Primary biliary cirrhosis is a type of cirrhosis that occurs when the bile ducts from the liver to the duodenum are inflamed and blocked. Some people suffering from cirrhosis have no symptoms until damage caused is already severe.
Cirrhosis is a potentially life-threatening condition that occurs when the inflammation of the fibrotic tissue affects the liver. A combination of tests can be used for diagnostic when physical examination and medical history suggests signs of cirrhosis. Partial thromboplastin time (PTT), prothrombin time (PT) or international normalized ratio (INR).
The level of Alpha-1-antitrypsin can diagnose the alpha-1-antitrypsin deficiency (ATT), a rare cause of cirrhosis.
Imaging tests check for tumors and biliary obstruction and evaluate liver size and hepatic blood flow. Paracentesis helps diagnose fluid accumulation in the abdominal cavity (ascites) or to detect the infection of the accumulated fluid (spontaneous bacterial peritonitis). Upper gastrointestinal endoscopy is performed to detect varicose veins in the digestive tract that may cause variceal bleeding.
The ammonia test detects high levels of ammonium in the blood which can cause hepatic encephalopathy.
There is currenly no treatment or cure for cirrhosis, nor is there a treatment that can heal the liver damage done. Liver transplant, if severe liver damage and if the patient is included on the transplant waiting list and a compatible donor is found.
Vein walls are composed of the same three layers as an artery but the media layer is much thinner. Venous valves normally allow flow to move in one direction in the vessel, toward the heart. Note the size difference between the two extremities which can be a sign of acute DVT, if it has an acute onset. Normal venous response to the Valsalva maneuver is cessation of venous flow toward the heart.Flow reversal upon release of the Valsalva maneuver indicates the presence of reflux. If flow reversal occurs at the onset of the Valsalva, the duration of the reflux flow must be measured. The distal augmentation maneuver is used to confirm the absence of DVT following the compression maneuvers. Ask a Doctor Online Now!It is important to have at least a basic knowledge of the anatomy of the hand when looking at hand pain. There are numerous joints that make up the hand which allow it a wide range of movement and flexibility, thus making it possible for it to perform various functions.
Carpometacarpal joints where some of the carpal bones (wrist bones) articulate with the long metacarpal bones (hand bones). Metacarpophalangeal joints where the five metacarpals (hand bones) connects with the phalanges (thumb and finger bones).
Interphalangeal joints where the two phalanges (finger bones) in the thumb and three phalanges in the other fingers connect.
Ask a Doctor Online Now!The radial, ulnar, and median nerves pass into the hand from the forearm and supply specific parts of the hand.
Injury to any of the structures of the hand, such as a tendon, ligament, muscle, bone, skin, nerve, or blood vessel. Overuse or repetitive hand movements, as in typing on a computer keyboard, repetitive wringing at the wrist, sports such as handball, or sewing can lead to problems such as carpal tunnel syndrome, tendinosis, De Quervain’s disease, or writer’s cramp. Surgery to the hand may result in post-operative pain or at times there is unintentional damage to the hand structures.
Carpal tunnel syndrome, causing hand pain, may also occur due to other causes such as diabetes, obesity, rheumatoid arthritis, hypothyroidism, and pregnancy. Dupuytren’s contracture – abnormal thickening of the fascia or the tissue beneath the skin of the palm.
Myocardial infarction (heart attack) may present with arm pain that can extend to the hand. Raynaud’s phenomenon – extreme cold or emotional stress precipitate this phenomenon in certain individuals, causing spasm and constriction of the blood vessels of the fingers and toes, resulting in pallor, tingling, numbness, and pain in the hand. Blood tests, including complete blood count (CBC), ESR, antistreptolysin-O-titer, rheumatoid factor, and serum uric acid level.
Please note that any information or feedback on this website is not intended to replace a consultation with a health care professional and will not constitute a medical diagnosis. Science, Technology and Medicine open access publisher.Publish, read and share novel research. Today, psoriasis is recognized as the most prevalent autoimmune disease caused by inappropriate activation of the cellular immune system.
People starting to develop lupus will experience low-grade fever and mild fatigue, which is enough to leave them restless, and disrupts their everyday activities. This occurs when the blood of the small blood vessels under the skin are disrupted, causing the fingers and toes to become numb, cold, tingly and painful; the fingers and toes may also turn blue or red.
Patients can experience hair loss, or thinning of hair, and then enter a period of abatement.  After hair loss, new and healthy hair grows back. Lupus is an intricate disorder that can be difficult to determine because it shares several characteristics with other diseases. Corticosteroids like prednisone diminish the inflammation of lupus, though it can pose side-effects like diabetes, infection, and weight gain. The stigmata of aging skin include wrinkles (rhytides), furrows, sagging, and sunken cheekbones (Fig. Photo (sun) damage is the most common and most pervasive change of aging (white) skin, commonly identified as solar lentigines and actinic keratoses (see Fig. Solar or traumatic purpura (also known as senile purpura) is a common and benign condition of extravasated blood in the dermis characterized by ecchymotic, purpuric patches on the forearms, arms, or legs of older persons.
Pruritus (itching) is a common condition of advanced age, affecting nearly one half of older adults (older than 60 years) at some time, usually without a rash. Seborrheic dermatitis is a common type of eczema characterized by scaly, red plaques on the scalp, face, and central chest. Other causes of leg ulcers in the elderly are neuropathy, trauma, neoplasia, infection, panniculitis, and pyoderma gangrenosum. Vascular insufficiency can represent venous insufficiency or perhaps even venous thrombosis, valvular incompetence, or arterial insufficiency. Varicosities (varicose veins) occur commonly with venous insufficiency, characteristically as tortuous vascular channels on calves, thighs, and popliteal fossa. Common skin conditions in the elderly include: actinic damage, benign and malignant growths, pruritus, eczematous dermatitis, purpura, and vascular insufficiency.
Intrinsic and extrinsic factors affect the structure and function of the skin and contribute to disorders of aging skin.
Some people suffer from cirrhosis without an obvious cause, a condition called cryptogenic cirrhosis (no known etiology).
The exact cause is unknown, but it appears to be related to the immune system.Autoimmune hepatitis. Sometimes, cirrhosis may be caused by a congenital disease such as Wilson’s disease, cystic fibrosis or hereditary hemochromatosis. Physical examination and medical history to assess symptoms are first performed to investigate whether liver damage is severe enough to cause signs of cirrhosis and to determine the cause of liver disease.
Blood tests can evaluate and determine the cause of the liver cirrhosis and reveal liver inflammation.
Measuring levels of certain substances synthesized by the liver may be helpful in assessing the liver function. It is produced by the liver by breaking down hemoglobin, which is a component of red blood cells with oxygen carrier role.
The flow will increase toward the heart with distal augmentation but will reverse in direction after the initial increase. Pain in any part, either the palm or back of the hand, can occur due to conditions affecting any of these structures and can lead to impairment of normal hand functions. The hand is formed by bones, tendons, ligaments, muscles, nerves, blood vessels, skin and nails. The collateral ligaments on either side of the bones of the fingers and thumb prevent sideways bending at each joint. The pain may be unilateral (in one hand) or bilateral (in both hands), localized in one area or spread throughout the whole hand. The symptoms of carpal tunnel syndrome occur due to compression of the median nerve in the carpal tunnel at the wrist. In other cases, diagnosis may be facilitated on eliciting a proper history and a thorough physical examination. There are two main hypotheses about the process that occurs in the development of Psoriasis. Lupus flares occur when the patient is exposed to ultraviolet light for a long period of time; it also aggravates other symptoms.
They become inflamed, and cause red spots to appear on the nails; they also become brittle. As lupus affects each person in different ways, it could take an uncertain period of time, even for the person, to perceive that he or she has lupus. An anti nuclear bodies test, or ANA, is done to gauge certain antibodies and proteins that appears in the blood. But there are variety of treatments that can be done to prevent bone deformity and aggravation of symptoms. The condition usually follows minor trauma and commonly affects those who take aspirin or other blood thinners (Fig.
Typically, they are greasy brown hyperkeratotic plaques that appear stuck to the skin surface; they can appear anywhere, except for palms and soles, and tend to congregate on the trunk. Patients with chronic renal or hepatic insufficiency, anemia, thyroid disease, diabetes mellitus, drug allergy, or underlying malignancy might have itch with or without a rash.
Treatment should include weight reduction when warranted, compression stockings to reduce edema, leg elevation as much as possible, and reduction of prolonged standing. Risk factors include immobility, fecal or urinary incontinence, diabetes, glucocorticoid use, and poor nutrition. Evaluation and treatment are usually straightforward, and diagnostic testing is usually not necessary.
Given the increasing number of elderly patients in the United States, disorders of aging skin are becoming a significant part of general dermatology. Most frequent causes of cirrhosis are excessive intake of alcohol for an extended period of time and infection with hepatitis B or C. Women develop alcoholic cirrhosis by a lower consumption of alcohol daily for the same period of time.
The disease becomes increasingly common and can cause multiple types of cirrhosis, currently classified as cirrhosis of unknown etiology (idiopathic). Other causes of cirrhosis that are less common include severe reactions to drugs, prolonged exposure to environmental pollutants, the disease called alpha-1-antitrypsin deficiency (AAT) (extremely rare cause) or a biliary tract disease with prolonged evolution, such as primary sclerosing cholangitis. Other tests that provide images of the liver are used to detect tumors and obstructed (blocked) bile ducts and to assess the size of the liver and intrahepatic blood flow. Cirrhosis may increase blood levels of bilirubin, the clinical manifestation being jaundice (yellowing of the skin and the whites of the eyes).
Commonly, hand pain occurs due to injury, inflammation, infection, overuse, problems related to normal aging, or certain medical conditions. Tendons join muscle to bones and contraction of the muscles result in movement of that area. The nerve that is most commonly affected is the median nerve as it passes through the carpal tunnel at the wrist giving rise to the condition known as carpal tunnel syndrome where there is pain along the distribution of the median nerve in the hand.
Shooshtary1[1] Farideh Zafari Zangeneh, Vali-e-Asr, Reproductive Health Research Center, Imam Khomaini Hospital, Tehran University of Medical Sciences, Tehran, Iran1.
The first considers psoriasis as primarily a disorder of excessive growth and reproduction of skin cells. Lupus also can affect organs such as the kidney, heart, skin, lungs, and the brain, resulting to inflammation and damage of tissues. Examinations that involve cell counts, organ function, and ability to clot blood are also performed. A patient could take nonsteroidal anti-inflammatory drugs like ibuprofen and naproxen to remedy pain, swelling, and tenderness of the joint. This chapter reviews the more common disorders of aging skin, such as actinic (photo) damage, pruritus, eczematous dermatitis, purpura, and venous insufficiency. Asteatotic eczema, or winter itch, often affects aging skin, usually as itchy, scaly, cracked, red plaques on the extremities, most commonly the legs.
Affected areas require regular lubrication with emollients and topical corticosteroids if eczema occurs.
Lipodermatosclerosis is an uncommon sequela of chronic venous insufficiency and is characterized by subcutaneous fibrosis with firm, indurated plaques on the legs.
An understanding of the changing structure and function of aging skin helps to address the disease processes and their treatment. As the cirrhosis develops, fibrotic tissue surrounds the normal liver cells, causing nodular aspect. However, in patients with chronic viral hepatitis who drink too much alcohol, cirrhosis is installed much faster than in patients with chronic viral hepatitis that don’t consume alcoholic drinks.
IntroductionAlthough the skin disease psoriasis was first recognized as a distinct disease as early as 1808 [1], its pathogenic mechanisms have eluded investigators for decades, its definition by Ferdinand von Hebra as a distinct entity dates back only to the year 1841 and estimates of its prevalence around 2-3% of the general population, and is characterized by an exaggerated proliferation of keratinocytes secondary to an activated immune system.
The problem is simply seen as a fault of the epidermis and its keratinocytes and is characterized by hyperproliferation with incomplete differentiation of epidermal keratinocytes and decreased keratinocyte apoptosis.
Certain races are also more vulnerable to lupus than others: Asian, Latino, and Africa-American. Their presence reflects appreciable sun exposure and can portend an increased risk of sun-induced skin cancer. For patients with a rash, the treatment is the same, plus treatment of the skin disease (usually a secondary eczema) with topical or systemic corticosteroids.
Treatment includes shampoo for the scalp, such as those containing zinc pyrithione, selenium sulfide, or ketoconazole, and a mild topical corticosteroid.
If venous or stasis ulcers develop, they are typically shallow and irregularly shaped and usually occur just above the medial malleolus.

Patients with stasis dermatitis and chronic leg ulcers have an increased risk for contact dermatitis, based on the likely use of multiple topical medications. All patients need an adequate diet, with vitamin supplementation, and treatment of any underlying conditions. Nodular liver tissue can block or inflame the bile ducts, causing bile reflux in the liver and bloodstream.
Every year over 26,000 people die due to cirrhosis, at least 40% having a history of chronic alcohol consumption. Some of the muscles controlling the fingers are also located in the forearm and its tendons run across the hand.
The incidence is highest at the age of 20–39 years in males and 40–59 years in females, with an equal male-to-female ratio [2]. The second hypothesis sees the disease as being an immune-mediated disorder (immunosuppressant medications can clear psoriasis plaques) in which the excessive reproduction of skin cells is secondary to factors produced by the immune system. Angiomas are benign vascular growths that commonly occur in adults as red macules and papules on the trunk and proximal extremities. Treatment involves compression, leg elevation, and often débridement, sometimes followed by skin grafting. Fibrotic tissue can also block bloodstream from the intestines to the liver, causing increased pressure in the portal venous system.
Psoriasis clinically manifests as raised, well defined erythematous plaques with irregular borders and silvery scales, affecting the upper and lower extremities equally, but with a predilection for the elbows, knees, scalp, and trunk. T cells become active, migrate to the dermis and trigger the release of cytokines which cause inflammation and the rapid production of skin cells.
Similar to seborrheic keratoses, therapy for angiomas is usually not necessary unless they are pruritic, irritated, or inflamed.
Aspirin or pentoxifylline is a helpful adjunctive treatment to improve peripheral blood flow, allowing ulcers to heal more rapidly. Selection depends on the state of the ulcer (infected, soupy, or clean), the amount of exudate, ulcer depth, and patient compliance. This complication, called portal hypertension, leads to ascites fluid accumulation in the abdominal cavity, the bleeding of enlarged vessels in the digestive tract and further serious complications. Psoriasis vulgaris or plaque psoriasis accounts for almost 90% of the dermatological presentation of the disease, but several other forms, including guttate, inverse, erythrodermal, pustular, and palmoplantar psoriasis may occur, as well as nail involvement. Malignant potential is extremely low, but left untreated, approximately 5% to 20% of actinic keratoses deteriorate to invasive squamous cell carcinoma within 10 to 25 years.3 Actinic keratoses deserve treatment to forestall progression into squamous cell carcinoma. Psoriasis may have significant systemic involvement, which is underscored by the coexistence of various clinical disorders, including eye, cardiovascular, and intestinal problems, metabolic syndrome, and joint inflammation. That work initially pointed towards a major role of T lymphocytes as inducers of the disease phenotype and the pathogenic contribution of this cell type has now been tested through clinical studies of more than a dozen immune modifying biological agents in patients with psoriasis. Options include local destruction with either cryotherapy (liquid nitrogen) or curettage and the topical application of 5-fluorouracil (Efudex, Fluoroplex, Carac), imiquimod (Aldara), or diclofenac (Solaraze) for more extensive disease. It has a very high negative impact on quality of life, requires long-term treatment which usually has a high social and economic impact and is also associated with a decreased life span [3] [4]. The inflammatory cytokines such as tumor necrosis factor (TNF) are likely to play major pathogenic roles in this disease and that other types of inflammatory leucocytes may also serve key pathogenic functions.
Obviously, sun avoidance and the use of sunscreens help to minimize photo damage, solar lentigines, and actinic keratoses. Here we will review some recent works on psoriasis that advances our overall understanding of disease pathophysiology regarding neuroendocrine immunology. Psoriasis typesPsoriasis classificationNo one classification of psoriasis satisfies all the mentioned requirements. Although the immune system has been often regarded as autonomous, the last two to three decades provided strong evidence that the central nervous system (CNS) receives messages from the immune system and vice versa messages from the brain modulate immune functions. Thus, the brain and the immune system are involved in functionally relevant cross-talk, whose main function is to maintain homeostasis [37].
In psoriasis it seems that the most important components of these supersystems are ?2 adenoceptors and tumor necrosis factor alpha (TNF?). Recent studies show that the ?2-adrenergic receptor is specifically associated with the homeostasis of skin barrier. Increasing evidences indicate that TNF may have immunosuppressive effects, since long-term exposure to TNF can directly prevent the activation of T cells.
Psoriasis vulgaris (chronic stationary psoriasis, plaque-like psoriasis)The commonest type of psoriasis, accounting for 90% of all cases, is psoriasis vulgaris, in which papulosquamous plaques are well-delineated from surrounding normal skin.
Is psoriasis a result of the bidirectional communication between the nervous and immune systems? The plaques are red or salmon pink in color, covered by white or silvery scales and may be thick, thin, large or small (Figure 1). They are most active at the edge: rapidly progressing lesions may be annular, with normal skin in the centre. Plaques are usually distributed symmetrically, and occur most commonly on the extensor aspects of elbows and knees; scalp (where they rarely encroach beyond the hairline), lumbosacral region, and umbilicus.
Epidermal homeostasis is understood as the maintenance of epidermal tissue structure and function by a fine tuned regulatory mechanism balancing proliferation and cell loss by desquamation and apoptosis [39].
Classification of psoriasis vulgaris according to phenotype: plaque-type psoriasis There is also variation of features of psoriasis dependent on anatomical sites. Stem cells of the basal layer or stratum basal in the epidermis have a crucial role in maintaining tissue homeostasis by providing new cells to replace those that are constantly lost during tissue turnover or following injury [40]. Until the reasons for this variation are fully understood, they are proposed to be recorded as a phenotypic entity, although subsequently they may be shown to be part of a common pathogenetic mechanism.
Skin: An indispensable and protective barrierThe first protective barrier is provided by the skin, our largest organ.
It serves as the interface between the organism and the outside world and it serves many functions, such as the retention of body fluids, maintenance of body temperature, and protection against UV-light, chemical influxes, wounds, and the invasion of micro-organisms. Plaque-type psoriasis: Chronic plaque psoriasisAs a consequence, chronic plaque psoriasis is the form of the disease entered into clinical trials and the object of the majority of investigations of genetics and pathogenesis of psoriasis. The protective barrier function is performed by the keratinocytes of the epidermis, which are continuously produced by proliferating stem cells of the basal layer or stratum basal and differentiate during a 14 day journey towards the surface [42].
It is characterized by red, scaly, discoid lesions varying in size from 0.5 cm in diameter to large confluent areas on the trunk and limbs (Figure 1). There is a sharp line of demarcation between a plaque and clinically normal, uninvolved skin. Longitudinal studies of individual plaques have demonstrated that plaques are dynamic [10] with an active and expanding edge, sometimes to the extent that the advancing edge may become annular (Figure. Lipid synthesis for skin barrier function takes place within the keratinocytes in all nucleated epidermal layers. Lipids are stored within the epidermal lamellar bodies (secretory organells) or keratinosomes, which are ultrastructurally visible at the level of the upper spinous layer and in the granular layer.
The variety of plaque is characterized by well-demarcated plaques with a loosely adherent silvery-white scale, which preferentially affect the elbows, knees, lumbosacral area, intergluteal cleft, and scalp.
In the outermost granular layer, the contents of lamellar bodies are secreted into the intercellular domains of the stratum granulosom–stratum corneum interface. Occasionally, pustular lesions may appear in the plaque (so-called psoriasis with pustules). Lamellar bodies mainly contain phospholipids, glucosylceramides and cholesterol as well as hydrolytic enzymes, which convert phospholipids, glucosylceramides and sphingomyelinase to free fatty acids and ceramides. Then, lamellar bodies cause in the formation of an impermeable, lipid-containing membrane that serves as a water barrier and is required for correct skin barrier function.
The Stratum Corneom (SC) contains three types of lipids -- ceramides, cholesterol and free fatty acids. Site-specific variants of Psoriasis Vulgaris (PV)Site-specific variants of psoriasis vulgaris exist. These lipids have different chemical compositions and different functions throughout the body. Flexural (inverse) psoriasis in intertriginous sites is shiny, red, and typically devoid of scales (figure 3); sebopsoriasis, which can be confused with seborrhoeic dermatitis, has greasy scales and occurs in eyebrows, nasolabial folds, and postauricular and presternal sites. There are nine different types of ceramides in the Stratum Corneom, conveniently named ceramide 1 through ceramide 9, and they account for 40-50% of the lipids in this outermost layer. It is particularly subject to irritation from rubbing and sweating because of its location in skin folds and tender areas (Figure 3). They are one of the component lipids that make up sphingomyelin, one of the major lipids in the lipid bilayer. The major clinical manifestation of inverse psoriasis is sharply demarcated erythematous plaques, with varying degrees of infiltration, which often tend to itch and burn [12].
The most well-known functions of ceramides as cellular signals include regulating the differentiation, proliferation, programmed cell death (PCD), and apoptosis (Type I PCD) of cells [43].The proliferation rate of keratinocytes to corneocytes is matched by the shedding of old corneocytes at the SC [44] and skin tissue maintains a steady number of SC layers regardless of age [45]. The most common lesions are found in inguinal, submammary, interglutaeal, umbilicus and genital folds, whereas the popliteus and axillae are rarely involved. Desquamation, the process of cell shedding from the surface of the stratum corneum, balances proliferating keratinocytes that form in the stratum basale. The humidity and heat typical of these sites, together with the combination of local traumatic factors often associated with infections caused by dermatophytes and Candida albicans, together contribute to the development of psoriasis in accordance with the Koebner phenomenon.
These cells migrate through the epidermis towards the surface in a journey that takes approximately fourteen days.
The Koebner phenomenon is an indicator of disease activity, may have a prognostic value, and is associated with early onset of psoriasis [13].
During cornification, the process whereby living keratinocytes are transformed into non-living corneocytes, the cell membrane is replaced by a layer of ceramides which become covalently linked to an envelope of structural proteins (the cornified envelope).
The Koebner phenomenon was first described by Heinrich Koebner (1838–1904) and refers to the fact that in people with certain skin diseases, especially psoriasis, trauma is followed by new lesions in the traumatized but otherwise normal skin, and these new lesions are clinically and histopathologically identical to those in the diseased skin [14]. This complex surrounds cells in the stratum corneum and contributes to the skin's barrier function [41]. SC serves as the principal barrier against the percutaneous penetration of chemicals and microbes and is capable of withstanding mechanical forces [46].
Sites of involvement are the nasolabial folds (Figure 4), medial cheeks, nose, ears, eyebrows, hair line, scalp, presternal and interscapular regions.
Scalp: The scalp is frequently the site of initial presentation and is the commonest anatomical site to be involved by psoriasis. Their expression starts in suprabasal keratinocytes where their inactive precursors undergo a processing by an unidentified trypsin-like protease [48]. Morphologies range from discrete plaques to total scalp involvement with either thick plaques or scaly nonthickened areas almost identical to seborrhoeic dermatitis. In stratum corneum, these enzymes appear in the intercellular spaces suggesting their involvement in the desquamation [49]. Recent discoveries have highlighted the importance of various proteases, protease-inhibitors, and protease targets as key players in epidermal barrier function [50]. An important and fascinating observation is that the scalp lesions rarely extend > 2 cm beyond the hairline. Skin: Epidermal proteases The specific differentiation program in stratified skin requires a specialized proteolytic system to detach the corneocytes from each other without causing a barrier defect.
A number of different proteases have been reported to be involved in the desquamation process and to contribute to the barrier function of the skin. Based on their proteolytic domain, proteases are classified into serine, threonine, cysteine, aspertate, metallo, and glutamate proteases. Especially serine proteases (SPs) seem to be involved in epidermal permeability barrier homeostasis as it was reported that SP activity was increased after acute barrier disruption and that blockade by topical SP inhibitors accelerated barrier recovery after acute abrogation [51]. Guttate psoriasisPsoriasis affects approximately 2% of the world population, and of these cases, 2% manifest as guttate psoriasis [16]. Skin: Adherent junction proteins (Epidermal junction)The Epidermal junction (EJ) plays a crucial role in the formation and maintenance of epithelial and endothelial barriers.
Guttate means "drop" in Latin; aka Teardrop Psoriasis, Raindrop Psoriasis or Psoriasis Exanthematic) is the second most common type of psoriasis. The EJ is a complex basement membrane synthesised by basal keratinocytes and dermal fibroblasts.
Guttate psoriasis (GP), an important clinical variant, most frequently occurs in adolescents and young adults.
It is characterized by the sudden onset of widely dispersed small red scaly plaques mainly over the trunk and proximal limbs. Basal keratinocytes are connected to adjacent cells by several types of intercellular junctions (including gap and adherens junctions), the most characteristic of which are the desmosomes. The symptoms of GP are numerous small, red, drop-like spots which cover a large portion of the skin. GP can clear up without treatment or disappear and resurface in the form of plaque psoriasis. This two compartment structures is renewed continuously and when the barrier function is damaged, it is repaired immediately. Guttate flares in patients with established psoriasis vulgaris (PV) are also frequently observed. These observations, taken together with investigative studies, indicate an important pathogenetic link between GP and PV [15].
3) The Epidermal junction (EJ) plays a crucial role in the formation and maintenance of epithelial and endothelial barriers. GP is often associated with a preceding streptococcal throat infection or a rise in anti-streptococcal serum titer [16] [18]. Bacterial streptococcal infections (strep throat, chronic tonsillitis) or a viral respiratory infection usually precede and trigger the first signs of Guttate Psoriasis in persons predisposed to psoriasis. 4) In epidermal keratinocytes, both extracellular and intracellular Ca++ is reported to be important to cell differentiation and proliferation.
This 15-year-old girl presented with a case of acute guttate psoriasis shortly after the onset of mononucleosis.
Skin’s sympathetic fibers: Neuroendocrin regulationThe skin is a complex organ containing afferent and efferent neural networks, glands, blood vessels, smooth muscle elements, connective tissues and immune cells, many of which are modulated by catecholamines and glucocorticoid hormones. The structural characteristics of her eruption and her skin biopsy findings are consistent with guttate psoriasis (Figure 7). Glucocorticoids and catecholamines reach skin tissues as circulating hormones and catecholamines are released in skin by projections of the sympathetic nervous system.
Figure 7.Clinical photographs of the abdomen with guttate psoriasiform papules and plaques. The sympathetic division of the autonomic nervous system within the skin is supplied by postganglionic fibers of the paravertebral chain ganglia.

Skin’s Beta2 adrenergic receptors (?-ARs)Beta2 adrenergic receptors were identified in keratinocytes more than 30 years ago, but their function in the epidermis continues to be elucidated [56]. The ?-adrenergic (?-ARs) agonists are capable of modulating the two distinct components of keratinocyte directional migration via divergent signaling pathways: 1) migration rate via a cAMP-independent, mitogen-activated-protein-kinase-dependent pathway [57] and 2) galvanotaxis by a cAMP-dependent one. Acute episodes may be triggered in patients with plaque psoriasis by irritating topical therapy or abrupt corticosteroid withdrawal [20]. Previous data have shown that both endogenous and exogenous catecholamines act to attenuate the permeability response to various inflammatory mediators via ?1- [58] and ?2-adrenoceptors [59] [60] [61] [62]. At the onset of an attack of acute GPP (von Zumbusch type) the skin becomes very red and tender. ?-ARs signaling cascadeIn skin, it has been proposed that epinephrine activates keratinocyte beta2AR to modulate calcium influx and begin the differentiation cascade crucial to the native architecture of the epidermis [54]. Within hours, myriads of pinhead-sized pustules appear, studding the erythematous background (Figure 8). The beta2AR desensitizes upon repeated activation through several mechanisms, including downregulation of the number of beta2AR receptors [63] [64]. Indeed, beta2AR expression is more highly expressed at the basal layers of the epidermis and decreases in expression toward the stratum corneum [54], suggesting that epinephrine may be activating the receptor to increase intracellular calcium levels and induce differentiation. Subsequently, the pustules dry out, and the skin peels off, leaving a glazed, smooth erythematous surface on which new crops of pustules may appear [21]. GPP should be distinguished from acute generalized exanthematic pustulosis, a self-limiting febrile drug reaction usually resolving in 2 weeks after withdrawal of the suspected agent, characterized by pinpoint nonfollicular pustules on erythematous patches mainly involving folds.
Single necrotic cells in the epidermis, eosinophils, and vasculitic changes in the dermis are peculiar pathologic features [22] [23]. They regulate the localization, duration, and amplitude of cyclic nucleotide signaling within subcellular domains. The PDE superfamily of enzymes is classified into 11 families, namely PDE1-PDE11, in mammals. Acrodermatitis continua, also known as dermatitis repens, is a rare, chronic, pustular eruption of the fingers and toes (Figure 9). Some are cAMP-selective hydrolases (PDE4, 7 and 8); others are cGMP-selective (PDE5, 6, and 9).
Classification of palmoplantar pustulosis within the spectrum of psoriasis is controversial. A phosphodiesterase type 4 inhibitor, commonly referred to as a PDE4 inhibitor, is a drug used to block the degradative action of phosphodiesterase 4 (PDE4) on cyclic adenosine monophosphate (cAMP).
The disease predominates in women (more than 70% of patients are women) and is much more strongly associated with smoking than plaque psoriasis [25]. They are predominantly responsible for hydrolyzing cAMP within both immune cells and cells in the central nervous system [65]. Since the late 1980s, PDE4 inhibitors have been under investigation as anti-inflammatory therapies against asthma and chronic obstructive pulmonary disease.
Due to the broad anti-inflammatory activity of PDE4 inhibitors, their possible use in the treatment of atopic dermatitis and psoriasis was examined. The transition to a more extensive involvement, due to frequently unidentifiable triggering factors, is frequently marked by the onset of an inflammatory phase with predominant erythema and limited scaling associated with itching and rapidly progressing lesions. These findings point to a role for the cutaneous ?2-AR network in maintaining epidermal function and integrity. Moreover, it has also been shown that ?2-AR density in the human epidermis depends on the calcium concentration [67] [54], where undifferentiated keratinocytes express approximately 7500 AR per cell and differentiated keratinocytes express only 2500 receptors underlining an important function for the 2-AR in the differentiation process in human skin [68]. The erythrodermic phase is dominated by generalized erythema, loss of peculiar clinical features of psoriasis, and skin failure, that is, inability to maintain homeostatic functions [26]. Stimulation of the beta2-AR leads to a transient increase in the keratinocyte intracellular calcium concentration [69] [70] and this likely occurs through several signaling cascades. Erythrodermic psoriasis characterized by severe scaling, itching, and pain that affects most of the body, erythrodermic psoriasis disrupts the body's chemical balance and can cause severe illness (Figure11).
The mean increase in intracellular calcium of psoriatic keratinocytes was significantly reduced compared with control keratinocytes when intracellular calcium stores were mobilized from endoplasmic reticulum with thapsigargin (an inhibitor of the endoplasmic reticulum Ca2+ ATPase was used to empty the Ca2+ stores from endoplasmic reticulum) [71]. Activation of the sympathetic system is the most common studied in literature, but other possibilities have to be considered, like impairment of epidermal barrier function, which is already described.
?2-AR density in the human epidermis depends on the calcium concentration and calcium plays an important part in the regulation of proliferation and differentiation of keratinocytes. Based on the several common clinical and radiological features, PsA is considered as a member of the family of spondyloarthritides [31]. Skin’s immunity function: Keratinocytes as immune sentinelsKeratinocytes can sense pathogens and mediate immune responses to discriminate between harmless commensal organisms and harmful pathogens.
Keratinocytes are continuously in contact with external stimuli and have the capacity to produce several soluble mediators.
PsA can be a severe form of arthritis with prognosis similar to that of rheumatoid arthritis (RA) [32]. Pathogen-associated molecular patterns (PAMPs) are recognized, among others, by Toll-like receptors (TLRs). Psoriatic arthritis (PsA) is characterized by focal bone erosions mediated by osteoclasts at the bone–pannus junction.
Epidermal keratinocytes express several TLRs, located either on the cell surface (TLR1, TLR2, TLR4, TLR5 and TLR6) or in endosomes (TLR3 and TLR9) [72]. Keratinocytes are also an important source of chemokines and express chemokine receptors, and therefore can modulate an immune response by attracting different cell types into the skin.
Recognition of bone as an active organ that interacts with its environment is a relatively new development. In the pathogenesis of bone destruction associated with rheumatoid arthritis, the synovium is a site of active interplay between immune and bone cells. Keratinocytes as a secretory organ of cytokinesKeratinocytes produce a wide array of cytokines, including tumor necrosis factor and interleukin 1? (IL-1?), IL-1?, and IL-6. The interaction between T cells and osteoclasts is a critical issue in the field of osteoimmunology [34]. Disruption of the permeability barrier increases the expression of these cytokines [73] [74]. Studies in mice deficient in these cytokines or their receptors have shown delays in permeability barrier recovery after acute disruption, suggesting that the increased cytokine production facilitates barrier repair [75] [76].
Cytokines are well known to stimulate lipid synthesis and metabolism, and one could anticipate that an increase in epidermal lipids induced by cytokines could facilitate lamellar body formation and permeability barrier recovery [75] [77] [78].
Sympathetic regulation of innate immunityActivation of the sympathetic nervous system (noradrenergic nerves and adrenal medulla) exerts a potent anti-inflammatory action upon the innate immune system. In the case of adaptive immune responses, however, signals from the brain are transmitted back to the periphery, primarily via activation of the HPA and the SNS [79].
The magnitude of an adaptive immune response appears to be regulated by the release of norepinephrine within the direct vicinity of activated CD4+ T cells and B cells located within lymphoid tissue.
The released norepinephrine stimulates the ?2AR expressed on the immune cells to regulate the level of gene activity.
The immune cell self-regulated immune response develops and progresses normally with the participation of norepinephrine to regulate the level of the response in an attempt to maintain immune homeostasis [80]. In vitiligo, there is a dysregulation of catecholamine biosynthesis with increased plasma and epidermal noradrenaline levels associated with high numbers of ?2-ARs in differentiating keratinocytes and with a defective calcium uptake in both keratinocytes and melanocytes. In atopic eczema, a point mutation in the ?-AR gene could alter the structure and function of the receptor, thereby leading to a low density of receptors on both keratinocytes and peripheral blood lymphocytes [81].
In psoriasis, ?-ARs are downregulated, because the increased circulating levels of catecholamines have been observed in psoriatic patients [82] [83] [84] and a 10-fold increase in the expression of the Phenylethanolamine N-methyltransferase (PNMT), the epinephrine sythetic enzyme is also found in basal keratinocytes in involved psoriatic epidermis [85]. It is tempting to propose that long-term exposure to increased levels of catecholamines, in the circulation or locally derived by the keratinocytes themselves, in combination with increased desensitization of beta 2AR in individuals, may predispose to psoriasis. Psoriasis & immune system Psoriasis is a chronic inflammatory, immune-mediated skin disease, which affects 2%-3% of the population worldwide [89]. Psoriasis was until recently regarded as a T-cell-driven disease with presumed (auto) immune mechanisms as its primary cause [90] [91].
Psoriasis & the innate immune system The innate immune system provides the first line of defense against infection by detecting the presence of invading pathogens in a non-specific manner. Cells of the innate immune system include macrophages, dendritic cell (DC), monocytes, neutrophils, mast cells, natural killer (NK), NKT cells and ?? T cells. Innate immune cells recruit additional leukocytes to the site of inflammation by releasing cytokines and chemokines. In addition, the innate immune system plays a crucial role in the initiation and direction of the adaptive immune response. Mechanisms regulating barrier integrity and innate immune responses in the epidermis are important for the maintenance of skin immune homeostasis and the pathogenesis of inflammatory skin diseases [92].
Data show that the nervous and immune systems communicate with one another to maintain immune homeostasis. Activated immune cells secrete cytokines that influence central nervous system activity, which in turn, activates output through the peripheral nervous system to regulate the level of immune cell activity and the subsequent magnitude of an immune response. One key mechanism responsible for such coordination involves the autonomic nervous system (norepinephrine), which serves as the messenger from the mind to the body for all organ systems, including the immune system [93]. The antigen-activated immune system regulates CNS activity through the release of cytokines that bind to receptors located peripherally on the vagus nerve or sympathetic nerve terminals or centrally within the CNS or at the blood-brain barrier.
Subsequently, the CNS communicates back to the immune system by activating the SNS or the HPA to release the neurotransmitter norepinephrine or a corticosteroid hormone, respectively.
Lymphocytes express receptors that bind norepinephrine and corticosteroids, providing a mechanism for these ligands to activate intracellular signaling pathways, which regulate the level of immune cell activity.
A bidirectional communication between the nervous and immune systems is to maintain homeostasis, whether this requires an increase or decrease in immune cell activity. Also, skin-brain axis fMRI studies on patients with psoriasis have revealed that the processing of facial expressions of disgust is significantly impaired in subjects with psoriasis as compared with normal controls in that blood flow in the anterior insular cortex is reduced. During an immune response the brain and the immune system “talk to each other” and this process is essential for maintaining homeostasis.
Two major pathway systems are involved in this cross-talk: the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). This overview focuses on the role of SNS in neuroimmune interactions, an area that has received much less attention than the role of HPA axis. The immune cell self-regulated immune response develops and progresses normally with the participation of norepinephrine to regulate the level of the response in an attempt to maintain immune homeostasis.
Cathecolamines regulate the immune system at regional, local and systemic levels via adrenergic receptors expressed on immune cells.
More recently, psoriasis has also been reported to be associated with metabolic disorders including obesity, dyslipidaemia and diabetes [97] [98]. Moreover, an increased mortality from cardiovascular disease in patients with severe psoriasis has been documented, and psoriasis may confer an independent risk of myocardial infarction especially in young patients [99]. Psoriasis & metabolic syndromeRecent studies of epinephrine stimulation at the ?2 adrenergic receptor reveal important potential long-term beneficial effects in the metabolic syndrome [100]. The association between psoriasis and metabolic disorders such as obesity, dyslipidemia, and type 2 diabetes has shown that severe psoriasis might be associated with increased mortality rate due to cardiovascular disorders [97] [98] [101].
Recent studies suggest that psoriasis, particularly if severe, may be an independent risk factor for atherosclerosis, myocardial infarction (MI), and stroke. Shared risk factorsThe existence of shared risk factors between psoriasis and both CV and metabolic conditions has been shown in several epidemiological studies which demonstrate that the same co- morbidities are present in psoriasis patients, regardless of age or ethnicity [104] [105].
Summary 4: Conclusive remarksThis review shows that the overactivity of sympathetic nervous system occurs in Psoriasis disease. Abnormalities of ?-ARs in their expression, signaling pathway, or in the generation of endogenous catecholamine agonists by keratinocytes have been implicated in the pathogenesis of cutaneous diseases such as atopic dermatitis, vitiligo and psoriasis.
These studies suggest that mainly the localization of Beta2-adrenergic receptors in the epidermis and play an important part in the calcium dynamics and barrier homeostasis of epidermal keratinocytes [106].The decrease expression of beta2 adrenergic receptor mRNA in involved psoriatic epidermis shown by RT-PCR [107].
Together, these findings suggest that the downregulation of the number of beta adrenergic receptors, rather than an inherent defect in the receptor itself, is the mechanism that is responsible for the reduced beta-adrenergic responsiveness seen in psoriatic epidermis. This decreased response to endogenous agonists then results in a decrease in intracellular cAMP and thus an increase in keratinocyte proliferation. Polimorphism studie show that inactivity of Beta2 adrenoceptor is the main cause in this disorder. Beta2 antagonists wreck this condition and reduction of cAMP could cause disruption in skin barrier hemostasis. The co-crystal structure reveals a binding configuration which is unique compared to classical catechol PDE4 inhibitors, with boron binding to the activated water in the bimetal center. These phenoxybenzoxaboroles can be optimized to generate submicromolar potency enzyme inhibitors, which inhibit TNF-?, IL-2, IFN-?, IL-5 and IL-10 activities in vitro and show safety and efficacy for topical treatment of human psoriasis [108]. However, it may be that currently utilized therapies also work by modifying this signaling pathway.
UVB irradiation, another mainstay in the treatment of psoriasis, has been shown to increase beta2AR-mediated cAMP accumulation [111].
There is no cure for psoriasis, but there are many treatments that can decrease the symptoms and appearance of the disease. Treatment optionsIn general, there are three treatment options for patients with psoriasis: Phototherapy, topical and systemic. Combining various topical, systemic and light treatments often allows lower doses of each and can result in increased effectiveness.
Topical treatment: Topical drugs First line management of adult mild-to-moderate adult plaque psoriasis is with topical treatment, including vitamin D analogues and topical corticosteroids.
Topical therapies are indicated for patients whose affected area is < 10% of the body surface area (BSA).
Topical vitamin D analogues (VD) and topical steroids (TS) are both widely used topical treatments for psoriasis. Calcipotriol is a vitamin D analogue that regulates epidermal cell proliferation and differentiation, as well as production and release of pro-inflammatory cytokines. TS present a wide range of biological effects such as inhibition of the recruitment and migration of inflammatory cells, modulation of cytokine synthesis, chemokines release and regulation of DNA synthesis [112].Topical corticosteroids are available in different potencies and formulations but despite more than 40 years of experience, their use remains mostly based on individual experience.
Published guidelines often specify the place of topical steroids within psoriasis treatment strategies [113] [114] [115] but not the efficacy and practical modalities of use. It should be noted that the majority of adverse events seen with topical therapies are cutaneous rather than systemic in nature and that the risk–benefit ratio for these patients is better with topical therapies than with biological [116].
Light therapy (phototherapy)Solar ultraviolet (UV) radiation has been used since ancient times to treat various diseases.

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