Life-threatening dermatoses due to metabolic and endocrine disorders

Clinics in Dermatology (2005) 23, 258 – 266

Life-threatening dermatoses due to metabolic and endocrine disorders Hetesh V. Pitambe, MD*, E. Joy Schulz Division of Dermatology, Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa

Abstract Cardiovascular heart disease due to atherosclerosis is the commonest cause of mortality and morbidity in the Western world. Atherosclerosis is directly related to disorders of lipid metabolism, diabetes mellitus (DM), and insulin resistance. Disorders of thyroid function and porphyrin metabolism occur less frequently but may cause life-threatening situations if unrecognized. All these disorders are associated with characteristic dermatoses, which should permit early diagnosis and meaningful intervention. D 2005 Elsevier Inc. All rights reserved.

Dyslipidemia (hyperlipidemia) The terms dyslipidemia and hyperlipidemia are used interchangeably, but dyslipidemia is preferable as the lipids may not only be raised but may be present in altered proportions. Under pathological conditions, blood lipids are deposited as atherosclerotic plaques in the walls of arteries in the skin, subcutaneous tissues, and tendons. Atherosclerosis causes coronary artery disease, aortic aneurysm, and occlusion of peripheral arteries. Dyslipidemias are often associated with other risk factors for atherosclerosis, such as hypertension, DM, and insulin resistance.

The lipoproteins Lipids are transported in the blood as small spherical particles, the lipoproteins. The function of the protein coating is to confer water solubility to the lipids and to provide cellular receptors and enzymes essential for lipid metabolism. Proteins in the coating with special functions are called apoproteins.1,2

* Corresponding author. 0738-081X/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.clindermatol.2004.06.001

The lipoproteins are derived from 2 sources—diet (exogenous) and liver (endogenous). They consist mainly of cholesterol, phospholipid, and triglyceride. By means of paper electrophoresis and ultracentrifugation, the lipoprotein fraction has been identified as follows. High-density lipoproteins (HDL). They are composed mostly of phospholipid and esterified cholesterol. They are beneficial because they clean up molecules released into the circulation during the transport of triglyceride-rich lipoprotein particles. Low-density lipoproteins (LDL). They consist mainly of cholesterol. LDL is the major atherogenic lipoprotein and raised serum levels are associated with coronary heart disease. Very low density lipoproteins (VLDL). They are the main carriers of endogenous triglycerides. The chylomicron band has the lowest density. The chylomicrons consist mainly of exogenous triglycerides and enter the circulation via the thoracic duct. Lipoprotein lipase hydrolyzes chylomicrons. The resulting chylomicron remnants are taken up by the liver via the action of apolipoprotein (apo) E. Apo C-II is needed for activation of lipoprotein lipase. Defective function of lipoprotein lipase leads to hypertriglyceridemia.

Life-threatening dermatoses due to metabolic and endocrine disorders Defective apo A-I results in HDL deficiency. Defective apo B-100 interferes with LDL receptor function resulting in increased serum LDL. The enzyme HMGCo reductase regulates the rate of cholesterol synthesis in the liver. The statins (3-hydroxy-3methylglutaryl coenzyme A reductase inhibitors) are the drugs of choice for hypercholesterolemia.

The hyperlipidemias Hyperlipidemias may be primary or secondary. Primary hyperlipidemias are due to severe genetic defects in lipid metabolism or less severe defects plus aggravating factors. Secondary hyperlipidemias are the result of other diseases and drugs. The hyperlipidemias are associated with characteristic skin lesions, the xanthomas. If the hyperlipidemia is mainly due to raised cholesterol than xanthelasma, tuberous and tendinous xanthomas will occur. If it is due to elevated triglycerides, eruptive xanthomas will result. Triglycerides are more easily mobilized from the cells than the cholesterol, and eruptive xanthomas clear rapidly with management of the underlying disease.

The xanthomas Xanthomas consist of accumulations of macrophages containing droplets of lipid, and thus cutaneous xanthomas present as yellow, orange to reddish, or brown macules, papules, plaques, or nodules. Deeper xanthomas are present as infiltrations around tendons and may be skin colored or yellowish in appearance.

Clinical types of xanthoma Xanthelasma (palpebrarum) are plane (flat) xanthomas localized to the eyelids. They are asymptomatic soft yelloworange macules, papules, and plaques. Fifty percent of affected individuals are normolipemic. Management consists of excision, electrodesiccation, laser treatment, and trichloroacetic acid treatment. Recurrences are uncommon.1,3 Tendon xanthomas are subcutaneous plaques that are attached to and moved with large extensor tendons. They may involve extensor tendons of the hands, knees, and elbows and the Achilles tendons of the ankles. Most patients with tendon xanthomas have familial hypercholesterolemia. Tendon xanthomas also occur in 2 rare disorders of sterol metabolism, cerebrotendinous xanthomatosis and sitosterolemia (phytosterolemia). Tuberous xanthomas present as nodules over the extensor surfaces of the knees, elbows, and knuckles and on the buttocks. Eruptive xanthomas appear suddenly as showers or groups of multiple reddish yellow papules. They are associated with hypertriglyceridemia and may be the first indication of uncontrolled diabetes. They occur anywhere

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on the body but particularly on the extensor surfaces of the limbs and the buttocks. The papules are discrete and dome shaped but may coalesce to form plaques and nodules when they are called btuboeruptive.Q Tuboeruptive lesions occur mainly over the elbows. Plane xanthomas typically develop in skin folds and especially in the palmar creases. Diffuse plane xanthomas occur in normolipemic patients associated with multiple myeloma and other paraproteinemias, lymphoma, or leukemia, presenting as multiple grouped papules and poorly defined yellowish plaques. Intertriginous plane xanthomas suggest homozygous familial hypercholesterolemia, whereas palmar crease xanthomas (xanthomata striata palmaris) occurring as flat or elevated yellow-orange infiltrations in the creases of the palms and fingers are highly characteristic of dysbetalipoproteinemia (remnant particle disease).

Primary hyperlipidemias The primary hyperlipidemias may be divided into 3 main groups: familial hypercholesterolemias, mixed hyperlipidemias, and hypertriglyceridemias.4 Their subgroups, underlying metabolic defects and clinical features, are summarized in Table 1.1,4 The primary hyperlipidemias are genetically determined, but environmental factors play an aggravating role. The hyperlipidemia may be predominantly due to raised cholesterol or raised triglycerides, or a combination of both. In general, the hypercholesterolemias cause atherosclerosis and are characterized by tendon xanthomas and arcus cornealis. Patients with mixed hyperlipidemias develop tuboeruptive xanthomas and atherosclerosis. The hypertriglyceridemias are associated with eruptive xanthomas, lipemia retinalis, and pancreatitis, and there is no associated increased risk for coronary heart disease.

Secondary hyperlipidemias Secondary hyperlipidemias are due to various causes, such as uncontrolled DM, hypothyroidism, biliary cirrhosis, and drugs.2 Diabetes mellitus Dyslipidemias in DM usually occur in young insulinresistant diabetics. Insulin is necessary for the normal clearing action of lipoprotein lipase on triglycerides. The associated hypertriglyceridemia results in eruptive xanthomas that clear on treatment. Myxedema Myxedema is associated with hypercholesterolemia because thyroid hormone is required for lipoprotein lipase activity and for the oxidation of cholesterol to bile salts. Xanthelasma and xanthomas may occur in myxedema. Biliary obstruction In biliary obstruction, raised serum phospholipid and cholesterol levels are associated with the formation of an

260 Table 1

H.V. Pitambe, E.J. Schulz Primary hyperlipidemias

Group

Defect

Lipid abnormality

Xanthomas

Associated features

Very high LDL and cholesterol Raised LDL and cholesterol High cholesterol

Tuberous, tendinous, xanthomatous plaques Tendinous, xanthelasma, tuberous (rare) Tendinous

Atherosclerosis, coronary heart disease (early) Coronary heart disease (later) Coronary heart disease

High TGL and cholesterol, low LDL and HDL, high VLDL remnants LDL overproduction, Very high VLDL defective TGL lipolysis and TGL

Tuboeruptive, tuberous, xanthoma striata palmaris, tendinous (rare), xanthelasma (rare) Eruptive, tuberous (rare), tendinous (rare)

Atherosclerosis, coronary heart disease, peripheral arterial disease

Lipoprotein lipase deficiency

Eruptive

Acute pancreatitis

Eruptive

Acute pancreatitis

Eruptive

Acute pancreatitis, diabetes, ischemic heart disease, peripheral arterial disease, cholelithiasis

Familial hypercholesterolemias Homozygous LDL receptor, very low/absent Heterozygous LDL receptor, low activity Familial defective apo B-100 Apo B-100 Mixed hyperlipidemias Dysbetalipoproteinemia (remnant particle disease)

Familial combined hyperlipidemia

Hypertriglyceridemias Familial lipoprotein deficiency Apoprotein CII deficiency

Apo E

Chylomicronemia (early), high VLDL (later) Very high TGL

Lipoprotein lipase activator deficiency Familial hypertriglyceridemia Hepatic VLDL Very high TGL, overproduction, VLDL, and raised apo CIII inhibits chylomicrons LPL activity

Coronary heart disease, diabetes, peripheral arterial disease, pancreatitis

HDL indicates high-density lipoprotein; LDL, low-density lipoprotein; TGL, triglycerides; and VLDL, very low density lipoprotein.

abnormal lipoprotein, called lipoprotein X, by the liver. Xanthelasma, tuberous xanthomas, and plane xanthomas including palmar and plantar lesions may occur.

of the global epidemic of obesity. Diabetes mellitus may also be secondary to pancreatic disease, hormonal abnormalities, or drugs, particularly systemic corticosteroids.3

Medication-induced hyperlipidemia Noteworthy drugs contributing to dyslipidemia include glucocorticoids, estrogens, and retinoids.

The role of insulin

Chronic renal failure Hypertriglyceridemia may also be due to renal failure with or without dialysis. Pancreatitis Pancreatitis due to alcohol abuse may cause insulin deficiency and decreased lipoprotein lipase activity. The resultant hypertriglyceridemia may further damage the pancreas, and pancreatic necrosis and death may occur.

Diabetes mellitus In 1997 it was estimated that 124 million people worldwide were suffering from DM; by 2010, the total number is projected to reach 221 million.5 Primary DM consists of types 1 and 2; genetic factors play a role in both. At least 97% of patients have type 2 diabetes,5 a lifestyle disease and largely preventable by diet, exercise, and weight control. Type 2 diabetes, previously called adult-onset diabetes, is affecting more and more children in the wake

Dietary carbohydrates are broken down into glucose that is absorbed from the intestine into the bloodstream. Rising levels of glucose in the blood trigger the pancreas to secrete insulin. The role of insulin is to promote storage of glucose in the liver, skeletal muscle, and adipose tissue where it also regulates protein and lipid metabolism. The action of insulin depends on binding of insulin to receptors on cell surfaces in these tissues. In type 1 or insulin-dependent DM, the b-islet cells of the pancreas are gradually destroyed by antibodies directed against them. In type 2 or non–insulin-dependent diabetes, there is end-organ resistance to insulin, which results in eventual exhaustion of the pancreatic b-cells resulting in decrease insulin release. Thus, hyperglycemia in type 1 diabetes is due to insufficient insulin secretion, whereas in type 2 diabetes, faulty insulin receptors prevent entry of glucose into cells and glucose builds up in the blood.

Insulin resistance Insulin resistance may be defined as decreased peripheral sensitivity to insulin. An excessive quantity of insulin is needed to maintain normal blood glucose levels, and the

Life-threatening dermatoses due to metabolic and endocrine disorders increased demand on the pancreatic beta cells gradually leads to a decreased ability to secrete insulin. Most patients with insulin resistance secrete enough insulin to maintain nondiabetic glucose levels; some go on, however, to develop type 2 diabetes. Age, obesity, and sedentary lifestyle are common and important predisposing factors. Insulin resistance is one of the major risk factors for the development of hypertension and coronary artery disease.6 It plays an essential role in the development of the metabolic syndrome.6

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atherosclerosis of large vessels increasing the risk for myocardial infarction, stroke, and peripheral vascular disease. The diabetic neuropathic foot is primarily due to the microangiopathy involving the peripheral nerve trunks. Hyperglycemia and ketoacidosis diminish chemotaxis and phagocytosis. In poorly controlled DM, there is an increase in cutaneous infections, including streptococcal and staphylococcal infections, candidiasis, erythrasma, mucormycosis, and necrotizing fasciitis. There is no overall increase in dermatophyte infections in DM.

The metabolic syndrome (insulin-resistance syndrome, syndrome X)

Skin lesions in DM

The metabolic syndrome affects about 24% of adult Americans.7 Clinical and laboratory findings include central obesity, hypertension, insulin resistance, hyperglycemia, and dyslipidemia.7,8 The dyslipidemia is characterized by hypertriglyceridemia and a low serum HDL cholesterol.8,9 Central obesity is a prominent feature of the metabolic syndrome. The major cause of the metabolic syndrome is the release of fatty acids and cytokines from the enlarged adipocytes in the intra-abdominal fat. These nonesterified fatty acids interfere with hepatic production of lipoproteins and coagulation factors, contributing to insulin resistance and atherogenicity. Management of the insulin resistance and the metabolic syndrome consists of sustained weight reduction, diet, and exercise.10

Necrobiosis lipoidica Necrobiosis lipoidica occurs only in a very small percentage of patients with DM, but it is regarded as an important marker of the disease.13,14 The pathogenesis is unclear. Lesions start as reddish brown papules and nodules that flatten to form well-demarcated, yellowish, waxy plaques with indurated violaceous borders and smooth glazed centers. The skin is atrophic with visible telangiectasia. Lesions may be single or multiple and most commonly affects the shins, but other parts of the body may be involved. Treatment is difficult. Potent topical corticosteroids may retard progression; intralesional steroids are not popular because of the risk of ulceration. Two patients with severely ulcerated necrobiosis lipoidica responded to cyclosporine therapy.15

Adiponectin Adiponectin is a protein secreted by adipocytes with antihyperglycemic, anti-inflammatory, and antiatherogenic properties.11 It suppresses expression of adhesion molecules in vascular endothelial cells and cytokine production from macrophages, thus inhibiting the inflammatory processes that occur in early phases of atherosclerosis.11 Both adiponectin and tumor necrosis factor a play a role in the insulin resistance of obesity.12

Pathophysiology of DM Prolonged hyperglycemia leads to the accumulation of advanced glycosylation end products in tissues. This results in thickening of the skin and limitation of the joint mobility. In sclerema diabeticorum, abnormal fibroblast activity results in the production of thickened collagen bundles and increases deposition of glycosaminoglycans, mainly hyaluronic acid. A decrease in lipoprotein lipase activity during insulin deficiency results in increased levels of triglycerides and VLDL. The hypertriglyceridemia causes eruptive xanthomas. Excess insulin activates insulinlike growth factor-1, promoting proliferation of epidermal cells and fibroblasts. This may result in acanthosis nigricans. Vascular involvement in DM involves small (microangiopathy) and large vessels (macroangiopathy).13 Microangiopathy is the primary cause of retinopathy, neuropathy, and nephropathy in DM. Macroangiopathy consists of

Scleredema diabeticorum Scleredema diabeticorum is associated with longstanding diabetes, usually type 2. It has been reported in 2.5% to 14% of patients with DM.13 It presents insidiously as a painless, woody induration of the skin. The distribution is symmetrical on the upper back and neck, and it may spread to the face, shoulders, and anterior trunk. Scleredema diabeticorum leads to decreased or full loss of mobility of neck and arms. It must be differentiated from scleredema associated with streptococcal pharyngitis, which is of sudden onset and remits with time. Treatment of scleredema diabeticorum is unsuccessful.13 Acanthosis nigricans Acanthosis nigricans presents clinically as velvety, brown to black plaques with a papillomatous surface, predominantly in intertriginous areas such as the neck, axillae, and groins. Acanthosis nigricans is commonly associated with obesity, insulin resistance, and hyperinsulinemia. Other causes include hyperandrogenetic states in women and estrogen and glucocorticoid administration.13 Its association with malignancy is rare.13 Treatment is ineffective but acanthosis nigricans may regress if the cause is removed. Diabetic thick skin: limited joint mobility and sclerodermalike syndrome Limited joint mobility is due to thickening of the skin and periarticular connective tissues of the fingers. It occurs

262 in both types of diabetes and is one of the earliest signs in young, type 1 diabetics. It is far less common today because of better diabetic control.13 A characteristic feature is the socalled prayer sign in which the patient is unable to approximate the interphalangeal joints and palms. Limited joint mobility may also affect larger joints such as the elbows and knees. In the sclerodermalike syndrome, the skin over the back of the hands and feet becomes thickened, waxy, and pebbly. Forearms and thighs may be involved. Sclerodermalike syndrome may occur alone or together with limited joint mobility.13 Eruptive xanthomas Diabetes mellitus is a common cause of hypertriglyceridemia and the resultant eruptive xanthomas may be the first indication of untreated DM. With strict control of the diabetes, the xanthomas may clear within a few months. Granuloma annulare The common form of granuloma annulare occurring in children and young adults presents as small skin-colored nodules and annular plaques with a papular border, presenting mainly on the back of hands and feet. Atypical forms include generalized, subcutaneous, and perforating types. Generalized granuloma annulare presents as multiple papules that coalesce to form small annular plaques, symmetrically distributed on the trunk and limbs. Generalized forms occur more frequently in older adults and run a more chronic and relapsing course. Types of granuloma annulare that are associated with DM include generalized and perforating forms.13 Diabetes mellitus should be excluded in these patients. Psoralen-UV-A therapy offers the best results in these patients. Diabetic dermopathy Lesions consist of small, asymptomatic, atrophic, brown scarlike macules on the shins. The cause is unknown, but unnoticed trauma and microangiopathy have been implicated. Similar lesions have been noted in a small percentage of healthy individuals and patients with other endocrine disorders.13 No treatment is indicated. Diabetic bullae This uncommon condition presents as an abrupt onset of blisters on the distal parts of the limbs, usually on the toes, feet, and shins. The blisters are usually asymptomatic, heal within several weeks, and rarely scar. Successive crops of blisters may occur over many years. The cause is unknown and no history of trauma is obtained. Perforating disorders This group of disorders is characterized by transepidermal elimination of altered dermal constituents. Lesions consist of pruritic papules with a central keratotic plug. The papules may be grouped or coalesce to form warty plaques. They may appear on the limbs, trunk, or face. There appears to be a causal relationship with DM and chronic

H.V. Pitambe, E.J. Schulz renal failure with or without hemodialysis. Treatment with topical steroids, retinoids, and psoralen-UV-A is partially successful.13 Calciphylaxis This condition occurs in end-stage renal disease with secondary hyperparathyroidism.3 Most patients are diabetics requiring dialysis and have a poor prognosis. There is a widespread systemic calcification of small- and mediumsized arteries. Skin lesions consist of painful angulated areas of ischemia, followed by necrosis and ulceration. Calcification of vessels is readily seen on biopsy.

Thyroid disorders There are many causes of thyroid dysfunction. Hyperthyroidism may be due to neoplasms, drugs, or autoimmune disorders such as Graves’ disease (GD). Causes of hypothyroidism include genetic defects, iodine deficiency, surgery, irradiation, and drugs such as iodides and lithium. Most cases of hypothyroidism are due to Hashimoto’s thyroiditis, which is autoimmune in origin. Hyperthyroidism and hypothyroidism may each be associated with medical emergencies, the thyrotoxic crisis and myxedema coma, respectively.

Thyroid hormone Thyroid-releasing hormone secreted by the hypothalamus acts on the anterior pituitary gland, which in turn secretes thyroid-stimulating hormone (TSH). TSH stimulates the thyroid gland to secrete thyroxine (T3 and T4), which enters cells, binds to nuclear receptors, and regulates cellular function. The TSH receptor is distributed in the thyroid, lymphocytes, fibroblasts, and adipocytes. Thyroid hormone regulates epidermal maturation by stimulating epidermal growth factor, regulates sterol biosynthesis, and controls the function of the sebaceous and sweat glands. Decreased activity of these glands in hypothyroidism results in dryness of the skin. Thyroid hormone stimulates fibroblasts to produce glycosaminoglycans. Acid mucopolysaccharides are hygroscopic, and in hyperthyroid states, mucin and water accumulate in the dermis. Thyroid hormone stimulates the sympathetic nervous system. Decreased function in hypothyroidism results in ptosis of the eyelids. In hyperthyroid states, cutaneous circulation is increased because of increased cardiac output and decreased peripheral resistance. In hypothyroid states, the circulation is decreased and the skin is pale and cool.16,17

Autoimmune thyroid disease Autoimmune thyroid disorders consist of GD and Hashimoto’s thyroiditis. In GD, autoantibodies are produced to TSH that bind to TSH receptor, stimulating them to increase production of thyroid hormone. Nearly all patients

Life-threatening dermatoses due to metabolic and endocrine disorders with GD and some patients with HT express autoantibodies against the TSH receptor, which are found in the thyroid, lymphocytes, fibroblasts, and adipocytes.17 There are 2 forms of HT. In the hypertrophic form, there is a massive lymphocytic infiltrate in the thyroid gland, and in the atrophic variety, there is extensive fibrosis. It is not known whether they are different stages of the same disease. Genetic and environmental factors play a role in autoimmune thyroid disease, but the exact causes are still to be determined.

Hyperthyroidism—Graves’ disease In GD, hyperthyroidism is associated with a diffuse goiter, ophthalmopathy, pretibial myxedema, and acropathy. In 10% to 20% of cases, there is a family history, but most cases occur sporadically.16,17 Systemic manifestations Patients may complain of weight loss, increased appetite, diarrhea, oligomenorrhea, tremor, dislike of hot weather, increased sweating, pruritus, and emotional lability. Clinical signs include resting tachycardia, a fine tremor, atrial fibrillation, hypertension, and exophthalmos.18 Cutaneous manifestations The skin is warm, moist, and smooth. Facial flushing and palmar erythema may be present. Hyperhidrosis tends to be generalized but is often most pronounced on the palms and soles. The scalp hair may be fine, soft, or friable, and diffuse nonscarring alopecia may result. Nails grow rapidly, are soft, and may have concave contours with distal onycholysis (Plummer’s nails). Hyperpigmentation of the skin occurs in 2% of patients. It may be diffused or localized to the palmar creases, soles, gingivae, and buccal mucosa. Pruritus, urticaria, and angioedema are uncommon manifestations. Other autoimmune disorders such as vitiligo, diabetes, and bullous disorders may be associated with GD.16,17 Pretibial myxedema is usually due to thyrotoxicosis, but patients may be euthyroid or hypothyroid. The clinical features are due to large deposits of mucin in the dermis. It occurs mainly on the shins but often spreads to the dorsal aspects of the feet. Less frequently, lesions may occur on the arms, shoulders, head, neck, or at sites of trauma or scars. Lesions are usually bilateral. They consist of waxy plaques, some with superimposed nodules, and vary from yellowish to reddish brown. The skin may have an edematous, peau d’orange appearance. In severe cases, thickened warty plaques on the shins and feet resemble lymphatic elephantiasis. Pretibial myxedema is usually associated with exophthalmos. Management of pretibial myxedema is problematic because lesions do not resolve with normalization of thyroid hormone levels. Topical, intralesional, and systemic corticosteroids have shown some value. Compression physiotherapy is an important part of routine

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treatment. A combination of surgery and octreotide, an insulinlike growth factor-1 antagonist, has given good results.19 Thyroid acropathy is rare. It consists of a triad of digital clubbing, soft tissue swelling of the hands and feet, and periosteal new bone formation.

Thyrotoxic crisis In thyrotoxic crisis, the systemic manifestations of hyperthyroidism are so severe as to be life threatening. They consist of pyrexia, vasodilation, marked tachycardia, and severe dysfunction of the central nervous, cardiovascular, and gastrointestinal systems. A crisis rarely arises de novo and is precipitated by infection, trauma, surgery, pulmonary embolus, treatment with radioactive iodine, or thyroid surgery in a patient with poorly controlled thyrotoxicosis. The clinical diagnosis is confirmed by elevated T4 and T3 serum levels.18

Hypothyroidism—Hashimoto’s thyroiditis Hashimoto’s thyroiditis is characterized by a diffuse goiter and hypothyroidism. It is the most common cause of hypothyroidism in the United States. Women account for 95% of all cases. There is a hypertrophic and an atrophic variety. In the former, there is a massive lymphocytic infiltrate, and in the latter, extensive fibrosis. It is not known whether they are different stages of the same disease.16,17 Disorders associated with autoimmune-related hypothyroid states include alopecia areata, vitiligo, pernicious anemia, dermatomyositis, polymyositis, and autoimmune bullous disorders. Systemic manifestations Patients may complain of insidious onset of weight gain, dryness of the skin, constipation, dislike of cold weather, menorrhagia, hoarse voice, lethargy, and depression. Clinically, they may present with bradycardia, hypotension, delayed tendon reflexes, and hypothermia.18 Cutaneous manifestations The most striking feature is dryness that can become so severe that it resembles ichthyosis. The skin is pale, cool, and doughy to the touch. Hair growth is slow and the hair shafts are dry and brittle. Diffuse alopecia and loss of the lateral third of the eyebrows may be present. The nails are brittle and grow slowly. The palms and soles are thickened and may resemble keratoderma; they may have a yelloworange color due to carotenemia.3,16,17 Generalized myxedema In longstanding hypothyroidism, the patient has a characteristic appearance. The entire skin is swollen, dry, pale, and waxy. The skin looks edematous but does not pit. The face has a characteristic appearance with a flat, broad nose, swollen lips, macroglossia, and puffy eyelids.

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Myxedema coma Myxedema coma occurs mainly in elderly women with features of chronic hypothyroidism. Most cases occur in winter and are associated with infection, anemia, heart failure, trauma, and/or exposure to cold. In addition to the usual systemic signs of hypothyroidism, seizures, stupor, coma, and psychotic behavior may be present.18

The porphyrias The porphyrias are a group of disorders resulting from inherited or acquired abnormalities in the biosynthesis of heme. Each form of porphyria is associated with deficient activity of a specific enzyme, of which there are 8 in all. These enzymes are under genetic control and many mutations have been detected. Because of the deficient enzyme activity, there is an excessive accumulation and excretion of specific porphyrins and their precursors. The toxic effects of these metabolites are responsible for the cutaneous and neurological features of the porphyrias. The clinical signs alone are characteristic enough to permit diagnosis, but this can be confirmed by laboratory investigations. The porphyrias are divided into 2 main groups, erythropoietic and hepatic, depending on the main site of defective metabolism. In 3 types of porphyria, lifethreatening situations arise during acute attacks presenting with abdominal pain and neuropsychiatric manifestations.

Porphyrins and the synthesis of heme Porphyrins occur universally in the protoplasm of plants and animals. They form the basis of the respiratory pigments, chlorophyll, and hemoglobin. Heme is the insoluble, nonprotein, iron protoporphyrin constituent of hemoglobin and is responsible for its characteristic color and oxygencarrying properties. Approximately 85% of heme synthesis occurs in the bone marrow where it is used by the developing erythrocyte for the production of hemoglobin. The rest of heme synthesis occurs in the liver.20 The synthesis of heme from porphyrins is regulated by 8 enzymes. Each successive enzyme catalyzes the formation of the next compound in the pathway. During normal heme synthesis, there are virtually no by-products, but where there is an enzyme deficiency, oxidation products accumulate and may be detected in the erythrocytes, plasma, urine, and feces. The increased amounts of porphyrins have unique photosensitizing properties because of the absorption of ultraviolet radiation in the Soret band (400-410 nm). These activated porphyrins are unstable and release free radicals that cause tissue damage. The first step of the porphyrin-heme biosynthetic pathway is the formation of d-aminolevulinic acid (ALA) in the liver, catalyzed by the mitochondrial enzyme, ALA synthase. It is the rate-limiting enzyme of the pathway and is under negative feedback control from heme. ALA

H.V. Pitambe, E.J. Schulz synthase activity is increased in patients with acute hepatic porphyrias. This increase in ALA synthase is a major marker for acute intermittent porphyria (AIP), variegate porphyria (VP), and hereditary coproporphyria (HCP). Certain factors such as drugs induce ALA synthase activity and may precipitate acute attacks. Acute attacks in porphyrias are associated with increased excretion of ALA. In the next step in the pathway, ALA is converted to porphobilinogen (PBG). In acute hepatic porphyrias, excessive PBG is often formed because of increased ALA synthase activity. The excessive urinary PBG reacts with Ehrlich reagent to give a positive red color, characteristic of acute attacks in hepatic porphyrias. Subsequently, further specific enzyme activity results in the successive formation of the following porphyrins— uroporphyrin III, coproporphyrin III, and protoporphyrin IX. This last compound is acted on by the enzyme ferrochelatase to produce heme.

The porphyrias There are 7 different types of porphyria (see Table 2). There are 2 erythropoietic porphyrias—congenital erythropoietic porphyria and erythropoietic protoporphyria. The hepatic porphyrias consist of acute AIP, hereditary coproporphyria, and VP and porphyria cutanea tarda (PCT). An additional type, hepatoerythropoietic porphyria, involves hepatocytes and erythrocytes. Acute attacks, which may be life threatening, occur in 3 of these porphyrias, namely, AIP, VP, and HCP.

Acute attacks Acute attacks may mimic various disorders because they are characterized by acute abdominal pain and neuropsychiatric manifestations. An acute attack may be precipitated by drugs. There are no skin lesions in AIP, whereas in VP and HCP, skin lesions resemble those of PCT. Acute attacks may precede the onset of skin lesions. Acute intermittent porphyria This is an autosomal dominant disorder characterized by PBG deaminase deficiency, resulting in excessive urinary and serum ALA and PBG levels. It is most common in Scandinavia and Lapland and rarely presents before puberty. In children, symptoms may be vague and laboratory investigations inconclusive.21 The acute attack may be precipitated by drugs, infections, fasting, dehydration, alcohol, surgery, and stress. The commonly used drugs that must be avoided include barbiturates, phenytoin, carbamazepine, chloramphenicol, sulfonamides, griseofulvin, pyrazinamide, imipramine, diazepam, sulfonylureas, and theophylline.3 Women with AIP are more prone to develop acute attacks while on oral hormonal contraceptives.22 An acute attack presents as acute abdominal pain associated with constipation, nausea, and vomiting. This may be accompanied by acute

Life-threatening dermatoses due to metabolic and endocrine disorders Table 2

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The porphyrias

Type of porphyria

Enzyme defect

Clinical features

Laboratory abnormalities

Acute intermittent porphyria

Porphobilinogen deaminase

Elevated urinary and blood ALA and PBG Stool usually normal

Variegate porphyria

Protoporphyrinogen oxidase

Acute abdominal pain and neuropsychiatric symptoms No skin lesions Precipitating factors—drug Photosensitivity Skin lesions as in PCT

Porphyria cutanea tarda

Uroporphyrinogen decarboxylase

Hereditary coproporphyria

Coproporphyrinogen oxidase

Acute attacks as in AIP Photosensitivity Skin fragility—blisters, scarring, milia Mottled pigmentation Hypertrichosis Sclerodermatous changes Precipitating factors—alcohol, hepatitis B/C, HIV, estrogen, hydrocarbons Skin lesions as in PCT Acute attacks as in AIP

Congenital erythropoietic porphyria

Uroporphyrinogen III cosynthase

Erythropoietic protoporphyria

Ferrochelatase

Hepatoerythropoietic porphyria

Uroporphyrinogen decarboxylase

Reddish urine from birth Fluorescent teeth Severe photosensitivity with erythema and blistering Mutilation Hypertrichosis Associated features—hemolysis, growth retardation Severe photosensitivity with erythema and blistering Thickened skin Linear scars Weather-beaten appearance Associations—liver disease, gall stones Severe photosensitivity with blistering Pigmentation Hypertrichosis Sclerodermatous changes

Increased urinary ALA, PBG, and coproporphyrin during acute attacks Increased stool proto- and coproporphyrin Urine normal between attacks Urinary uroporphyrin: coproporphyrin = 3:1 Elevated urinary uroporphyrin and stool isocoproporphyrin

Increased stool and urine coproporphyrin Increased urinary ALA, PBG, and uroporphyrin during acute attacks Elevated uro- and coproporphyrin in blood, urine, and stool

Normal urine Elevated plasma, RBC, and stool protoporphyrin (serum—RBC fluorescence) Elevated stool coproporphyrin Increased urine uroporphyrin Elevated stool copro- and isocoproporphyrins Elevated blood protoporphyrin

ALA indicates d-aminolevulinic acid; PBG, porphobilinogen; and RBC, red blood cell.

neuropsychiatric symptoms such as seizures, coma, delirium, personality changes, depression, and rarely cranial nerve palsies. Bulbar paralysis, acute peripheral neuropathy with sensory loss, parasthesias, and muscle weakness, may also occur. There are no cutaneous manifestations because the elevated porphyrin precursors (ALA and PBG) are not photosensitizers. The increased PBG causes freshly voided urine to become deep red on exposure to sunlight for several hours. In the Hoesch test, 2 drops of freshly voided urine are added to 2 mL of Ehrlich reagent causing a cherry-red color. Excessive urinary excretion of ALA and PBG during and between attacks differentiates it from VP.

There is still no specific treatment for AIP, and acute attacks are best managed supportively. Several therapeutic modalities such as glucose loading, heme arginate infusions, and gonadotropin-releasing hormone analogues (luteinizing hormone-releasing hormone agonists) have been recommended. Variegate porphyria In VP, there is a decrease in protoporphyrinogen oxidase activity, with accumulation of protoporphyrinogen in the liver. This is excreted in the bile and nonenzymatically converted to protoporphyrin; this accounts for the high fecal porphyrin.

266 This autosomal dominant disorder is especially prevalent in white South Africans, most of whom have an R59W mutation in the protoporphyrinogen oxidase gene.23 Onset is after puberty with a peak incidence between the second and fourth decades. It is characterized by skin lesions identical to those in PCT, and acute attacks of abdominal pain and neuropsychiatric manifestations as seen in AIP. Skin lesions are due to photosensitizing effects of porphyrins and occur on sun-exposed areas such as the face and the dorsa of hands and feet. They consist of skin fragility, vesicles and bullae, erosions, scars, milia, and scleroderma-like changes. Diffuse melanoderma may occur on sun-exposed areas. Hypertrichosis is common on the temples and cheeks. The main biochemical feature of VP is increased fecal excretion of porphyrins (especially protoporphyrin and to a lesser extent, coproporphyrin), during and between attacks. Urinary PBG, ALA, and coproporphyrin are elevated only during acute attacks. A distinctive fluorescence emission peak of plasma at 626 nm is characteristic.3 Prognosis of VP is good if precipitating factors, which are identical to those in AIP, are avoided. Hereditary coproporphyria Hereditary coproporphyria is a rare autosomal dominant disorder due to a partial deficiency of coproporphyrinogen oxidase. It appears to occur worldwide. It is more common in women and may be precipitated by pregnancy, menses, and oral contraceptives.20 The acute attacks of HCP are similar to AIP and VP, and are also precipitated by the same drugs. Cutaneous photosensitivity with blistering is less prominent than in VP, occurring in 20% of cases. It is characterized by markedly elevated fecal coproporphyrin III. Urinary coproporphyrin III, ALA, and PBG are normal or slightly raised in remission but rise sharply during an acute attack.

Acknowledgment Professor FJH Raal, Head of the Division of Endocrinology and Metabolism, Department of Medicine, University of the Witwatersrand, Johannesburg, provided his expert opinion and advice.

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