Hypervitaminosis D

Definition and Overview

• Hypervitaminosis D is a condition of Vitamin D toxicity resulting from excessive intake of Vitamin D or its active metabolites.
• It is characterized principally by hypercalcemia and its associated systemic manifestations.
• Toxic levels are generally defined as serum 25-hydroxyvitamin D (25-OHD) levels >100 ng/mL (>250 nmol/L).
• It is a potential complication of the treatment of rickets or hypoparathyroidism, or the result of accidental overdose.

Etiology

Hypervitaminosis D is almost exclusively caused by exogenous intake; it does not occur due to excessive sunlight exposure because cutaneous synthesis is self-regulated (UVB converts excess previtamin D3 into inactive metabolites).

• Excessive Supplementation:
  • Misuse of prescribed or non-prescription Vitamin D supplements is the most common cause.
  • "Stoss therapy" (mega-dose therapy) for rickets, involving doses like 600,000 IU, has been associated with hypercalcemia and hypercalciuria.
  • Prolonged administration of high daily doses (e.g., >2,000–3,000 IU/day in infants) can lead to toxicity.
• Fortification Errors:
  • Accidental over-fortification of milk or other foods (e.g., table sugar) by manufacturers has led to outbreaks of hypercalcemia.
• Inadvertent Ingestion:
  • Use of concentrated Vitamin D preparations (e.g., intended for livestock or concentrated drops) mistaken for cooking oil or standard infant drops.
• Use of Active Metabolites:
  • Toxicity can result from the intake of synthetic analogs like calcitriol (1,25-dihydroxyvitamin D) or alfacalcidol.
• Individual Susceptibility:
  • Certain conditions like Williams syndrome (idiopathic infantile hypercalcemia) were historically linked to hypersensitivity to Vitamin D, though they are now understood as distinct genetic entities often included in the differential diagnosis,.

Pathophysiology

The primary driver of morbidity in hypervitaminosis D is severe hypercalcemia.

• Mechanisms of Hypercalcemia:
  • Excessive Bone Resorption: This is the dominant mechanism. High levels of Vitamin D metabolites stimulate osteoclasts to resorb bone, releasing calcium into the extracellular fluid.
  • Increased Intestinal Absorption: Vitamin D enhances the absorption of calcium and phosphorus from the gut,.
• Metabolite Interactions:
  • Elevated 25-OHD: In typical toxicity, 25-OHD levels are massively elevated (>100 ng/mL).
  • Displacement of 1,25(OH)2D: Massive amounts of 25-OHD can saturate Vitamin D-binding proteins (DBP). This displaces 1,25(OH)2D, increasing the concentration of free (unbound) 1,25(OH)2D, which is biologically active, even if the total serum 1,25(OH)2D is normal or low.
  • Receptor Binding: At very high concentrations, 25-OHD itself may bind to and activate the Vitamin D receptor (VDR), mimicking the action of the active hormone.
• Renal Effects:
  • Hypercalcemia leads to nephrogenic diabetes insipidus by impairing the concentrating ability of the kidney, causing polyuria and dehydration.
  • Hypercalciuria (excess calcium in urine) predisposes to nephrocalcinosis and nephrolithiasis,.
  • The combination of dehydration (prerenal) and nephrocalcinosis can lead to acute or chronic renal insufficiency.

Clinical Manifestations

Symptoms are primarily sequelae of hypercalcemia and can involve multiple organ systems.

Gastrointestinal

• Anorexia (loss of appetite),.
• Nausea and vomiting.
• Constipation (due to decreased smooth muscle tone),.
• Abdominal pain.
• Pancreatitis (rare complication of hypercalcemia),.

Renal

• Polyuria and Polydipsia: Due to compromised renal concentrating mechanisms,.
• Dehydration: Secondary to vomiting and polyuria.
• Nephrocalcinosis: Deposition of calcium in the renal parenchyma.
• Renal Failure: Azotemia and rising creatinine due to renal damage and dehydration.

Central Nervous System (CNS)

• Irritability.
• Headache.
• Lethargy, stupor, or coma in severe cases.
• Hypotonia (muscle weakness).
• Pseudotumor cerebri (increased intracranial pressure) has been described, though more typical of Vitamin A toxicity,.

Cardiovascular

• Hypertension,.
• Arrhythmias (shortened QT interval).
• Metastatic calcification (calcification of soft tissues and blood vessels).

Other

• Failure to thrive or poor weight gain in infants.
• Pallor and anemia (mechanism unknown).

Biochemical and Radiological Findings

Laboratory Investigations

• Serum Calcium: Elevated (Hypercalcemia).
• Serum Phosphate: Often elevated (Hyperphosphatemia).
  • Note: This helps distinguish Vitamin D toxicity from Primary Hyperparathyroidism, where phosphate is typically low.
• Serum Alkaline Phosphatase (ALP): Usually normal or low (suppressed bone turnover contrary to rickets).
• Parathyroid Hormone (PTH): Suppressed/Low. The parathyroid glands are inhibited by high calcium and Vitamin D levels.
• 25-Hydroxyvitamin D (25-OHD): Markedly elevated (>100 ng/mL or >250 nmol/L),.
• 1,25-Dihydroxyvitamin D (1,25(OH)2D): Usually normal or even low.
  • Reason: The renal 1$\alpha$-hydroxylase enzyme is downregulated by low PTH, high phosphate, and the high Vitamin D levels themselves.
• Urine: Hypercalciuria (increased calcium excretion).

Radiology

• Renal Ultrasound: May show nephrocalcinosis (medullary calcium deposition) or kidney stones.
• Skeletal X-rays: May show increased bone density (metastatic calcification) or, in chronic cases, cortical thickening (hyperostosis). However, radiographic changes are less specific than biochemical markers.

Differential Diagnosis

The differential diagnosis focuses on other causes of hypercalcemia:

1. Williams Syndrome: Associated with "elfin facies," supravalvular aortic stenosis, and transient idiopathic hypercalcemia.
2. Primary Hyperparathyroidism: Characterized by high Calcium but Low Phosphate and High PTH (unlike Vitamin D toxicity where PTH is low and Phosphate is high).
3. Idiopathic Infantile Hypercalcemia: Hypercalcemia occurring in children taking appropriate/normal doses of Vitamin D (suspected CYP24A1 mutations).
4. Subcutaneous Fat Necrosis: Seen in newborns; associated with skin nodules and hypercalcemia.
5. Familial Hypocalciuric Hypercalcemia (FHH): Asymptomatic mild hypercalcemia with low urinary calcium.
6. Malignancy: Hypercalcemia of malignancy.
7. Granulomatous Diseases: Sarcoidosis or Tuberculosis (endogenous production of 1,25(OH)2D by macrophages).

Management

Treatment is a medical emergency aimed at reducing serum calcium levels and preventing renal damage.

1. General Measures

• Discontinuation: Immediately stop all sources of Vitamin D and Calcium supplements.
• Dietary Restriction: Eliminate Vitamin D-fortified foods (milk, cereals) and restrict dietary calcium.
• Sunlight Avoidance: Limit sun exposure and use sunscreen to prevent cutaneous activation.

2. Acute Management of Hypercalcemia

• Hydration (First-line):
  • Aggressive rehydration with Intravenous Normal Saline (0.9% NaCl).
  • Mechanism: Dilutes serum calcium and corrects prerenal azotemia. Sodium load inhibits renal calcium reabsorption, promoting excretion.
• Loop Diuretics:
  • Furosemide (Lasix) may be used after volume repletion.
  • Mechanism: Further increases urinary calcium excretion.
• Glucocorticoids:
  • Prednisone: Dosage 1–2 mg/kg/24 hr.
  • Mechanism: Blocks intestinal calcium absorption (antagonizes Vitamin D action), decreases 1,25(OH)2D synthesis, and reduces bone resorption.
• Calcitonin:
  • May be used as an adjunct.
  • Mechanism: Inhibits osteoclastic bone resorption.
• Bisphosphonates:
  • IV (e.g., pamidronate) or oral bisphosphonates are highly effective in severe cases.
  • Mechanism: Potent inhibitors of osteoclast-mediated bone resorption.

3. Management of Severe Refractory Cases

• Hemodialysis:
  • Dialysis with a low-calcium or zero-calcium dialysate is indicated for severe, life-threatening hypercalcemia refractory to medical management.

Prognosis and Complications

• Prognosis: Most children recover fully if diagnosed and treated promptly.
• Duration: Because Vitamin D is fat-soluble and stored in adipose tissue, serum levels can remain elevated for months after stopping intake. This necessitates prolonged monitoring of serum calcium, 25-OHD, and urine calcium.
• Complications:
  • Nephrocalcinosis: Can be permanent.
  • Chronic Kidney Disease (CKD): Severe or prolonged toxicity can lead to permanent renal damage and hypertension.
  • Fatalities: Extreme hypercalcemia can lead to cardiac arrest or renal failure and death,.