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DERMATOLOGIC MANIFESTATIONS OF GASTROINTESTINAL DISORDERS
GASTRONTESTINAL DISORDERS AND SYSTEMIC DISEASE, PART I
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DERMATOLOGIC MANIFESTATIONS OF GASTROINTESTINAL DISORDERS Sara K. Ward, MD, Henry H. Roenigk, MD, and Kenneth B. Gordon, MD
Many disorders of the gastrointestinal tract have cutaneaous manifestations. Thus, a careful examination of the skin may uncover clues to underlying diseases of the liver, gastrointestinal tract, and pancreas. This article explores the alimentary-cutaneous relationship. LIVER DISEASE Viral Hepatitis Hepatitis A Virus Infection
Cutaneous involvement from hepatitis A virus infection is a rare occurrence. Jaundice is the main cutaneous manifestation in more fulminant cases of hepatitis A virus infection. There are a limited number of cases of cryoglobulinemia and associated vasculitis in the literature. The reported cases are in patients with the persistent forms of infection with cholestasis.m
From the Department of Dermatology, Northwestern University Medical School (HHR, KBG); Department of Dermatology, Northwestern Community Medical Group (SKW); Section of Dermatology, Chicago Veterans Administration Medical Center, Lakeside Division (KBG), Chicago, Illinois; and Arizona Advanced Dermatology (HHR), Phoenix, Arizona GASTROENTEROLOGY CLINICS OF NORTH AMERICA
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Hepatitis B Virus Infection
The cutaneous manifestations of hepatitis B virus infection (HBV) can mainly be attributed to the immune response to the infection. In the prodromal phase of the illness, the patient may suffer from a serum sickness-like illness with arthralgias and polyarthritis along with an urticarial-type rash with wheals that persist for less than 24 hours. High titers of circulating antibodies to the virus can lead to a vasculitis. Patients may develop a necrotizing vasculitis, which can be systemic or limited to the skin.56An association between HBV and polyarteritis nodosa has been well established?* Clinically, these patients present with fever, malaise, and arthralgias. Less frequent symptoms include abdominal pain from a mesenteric vasculitis, mononeuritis multiplex from vasculitis of the vaso-nervorum, and nephritis. The skin shows socalled palpable purpura, nonblanching purple nodules that usually first develop on the lower legs or other dependent areas and spread centrally (Fig. 1). The usual treatment of vasculitis, including immunosuppressive drugs, can lead to a worsening of the underlying hepatitis. Another form of immune complex disease associated with HBV infection is cryoglobulinemia. The presence of cryoglobulins in the blood of patients with persistent HBV has been estimated as high as 15%.The cryoprecipitate is primarily of the mixed form. The symptoms are similar to those of polyarteritis nodosa with fever, malaise, arthritis, glomerulonephritis, and palpable purpura. These symptoms are frequently associated with Raynaud’s phenomenon and may be exacerbated by the cold. Nonvasculitic cutaneous eruptions associated with HBV include erythema multiforme, pyoderma gangrenosum, and erythema nodosum. Another cutaneous eruption that was first reported in conjunction with HBV is papular acrodermatitis of childhood, or Gianotti-Crosti syndrome. This eruption is characterized by asymptomatic erythematous papules and nodules that develop on the face and extremities (Fig. 2).
Figure 1. Cutaneous vasculitis. Palpable, violaceous nodules occurring on the hand in this case.
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Figure 2. Papular acroderrnatitis of childhood (Gianotti-Crosti syndrome). Erythernatous papules and nodules on the extremities, sparing the trunk.
Typically, there is sparing of the trunk, which can help to distinguish this syndrome from other viral exanthems or drug eruptions. The course is benign with clearing typically in about 3 weeks. In recent years, this eruption has been associated with viral syndromes other than HBV. Hepatitis C Infection
Hepatitis C infection (HVC) has among the most unusual and interesting cutaneous responses of any systemic infection. Similar to HBV, HCV has been associated with cryoglobulinemia, primarily of the mixed (type I1 or 111) forms.' HCV RNA can be found by polymerase chain reaction in the serum of up to 85% of patients with mixed cryoglobulinemia and in 90% of their cryoprecipitates. Some authors suggest that HCV may be the leading cause of essential mixed cryoglobulinemia, and infection with HCV should be evaluated in all patients presenting with this ~yndrome.~ Polyarteritis nodosa is also noted in patients with HCV, although not as frequently as in patients with HBV. Antibodies to HCV have been noted in 5% to 20% of patients with polyarteritis nodosa, although there have been reports of false-postitive anti-HCV antibodies in these patient^.'^
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Lichen planus is a cutaneous eruption of pruritic, violaceous, polygonal, scaly papules and nodules along with ulceration and reticular lesions on the mucous membranes. Although the cutaneous lesions have a predilection for the flexor surfaces of the extremities, they may occur anywhere on the body. Lichen planus has been associated with a number of liver diseases, including primary biliary cirrhosis. The prevalence of HCV antibodies in patients is higher than in the general population. The absolute prevalence varies from 4% to 38% based on where the study is done.16,33, 41 The eruption is likely a reaction to the chronic inflammatory process in these diseases. In fact, immunotherapy with interferon-a can exacerbate lichen planus or even induce the lesions as well as cause their impr~vernent.~~ An absolute relationship between the immune response to HCV and lichen planus, however, has not been established. Treatment of lichen planus is primarily potent topical steroids or systemic steroids. Dapsone and psoralen and ultraviolet A (PUVA) therapy has been reported to be of benefit in lichen planus, even for mucous membrane lesions. Porphyria cutanea tarda is a rare disorder of porphyrin metabolism resulting in the accumulation of heme precursors in the skin. The functional abnormality is in the enzyme uroporphyrinogen decarboxylase. This abnormality can be hereditary, inherited as an autosomal recessive trait, or acquired, usually in conjunction with liver disease. Extrinsic factors, most often alcohol or estrogens, are generally needed to induce the clinical manifestations of disease. These clinical findings are related to sun exposure and include bullae and milia on the dorsal surface of the hands and hyperpigmentation and hypertrichosis on the face. A number of studies have shown a high incidence of anti-HCV antibodies in patients with porphyria cutanea tarda with infection rates as high as 95% in some pop~lations.~, 23, 26 Lending credence to a causal relationship of HCV for porphyria cutanea tarda is that in some cases treatment with intereferon-a has not only improved the clinical lesions, but has also made porphyrins undetectable in the urine.” Other than treating the underlying hepatitis, porphyria cutanea tarda can be treated with phlebotomy or chelating agents. In alcohol-related porphyria cutanea tarda, the disease often remits when the offending agent is withdrawn. Finally, therapy for HCV with recombinant interferon-a can induce cutaneous changes. The most striking of these changes is cutaneous necrosis at the site of interferon injection. These patients develop ulcers and necrosis and necrobiosis of the Also, patients receiving interferon treatment for HCV can develop worsening of inflammatory skin condition^.^^ Inclusive in these conditions are ps0riasis,2~sarcoidosis,15 and contact dermatitis (personal observation of one of the authors [KBGI). Cholestatic Liver Disease
Pruritus Among the most debilitating symptoms of hepatic failure is severe pruritus. Patients with acute or chronic cholestasis retain a number of
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chemicals that are normally secreted in the bile. These substances include bilirubin, bile acids, and cholesterol. Of these, the most commonly discussed cause of the pruritus of cholestasis is the retention of bile acids, which can act as hepatotoxins,70 although a direct correlation between blood or tissue levels of bile acids and pruritus has not been made.30 Other theories include cholestasis leading to increased levels of a centrally acting opioid agonist causing the sensation of pruritus6 Because the pathogenesis of cholestatic pruritus is still unknown, therapy is empiric. Much of the therapy for the pruritus of hepatic failure is directed toward reducing the amount of circulating bile salts and antagonizing opioid receptors. Bile acid-sequestering agents, such as cholestyramine and cholestipol, have been shown to be moderately efficacious and are usually the first line of therapy.14 These medications might work through a mechanism independent of bile acids because therapy with these agents has also been shown to be beneficial in the treatment of the pruritus of polycythemia Vera or uremia. Patient compliance is often limited because of gastrointestinal discomfort. Ursodeoxycholate is a bile acid with less inherent toxicity than the naturally synthesized bile acids in the human liver. Treatment with this compound can lower the circulating levels of the primary bile acids and reduce Similar to the bile acid sequestrants, the improvement with ursodeoxycholate is usually not complete. A well-controlled trial with the opioid antagonist naloxone showed significant benefit, lending credence to the theory that the pruritus might be of central rigi in.^ A small trial has found that the centally acting 5-hydroxytryptamine receptor antagonist ondansetron also may have some efficacy in the treatment of cholestatic pruritus.72Dilution of a possible circulating toxin responsible for pruritus with plasma infusion has also been reported to be successful.76Finally, some patients may benefit from treatment with ultraviolet light with either short wavelength (ultraviolet B) or long wavelength with the addition of a photosensitizing agent (PUVA). Pigmentary Changes
Jaundice. Jaundice refers to the yellowish discoloration of the skin and mucous membranes that accompanies the accumulation of bilirubin or its metabolites in the skin. In the case of liver disease, the bilirubin typically accumulates as a result of impaired excretion of bilirubin by the liver and is primarily of the conjugated or direct form. There is no absolute bilirubin level at which jaundice is always evident, but generally bilirubin levels greater than 2.5 mg/dL result in a clinically apparent alteration in skin color. The skin color itself can vary from light yellow to dark green depending on the bilirubin level and the patient's own skin color. Hyperbilirubinemia can develop with almost any class of liver disease, including infections, biliary obstruction, or primary enzymatic deficiencies of the liver such as Gilbert's or Crigler-Najjar syndromes. Although the deposition of bilirubin is in itself harmless, it usually indicates an underlying abnormality that does require treatment. Jaun-
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dice normally subsides with the appropriate therapy for the underlying pathologic process. Hypermelanosis. Patients with long-standing cirrhosis or with hemochromatosis, a hereditary abnormality resulting in iron overload, develop a grayish pigmentation that can be diffuse, patchy, or limited to the rnu~osa.'~ These changes are likely due to an increase in the melanin content of the skin in giant melano~omes.5~ The cause of this finding is unknown. A likely connection between pigmentation and iron in the skin could account for the increased melanin in patients with conditions that can result in iron overload.60Other theories include an endocrinologic effect via adrenocorticotropic hormone (ACTH) or melanocytestimulating hormonemor by the deposition of hemosiderin in the skin. Liver Dysfunction Vascular Changes
The cutaneous vasculature is also frequently affected by acute and especially chronic liver disease. The most recognized vascular lesions are spider angiomas (Fig. 3). Clinically, these lesions most often occur on the face, upper tmnk, and distal upper extremities. They are formed by a central vessel surrounded by branching small vessels. Compression of the central punctum results in blanching of the entire lesion. The spider angiomas can be treated with fine cautery or pulse dye laser. Palmar erythema is another clinical sign associated with liver disease. Palmar erythema may present clinically as increased mottling of the
Figure 3. Spider angiomas. A central vessel is surrounded by branching small vessels.
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hands or discrete erythematous patches on the thenar or hypothenar eminences. Both of these lesions have been associated with faulty metabolism of estrogens by a diseased liver. This theory would account for their development during pregnancy. Spider angiomas and palmar erythema, however, may also develop in patients devoid of liver disease or estrogen therapy, particularly in alcoholics without liver disease, and in patients with chronic inflammatory diseases. Thus, the true pathogenesis of these vascular abnormalities remains uncertain. Nail Changes
Alterations in the normal appearance of the fingernails and toenails can be an important tool in the diagnosis of liver disease. These changes are often overlooked and do not always suggest a specific underlying disease. Hepatolenticular degeneration (Wilson’s disease) is an abnormality in copper metabolism that leads to hepatic necrosis and central nervous system abnormalities. The most prominent cutaneous abnormality associated with this condition is azure lunulae, a bluish discoloration of the white half-moon at the proximal portion of the nail bed. The discoloration is limited to the lunula, differentiating the nails of hepatolenticular degeneration from diseases in which the entire nail bed can look blue. These conditions include argyria, pseudomonal infections, and in patients taking antimalarial medications. Terry’s nails are clinically defined as a whitish discoloration of the nail with accentuation of the distal pink portion of the nail plate just proximal to the free end of the nail. This distal line is termed the onychodermal band.76 Initially, this finding was thought to be suggestive of cirrhosis, mainly primary biliary cirrhosis. More recent findings, however, have noted Terry’s nails in about 25% of all hospitalized patients with or without liver disease.39Other nonspecific nail changes associated with hepatic diseases include clubbing with primary biliary cirrhosis and chronic active hepatitis, double white transverse lines (Muehrcke’s lines) in hepatic failure, and splinter hemorrhages in he pa ti ti^.'^ GASTROINTESTINAL HEMORRHAGE Hereditary Hemorrhagic Telangiectasia (Osler-WeberRendu Disease) Hereditary hemorrhagic telangiectasia is an autosomal dominant disorder characterized by vascular dilations of the skin and the oral, nasal, and gastrointestinal mucosa. Vascular malformations may also involve the lung, central nervous system, or retina. Recurrent epistaxis caused by spontaneous bleeding from nasal mucosa telangiectasias is the most common presentation of this disease, occurring in 80% of patients.67The skin lesions may not appear until adult life and consist
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of small macular telangiectasias, which often increase in number and size with age.62The telangiectasias occur on the lips, tongue, palate, face, ears, nares, conjunctiva, chest, hands, and feet (Fig. 4). Recurrent gastrointestinal bleeding is painless and occurs from vascular malformations throughout the gastrointestinal tract. The bleeding is chronic, periodic, and progressive, often leading to considerable blood Sites of bleeding may be visualized by endoscopy in the stomach, duodenum, small bowel, or colon. Angiography may identify large arteriovenous malformations. Treatments include iron supplementation, surgical resection of involved bowel (difficult given the degree of the gastrointestinal tract involved), endoscopic techniques, and estrogen or estrogen and progesterone therapy." Blue Rubber Bleb Nevus Syndrome
Blue rubber bleb nevus syndrome is a rare disorder characterized by large cutaneous hemangiomas and gastrointestinal bleeding from vascular malformations. It is usually identified at birth or early childhood but has been noted to present in adulthood.35,58 Three types of skin lesions have been described, which, in contrast to classic hemangiomas, do not regress ~pontaneously.~~ The most characteristic cutaneous lesion is the blue rubber nipple, described as a soft, rubbery, compressible nodule, which, after being compressed, leaves an empty bluish sac that swiftly refills with blood. The second type are tender, irregular, blue-black, punctate macules distributed on the extremities and trunk. The third type consists of large disfiguring hemangiomas 49 that may interfere with vital limb or organ
Figure 4. Osler-Weber-Rendu disease. Many discrete macular telangiectasias occuring on the lower lip.
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The gastrointestinal vascular malformations are most often found in the small intestine or colon. Gastrointestinal bleeding may be frank melena but is most often detected as occult blood in the 49 Therapy is mainly symptomatic, including blood transfusions and iron supplementation for anemia, surgery or endoscopy to control gastrointestinal bleeding, and laser or surgical removal of cutaneous hemangiomas. Kaposi’s Sarcoma Kaposi’s sarcoma is a neoplasm of vascular endothelium and pericapillary cells that often presents on the skin and may involve other visceral organs, including the gastrointestinal tract. The epidemic form of Kaposi’s sarcoma, the most common form in North America, is associated with the human immunodeficiency virus (HIV).36The gastrointestinal tract is involved in 50% to 80% of those with the cutaneous lesions and in nearly 100% of those with oral lesion^.^^,^^ Gastrointestinal tract involvement is most common in the male homosexual population with the epidemic form of the disease.49Classic Kaposi’s sarcoma primarily occurs in elderly men of Eastern European or Mediterranean origin and typically has an indolent course. Iatrogenic Kaposi’s sarcoma occurs in patients receiving immunosuppressive therapy. Herpesvirus type 8 has been found in all forms of Kaposi’s sarcoma and is thought 57 to be involved in the pathogenesis of Kaposi’s sarcoma.46, The cutaneous lesion is a red-purple macule, which, as it enlarges, becomes a deeper violet papule or plaque (Fig. 5). The lesions are usually multiple and can occur anywhere on the skin, with a propensity for the legs and feet in the classic non-HIV form. The cutaneous lesions are more likely to be disseminated over the trunk and face in acquired immunodeficiency syndrome (AIDS)-related Kaposi’s sarcoma. The gastrointestinal tract may be involved in any area, and gastrointestinal bleeding may lead to death. Epidemic AIDS-related Kaposi’s sarcoma portends a poor prognosis with a fatal outcome within 2 years.35Treatment of Kaposi’s sarcoma is mainly palliative. Therapy of localized cutaneous lesions includes excision, radiation therapy, or intralesional therapy with vinblastine or interferon a. More widespread disease requires treatment with systemic antineoplastic chemotherapy or interferon alfa. Pseudoxanthoma Elasticum Pseudoxanthoma elasticum is a genetic disorder of elastic fibers that become calcified and weakened. It is characterized by specific skin lesions, angioid streaks and other degenerative changes of the retina, and widespread vascular calcification leading to gastrointestinal bleeding, premature myocardial infarction, cerebrovascular disease, peripheral
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Figure 5. Kaposi's sarcoma. Violaceous plaques and nodules on the foot.
vascular disease, and hypertension." Four major types have been described: type I dominant and recessive and type I1 dominant and recessive. Type I recessive is the classic form of the disease displaying the typical skin findings and a high incidence of gastrointestinal di~ease.3~ The skin findings are distinctive: small, yellow papules coalescing to form plaques with a pZuckd chicken or cobblestone appearance distributed in the flexural areas, including neck and axilla. In addition, generalized laxity of the face, neck, and trunk may be found." Gastrointestinal bleeding occurs early in the course of the disease, is recurrent and severe, and usually originates from the upper gastrointestinal tract, although lower gastrointestinal tract bleeding may occur.35,49 Endoscopy may reveal the characteristic yellow cobblestonelike lesions similar to those occurring in the mouth and skin." There is no effective therapy, and the prognosis is poor, with death occurring from premature cardiovascular disease." Ehlers-Danlos Syndrome
Ehlers-Danlos syndrome is a group of inherited disorders of collagen. The characteristic findings include fragility of the skin and blood
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vessels, hyperextensibility of joints, and hyperelasticity of the skin. Type IV Ehlers-Danlos syndrome, the ecchymotic type, is most closely associated with gastrointestinal hem0rrhage.4~There is no effective therapy, and patients have a poor prognosis, with rupture of major blood vessels and hemorrhage of internal organs as the main causes of death. Malignant Atrophic Papulosis (Degos’ Disease) Malignant atrophic papulosis (Degos’ disease) is a rare disorder of young adults affecting the skin, gastrointestinal tract, and central nervous system. The characteristic skin lesions are asymptomatic multiple papules with atrophic, white scarlike centers surrounded by an erythematous border (Fig. 6). The skin lesions often precede the development of infarcts involving the gastrointestinal and central nervous systems. Gastrointestinal infarctions may cause gastrointestinal bleeding or perforation. With systemic involvement, the prognosis is poor with death occurring within a few years from intestinal or central nervous system infarctions. There have been reports of patients with only cutaneous involvement who have not developed systemic involvement, suggesting a benign form of the disease. Although Degos’ disease is not regarded as a genetic disorder, there have been reports of familial clustering of the disease.45
Figure 6. Malignant atrophic papulosis (Degos’ disease). Papules with porcelain white, scar-like centers surrounded by a border.
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GASTROINTESTINAL POLYPOSIS Gardner’s Syndrome
Gardner’s syndrome refers to the clinical triad of adenomatous polyps of the gastrointestinal tract with a high risk of malignant transformation, epidermal cysts, and desmoid tumors. This is an autosomal dominant disease with high penetrance and variable expressivity. Patients with this disorder are thought to have a lifetime risk of adenocarcinoma of the colon of loo%.= The adenomatous polyps are multiple, usually greater than 100; occur in any part of the colon; have a diameter larger than 1 cm; and have an average age of onset of 22 years.1° In one study, rectal polyps were found in all patient^.^ Thus, sigmoidoscopy allows screening of the disease. Adenomatous polyps also may be found in the small intestine, duodenum, stomach, or gallbladder. Acute pancreatitis has been reported secondary to obstruction of the pancreatic duct by polyps.8Most patients develop colon cancer between the ages of 20 and 30 if not treated. The most common treatment is prophylactic colectomy with ileorectal anastomosis, but patients require close follow-up given the risk of rectal cancer of the remaining rectal mucosa.54 The skin and bone lesions occur before the intestinal polyps and may predate the polps by as many as 10 years. Epidermal cysts are multiple; appear before puberty; and are located predominantly on the extremities, face, and scalp. Desmoid tumors occur in young patients, have a female predominance, are locally aggressive, and do not metastasize but can lead to deathFs Osteomas also occur in Gardner’s syndrome; they are benign tumors that occur on the mandible and maxilla. Gardner’s syndrome also has an association with fibromas, lipomas, dental abnormalities, pigmented ocular fundal lesions, brain tumors, and endocrine tumors.28 Peutz-Jeghers Syndrome
Peutz-Jeghers syndrome describes hamartomatous polyps occurring mainly in the small intestine in association with mucocutaneous hyperpigmented macules, gonadal tumors, and breast cancer.= Gastrointestinal bleeding or intussusception with obstruction, abdominal pain, or rectal prolapse may be presentations of this syndrome. The intestinal hamartomas are usually pedunculated and most commonly found in the jejunum but may also occur in the ileum, stomach, duodenum, and Because the histology of the hamartomas may imply malignancy, the risk of malignancy has been overestimated in the past. Although the hamartomatous polyps have a lower malignant potential than adenomatous polyps, evidence implies an increased risk of gastrointestinal carcinoma in addition to an increased risk of malignancy in general in this syndrome.31,47, 73 Gastrointestinal carcinoma occurs in 2% to 3% of pa-
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tients, and there is also an increased incidence of breast, ovarian, and testicular car~inornas.~~ Treatment is usually conservative, with endoscopic removal for symptomatic or large polyps. Small dark freckles are found most commonly on the lips and buccal mucosa but also occur on distal fingers and toes and periorificially (Fig. 7). With age, the nonspecific mucosal pigmentation persists, whereas the other characteristic and more apparent cutaneous freckles tend to fade. There is no relationship between the extent or location of the pigmentation and the extent of the polyps. The mouth pigmentation has been treated with ruby and argon lasers.59 Canada-Cronkhite Syndrome
Canada-Cronkhite syndrome is a rare, acquired disease of adulthood characterized by inflammatory polyps, cutaneous hyperpigmentation, patchy alopecia, and nail changes. There is a protein-losing enteropathy with presenting symptoms including chronic diarrhea, abdominal pain, anorexia, and wasting. Although the polyps are hamartomatous, as in Peutz-Jeghers syndrome, malignant degeneration of the polyps has been described.20 The cutaneous triad, which consists of hyperpigmentation, alopecia, and nail changes, is found in most patients. The alopecia is rapidly
Figure 7. Puetz-Jeghers syndrome. Multiple dark brown freckles on the lips and gingiva.
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progressive, initially patchy and leading to complete hair loss. Extensive hyperpigmented macules and plaques are distributed diffusely but most commonly occur on the hands and arms and may be reversible. The nail dystrophy involves all fingernails and toenails, with changes including onycholysis (separation of the nail plate from the nail bed) and a unique pattern of an inverted triangle of normal nail bordered by dystrophic nail.17.21.26 Therapy is mainly supportive with fluid, electrolytes, and nutrition. There have been reports of favorable responses to systemic steroids with resolution of both gastrointestinal symptoms and polyps.", Neurofibromatosis Neurofibromatosis is an autosomal dominantly inherited disease with cutaneous manifestations, including many caf6-au-lait macules, multiple neurofibromas, and axillary freckling (Fig. 8). Gastrointestinal tumors, usually neurofibromas, have been said to occur in 25% of patients with neurofibromatosis.22The gastrointestinal neurofibromas are generally asymptomatic, but there may be abdominal pain, gastrointestinal bleeding, obstruction, or intussusception. Malignant transformation may rarely occur in the neurofibromas of the gastrointestinal tract as well as the skin. Cowden's Disease (Multiple Hamartoma Syndrome) Cowden's disease is an autosomal dominant disorder with variable expression. It is characterized by certain mucocutaneous lesions, gastrointestinal tract polyps, and an increased risk of internal malignancies.
Figure 8. Neurofibromatosis. Characteristic flesh-colored, soft papules or nodules (i.e., neurofibromas) on the trunk.
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The skin findings are often the presenting evidence of the disease. The mucocutaneous manifestations include facial trichilemmomas (fleshcolored, flat-topped or elongated verrucous papules in a periorificial and centrofacial distribution), oral papillomatosis (small, smooth, fleshcolored papules on labial, gingival, or palatal surfaces resulting in a cobblestone appearance), Cowden’s fibromas (firm, white papules or nodules involving the face, scalp, or hands), acral keratoses (flesh-colored, flat-topped smooth or rough papules on dorsa of hands and feet that may resemble common warts), and palmoplantar keratoses (firm 34 Less common skin findings include lipomas, hyperkeratotic papules).28, hemangiomas, scrota1 tongue, and n e ~ r o m a s . ~ ~ Hamartomatous gastrointestinal polyps are found in one third of 74 The patients with Cowden’s disease and are usually a~ymptomatic.~~, polyps have a predilection for the rectosigmoid area, and they do not appear to be premalignant.12 Recognition of Cowden’s disease is important because of the associated malignancies. This syndrome is associated with an increased risk of breast, endometrial, and thyroid cancers. The incidence of fibrocystic disease of the breast and thyroid disease (goiter and adenomas) is also increased in this syndrome. Management includes close follow-up for detection of carcinoma, genetic counseling, and screening of family members. Muir-Torre Syndrome Muir-Torre syndrome describes multiple sebaceous neoplasms associated with internal malignancy, including adenocarcinoma of the gastrointestinal tract. Adenomatous colonic polyps occur with an increased frequency, but they are not a constant or defining feature of this syndrome. Muir-Torre syndrome is inherited as an autosomal dominant disorder and is caused by a germline mutation in a DNA mismatch repair gene.25This syndrome may share a common genetic basis with the Lynch I1 cancer family syndrome.37The visceral carcinomas are often multiple. Colorectal carcinoma is the most common internal cancer and usually arises in the presence of the adenomatous polyps. The incidence of genitourinary carcinoma is also increased in this syndrome. Both the internal and sebaceous malignancies are less aggressive than those malignancies not associated with the syndrome; thus, Muir-Torre syndrome portends a better prognosis than expected given the multiple car~inornas.~~ Multiple sebaceous adenomas occur on the head, neck, and trunk .~ cutaneous neoplasms that have in patients in their 40s and ~ O S Other been reported include sebaceous epithelioma, sebaceous carcinoma, keratoacanthomas (rapidly growing benign epithelial neoplasm), squamous cell carcinoma, epidermal cysts, and basal cell carcinoma with sebaceous 71 Sebaceous adenomas appear to be the most common differentiati~n.~~, and specific lesion for the diagnosis of the syndrome. Sebaceous hyper-
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plasia (proliferation of sebaceous glands appearing as yellowish papules frequently found on the face of elderly people) is not associated with this syndrome. Multiple sebaceous tumors represent a marker for internal malignancy and may warrant a search for occult malignancy in the patient and the patient’s family. Acrochordons
Several studies have attempted to determine an association between acrochordons (skin tags) and colonic 66 Because acrochordons are frequently found in the general population, this association is difficult to make. Given the potential for malignant degeneration of colonic adenomatous polyps, identifymg a cutaneous marker for colonic polyps would be beneficial. Currently, this issue remains unsettled, and further research is needed. Colonoscopy is not warranted for asymptomatic patients with multiple skin tags. GASTROINTESTINALCANCER Cutaneous Metastatic Disease
Cutaneous metastatic disease from gastrointestinal tract neoplasms is most often found on abdominal skin or scalp. Metastatic cancer to the skin is characterized by one or more firm, indurated, and often ulcerated nodules or plaques (Fig. 9). Sister Mary Joseph’s nodule describes firm, indurated nodules in the umbilicus, which is a sign of metastatic disease. Adenocarcinoma of the gastrointestinal tract, most commonly stomach,
Figure 9. Metastatic cancer to the skin. Firm, indurated plaques and nodules.
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is the most common primary site. Most patients die within months of the appearance of the umbilical nodule.65 Acanthosis Nigricans
Acanthosis nigricans is characterized by velvety hyperpigmentation of axillae and other body folds (Fig. 10). It can occur in various clinical settings, including benign hereditary forms, endocrinopathies, obesity, and paraneoplastic conditions. When acanthosis nigricans is associated with malignancy, two thirds of the time the tumor is gastric. Acanthosis nigricans may regress after removal of the rnalignan~y.~~ Sign of Leser-Trelat
Leser-Trklat sign describes the sudden appearance of seborrheic keratoses (common benign s tuck-on-appearing discrete papules or plaques) associated with internal malignancy. Some regard this as a variant of acanthosis nigricans. Multiple seborrheic keratoses are common in many elderly patients and may not be an indicator of internal malignancy. Tylosis Palmaris et Plantaris
Tylosis palmaris et plantaris describes a familial association of punctate keratoses of the palms and soles with esophageal carcinoma.
Figure 10. Acanthosis nigricans. Velvety hyperpigmentation of axillae.
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Carcinoid Syndrome
Carcinoid syndrome is caused by tumors producing vasoactive substances, including serotonin, kallikrein, and histamine. The clinical manifestations include paroxysms of flushing, wheezing, diarrhea, abdominal pain, and often hypotension. Although the appendix and small bowel are the most common locations for carcinoid tumor, symptomatic carcinoid syndrome usually indicates metastasis to locations allowing the vasoactive substances to reach the circulation. Diagnosis is made by detecting 5-hydroxyindoleacetic acid in the urine. Symptoms improve with removal of the tumor.
Glucogonoma Syndrome
Glucogonoma, a tumor of the pancreatic alpha cell, is associated with necrolytic migratory erythema in a syndrome called glucogonoma syndrome. Necrolytic migratory erythema is a distinctive eruption characterized by recurrent cycles of erythema followed by blisters, erosions, crusting, and scaling on the lower abdomen, groin, and buttocks. Other cutaneous manifestations of glucagonoma syndrome include angular cheilitis and painful glossitis. The clinical syndrome also includes glucose intolerance, anemia, diarrhea, weight loss, venous thromboses, and psychiatric disturbances. Elevated plasma glucagon levels may aid in the diagnosis. Removal of the tumor is associated with improvement of the cutaneous lesions.
INFLAMMATORY BOWEL DISEASE: ULCERATIVE COLITIS AND CROHN’S DISEASE
Cutaneous findings are common in both ulcerative colitis and Crohn’s disease. Fissures and fistulas are, although not specific, the most frequent cutaneous manifestations, occurring mainly in Crohn’s disease.35They most commonly occur on the perianal skin, but they can also be found in the region of stomas or on the abdominal wall. The perianal fissures are usually multiple and may lead to ulcers or abs c e ~ s e sCrohn’s .~~ disease may also affect the oral mucosa, as represented by a cobblestone pattern, ulcerations, and nodules. Metastatic Crohn’s disease describes nodules, plaques, or ulcerated lesions that are histopathologically identical to Crohn’s disease. They may be located on any area of the skin and are often correlated with disease activity.”, 35 Erythema nodosum, aphthous stomatitis, and pyoderma gangrenosum represent some of the cutaneous lesions observed in association with Crohn’s disease and ulcerative colitis.
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Erythema Nodosum
Erythema nodosum presents as tender red nodules on the anterior aspects of the legs. It may occur at any point in the course of inflammatory bowel disease or may be associated with a flare of enteric disease.35 Treatment consists of controlling the bowel disease, bed rest, nonsteroidal anti-inflammatory drugs, corticosteroids, potassium iodide, dapsone, or colchicine. Oral Aphthous Ulcers
Oral aphthous ulcers have been recognized in association with inflammatory bowl disease and reflect disease activity. These lesions are nonspecific and cannot be distinguished clinically or histologically from common aphthous ulcers.35 Pyoderma Gangrenosum
Pyoderma gangrenosum has been observed in association with Crohn‘s disease and ulcerative colitis. This lesion usually begins as a hemorrhagic pustule or papule after minimal trauma and rapidly evolves into a purulent, painful, necrotic ulcer with dusky undermined borders. Lesions are sterile and heal with scarring. Pyoderma gangrenosum may occur without an associated underlying disease, or it may be associated with various systemic diseases, including inflammatory bowel disease, arthritis, and hematologic disorders. It has been estimated that 50% of patients with pyoderma gangrenosum have ulcerative colitis.34 The relationship between the activity of pyoderma gangrenosum seems to be correlated with the underlying inflammatory bowel disease; however, the courses of the two diseases may also be independent. Therapy should be directed at controlling not only the pyoderma gangrenosum, but also the inflammatory bowel disease. Treatment of pyoderma gangrenosum includes topical therapy, which is usually unsuccessful; systemic corticosteroids; dapsone; minocycline; sulfapyridine; sulfasalazine; cyclosporin; clofazimine; and thalidomide. PANCREAS
Acute pancreatitis can be associated with Turner’s sign (periumbilical ecchymosis) and Cullen’s sign (ecchymosis of the flank), both caused by extravasation of hemorrhagic peritoneal fluid into the skin. Pancreatic panniculitis is a rare lobular panniculitis (inflammation of the subcutaneous fat lobules with fat necrosis and calcification)associated with pancreatitis or pancreatic carcinoma. Lesions consist of tender erythematous subcutaneous nodules occurring on the distal extremities, often periar-
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ticular. The lipolytic process also involves the periarticular tissue and medullary bone.I8
References 1. Angel0 V, Chung RT, Kaplan LM: A role for hepatitis C virus in type II cryoglobinemia. N Engl J Med 327:1490-1495, 1992 2. Apgar JT: Newer aspects of inflammatory bowel disease and its cutaneous manifestations: A selective review. Semin Dermatol 10:138-147, 1991 3. Banse-Kupin L, Morales A, Barlow M: Torre’s syndrome: Report of two cases and review of the literature. J Am Acad Dermatol 10:803-817, 1984 4. Barrace T, Corsini G, Granceschini R, et al: Lichen planus induced by interferon-alpha2a therapy for chronic active hepatitis C. Eur J Gastroenterol Hepatol4:367-368, 1995 5. Bergasa NV, Alling DW, Talbot TL, et al: Effects of naloxone infusions in patients with the pruritus of cholestasis: A double-blind, randomized, controlled trial. Ann Intern Med 123:181-187, 1995 6. Bergasa NV, Jones EA: The pruritus of cholestasis. Semin Liver Dis 13:319-327, 1993 7. Bloch KJ: Cryoglobulinemia and hepatitis C virus. N Engl J Med 327:1521-1522,1992 8. Burt BW, Rikkers LF, Gardner EJ, et a1 Villous adenoma of the duodenal papilla presenting as necrotizing pancreatitis in a patient with Gardner’s syndrome. Gastroenterology 92:532, 1987 9. Bussey HJR The management of familial polyposis coli. Roy Coll Curr Med Lit Gastroenterol4:61, 1985 10. Bussey HJR: Familial Polyposis Coli. Baltimore, The Johns Hopkins University Press, 1975 11. Callen JP: Skin manifestations of digestive disease. In Berk EJ (ed): Gastroenterology. Philadelphia, WB Saunders, 1995, pp 3324-3344 12. Carlson GJ, Nivatvongs S, Snover DC:Colorectal polyps in Cowden’s disease (multiple hamartoma syndrome). Am J Surg Pathol8763, 1894 13. Carson CW, Conn DL, Czaja AJ, et al: Frequency and significance of antibodies to hepatitis C virus in polyarteritis nodosa. J Rheumatol 20:304-309, 1993 14. Chevrant-Breton J, Simon M, Bourel M, et a1 Cutaneous manifestations of idiopathic hemochromatosis. Arch Dermatol 131:161-165, 1977 15. Colon KC, Urba WJ, Smith JW, et al: Exacerbation of symptoms of autoimmune disease in patients receiving alpha-interferon therapy. Cancer 65:2237-2242, 1990 16. Cribier B, Gamier C, Laustriat D, et al: Lichen planus and hepatitis C v y infection: An epidemiologic study. J Am Acad Dermatol31:1070-1072, 1994 17. Cronkhite LW, Canada WJ: Generalized gastrointestinal polyposis, alopecia, and onychotrophia. N Engl J Med 25299S1005, 1955 18. Dahl PR, Su WPD, Cullimore KC, et al: Pancreatic panniculitis. J Am Acad Dermatol 33:413417, 1995 19. Daniel CR, Sams WM, Scher RK: Nails in systemic disease. Dermatol Clin 3:465-483, 1985 20. Daniel E, Ludwig S, Lewin K, et al: The Cronkhite-Canada syndrome: An analysis of clinical and pathological features and therapy in 55 patients. Medicine 61:293-308,1982 21. Datta D, Sherlock S Colestyramine for long term relief of the pruritus complicating intrahepatic cholestasis. Gastroenterology 50323-332, 1966 22. Davis GB, Berk RN: Intestinal neurofibromatosis in Von Recklinhausen’s disease. Am J Gastroenterol 60410, 1973 23. DeCastro M, Sanchez J, Hemra JF,et al: Hepatitis C virus antibodies and liver disease in patients with porphyria cutanea tarda. Hepatology 17551-557,1993 24. Dubertret L Malignant atrophic papulosis (Degos’ disease). In Fitzpatrick TB, Eisen AZ, Wolff K, et a1 (eds): Dermatology in General Medicine. New York, McGraw-Hill, 1993, pp 1192-1195 25. Esche C, Kruse R, Lamberti C, et a1 Muire-Tom syndrome: Clinical features and molecular genetic analysis. Br J Dermatol 13691%917,1997
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26. Fargion S, Piparno A, Cappellini MD, et al: Hepatitis C virus and porphyria cutanea tarda: Evidence of a strong association. Hepatology 16:1322-1326, 1992 27. Fattovich G, Giustina G, Favorato S, et al: A survey of adverse events in 11,241patients with chronic viral hepatitis treated with alfa interferon. J Hepatol 24:3847, 1996 28. Finan MC, Ray MK: Gastrointestinal polyposis syndromes. Dermatol Clin 7419434, 1989 29. Funk J, Langeland T, Schrumpf E, et al: Psoriasis induced interferon alpha. Br J Dermatol 125:463-465, 1991 30. Ghent CN, Bloomer JR, Klatskin G: Elevations in skin tissue levels of bile acids in human cholestasis: Relation to serum levels and to pruritus. Gastroenterology 731125-1129, 1977 31. Giardiello FM, Welsh SB, Hamilton SR, et al: Increased risk of cancer in Peutz-Jeghers syndrome. N Engl J Med 316:1511, 1987 32. Gocke DJ, Morgan C, Lockshin M, et al: Association between polyarteritis and Australian antigen. Lancet 2:1149-1153, 1970 33. Graham-Brown R, Sarkany I, Sherlock S Lichen planus and primary biliary cirrhosis. Br J Dermatol 106:699-703, 1982 34. Gregory B, Ho VC: Cutaneous manifestations of gastrointestinal disorders: Part 1. J Am Acad Dermatol 26153-166, 1992 35. Gregory B, Ho VC: Cutaneous manifestations of gastrointestinal disorders: Part 11. J Am Acad Dermatol 26:371-383, 1992 36. Guarda LA, Luna MA, Smith JL, et al: Aquired immunodeficiency syndrome: Postmortem findings. Am J Clin Pathol81:549-557, 1986 37. Hall NR, Murday VA, Chapman P, et al: Genetic linkage in Muir-Torre syndrome to the same chromosomal region as cancer family syndrome. Eur J Cancer 30A:180-182, 1994 38. Herzberg AJ, Kaplan DL: Cronkhite-Canada syndrome. Int J Dermatol29:121-125,1990 39. Holzberg M, Walker H K Terry’s nails: Revised definition and new correlations. Lancet 1S96-899, 1984 40. Ilan Y, Hillman M, Oran R, et al: Vasculitis and cryoglobulinemia associated with persisting cholestatic hepatitis A virus infection. Am J Gastroenterol 85:586-587, 1990 41. Imhof M, Popal H, Lee JH, et al: Prevalence of hepatitis C virus antibodies and evaluation of hepatitis C virus genotypes in patients with lichen planus. Dermatology 195:l-5, 1997 42. Jones AF, Paone DB: Canada-Chronkhite syndrome in a 82 year old woman. Am J Med 77555-557, 1984 43. Jubert C, Pawotsky JM, Pouget F, et al: Lichen planus and hepatitis C virus-related chronic active hepatitis. Arch Dermatol 130:73-76, 1994 44. Katz SK, Gordon KB, Roenigk H H The cutaneous manifestations of gastrointestinal disease. Prim Care 23:455476, 1996 45. Katz SK, Mudd LJ, Roenigk HH: Malignant atrophic papulosis (Degos’ disease) involving three generations of a family. J Am Acad Dermatol37480484, 1997 46. Kemeny L, Gyulai R, Kiss M, et al: Kaposi’s sarcoma-associated herpesv;rus/human herpesvirus-8 A new virus in human pathology. J Am Acad Dermatol37107-113,1997 47. Kitagawa S, Townsend BL, Herbert AA: Peutz-Jeghers syndrome. Dermatol Clin 13~127-133,1995 48. Kubo T, Hirose S, Aoki S, et al: Canada-Cronkhite syndrome associated with systemic lupus erythematosus. Arch Intern Med 146:995-996, 1986 49. Lamberts RJ: Gastrointestinal hemorrhage and the skin. Dermatol Clin 7403415, 1989 50. Lemer AB, NcGuire J S Melanocyte-stimulating hormone and adrenocorticotrophic hormone. N Enal J Med 270593,1964 51. Mallory SB Cowden syndrome (multiple hamartoma syndrome). Dermatol Clin 13:2731, 1995 52. Mallory SB, Stough DB: Genodermatoses with malignant potential. Dermatol Clin 5:221, 1987 53. Marks JM: The skin and disorders of the alimentary tract. In Fitzpatrick TB, Eisen AZ, Wolff K, et a1 (eds): Dermatology in General Medicine. New York, McGraw-Hill, 1993, pp 2045-2057 54. Matsumoto T, Iida M, Mibu R, et al: Risk of cancer development in the rectal remnant
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of patients with familial adenomatous polyposis/Gardner’s syndrome. Hepatogastroenterology 42:765-770, 1995 55. Mills PR, Skerrow LJ, Machie AM: Melanin pigmentation of the skin in primary biliary cirrhosis. J Cutan Pathol 8:404-410, 1981 56. Minkowitz G, Smoller BR, McNutt NS: Benign cutaneous polyarteritis nodosa: Relationship to systemic polyarteritis nodosa and to hepatitis B infection. Arch Dermatol 1271520-1523, 1991 57. Moore PS, Chang Y Detection of herpesvirus-like DNA sequences in Kaposi’s sarcoma in patients with and without HIV infection. N Engl J Med 332:1181-1185,1995 58. Oranje AP: Blue rubber bleb nevus syndrome. Pediatr Dermatol3304-310, 1986 59. Oshiro T, Maruyama Y, Nakajima H, et a1 Treatment of pigmentation of lips and oral mucosa in Peutz-Jeghers syndrome using ruby and argon lasers. Br J Plast Surg 33346,1980 60. Perdrup A, Poulsen H Hemochromatosis and vitiligo. Arch Dermatol 9 0 3 , 1964 61. Pemiciaro G: Gardner’s syndrome. Dermatol Clin 13:51-56, 1995 62. Perry WH: Clinical spectrum of hereditary hemorrhagic telangiectasia (Osler-WeberRendu Disease). Am J Med 82989-997, 1987 63. Piette AM, Meduri B, Fritsch J, et a1 Do skin tags constitute a marker for colonic polyps? A prospective study of 100 asymptomatic patients and metaanalysis of the literature. Gastroenterology 95:1127-1129, 1988 64.Poupon R, Chretien Y, Poupon RE: Is ursodeoxycholic acid an effective treatment for primary biliary cirrhosis? Lancet 153344336, 1987 65. Powell FC, Cooper AJ, Massa MC, et a1 Sister Mary Joseph’s nodule: A clinical and histologic study. J Am Acad Dermatol 10610-615, 1984 66. Radack K, Park S: Is there a valid association between skin tags and colonic polyps: Insights from a quantitative and methodologic analysis of the literature. J Gen Intern Med 8:413-421, 1993 67. Reilly PJ, Nostrant TT. Clinical manifestations of hereditary hemorrhagic telangiectasia. Am J Gastroenterol79:363-367, 1984 68. Saltz RK, Kurtz RC, Lightdale CJ, et al: Gastrointestinal involvement in Kaposi’s sarcoma [abstr]. Gastroenterology 821168, 1982 69. Santander C, Decastro M, Carcia-Monzon C, et al: Prevalence of hepatitis C virus and liver damage in patients with lichen planus. Hepatology 20238A, 1994 70. Schmucker DL, Ohta M, Kania S Hepatic injury induced by bile salts: Correlation between biochemical and morphological events. Hepatology 121216-1221, 1990 71. Schwartz RA, Torre DP: The Muir-Torre syndrome: A 25-year retrospect. J Am Acad Dermatol33:90-104, 1995 72. Schworer H, Hartmann H, Ramadori G: Relief of cholestatic pruritus by a novel class of drugs: 5-Hydroxytryptamine type 3 receptor antagonists: Effectiveness of ondansetron. Pain 61:33-37,1995 73. Spigelman AD, et al: Cancer and the Peutz-Jeghers syndrome. Gut 301588, 1989 74. Starink TM, van der Veen JPW, Arwert F, et al: The Cowden syndrome: A clinical and genetic study in 21 patients. Clin Genet 29:222-233,1986 75. Takikawa H, Yamazaki R, Shoji S, et al: Normalization of urinary porphyrin level and disappearance of skin lesions after successful interferon therapy in a case of chronic hepatitis C complicated with porphyria cutanea tarda. J Hepatol22249-250, 1995 76. Terry RB: The onychodermal band in health and disease. Lancet 1:179,1955 77. Trautinger F, Knobler RM: More on interferon-induced cutaneous necrosis. N Engl J Med 333:1222-1223, 1995
Address reprint requests to Kenneth B. Gordon, MD Assistant Professor of Dermatology Department of Dermatology Northwestern University Medical school 303 East Chicago Avenue Chicago, IL 60611
0889-8553/98 $8.00
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DERMATOLOGIC MANIFESTATIONS OF GASTROINTESTINAL DISORDERS Sara K. Ward, MD, Henry H. Roenigk, MD, and Kenneth B. Gordon, MD
Many disorders of the gastrointestinal tract have cutaneaous manifestations. Thus, a careful examination of the skin may uncover clues to underlying diseases of the liver, gastrointestinal tract, and pancreas. This article explores the alimentary-cutaneous relationship. LIVER DISEASE Viral Hepatitis Hepatitis A Virus Infection
Cutaneous involvement from hepatitis A virus infection is a rare occurrence. Jaundice is the main cutaneous manifestation in more fulminant cases of hepatitis A virus infection. There are a limited number of cases of cryoglobulinemia and associated vasculitis in the literature. The reported cases are in patients with the persistent forms of infection with cholestasis.m
From the Department of Dermatology, Northwestern University Medical School (HHR, KBG); Department of Dermatology, Northwestern Community Medical Group (SKW); Section of Dermatology, Chicago Veterans Administration Medical Center, Lakeside Division (KBG), Chicago, Illinois; and Arizona Advanced Dermatology (HHR), Phoenix, Arizona GASTROENTEROLOGY CLINICS OF NORTH AMERICA
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Hepatitis B Virus Infection
The cutaneous manifestations of hepatitis B virus infection (HBV) can mainly be attributed to the immune response to the infection. In the prodromal phase of the illness, the patient may suffer from a serum sickness-like illness with arthralgias and polyarthritis along with an urticarial-type rash with wheals that persist for less than 24 hours. High titers of circulating antibodies to the virus can lead to a vasculitis. Patients may develop a necrotizing vasculitis, which can be systemic or limited to the skin.56An association between HBV and polyarteritis nodosa has been well established?* Clinically, these patients present with fever, malaise, and arthralgias. Less frequent symptoms include abdominal pain from a mesenteric vasculitis, mononeuritis multiplex from vasculitis of the vaso-nervorum, and nephritis. The skin shows socalled palpable purpura, nonblanching purple nodules that usually first develop on the lower legs or other dependent areas and spread centrally (Fig. 1). The usual treatment of vasculitis, including immunosuppressive drugs, can lead to a worsening of the underlying hepatitis. Another form of immune complex disease associated with HBV infection is cryoglobulinemia. The presence of cryoglobulins in the blood of patients with persistent HBV has been estimated as high as 15%.The cryoprecipitate is primarily of the mixed form. The symptoms are similar to those of polyarteritis nodosa with fever, malaise, arthritis, glomerulonephritis, and palpable purpura. These symptoms are frequently associated with Raynaud’s phenomenon and may be exacerbated by the cold. Nonvasculitic cutaneous eruptions associated with HBV include erythema multiforme, pyoderma gangrenosum, and erythema nodosum. Another cutaneous eruption that was first reported in conjunction with HBV is papular acrodermatitis of childhood, or Gianotti-Crosti syndrome. This eruption is characterized by asymptomatic erythematous papules and nodules that develop on the face and extremities (Fig. 2).
Figure 1. Cutaneous vasculitis. Palpable, violaceous nodules occurring on the hand in this case.
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Figure 2. Papular acroderrnatitis of childhood (Gianotti-Crosti syndrome). Erythernatous papules and nodules on the extremities, sparing the trunk.
Typically, there is sparing of the trunk, which can help to distinguish this syndrome from other viral exanthems or drug eruptions. The course is benign with clearing typically in about 3 weeks. In recent years, this eruption has been associated with viral syndromes other than HBV. Hepatitis C Infection
Hepatitis C infection (HVC) has among the most unusual and interesting cutaneous responses of any systemic infection. Similar to HBV, HCV has been associated with cryoglobulinemia, primarily of the mixed (type I1 or 111) forms.' HCV RNA can be found by polymerase chain reaction in the serum of up to 85% of patients with mixed cryoglobulinemia and in 90% of their cryoprecipitates. Some authors suggest that HCV may be the leading cause of essential mixed cryoglobulinemia, and infection with HCV should be evaluated in all patients presenting with this ~yndrome.~ Polyarteritis nodosa is also noted in patients with HCV, although not as frequently as in patients with HBV. Antibodies to HCV have been noted in 5% to 20% of patients with polyarteritis nodosa, although there have been reports of false-postitive anti-HCV antibodies in these patient^.'^
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Lichen planus is a cutaneous eruption of pruritic, violaceous, polygonal, scaly papules and nodules along with ulceration and reticular lesions on the mucous membranes. Although the cutaneous lesions have a predilection for the flexor surfaces of the extremities, they may occur anywhere on the body. Lichen planus has been associated with a number of liver diseases, including primary biliary cirrhosis. The prevalence of HCV antibodies in patients is higher than in the general population. The absolute prevalence varies from 4% to 38% based on where the study is done.16,33, 41 The eruption is likely a reaction to the chronic inflammatory process in these diseases. In fact, immunotherapy with interferon-a can exacerbate lichen planus or even induce the lesions as well as cause their impr~vernent.~~ An absolute relationship between the immune response to HCV and lichen planus, however, has not been established. Treatment of lichen planus is primarily potent topical steroids or systemic steroids. Dapsone and psoralen and ultraviolet A (PUVA) therapy has been reported to be of benefit in lichen planus, even for mucous membrane lesions. Porphyria cutanea tarda is a rare disorder of porphyrin metabolism resulting in the accumulation of heme precursors in the skin. The functional abnormality is in the enzyme uroporphyrinogen decarboxylase. This abnormality can be hereditary, inherited as an autosomal recessive trait, or acquired, usually in conjunction with liver disease. Extrinsic factors, most often alcohol or estrogens, are generally needed to induce the clinical manifestations of disease. These clinical findings are related to sun exposure and include bullae and milia on the dorsal surface of the hands and hyperpigmentation and hypertrichosis on the face. A number of studies have shown a high incidence of anti-HCV antibodies in patients with porphyria cutanea tarda with infection rates as high as 95% in some pop~lations.~, 23, 26 Lending credence to a causal relationship of HCV for porphyria cutanea tarda is that in some cases treatment with intereferon-a has not only improved the clinical lesions, but has also made porphyrins undetectable in the urine.” Other than treating the underlying hepatitis, porphyria cutanea tarda can be treated with phlebotomy or chelating agents. In alcohol-related porphyria cutanea tarda, the disease often remits when the offending agent is withdrawn. Finally, therapy for HCV with recombinant interferon-a can induce cutaneous changes. The most striking of these changes is cutaneous necrosis at the site of interferon injection. These patients develop ulcers and necrosis and necrobiosis of the Also, patients receiving interferon treatment for HCV can develop worsening of inflammatory skin condition^.^^ Inclusive in these conditions are ps0riasis,2~sarcoidosis,15 and contact dermatitis (personal observation of one of the authors [KBGI). Cholestatic Liver Disease
Pruritus Among the most debilitating symptoms of hepatic failure is severe pruritus. Patients with acute or chronic cholestasis retain a number of
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chemicals that are normally secreted in the bile. These substances include bilirubin, bile acids, and cholesterol. Of these, the most commonly discussed cause of the pruritus of cholestasis is the retention of bile acids, which can act as hepatotoxins,70 although a direct correlation between blood or tissue levels of bile acids and pruritus has not been made.30 Other theories include cholestasis leading to increased levels of a centrally acting opioid agonist causing the sensation of pruritus6 Because the pathogenesis of cholestatic pruritus is still unknown, therapy is empiric. Much of the therapy for the pruritus of hepatic failure is directed toward reducing the amount of circulating bile salts and antagonizing opioid receptors. Bile acid-sequestering agents, such as cholestyramine and cholestipol, have been shown to be moderately efficacious and are usually the first line of therapy.14 These medications might work through a mechanism independent of bile acids because therapy with these agents has also been shown to be beneficial in the treatment of the pruritus of polycythemia Vera or uremia. Patient compliance is often limited because of gastrointestinal discomfort. Ursodeoxycholate is a bile acid with less inherent toxicity than the naturally synthesized bile acids in the human liver. Treatment with this compound can lower the circulating levels of the primary bile acids and reduce Similar to the bile acid sequestrants, the improvement with ursodeoxycholate is usually not complete. A well-controlled trial with the opioid antagonist naloxone showed significant benefit, lending credence to the theory that the pruritus might be of central rigi in.^ A small trial has found that the centally acting 5-hydroxytryptamine receptor antagonist ondansetron also may have some efficacy in the treatment of cholestatic pruritus.72Dilution of a possible circulating toxin responsible for pruritus with plasma infusion has also been reported to be successful.76Finally, some patients may benefit from treatment with ultraviolet light with either short wavelength (ultraviolet B) or long wavelength with the addition of a photosensitizing agent (PUVA). Pigmentary Changes
Jaundice. Jaundice refers to the yellowish discoloration of the skin and mucous membranes that accompanies the accumulation of bilirubin or its metabolites in the skin. In the case of liver disease, the bilirubin typically accumulates as a result of impaired excretion of bilirubin by the liver and is primarily of the conjugated or direct form. There is no absolute bilirubin level at which jaundice is always evident, but generally bilirubin levels greater than 2.5 mg/dL result in a clinically apparent alteration in skin color. The skin color itself can vary from light yellow to dark green depending on the bilirubin level and the patient's own skin color. Hyperbilirubinemia can develop with almost any class of liver disease, including infections, biliary obstruction, or primary enzymatic deficiencies of the liver such as Gilbert's or Crigler-Najjar syndromes. Although the deposition of bilirubin is in itself harmless, it usually indicates an underlying abnormality that does require treatment. Jaun-
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dice normally subsides with the appropriate therapy for the underlying pathologic process. Hypermelanosis. Patients with long-standing cirrhosis or with hemochromatosis, a hereditary abnormality resulting in iron overload, develop a grayish pigmentation that can be diffuse, patchy, or limited to the rnu~osa.'~ These changes are likely due to an increase in the melanin content of the skin in giant melano~omes.5~ The cause of this finding is unknown. A likely connection between pigmentation and iron in the skin could account for the increased melanin in patients with conditions that can result in iron overload.60Other theories include an endocrinologic effect via adrenocorticotropic hormone (ACTH) or melanocytestimulating hormonemor by the deposition of hemosiderin in the skin. Liver Dysfunction Vascular Changes
The cutaneous vasculature is also frequently affected by acute and especially chronic liver disease. The most recognized vascular lesions are spider angiomas (Fig. 3). Clinically, these lesions most often occur on the face, upper tmnk, and distal upper extremities. They are formed by a central vessel surrounded by branching small vessels. Compression of the central punctum results in blanching of the entire lesion. The spider angiomas can be treated with fine cautery or pulse dye laser. Palmar erythema is another clinical sign associated with liver disease. Palmar erythema may present clinically as increased mottling of the
Figure 3. Spider angiomas. A central vessel is surrounded by branching small vessels.
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hands or discrete erythematous patches on the thenar or hypothenar eminences. Both of these lesions have been associated with faulty metabolism of estrogens by a diseased liver. This theory would account for their development during pregnancy. Spider angiomas and palmar erythema, however, may also develop in patients devoid of liver disease or estrogen therapy, particularly in alcoholics without liver disease, and in patients with chronic inflammatory diseases. Thus, the true pathogenesis of these vascular abnormalities remains uncertain. Nail Changes
Alterations in the normal appearance of the fingernails and toenails can be an important tool in the diagnosis of liver disease. These changes are often overlooked and do not always suggest a specific underlying disease. Hepatolenticular degeneration (Wilson’s disease) is an abnormality in copper metabolism that leads to hepatic necrosis and central nervous system abnormalities. The most prominent cutaneous abnormality associated with this condition is azure lunulae, a bluish discoloration of the white half-moon at the proximal portion of the nail bed. The discoloration is limited to the lunula, differentiating the nails of hepatolenticular degeneration from diseases in which the entire nail bed can look blue. These conditions include argyria, pseudomonal infections, and in patients taking antimalarial medications. Terry’s nails are clinically defined as a whitish discoloration of the nail with accentuation of the distal pink portion of the nail plate just proximal to the free end of the nail. This distal line is termed the onychodermal band.76 Initially, this finding was thought to be suggestive of cirrhosis, mainly primary biliary cirrhosis. More recent findings, however, have noted Terry’s nails in about 25% of all hospitalized patients with or without liver disease.39Other nonspecific nail changes associated with hepatic diseases include clubbing with primary biliary cirrhosis and chronic active hepatitis, double white transverse lines (Muehrcke’s lines) in hepatic failure, and splinter hemorrhages in he pa ti ti^.'^ GASTROINTESTINAL HEMORRHAGE Hereditary Hemorrhagic Telangiectasia (Osler-WeberRendu Disease) Hereditary hemorrhagic telangiectasia is an autosomal dominant disorder characterized by vascular dilations of the skin and the oral, nasal, and gastrointestinal mucosa. Vascular malformations may also involve the lung, central nervous system, or retina. Recurrent epistaxis caused by spontaneous bleeding from nasal mucosa telangiectasias is the most common presentation of this disease, occurring in 80% of patients.67The skin lesions may not appear until adult life and consist
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of small macular telangiectasias, which often increase in number and size with age.62The telangiectasias occur on the lips, tongue, palate, face, ears, nares, conjunctiva, chest, hands, and feet (Fig. 4). Recurrent gastrointestinal bleeding is painless and occurs from vascular malformations throughout the gastrointestinal tract. The bleeding is chronic, periodic, and progressive, often leading to considerable blood Sites of bleeding may be visualized by endoscopy in the stomach, duodenum, small bowel, or colon. Angiography may identify large arteriovenous malformations. Treatments include iron supplementation, surgical resection of involved bowel (difficult given the degree of the gastrointestinal tract involved), endoscopic techniques, and estrogen or estrogen and progesterone therapy." Blue Rubber Bleb Nevus Syndrome
Blue rubber bleb nevus syndrome is a rare disorder characterized by large cutaneous hemangiomas and gastrointestinal bleeding from vascular malformations. It is usually identified at birth or early childhood but has been noted to present in adulthood.35,58 Three types of skin lesions have been described, which, in contrast to classic hemangiomas, do not regress ~pontaneously.~~ The most characteristic cutaneous lesion is the blue rubber nipple, described as a soft, rubbery, compressible nodule, which, after being compressed, leaves an empty bluish sac that swiftly refills with blood. The second type are tender, irregular, blue-black, punctate macules distributed on the extremities and trunk. The third type consists of large disfiguring hemangiomas 49 that may interfere with vital limb or organ
Figure 4. Osler-Weber-Rendu disease. Many discrete macular telangiectasias occuring on the lower lip.
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The gastrointestinal vascular malformations are most often found in the small intestine or colon. Gastrointestinal bleeding may be frank melena but is most often detected as occult blood in the 49 Therapy is mainly symptomatic, including blood transfusions and iron supplementation for anemia, surgery or endoscopy to control gastrointestinal bleeding, and laser or surgical removal of cutaneous hemangiomas. Kaposi’s Sarcoma Kaposi’s sarcoma is a neoplasm of vascular endothelium and pericapillary cells that often presents on the skin and may involve other visceral organs, including the gastrointestinal tract. The epidemic form of Kaposi’s sarcoma, the most common form in North America, is associated with the human immunodeficiency virus (HIV).36The gastrointestinal tract is involved in 50% to 80% of those with the cutaneous lesions and in nearly 100% of those with oral lesion^.^^,^^ Gastrointestinal tract involvement is most common in the male homosexual population with the epidemic form of the disease.49Classic Kaposi’s sarcoma primarily occurs in elderly men of Eastern European or Mediterranean origin and typically has an indolent course. Iatrogenic Kaposi’s sarcoma occurs in patients receiving immunosuppressive therapy. Herpesvirus type 8 has been found in all forms of Kaposi’s sarcoma and is thought 57 to be involved in the pathogenesis of Kaposi’s sarcoma.46, The cutaneous lesion is a red-purple macule, which, as it enlarges, becomes a deeper violet papule or plaque (Fig. 5). The lesions are usually multiple and can occur anywhere on the skin, with a propensity for the legs and feet in the classic non-HIV form. The cutaneous lesions are more likely to be disseminated over the trunk and face in acquired immunodeficiency syndrome (AIDS)-related Kaposi’s sarcoma. The gastrointestinal tract may be involved in any area, and gastrointestinal bleeding may lead to death. Epidemic AIDS-related Kaposi’s sarcoma portends a poor prognosis with a fatal outcome within 2 years.35Treatment of Kaposi’s sarcoma is mainly palliative. Therapy of localized cutaneous lesions includes excision, radiation therapy, or intralesional therapy with vinblastine or interferon a. More widespread disease requires treatment with systemic antineoplastic chemotherapy or interferon alfa. Pseudoxanthoma Elasticum Pseudoxanthoma elasticum is a genetic disorder of elastic fibers that become calcified and weakened. It is characterized by specific skin lesions, angioid streaks and other degenerative changes of the retina, and widespread vascular calcification leading to gastrointestinal bleeding, premature myocardial infarction, cerebrovascular disease, peripheral
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Figure 5. Kaposi's sarcoma. Violaceous plaques and nodules on the foot.
vascular disease, and hypertension." Four major types have been described: type I dominant and recessive and type I1 dominant and recessive. Type I recessive is the classic form of the disease displaying the typical skin findings and a high incidence of gastrointestinal di~ease.3~ The skin findings are distinctive: small, yellow papules coalescing to form plaques with a pZuckd chicken or cobblestone appearance distributed in the flexural areas, including neck and axilla. In addition, generalized laxity of the face, neck, and trunk may be found." Gastrointestinal bleeding occurs early in the course of the disease, is recurrent and severe, and usually originates from the upper gastrointestinal tract, although lower gastrointestinal tract bleeding may occur.35,49 Endoscopy may reveal the characteristic yellow cobblestonelike lesions similar to those occurring in the mouth and skin." There is no effective therapy, and the prognosis is poor, with death occurring from premature cardiovascular disease." Ehlers-Danlos Syndrome
Ehlers-Danlos syndrome is a group of inherited disorders of collagen. The characteristic findings include fragility of the skin and blood
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625
vessels, hyperextensibility of joints, and hyperelasticity of the skin. Type IV Ehlers-Danlos syndrome, the ecchymotic type, is most closely associated with gastrointestinal hem0rrhage.4~There is no effective therapy, and patients have a poor prognosis, with rupture of major blood vessels and hemorrhage of internal organs as the main causes of death. Malignant Atrophic Papulosis (Degos’ Disease) Malignant atrophic papulosis (Degos’ disease) is a rare disorder of young adults affecting the skin, gastrointestinal tract, and central nervous system. The characteristic skin lesions are asymptomatic multiple papules with atrophic, white scarlike centers surrounded by an erythematous border (Fig. 6). The skin lesions often precede the development of infarcts involving the gastrointestinal and central nervous systems. Gastrointestinal infarctions may cause gastrointestinal bleeding or perforation. With systemic involvement, the prognosis is poor with death occurring within a few years from intestinal or central nervous system infarctions. There have been reports of patients with only cutaneous involvement who have not developed systemic involvement, suggesting a benign form of the disease. Although Degos’ disease is not regarded as a genetic disorder, there have been reports of familial clustering of the disease.45
Figure 6. Malignant atrophic papulosis (Degos’ disease). Papules with porcelain white, scar-like centers surrounded by a border.
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GASTROINTESTINAL POLYPOSIS Gardner’s Syndrome
Gardner’s syndrome refers to the clinical triad of adenomatous polyps of the gastrointestinal tract with a high risk of malignant transformation, epidermal cysts, and desmoid tumors. This is an autosomal dominant disease with high penetrance and variable expressivity. Patients with this disorder are thought to have a lifetime risk of adenocarcinoma of the colon of loo%.= The adenomatous polyps are multiple, usually greater than 100; occur in any part of the colon; have a diameter larger than 1 cm; and have an average age of onset of 22 years.1° In one study, rectal polyps were found in all patient^.^ Thus, sigmoidoscopy allows screening of the disease. Adenomatous polyps also may be found in the small intestine, duodenum, stomach, or gallbladder. Acute pancreatitis has been reported secondary to obstruction of the pancreatic duct by polyps.8Most patients develop colon cancer between the ages of 20 and 30 if not treated. The most common treatment is prophylactic colectomy with ileorectal anastomosis, but patients require close follow-up given the risk of rectal cancer of the remaining rectal mucosa.54 The skin and bone lesions occur before the intestinal polyps and may predate the polps by as many as 10 years. Epidermal cysts are multiple; appear before puberty; and are located predominantly on the extremities, face, and scalp. Desmoid tumors occur in young patients, have a female predominance, are locally aggressive, and do not metastasize but can lead to deathFs Osteomas also occur in Gardner’s syndrome; they are benign tumors that occur on the mandible and maxilla. Gardner’s syndrome also has an association with fibromas, lipomas, dental abnormalities, pigmented ocular fundal lesions, brain tumors, and endocrine tumors.28 Peutz-Jeghers Syndrome
Peutz-Jeghers syndrome describes hamartomatous polyps occurring mainly in the small intestine in association with mucocutaneous hyperpigmented macules, gonadal tumors, and breast cancer.= Gastrointestinal bleeding or intussusception with obstruction, abdominal pain, or rectal prolapse may be presentations of this syndrome. The intestinal hamartomas are usually pedunculated and most commonly found in the jejunum but may also occur in the ileum, stomach, duodenum, and Because the histology of the hamartomas may imply malignancy, the risk of malignancy has been overestimated in the past. Although the hamartomatous polyps have a lower malignant potential than adenomatous polyps, evidence implies an increased risk of gastrointestinal carcinoma in addition to an increased risk of malignancy in general in this syndrome.31,47, 73 Gastrointestinal carcinoma occurs in 2% to 3% of pa-
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tients, and there is also an increased incidence of breast, ovarian, and testicular car~inornas.~~ Treatment is usually conservative, with endoscopic removal for symptomatic or large polyps. Small dark freckles are found most commonly on the lips and buccal mucosa but also occur on distal fingers and toes and periorificially (Fig. 7). With age, the nonspecific mucosal pigmentation persists, whereas the other characteristic and more apparent cutaneous freckles tend to fade. There is no relationship between the extent or location of the pigmentation and the extent of the polyps. The mouth pigmentation has been treated with ruby and argon lasers.59 Canada-Cronkhite Syndrome
Canada-Cronkhite syndrome is a rare, acquired disease of adulthood characterized by inflammatory polyps, cutaneous hyperpigmentation, patchy alopecia, and nail changes. There is a protein-losing enteropathy with presenting symptoms including chronic diarrhea, abdominal pain, anorexia, and wasting. Although the polyps are hamartomatous, as in Peutz-Jeghers syndrome, malignant degeneration of the polyps has been described.20 The cutaneous triad, which consists of hyperpigmentation, alopecia, and nail changes, is found in most patients. The alopecia is rapidly
Figure 7. Puetz-Jeghers syndrome. Multiple dark brown freckles on the lips and gingiva.
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progressive, initially patchy and leading to complete hair loss. Extensive hyperpigmented macules and plaques are distributed diffusely but most commonly occur on the hands and arms and may be reversible. The nail dystrophy involves all fingernails and toenails, with changes including onycholysis (separation of the nail plate from the nail bed) and a unique pattern of an inverted triangle of normal nail bordered by dystrophic nail.17.21.26 Therapy is mainly supportive with fluid, electrolytes, and nutrition. There have been reports of favorable responses to systemic steroids with resolution of both gastrointestinal symptoms and polyps.", Neurofibromatosis Neurofibromatosis is an autosomal dominantly inherited disease with cutaneous manifestations, including many caf6-au-lait macules, multiple neurofibromas, and axillary freckling (Fig. 8). Gastrointestinal tumors, usually neurofibromas, have been said to occur in 25% of patients with neurofibromatosis.22The gastrointestinal neurofibromas are generally asymptomatic, but there may be abdominal pain, gastrointestinal bleeding, obstruction, or intussusception. Malignant transformation may rarely occur in the neurofibromas of the gastrointestinal tract as well as the skin. Cowden's Disease (Multiple Hamartoma Syndrome) Cowden's disease is an autosomal dominant disorder with variable expression. It is characterized by certain mucocutaneous lesions, gastrointestinal tract polyps, and an increased risk of internal malignancies.
Figure 8. Neurofibromatosis. Characteristic flesh-colored, soft papules or nodules (i.e., neurofibromas) on the trunk.
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629
The skin findings are often the presenting evidence of the disease. The mucocutaneous manifestations include facial trichilemmomas (fleshcolored, flat-topped or elongated verrucous papules in a periorificial and centrofacial distribution), oral papillomatosis (small, smooth, fleshcolored papules on labial, gingival, or palatal surfaces resulting in a cobblestone appearance), Cowden’s fibromas (firm, white papules or nodules involving the face, scalp, or hands), acral keratoses (flesh-colored, flat-topped smooth or rough papules on dorsa of hands and feet that may resemble common warts), and palmoplantar keratoses (firm 34 Less common skin findings include lipomas, hyperkeratotic papules).28, hemangiomas, scrota1 tongue, and n e ~ r o m a s . ~ ~ Hamartomatous gastrointestinal polyps are found in one third of 74 The patients with Cowden’s disease and are usually a~ymptomatic.~~, polyps have a predilection for the rectosigmoid area, and they do not appear to be premalignant.12 Recognition of Cowden’s disease is important because of the associated malignancies. This syndrome is associated with an increased risk of breast, endometrial, and thyroid cancers. The incidence of fibrocystic disease of the breast and thyroid disease (goiter and adenomas) is also increased in this syndrome. Management includes close follow-up for detection of carcinoma, genetic counseling, and screening of family members. Muir-Torre Syndrome Muir-Torre syndrome describes multiple sebaceous neoplasms associated with internal malignancy, including adenocarcinoma of the gastrointestinal tract. Adenomatous colonic polyps occur with an increased frequency, but they are not a constant or defining feature of this syndrome. Muir-Torre syndrome is inherited as an autosomal dominant disorder and is caused by a germline mutation in a DNA mismatch repair gene.25This syndrome may share a common genetic basis with the Lynch I1 cancer family syndrome.37The visceral carcinomas are often multiple. Colorectal carcinoma is the most common internal cancer and usually arises in the presence of the adenomatous polyps. The incidence of genitourinary carcinoma is also increased in this syndrome. Both the internal and sebaceous malignancies are less aggressive than those malignancies not associated with the syndrome; thus, Muir-Torre syndrome portends a better prognosis than expected given the multiple car~inornas.~~ Multiple sebaceous adenomas occur on the head, neck, and trunk .~ cutaneous neoplasms that have in patients in their 40s and ~ O S Other been reported include sebaceous epithelioma, sebaceous carcinoma, keratoacanthomas (rapidly growing benign epithelial neoplasm), squamous cell carcinoma, epidermal cysts, and basal cell carcinoma with sebaceous 71 Sebaceous adenomas appear to be the most common differentiati~n.~~, and specific lesion for the diagnosis of the syndrome. Sebaceous hyper-
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plasia (proliferation of sebaceous glands appearing as yellowish papules frequently found on the face of elderly people) is not associated with this syndrome. Multiple sebaceous tumors represent a marker for internal malignancy and may warrant a search for occult malignancy in the patient and the patient’s family. Acrochordons
Several studies have attempted to determine an association between acrochordons (skin tags) and colonic 66 Because acrochordons are frequently found in the general population, this association is difficult to make. Given the potential for malignant degeneration of colonic adenomatous polyps, identifymg a cutaneous marker for colonic polyps would be beneficial. Currently, this issue remains unsettled, and further research is needed. Colonoscopy is not warranted for asymptomatic patients with multiple skin tags. GASTROINTESTINALCANCER Cutaneous Metastatic Disease
Cutaneous metastatic disease from gastrointestinal tract neoplasms is most often found on abdominal skin or scalp. Metastatic cancer to the skin is characterized by one or more firm, indurated, and often ulcerated nodules or plaques (Fig. 9). Sister Mary Joseph’s nodule describes firm, indurated nodules in the umbilicus, which is a sign of metastatic disease. Adenocarcinoma of the gastrointestinal tract, most commonly stomach,
Figure 9. Metastatic cancer to the skin. Firm, indurated plaques and nodules.
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631
is the most common primary site. Most patients die within months of the appearance of the umbilical nodule.65 Acanthosis Nigricans
Acanthosis nigricans is characterized by velvety hyperpigmentation of axillae and other body folds (Fig. 10). It can occur in various clinical settings, including benign hereditary forms, endocrinopathies, obesity, and paraneoplastic conditions. When acanthosis nigricans is associated with malignancy, two thirds of the time the tumor is gastric. Acanthosis nigricans may regress after removal of the rnalignan~y.~~ Sign of Leser-Trelat
Leser-Trklat sign describes the sudden appearance of seborrheic keratoses (common benign s tuck-on-appearing discrete papules or plaques) associated with internal malignancy. Some regard this as a variant of acanthosis nigricans. Multiple seborrheic keratoses are common in many elderly patients and may not be an indicator of internal malignancy. Tylosis Palmaris et Plantaris
Tylosis palmaris et plantaris describes a familial association of punctate keratoses of the palms and soles with esophageal carcinoma.
Figure 10. Acanthosis nigricans. Velvety hyperpigmentation of axillae.
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Carcinoid Syndrome
Carcinoid syndrome is caused by tumors producing vasoactive substances, including serotonin, kallikrein, and histamine. The clinical manifestations include paroxysms of flushing, wheezing, diarrhea, abdominal pain, and often hypotension. Although the appendix and small bowel are the most common locations for carcinoid tumor, symptomatic carcinoid syndrome usually indicates metastasis to locations allowing the vasoactive substances to reach the circulation. Diagnosis is made by detecting 5-hydroxyindoleacetic acid in the urine. Symptoms improve with removal of the tumor.
Glucogonoma Syndrome
Glucogonoma, a tumor of the pancreatic alpha cell, is associated with necrolytic migratory erythema in a syndrome called glucogonoma syndrome. Necrolytic migratory erythema is a distinctive eruption characterized by recurrent cycles of erythema followed by blisters, erosions, crusting, and scaling on the lower abdomen, groin, and buttocks. Other cutaneous manifestations of glucagonoma syndrome include angular cheilitis and painful glossitis. The clinical syndrome also includes glucose intolerance, anemia, diarrhea, weight loss, venous thromboses, and psychiatric disturbances. Elevated plasma glucagon levels may aid in the diagnosis. Removal of the tumor is associated with improvement of the cutaneous lesions.
INFLAMMATORY BOWEL DISEASE: ULCERATIVE COLITIS AND CROHN’S DISEASE
Cutaneous findings are common in both ulcerative colitis and Crohn’s disease. Fissures and fistulas are, although not specific, the most frequent cutaneous manifestations, occurring mainly in Crohn’s disease.35They most commonly occur on the perianal skin, but they can also be found in the region of stomas or on the abdominal wall. The perianal fissures are usually multiple and may lead to ulcers or abs c e ~ s e sCrohn’s .~~ disease may also affect the oral mucosa, as represented by a cobblestone pattern, ulcerations, and nodules. Metastatic Crohn’s disease describes nodules, plaques, or ulcerated lesions that are histopathologically identical to Crohn’s disease. They may be located on any area of the skin and are often correlated with disease activity.”, 35 Erythema nodosum, aphthous stomatitis, and pyoderma gangrenosum represent some of the cutaneous lesions observed in association with Crohn’s disease and ulcerative colitis.
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Erythema Nodosum
Erythema nodosum presents as tender red nodules on the anterior aspects of the legs. It may occur at any point in the course of inflammatory bowel disease or may be associated with a flare of enteric disease.35 Treatment consists of controlling the bowel disease, bed rest, nonsteroidal anti-inflammatory drugs, corticosteroids, potassium iodide, dapsone, or colchicine. Oral Aphthous Ulcers
Oral aphthous ulcers have been recognized in association with inflammatory bowl disease and reflect disease activity. These lesions are nonspecific and cannot be distinguished clinically or histologically from common aphthous ulcers.35 Pyoderma Gangrenosum
Pyoderma gangrenosum has been observed in association with Crohn‘s disease and ulcerative colitis. This lesion usually begins as a hemorrhagic pustule or papule after minimal trauma and rapidly evolves into a purulent, painful, necrotic ulcer with dusky undermined borders. Lesions are sterile and heal with scarring. Pyoderma gangrenosum may occur without an associated underlying disease, or it may be associated with various systemic diseases, including inflammatory bowel disease, arthritis, and hematologic disorders. It has been estimated that 50% of patients with pyoderma gangrenosum have ulcerative colitis.34 The relationship between the activity of pyoderma gangrenosum seems to be correlated with the underlying inflammatory bowel disease; however, the courses of the two diseases may also be independent. Therapy should be directed at controlling not only the pyoderma gangrenosum, but also the inflammatory bowel disease. Treatment of pyoderma gangrenosum includes topical therapy, which is usually unsuccessful; systemic corticosteroids; dapsone; minocycline; sulfapyridine; sulfasalazine; cyclosporin; clofazimine; and thalidomide. PANCREAS
Acute pancreatitis can be associated with Turner’s sign (periumbilical ecchymosis) and Cullen’s sign (ecchymosis of the flank), both caused by extravasation of hemorrhagic peritoneal fluid into the skin. Pancreatic panniculitis is a rare lobular panniculitis (inflammation of the subcutaneous fat lobules with fat necrosis and calcification)associated with pancreatitis or pancreatic carcinoma. Lesions consist of tender erythematous subcutaneous nodules occurring on the distal extremities, often periar-
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ticular. The lipolytic process also involves the periarticular tissue and medullary bone.I8
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Address reprint requests to Kenneth B. Gordon, MD Assistant Professor of Dermatology Department of Dermatology Northwestern University Medical school 303 East Chicago Avenue Chicago, IL 60611