Chapter 054. Skin Manifestations of Internal Disease (Part 12) In the diffuse forms of hyperpigmentation, the darkening of the skin may be of equal intensity over the entire body or may be accentuated in sun-exposed areas. The causes of diffuse hyperpigmentation can be divided into four major groups—endocrine, metabolic, autoimmune, and drugs. The endocrinopathies that frequently have associated hyperpigmentation include Addison's disease, Nelson syndrome, and ectopic ACTH syndrome. In these diseases, the increased pigmentation is diffuse but is accentuated in the palmar creases, sites of friction, scars, and the oral mucosa. An overproduction of the pituitary hormones α-MSH (melanocyte-stimulating hormone) and ACTH can lead to an increase in melanocyte activity. These peptides are products of the proopiomelanocortin gene and exhibit homology; e.g., α-MSH and ACTH share 13 amino acids. A minority of the patients with Cushing's disease or hyperthyroidism have generalized hyperpigmentation. The metabolic causes of hyperpigmentation include porphyria cutanea tarda (PCT), hemochromatosis, vitamin B 12 deficiency, folic acid deficiency, pellagra, malabsorption, and Whipple's disease. In patients with PCT (see "Vesicles/Bullae," below), the skin darkening is seen in sun-exposed areas and is a reflection of the photoreactive properties of porphyrins. The increased level of iron in the skin of patients with hemochromatosis stimulates melanin pigment production and leads to the classic bronze color. Patients with pellagra have a brown discoloration of the skin, especially in sun-exposed areas, as a result of nicotinic acid (niacin) deficiency. In the areas of increased pigmentation, there is a thin varnish-like scale. These changes are also seen in patients who are vitamin B 6 deficient, have functioning carcinoid tumors (increased consumption of niacin), or take isoniazid. Approximately 50% of the patients with Whipple's disease have an associated generalized hyperpigmentation in association with diarrhea, weight loss, arthritis, and lymphadenopathy. A diffuse slate-blue color is seen in patients with melanosis secondary to metastatic melanoma. Although there is a debate as to whether the color is due to single-cell metastases in the dermis or to a widespread deposition of melanin resulting from the high concentration of circulating melanin precursors, there is more evidence to support the latter. Of the autoimmune diseases associated with diffuse hyperpigmentation, biliary cirrhosis and scleroderma are the most common, and occasionally both disorders are seen in the same patient. The skin is dark brown in color, especially in sun-exposed areas. In biliary cirrhosis the hyperpigmentation is accompanied by pruritus, jaundice, and xanthomas, whereas in scleroderma it is accompanied by sclerosis of the extremities, face, and, less commonly, the trunk. Additional clues to the diagnosis of scleroderma are telangiectasias, calcinosis cutis, Raynaud's phenomenon, and distal ulcerations (see "Telangiectasias," above). The differential diagnosis of cutaneous sclerosis with hyperpigmentation includes the POEMS [polyneuropathy; organomegaly (liver, spleen, lymph nodes); endocrinopathies (impotence, gynecomastia); M-protein; and skin changes] syndrome. The skin changes include hyperpigmentation, skin thickening, hypertrichosis, and angiomas. Diffuse hyperpigmentation that is due to drugs or metals can result from one of several mechanisms—induction of melanin pigment formation, complexing of the drug or its metabolites to melanin, and deposits of the drug in the dermis. Busulfan, cyclophosphamide, 5-fluorouracil, and inorganic arsenic induce pigment production. Complexes containing melanin or hemosiderin plus the drug or its metabolites are seen in patients receiving chlorpromazine and minocycline. The sun-exposed skin as well as the conjunctivae of patients on long-term, high-dose chlorpromazine can become blue-gray in color. Patients taking minocycline may develop a diffuse blue-gray, muddy appearance in sun-exposed areas in addition to pigmentation of the mucous membranes, teeth, nails, bones, and thyroid. Administration of amiodarone can result in both a phototoxic eruption (exaggerated sunburn) and/or a brown or blue-gray discoloration of sun-exposed skin. Biopsy specimens of the latter show yellow-brown granules in dermal macrophages, which represent intralysosomal accumulations of lipids, amiodarone, and its metabolites. Actual deposits of a particular drug or metal in the skin are seen with silver (argyria), where the skin appears blue-gray in color; gold (chrysiasis), where the skin has a brown to blue-gray color; and clofazimine, where the skin appears reddish brown. The associated hyperpigmentation is accentuated in sun-exposed areas, and discoloration of the eye is seen with gold (sclerae) and clofazimine (conjunctivae). Vesicles/Bullae (Table 54-12) Depending on their size, cutaneous blisters are referred to as vesicles (<0.5 cm) or bullae (>0.5 cm). The primary blistering disorders include pemphigus vulgaris, pemphigus foliaceus, pemphigus erythematosus, paraneoplastic pemphigus, bullous pemphigoid, gestational pemphigoid, cicatricial pemphigoid, epidermolysis bullosa acquisita, linear IgA bullous dermatosis, and dermatitis herpetiformis (Chap. 55). . Chapter 054. Skin Manifestations of Internal Disease (Part 12) In the diffuse forms of hyperpigmentation, the darkening of the skin may be of equal intensity over. of iron in the skin of patients with hemochromatosis stimulates melanin pigment production and leads to the classic bronze color. Patients with pellagra have a brown discoloration of the skin, . Whipple's disease. In patients with PCT (see "Vesicles/Bullae," below), the skin darkening is seen in sun-exposed areas and is a reflection of the photoreactive properties of porphyrins.