Pathophysiology of Skin.pdf

Pathophysiology of Skin Joshua D Stone, Ph.D. Division of Physician Assistant Studies Medical University of South Carolina Lecture Outline • Normal Anatomy and Physiology of Skin • Select Pathologies of the Skin Skin • Skin, known as the integument • Includes skin “adenexa”: hair, nails, sweat...

Pathophysiology of Skin Joshua D Stone, Ph.D. Division of Physician Assistant Studies Medical University of South Carolina Lecture Outline • Normal Anatomy and Physiology of Skin • Select Pathologies of the Skin Skin • Skin, known as the integument • Includes skin “adenexa”: hair, nails, sweat and other glands • Largest organ • • • • 1.5 – 2 square meters 4 kg (2.24 lbs/kg = 9 lbs) Covers entire external body surface (mucosa covers inner surfaces) Thickness varies • 1 mm to 6 mm (eyelid thinnest, palms and soles thickest) • Males have thicker skin than females • Thinner in young and old (maximum thickness at 40-50 years) Skin: Functions • Interface between the body’s tissues and the environment • • • • Provides physical protection (trauma, radiation, infection, water loss) Integral to immunity: first line of defense Regulation of body temperature by capillary dilation / contraction (radiant heat) and sweating Evaluation of the environment (touch, pressure, stretch, temperature, pain) • Synthesis of vitamin D Skin: Structure • 3 Layers • Epidermis • Most superficial, thin • No blood vessels, nerves • Dermis • Deeper, thicker connective tissue • Nerves, blood vessels, glands • Hypodermis (the “subcutaneous” tissue) • Subcutaneous fat, connective tissue, blood vessels, nerves • Basement membrane zone • Protein sheet separating epidermis from dermis Epidermis • Composed primarily of stratified keratinized epithelial cells • 4 cell types: • Keratinocytes • Melanocytes • Langerhans cells (dendritic cells) • Merkel cells Epidermis: Keratinocytes • The principal cell type of epidermis • Produce keratin • Form 5 layers (“strata”) • • • • • Stratum corneum – “surface”, fully keratinized Stratum lucidum Stratum granulosum Stratum spinosum Stratum germinativum (basale) Keratinocytes: Stratum Germinativum • A one cell thick layer of basal cells attached to basal (basement) membrane • The only epidermal cells that are mitotically active • All epidermal cells arise from this layer • New cells that form in basal layer are pushed up toward surface • 3 to 4 week replication cycle • Epidermal injury (burns, abrasions) causes accelerated division of basal cells, results in healing Other Epidermal Cells: Melanocytes • Round to columnar cells found scattered in the stratum germinativum with long processes that extend into the stratum spinosum • Produce melanin in melanosomes • Melanin synthesized from the amino acid tyrosine • The enzyme tyrosinase is activated by UV light • Melanin is packaged and secreted in vesicles called melanosomes which penetrate superficial strata • Results in skin color (innate and following UV exposure) • Melanosomes are transferred to keratinocytes, giving the keratinocytes color • Darker skin has more melanin, lighter skin has less melanin (not a significant difference in melanocyte numbers or size) Other Epidermal Cells: Dendritic Cells • Dendritic cell (Langerhans cells) • Immune antigen-presenting cells • Derived from the monocyte-macrophage lineage, generated in bone marrow • Primary role in supporting immune function • Phagocytize and process foreign proteins (antigens), then circulate to regional lymph nodes via lymphatic vessels • Involved in contact hypersensitivity reactions (e.g., poison ivy rash, nickel hypersensitivity) Basement Membrane • A thin membrane of fibrous proteins which adheres the epidermis to dermis • Selectively filters molecules moving across membrane • Blocks movement of large proteins (albumin, immunoglobulins, complement) • Site of blister and vesicle formation (basement membrane separates from dermis) Blister histology Basement membrane Dermis • Connective tissue-rich layer with nerves and blood vessels • Separates epidermis from the subcutaneous tissue layer (made up of fat and connective tissues) • Supports epidermis • Provides blood flow and sensory nervous input from skin • Provides mobile, flexible connection of epidermis to deeper tissues and added protection • Type I collagen is the major connective tissue component • Tough, fibrous proteins which form a sponge-like meshwork • Allows flexibility, stretch (elastin), resiliency without tearing • 70% of dry skin weight Layers of the Dermis Papillary Dermis • Superficial • Areolar (loose) CT • Dermal papillae – conical projections into epidermis (epidermal side called “rete ridges”) Reticular Dermis • Deeper • Tough/flexible layer • Collagen fiber bundles: dense irregular CT Reticular Dermis • Orientation of reticular dermis collagen fibers results in formation of Langer's lines • Incisions and excisional biopsies have the best cosmetic outcomes when made parallel to the Langer’s lines Skin Structure: Vascular Supply • Two intercommunicating plexuses: 1. Subpapillary plexus/upper horizontal network • At junction of the papillary and reticular dermis (gives pink color of skin below epidermis) • Supplies the dermal papilla 2. Lower horizontal plexus • Provides blood to the entire dermis • At the dermal-subcutaneous interface, in the reticular layer • Larger blood vessels • Lymphatics also in dermis, contribute to immune defense and recirculation of interstitial fluid Dermis: Immune Cells • Dendritic cells (Langerhans cells) • Phagocytes which present antigen to cells of the immune system to stimulate an immune response • Role in wound healing, blood clotting, inflammation • Mast cells • Role in immunoglobulin E-mediated hypersensitivity reaction • Release histamine • Activation causes inflammation, swelling, vasodilation Mast cells Epidermal Appendages: Sweat Glands • Eccrine sweat glands • Located over the entire skin surface • Simple tubular structures which originate in dermis and open directly onto skin surface • Most abundant on the palms, soles, forehead and axilla • Regulate temperature by secreting sweat for evaporation on skin • Most prevalent sweat glands (vs apocrine glands) Epidermal Appendages: Sweat Glands • Apocrine sweat glands • Open into hair follicles (rather than directly on skin surface) • Most common in axillae and groin • Sweat contains fatty acids • Fatty acids are bacteriostatic, however when oxidized by skin bacteria they produce body odor Epidermal Appendages: Sebaceous Glands • Located on the entire skin surface except the palms, soles, and sides of feet • Secrete sebum, a wax-like mix of triglycerides, cholesterol, and debris • Lubricates hair and skin • These glands enlarge in puberty • Skin becomes oily • Gland ducts can become blocked or inflamed in acne vulgaris • Sebaceous gland ducts open into upper 1/3 of hair follicle (part of pilosebaceous unit) Epidermal Appendages: Nails • Matrix of keratin formed in the nail plate at base of the nail fold • Grow an average of 0.1 mm/day, toenails grow slower than finger nails • Continuous growth • Cuticle is the stratum corneum • A “window” to observe perfusion and oxygenation (capillary refill), changes with disease (clubbing) Clubbing Cyanosis Skin Physiology: Vit-D Synthesis • skin (melanocytes) utilize radiation energy to convert cholesterol → cholecalciferol which goes to the liver → 25-OHD3 which is then transported to the kidneys → 1,25-(OH)2-D3 where it is stored • Vit-D3 helps maintain a healthy calcium balance AND has MANY physiologically important functions systemically Lecture Outline • Normal Anatomy and Physiology of Skin • Select Pathologies of the Skin Skin Pathology Nomenclature: Primary Lesions Skin Pathology Nomenclature: Secondary Lesions Classification of Skin Wounds • Open skin wounds • Incisions are regular/linear wounds caused by a clean, sharpedged object • Lacerations are irregular tear-like wounds caused by blunt trauma • Abrasions are superficial wounds to the epidermis and dermis caused by friction (scraped off) • Avulsions occur when skin (or another tissue) is forcibly torn off or detached from its normal point of attachment • Puncture wounds are caused by an object puncturing the skin • Penetrating wounds are caused by an object puncturing the skin and penetrating into deeper tissues • Amputation results in removal of a large portion of tissue, usually a tissue extension (e.g., finger, ear) Open Skin Wounds Laceration Incision Abrasion Avulsion Puncture Amputation Classification of Skin Wounds • Closed skin wounds occur when the skin is intact but trauma to underlying structures has occurred • Hematomas are caused by blood vessel damage causing blood to collect within tissue, may be small (petechiae) or large (echymosis) with minimal blood collection (purpura) or pools of blood (“hematoma”) • • • • Petechiae Purpura Ecchymosis Contusions (bruises) are hematomas caused by external trauma • Crush injury is caused by a great amount of force applied to tissue, injuring the compressed tissues (may be open) Closed Skin Wounds Hematoma Petechiae Ecchymosis Purpura Crush injury Stages of Scar Formation Scar Descriptors • All scars result from healing of injured tissues, but depending on a number of factors (e.g., heredity, amount of injury, stresses on site of healing), can vary in the form • Hyperpigmented scars – caused by the presence of a large amount of vasculature (usually more recent) • Hypopigmented scars – caused by loss of vasculature (usually older) • Hypertrophic scars – scars which continue to thicken due to excessive collagen formation but do not extend beyond the boundary of the original wound • Keloids – result from overgrowth of granulation tissue which is slowly replaced by mature scar; firm, rubbery lesions • Atrophic scars – sunken recess in the skin, caused when underlying structures are destroyed, such as fat or muscle; associated with acne, chickenpox, MRSA Scar Formation Hyperpigmented scarring Atrophic scar Hypertrophic scar Hypopigmented scar Keloids Traumatic Injury: Burns • Heat or chemical induced injury of the skin and subcutaneous tissues (thermal injury) • Injury determined by • Length of exposure • Temperature of heating agent • Surface area involved • Epidermal burns heal by epithelial regeneration but dermal and SC tissues heal by scar replacement (second intention), may result in contractures Traumatic Injury: Burns • Classified according to depth of injury • First degree • Epidermis primarily (dermis injury minor and reversible) • Second degree • Epidermis and dermis • Partial thickness • Blister formation • Third degree • Destruction of epidermis and some/all dermis, may affect subcutaneous and deeper tissues • Chemical burns follow the same grading/injury process Traumatic Injury: Burns • First-degree burns • Primarily injury to the epidermis with inflammation of the superficial dermis (dilated dermal blood vessels) • Painful, red but no blister formation • Heals in 3 to 10 days and requires palliative (pain relieving) treatment only Traumatic Injury: Burns • Second degree (partial-thickness) burns • Involve the epidermis and deeper dermis, resulting in dermal capillaries leaking • Painful, red, with blister formation • Maintain intact blisters for as long as possible • Heals with supportive care in 1 to 2 weeks Traumatic Injury: Vesicles and Blisters • Basement membrane (basal lamina) is the interface between the dermis and epidermis • This is the site of vesicle and blister formation, when the two layers become separated by fluid accumulation (serous, purulent, or haemorrhagic) beneath the basement membrane Herpes simplex (herpes labialis) Second degree burn Traumatic Injury: Burns • Third degree burns • Extend through the dermis, may involve underlying tissue (muscle, bone, tendons) • Vary in color from white to yellow to black • Sometimes called “fourth degree” burns when deeper tissues (fat, muscle, bone) involved • Hard, leathery, painless since sensory nerves are destroyed • Require skin grafts as epidermal and dermal cells and tissues have been destroyed • Admission, antibiotics, hydration, analgesia • Disfiguring, extensive contractures likely Traumatic Injury: Burns • Body surface area: rule of 9’s • • • • • • • Head = 9% Chest (front) = 9% Abdomen (front) = 9% Upper/mid & low back and buttocks = 18% Each arm = 9% (front = 4.5%, back = 4.5%) Groin = 1% Each leg = 18% total (front = 9%, back = 9%) • Example, if both legs (18% x 2 = 36%), the groin (1%) and the front chest and abdomen (18%) were burned, this would involve 55% of the body Traumatic Injury: Burns • Effects of extensive burn injury to skin • Initiates an acute phase response • Fever, leukocytosis, anorexia, hypermetabolism, acute phase protein changes (e.g., hypoalbuminemia), cortisol elevation • Risk of infection due to immune suppression, loss of epithelial barrier • Dehydration and protein loss (epithelial barrier) • Difficulty with temperature regulation (epithelial barrier loss) • Organ dysfunction due to blood flow disruption (CV, renal, respiratory, GI) Infectious Skin Disorders • Epidermal and dermal infections by bacteria, viruses, fungi • Organisms grow within epidermis and in interstitial space of dermis • May injure or destroy host cells and tissue • Cause inflammation (cardinal signs) • May spread through interstitial fluid (cellulitis) and along fascial planes (fasciitis) Infectious Skin Disorders: Bacterial • Bacterial infections are classified as primary (starts as an infection, e.g., impetigo) or secondary (complication of another disorder, e.g., infected pressure ulcers) • Characteristics of infection determined by organism, host immune competence, tissue health • Characterized by presence of inflammation, purulent exudate, crusting • Exo- or endotoxins may be released causing rash, skin injury • May be localized (hair follicles, nail beds), in dermis only, extend into deeper tissues, or become systemic Infectious Skin Disorders: Bacterial Impetigo (acute streptococcal or staphlococcal infection of dermis) Erysipelas (acute streptococcal infection of dermis, rash due to exotoxin) Infectious Skin Disorders: Bacterial Pseudomonas folliculitis Furuncle Carbuncle Paronychia Infectious Skin Disorders: Bacterial • Cellulitis • A bacterial infection of the dermis (in interstitial fluid) following the pattern of lymphatic drainage • Characterized by • Skin erythema / swelling that expands from distal to proximal (edema) • Tight, glossy appearance to skin (edema) • Tenderness or pain • Systemic signs of infection (APR) including fever, chills and muscle aches Infectious Skin Disorders: Bacterial • Fasciitis • Infection progresses along fascial planes • Bacteria grow and release toxins which kill tissue (multiple pathogens including Streptococcus pyogenes) • Signs and progression like cellulitis but subcutaneous tissue (and deeper) becomes involved, eventually necrotic skin and tissues • Results in thrombosis of the subcutaneous vessels, gangrene of the underlying tissues, sepsis Infectious Skin Disorders: Viral • Viruses can infect cells of the epidermis and dermis • Result in direct tissue injury, immune reactions, sometimes neoplasm • Neoplasm most commonly associated with infections of the mucosal epithelium, but skin also can be affected (HPV) • Examples • Human papilloma virus (HPV, causes warts – verruca vulgaris, venereal) • Herpes simplex virus 1 and 2 (cold sores, genital herpes) • Herpes varicella-zoster virus (chicken pox, shingles) Infectious Skin Disorders: Viral • Verrucae are warts • Verruca vulgaris, common wart • Common and benign, caused by human papilloma virus (HPV) • Over 50 types of HPV having different infectious characteristics • Cause overproliferation of stratum germinativum with thickening of the stratum corneum • Common skin warts do not cause neoplasm Infectious Skin Disorders: Viral • Herpes simplex 1 and 2 • Causes typical herpes infections • Type 1, most common cause of cold sores (fever blisters) • Type 2, most common cause of genital herpes • Either virus may cause disease in either location • Painful, small vesicles resulting from tissue injury and exudate formation below basement membrane at site of infection, eventually vesicles lyse and form shallow ulcers with erythematous base, crust • Herpes viruses lie dormant in dorsal root sensory ganglia, resurface in same location (e.g., Herpes labialis, Herpes zoster), exaggerated manifestations with immunosuppression (e.g., stress, disease, age) • May continue to shed virus even without obvious lesions Infectious Skin Disorders: Herpes Herpes zoster (shingles) Herpes gingivostomatitis Herpes labialis Herpetic whitlow Genital Herpes Infectious Skin Disorders: Viral • Herpes varicella-zoster • Primary infection causes chicken pox • Systemic infection with characteristic skin rash progressing like other herpes viruses, from erythematous vesicles to ulcerations with crust • Fever, itch (usually not particularly painful in primary infection), symptoms worse in adults • Like other herpes viruses, lies dormant in dorsal root sensory ganglia • Recurrent expression results in shingles • Rash similar to chicken pox except usually painful paraesthesia (abnormal sensations ranging from numbness to itch to burning pain) • Pain may become persistent (zoster neuropathy) • Follows dermatomal distribution, does not cross midline • May cause blindness if trigeminal nerve’s ophthalmic branch is affected Varicella-Zoster Reactivation The varicella virus creates the chickenpox rash and can travel from the skin to sensory nerves. Once in the sensory nerves, the virus moves to the sensory ganglia where it becomes latent. If reactivated, the virus travels from the sensory ganglia back to the skin where it creates the shingles rash. Infectious Skin Disorders: Herpes Zoster Shingles (herpes zoster) Chicken pox (herpes varicella) Infectious Skin Disorders: Fungal • Fungi can invade skin (dermatophytosis, primarily epidermis), nails (onychomycosis), oral cavity (thrush) and other mucosal surfaces • Most common in immunocompromized (e.g., diabetes, young, old, malnourished) • Frequently prefer warm, moist, non-sun exposed skin • Presents as • Raw, “beefy” red painful lesions in oral cavity (thrush – covered with removable white debris), intertriginous and other moist areas (e.g., body folds, diaper) • Dry, flaking areas with central clearing (tinea) on exposed areas of the skin • Flaking, yellow, thickened nails (onychomycosis) Infectious Skin Disorders: Fungal Thrush (oral candidiasis) Tinea curis (ringworm) Tinea curis (intertriginous candidiasis) Onychomycosis Infectious Skin Disorders: Abscess • An abscess is a local area of inflammation which contains a core of necrotic tissue and many neutrophils (which together make up a purulent exudate) • Purulent exudate often surrounded with a fibrous capsule (due to a chronic inflammatory reaction) • May be associated with signs of localized (cardinal inflammatory signs) or generalized inflammation (APR, fever) • Risk of cellulitis, fasciitis, sepsis • Only effective treatment for abscess > 5 mm is incision and drainage Infectious Skin Disorders: Abscess Abscess Infected sebaceous cyst Chalazion (infected meibomian gland) Peritonsilar abscess Hypoxic Skin Disorders • Lesions caused by vascular compromise, resulting in necrosis of skin and deeper tissues • Decubitus ulcers (pressure) • Unrelieved pressure causes tissue hypoxia and death, mostly over bony prominences; painful ulcers • Venous stasis ulcers (high venous pressure) • Venous stasis results in tissue swelling, causes tissue hypoxia and death; usually located proximal to the medial malleolus; not very painful • Arterial insufficiency ulcers (low arterial pressure) • Arterial insufficiency (e.g., due to obstruction) causes tissue hypoxia and death with necrosis; very painful • Neuropathic ulcers • Caused by repeated trauma due to disrupted pain perception; painless Hypoxic Skin Disorders Decubitus ulcers Arterial insufficiency ulcer Venous stasis (insufficiency) ulcers Diabetic neuropathic ulcer Skin Pigmentation Disorders • Albinism • Autosomal recessive disruption of melanin production by melanocytes • Melanocytes are present but usually no melanin produced • Potential differential expression, skin, hair, irises and retina may be affected • Increased risk for sun damage to tissues, cancer • Vitiligo • Acquired disorder (not congenital) • Manifested by flat (macules / patches), irregular lesions of pigment loss • Autoimmune response against melanocytes, causes localized melanocyte death and depigmentation • May be associated with other autoimmune diseases Skin Pigmentation Disorders Ocular albinism Oculocutaneous albinism Oculocutaneous albinism Vitiligo Inflammatory Skin Disorders • Related to • Autoimmune reactions (lupus, psoriasis) • Hypersensitivity reactions (eczematous dermititis, urticaria, contact dermatitis, viral xanthems, erythema multiforme, drug reactions) • Mechanisms • Stimulation of epidermis (stratus germinativum) results in overproduction (e.g., psoriasis) – type 4 hypersensitivity • Localized acute inflammation with histamine release (e.g., urticaria) – type 1 hypersensitivity Psoriasis Urticaria Inflammatory Skin Disorders • Mechanisms • Type 3 hypersensitivity reactions → (Ag-Ab) deposits in skin or capillaries → activates complement → resulting in inflammation and rash • Erythema multiforme, lupus rash, viral xanthems, Stevens-Johnson syndrome, drug reactions Stevens-Johnson syndrome/ Toxic epidermal necrolysis Erythema multiforme Malar rash of lupus Inflammatory Skin Disorders • Mechanisms • Type 4 hypersensitivity reaction attracting macrophages and T lymphocytes (e.g., poison ivy rash, contact dermatitis) Contact dermatitis (nickel) Atopic dermatitis Poison ivy rash Neoplastic Skin Disorders • Actinic keratosis (AK) • UV light–induced dysplastic lesion of the keratinocytes, originates in the basal epidermis • May also be associated with HPV • Brown, red, or skin-colored, rough, sandpaper-like texture, may produce so much keratin that a “cutaneous horn” forms • Common in sun exposed body areas (face, ears, scalp, forearms, backs of the hands), fair skinned persons, areas with lots of sunshine • Not cancer but may progress to squamous cell carcinoma Actinic keratoses (upper) and cutaneous horn (left) Neoplastic Skin Disorders • Seborrheic keratosis (SK) • Sharply demarcated, hyperkeratotic, variably pigmented, round, flat, “waxy” plaques with a velvety to rough, granular surface (“stuck-on” appearance) • Particularly numerous on sun exposed areas such as the trunk, extremities, head, and neck (sometimes found on areas not exposed to sun) • Do not progress to carcinoma Neoplastic Skin Disorders • Nevus (nevi), also freckle, lentigo, melanocytic nevus, “mole” • Localized hyperplasia of melanocytes in skin or mucous membranes • Tan to brown, uniformly pigmented, small macules to papules with welldefined, rounded borders • May be congenital or acquired Congenital nevi Acquired nevi Neoplastic Skin Disorders • Dysplastic nevus • Larger than most nondysplastic nevi (often >5 mm across), flat macules, slightly raised plaques with a “pebbly” surface, or target-like lesions with a darker raised center and irregular flat periphery, uniform or variable color • Not cancerous but may progress to melanoma • Dysplastic nevus syndrome (CDKN2A gene) • Patient may have hundreds of dysplastic nevi • Over 50% will develop melanoma by age 60 Neoplastic Skin Disorders • Basal cell carcinoma • Most common nonmelanoma skin cancer • 75% of nonmelanoma skin cancers • Areas of sun exposure, usually in 60+ year old persons • Derived from basal epidermal layers (stratum germinativum) • Flesh-colored to red, with telangiectasias (dilated vessels), pearly, raised, smooth border, often with central ulceration (not painful) • Slow growing, rarely metastasize, may invade locally Telangiectasia Neoplastic Skin Disorders • Squamous cell carcinoma (SCC) • Second most common nonmelanoma skin cancer • Areas of sun exposure, usually in 40+ year old persons • Up to 5% metastasize • Derived from actinic keratoses • Lesions which have not invaded through the basement membrane are sharply defined, red, scaling plaques (“carcinoma in situ”) • Advanced, invasive lesions are nodular, show variable keratin production (hyperkeratotic scale), may ulcerate (not painful) • Keratocanthoma is a type of well-differentiated squamous cell carcinoma Neoplastic Skin Disorders: Squamous Cell Squamous cell carcinoma in situ Keratocanthoma Squamous cell carcinoma Neoplastic Skin Disorders • Melanoma • Derived from melanocytes (normally in epidermis only) • Occur in skin (most common) also on mucosal surfaces, meninges, eye • Relatively common, highly metastatic skin cancer • Does not require sun exposure (but sun increases risk) • The most consistent clinical signs are changes in the color, size, or shape of a pigmented lesion • Risk evaluated by “Breslow scale” or “Clark level”, related to depth of penetration in the epidermis, dermis or into deeper tissues • Scales associated with the metastatic potential at the time of diagnosis (and 5-year survival rate) Neoplastic Skin Disorders: Melanoma Neoplastic Skin Disorders: Melanoma Neoplastic Skin Disorders: Melanoma Mucosal melanoma (Buccal membrane [L, C] and labia minora [R]) Ocular melanoma (iris) Subungual melanoma (nail)