Vitamin D Deficiency

Vitamin D and Its Role

Serum 25-Hydroxyvitamin D Concentration Ranges

• Vitamin D Deficiency: Serum ≤50 nmol/L (≤20 ng/mL).
• Vitamin D Insufficiency: Serum 52-72 nmol/L (21-29 ng/mL).
• Vitamin D Sufficiency: Serum 75-250 nmol/L (30-100 ng/mL).
• Vitamin D Toxicity: Usually occurs at serum levels >375 nmol/L (>150 ng/mL), with risks of hypercalcaemia and related complications.
  
  

International Consensus on Optimal Levels

• The Endocrine Society (2019) defines sufficiency as ≥75 nmol/L (≥30 ng/mL) and deficiency as <50 nmol/L (<20 ng/mL).
• The National Academy of Medicine (NAM) supports sufficiency at ≥50 nmol/L (≥20 ng/mL), based primarily on bone health outcomes.
• The National Osteoporosis Foundation (NOF), International Osteoporosis Foundation (IOF), and American Geriatrics Society (AGS) suggest a minimum level of ≥75 nmol/L (≥30 ng/mL) for older adults to reduce fall and fracture risk.
  
  

Subclinical Vitamin D Deficiency

Toxicity and Upper Limits

 Inadequate Sunlight Exposure

• The primary source of vitamin D for most individuals is cutaneous synthesis from ultraviolet B (UVB) exposure. Several factors influence vitamin D production:
  • Sun avoidance due to lifestyle choices, cultural practices, or medical advice.
  • Use of sunscreen reduces UVB penetration and vitamin D synthesis.
  • Season, latitude, and time of day affect UVB availability, with minimal synthesis occurring during winter months in high-latitude regions.
  • Increased skin pigmentation reduces photoproduction efficiency.
  • Ageing diminishes the skin’s capacity to synthesise vitamin D, with older adults producing three times less vitamin D than younger individuals after UVB exposure.
    
    

Inadequate Dietary Intake

• Dietary sources of vitamin D are limited, primarily found in:
  • Oily fish (salmon, mackerel, sardines).
  • Fortified dairy products and cereals.
  • Egg yolks and liver.
• Exclusive breastfeeding without supplementation puts infants at risk, as human breast milk contains minimal vitamin D.
• Extremely preterm infants are particularly vulnerable due to inadequate stores at birth.
  
  

Gastrointestinal Malabsorption

• Intestinal disorders impair vitamin D absorption, including:
  • Coeliac disease, cystic fibrosis, Crohn’s disease, Whipple’s disease, and short bowel syndrome.
  • Gastric bypass surgery significantly reduces vitamin D absorption.
  • Chronic cholestatic liver disease impairs fat-soluble vitamin absorption, reducing vitamin D levels.
    
    

Chronic Liver Disease

• Severe liver dysfunction affects vitamin D metabolism through:
  • Reduced dietary vitamin D absorption due to cholestasis.
  • Decreased hepatic hydroxylation of vitamin D to its active form.
  • Impaired vitamin D binding protein production, reducing circulating vitamin D.
    
    

Chronic Kidney Disease (CKD)

• The kidneys play a vital role in converting 25-hydroxyvitamin D to its active form (1,25-dihydroxyvitamin D).
• In CKD:
  • Early stages (GFR 60–89 mL/min/1.73m²): Elevated fibroblast growth factor 23 (FGF-23) suppresses vitamin D activation.
  • Later stages (GFR <30 mL/min/1.73m²): The kidneys lose the ability to synthesise sufficient 1,25-dihydroxyvitamin D, leading to secondary hyperparathyroidism and metabolic bone disease.
    
    

Obesity

• Vitamin D is fat-soluble, and excess body fat sequesters vitamin D, making it less bioavailable.
• Obese individuals (BMI >30) require two to three times more vitamin D to maintain adequate levels.
  
  

Medications and Drug Interactions

• Certain medications increase vitamin D catabolism via hepatic enzyme induction:
  • Anticonvulsants (phenytoin, phenobarbital).
  • Rifampicin (used for tuberculosis treatment).
  • Highly active antiretroviral therapy (HAART).
  • Glucocorticoids, which interfere with vitamin D metabolism.
    
    

Genetic Disorders Affecting Vitamin D Metabolism

• Vitamin D-dependent rickets type 1: Mutations in 25-hydroxyvitamin D-1α-hydroxylase gene impair activation.
• Vitamin D-dependent rickets type 2: Mutations in the vitamin D receptor (VDR) gene cause resistance to active vitamin D.
• X-linked hypophosphataemic rickets: Overproduction of FGF-23 reduces phosphate reabsorption and vitamin D activation.
  
  

Granulomatous Diseases

• Conditions such as sarcoidosis and tuberculosis lead to increased conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, accelerating vitamin D depletion.
  
  

Tumour-Induced Osteomalacia

• Some benign and malignant tumours overproduce FGF-23, leading to:
  • Severe hypophosphataemia.
  • Suppressed 1,25-dihydroxyvitamin D production.
  • Skeletal manifestations of osteomalacia.
    
    

Vitamin D Metabolism and Its Role in Calcium and Phosphate Homeostasis

• Vitamin D3 from cutaneous UVB synthesis and dietary vitamin D2/D3 are biologically inactive and undergo hepatic hydroxylation to 25-hydroxyvitamin D, the primary circulating form used to assess vitamin D status.
• Renal hydroxylation converts 25-hydroxyvitamin D into 1,25-dihydroxyvitamin D, the biologically active form, which regulates calcium and phosphate homeostasis.
• In a vitamin D-deficient state, intestinal calcium absorption drops to 10–15%, whereas adequate vitamin D levels improve absorption to 30–40%. During periods of high calcium demand (e.g., adolescence, pregnancy, lactation), absorption efficiency can reach 60–80%.
• Phosphate absorption, primarily occurring in the jejunum, increases from 60% in deficiency states to 80% with sufficient vitamin D.
  
  

Secondary Hyperparathyroidism in Vitamin D Deficiency

• Inadequate 25-hydroxyvitamin D leads to reduced 1,25-dihydroxyvitamin D synthesis, impairing intestinal calcium absorption and triggering secondary hyperparathyroidism.
• Elevated PTH mobilises calcium from bone to maintain serum calcium levels, leading to reduced bone mineralisation.
  
  

Protective Mechanisms Against Vitamin D Toxicity

• Excessive sun exposure does not cause vitamin D toxicity, as UVB-induced vitamin D is further degraded into inactive metabolites (tachysterol and lumisterol).
  
  

Extraskeletal Effects of Vitamin D

• Cell Proliferation and Immune Function: Vitamin D receptors (VDRs) are present in various tissues, including immune cells (T and B lymphocytes, macrophages). 1,25-dihydroxyvitamin D modulates immune responses by regulating cytokine and immunoglobulin synthesis and enhancing macrophage-mediated antimicrobial actions (e.g., Mycobacterium tuberculosis killing).
• Cancer and Metabolic Health: Observational studies suggest that adequate vitamin D levels reduce the risk of common cancers (breast, colon, prostate) and may regulate cell proliferation and differentiation. It may also influence insulin secretion by downregulating renal renin production and modulating pancreatic beta-cell function, potentially reducing type 2 diabetes risk.
• Muscle and Cardiovascular Effects: Vitamin D deficiency has been associated with muscle weakness, increased fall risk, and potential contributions to cardiovascular disease through vascular and metabolic actions.
  
  

Global Prevalence

• Affects approximately 1 billion people worldwide.
• An estimated 40% of children and adults are vitamin D deficient, and 60% are either deficient or insufficient.
  
  

Regional Variation

• United States: NHANES (2011–2014) data show that 5% of individuals aged ≥1 year are at risk of vitamin D deficiency, while 18% are at risk of inadequacy.
• Europe: Over 40% of the population is vitamin D deficient, with seasonal variation.
  • In the United Kingdom, deficiency rates range from 30%–40% in winter compared to 2%–13% in summer.
• Middle East: The highest prevalence (30%–90%) due to cultural clothing practices limiting sun exposure.
  
  

High-Risk Groups

• Older adults, institutionalised individuals, and hospitalised patients are at the greatest risk.
  • 60% of nursing home residents and 57% of hospitalised patients are vitamin D deficient.
• Ethnic and Racial Differences:
  • Darker-skinned individuals require significantly more UVB exposure for vitamin D synthesis.
  • In the U.S., 73% of elderly Black individuals are vitamin D insufficient, compared with 35% of elderly White individuals.
• Chronic Conditions:
  • Individuals with chronic kidney disease (CKD), liver disease, or on haemodialysis have deficiency rates of 85%–99%.
  • Obese individuals require 2–3 times more vitamin D than those with a healthy BMI.
    
    

Association with Chronic Diseases

• Cancer, autoimmune diseases, type 2 diabetes, cardiovascular disease, and neurocognitive disorders are linked to vitamin D deficiency.
• Severe COVID-19 outcomes: Observational studies indicate a 54% reduced risk of infection in individuals with sufficient vitamin D levels.
  
  

Risk Factors

• Increased skin pigmentation – Darker skin reduces UVB absorption, lowering cutaneous vitamin D synthesis.
• Obesity – Adipose tissue sequesters vitamin D, reducing its bioavailability.
• Malabsorption syndromes – Coeliac disease, cystic fibrosis, Crohn’s disease, short bowel syndrome impair vitamin D absorption.
• History of liver failure or chronic kidney disease – Liver hydroxylation and renal activation of vitamin D are impaired.
• Age >50 years – Reduced cutaneous vitamin D production and dietary intake.
• Tumour history – Some malignancies increase vitamin D metabolism.
• Use of medications – Glucocorticoids, antiepileptic drugs, highly active antiretroviral therapy, rifampicin, and St John's wort accelerate vitamin D breakdown.
• Limited sun exposure or consistent use of sun protection – Reduces UVB-mediated vitamin D synthesis.
• Neonates solely breastfed without vitamin D supplementation – Breast milk alone provides insufficient vitamin D.
  
  

Common Symptoms

• Skeletal Symptoms: Bowing of the legs, widening of long bone ends, chest deformities, delayed tooth eruption.
• Pain and Discomfort: Throbbing bone pain, localised bone tenderness, muscle weakness, worsening with movement or pressure.
• Neuromuscular Signs: Head sweating (due to neuromuscular excitability), proximal muscle weakness causing difficulty rising from a seated position.
• Growth and Development: Faltering growth, delayed motor milestones, irritability in infants.
  
  

Uncommon Symptoms

• Rachitic rosary – Beaded appearance of ribcage at costochondral junctions.
• Frontal bossing – Prominent forehead due to defective skull mineralisation in children.
• Waddling gait – Hip pain and proximal muscle weakness leading to an abnormal walking pattern.
• Hypocalcaemia symptoms – Muscle cramps, paraesthesia, tetany, seizures in severe deficiency.
  
  

Skeletal Deformities

• Bowing of the Legs: Classic sign of rickets, manifesting as genu varum (outward bowing) or genu valgum (inward bowing) of the femur and tibia once the child begins to stand and walk.
• Widening of the Ends of Long Bones: Due to hypertrophy of the epiphyseal growth plates, particularly evident at the wrists, knees, and ankles. X-rays may show poorly mineralised, ragged epiphyseal plates.
• Frontal Bossing: Protrusion of the forehead due to defective skull mineralisation from prolonged vitamin D deficiency.
• Rachitic Rosary: Beaded appearance of the costochondral junctions in the ribcage due to overgrowth of cartilage and defective mineralisation.
• Chest Deformities: Pectus carinatum (protruding chest), thoracic asymmetry, and flaring of the lower rib margins due to softened ribs and abnormal mechanical forces.
  
  

Musculoskeletal and Neuromuscular Signs

• Proximal Muscle Weakness: Evident in adults, particularly in the hip girdle and quadriceps, leading to difficulty rising from a seated position (positive Gower’s sign) or climbing stairs.
• Waddling Gait: Due to hip pain and proximal muscle weakness, characteristic of osteomalacia.
• Localised or Generalised Bone Tenderness: Elicited by firm pressure on the sternum, radius, and anterior tibia, consistent with periosteal bone pain due to defective mineralisation.
• Delayed Closure of Fontanelles: In infants, persistent open anterior fontanelle beyond 18 months of age suggests underlying rickets.
  
  

Dental and Craniofacial Features

• Delayed Tooth Eruption and Enamel Hypoplasia: Common in children with rickets due to impaired dentin and enamel formation.
• Increased Dental Caries: Secondary to defective mineralisation of enamel.
• Mandibular and Maxillary Bone Deformities: Leading to abnormal bite alignment and increased dental spacing.
  
  

Neuromuscular and Reflex Abnormalities

• Exaggerated Deep Tendon Reflexes: Hypocalcaemia due to vitamin D deficiency can lead to increased neuromuscular excitability, causing hyperreflexia.
• Carpopedal Spasms: Trousseau’s sign (carpal spasm with inflated blood pressure cuff) and Chvostek’s sign (facial twitching with tapping of facial nerve) may be present in severe cases.
• Muscle Fasciculations and Tetany: Seen in advanced hypocalcaemia due to prolonged vitamin D deficiency.
  
  

Primary Laboratory Tests

• Serum 25-Hydroxyvitamin D:
  • The best indicator of vitamin D status.
  • Deficiency: ≤50 nmol/L (≤20 ng/mL).
  • Insufficiency: 52-72 nmol/L (21-29 ng/mL).
  • Sufficiency: ≥75 nmol/L (≥30 ng/mL).
  • Toxicity: >374 nmol/L (>150 ng/mL).
• Serum Calcium:
  • Usually normal due to compensatory secondary hyperparathyroidism.
  • May be low in cases of prolonged deficiency or inherited disorders affecting vitamin D metabolism.
• Fasting Serum Phosphate:
  • Low-normal to low, secondary to PTH-induced phosphaturia.
  • Elevated in rickets and osteomalacia, reflecting fasting sample is required for accuracy.
• Serum Alkaline Phosphatase:
  •  increased bone turnover.
    
    

Additional Tests When Indicated

• Parathyroid Hormone (PTH):
  • Elevated in secondary hyperparathyroidism due to chronic vitamin D deficiency.
  • Helps differentiate vitamin D deficiency from primary hyperparathyroidism.
• Serum 1,25-Dihydroxyvitamin D:
  • Not useful for diagnosing deficiency.
  • May be normal or high due to compensatory PTH stimulation.
  • Low in cases of chronic kidney disease or rare genetic disorders.
    
    

Imaging Studies

• Plain Radiographs (X-rays of knees, wrists, and long bones):
  • Children: Early signs of rickets include widening of epiphyseal plates, fraying, and loss of calcification at the metaphyseal-epiphyseal junction.
  • Adults: May show Looser’s zones (pseudofractures), cortical thinning, and osteopenia.
• Dual-Energy X-ray Absorptiometry (DEXA) Scan:
  • Assesses bone mineral density.
  • Useful in detecting osteopenia and osteoporosis in chronic vitamin D deficiency.
    
    

Other Considerations

• Assess for Underlying Causes:
  • Malabsorption syndromes (e.g., coeliac disease, Crohn’s disease, short bowel syndrome).
  • Liver or renal disease impairing vitamin D metabolism.
  • Genetic conditions affecting vitamin D metabolism.
  • Long-term use of medications that accelerate vitamin D degradation (e.g., glucocorticoids, anticonvulsants, rifampicin).
    
    

Primary Hyperparathyroidism

• Signs/Symptoms: Fatigue, poor sleep, depression, memory loss, bone pain, constipation.
• Examination Findings: Rarely, a firm mass in the neck (suggestive of parathyroid carcinoma), eye findings such as band keratopathy (calcium deposition).
• Investigations: Elevated serum calcium, elevated intact PTH, low-normal or low fasting serum phosphate.
  
  

Idiopathic Infantile Hypercalcaemia

• Signs/Symptoms: Hypercalcaemia in infancy; in older children/adults, presents with unexplained hypercalcaemia and kidney stones.
• Investigations:
  • Serum 25-hydroxyvitamin D & 1,25-dihydroxyvitamin D: High normal or elevated.
  • PTH: Suppressed.
  • Diagnosis: Genetic testing for 25-hydroxyvitamin D-24-hydroxylase gene mutation.
    
    

Paget’s Disease of Bone

• Signs/Symptoms: Often asymptomatic; may present with bone pain (long bones, skull, or facial areas).
• Investigations:
  • Serum calcium: Normal.
  • Serum alkaline phosphatase: Markedly elevated.
  • X-ray: Mottled bone appearance, deformities (e.g., skull enlargement, femur bowing).
    
    

Fibromyalgia

• Signs/Symptoms: Widespread body pain affecting four of five regions for at least three months.
• Investigations: Clinical diagnosis; serum 25-hydroxyvitamin D is normal.
  
  

Blount’s Syndrome

• Signs/Symptoms: Osteochondrosis of the tibia, bowing of legs, associated with obesity.
• Investigations:
  • Normal calcium, phosphate, alkaline phosphatase, and vitamin D metabolites.
    
    

Multiple Myeloma

• Signs/Symptoms: Bone pain, anaemia, weight loss.
• Investigations:
  • Elevated serum calcium, low intact PTH, low 1,25-dihydroxyvitamin D.
  • X-ray findings: Lytic bone lesions.
  • Serum and urine protein electrophoresis: Diagnostic.
  • Serum creatinine and urea abnormalities: Found in ~50% of cases.
    
    

Myalgic Encephalomyelitis (Chronic Fatigue Syndrome)

• Signs/Symptoms: Persistent fatigue >6 months, post-exertional malaise, musculoskeletal pain, sleep disruption, cognitive dysfunction.
• Examination Findings: Low-grade fever, tender lymph nodes, tachycardia, orthostatic hypotension.
• Investigations: Clinical diagnosis; normal serum 25-hydroxyvitamin D.
  
  

Hypophosphatasia

• Signs/Symptoms: Resembles rickets radiographically.
• Investigations:
  • Serum alkaline phosphatase: Low.
  • Urine: Increased phosphoethanolamine excretion.
    
    

Metaphyseal Dysostoses (e.g., Pyle’s Disease)

• Signs/Symptoms: Short stature, bowing of legs, waddling gait.
• Investigations:
  • Normal calcium, phosphate, alkaline phosphatase, and vitamin D metabolites.
    
    

Other Considerations in Differential Diagnosis

• Coeliac Disease, Cystic Fibrosis, End-stage Liver Disease: Associated with malabsorption and secondary vitamin D deficiency.
• Inadequate Sunlight Exposure, Poor Dietary Intake, Antiepileptic Drug Use: Can contribute to deficiency and should be considered.
  
  

Vitamin D Supplementation

• The goal is to achieve and maintain serum 25-hydroxyvitamin D levels between 75-250 nmol/L (30-100 ng/mL).
• Oral vitamin D2 (ergocalciferol) or D3 (colecalciferol) is the preferred treatment for deficiency.
• Dosing recommendations:
  • Infants (<1 year): 400 IU daily.
  • Children (≥1 year): 600 IU daily.
  • Adults: 1500-2000 IU daily.
  • Severe deficiency: 50,000 IU of vitamin D2/D3 weekly for 6-8 weeks, followed by maintenance therapy.
    
    

Considerations for Special Populations

• Malabsorption Syndromes (e.g., coeliac disease, short bowel syndrome, cystic fibrosis):
  • Require higher oral doses or UV-B therapy if oral absorption is inadequate.
• Obese Patients and Those on Certain Medications (e.g., glucocorticoids, antiepileptics, HAART, rifampicin, St John's wort):
  • May require 6000-10,000 IU daily for correction, followed by 3000-6000 IU daily maintenance.
• Pregnancy:
  • Data on optimal dosing is lacking; specialist consultation recommended before initiation.
    
    

Sun Exposure

• Sunlight exposure is a key source of vitamin D and should be encouraged alongside supplementation.
• Recommended exposure:
  • Arms and legs exposed (with face protection) for 5-30 minutes, twice weekly, between 10 a.m. and 3 p.m..
  • Duration depends on skin pigmentation, latitude, season, and age.
  • Smartphone apps can help monitor exposure and prevent sunburn.
    
    

Calcium and Phosphate Replacement

• Calcium supplementation is required if dietary intake is insufficient.
  • Adults: 1-2 g/day in divided doses.
• Phosphate replacement is not usually needed, except in conditions causing renal phosphate wasting (e.g., hypophosphataemic rickets, oncogenic osteomalacia).
• High-dose phosphate should be divided into smaller doses to prevent tertiary hyperparathyroidism.
  
  

Management of Disorders Affecting Vitamin D Metabolism

• Inherited and Acquired Disorders (e.g., vitamin D-resistant rickets, chronic kidney disease):
  • Require vitamin D supplementation along with calcitriol or active analogues (e.g., paricalcitol, doxercalciferol).
• Chronic Kidney Disease (CKD):
  • Patients may have high phosphate levels and reduced 1,25-dihydroxyvitamin D production, leading to secondary hyperparathyroidism.
  • Management: Maintain serum 25-hydroxyvitamin D at 75-250 nmol/L, use phosphate binders (e.g., calcium carbonate), and provide calcitriol if GFR <50% of normal.
    
    

Long-Term Monitoring

• Check serum 25-hydroxyvitamin D levels after 3 months of treatment.
• Persistent deficiency despite supplementation may require UV-B therapy.
• Routine screening is not recommended for the general population, but high-risk groups should be monitored.
  
  

Asymptomatic Vitamin D Deficiency

• Most children and adults do not present with overt symptoms.
• Treatment with pharmacological doses of vitamin D corrects deficiency within 2-3 months, provided no underlying absorption or metabolic disorders are present.
  
  

Symptomatic Vitamin D Deficiency

• Children with Rickets:
  • Early intervention leads to favourable outcomes, particularly in leg deformities.
  • Biochemical changes (rise in phosphorus and calcium) appear within one week.
  • Radiographic and physical improvements occur within six months.
• Adults with Osteomalacia:
  • Bone mineral density improves within 1-2 years.
  • Secondary hyperparathyroidism and muscle strength improve within 3-6 months.
    
    

Impact on Fracture Risk

• Vitamin D supplementation reduces the risk of hip and nonvertebral fractures.
• Meta-analyses suggest:
  • 18% reduction in hip fractures when vitamin D and calcium are co-administered.
  • 20% reduction in fractures in individuals ≥65 years receiving >400 IU/day.
  • Vitamin D deficiency contributes to osteoporosis by reducing calcium absorption, but treatment improves bone mineral density.
    
    

Muscle Strength and Fall Prevention

• Vitamin D improves muscle function and reduces fall risk by 22% in the elderly.
• Meta-analyses confirm benefits in postural stability, gait, and lower limb strength.
  
  

Associations with Chronic Diseases

• Cancer Risk: Observational studies suggest links to breast, colon, and prostate cancer, though RCTs show inconsistent findings.
• Diabetes: Lower vitamin D levels correlate with higher fasting glucose and insulin resistance.
• Cardiovascular Disease: Deficiency is associated with hypertension, inflammation, and increased stroke risk.
  
  

Vitamin D and COVID-19

• Low vitamin D levels correlate with increased hospitalisation and mortality.
• Deficient patients had a 4-fold increased mortality risk in observational studies.
• No conclusive evidence from RCTs on COVID-19 outcomes.
  
  

Long-Term Mortality Benefits

• 7% reduction in all-cause mortality observed in meta-analyses.
• Severe deficiency (<10 ng/mL) linked to increased in-hospital mortality.
  
  

Rickets

• Occurs due to nutritional deficiency of vitamin D, leading to deficient mineralisation of the skeleton.
• Impaired chondrocyte maturation results in defective mineralisation at the growth plates of long bones.
• Clinical features: Widening of bones at the wrists, knees, costochondral junctions, bowing of the legs, spinal deformities, fractures, bone pain, and dental abnormalities.
• Prevention: Ensuring adequate vitamin D and calcium intake in children and pregnant women.
  
  

Osteopenia and Osteoporosis

• Secondary hyperparathyroidism due to vitamin D deficiency increases bone resorption, reducing bone mineral density (BMD).
• Diagnosis:
  • Bone densitometry (DEXA scan) at lumbar spine, hip, wrist.
  • T-score:
    • -1.0 to -2.5: Osteopenia.
    • ≤ -2.5: Osteoporosis.
• Monitoring: Repeat bone mineral density study after 1-2 years of vitamin D therapy.
  
  

Falls and Fractures

• Increased risk due to:
  • Low BMD from increased bone resorption.
  • Muscle weakness, increasing fall risk.
• Intervention:
  • Calcium plus vitamin D supplementation reduces hip fracture risk.
  • Meta-analysis suggests loading doses of vitamin D may improve fracture healing.
  • Oral multinutrient supplements pre- or post-hip fracture show limited evidence in reducing complications.
    
    

Other Chronic Diseases (Long-Term, Medium Likelihood)

• Vitamin D deficiency is linked to increased risk of:
  • Cancer (breast, prostate, colon).
  • Autoimmune diseases (rheumatoid arthritis, multiple sclerosis).
  • Type 2 diabetes, cardiovascular disease, neurocognitive dysfunction.
• Evidence from meta-analyses and RCTs:
  • Some trials dispute non-skeletal benefits of vitamin D supplementation.
  • The VITAL study found no reduction in cardiovascular disease but reduced cancer mortality.
  • A meta-analysis linked low vitamin D to increased COPD exacerbations.
    
    

Vitamin D Intoxication

• Rare condition, occurs with prolonged high-dose vitamin D intake (>10,000 IU/day).
• Toxicity threshold: Serum 25-hydroxyvitamin D > 374 nmol/L (>150 ng/mL).
• Complications:
  • Hypercalcaemia, hyperphosphataemia.
  • Soft tissue calcification (kidneys, blood vessels).
  • Increased risk of cardiovascular mortality, nephrocalcinosis, renal failure.
• Special populations at risk:
  • Granulomatous disorders, lymphoma → dysregulated 1,25-dihydroxyvitamin D production.
  • Risk increases when 25-hydroxyvitamin D > 75 nmol/L (>30 ng/mL).
    
    

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