Chapter 150. The Skin and Disorders of the Alimentary Tract, the Hepatobiliary System, the Kidney, and the Cardiopulmonary System

Diseases of the skin frequently indicate, or associate with, diseases of the alimentary tract, the hepatobiliary system, the kidneys, and the cardiopulmonary system. Just as a full physical examination should be part of a full dermatologic assessment, it is important to examine the skin in a patient presenting with a systemic problem. This chapter is presented in the same order that a physician performing a full physical examination might approach the patient. The cutaneous manifestations that indicate internal disease are discussed for each step of the examination.

Alterations in Skin Quality

The presence of pallid, dry, rough, and scaly skin that is usually itchy in patients with malabsorption, chronic renal disease, or chronic hepatic disease is nonspecific. Asteatotic eczema may develop. Some patients itch without any visible abnormality of their skin.

Cardiac Disease

Ehlers–Danlos Syndrome

Hyperelastic velvety skin that rebounds to the original position after being stretched, “cigarette-paper” scars, and hyperextensible joints are characteristic of the Ehlers–Danlos syndrome. Mitral and tricuspid prolapse, dilatation of the aorta and pulmonary artery, arterial rupture, myocardial infarction, and emphysema may accompany this syndrome (see Chapter 137).1

Cutis Laxa

Progressive looseness of the skin with pendulous folds and droopy eyelids may be associated with generalized hyperelastosis leading to aortic dilatation and rupture, congestive heart failure, or cor pulmonale with pulmonary artery stenosis and progressive emphysema (see Chapter 137).

Pseudoxanthoma Elasticum

The skin of patients with pseudoxanthoma elasticum (PXE) is thick, lax, and yellowish, especially over the axillae, antecubital area, and neck. Yellow patches may occur on mucous membranes, especially the labia. The alterations in the ABCC6 gene responsible for PXE may also lead to arteries becoming calcified, the aortic and mitral valves thickened, and cardiovascular symptoms, such as angina pectoris and claudication are frequent symptoms (see Chapter 137).2

Progeria

In Hutchinson–Gilford syndrome (progeria) and progeroid states such as Werner's syndrome, the skin appears atrophic and tight from a very early age. There is marked loss of subcutaneous tissue, with leg ulceration. Coronary atherosclerosis frequently leads to premature death by myocardial infarction (see Chapter 139).

Liver Disease

Skin changes are very common in chronic liver disease.3 Hormone-induced changes of the skin include loss of forearm, axillary, and pubic hair in both sexes. Men may experience a decreased rate of growth of facial hair, pectoral alopecia, and a female pubic hair distribution, as well as loss of libido, testicular atrophy, and oligospermia. Striae distensae occur in both men and women (Fig. 150-1). Gynecomastia, together with Dupuytren contracture and swelling of the parotid gland, is associated with cirrhosis.

Many of these changes occur more commonly in those where alcohol is the underlying cause. Patients with chronic alcoholism also develop a “pseudo-Cushing syndrome,” even in the absence of liver disease; signs include facial mooning, truncal obesity, and proximal muscle wasting. These changes may regress if the patient discontinues alcohol.

Patients with chronic liver disease often have telangiectatic changes, mainly on light-exposed skin. Numerous tiny telangiectases sometimes give the impression of a diffuse, almost exanthematic redness. They are known as “dollar paper markings” after the small threads visible in paper money held up against the light. They fade on pressure with a glass slide and rarely pulsate.

Renal Disease

The skin of patients with chronic renal failure (CRF) is frequently dry, often with ichthyosis-like scaling,4 possibly resulting in part from altered vitamin A metabolism.5 The fluid volume shifts of dialysis may exaggerate this.

Color Changes

Skin color is altered in CRF. The skin is pale due to anemia and often exhibits a distinctive muddy hue, due to accumulation of carotenoid and nitrogenous pigments (urochromes) in the dermis, although its etiology is complicated and may depend in part on treatment modalities used.6

Cyanosis

An increase in the absolute amount of desaturated (reduced) hemoglobin results in a purple–blue discoloration of the skin. Cyanosis is classified into “central” and “peripheral” types: the terms referring to the level of arterial oxygen saturation rather than the anatomic source of cyanosis. Thus, central cyanosis occurs in states that produce low arterial oxygen saturation, such as congenital heart disease with intracardiac or intrapulmonary right-to-left shunting, or severe lung disease. Peripheral cyanosis develops when there is normal arterial oxygen saturation but reduced blood flow, such as low-output cardiac failure and local vasoconstriction. Pulmonary embolism may result in a combination of central cyanosis and peripheral cyanosis.

Central cyanosis is usually visible on warm areas of the skin like the tongue, oral mucosae, and conjunctivae. Peripheral cyanosis is seen on cooler areas such as the nose, lips, earlobes, and fingertips. In the anemic patient, detection of cyanosis may be impossible because the absolute amount of reduced hemoglobin is not increased. Cyanosis fades when pressure is applied because the coloration is within the blood vessels.

Erythema

Redness of the skin is caused by an increase in the amount of saturated hemoglobin, an increase in the diameter or actual number of skin capillaries, or a combination of these factors. Edema of the face, arms, and hands associated with redness and/or cyanosis may indicate obstruction of the superior vena cava due to mediastinal disease.

Primary polycythemia may produce a characteristic “ruddy” complexion but, in secondary disease especially, may also cause a peculiar ruddy cyanosis. This is most pronounced on the tongue, lips, nose, earlobes, conjunctivae, and fingertips. It is due to increased amounts of saturated hemoglobin producing erythema with increased amounts of desaturated hemoglobin producing cyanosis because of the inability of the body to fully oxygenate the increased absolute amounts of hemoglobin. The absence of nail clubbing in polycythemia vera may help differentiate patients with from those patients with cardiopulmonary disease who develop secondary polycythemia. In addition, the hypervolemic state of polycythemia vera is associated with increased stroke volume and may lead to high-output cardiac failure. Pulmonary emboli may result from venous thrombosis secondary to hyperviscosity.

Flushing

Paroxysmal intense flushing of the face, neck, chest, and abdomen, often with telangiectases of the face and neck, may occur in patients with carcinoid tumors, systemic mastocytosis, and pheochromocytoma, alone or in Sipple syndrome.

Pigmentary Changes

In addition to jaundice (see below), both diffuse and circumscribed pigmentary changes may occur in chronic liver disease. A diffuse muddy gray color in patients with long-standing cirrhosis is due to basal cell melanin.

Cirrhosis

Melanosis is common in primary biliary cirrhosis (PBC) and may be an early presenting sign. It initially involves exposed areas, but gradually becomes generalized. Blotchy, circumscribed areas of dirty brown pigmentation are also occasionally evident. Accentuation of normal freckling and areolar pigmentation can occur. Localized linear pigmentation may appear in the creases of the fingers and palms. Pigmentation resembling chloasma may localize to the perioral and periorbital areas. Guttate hypomelanosis, a condition in which small white macules, sometimes with a central spider, appear on the skin of the buttocks, back, thighs, and forearms, may occur in cirrhosis and, rarely, in PBC.7 The yellow and orange lesions of dermal, subcutaneous, and tendon xanthomas and also xanthelasma are common in PBC and can be extensive (see Chapter 135).

Hemochromatosis

The generalized metallic gray or bronze-brown color of the skin in hemochromatosis can be striking. There is accentuation in sun-exposed and traumatized skin, and occasionally there is buccal and conjunctival pigmentation.8

The etiology and pathogenesis of hyperpigmentation in chronic liver disease remains obscure and varies from disease to disease. The pigmentation in PBC is due predominantly to excess melanin with no stainable iron, while in hemochromatosis, pigmentation results both from the presence of hemosiderin in the skin and excess melanin. After phlebotomy, histologic siderosis and pigmentation decrease, even though melanosis remains histologically.

Vitamin Deficiency

Pellagra gives rises to lichenified, and often deeply pigmented skin in sun-exposed sites and can develop in patients with alcoholic liver disease. Vitamin B12 deficiency causes pigmentation of the distal extremities in a glove and stocking distribution. Diffuse hyperpigmentation occurs in folate deficiency. Kwashiorkor produces generalized depigmentation (see Chapter 130).

Jaundice

(Box 150-1)

In jaundice, raised plasma bilirubin produces a generalized coloration of the skin, mucous membranes, and other body tissues varying in hue from faint golden to dark green–yellow. Both jaundice and pigmentation are most prominent in extrahepatic biliary obstruction and in PBC.

Jaundice results from increased cellular or connective tissue binding of bilirubin and its metabolites in the skin. Bilirubin has an affinity for elastin, but circulates almost exclusively as a tightly bound complex with albumin. Eighty-five percent of bilirubin comes from the degradation of heme, the remainder from other heme-containing proteins, such as myoglobin and cytochromes. Jaundice results from an imbalance between tissue production and hepatic clearance of bilirubin.

Tissue-serum equilibration is slow, and so the intensity of clinical jaundice often fails to reflect the concurrent serum bilirubin level. Hyperbilirubinemia may, therefore, antedate the onset of detectable jaundice, and jaundice may persist despite falling or normal serum bilirubin levels. The correlation between skin color and serum pigment levels is especially poor in newborns. The intensity of jaundice and levels of serum bilirubin in patients with biliary atresia, acquired bile duct obstruction, or defective bilirubin conjugation tend to stabilize despite continued pigment production. Congestive cardiac failure may cause hyperbilirubinemia and jaundice secondary to raised intrahepatic pressure.

Clinical Features

Clinically detectable jaundice appears when sufficient amounts of bilirubin become tissue bound. Involvement of the sclerae differentiates jaundice from other causes of skin pigmentation, including carotenemia, the yellow skin pigmentation produced by quinacrine and busulfan, and lycopenemia due to the ingestion of tomato juice.

The urine becomes dark yellow and even brown in color as conjugated serum bilirubin rises. Because most of the brown color of normal feces is due to urobilins derived from degradation of bilirubin in the intestine, the jaundice of impaired bilirubin excretion or bile obstruction is associated with “clay-colored” stools. Ultraviolet radiation enhances degradation of bilirubin; this is the rationale for phototherapy to prevent kernicterus in severe neonatal jaundice.

The jaundice of biliary obstruction resolves after the obstruction is relieved. Jaundice in patients with acute hepatitis resolves spontaneously. The jaundice of chronic liver disease may improve after transplantation. Jaundice in chronic active hepatitis can decrease after glucocorticoid therapy. Neonatal jaundice may respond to phototherapy (see Chapter 237).

Cholestatic Pruritus

Pathogenesis of Cholestatic Pruritus

One of the most common and distressing symptoms of hepatobiliary disease is pruritus. Although retained cutaneous bile acids have been implicated, there is a poor correlation between the plasma bilirubin and the severity of pruritus. However, the partial relief of itching by bile salt-chelating resins and the disappearance of pruritus when liver cells fail strongly indicates that the liver must manufacture at least one of the contributing agents.

Opiate agonists, such as morphine, induce pruritus. Animal studies show that the intracerebral presence of morphine induces pruritus that is reversed by the opiate antagonist nalaxone,9 demonstrating that opiate agonists induce itching centrally. In addition, the administration of the opioid antagonist nalmefene to patients with PBC produces a reaction similar to that of opiate withdrawal, and the injection of plasma from patients with PBC into monkeys produces pruritus. Taken together, these studies suggest that opioidergic tone increases in cholestasis.9 These studies do not, of course, tell us which agent(s) cause the pruritus of cholestasis, nor whether it originates peripherally (e.g., in the liver) or centrally.10

Clinical Features

Pruritus more commonly occurs in conditions causing cholestasis and ranges from mild and transient to severe and prolonged. Pruritus may be debilitating in patients with PBC, mechanical biliary obstruction, or intrahepatic obstruction. Drugs, especially erythromycin, oral contraceptives, phenothiazines, chlorpropamide, para-aminosalicylic acid, and nitrofurantoin, induce cholestasis accompanied by pruritus. Pruritus is the presenting symptom in more than 50% of cases of PBC and may precede jaundice by months or even years. However, in viral hepatitis, itching is frequently missed as an early sign of the disease until it occurs in the later, icteric phase.

Pruritus is usually most marked on the extremities and only rarely involves the neck and face, and genitalia. There is little correlation between the severity of cholestasis and the severity of perceived pruritus: a spontaneous decrease in the intensity of pruritus may signal the development of hepatocellular failure rather than improvement. Scratching gives only very temporary relief in the pruritus of cholestasis. There may be no visible skin changes except excoriations, although lichenified plaques, nodular prurigo or peforating collagenoses may be seen (see Chapter 69).

Management

Pruritus rapidly decreases when cholestasis secondary to mechanical bile duct obstruction is relieved. Drugs to relieve cholestasis such as ursodeoxycholic acid do not consistently relieve pruritus, nor do the anion exchange resins cholestyramine and cholestipol, which are thought to bind intestinal pruritogens and prevent them making their way to the skin. Neurotransmitter receptor antagonists such as oral nalmefene have been advocated for the pruritus of cholestasis11 Intravenous naloxone has short-term efficacy12 as has oral naltrexone.13 However, while these, together with sedating antihistamines or ultraviolet light can help, long-term results with any approach, including plasmapheresis, charcoal hemoperfusion, and hepatic enzyme inducers (such as rifampicin) have been disappointing.14

Renal Pruritus

Renal pruritus is a major problem4 and reported to be as high as 90% in patients undergoing hemodialysis.15–17

Pathogenesis of Renal Pruritus

Renal pruritus has been thought to be caused by a combination of increased serum histamine, vitamin A, and parathyroid hormone (PTH); mast cell hyperplasia; peripheral polyneuropathy; xerosis.16,18; and inflammatory factors.19 Clinically, the skin may appear normal or demonstrate a variety of lichenified or hyperkeratotic lesions.20

Management

Topical moisturizers alleviate pruritus associated with xerotic skin. Topical glucocorticoids and ultraviolet phototherapy21,22 are often used to suppress inflammation in treated areas. Topical capsaicin depletes substance P from nerve endings, thereby suppressing itch sensation.23 Gabapentin and the κ-opioid-receptor-agonist nalfurafine have also been found useful.19 Improving the efficacy of dialysis and/or changing the dialysate concentration may help to alleviate pruritus.24 Some patients have responded to treatments with intravenous lidocaine, heparin, and cholestyramine.22 Surgical options include subtotal parathyroidectomy, electric needle stimulation, and renal transplantation. Erythropoietin lowers plasma histamine concentrations with subsequent improvement in pruritus.25 There are reports of success with oral evening primrose oil,26 and endocannibinnoids.27 Thalidomide, pentoxiphylline, and topical tacrolimus ointment may help some patients.19,28

Alterations in Sweating

Sweating may be prominent in a number of cardiopulmonary states such as acute myocardial infarction, cardiogenic shock, left ventricular failure, massive pulmonary emboli, and pulmonary edema. Pallor and clamminess/coldness of the extremities and exposed surfaces are also often found. Excessive sweating may suggest pheochromocytoma when associated with hypertension.

The sodium and chloride content of sweat is increased in patients with cystic fibrosis and may lead to an increase in skin wrinkling after immersion, as when bathing.29

Skin Changes in Malignancy

(See also Chapter 153)

Many skin changes occur in association with malignancies.

Dry skin (acquired ichthyosis) with asteatotic dermatitis as well as hyperpigmentation is not uncommon.

Dermatomyositis

(See Chapter 156)

Adult onset dermatomyositis is associated with underlying malignant disease in a significant minority of cases.30 Blind CT scans may help uncover occult malignancy in these patients.31 Pancreatic, gastric, and colorectal cancers are the third most common after bronchogenic and ovarian cancers in Europe and North America. In China, nasopharyngeal carcinoma is common. The rash and myopathy can regress after removal of the tumor.

Interstitial lung disease occurs32 with bronchiolitis obliterans, subcutaneous emphysema, and spontaneous pneumothorax. Upper pharyngeal weakness can lead to chronic aspiration an, exertional dyspnea can occur because of weakness of the respiratory muscles. Lung disease is associated with anti-Jo-1 antibodies.

Acanthosis Nigricans

(See Chapter 151 and 153)

In two-thirds of patients with acanthosis nigricans and cancer, the tumor is gastric. The changes may regress if the tumor, usually an adenocarcinoma of the stomach or bowel, is removed.

Hypertrichosis Lanuginosa

Excessive growth of lanugo hair is a rare complication of gastrointestinal cancer.

Other Skin Changes in Malignancy

Diverse cutaneous paraneoplastic syndromes may arise from underlying tumors.33 They may precede, coincide with, or follow the diagnosis of cancer and usually indicate a poor prognosis. They include reactive erythemas, such as erythema gyratum repens and necrolytic migratory erythema; the vascular dermatoses (trousseau syndrome); and papulosquamous disorders, including tripe palms (Fig. 150-2), palmar hyperkeratosis, acquired ichthyosis, pityriasis rotunda, Bazex syndrome, florid cutaneous papillomatosis, the sign of Leser–Trélat, and extramammary Paget disease. Migratory superficial thrombophlebitis occurs in association with neoplasia, particularly carcinoma of the pancreas. Glucagonoma, one of the amine precursor uptake and decarboxylation (APUD) cell tumors, usually arises in the islet cells of the pancreas, and occurs in association with a distinctive necrolytic migratory erythema (see Chapter 153).

Any tumor may metastasize to the skin. The scalp is a common site. Metastases at the umbilicus (Sister Joseph nodules) occur particularly with carcinoma of the stomach, colon, or ovary (Fig. 150-3).

Erythroderma

(See Chapter 23)

The systemic effects of erythroderma can be considerable. Patients can develop hypothermia, hypoalbuminemia, hypovolemia, secondary sepsis, the initial stages of renal failure, and high-output cardiac failure with secondary effects on hepatic function. Death from sepsis, cardiac failure, adult respiratory distress syndrome, and capillary leak syndrome occur.34

Nails

(See Chapter 89)

Lindsey, or half-and-half, nails are normal in their distal 50% and white in the proximal 50% and found in CRF.

In malabsorption or malnutrition, nails grow more slowly, become brittle, and may develop fissures.35,36 Multiple pigmented bands can appear. Koilonychia usually indicates iron deficiency, even without anemia (see below). White nails, thought to be due to selenium deficiency, have occurred with total parenteral nutrition.

Flushing of the nail beds that is synchronous with the heartbeat is a sign of aortic regurgitation called Quincke pulsation.

Nail Changes in Liver Disease

Nail abnormalities are a less constant physical sign than spider nevi or liver palms. In cirrhosis, however, a number of changes may occur: clubbing, curved nails, thickened nails, longitudinally ridged nails, white nails, watch-glass deformity, flattened nails, white bands, striations, and brittleness.36

White nails may occasionally be seen in healthy individuals or in association with systemic disease, including congestive heart failure, diabetes, cryoglobulinemia, Raynaud syndrome, and systemic sclerosis. Intensely white nails (Terry nails) are characteristic of cirrhosis (Fig. 150-4).37 Thumbs and forefingers are often most affected. The whiteness does not alter with nail growth or with compression of digital vessels and is thought to be due to the opacity of the nail plate itself. The so-called watch-glass deformity may accompany white nails (see Fig. 150-5).

Azure lunulae, a bluish color of the lunular portion of nails, occurs in hepatolenticular degeneration (Wilson disease). Azure lunulae and corneal changes resembling Kayser–Fleischer rings may also be evident in patients with argyria or following treatment with busulfan or antimalarials.36

The characteristic nail changes of lichen planus, including longitudinal ridging, pterygium formation, and permanent nail loss, occur both with and without skin changes in PBC (see Section “Cutaneous Manifestations of Primary Biliary Cirrhosis”).

Splinter hemorrhages also occur in cirrhosis. Flat or spoon nails are less common in patients with liver disease. The nails are flat or concave, pale in color, and frequently show longitudinal ridging. In hemochromatosis, koilonychia is probably the most common of the nail abnormalities, but it is not related to anemia.36

Nail Clubbing

Nail clubbing most commonly occurs in patients with bronchogenic carcinoma, suppurative lung disease, endocarditis, and congenital heart disease, but it may be idiopathic or familial (Fig. 150-6). Clubbing is quite common in all forms of cirrhosis, especially PBC and chronic active hepatitis. Signs include beaking or distal curvature of the nail. There may be loss of the angle between the nail and cuticle. Sponginess or “floating” of the nail when pressure is applied is also characteristic and the size of the terminal tuft may increase.

Anatomically, there is an increased thickness of the nail bed. This is due to edematous infiltration of the soft parts of the terminal segment followed by hyperplasia of the dermal fibrovascular tissue with increased vascularity.36

Yellow Nail Syndrome

This is the triad of yellow nails, primary lymphedema, and pleural effusion(s). The characteristics of the nails include thickening, transverse ridging, diminished growth, increased curvature with a “hump,” and onycholysis. The lunulae and cuticles may be absent. The color may vary from pale yellow to green (Fig. 150-7). The nail changes are secondary to congenitally hypoplastic lymphatics,38 leading to lymphedema, which is characteristically slowly progressive and somewhat asymmetric, with induration and hyperkeratosis extending to the thighs. Periodic lymphangitis is frequent and may contribute to the swelling.

Respiratory findings include sinusitis, bronchiectasis, and pleural effusions. Patients may have frequent upper respiratory infections, and pneumonia. The appearance of pulmonary features and lymphedema may be late and lymphoma or sarcoma have been reported.

Erythromelalgia

(See also Chapter 173)

Erythromelalgia (labile hyperthermia) is a chronic clinical syndrome that is characterized by recurrent attacks of burning pain in the hands and/or feet with redness and warmth.39 There may be swelling that extends to the elbows and knees. Erythromelalgia may be primary or secondary to a disorder such as atherosclerosis, hypertension, and polycythemia. Symptoms are thought to be caused by vascular dysfunction including arteriovenous shunting and reduced capillary perfusion with subsequent tissue hypoxemia.40 Management includes analgesia, controlling secondary and underlying factors, and use of drugs such as aspirin and calcium channel blockers.41 A possible role for high-dose oral magnesium has been proposed42 and the use of a combination gel of 1% amitriptyline and 0.5% ketamine used to treat refractory erythromelalgia pain.43

Hands

Hypertrophic Osteoarthropathy

Clubbing is often a feature of hypertrophic osteoarthropathy (HOA) but there is also associated arthralgia and/or arthritis of the fingers, wrists, knees, and ankles. There is a painful periostitis with subperiosteal new bone formation on X-ray. There may be pitting edema, shiny skin, increased sweating, and paronychial thickening. HOA is most often secondary to malignant tumors of the chest.

Pachydermoperiostosis, a primary form of HOA, is frequently familial with an onset around puberty, and has a number of cutaneous manifestations. Distinctive thickening and furrowing of the skin of the scalp, forehead, and cheeks may create leonine facies. Other features include excessive sweating and dermatitis, especially of the hands and feet, severe seborrhea of the scalp and face. Familial clubbing alone may also be found and may represent a partial expression of this syndrome. Thyroid acropachy (Chapter 151) may mimic osteoarthropathy but is most often painless.

Reflex Sympathetic Dystrophy

The shoulder–hand syndrome is a painful periarthritis or adhesive capsulitis of the shoulder (“frozen shoulder”), usually on the left side, associated with erythema, increased sweating, shiny induration, edema, tenderness, pain, and immobility of the ipsilateral hand. Reduction of finger flexion, loss of movement, temperature changes, sensory disturbances, and, hair/nail growth changes have been reported.44 Neurotrophic ulcerations of the fingers and thickening of the palmar aponeurosis with nodules and/or Dupuytren contracture may be late sequelae.45 Predisposing conditions include arterial embolization, cerebrovascular accidents, and protective disuse of the arms for any reason.46

Palms

Palmar Erythema

There are two clinical forms of palmar erythema. In the first (Fig. 150-8), there is an exaggeration of normal mottling; the hands are warm and bright red, especially on the palm, the dorsae of the hands, the fingers, and the nail bases. In the second, there is well-demarcated redness of the hypothenar eminence that gradually spreads to the fingertips and then to other areas of the palm. The soles of the feet may show similar changes. The mottling blanches on pressure and flushes synchronously with the pulse rate under a glass slide. Patients may complain of throbbing or tingling. Often termed “liver palms” these changes also occur in pregnancy and thyrotoxicosis. In cirrhosis, though, atrophy of the muscles of the thenar and hypothenar eminence may coexist. This is of myogenic rather than neurogenic origin.47

Face

Spider Nevus

The spider nevus, or spider angioma, is the most representative and classic vascular lesion of chronic liver disease. Clinically, it has a central arteriole from which numerous small, twisted vessels radiate (Fig. 150-9). Spider nevi range in size from a pinhead to 2 cm. Larger lesions can be seen to pulsate when pressed with a glass slide. Pressure over the central arteriole causes blanching of the whole lesion. Spider nevi are characterized by the abnormal permanent dilatation of end vessels. Histologically, spider nevi consist of a central ascending arteriole ending in a thin-walled ampulla beneath the epidermis from which small arterial branches radiate outward into the papillary dermis.3

Spider nevi are most common on the face, neck, and upper part of the chest (i.e., over the region drained by the superior vena cava; see Fig. 150-9). They may be seen in 15% of healthy adults and not infrequently in children, where they tend to affect the hands and fingers. They may appear in large numbers during pregnancy, but usually disappear after parturition. They may also be seen in thyrotoxicosis or due to oral contraceptives.

In liver disease, spider nevi usually persist but can regress with improvement of the underlying condition. Spider nevi are more common in patients with alcoholic cirrhosis than in those with viral or idiopathic cirrhosis. In alcoholic cirrhosis, they are associated with the presence of esophageal varicosities, and their presence may be a useful predictive marker for the future risk of esophageal bleeds.48

Vascular spider nevi and palmar erythema (see above) are generally attributed to estrogen excess, particularly because they also occur during pregnancy and because estrogens have an enlarging, dilating effect on the spiral arterioles of the endometrium. This would also explain spider nevi in men receiving estrogen therapy for prostatic cancer. However, in addition to higher plasma estradiol:testosterone ratios, patients with nonalcoholic cirrhosis have been shown to have higher substance P levels than healthy controls.49 Vascular endothelial growth factor (VEGF) may also have an etiopathogenic role.50 In alcoholic cirrhosis, the presence of alcoholism and elevated serum bilirubin are both important predictors of the presence of spider nevi.51

Eyes

Corkscrew scleral vessels (tortuous small arteries that traverse the margins of the ocular sclerae) can develop in patients with chronic liver disease.

Mouth and Esophagus

Dysphagia

When dermatologic diseases extend into the pharynx and esophagus, dysphagia may occur. Cutaneous and oral infections are discussed elsewhere. Symptoms resulting from infections of the esophagus occur in patients taking oral or inhaled glucocorticoids or in those who have an immunodeficiency. Candida albicans is the most frequent pathogen, although opportunistic bacteria and viruses can also be responsible.

Extensive esophageal involvement with blisters, erosions, and strictures can occur in hereditary epidermolysis bullosa particularly in the recessive dystrophic and junctional forms (see Chapter 62).52 The acquired immunobullous disorders can affect mucosae. Dysphagia is most troublesome in cicatricial pemphigoid where half of patients have pharyngeal involvement and up to 13% esophageal involvement (see Chapter 57).53

Esophageal lichen planus has been reported only in women, typically middle-aged with oral involvement (see Chapter 26). Therapeutic dilatation can lead to a Koebner-like exacerbation of the stricture.54 Esophageal involvement also occurs in Darier disease, sometimes in association with esophageal carcinoma (see Chapter 51),55 and in acanthosis nigricans. The mucosae may be extensively involved in Stevens–Johnson syndrome and toxic epidermal necrolysis (see Chapters 39 and 40).

In Behçet syndrome (see Chapter 166), which should always be considered in a patient with three episodes of oral ulceration in a 12-month period, isolated mucosal ulcers can occur at any point along the gastrointestinal tract.56 A typical site is the ileocecal region. Oral ulceration can sometimes be difficult to distinguish from the mouth ulceration associated with Crohn disease.

In Plummer–Vinson (Paterson–Kelly) syndrome, a postcricoid web is associated with koilonychia, angular stomatitis, a sore tongue, and, usually, iron deficiency. Up to 10% of patients with a postcricoid web develop carcinoma at the site. The form of tylosis in which 95% of patients develop esophageal cancer is exceedingly rare.57

Up to 90% of patients with systemic sclerosis have gastrointestinal involvement, but this is subclinical in one-third (see Chapter 157). Dyspepsia due to gastroparesis is common; decreased peristalsis, esophageal dilation, and stricture formation occur. Gastric antral vascular ectasia is a rare manifestation that may cause significant bleeding.58 In dermatomyositis and polymyositis, decreased esophageal motility and difficulty swallowing are indications for urgent systemic treatment with high-dose glucocorticoids and immunosuppressive drugs (see Chapter 156). Vasculitic ulcers in the mouth and pharynx may occur in systemic lupus erythematosus (see Chapter 155).

Ears

Earlobe Crease

The presence of a diagonally positioned skin crease along the earlobe, either unilateral or bilateral, suggests an increased risk for coronary artery disease (CAD) in men under 60 years of age.59

Relapsing Polychondritis

(See Chapter 159)

Relapsing polychondritis is characterized by inflammation and destruction of cartilage and connective tissues, including those of the cardiopulmonary system. It is idiopathic but frequently associated with other immunologic disorders such as systemic lupus erytematosus (SLE). Auricular chondritis with pain, swelling, and redness of the pinna but complete sparing of the lobes is characteristic. Respiratory tract involvement may begin with hoarseness or tenderness of the anterior trachea. Degeneration of the laryngeal, tracheal, and/or bronchial rings may lead to progressive insufficiency or to sudden collapse. Cardiac involvement includes degeneration of the aortic ring with valvular insufficiency and aneurysmal dilatation. “Floppy” mitral valve syndrome also occurs. Pericardial and myocardial abnormalities have been reported.

Hair

(See Chapter 88)

Malnutrition causes hair to grow more slowly, fall out more easily, and become gray. The hair root diameter and the proportion of anagen hairs decrease. Lanugo hair may develop. Kwashiorkor, a form of protein–energy malnutrition, causes hair to become hypopigmented, varying from red–yellow to white, and curly. There may be alternating bands of pale and dark hair.35 Total parenteral nutrition has been associated with hair loss and pigmentation of remaining hair. Type 2 vitamin D-dependent rickets is associated with alopecia totalis.

Male Balding

Frontoparietal male pattern baldness is more prevalent in men admitted with nonfatal myocardial infarction.59 Vertex hair loss may be more strongly associated with cardiovascular risk factors, such as hypertension and hypercholesterolemia.60

The Cardiovascular System

(Box 150-2)

Cardiac output frequently increases in patients with cirrhosis, and total peripheral resistance may decrease.

Coronary Heart Disease

Familial Hyperlipidemia

The familial hyperlipidemias comprise a group of metabolic disorders with elevated plasma cholesterol and/or triglycerides, associated with a high incidence of CAD. Xanthelasmata and cutaneous xanthomata are important clinical features (see Chapter 135).

Cardiomyopathy

Naxos Disease

This is an autosomal recessive mutation in desmoplakin, a desmosomal protein important in cell adhesion.61 Generalized striate keratodermas are seen, particularly on the palmoplantar epidermis, with woolly hair and dilated left ventricular cardiomyopathy leading to arrhythmias, heart failure, and early sudden death (see Chapter 50).

Atrial Myxoma

Atrial myxomas, the most common primary tumors of the heart, are benign hamartomatous intracardiac tumors. The cardiopulmonary findings include, in order of frequency, congestive heart failure, mitral murmur, chest pain, pulmonary edema, and pulmonary emboli. Additionally, valvular insufficiency, constrictive pericarditis, conduction blocks, and arrhythmias may occur. Variable murmurs can be an important clue. Other systemic findings include fever, cachexia, arthralgia, clubbing, hypergammaglobulinemia, and leukocytosis.

The cutaneous manifestations of atrial myxomas may be dramatic. In addition to biphasic digital color changes on cold exposure, skin lesions may simulate collagen vascular disease or vasculitis with tender, violaceous, nonblanching, annular, and serpiginous lesions of the digital pads, as well as splinter hemorrhages presenting as a systemic vasculitis or infective endocarditis. Characteristic pruritic, erythematous papules as well as cyanosis and ecchymosis of the extremities may also occur. Histologically myxomatous emboli with large pale cytoplasm and stellate nuclei may be found among occluded blood vessels. Mucocutaneous pigmented lesions, including lentigines (Fig. 150-10), melanocytic nevi, and dermal myxomatous nodules, have been described (NAME/LAMB/Carney Complex).62

Leopard Syndrome

Multiple lentigines syndrome is an autosomal dominant disorder comprising lentigines; electrocardiogram conduction defects; ocular hypertelorism; pulmonary stenosis; abnormalities of genitalia; retardation of growth and sensorineural deafness. Electrocardiographic features include axis deviation; prolonged P–R interval, bundle branch block, and complete heart block. Hypertrophic cardiomyopathy appears to be the most common anatomic abnormality. Subaortic stenosis is the most common valvular lesion.

Subacute Bacterial Endocarditis

(See also Chapter 181)

The cutaneous manifestations of bacterial endocarditis include Osler nodes, Janeway lesions, subungual splinter hemorrhages, cutaneous purpura and petechiae, and conjunctival petechiae (Roth spots).

Petechiae are the commonest manifestation with small, red, or violaceous nonblanching macules especially on the heels, shoulders, and legs.

Osler nodes and Janeway lesions may both present as erythematous or hemorrhagic macules, papules, or nodules (Fig. 150-11). However, while Osler nodes are exquisitely painful, tender, and located distally on the digital tufts, Janeway lesions are nontender and located proximally on the palms and soles. Histologically, Osler nodes are a perivasculitis or necrotizing vasculitis without microabscess formation or other evidence of infection or emboli whereas Janeway lesions have been described as a vasculitis with microabscess formation. Both are found in patients with other conditions, particularly systemic lupus erythematosus, gonococcemia, hemolytic anemia, and typhoid fever.

Collagen Vascular Disease and the Heart

Systemic Lupus Erytematosus

(See Chapter 155).

Pericarditis may be more common in patients with drug-induced lupus or photosensitive discoid lesions. Myocarditis is often undiagnosed and may be associated with prolonged P–R intervals, heart block, and arrhythmias. Valvular heart disease in patients with SLE, most often of the Libman–Sacks type, is frequently associated with antiphospholipid antibodies.63 Diastolic murmurs may occur with mitral stenosis or aortic insufficiency but the onset of a new diastolic murmur should provoke a search for subacute infective endocarditis. Splinter hemorrhages, Osler nodes, Janeway lesions, and Roth spots may occur in SLE per se without infection. SLE is associated with complete heart block in newborns because of placental transfer of maternal antibodies, especially the anti-Ro antibody.64 The newborn infants of patients with SLE or of clinically normal but Ro-antibody-positive mothers may also have distinctive evanescent eruptions, including prominent telangiectasia and periorbital erythema.65

Systemic Sclerosis

(See Chapter 157). Acute or chronic pericarditis is an important feature of systemic sclerosis. Pericardial effusions may be occult, and constrictive pericarditis and tamponade may occur. Additionally, small-vessel involvement of the myocardium may lead to fibrosis.66 Fibrosis of the conduction system may cause arrhythmias and sudden death.

Pulmonary Arteriovenous Fistulas

Pulmonary arteriovenous fistulas are congenital abnormalities of capillary development that may not become clinically apparent until late adolescence. Osler–Weber–Rendu disease67 is an autosomal dominant trait, characterized clinically by punctate, linear, or spider-like telangiectasias of the skin, especially on the upper body, oral and nasal mucous membranes, and nail beds (Fig. 150-12). Radiating arms about an elevated punctum are the most characteristic feature, especially on the lips and tongue. They are distinguished from spider nevi in that they do not pulsate. Recurrent epistaxis, often beginning in childhood or adolescence, is the most frequent presenting symptom. The liver, gastrointestinal, and central nervous system can be involved (see below) and recurrent hemorrhage may result. Bleeding may be enhanced by associated disorders such as von Willebrand disease. In those with an arteriovenous fistula of the lungs pulmonary bruits accentuated by inspiration can be heard.

In cirrhosis, arteriovenous shunting may occur within the lungs (the hepatopulmonary syndrome),68 liver, and extremities. These arteriovenous malformations, including spider nevi, may regress after transplantation.69

Larva Migrans

(See Chapter 207)

Cutaneous larva migrans, may cause mild respiratory symptoms and be associated with transient pulmonary infiltrates and a peripheral eosinophilia (Löffler syndrome). Visceral larva migrans, or toxocariasis, may lead to granulomatous involvement of the liver, lungs, heart, muscle, brain, and eyes. Marked eosinophilia, hyperglobulinemia, pneumonitis with wheezing, recurrent bronchitis, fever, and tender hepatomegaly frequently occur. Skin lesions may present as patchy urticaria or erythematous papular eruptions.

Fat Embolism Syndrome

Petechiae, respiratory insufficiency, and cerebral dysfunction after long bone fracture are termed the fat embolism syndrome. Petechiae alone after fractures should suggest this diagnosis. The petechiae are most common on the neck, axillae, shoulders, chest, and conjunctivae. They often appear before other manifestations on the second or third day after injury, and appear in crops. When widespread, they herald more significant cerebral and pulmonary dysfunction. Histologically, fat globules are present within dermal and pulmonary vessels. Respiratory involvement includes cyanosis, hemoptysis and pulmonary edema. Jaundice and thrombocytopenia may occur.70

Lipoid Proteinosis (Hyalinosis Cutis ET Mucosae)

(See Chapter 137)

Skin changes include confluent, waxy papules, plaques, and scarring, particularly on the face. The tongue is enlarged. Oropharyngeal and laryngeal mucous membranes are usually affected early in the course of the disease, during infancy or childhood. Laryngeal infiltration may present early on as hoarsness, and may progress to obstruction and respiratory insufficiency. The trachea and main stem bronchus may be thickened and studded with warty projections.

Multicentric Reticulohistiocytosis

(See Chapter 148)

Multicentric reticulohistiocytosis is an uncommon disorder presenting with characteristic mucocutaneous lesions consisting of deeply set, firm, small papules in association with a deforming arthritis, fever, malaise, weight loss, and myopathy. Neurofibroma-like, soft, sessile, larger lesions have been reported, as has an association with malignancy.71 Cardiopulmonary complications include pleural effusions, pulmonary infarctions, pericarditis, angina pectoris, myocardial infarction, and congestive heart failure.

Sarcoidosis

(See Chapter 152)

Cardiac involvement in sarcoidosis may be occult and results from myocardial or conduction system granulomata. Ventricular arrhythmias and conduction disturbances present as palpitations and syncope. Congestive heart failure and chest pain occur as do cardiomyopathy or cor pulmonale. The prognosis for patients with cardiac involvement is unfavorable. Sarcoidosis affecting the pulmonary system is relatively common in association with lupus pernio: involvement of the hilar nodes, bronchi, and/or alveoli may result in obstructive and/or restrictive dysfunction and respiratory failure.72 Indwelling vascular catheters can, rarely, disintegrate and embolise into small pulmonary vessels and lymphatics, causing granulomatous changes and dyspnoeic symptoms. These lesions have also been reported in the skin.73

Amyloidosis

(See Chapter 133)

Systemic amyloidosis may cause waxy induration of the skin, with hemorrhagic skin changes on stroking (pinch purpura). Amyloid deposition within the vessels is found in clinically normal skin in up to 50% of patients.

Cutaneous involvement occurs most often in the primary and myeloma-associated types, and therefore serves as a marker for cardiopulmonary involvement. Congestive heart failure with cardiomegaly or a restrictive cardiomyopathy occurs. Pathologically, there is infiltration of the endocardium, myocardium, pericardium, valves, and coronary vessels.74 Senile amyloidosis may also affect the heart but is often asymptomatic.

Respiratory tract involvement is also commonest in primary and myeloma-associated types. Macroglossia may impede respiration, the larynx and trachea may become infiltrated, causing stridor and bronchial and parenchymal involvement cause asthma-like symptoms.

Lymphomatoid Granulomatosis

(See Chapter 145)

Lymphomatoid granulomatosis is a rare angiocentric and angiodestructive, Epstein–Barr virus-associated B cell lymphoproliferative disorder, varying from an indolent process to an aggressive large cell lymphoma. The skin is the extrapulmonary organ most commonly involved. The disease also affects the lungs,75 heart, central nervous system, and kidneys. Although many patients remain asymptomatic, cough, dyspnea, and chest pain may occur. Chest X-rays show transient infiltrates which may progress to nodules that cavitate and cause profuse hemoptysis.

Collagen Vascular Disease and the Lungs

The pulmonary complications of the various collagen vascular diseases may sometimes be associated with a specific cutaneous sign or constellation of features.

Rheumatoid Arthritis

(See Chapter 160). Extra-articular manifestations of rheumatoid arthritis, especially in the lungs, appear to correlate with subcutaneous nodules and vasculitic skin lesions. Skin lesions are also associated with high-titer rheumatoid factor, hypocomplementemia, cryoimmunoglobulinemia, and hypereosinophilia. These occur more commonly in men with long-standing disease, but may not correlate with current arthritis activity. The pulmonary symptoms include cough and hemoptysis.

Systemic Lupus Erythematosus

(See Chapter 155). Pleuritis may be present half of patients with SLE and pleural effusions also occur. Parenchymal lung involvement in SLE is usually a result of secondary factors such as infections or pulmonary emboli. Primary lung involvement in SLE may be classified as (1) diffuse interstitial pneumonitis, (2) acute pneumonitis, (3) intrapulmonary hemorrhage, (4) diaphragm dysfunction with decreased lung volume, (5) pulmonary hypertension with cor pulmonale, and (6) fibrosing alveolitis.76

Systemic Sclerosis

(See Chapter 157). Raynaud phenomenon, telangiectases, and dilated and distorted capillary loops of the nails are cutaneous clues. Exertional dyspnea chronic, nonproductive cough, and pleuritic chest pain indicate lung involvement.77 Pulmonary hypertension with cor pulmonale and congestive heart failure may develop independently of parenchymal disease. Esophageal dysmotility causing aspiration pneumonia is associated with a higher incidence of interstitial lung disease.64

The Gastrointestinal System

On examining the abdomen in patients with cirrhosis portal-systemic collateral vessels may be seen and are a clue to the existence of portal hypertension. Often, the umbilical vein is dilated and visible in the epigastrium, an occurrence more common than the well recognized, but rare, caput medusae.

Gastrointestinal Bleeding

Hematemesis, melena, or passing of fresh blood in the stools are signs of gastrointestinal bleeding (Box 150-3). The characteristic picture of hereditary hemorrhagic telangiectasia is of a familial pattern of epistaxis with telangiectases on mucosal surfaces (see Fig. 150-12) and arteriovenous malformations in multiple organs.67 Hemorrhage from the gut, usually from the stomach or duodenum, occurs in up to 40% of patients and at an average age of 55 years.

Most cases of blue rubber bleb nevus syndrome are sporadic, but there are some autosomal dominant pedigrees. The gastrointestinal venous malformations look and feel as their name suggests and project into the gut lumen, particularly the small intestine. In contrast to cutaneous lesions, they bleed easily, causing chronic anemia and, less commonly, acute hemorrhage (see Chapter 172).78

In the autosomal dominant vascular type of the Ehlers–Danlos syndrome rupture of the bowel, often involving the sigmoid colon, accounts for one-quarter of all complications and 8% of all deaths.1 Diverticula, and hernias, may also occur (see Chapter 137).

Gastrointestinal bleeding, usually from the stomach, is an important complication of PXE.2 This may be the first clinical manifestation of the disease (see Chapter 137).

The gut, particularly the small intestine, is a common site for Kaposi sarcoma. While involvement is commonly asymptomatic, severe bleeding may occur (see Chapter 128).

Gastrointestinal bleeding in a patient with a dermatologic disease may also be due to drug therapy. The systemic administration of glucocorticoids commonly causes dyspepsia but may, more significantly, result in gastric erosions, ulceration, and hemorrhage. Methotrexate may cause enteritis, gastrointestinal ulceration, and hemorrhage.

Abdominal Pain

(Box 150-4)

Involvement of the sensory roots of the vertebrae T6–L1 in herpes zoster may produce abdominal pain even before skin lesions appear. Occasionally, herpes zoster in the distribution of S2, S3, and S4 is associated with perineal pain and disturbances of urination and defecation.

Acute attacks of urticaria or angioedema may present as abdominal pain. Edema of the bowel wall and mucosal thickening, often in association with free peritoneal fluid, is evident ultrasonographically—an aid to avoiding unnecessary surgery.79 This is especially true in hereditary angioedema where colicky abdominal pain and life-threatening laryngeal edema occur and require treatment with injection of purified C1 inhibitor concentrate.80

It is only in the rare variegate porphyria that skin involvement and attacks of abdominal pain coexist (see Chapter 132). The skin shows changes identical to those in porphyria cutanea tarda (PCT). Pregnancy or drugs such as estrogen and griseofulvin may precipitate acute attacks. Although the detection of urinary uroporphyrin and fecal protoporphyrin indicates the diagnosis, plasma fluorescence with emission maxima at 626 nm is faster, easier and more sensitive it revealing the condition even in patients who are in remission.81

One-third of patients with systemic mastocytosis have gastrointestinal involvement. Symptoms include vomiting, abdominal pain, malabsorption, diarrhea, peptic ulceration, and gastrointestinal bleeding. Patients with more aggressive disease may develop hepatosplenomegaly with ascites and lymphadenopathy.82–85

Angiokeratoma Corporis Diffusum and Anderson–Fabry Disease

Angiokeratoma corporis diffusum is the cutaneous marker for several inherited lysosomal disorders, due to deficiency of a number of enzymes, notably α-galactosidase A (the cause in Anderson–Fabry disease) (see Chapter 136). Signs include severe, painful neuropathy; progressive renal, cardiovascular, and cerebrovascular dysfunction. Gastrointestinal symptoms include abdominal pain and diarrhea. The diagnosis may be missed without the skin signs. Angiokeratomas may not appear until adolescence and, even then, can be subtle. Assay of α-galactosidase A is possible not only in established cases, but also before birth, and female carriers often identifiable. Treatment with intravenous infusions of α-galactosidase A is safe and efficacious.86

Vasculitis

(See Chapter 163). Henoch–Schönlein purpura is palpable, especially on the legs and buttocks, and may occur in conjunction with joint swelling. Up to 76% of patients have gastrointestinal involvement, ranging from colicky abdominal pain, nausea, and vomiting to bloody diarrhea, intussusception, and pancreatitis. Renal involvement is common, especially in patients with bloody stools.87 Upper gastrointestinal endoscopy reveals multiple raised erythematous lesions or ulceration that resolves after systemic treatment with glucocorticoids.88

Malignant atrophic papulosis is an idiopathic, systemic, obliterative vasculopathy (see Chapter 171). The characteristic skin lesions are recurrent crops of porcelain-white atrophic papules with an elevated erythematous border. These may have been present for years with no other apparent disease although gut vessels are involved in half of the cases.89 Clinically bleeding, abdominal pain, diarrhea, malabsorption, and bowel perforation with peritonitis occur.

Polyposis

True polyps are rare except in the colon and rectum. Polyp-like lesions that are hamartomatous or inflammatory occur in all parts of the gut. The term hamartoma implies a nonneoplastic tumor composed of tissue elements normally present in that organ. The hamartomatous polyposis syndromes (e.g., Peutz–Jeghers, Cronkhite-Canada) should be distinguished from the adenomatous polyposis syndromes (e.g., Gardner). In many of these syndromes, hamartomatous polyps of the gastrointestinal tract coexist with adenomas, and adenomas may develop within hamartomatous polyps contributing to the frequent occurrence of adenocarcinoma in most of these syndromes.90

Gardner syndrome is an autosomal dominant disorder characterized by cutaneous cysts and premalignant adenomatous polyps, particularly in the colorectum. Duodenal and hepatic carcinoma can also occur. The cutaneous lesions frequently predate the gastrointestinal lesions and include solitary or multiple epidermoid cysts, fibromas, lipomas, pilomatricomas, facial osteomas, and distinctive ocular lesions.91

Peutz–Jeghers syndrome is autosomal dominant and characterized by small darkly pigmented macules around the mouth, on the lips, buccal mucosa, and digits. A histologically unique type of hamartomatous polyp occurs, mainly in the small intestine, which predisposes to recurrent intussusception. Bleeding is relatively rare, but up to 2% of patients develop adenocarcinoma of the stomach, duodenum, and colon.90 There is also an increased risk of malignancy in general.92

In Cronkhite-Canada syndrome, there is patchy alopecia and characteristic, nail changes.90 Inflammatory polyps are present in the stomach and bowel, and abdominal pains with a severe protein-losing enteropathy are common.

Both ulcerative colitis and Crohn disease present with abdominal pain, gastrointestinal bleeding, or diarrhea. Ulcerative colitis predisposes to carcinoma of the colon. The skin complications of the two diseases are similar, although some occur with different frequencies. Up to one-half of patients with pyoderma gangrenosum may have inflammatory bowel disease, although only 12% of patients with ulcerative colitis and 2% of patients with Crohn disease will develop the condition (see Chapter 33).93 The severity and extent of ulceration in pyoderma gangrenosum may be linked to the activity of the underlying disease, and pyoderma gangrenosum can heal with effective treatment of the underlying bowel disease. Erythema nodosum is well recognized.

Oral granulomatous nodules are common in Crohn disease, where they may coalesce to give a “cobblestone” appearance. Crohn disease is one cause of granulomatous cheilitis, which may predate bowel disease by several years. Granulomas may also occur in the perineum, at colostomy and ileostomy sites, and in association with scars, sinuses, and fistulas. Very rarely, granulomas occur at sites not contiguous with the bowel, such as the trunk and limbs: the so-called “metastatic” cutaneous Crohn disease.94 Aphthous ulcers may be a presenting feature. Bruising of the skin around the umbilicus (Cullen sign) or in the flanks (Grey Turner sign) are well-known features of acute pancreatitis, but occur in less than 3% of cases.95 Chronic pancreatitis may cause tender, subcutaneous nodular areas of fat necrosis that may ulcerate (see Chapter 70).

Diarrhea and Malabsorption

(Box 150-5)

Gastric bypass surgery or reduction with jejunoileal and jejunocolic anastomoses is used to treat morbid obesity. Dryness of the skin, hair loss, recurrent fever, arthralgia, and inflammatory and vasculitic skin lesions have been reported post operatively. “Bowel bypass syndrome without bowel bypass” is recognized as the same constellation of symptoms, but with other gastrointestinal disorders.96

Cutaneous Effects of Malabsorption of Specific Nutrients

Vitamin deficiency can follow intestinal surgery, pancreatic disease, malabsorption syndromes, and malnutrition, including that associated with alcoholism (see Chapter 130).35

• Vitamin A deficiency causes xerotic wrinkled skin covered with fine scales, occasionally accompanied by deep erosions (dermomalacia).
• Deficiency of vitamin B3 causes pellagra with its triad of diarrhea, dermatitis, and dementia.
• Vitamin B12 (cyanocobalamin) deficiency is common in ileal malabsorption syndromes such as pancreatic disease. There is a symmetric “glove and stocking” hyperpigmentation, but a lemon yellow pallor to the skin elsewhere.
• Vitamin C deficiency classically causes follicular keratoses, hemorrhage, and corkscrew hairs.
• Malabsorption of vitamin K occurs in obstructive jaundice and leads to impaired coagulation, resulting in cutaneous hemorrhage with ecchymoses and purpura.
• A diffuse hyperpigmentation, cheilitis, and perineal ulceration or dermatitis can occur in folic acid deficiency states. Theoretically, drugs used for dermatologic diseases such as methotrexate, a folate antagonist, can exacerbate folic acid deficiency.
• Iron deficiency presents with angular stomatitis, smooth painful tongue, and fragile/brittle nails, which have longitudinal ridging and lamellation. In marked iron deficiency anemia koilonychia, a spoonlike convexity of the nails, develops. Hair changes include diffuse scalp alopecia with brittle, split hairs. All take a long time to resolve on replacement therapy.
• Zinc deficiency can result from acrodermatitis enteropathica, malabsorption, or a lack of zinc in long-term parenteral nutrition. Acrodermatitis enteropathica usually presents at weaning or in very early infancy with dermatitic or vesicobullous lesions of the hands, on the feet, and around the mouth and anus, together with progressive alopecia and “failure to thrive.”

Malabsorption Due to Skin Disease

Malabsorption can result from poor intestinal peristalsis in systemic sclerosis or chronic obliteration of mesenteric vessels in polyarteritis and other forms of vasculitis. In systemic sclerosis, 8% of patients develop malabsorption or recurrent intestinal pseudo-obstruction, usually within 3 years of disease onset.66,97 Vasculopathy interferes with peristalsis and leads to malabsorption by allowing bacterial colonization higher up the bowel than is usual.

Small bowel tumors produce a variety of hormones and vasoactive amines of which the best characterized is serotonin. The most common tumors are in the appendix, rectum, and ileum, where they are usually multiple. Episodic flushing, wheezing, or diarrhea does not occur until the vasoactive amines reach the systemic circulation. Therefore, flushing usually indicates metastasis to the lymph nodes or liver or a primary tumor at a different site (e.g., lung or ovary).98,99

The Hepatobiliary System

Skin lesions occurring in association with liver disease are usually not specific to a particular disease. The most florid cutaneous lesions appear in patients with chronic active hepatitis or alcoholic liver disease, but may also occur in physiologic states such as spider nevi in pregnant women. There may be no visible skin changes in patients with severe liver disease and, conversely, dramatic cutaneous manifestations may develop in those with minimal hepatic dysfunction.

Hepatitis and the Skin

Cutaneous striae may appear in patients with chronic hepatitis, whatever the underlying cause and even before glucocorticoid therapy (see Fig. 150-1). Pyoderma gangrenosum, urticaria, vasculitis, acne, scleroderma, and splinter nail hemorrhages occur, depending on the underlying cause of the hepatitis.

The clinical features of infection with the different hepatotrophic viruses that cause acute viral hepatitis are similar. In the preicteric phase, malaise, lethargy, nausea, and abdominal pain occur. A discrete, transient, maculopapular, urticarial, or petechial rash may develop, together with arthritis or arthralgia. These symptoms may worsen with the appearance of jaundice, dark urine, and pale stools. Malaise and fatigue may persist for some time after resolution of the disease.

Hepatitis A

Transmission of hepatitis A virus takes place via the fecal–oral route. Although relapses occur, hepatitis A does not progress to chronic hepatitis.

Hepatitis B

Hepatitis B virus (HBV) is transmitted by percutaneous and permucosal routes. It is endemic in many countries, and health care professionals are at risk. A recombinant DNA vaccine is available, but has been associated with cutaneous side effects.100–102 Five percent of HBV-infected subjects become carriers, and 90% of infants born of infected mothers develop chronic infection.

There are four main cutaneous associations of hepatitis B: (1) a serum sickness-like syndrome, (2) cryoglobulinemia, (3) polyarteritis nodosa, and (4) papular acrodermatitis of childhood. The serum sickness-like syndrome occurs in approximately 10% of patients in the preicteric phase of acute hepatitis B infection. Urticaria may be the predominant or sole feature, but is usually accompanied by a low-grade fever, arthralgia of the peripheral joints, proteinuria, and hematuria. There may be vasculitis.

Both HBV and hepatitis C virus (HCV) infection are associated with cryoglobulinemia although HCV infection is more common. Mixed cryoglobulinemia in HCV infection is usually of type III,103 and the cryoglobulinemia may indicate the presence of active viral replication.104 Patients develop recurrent purpura, acrocyanosis, arthralgia, lymphadenopathy, peripheral neuropathy, and hepatosplenomegaly. Renal involvement is common. Histopathologically, there is a necrotizing vasculitis (see Chapter 169).104

Polyarteritis nodosa can occur in the acute phase of HBV infection, or it may not present for several years. Circulating immune complexes containing hepatitis B surface antigen (HBsAg) and immunoglobulin occur. Leukocytoclastic vasculitis may develop.

Papular acrodermatitis (Gianotti–Crosti syndrome) (see Chapter 192) usually affects children. The appearance of monomorphic, flat-topped, erythematous papules on the face and limbs is characteristic. This eruption is self-limiting and asymptomatic in most, but may be accompanied by lymphadenopathy.105 Other infectious agents and immunizations have been implicated in papular acrodermatitis.106 Sweet syndrome has recently been reported with both acute107 and chronic HBV infection.

Hepatitis C

The majority of cases of posttransfusion hepatitis have been due to HCV infection, but screening has reduced the number of new cases dramatically. Cutaneous manifestations of acute and chronic HCV infection include leukocytoclastic vasculitis, usually due to cryoglobulinemia (see above); cutaneous necrosis104 pruritus108; acquired angioedema109 PCT; erythema nodosum; urticaria; erythema multiforme; and polyarteritis nodosa.110

Lichen planus occurs more commonly in patients infected with HCV,111 although studies disagree on the incidence.112 There is an increased frequency of the HLA-DR6 allele in Italian patients with HCV-associated oral lichen planus,113,114 suggesting that host factors may play a part in this association.

Treating psoriasis in patients with hepatits C poses particular problems, partly because systemic therapies for psoriasis may be more hazardous but also because interferon α, which is frequently used in such patients, may exacerbate psoriasis.115

Disorders of Both Skin and Liver

(Box 150-6)

Argininosuccinic aciduria is a rare autosomal recessive disorder characterized by ataxia, seizures, severe mental retardation, hepatomegaly with liver dysfunction, and brittle hair. Dermatomyositis may be the presenting sign of a primary116 or secondary hepatic tumour. In eruptive neonatal angiomatosis, multiple angiomas may occur anywhere on the skin surface; in addition, vascular lesions may occur in internal organs, including the liver. Both acute and chronic phases of graft-versus-host reactions may have prominent effects on both skin and liver, most commonly in patients receiving bone marrow transplants. In hereditary hemorrhagic telangiectasia, arteriovenous fistulas can cause shunting, and “cirrhosis” (i.e., multiple small telangiectatic hepatic vessels) occurs.67 Several of the histiocytoses, including Langerhans cell histiocytosis and malignant histiocytosis, may involve both skin and liver. Immunodeficiency states may result in multiple infections of skin and liver. Examples include congenital disorders (e.g., ataxia telangiectasia, Chediak–Higashi syndrome, chronic granulomatous disease) and acquired disorders (e.g., AIDS).

Hepatomegaly occurs in systemic mastocytosis.82–85 In Kawasaki disease, children may develop upper abdominal pain associated with hepatobiliary changes, nonspecific elevation of liver enzyme levels due to vasculitic changes, or bile duct inflammation.117 Sarcoidal infiltration of the liver may accompany the cutaneous signs of sarcoidosis. Hepatic granulomas may also occur in tuberculosis, glandular fever, and syphilis, or as a side effect of drugs such as phenylbutazone, allopurinol, and the sulfonamides. True syphilitic hepatitis is rare but may present with pruritus and cholestatic jaundice.

Patients with systemic lupus erythematosus can have abnormal liver tests.118 The most common cause is drug-induced hepatitis. Thrombotic conditions, including Budd–Chiari syndrome and veno-occlusive disease, occur with or without lupus anticoagulant. Rare abnormalities include nodular regenerative hyperplasia, perihepatitis, and hepatic or splenic rupture. Autoimmune hepatitis, PBC,119 granulomatous hepatitis, cryptococcal infection, porphyria, or idiopathic portal hypertension120 may also occur.

Cholestatic hepatitis occurs as a rare complication of Stevens–Johnson syndrome and has been reported to precede the skin signs.121

Angiomyolipomas are frequently seen on ultrasound examination of the livers of patients with tuberous sclerosis but are usually asymptomatic. Liver function abnormalities are common in patients with vinyl chloride disease and may be associated with hepatosplenomegaly, cirrhosis, and, rarely, angiosarcoma.

Cutaneous Manifestations of Primary Biliary Cirrhosis

The basis for a diagnosis of PBC is a clinical picture of a middle-aged female with jaundice and pruritus, cholestatic liver function tests, antimitochondrial antibodies, and histologic changes in the liver of inflammatory duct destruction with fibrosis and cirrhosis. Severe itching may antedate other features of biliary cirrhosis by months or years.

The combination of the CREST syndrome (calcinosis cutis, Raynaud phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia) and PBC occurs more often than would be expected by chance and has been termed Raynaud syndrome. Patients have a higher incidence of anticentromere antibodies (especially the antiprotein C isotype) and Sjögren syndrome.122

Lichen planus has a well-recognized association with PBC and may occur in either the presence or the absence of penicillamine treatment for PBC,123 and isolated nail involvement has been described.124 The skin lesions can resolve following liver transplantation.125 Cutaneous xanthomas also occur with PBC. Rarely, both lichenoid and xanthomatous changes appear in the same lesion.126

Effects of Skin Disease on the Liver

Several systemic complications occur as a consequence of skin disease, and some of them reflect abnormalities of hepatic function.

Extensive Loss of Skin

Patients may lose large areas of skin because of thermal burns, immunobullous disease, or toxic epidermal necrolysis. In experimental animal models, extensive thermal injury results in a halving of the hepatic arterial blood flow.127 Postburn sepsis amplifies this injury and induces portal hypertension.128 This may in turn account for a gut barrier dysfunction (the so-called “dermatogenic enteropathy”), but research has not convincingly demonstrated this relationship in humans with extensive skin disease.

Psoriasis

The high incidence of abnormalities of the liver architecture in patients with psoriasis has been attributed to alcohol misuse. Psoriasis is more common than expected in alcoholic cirrhosis than in cirrhosis due to other causes.8,129 Those who misuse alcohol are said to have a unique, acral, distribution of psoriasis.8 Alcohol appears not only to trigger psoriasis, especially in men, but also to influence the course of the disease, as heavy drinkers have more severe, extensive, inflamed disease. Patients who decrease alcohol consumption may decrease the extent of their disease and increase their response to treatment.129

Dermatitis Herpetiformis

Results of liver function tests are sometimes abnormal in patients with dermatitis herpetiformis130 and can also occur secondary to treatment or as a result of associated conditions.131

Skin Cancer

Primary cutaneous neoplasms, including melanoma, squamous cell carcinoma, Merkel cell tumor, and Kaposi sarcoma, occasionally metastasize to the liver.

Hepatotoxic Effects of Drugs Used in the Treatment of Skin Disease

Several drugs used in managing patients with skin disease are hepatotoxic (Table 150-1). Many others, such as antimalarials or terbinafine, warrant caution in patients with hepatic impairment.

Patients who have psoriasis and who are undergoing long-term treatment with methotrexate are at risk of liver fibrosis and cirrhosis, especially if their total doses exceed 1.5 g, and/or if there is a history of alcohol misuse, impaired renal function, diabetes, and obesity. The definitive diagnosis of fibrosis is histologic but the morbidity of liver biopsy can be as high as 10%, and the mortality up to 0.1%.133 Reducing the risk factors and careful monitoring probably reduces the need for invasive investigation considerably,132 especially if more sophisticated screening methods are used. In hepatic fibrosis, the synthesis of predominantly type III collagen is increased, and the amino-terminal propeptide of type III procollagen (PIIINP) is cleaved off and released into the circulation.134,135 Because it is now possible to measure serum PIIINP levels accurately, this test has become a valuable noninvasive marker of active hepatic fibrogenesis during methotrexate treatment of psoriasis.136 Thus, the number of liver biopsies taken in patients with normal serial serum PIIINP levels can be reduced to a minimum.137 Another technique that may prove useful is transient elastography, which has already been used for monitoring patients with Crohn disease.138 Some preliminary work in methotrexate-treated psoriatics has been reported,139 but further studies are required.140

The Renal System

The cutaneous manifestations of renal disease are primarily encountered in patients with CRF. In contrast, only two skin changes—edema and uremic frost—occur in acute renal failure (ARF). 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. It is now rare because of the wide availability of acute hemodialysis.

Calcification

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.141 Vascular calcification is 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 livedoid areas that are excruciatingly painful due to ischemia, and quickly become hemorrhagic and ulcerate (Fig. 150-13). Calciphylaxis is associated with a high mortality, particularly when the skin of the trunk is involved.141 PTH is usually markedly elevated. The serum calcium and phosphate levels, and the calcium-phosphate product, are frequently only minimally elevated and may be normal. Treatment of calciphylaxis includes analgesia debridement of gangrenous tissue, and parathyroidectomy.141,142

In addition to vascular calcification and calciphylaxis, nodular calcification may occur in the skin and fat of patients with CRF. These calcium deposits are identical to calcinosis cutis in other disorders, such as tumoral calcinosis or CREST syndrome. The involved skin may ulcerate, but this process occurs in a subacute fashion, without livedo or ischemic pain.

Bullous Disease of Hemodialysis

PCT has been described in patients with CRF undergoing hemodialysis.143 Although the etiology of this phenomenon is still unclear, inadequate clearance of plasma-bound porphyria precursors by urine excretion or hemodialysis144 may lead to porphyrin deposition in the skin manifested clinically as photosensitivity and subepidermal bullae.143–147 Patients undergoing hemodialysis may also produce or be exposed to compounds that alter normal heme synthesis.

Bullous dermatosis of dialysis or pseudoporphyria may occur in up to a fifth of patients undergoing hemodialysis.143,145,147 This condition is often clinically indistinguishable from PCT with marked skin fragility and blister formation on sun-exposed skin (see Chapter 132). However, hypertrichosis is less common, and plasma porphyrin levels are typically normal.143,145 Pseudoporphyria may also occur in some patients taking tetracycline, nabumetone, nalidixic acid, furosemide, and phenytoin.143

When treating PCT or pseudoporphyria, phlebotomy can reduce iron levels in the liver, allowing new hepatic uroporphyrinogen decarboxylase to be formed.148 However, patients with end-stage renal disease often have significant anemia and cannot tolerate phlebotomy. Intravenous erythropoietin147 may both lower total body iron stores and support phlebotomy as needed.146,148 Chloroquine effectively clears porphyrins from the liver. In patients with CRF, however, porphyrins may not be effectively cleared by hemodialysis or excreted in the urine.147 Deferoxamine may lower serum porphyrin levels in some patients.146 Others may require renal transplantation to obtain complete resolution of symptoms.146

Acquired Perforating Dermatoses

Acquired perforating dermatosis can occur in association with CRF and diabetes mellitus (see Chapter 69)149 This condition occurs in up to 10% of patients undergoing hemodialysis150,151 and appears to be distinct from the four primary perforating disorders elastosis perforans serpiginosa, Kyrle disease, perforating folliculitis, and reactive perforating collagenosis.152 Clinically, patients develop hyperkeratotic papules with a central crust-filled crater on the trunk and extensor surfaces, often in a linear distribution.150 Simultaneous transepidermal elimination of both collagen and elastic fibers has been detected.151

Proposed mechanisms for the etiology of this process include diabetic microangiopathy, dysregulation of vitamin A or vitamin D metabolism, abnormality of collagen or elastic fibers, or inflammation and connective tissue degradation caused by dermal deposition of substances such as uric acid and calcium pyrophosphate.153 Many authorities regard this entity as a response to trauma caused by scratching in chronic renal pruritus. Successful treatment depends on addressing the underlying etiology of pruritus. Topical and intralesional glucocorticoids, topical and systemic retinoids, cryotherapy, and ultraviolet light may be useful.150,151

Nephrogenic Fibrosing Dermopathy

Nephrogenic fibrosing dermopathy (NFD),154 resembling scleromyxedema in some of its aspects,155 largely occured in patients with end stage renal disease, most of whom were on hemodialysis. NFD also has been described in a few patients with ARF. Clinically, patients progressively develop erythematous, sclerotic dermal plaques on the arms and legs, with sparing of the head and neck. Pruritus is a common feature. The histopathology of NFD similarly resembles that of scleromyxedema, with proliferation of fibroblasts in the dermis and subcutaneous septae, accompanied by increased dermal and septal collagen and mucin.156 It is now clear that NFD is closely linked to the use of gadolinium contrast in magnetic resonance procedures.157

Lower Limbs

In acquired clotting defects, such as thrombocytopenia and vascular fragility, purpuric lesions, ranging from pinpoint-sized spots to large ecchymoses, occur. They may be transient and recurrent, and they are sometimes accompanied by follicular hyperkeratosis.3

Cholesterol Emboli

In patients with advanced atherosclerosis of the abdominal aorta, cholesterol crystals may microembolize to the lower extremities, particularly after invasive vascular procedures or surgery (see Chapter 173). The pulses may remain normal. Patients complain of pain in the legs, buttocks, and low back, as well as myalgia, restless legs, and abdominal symptoms. Livedo reticularis may affect the lower abdomen and back, buttocks, and legs. Ulcers on the legs and feet, surrounded by an erythematous or violaceous halo and a small scab, may be present. Digital cyanosis and gangrene may simulate necrotizing vasculitis (Fig. 150-14). Indurated plaques and nodules are firm, violaceous, painful, and necrotic in the center. Deep skin biopsy of areas of livedo reticularis or adjacent to nodules or ulceration reveal occlusions of arterioles by multinucleated foreign-body giant cells and fibrosis surrounding biconvex, needle-shaped clefts corresponding to the cholesterol crystal microemboli.158

Postbypass Skin Changes

Coronary artery bypass surgery is commonly performed using the superficial veins of the legs as donor-graft sites. Dermatitis has been reported to occur along the saphenous vein graft scars on the medial aspect of the legs 2–6 months after surgery. Patients have no history of venous stasis, thrombophlebitis, ankle edema, or skin disease. Examination reveals a reddish-brown, scaling and fissured dermatitis along the distal part of a well-healed saphenous vein graft scar. The dermatitis responds to topical steroids but recurrence is usual and most patients require continued treatment. The cause may be due to postoperative thrombophlebitis and stasis dermatitis.

Recurrent cellulitis may develop in the healed vein graft many months after surgery. Erythema may extend along the entire vein graft site, accompanied by pain and tenderness. Swelling may be significant. Beta-hemolytic streptococcus has been isolated. The presence of tinea pedis has been reported and patients should be assessed and treated prior to surgery.