Abstract
Treatment of hypoparathyroidism with activated vitamin D and calcium carbonate is associated with increased risk of hypercalcemia, hypercalciuria, and nephrocalcinosis. These complications are usually due to inadvertent overdose of medications. We present a case of a 6-year-old boy with hypoparathyroidism, sensorineural deafness, and renal dysplasia (HDR) syndrome and feeding difficulties who developed severe hypercalcemia twice, which was caused not just by medication. Both episodes of calcium overload were related to excessive dietary calcium intake from enteral formula. After rehydration and diet change, his blood calcium and urine calcium/creatinine ratio normalized and remained normal with the same dose of calcitriol without calcium carbonate during the following 2 years. This case underscores the importance of assessment of dietary calcium intake in children with hypoparathyroidism, especially those receiving enteral formula. It shows that calcium intake from enteral formula may even become excessive when the volume of formula is increased in pursuit of more calories, and long-term treatment of hypoparathyroidism could be successful with calcitriol without calcium supplement if dietary calcium intake is sufficient. Use of blenderized tube feeding instead of commercial enteral formula in a child with hypoparathyroidism makes it possible to increase calorie intake without causing dietary calcium excess.
Keywords: hypoparathyroidism, hypocalcemia, hypercalcemia, HDR syndrome, vitamin D, enteral nutrition
Introduction
Hypoparathyroidism is a rare disorder characterized by parathyroid hormone (PTH) deficiency leading to hypocalcemia [1]. Treatment of hypoparathyroidism with activated vitamin D and calcium carbonate is associated with increased risk of hypercalcemia, hypercalciuria, and nephrocalcinosis reported in more than a third of patients [2, 3]. These complications are usually due to inadvertent overdose of medications.
We present a case of a 6-year-old boy with hypoparathyroidism, sensorineural deafness, and renal dysplasia (HDR) syndrome, also known as Barakat syndrome, and feeding difficulties who developed severe hypercalcemia twice during 6 years of treatment, and it was caused not just by medication. Both episodes of calcium overload were related to excessive dietary calcium intake from enteral formula. Calcium carbonate also played a role in the first episode of hypercalcemia; the second time hypercalcemia resulted entirely from dietary calcium excess.
Based on this case and review of literature, we highlight 4 possible reasons for hypercalcemia during treatment of hypoparathyroidism. Given the severity of hypercalcemia in our patient, this case underscores the importance of assessment of dietary calcium intake in children with hypoparathyroidism, especially those receiving enteral formula.
Case presentation
A 2-week-old infant presented with irritability, blood calcium of 6.2 mg/dL (SI: 1.55 mmol/L) (reference range, 8.6-10.3 mg/dL [SI: 2.1-2.6 mmol/L]), phosphate of 8.6 mg/dL (SI: 2.77 mmol/L) (reference range, 2.5-4.5 mg/dL [SI: 0.81-1.45 mmol/L]), and inappropriately normal PTH of 18 pg/mL (SI: 1.90 pmol/L) (reference range, 15-65 pg/mL [SI: 1.6-6.9 pmol/L]) consistent with hypoparathyroidism. Physical examination was significant for choanal atresia, hypertelorism, micrognathia, heart murmur, and undescended testicles. Auditory brainstem response demonstrated bilateral sensorineural hearing loss. Renal ultrasound showed poor corticomedullary differentiation. Chromosomal microarray analysis revealed de novo unbalanced 4;10 translocation with 26.9-Mb 4q32.2-4q35.2 duplication and 9.5-Mb 10p15.3-10p14 terminal deletion that included the GATA3 gene responsible for HDR syndrome [4-7]. Hypocalcemia was corrected with calcitriol and calcium carbonate (each 1 g of salt contains 400 mg of elemental calcium). Transthoracic echocardiography showed ventricular septal defect. Testicular ultrasound found testicles situated within the pelvis. He underwent repair of choanal atresia, closure of ventricular septal defect with a patch, and orchiopexy for undescended testicles. He had feeding difficulties that prompted insertion of gastrostomy tube, and he exhibited developmental delay.
At age 5 years, his blood calcium and urine calcium/creatinine ratio were normal when he was treated with calcitriol 0.25 mcg twice daily and calcium carbonate at a dose of 18 mg/kg/day of elemental calcium, which provided him with extra calcium 300 mg/day. His blood calcium “dropped” to 6.6 mg/dL (SI: 1.65 mmol/L) when he did not receive his medications, which required admission to the Children's Hospital. Hypocalcemia was corrected, and he was discharged to home with calcitriol 0.25 mcg twice daily and calcium carbonate at the same dose of 75 mg/kg/day of elemental calcium that was used to correct hypocalcemia. He missed blood calcium checks due to technical difficulties obtaining his blood samples, continued taking the same doses of medications, and presented 3 months later with blood calcium of 17.8 mg/dL (SI: 4.45 mmol/L). Hypercalcemia was corrected, and he was subsequently treated with calcitriol without calcium carbonate.
At age 6 years, he had blood calcium of 9.3 mg/dL (SI: 2.32 mmol/L), phosphate of 4.5 mg/dL (SI: 1.45 mmol/L), PTH of 9 pg/mL (SI: 0.95 pmol/L), and urine calcium/creatinine ratio of <0.20 mg/mg (SI: <0.07 mmol/mmol) (reference range, <0.30 mg/mg [SI: <1.1 mmol/mmol]) when he received calcitriol 0.25 mcg twice daily and no calcium carbonate. Four months later, he presented with blood calcium of 15.0 mg/dL (SI: 3.75 mmol/L) and urine calcium/creatinine ratio of 0.62 mg/mg (SI: 1.76 mmol/mmol).
Diagnostic assessment
Upon hospital admission, his physical examination revealed short stature, hypertelorism, micrognathia, and developmental delay (Fig. 1). His workup showed PTH of <4 pg/mL (SI: <0.42 pmol/L), 25-hydroxyvitamin D of 46 ng/mL (SI: 114.8 nmol/L) (reference range, 30-100 ng/dL [SI: 75-249 nmol/L]), 1,25-dihydroxyvitamin D of 35 pg/mL (SI: 84 pmol/L) (reference range, 24-86 pg/mL [SI: 58-206 pmol/L]), and parathyroid hormone-related protein (PTHrP) of 2.5 pmol/L (reference range, <4.2 pmol/L). There was no evidence of nephrocalcinosis on renal ultrasound.
Figure 1.
Photographs of the patient with hypoparathyroidism, sensorineural deafness, and renal dysplasia (HDR) syndrome at age 6 years. Photo consent provided by family.
It turned out that because of feeding difficulties and poor weight gain his dietitian switched his diet to enteral formula for toddlers and young children via gastrostomy tube to give him more calories. His formula contained 330 mg of calcium per 237 mL bottle, and he received 5 bottles of formula per day that provided him with calcium intake of 1650 mg/day, which was significantly higher than recommended for children aged 4 through 8 years [8, 9].
Treatment
During hospital admission, he was rehydrated, his diet was switched from synthetic commercial enteral formula to natural food blenderized tube feeding (BTF), and calcitriol was held to facilitate negative calcium balance. His calcium intake from his diet was adjusted to be appropriate for his age. His blood calcium decreased from 15.0 mg/dL (SI: 3.75 mmol/L) to 10.8 mg/dL (SI: 2.7 mmol/L) by hospital day 4, and the level was down to 10.4 mg/dL (SI: 2.6 mmol/L) by hospital day 9. He resumed taking calcitriol 0.25 mcg twice daily when hypercalcemia resolved.
Outcome and follow-up
The patient's blood calcium and urine calcium/creatinine ratio remained normal with the same dose of calcitriol without calcium carbonate during the following 2 years (Fig. 2). He tolerated his BTF well, and his dietary calcium intake met the recommended daily allowance established by the Institute of Medicine [8, 9].
Figure 2.
Changes in blood calcium during treatment of hypoparathyroidism.
At age 8 years, he had blood calcium of 9.1 mg/dL (SI: 3.75 mmol/L), phosphate of 4.6 mg/dL (SI: 1.48 mmol/L), PTH of 8.0 pg/mL (SI: 0.85 pmol/L), 25-dihydroxyvitamin D of 38 ng/mL (SI: 94.8 nmol/L), 1,25-dihydroxyvitamin D of 33 pg/mL (SI: 85.8 pmol/L), and urine calcium/creatinine ratio of 0.14 mg/mg (SI: 0.39 mmol/mmol).
Discussion
The amount of calcium absorbed from the intestine depends on the interplay between calcium intake and vitamin D level [10, 11]. Based on this case and review of literature, we identified 4 reasons for hypercalcemia during treatment of hypoparathyroidism, which could be coexistent. Two of them were observed in our patient.
His first episode of hypercalcemia was related in part to calcium carbonate overdose after 3 months of taking calcium carbonate at the dose of 75 mg/kg/day of elemental calcium, which was more than recommended to correct hypocalcemia at his age [12]. Moreover, in our experience, the need for calcium supplement to maintain normal blood calcium may decrease after hypocalcemia is corrected and may vary depending on dietary calcium intake. Serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels were normal, which ruled out vitamin D intoxication (Table 1).
Table 1.
Two episodes of unexpected hypercalcemia during treatment of hypoparathyroidism
| Laboratory tests | Reference values | At age 5 years (the first episode of hypercalcemia) | At age 6 years (the second episode of hypercalcemia) | At age 8 years |
|---|---|---|---|---|
| Calcium total | 8.8-10.8 mg/dL (SI: 2.1-2.6 mmol/L) | 17.8 mg/dL (H) (SI: 4.45 mmol/L) | 15.0 mg/dL (H) (SI: 3.75 mmol/L) | 9.2 mg/dL (SI: 2.3 mmol/L) |
| Calcium ionized | 4.9-5.5 mg/dL (SI: 1.13-1.32 mmol/L) | 9.17 mg/dL (H) (SI: 2.29 mmol/L) | — | — |
| Phosphate | 3.2-5.8 mg/dL (SI: 0.81-1.45) | 3.8 mg/dL (SI: 1.22 mmol/L) | 4.8 mg/dL (SI: 1.55 mmol/L) | 4.6 mg/dL (SI: 1.48 mmol/L) |
| PTH | 15-65 pg/mL (SI: 1.6-6.9 pmol/L) | <4 pg/mL (L) (SI: <0.42 pmol/L) | <4 pg/mL (L) (SI: <0.42 pmol/L) | — |
| 25(OH)D | 30-50 ng/mL (SI: 60-125 nmol/L) | 35 ng/mL (SI: 87.3 nmol/L) | 46 ng/mL (SI 114.8 nmol/L) | 38 ng/mL (SI: 94.8 nmol/L) |
| 1,25(OH)2D | 19.9-79.3 pg/mL (SI: 59-159 pmol/L) | 47 pg/mL (SI: 122.2 pmol/L) | 35 pg/mL (SI: 91 pmol/L) | 33 pg/mL (SI: 85.8 pmol/L) |
| Albumin | 3.4-5.4 g/dL (SI: 34-54 g/L) | 4.1 g/dL (SI: 41 g/L) | 4.7 g/dL (SI: 47 g/L) | 4.1 g/dL (SI: 41 g/L) |
| Calcium/creatinine ratio (urine) | <0.30 mg/mg (SI: <1.1 mmol/mmol) | 0.47 mg/mg (H) (SI: 1.35 mmol/mmol) | 0.62 mg/mg (H) (SI: 1.76 mmol/mmol) | 0.14 mg/mg (SI: 0.39 mmol/mmol) |
| Medications | Calcitriol and Calcium Carbonate | Calcitriol | Calcitriol |
Abbreviations: 1,25(OH)2D, 1,25-dihydroxyvitamin D; 25(OH)D, 25-hydroxyvitamin D; PTH, parathyroid hormone.
The second time hypercalcemia in our patient resulted entirely from dietary calcium excess when he received calcitriol without calcium carbonate (Table 1). His calcium intake from enteral formula was increased to 1650 mg/day, which was more than one-and-a-half times higher than 1000 mg/day recommended at his age, but less than the upper limit of 2500 mg/day above which there was known risk of adverse events [8, 9]. We speculate that a lesser dietary calcium excess caused hypercalcemia in our patient because he was taking calcitriol to enhance intestinal calcium absorption. Normalization of blood calcium and urine calcium/creatinine ratio after diet change which reduced his dietary calcium intake to the age-appropriate amount confirmed that the source of calcium overload was his diet.
When we discovered that the second calcium overload was caused by excessive dietary calcium intake from enteral formula, we analyzed his dietary calcium intake leading up to the first episode of hypercalcemia and found that it was a major contributor to it. He was given the same formula containing 330 mg of calcium per 237 mL bottle in the amount of 1152 mL/day which provided him with calcium intake of 1604 mg/day in addition to extra calcium 1417 mg/day from calcium carbonate. His total calcium intake from formula and medication was 3021 mg/day, which was more than 3 times higher than 1000 mg/day recommended at his age [8, 9]. The first episode of hypercalcemia was worse than the second one because he received more calcium from enteral formula and calcium carbonate than from enteral formula alone.
To our knowledge, this is the first report of excessive dietary calcium intake from enteral formula during treatment of hypoparathyroidism that resulted in severe hypercalcemia and hypercalciuria. The European Society of Endocrinology clinical guidelines for treatment of hypoparathyroidism in adults stated that intake of calcium from dietary source (mainly dairy products) could be equivalent to intake from calcium supplements [13]. This case shows that dietary calcium intake from enteral formula may even become excessive in children when the volume of formula is markedly increased in pursuit of more calories.
It is also the first reported case of successful use of natural food blenderized tube feeding (BTF) instead of synthetic commercial enteral formula in a child with hypoparathyroidism. Our patient used a combination of homemade BTF, which incorporated dairy products such as milk, yogurt, and cottage cheese, and commercial BTF. Milk and yogurt were simply added to commercial BTF, and cottage cheese was mixed with water and blenderized. He received calcium about 300 mg/day from dairy products and 600 mg/day from commercial BTF, according to his dietitian. Studies of BTF in children with feeding difficulties reported improvement in gastrointestinal symptoms, including reductions in gagging, retching, vomiting, abdominal pain, and diarrhea compared with commercial enteral formula [14-16]. The use of BTF in our patient made it possible to markedly increase his calorie intake without causing dietary calcium excess.
Besides calcium carbonate overdose and excessive dietary calcium intake from enteral formula, the 2 other causes of hypercalcemia during treatment of hypoparathyroidism are vitamin D intoxication and prolonged immobilization. Paterson [17] described 3 adult women with postsurgical hypoparathyroidism who developed symptomatic hypercalcemia with anorexia, muscle weakness, and blood calcium as high as 13.6 to 15.2 mg/dL (SI: 3.4-3.8 mmol/L) within 1 to 2 months of treatment with large doses of 1α-hydroxyvitamin D converted to 1,25-dihydroxyvitamin D in the liver. In a retrospective study of 29 children with hypoparathyroidism, Levy et al [2] observed that higher doses of calcitriol were associated with higher blood calcium and increased urine calcium excretion.
Schroth et al [18] reported a 14-year-old boy with hypoparathyroidism treated with calcium carbonate and calcitriol who developed severe hypercalcemia with calcium of 14.03 mg/dL (SI: 3.5 mmol/L) and nephrocalcinosis within 2 months of immobilization for tibial fracture, which required temporarily suspension of substitution therapy. Prolonged immobilization results in imbalance of bone remodeling where the rate of bone resorption exceeds the rate of bone formation, which may lead to hypercalcemia and hypercalciuria particularly in young patients [19].
In conclusion, this report underscores the importance of assessment of dietary calcium intake in children with hypoparathyroidism. Their need for calcium carbonate may depend on dietary calcium intake. Long-term treatment of hypoparathyroidism could be successful with calcitriol without calcium supplement if dietary calcium intake is sufficient. Use of blenderized tube feeding instead of commercial enteral formula makes it possible to increase calorie intake without causing dietary calcium excess.
Learning points
Treatment of hypoparathyroidism is associated with increased risk of hypercalcemia, hypercalciuria, and nephrocalcinosis reported in more than a third of patients.
Possible reasons for hypercalcemia during treatment of hyperparathyroidism include calcium carbonate overdose, excessive dietary calcium intake from enteral formula, vitamin D intoxication, and prolonged immobilization.
It is important to assess dietary calcium intake in children treated for hypoparathyroidism, especially those dependent on enteral formula.
Treatment of hypoparathyroidism could be successful with calcitriol without calcium supplement if dietary calcium intake is sufficient.
Use of blenderized tube feeding instead of commercial enteral formula in a child with hypoparathyroidism makes it possible to increase calorie intake without causing dietary calcium excess.
Contributors
All authors made individual contributions to authorship. M.T. was involved in the diagnosis and management of the patient, and conceptualization and writing of the manuscript. M.T. and M.M. were involved in reviewing the literature and editing the manuscript. All authors reviewed and approved the final draft.
Abbreviations
- BTF
blenderized tube feeding
- HDR
hypoparathyroidism, sensorineural deafness, and renal dysplasia syndrome
- PTH
parathyroid hormone
Contributor Information
Michael Yuri Torchinsky, Department of Pediatrics, University of Illinois College of Medicine, Peoria, IL 61603, USA.
Mark Daniel Miller, Department of Pediatrics, University of Illinois College of Medicine, Peoria, IL 61603, USA.
Funding
No public or commercial funding.
Disclosures
None declared.
Informed patient consent for publication
Signed informed consent obtained directly from the patient's relatives or guardians.
Data availability statement
Original data generated and analyzed for this case report are included in this published article.
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Associated Data
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Data Availability Statement
Original data generated and analyzed for this case report are included in this published article.