Vitamin D Toxicity

Etiology

In healthy individuals, vitamin D toxicity can result from taking excessive vitamin D supplementation, knowingly or accidentally.[5] Prescription errors without frequent monitoring of vitamin D levels can also result in toxicity.[6] Toxicity resulting from lack of monitoring is frequently seen in patients requiring high doses to treat ailments like osteoporosis, renal osteodystrophy, psoriasis, gastric bypass surgery, celiac, or inflammatory bowel disease.[4][7]

Fortification of foods or supplements with higher than intended amounts of vitamin D has led to toxicity. In 2015, the FDA announced a voluntary recall of multivitamins by Glades Drugs due to excessive amounts of vitamin D. In 2016, the Danish health authority issued a recall for a supplement that had vitamin D levels 75 times higher than recommended. At least 20 children developed toxicity after taking this supplement.

Vitamin D is present in fish, meat, and dairy products, and the dose is rarely enough to cause toxicity.[8] Patients who are on high doses of Vitamin D and taking inadvertently increased amounts of highly fortified milk are also at increased risk for vitamin D toxicity. It can also result from excessive 1,25(OH)2D production in medical ailments like granulomatous disorders and lymphomas.[9]

Excessive sun exposure does not cause vitamin D toxicity due to the regulation and conversion of Vitamin D to its inactive metabolites.[8]

Although mainly reported in animals, exposure to rodenticides containing cholecalciferol can also lead to vitamin D toxicity.[10][11]

Epidemiology

From 2000 to 2014, a total of 25,397 cases of vitamin D toxicity were reported. Between 2000 and 2005, the annual mean of vitamin D toxicity cases was 196. However, there was a substantial increase of 1600% in exposures from 2005 to 2011, resulting in a new annual mean of 4535 cases.[12] 

According to the latest report from America's Poison Centers (APC), there were 11,718 cases of vitamin D exposure recorded in the National Poison Data System. More than half of these cases were in children younger than 5 years. The vast majority of cases were from unintentional exposures. The total number of vitamin D toxicity cases was greater than the total number of vitamin (vitamins B, A, C, and E) toxicity cases combined. This illustrates the widespread use of vitamin D supplements.[13]

Pathophysiology

Vitamin D is a fat-soluble vitamin stored in the liver and adipose tissue. It is available from exogenous sources and synthesized endogenously by the human body. The Endocrine Society clinical practice guidelines suggest that the daily requirement of vitamin D for adults aged 19 to 50 years is 600 IU/d. For those aged 50 to 70, the daily requirement is at least 600 IU/d. For those older than 70, the daily requirement is at least 800 IU/d. The maximum suggested daily requirement is 4000 IU/d for everyone older than 8 years.[14]

Vitamin D is metabolically inactive and requires a series of metabolic transformations to become its active form. This includes forms acquired from external sources or through endogenous synthesis. 

Endogenously, the skin converts 7-dehydrocholesterol (provitamin D3) to cholecalciferol (vitamin D3). This reaction is catalyzed by ultraviolet B irradiation. Vitamin D3 (from dietary sources and sunlight exposure) is carried by vitamin D-binding protein (VDBP) in the serum. Vitamin D3 is subsequently converted to 25-hydroxyvitamin D3 [25(OH)D] in the liver by the enzyme vitamin D-25-hydroxylase. After formation, 25(OH)D is transported to the kidneys via VDBP. In the proximal convoluted tubules, it is converted by 25(OH)D-1-α-hydroxylase into calcitriol, also known as 1,25-dihydroxy vitamin D3 [1,25(OH)2D]. The final product, 1,25(OH)2D, is then transported to the rest of the body via VDBP, where it serves primarily to regulate calcium metabolism.[15] Vitamin D plays an essential role in calcium resorption from bone by increasing osteoclast activity.

Vitamin D is primarily stored in the liver. There is a negative feedback regulation of the enzyme vitamin D-25-hydroxylase in the liver; however, it is not enough to prevent toxicity. Ingesting high doses of vitamin D leads to its storage in the liver and adipose tissue, causing saturation of the vitamin D-binding receptors. This increases the concentration of many other vitamin D metabolites, especially 25(OH)D.

In hypervitaminosis D, the concentrations of vitamin D metabolites, such as 25(OH)D; 24,25(OH)2D; 25,26(OH)2D; and 25(OH)D-26,23-lactone, increase significantly.[16] Abnormally high concentrations of vitamin D metabolites exceed the VDBP-binding capacity, resulting in a release of free 1,25(OH)2D. The toxicity of vitamin D is believed to stem from elevated levels of 25(OH)D and free 1,25(OH)2D concentrations, although this hypothesis has yet to be definitively proven.[16]

History and Physical

A detailed history is essential in making a diagnosis of Vitamin D toxicity. A thorough review of the medication list, including the use of over-the-counter supplements, is pertinent. History should also focus on acquiring details of chronic medical ailments that require high doses of vitamin D supplementation, such as osteoporosis, renal osteodystrophy, psoriasis, gastric bypass surgery, and celiac or inflammatory bowel disease. A dietary history is essential, especially the excessive use of vitamin D-fortified milk and supplementary vitamin D. 

The clinical signs and symptoms of vitamin D toxicity manifest from hypercalcemia's effects. Often, symptoms can be nonspecific and subtle, such as weakness, fatigue, anorexia, and bone pains.[17][18] More severe symptoms include neurological symptoms like confusion, apathy, agitation, irritability, and sometimes, ataxia, stupor, and coma. Gastrointestinal symptoms include abdominal pain, nausea, vomiting, constipation, peptic ulcers, and pancreatitis (from malignant calcifications). Renal symptoms manifest as polyuria, polydipsia, and nephrolithiasis.[19] Severe hypercalcemia can also lead to cardiac arrhythmias.

Physical exams of patients with signs of toxicity can show loss of skin turgor and dry mucous membranes (due to dehydration); changes in mental status; and abdominal tenderness without rebound, rigidity, or guarding. Physical exam findings can be unremarkable, but high clinical suspicion should be maintained based on historical information.

Evaluation

The diagnosis of vitamin D toxicity relies on a comprehensive evaluation of the patient's medical history and clinical symptoms. Laboratory evaluation includes checking serum calcium (often >11 mg/dL), ionized calcium, phosphate levels, and parathyroid hormone (PTH), which often are suppressed due to a negative feedback loop.[20]

In cases of vitamin D toxicity, serum levels of 25(OH)D concentration often exceed 150 ng/mL (375 nmol/L), accompanied by normal or elevated values of 1,25(OH)2D concentration.[4] Patients with coexisting granulomatous diseases may present with decreased or normal 25(OH)D concentration and elevated 1,25(OH)2D levels. A basic metabolic panel should be performed to evaluate kidney function for potential hypercalcemia effects and to assess for any electrolyte imbalances resulting from excessive vomiting.

The most common EKG finding is a shortened QT interval. Additionally, EGG may reveal a prolonged PR interval, a shortened ST segment, flattened T waves, and Osborn waves (J wave), indicated by a positive deflection at the J point in precordial leads.[21]

Imaging studies are usually not required to diagnose vitamin D toxicity but can reveal incidental findings of chronic toxicity due to pathologic calcifications. Skeletal radiographs typically show periosteal calcifications. Abdomen and pelvic CT scans can reveal nephrolithiasis. In addition, other pathologic calcifications may be observed in the blood vessels, myocardium, lung, and skin. When a patient presents with significant alteration in mental status upon admission, it is advisable to perform a baseline brain CT scan to assess for possible intracranial pathologies or alternative causes.

Treatment / Management

Clinical management of vitamin D toxicity is mainly supportive and focuses on lowering calcium levels.

• Vitamin D and calcium supplements should be discontinued. In addition, excessive bed rest should be avoided to prevent hypercalcemia due to immobilization.
• Isotonic saline should be used to correct dehydration and increase renal calcium clearance.[17]
• In severe toxicity resulting in severe hypercalcemia (serum calcium >14 gm/dL), calcitonin and bisphosphonates can be used. Dosing is recommended as follows:
  • Calcitonin at 4 U/kg intramuscularly can be administered and repeated every 12 hours up to 48 hours.
  • IV bisphosphonates can be administered concurrently: Pamidronate 90 mg IV over 2 hours and zoledronic acid 4 mg IV over 15 minutes.[22][23]
  • Coadministration of calcitonin and bisphosphonates has been shown to increase the efficacy of calcitonin.[24]
• Calcitonin can lead to tachyphylaxis, while the effect of bisphosphonates can persist for a longer duration. Therefore, calcium levels should be carefully monitored when using these medications.
• The use of IV glucocorticoids is controversial and usually reserved for treating vitamin D toxicity related to granulomatous disease. This medication works by reducing calcitriol levels, which in turn lowers plasma calcium levels. By decreasing intestinal absorption and increasing urinary excretion of calcium, it helps regulate calcium levels in the body.[25]
  • Hydrocortisone 100 mg/d or prednisone 40mg/d for 5 d.  
• Patients may need hemodialysis due to renal failure or correct refractory hypercalcemia.
• The patient’s medication list should be reviewed to adjust the future doses of vitamin D supplements.
• Patient counseling is needed to avoid vitamin supplement overuse.
• The Endocrine Society suggests monitoring 25-hydroxy vitamin D and calcium serum levels for patients on high-dose vitamin D replacement therapy.
(B3)

Differential Diagnosis

Vitamin D hypervitaminosis should be differentiated from other causes leading to hypercalcemia.  Other diseases that mimic the signs and symptoms of hypervitaminosis are as follows:

• Hypercalcemia of malignancy
• Hypercalcemia of granulomatous diseases
• Primary, secondary, and tertiary hyperparathyroidism
• Vitamin A toxicity
• Thyrotoxicosis
• Paget disease
• Hypercalcemia caused by prolonged immobilization
• Milk-alkali syndrome

Prognosis

Most cases of vitamin D toxicity resolve without serious complications or sequelae. However, in some instances, severe hypercalcemia can lead to acute renal failure requiring hemodialysis. Cases of permanent renal damage due to vitamin D toxicity are rare.

Complications

The complication of vitamin D toxicity rarely leads to renal failure requiring hemodialysis.[26]