Vipin Khetarpal, MD

• Fellow in Cardiology, Division of Cardiology, Department of Internal
• Medicine, Harper Hospital Wayne State University School of Medicine,
• Detroit, MI, USA

Necrolytic migratory erythema in a patient with glucagonoma treatment of gout order genuine frumil on-line, characterized by rapidly eroding symptoms 4dp3dt 5mg frumil visa, superficial blisters treatment skin cancer cheap 5 mg frumil with mastercard. Lesions are usually localized to the buttocks treatment 5th metatarsal base fracture discount 5 mg frumil, groin symptoms endometriosis cheap 5mg frumil with amex, perineum symptoms restless leg syndrome buy frumil 5 mg cheap, elbows, hands, feet, and perioral area. Associated manifestations include glossodynia, papillary hypertrophy of the tongue, dis turbances of taste and smell, diarrhea, scleroderma, acanthosis nigricans, seborrheic keratoses, adenopathy, and weight loss. Colorectal carcinomas are second only to lung carcinoma in frequency of associated malignancies. Carcinoid tumors produce a number of vasoactive sub stances that can induce cutaneous flushing (see Chapter 33). The most common carcinoid tumors (appendix and small bowel) do not produce flushing until the vasoactive sub stances reach the systemic circulation. Flushing, therefore, generally denotes metastasis to the liver or a different primary tumor site. Glucagonoma is a very rare neuroendocrine tumor of the alpha cells of the pancreas that may cause a necrolytic migratory erythema of the skin. Patients can also often have weight loss, diarrhea, anemia, psychiatric disturbances, hypoaminoacidemia, and diabetes. The rash typically clears with successful removal of the tumor (discussed in more detail in Chapter 33). Subcutaneous fat necrosis and polyarthralgia is associated with pancreatic acinar cell carcinoma, pancreatitis, and pan creatic pseudocysts. Deep subcutaneous, erythematous nodules ranging from 1 to several centimeters in diameter usually appear on the legs. A 69-year-old alcoholic man with chronic calcific pancreatitis, a pseudocyst, and marked hyperlipasemia (>6000 U/L) developed acute bilateral ankle pain with redness and swelling. Three days later he noticed painful red bumps in his right posterior forearm and right ankle area, with later spread to the right ankle. He had pain and swelling in several metacarpophalangeal and interphalangeal joints, and bilateral swelling of the Achilles tendon. Histopathologic evaluation of skin lesions usually reveals diagnostic findings-pale staining necrotic fat cells (ghost cells) and deposits of calcium in the necrotic fat. Some cutaneous markers historically thought to be associ ated with internal malignancies have more recently been dis missed as having no direct relationship. They may appear anywhere on the skin and are often nonspe cific, very firm, dermal or subcutaneous nodules. Immunoperoxi dase markers have assisted pathologists in predicting the primary site of origin from biopsy specimens of metastatic nodules. Pruritus is a distressing complication of cholestatic, inflam matory, and malignant liver diseases. Amelioration of pruritus with ultravio let B light treatment, cholestyramine, or rifampin does not help in elucidating the pathogenesis of this distressing condi tion. Opiate antagonists may relieve pruritus, which suggests that endogenous opioids are involved in its pathogenesis. Large, erythematous, indurated, pruritic plaques occur within a few days to a few weeks. These reac tions may be a delayed hypersensitivity reaction, in that dermal testing can reproduce the reactions. When tested, patients have been found to be allergic to the vitamin K, not the benzoyl alcohol vehicle. However, vitamin K3 (Synkay vite), which is watersoluble, has not been reported to cause similar reactions. If reactions occur after buttock injections of vitamin K, there is an almost diagnostic tendency of these plaques to spread around the waist and down the thigh, repro ducing what has been called a "cowboy gun belt and holster" pattern. These reaction sites resolve over days to weeks but may persist for months to years. After an erythematous reac tion, or without prior reaction, expanding sclerotic plaques with violaceous borders similar to those of morphea have occurred months to years after injections. In addition to these local reactions, anaphylaxis after intravenous administration that may be fatal may occur. Urticaria and serum sickness classically occur in patients with hepatitis B, although both have been reported in association with hepatitis C (see Chapters 79 and 80). Chronic hepatitis C virus is associated with leukocytoclas tic vasculitis with cryoglobulinemia. Porphyria cutanea tarda characterized by noninflammatory blisters and erosions of the dorsa of the hands. Diagnosis is typically made with a 24hour urine collec tion demonstrating elevated uroporphyrin levels. Lichen planus is a common idiopathic inflammatory disor der that can affect skin, hair, mucous membranes, and nails (see earlier). The prototypical presentation of lichen planus is violaceous, polygonal, flattopped papules of flexural areas of the wrists, arms, and legs. Retinoids may be used for patients with psoriasis who were previously treated with methotrexate or who have preexisting liver disease contrain dicating the use of methotrexate. Limited experience suggests that these patients do not suffer progression of their liver disease with such retinoid therapy. As with methotrexate, there is a poor correlation between liver chemistry test results and liver histology during retinoid therapy. Therefore, pre treatment and intermittent liver biopsies may be required for certain highrisk patients being chronically treated with oral retinoids. Methotrexate is commonly used for severe psoriasis and psoriatic arthritis but is also used for cutaneous T cell lymphoma, connective tissue diseases such as rheumatoid arthritis, and other inflammatory disorders. Methotrexate is usually given as a single weekly dose of 10 to 25 mg, but may be used in higher dosages in selected patients. A grading system for liver biopsies has been established and is generally followed by dermatologists, with decisions on continuation or discontinuation of treatment fre quently based on the results of these biopsies (Table 244). Similarly, pru ritus has been reported in 47% of patients who received telaprevirbased triple therapy, compared to 28% of patients treated with peginterferon and ribavirin. Exceptional circumstances, however, may require continued methotrexate, with follow-up liver biopsies. However, severe rash, defined as a generalized rash, a rash with vesicles, or a rash with bullae or ulcerations, was reported in 4% of telaprevirtreated patients but in less than 1% of patients treated with peginterferon and ribavirin alone. Treatment discontinuations due to rash are rare; 6% of patients had to stop telaprevir but continued pegin terferon and ribavirin, and 1% of patients had to stop all 3 medications. The cutaneous eruption consists of urti carial, vesicular, or bullous lesions characteristically localized to the scalp, shoulders, elbows, knees, and buttocks. Deposits of IgA are found in the dermal papillae at sites of itching and where vesicles are forming. Even patients with such minimal bowel disease that bowel biopsy findings are normal improve on a glutenfree diet. Reintroduction of gluten in a symptomfree patient on a glutenfree diet leads to the reap pearance of pruritus and skin lesions. Pruritic linear papules migrate at a rate of 1 to 2 cm daily on skin sites that have come in contact with fecally contaminated soil, usually the feet, buttocks, or back. It occurs in 2 forms, one localized to the perirectal skin in immunocompe tent hosts and another disseminated form occurring in immu nosuppressed hosts. These infective larvae may invade the perirectal skin in infected immunocompetent individuals, causing urticarial, erythematous, linear lesions that migrate up to 10 cm a day, usually within 30 cm of the anus. In immunosup pressed hosts, repeated autoinfection through the intestine leads to a tremendous parasite burden (hyperinfection), manifested most commonly by pulmonary disease. Parasitic infections are classically considered in the dif ferential diagnosis of urticaria. Cutaneous larva migrans characterized by a serpiginous erythematous migratory lesion caused by an infection with dog hookworm. Dermatitis herpetiformis characterized by pruritic, urticarial papules and small blisters concentrated over the elbows, knees, and buttocks. Treatment with a glutenfree diet leads to gradual clearing of skin lesions, improvement of the intestinal abnormality, disappearance of the IgA from the skin, and decreased dependence on dapsone for control of the cutane ous eruption. Infant girl with acrodermatitis enteropathica secondary to nutritional zinc deficiency. Nonnucleoside reverse transcriptase inhibitors, entry and fusion inhibitors, integrase inhibitors, and immune reconstitution syndrome. The association between atrophic glossitis and proteincalorie malnutrition in old age. Clinical assessment and outcome in 70 patients with complaints of burning or sore mouth symptoms. Serum zinc and copper in oral/oropharyngeal carcinoma: A study of seventyfive patients. Oral mucositis with features of psoriasis: Report of a case and review of the literature. Clinical and pathological features of bacillary peliosis hepatis in association with human immunodeficiency virus infection. The effect of gastric Helicobacter pylori eradication on recurrent aphthous stomatitis. Paraneoplastic pemphigus: An autoimmune mucocutaneous disease associated with neoplasia. Management of esophogeal strictures in children with recessive dystrophic epidermolysis bullosa. The association of chronic inflammatory disease in lichen planus with cancer of the oral cavity. Esophageal lichen planus: A series of eight cases including a patient with esophageal verrucous carcinoma. Hereditary hemorrhagic telangiectasia: An overview of diagnosis, management, and pathogenesis. Elevated cancer incidence in patients with dermatomyositis: A populationbased study. Frequency of specific cancer types in dermatomyositis and polymyositis: A populationbased study. Subcutaneous fat necrosis/panniculitis, and polyarthritis associated with acinar cell carcinoma of the pancreas. A rare presentation of the pancreatitis, panniculitis, and polyarthritis syndrome. Porphyria cutanea tarda and hepatitis C virus: A casecontrol study and meta analysis of the literature. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents. Tissue transglutaminase and endomysial antibodies-Diagnostic markers of glutensensitive enteropathy in dermatitis herpetiformis. True diverticula involve all layers of the intestinal wall, whereas false diverticula are due to herniation of mucosa and submucosa through the muscular wall. Many diverticula contain attenuated portions of the muscular wall of the intestine, and hence may be difficult to define as true or false. True diverticula are often assumed to be congenital lesions, and false diverticula are assumed to be acquired, but this is not always the case. Some authors reserve the terms false diverticula or pseudodiverticula for diverticula caused by an inflammatory process. Barium swallow in the lateral view using video fluoroscopy is helpful for detecting small diverticula. In such cases, the endoscopy should be stopped and the patient sent for a barium study. The tip of the intubation instrument is often directed preferentially into the diverticulum. It is often difficult to distinguish the lumen of the esophagus from the lumen of the diverticulum. B, Barium esophagogram showing a diverticulum large enough to cause esophageal obstruction when it fills. In such cases, a forward-viewing endoscope can be used to pass a soft-tipped guidewire into the esophageal lumen. An alternative technique consists of passing a forward-viewing endoscope loaded with an overtube. Once the endoscope has been passed into the esophagus, the overtube is advanced, the forward-viewing endoscope is withdrawn, and the side-viewing or ultrasound endoscope is passed through the overtube. To avoid damage to mediastinal structures, an open surgical approach through the left neck is the safest alternative for patients with large (>5 cm) diverticula that extend into the thorax. Cricopharyngeal myotomy is typically part of the procedure because the causative factor is actually the hypertonic cricopharyngeus muscle. If diverticula are resected without myotomy, there is an increased risk of postoperative leaks and an increased frequency of recurrence. Specially designed rigid diverticuloscopes and conventional flexible endoscopes have been used. Effectively, a cricopharyngeal myotomy is performed as the septum is divided between the diverticulum and esophagus. Endoscopic stapling techniques rely on the placement of 1 leg of the stapler in the esophagus and the other into the diverticulum.

Other hamartomas and tumours include cerebellar haemangioblastomas treatment quincke edema frumil 5 mg mastercard, cervical neuroblastoma treatment variance cheap frumil 5mg with amex, pituitary adenomas and pinealomas [9] medications education plans discount frumil 5 mg on-line. Multiple endocrine neoplasia type 2B this is characterized by mucosal neuromas that are apparent at birth or in the first years of life [14] treatment programs purchase 5mg frumil with mastercard. Neuromas typically affect the mucosal surfaces treatment high blood pressure 5mg frumil sale, especially the anterior border of the tongue and the buccal mucosa inside the commissures of the lips; gingival symptoms multiple myeloma purchase frumil once a day, palatal and pharyngeal surfaces may occasionally be affected. Cutaneous nodules or plaques, often linear in shape and hyperpigmented, are occasionally reported, with the histopathological picture of dermal nerve hypertrophy and clinical hyperpigmentation due to chronic scratching and trauma [14]. About 75% of patients have a marfanoid appearance; muscle weakness and musculoskeletal anomalies (especially kyphoscoliosis, pes cavus and bilateral slipped upper femoral epiphysis) may also be present [10]. Intestinal ganglioneuromatosis is more common in type 2B than 2A, occurring in 30% and often presenting early in life due to constipation or abdominal pain. The association with myxomas has led to many other names; some prefer to use myxoma syndrome, or the combined term Carney complex/myxoma syndrome [2]. Three of the major diagnostic criteria involve the skin: spotty cutaneous pigmentation (lips, conjunctiva, eyelids, genital mucosa), mucocutaneous myxomas and multiple blue naevi [3]. The adrenal tumours in Carney complex are typically of the primary pigmented nodular type, an otherwise rare condition. Testicular tumours, often largecell calcifying Sertoli cell tumours, occur in about 30% of males, and are often bilateral and multicentric. Psammomatous melanotic schwannoma, usually of the upper gastrointestinal tract or of the paravertebral sympathetic nerves, is very suggestive of this syndrome. Myxoid fibroadenomas of the breast, and mammary ductal adenomas, may be found [2], and myxoid leiomyomas and uterine tumours are described. Multiple mucocutaneous myxomas are the most specific cutaneous marker for Carney complex, however these lesions are difficult to recognize clinically [3]. Periorificial facial papules, acral warty keratoses and palmoplantar, semitranslucent, punctate keratosis are characteristic. Multiple hamartomatous lesions of ectodermal, endodermal and mesodermal origin occur. The other cutaneous lesions include ganglioneuromas, lipomas, fibromas, angiomas, angiolipomas, epidermoid cysts and a variety of pigmentary changes. Craniomegaly is common; there may be an adenoid facies, kyphoscoliosis and a higharched palate. Seizures and learning difficulties occur (the latter is a minor diagnostic criterion) and there may be an association with meningioma. Benign internal anomalies are numerous, most commonly affecting the breast (severe fibrocystic disease occurs in the majority of women) and the thyroid (mainly multinodular goitres and adenomas). Gastrointestinal polyposis and cysts or polyps of the female genitourinary system are also frequent. The most frequently reported cancers are female breast cancer (bilateral in almost half of the cases) and thyroid cancer [9]. Fibrocystic breast disease and cancers may have an early onset, and screening of atrisk family members is therefore recommended. Breast, endometrial and thyroid cancers all contribute to a higher mortality in females. Also, renal carcinomas have been linked with this syndrome, and an increased likelihood of melanoma has been suggested [9]. Inheritance of this syndrome is autosomal dominant with Part 13: SyStemic DiSeaSe Sebaceous tumours, keratoacanthomas and visceral malignancy 147. Although sebaceous adenoma is the commonest, sebaceous carcinoma and epithelioma frequently occur, and within the same patient a variety of different pilosebaceousderived skin lesions including keratoacanthomas may arise. Most skin tumours occur in middle age, keratoacanthomas occurring in a quarter of affected subjects. Multiple or early onset of keratoacanthomas are suggestive of this diagnosis, as are multiple (especially eyelid) sebaceous tumours. Up to 60% of affected individuals develop sebaceous neoplasms preceding visceral malignancies [4]. It has been suggested that when a sebaceous neoplasm is identified individuals should be screened for internal malignancies [4]. Criteria for diagnosis (Amsterdam and Bethesda criteria) and recommendations for screening of patients and relatives have been reviewed [5]. Urogenital malignancies are also common, occurring in 25% [6]; bladder, renal, pelvis and endometrial cancers each account for about 5% of cancers in this syndrome. Other notable malignancies are breast cancers, haematological malignancies [6], small intestine adenocarcinoma, head and neck squamous cellcarcinoma and lung carcinoma [7]. Despite the high risk of malignancy, both the malignant cutaneous sebaceous tumours and the colonic tumours tend to have relatively indolent behaviour (the 50% survival time for colonic cancers is about 12 years [2]) and the incidence of metastases is relatively low. Eleven out of 21 female mutation carriers underwent surgical treatment for symptomatic uterine leiomyomas, at an average of 35 years. These conditions are considered together as they are all caused by RecQ helicase gene mutations, and they all predispose to abnormal growth, premature ageing and increased incidence of sitespecific malignancies (see Chapters 77, 78 and 79) [1,2]. The occurrence of lymphoproliferative neoplasia (approximately equally divided between leukaemias and lymphomas) and epithelial tissue cancers, particularly of the aerodigestive tract and lower gastrointestinal tumours, is very high; they typically occur at an early age, and the mean age of death is 23 years [1]. There is a predisposition to malignancy through mutations in other target genes [2]. The syndrome comprises multiple cutaneous leiomyomas with uterine leiomyomas; in some cases there is also an association with aggressive renal cell carcinoma, mainly of the papillary cell type. For cutaneous leiomyomas, the indication for treatment is the alleviation of cosmetic and painrelated complications. There is a predisposition to certain malignancies, including a 30% incidence of osteosarcoma. Noninfectious cutaneous granulomas, with a tendency to ulcerate, are frequent [2]. Peripheral blood lymphocytes are abnormal, and there is a variable but progressive immune deficiency of both the cellmediated and humoral types [2,4]. Chronic and recurrent sinopulmonary infections occurs in a majority of patients with ataxiatelangiectasia, and represent the most common cause of death [2]. The majority (around 80%) of tumours are lymphoproliferative or leukaemic, although carcinomas of various sites also occur, the latter usually in older subjects [7,8,9]. Most haematological malignancies are Bcell lymphomas but 25% are leukaemias, notably chronic Tcell leukaemia with chromosome 14 translocations occurring in older patients. However, Tcell leukaemias do occur in younger patients, and both Tcell lymphomas and Bcell leukaemias are also encountered. Most tumours have early onset and may precede diagnosis of ataxiatelangiectasia from the cutaneous features; this is of considerable importance as standard radiotherapy doses are contraindicated. This is a condition of premature ageing, with onset in the second to third decade of life. The key clinical findings include short stature, early greying and loss of hair, bilateral cataracts and sclerodermalike skin changes. Neoplasms develop in about 10% of cases, although the commonest cause of death is arteriosclerosis. In addition to bleeding and susceptibility to infections, severe eczema may occur; older patients also reveal an increased risk of autoimmune disorders and lymphoid malignancies [1]. NonHodgkin lymphoma occurs in almost all subjects who survive infections or bleeding due to thrombocytopenia, usually by the age of 30 years. Lymphoma (especially large cell or immunoblastic) and leukaemia also occur; the small intestine is a particular site for lymphomatous involvement. Recently, haematopoietic stem cell transplantation treatment with good outcome has been reported [1,5]. Patients develop fever, jaundice, hepatosplenomegaly, lymphadenopathy, leukaemialike gingival lesions and sloughing of the oral mucosa, pancytopenia and neurological deterioration. Although strongly suggestive of lymphoma, the infiltrate of affected organs is reported to be of a reactive, diffuse, mononuclear cell type, rather than neoplastic [1]. Most cases have Xlinked recessive inheritance but autosomal recessive and autosomal dominant forms also occur [10]. A triad of abnormalities are the most consistent and diagnostic mucocutaneous features, comprising reticulate hyperpigmentation of the skin, nail dystrophy and leukoplakia of the mucous membranes. Dental, skeletal, ocular and gastrointestinal abnormalities are common; learning difficulties, short stature and premature ageing also occur. Aplastic anaemia occurs in 50%, typically in the early teens, and is the main cause of mortality. Oropharyngeal carcinomas secondary to the mucous membrane lesions are the commonest form of malignancy. There is also increased incidence of internal malignancy, particularly gastrointestinal, including pancreatic adenocarcinoma and other haematological disorders, similar to those found in Fanconi anaemia [12,13]. Fanconi anaemia this is a genetically and phenotypically heterogeneous recessive disorder, characterized by diverse congenital malformations, progressive pancytopenia and predisposition to haematological malignancies and solid tumours [14]. To date, 16 genes have been identified as mutated in these patients and many more interacting genes have been discovered [15,16]. The main abnormality is progressive pancytopenia, which may lead eventually to the development of leukaemia. Multiple skeletal abnormalities occur, including digital hypoplasias, scoliosis and short stature. The relative risk of cancer in Fanconi anaemia is exceedingly high in comparison with the incidences expected in the general population [16]. Acute myeloid leukaemia and solid tumours are common, especially head and neck or gynaecological squamous cell carcinomas. Some authors include genodermatoses within the spectrum of paraneoplastic disorders [1] whilst others view these as a separate group [2,3], or distinguish between paraneoplastic dermatoses [4], hereditary paraneoplastic syndromes [5] and hormonally mediated paraneoplastic syndromes [6]. They may be classified according to strength of association with malignancy, association with certain types of malignancy [7], by the type of eruption that occurs (papulosquamous, vascular, etc. The likelihood of finding a neoplasm in some of the better known paraneoplastic disorders may be graded as high, intermediate or low (Table 147. Benign acanthosis nigricans is often associated with obesity or insulin resistance, and is common and usually mild (see Chapter 87). It has been documented in up to 7% of children, mainly in the teenage years; virtually all childhood cases are of the benign type although malignant acanthosis nigricans (functional adrenocortical tumour) has been reported in a paediatric patient [2]. The axillae and other flexures are particularly affected, along with the areolar area and nape of the neck and, less commonly, mucosal surfaces. De novo development of acanthosis nigricans in adults, especially if progressive and associated with weight loss (most patients with insulin resistance have a rather stocky build), should raise suspicions that there is an underlying neoplasm, although cases have been described in which acanthosis nigricans has preceded a malignancy by 10 years or more [3]. If there is also generalized pruritus or the skin changes of tripe palms, then a malignancy is even more likely. Production by tumour cells of either transforming growth factor or cytokines that activate insulinlike growth factors or their cutaneous receptors have been proposed as the pathogenetic mechanism. At least one of the following defining characteristics should be present in order to consider a dermatosis as being related to an underlying malignancy: 1 the malignancy and the cutaneous disorder should occur concurrently. Other tumours include lung, breast, endometrium, kidney, bladder, prostate, testis, cervix, thyroid and adrenal. The prognosis with malignant acanthosis nigricans is related to the survival rate from the neoplasia concerned. However, the skin changes may improve or resolve with eradication of the cancer [7,8]. Rarely, malignancyassociated acanthosis nigricans has been associated with other paraneoplastic conditions including pachydermoperiostosis, paraneoplastic pemphigus and acquired hypertrichosis lanuginosa.

In young and photoprotected skin symptoms renal failure discount 5mg frumil overnight delivery, fibroblasts bound to intact collagen fibrils apply tension to the extracellular matrix and achieve stretch medications breastfeeding buy discount frumil line. In this stretched state treatment centers for alcoholism buy cheap frumil 5mg on-line, fibroblasts display a biosynthetic phenotype that maintains optimal collagen fibril homeostasis treatment ingrown toenail order frumil overnight delivery. With the loss of collagen fibril binding 5 asa medications purchase frumil 5mg without prescription, fibroblasts are unable to apply tension to the surrounding extracellular matrix and are unable to stretch medicine 027 pill 5 mg frumil otc. In aged skin, collapsed fibroblasts occupy amorphous space containing fragmented collagen fibrils. Thus, fragmented collagen is a common driving force that mediates the convergence of many of the molecular and cellular features of extrinsic and intrinsic skin ageing. Implications of skin ageing It is easy to view skin ageing as a purely cosmetic concern; however, this would be a shortsighted perspective. Though the annual amount of money spent on skin rejuvenation therapies and procedures continues to escalate, skin ageing has broader implications such as the medical conditions that may arise in the setting of ageing skin and social implications of an aged appearance. Photoageing and natural ageing the linkage between fibroblast form and function is critically important for the ageing process in human skin, and forms a conceptual basis that unites the pathophysiology of photoageing and natural ageing. The lynchpin that connects these two forms of skin ageing is the accumulation of crosslinked collagen fibril fragments. This accumulation leads to both impairment of the mechanical properties of the dermis and reduced spreading of fibroblasts. The selfperpetuating nature of this process ultimately results in permanent collagen loss, Medical implications A study investigating whether skin appearance plays a role in predicting disease risk determined that individuals from longlived families (at least two siblings living to be nonagenarians) had less skin wrinkling on photoprotected sites compared with age matched controls. The study also found that perceived facial age was a marker of longevity in men and cardiovascular disease in women independent of other factors such as smoking, sun damage and body mass index [97]. This study suggests that the implications of skin ageing surpass cosmetic concerns and may indeed be predictive of certain disease states. In natural ageing, normal collagen fibril turnover, occurring over many years, causes the accumulation of fragmented collagen, which results in mechanical instability and fibroblast collapse, as seen in photoageing. Thus, collagen fibril damage drives a self perpetuating cycle (shown in blue) that is common to photoageing and natural ageing. The conditions of xerosis, pruritus and asteatosis in ageing skin, on the other hand, deserve special mention. The epidermal barrier is defective in ageing and this probably accounts for many of the clinical findings. Lipids processed by enzymes requiring an acidic pH compose the epidermal water barrier. In ageing skin, the pH of the skin surface becomes less acidic such that lipid production is decreased to the degree that the barrier cannot be maintained to the same extent as in younger skin [98]. In addition, ceramides that maintain the epidermal barrier have been noted to be reduced in elderly skin [99]. Aquaporin3 is a channel that allows for the flow of water and glycerol that maintains skin hydration. In ageing skin, aquaporin gene expression is reduced, leading to poor hydration [100]. These changes in lipids, ceramides and aquaporin gene expression leading to barrier dysfunction with ageing probably account for the resulting xerosis, asteatosis and pruritus. In addition, the altered barrier function likely results in an increased incidence of irritant and contact dermatitis in aged skin [101]. Dermatoporosis Dermatoporosis refers to a chronic cutaneous syndrome associated with advanced age and sun exposure in which the integrity of skin is severely compromised [102]. In this syndrome, the skin appears atrophic, has lacerations, and bruises and bleeds easily. Though there are cosmetic implications of these findings, the emphasis in this syndrome is on the loss of the functional integrity of the skin to confer protection. Dermatoporosis conveys the ageassociated functional impairment in skin similar to osteoporosis in which bone fragility can lead to significant morbidity and mortality. In stage I disease, pronounced skin thinning, purpura and stellate pseudoscars are observed. The mainstay of topical therapy for intrinsically and extrinsically aged skin is topical retinoids, which include both the natural and synthetic forms. The natural molecules, of which retinoic acid (tretinoin) is the gold standard, have been extensively investigated for their effects in aged skin. In addition, retinoic acid and retinol block collagenase, thereby preventing further collagen degradation in the skin. The actions of new collagen production and the reduction of further breakdown of existing collagen together lead to clinical improvement in wrinkling. Retinoic acid use, through mechanisms not completely understood, also results in improvement in dyspigmentation and lentigines. Early in retinoic acid therapy, notable epidermal spongiosis and accumulation of glycosaminoglycans are noted in the epidermis, imparting skin smoothening. Social implications Skin is one of the key indicators of beauty, conveying attractiveness and youth to the outside world. Features seen in ageing such as wrinkles, dyspigmentation and textural irregularities significantly detract from a youthful experience. Skin colour homogeneity was found to significantly influence perception of age, attractiveness, health and youth [105]. It is well established that a youthful and attractive appearance is associated with greater success and opportunities in the work force, increased mating opportunities and overall happiness [106,107]. Continued strides in understanding molecular mechanisms, and the development of more sophisticated tools to quantify skin ageing, will hopefully lead to substantial prevention and repair of this cosmetically and medically debilitating condition. Many patients presenting for cosmetic concerns are specifically concerned about fine and coarse wrinkling, skin laxity, dyspigmentation, erythema and telangiectases, and textural irregularities such as dullness and roughness. Most of these concerns are attributable to the results of both intrinsic and extrinsic ageing. Courses of treatment available to improve and even reverse skin damage include topical therapies, neurotoxin injections, soft tissue injectables and various nonablative and ablative laser procedures. Prophylaxis of photoageing is achieved with stringent sun protective measures including, but not limited to , sun avoidance and sun protection through both physical and chemical means. Retinoic acid inhibits induction of cJun protein by ultraviolet radiation that occurs subsequent to activation of mitogenactivated protein kinase pathways in human skin in vivo. Today, the term is used predominantly by the cosmetics industry to describe products that are purported to have therapeutic action capable of affecting the appearance of skin beyond the time of application [1]. Thus, cosmeceuticals are not subject to the stringent review and approval processes associated with drugs and, consequently, are readily made available to the public. While the demand is high for these types of products, many consumers are unaware of their regulatory control and the limited scientific evidence supporting many of their claims. In other words, while marketing implies therapeutic effect, there is often limited evidence for a true effect. Additionally, a low tolerance for side effects often keeps active ingredients at ineffective concentrations, further obscuring the true efficacy of a product. As the number of different cosmeceutical formulations on the market continues to rise, it is becoming more difficult for physicians to attest to the efficacy and safety of each. This article attempts to summarize the ingredients often encountered in cosmeceuticals, with attention to their proposed mechanisms and efficacy and some of their associated side effects. Herbals and phytochemicals, which have greater antiinflammatory potential are also addressed in the chapter. It is one of the better studied ingredients with several investigations corroborating these in vitro findings clinically, demonstrating that niacinamide use can lead to visible improvements in skin tone, texture and pigmentation, in addition to the attenuation of fine lines and wrinkles [23]. Overall, vitamin B is a welltolerated and chemically stable ingredient, which has fuelled its popularity in cosmeceutical products. Vitamin C Vitamin C, the most abundant antioxidant found in skin, is known to attenuate sun damage. An in vivo porcine study using 15% lascorbic acid and 1% tocopherol on pig skin yielded a fourfold increase in sun protection with fewer sunburn cells and thymine dimers following irradiation [24]. Vitamin C is also a necessary component in proper collagen synthesis and wound healing. Vitamin C inhibits elastin synthesis, and in vitro studies have discovered that vitamin C can inhibit tyrosinase, interrupting melanogenesis and reducing pigmentation [27]. These actions may contribute to its ability to prevent solar elastosis and diminish signs of photodamage [28]. A randomized, double blind, vehicle controlled study of 19 patients showed a 58% greater improvement in signs of photoageing over placebo [29]. Another study of 20 females showed similar findings with statistically significant improvements in global scores of photoageing with the use of a cream containing 5% vitamin C as compared with placebo; however, electron microscopy and biopsy did not detect any differences in the amount of collagen [30]. Investigators have found that lascorbic acid must be formulated at a pH of less than 3. A separate study found that after 2 months, 0% of lascorbic acid remained in various solution and topical formulations [32]; however, another group noted that more than 90% lascorbic acid was present at 2 months when formulated with ferulic acid [33]. Thus, vitamin C, when properly formulated, could be feasibly used in cosmeceutical preparations with some expected benefits. Coenzyme Q10 Coenzyme Q10 (CoQ10, also known as ubiquinone) is a naturally occurring vitaminlike substance and a renown antioxidant [11]. In addition to its antioxidant and photoprotective activity, CoQ10 has been suggested to have other mechanisms by which it exerts its beneficial effects on the skin. While in vitro evidence appears robust, in vivo evidence supporting cosmetic use of CoQ10 has not been published. Serious side effects have not been reported with the use of CoQ10, although there have been reports of allergic dermatitis to idebenonesupplemented overthecounter creams [18,19]. Vitamin B Though the mechanisms of action remain somewhat unclear, it is thought that B vitamins are potent antioxidants. Niacinamide and other B vitamin derivatives, such as panthenol (vitamin B5), have also been found to stimulate fibroblast proliferation and epidermal reepithelialization probably via the promotion of lipids, fatty acids, cholesterol, ceramide and sphingolipid synthesis, which are crucial in maintaining skin barrier function and integrity [21]. Multiple animal studies, as well as human studies, have demonstrated protective effects in the setting of Antiageing: rhytide reduction 156. Although these findings have been well corroborated in animal models, human skin studies have largely focused on erythema reduction and not antiageing effects. Other studies have investigated the antioxidant potential of vitamin E, which appears to be the most marketed attribute of this compound. Experiments using murine and porcine in vitro skin models have assessed the degree of lipid peroxidation, for example, and have shown a lesser degree of oxidative damage in skin treated with topical vitamin E, corroborating in vitro findings of antioxidant potential [37]. These effects have been demonstrated to be enhanced in combination formulations containing vitamin C, which regenerates oxidized vitamin E. Effects are even more pronounced when used in combination formulae containing vitamins E and C and other antioxidants such as ferulic acid and phloretin, which stabilize the vitamins and increase delivery to the skin [38]. Finally, vitamin E is also known for its ability to act as a rather effective moisturizer, its lipophilicity acting as an effective occlusive to seal in moisture [39]. However, there have been several case reports describing local and generalized contact dermatitis, contact urticaria and erythema multiformelike eruptions in the setting of vitamin Econtaining topical agents [40], which may limit its use. Antiageing: rhytide reduction Hydroxy acids Although hydroxy acids were first utilized for their beneficial effects on pathological skin conditions such as ichthyosis, xerosis and keratoses, they have become a popular staple in the cosmeceutical industry. This is due to more in vitro studies showing an ability to increase glycosaminoglycans and collagen, thereby increasing epidermal and dermal thickness [48,49]. In vivo studies have also suggested that they may improve the quality of elastic fibres [27]. Further, they enhance skin surface texture and colour, probably by accelerating exfoliation of the stratum corneum [21]. Hydroxy acids, combined with other whitening agents such as hydroquinone, are also effective at diminishing the appearance of hyperpigmented lesions [48,52]. In a human study investigating glycolic acid, lactic acid, tartaric acid and gluconolactone, it was found that the various acids could modify stratum corneum to enhance protection against chemical and mechanical irritants [53]. A single centre, 22week, double blind, vehiclecontrolled, randomized clinical trial on 74 women showed that glycolic and llactic acid creams were superior to vehicle in reducing overall severity of photodamage and sallowness as determined by self and physician assessments [54]. Side effects include redness, swelling, blistering, burning, pruritus, discoloration and increased photosensitivity [48,50]. Citric acid has been documented to have antiageing effects, potentially derived from its antioxidant properties. Salicylic is very commonly encountered in overthecounter acne treatments, but is much rarer in antiagein preparations. Extensive study has revealed at least a twofold mechanism of action for this whitening effect. Several clinical studies have illustrated its utility in pigmentary disorders, such as melasma [42,43] and pigmentary changes associated with photodamage [44]. Concerns over its safety from animal studies and case reports have generated a lengthy list of shortterm and potential longterm detrimental effects, including irritant contact dermatitis, vitiligo, exogenous ochronosis, renal and hepatic toxicity and carcinogenesis [46]. Safety concerns have led to the development of regulatory limitations on the maximum allowed concentration and, in some countries, bans on hydroquinone in products. Omega 6 can be encountered in a number of foods, including poultry, eggs, avocado, nuts and most vegetable oils, while omega 3 is primarily found in fish. Both fatty acids have been extensively studied to reveal benefits in all realms of medicine, ranging from oncology to psychiatry.

Obtaining written informed consent if phentermine is prescribed for longer than 12 weeks is good medical practice because of the paucity of published reports on its longterm use treatment 3rd degree hemorrhoids discount 5 mg frumil fast delivery. Topiramate and Phentermine Extended Release Topiramate is an anticonvulsant drug that was shown to reduce food intake but was not developed clinically because of the side effects at the doses selected medicine nobel prize 2016 purchase frumil 5 mg with amex. Phentermine is a long-established sympathomimetic drug approved for the short-term treatment of obesity in 1968 911 treatment for hair purchase frumil with visa. Drug Enforcement Agency has concluded that this drug carries risk for habituation and/ or addiction medicine university buy 5mg frumil otc. Two clinical trials have been conducted to evaluate longterm efficacy and safety of these combinations medicine rap song buy cheap frumil line. In the Obesity with Comorbidities Trial treatment yersinia pestis cheap frumil, topiramate and phentermine were used at the middle and high dose. The Lorcaserin the neurotransmitter serotonin is involved in regulating food intake and food preference. These mice are also resistant to fenfluramine, a serotonin agonist that causes weight loss. The precursor of serotonin, 5-hydroxytryptophan, has been shown to reduce food intake and body weight in clinical studies. Weight loss among those who completed the trial was similar for the high dose in both trials. The categorical response for those losing more than 5%, more than 10%, or more than 15% was also similar between the 2 trials. The prevalence of mental and behavioral side effects noted with topiramate alone were not as prominent as when phentermine was combined with topiramate. Only with weight losses over 10% did blood pressure and pulse show a significant decrease. There was no evidence of increased suicidal thoughts, a problem that had occurred with another drug, rimonabant, leading to its removal from the market. This drug reduces hepatic glucose production, decreases glucose absorption from the gastrointestinal tract, and enhances insulin sensitivity. Those treated with metformin lost significantly more weight (1 to 2 kg) than the placebo group, and the study concluded that metformin may have a role in primary prevention of type 2 diabetes. A meta-analysis of 3 studies with metformin in children and adolescents also found a non-significant loss of body weight (-0. This differential weight loss persisted throughout the 8 years of follow-up, with highly adherent patients remaining 3 to 4 kg below baseline, and those who were not adherent being no different from placebo. In a systematic review, Bushe and colleagues170 found that metformin may have some value to reduce or prevent weight gain and change in metabolic parameters during treatment with antipsychotic medications. Bupropion and Naltrexone Bupropion reduces food intake by acting on adrenergic and dopaminergic receptors in the hypothalamus. With this rationale, the combination of bupropion and naltrexone was tested to validate the concept and then to show long-term effects. Naltrexone has been tested at 16, 32, and 48 mg/ day in a dose-ranging study, but in the later trials was used in doses of 32 and 48 mg/day. In a 24-week dose-ranging study, 419 obese subjects were randomized, but only 244 (64%) completed the trial. When combined with bupropion, weight loss was greater but gave similar weight losses at all 3 doses of naltrexone (7. In a 52-week multicenter randomized placebo-controlled trial, participants were predominantly younger women whose body weight was nearly 100 kg. The combination of bupropion (360 mg) and naltrexone at 16 or 32 mg produced greater weight loss and decrease in waist circumference than placebo. The decrease in blood Bupropion Bupropion is a norepinephrine and dopamine reuptake inhibitor approved for the treatment of depression and for help Chapter 7 Obesity 117 in smoking cessation. Two multicenter clinical trials, 1 in obese subjects with depressive symptoms and 1 in uncomplicated overweight patients, have tested this drug. In the study of overweight patients with depressive symptom ratings of 10 to 30 on a Beck Depression Inventory, 213 patients were randomized to 400 mg/day of bupropion, and 209 subjects were assigned to placebo over a 24-week period. The placebo group was randomized to the 300- or 400-mg group at 24 weeks, and the trial was extended to week 48. By the end of the trial, the dropout rate was 41%, and the weight losses in the bupropion 300- and 400-mg groups were 6. This molecular change extends the circulating halflife from 1 to 2 minutes to 13 hours. In a 20-week multicenter European clinical trial, Astrup and coworkers179 reported that daily injections of liraglutide at 1. In the group treated with 3 mg/day, 76% achieved a greater than 5% weight loss compared with 30% in the placebo group. In a head-to-head comparison, liraglutide and exenatide produced similar amounts of weight loss (3. In poorly controlled type 2 diabetics on maximally tolerated doses of metformin and/or sulfonylurea, liraglutide reduced mean HbA1c significantly more than exenatide (-1. The principal concern about liraglutide is the report of C-cell thyroid tumors in animals and the appearance of more thyroid tumors in liraglutide-treated than in placebo-treated patients. These 2 peptides by themselves have little effect on insulin secretion from the pancreas, but in the presence of glucose each produces a synergistic increase in insulin, thus the name incretin. Pramlintide Amylin is a peptide found in the beta cell of the pancreas; it is secreted along with insulin and circulates in the blood. Amylin is deficient in type 1 diabetes, where beta cells are immunologically destroyed. Pramlintide is associated with weight loss, unlike some of the other antidiabetic medications that produce weight gain. Improvement in diabetes correlated with weight loss, suggesting that pramlintide is effective in ethnic groups with the greatest burden from overweight. The most common adverse event was nausea, which was usually mild and confined to the first 4 weeks of therapy. In humans, exenatide reduces fasting and postprandial glucose levels, slows gastric emptying, and decreases food intake by 19%. Treatment was single-blind for subjects who received subcutaneous medication only and open-label for subjects in the combination arms. Weight loss achieved at week 24 with either combination treatment was greater than with pramlintide alone or placebo (11. Elevations from baseline in heart rate and diastolic blood pressure were demonstrated with both pramlintide + sibutramine (3. In the majority of subjects receiving these treatments, however, blood pressure remained with normal ranges. These results support the potential of combining pramlintide with either sibutramine or phentermine to treat obesity. Obesity and cardiovascular disease: Pathophysiology, evaluation, and effect of weight loss: An update of the 1997 American Heart Association scientific statement on obesity and heart disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Effects of liraglutide in the treatment of obesity: A randomised, double-blind, placebo-controlled study. Zonisamide Zonisamide is an antiepileptic drug that has serotonergic and dopaminergic activity; it also is a carbonic anhydrase inhibitor, and inhibits sodium and calcium channels. Weight loss was noted in clinical trials for the treatment of epilepsy and in a 1-year randomized controlled trial. Surgery Surgical intervention for obesity has become ever more popular (see Chapter 8). The control group included obese Swedish patients who did not get surgical treatment but were treated with the best alternatives in the Swedish health care system. The effect of weight change on dyslipidemia, blood pressure, and serum insulin levels in the surgically treated group 2 and 10 years after surgery was compared with these parameters in the control group. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults-the evidence report. Accuracy of body mass index in diagnosing obesity in the adult general population. Effect of dietary protein content on weight gain, energy expenditure, and body composition during overeating: A randomized controlled trial. Is the gut microbiota a new factor contributing to obesity and its metabolic disorders Early adiposity rebound: Review of papers linking this to subsequent obesity in children and adults. Weight gain as an adverse effect of some commonly prescribed drugs: A systematic review. H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Energy and fructose from beverages sweetened with high fructose corn syrup pose a health risk for some people. Association between child and adolescent television viewing and adult health: A longitudinal birth cohort study. Exercise capacity and body composition as predictors of mortality among men with diabetes. Harmonizing the metabolic syndrome: A joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Potential health risks from beverages containing fructose found in sugar or high-fructose corn syrup. Overweight, obesity, and mortality in a large prospective cohort of persons 50 to 71 years old. Association of all-cause mortality with overweight and obesity using standard body mass index categories: A systematic review and metaanalysis. Clinical implications of obesity with specific focus on cardiovascular disease: A statement for professionals from the American Heart Association Council on Nutrition, Physical Activity, and Metabolism: Endorsed by the American College of Cardiology Foundation. Long-term influences of body-weight changes, independent of the attained weight, on risk of impaired glucose tolerance and type 2 diabetes. Association of overweight with increased risk of coronary heart disease partly independent of blood pressure and cholesterol levels: a meta-analysis of 21 cohort studies including more than 300 000 persons. Obesity and cardiovascular disease: Pathophysiology, evaluation, and effect of weight loss: An update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Lifestyle and cardiovascular disease in middle-aged British men: the effect of adjusting for within-person variation. Obesity and the risk of myocardial infarction in 27,000 participants from 52 countries: A case-control study. Disparate effects of left ventricular geometry and obesity on mortality in patients with preserved left ventricular ejection fraction. Gallbladder volume in adults and its relationship to age, sex, body mass index, body surface area and gallstones. Obesity and nonalcoholic fatty liver disease: Biochemical, metabolic, and clinical implications. Meta-analysis: obesity and the risk for gastroesophageal reflux disease and its complications. Body mass index, height and risk of renal cell cancer in a pooled analysis of 13 cohort studies. Adolescent girls with polycystic ovary syndrome have an increased risk of the metabolic syndrome associated with increasing androgen levels independent of obesity and insulin resistance. Maternal obesity and diabetes as risk factors for adverse pregnancy outcomes: differences among 4 racial/ethnic groups. Maternal obesity in early pregnancy and risk of spontaneous and elective preterm deliveries: A retrospective cohort study. A prospective study of age and lifestyle factors in relation to community-acquired pneumonia in U. Obesity and osteoarthritis in knee, hip and/or hand: An epidemiological study in the general population with 10 years follow-up. Weight loss reduces knee-joint loads in overweight and obese older adults with knee osteoarthritis. Paradoxical effect of body mass index on survival in rheumatoid arthritis: Role of comorbidity and systemic inflammation. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. Weight loss in overweight adults and the long-term risk of hypertension: the Framingham study. Systematic review of long-term weight loss studies in obese adults: Clinical significance and applicability to clinical practice. Healthy percentage body fat ranges: An approach for developing guidelines based on body mass index. The role of low-fat diets in body weight control: A meta-analysis of ad libitum dietary intervention studies. Effect of a low-carbohydrate diet on appetite, blood glucose levels, and insulin resistance in obese patients with type 2 diabetes. Effects of low-carbohydrate vs low-fat diets on weight loss and cardiovascular risk factors: A meta-analysis of randomized controlled trials. Comparison of the Atkins, Ornish, Weight Watchers, and Zone diets for weight loss and heart disease risk reduction: A randomized trial. Comparison of weight loss diets with different compositions of fat, protein, and carbohydrates. Metabolic and weight loss effects of long-term dietary intervention in obese patients: Four-year results. Systematic review: An evaluation of major commercial weight loss programs in the United States. Weight loss with self-help compared with a structured commercial program: A randomized trial.

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