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Correlation of Serum Vitamin D Receptor Level with Bacterial Index in Multibacillary Leprosy Patients at Sanglah General Hospital, Bali-Indonesia.

Leprosy that caused by Mycobacterium leprae is still a common problem in Indonesia because Indonesia has the third most multibacillary cases in the world after India and Brazil with 14.213 cases. It has more burden also because there is still stigmatization in the society against leprosy patients. (1)

The course of leprosy is not merely caused by the infection of organism, but also complicated by host factors such as genetic and immunity. This interaction has given a variety of clinical appearance and disease spectrum and generally divided this disease into paucibacillary and multibacillary classification. Host immune system that acts as the first barrier in M.leprae infection is cellular immunity especially macrophage. (2,3) Macrophage will respond to infection by several different ways, and one of the pathways is mediated by vitamin D and vitamin D receptor (VDR). (3,4) In Leprosy, vitamin D, through its interaction with VDR, were thought to act as immunomodulator that influences macrophage in killing the pathogen by increasing the expression of antimicrobial peptide cathelicidin. (1,5) For the immunological activity of vitamin D to happen, it needs to interact with its receptor, the VDR. This study aimed to find correlation between the level of VDR, examine in blood plasma, with bacterial index in multibacillary leprosy patients.

MATERIAL AND METHOD

This is an observational analytic study with cross-sectional design to correlate the plasma level of VDR with bacterial index in multibacillary leprosy patients. This study was conducted in Sanglah General Hospital from July until October 2017. This study involved 47 patients of multibacillary leprosy patients aged five until 65 years old that came to Morbus Hansen Subdivision Dermatology Polyclinic that came in period of the study and taken consecutively following the inclusion and exclusion criteria. The inclusion criteria include all multibacillary leprosy cases, aged 5 to 75 years old with slit skin smear examination based on Ridley's scales of bacterial index, with good general condition, and willing to participate in the study, whereas the exclusion criteria include patients that already released from treatment (RFT), had hormonal imbalance condition such as thyroid and parathyroid disease, pregnancy, lactating, menstruation, and ovarian tumor, had systemic condition such as chronic kidney disease, chronic liver disease, multiple sclerosis, and cardiovascular disease, had chronic systemic infection such as tuberculosis, had autoimmune condition such as diabetes mellitus, arthritis rheumatoid, systemic lupus erythematosus, psoriasis, and vitiligo, and had history of taking anti-inflammatory drugs in the past 2 weeks (any systemic condition that affect VDR plasma directly). The bacterial index was determined by slit skin smear with Ziehl-Nielsen staining following logarithm of Ridley's bacterial scales. Specimens for examination of VDR plasma level were taken from blood drawn from venous vein in fossa cubiti. Level of VDR was determined by quantitative method with enzyme link immune sorbent assay (ELISA).

Statistical analysis in this study using software SPSS version 16.0 for windows. Spearman correlation test was used to determine the correlation between serum VDR levels and bacterial index. This research has been approved by the ethics committee of the Faculty of Medicine, Udayana University / Sanglah General Hospital Denpasar. All participant in this study has signed an inform consent of every procedural done in this study.

RESULTS

This study involved 47 patients with multibacillary leprosy, consist of 29 (61,7%) male patients and 18 (38,3%) female patients. The mean age of the sample was 38,83 years old, with the youngest was 11 years old and the oldest was 75 years old. Based on bacterial index, most patients had bacterial index of +3. Table 1 showed the descriptive characteristic of the sample.

Mean level of VDR among multibacillary patients in this study was 27.80 pg/ml, with the lowest level was 19.51 pg/ml and the highest was 34.56 pg/ml. For the correlation of plasma VDR level and the bacterial index, using Spearman correlation, there was strong negative correlation between plasma VDR level and bacterial index (r = - 0.954; p < 0.001). This result suggests that the lower plasma VDR level, the higher the index bacterial of the leprosy patients (Table 2).

DISCUSSION

Mycobacterium leprae as the causative organism of leprosy has a low virulence and very slow doubling time, but yet this organism is capable of provoking an intricate immune response that influences the clinical outcome and course of the disease. The first response against M.leprae infection was macrophage from innate immune response and then followed by response of adaptive immunity. (2,6) One of macrophage activation pathway involved the role of vitamin D and its receptor. (3,4,7) Recently, there was plenty study that elaborates the role of vitamin D in infectious disease and suggests that deficiency of vitamin D will result in deterioration of the infection. Mechanism of vitamin D as immunomodulator in mycobacterial infection is not entirely understood yet, but some theory has been proposed. (8,9) In leprosy, vitamin D through its interaction with VDR were thought to influence macrophage capability in killing the pathogen by increasing expression of antimicrobial peptide cathelicidin. (7,9) Other study suggest a more comprehensive role of vitamin D as an antiinflammatory and regulator of immune system. (8,12)

Macrophage was found to produce 1a,25 hydroxyvitamin D3 (1,25(OH)2D3) and VDR was expressed by varies of immune cells such as CD4+, CD8+, T-cells, B-cells, neutrophils, antigen presenting cell (APC), and dendritic. (8,10) Interaction between 1,25(OH)2D3 and VDR will provoke phagocytosis, chemotaxis, and proliferation B cells, also the production of immunoglobulin. (11) Previous study by Mandal et al. (10) in 2015 found level of vitamin D in leprosy patients was significantly lower than normal control. Another study by Goulart et al. (13) found a significant relationship between VDR polymorphism against bacilloscopic index, this illustrates that VDR acts as a susceptibility factor for leprosy infection. Study by Mandal et al. (10) also found that VDR expression levels may determine the complexity and severity of the progression of leprosy. The VDR mRNA was found significantly lower in leprosy patients compared to healthy controls. Furthermore, patients with very low VDR mRNA were more likely to be associated with neuritis, leprosy reaction and high bacterial index. (10,12) This result had shown more of the role of Vitamin D and its receptor in leprosy infection and lead to reconsideration in using vitamin D or VDR therapy in treating individuals with leprosy.

Through these findings a recommendation can be given, in addition to using multidrug therapy, vitamin D supplementation is also needed to increase the expression of plasma VDR which will then help mediate the immune system.

The limitation of this study is that the number of samples used in this study is still very small so that this situation tends to be less representative of the actual state of the population

CONCLUSION

From this study we found that plasma level of VDR had a significantly strong negative correlation with bacterial index in multibacillary leprosy patients.

http://dx.doi.org/10.13005/bpj/1662

(Received: 08 October 2018; accepted: 19 March 2019)

REFERENCES

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(2.) Modlin R. L. The Innate Immune Response in Leprosy. Curr Opin Immunol, 22(1): 48-54 (2010).

(3.) Goulart L. R, Goulart I. M. B. Leprosy Pathogenetic Background; A Review and Lessons From Other Mycobacterial Disease. Arch. Dermatol. Res., 3: 1-15 (2008).

(4.) Matzner M, Al Samie A. R., Winkler H. M., Nemeth J, Andreas G, Indra A, Bieglmayer C, Winkler S. Low serum levels of cathelicidin LL-37 in leprosy. Acta Tropica, 117(1): 55-59 (2011).

(5.) Mandal D, Reja A. H. H., Biswas N, Bhattacharyya P, Patra P. K., Battacharya B. Vitamin D receptor expression levels determine the severity and complexity of disease progression among leprosy reaction patients. New Microbe. And New Infec., 6: 35-39 (2015).

(6.) Luong K. V. Q., Nguyen L. T. H. Role of vitamin D in Leprosy. The American Journal of Medical Science; 343: 471-482 (2012).

(7.) Oliviera A. L. G., Chaves A. T., Menezes C. A., Guimares N. S., Bueno L. L., Fujiwara R. T., Rocha M. O. C. Vitamin D receptor expression and hepcidin in the protection or severity of leprosy: a systematic review. Microbes and Infection; 19(6): 311-322 (2017).

(8.) De Luca H. F. History of the Discovery of Vitamin D and Its Active Metabolites. Bone Key Reports, 3: 479-482 (2013).

(9.) Gupta V. Vitamin D: Extra Skeletal Effects. Journal of Medication Nutrition and Neutraceuticals, 1(1): 17-26 (2012).

(10.) Mandal D, RejaA. H. H., Biswas N, Bhattacharyya P, Patra P. K., Bhattacharyya B. Vitamin D Receptor Expression Levels Determine The Severity and Complexity of Disease Progression among Leprosy Reaction Patients. New Microbe and New Infect, 6: 35-39 (2015).

(11.) Norman A.W. From Vitamin D to Hormone D: Fundamentals of the Vitamin D Endocrine System Essential for Good Health. Am. J. Nutr., 88: 491s-499s (2008).

(12.) Rippel C, South M, Butt W. W, Shekerdemian L. S. Vitamin D Status in Critically Ill Children. Intensive Care Medicine, 38(12): 2055-2062 (2012).

(13.) Goulart L. R., Ferreira F. R., Goulart I. M. B. interaction of TaqI polymorphism at exon 9 of the vitamin D receptor gene with negative lepromin response may favor the occurrence of leprosy. FEMS Immunology & Medical Microbiology, 48(1): 91-98 (2006).

L.M. Rusyati *, M.S. Adiguna, A.A.G.P. Wiraguna, N.M.D. Puspawati and P. Sudarsa

Department of Dermato-Venereology, Medical Faculty of Udayana University, Sanglah General Hospital, Denpasar-Bali, Indonesia.

* Corresponding author E-mail: rusyati@unud.ac.id
Table 1. Descriptive Characteristic of Sample

Characteristics                       MB Leprosy   Percentage
                                       (n= 47)        (%)

Gender
Male                                      29          61.7
Female                                    18          38.3

Age (years old)
5-15                                      1           2.1
16-25                                     7           14.9
26-35                                     9           19.1
36-45                                     10          21.3
46-55                                     6           12.8
56-65                                     8            17
[greater than or equal to] 66             6           12.8

Bacterial Index
0                                         7           14.9
1                                         11          23.4
2                                         6           12.8
3                                         12          25.5
4                                         10          21.3
5                                         1           2.1

VDR Plasma (Mean [+ or -] SD)27.80 [+ or -] 2.24

Table 2. Correlation between plasma
VDR level and bacterial index

                              Bacterial Index

Plasma level of VDR     r         -0.954
                        P         <0.001
                        n           47
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Author:Rusyati, L.M.; Adiguna, M.S.; Wiraguna, A.A.G.P.; Puspawati, N.M.D.; Sudarsa, P.
Publication:Biomedical and Pharmacology Journal
Date:Mar 1, 2019
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