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Vitamin D toxicity
Vitamin D toxicity
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Vitamin D toxicity
Cholecalciferol (shown above) and ergocalciferol are the two major forms of vitamin D.
SpecialtyEndocrinology, toxicology

Vitamin D toxicity, or hypervitaminosis D, is the toxic state of an excess of vitamin D. The normal range for blood concentration of 25-hydroxyvitamin D in adults is 20 to 50 nanograms per milliliter (ng/mL). Blood levels necessary to cause adverse effects in adults are thought to be greater than about 150 ng/mL, leading the Endocrine Society to suggest an upper limit for safety of 100 ng/mL.[1]

Signs and symptoms

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An excess of vitamin D causes abnormally high blood concentrations of calcium, which can cause overcalcification of soft tissues, including arteries and kidneys. Symptoms appear several months after excessive doses of vitamin D are administered. A mutation of the CYP24A1 gene can lead to a reduction in the degradation of vitamin D and thus to vitamin toxicity without high oral intake (see Vitamin D § Excess). Symptoms of vitamin D toxicity may include the following:[2]

Treatment

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In almost every case, ceasing vitamin D intake, combined with a low-calcium diet and corticosteroid drugs, will allow for a full recovery within a month. Bisphosphonate drugs (which inhibit bone resorption) can also be administered.[2]

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The U.S National Academy of Medicine has established a Tolerable Upper Intake Level (UL) to protect against vitamin D toxicity ("The UL is not intended as a target intake; rather, the risk for harm begins to increase once intakes surpass this level.").[3] These levels in microgram (mcg or μg) and International Units (IU) for both males and females, by age, are:
(Conversion : 1 μg = 40 IU and 0.025 μg = 1 IU.[4])

  • 0–6 months: 25 μg/d (1000 IU/d)
  • 7–12 months: 38 μg/d (1500 IU/d)
  • 1–3 years: 63 μg/d (2500 IU/d)
  • 4–8 years: 75 μg/d (3000 IU/d)
  • 9+ years: 100 μg/d (4000 IU/d)
  • Pregnant and lactating: 100 μg/d (4000 IU/d)

The recommended dietary allowance is 15 μg/d (600 IU per day; 800 IU for those over 70 years). Overdose has been observed at 1,925 μg/d (77,000 IU per day).[citation needed] Acute overdose requires between 15,000 μg/d (600,000 IU per day) and 42,000 μg/d (1,680,000 IU per day) over several days to months.

Suggested tolerable upper intake level

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Based on risk assessment, a safe upper intake level of 250 μg (10,000 IU) per day in healthy adults has been suggested by non-government authors.[5][6] Blood levels of 25-hydroxyvitamin D necessary to cause adverse effects in adults are thought to be greater than about 150 ng/mL, leading the Endocrine Society to suggest an upper limit for safety of 100 ng/mL.[1]

Long-term effects of supplementary oral intake

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Excessive exposure to sunlight poses no risk of vitamin D toxicity through overproduction of vitamin D precursor, cholecalciferol, regulating vitamin D production. During ultraviolet exposure, the concentration of vitamin D precursors produced in the skin reaches an equilibrium, and any further vitamin D that is produced is degraded.[7] This process is less efficient with increased melanin pigmentation in the skin. Endogenous production with full body exposure to sunlight is comparable to taking an oral dose between 250 μg and 625 μg (10,000 IU and 25,000 IU) per day.[7][8]

Vitamin D oral supplementation and skin synthesis have a different effect on the transport form of vitamin D, plasma calcifediol concentrations. Endogenously synthesized vitamin D3 travels mainly with vitamin D-binding protein (DBP), which slows hepatic delivery of vitamin D and its availability in the plasma.[9] In contrast, orally administered vitamin D produces rapid hepatic delivery of vitamin D and increases plasma calcifediol.[9]

It has been questioned whether to ascribe a state of suboptimal vitamin D status when the annual variation in ultraviolet will naturally produce a period of falling levels, and such a seasonal decline has been a part of Europeans' adaptive environment for 1000 generations.[10][11] Still more contentious is recommending supplementation when those supposedly in need of it are labeled healthy and serious doubts exist as to the long-term effect of attaining and maintaining serum 25(OH)D of at least 80 nmol/L by supplementation.[12]

Current theories of the mechanism behind vitamin D toxicity (starting at a plasmatic concentration of ≈750 nmol/L[13]) propose that:

  • Intake of vitamin D raises calcitriol concentrations in the plasma and cell
  • Intake of vitamin D raises plasma calcifediol concentrations, which exceed the binding capacity of the DBP, and free calcifediol enters the cell
  • Intake of vitamin D raises the concentration of vitamin D metabolites, which exceed DBP binding capacity, and free calcitriol enters the cell

All of these affect gene transcription and overwhelm the vitamin D signal transduction process, leading to vitamin D toxicity.[13]

Cardiovascular disease

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Evidence suggests that dietary vitamin D may be carried by lipoprotein particles into cells of the artery wall and atherosclerotic plaque, where it may be converted to active form by monocyte-macrophages.[9][14][15] This raises questions regarding the effects of vitamin D intake on atherosclerotic calcification and cardiovascular risk as it may be causing vascular calcification.[16] Calcifediol is implicated in the etiology of atherosclerosis, especially in non-Whites.[17][18]

The levels of the active form of vitamin D, calcitriol, are inversely correlated with coronary calcification.[19] Moreover, the active vitamin D analog, alfacalcidol, seems to protect patients from developing vascular calcification.[20][21] Serum vitamin D has been found to correlate with calcified atherosclerotic plaque in African Americans as they have higher active serum vitamin D levels compared to Euro-Americans.[18][22][23][24] Higher levels of calcidiol positively correlate with aorta and carotid calcified atherosclerotic plaque in African Americans but not with coronary plaque, whereas individuals of European descent have an opposite, negative association.[18] There are racial differences in the association of coronary calcified plaque in that there is less calcified atherosclerotic plaque in the coronary arteries of African-Americans than in whites.[25]

Among descent groups with heavy sun exposure during their evolution, taking supplemental vitamin D to attain the 25(OH)D level associated with optimal health in studies done with mainly European populations may have deleterious outcomes.[12] Despite abundant sunshine in India, vitamin D status in Indians is low and suggests a public health need to fortify Indian foods with vitamin D. However, the levels found in India are consistent with many other studies of tropical populations which have found that even an extreme amount of sun exposure, does not raise 25(OH)D levels to the levels typically found in Europeans.[26][27][28][29]

Recommendations stemming from a single standard for optimal serum 25(OH)D concentrations ignore the differing genetically mediated determinants of serum 25(OH)D and may result in ethnic minorities in Western countries having the results of studies done with subjects not representative of ethnic diversity applied to them. Vitamin D levels vary for genetically mediated reasons as well as environmental ones.[30][31][32][33]

Ethnic differences

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Possible ethnic differences in physiological pathways for ingested vitamin D, such as the Inuit, may confound across-the-board recommendations for vitamin D levels. Inuit compensate for lower production of vitamin D by converting more of this vitamin to its most active form.[34]

Studies on the South Asian population uniformly point to low 25(OH)D levels, despite abundant sunshine.[35] Rural men around Delhi average 44 nmol/L. Healthy Indians seem to have low 25(OH)D levels, which are not very different from healthy South Asians living in Canada. Measuring melanin content to assess skin pigmentation showed an inverse relationship with serum 25(OH)D.[36] The uniform occurrence of very low serum 25(OH)D in Indians living in India and Chinese in China does not support the hypothesis that the low levels seen in the more pigmented are due to lack of synthesis from the sun at higher latitudes.

Comparative Toxicity: Use of Vitamin D in Rodenticides

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Further information: Rodenticide § Hypercalcemia

Vitamin D compounds, specifically cholecalciferol (D3) and ergocalciferol (D2), are used in rodenticides due to their ability to induce hypercalcemia, a condition characterized by elevated calcium levels in the blood. This overdose leads to organ failure and is pharmacologically similar to vitamin D's toxic effects in humans.

Concentrations used in these rodenticides are several orders of magnitude higher than the maximum recommended human intake, with acute baits containing 3,000,000 IU/g for D3 and 4,000,000 IU/g for D2. This leads to hypercalcemia in the rodents and subsequent death several days after ingestion.[37][38]

See also

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References

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Vitamin D toxicity

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from Grokipedia
Vitamin D toxicity, also known as hypervitaminosis D, is a rare condition resulting from excessive intake of , most commonly through high-dose supplements rather than diet or sun exposure, leading to elevated blood levels of the vitamin and subsequent hypercalcemia (abnormally high calcium levels in the blood). This imbalance disrupts normal physiological functions, particularly affecting the kidneys, bones, and gastrointestinal system, and can manifest acutely or chronically depending on the dose and duration of exposure. The primary cause of vitamin D toxicity is the of supplements exceeding recommended upper limits, with toxicity typically occurring at chronic daily doses above 10,000 international units (IU) for adults, though individual susceptibility varies based on factors like age, function, and concurrent calcium intake. Unlike , which is widespread and linked to conditions like and , toxicity is uncommon in the general due to the body's regulatory mechanisms for endogenous production from , but it has risen with increased supplement use for purported health benefits such as immune support or health; as of 2025, studies indicate an increasing prevalence of potential toxicity, particularly among females, young children, and older adults. The tolerable upper intake level (UL) set by health authorities is 4,000 IU per day for adults to prevent adverse effects, emphasizing the importance of monitoring supplementation under medical guidance. Symptoms of vitamin D toxicity arise mainly from hypercalcemia and may include nausea, vomiting, constipation, weakness, fatigue, polyuria (excessive urination), polydipsia (increased thirst), abdominal pain, and confusion, with severe cases potentially leading to dehydration, kidney stones, renal failure, or cardiac arrhythmias. Diagnosis involves measuring serum 25-hydroxyvitamin D levels (typically >150 ng/mL indicating toxicity), serum calcium, and parathyroid hormone, alongside ruling out other causes of hypercalcemia such as primary hyperparathyroidism or malignancy. Treatment focuses on discontinuing vitamin D and calcium sources, intravenous hydration to promote calciuresis, and in refractory cases, medications like corticosteroids, bisphosphonates, or calcitonin to lower calcium levels, with most patients recovering fully upon prompt intervention. Prevention strategies include adhering to recommended dietary allowances (600–800 IU daily for most adults) and consulting healthcare providers before high-dose supplementation, particularly for at-risk groups like children or those with renal impairment.

Overview and Pathophysiology

Definition and Causes

Vitamin D toxicity, also known as D, is a rare condition characterized by excessive accumulation of in the body, primarily resulting from overconsumption of supplements or fortified products. This leads to elevated levels of serum 25-hydroxyvitamin D, the main circulating form, often exceeding 150 ng/mL, and manifests biochemically as hypercalcemia (serum calcium >11 mg/dL) and (excess calcium in urine). Unlike , which affects a significant portion of the population due to limited sun exposure and dietary sources, toxicity arises only from intakes far exceeding physiological needs, typically involving chronic daily doses greater than 10,000 international units (IU) for weeks to months. While toxicity typically requires chronic intakes greater than 10,000 IU daily, doses of 2,000–5,000 IU per day are generally safe for most people and commonly used to correct deficiencies without adverse effects. Toxicity at these levels is rare and usually occurs only in the presence of underlying conditions, with potential symptoms including nausea, vomiting, weakness, confusion, or kidney issues if hypercalcemia develops. The primary causes of vitamin D toxicity stem from exogenous sources, with over-supplementation being the most common culprit. This includes misuse of over-the-counter or prescription vitamin D2 (ergocalciferol, derived from plant sources) or D3 (cholecalciferol, from animal sources and sunlight), often in attempts to treat perceived deficiencies or conditions like without medical supervision. Iatrogenic factors, such as erroneous dosing in medical treatments for renal disease or , also contribute, as do manufacturing errors in supplements that result in unintended high concentrations. Rare instances involve overfortified foods or mislabeled products, though endogenous overproduction from conditions like granulomatous diseases is not considered true toxicity from intake. Historically, vitamin D toxicity was first widely recognized in the and due to overfortification of in the and , where campaigns added excessive amounts—up to 232,565 IU per in some U.S. cases, far above the standard 400 IU—to combat . This led to outbreaks of hypercalcemia in infants and adults, prompting regulatory limits on fortification levels by the mid-1950s. In recent years, particularly in the , cases have surged from contaminated supplements; for example, a manufacturing error in a Canadian creatine product not labeled for resulted in doses of 425,000 IU per serving, causing severe hypercalcemia and in multiple users, including adolescents. Similar incidents, such as FDA recalls of multivitamins with excess in 2015 and a Danish supplement overage affecting children in 2016, underscore ongoing risks from poor in the supplement industry. More recently, in August 2024, Perrigo Company voluntarily recalled approximately 16,500 cans of store-brand sold at retailers like CVS and due to elevated levels exceeding the maximum permitted, highlighting continued challenges.

Mechanisms of Toxicity

Vitamin D plays a central role in calcium homeostasis by binding to the vitamin D receptor (VDR) in target tissues, which regulates gene expression to enhance intestinal calcium absorption, promote bone resorption, and increase renal calcium reabsorption. In cases of excess vitamin D, particularly elevated levels of 25-hydroxyvitamin D [25(OH)D], the vitamin D binding protein (VDBP) becomes saturated, allowing free 25(OH)D and its active metabolite, 1,25-dihydroxyvitamin D [1,25(OH)₂D or calcitriol], to excessively activate VDRs. This upregulation leads to overproduction of calcium-transporting proteins such as TRPV6 in the intestine and RANKL in osteoblasts, resulting in uncontrolled calcium influx from dietary sources and skeletal stores. The pathophysiological cascade begins with this hyperactivation, driving a surge in serum calcium levels above the normal range, typically exceeding 10.5 mg/dL, known as hypercalcemia. This excess calcium spills into the urine, causing , which further promotes the deposition of calcium-phosphate complexes in soft tissues, including the kidneys, vasculature, and heart, potentially leading to . High doses of vitamin D3, particularly without sufficient cofactors such as magnesium or vitamin K2, can exacerbate these mechanisms. Magnesium is essential for the activation and metabolism of vitamin D; insufficient magnesium may reduce its efficacy and contribute to imbalances in calcium homeostasis, potentially heightening toxicity risks. Similarly, the lack of vitamin K2 may lead to theoretical risks of vascular calcification, as vitamin D promotes the production of vitamin K-dependent proteins like matrix Gla protein, which require K2 for carboxylation to inhibit soft tissue calcification; without adequate K2, excess calcium may deposit in vascular tissues. Concurrently, the elevated calcium suppresses (PTH) secretion through on the parathyroid glands, reducing PTH-mediated and renal calcium , though the dominant effect remains the vitamin D-driven hyperabsorption. Biochemical markers of vitamin D toxicity prominently feature serum 25(OH)D concentrations greater than 150 ng/mL, which serves as the primary indicator of excessive intake, while 1,25(OH)₂D levels are often normal or only mildly elevated due to feedback inhibition of its production. The conversion to occurs primarily in the kidneys via the 1α-hydroxylase (CYP27B1), as depicted in the reaction: 25(OH)D+1α-hydroxylase (CYP27B1)→1,25(OH)2D25(\mathrm{OH})D + 1\alpha\text{-hydroxylase (CYP27B1)} \rightarrow 1,25(\mathrm{OH})_2D This process is tightly regulated under normal conditions but becomes dysregulated in toxicity, contributing to the observed imbalances. Unlike other hypercalcemic states such as , which features elevated PTH and normal or low 25(OH)D levels, vitamin D toxicity is characterized by markedly high 25(OH)D without primary parathyroid involvement, distinguishing it biochemically and aiding . In contrast to endogenous forms like those in granulomatous diseases, where 1,25(OH)₂D is disproportionately elevated due to extrarenal 1α-hydroxylase activity, exogenous toxicity from supplementation primarily overloads the 25(OH)D pool.

Clinical Presentation

Signs and Symptoms

Vitamin D toxicity primarily manifests through hypercalcemia, the hallmark biochemical abnormality driving clinical symptoms across various organ systems. Acute symptoms often emerge prominently in the gastrointestinal and renal systems. Common presentations include , , , and , reflecting direct effects of elevated calcium on gut and secretion. and arise from hypercalcemia-induced , leading to as fluid losses exceed intake. These features typically represent early indicators of toxicity following excessive supplementation. In chronic cases, symptoms extend to neuromuscular, renal, and skeletal involvement. Neuromuscular effects encompass , , , and , stemming from calcium-mediated neuronal and muscular dysfunction. Renal complications feature nephrolithiasis and due to and tubular damage. Skeletal manifestations include from excessive resorption and potential periosteal calcifications. Severity of vitamin D toxicity correlates with the degree of hypercalcemia and can be graded as mild, moderate, or severe. Mild cases involve or subtle hypercalcemia, often limited to or mild . Moderate presentations include gastrointestinal and neurologic symptoms such as , , , and confusion. Severe toxicity progresses to life-threatening features like cardiac arrhythmias, seizures, , and profound organ impairment. Pediatric cases differ from adults, with children exhibiting heightened vulnerability due to immature renal handling of calcium and smaller body mass. In infants and young children, symptoms often include irritability, poor feeding, vomiting, constipation, lethargy, and , alongside in some instances. Adults more commonly present with insidious fatigue and before escalating to . Symptoms typically onset within weeks to months after initiating excessive dosing, with resolution anticipated upon prompt intervention such as discontinuation of vitamin D and supportive care. For example, in a 2016 incident involving contaminated supplements, 20 Danish children developed toxicity symptoms including hypercalcemia and gastrointestinal distress within weeks of exposure, which improved with treatment. Similarly, case reports of over-supplementation in breastfed infants have shown onset of vomiting and dehydration after 1-2 months of high-dose intake, resolving with standard hypercalcemia management.

Diagnosis

Diagnosis of vitamin D toxicity begins with clinical suspicion, typically arising from a history of high-dose supplementation exceeding 4,000 IU per day, often in the context of or unregulated products, combined with symptoms suggestive of hypercalcemia such as , , , or . Patients at risk include those treating conditions like or without medical supervision, where excessive intake leads to elevated serum levels. Laboratory confirmation relies on key biomarkers: serum 25-hydroxyvitamin D [25(OH)D] levels greater than 150 ng/mL (375 nmol/L), which is the hallmark of toxicity; serum calcium exceeding 10.5 mg/dL (2.63 mmol/L), indicating hypercalcemia; suppressed (PTH) due to ; normal or elevated ; and 24-hour calcium excretion above 300 mg/day, reflecting . These tests differentiate vitamin D toxicity from other causes of hypercalcemia, with intact PTH measurement helping to exclude (where PTH is elevated) and (SPEP) ruling out malignancy-associated hypercalcemia. Additional evaluations include renal ultrasound to detect nephrolithiasis or and (ECG) to assess for arrhythmias related to hypercalcemia. Diagnostic challenges arise in cases, which may be incidentally identified through routine serum 25(OH)D screening in at-risk populations, such as those on high-dose . Recent 2025 guidelines from health authorities emphasize targeted 25(OH)D testing for patients with risk factors for , including excessive supplementation history or unexplained hypercalcemia, to facilitate early detection without routine population screening.

Management and Prevention

Treatment

The primary intervention for vitamin D toxicity involves the immediate discontinuation of all sources of vitamin D, including supplements, prescription medications, and fortified foods, to halt further accumulation and allow natural clearance from the body. This step is crucial as vitamin D stored in fat tissues can prolong hypercalcemia for weeks to months, but cessation typically initiates resolution. Management of hypercalcemia, the hallmark of toxicity, begins with aggressive intravenous hydration using normal saline at rates of 200-300 mL/hour in adults to correct and promote renal calcium excretion, provided renal function is adequate. Once euvolemia is achieved, such as (typically 20-40 mg IV every 6-8 hours) are administered to enhance calciuresis while replacing urinary losses of , , and to avoid imbalances. For severe hypercalcemia (serum calcium >14 mg/dL), bisphosphonates like pamidronate (60-90 mg IV over 2-4 hours) or (4 mg IV over 15 minutes) are recommended to inhibit and lower calcium levels within 24-48 hours, with effects lasting weeks. Calcitonin (4 international units/kg subcutaneously or intramuscularly every 12 hours for up to 48 hours) provides rapid but short-term reduction in serum calcium by inhibiting activity, often used adjunctively due to . Supportive care includes close monitoring of renal function, serum electrolytes, and calcium levels to guide therapy adjustments and prevent complications such as . In cases of acute renal failure or refractory hypercalcemia unresponsive to medical therapy, is indicated to directly remove calcium and metabolites, particularly when serum calcium exceeds 14 mg/dL or renal impairment is severe. With prompt treatment, symptoms of vitamin D toxicity typically resolve within days to weeks, and full recovery is expected in most patients without underlying chronic damage. In pediatric cases, which often arise from accidental overdose, dosing adjustments are essential; for example, pamidronate is given at 1 mg/kg IV, showing superior efficacy and lower recurrence rates compared to glucocorticoids alone, with normocalcemia achieved in a median of 3-4 days. The Tolerable Upper Intake Level (UL) for vitamin D, established by the Institute of Medicine (now National Academy of Medicine) in its 2011 Dietary Reference Intakes and reaffirmed in subsequent reviews, represents the maximum daily intake unlikely to pose risks of adverse health effects for nearly all individuals. For adults and children aged 9 years and older, the UL is 4,000 IU (100 mcg) per day; for children aged 4–8 years, it is 3,000 IU (75 mcg); for ages 1–3 years, 2,500 IU (63 mcg); for infants 7–12 months, 1,500 IU (38 mcg); and for infants 0–6 months, 1,000 IU (25 mcg). These limits apply specifically to total intake from supplements and fortified foods, as endogenous vitamin D production from sunlight exposure is self-regulated by the skin and does not contribute to toxicity. Dietary sources alone, such as fatty fish or fortified dairy, rarely approach these levels and have not been associated with toxicity.
Age GroupTolerable Upper Intake Level (UL)
0–6 months1,000 IU (25 )
7–12 months1,500 IU (38 )
1–3 years2,500 IU (63 )
4–8 years3,000 IU (75 )
9 years and older4,000 IU (100 )
The Recommended Dietary Allowance (RDA) for is 600 IU (15 ) daily for most individuals aged 1–70 years and 800 IU (20 ) for those over 70 years, aimed at maintaining adequate serum 25-hydroxyvitamin D [25(OH)D] levels to support health. Doses of 2,000–5,000 IU daily are generally safe for most people and often used to correct deficiency, with no common side effects reported. Toxicity, including hypercalcemia leading to nausea, vomiting, weakness, confusion, or kidney issues, is uncommon below 10,000 IU daily and rare at 5,000 IU or less, particularly without underlying conditions. When taking prolonged high doses of vitamin D3 exceeding 10,000 IU per day without monitoring, risks include hypercalcemia manifesting as nausea, kidney stones, and potential vessel damage. Additionally, without sufficient magnesium, the efficacy of vitamin D may be reduced due to impaired metabolism, as magnesium is essential for vitamin D activation and catabolism. Without vitamin K2, there is a theoretical risk of vascular calcification, as vitamin D increases calcium absorption while vitamin K2 helps direct calcium to bones rather than soft tissues. However, toxicity remains rare but possible in such scenarios. Chronic intakes exceeding approximately 10,000 IU per day from supplements can lead to , characterized by elevated 25(OH)D levels above 150 ng/mL (375 nmol/L) and potential hypercalcemia, while typically requires massive single doses, such as 300,000 IU or more, though such cases are rare and often linked to manufacturing errors or misuse. authorities, including the FDA, have issued warnings against mega-doses, particularly following during the 2020 that promoted unproven high-dose regimens, emphasizing adherence to established guidelines to avoid risks. Monitoring serum 25(OH)D levels is recommended annually for high-risk groups, such as those with , disorders, or limited sun exposure, to ensure levels remain between 20–50 ng/mL (50–125 nmol/L) without exceeding thresholds. Factors influencing these intake limits include age, with younger children requiring lower ULs due to smaller body size; body weight, as sequesters in fat tissue, potentially necessitating higher doses for efficacy but not increasing risk; and baseline 25(OH)D status, which guides personalized supplementation.

Long-Term Effects

Organ Damage and Complications

Vitamin D toxicity can lead to significant renal damage, primarily through the development of , where calcium deposits accumulate in the and cortex, resulting in (CKD) and reduced (GFR). This complication arises from prolonged hypercalciuria and hypercalcemia, which promote intratubular and interstitial fibrosis. In severe cases, occurs in approximately 25% of patients with vitamin D intoxication, often leading to persistent impairment in renal function if not addressed promptly. Beyond the kidneys, toxicity induces metastatic calcification in soft tissues and skeletal structures, depositing calcium in blood vessels, lungs, heart, and skin, which can impair organ function and contribute to long-term morbidity. Skeletal effects present a paradoxical pattern: initial hypercalcemia stimulates osteoclastic bone resorption, potentially weakening bone structure, while subsequent high calcium levels disrupt normal mineralization processes, leading to reduced bone density akin to osteoporosis. Studies indicate that excessive vitamin D supplementation can directly contribute to bone loss, exacerbating fragility in affected individuals. Neurological sequelae from unresolved toxicity are less common but notable, particularly in the elderly, where severe hypercalcemia may cause persistent , including and altered mental status that lingers beyond acute resolution. Rare complications also include due to pancreatic and cardiac arrhythmias from imbalances and myocardial involvement. The overall for organ damage in vitamin D toxicity is generally favorable with early intervention, but irreversible effects, such as permanent renal impairment, occur in rare cases, particularly when serum 25(OH)D levels exceed 150 ng/mL and treatment is delayed. Recent analyses confirm heightened risks of severe complications at levels above 200 ng/mL, with potential for lasting damage in vulnerable populations.

Cardiovascular and Metabolic Impacts

Chronic vitamin D toxicity, characterized by serum 25(OH)D levels exceeding 100 ng/mL, promotes hypercalcemia, which contributes to by enhancing calcium deposition in arterial walls. Furthermore, high doses of vitamin D3 without sufficient vitamin K2 may exacerbate these vascular calcification risks, as vitamin K2 activates matrix Gla protein (MGP) to inhibit arterial calcium deposition, with theoretical mechanisms and observational data indicating synergies between vitamin D3 and K2 for preventing such complications. This process can accelerate and elevate the risk of , as excess calcium disrupts function and promotes stiffness. Animal models and human case reports demonstrate that hypervitaminosis D induces widespread arterial , potentially increasing (CVD) events. Meta-analyses of observational data indicate a U-shaped relationship between serum 25(OH)D levels and CVD risk, where concentrations above 75-100 ng/mL are associated with heightened incidence of CVD outcomes compared to optimal levels around 30-50 ng/mL. Regarding metabolic impacts, altered lipid profiles have also been noted, with some cases of toxicity showing elevated triglycerides due to disrupted hepatic and increased intestinal absorption. Histopathological studies confirm cardiac tissue calcification and in models of vitamin D overdose, linking these changes to broader metabolic disturbances. Conflicting evidence exists, as certain population studies suggest high-normal 25(OH)D levels (50-80 ng/mL) correlate with reduced CVD risk via effects, forming the ascending arm of the U-shaped curve; however, thresholds beyond 100 ng/mL consistently show adverse outcomes. Ethnic variations may influence susceptibility, with darker-skinned individuals facing higher vascular risk during repletion due to their lower baseline endogenous synthesis from reduced UVB penetration.

Special Considerations

Use in Rodenticides

Cholecalciferol, a form of vitamin D3, has been employed as an active ingredient in rodenticides since the 1980s, with commercial products like Rampage developed and registered by Bell Laboratories in 1984. These baits typically contain 0.075% cholecalciferol, which ingest and metabolize to induce severe hypercalcemia within 1–3 days, resulting in of soft tissues, renal failure, and death typically within 3–7 days. The toxic mechanism in parallels the hypercalcemia pathway observed in humans, involving increased intestinal calcium absorption and , but progresses more rapidly due to higher metabolic sensitivity; the oral (LD50) in rats is approximately 88 mg/kg. This formulation provides advantages over traditional rodenticides, including no documented resistance in target and reduced risk of secondary in non-target . Accidental exposure poses risks to humans, particularly children who may ingest bait, and to pets; in 2024, multiple reports documented fatal cholecalciferol toxicity in dogs from consuming rodenticidal bait, leading to acute kidney failure. Cholecalciferol rodenticides are approved for use by the U.S. Environmental Protection Agency (EPA), with mandatory child-resistant packaging to limit unintended access. On a per-weight basis, the compound exhibits 100- to 1,000-fold greater lethality in rodents compared to humans, enhancing its efficacy as a targeted pest control agent while minimizing human risk at typical exposure levels.

Ethnic and Genetic Variations

Individuals of African or Asian descent, who often have darker pigmentation, exhibit reduced cutaneous synthesis of due to higher content, leading to a higher prevalence of and subsequent reliance on supplementation. This lower baseline production often leads to and greater reliance on supplementation. Although the threshold for 25-hydroxyvitamin D levels remains the same, the higher doses typically needed to correct deficiency can increase the risk of if not properly monitored. For instance, in populations with darker , such as northern Native peoples, excessive dosing has been linked to potential risks, particularly with high-dose regimens intended to correct deficiency. Genetic variations significantly influence susceptibility to vitamin D toxicity by altering receptor function and metabolic inactivation. Polymorphisms in the (VDR) gene, such as the FokI variant (rs2228570), can affect VDR sensitivity and vitamin D status, potentially increasing the risk of hypercalcemia in response to supplementation, though direct links to toxicity remain under investigation. More definitively, loss-of-function mutations in the CYP24A1 gene impair the 24-hydroxylation of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, reducing inactivation and leading to accumulation of active metabolites, which predisposes individuals to idiopathic hypercalcemia and heightened toxicity even at moderate intakes. These mutations have been identified in cases of infantile hypercalcemia and adult-onset , with recent reports confirming their role in unexplained hypercalcemia as of 2025. Certain demographic and clinical groups face elevated risks due to physiological factors that alter handling. In the elderly, diminished renal function and reduced synthesis contribute to lower baseline levels, often necessitating higher supplementation doses that heighten toxicity potential if not monitored. Obese individuals experience sequestration of in , resulting in lower circulating 25-hydroxyvitamin D concentrations and a propensity for higher dosing, which can inadvertently lead to toxic levels upon correction. Patients with granulomatous diseases, such as , are particularly vulnerable due to ectopic production of 1,25-dihydroxyvitamin D by activated macrophages in granulomas, amplifying hypercalcemia risk from even standard supplementation. Research on ethnic and genetic variations in vitamin D toxicity remains limited, especially among Indigenous populations, where studies as of 2024-2025 highlight gaps in understanding optimal dosing to avoid toxicity in and tropical groups adapted to low-sunlight or high-melanin environments. These populations may require tailored approaches, as generic supplementation guidelines risk pushing levels toward toxicity thresholds. As of 2025, emerging research supports the use of genetic profiling for VDR and CYP24A1 variants to inform personalized supplementation dosing, particularly for high-risk ethnic groups, to prevent toxicity while addressing deficiency. Emerging evidence supports personalized dosing based on genetic profiling of VDR and CYP24A1 variants to mitigate risks, emphasizing the need for genotype-guided recommendations in clinical practice.

References

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