https://orcid.org/0009-0009-4466-9631
Abstract
Excessive 1, 25-dihydroxy vitamin D (calcitriol) is a pathophysiological cause of hypercalcemia. This form of hypercalcemia is seen in autoimmune conditions, fungal infections, lymphoma, and rare genetic diseases. A factious disorder manifesting as intentional ingestion of calcitriol leading to hypercalcemia has not been previously reported. We report a case of a female in the fourth decade with recurrent episodes of hypercalcemia seen at multiple clinics across the United States over a period of 20 years. Several extensive medical workups were unable to identify a specific cause of her non-PTH mediated hypercalcemia. We used a novel approach to determine that her hypercalcemia was secondary to exogenous calcitriol administration. When the patient realized that the etiology had been identified, she refused all further contact with the physician. It is not uncommon for patients with a factitious disorder to deny self-inflicting behavior or to seek care somewhere else. Ingestion of calcitriol should be considered when the etiology of recurrent hypercalcemia cannot be identified by traditional medical testing.
Introduction
Hypercalcemia is a common clinical condition. Elevated calcium levels can result from increased bone resorption, increased calcium absorption from the gut, and decreased renal excretion of calcium. Patients with mild hypercalcemia are typically asymptomatic. Severe or persistent elevations in calcium can affect multiple organ systems [1]. Primary hyperparathyroidism and humoral hypercalcemia of malignancy are the most common causes of hypercalcemia, accounting for 90% of cases. Less frequent causes of hyerpercalcemia are calcitriol-mediated hypercalcemia, excessive calcium consumption, ectopic PTH secretion, and PTH and PTH-related peptide cosecretion. In addition, some medications are associated with hypercalcemia such as a combination of trans-retinoic acid and voriconazole. Rebound hypercalcemia from denosumab withdrawal may also be associated with hypercalcemia [2].
The active metabolite of vitamin D, calcitriol, is crucial for maintaining calcium and phosphorus homeostasis. PTH activates the kidney's 1 α hydroxylase's conversion of 25-hydroxyvitamin D to calcitriol when serum calcium levels are low. Calcitriol facilitates active transcellular absorption of calcium in the intestine, increases calcium and phosphorus reabsorption in the kidneys, and increases calcium resorption from the bone. Calcitriol is inactivated by vitamin D 24-hydroxlyase [3].
Factious disorder manifesting as excessive and intentional ingestion of active vitamin D leading to hypercalcemia has not been previously reported. Factitious disorder is a mental health condition in which a patient fabricates illness, injury, or impairment for psychological reasons [4]. These patients often undergo extensive diagnostic evaluations, exhausting medical resources. We report a challenging case of hypercalcemia shown to be secondary to intentional administration of calcitriol.
Case Presentation
A female in the fourth decade of life presented to the endocrinology clinic at our institution for the evaluation of recurrent episodes of hypercalcemia with a duration of 20 years. She had been seen at multiple endocrinology clinics throughout the United States prior to presenting to our clinic. The episodes of hypercalcemia started after a motor vehicle accident in 2000. During these hypercalcemic episodes, her headaches became worse. She denied any nausea or vomiting, muscle cramps, polydipsia, polyuria, or mental status changes. She was either hospitalized or treated at an urgent care clinic with hydration when her lab work demonstrated significant hypercalcemia. Her calcium level always declined to normal levels following hydration. She denied any prior fractures or renal stones. She denied taking any supplements. The patient's mother was actively involved in her care. The patient was not on any medications that can cause hypercalcemia. There were no abnormal findings on the physical exam.
One year prior to presenting to our clinic, she was treated with IV zoledronic acid for hypercalcemia at another institution. Her last hospitalization for hypercalcemia was 7 months prior to presentation at our clinic. At that institution, her admitting calcium was 13.8 mg/dL (3.44 mmol/L) (normal range: 8.6-10.3 mg/dL or 2.12-2.62 mmol/L). She was subsequently hydrated with normal saline at 175 mL/hour. The next morning, her calcium improved to 9.8 mg/dL (2.45 mmol/L) (normal range: 8.6-10.3 mg/dL or 2.12-2.62 mmol/L). She was administered denosumab 120 mg subcutaneously prior to discharge. During that hospitalization, PTH was suppressed at 6.9 pg/mL (6.9 ng/L) (normal range 15-65 pg/mL or 15-65 ng/L), PTH–related peptide was 0.6 pmol/L (normal value less than 4.2 pmol/L), and calcitriol was less than 8 pg/mL (29.37 pmol/L) (normal range 18-78 pg/mL or 47.76-190.32 pmol/L). Serum protein electrophoresis was normal. A computed tomography of the chest, abdomen, and pelvis did not show any abnormalities. The previous lab work done in 2008 and 2010 at the same outside hospital was consistent with non-PTH mediated hypercalcemia. In 2008, the patient had a calcium of 11.3 mg/dL (2.82 mmol/L) (normal range: 8.6-10.3 mg/dL or 2.12-2.62 mmol/L) and a corresponding PTH of 11 pg/mL (11 ng/L) (normal range 15-65 pg/mL or 15-65 ng/L). In 2010 the calcium was 10.5 mg/dL (2.62 mmol/L) and the corresponding PTH was 15.9 pg/mL (15.9 ng/L).
After initial evaluation, a non-PTH mediated hypercalcemia was suspected, and vitamin A toxicity, adrenal insufficiency, hyperthyroidism, and pheochromocytoma were considered A 24-hour urine calcium measured in 2008 was elevated at 377 mg/24 hours (9.425 mmol/24 hour)(normal range 100-300 mg/24 hours or 2.50-7.50 mmol/24 hour). A bone density scan performed within 1 year prior to presentation was negative for osteoporosis. Prior evaluations for hyperthyroidism and adrenal insufficiency were normal. Genetic testing for familial hypocalciuric hypercalcemia and 24-hydoxylase deficiency was negative. The patient has a history of mental health issues including a concern for self-harm more than 10 years prior to presenting to our clinic.
Diagnostic Assessment
Because the patient did not have any history of nephrolithiasis or osteoporosis that can result from chronic hypercalcemia, we suspected that a transient process was causing the hypercalcemia. Laboratory evaluation at our clinic demonstrated corrected calcium of 12.8 mg/dL (3.19 mmol/L) (normal range 8.5-10.2 mg/dL or 2.12-2.62 mmol/L). Vitamin A levels were normal at 0.75 mg/liter (normal range 0.30-1.20 mg/liter). In spite of the fact that the patient stated that she was “always hypercalcemic,” the patient was asked to obtain morning blood draws on 5 consecutive days. Lab work revealed hypercalcemia, suppressed PTH, and normal 25-hydroxyvitamin D levels (Fig. 1). At baseline, the patient had elevated calcitriol levels on the first day, consistent with causing her hypercalcemia. However, calcitriol levels declined rapidly thereafter, confirming our suspicion of exogenous calcitriol consumption (Table 1). Angiotensin-converting enzyme levels were normal at 16 units/L (normal 16-85 units/L). The ratio of 25-hydroxyvitamin D to 24,25-dihydroxyvitamin D was 6.38 (<25 normal), making CYP21A1 loss of function mutations extremely unlikely.
Shows declining 1,25-dihydroxyvitamin D levels (calcitriol), PTH, and corrected calcium levels over the 5-day period.
Labs on 5 consecutive days
| Analyte | Normal range | Day 1 | Day 2 | Day 3 | Day 4 | Day 5 |
|---|---|---|---|---|---|---|
| Calcium | 8.5-10.2 mg/dL (2.12-2.62 mmol/L) | 11.3 mg/dL (2.82 mmol/L) | 11.7 mg/dL (2.92 mmol/L) | 10.8 mg/dL (2.69 mmol/L) | 10.8 mg/dL (2.69 mmol/L) | 10.7 mg/dL (2.67 mmol/L) |
| Corrected calcium | 8.5-10.2 mg/dL (2.12-2.62 mmol/L) | 10.9 mg/dL (2.72 mmol/L) | 11.3 mg/dL (2.82 mmol/L) | 10.4 mg/dL (2.59 mmol/L) | 10.4 mg/dL (2.59 mmol/L) | 10.3 mg/dL (2.57 mmol/L) |
| 25-hydroxyvitamin D | 30-100 ng/mL (74-250 nmol/L) | 41 ng/mL (102 nmol/L) | ||||
| Calcitriol/1,25-dihydroxyvitamin D | 19.9-79.3 pg/mL (47.76-190.32 pmol/L) | 91.5 pg/mL (219 pmol/L) | 44.8 pg/mL (107.5 pmol/L) | 21.8 pg/mL (52.3 pmol/L) | 16.2 pg/mL (38.9 pmol/L) | 18.9 pg/mL (45.4 pmol/L) |
| PTH | 15-65 pg/mL (15-65 ng/L) | 11 pg/mL (11 ng/L) | 7 pg/mL (7 ng/L) | 9 pg/mL (9 ng/L) | 7 pg/mL (7 ng/L) | 8 pg/mL (8 ng/L) |
| Analyte | Normal range | Day 1 | Day 2 | Day 3 | Day 4 | Day 5 |
|---|---|---|---|---|---|---|
| Calcium | 8.5-10.2 mg/dL (2.12-2.62 mmol/L) | 11.3 mg/dL (2.82 mmol/L) | 11.7 mg/dL (2.92 mmol/L) | 10.8 mg/dL (2.69 mmol/L) | 10.8 mg/dL (2.69 mmol/L) | 10.7 mg/dL (2.67 mmol/L) |
| Corrected calcium | 8.5-10.2 mg/dL (2.12-2.62 mmol/L) | 10.9 mg/dL (2.72 mmol/L) | 11.3 mg/dL (2.82 mmol/L) | 10.4 mg/dL (2.59 mmol/L) | 10.4 mg/dL (2.59 mmol/L) | 10.3 mg/dL (2.57 mmol/L) |
| 25-hydroxyvitamin D | 30-100 ng/mL (74-250 nmol/L) | 41 ng/mL (102 nmol/L) | ||||
| Calcitriol/1,25-dihydroxyvitamin D | 19.9-79.3 pg/mL (47.76-190.32 pmol/L) | 91.5 pg/mL (219 pmol/L) | 44.8 pg/mL (107.5 pmol/L) | 21.8 pg/mL (52.3 pmol/L) | 16.2 pg/mL (38.9 pmol/L) | 18.9 pg/mL (45.4 pmol/L) |
| PTH | 15-65 pg/mL (15-65 ng/L) | 11 pg/mL (11 ng/L) | 7 pg/mL (7 ng/L) | 9 pg/mL (9 ng/L) | 7 pg/mL (7 ng/L) | 8 pg/mL (8 ng/L) |
Labs on 5 consecutive days
| Analyte | Normal range | Day 1 | Day 2 | Day 3 | Day 4 | Day 5 |
|---|---|---|---|---|---|---|
| Calcium | 8.5-10.2 mg/dL (2.12-2.62 mmol/L) | 11.3 mg/dL (2.82 mmol/L) | 11.7 mg/dL (2.92 mmol/L) | 10.8 mg/dL (2.69 mmol/L) | 10.8 mg/dL (2.69 mmol/L) | 10.7 mg/dL (2.67 mmol/L) |
| Corrected calcium | 8.5-10.2 mg/dL (2.12-2.62 mmol/L) | 10.9 mg/dL (2.72 mmol/L) | 11.3 mg/dL (2.82 mmol/L) | 10.4 mg/dL (2.59 mmol/L) | 10.4 mg/dL (2.59 mmol/L) | 10.3 mg/dL (2.57 mmol/L) |
| 25-hydroxyvitamin D | 30-100 ng/mL (74-250 nmol/L) | 41 ng/mL (102 nmol/L) | ||||
| Calcitriol/1,25-dihydroxyvitamin D | 19.9-79.3 pg/mL (47.76-190.32 pmol/L) | 91.5 pg/mL (219 pmol/L) | 44.8 pg/mL (107.5 pmol/L) | 21.8 pg/mL (52.3 pmol/L) | 16.2 pg/mL (38.9 pmol/L) | 18.9 pg/mL (45.4 pmol/L) |
| PTH | 15-65 pg/mL (15-65 ng/L) | 11 pg/mL (11 ng/L) | 7 pg/mL (7 ng/L) | 9 pg/mL (9 ng/L) | 7 pg/mL (7 ng/L) | 8 pg/mL (8 ng/L) |
| Analyte | Normal range | Day 1 | Day 2 | Day 3 | Day 4 | Day 5 |
|---|---|---|---|---|---|---|
| Calcium | 8.5-10.2 mg/dL (2.12-2.62 mmol/L) | 11.3 mg/dL (2.82 mmol/L) | 11.7 mg/dL (2.92 mmol/L) | 10.8 mg/dL (2.69 mmol/L) | 10.8 mg/dL (2.69 mmol/L) | 10.7 mg/dL (2.67 mmol/L) |
| Corrected calcium | 8.5-10.2 mg/dL (2.12-2.62 mmol/L) | 10.9 mg/dL (2.72 mmol/L) | 11.3 mg/dL (2.82 mmol/L) | 10.4 mg/dL (2.59 mmol/L) | 10.4 mg/dL (2.59 mmol/L) | 10.3 mg/dL (2.57 mmol/L) |
| 25-hydroxyvitamin D | 30-100 ng/mL (74-250 nmol/L) | 41 ng/mL (102 nmol/L) | ||||
| Calcitriol/1,25-dihydroxyvitamin D | 19.9-79.3 pg/mL (47.76-190.32 pmol/L) | 91.5 pg/mL (219 pmol/L) | 44.8 pg/mL (107.5 pmol/L) | 21.8 pg/mL (52.3 pmol/L) | 16.2 pg/mL (38.9 pmol/L) | 18.9 pg/mL (45.4 pmol/L) |
| PTH | 15-65 pg/mL (15-65 ng/L) | 11 pg/mL (11 ng/L) | 7 pg/mL (7 ng/L) | 9 pg/mL (9 ng/L) | 7 pg/mL (7 ng/L) | 8 pg/mL (8 ng/L) |
Treatment
Multiple attempts to further contact the patient and her mother to discuss the results were unsuccessful, making it impossible to offer any support and treatment to the patient.
Outcome and Follow-up
We believe that the patient and her mother understood that we had identified factious behavior by ingesting calcitriol. We were not able to reach the patient and offer any therapy for her factitious disorder. Therefore, this remains a weakness in our attempts to correct her hypercalcemia.
Discussion
Factitious disorder has been reported in endocrinology practice causing brittle diabetes, hypoglycemia, and Cushing syndrome [5-7]. To date, there are no reported cases of hypercalcemia resulting from intentional calcitriol ingestion. Active vitamin D-mediated hypercalcemia resulting from endogenous excessive production of calcitriol is seen in granulomatous diseases such as sarcoidosis, tuberculosis, leprosy, fungal infections, granulomatosis with polyangitis, and lymphoma [3]. Rarely, genetic diseases can cause elevated calcitriol levels, leading to hypercalcemia. CYP24A1 encodes vitamin D 24-hydroxlyase, which inactivates calcitriol. Loss of function mutations in CYP24A1 cause elevated calcitriol-mediated hypercalcemia [8]. Mutations in SCL34A1 cause loss of function of the NaPi-IIa cotransporter, leading to phosphate wasting in the urine, resulting in decreased fibroblast growth factor 23 levels. The reduced fibroblast growth factor 23 levels lead to excessive calcitriol levels, causing hypercalcemia. In both of these conditions, patients present with hypercalcemia starting in infancy [8, 9].
Vitamin D-mediated hypercalcemia can also result from exogenous causes, such as the inadvertent excessive administration of calcitriol or 25-hydroxyvitamin D [10].
The biological half-life of calcitriol is 4 to 6 hours, thereby making it difficult to identify surreptitious calcitriol ingestion after treating the hypercalcemia acutely with rehydration. However, the calcemic response can persist for more than 24 hours after a single dose [11]. Our patient demonstrated the highest concentration of calcitriol on the first day of the 5-day trial, and the highest concentration of calcium was seen on the next day. As anticipated for a single factitious ingestion, calcitriol levels declined and calcium levels improved during the subsequent 5 days. If her elevated calcitriol levels were from a pathological process (eg, chronic infection), a dramatic decline in its blood level would not be expected. In addition, a pathological process such as lymphoma elevating calcitriol levels would rarely remain indolent for 20 years. How the patient obtained calcitriol for exogenous ingestion is not known, although it can be obtained through the internet for either human or animal administration. Alternatively, in our southwest geographical location, it may be obtained from Mexican border towns without a prescription.
Diagnosing a factitious disorder can be very challenging. There are no traditional diagnostic tests for this disorder. Patients with this condition undergo unnecessary medical interventions, and healthcare costs can be exceptionally high. Usually, an etiological factitious disorder is diagnosed after an exhaustive list of possible diagnoses is excluded. Patients suffering from factitious disorder are likely to be working in healthcare and claim to have unusual medical knowledge, which is not difficult in the era of the internet. They usually present to healthcare institutions in early adulthood. The majority of these patients must be considered at high risk for self-injury. Although factitious disorder can present in any medical specialty, it is most common in endocrinology, followed by cardiology, and dermatology [7]. It is very important to gather as much information as possible about previous diagnostic workups. Treatment of factitious disorder requires psychiatric care. Our patient was evaluated at many endocrinology clinics throughout the United States without identification of any underlying hypercalcemic etiology. The patient had undergone extensive evaluations and received unnecessary treatments. Physicians need to always consider factitious causes of disease when confronted by a confusing medical presentation.
Learning Points
Vitamin D-mediated hypercalcemia can result from excessive exogenous administration of vitamin D supplements or surreptitious ingestion of calcitriol.
Whenever the clinical picture is inconsistent with the disease model, physicians should be vigilant about the possibility of factitious disorder.
Once objective evidence of factitious disorder is obtained, the patient should be referred to psychiatry for evaluation.
Contributors
B.N.G. and D.S.S. were involved in the diagnosis and management of this patient and manuscript submission.
Funding
There is no external funding for this manuscript.
Disclosures
None reported.
Informed Patient Consent for Publication
Signed informed consent could not be obtained from the patient or a proxy but has been approved by the treating institution.
Data Availability Statement
Original data generated and analyzed for this case report are included in this published article.
