Bansal et al. Journal of Medical Case Reports 2014, 8:74 JOURNAL OF MEDICAL http://www.jmedicalcasereports.com/content/8/1/74 CASE REPORTS

CASE REPORT Open Access Iatrogenic D as an unusual cause of persistent vomiting: a case report Rinkesh Kumar Bansal, Pankaj Tyagi, Praveen Sharma, Vikas Singla, Veronica Arora, Naresh Bansal, Ashish Kumar and Anil Arora*

Abstract Introduction: D is increasingly recognized to have several beneficial effects. is widely prevalent. Physicians often treat patients with high doses of vitamin D for various ailments without any monitoring for adverse effects and the prescribed doses often far exceed requirements resulting in toxicity. We present here a classic case of iatrogenic hypervitaminosis D, which presented with persistent vomiting and acute renal failure. Case presentation: Here we present a case of a 45-year-old Asian Indian woman who presented to us with persistent vomiting the cause of which was iatrogenic hypervitaminosis D. She was treated with intravenous fluid, diuretics and calcitonin and had clinical improvement. Conclusions: We suggest that in any patient presenting with persistent vomiting and hypercalcemia, particularly in the presence of normal parathyroid hormone, a diagnosis of overdose of vitamin D should be suspected. Its treatment not only alleviates symptoms but also prevents ongoing acute kidney injury. Keywords: Hypercalcemia, Hypervitaminosis, Vitamin D

Introduction foods are the methods by which mild vitamin D defi- Vitamin D is an important prohormone which plays an ciency can be corrected. Moderate to severe vitamin D important role in calcium homeostasis and bone deficiency can be treated by oral administration of metabolism. Vitamin D also subserves in a wide range of pharmacological dose of vitamin D 50,000IU/week for 6 fundamental biological functions like cell differentiation, to 8 weeks [1]. Due to a wide therapeutic index, vitamin inhibition of cell growth as well as immune modulation. D toxicity is extremely rare; however, it does occur at ex- In adults, vitamin D deficiency leads to a mineralization cessively high doses. defect in the skeleton causing . In addition, We present here a classic case of iatrogenic hypervita- the secondary hyperparathyroidism associated with vita- minosis D, which presented with persistent vomiting min D deficiency enhances mobilization of calcium from and acute renal failure. the skeleton, resulting in porotic bone and increasing fracture risk. Although no minimum daily dietary intake Case presentation of vitamin D has been identified, for adults exposed to A 45-year-old Asian Indian woman was admitted to our ample sunlight less than 2.0μg/day (that is 80 units/day) hospital with a history of recurrent vomiting, pain in her of dietary intake is associated with its overt deficiency in abdomen, polydipsia, and constipation for 1.5 adults. The US National Academy of Science sets a rec- months. There was no history of fever, altered sensor- ommended daily allowance for vitamin D as 15μg/day ium, headache, cough, shortness of breath, or urinary (that is 600 units/day) for people below 70 years, and for symptoms. She had been hypertensive for the past year; people older than 70 years as 20μg/day (that is 800 2 months ago she underwent arthroscopic repair of her units/day). Sun exposure and use of fortified or enriched right knee cruciate ligament. On physical examination, she was conscious and ori- ented. Pallor was present; icterus and edema were absent. * Correspondence: [email protected] Department of Gastroenterology & Hepatology, Sir Ganga Ram Hospital, Her vitals were: blood pressure 140/100mmHg, pulse 84/ Rajinder Nagar, New Delhi 110 060, India minute, respiratory rate 20/minute, and temperature 37.6°C.

© 2014 Bansal et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. Bansal et al. Journal of Medical Case Reports 2014, 8:74 Page 2 of 4 http://www.jmedicalcasereports.com/content/8/1/74

An abdominal examination revealed no abnormalities. of her chest and magnetic resonance imaging of her brain The results of her chest and cardiovascular examinations were also essentially normal. were also normal. An examination of her central nervous Hence the biochemical evaluation revealed only raised system showed generalized muscle weakness without any BUN and serum creatinine suggesting acute renal failure focal neurological deficit. Her deep tendon reflexes were with hypercalcemia, in the absence of evidence of normal. chronic kidney disease, multiple myeloma or hyperpara- On laboratory investigation the following results were thyroidism. A detailed history of previous treatment re- obtained: hemoglobin 9.2g/dL, white blood cell count vealed that she had received an injection of Arachitol 12.2×103/mm3, platelet count 242×103/mL, blood urea (vitamin D3) 600,000IU intramuscularly, every alternate nitrogen (BUN) 57mg/dL, creatinine 4.1mg/dL, sodium day for 10 doses just after her knee surgery 2 months 139mEq/L, potassium 3.7mEq/L, serum calcium 11.54mEq/L, back. We found her serum 25-hydroxyvitamin D (25 phosphorous 2.8mEq/L, serum bilirubin 0.60mg/dL, (OH)D) level to be 150ng/mL which was in the toxic protein 6.3g/dL, albumin 3.6g/dL, globulin 2.7g/dL, ala- range (normal 20 to 30ng/mL). So a diagnosis of vitamin nine transaminase 22IU/L, aspartate transaminase 20IU/L, D toxicity-induced acute kidney injury and hypercalce- alkaline phosphatase 22IU/L, and erythrocyte sedimenta- mia was established. To rule out chronic kidney disease tion rate 76mm. The result of her Mantoux test was nega- a nephrology consultation was sought and ultrasound tive, her angiotensin-converting enzyme was 18.20mg/dL for her kidneys and routine urine microscopy were or- and her parathyroid hormone was 11.60pg/mL. The refer- dered, which were normal. ence ranges of our lab for analytes are given in Table 1. For hypercalcemia, she was treated with intravenous Her urine analysis and microscopy were normal. Her urine fluid, diuretics and calcitonin and had clinical improve- for Bence Jones protein was negative. Protein electrophor- ment. Her serum calcium and creatinine levels were esis did not reveal any monoclonal bands. Her chest X-ray monitored regularly; they gradually declined to normal was normal and her electrocardiogram showed low- levels in the next 15 days. She was discharged with a pre- voltage complexes. An ultrasound of her abdomen was scription of an antihypertensive and calcium-restricted normal. An ultrasound of her neck did not reveal any diet along with good hydration; she is doing well. parathyroid mass. High-resolution computed tomography Discussion In this case report a classic case of iatrogenic hypervita- Table 1 Reference ranges for analytes minosis D, which presented with persistent vomiting Hb 13–15g/dL and acute renal failure, has been described. Hypervita- WBC 4000–10,000 per mm3 minosis D can occur when pharmaceutical vitamin D is Platelet count 150–400×103/mL taken in excess, as in our case. The manifestation could BUN 5–23mg/dL be related to hypercalcemia, or acute kidney injury, or both as in our case [2]. Creatinine 0.6–1.3mg/dL The biologically active metabolite of vitamin D, 1,25- – Sodium 132 148mEq/L dihydroxyvitamin D(3), affects mineral homeostasis and Potassium 3.5–5.5mEq/L has numerous other diverse physiologic functions in- Calcium 8.2–10.4mg/dL cluding effects on growth of cancer cells and protection Phosphorous 2.8mg/dL against some immune disorders [3]. Adequate vitamin D Serum bilirubin 0.2–1mg/dL status has been linked to decreased risks of developing specific cancers, including cancers of the esophagus, Protein 6.6–8.7g/dL stomach, colon, rectum, gallbladder, pancreas, lung, – Albumin 3.5 5g/dL breast, uterus, ovary, prostate, urinary bladder, kidney, Globulin 1.5–3.5g/dL skin, thyroid, and hematopoietic system (for example, ALT 0–60IU/L Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, mul- AST 0–40IU/L tiple myeloma); bacterial infections; rheumatoid arthritis; ’ ALP 39–117IU/L Crohns disease; periodontal disease; multiple sclerosis; asthma; type 2 diabetes; cardiovascular disease; stroke; ESR 0–10mm after end of first hour peripheral artery disease; hypertension; chronic kidney dis- ACE <40mg/dL ease; muscle weakness; cognitive impairment; Alzheimer’s PTH 12–64pg/mL disease; clinical depression; and premature death [4]. Abbreviations: ACE, angiotensin-converting enzyme; ALP, alkaline phosphatase; Whereas inadequate vitamin D status during human preg- ALT, alanine transaminase; AST, aspartate transaminase; BUN, blood urea nitrogen; ESR, erythrocyte sedimentation rate; Hb, hemoglobin; PTH, parathyroid nancy may be associated with increased risk for the devel- hormone; WBC, white blood cell count. opment of type 1 diabetes in the offspring [4]. Bansal et al. Journal of Medical Case Reports 2014, 8:74 Page 3 of 4 http://www.jmedicalcasereports.com/content/8/1/74

Vitamin D deficiency can be treated by oral ad- vitamin D toxicity the authors suggested that awareness ministration of a pharmacological dose of vitamin D should be increased among healthcare providers regard- 50,000IU/week for 6 to 8 weeks [1]. Even though vitamin ing the toxic potential of mega doses of vitamin D, des- D toxicity is extremely rare, due to the wide therapeutic pite its wide margin of safety [9]. In another case series index, it does occur at excessively high doses. The guide- by Koul et al. [10] 10 cases of hypercalcemia due to vita- lines of the Food and Nutrition Board of the USA spe- min D intoxication were reported with features of cify 2000IU as the highest vitamin D intake that healthy vomiting, polyuria, polydipsia, encephalopathy and renal adults can consume daily without risk of hypercalcemia dysfunction. All the patients had demonstrable hypercal- [5]. However, these patients should be monitored by cemia and vitamin D levels were high in nine of the 10 periodic estimation of 24-hour urinary calcium excre- cases. The patients had received high doses of vitamin D tion, which should not exceed 250mg. Very little is and no other cause of hypercalcemia was identified. known about the mechanism of vitamin D toxicity [6]. Treatment of hypercalcemia resulted in clinical recovery The lipophilic nature of vitamin D explains its adipose in nine cases [10]. tissue distribution and its slow turnover in the body (half-life approximately 2 months), whereas its main Conclusions transported metabolite, 25-hydroxyvitamin D(3) (25 Thus we conclude that if a patient presents with persist- (OH)D(3)), has a half-life of approximately 15 days. Ani- ent vomiting and hypercalcemia particularly in the pres- mal experiments involving vitamin D3 intoxication have ence of normal parathyroid hormone, then a diagnosis established that 25(OH)D(3) can reach concentrations of overdose of vitamin D should be suspected because up to 2.5micromol/L, at which it is accompanied by hy- its correction not only alleviates symptoms but can also percalcemia and other pathological sequelae resulting prevent acute kidney injury. from a high calcium/phosphate product [6]. Although current data support the viewpoint that the biomarker Consent plasma 25(OH)D concentration must rise above Written informed consent was obtained from the patient 750nmol/L to produce vitamin D toxicity, the more pru- for publication of this manuscript and accompanying dent upper limit of 250nmol/L might be retained to en- images. A copy of the written consent is available for re- sure a wide safety margin. There also is evidence that view by the Editor-in-Chief of this journal. despite the current heavy reliance on serum 25(OH)D(3) concentration for the diagnosis of an individual’s vitamin Abbreviations 25(OH)D: 25-hydroxyvitamin D; 25(OH)D(3): 25-hydroxyvitamin D(3); D status, local tissue vitamin D intoxication may be BUN: Blood urea nitrogen. present in individuals with much lower serum 25(OH)D (3) concentrations than are currently appreciated [6]. Competing interests Only rarely are the symptoms of local tissue vitamin D The authors declare that they have no competing interests. intoxication associated with vitamin D status or intake. Authors’ contributions An individual’s serum 25(OH)D(3) concentration may RKB was the resident in charge of the case and was a major contributor in appear to be “low” for reasons totally independent of writing the initial draft of the manuscript. PT, PS, VS, NB, VA and AK contributed in writing and editing the manuscript. NB was the attending sunlight exposure or vitamin D intake. Serum 25(OH)D physician in charge of the case and was responsible for sections on the (3) concentration is only poorly responsive to increases diagnosis and management of the patient. AA was the unit head and was in vitamin D intake, and the prolonged routine con- responsible for management of the patient and supervised and edited the sumption of thousands of international units of vitamin case report. All authors read and approved the final manuscript. D may interfere with the regulation of phosphate Received: 22 April 2013 Accepted: 16 December 2013 homeostasis by fibroblast growth factor-23 and the Published: 26 February 2014 Klotho gene product, with consequences that are detri- References mental to human health [6]. 1. Robert MR, Paolo MS: Vitamin and trace mineral deficiency and excess.In Clinical manifestations of vitamin D toxicity include: Harrison’s Principles of Internal Medicine, Volume 1. 18th edition. Edited by hypercalcemia, hypercalciuria, kidney stones, hyperpho- Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J. New York: Mc Graw Hill; 2012:594–605. sphatemia, polyuria, polydipsia, ectopic calcification of 2. Hathcoch JN, Glao A, Vieth R, Haeny R: Risk assessment for vitamin D. soft tissues (kidney and lung), nausea, vomiting, an- Am J Clin Nutr 2007, 85:6–18. orexia, constipation, headache, and hypertension [7,8]. 3. Christakos S, Ajibade DV, Dhawan P, Fechner AJ, Mady LJ: Vitamin D: et al. metabolism. Endocrinol Metab Clin North Am 2010, 39(2):243–253. In a recent paper Pandita [9] reported a case series 4. Glade MJ: Vitamin D: health panacea or false prophet? Nutrition 2013, of 15 patients (most of them elderly) with iatrogenic 29(1):37–41. symptomatic hypercalcemia in whom toxicity occurred 5. John TP Jr, Harald J: Disorders of the parathyroid gland and calcium homeostasis.InHarrison’s Principles of Internal Medicine, Volume 2. 18th due to empirical excessive administration of vitamin D edition. Edited by Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, by oral and parenteral route. To prevent iatrogenic Loscalzo J. New York: Mc Graw Hill; 2012:3096–3120. Bansal et al. Journal of Medical Case Reports 2014, 8:74 Page 4 of 4 http://www.jmedicalcasereports.com/content/8/1/74

6. Jones G: Pharmacokinetics of vitamin D toxicity. Am J Clin Nutr 2008, 88(2):582S–586S. 7. Bouillon R: Vitamin D: from photosynthesis, metabolism, and action to clinical application.InEndocrinology. 6th edition. Edited by DeGroot LJ, Jameson JL. Philadelphia: WB Saunders; 2010:1089–1110. 8. Maji D: Vitamin D toxicity. Indian J Endocrinol Metab 2012, 16(2):295–296. 9. Pandita KK, Razdan S, Kudyar RP, Beigh A, Kuchay S, Banday T: Excess good can be dangerous. A case series of iatrogenic symptomatic hypercalcemia due to hypervitaminosis D. Clin Cases Miner Bone Metab 2012, 9(2):118–120. 10. Koul PA, Ahmad SH, Ahmad F, Jan RA, Shah SU, Khan UH: Vitamin d toxicity in adults: a case series from an area with endemic hypovitaminosis d. Oman Med J 2011, 26(3):201–204.

doi:10.1186/1752-1947-8-74 Cite this article as: Bansal et al.: Iatrogenic hypervitaminosis D as an unusual cause of persistent vomiting: a case report. Journal of Medical Case Reports 2014 8:74.

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