Aysha Habib Khan  ( Department of Pathologist and Laboratory Medicine, Aga Khan University Hospital,Karachi. )

Pakistan has one of the highest reported incidence of vitamin D deficiency (VDD) in studies conducted worldwide and within Pakistan. Data mining of vitamin D (VD) testing and small scale community studies from our center in the last decade indicates that VDD in Pakistan is not limited to gender, age group or province ^1,2 .Significant correlates of bone health in community dwelling females in Karachi are serum 25-hydroxy vitamin D (25OHD) levels, duration of sun exposure, and wearing veil while determinants of VD levels were identified to be age, town of residence and housing structure. High and low-income localities of both urban and rural environments are identified at risk of VDD. ^3,4M. Secondary hyperparathyroidism (sHPT), high bone turnover and other parathyroid hormone related disorders are identified.⁵. GC genotype of R990G SNP of calcium sensitive receptor (CaSR) was found to be associated with higher iPTH levels and lower calcium levels.6Replenishing and maintaining D stores and optimum 25OHD levels to achieve peak bone mass is a challenge. While VD is required for intestinal absorption of calcium, no change in calcium absorption was found before and after VD correction using calcium as surrogate, suggesting the possibility that maximum vitamin D-dependent calcium absorption is achieved in our subjects at a lower 25OHD status, with higher mean parathyroid hormone levels and normal1, 25 dihydroxy vitamin D levels.⁷ Association of low levels of VD with health or disease has been emphasized a lot over the last decade, while impact of high VD levels has not been studied. Hypervitaminosis D and toxicity is rare and results after prolonged ingestion of large VD doses or use of overzealous VD supplementation with mega dose preparations and can give rise to hypercalcaemia and hypercalciuria. Higher mortality rates have been reported at both the lower and upper ends of the 25OHD spectrum. In this context a study in 24,000 adults admitted for acute care by Amrein et al has performed analysis of the association between 25OHD levels measured in the year preceding hospital admission with all-cause mortality after hospitalization. After adjustment for multiple confounders, significantly increased risk for all-cause 90-day mortality was identified in patients with 25OHD level <30 ng/mL or >60 ng/mL, measured before hospitalization, compared to patients with levels between 30 and 60 ng/mL8. A U-shaped optimal25OHD range has been proposed for VD. However, it is debated that the reports recommending U shaped distribution are not representative of findings for disease outcome and are due either to statistical fluctuations associated with low numbers of cases or confounding factors not considered ⁹. A review of VD results reported from our laboratory shows increase trend in the results of VD with hypervitaminosis and toxicity (unpublished data). This is also evident in children under 1 year of age.In addition, a recently published study identified 27% of patients admitted to a tertiary care hospital with hypercalcaemia had VD toxicity.^10,11 Variable practice pattern in treating VD deficiency continue to exist in Pakistan. With the two most commonly available VD preparations in Pakistan, we have shown that single dose of 600,000 IU or 200,000 IU of VD given per oral or intramuscular achieved optimal VD levels in 70% of the subjects after two months of intervention. We have previously demonstrated important implications of dose difference and administration routes in our subjects^12,13. But due toabsence of clear guidelines for the replacement strategies of VD in deficient states, there is inadvertent use of higher doses of VD in patients usually by repeated injectable mega doses of cholecalciferol resulting in hypervitaminosis D and toxicity. In the study by Qamar et al, 27% of the patients with hypercalcaemia were identified to be due to vitamin D toxicity where multiple injections of high dose preparations were given to these patients and in many it was Vitamin D3 600,000IU injection given weekly for 6-8 weeks.¹³ Life style measures including dietary interventions, education and awareness of pharmacist, physicians, nutritionists, patients and general public is the way forward. The road to bone health and life-long productivity can be achieved through a multidisciplinary approach. There is a need to perform meaningful research to develop local guidelines
considering our life style risk factors and available information.

Keywords & abbreviation: Vitamin D (VD) Vitamin D deficiency (VDD), Hypervitaminosis D, Vitamin D toxicity.
Disclaimer: None to declared.
Conflict of Interest: None to declared.
Funding Source: None to declared.

References

1. Hassan S, Muzammil SM, Jafri L, Khan AH. An audit of clinical laboratory data of 25 [OH]D at Aga Khan University as reflecting vitamin D Deficiency in Pakistan. J Pak Med Assoc 2015; 65: 1247- 50.
2. Iqbal R, Jafri L, Khan AH. Illuminating the Dark Side- Vitamin D in Different Localities of Karachi. J Coll Physician Surg Pak 2013; 23: 604-6.
3. Dar FJ, Iqbal R, Ghani F, Siddiqui I, Khan AH. Bone health status of Pre-menopausal healthy adult females in Pakistani females. Arch Osteoporos 2012; 7: 93-9.
4. Khan AH, Naureen G, Iqbal R, Dar FJ. Assessing the Effect of Dietary Calcium Intake and 25 OHD Status on Bone Turnover in Women in Pakistan. Arch Osteoporos 2013; 8: 151.
5. Majid H, Khan AH, Riaz M, Karimi H, Talati J. Identifying parathyroid hormone disorders and their phenotypes through a bone health screening panel: It’s not a simple vitamin D Deficiency. Endocr Pract 2016;22: 814-21.
6. Majid H, Khan AH, Moatter T. R990G Polymorphism Of Calcium Sensing Receptor Gene Is Associated With High Parathyroid Hormone Levels In Subjects With Vitamin D Deficiency: A Cross-Sectional Study. BioMed Res Int 2015; 2015: 407159
7. Khan AH, Rohra DK, Saghir SA, Udani SK, Wood RJ, Jabbar A. No change in calcium absorption in adult Pakistani population before and after Vitamin D administration using strontium as surrogate. Osteoporos Int 2013; 24: 1057–62.
8. Amrein K, Quraishi SA, Litonjua AA, Gibbons FK, Pieber TR, Camargo CA Jr, et al. Evidence for a U-Shaped Relationship between Prehospital Vitamin D Status and Mortality: A Cohort Study. J Clin Endocrinal Metab 2014; 99: 1461–9
9. Grant WB. Critique of the U-shaped serum 25-hydroxyvitamin D level-disease response relation. Dermatoendocrinol 2009; 1: 289- 93
10. Khan AH, Majid H, Iqbal R. Shifting of Vitamin D Deficiency to Hypervitaminosis and Toxicity. J Coll Physicians Surg Pak 2014; 24:536
11. Khan MN, Masood MQ, Siddiqui MA, Naz S, Islam N. Vitamin D toxicity and other non-malignant causes of hypercalcemia: A retrospective study at a Tertiary care hospital in Pakistan. J Ayub Med Coll Abbottabad 2017; 29: 436-40
12. Khan AH, Rohra DK, Saghir SA, Udani SK, Wood R, Jabbar A. Response of a single \'mega intramuscular dose\' of vitamin D on serum 25OHD and parathyroid hormone levels. J Coll Physician Surg Pak 2012; 22: 207-12.
13. Masood MQ, Khan A, Awan S, Dar F, Naz S, Naureen G, et al. Comparison of Vitamin D Replacement Strategies with High dose Intramuscular or Oral Cholecalciferol: A Prospective Intervention Study. Endocr Pract 2015; 21: 1125-33