorus, 25OHD and intact PTH from fasting blood samples collected without using a tourniquet. Urine calcium: creatinine ratio was also evaluated on a fasting sample. We evaluated the biochemical parameters serum calcium, phosphorous, alkaline phosphatase – SAP, creatinine and albumin by UniCel DxE860 (i) (Beckman Coulter, Inc., USA). We used UniCel Dxl 600 Access Immunoassay System (Beckman Coulter, Inc., USA) autoanalyser to analyse 25OHD and intact parathormone. The normal range of biochemical parameters in the serum was as follows: calcium 8.9–10.5 mg/DL, phosphorous 2.5–4.6 mg/dL, SAP 32–126 IU/L, albumin 3.5–5.0 g/dL, creatinine 0.61–1.2 mg/dL, 25OHD >30 ng/mL and PTH 12–88 pg/mL. We corrected serum calcium for albumin. We used albumin corrected serum calcium (ACSC) for the analysis of data. We calculated the C/P ratio and PF index from the biochemical parameters obtained. We calculated the C/P ratio by dividing serum calcium and serum phosphorous in mM (Ca/P). We calculated the PF index by multiplying PTH (mM) by ACSC (mM) and divided by serum phosphorous (mM) (PTH × ACSC/serum phosphorous).[11],[12]

We recorded BMD of the spine and hip. We excluded patients with creatinine clearance <30 mL/Min and on medications including corticosteroids, antiepileptics, loop diuretics, thiazides, lithium, bisphosphonates or denosumab from the study [Figure 1]a.
Figure 1: Flow chart for analysis of patients of PHPT (a). Flow chart of data mining and acquisition for evaluation of C/P ratio and PF index (b) ACSC = Albumin-corrected serum calcium; PHPT = Primary hyperparathyroidism; NCPHPT = Normocalcaemic primary hyperparathyroidism as per the criteria defined in the methodology; eGFR = Estimated GFR calculated using Modification of Diet in Renal Disease (MDRD) formula

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An elevated ACSC >10.5 mg/dL (hypercalcaemic) and ACSC between 8.9–10.5 mg/dL (normocalcaemic) with elevated parathormone (PTH) levels along with localisation of hyperfunctioning parathyroid gland by imaging modalities were considered diagnostic of PHPT. We analysed the data based on (a) symptoms symptomatic PHPT – biochemical evidence of PHPT with symptoms of osseous, renal involvement or pancreatitis and asymptomatic PHPT – biochemical evidence of PHPT with lack of symptoms of PHPT [Figure 1]a and [Figure 1]b ACSC – hypercalcaemic and normocalcaemic variant of PHPT. The latter subset was further subclassified into those with and without adequate 25OHD levels.

From the hospital, electronic records of all patients attending the endocrinology department outpatient, we retrieved subjects evaluated for serum calcium phosphorus, albumin, alkaline phosphatase, 25OHD and parathormone. We used the MDRD equation to calculate the estimated glomerular filtration rate (eGFR).[13] We excluded subjects with eGFR <60, those who were <18 and >80 years, if any one of the variables measured missing and duplicates from the analysis. We coded the subjects for analysis based on ACSC, PTH and 25OHD levels as four categories: (1) PHPT, (2) NCPHPT with adequate 25OHD level, (3) SHPT due to 25OHD deficiency (low or normal ACSC, raised PTH and low 25OHD) and (4) normal subjects with all three parameters being normal [Figure 1]b. Patients from the study group were also included except for NCPHPT with low 25OHD levels for deriving the C/P ratio and PF index. We applied the new C/P ratio and PF index derived to our group of NCPHPT with low 25OHD levels to validate the indices derived. We used mmol (Standard International) whilst calculating CP and PF ratio.

Statistical analysis

To check the normality of data, one-sample Kolmogorov–Smirnov test was used. Continous variables Normal Mean ± SD is used to depict variables that are normally distributed. Median with interquartile range (IQR) is used for variables that do not conform to normality. Comparison of the biochemical variables between two groups is performed either by unpaired t-test or Mann–Whitney U-tests. Comparison amongst more than two groups was carried out by using the Kruskal–Wallis test followed by multiple comparison tests. Group difference means having P < 0.05 were considered statistically significant. Correlation amongst variables within groups is performed by Pearson's correlation coefficient, with P < 0.05 being considered significant. We performed statistical analysis using Statistical Package for Social Sciences (SPSS) version 25 (IBM Corp, Chicago, IL, USA).

Using MedCalc version 15·2 (Ostend Belgium), we carried out ROC curve analysis to test the diagnostic ability of C/P ratio and PF index. From the ROC plot, we derived the balance between sensitivity and specificity. Youden index was calculated to compare the diagnostic value of C/P ratio and PF index with PTH and serum calcium concentrations. A new ideal cut-off was obtained for both the C/P ratio and PF index. Further statistical analysis is performed to decide the superiority of the C/P ratio and PF index one over the other. P < 0.05 is taken as statistically significant. From the ROC analysis, we calculated the Youden index, positive predictive value and negative predictive value for all categories, namely PHPT, NCPHPT, SHPT and normal subjects.


  Results Top


The mean age at presentation was 54 ± 15 years; there were 37 (71%) females. There was no significant difference in the age between genders, symptomatic (20/52; 38.5%) versus asymptomatic (32/52; 61.5%) groups or between hypercalcaemic variant PHPT (31/52; 59%) versus normocalcaemic variant PHPT (21/52; 41%). In the group, none of them had an overt bone disease. Nephrocalcinosis was found in 3.8% (n = 2), ureteric stones in 5.8% (n = 3), renal stones in 28.8% (n = 15) and pancreatitis in 9.6% (n = 5) of patients. Statistically, there was no significant difference in various biochemical parameters between symptomatic and asymptomatic patients with PHPT except for the Cr/Cl (P < 0·04) and the 25OHD levels which were higher in the asymptomatic group (P < 0·06) [Table 1]. In the whole group, there was a positive correlation between ACSC with SAP (r = 0.312; P < 0.029) and SAP and PTH (r = 0.898; P < 0.0001). Age negatively correlated with BMD, t-score at lumbar spine (LS) (r = −0.482; P < 0.015) and left and right hip (r = −0.532; P < 0.007).
Table 1: The biochemical, bone mineral density variables of various categories of primary hyperparathyroidism patients

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Hypercalcaemic variant PHPT had much lower 25OHD levels, higher C/P ratio, PF index and weight of the adenomas compared to the normocalcaemic variant PHPT group [Table 1]. The 25OHD levels were the highest in the NCPHPT group compared to the hypercalcaemic variant PHPT group (P < 0·01). A similar trend was followed with C/P ratio, LS-BMD and LS t-score. In the hypercalcaemic variant PHPT, ACSC correlated with creatinine (r = 0.407; P < 0.026) and weight of adenoma (r = 0.742; P < 0.0001), serum calcium with SAP (r = 0.388; P < 0.038) and SAP with PTH (r = 0.939; P < 0.0001). In the normocalcaemic variant PHPT, there was a negative correlation between PTH with serum calcium (r = −0.535; P < 0.012). Age correlated negatively with LS-BMD and t-score (r = −0.733; P < 0.025), left hip BMD and t-score (r = −0.722; P < 0.28) and right hip BMD and t-score (r = −0.743; P < 0.02). In patients with normocalcaemic variant PHPT with low 25OHD, serum calcium is negative with PTH (r = −0.606; P < 0.048).

In view of methodological differences in the estimation of various analytes in our previous work (1990)[6] and the present cohort (2021), in the NCPHPT group of the 2012 cohort the 25OHD levels were four times higher, with lower Ca/Cr ratio and lower SAP levels. The weight of the adenoma was lower by one-third compared to the 1990 cohort. In the hypercalcaemic PHPT group, the 25OHD level was three times higher with lower SAP and Ca/Cr ratio. The weight of the adenoma was one-fifth in the present cohort compared to that reported in our previous study [Table 2].
Table 2: Comparison of biochemical parameters between 1990 cohort and 2021 cohort of patient with PHPT

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The mean ± SD and statistical significance of C/P ratio and PF index of various categories of PHPT, NCPHPT, SHPT and normal subjects are shown in box plots [Figure 2]. Both indices help in differentiating various categories of patients studied. ROC curves were drawn to decide the cut-off values for identifying the C/P ratio and PF index in comparison with normal [Figure 2] and [Figure 3]. Across all categories, PF index was more sensitive, specific and much superior compared to C/P ratio in the diagnosis of PHPT (P = 0·02), NCPHPT (P = 0·03) and SHPT (P < 0·0001). PF index (>25·8) was more sensitive (90%) and specific (96.51%) with an AUC of 0.96 and Youden index of 0.87 compared to C/P ratio (>0·211) (P 0·04) in differentiating NCPHPT from SHPT. We applied this PF index cut-off (>25·8) to our group of patients with NCPHPT with low Vitamin D and found the PF index (median with IQR) 36.92 (28.16–68.68; 40.52) validating the usefulness of PF index in differentiating NCPHPT from SHPT in these PHPT subjects with a proven histopathological diagnosis of parathyroid adenoma [Table 1]. More details are available in Online Supplementary Table 1, Online Supplementary Table 2 and Online Supplementary Figure 1.
Figure 2: Box plot showing C/P ratio and PF index in various groups
*Data are presented as mean ± standard deviation
†Data are presented as median (interquartile range)
PHPT = Primary hyperparathyroidism; NCPHPT = Normocalcaemic primary hyperparathyroidism; SHPT = Secondary hyperparathyroidism; ACSC = Albumin-corrected serum calcium; Calcu GFR = Calculated glomerular filtration rate; C/P ratio = Calcium/phosphate ratio PF Index = Index is calculated by multiplying PTH (mM/L) by ACSC (mM/L) and dividing by serum phosphorous (mM/L) [(PTH (mM/L) × ACSC (mM/L)]/[serum phosphorous (mM/L)]


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Figure 3: ROC plots of C/P ratio and PF index of various categories
PPV=Positive predictive value; NPV=Negative predictive value; AUC=Area under curve; PF=Parathyroid function index; CP=Calcium-to-phosphate ratio; PHPT=Primary hyperparathyroidism; NCPHPT=Normocalcaemic PHPT, SHPT=Secondary hyperparathyroidism; PTH=Parathyroid hormone; Ca/P=calcium and serum phosphorous


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  Discussion Top


The clinical presentation of PHPT has undergone a paradigm shift. In the present cohort, the subjects were older, with none of them having an overt bone disease. The subjects have improved 25OHD levels, lower SAP and Ca/Cr ratio with smaller size and lower weight of the adenoma compared to 1990 cohort documented earlier. With improved vitamin D status and dietary calcium intake[8],[13] we believe is thought to be the reason for less severe manifest bone disease, lower SAP levels and Ca/Cr ratio and lowered size and weight of parathyroid adenoma. A systematic review of all published literature from developing countries shows that the symptomatic disease amongst PHPT patients varies between 79.6% and 95%.[14],[15] Nevertheless, an asymptomatic presentation has been increasingly reported.[16] A retrospective review of medical records of PHPT patients in tertiary care centres from India showed that 18%–39% of patients are asymptomatic.[17],[18] Subset analysis of data from the Indian PHPT registry showed that, although symptomatic disease predominates, the overall prevalence of asymptomatic patients has increased significantly from the first decade (2000–2009) to the second decade (2010–2019) (3% vs. 13%; P = 0.003).[19] Despite a rather small number in our study, nearly 62% (32/52) of our patients presented with asymptomatic disease, which is higher than what is now reported from India and reflects the changing pattern of presentation in India, just as seen in the Western world.

Data on the prevalence and presentation of the normocalcaemic variant have been sparse in the published literature. In an earlier study from India involving patients with PHPT, only 13.5% (7/52) of patients reported normocalcaemia.[20] Besides this, there are only a few cases reported about NCPHPT from India to date.[21],[22],[23] We have found that 41% (21/52) of our patients have normocalcaemia. Results from this study reiterate our earlier observation from a similar study done in 1990 of the very high prevalence of normocalcaemic variant[8] despite changing definitions with time.

Globally, in a study published as early as 1997, looking at population-based mammography screening on 5202 women from Sweden, only 28 of them (0.5%) were NCPHPT. This study was done before the current definition of NCPHPT came into vogue and 25OHD levels were not measured.[6] A community-based study involving 2364 subjects (all men), who were asymptomatic, showed a very low prevalence of NCPHPT (0.4%). They used a 25OHD value of 20 ng/mL as a cut-off to define sufficiency.[24] Swedish retrospective data involving 608 subjects aged between 25 and 64 years studied as part of the WHO MONICA Study in 1995 and later followed up in 2008 showed an increased prevalence of NCPHPT (11%) in 2008 compared to 1995 (3%). Serum 25OHD levels of more than 20 ng/mL were enough for inclusion in the study.[25] Interestingly, a Brazilian prospective study on 676 patients undergoing thyroid surgery looked at PTH and calcium levels and subclassified them variably based on 25OHD levels. The authors found the NCPHPT prevalence dropped from 4.4% to 0.74% when the 25OHD threshold changed from 20 ng/mL to 30 ng/mL, clearly highlighting the role of 25OHD.[26] The NCPHPT prevalence in our study population is very high compared to these studies. Our endocrine unit is a tertiary care referral centre with a special interest in metabolic bone diseases. Patient referral patterns may have influenced the prevalence.

Guo et al.[12] were the first to find the usefulness of the PF index in helping to differentiate NCPHPT from SHPT. Data from their study involved patients with 25OHD deficiency in all categories selected to derive at PF index. This we believe is an important confounding reason that would influence the value and makes its usefulness questionable particularly when applied on patients to distinguish NCPHPT with low 25OHD level from SHPT. Furthermore, the method used by the authors to arrive at a single cut-off value of >34 as against four different values for different groups remains unclear. Whereas, we have carefully analysed our data by clearly selecting the groups that included those with (1) PHPT, (2) NCPHPT with adequate 25OHD levels and selected, (3) SHPT patients and (4) normal subjects as controls from our hospital registry. We calculated the PF index, compared various groups and arrived at cut-off values that could help differentiate these groups. We have then applied the newly derived cut-off value of PF index (>25.8) (SHPT vs. NCPHPT with adequate Vitamin D status) on our group of NCPHPT patients with low 25OHD levels and found it 100% correct in diagnosing PHPT [Table 1]. Our data show that while the C/P ratio is largely unhelpful on its own as a measure to distinguish NCPHPT versus SHPT, the PF index was found useful, thereby helping us to differentiate between these two conditions without having to wait for a few weeks for correction of 25OHD status. This has enormous potential as a very practical and useful tool in clinical settings where compliance to outpatient remains a challenge. To the best of our knowledge, this is the first study that comprehensively evaluated PF index and Ca/P ratio by including patients with adequate 25OHD levels in PHPT and NCPHPT patients.

There was a lack of estimation of ionised calcium, Ca: Cr ratio and BMD in all subjects. The small sample size in our study could exaggerate the calculated proportions of all categories and subgroups. PHPT presentation has undergone a paradigm shift with a significant rise in asymptomatic and normocalcaemic presentation. While the C/P index categorically diagnoses PHPT, the PF index is more sensitive and specific, with a higher Youden index to differentiate NCPHPT from SHPT. Although correcting 25OHD levels and reassessing patients post-correction for PHPT remain a valid approach, the PF index could be an extremely useful tool to predict the same without the time lag and hence may hasten right patient care.

Acknowledgement

The authors wish to acknowledge the Department of Laboratory Sciences, Information Technology Department and the Administration of Sakra World Hospital for their continued support.

Financial support and sponsorship

Nil.

Conflicts of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.



 
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[PUBMED]  [Full text]  
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2]



 

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Abstract
Introduction
Material and Methods
Results
Discussion
References
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