Cutaneous Manifestations of Systemic Disease

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[edit] Cutaneous Manifestations of Systemic Disease

James C. Shaw

[edit] VASCULITIS, PURPURA, AND COAGULOPATHIES AFFECTING THE SKIN

Vasculitis represents a disease group that encompasses numerous disorders with varied etiologies (see Chapter 138 ). Vasculitis can affect large, medium, or small vessels, the latter two being most common in the skin. Purpuric lesions can be seen in the setting of vasculitis or can be a manifestation of hemorrhage into the skin. Hypercoagulable states frequently cause thromboses in the skin, with subsequent necrosis. The most common of these vasculopathies is discussed here.

[edit] Hypersensitivity Vasculitis

Hypersensitivity vasculitis, also known as leukocytoclastic vasculitis or cutaneous small vessel vasculitis,^[1] is the most common of the cutaneous vasculitides and can be associated with numerous disorders and diseases (Box 88-1).

The clinical presentation of leukocytoclastic vasculitis is usually “palpable purpura,” which translates to multiple nonblanchable hemorrhagic papules, usually on lower extremities and almost always bilateral ( Plate 61 ). Symptoms are usually mild and can include pruritus, tenderness, and burning. Organ involvement other than skin is not common except in Henoch-Schönlein purpura and systemic lupus erythematosus (SLE) where renal, gastrointestinal, and occasionally other organ involvement can occur.

Skin biopsy is helpful in diagnosing leukocytoclastic vasculitis. Other directed tests, such as cryoglobulins, antinuclear antibodies, urinalysis, may be needed to confirm the etiology.

Treatment is frequently not required in leukocytoclastic vasculitis, which tends to be self-limited. In severe cases, systemic corticosteroids are helpful.

[edit] Churg-Strauss Vasculitis

Churg-Strauss vasculitis is a small-to medium-sized vessel vasculitis with a characteristic clinical picture and cutaneous involvement in 40% of patients.^[2] The vasculitis is preceded commonly by adult-onset asthma and allergic symptoms that can be present for several years. Since medium-sized vessels become involved, the clinical picture includes linear or livedo pattern inflammation, as well as small nodules ( Plate 62 ). There is frequently a marked eosinophilia. Antineutrophil cytoplasmic antibody (ANCA) is usually negative, although a perinuclear pattern (P-ANCA) has been reported to be helpful in distinguishing Churg-Strauss syndrome from Wegener's granulomatosis. Most cases respond to treatment with systemic corticosteroids.

[edit] Wegener's Granulomatosis

Wegener's granulomatosis is a vasculitis involving arterioles that can affect the skin with palpable purpura and ulcerations. Noncutaneous involvement usually dominates the clinical picture.

[edit] Polyarteritis Nodosa

Polyarteritis nodosa (PAN), is a rare vasculitis involving medium-sized vessels. It can be localized to skin or be a systemic and life-threatening disease. In localized cutaneous PAN, a livedo pattern of vascular erythema, nodules, and painful ulceration is common. Biopsy is diagnostic if deep enough to visualize the larger vessels in the deep dermis and fascia. The systemic form can involve the kidneys, gastrointestinal tract, heart, and central nervous system (CNS). Immunosuppressive therapy with corticosteroids and cyclophosphamide are frequently helpful.

[edit] Disseminated Intravascular Coagulation

Rapidly evolving widespread purpura usually represents activation of the coagulation cascade as a result of severe multisystem disease. Coagulation factors are consumed, resulting eventually in hypocoagulability. A variant of disseminated intravascular coagulation (DIC), called purpura fulminans (see Plate 20 ), is seen in children after meningococcal, streptococcal, and sometimes viral infection.

[edit] Antiphospholipid Antibody Syndrome

Antiphospholipid antibody syndrome^[3] is a hypercoagulable state associated frequently with underlying collagen vascular diseases such as SLE and scleroderma. The syndrome can also be idiopathic. Clinical manifestations are those of thrombosis; cutaneous findings include a livedo reticularis pattern on lower extremities ( Plate 63 ), with areas of necrosis if the disease progresses or is not treated. Laboratory evidence of the syndrome includes the presence of (1) lupus anticoagulant, (2) anticardiolipin antibody, and (3) β-2 glycoprotein 1. Treatment is anticoagulation with heparin initially, followed by warfarin for maintenance of an international normalized ratio (INR) of 3 or higher.

[edit] CUTANEOUS MANIFESTATIONS OF DIABETES MELLITUS

Diabetic dermopathy is a common cutaneous finding in patients with diabetes that consists of tan-brown macular areas on the pretibial areas. Whether these lesions represent a form of diabetic vasculopathy or are from minor trauma remains uncertain. There appear to be no potential complications from this disorder.

Necrobiosis lipoidica (NL) occurs only in approximately 1% of diabetics, but approximately two-thirds of patients who develop NL have overt diabetes. NL is a granulomatous skin disorder of uncertain etiology consisting of red-brown or red-orange plaques occurring mostly on the pretibial areas ( Plate 64 ). Atrophy and telangiectasia are common features of NL plaques. Symptoms are mild, but disfigurement can be significant when lesions become large or ulceration occurs. Biopsy is diagnostic, showing pathognomonic granulomatous changes throughout the dermis. Treatment consists of potent topical or intralesional corticosteroids and standard ulcer care when ulcerated. Inhibition of platelet aggregation and pentoxyphylline have been helpful in isolated case reports. Treatment failures are common.

Eruptive xanthomas are described in the section on xanthomas (see below).

PRURITUS without primary cutaneous lesions is a common complaint in patients with diabetes (see Chapter 96 ). Treatment consists of diabetic control, keeping the skin temperature cool, and judicious use of antihistamines.

Neurotrophic ulcers occur in patients with diabetes with peripheral neuropathy and loss of sensation. They are pressure-induced ischemic ulcers similar to those seen in patients with spinal cord injuries. Therapy, which requires avoidance of pressure, can be complicated by diabetic vasculopathy, which can compromise tissue perfusion.

Bullous disease of diabetes is an idiopathic disorder consisting of bullae on the distal extremities with little or no inflammation. The bullae can reach considerable size. The differential diagnosis can include bullous pemphigoid, burns, mechanical blisters, and porphyria cutanea tarda. Treatment is supportive, with attention to tight glucose regulation.

[edit] XANTHOMAS

Xanthomas are clinical lesions with a characteristic yellowish color resulting from lipid-filled histiocytes present in the dermis or deeper tissues. Several types of xanthomas have been described and are associated with different lipoprotein abnormalities, both familial and acquired (Table 88-1).

Table 88-1 XANTHOMAS

Eruptive xanthomas occur from acute elevations in triglycerides as a result of lipoprotein lipase deficiency or familial hypertriglyceridemia seen in types I, II, IV, and V dyslipidemias (see Table 71-2 ). Most cases are secondary to poorly controlled diabetes mellitus. A patient presenting with eruptive xanthomas requires evaluation of lipids, glucose, and thyroid function. Insulin and thyroid hormone stimulate lipoprotein lipase, the enzyme responsible for moving triglycerides from blood to tissues. Multiple yellow papules on the buttocks or extremities are typical ( Plate 65 ). Diagnosis is made by clinical picture, history of rapid onset of lesions, and skin biopsy. When possible, correction of underlying disease and triglyceride levels result in gradual resolution of the lesions.

[edit] CUTANEOUS SARCOIDOSIS

Sarcoidosis is a granulomatous disease of uncertain etiology that can affect any organ (see Chapter 78 ). Cutaneous sarcoidosis is present in approximately 25% of patients with systemic sarcoidosis. Nonspecific cutaneous findings, such as erythema nodosum, can be associated with sarcoidosis but do not represent sarcoidal involvement of the skin.

The typical presentation of cutaneous sarcoidosis is papules or small plaques. These are common around the mouth, nose, and eyes ( Plate 66 ). A red-brown color is common and is caused by the presence of histiocytes in the dermis. Larger plaques can be present elsewhere on the trunk and extremities ( Plate 67 ). A less common presentation is a purple-red firm nodular plaque that commonly presents on the nose or ears ( Plate 68 ). This lesion has been called “lupus pernio” from original descriptions but consists in fact of dermal infiltrates of sarcoidal granulomas.

Diagnosis is made by clinical presentation and biopsy confirmation. Treatment options for cutaneous sarcoidosis include potent topical or intralesional corticosteroids, systemic corticosteroids, antimalarial therapy, and immunosuppressive agents such as methotrexate and cyclosporin. Evaluation for systemic disease should be considered in all patients with cutaneous sarcoidosis.

[edit] PORPHYRIA CUTANEA TARDA

Porphyria cutanea tarda (PCT) is a cutaneous manifestation of a rare disorder of porphyrin and heme metabolism resulting in high levels of circulating porphyrins. There are several types of porphyria; PCT is the most common form. PCT requires a genetic defect in the hepatic enzyme porphyrinogen decarboxylase. In homozygous individuals, PCT occurs spontaneously in childhood and early adulthood. In heterozygotes, a second hepatic insult is usually required to produce the disease. Ethanol, other hepatotoxic drugs, and more recently, hepatitis B and C virus (HBV and HCV) infections have been associated with PCT.^[4]

The skin findings in PCT are primarily from photodamage. Circulating porphyrins absorb ultraviolet (UV) light and cause cellular damage. Patients typically present with skin fragility and bullae on the dorsal hands ( Plate 69 ). Facial hypertrichosis is a common finding of uncertain etiology.

Diagnosis is made by clinical presentation, skin biopsy, and serum and urine porphyrin studies. Serum studies show elevation in total body iron stores (ferritin >500μg/L), and urine porphyrin studies show a pattern characteristic of PCT.

[edit] Management.

Patients with new onset of PCT need to be screened for underlying liver disease, including HBV and HCV infections. Sun protection is of utmost importance; complete avoidance of exposure to UV light can prevent blisters. Treatment of underlying liver disease is essential, as is avoidance of hepatotoxins. Specific treatment for PCT consists of removal of 500 ml of whole blood every 2 to 4 weeks until the serum ferritin and urine porphyrins return to normal levels and the clinical picture improves. An alternative therapy is the use of antimalarial drugs that facilitate renal excretion of porphyrins. This therapy can be associated with acute worsening of the disease before improvement is observed.

[edit] PYODERMA GANGRENOSUM

Pyoderma gangrenosum is an inflammatory, neutrophil-mediated skin disease of unknown etiology that can be associated with several internal diseases^[5](Box 88-2).

[edit] History and Physical Examination.

The clinical presentation of pyoderma gangrenosum is usually a pustule that enlarges over days into a violaceous-erythematous plaque that frequently ulcerates ( Plate 70 ). A typical appearance is a plaque with a reticulated (cribriform) ulceration pattern. Plaques can enlarge to greater than 10 cm within two to four weeks, and ulceration can progress in the same time period to depths that can expose subcutaneous fat and tendons. Pain is moderate to severe. Obtaining a complete history of underlying illness is important.

[edit] Diagnosis.

The differential diagnosis of pyoderma gangrenosum includes numerous infectious diseases, including mycobacterial infection, deep fungal infection, and tertiary syphilis. It is common for pyoderma gangrenosum to be misdiagnosed and unsuccessfully treated multiple times with antibiotics before a correct diagnosis is made. Skin biopsy, while supportive, is not specific.

[edit] Management.

Nonpharmacologic therapy consists of wound care (see Chapter 83 ). Pharmacologic therapy is essential and includes, as the mainstay of treatment, systemic corticosteroids in doses that range from 60 mg/day orally to intravenous methylprednisolone 1 gm daily. Cyclosporin A, 5 mg/kg/day, has been successful in steroid-resistant cases and has been recommended as first-line therapy by some authors.^[6] Dapsone has been used for many years in acute disease and as maintenance therapy. Doses range from 50 to 200 mg per day orally.

[edit] ACANTHOSIS NIGRICANS

Acanthosis nigricans is associated with endocrine disorders that include obesity, with an underlying malignancy, or with a familial occurrence. Clinically, acanthosis nigricans consists of hyperpigmented areas of hyperkeratosis that result in plaques or patches of thickened skin with a velvety or slightly verrucous texture. Common sites of involvement are the skin fold areas of the neck, axillae, groin, and antecubital/popliteal fossae. In paraneoplastic acanthosis nigricans, involvement of the dorsal and palmar hands or other atypical sites are clues to the malignant association.

[edit] PRURITUS

Generalized pruritus (see Chapter 89 ) is associated with several systemic diseases, most notably obstructive liver disease, renal disease, diabetes mellitus, and iron deficiency. The most common malignancies associated with pruritus are lymphomas, polycythemia, and multiple myeloma.

[edit] SWEET'S SYNDROME

Sweet's syndrome (acute febrile neutrophilic dermatosis) may be associated with malignancy in approximately 10% of cases.^[7] Hematologic malignancy is most common, usually acute myelogenous leukemia. Clinically, Sweet's syndrome consists of tender, erythematous dermal nodules anywhere on the body ( Plate 71 ), with associated systemic findings of fever, malaise, arthralgias, and neutrophilia. Biopsy of skin lesions shows a neutrophilic dermal infiltrate. Response to treatment with systemic corticosteroids (i.e., prednisone 40 to 60 mg/day) is usually excellent regardless of whether or not there is an associated malignancy. Recurrences are common.

[edit] GLUCAGONOMA SYNDROME

There is a specific cutaneous finding associated with the α cell pancreatic malignancy, glucagonoma. The skin change, termed necrolytic migratory erythema (NME), consists of shallow erythematous erosions from superficial blisters, along with some scaling. The most common sites are the perineum and other periorificial areas, distal legs, and sites of trauma. Associated findings include stomatitis and glossitis, anemia, and hyperglycemia with glycosuria. Histopathology of the skin lesions can demonstrate pallor and necrotic cells in the epidermis that are characteristic of NME. The clinical and histologic differential diagnosis includes nutritional deficiencies (zinc, amino acid, thiamine), acrodermatitis enteropathica, and superficial blistering diseases such as bullous impetigo and pemphigus foliaceus. The definitive test is a serum glucagon level that is markedly elevated. The precise mechanism of the skin lesions is not clear, but rapid resolution occurs when the tumor is resected.

[edit] REFERENCES