Skin: Anatomy, Physiology, Functions, and Appendages

1. Overview of the Integumentary System

• Thick skin - palms of hands and soles of feet; hairless, thicker epidermis, greater abrasion resistance
• Thin skin - everywhere else; thinner epidermis, contains hair follicles

2. Structure: Layers of the Skin

A. Epidermis (5% of skin)

Keratinocytes are classified according to their depth and degree of differentiation - they proliferate in the basal layer, ascend, lose nuclei and organelles, and ultimately form the stratum corneum. - Bailey and Love's Short Practice of Surgery, 28th ed.

Cells of the Epidermis

• Keratinocytes - predominant cell type (~90%); produce keratin
• Melanocytes - neural crest-derived dendritic cells in the basal layer; synthesize melanin (brown-black pigment) transferred to keratinocytes via membrane processes; protect against UV radiation. Ethnic differences in skin colour are determined by variations in melanin amount, combination, and distribution, not by differences in melanocyte number. - Bailey and Love's
• Langerhans cells - dendritic antigen-presenting cells in the stratum spinosum; part of the skin immune system
• Merkel cells - mechanoreceptors in the basal layer; associated with nerve endings; function in light touch discrimination

Epidermal Water Barrier

B. Dermis (95% of skin)

• Collagen (type I - reticular; type III - papillary)
• Elastic fibres (elastin + fibrillin microfibrils)
• Ground substance (glycosaminoglycans, proteoglycans)
• Blood vessels, lymphatics
• Nerve fibres and sensory receptors
• Fibroblasts, mast cells, macrophages
• Skin appendages (hair follicles, sweat glands, sebaceous glands)

C. Hypodermis (Subcutaneous Layer)

• Deep to the dermis; equivalent to subcutaneous fascia
• Contains variable amounts of adipose tissue arranged in lobules separated by connective tissue septa
• Functions: energy storage, thermal insulation, mechanical cushioning, attachment of skin to underlying structures - Histology: A Text and Atlas, 9e

3. Functions of the Skin

1. Barrier / Protection

• Mechanical barrier - keratin and stratified epithelium resist abrasion and injury
• Permeability barrier - lipid envelope prevents transcutaneous water loss (TEWL); also prevents absorption of harmful external substances
• UV barrier - melanin absorbs and dissipates UV radiation, protecting DNA
• Chemical barrier - acid surface pH (~4.5-5.5) protects against pathogenic microorganisms
• Infection barrier - intact skin prevents microbial invasion; skin microbiome contributes to protection

2. Thermoregulation

• Sweat glands - eccrine sweating dissipates heat through evaporation
• Cutaneous blood vessels - vasodilation cools the body; vasoconstriction conserves heat
• Subcutaneous fat - acts as thermal insulator
• Hair erection (piloerection) via arrector pili muscles traps warm air in cold conditions

3. Sensory Function

4. Immune Function

• Langerhans cells process antigens and present to T-lymphocytes
• Skin-associated lymphoid tissue (SALT) participates in immune surveillance
• Provides immunologic information to effector cells in lymphatic tissue

5. Endocrine / Metabolic Functions

• Vitamin D synthesis - UV-B converts 7-dehydrocholesterol in the skin to cholecalciferol (vitamin D3)
• Secretes hormones, cytokines, and growth factors
• Converts precursor molecules into hormonally active substances

6. Excretion

• Eccrine sweat glands excrete water, electrolytes (Na⁺, Cl⁻, K⁺), urea, lactate
• Sebaceous glands secrete sebum
• Apocrine glands contribute to excretion

7. Absorption

• Lipid-soluble substances can be absorbed transdermally (basis of transdermal drug delivery systems - nicotine patches, steroid hormones, antiemetics)

4. Skin Appendages (Epidermal Derivatives)

A. Hair Follicles and Hair

• Hair bulb - base of follicle; contains the dermal papilla (vascular connective tissue) and matrix cells (rapidly dividing stem cells that produce hair)
• Inner root sheath - surrounds and shapes the hair
• Outer root sheath - continuity with the epidermis
• Bulge region - in the isthmus; contains hair follicle stem cells important for hair cycling and wound repair
• Arrector pili muscle - smooth muscle; causes piloerection ("goose bumps")

• Anagen (growth phase) - matrix cells actively divide and differentiate
• Catagen (transition) - regression and apoptosis of lower follicle
• Telogen (resting/shedding) - hair shed; follicle rests before new anagen

B. Nails

• Nail plate - hard, translucent keratinized structure
• Nail bed - epithelium under the nail plate
• Nail matrix (root) - beneath the proximal nail fold; site of nail formation (keratinisation of matrix cells)
• Lunula - whitish crescent-shaped area at the proximal nail; visible part of the matrix
• Hyponychium - junction of nail bed and fingertip skin
• Eponychium (cuticle) - proximal fold of skin overlying the nail matrix
• Paronychium - lateral nail folds

C. Sebaceous Glands

• Holocrine glands - entire cell disintegrates to release secretion (sebum)
• Found almost everywhere on the skin except palms and soles
• Open into hair follicle canal (pilosebaceous unit); independent sebaceous glands open directly on certain surfaces (lips, eyelids - Meibomian glands, areola - Montgomery glands)
• Secretion: Sebum - mixture of triglycerides, wax esters, squalene, cholesterol, free fatty acids
• Functions of sebum: lubricates and waterproofs skin and hair, antimicrobial properties (acidic pH), may have roles in vitamin E delivery and pheromone communication
• Stimulated by androgens (especially testosterone/DHT); active at puberty; overactivity leads to acne
• Inactive in childhood, become active at puberty

D. Sweat Glands (Sudoriferous Glands)

1. Eccrine (Merocrine) Sweat Glands

• Most numerous sweat glands (~3-4 million on the body)
• Found over most of the body surface; greatest density on palms, soles, and forehead
• Not associated with hair follicles - open directly onto the skin surface
• Structure: simple coiled tubular gland; coiled secretory portion in deep dermis/hypodermis; straight/coiled duct rising to the surface
• Secretion: watery sweat - water, NaCl, KCl, urea, lactic acid, ammonia, IgA
• Functions:
  • Thermoregulation (primary function) - evaporative cooling
  • Minor excretory role
  • Helps maintain acidic skin pH
• Innervated by cholinergic sympathetic nerve fibres (unusual - sympathetic but uses ACh)

2. Apocrine Sweat Glands

• Larger than eccrine glands
• Found in limited locations: axillae, areola of nipple, perianal region, external ear canal (ceruminous glands), eyelids (Moll's glands)
• Associated with hair follicles - drain into the upper portion of the follicle above the sebaceous gland
• Become active at puberty (androgen-dependent)
• Secretion: viscous, oily, protein-rich fluid containing carbohydrates, lipids, proteins, and pheromone-like compounds; odourless when secreted but odour develops when broken down by skin bacteria
• Function: pheromone secretion (sex attractant function - well-established in animals, possible in humans); emotional sweating (anxiety, fear, sexual excitement)
• Innervated by adrenergic sympathetic nerve fibres

E. Mammary Glands

5. Sensory Receptors of the Dermis

• Encapsulated mechanoreceptors: Meissner's corpuscles, Pacinian corpuscles, Ruffini corpuscles, Krause end bulbs
• Unencapsulated receptors: Merkel's discs (associated with Merkel cells in the epidermis), free nerve endings

6. Summary Diagram

SKIN
├── Epidermis (5%)
│   ├── Stratum Corneum      ← dead, keratinized cells
│   ├── Stratum Lucidum      ← only in thick skin
│   ├── Stratum Granulosum   ← lamellar bodies, water barrier
│   ├── Stratum Spinosum     ← Langerhans cells, desmosomes
│   └── Stratum Basale       ← stem cells, melanocytes, Merkel cells
│
├── Dermis (95%)
│   ├── Papillary layer      ← delicate collagen, capillaries, receptors
│   └── Reticular layer      ← coarse collagen, elastic fibres
│
├── Hypodermis
│   └── Adipose tissue, loose connective tissue
│
└── Appendages (epidermal origin)
    ├── Hair follicles + arrector pili
    ├── Nails
    ├── Sebaceous glands      (holocrine; sebum; androgen-driven)
    ├── Eccrine sweat glands  (thermoregulation; cholinergic)
    └── Apocrine sweat glands (pheromones; adrenergic; puberty onset)

• Histology: A Text and Atlas with Correlated Cell and Molecular Biology, 9e (Pawlina), pp. 1278-1342
• Bailey and Love's Short Practice of Surgery, 28th ed. - Functional Anatomy and Physiology of Skin; Surgical Anatomy of the Skin
• Rosen's Emergency Medicine, Surface Anatomy and Skin

Skin Pathology: Morphology of Skin Lesions

PRIMARY SKIN LESIONS

1. Macule

• Definition: Flat, circumscribed area of colour change, < 1-2 cm in diameter; NOT elevated or depressed; not palpable
• Pathology: Change in melanin, blood (haemoglobin), or exogenous pigment in the epidermis or superficial dermis; no structural change in skin surface
• Examples: Freckle (ephelid), cafe-au-lait spot, vitiligo, early measles rash, petechia (small)
• Key point: You can SEE it but cannot FEEL it

2. Patch

• Definition: A large macule, > 1-2 cm (some sources say > 0.5 cm); flat, non-palpable area of colour change
• Examples: Vitiligo patches, port-wine stain (nevus flammeus), Mongolian spot, large areas of tinea versicolor
• Key point: Differs from macule only in SIZE

3. Papule

• Definition: Small, solid, elevated, well-circumscribed lesion < 0.5-1 cm in diameter; palpable; raised above surrounding skin
• Pathology: May result from epidermal hyperplasia, dermal infiltration, or accumulation of metabolic products
• Examples: Warts (verruca vulgaris), molluscum contagiosum, closed comedone (whitehead), lichen planus (flat-topped violaceous papule), acne lesions, insect bites
• Key point: You can SEE it AND FEEL it; it is SOLID (no fluid)

4. Plaque

• Definition: Large (> 1 cm), flat-topped, raised lesion - essentially a large papule or confluence of papules
• Pathology: Same processes as papule but larger; edges may be distinct (psoriasis) or gradually blend (eczema)
• Examples: Psoriasis (well-demarcated silvery-scaled plaques), eczematous dermatitis, mycosis fungoides, discoid lupus erythematosus
• Key point: Think of it as a "raised plateau" - large surface area, flat top

5. Nodule

• Definition: Solid, firm lesion raised above the skin surface, 0.5-5 cm in diameter; extends deeper into the dermis or subcutaneous tissue than a papule
• Pathology: Dermal or subcutaneous infiltration (inflammatory cells, neoplastic cells, deposits)
• Examples: Lipoma, rheumatoid nodule, erythema nodosum, dermatofibroma, large melanocytic nevus, lymphoma cutis
• Key point: DEEPER than a papule; can be felt rolling under the fingers

6. Tumor / Mass

• Definition: Solid, raised growth > 5 cm in diameter (some sources: > 2 cm); extends into the dermis/subcutis
• Examples: Large cutaneous malignancies, large lipoma, pilomatrixoma
• Key point: Distinguished from nodule by SIZE only

7. Vesicle

• Definition: Small, fluid-filled blister < 0.5-1 cm in diameter; raised above surrounding skin; fluid often visible and translucent
• Pathology: Intraepidermal oedema (spongiosis), acantholysis, or subepidermal separation; roof = epidermis; content = clear serous fluid
• Examples:
  • Herpes simplex / herpes zoster (varicella) - grouped vesicles on erythematous base
  • Allergic contact dermatitis (poison ivy/oak)
  • Dyshidrotic eczema (pompholyx) - vesicles on palms and soles
  • Early chickenpox
• Key point: Fluid-filled; SMALL (< 1 cm); translucent

8. Bulla

• Definition: A large vesicle (fluid-filled blister) > 0.5-1 cm in diameter; elevated, often tense or flaccid
• Pathology: Subepidermal (tense bullae - BP, EBA) or intraepidermal (flaccid bullae - pemphigus vulgaris) blister formation
• Sub-types by location:
  • Intraepidermal - flaccid, easily ruptured (e.g., pemphigus vulgaris - acantholysis above the basal layer)
  • Subepidermal - tense, more durable (e.g., bullous pemphigoid - IgG + complement at BMZ)
• Examples:
  • Bullous pemphigoid - tense bullae, elderly, autoimmune (anti-BP180/BP230)
  • Pemphigus vulgaris - flaccid bullae, mucosal involvement, Nikolsky sign positive
  • Epidermolysis bullosa - inherited fragility
  • Impetigo (bullous type) - honey-coloured rupturing bullae, Staph. aureus
  • Burns, severe contact dermatitis
• Key point: Fluid-filled; LARGE (> 1 cm); may be tense or flaccid

9. Pustule

• Definition: Well-circumscribed, elevated lesion filled with purulent material (pus = dead neutrophils + bacteria/debris); any size
• Pathology: Intraepidermal or subepidermal collection of neutrophils
• Key point: Presence of pustules does NOT necessarily indicate infection - sterile pustules occur in many inflammatory conditions
• Examples:
  • Infected: Folliculitis, impetigo, furuncle
  • Sterile: Psoriasis (pustular psoriasis), acne vulgaris, rosacea, palmoplantar pustulosis

10. Wheal (Urtica / Hive)

• Definition: Transient (typically < 24 hours), raised, well-circumscribed lesion with an erythematous periphery and central pallor; an inflamed oedematous papule or plaque formed by superficial local oedema
• Pathology: Mast cell degranulation → histamine release → transient vasodilation and increased vascular permeability in the dermis → localised oedema
• Examples: Urticaria (hives), allergic reactions, dermatographism
• Key point: TRANSIENT - comes and goes within hours; oedematous; itchy

11. Cyst

• Definition: Encapsulated, fluctuant lesion filled with soft semi-solid or liquid material (not just fluid); has an epithelial lining
• Examples: Epidermal inclusion cyst, sebaceous cyst, pilar cyst, dermoid cyst, milia
• Key point: Has a WALL (cyst capsule) - distinguishes it from a simple vesicle/bulla

12. Comedone

• Definition: A plug of keratinous material and skin oils retained in a hair follicle
• Open comedone (blackhead): Open to the air; black colour from oxidised melanin (not dirt)
• Closed comedone (whitehead): Covered by thin layer of skin; flesh-coloured or pinkish
• Pathology: Sebaceous duct obstruction; precursor of acne vulgaris
• Symptom to Diagnosis, 4e

13. Telangiectasia

• Definition: Dilated, superficial blood vessel visible on the skin surface; does not blanch with pressure (unlike erythema)
• Examples: Rosacea, hereditary haemorrhagic telangiectasia (HHT/Osler-Weber-Rendu), CREST syndrome, spider naevi, ataxia-telangiectasia

SECONDARY SKIN LESIONS

SPECIAL / VASCULAR LESIONS

Purpura is caused by extravasation of red blood cells into the skin, resulting in a reddish to dark purple to black colour. Palpable purpura suggests small vessel leukocytoclastic vasculitis. Retiform purpura - with concave, net-like, scalloped borders - can signal a life-threatening disorder. - Goldman-Cecil Medicine

CONFIGURATION PATTERNS (Arrangement of Lesions)

QUICK REFERENCE SUMMARY TABLE

• Harrison's Principles of Internal Medicine, 22e (2025) - Tables 39-1 and 39-2
• Goldman-Cecil Medicine, International Edition - Chapter 403: Morphology, Configuration, Palpation
• The Harriet Lane Handbook, 23e (Johns Hopkins) - Evaluation and Clinical Descriptions of Skin Findings
• Symptom to Diagnosis: An Evidence-Based Guide, 4e - Constructing a Differential Diagnosis

Everything About the Olfactory System

1. Overview

2. Anatomy of the Olfactory Region

Location: The Olfactory Membrane / Epithelium

• Located in the superior part of the nasal cavity - roof near the septum, folds over the superior turbinate and upper surface of the middle turbinate
• Total surface area: ~5 cm² (Guyton & Hall) to ~10 cm² (Ganong)
• Appears yellowish in colour (due to pigmentation) - macroscopically indistinguishable from respiratory epithelium
• Bounded by the olfactory cleft (cribriform plate superiorly, superior turbinate laterally, superior septum medially)

3. Histology of the Olfactory Epithelium

A. Olfactory Receptor Neurons (ORNs)

• ~100 million bipolar neurons in the olfactory epithelium (Guyton) / 6-30 million in young adults (Cummings)
• Bipolar neurons - unique because they are both primary sensory neurons AND CNS-derived (originally from the CNS/neural placode, not peripheral nervous system)
• Dendrite - projects apically toward the epithelial surface, ending in an olfactory vesicle (knob)
• Olfactory cilia - 4 to 25 nonmotile cilia per cell (0.3 µm diameter, up to 200 µm long) project from the knob into the overlying mucus layer; contain the odorant receptor proteins; greatly increase surface area for odorant binding
• Axon - single, unmyelinated axon at the basal pole; among the smallest and slowest fibres in the nervous system; forms bundles (fila olfactoria) surrounded by olfactory ensheathing cells (specialised glia)
• Axons pass through foramina of the cribriform plate of the ethmoid bone to reach the olfactory bulb

ORNs are unique first-order sensory neurons in that they simultaneously contact the outside environment (cilia in nasal mucus) AND the central nervous system. - Cummings Otolaryngology

B. Supporting (Sustentacular) Cells

• Columnar epithelial cells interspersed among ORNs; lined with microvilli at their mucosal surface
• Secrete mucus that provides the appropriate molecular and ionic environment for odour detection
• Contain secretory granules
• Also release neurotrophic factors stimulating genesis of new olfactory sensory neurons

C. Basal Cells (Stem Cells)

• Located at the base of the olfactory epithelium
• Undifferentiated stem cells - undergo mitosis to replace ORNs that are continuously lost due to environmental damage
• Source of adult neurogenesis in the olfactory system - one of the few sites in the body where new neurons are generated throughout life
• ORNs survive only 1-2 months (Ganong) before being replaced
• In animals, the global ORN population undergoes complete regeneration every 4-6 weeks; human turnover rate is less certain

D. Other Cell Types

• Bowman glands - submucosal seromucous glands in the lamina propria beneath the basement membrane; secrete mucus onto the olfactory surface; the mucus dissolves odorant molecules and facilitates their diffusion to receptor cilia
• Olfactory ensheathing cells - specialised glial cells in the lamina propria AND olfactory bulb; surround axon bundles; guide axonal regeneration after injury; being investigated for therapeutic transplantation in nerve repair
• Microvillar cells and duct cells - present in smaller numbers

4. Odorant Receptors

• There are approximately 1000 olfactory receptor genes in humans, accounting for ~3% of the human genome; approximately 400 functional odorant receptors are encoded (the rest are pseudogenes)
• All odorant receptors are G-protein-coupled receptors (GPCRs) - 7-transmembrane proteins
• The olfactory system can discriminate perhaps more than 1 million distinct odours
• Each ORN expresses only ONE type of odorant receptor gene
• Each receptor type is expressed in approximately 5,000 neurons confined to one spatial zone of the epithelium
• The epithelium is divided into spatial zones, each expressing different receptor types - Principles of Neural Science (Kandel)

5. Signal Transduction (How We Detect Smell)

This cAMP amplification cascade greatly multiplies the excitatory effect of even a small number of odorant molecules binding to the receptors. - Guyton & Hall

6. Olfactory Encoding - How Do We Recognise Smells?

• Olfactory receptor proteins are NOT dedicated to a single odorant; each responds to a variety of odorants
• Different receptor proteins have different response profiles to the same odorant
• Each odorant produces a unique across-fiber pattern of activity across a population of receptors
• This pattern is projected onto targeted glomeruli in the olfactory bulb, creating an "odour map"
• The CNS interprets these odour maps to identify the specific smell - Costanzo Physiology

7. The Olfactory Bulb

8. The Olfactory Pathway

Odorant → Olfactory Receptor Neuron (ORN) in nasal epithelium
                    ↓ (unmyelinated axons through cribriform plate)
           Olfactory Bulb (CN I = Olfactory Nerve)
           Synapse in Glomeruli (ORN → Mitral cells)
                    ↓
           Olfactory Tract
           Divides into:
           ├── LATERAL olfactory stria
           │     → Primary Olfactory Cortex:
           │       • Piriform (prepiriform) cortex ← main; conscious discrimination
           │       • Olfactory tubercle
           │       • Amygdala ← emotional responses to smell
           │       • Entorhinal cortex ← olfactory memory
           │       • Anterior olfactory nucleus
           │
           └── MEDIAL olfactory stria
                 → Anterior commissure → contralateral olfactory bulb
                    (inhibition of mitral cells - enhances localization)
                 → Septal area / diagonal band

From Piriform cortex → Orbitofrontal cortex (via thalamus) ← conscious odour identification
From Piriform cortex → Hypothalamus / Brainstem (via MFB) ← autonomic responses
                                                              (salivation, gastric contraction)

• → Orbitofrontal cortex - conscious discrimination of odours
• → Amygdala - emotional and fear responses to odours (e.g., smell of smoke triggers alarm)
• → Entorhinal cortex - olfactory memory (explains why smells trigger vivid memories - Proust phenomenon)
• → Hypothalamus/brainstem (via medial forebrain bundle, MFB) - autonomic responses: salivation, gastric contraction, arousal via reticular formation

9. Olfactory Adaptation

• With prolonged exposure to an odour, adaptation occurs rapidly - sensitivity to that particular odorant decreases
• Adaptation is specific - sensitivity to other odours is not affected
• Mechanisms include receptor desensitisation and central adaptation
• The olfactory system is extremely sensitive: some odorants detected at <1 part per trillion (e.g., mercaptans)
• Odorants typically contain 1-30 carbon atoms with functional groups (ketones, aldehydes, esters, thiols, etc.)

10. The Vomeronasal Organ (Accessory Olfactory System)

• A separate patch of olfactory epithelium along the nasal septum (more developed in other mammals)
• Concerned with perception of pheromones
• Contains ~100 GPCRs structurally different from main olfactory receptors
• Projects to the accessory olfactory bulb → amygdala and hypothalamus → regulation of reproductive and ingestive behaviour
• Rudimentary in adult humans (debated whether functional) - Ganong's

11. Olfactory Dysfunction - Definitions

12. Causes of Olfactory Dysfunction

13. Olfactory Neuroblastoma (Esthesioneuroblastoma)

14. Olfactory Nerve - CN I Summary

15. Clinical Correlates

• Cribriform plate fractures are the most common traumatic cause of anosmia - ORN axons are severed as they pass through the tiny foramina
• COVID-19 causes anosmia and parosmia by damaging supporting cells and sustentacular cells in the OE (not primarily the ORNs themselves), disrupting the microenvironment for receptor function
• Kallmann syndrome - congenital anosmia + hypogonadism; GnRH neurons fail to migrate from the olfactory placode; associated with aplasia/hypoplasia of the olfactory bulbs
• Early Parkinson's / Alzheimer's - hyposmia often precedes motor or cognitive symptoms; olfactory testing is being explored as a biomarker
• Olfactory training - repeated exposure to strong odorants (rose, lemon, eucalyptus, clove) may facilitate ORN regeneration and improve post-viral and post-COVID anosmia/parosmia - Cummings Otolaryngology
• Foster-Kennedy syndrome - anosmia + ipsilateral optic atrophy + contralateral papilloedema from a frontal lobe tumour compressing the olfactory tract

• Guyton and Hall Textbook of Medical Physiology, 14e - Olfactory Membrane, Stimulation of Olfactory Cells
• Ganong's Review of Medical Physiology, 26e - Olfactory Epithelium, Odorant Receptors, Signal Transduction, Olfactory Sensory Pathway
• Costanzo Physiology, 7e - Olfactory Transduction, Pathways, Encoding
• Gray's Anatomy for Students - Olfactory System (no thalamic relay, limbic connections)
• Cummings Otolaryngology Head and Neck Surgery - Olfactory Neuroepithelium, Olfactory Dysfunction, Olfactory Training
• Principles of Neural Science (Kandel), 6e - Odorant encoding, spatial zones, receptor targeting