Introduction
Case report
Discussion
Conclusion
References

 

 

 

 

Introduction

Vitamin D and sunlight play a pivotal role in the homeostasis of calcium and bone strength in our body, but an excess amount can lead to hypervitaminosis D, which is a rare but potentially serious condition.

This is a case of a 92-year-old woman who presented with confusion, renal failure (acute on chronic kidney disease—stage 3) and hypercalcemia. She was recurrently admitted and her investigations showed high calcium, low phosphate and high vitamin D levels. A thorough series of tests were carried out to find the cause of hypercalcemia.

A medication review of the patient suggested that she had been on a maintenance dose of vitamin D3 (ergocalciferol). It was stopped and added to the sensitivity list of her drug history on her records.

Although it is uncommon, vitamin D excess can be harmful.1 It mostly occurs when high doses are taken, especially in susceptible individuals like the elderly, people with primary hyperparathyroidism or renal insufficiency.2 Alterations in calcium and phosphate homeostasis occur early and the process progresses as the kidney function declines.3 The toxicity cases are usually missed as the serum level between the toxicity and therapeutic is wide.4

 

Case report

A 91-year-old woman was referred by her GP presenting with confusion for two weeks and a high calcium level. She complained of getting tired easily, but there was no history of weight loss, palpable lymph nodes, type B symptoms (such as night sweat or weight loss) or any change in bowel habits. She had explained falls at home and had a background history of microcytic anaemia, chronic renal impairment, rheumatoid arthritis, goiter, previous clostridium difficile infection, total hip replacement, and lumbar laminectomies.

She had two hospital admissions previously and was found to be hypercalcemic on both occasions. Her medication review suggested she was on gabapentin, ferrous fumarate, butrans (buprenorphine) patch 10mcg/hr, ergocalciferol (vitamin D) 1.25mg and lorazepam.

Her general physical examination revealed an abbreviated mental test score of 7 out of 10 and she was clinically dehydrated with some crepts at lung bases. The first set of blood tests demonstrated haemoglobin 72, MCV 94.7fl, leucocyte count 11.3, urea 6mmol/L and creatinine 374umol/l. It was noted that her adjusted calcium level was 3.14mmol/l, with phosphate of 1.7mmol/l. Her eGFR was 10ml/min/1.17m2 with albumin of 32g/l.

The medical team did address for pneumonia, acute on chronic kidney failure, hypercalcemia and anaemia and the patient was treated with fluids and antibiotics.

Further investigations revealed a normal thyroid-stimulating hormone (TSH) (0.93mU/L), vitamin B12 and folate. Her vitamin D (25 OH vitamin D) levels were 524nmol/l, 1-25, OH vitamin D levels were 113nmol/L (20-123nmol/L) and parathyroid hormone (PTH) 0.9pmol/L0.8-1.5mmol/L. Ferritin was high, transferrin saturation was low and iron was 9umol/L. A myeloma screen showed B2 macroglobulin of 8.6, but the rest of the serum electrophoresis was normal. The chest x-ray was consistent with infection and there were no stones on the ultrasound abdomen. There was no evidence of malignancy on the CT thorax, abdomen and pelvis other than an incidental heterogeneous retrosternal goiter.

Renal physicians input was taken as the patient developed an erythematous maculopapular rash on her legs with a suspicion of erythema nodosum in relation to the raised levels of calcium levels. She was started on prednisolone although angiotensin converting enzymes levels were found to be normal 17U/L (8-65U/L). A skeletal survey conducted did not show any lytic lesions.

Haematologist advice was sought due to anaemia and the bone marrow trephine biopsy showed ring sideroblasts consistent with myelodysplastic syndrome with an iron of 18umol/L (98-34umol/L) and transferrin saturation of 48% (15-50%).

The patient was discharged after stopping ergocalciferol and followed up in the clinic six weeks later. Repeat bloods showed hypercalcemia 3.11mmol/L, vitamin D 487nmol/L and PTH 0.9pmol/L.

Her medications review showed that the patient had been put back on ergocalciferol so it was stopped again. She was seen in the endocrinology clinic three months later and her adjusted calcium was 2.64mmol/L, vitamin D 343.6nmol/L and e-GFR 16ml/min/1.17m2.

Suggestions were made that if her vitamin D levels reduced, she should not be replaced with conventional vitamin D but to use 1-25OH vitamin D instead due to a shorter half-life. It was decided to not to treat her for hypercalcemia as she was asymptomatic. Her GP was advised to enter in the summary care record to not prescribe vitamin D due to sensitivity.

 

Discussion

This is an interesting case of iatrogenic toxicity of vitamin D on the background of chronic kidney disease. Vitamin D is metabolised in the liver and kidney to its active form and is represented by cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2). Its active metabolites are calcidiol with a half-life of 60 days or calcitriol which has 2-3 days’ half-life.5,6 Vitamin D intoxication can be precipitated by inappropriate preparations or high doses administered.4,5 It is wise to monitor vitamin D, calcium, phosphate and PTH levels in anyone who has renal function impairment and is on a vitamin D replacement.7

The safe upper limit levels of vitamin D as suggested by the Institute of Medicine is under 4000 international units (IU) at maximum. The recommended daily allowance is around 800 IU, which is around 20ng/l in the serum.8,9,10 The Institute of Medicine concludes that vitamin D <10,000 IU/day is not usually associated with toxicity, whereas above 50,000 IU/day for several weeks or months is frequently associated with toxicity, including documented hypercalcemia.9

Toxicity was usually identified through raised urinary calcium levels with high serum vitamin D levels being more than 200ng/ml, although levels above 50ng/ml(125nmol/L) may still be concerning.11 Prolonged exposure to sunlight results in a maximum level of <80ng/ml (200nmol/L).12,13,14 Fad dieters, patients with malabsorption syndromes and renal osteodystrophy psoriasis can be predisposed to hypervitaminosis D if unmonitored.14 The liver naturally converts vitamin D into inactive metabolites and acts as the main storage organ for it, followed by the adipose tissue when it gets saturated.12

Symptoms of acute intoxication are due to raised calcium levels and include confusion, polyuria, polydipsia, anorexia, nausea, vomiting and muscle weakness.

Chronic intoxication may cause nephrocalcinosis, bone demineralisation and pain, ectopic calcification of soft tissues (kidney and lung), constipation, headache, and hypertension.5,16,17

Patients with chronic kidney disease are likely to have hyperparathyroidism and vitamin D insufficiency due to an inability to convert 25-OH vitamin D3 to its active form. This is secondary to poor renal function, sedentary life style, curtailment of nutritional intake of vitamin D3 rich diet and increased melanin of the skin.18

Alterations in calcium and phosphate homeostasis occur early and progress as kidney function tends to decline. Stage 5 CKD patients tend to have low levels of calcitriol as a result of the decline in renal mass. There is also renal loss of vitamin D binding protein because of proteinuria.19

It is vital to measure serum calcium, phosphate, parathyroid hormone concentrations in GFR of less than 30 and determine the subsequent frequency of testing by the measured values and the clinical circumstances.19,20

Bisphosphonates, if indicated, may be for the prevention and treatment of osteoporosis in people with a GFR of 30 or more.19 Fluctuation in vitamin D has an adverse effect and it can occur due to annual dosing, seasonal variations, variable exposure to UV sunlight and the activity of 25OHlase enzyme.21 Monitoring should be the responsibility of the prescriber. The Kidney Disease Outcomes of Quality Initiative (K/DOQI) recommend to measure PTH and vitamin D levels in patients with CKD 3-5; but in patients with stage 5 CKD it is not clear whether replacement with calcidiol is effective as a result of inability to produce optimal levels of 1,25 (OH)2D3.19,20,21

High risk patients’ levels should be checked at one, four and eight weeks. The National Kidney Foundation impresses that the optimal level of vitamin D should be more than 30ng/ml and may be replaced with ergocalciferol unless bone disease persists, then alfacalcidol or calcitriol can be offered.19,20 Hypercalcemia tends to last only for 1-2 days in patients taking calcitriol because of the short half-life thus, stopping the calcitriol, increasing fluid intake and hydration with intravenous saline may be the only therapy that is needed.22 However, hypercalcemia caused by vitamin D or calcidiol lasts longer and may be difficult to manage as it requires a more aggressive therapy such as glucocorticoids and intravenous bisphosphonates.23 It was interesting to note that the levels were quite high only on the maintenance dose as mentioned in the case report of 524nmol/l.

 

Conclusion

It was concluded from the case that it is important to monitor calcium and phosphorous levels in patients with renal failure as hypercalcemia secondary to vitamin D toxicity is potentially a reversible cause and requires appropriate follow-up and monitoring.

Our patient interestingly had very high levels of vitamin D despite only being on maintenance doses. The cause for it is still unclear and the best action for such situations is withdrawal of the vitamin D, addressing the hypercalcemia and correction of revisable causes for the renal impairment.

It may take some time for the biochemical correction once predisposed to toxicity and hypercalcemia may take around six months to improve because of the storage of 25 OH vitamin D in the adipose tissue.

It is worth noting that vitamin D toxicity itself can contribute to acute renal failure due to renal vasoconstriction. The long-term consequences of hypercalcemia are gastrointestinal, renal calculi and neurological.

 

Dr Uzma Tazeen, ST6 Geriatric Medicine, Mid Yorks Hospital NHS trust

Dr Tun Aung

Conflict of interest: none declared

 

References

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2. Williams S, Malatesta K, Norris K, et al. Vitamin D and Chronic Kidney Disease. Ethn Dis 2009; 19(4 Suppl 5): S5–8-11

3. Craver L, Marco MP, Martinez I, et al. Mineral metabolism parameters throughout chronic kidney disease stages 1–5 - Achievement of K/DOQI target ranges. Nephrology Dialysis and Transplantation 2007; 22(4): 1171–76

4. Koul PA, Ahmad S, Ahmad F, et al. Vitamin D Toxicity in Adults: A Case Series from an Area with Endemic Hypovitaminosis D. Oman Med J 2011; 26(3): 201–204

5. Morgan SL, Weinsier RL. Up-to-date Fundamentals of clinical nutrition, Mosby, St. Louis 1998. p.3.

6. Calcitrol overview and side-effect; https://www.drugs.com/sfx/calcitriol-side-effects.html

7. Nair-Shalliker V, Clements M, Fenech M, Armstrong BK. Personal sun exposure and serum 25-hydroxy vitamin D concentrations. Photochem Photobiol 2013; 89: 208.

8. Ross AC, Manson JE, Abrams SA, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab 2011 Jan; 96(1): 53–58

9. Ross C, Manson JE, Abrams SA, et al. The 2011 Report on Dietary Reference Intakes for Calcium and Vitamin D from the Institute of Medicine: What Clinicians Need to Know.

10. Jones G. Expanding role of vitamin D in chronic kidney disease: importance of blood 25-OH-D levels and extra-renal 1-hydroxylase in the classical and nonclassical actions of 1,25-dihydroxyvitamin D3. Seminars in Dialysis 2007; 20(4): 316–24

11. Ross AC, Manson JE, Abrams SA, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J. Clin. Endocrinol. Metab 2011; 96(1), 53-58

12. Holick MF, MacLaughlin JA, Doppelt SH. Regulation of cutaneous previtamin D3 photosynthesis in man: skin pigment is not an essential regulator. Science 1981; 211: 590

13. Binkley N, Novotny R, Krueger D, et al. Low vitamin D status despite abundant sun exposure. J Clin Endocrinol Metab 2007; 92: 2130–135

14. Barger-Lux MJ, Heaney RP. Effects of above average summer sun exposure on serum 25-hydroxyvitamin D and calcium absorption. J Clin Endocrinol Metab 2002; 87: 4952.

15. Dietary intake of calcium and vitamin D by institute of Medicine November 30, 2010

16. Bouillon R: Vitamin D: from photosynthesis, metabolism, and action to clinical application. Endocrinology. Edited by: DeGroot LJ, Jameson JL. 2010, Philadelphia: WB Saunders, 1089-1110. 6

17. Vieth R. Why the optimal requirement for Vitamin D3 is probably much higher than what is officially recommended for adults. J Steroid Biochem Mol Biol 2004; 89–90(1-5): 575–79

18. Clemens TL, Adams JS, Henderson SL, Holick MF: Increased skin pigment reduces the capacity of skin to synthesise vitamin D3. Lancet 1982: 74–76

19. Chronic Kidney Disease (Partial Update): Early Identification and Management of Chronic Kidney Disease in Adults in Primary and Secondary Care. NICE Clinical Guidelines, No. 182

20. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease Am J Kidney Dis 2003, 42(4 Suppl 3): S1-S201

21. Influence of season and latitude on the cutaneous synthesis of vitamin D3: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin. J Clin Endocrinol Metab 1988; 67(2): 373-8

22. Al-Badr W, Martin KJ. Vitamin D and kidney disease. Clin J Am Soc Nephrol 2008; 3(5): 1555–60 23. Jensterle M, Pfeifer M, Sever M, Kocjan T. Dihydrotachysterol intoxication treated with pamidronate: a case report. Cases J 2010; 3: 78

23. Jensterle M, Pfeifer M, Sever M, Kocjan T. Dihydrotachysterol intoxication treated with pamidronate: a case report. Cases J 2010; 3: 78