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Physiology, Integument


Physiology, Integument

Article Author:
Joyce Kim
Article Editor:
Harry Dao
Updated:
5/17/2020 7:21:46 PM
For CME on this topic:
Physiology, Integument CME
PubMed Link:
Physiology, Integument

Introduction

The integumentary system is the largest organ of the body that forms a physical barrier between the external environment and the internal environment that it serves to protect and maintain. The integumentary system includes the epidermis, dermis, hypodermis, associated glands, hair, and nails. In addition to its barrier function, this system performs many intricate functions such as body temperature regulation, cell fluid maintenance, synthesis of Vitamin D, and detection of stimuli. The various components of this system work in conjunction to carry out these functions—for example, body temperature regulation occurs through thermoreceptors that lead to the adjustment of peripheral blood flow, degree of perspiration, and body hair.

Organ Systems Involved

Components of the Integumentary system:

Skin: The skin is made up of two layers—the superficial epidermis and the deeper dermis.

The epidermis is the tough, outer layer that acts as the first line of defense against the external environment. It is composed of stratified squamous epithelial cells that further break down into four to five layers. From superficial to deep, the primary layers are the stratum corneum, stratum granulosum, stratum spinosum, and stratum basale. In the palms and soles where the skin is thicker, there is an additional layer of skin between the stratum corneum and stratum granulosum called the stratum lucidum. The epidermis regenerates from stem cells located in the basal layer that grow up towards the corneum. The epidermis itself is devoid of blood supply and derives its nutrition from the underlying dermis.

The dermis is the underlying connective tissue framework that supports the epidermis. It further subdivides into two layers—the superficial papillary dermis and the deep reticular layer. The papillary layer forms finger-like projections into the epidermis, known as dermal papillae, and consists of highly vascularized, loose connective tissue. The reticular layer has dense connective tissue that forms a strong network.[1] The dermis as a whole contains blood and lymph vessels, nerves, sweat glands, hair follicles, and various other structures embedded within the connective tissue. 

Hypodermis: The hypodermis lies between the dermis and underlying organs. It is commonly referred to as subcutaneous tissue and is composed of loose areolar tissue and adipose tissue. This layer provides additional cushion and insulation through its function of fat storage and connects the skin to underlying structures such as muscle. 

Hair: Hair is derived from the epidermis but grows its roots deep into the dermis. Its structure divides into the externally visible hair shaft and the hair follicle within the skin. The hair follicle has an intricate structure that contains the hair bulb that actively divides to extend the hair shaft vertically.[2] Hair generally categorizes into hormone-dependent, thicker terminal hairs in regions such as the axilla, pubic areas, scalp, chest, etc. and androgen-independent vellus hairs that cover the rest of the areas.[2] Hair growth has multiple phases called anagen (growth phase), catagen (nonproliferative phase), and telogen (resting phase) that cycles depending on hormones and nutrients.[3] Hair covers the majority of the body with the few exceptions of the palms, soles, lips, and portions of external genitalia. Hair serves as mechanical protection for the skin, increases sensory function, and aids in the regulation of body temperature. Arrector pili muscles located in the dermis attach to hair follicles, helping the shaft to stand and trap air close the epidermis for temperature control.

Nails: Nails form as layers of keratin and appear at the dorsal tips of the fingers and toes.[4] The nail growth begins at the nail matrix that creates new cells and pushes old cells out distally. The visible portion of the nail is the nail plate that covers the nail bed, where it adheres to the finger. Nails function to protect the fingers and toes while increasing the precision of movements and enhancing sensation.

Associated Glands: There are four types of exocrine glands within human skin—sudoriferous, sebaceous, ceruminous, and mammary glands.

Sudoriferous glands, also known as sweat glands, are further divided into eccrine and apocrine glands. Eccrine glands are distributed throughout the body and primarily produce serous fluid to regulate body temperature.[5] Apocrine glands are present in the axilla and pubic area and produce milky protein-rich sweat.[5] These glands are responsible for odor as bacteria break down the secreted organic substances.

Sebaceous glands are part of the pilosebaceous unit, which includes the hair, hair follicle, and arrector pili muscle.[6] It secretes an oily substance called sebum, a mixture of lipids that forms a thin film on the skin. This layer adds a protective layer, prevents fluid loss, and also plays an antimicrobial role.[7][8] 

Function

Physical protection: Given that the integumentary is the covering of the human body, its most apparent function is physical protection. The skin itself is a tightly knit network of cells, with each layer contributing to its strength. The epidermis has an outermost layer created by layers of dead keratin that can withstand wear and tear of the outer environment, while the dermis provides the epidermis with blood supply and has nerves that bring danger to attention amongst other functions. The hypodermis provides physical cushioning to any mechanical trauma through adipose storage, and the glands secrete protective films throughout the body. The nails protect the digits, which are prone to repeated trauma by creating a hard covering and hairs throughout the body filter harmful particles from entering the eyes, ears, nose, etc.   

Immunity: The skin is the body’s first line of defense as it acts as the physical barrier that prevents direct entry of pathogens. Cells are connected through junction proteins with reinforcement by keratin filaments.[9]

Antimicrobial peptides (AMPs) and lipids on the skin also act as a biomolecular barrier that disrupts bacterial membranes. AMPs, such as defensins and cathelicidins, are produced by various cells in the skin such as dendritic cells, macrophages, glands, etc. and are activated by proteolytic cleavage with stimulation. Lipids, such as sphingomyelin and glucosylceramides, are stored in lamellar bodies found in the stratum corneum and display antimicrobial activity.[9]

An additional aspect of the skin’s immunity lies in the resident immune cells. Both myeloid and lymphoid cells are present in the skin, and some, such as the Langerhans cells or dermal dendritic cells, possess the capability to travel to the periphery and activate the greater immune system.[9]

Wound healing: When our body undergoes trauma with a resulting injury, the integumentary system orchestrates the wound healing process through hemostasis, inflammation, proliferation, and remodeling.[9]

Hemostasis occurs through tissue factor, located in subendothelial spaces of the skin, which triggers the coagulation cascade to form a fibrin clot.

In the following inflammatory phase, immune cells such as neutrophils and monocytes will infiltrate the injury site to attack pathogens and clear out debris.

The proliferative phase involves the multiplication of resident cells such as keratinocytes and fibroblasts that contribute to the formation of granulation tissue. Through a matrix of immune cells and the eventual formation of a collagen network by fibroblasts and myofibroblasts, the new extracellular matrix forms.[9]

The final remodeling phase consists of apoptosis as cells are no longer needed and excess structures are broken down in efforts to restore the original architecture. Macrophages secrete matrix metalloproteases that remove excess collagen and remaining immature collagen matures to finalize the extracellular matrix.[9]

Vitamin D synthesis: The primary sources of vitamin D are sun exposure and oral intake. With ultraviolet sunlight exposure, 7-dehydrocholesterol converts to vitamin D3 (cholecalciferol) in the skin. Cholecalciferol is then hydroxylated in the liver then kidney into its active metabolite form, 1,25-dihydroxy vitamin D (calcitriol).[10] This metabolite ultimately leads to increased calcium absorption in the gut and is crucial for bone health. 

Regulation of body temperature: The skin has a large surface area that is highly vascularized, which allows it to conserve and release heat through vasoconstriction and vasodilation, respectively. When body temperatures rise, blood vessels dilate to increase blood flow and maximize the dissipation of heat.[11] In conjunction with this method, the evaporation of sweat secreted by the skin allows for greater heat loss. The hair on the body also affects the regulation of body temperature as erect hair can trap a layer of heat close to the skin. Various inputs from central and skin thermoreceptors provide fine-tuning for this thermoregulatory system.   

Sensation: Skin innervation is by various types of sensory nerve endings that discriminate pain, temperature, touch, and vibration. Mediation of innocuous touch in glabrous skin by four types of mechanoreceptors—Meissner corpuscle, Pacinian corpuscle, Ruffini endings, and Merkel cells.[12] Meissner corpuscles can detect movement across the skin, Pacinian corpuscles detect high-frequency vibration, Ruffini endings detect stretch and Merkel cells aid in spatial imaging.  In hairy skin, tactile stimuli are picked up by three types of hair follicles and their associated longitudinal and circumferential lanceolate endings.[12] Noxious stimuli in both glabrous and hairy skin are detectable by free nerve endings located in the epidermis.[12] Each type of receptor and nerve fiber varies in its adaptive and conductive speeds, leading to a wide range of signals that can be integrated to create an understanding of the external environment and help the body to react appropriately. 

Pathophysiology

Pathology  

Given that the integumentary system has direct exposure to external threats such as physical trauma, radiation, extreme temperatures, microorganisms, etc., it can fall susceptible to wounds, infections, burns, cancers, and more. The integumentary system is unique in that pathologic conditions are often directly visible to patients, and at times the system reflects pathologic conditions that may be occurring internally. The following are common conditions that can appear throughout components of the integumentary system:

Skin: 

Acne – Acne is a very common condition that involves inflammation of the pilosebaceous unit caused by overproduction of keratin within hair follicles, increased sebum production, and Cutibacterium acnes mediated inflammation.[13] Acne can have varying morphologies, including comedones (open and closed), papules, nodules, and pustules, that all vary in appearance and size. Various factors correlate with the development of acne, such as skin trauma, diet, and stress.[14] In women, hormonal acne is characterized by flares involving the jawline, characteristically flaring with menstrual cycles. Increased androgen circulation also contributes to acne, as sebaceous glands produce sebum in response to androgens, which can provide a growth medium for C. acnes and increase inflammation.[13]

Atopic dermatitis – More commonly referred to as eczema, this is a chronic condition that affects both children and adults. Multiple factors such as defects in epidermal junctions, reduced innate immunity in the skin, and genetics appear to contribute to the development of this condition.[15][16] Filaggrin is a protein located within the stratum corneum and functions to link keratin intermediate filaments and create an impenetrable outer layer. A defect in filaggrin will lead to a defective barrier function and increased water loss from the skin, which leads to characteristic symptoms of atopic dermatitis.[17] In young patients, atopic dermatitis is commonly on extensor surfaces and cheeks. It then involves flexural areas in older patients. The hallmark symptom is itching, and environmental factors can often trigger atopic dermatitis. A vicious itch-scratch cycle can then ensue, leading to lichenification of the skin. 

Psoriasis – Chronic plaque psoriasis is the most common subtype of psoriasis and involves well-demarcated, erythematous plaques with an overlying silvery scale.[18] Lesions are pruritic in about 50% of patients. The lesions are typically located on extensor surfaces and tend to have a symmetric distribution. The pathophysiology involves the hyperproliferation of keratinocytes within the epidermis and immune system dysfunction.

Cellulitis – Cellulitis is an infection of the deep dermis and subcutaneous fat that presents with areas of erythema, edema, and warmth.[19][20] It most often results from Streptococcus pyogenes and less often Staphylococcus aureus due to skin barrier disruption, and patients with non-purulent cellulitis should receive empiric therapy for these organisms.[21][22] Cellulitis with purulent drainage should undergo incision and drainage before antibiotic treatment.

Cancer

Squamous cell carcinoma is a malignant tumor originating from epidermal keratinocytes that commonly arise in areas of sun exposure.[23] In darker individuals, lesions can occur unrelated to sun exposure.[23] The appearance can vary but generally present as erythematous papules, plaques, or nodules that may either ulcerate or become hyperkeratotic. The diagnosis requires a biopsy for pathologic confirmation. 

Basal cell carcinoma is the most common skin cancer and is a locally invasive cancer that arises from the basal layer of the epidermis. Ultraviolet radiation is the most significant risk factor that causes mutations in several tumor suppressor genes and proto-oncogenes.[24] The characteristic appearance is a pink, pearly papule with telangiectasia, and a biopsy is necessary to confirm the diagnosis.

Melanoma is a serious form of skin cancer, due to its potential to metastasize quickly, and can be divided into four subtypes—superficial spreading, nodular, lentigo maligna, and acral lentiginous. They arise as a superficial tumor confined to the epidermis but can undergo a vertical growth phase, resulting in increased tumor thickness. Thickness is measured by Breslow's depth, which is a measurement starting from the granular cell layer of the epidermis and is the most important prognostic factor. Melanomas can be detected clinically using the ABCDE criteria (asymmetry, border irregularity, color variation, diameter >6mm, and evolution over time).[25]

Burns—Burns result from excessive heat, radiation, or chemical exposure, and grading of the severity of the burn is by the depth and area of skin involvement. Burns are treated as emergencies, as severe burns can lead to dehydration, sepsis, and death.[26] Burn depth can classify as follows [27]:

  • Superficial: involves only the epidermal layer and does not blister. Lesions are painful, dry, red, and blanch. Injuries generally heal without scarring.
  • Partial-thickness: involves the epidermis and dermis partially. This type of burn can further subcategorize into superficial and deep, depending on the extent of dermis involvement. Superficial partial-thickness lesions form blisters, are painful, blanch with pressure, and weep. Deep partial-thickness burns damage hair follicles and glandular tissue. They are painful to pressure only, do not blanch, and have mottled colorization. They can cause hypertrophic scarring and functional impairment with delayed healing.
  • Full-thickness: extend through all layers of the dermis and often subcutaneous tissue. The lesions are generally dry without blistering and do not blanch with pressure. Eschar (dead dermis) may be present and can compromise a limb if circumferential.
  • Fourth degree: these are the most severe burns that extend beyond the skin into soft tissue and can involve any underlying structures.

Hair:

Alopecia areata – This is an autoimmune condition that involves loss of immune privilege at the hair follicle in addition to T cell-mediated attack on cells of the hair bulb, leading to hair follicles that transition from the growth phase (anagen) to nonproliferative (catagen) and resting (telogen) phases. This situation results in hair shedding in any hair-bearing area, though it most commonly occurs on the scalp. It is a nonscarring condition that can sometimes self-remit with spontaneous hair regrowth, sometimes even without treatment. There are several patterns of hair loss, such as patchy, ophiasis, sisaipho, and diffuse, with patchy alopecia being the most common subtype.[28]

Folliculitis – Folliculitis is inflammation of the hair follicle that presents clinically with follicular pustules and erythematous papules. It may have an infectious or noninfectious etiology and can be due to bacterial, fungal, viral, or parasitic infections. A bacterial infection is the most common etiology, with Staphylococcus aureus being the most common causative bacteria. People will generally experience pruritus over hair-bearing areas and can occasionally have painful pustules and papules. Folliculitis barbae is a subtype of bacterial folliculitis that affects deep portions of the hair follicles in the beard areas.[29]

Male pattern balding – This is a condition with a genetic predisposition in which hair loss occurs in an androgen-dependent manner. Hair follicles undergo follicular miniaturization, which is shortening of the growth phase (anagen), and transition from dark terminal hairs to thin vellus hairs. This process initiates when dihydrotestosterone binds to androgen receptors in the hair follicle and progresses as an increasing number of follicles are affected.[30]

Nails:

Onychomycosis – Onychomycosis is a fungal infection of the toenails or fingernails and can result from dermatophytes, yeasts, and non-dermatophyte molds. The condition is acquired through direct contact, and a compromised nail barrier increases the chances of infection.[31] The common clinical presentation involves nail discoloration, subungual hyperkeratosis, onycholysis, and splitting or destruction of the nail plate, dependent on the specific subtype.[32]

Pitting – Nail pitting occurs due to focal abnormal keratinization of the nail matrix that results in irregular, deep pits within the nail plate as it grows beyond the cuticle. It can affect a single nail or multiple, can involve the fingernails and/or toenails. It presents in conditions such as psoriasis, eczema, and alopecia areata.[33][34]

Koilonychia – Also called spoon nail, this condition involves the upward curving of the distal nail plate that gives the appearance of a spoon. It has been associated with iron deficiency anemia but can be due to idiopathic changes.  

Clubbing – Digital clubbing is characterized by increased nail plate curvature and thickness of the distal fingertip. Clinically, there is flattening of the angle between the nail plate and the nail fold on the side view. It is caused by platelet precursors that fail fragmentation and later get trapped in the distal digit vasculature. There they will release platelet-derived growth factor and vascular endothelial growth factor, which results in clubbing. It is the most common manifestation of hypertrophic osteoarthropathy and correlates with many systemic conditions.[35]

Glands:

Seborrheic dermatitis-Seborrheic dermatitis is a form of chronic dermatitis with unknown pathogenesis that tends to occur in regions with sebaceous glands, such as the scalp, external ears, and center of the face. It presents clinically with erythematous plaques with a yellowish scale and often appears as dandruff when located on the scalp. The cause and predilection for sebaceous glands are not well understood, though studies have suggested that the fungus Malassezia and its byproducts may play a role in the pathogenesis.[36][37][38]

Hyperhidrosis – Hyperhidrosis is excessive secretion of sweat from eccrine glands with possible apocrine gland involvement in axillary hyperhidrosis.[39] Pathogenesis is an abnormal central response to normal emotional stress, which leads to increased sympathetic signaling to endocrine glands through cholinergic autonomic neurons leading to sweating beyond the physiological need for temperature regulation.[40]

Clinical Significance

The integumentary system provides numerous functions necessary for human life while also maintaining an optimal internal environment for other critical components to thrive. When there is an imbalance in this system, any of the disorders mentioned above can manifest. The integumentary system also acts as a reflection of underlying pathologies such as showing jaundice with liver disfunction, displaying petechiae with thrombocytopenia, or decreased skin turgor with dehydration. It is a system that can provide many external clues regarding an individual’s physiological state and is a vital component of a complete clinical picture.


References

[1] Brown TM,Krishnamurthy K, Histology, Dermis 2020 Jan;     [PubMed PMID: 30570967]
[2] Buffoli B,Rinaldi F,Labanca M,Sorbellini E,Trink A,Guanziroli E,Rezzani R,Rodella LF, The human hair: from anatomy to physiology. International journal of dermatology. 2014 Mar;     [PubMed PMID: 24372228]
[3] Breitkopf T,Leung G,Yu M,Wang E,McElwee KJ, The basic science of hair biology: what are the causal mechanisms for the disordered hair follicle? Dermatologic clinics. 2013 Jan;     [PubMed PMID: 23159172]
[4] Haneke E, Anatomy of the nail unit and the nail biopsy. Seminars in cutaneous medicine and surgery. 2015 Jun;     [PubMed PMID: 26176287]
[5] Sato K,Kang WH,Saga K,Sato KT, Biology of sweat glands and their disorders. I. Normal sweat gland function. Journal of the American Academy of Dermatology. 1989 Apr;     [PubMed PMID: 2654204]
[6] Schneider MR,Schmidt-Ullrich R,Paus R, The hair follicle as a dynamic miniorgan. Current biology : CB. 2009 Feb 10;     [PubMed PMID: 19211055]
[7] Picardo M,Ottaviani M,Camera E,Mastrofrancesco A, Sebaceous gland lipids. Dermato-endocrinology. 2009 Mar;     [PubMed PMID: 20224686]
[8] Zouboulis CC,Picardo M,Ju Q,Kurokawa I,Törőcsik D,Bíró T,Schneider MR, Beyond acne: Current aspects of sebaceous gland biology and function. Reviews in endocrine     [PubMed PMID: 27726049]
[9] Nguyen AV,Soulika AM, The Dynamics of the Skin's Immune System. International journal of molecular sciences. 2019 Apr 12;     [PubMed PMID: 31013709]
[10] Lips P, Vitamin D physiology. Progress in biophysics and molecular biology. 2006 Sep;     [PubMed PMID: 16563471]
[11] Gleeson M, Temperature regulation during exercise. International journal of sports medicine. 1998 Jun;     [PubMed PMID: 9694408]
[12] Abraira VE,Ginty DD, The sensory neurons of touch. Neuron. 2013 Aug 21;     [PubMed PMID: 23972592]
[13] O'Neill AM,Gallo RL, Host-microbiome interactions and recent progress into understanding the biology of acne vulgaris. Microbiome. 2018 Oct 2;     [PubMed PMID: 30285861]
[14] Gollnick H,Cunliffe W,Berson D,Dreno B,Finlay A,Leyden JJ,Shalita AR,Thiboutot D, Management of acne: a report from a Global Alliance to Improve Outcomes in Acne. Journal of the American Academy of Dermatology. 2003 Jul;     [PubMed PMID: 12833004]
[15] Kuo IH,Yoshida T,De Benedetto A,Beck LA, The cutaneous innate immune response in patients with atopic dermatitis. The Journal of allergy and clinical immunology. 2013 Feb;     [PubMed PMID: 23374259]
[16] Boguniewicz M,Leung DY, Atopic dermatitis: a disease of altered skin barrier and immune dysregulation. Immunological reviews. 2011 Jul;     [PubMed PMID: 21682749]
[17] Sandilands A,Sutherland C,Irvine AD,McLean WH, Filaggrin in the frontline: role in skin barrier function and disease. Journal of cell science. 2009 May 1     [PubMed PMID: 19386895]
[18] Merola JF,Li T,Li WQ,Cho E,Qureshi AA, Prevalence of psoriasis phenotypes among men and women in the USA. Clinical and experimental dermatology. 2016 Jul;     [PubMed PMID: 26890045]
[19] Liu C,Bayer A,Cosgrove SE,Daum RS,Fridkin SK,Gorwitz RJ,Kaplan SL,Karchmer AW,Levine DP,Murray BE,J Rybak M,Talan DA,Chambers HF, Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2011 Feb 1;     [PubMed PMID: 21208910]
[20] Stevens DL,Bisno AL,Chambers HF,Dellinger EP,Goldstein EJ,Gorbach SL,Hirschmann JV,Kaplan SL,Montoya JG,Wade JC, Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2014 Jul 15;     [PubMed PMID: 24973422]
[21] Raff AB,Kroshinsky D, Cellulitis: A Review. JAMA. 2016 Jul 19;     [PubMed PMID: 27434444]
[22] Stevens DL,Bisno AL,Chambers HF,Dellinger EP,Goldstein EJ,Gorbach SL,Hirschmann JV,Kaplan SL,Montoya JG,Wade JC, Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the infectious diseases society of America. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2014 Jul 15;     [PubMed PMID: 24947530]
[23] Waldman A,Schmults C, Cutaneous Squamous Cell Carcinoma. Hematology/oncology clinics of North America. 2019 Feb;     [PubMed PMID: 30497667]
[24] Pellegrini C,Maturo MG,Di Nardo L,Ciciarelli V,Gutiérrez García-Rodrigo C,Fargnoli MC, Understanding the Molecular Genetics of Basal Cell Carcinoma. International journal of molecular sciences. 2017 Nov 22;     [PubMed PMID: 29165358]
[25] Abbasi NR,Shaw HM,Rigel DS,Friedman RJ,McCarthy WH,Osman I,Kopf AW,Polsky D, Early diagnosis of cutaneous melanoma: revisiting the ABCD criteria. JAMA. 2004 Dec 8;     [PubMed PMID: 15585738]
[26] Nunez Lopez O,Cambiaso-Daniel J,Branski LK,Norbury WB,Herndon DN, Predicting and managing sepsis in burn patients: current perspectives. Therapeutics and clinical risk management. 2017;     [PubMed PMID: 28894374]
[27] Mertens DM,Jenkins ME,Warden GD, Outpatient burn management. The Nursing clinics of North America. 1997 Jun;     [PubMed PMID: 9115481]
[28] Strazzulla LC,Wang EHC,Avila L,Lo Sicco K,Brinster N,Christiano AM,Shapiro J, Alopecia areata: Disease characteristics, clinical evaluation, and new perspectives on pathogenesis. Journal of the American Academy of Dermatology. 2018 Jan;     [PubMed PMID: 29241771]
[29] van Lunteren E,Coreno A, Inhaled albuterol powder for pulmonary function testing. Chest. 1992 Apr;     [PubMed PMID: 1555473]
[30] Ellis JA,Sinclair R,Harrap SB, Androgenetic alopecia: pathogenesis and potential for therapy. Expert reviews in molecular medicine. 2002 Nov 19;     [PubMed PMID: 14585162]
[31] Grover C,Khurana A, Onychomycosis: newer insights in pathogenesis and diagnosis. Indian journal of dermatology, venereology and leprology. 2012 May-Jun;     [PubMed PMID: 22565425]
[32] Hay RJ,Baran R, Onychomycosis: a proposed revision of the clinical classification. Journal of the American Academy of Dermatology. 2011 Dec;     [PubMed PMID: 21501889]
[33] de Jong EM,Seegers BA,Gulinck MK,Boezeman JB,van de Kerkhof PC, Psoriasis of the nails associated with disability in a large number of patients: results of a recent interview with 1,728 patients. Dermatology (Basel, Switzerland). 1996;     [PubMed PMID: 8993953]
[34] Kasumagic-Halilovic E,Prohic A, Nail changes in alopecia areata: frequency and clinical presentation. Journal of the European Academy of Dermatology and Venereology : JEADV. 2009 Feb;     [PubMed PMID: 18540984]
[35] Spicknall KE,Zirwas MJ,English JC 3rd, Clubbing: an update on diagnosis, differential diagnosis, pathophysiology, and clinical relevance. Journal of the American Academy of Dermatology. 2005 Jun;     [PubMed PMID: 15928621]
[36] Arsic Arsenijevic VS,Milobratovic D,Barac AM,Vekic B,Marinkovic J,Kostic VS, A laboratory-based study on patients with Parkinson's disease and seborrheic dermatitis: the presence and density of Malassezia yeasts, their different species and enzymes production. BMC dermatology. 2014 Mar 14;     [PubMed PMID: 24628775]
[37] Faergemann J,Bergbrant IM,Dohsé M,Scott A,Westgate G, Seborrhoeic dermatitis and Pityrosporum (Malassezia) folliculitis: characterization of inflammatory cells and mediators in the skin by immunohistochemistry. The British journal of dermatology. 2001 Mar;     [PubMed PMID: 11260013]
[38] Riciputo RM,Oliveri S,Micali G,Sapuppo A, Phospholipase activity in Malassezia furfur pathogenic strains. Mycoses. 1996 May-Jun;     [PubMed PMID: 8909036]
[39] Lonsdale-Eccles A,Leonard N,Lawrence C, Axillary hyperhidrosis: eccrine or apocrine? Clinical and experimental dermatology. 2003 Jan;     [PubMed PMID: 12558618]
[40] Sato K,Kang WH,Saga K,Sato KT, Biology of sweat glands and their disorders. II. Disorders of sweat gland function. Journal of the American Academy of Dermatology. 1989 May;     [PubMed PMID: 2654213]