Vitamin Deficiencies

Slide 1 · Vitamin Deficiencies

Mechanisms, morphology and clinicopathologic correlations

Fat-soluble vitamins • water-soluble vitamins • deficiency patterns

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Distinguish primary deficiency from malabsorption, transport and metabolic defects.

Connect vitamin function to tissue-specific pathology and clinical syndromes.

Explain vitamin A deficiency, ocular injury and epithelial metaplasia.

Explain vitamin D regulation, defective mineralization and skeletal disease.

Recognize toxicity and interpret major clinical patterns.

Slide 3 · Thirteen vitamins: Two physiologic groups

Solubility predicts absorption, storage and clinical vulnerability.

Fat-soluble

A, D, E and K; More readily stored in tissues.

Water-soluble

Nine vitamins: The B group and vitamin C.

Clinical implication

Fat malabsorption can simultaneously reduce several fat-soluble vitamins.

Slide 4 · Fat-soluble versus water-soluble vitamins

Fat-soluble: A, D, E, K

Water-soluble: B vitamins and C

More readily stored in the body

Require adequate intestinal fat absorption

Several deficiency syndromes share a malabsorptive origin

Often function as coenzymes in metabolic reactions

Includes redox, one-carbon and collagen pathways

Clinical patterns depend on affected biochemical processes

Slide 5 · Four mechanisms of secondary deficiency

Vitamin deficiency

Inadequate intake

Primary nutritional deficiency

Poor absorption

Intestinal and fat-malabsorption disorders

Delivery or storage

Impaired blood transport or tissue reserves

Metabolic conversion

Reduced activation to functional vitamin forms

Slide 6 · From nutrient shortage to tissue dysfunction

Supply

Dietary insufficiency or impaired delivery

Metabolism

Reduced cofactor or active metabolite

Cellular effect

Disrupted enzyme, receptor or structural pathway

Phenotype

Target-organ dysfunction or morphology

The same clinical syndrome can arise from different points in this chain.

Slide 7 · Mixed deficiencies are clinically important

An isolated deficiency of only one vitamin is uncommon in severe malnutrition.

Severe acute malnutrition may involve multiple vitamin deficits.

A single organ phenotype can coexist with broad nutritional or immune impairment.

The cause must be sought beyond the most obvious symptom.

Slide 8 · Endogenous synthesis is not complete protection

Contributions

Practical limitation

Vitamin D: Produced from skin precursor steroids

Vitamin K and biotin: Intestinal microflora

Niacin: Synthesized from essential amino acid tryptophan

Dietary supply remains essential for health

Deficiency may reflect inadequate intake or altered conversion

Synthesis does not exclude malabsorption or illness-associated deficiency

Slide 9 · Fat-soluble vitamins: Functions and syndromes

Vitamin

Major function

Deficiency consequence

A

Vision; epithelial differentiation; immunity

Night blindness; xerophthalmia; metaplasia

D

Calcium/phosphate homeostasis; bone mineralization

Rickets; osteomalacia

E

Antioxidant defense

Spinocerebellar degeneration; hemolytic anemia

K

Carboxylation of coagulation-related proteins

Abnormal bleeding

Slide 10 · Water-soluble vitamins: Metabolic functions

Vitamin

Biochemical role

Deficiency syndrome

B1, thiamine

Cofactor in decarboxylation

Beriberi; Wernicke–Korsakoff

B2, riboflavin

FMN/FAD in intermediary metabolism

Cheilosis, glossitis, dermatitis

B3, niacin

NAD/NADP redox reactions

Pellagra

B6, pyridoxine

Coenzyme in intermediary reactions

Neuropathy, cheilosis, dermatitis

B12, cobalamin

Folate metabolism; DNA synthesis

Megaloblastic anemia; tract degeneration

Slide 11 · Other water-soluble vitamins: Deficiency patterns

Vitamin

Core role

Deficiency consequence

Folate

One-carbon transfer for DNA synthesis

Megaloblastic anemia; neural tube defects

Vitamin C

Redox reactions; collagen hydroxylation

Scurvy

Pantothenic acid

Component of coenzyme A

No nonexperimental syndrome recognized

Biotin

Cofactor in carboxylation

No clearly defined clinical syndrome in source table

Slide 12 · Thiamine deficiency: Metabolic and neurologic injury

Biochemistry

Clinicopathologic patterns

Thiamine pyrophosphate acts in decarboxylation reactions

Energy-requiring tissues are vulnerable to disruption

Dry beriberi: Predominant neuropathic manifestations

Wet beriberi: Predominant cardiovascular manifestations

Wernicke–Korsakoff syndrome: Characteristic CNS syndrome

Slide 13 · Riboflavin deficiency: Mucocutaneous pattern

Molecular function

Clinical findings

Precursor of flavin mononucleotide (FMN)

Precursor of flavin adenine dinucleotide (FAD)

Both serve as cofactors in intermediary metabolism

Cheilosis and stomatitis

Glossitis and dermatitis

Corneal vascularization

Slide 14 · Niacin deficiency: Pellagra

Niacin supplies NAD and NADP for oxidation–reduction reactions.

Dermatitis

Characteristic cutaneous disease pattern

Diarrhea

Gastrointestinal involvement

Dementia

Neurologic and cognitive involvement

Slide 15 · Pyridoxine deficiency: Skin and nerve findings

Biochemical function

Deficiency phenotype

Vitamin B6 derivatives participate in many intermediary reactions

Multiple metabolic pathways depend on B6-derived coenzymes

Peripheral neuropathy

Cheilosis and glossitis

Dermatitis

Slide 16 · Vitamin B12 and folate: Shared and distinct patterns

Shared hematologic consequence

Distinguishing consequence

Both support DNA synthesis

Deficiency can produce megaloblastic anemia

Vitamin B12 deficiency can injure posterolateral spinal cord tracts

Folate deficiency is linked to neural tube defects

Neurologic patterns should not be treated as interchangeable

Slide 17 · Vitamin E and K: Two distinct failure modes

Vitamin E: Antioxidant protection

Vitamin K: Hemostatic function

Scavenges free radicals

Deficiency associated with spinocerebellar degeneration

Hemolytic anemia may occur

Cofactor for hepatic carboxylation

Factors II, VII, IX, X; Proteins C and S

Deficiency predisposes to abnormal bleeding

Slide 18 · Clinical pattern recognition across vitamins

Dominant presentation

Relevant vitamin(s)

Pathologic rationale

Night blindness / dry eye

A

Visual pigment and epithelium

Rickets / osteomalacia

D

Defective mineralization

Bleeding

K or C

Coagulation vs collagen vessel integrity

Megaloblastic anemia

B12 or folate

Impaired DNA synthesis

Pellagra

Niacin

Impaired NAD/NADP-linked metabolism

Slide 19 · Vitamin A: Three critical tissue functions

Retinoids connect vision, epithelial differentiation and immune defense.

Retinal participates in visual pigments of rods and cones.

Retinoic acid regulates growth and cellular differentiation.

Deficiency disrupts mucosal epithelial integrity and increases infection vulnerability.

Slide 20 · Vitamin A forms and their roles

Biologically active family

Broader chemical terminology

Retinol: Transport/storage precursor

Retinal: Central to visual pigment chemistry

Retinoic acid: Nuclear receptor–mediated gene regulation

Retinoids include natural and synthetic related compounds

Structural similarity does not ensure identical biologic activity

β-Carotene is an important dietary provitamin

Slide 21 · Where dietary vitamin A comes from

Preformed vitamin A

Provitamin A carotenoids

Liver and fish

Eggs, milk and butter

Animal-derived retinyl esters

Carrots and squash

Spinach and other leafy green vegetables

β-Carotene converted into vitamin A in the body

Slide 22 · Vitamin A absorption and transport

Intestine

Retinyl esters and β-carotene absorbed

Enterocyte

β-Carotene converted to retinol

Chylomicrons

Retinol carried toward the liver

Liver

Re-esterification and storage

Requires bile, pancreatic enzymes and adequate intestinal fat handling.

Slide 23 · Vitamin A: Hepatic storage is a buffer

Liver stores account for most of the body’s vitamin A reserves.

Storage site

Predominantly perisinusoidal stellate (Ito) cells

Stored form

Retinyl esters available for mobilization

Clinical significance

Chronic deficiency may appear after depletion of substantial reserves

Slide 24 · From hepatic storage to peripheral tissues

Liver store

Stored retinyl esters

Release

Retinol binds retinol-binding protein

Tissue uptake

Cell-surface RBP receptor mediates entry

Local conversion

Retinoic acid drives nuclear signaling

Low hepatic synthesis of retinol-binding protein may reduce circulating retinol.

Slide 25 · The vitamin A visual cycle

11-cis-retinal

Chromophore binds opsin

Rhodopsin

Functional rod photopigment

Light exposure

11-cis → all-trans retinal

Regeneration

Reconversion supports dark adaptation

Insufficient retinal compromises vision in dim light before advanced ocular disease.

Slide 26 · Rods and cones require distinct visual pigments

Rods

Cones

Rhodopsin is highly light-sensitive

Rod function is central to reduced-light vision

Deficiency causes impaired dark adaptation

Three iodopsin types support color discrimination

Cones function primarily in brighter light

Vitamin A participates in cone visual pigments

Slide 27 · Retinoic acid controls epithelial differentiation

Retinoic acid

Ligand activates RAR

Nuclear dimer

RAR pairs with RXR

Gene response

Receptor complex binds response elements

Cell phenotype

Differentiation and growth programs alter

Absence of proper signaling predisposes mucosal epithelium to keratinizing metaplasia.

Slide 28 · Retinoid nuclear receptor pathways

RAR/RXR signaling

RXR and metabolism

Retinoic acid receptor heterodimerization

Binding to regulatory DNA sequences

Control of growth and differentiation genes

RXR also partners with PPAR receptors

PPAR pathways regulate lipid metabolism

Effects include adipogenesis and lipoprotein handling

Slide 29 · Vitamin A supports mucosal barrier defense

A deficiency produces epithelial change and greater infection vulnerability.

Airway

Loss of normal mucociliary lining predisposes to infection

Ocular surface

Loss of mucin-secreting epithelium causes dryness

Host response

Deficiency is associated with increased susceptibility to common infections

Slide 30 · Why vitamin A deficiency develops

Primary and age-related

Secondary causes

Insufficient intake, particularly with severe malnutrition

Infections deplete reserves in children

Newborns have less efficient vitamin A absorption

Fat malabsorption: Celiac disease, Crohn disease or colitis

Bariatric surgery

Continuous mineral-oil laxative exposure

Slide 31 · Vitamin A deficiency: Ocular progression

Night blindness

Reduced rhodopsin availability

Conjunctival xerosis

Loss of secretory epithelium

Bitot spots

Keratin debris forms opaque plaques

Corneal injury

Erosion → softening → blindness

Early functional impairment may precede irreversible structural damage.

Slide 32 · Early vitamin A eye disease

Night blindness

Conjunctival xerosis

Impaired dim-light vision

Reflects visual pigment deficiency

Can precede visible ocular changes

Mucus-secreting epithelium replaced by keratinizing epithelium

Dry conjunctival surface

Establishes a structural basis for later lesions

Slide 33 · Advanced ocular pathology of vitamin A deficiency

Bitot spots

Keratomalacia

Local accumulation of keratin debris

Small opaque plaque-like lesions

Reflect persistent abnormal surface differentiation

Roughening and erosion of corneal surface

Corneal softening and tissue destruction

May progress to permanent blindness

Slide 34 · Squamous metaplasia extends beyond the eye

Vitamin A deficiency

Upper airway

Loss of mucociliary epithelium → infection risk

Urinary tract

Keratinized epithelium; Debris contributes to stones

Epidermis

Follicular hyperkeratosis and papular dermatosis

Slide 35 · Epithelial changes: Why morphology matters

Respiratory system

Urinary and skin changes

Squamous metaplasia replaces specialized mucociliary lining

Reduced clearance predisposes to secondary pulmonary infections

Desquamated keratin can contribute to urinary stones

Follicular duct plugging and hyperkeratinization cause dermatosis

Slide 36 · Vitamin A deficiency creates an infection–deficiency cycle

Deficiency

Impaired epithelial and immune defense

Infection

Greater illness burden

Acute-phase response

Reduced hepatic RBP synthesis may occur

Lower delivery

Less retinol reaches tissues

The source describes immune effects but does not establish a complete molecular mechanism.

Slide 37 · Integrating vitamin A deficiency findings

One vitamin deficit explains multi-organ dysfunction.

Dark-adaptation loss reflects deficient visual pigment regeneration.

Xerophthalmia and respiratory metaplasia reflect disordered epithelial differentiation.

Infections are amplified by impaired barriers and immune responses.

Slide 38 · Acute hypervitaminosis A

Exposure and mechanism

Clinical syndrome

Acute overconsumption of preformed vitamin A

High-vitamin-A animal liver can cause toxicity

Headache, dizziness and vomiting

Blurred vision and stupor

Symptoms may resemble intracranial pressure disorders

Slide 39 · Chronic hypervitaminosis A

Constitutional symptoms

Skeletal effects

Weight loss and anorexia

Nausea and vomiting

Bone and joint pain

Retinoic acid stimulates osteoclast production/activity

Increased bone resorption

Higher risk of fractures

Slide 40 · Retinoids in clinical practice: Benefit and risk

Therapeutic contexts

Important caution

Some severe acne and psoriasis

All-trans-retinoic acid in acute promyelocytic leukemia

13-cis-retinoic acid in selected neuroblastoma treatment regimens

Therapeutic retinoids are not identical to nutritional supplementation

Retinoid teratogenicity requires avoidance in pregnancy

Assess formulation and exposure before attributing toxicity

Slide 41 · Clinical reasoning: Dim-light visual impairment

Clinical vignette

A child with restricted nutrition has difficulty seeing at dusk. Examination later reveals dry conjunctiva and focal pale plaques.

Reason through the pathology

Which vitamin deficiency unifies the findings?

What is the biochemical basis for night blindness?

Which epithelial change produces the surface lesions?

Slide 42 · Vitamin D: Mineralization depends on systemic regulation

Vitamin D protects mineral homeostasis through intestine, kidney and bone.

Skin synthesis and diet supply precursor vitamin D.

Hepatic and renal hydroxylation generate the active hormone.

PTH, phosphate and FGF23 adjust activation and calcium–phosphate handling.

Slide 43 · Vitamin D and the skeleton

Principal physiologic objectives

When deficiency develops

Maintain plasma calcium and phosphorus

Support skeletal mineralization and neuromuscular function

Prevent rickets and osteomalacia

Reduced substrate availability for mineral deposition

PTH compensation can preserve serum calcium

Persistent phosphate depletion can worsen mineralization

Slide 44 · Vitamin D: Sources and activation

Skin + diet

UVB-generated D3 and dietary vitamin D

Liver

25-hydroxylation → 25(OH)D

Kidney

1α-hydroxylase activation

Active form

1,25(OH)₂D mediates downstream responses

Vitamin D–binding protein transports circulating forms.

Slide 45 · Vitamin D production: Ultraviolet exposure matters

Cutaneous source

Dietary source

7-dehydrocholesterol is the skin precursor

UVB radiation enables production of vitamin D3

Higher melanin may reduce cutaneous production

Fish and other dietary sources contribute

Dietary uptake depends on fat absorption

Reduced sunlight makes dietary contribution more important

Slide 46 · Renal 1α-hydroxylase: Opposing regulators

Active vitamin D synthesis

PTH: Stimulation

Released with hypocalcemia

Low phosphate

Upregulates hydroxylase

1,25(OH)₂D

Negative feedback inhibition

FGF23

Inhibits activation

Slide 47 · Hypocalcemia evokes endocrine compensation

Low ionized Ca²⁺

Parathyroid calcium sensing

Increased PTH

Renal and skeletal responses

Active vitamin D

More intestinal calcium uptake

Bone mobilization

Calcium released from bone

Compensation can limit overt tetany while skeletal injury progresses.

Slide 48 · FGF23 and vitamin D feedback

FGF23 action

Pathologic implication

Produced by osteoblasts and osteocytes

Inhibits renal 1α-hydroxylase expression

Influences phosphate homeostasis

Excess FGF23 can produce hypophosphatemia

Rare inherited or tumor-related syndromes may lead to rickets/osteomalacia

Not every mineralization defect is due to poor dietary intake

Slide 49 · Vitamin D: Transcriptional signaling

1,25(OH)₂D

Active ligand enters target cell

VDR

Ligand binds vitamin D receptor

VDR–RXR

Nuclear heterodimer binds DNA

Gene regulation

Calcium transport and skeletal effects

VDR is widely expressed; Not all described nonskeletal effects are proven therapeutic benefits.

Slide 50 · Intestinal calcium transport: TRPV6

Mechanism

Functional outcome

Active vitamin D engages nuclear VDR–RXR

Target-gene activation includes TRPV6

TRPV6 supports calcium entry across enterocytes

Improved intestinal calcium absorption

Supports circulating calcium availability

Deficiency impairs absorption and contributes to secondary hyperparathyroidism

Slide 51 · Renal tubular calcium transport: TRPV5

Vitamin D effect

Coordination with PTH

Active vitamin D increases TRPV5 expression

Distal tubular calcium influx is enhanced

Hypocalcemia stimulates PTH release

PTH also regulates TRPV5

Renal conservation complements intestinal uptake

Slide 52 · Vitamin D, RANKL and osteoclast activation

VDR/PTH

Signals regulate osteoblast RANKL

RANKL

Engages RANK on precursors

Osteoclasts

Mature and resorb bone

Mineral release

Calcium and phosphate enter blood

Bone-resorptive signaling maintains extracellular calcium at a skeletal cost.

Slide 53 · Bone mineralization: Two developmental settings

Intramembranous ossification

Endochondral ossification

Mesenchymal cells differentiate into osteoblasts

Osteoblasts deposit collagenous osteoid

Osteoid then becomes mineralized

Epiphyseal cartilage grows and provisionally mineralizes

Cartilage is replaced with osteoid matrix

Mineralization produces mature bone

Slide 54 · Vitamin D deficiency: Why phosphate falls

Low vitamin D

Reduced intestinal mineral absorption

Falling calcium

Secondary PTH secretion

PTH action

Calcium retained; Bone resorption increases

Renal phosphate loss

Persistent hypophosphatemia

Inadequate phosphate contributes to defective mineralization despite calcium compensation.

Slide 55 · Secondary hyperparathyroidism masks hypocalcemia

Calcium-preserving responses

The trade-off

PTH enhances renal calcium conservation

PTH increases bone resorption

PTH stimulates renal vitamin D activation

Phosphate wasting may persist

Bone mineral substrate remains inadequate

Normal calcium alone cannot exclude deficiency-related bone disease

Slide 56 · Rickets and osteomalacia share defective mineralization

The age and location of growing skeletal tissue determine the morphology.

Rickets

Children with open growth plates; Growth-plate cartilage and osteoid affected

Osteomalacia

Adults; Mineralization of osteoid matrix is defective

Common mechanism

Excess unmineralized matrix due to mineralization failure

Slide 57 · Rickets: Disrupted endochondral ossification

Normal costochondral / growth-plate organization

Deficient mineralization in rickets

Orderly cartilage columns

Expanded, disordered cartilage

Schematic growth-plate architecture; Not histology

Slide 58 · Rickets: Histomorphologic sequence

Calcification fails

Poor provisional mineralization of epiphyseal cartilage

Cartilage persists

Cells fail orderly maturation and removal

Osteoid is laid down

Matrix overlays retained cartilage

Growth plate distorts

Junction enlarges and expands laterally

The source describes excess unmineralized matrix and disordered cartilage palisades.

Slide 59 · Rickets: Clinically important structural effects

Developing skeleton

Representative phenotype

Growth plates remain open

Defective mineralization distorts cartilage–bone junctions

Expansion occurs at osteochondral junctions

Bowing of weight-bearing long bones

Abnormal growth-plate architecture

Effects differ from adult osteomalacia

Slide 60 · Osteomalacia: Defective osteoid mineralization

Pathologic substrate

Clinicopathologic association

Osteoid is deposited but insufficiently mineralized

Unmineralized matrix accumulates

Affects adult skeleton after growth-plate closure

Bone pain may be present

Decreased skeletal integrity reflects impaired mineralization

Distinguish from rickets of open growth plates

Slide 61 · Rickets versus osteomalacia

Feature

Rickets

Osteomalacia

Age-related setting

Open growth plates in children

After growth-plate closure

Primary lesion

Growth-plate cartilage and bone mineralization

Osteoid matrix mineralization

Source-described morphology

Cartilage palisade loss; widened junction

Accumulation of unmineralized osteoid

Illustrative consequence

Long-bone bowing

Skeletal pain / fragility

Slide 62 · Who is vulnerable to vitamin D deficiency?

Reduced supply

Impaired metabolism or availability

Limited UVB exposure

Northern latitude or substantial skin covering

Low dietary vitamin D and calcium

Fat-malabsorption disorders

Renal dysfunction affecting activation

Phosphate depletion or rare inherited disorders

Slide 63 · Clinical assessment: 25-hydroxyvitamin D

Why measure 25(OH)D?

Textbook threshold (11th edition)

Circulating 25(OH)D represents the principal assessment analyte discussed by the source

Evaluate biochemical status in appropriate clinical context

The source lists 20–100 ng/mL as its reference interval

Values below 20 ng/mL are described as deficiency

Interpretation depends on clinical and laboratory context

Slide 64 · Vitamin D outside the skeleton

Experimental and biologic observations

Limits of clinical inference

VDR is expressed in diverse tissues

Macrophages can locally generate active vitamin D

Antiproliferative and immunomodulatory effects are described

Biologic activity does not ensure supplementation benefit

The source reports negative trials for respiratory infections, including tuberculosis

Avoid presenting nonskeletal effects as established clinical indications

Slide 65 · Granulomatous inflammation and local vitamin D

Activated macrophage

Induced local vitamin D pathways

Active metabolite

Extrarenal 1,25(OH)₂D production

Mineral effect

Calcium homeostasis may be altered

Clinical finding

Some granulomatous diseases show hypercalcemia

The net immunologic effect of altered macrophage vitamin D signaling remains uncertain.

Slide 66 · Vitamin D excess: Toxicity differs from deficiency

Source of excess

Consequences

Normal prolonged sunlight is not a typical toxicity mechanism

Oral megadoses can produce hypervitaminosis D

Hypercalcemia and bone pain in adults

Metastatic soft-tissue calcification, including kidneys, in children

Toxicity is a distinct mechanism from rickets/osteomalacia

Slide 67 · Clinical reasoning: Impaired skeletal mineralization

Clinical vignette

A child has bowing of the legs and evidence of expanded, disorganized cartilage at developing bone ends. Sunlight exposure has been limited.

Reason through the pathology

What pathologic process explains the skeletal change?

Why can calcium be partially restored while phosphate remains low?

How does this differ from adult osteomalacia?

Slide 68 · Integrated differential: Follow the affected pathway

Clue

Most relevant deficiency

Mechanism to test

Reduced-light vision + xerosis

Vitamin A

Visual pigments + epithelial differentiation

Growth-plate distortion

Vitamin D

Impaired cartilage/osteoid mineralization

Peripheral neuropathy + dermatitis

Vitamin B6 (among others)

B6-dependent intermediary reactions

Megaloblastic anemia + tract degeneration

Vitamin B12

DNA synthesis + neural pathway injury

Mucosal bleeding from impaired coagulation

Vitamin K

Defective clotting-factor carboxylation

Slide 69 · Diagnostic reasoning: Deficiency versus excess

Deficiency

Excess

Dietary or absorptive compromise

Specific dysfunctional cellular pathways

Findings such as night blindness, rickets and bleeding

High-dose vitamin or retinoid exposure

Vitamin A: Neuro-ocular and skeletal manifestations

Vitamin D: Hypercalcemia and metastatic calcification

Slide 70 · Core clinicopathologic synthesis

Symptoms become interpretable when traced to the vitamin-dependent pathway.

Vitamin A: Visual cycle + epithelial differentiation → ocular and barrier injury.

Vitamin D: Endocrine calcium–phosphate regulation → rickets / osteomalacia.

Other vitamins: Recognizable neurologic, hematologic, dermatologic and bleeding patterns.

Slide 71 · Source and scope of this lecture

Robbins, Cotran & Kumar: Pathologic Basis of Disease, 11th ed. (2026).

Chapter 9, Environmental and Nutritional Diseases, pp. 397–403.

Table 9.9: vitamins, core functions and deficiency syndromes.

Vitamin A and vitamin D sections: mechanisms, morphology and toxicity.

Vitamin C / scurvy is addressed in its own succeeding teaching unit.