Week 9 - 7MNT0004 - Vitamin D

Vitamin D Overview

Course Information

  • Module: Vitamin D 7MNT0004

  • Date: Nov 27th, 2025

  • Instructor: Dr. Karen O'Callaghan

  • Institution: School of Life Course & Population Sciences, Faculty of Life Sciences & Medicine

Learning Outcomes

  • Understand sources of vitamin D

  • Understand current recommendations for vitamin D intake in the UK

  • Understand the risk factors for vitamin D deficiency

  • Understand the consequences of vitamin D deficiency

Vitamin D Metabolism

  • Definition: Vitamin D is a seco-sterol and a fat-soluble vitamin.

  • Types of Vitamin D:

    • Ergocalciferol: Vitamin D2

    • Cholecalciferol: Vitamin D3

  • Production of Vitamin D:

    • D3: Produced endogenously in the skin.

    • D2 and D3: Found in a limited number of foods.

Hydroxylation Reactions

Overview: Vitamin D undergoes two hydroxylation reactions for activation.

  • First Hydroxylation:

  • Location: Liver

  • Reaction: Vitamin D → 25-hydroxyvitamin D

  • Product: 25(OH)D [main circulating metabolite]

  • Enzyme: Catalyzed by cytochrome P450 enzyme CYP2R1 and other 25-hydroxylases.

  • Second Hydroxylation:

  • Location: Kidney

  • Reaction: 25(OH)D → 1,25-dihydroxyvitamin D

  • Product: 1,25(OH)2D [active hormonal metabolite]

  • Enzyme: Catalyzed by mitochondrial enzyme CYP27B1.

Mechanism of Action

  • Receptor Binding:

    • 1,25(OH)2D binds to intracellular vitamin D receptor (VDR) in target tissues.

    • Exerts biological effects via gene transcription.

  • Inactivation:

    • Subsequent hydroxylation reactions yield inactive metabolites.

    • Enzymes involved: 24-hydroxylase converts to 24,25-dihydroxyvitamin D and 1,24,25-trihydroxyvitamin D.

Dietary Reference Values (DRVs) for Adults

Dietary Sources of Vitamin D

  • UK Context:

    • Dairy fortification is not mandatory.

    • Some plant-based milks are fortified.

    • Importance of fortified cereals, especially for children.

  • Food Sources:

    • Limited sources of vitamin D include:

    • Egg yolk

    • Oily fish

    • Liver

    • Trace amounts found in some plant foods.

    • Cereals when fortified, may aid children

Sunlight as a Source of Vitamin D

  • Overview: Sunlight is the most significant source of vitamin D in the UK.

  • Process: Photochemical reaction involving UVB converting 7-dehydrocholesterol to pre-vitamin D3.

  • Wavelength Requirement: Needs UVB rays in the wavelength range of 290-320 nm.

  • Seasonal Consideration:

    • Vitamin D production is latitude-dependent.

    • Limited vitamin D production above 40°N or Southern latitude.

    • In the UK, sunlight conversion occurs only from approximately April to September.

    • October to March referred to as “Vitamin D Winter”

    • Supplementation Recommendation:

    • Daily vitamin D supplementation of 400 IU (10 µg) recommended from October to March.

Recommendations from SACN

  • Serum 25(OH)D Concentration: Should be ≥ 25 nmol/L year-round.

  • Sunlight Exposure: No specific recommendations on the amount of sunlight exposure to maintain serum concentrations.

  • Recommended Nutrient Intake (RNI) for Vitamin D:

    • 10 µg/d from all dietary sources for the UK population aged > 4 years.

    • Assumes minimal UVB exposure.

    • Applicable throughout the year.

  • Pregnant and Lactating Women: RNI is equivalent to non-pregnant adults.

  • Children < 4 years: Data insufficient to set RNI; safe intake is 8.5-10 µg/d for infants (0-1 years) and 10 µg/d for ages 1-4 years.

  • The median intake in UK adults is around 3µg

Risk Factors for Vitamin D Deficiency

  • Analysis: Refers to studies and population surveys assessing vitamin D levels.

Low Dietary Vit D Intake

  • Vegan/vegetarian w/o supplementation

  • Exclusive breastfeeding w/o infantile supplementation

Reduced Skin Exposure to sunlight

  • High latitude

  • Clothing

  • Skin pigmentation

  • Suncream

  • Environmental Pollution

Ageing: Reduction in dermal 7-dehydrocholesterol

Smokers

Vitamin D Deficiency in the UK (NDNS 2019-2023)

  • Source: National Diet and Nutrition Survey (NDNS) 2019-2023, provided by UK Government.

Geographical Variation in Vitamin D Status

  • Data from UK Biobank (2006-2010) among adults ages 40-69:

    • Trend: 25(OH)D highest in southern regions.

    • Findings: Highest prevalence of deficiency (25(OH)D < 25 nmol/L) noted in Scotland.

Seasonal Variation in Vitamin D Status

  • Proportion of individuals with 25(OH)D < 25 nmol/L by season.

  • Winter: Highest deficiency rates observed due to limited sunlight exposure.

  • Spring: Gradual improvement in vitamin D levels as sunlight increases.

  • Summer: Peak vitamin D levels recorded, with lower deficiency rates.

  • Autumn: Levels begin to decline again, with a rise in deficiencies as days shorten.

Demographic Variation in Vitamin D Status

  • Vitamin D deficiency varies by:

    • Ethnicity Prevalence:

    • Asian: 54%

    • Black: 35%

    • Chinese: 27%

    • White: 12%

    • Smoking Status:

    • Current smokers: 22%

    • Non-smokers: 13%

    • Socio-Economic Status:

    • Least deprived: 10%

    • Most deprived: 20%

Vitamin D Toxicity / Hypervitaminosis D

  • Status: Vitamin D is a fat-soluble vitamin.

  • Half-life: Approximately 15 days for 25(OH)D.

  • Toxicity Threshold: Typically associated with 25(OH)D concentrations > 375 – 500 nmol/L1.2.

  • Tolerable Upper Intake Level: Established at 4000 IU/d or 100 µg/d.

  • Consequences of Toxicity:

    • Characteristic feature is hypercalcemia (high blood calcium levels) or hypercalciuria (high urinary calcium).

    • Long-term toxicity may lead to cardiovascular and renal damage due to tissue calcification.

  • Causes of Toxicity:

    • Prolonged dietary exposure (high dose supplementation).

    • Skin synthesis of vitamin D ceases once skin reddening occurs; therefore, prolonged sun exposure does not result in toxicity.

Role of Vitamin D and Consequences of Deficiency

Vitamin D and Bone Health

  • Main Role: Maintenance of calcium and phosphate homeostasis.

    • Aids in absorption of calcium and phosphorus.

    • Triggers mobilization of calcium from bones when blood calcium is low.

    • Activation of osteoclasts to dissolve bone matrix.

    • Facilitates renal calcium reabsorption.

  • Mechanism Overview:

    • Increased parathyroid hormone (PTH) when serum calcium is low stimulates calcium absorption and renal reabsorption.

    • Higher levels of 1,25(OH)2D lead to decreased PTH levels.

  • When serum calcium (Ca²⁺) is low, the parathyroid gland increases parathyroid hormone (PTH) secretion.

  • PTH acts on three main targets to restore blood calcium:

1. Kidneys

  • ↑ Renal Ca reabsorption → ↓ urinary Ca loss

  • ↑ 1α-hydroxylase activity → ↑ production of 1,25(OH)₂D (active vitamin D)

  • ↓ Renal Ca excretion

2. Intestine (via 1,25(OH)₂D)

  • 1,25(OH)₂D increases intestinal Ca absorption

  • This raises serum/plasma calcium

3. Bone

  • PTH stimulates skeletal Ca resorption (osteoclast activity)

  • Ca is released from bone into the blood

Negative feedback regulation

  • As serum Ca rises, it:

    • Suppresses PTH secretion

    • Reduces further Ca release and conservation

  • 1,25(OH)₂D also suppresses PTH and:

    • Stimulates 24,25-hydroxylase, which breaks down active vitamin D (termination mechanism)

  • FGF-23 (from bone) acts on kidneys to:

    • Reduce 1,25(OH)₂D synthesis

    • Fine-tune mineral balance

Clinical Features of Vitamin D Deficiency

  • Common Symptoms:

    • Characteristic feature is an under-mineralized or under-calcified bone matrix.

    • Secondary hyperparathyroidism.

    • Severe deficiency leads to hypocalcemia causing muscle cramps and twitching.

  • Conditions Due to Deficiency:

    • Adults: Osteomalacia.

    • Children/Adolescents: Rickets.

Osteomalacia Symptoms

  • Description: “Softening of the bones”.

    • Impaired bone remodeling due to lack of vitamin D.

    • Typical findings:

    • Low 25(OH)D.

    • High PTH.

    • Serum calcium often maintained within normal range due to regulation by PTH.

    • Pseudo-fractures resulting from under-mineralized bone.

Rickets Symptoms (Disorder of growth plates)

  • Clinical features include:

    • Bending/bowing of the long bones.

    • Bow-legs (genu varum)

    • Knock-knees (genu valgum).

    • Enlarged wrists.

    • Rachitic rosary.

    • Difficulty breathing; severe cases may lead to pneumonia.

    • Deformities of pelvis impacting childbirth.

    • Softening of skull bones (craniotabes).

    • Widening of growth plate (epiphyses).

It is essentially impaired bone mineralization and long bone growth

It is treated with Vitamin D (+Calcium)

Historical Context of Vitamin D Deficiency

  • Industrial revolution (18th and 19th centuries) linked to lower sun exposure and increased nutritional rickets in northern European cities.

  • Rickets is caused by impaired bone mineralization and long bone growth, often treated with vitamin D and calcium supplementation.

Treatment and Prevention of Rickets

  • UV Light Exposure: Used historically for treatment.

    • Effective elimination of rickets as illuminated by Hernigou et al. 2019.

Vitamin D Supplementation in Infancy

  • Policy: Routine vitamin D supplementation for infants <1 year to prevent nutritional rickets (5-10 µg/d).

    • In the UK, 8.5-10 µg/d recommended for:

    • Breastfed infants

    • Infants receiving <500ml/d of infant formula.

    • Children aged 1-4 years recommended to take 10 µg/d.

    • Free supplements available through the Healthy Start scheme.

Non-Skeletal Roles of Vitamin D

  • Vitamin D Receptor (VDR): Found in various cell types; plays a significant role in gene expression regulation.

  • Local expression 1-alpha hydroxylase suggests 1,25 (OH)2D production and regulation of VDR-mediated gene expression is important for functioning of various tissues.

  • Health Correlations:

    • Epidemiological studies link lower 25(OH)D levels with increased risks of cardiovascular diseases, certain cancers, and autoimmune diseases.

    • Causation from observational data is not confirmed, as low vitamin D may also result from poor health.

    • RCTs often show no effects from additional vitamin D on health outcomes.

The VITamin D and OmegA-3 TriaL (VITAL)

  • A nationwide RCT conducted in the US involved >25,000 participants randomized to receive 2000 IU/d (50 µg/d) of vitamin D vs placebo.

  • Main findings indicated no effect on the prevention of cancer or cardiovascular events, with secondary outcomes showing no effect on fracture prevention.

Vitamin D and Immune Function

  • Mechanism: Regulation by synthesis of 1,25(OH)2D by macrophages and dendritic cells.

  • Antimicrobial Activity: 1,25(OH)2D regulates expression of antimicrobial proteins, enhancing immune responses.

    • Suppresses inflammatory T-cells and production of proinflammatory cytokines (IL-6, TNFα, IFN-γ).

    • Hepcidin (antibacterial protein); facilitates iron exportation from cells

Vitamin D and COVID-19

  • Observational evidence suggests lower 25(OH)D levels correlate with greater severity of COVID-19 symptoms.

  • The cause-effect relationship is confounded by shared risk factors for both vitamin D deficiency and COVID-19 severity.

  • Recommendations from NICE, PHN, and SACN included provision of free vitamin D supplements to vulnerable populations.

Media Coverage and Public Response

  • During the COVID-19 pandemic, significant misinformation regarding vitamin D and its association with COVID-19 circulated on social media.

CORONAVIT Trial

  • 3-arm open-label RCT in the UK (Dec 2020 - Jun 2021) enrolled 6200 adults.

  • Participants with 25(OH)D < 75 nmol were randomized to receive either 20 µg/d or 80 µg/d of supplemental vitamin D or no intervention.

  • Findings: Increased 25(OH)D concentrations were observed, but no significant effect on acute respiratory infections or COVID-19 infection related risks.

Summary

  • Vitamin D deficiency is a global issue

  • Dietary and/or supplemental vitamin D is needed to meet year-round vitamin D requirements at Northern latitude

• Most well established role for vitamin D is in maintenance and development of the skeleton

• Role of vitamin D for many non-skeletal health outcomes is debated due to inadequately designed trials

Related Lectures

  • Bone Minerals: 7MNT0004 (semester 1)

  • Nutrition and Bone Health: 7MNT0003 (semester 2)

  • Content is complementary; integrated study suggested instead of silos learning.

  • Formative quiz is available on KEATS for self-directed learning.

Key References

  • Scientific Advisory Committee on Nutrition. Vitamin D and Health, 2016. Available at: SACN Report.

  • Manson et al. (2020). Principal results of the VITamin D and OmegA-3 TriaL (VITAL) and updated meta-analyses of relevant vitamin D trials. J Steroid Biochem Mol Biol.

  • National Institute for Health and Care Excellence. COVID-19 rapid guideline: vitamin D (nice.org.uk).

  • Jolliffee et al. (2022). Effect of a test-and-treat approach to vitamin D supplementation on risk of all-cause acute respiratory tract infection and COVID-19: Phase 3 randomized controlled trial (CORONAVIT). BMJ.