Hypercalcemia with the Oral Administration of Active Vitamin D3 and Chinese Herbal Medicine

Abstract

The causes of hypercalcemia vary. There are high-calcium-containing preparations in Chinese herbal medicine, which may contribute to drug-induced hypercalcemia. We encountered a case of hypercalcemia following the simultaneous administration of an active vitamin D3 preparation and several Chinese herbal medicines. The patient had been treated at several medical institutions, with one institution administering eldecalcitol and another institution administering Keishikaryukotsuboreito, Borei powder, and Goreisan. The patient presented with drug-induced hypercalcemia due to an unexpected synergistic effect. Confirmation of prescriptions for patients with multiple medical visits and recognition of the components and side effects of Chinese herbal medicines is thus considered to be extremely important.

Introduction

Hypercalcemia is an electrolyte abnormality that is routinely encountered, but it has diverse causes. Approximately 90% of hypercalcemia cases involve primary hyperparathyroidism or malignancy (1). Other causes include tertiary hyperparathyroidism, granulomatous disorders (principally sarcoidosis), thyrotoxicosis, drugs, excessive ingestion of calcium carbonate (‘milk alkali syndrome'), vitamin D toxicity, vitamin A intoxication, immobilization, familial hypocalciuric hypercalcemia and untreated Addison's disease (2). The mechanisms of hypercalcemia due to malignancy can be divided into two major categories: bone destruction due to bone metastases, and parathyroid hormone (PTH)-related protein-producing tumors (2).

The most common causes of drug-induced hypercalcemia are active vitamin D preparations, natural vitamin D supplements, thiazide diuretics, theophylline preparations, and lithium preparations (3). However, there are also some so-called Chinese herbal preparations which demonstrate a high calcium content, such as oysters (main ingredients: calcium carbonate and calcium phosphate), longgu (Fossilia Ossis Mastodi, “dragon bone”) (main ingredient: calcium carbonate), and gypsum (main ingredient: hydrous calcium sulfate), which may be a factor in drug-induced hypercalcemia.

We herein report a case of hypercalcemia with the simultaneous administration of an active vitamin D3 preparation and several Chinese herbal preparations.

Case Report

A 73-year-old woman had been treated for Hashimoto's disease for X-10 years by her primary care physician A. She was receiving levothyroxine sodium 50 μg/day. She had been treated for dyslipidemia, osteoporosis, and reflux esophagitis at her primary care physician B for 7 years, and was receiving pravastatin sodium 5 mg/day, eldecalcitol 0.75 μg/day, and famotidine 40 mg/day. She had been treated for lightheadedness at her primary care physician C for 3 years and had been receiving Keishikaryukotsuboreito 7.5 g/day (containing approximately 720 mg of calcium), Goreisan 7.5 g/day (containing almost no calcium), Borei powder 3 g/day (containing approximately 960 to 1,140 mg of calcium), butyric acid bacteria 60 mg/day, and metoclopramide 15 mg/day. In addition, she had been under observation without treatment for Sjögren's syndrome at primary care physician D for 1 year. Six months prior to the visit, she was normocalcemic with corrected Ca levels of 10.2 mg/dL and serum Cr levels of 0.92 mg/d (eGFR 46.6 mL/min/1.73 m²).

Sixteen days prior to the visit, abdominal pain and thirst appeared, and four days prior to the visit, vomiting symptoms appeared. During a semiannual visit to physician D, hypercalcemia with serum corrected Ca levels of 14.5 mg/dL and renal dysfunction with serum Cr levels of 2.06 mg/dL (eGFR 19.6 mL/min/1.73 m²) were found, and the patient was referred to our hospital for consultation. She was conscious and clear at the time of visit, but had severe thirst and dry mouth, and her corrected Ca and Cr levels were still high at 13.3 mg/dL and 1.79 mg/dL (eGFR 22.1 mL/min/1.73 m²), respectively (Table 1). Ureteral or renal stones and hydronephrosis were not detected on computed tomography. Although tubulointerstitial markers were not measured, imaging studies revealed no renal swelling, atrophy, or tumors, suggesting renal parenchymal damage. Based on the above exclusion criteria, we considered that the patient had renal failure associated with hypercalcemia. Diagnostic imaging did not reveal any renal artery calcification or unilateral renal atrophy, suggesting renal vascular hypertension, granulomatosis, or tumors. She was immediately started on 500 mL/day of saline solution and 40 units/day of elcatonin on an outpatient basis, discontinued eldecalcitol, and was admitted to our department for further examination and treatment the following afternoon.

Table 1.

Laboratory Data on Admission.

WBC (/mL)	8,500	TP (g/dL)	7.6	BUN (mg/dL)	24
RBC (104/mL)	379	Alb (g/dL)	4.22	Cr (mg/dL)	1.79
Hb (g/dL)	11.4	T-Bil (mg/dL)	0.51	eGFR (mL/min/1.73m2)	22.1
Hct (%)	35.7	AST (IU/L)	21	UA (mg/dL)	9.0
Plt (104/µL)	15.4	ALT (IU/L)	14	CK (IU/L)	158
		LDH (IU/L)	191	HbA1c (%)	5.6
Urinary occult blood	2+	ALP (IU/L)	55	Glucose (mg/dL)	111
Urinary protein	-	γ-GTP (IU/L)	12	CRP (mg/dL)	0.07
Urinary glucose	-	Na (mEq/L)	144	Free T4 (ng/dL)	1.39
Urinary calcium (mg/dL)	23.8	K (mEq/L)	3.0	TSH (mU/mL)	4.28
Urinary creatinine (mg/dL)	33.3	Cl (mEq/L)	104	pH	7.359
		Ca (mg/dL)	13.3	SBE (mmol/L)	6.8
		Mg (mg/dL)	1.9	HCO3-(mmol/L)	32.2
		IP (mg/dL)	1.7	Lactate (mg/dL)	12.2

The observed symptoms at the time of admission were as follows: height, 160.5 cm; body weight, 45.5 kg; clear consciousness; body temperature, 36.1°C; blood pressure. 179/93 mmHg; pulse, 61 bpm; no anemia of the eyelid conjunctiva; no yellowing of the ocular conjunctiva; no abnormalities in the neck, chest, or abdomen; and no edema or skin rash on the extremities. Electrocardiogram findings showed a normal sinus rhythm with 55 beats/min, multiple premature ventricular contractions, and no QT shortening. The subjective symptoms included nausea, vomiting, anorexia, malaise, and lightheadedness. She had no family or history of other significant medical or psychiatric illnesses.

Upon admission, the patient was treated with 500-1,000 mL/day of saline solution and 40-80 units/day of elcatonin until the sixth day after admission and 40 mg/day of furosemide due to concurrent renal failure until the third day after admission. hypercalcemia and renal dysfunction gradually improved. After admission, endocrine and calcium-related data (Table 2) and a diagnosis of exclusion by imaging studies suggested the occurrence of drug-induced hypercalcemia, and the above three Chinese herbal medicines were therefore discontinued on the fourth day of admission. The blood pressure improved naturally to 112/74 mmHg by the morning following admission, with no medication. On the 8th day of admission, the patient improved with 8.67 mg/dL of serum corrected Ca levels and 0.91 mg/dL and serum Cr levels (eGFR 46.4 mL/min/1.73 m²) and was discharged on the 10th day of admission. Her urine volume was 2,900 mL/day on the first day of hospitalization, 2,450 mL/day on the second day, and thereafter between 1,800 and 2,200 mL/day. At the outpatient visit two months after discharge, the serum corrected Ca and Cr levels remained stable at 9.6 mg/dL and 0.85 mg/dL (eGFR 50.0 mL/min/1.73 m²), respectively (Figure). The serum levels of potassium and phosphorus also improved to 4.5 mEq/L and 3.7 mg/dL, respectively.

Table 2.

Endocrine and Calcium-related Laboratory Data (postprandial).

	Measured value	Normal range		Measured value	Normal range
Cortisol (mg/dL)	5.98	7.07-19.6	TRACP-5b (mU/dL)	176	120.0-420.0
Bone ALP (mg/L)	6.5	3.8-22.6	Osteocalcin (ng/mL)	8.8	14.2-54.8
GH (ng/mL)	0.54	0.13-9.88	25(OH)vitamin D (ng/mL)	0.54	20-60
ACTH (pg/mL)	35.3	7.2-63.3	Somatomedin C (ng/mL)	35.3	54-167
i-PTH (pg/mL)	11	10-65	PTHrP (pmol/L)	<1.0	<1.0
Whole PTH (pg/mL)	14.9	8.3-38.7	1,25(OH)2 vitamin D (pg/mL)	23.3	20-60

Figure.

Clinical course. Day Z is the day of admission. cCa: calculated serum Ca levels

Discussion

Chinese herbal medicines, or so-called Kampo medicines, are a generic term for drugs used in traditional Chinese medicine. Because they are prepared by combining herbal medicines obtained from nature, they are generally considered to have fewer side effects than Western medicine; however, there have been reports of serious side effects even with Chinese herbal medicine in the past. In 1989, interstitial pneumonia was reported as a serious side effect of shosaikoto (4). Pseudohyperaldosteronism with licorice-containing preparations is another typical side effect of Chinese herbal medicine (5).

Borei, an herbal medicine used in Chinese herbal medicine, is an edible oyster shell and 80-95% of its composition is calcium carbonate and other components including calcium phosphate, ferric oxide, and silicates. Longgu is a fossilized bone of large mammals and is mainly composed of calcium carbonate. Keishikaryukotsuboreito is a high-calcium-containing preparation containing 14% borei and 14% longgu (6), which means that it contains approximately 25% calcium carbonate. In this case, the Borei powder itself was also used concomitantly, thus suggesting that the patient may have been in a state of calcium overdose. In this case, the hypercalcemia may have improved simply by discontinuing eldecalcitol. However, the amount of calcium intake from herbal medicine is very large, and its effect on hypercalcemia cannot be ignored. In addition to the active vitamin D3 preparation, goreisan, a diuretic via aquaporin (7), was also administered at the same time, and these medicines in combination might have led to the onset of drug-induced hypercalcemia.

Active vitamin D3 preparations are expected to maintain or increase lumbar spine bone density and are frequently used in the elderly to treat osteoporosis (8). However, prolonged and random administration can induce hypercalcemia (9), and hypercalcemia and renal dysfunction have been observed in approximately 1% of patients treated with active vitamin D3 preparations (10,11). Hypercalcemia should be noted in elderly patients taking orally activated vitamin D3 preparations as they may have physiological and renal dysfunction. In addition, because vitamin D is fat-soluble, it can accumulate in fat cells and cause hypercalcemia several years after the initiation of oral administration (8-10). Regarding the background factors for hypercalcemia induced by activated vitamin D3 preparations in osteoporosis, half of the patients were taking concomitant medications, including angiotensin II receptor blockers, magnesium oxide preparations, and diuretics, although calcium supplements are rarely used to treat osteoporosis (8-10). In this case, the serum 1,25(OH)₂D concentration was low. However, vitamin D toxicity cannot be ruled out. With eldecalcitol treatment, the serum 1,25(OH)₂D concentration was reduced by approximately 50%, whereas the serum levels of parathyroid hormone and 25(OH)D were not affected (12).

In hypercalcemia due to vitamin D and its analogs, laboratory findings other than hypercalcemia include hyperphosphatemia and suppressed serum PTH concentrations. Absorptive hypercalciuria is a common condition. In patients with hypervitaminosis D, urinary calcium excretion is generally elevated before the development of hypercalcemia. In most cases, serum 1,25-dihydroxyvitamin D levels are normal (3). In the present case, the serum phosphorus concentration was low (1.7 mg/dL). It is possible that the effect of eldecalcitol on vitamin D was not excessive. Although the patient was in a state of vitamin D toxicity, it might be temporarily decreased due to an insufficient intake before hospitalization. Low levels of 25(OH) D are also thought to be due to an inadequate intake.

No reports have directly compared the risks between monotherapy with active vitamin D preparations and combination therapy with active vitamin D and calcium preparations. However, an increase in the serum calcium concentration has been observed in groups receiving a combination of calcium and vitamin D compared with those receiving calcium alone (13). The calcium content of commonly used calcium supplements, such as calcium aspartate (approximately 130 mg per 1 g) and calcium lactate (approximately 130 mg per 1 g), is relatively modest. In contrast, the calcium content of the Chinese herbal medicines administered in this case was exceedingly high, containing 5-10 times more calcium than the standard supplements. Therefore, this case suggests that the patient may have been at a higher risk of developing hypercalcemia than those receiving standard doses of calcium supplements combined with vitamin D preparations.

Aging often leads to a decline in the physical and mental function and the development of multiple chronic conditions, thus resulting in an increased number of medications. The term “polypharmacy” refers to the adverse events that arise from the use of multiple medications, including drug-drug interactions, medication errors such as taking the wrong dose or forgetting doses, and improper medication use. The primary concerns associated with polypharmacy include drug interactions and side effects. Additionally, excessive prescription of medications can lead to issues such as leftover medications owing to missed doses and increased healthcare costs. In elderly patients, the issue of polypharmacy is key in diagnostic evaluation because several competing etiologies may contribute to hypercalcemia. These issues naturally extend to the inclusion of Chinese herbal medicines. However, there are few reports of hypercalcemia induced by Chinese herbal medicines. In this case, active vitamin D3 preparations and Chinese herbal medicines (diuretic goreisan, calcium-containing Keishikaryukotsuboreito, and Borei powder) were prescribed by different medical institutions. Therefore, the patient developed drug-induced renal dysfunction due to the unexpected synergistic effects triggered by dehydration.

It is extremely important to check the prescriptions of patients who visit multiple medical institutions and be aware of the components and side effects of Chinese herbal medicines.

The authors state that they have no Conflict of Interest (COI).