1. بنام خداوند بخشنده و مهربان

2. دکتر مجيد رستمی متخصص پوست مو و زيبايی استاديار دانشگاه علوم پزشکی اردبيل (عضو هيئت علمی دانشگاه)

3. Cutaneous Changes in Renal Disorders

4. ► The protean cutaneous manifestations of renal disease are primarily encountered in patients with chronic renal failure (CRF). In contrast, although acute renal failure (ARF) causes uremia, hypertension, congestive heart failure, and other serious conditions, only two skin changes — edema and uremic frost — occur in the acute setting. Edema is a particular feature of ARF with nephrotic syndrome. Uremic frost results from eccrine deposition of urea crystals on the skin surface of individuals with severe uremia, and it is now rarely encountered because of the wide availability of acute hemodialysis.

5. CUTANEOUS MANIFESTATIONS OF CHRONIC RENAL FAILURE

6. ► The skin of patients with CRF is typically dry, often with ichthyosis-like scaling. This condition may result in part from altered vitamin A metabolism in CRF, along with fluid volume shifts from dialysis. Skin color is also altered in CRF. The skin is pale (from anemia) and often exhibits a distinctive gray-yellow hue, because of the accumulation of carotenoid and nitrogenous pigments (urochromes) in the dermis. The nails also exhibit color changes. Lindsey's, or half-and-half, nails are normal in their distal 50 percent and white in the proximal 50 percent. The term Terry's nails has been applied to nails in which only the distal 20 percent is normal. These nail changes are fairly specific to CRF but may be encountered in patients with chronic liver disease and in healthy individuals.

7. Pruritus

8. ► Pruritus is frequently reported by patients with chronic end-stage renal disease. The incidence of renal pruritus is reported to approach 50 to 90 percent of patients undergoing hemodialysis. Some patients complain of pruritus only during or soon after dialysis, whereas others report symptomatic exacerbation during this same period. Although the etiology is poorly understood, localized and generalized forms of renal pruritus are likely caused by a combination of several mechanisms: increased serum levels of histamine, vitamin A, and parathyroid hormone (PTH); mast cell hyperplasia; peripheral polyneuropathy; and xerosis. Clinically, the skin may appear normal or demonstrate a varied pattern of lichenified or hyperkeratotic lesions.

9. ► Treatment of renal pruritus is often empirical. Topical moisturizers alleviate pruritus associated with xerotic skin. Topical glucocorticoids and ultraviolet phototherapy are often used to suppress inflammation in treated areas. Topical capsaicin depletes substance P from nerve endings, thereby suppressing itch sensation. Improving the efficacy of dialysis and/or changing the dialysate concentration may help to alleviate pruritus. Some patients have responded to treatments with intravenous lidocaine, heparin, and cholestyramine. Surgical options include subtotal parathyroidectomy, electric needle stimulation, and renal transplantation. Erythropoietin to be effective in lowering plasma histamine concentrations with subsequent improvement in pruritus. Preliminary studies indicate that topical tacrolimus ointment may each have some therapeutic effect.

10. Calcification

11. ► Metastatic calcification of the skin in CRF results from secondary or tertiary hyperparathyroidism. Abnormally elevated levels of PTH may trigger deposition of crystalline calcium pyrophosphate in the dermis, subcutaneous fat, or arterial walls. Vascular calcification is, in fact, very common in patients with long-term CRF, and is seldom symptomatic. Occasionally however, calcified vessels may thrombose acutely, resulting in a syndrome that has been called calciphylaxis. This acute thrombosis produces symmetrical livedo reticularis. Livedoid areas are excruciatingly painful due to ischemia, and they quickly become hemorrhagic and ulcerate. Calciphylaxis is associated with a high mortality rate, particularly when the skin of the trunk is involved (as opposed to a somewhat better prognosis if skin infarction is limited to the extremities). Laboratory evaluation usually demonstrates marked elevation of intact PTH.

12. ► In addition to vascular calcification and calciphylaxis, nodular calcification may occur in the skin and fat of patients with CRF. ► The involved skin may ulcerate, the prognosis for patients with this nonvascular form of calcification is excellent. ► Treatment of calciphylaxis is extraordinarily difficult. Pain management, careful d é bridement of gangrenous tissue, and, especially, parathyroidectomy have been successful. However, no prospective trial of parathyroidectomy has been conducted, and convincing evidence of improved prognosis for patients with calciphylaxis after this procedure is lacking. Studies to evaluate the role of anticoagulation or thrombolytic therapy in calciphylaxis have yet to be conducted. The nonvascular form of CRF-associated calcinosis may be managed with surgical excision of calcific nodules and treatment of ulcers with hydrocolloid dressings and the like.

14. Bullous Disease of Hemodialysis

15. ► Porphyria cutanea tarda (PCT) has been described in patients with CRF undergoing hemodialysis. Although the etiology of this phenomenon is still unclear, inadequate clearance of plasma-bound porphyria precursors by urine excretion or hemodialysis may lead to porphyrin deposition in the skin manifested clinically as photosensitivity and subepidermal bullae. ► Bullous dermatosis of dialysis or pseudoporphyria may occur in 8 to 18 percent of patients undergoing hemodialysis. This condition is often clinically indistinguishable from PCT with marked skin fragility and blister formation on sun-exposed skin. However, hypertrichosis is less common, and plasma porphyrin levels are typically normal. Pseudoporphyria may also occur in some patients taking tetracycline, nabumetone, nalidixic acid, furosemide, and phenytoin. ► Treatment of PCT or pseudoporphyria in most patients with CRF may be difficult. Phlebotomy can reduce iron levels in the liver, allowing new hepatic uroporphyrinogen decarboxylase to be formed. ►

16. ► Intravenous erythropoietin may both lower total body iron stores and support phlebotomy, Chloroquine effectively clears porphyrins from the liver.

18. Acquired Perforating Dermatoses

19. ► Acquired perforating dermatosis can occur in association with CRF and diabetes mellitus.This condition, which occurs in up to 10 percent of patients undergoing hemodialysis, may be more common in blacks, and appears to be distinct from the four primary perforating disorders (elastosis perforans serpiginosa, Kyrle's disease, perforating folliculitis, and reactive perforating collagenosis. Clinically, patients develop hyperkeratotic papules with a central crust-filled crater on the trunk and extensor surfaces, often in a linear distribution Simultaneous transepidermal elimination of both collagen and elastic fibers has been detected.The etiology of this process is unclear. Proposed mechanisms include diabetes microangiopathy, microtrauma caused by chronic pruritus, dysregulation of vitamin A or vitamin D metabolism, abnormality of collagen or elastic fibers, or local inflammation and connective tissue degradation caused by dermal microdeposition of substances such as uric acid and calcium pyrophosphate.

21. Diabetes Mellitus

22. ► Diabetes mellitus (DM) is a major cause of morbidity and mortality in the United States. More than 15 million Americans have the disease. ► Major studies show that tight glycemic control decreases retinopathy, neuropathy, nephropathy, and coronary artery disease, which remain the major contributors to morbidity and mortality. Likewise, tight glycemic control may have a beneficial effect on a subset of skin-related, DM- associated disorders.

23. ► DM is characterized by a state of relative or complete insulin deficiency leading to gross defects in glucose, fat, and protein metabolism. In type 1 DM [insulin-dependent DM (IDDM)], an insufficiency of insulin occurs through a gradual, antibody-driven destruction of beta islet cells in the pancreas. In type 2 diabetes [non-insulin-dependent DM (NIDDM)], chronic hyperglycemia occurs mainly through end-organ insulin resistance followed by a progressive decrease in pancreatic insulin release associated with aging. A genetic predisposition and a strong association with obesity exist in type 2 DM. In both types of DM, abnormalities of insulin and elevated blood glucose levels lead to metabolic, vascular, neuropathic, and immunologic abnormalities. Affected organs include the cardiovascular, renal, and nervous systems, the eyes, and the skin.

24. ► Nearly all patients with DM have cutaneous manifestations. ► Hyperglycemia leads to nonenzymatic glycosylation (NEG) of various structural and regulatory proteins, including collagen. ► Hyperglycemia leads to nonenzymatic glycosylation (NEG) of various structural and regulatory proteins, including collagen. Although NEG occurs normally with aging, the process is greatly accelerated in DM. NEG leads to formation of nondegradable advanced glycosylation end products (AGEs) that are responsible for decreases in both acid solubility and enzymatic digestion of cutaneous collagen. Disorders such as diabetic thick skin and limited joint mobility (LJM) are thought to result directly from accumulation of AGEs. Studies show that the degree of cutaneous AGEs correlates strongly with retinopathy, nephropathy, and other microvascular complications of DM.

25. ► Macro- and microangiopathy contribute significantly to the cutaneous complications of DM. ► In addition, a loss of cutaneous sensory innervation occurs with DM, predisposing patients to infection and injury. ► Derangements of immunoregulatory mechanisms also occur in DM. Hyperglycemia and ketoacidosis diminish chemotaxis, phagocytosis, and bactericidal ability of white blood cells.

26. CUTANEOUS DISORDERS OF DIABETES MELLITUS

27. ► LIMITED JOINT MOBILITY AND SCLERODERMA-LIKE SYNDROME Diabetic LJM, or cheiroarthropathy, presents as tightness and thickening of the skin and periarticular connective tissue of the fingers, resulting in a painless loss of joint mobility. Initial involvement of the distal interphalangeal joints of the fifth digit usually progresses proximally to involve all fingers. Larger joints of the elbow, knee, and foot may be affected. The actual joint space, however, remains uninvolved, so that LJM is not a true arthropathy ► This disorder is characterized by the “ prayer sign ” which is an inability to approximate the palmar surfaces and interphalangeal joint spaces with the hands pressed together and fingers separated. ► Thirty to 50 percent of adult patients with type 1 DM have LJM; some authors believe this to be the earliest clinically apparent complication of diabetes in childhood and adolescence. It also is common in type 2 DM. ► Most importantly, LJM is directly correlated with microvascular disease.

28. ► Evidence indicates that intensive insulin therapy is important in prevention, and possibly treatment of LJM and scleroderma- like syndrome (SLS). ► Treatment for LJM is difficult and should focus on tight control of blood sugar as well as physical therapy to preserve active range of motion.

30. Acanthosis Nigricans

31. ► Clinically, acanthosis nigricans (AN) presents as brown to gray-black papillomatous cutaneous thickening in the flexural areas including the posterolateral neck, axillae, groin, and abdominal folds. The affected skin has a dirty, velvety texture. In some cases, oral, esophageal, pharyngeal, laryngeal, conjunctival, and anogenital mucosal surfaces may be involved. In general, however, the back of the neck is the most consistently and severely affected area. ► Although some reports on AN suggest an association with malignancy, other studies show that AN is common in the general population and most cases are associated with obesity, insulin resistance, and hyperinsulinemia.

32. ► In addition to hyperinsulinemia, other associations with AN include hyperandrogenic states in females and certain medications. Systemic glucocorticoids, nicotinic acid, and estrogens such as diethylstilbestrol have all been implicated. ► AN may be considered as a prognostic indicator for development of type 2 DM. ► In states of insulin resistance and hyperinsulinemia, AN may result from excess insulin binding to IGF-1 receptors on keratinocytes and fibroblasts. ► In AN associated with malignancy, evidence suggests that transforming growth factor -α released from the tumor cells may stimulate keratinocyte proliferation via epidermal growth factor (EGF) receptors.

34. ► SCLEREDEMA DIABETICORUMRecognized in 1970 as a syndrome, scleredema of diabetes [scleredema diabeticorum (SD)] presents with the insidious onset of painless, symmetric induration and thickening of the skin on the upper back and neck. Spread to the face, shoulders, and anterior torso may occur. The skin retains a nonpitting, woody, “ peau d'orange ” quality. ► Identical changes occur with postinfectious scleredema, usually associated with streptococcal pharyngitis. In scleredema associated with infection, however, the onset is often sudden, and the symptoms usually remit over time. ► Reported in 2.5 to 14 percent of patients with DM, SD is not uncommon.

35. ► SD is a disease of long-standing diabetes, associated with obesity. Most patients have type 2 DM. This disorder has not been reported in children. ► Treatment for SD is usually unsuccessful. Case reports describe treatment with radiotherapy, low-dose methotrexate, and prostaglandin E 1.

36. Eruptive Xanthomas

37. ► Eruptive xanthomas present clinically as 1- to 4-mm reddish-yellow papules on the buttocks and extensor surfaces of the extremities. The lesions occur in crops, and may coalesce into plaques over time. Although eruptive xanthomas are generally asymptomatic, correct diagnosis is crucial because these lesions are often the first harbingers of untreated DM and severe hypertriglyceridemia. ► The main acquired forms of hypertriglyceridemia result from medications (estrogens, retinoids), alcohol, and, importantly, untreated DM. In fact, DM is the most common cause of massive hypertriglyceridemia in genetically susceptible individuals. ► Treatment of hypertriglyceridemia involves strict dietary fat restrictions and control of the underlying DM. LPL activity returns to normal after treatment with long-term insulin or oral glucose-lowering agents. The eruptive xanthomas respond rapidly and usually resolve completely in 6 to 8 weeks.

39. ► BACTERIAL INFECTIONS Patients with DM are at a higher risk for contracting certain bacterial infections, including Group A and Group B streptococcal infections, necrotizing fasciitis, and malignant otitis media. ► Malignant external otitis Invasive “ malignant ” otitis externa is an uncommon, life-threatening infection of the external auditory canal with potential cranial bone and intracranial involvement. Pseudomonas aeruginosa is usually implicated, and preceding aural irrigation with tap water may play an etiologic role. This painful infection, which occurs in older patients with DM, is characterized by purulent discharge, unilateral facial swelling, hearing loss, and granulation tissue in the ear canal. Approximately 70 to 94 percent of patients with malignant external otitis have underlying diabetes. Diagnosis is often delayed, and mortality rates are as high as 20 to 40 percent despite appropriate antibiotic therapy.

40. ► Necrotizing fasciitis Ten to 60 percent of all cases of necrotizing fasciitis occurs in patients with DM. Necrotizing fasciitis is a life- threatening bacterial infection of the soft tissues with spread along fascial planes. The perineum, trunk, abdomen, and upper extremities are most commonly involved. Clinical presentation includes erythema, swelling, induration, necrosis, and possible bullae formation. The degree of pain and toxicity are often out of proportion to the severity of the findings. Although most cases result from polymicrobial facultative gram-negative bacilli such as Escherichia coli and anaerobes such as Bacteroides, Peptostreptococcus, and clostridium species, approximately 10 percent of cases are monomicrobial, often dstreptococcal species. Treatment includes urgent surgical debridement and appropriate antibiotics. Mortality rates of 40 percent have been reported.

41. ► FUNGAL AND YEAST INFECTIONS ► Candidal infections Most authors believe that mucocutaneous Candida infections occur more frequently among patients with DM, especially those with poorly controlled disease.( Intertrigo (axillary, inguinal, web space), vulvovaginitis, balanitis, paronychia, onychomycosis, glossitis, and angular cheilitis are most common. ► Postmenopausal females with recurrent vulvovaginal candidiasis should undergo screening for diabetes. Treatment for candidal infections includes topical and oral antifungals..

42. ► Dermatophyte infections Rate of toenail onychomycosis was 2.77 times greater for patients with DM as compared to controls. In addition, peripheral vascular disease to be a significant predictor. Probably the most important aspect of dermatophyte infection in patients with DM is aggressive diagnosis and treatment of tinea foot infections because of the potential portal of entry for subsequent bacterial infections.

43. Diabetic Ulcers

44. ► Chronic, nonhealing foot ulcers are a significant problem for patients with DM, It has been estimated that 15 percent of individuals with DM will develop lower-extremity ulcers and that 14 to 24 percent of patients with DM who have foot ulcers will eventually undergo amputation. ► Neuropathy (associated with uncontrolled hyperglycemia) is one of the major predictors of diabetic ulcers. ► vasculopathy, a major contributing factor in the formation of lower-extremity ulcers leading to amputation. ► Standard therapy for neuropathic diabetic ulcers includes debridement, pressure relief (often non – weight bearing), wet compresses, and protective dressings.

45. Necrobiosis Lipoidica

46. ► The classic clinical picture of NL is one to several sharply demarcated yellow-brown plaques on the anterior pretibial region. The lesions have a violaceous, irregular border that may be raised and indurated. Initially, NL often presents as red-brown papules and nodules that may mimic sarcoid or granuloma annulare (GA). Over time, the lesions flatten, and the central yellow area becomes atrophic and develops telangiectasias, taking on the characteristic “ glazed-porcelain ” sheen. Aside from the shins, other sites of predilection include ankles, calves, thighs, and feet. Fifteen percent of patients develop lesions on the upper extremities and trunk that tend to be more papulonodular. Although pain and pruritus have been reported, most lesions are asymptomatic. Anesthesia of the plaques does occur. Epidemiologic data show that the mean age of onset is around 30 years and that NL occurs three times more often in women than in men.

47. ► The course of NL is often indolent, with spontaneous remission in less than 20 percent of cases. However, the possibility of ulceration, a poor spontaneous remission rate, and cosmetic concerns lead patients to seek treatment. Ulceration, the most serious complication, occurs in approximately 13 to 35 percent of cases on the legs. A few cases of squamous cell carcinoma arising in chronic ulcerative NL have been reported. ► The prevalence of NL has been found to be only 0.3 to 3 percent in patients with DM.

48. ► Early application of potent topical glucocorticoids might slow progression. Although some authors report improvement with intralesional injection of glucocorticoids to the active border, the risk of ulceration with this treatment modality should be considered. A few case reports and one series of six patients showed benefit with short- term systemic glucocorticoids. Aspirin and dipyridamole have produced variable results. ► Focus should be on prevention of ulcers. When ulceration occurs in patients with NL, the same wound care principles apply as for all diabetic ulcers. Recently, cyclosporine resulted in ulcer closure and sustained response in two patients. Surgical excision down to fascia and split-thickness skin grafting remain as the last resort for very recalcitrant NL ulcers.

50. Granuloma Annulare

51. ► Clinically, GA presents as erythematous to violaceous domed-shaped papules arranged in an annular configuration. They may form indurated, circular or semicircular plaques with central clearing. Localized GA, the most common form, occurs more frequently in children and young adultsWomen are affected two to three times more often than men. Atypical forms of GA include generalized, subcutaneous, and perforating types. Seven to 10 percent of patients have generalized GA, which presents as hundreds to thousands of 1- to 2-mm flesh-colored papules that may form small annular plaques. The lesions are symmetric, and appear more commonly on the abdomen, chest, thighs, and extensor elbows. Generalized GA occurs more frequently in older adults (mean age of onset is 52) and has a more chronic and relapsing course. Only 8 percent clear spontaneously.

52. ► The association of GA with DM is widely discussed and appears to be less strong than that of NL. ► Although controversial, many authors agree that DM is found more frequently in patients with adult onset GA, and in those with generalized or perforating GA, and that these patients tend to experience a more chronic, relapsing course of GA. ► The mainstay of treatment remains potent topical or intralesional glucocorticoids. Because generalized GA may be pruritic and also cosmetically crippling, systemic treatments have been tried including systemic glucocorticoids, niacinamide, chloroquine, aspirin, and potassium iodide. There is no clear drug of choice. Clofazimine has shown promise, and treatment with PUVA resulted in complete clearance in one case and in a series of five patients chronic, relapsing course of GA

54. Diabetic Dermopathy

55. ► Diabetic dermopathy presents as small (<11 mm), atrophic, brown, scarlike macules on the pretibial areas. The lesions are asymptomatic and clear within 1 to 2 years with slight residual atrophy or hypopigmentation. New lesions usually arise, giving the sense that the pigmentation and atrophy are persistent. ► Diabetic dermopathy occurs more often in patients with an increased duration of DM and is more frequent in men. ► An association does seem to exist between diabetic dermopathy and the more serious complications of DM. In a study of 173 patients with DM, the incidence of shin spots was significantly increased in patients with retinopathy, nephropathy, and neuropathy. ► No treatment is necessary for the individual atrophic tibial lesions. They are asymptomatic and are not directly associated with an increase in morbidity.

57. Bullosis Diabeticorum

58. ► Bullosis diabeticorum (BD) is characterized by abrupt onset of bullae on the lower extremities, usually the toes, feet, and shins. Occasionally, the distal upper extremities are involved. The blisters are usually painless and not pruritic. Healing occurs within 2 to 5 weeks and rarely leaves scarring. The condition may recur as successive crops of bullae over many years. ► The differential diagnosis of diabetic bullae includes bullous impetigo, bullous pemphigoid, pemphigus vulgaris, epidermolysis bullosa acquisita, porphyria cutanea tarda, bullous erythema multiforme (e.g., to drugs), and insect bite reaction. ► BD runs a benign course, without involvement of large body surface areas. The only serious complication is that of secondary infection, which should be managed with culture and appropriate antibiotics if suspected. Otherwise, therapy is supportive.

59. GLUCAGONOMA SYNDROME

60. ► Glucagonoma syndrome is a rare paraneoplastic syndrome consisting of DM, an erosive rash [necrolytic migratory erythema (NME)], glossitis, weight loss, diarrhea, anemia, and hypoalbuminemia. It is caused by a glucagon- secreting pancreatic tumor of the alpha islet cells. Age of onset is typically 50 to 60 years, and no gender predilection has been observed. More than 15 percent of patients may not have DM. Malignancy as defined by presence of metastases is reported to be 60 to 70 percent, but the true malignancy rate may be as high as 100 percent. Metastases occur with most frequency in the liver, and then adjacent lymph nodes, bone, adrenals, kidney, and lung.

61. ► All patients with untreated glucagonoma eventually develop NME. Sites of involvement include groin, thighs, buttock, central face, frictional areas, and distal extremities. Initial clinical presentation is usually erythematous macules and papules, often in the groin. The lesions evolve into blistering plaques resulting in a scalded appearance with erosion and crusting. pain and intense pruritus are common. In addition to NME, approximately 30 percent of patients develop glossitis and angular chelitis. ► The differential diagnosis of NME includes bullous and papulosquamous disorders, as well as certain nutritional deficiencies in which clinical and histologic skin findings closely resemble those of NME.

62. In glucagonoma syndrome, excessive levels of glucagon promote amino acid catabolism, leading to a deficiency of the proteins needed for cellular growth and division. This chronic state of amino acid deficiency is thought to be responsible for the cellular necrosis of the epidermis in NME. In glucagonoma syndrome, excessive levels of glucagon promote amino acid catabolism, leading to a deficiency of the proteins needed for cellular growth and division. This chronic state of amino acid deficiency is thought to be responsible for the cellular necrosis of the epidermis in NME. ► In the correct clinical setting, an elevated serum glucagon level is usually diagnostic. Levels generally range from 1000 to 5000 pg/mL (normal, 50 to 150 pg/mL). ► Contrast-enhanced computed tomography is recommended for visualization of the tumor. The gold standard, however, remains selective celiac axis arteriography for localization of tumor as well as liver metastases. ► The mainstay of treatment is surgical resection of the primary tumor. ► Octreotide and other new longer acting somatostatin analogs have been shown to significantly reduce serum glucagon levels and improve symptoms.

64. Acquired Perforating Disorders

65. ► Clinically, lesions grouped under the heading of APDs appear as pruritic, keratotic papules mainly on the extensor surfaces of the extremities. Papules and nodules with a perforating component may also occur on the trunk and face. Many are follicular and contain a prominent central keratotic plug. The papules may be grouped, or coalesce to form verrucous plaques. ► The APDs include Kyrle's disease, reactive perforating collagenosis, perforating folliculitis, and elastosis perforans serpiginosa. ► Several studies in the literature suggest a causal relationship of APDs with chronic renal failure and DM with or without hemodialysis. The prevalence among patients on hemodialysis is reported at 4.5 to 10 percent.

66. ► The pathogenesis of the APDs is unknown. One possible factor may be deposition of “ uremic substances, ” such as uric acid or hydroxyapatite, that incite an inflammatory response and foreign body reaction resulting in transepidermal elimination of dermal constituents. Local trauma and chronic rubbing secondary to pruritus appear to play a role. Microangiopathy and dysregulation of vitamins A or D have also been proposed. ► Treatment for APDs is usually unsuccessful. Retinoic acid, topical glucocorticoids, and PUVA have been found to be partially successful.