Module 2 Disorders of the Integumentary System PDF

Disorders of the Integumentary System Module 2  Outline Background Inflammatory Skin Disorders Papulosquamous Disorders Bacterial Skin Infections Viral Skin Infections Fungal Skin Infections Vitamin D, Sunlight and Skin Cancer BACKGRO...

Disorders of the Integumentary System Module 2  Outline Background Inflammatory Skin Disorders Papulosquamous Disorders Bacterial Skin Infections Viral Skin Infections Fungal Skin Infections Vitamin D, Sunlight and Skin Cancer BACKGROUND  Functions of the Integumentary System Primary function is to protect the body – Barrier against microorganisms, ultraviolet radiation, loss of body fluids, and the stress of mechanical forces – “First line of defense” – Skin microbiome protects against pathologic bacteria Regulates body temperature Involved in the production of vitamin D Touch and pressure receptors provide important protective functions and pleasurable sensations  Composition of the Integumentary System Integumentary system = skin + accessory structures Skin – Largest organ of the body – 20% of the body’s weight – Epidermis, dermis and subcutaneous layer Accessory structures – Hair – Nails – Glands Fig. 46.1A Layers of the Epidermis Merkel Cell Fig. 46.1B  Cells of the Epidermis Keratinocytes -> keratin – Insoluble protein – Main constituent of skin, hair, and nails – Forms in basal layer, cells move upward, differentiate and flattens as they ascend to stratum corneum – Protection form mechanical stress Melanocytes -> melanin – Found alongside keratinocytes in stratum basale layer; – Derived from amino acids (tyrosine) – Absorbs UV light, which stimulates melanin production, to prevent DNA damage to cells below the epidermis  Cells of the Epidermis Langerhans cells – Specialized dendritic cells of the skin – Migrate from bone marrow to epidermis – Present antigens to T cells to initiate adaptive immune responses Merkel cells – Sensory cells involved in touch  Dermis A connective tissue matrix: 1. Collagen 2. Elastin 3. Reticulin Allows the skin to stretch and contract Contains hair follicles, sebaceous glands, sweat glands, blood vessels, lymphatic vessels, nerves Also contains fibroblasts, mast cells, macrophages Kawasumi et al, 2012  Subcutaneous Layer Consists of fat cells (adipocytes) that are organized into lobules by fibrous walls of collagen and large blood vessels http://faculty.ivytech.edu/~jrosentr/anp/gallery/Week_005_Integumen https://www.ncbi.nlm.nih.gov/books/NBK499819/figure/article-36746.image.f5/?report= t_Layers_1.html objectonly  Clinical Manifestations of Skin Dysfunction PRIMARY SKIN LESIONS SECONDARY SKIN LESIONS Macule Telangiectasia Scale Erosion Plaque Tumor Scar Atrophy Papule Pustule Lichenification Ulcer Wheal Vesicle Excoriation Patch Cyst Keloid Nodule Fissure ** Tables 46.3 – 46.4 11 INFLAMMATORY SKIN DISORDERS  Inflammatory Skin Disorders Dermatitis Otherwise known as eczema General term that is used to describe skin inflammation Characterized by pruritus, lesions with indistinct borders, and epidermal changes Lesions can appear as either erythema, papules, or scales Figure 4; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317931/  Types of Eczema (Dermatitis) Atopic (‘Allergic’) Dermatitis (Type I/Acute) Allergic Contact Dermatitis (Type IV/Delayed) NonAllergic Contact Dermatitis Irritant Contact Dermatitis Stasis Dermatitis Seborrheic Dermatitis  Hypersensitivity Reactions Hypersensitivity: defined as an altered immunologic reaction to an antigen that results in disease or inflammation causing damage to the host. Four mechanisms of hypersensitivity: – Type I is mediated by IgE and is known as allergy. – Type II includes tissue-specific reactions. – Type III is mediated by immune complex deposition. – Type IV consists of cell-mediated reactions (delayed hypersensitivity).  Atopic dermatitis Chronic inflammation of the skin Figure 47.2A Relapsing and remitting course Cause is unclear, but is thought to occur through a type I hypersensitivity mechanism Altered skin barrier function Often accompanied by asthma, allergic rhinitis, and food allergies Causes erythema, pruritis, scaling and lichenification (thickening of skin) In dark-skinned individuals Figure 4; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317931/ papules are often present and erythema appears violet in color More common in infancy and childhood  Allergic Contact Dermatitis Caused by a hypersensitivity type IV reaction Allergens include: microorganisms, chemicals, foreign proteins, drugs, metals, latex (can also form a type 1) Steps involved: Allergen interacts with skin Binds to carrier protein to form sensitizing antigen Langerhans cells process antigen, present it to T cells, which become sensitized to antigen T cells release cytokines and chemokines leading to leukocyte infiltration and inflammation Manifestations Erythema, swelling, pruritus, vesicular lesions typically seen in areas of allergen contact Allergic Contact Dermatitis  Clinical Example of Allergic Contact Dermatitis https://www.medicalnewstoday.com/articles/265375#poison Figure 46-5: Poison Ivy https://www.mayoclinic.org/diseases-conditions/contact-dermatitis/symptoms-causes/syc-20352742 https://www.healthline.com/health/contact-dermatitis  Hypersensitivity Reactions: Urticaria Known as hives; caused by type I hypersensitivity reactions to allergens Drugs, foods, environmental agents Histamine release causes endothelial cells of the skin to contract Causes leakage of fluid from the vessels Figure 46-23 Appears as wheals, welts or hives Treatment Antihistamines and steroids https://www.mayoclinic.org/diseases-conditions/chronic-hives/symptoms-causes/syc-20352719#dialogId39233562 PAPULOSQUAMOUS DISORDERS  Papulosquamous Disorders A series of disorders that are associated with the development of papules, scales, plaques and erythema, including: – Psoriasis – Pityriasis Rosea – Lichen Planus – Acne Vulgaris – Acne Rosacea – Lupus Erythematosus 22  Psoriasis Chronic, noncontagious, relapsing, proliferative, autoimmune skin disorder Scaly, thick, silvery, elevated well-demarcated erythematous lesions, – Usually on the scalp, elbows, or knees caused by a high rate of mitosis Involves complex interaction between keratinocytes, fibroblasts, and immune cells 23 https://www.healthline.com/health/psoriasis-on-black-skin#different-types Figure 46-8 – Plaque Psoriasis  Papulosquamous Disorders Plaque psoriasis – most common Less common: Inverse psoriasis Guttate psoriasis Pustular psoriasis Erythrodermic psoriasis https://onlinelibrary.wiley.com/doi/full/10.1002/2327-6924.12443 Secretion of mediators promote keratinocyte proliferation, activation, and infiltration of other immune cells Thickening of dermis and epidermis caused by keratinocyte hyperproliferation and altered differentiation Epidermal turnover goes from 26-30 days to 3-4 days, resulting in thickening and plaque formation Cells do not have time to mature or adequately keratinize  Psoriasis Antigenic trigger is unknown Antigen taken in by DCs and becomes activated DCs present antigen and activates Th1 and Th17 cells Through IL-12 and IL-23 production T cells migrate to the skin – Release cytokines E.g. IL-17 IFN-γ, TNF-α – Release chemokines Recruits more immune cells that cross into the epidermis Cell are activated, produce cytokine to enhance inflammation and activate keratinocytes Hyperplasia of keratinocytes – Influx of inflammatory cells to the epidermis damages basement membrane, triggers keratinocyte proliferation and plaque formation  Psoriasis In people with psoriasis and psoriatic arthritis, TNF-a, IL-17 and IL-23 is produced in excess amounts by immune cells The messages communicated by these cytokines lead to rapid growth of skin cells found in psoriasis joint pain and stiffness associated with psoriatic arthritis Several biologic medications work by binding to and inhibiting to these cytokines Others target T cells by preventing its activation and/or migration 27  Acne Vulgaris Common skin disease Occurs in 12–25-year-olds Develops in sebaceous follicles located on face, upper chest, back Large sebaceous glands + thin hair + follicular canal (i.e. pore) Noninflammatory acne – Blackheads – open comedones – Whiteheads – closed comedones Inflammatory acne – Caused by follicular wall rupture in closed comedones – Expels sebum into surrounding dermis 🡪 inflammation 28 – Cystic nodules develop when inflammation is deeper, may cause scarring  Acne Vulgaris Plugging of sebaceous follicles Pathophysiological Factors: 1) Hyperkeratination of follicular epithelium 2) Altered sebum production -Excessive production related to hormones (i.e. androgens) 3) Colonization of Cutibacterium acnes -Shifts from symbiotic to pathogenic strain 4) Inflammation and rupture of a follicle due to accumulated debris and bacteria 29  Acne Vulgaris Noninflammatory Inflammatory http://acnehubs.com/types-of-acne/acne-vulgaris-treatment/  Acne Vulgaris Pustules Papules Closed comedones Open comedones VIRAL SKIN INFECTIONS  Varicella-Zoster Virus Herpesvirus that causes Figure 47-9 varicella and herpes zoster Highly contagious; spread via airborne droplets or close person-to-person contact Incubation period is usually 14 days Characterized by an itchy, blistering rash on trunk, scalp or face that lasts ~5-10 days Patients are contagious 24 hours before lesions appear and continue to be until lesions crusted over in ~5-6 days http://www.zimbio.com/Black+pox/articles/X9GPqIcdKyg/Chicken+Pox+Images+Identify+Stages+ Chicken  Herpes Zoster Varicella-zoster herpes virus can infect trigeminal and dorsal root ganglia during course of chicken pox and remain dormant for years Virus can re-activate during a state of immunosuppression, caused by severe stress, injury, certain medications or aging 🡪 Resulting in Herpes Zoster (Shingles) – Impacts 10% of individuals that experienced chickenpox Shingles is an acute infectious disorder characterized by sensations of itching, tingling or pain in a defined area that later develops a rash with vesicular eruptions then crusting Thoracic or lumbar dermatome are the most common sites affected Only one attack of shingles typically occurs in a given patient’s lifetime Varicella-Zoster Virus BACTERIAL SKIN INFECTIONS  Bacterial Skin Infections Caused by local invasion of pathogens Common pathogens: – Staphylococcus aureus (most common) – Streptococci – CA-MRSA (community acquired-MRSA) Main types of Infection – Folliculitis – Cellulitis – Impetigo – http://www.dermnetnz.org/bacterial/index.html  Bacterial Skin Infections: Folliculitis Folliculitis: Infection of hair follicles Common culprit: Staphylococcus aureus – Bacteria multiply, secrete factors resulting in lesions including papules, pustules, surrounding area of erythema Hyperpigmented and skin-colored papules in African American patient https://www.sportsmedreview.com/blog/recognizing-and-treating-bacterial- folliculitis/ https://www.aafp.org/pubs/afp/issues/2013/0615/p859.html  Bacterial Skin Infections: Cellulitis Cellulitis: Infection of the dermis and subcutaneous tissue Caused by: Staphylococcus aureus, group A Streptococcus, and Streptococcus pyogenes Risk factors: diabetes, edema, PVD, tinea pedis, insect bites, immune suppression Infected area: erythematous, warm, edematous, painful without distinct border https://www.nhs.uk/conditions/cellulitis/  Figure 47.4 Bacterial Skin Infections: Impetigo Impetigo: Superficial infection with lesions located on face and hands More common in children aged 2-5 years Higher incidence in hot humid climates Caused by: Staphylococcus aureus and/or Streptococcus pyogenes Bacterial toxins disrupt skin barrier causing blister formation – Two forms: nonbullous and bullous https://dermnetnz.org/topics/impetigo – Superficial skin lesions that rupture, creating a thin, flat, honey-colored crust FUNGAL SKIN INFECTIONS  Fungal Infections Dermatophytes: Fungi causing superficial skin lesions – Thrive on keratin Mycoses: Fungal disorders – Tinea infections: fungal skin infections caused by dermatophytes and classified by location – Candidiasis: caused by yeastlike fungus Candida albicans infection of mucous membranes on skin, GI tract, and vagina, penis, nail folds, large skin folds, or mouth (Table 46-9) – Fungus switches from commensal to pathogenic in immunosuppressed individuals  Fungal Infections Tinea infections can be broken down based on location (Table 46-8) – Tinea capitis: Scalp – Tinea pedis: Foot, “Athlete’s foot” – Tinea corporis: “Ringworm” – Tinea cruris: Groin, “Jock itch” – Tinea manuum: palmar surface of hand – Tinea unguium or onychomycosis: Nail Tinea pedis – Figure 46-21 https://www.nhs.uk/conditions/ringworm/ VITAMIN D, SUNLIGHT, AND SKIN CANCER  Ultraviolet Radiation Sunlight sustains life on earth Ultraviolet (UV; left of violet light in the visible spectrum) radiation wavelength ~10-400 nm – UVA = long wave, 400-315 nm – UVB = medium range, 315-290 nm UVB sometimes referred to as short wave (relative to UVA), since UVC is rare at Earth’s surface – UVC = short range, 290-200 nm UVC mostly in the ozone absorbedVisible Ultraviolet layer Infrared  Ultraviolet Radiation UV light at the Earth’s surface is ~95% UVA 5% UVB – Ozone layer does not have universal thickness, sometimes more UVB penetrates – Greater intensity in summer, at equator, higher altitudes – UVB rays produce most carcinogenic effects on skin cells Can penetrate water https://www.cdc.gov/nceh/features/uv-radiation-safety/index.html#:~:text=Almost%20all%20the%20UV%20radiation,more%20constant%20throughout%20the%20year.  Ultraviolet Radiation Sunburn: Acute reaction to excessive amounts of UV radiation – UVA: penetrates deep skin layers – UVB: penetrates skin more superficially 🡪 sunburn – Vasodilatation and increased blood volume in dermis, resulting in erythema on white skin but may be harder to see on darker colored skin – Skin hot to the touch – Appears within a few hours of prolonged exposure https://www.mountsinai.org/health-library/symptoms/sunburn  Ultraviolet Radiation Exposure to UV radiation elevates skin cancer risk Sources: sun, tanning beds, certain light sources, some lasers Two main groups: – Nonmelanoma Squamous cell carcinoma Basal cell carcinoma – Melanoma Malignant melanoma Benefits to sunlight exposure - production of vitamin D Calcium and phosphorus absorption and retention Bone health  Vitamin D Skin is involved in the production of vitamin D through exposure to sunlight Vitamin D: – Fat soluble steroid hormone – Obtained by photoexposure, diet, supplements – Important for calcium homeostasis and bone health – Beneficial influence of vitamin D on various health conditions Valdivielso et al., 2009  Vitamin D UV light at ~300 nm converts 7-dehydrocholesterol in the plasma membrane of keratinocytes and fibroblasts into previtamin D3 Same UVB wavelength is also HEAT responsible for sunburn and cancer (photocarcinogenesis) Dietary intake Vitamin D2/D3 and epidermal D3 bound to carrier proteins🡪 Circulation 🡪 Liver undergo hydroxylation Kitson & Roberts, 2012  Vitamin D 25-hydroxyvitamin D = 25(OH)D = major circulating form of vitamin D – Serum levels are widely used as a reflection of total body stores – Biologically inactive, requires hydroxylation in the kidney – forms the biologically active 1,25-dihydroxyvitamin D (1,25[OH2]D) Kitson & Roberts, 2012 Vitamin D  Vitamin D Can you overdose on vitamin D by being in the sun all day? No: feedback loop – Previtamin D levels stop increasing – Further UV exposure results in production of inactive metabolites Sunscreen usage and vitamin D Contribution from dietary sources should be considered Foods and supplements https://www.forbes.com/health/supplements/vitamin-d-guide/  Skin Cancer Many factors can contribute to skin cancer – Environmental factors – Host factors – Genetic predisposition International Agency for Research on Cancer classified solar radiation as carcinogenic to Fitzpatrick skin type humans Classification of sun-reactive skin types UVR damage DNA / DNA Pediatrics 2011;127:e791–e817 repair mechanisms, suppress cell mediated immunity Connection between skin type and cancer risk Box 46.5  Nonmelanoma Skin Cancer 2-3 million new cases each year Rates appear to be increasing in Canada/US between 3-8%/year Basal cell carcinoma and Squamous cell carcinoma Basal cell carcinoma most frequently observed – ~80% of nonmelanoma skin cancers Incidences greater in men than women Risk increases with age  Basal Cell Carcinoma Most common type of skin cancer ~80-85% occur on the head and neck Mainly caused by UV radiation exposure Surface epithelial tumor originating from undifferentiated basal or stem cells Arise from mutation in p53 tumor suppressor genes Rarely metastasize Spread along paths of least resistance (periosteum, perichondrium, fascia, or tarsal plate) – Bone, cartilage, and muscle invasion are uncommon but can occur Low mortality, but high burden on healthcare system  Basal Cell Carcinoma Lesions: nodule, slightly elevated above the skin surface The tumors grow upward and laterally or downwards Usually have depressed centers and rolled borders As they grow often ulcerate, develop crusting, and become firm https://www.mayoclinic.org/diseases-conditions/basal-cell-carcinoma/symptoms-causes/syc-20354187  Squamous Cell Carcinoma Tumor of the epidermis Most common in head and neck UV radiation promotes mutation in p53 tumor suppressor genes Two types: Figure 46-30 In situ – confined to epidermis and dermis Invasive – arise from premalignant lesions More likely to metastasize Grows more rapidly than Basal CC https://www.goodrx.com/conditions/skin-cancer/skin-cancer-people-of-color-pictures-prevention Penetrates basement membrane between epidermis and dermis  Melanoma Malignant tumor of the skin originating from melanocytes Malignant degeneration of melanocytes lead to melanoma Mole= nevus, plural nevi; aggregated melanocytes https://www.goodrx.com/conditions/skin-cancer/skin-cancer-people-of-color-pictures-p Suspicious nevi can be revention removed, easy process when no evidence of metastasis Caused by mutations that: Activate oncogenes Inactive tumor suppressor https://www.cancer.org/research/acs-research-news/study-lack-of-education-about-melano ma-may-contribute-to-black-white-survival-disparities.html genes Impair DNA repair genes Staging Criteria: Melanoma Asymmetry One side does not look like the other side. Border irregular The edges are ragged or uneven. Color varies More than one color is present. Melanoma may include streaks of tan, brown, black, red, blue and white. Diameter larger It is larger than the size of a pencil eraser (6 millimeters) or has changed shape Elevation or Evolution http://www.basalcellcarcinoma.info/what-is-basal-cell-carcinoma  UV Radiation Induced DNA Damage UVB radiation produces: – Damaged DNA UVR induces formation of covalent interactions between adjacent bases forming cyclobutane pyrimidine dimers (from thymine and cytosine bases) – Mutations to p53 tumor suppression genes UVA radiation does not directly damage DNA, but damages cells by causing reactive oxygen species which can damage DNA crosslinks  UV Radiation Induced DNA Damage The body can repair damaged UV Radiation DNA – E.g. Nucleotide excision repair Damaged DNA segment identified DNA segment unwound, cut away DNA Damage DNA polymerase matches appropriate nucleotides Normal sequence restored Nucleotide-Excisio n Repair Repetitive UV exposure can exceed capacity to repair damaged DNA  DNA Damage in Skin Cancer If DNA damage > DNA repair, UV Radiation p53 is activated to induce cell death – p53 = transcription factor regulating cell cycle control and cellular apoptosis DNA Damage UV-induced mutations affect genes encoding critical proteins or enzymes p53 contributing to DNA repair – High percentage of p53 mutations found SCC Adapted from Gnanasundram et al., 2021  DNA Damage in Skin Cancer Oncogenes vs. Tumor Suppressor Genes – Proto-oncogenes promote cell proliferation E.g. epidermal growth factor – Tumor suppressor genes encode proteins that stop proliferation – Work as a balance Oncogenes are mutated, cells continue to proliferate When combined with inactivated tumor suppressor genes, can cause cancer – Tumor suppressors must be inactivated for cancer to occur – We have two alleles of each gene, requires “two hits” to inactivate the two alleles of a tumor suppressor gene Questions?