Table of contents
American Journal of Medicine, DOI: http://dx.doi.org/10.1016/j.amjmed.2014.02.044
Received: February 4, 2014; Received in revised form: February 28, 2014; Accepted: February 28, 2014; Published Online: March 20, 2014
Paulette D. Chandler, MD, MPH , Jamil B. Scott, PhD, MPH, Bettina F. Drake, PhD, MPH, Kimmie Ng, MD, MPH, John P. Forman, Andrew T. Chan, MD, Gary G. Bennett, PhD, Bruce W. Hollis, PhD, Edward L. Giovannucci, MD, ScD, Karen M. Emmons, PhD, Charles S. Fuchs, MD, MPH
Hydrochlorothiazide, an effective antihypertensive medication commonly prescribed to blacks, decreases urinary calcium excretion. Blacks have significantly higher rates of hypertension and lower levels of 25-hydroxyvitamin D. Thus, they are more likely to be exposed to vitamin D supplementation and thiazide diuretics. The risk for hypercalcemia among blacks using vitamin D and hydrochlorothiazide is undefined.
We assessed the frequency of hypercalcemia in HCTZ users in a post-hoc analysis of a randomized, double-blind, dose-finding trial of 328 blacks (median age, 51 years) assigned to either placebo, or 1000, 2000, or 4000 international units of cholecalciferol (vitamin D3) daily for 3 months during the winter (2007-2010).
Of the 328 participants, 84 reported hydrochlorothiazide use and had serum calcium levels assessed. Additionally, a comparison convenience group of 44 enrolled participants who were not taking hydrochlorothiazide had serum calcium measurements at 3-months but not at baseline. At 3-months, hydrochlorothiazide participants had higher calcium levels (0.2 mg/dL, p<.001) than non-hydrochlorothiazide participants, but only one participant in the hydrochlorothiazide group had hypercalcemia. In contrast, none of the non-hydrochlorothiazide participants had hypercalcemia. In linear regression model adjusted for age, sex, 25-hydroxyvitamin D at 3-months, and other covariates, only hydrochlorothiazide use [Estimate (SE):0.05(0.01) p=0.01] predicted serum calcium at 3-months.
In summary, vitamin D3 supplementation up to 4000 IU in hydrochlorothiazide users is associated with a rise in serum calcium but a low frequency of hypercalcemia. These findings suggest that participants of this population can use HCTZ with up to 4000 IU of vitamin D3 daily and experience a low frequency of hypercalcemia.
- Fiscella, K. and Holt, K. Racial disparity in hypertension control: tallying the death toll. Ann Fam Med. 2008 Nov-Dec; 6: 497–502 (PubMed PMID: 19001301. Pubmed Central PMCID: 2582461. Epub 2008/11/13. eng) CrossRef | PubMed | Scopus (34)
- Cooper, R. and Rotimi, C. Hypertension in blacks. American journal of hypertension. 1997 Jul; 10: 804–812 (PubMed PMID: 9234837. Epub 1997/07/01. eng) CrossRef | PubMed | Scopus (124)
- Artaza, J.N., Contreras, S., Garcia, L.A., Mehrotra, R., Gibbons, G., Shohet, R. et al. Vitamin D and cardiovascular disease: potential role in health disparities. J Health Care Poor Underserved. 2011; 22: 23–38 (PubMed PMID: 22102304. Pubmed Central PMCID: 3417128. Epub 2011/12/07. eng) CrossRef | PubMed
- Chapman, A.B., Schwartz, G.L., Boerwinkle, E., and Turner, S.T. Predictors of antihypertensive response to a standard dose of hydrochlorothiazide for essential hypertension. Kidney international. 2002 Mar; 61: 1047–1055 (PubMed PMID: 11849460. eng) CrossRef | PubMed | Scopus (65)
- Messerli FH, Makani H, Benjo A, Romero J, Alviar C, Bangalore S. Antihypertensive efficacy of hydrochlorothiazide as evaluated by ambulatory blood pressure monitoring: a meta-analysis of randomized trials. Journal of the American College of Cardiology. Feb 1;57(5):590–600. PubMed PMID: 21272751. eng.
- Vardan, S., Rapacke, J., and Mookherjee, S. Clinical efficacy and cost comparison of an amiloride-hydrochlorothiazide combination versus hydrochlorothiazide and wax-matrix potassium supplement in the treatment of essential hypertension. Clinical therapeutics. 1986; 8: 420–426 (PubMed PMID: 3731211. eng) PubMed
- Wright, J.T. Jr., Dunn, J.K., Cutler, J.A., Davis, B.R., Cushman, W.C., Ford, C.E. et al. Outcomes in hypertensive black and nonblack patients treated with chlorthalidone, amlodipine, and lisinopril. JAMA. the journal of the American Medical Association. 2005 Apr 6; 293: 1595–1608 (PubMed PMID: 15811979. Epub 2005/04/07. eng) CrossRef | Scopus (176)
- Cushman, W.C., Ford, C.E., Einhorn, P.T., Wright, J.T. Jr., Preston, R.A., Davis, B.R. et al. Blood pressure control by drug group in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). J Clin Hypertens (Greenwich). 2008 Oct; 10: 751–760 (PubMed PMID: 19090876. Pubmed Central PMCID: 2897821. Epub 2008/12/19. eng) CrossRef | PubMed | Scopus (31)
- Chen, J.M., Heran, B.S., Perez, M.I., and Wright, J.M. Blood pressure lowering efficacy of beta-blockers as second-line therapy for primary hypertension. Cochrane database of systematic reviews (Online). 2010; : CD007185 (PubMed PMID: 20091622. eng) PubMed
- Forman, J.P., Scott, J.B., Ng, K., Drake, B.F., Suarez, E.G., Hayden, D.L. et al. Effect of vitamin D supplementation on blood pressure in blacks. Hypertension. 2013 Apr; 61: 779–785 (PubMed PMID: 23487599. Epub 2013/03/15. eng) CrossRef | PubMed | Scopus (26)
- Agarwal, R. and Sinha, A.D. Thiazide diuretics in advanced chronic kidney disease. J Am Soc Hypertens. 2012. 2012 Sep-Oct; 6: 299–308 (PubMed PMID: 22951101. eng) Abstract | Full Text | Full Text PDF | PubMed | Scopus (8)
- Aldinger, K.A. and Samaan, N.A. Hypokalemia with hypercalcemia. Prevalence and significance in treatment. Ann Intern Med. 1977 Nov; 87: 571–573 (PubMed PMID: 921086. eng) CrossRef | PubMed
- Aroldi, A., Graziani, G., Mioni, G., Cecchettin, M., Brancaccio, D., Galmozzi, C. et al. Thiazide diuretics in renal hypercalciuria. Proc Eur Dial Transplant Assoc. 1979; 16: 571–576 (PubMed PMID: 549001. eng) PubMed
- Alon, U., Costanzo, L.S., and Chan, J.C. Additive hypocalciuric effects of amiloride and hydrochlorothiazide in patients treated with calcitriol. Miner Electrolyte Metab. 1984; 10: 379–386 (PubMed PMID: 6548793. eng) PubMed
- Desai HV, Gandhi K, Sharma M, Jennine M, Singh P, Brogan M. Thiazide-induced severe hypercalcemia: a case report and review of literature. American journal of therapeutics. Nov-Dec;17(6):e234–e236. PubMed PMID: 20068444. eng.
- Skendzel, L.P. How physicians use laboratory tests. JAMA. the journal of the American Medical Association. 1978 Mar 13; 239: 1077–1080 (PubMed PMID: 628059. Epub 1978/03/13. eng) CrossRef
- Brickman, A.S., Massry, S.G., and Coburn, J.W. changes in serum and urinary calcium during treatment with hydrochlorothiazide: studies on mechanisms. J Clin Invest. 1972 Apr; 51: 945–954 (PubMed PMID: 4552338. Pubmed Central PMCID: PMC302208. eng) CrossRef | PubMed
- Peterlik, M. and Cross, H.S. Vitamin D and calcium insufficiency-related chronic diseases: molecular and cellular pathophysiology. European journal of clinical nutrition. 2009; 63: 1377–1386 CrossRef | PubMed | Scopus (43)
- Slomski, A. IOM endorses vitamin D, calcium only for bone health, dispels deficiency claims. JAMA. the journal of the American Medical Association. 2011; 305: 453–454 (6) CrossRef | Scopus (29)
- Avioli, L.V. The therapeutic approach to hypoparathyroidism. Am J Med. 1974 Jul; 57: 34–42 (PubMed PMID: 4601117. eng) Abstract | Full Text PDF | PubMed
- McNeill, L.H., Coeling, M., Puleo, E., Suarez, E.G., Bennett, G.G., and Emmons, K.M. Colorectal cancer prevention for low-income, sociodemographically-diverse adults in public housing: baseline findings of a randomized controlled trial. BMC Public Health. 2009; 9: 353 (PubMed PMID: 19765309. eng) CrossRef | PubMed | Scopus (11)
- Hollis, B.W. Quantitation of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D by radioimmunoassay using radioiodinated tracers. Methods Enzymol. 1997; 282: 174–186 (PubMed PMID: 9330287) CrossRef | PubMed | Scopus (65)
- More on thiazide-induced hypercalcemia. Am J Psychiatry. 1981 Apr;138(4):534–536. PubMed PMID: 7212121. eng.
- Aadland, E. and Jørgensen, H. [Hypercalcemia and other metabolic disorders during long-term treatment with thiazides]. Tidsskr Nor Laegeforen. 1978 Feb; 98: 256–259 (PubMed PMID: 628919. Nor) PubMed
- Assadi, F. Hypercalcemia: an evidence-based approach to clinical cases. Iran J Kidney Dis. 2009 Apr; 3: 71–79 (PubMed PMID: 19395781. eng) PubMed
- Ackermann, D. [Hypercalcemia in sarcoidosis–case report, prevalence, pathophysiology and therapeutic options]. Ther Umsch. 2007 May; 64: 281–286 (PubMed PMID: 17685088. Ger) CrossRef | PubMed | Scopus (6)
- Carroll, M.F. and Schade, D.S. A practical approach to hypercalcemia. Am Fam Physician. 2003 May; 67: 1959–1966 (PubMed PMID: 12751658. eng) PubMed
- Gallagher, J.C., Peacock, M., Yalamanchili, V., and Smith, L.M. Effects of vitamin d supplementation in older african american women. J Clin Endocrinol Metab. 2013 Mar; 98: 1137–1146 (PubMed PMID: 23386641. Epub 2013/02/07. eng) CrossRef | PubMed | Scopus (6)
- Gallagher JC, Sai A, Templin T, 2nd, Smith L. Dose response to vitamin D supplementation in postmenopausal women: a randomized trial. Ann Intern Med. 156. United States2012. p. 425–37.
- Holick, M.F., Binkley, N.C., Bischoff-Ferrari, H.A., Gordon, C.M., Hanley, D.A., Heaney, R.P. et al. Guidelines for preventing and treating vitamin D deficiency and insufficiency revisited. J Clin Endocrinol Metab. 2012 Apr; 97: 1153–1158 (PubMed PMID: 22442274. Epub 2012/03/24. eng) CrossRef | PubMed | Scopus (70)
- Nesby-O'Dell, S., Scanlon, K.S., Cogswell, M.E., Gillespie, C., Hollis, B.W., Looker, A.C. et al. Hypovitaminosis D prevalence and determinants among African American and white women of reproductive age: third National Health and Nutrition Examination Survey, 1988-1994. Am J Clin Nutr. 2002 Jul; 76: 187–192 (PubMed PMID: 12081833. Epub 2002/06/26. eng) PubMed
- Schwartzman, M.S. and Franck, W.A. Vitamin D toxicity complicating the treatment of senile, postmenopausal, and glucocorticoid-induced osteoporosis. Four case reports and a critical commentary on the use of vitamin D in these disorders. The American journal of medicine. 1987 Feb; 82: 224–230 (PubMed PMID: 3812514. Epub 1987/02/01. eng) Abstract | Full Text PDF | PubMed
- Drinka, P.J. and Nolten, W.E. Hazards of treating osteoporosis and hypertension concurrently with calcium, vitamin D, and distal diuretics. J Am Geriatr Soc. 1984 May; 32: 405–407 (PubMed PMID: 6715769. eng) PubMed
- Crowe, M., Wollner, L., and Griffiths, R.A. Hypercalcaemia following vitamin D and thiazide therapy in the elderly. Practitioner. 1984 Mar; 228: 312–313 (PubMed PMID: 6709583. eng) PubMed
- Sharma OP. Vitamin D, calcium, and sarcoidosis. Chest. 1996 Feb;109(2):535–539. PubMed PMID: 8620732. Epub 1996/02/01. eng.
- Heaney RP. Vitamin D depletion and effective calcium absorption. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2003 Jul;18(7):1342; author reply 3. PubMed PMID: 12854846. Epub 2003/07/12. eng.
- Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr. 1999 May;69(5):842–856. PubMed PMID: 10232622. Epub 1999/05/08. eng.
- Hathcock, J.N., Shao, A., Vieth, R., and Heaney, R. Risk assessment for vitamin D. Am J Clin Nutr. 2007 Jan; 85: 6–18 (PubMed PMID: 17209171. Epub 2007/01/09. eng) PubMed
- Heaney RP. Vitamin D: criteria for safety and efficacy. Nutr Rev. 2008 Oct;66(10 Suppl 2):S178–S181. PubMed PMID: 18844846. Epub 2008/12/05. eng.
- Heaney, R.P. Vitamin D and calcium interactions: functional outcomes. Am J Clin Nutr. 2008 Aug; 88: 541S–544S (PubMed PMID: 18689398. Epub 2008/08/12. eng) PubMed
- Parfitt, A.M. Thiazide-induced hypercalcemia in vitamin D-treated hypoparathyroidism. Ann Intern Med. 1972 Oct; 77: 557–563 (PubMed PMID: 4642736. eng) CrossRef | PubMed
- Caló, L., Cantaro, S., Marchini, F., Giannini, S., Castrignano, R., Gambaro, G. et al. Is hydrochlorothiazide-induced hypocalciuria due to inhibition of prostaglandin E2 synthesis?. Clin Sci (Lond). 1990 Mar; 78: 321–325 (PubMed PMID: 2156653. eng) PubMed
- Christensen, S.E., Nissen, P.H., Vestergaard, P., and Mosekilde, L. Familial hypocalciuric hypercalcaemia: a review. Curr Opin Endocrinol Diabetes Obes. 2011 Dec; 18: 359–370 (PubMed PMID: 21986511. eng) CrossRef | PubMed | Scopus (18)
- Audran M, Legrand E. Hypercalciuria. Joint Bone Spine. 2000;67(6):509–515. PubMed PMID: 11195313. eng.
- De Sanctis, V., Fiscina, B., and Ciccone, S. Severe hypercalcemia in a patient treated for hypoparathyroidism with calcitriol. Pediatr Endocrinol Rev. 2010 Jun; 7: 363–365 (PubMed PMID: 20679997. eng) PubMed
- Kumari, M., Khazai, N.B., Ziegler, T.R., Nanes, M.S., Abrams, S.A., and Tangpricha, V. Vitamin D-mediated calcium absorption in patients with clinically stable Crohn's disease: a pilot study. Mol Nutr Food Res. 2010 Aug; 54: 1085–1091 (PubMed PMID: 20306476. Pubmed Central PMCID: PMC2950313. Epub 2010/03/23. eng) PubMed
- Lemann, J. and Gray, R.W. Idiopathic hypercalciuria. J Urol. 1989 Mar; 141: 715–718 (PubMed PMID: 2645429. eng) PubMed
- Artaza JN, Mehrotra R, Norris KC. Vitamin D and the cardiovascular system. Clin J Am Soc Nephrol. 4. United States2009. p. 1515–1522.
- Bertone-Johnson, E.R., Chlebowski, R.T., Manson, J.E., Wactawski-Wende, J., Aragaki, A.K., Tamimi, R.M. et al. Dietary vitamin D and calcium intake and mammographic density in postmenopausal women. Menopause. 2010 Nov-Dec; 17: 1152–1160 (PubMed PMID: 20613676. Pubmed Central PMCID: 2953586) CrossRef | PubMed | Scopus (5)
Am J Ther. 2010 Nov-Dec;17(6):e234-6. doi: 10.1097/MJT.0b013e3181c6c21b.
Desai HV1, Gandhi K, Sharma M, Jennine M, Singh P, Brogan M.
1Department of Medicine, New York Medical College/Westchester Medical Center, Valhalla, NY, USA. haritvdesai at yahoo.com
Most common causes of hypercalcemia are hyperparathyroidism, malignancy, vitamin D-mediated conditions such as sarcoidosis, and vitamin D toxicity. Less commonly, hypercalcemia can be caused by drugs such as thiazide diuretics and lithium. Mild hypercalcemia is usually asymptomatic but severe hypercalcemia is associated with nausea, vomiting, abdominal pain, excessive thirst, muscle weakness, lethargy, confusion, and fatigue. We are reporting a case of abdominal pain and altered mental status caused by thiazide-induced severe hypercalcemia of 19.8 mg/dL. This is the most severe case of thiazide-induced hypercalcemia that we have seen reported. Patients on thiazide diuretics should have their electrolytes frequently checked, especially patients on calcium supplements. Management usually includes hydration and discontinuation of drugs causing hypercalcemia.
101 year-old man (father-in-law) had been a taking 12,000 IU of vitamin D, Calcium supplements, and Hydrochlorothiazide for several years. Got a mild case of hypercalcemia when he added tums (Calcium Carbonate) for his upset stomach. He stopped taking the Hydrochlorothiazide, Calcium, and tums and the problem went away in a few weeks.
- Search VitaminDWiki for hypercalcemia 538 items May 2014
- No risk of hypercalcemia with prolonged 10000 IU of vitamin D3 – July 2010
- Calcium levels can be measured with ionized calcium tests – Aug 2012
- 10,000 IU vitamin D daily is safe, toxicity start at 150 ng (for monotherapy)– Jan 2013