You are in: eMedicine Specialties > Dermatology > INTERNAL MEDICINE Dermatologic Manifestations of Gastrointestinal DiseaseArticle Last Updated: Aug 29, 2006AUTHOR AND EDITOR INFORMATIONSection 1 of 11
  Author: Karen Guerrero, MD, Staff Physician, Department of Dermatology, Brooke Army Medical Center Coauthor(s): Gregory J Raugi, MD, PhD, Professor, Department of Internal Medicine, Division of Dermatology, University of Washington at Seattle; Chief, Dermatology Section, Primary and Specialty Care Service, Veterans Administration Medical Center of Seattle; Mark A Mallory, MD, Head of Endoscopy, Boise Gastroenterology Associates, St Alphonsus Regional Medical Center Editors: Robin Travers, MD, Professor, Department of Dermatology, Boston University School of Medicine; Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University School of Medicine; Consulting Staff, Mountain View Dermatology, PA; Christen M Mowad, MD, Assistant Professor, Department of Dermatology, Geisinger Medical Center; Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University; Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center Author and Editor Disclosure Synonyms and related keywords: Kaposi sarcoma, Plummer-Vinson syndrome, Patterson-Brown-Kelly syndrome, epidermolysis bullosa, EB, scleroderma, systemic sclerosis, pemphigus vulgaris, PV, acanthosis nigricans, Sister Mary Joseph nodule, Osler-Weber-Rendu syndrome, hereditary hemorrhagic telangiectasia, hemochromatosis, porphyria cutanea tarda, PCT, pancreatic fat necrosis, lichen planus, Peutz-Jeghers syndrome, PJS, Henoch-Schönlein purpura, dermatitis herpetiformis, DH, blue rubber bleb nevus syndrome, familial adenomatous polyposis, Gardner syndrome, Muir-Torre syndrome, MTS, Cowden disease, multiple hamartoma syndrome, Cronkhite-Canada syndrome, inflammatory bowel disease, Crohn disease, Crohn's disease, CD, ulcerative colitis, UC INTRODUCTIONSection 2 of 11
  Many disorders of the alimentary tract have dermatologic manifestations. A thorough understanding of the cutaneous/GI relationship can alert the astute clinician to occult disease within the GI tract. This review attempts to explore this relationship by taking a sequential look at the GI disorders that have dermatologic findings from the mouth to the anus. DERMATOLOGY AND THE PHARYNXSection 3 of 11
Kaposi sarcoma Kaposi sarcoma (KS) is a neoplasm of vascular endothelial and lymphoreticular cells that can involve the skin and numerous visceral organs. The disease can manifest in 4 distinct forms: classic, endemic, iatrogenic, and epidemic. Originally described by Kaposi in 1872, the prevalence of the disease has risen dramatically in the United States over the past 20 years with the spread of AIDS (the epidemic form of KS). Human herpesvirus type 8 (HHV-8) has been implicated in the pathogenesis of KS in both HIV-infected and non-HIV–infected patients. The name may be a misnomer given recent elucidation of the pathogenesis of HHV-8 in Kaposiform lesions. KS may in fact be a hyperplasia caused by infection with HHV-8, rather than a sarcoma. Supporting evidence for this proposition includes lack of clonality, multifocality, symmetry, absence of metastasis, and spontaneous regression with immune reconstitution. The cutaneous lesions of KS (occurring primarily in the classic and epidemic forms) begin as pink or red macules, which darken and become increasingly papular as they enlarge. Although the classic KS lesions tend to occur on the legs and feet, the epidemic KS lesions are more common on the face and trunk. Treatment of localized cutaneous disease includes radiotherapy, surgical excision, systemic therapy, or intralesional chemotherapy. In patients with widespread disease, therapy involves careful consideration of the possible agents as well as their potential adverse effects. Amongst the agents that attain a 30% response rate are interferons, antiviral agents (eg, zidovudine), cytotoxic agents (eg, vinblastine, etoposide), and combination therapy. For HIV-related KS with a low CD4 count or high viral load, antiretroviral therapy is the first-line therapy. In aggressive disease, liposomal doxorubicin or daunorubicin are the first-line chemotherapeutics. GI involvement occurs in 50-80% of patients with cutaneous KS and in almost 100% of those with oral lesions (see Media File 1). The GI tract may be involved at any level, although the most frequently afflicted sites (in order) are the small intestine, stomach, and esophagus. Oral lesions are most likely to affect the hard palate, followed in order of frequency by the gingiva and the tongue. In patients with non-HIV–associated KS, both the skin and GI lesions tend to have a relatively indolent course. In contrast, HIV-associated Kaposi lesions of the GI tract can have an aggressive clinical course, leading to extensive hemorrhage or partial small bowel obstruction. Treatment of symptomatic GI lesions involves laser ablation or surgical excision. DERMATOLOGY AND THE ESOPHAGUSSection 4 of 11
Plummer-Vinson syndrome (Patterson-Brown-Kelly syndrome) The pentad of Plummer-Vinson syndrome includes the mucocutaneous findings of koilonychia (brittle, spoon-shaped nails; see Media File 4) early loss of teeth, development of cheilosis, atrophy of the tongue, and angular stomatitis, along with iron deficiency anemia and the clinical complaint of dysphagia. The disease is rare in patients younger than 30 years, and women are affected in 80-90% of cases. Although the earlier diagnosis of iron deficiency and the ready availability of iron replacement have made this disease less common, the diagnosis of Plummer-Vinson syndrome nonetheless should be considered in patients presenting with long-standing intermittent dysphagia. Splenomegaly and edentia may aid in the diagnosis. Complications include progressive painless dysphagia, which is described by patients as a choking sensation that worsens with solid foods. Severe iron deficiency anemia can lead to devastating neurodegenerative consequences in children via hypomyelination. Iron is critical for oligodendrocyte and dopaminergic metabolism. In 5-10% of patients with a postcricoid web, esophageal carcinoma eventually may develop (see Media File 10). Diagnosis involves laboratory evaluation to confirm the presence of iron deficiency anemia and cineradiography to detect esophageal webs, which occur in the first 2-4 cm of the esophagus. Treatment involves iron supplementation, which often leads to rapid resolution of the dysphagia. In patients who continue to complain of dysphagia, therapy involves rupturing of the esophageal web either by endoscopy or bougienage. Epidermolysis bullosa The name epidermolysis bullosa (EB) is given to a diverse group of rare inherited diseases that cause fragile skin. The skin of these patients tends to form blisters at sites of minimal trauma, with symptomatology beginning at birth or early infancy. Clinical phenotypes include marked skin fragility, blisters, and erosions over trauma-prone parts of the body. Chronic trauma and healing leads to significant scarring and milia formation. The disease is divided clinically into the following 3 forms depending on the layer of blister formation: dystrophic (beneath lamina densa), junctional (within the lamina lucida), and simplex (intraepidermal). In dystrophic EB, oral erosions and early tooth decay are frequent manifestations. In addition, these patients have esophageal strictures, which tend to be located in the upper third of the esophagus, but they also can be seen in the lower third of the esophagus. The cause of these strictures is likely caused by repetitive trauma of food ingestion. Lesions generally become symptomatic before age 30 years. Therapy focuses on strict adherence to a soft diet, with mechanical dilation, surgical excision, and feeding gastrostomy as alternative choices. Other complications of dystrophic EB include the development of esophageal webs, constipation, and anal stenosis. An analysis of 20 consecutive patients with recessive dystrophic EB evaluated at a regional center demonstrated that all 20 had upper GI complaints, with most patients exhibiting abnormalities on endoscopic evaluation. Patients with junctional EB have many of the complications of dystrophic EB and may develop pyloric atresia. In patients with severe EB of any type, nutritional deficiency, anemia, and growth retardation may develop over time, principally from the presence of oral and GI complications. Scleroderma (systemic sclerosis) Scleroderma describes a multisystem disease of unknown etiology that causes fibrotic change in the skin, blood vessels, lungs, heart, kidneys, and GI tract. The disease affects all races and occurs worldwide, with clinical manifestations appearing most often in the third to fifth decade of life. In population studies, the prevalence of scleroderma has varied from 19-75 cases per 100,000 population. The systemic form of the disease is divided broadly into diffuse cutaneous scleroderma and limited cutaneous scleroderma. The dermatologic changes in scleroderma are progressive over time, generally beginning with the appearance of pitting edema on the face, hands, or feet (see Media File 5). Skin sclerosis begins, initially on the fingertips, and then spreads to the hands, with a relative sparing of the feet. A careful examination may reveal curved nails (a result of the underlying skin shrinking away while the nail does not) or periungual telangiectasia. On the face, hyperpigmentation and hypopigmentation can occur, along with a tightening of the skin over the nose, mouth, and forehead. The disease exhibits a variable course. Patients who demonstrate a rapid progression to total body involvement (2-3 y) are also more likely to develop changes in the visceral organs, such as the heart, lungs, and kidneys. Diffuse cutaneous disease manifests early with fatigue, arthralgias, carpal tunnel syndrome, puffy fingers, swollen feet and legs, or a positive serum antinuclear antibody test before developing either Raynaud phenomenon or definite skin thickening. Few patients develop systemic manifestations of disease without ever presenting with Raynaud phenomenon. Findings distinct to diffuse cutaneous disease include capillary dropout, the presence of palpable tendon friction rubs, and the appearance of finger joint contractures. The pace of skin thickening is rapid in diffuse cutaneous systemic sclerosis, with extension proximally to forearms, arms, and legs within several months. Internal organ dysfunction is frequent in the early diffuse cutaneous form, with severe visceral dysfunction most often occurring during the first 3 years of disease. Patients with the limited cutaneous form most frequently have Raynaud phenomenon with eventual progression in years to CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) syndrome (see Media File 9). Mat telangiectasias, which appear on peripheral sites (eg, hands, feet, mouth), are macular lesions ranging from 2-10 mm and are polygonal or oval. The presence of serum anticentromere antibody is a strong clue to the classification into the localized cutaneous form. As many as 90% of patients with scleroderma demonstrate some GI manifestations. Indeed, these symptoms may be the first manifestation of scleroderma and may precede the diagnosis by months or years. As in other organ systems, GI disease in scleroderma results from the excess collagen production, enhanced immunologic activity, and flawed cellular immune response. The most commonly affected areas are the lower two thirds of the esophagus, the mid duodenum, jejunum, and large intestine. The esophageal symptoms of scleroderma include a feeling of premature fullness, reflux esophagitis, dysphagia, and epigastric pain, all of which stem from an incompetent lower esophageal sphincter. As with other forms of reflux esophagitis, Barrett esophagus may develop, with the accompanying potential to transform to adenocarcinoma. Involvement of the stomach and small bowel in scleroderma is seen in approximately 50% of cases. Symptoms include anorexia, early fullness, diarrhea, nausea/vomiting, and obstipation. The causes of these ailments stem from impaired motility, which, in turn, leads to chronic intestinal pseudo-obstruction, malnutrition, and bacterial overgrowth. Treatment of the underlying causes involves the use of promotility agents on a regular basis, with antibiotic therapy used intermittently to reduce bacterial growth. As in many chronic bacterial infections, the development of resistant organisms is a concern with long-term use of antibiotics. When prolonged antimicrobial therapy is necessary, multiple broad-spectrum antibiotics on a rotating basis have been used with some success. Colonic involvement has been demonstrated by barium studies to affect between 10-50% of patients with scleroderma. Changes within the large intestine may result in chronic constipation, fecal impaction, and bowel obstruction. Involvement of the anal sphincter may lead to incontinence or even prolapse. Finally, overt or occult bleeding may develop as a result of trauma to telangiectasias, which may appear anywhere throughout the bowel. Treatment is symptomatic in all cases. Because the patient may require many years of therapy, careful consideration for the adverse effects of various promotility or antimotility agents should be undertaken. Pemphigus vulgaris Pemphigus vulgaris (PV) is an autoimmune blistering disorder characterized by loss of cell-to-cell adhesion in the epithelial suprabasal layer. Clinical manifestations include skin and mucous membranes findings that can also affect the esophagus. The incidence of PV is approximately 1 case in 100,000 population, with a higher prevalence in people of Jewish or Mediterranean descent; the prevalence of esophageal involvement has not yet been firmly established, although a recent paper in The Lancet found evidence of esophageal involvement in 7 of 8 patients with PV who underwent endoscopy (87.5%). Skin lesions range in size from 1-10 cm, and they are bullous, superficial, and easily ruptured by trauma. Denuded areas are partially or totally covered with crust that heal poorly. Characteristic findings on examination include lateral extension into adjacent tissue with palpation of normal-appearing skin or the bullae spread phenomenon, which is when pressure on an intact bulla forces fluid to spread under adjacent tissue. Mucosal sites also commonly are involved, including the oral mucosa (often the presenting site), anus, cervix, and conjunctivae. In 1970, Raque et al first described involvement of the esophagus, and it has been noted in multiple subsequent case reports. Antigenic confirmation of the disease correlation occurred in 1998, with the discovery that the target cell adhesion molecule of the PV autoantibodies to desmoglein 3 is strongly expressed in the esophageal epithelia. Symptoms of esophageal involvement include persistent sore throat, dysphagia, and odynophagia. In extreme cases, serious problems such as esophageal stenosis have been described. On endoscopy, the lesions can appear as bullae or red irregular erosions (likely ruptured bullae) with a red border covered by a white exudate. Sloughing of the entire esophageal lining in the form of a cast (esophagitis dissecans superficialis) may occur. Treatment for PV (oral and esophageal) involves the administration of steroids or other immunosuppressive agents such as azathioprine and methotrexate. DERMATOLOGY AND THE STOMACHSection 5 of 11
Acanthosis nigricans This relatively common skin finding appears as a brown-to-black, smooth, velvety plaque found in areas of skin folds, most commonly the neck, axillae, and groin (see Media File 6). An infrequent but important accompanying finding is the presence of acanthosis palmaris, or tripe palms, which appear as pronounced skin markings on the palmar surfaces of the hands together with diffuse velvety cobbled or honeycombed surface. It was first described in 1890 by Pollitzer and Janovsky in a case suspected to be associated with an occult abdominal neoplasm. The mechanism responsible for the cutaneous lesions has not been identified. Tumor products may have their effect on skin through activation of insulinlike growth factors or their receptors in the skin. Alpha-transforming growth factors produced by tumor cells may have a role in malignant acanthosis nigricans through epidermal growth factor receptors found in the skin. One other hypothesis is that lytic factors produced by tumor cells may weaken the extracellular matrix of the skin, predisposing to acanthosis nigricans. Independent of the malignant variant, other identified associations include obesity, familial trait, diabetes mellitus, other endocrine disorders, or drugs (eg, corticosteroids, estrogens, nicotinic acid). Although the lesions are asymptomatic, relief from any associated irritation can be attempted with oral and topical retinoids, keratolytics, topical steroids, and oral cyproheptadine. In patients with acanthosis nigricans, the possibility of an intra-abdominal malignancy should be considered, especially in patients without an obvious predisposing condition. Clinical features such as a large number of plaques, weight loss, rapid progression of lesions, or the discovery of plaques in unusual locations, such as the lips, oral mucosa, hands, and genitalia, should be additional alerting factors. Indeed, the skin lesions of malignant acanthosis nigricans often are discovered prior to the cancer diagnosis. The presence of tripe palms heralds an underlying cancer in 94% of patients. The malignancies associated with acanthosis nigricans include adenocarcinoma (85% of cases), of which gastric carcinoma is present in 60%. Other reported sites of malignancy include the lung, bladder, endometrium, adrenal, bile duct, kidneys, thyroid, breast, liver, larynx, cervix, ovaries, prostate, and testicles. Nearly all cases are adenocarcinoma despite the site of origin. Prognosis is very poor for these patients, with a 1-year mortality rate of greater than 50%. In patients with successful tumor resection, the skin lesions often disappear spontaneously over time. Sister Mary Joseph nodule As head nurse and eventually skilled surgical assistant to William Mayo, MD, Sister Mary Joseph was the first to note that the presence of a periumbilical nodule heralded an advanced intra-abdominal malignancy (see Media File 7). The lesion was first coined "pants button umbilicus" by Dr. Mayo in 1928, and the Sister's name was not attached to the lesion until the 11th edition of Hamilton Bailey's Physical Signs in Clinical Surgery. The cutaneous finding is a firm, nontender nodule of red or purple hue that represents a metastasis from the primary tumor. The nodule most often results from contiguous extension of the tumor from the peritoneum, although lymphatic and venous pathways likely contribute in some cases. As recognized by Sister Mary Joseph, the presence of the umbilical nodule is associated with advanced intra-abdominal malignancies. Approximately 90% of these malignancies are adenocarcinoma, with gastric and ovarian being the most commonly discovered primary malignancy. Other cited primary sites include the pancreas and bowel. Because the nodule is so easy to biopsy and because most associated cancers are inoperable at the time of diagnosis, the ability to identify this lesion may save a patient an unnecessary diagnostic surgery. However, keep in mind that the biopsy will aid in successfully diagnosing the primary site in only approximately half the cases. Osler-Weber-Rendu syndrome (hereditary hemorrhagic telangiectasia) This autosomal dominant disorder occurs at a frequency of 1-2 cases per 10,000 population and is characterized by vascular dilatations of the skin as well as the oral, nasal, and GI mucosa (see Media File 8). First described by Babington in 1865 and further characterized by Rendu, Osler, and Weber, the diagnosis is based on the presence of three of the 4 following criteria: epistaxes, telangiectasia, visceral lesions, and an appropriate family history. The dermatologic examination reveals numerous 1- to 3-mm macular or papular, sharply demarcated telangiectases on the face, lips, palate, tongue, ears, chest, or extremities, with occasional presentation under nails. The age of onset for the telangiectases is most often the third decade of life, although earlier presentations may occur during adolescence. Although the distribution of lesions and associated bleeding diathesis are clinically suggestive of hereditary hemorrhagic telangiectasia, it may occasionally be difficult to distinguish from similar cutaneous findings seen in generalized essential telangiectasia. Treatment of the dermatologic lesions involves electrosurgery or laser therapy if warranted for cosmetic reasons. The most common and often cardinal clinical manifestation of Osler-Weber-Rendu disease is epistaxis, which generally starts in childhood and occurs in up to 80% of patients during their lifetime. The epistaxis results from spontaneous bleeding from telangiectases of the nasal mucosa and is generally recurrent. In about one half of patients, the frequency and seriousness of the epistaxis increases as the patient ages, leading to blood transfusions in as many as 30% of patients. Treatment with topical estrogen, laser therapy, and skin grafting have been attempted to reduce the incidence of epistaxis. The second most common manifestation involves spontaneous hemorrhage from vascular telangiectasia within the GI tract. The culprit lesions resemble the skin lesions in form and size and most often are found in the stomach or the duodenum. A ring of less vascularized tissue surrounding the GI lesions is a characteristic finding on endoscopy. Bleeding from these telangiectases tends to begin in the fifth or sixth decade of life and often can be severe. Treatment modalities include endoscopic laser coagulation, bipolar electrocoagulation, surgical excision of severely affected bowel segments, or medical management with low-dose combination estrogen/progesterone or aminocaproic acid. Another less frequent GI correlate is the presence of large arteriovenous malformations that can develop within the liver, leading to substantial shunt formation. Although the prevalence of these lesions is unknown, they have been blamed for portal hypertension with esophageal varices in some cases. Diagnosis involves the presence of elevated gamma-glutamyltransferase (GGT) or alkaline phosphatase levels, with confirmation by CT scan or color Doppler ultrasound. Treatment has tended to be conservative, with limited data on chemoembolization and surgical ligation suggesting that both may be effective when therapeutic intervention is deemed necessary. DERMATOLOGY AND THE LIVER AND THE PANCREASSection 6 of 11
Hemochromatosis Hemochromatosis is a disorder of iron overload leading to excess deposition in multiple body organs. The hereditary form was first identified in the late 19th century as the classic triad of glycosuria (diabetes), bronze skin pigmentation, and cirrhosis. The dermatologic manifestation of the disease involves skin hyperpigmentation, which is present in more than 90% of patients at the time of diagnosis. This discoloration has a characteristic metallic gray or bronze-brown color that is generally diffuse, but it may be increased in areas of scars or on the face, neck, extensor surfaces of the arms, or genitalia. Approximately 20% of patients also have pigmentation of the buccal mucosa or the conjunctiva. Other characteristic skin findings in hemochromatosis include skin atrophy, ichthyosis, partial hair loss (most often in the pubic region), and koilonychia. The characteristic skin changes of hemochromatosis are believed to result from increased melanin. The actual presence of iron seen in dermal sweat glands and the basal layer of the epidermis lead to the pigmentation seen in the late stages. Treatment of these patients with phlebotomy or chelating agents results in a decrease in skin pigmentation over time. The most common GI finding in hemochromatosis is hepatomegaly, which is observed in more than 95% of symptomatic patients. Despite clinical findings of functional liver impairment (eg, hair loss, gynecomastia, testicular shrinkage), laboratory findings are generally unimpressive. Because hemochromatosis is not an inflammatory disease, liver enzyme (ie, aspartate aminotransferase, alanine aminotransferase) levels can be normal, even in advanced disease. In patients with long-standing untreated hemochromatosis, cirrhosis may develop, leading to hepatocellular carcinoma in as many as 30% of patients. Cirrhosis or its complications account for approximately 89% of hemochromatosis related deaths. Overall, patients with hereditary hemochromatosis have an estimated 5% annual risk for hepatocellular carcinoma after the development of cirrhosis. Primary treatment involves phlebotomy and chelating agents, with conventional management of hepatic failure should this condition arise. A 1998 National Institutes of Health consensus conference suggested weekly phlebotomy until serum ferritin concentration is less than 50 mcg/L and transferrin saturation is less than 50%. Porphyria cutanea tarda Porphyria cutanea tarda is the most common porphyria occurring in adults, with a prevalence ranging from 1 case in 5,000 to 1 case in 36,000 people. Cutaneous findings are characterized by skin photosensitivity with increased skin fragility, facial hypertrichosis, blisters, scarring with milia formation, and skin hyperpigmentation on the hands and other sun-exposed areas. Porphyria cutanea tarda results from the decreased activity of the enzyme uroporphyrinogen decarboxylase (UROD), the fifth enzyme in the heme biosynthetic pathway. The disease can be either sporadic or familial, but, in either case, it is clear that extrinsic factors play an important role in producing a clinical manifestation of the disease. Endogenous and exogenous factors (eg, alcohol, iron, estrogen, porphyrins, chronic hepatitis C virus infection, polychlorinated biphenyls, polychlorinated cyclic hydrocarbons) produce oxidative stress on the liver, leading to inhibition or decreased production of UROD. The pathogenesis of iron in porphyria cutanea tarda also provides the link to hereditary hemochromatosis. All patients with porphyria cutanea tarda should undergo screening for the gene mutation identified in hereditary hemochromatosis. Diagnosis involves the discovery of increased porphyrins in the blood, liver, stool, and urine. The first step of treatment involves the removal of possible triggers, including iron supplementation, alcohol, and estrogens. If symptoms persist, repeated phlebotomy decreases the total iron load and lead to significant clinical improvement. Phlebotomy may induce clinical remission, reduce urinary porphyrins, and improve the sclerodermalike skin changes, but it is not proven to improve liver histology. Other options include chloroquine and hydroxychloroquine, which form water-soluble complexes with the porphyrins, facilitating their excretion in the urine. Antimalarial therapy can be quite dangerous in patients with porphyria; it may precipitate massive hepatic injury. Therefore, doses should be initiated at low doses (125 mg, 2-3 times per wk) to reduce the likelihood of acute hepatic injury and retinopathy. Such therapy should be attempted only when other therapy has failed and with a clear understanding of the risks involved. The prevalence of hepatitis C in patients with PCT has been measured in series of patients from many countries, with rates of as high as 85% in these patients. Interestingly, multiple studies into the extrahepatic manifestations of patients with hepatitis C have failed to find an increased rate of PCT. This disparity may be explained by the fact that the background rate of PCT is relatively low in the populations in these latter studies and that finding an association would require study of larger populations of patients. The cause of the probable association between hepatitis C and PCT has been debated extensively in the literature. Some contend that hepatitis C serves to trigger attacks of PCT in predisposed patients, but this theory remains to be conclusively proven. Alternatively, others have hypothesized that patients with PCT are somehow more susceptible to hepatitis C infection. In either case, the probable linkage between these 2 diseases suggests that patients with PCT should be tested for hepatitis C and that their treatment may be augmented by considering concomitant therapy for hepatitis C. Pancreatic fat necrosis First identified in 1883 by Chiari, the term pancreatic fat necrosis describes the association of skin nodules with pancreatic disease. The dermatologic lesions can be painless or painful and tend to appear first on the legs followed by the buttocks and trunk. Initial presentation may include pruritus of lower extremities with associated splotchy erythema. Progression to a nodular component is associated with tenderness. Nodules, usually no more than 30, have been described to spontaneously drain white creamy exudate, after which the lesion heals with hyperpigmentation and local scar formation. The pathologic correlate includes the presence of subcutaneous fat necrosis together with ghostlike calcified fat cells containing thick shadowy walls and no nucleus. The presence of these fluctuant lesions on the skin surface has been used to identify underlying pancreatic disease. Often, it is the skin eruption that leads the patient to medical care in the first place. Pancreatic fat necrosis occurs in up to 65% of patients with pancreatic cancer and in up to 22% of patients with pancreatitis. More than half the patients with pancreatic cancer–associated subcutaneous fat necrosis have the acinar form. The presence of subcutaneous fat necrosis along with pancreatic disease is a poor prognostic indicator; one series of 27 patients demonstrated that all 8 patients with associated pancreatic carcinoma and 8 of the 19 patients with pancreatitis died as a result of their disease. The development of subcutaneous nodules in cases of pancreatic disease may derive from the release of pancreatic lipolytic enzymes, a hypothesis confirmed by the biochemical discovery of persistently elevated serum lipase and trypsin levels 100-fold in one case report. The relief of pancreatic insult by endoscopic retrograde cholangiopancreatography (ERCP) in another recent case report not only halted serum amylase release but also resolved the symptoms of panniculitis. Lichen planus Lichen planus is an idiopathic inflammatory disorder of the skin and mucous membranes known to be associated with a variety of liver diseases. The skin lesions are purple, polygonal, flat-topped papules that are usually pruritic. A characteristic finding on close (through a lens) examination is the presence of white or gray linear markings known as Wickham striae. They may be found anywhere on the skin, although certain sites, such as the wrists, ankles, shins, lower back, and genitalia, are most commonly affected. The mucous membranes also are affected quite frequently and sometimes are the only site involved. The lesions are most frequently white reticulated papules that form a lacelike pattern. Both cutaneous and oral lesions exhibit Köbner phenomenon, occurring at sites of previous trauma, leading to oral lesions on buccal mucosa and lateral surfaces of the tongue. Nail dystrophy is common, including the presence of pterygia and longitudinal ridges. Treatment for both the skin and mucous membrane lesions involves the use of local or systemic steroids, specially formulated oral preparations of topical immunomodulators and systemic immunosuppressives for treatment-resistant cases to include thalidomide, azathioprine, mycophenolate mofetil, and systemic retinoids. Almost two thirds of patients have spontaneous remission of the skin lesions within 1 year. The pathogenesis of lichen planus is not clear, but several authors have postulated an association with both primary biliary cirrhosis (PBC) and chronic hepatitis B and C. The association of PBC is particularly compelling because both diseases involve immunopathologic mechanisms that are not yet fully understood. However, not all authors have agreed that these associations occur at any more than the expected random frequency. Precipitating factors for oral lesions include mechanical trauma from dental procedures and dental prostheses, heat and irritation from tobacco products, and oral habits to include lip and cheek chewing. DERMATOLOGY AND THE SMALL INTESTINESection 7 of 11
Peutz-Jeghers syndrome An autosomal dominant disorder affecting approximately 1 in 10,000 live births, Peutz-Jeghers syndrome (PJS) is characterized by the presence of mucocutaneous hyperpigmentation together with GI polyposis. Clinical diagnosis requires histologic identification of intestinal hamartomatous polyps in conjunction with 2 of 3 additional clinical criteria that include small bowel polyposis, mucocutaneous melanotic pigmentation, and a family history of PJS. The skin findings first appear in infancy or early childhood and involve blue-brown macular lesions of 1-10 mm. The lesions most commonly are found on the lips (95% of patients) and buccal mucosa (83%). Other frequently affected sites include the palms of the hands, fingers, nose, gingiva, eyelids, and hard palate. Over time, the mucosal lesions tend to persist, while the cutaneous lesions fade away. Ruby and argon lasers have been used successfully to eradicate the mouth pigmentation. GI manifestations of PJS involve the presence of multiple hamartomatous polyps occurring most commonly in the jejunum (see Media File 2). Other sites include the stomach, duodenum, ileum, and colon. Symptoms may include abdominal pain, bleeding, rectal prolapse, or obstruction due to intussusception. In addition, 2-3% of patients develop GI carcinoma during their lifetimes, a frequency that has led to the recommendation of upper and lower endoscopy every 2 years in patients with PJS, with removal of all large polyps. Care of these patients also involves regular surveillance for cancers involving the breast, ovary, testicle (Sertoli cell testicular tumors, leading to associated gynecomastia), cervix, thyroid, and other tissues. These recommendations are supported by a recent long-term cohort study of 34 patients with PJS that demonstrated both a disproportionate number of noncutaneous cancers (26 cases, 16 non-GI tract, relative risk 9.9) and an unusually young age of diagnosis of these carcinomas (average age 39.4 y). Patients with a clinical diagnosis of PJS should have ongoing surveillance of all these organ systems. Henoch-Schönlein purpura This small vessel vasculitis manifests clinically by the syndrome of palpable purpura, arthralgias, abdominal symptoms, and glomerulonephritis. Males are affected twice as frequently as females, with an overall incidence of 14 cases per 100,000 population. The diagnosis usually is made in early childhood, but it also can present in infancy or adulthood. The disease is believed to be due to the deposition of immunoglobulin A (IgA)–mediated immune complexes throughout the body. A variety of triggers for this process have been proposed, including insect bites, seasonal allergens, upper respiratory tract infections, various medications, and foods. The skin abnormalities are present in all patients at some point in their disease process and involve the presence of palpable purpuric lesions found most commonly on the buttocks and legs. The lesions may appear in groups and may be vesicular or ulcerating in some cases. Definitive diagnosis can be obtained through direct immunofluorescence of early lesions (aged <24 h), revealing a perivascular deposition of IgA. Renal findings in patients with this disease include glomerulonephritis with the presence of proteinuria, microscopic hematuria, and often red cell casts. Musculoskeletal pain can be diffuse and severe in some cases, although less than 20% of patients initially present with this symptom. Adults, in comparison to children, seem to more commonly present with symmetric arthralgias and arthritis of knees and ankles. Gastroenterologic symptoms, which are found in more than 50% of patients with Henoch-Schönlein purpura, include colicky abdominal pain, diarrhea/constipation, occult or occasionally overt bleeding, and rarely intussusception or perforation. These symptoms may appear simultaneously with the skin lesions, or they may appear several days to weeks earlier. Endoscopic evaluation may demonstrate marked generalized redness, raised lesions, multiple ulcerations, or diffuse erosive lesions. A recent retrospective study aimed at determining the distribution of GI involvement in 7 patients with Henoch-Schönlein purpura found the duodenum and small intestine to be the most frequently involved sites. The natural course of the disease is complete resolution over weeks to months. However, the presentation of Henoch-Schönlein purpura differs significantly with age; older patients exhibit much more severe renal and extrarenal manifestations than younger patients. The use of corticosteroids has been reported to be helpful in reducing the GI symptoms, although no placebo-controlled trials have been performed to demonstrate a clear benefit. A reasonable management strategy involves a short (1 wk) course of steroids in patients with severe discomfort. Dermatitis herpetiformis This uncommon blistering disorder is characterized by the development of small vesicular lesions found in a symmetric distribution of both upper and lower extensor surfaces and the scalp. First described in 1884 by Louis Duhring, MD, the usual age of onset of dermatitis herpetiformis is in the third decade of life. Most patients experience severe pruritus as a result of the skin lesions, although some are almost completely asymptomatic. Pruritus can lead to significant excoriation and secondary changes, leading to misdiagnosis of atopic dermatitis. Diagnosis is made when a biopsy specimen demonstrates the presence of IgA at the dermoepidermal junction or within the dermal papillae on direct immunofluorescence. In patients with dermatitis herpetiformis, 20% have a clinically overt celiac disorder while almost 100 percent of patients with dermatitis herpetiformis have demonstratable pathologic changes of celiac disease on small intestinal biopsy. Indeed, both dermatitis herpetiformis and celiac disease have been found to share class II HLA allele sites in recent immunogenetic studies, a finding confirmed clinically by case reports of monozygotic twins afflicted by both diseases. The clinical manifestations of the celiac disease (also known as gluten-sensitive enteropathy and celiac sprue) are caused by the inability to absorb gluten from the diet. Patients experience weight loss, diarrhea, bloating, and steatorrhea. Chronic problems with malabsorption eventually may lead to iron or folate-deficient anemia states. Therapy involves the adoption of a gluten-free diet, with avoidance of foods such as wheat, barley, and rye. The initiation of therapy with dapsone or sulfapyridine results in a dramatic improvement in both GI and dermatologic symptoms; a prompt improvement following therapy can confirm the diagnosis. Blue rubber bleb nevus syndrome This rare disorder is characterized by the combination of cutaneous hemangiomas and GI bleeding due to the presence of vascular malformations. A clinical syndrome first described by Bean in 1958, transmission may be sporadic or autosomal dominant. The clinical manifestations most often present in birth or early childhood, although some cases may not be identified until adulthood. The skin lesions can number from 1 to more than 100 and may come in 3 forms:
The GI manifestations of the blue rubber bleb nevus syndrome involve the presence of vascular malformations found most frequently in the small intestine and colon (although lesions have been identified in the mesentery, lung, liver, eye, and CNS.) The malformations project into the gut lumen and resemble the nodular skin lesions in appearance. Clinically, these malformations usually cause occult bleeding, although frank melena, hematochezia, or even intussusception may occur. The treatment is largely dependent upon the extent of the disease course; for mild blood losses over time, therapeutic intervention can involve monitoring, iron replacement, and blood transfusions when needed. In severe cases, treatment may require endoscopic therapy with bipolar electrocautery or YAG laser, or even surgical resection of affected areas. DERMATOLOGY AND THE LARGE INTESTINESection 8 of 11
Familial adenomatous polyposis (Gardner syndrome) Gardner syndrome describes an autosomal dominant disorder involving the triad of epidermal cysts, osteomas, and adenomatous GI polyposis. Originally described by Gardner in 1953, the disease is now known to involve a single gene defect on chromosome 5. The epidermal cysts are found in more than 50% of patients and tend to appear in decreasing likelihood of occurrence on the lower extremities, face, scalp, and upper extremities. The age of onset is the early teenage years, and they are almost always multiple. Cutaneous cysts frequently predate intestinal polyps. Osteomas, located most frequently in the mandible or maxilla, occur in at least 75% of patients with Gardner syndrome. Other associated findings include desmoid tumors (visceral and nonvisceral types), pilomatricomas, dental abnormalities, and pigmented ocular fundal lesions termed congenital hypertrophy of the retinal epithelium. The GI manifestation of Gardner syndrome involves the presence of adenomatous polyps, which are believed to occur in 100% of patients at some point in their lifetime. The polyps are first noted at an average age of 22 years and tend to occur in large numbers (>100) in any part of the colon. These lesions, which also can be found in the duodenum around the ampulla of Vater, eventually progress to carcinoma in almost all patients if left untreated. Therapy involves regular colonoscopy and excision of polyps. Muir-Torre syndrome As another autosomal dominant disorder with variable expressivity, the Muir-Torre syndrome (MTS) also links abnormal skin findings with colonic malignant potential. Described separately by Muir and Torre in 1967, the syndrome associates sebaceous adenomas with an increased propensity for colorectal carcinoma. The defect has been attributed to a DNA mismatch repair gene mutation, a discovery that now allows physicians to screen relatives of affected patients. The skin findings in Muir-Torre syndrome are a diverse lot, including sebaceous neoplasms such as adenoma, epithelioma, carcinoma, basal cell carcinoma with sebaceous cell differentiation, and keratoacanthomas. The lesions most often appear in adulthood and usually are located on the head or neck with sebaceous carcinomas appearing on the eyelid with origins from the meibomian gland or from the Zeiss glands. Unlike the universal presence of polyps in Gardner syndrome, patients with Muir-Torre have colonic polyposis in only approximately half the cases. However, visceral malignancies develop in a large proportion of patients, most frequently in the colon (51% of all primary tumors). Other sites of carcinoma include the larynx, duodenum, ileum, stomach, uterus, ovary, ureter, kidney, and bladder. The malignancies associated with MTS tend to be less aggressive than those unassociated with the syndrome, leading to a better prognosis than one might otherwise suppose given the malignancy. Treatment of patients with MTS involves regular screening for GI and genitourinary cancers, including annual colonoscopy beginning at age 25 years. Cowden disease (multiple hamartoma syndrome) Cowden disease is a rare disease of autosomal dominant inheritance that is characterized by hamartomas of various tissues. Dermatologic findings include trichilemmomas (ie, skin colored papules around facial orifices), acral keratoses, and oral papillomas. The disease is associated with a variety of malignancies, including breast, thyroid, endometrial, cervical, and colon cancer. GI polyposis occurs in at least 35% of patients with Cowden disease, a figure that may be an underestimate because of incomplete endoscopic examination in many patients. The most common sites of polyposis are the colon and rectum, although polyps have been documented in the esophagus, stomach, gallbladder, and small bowel. A review of the 67 patients with Cowden disease who have undergone endoscopic evaluation over the past 30 years (Marra, 1994) demonstrates that most polyps discovered are nonadenomatous, although approximately 24% were adenomatous. Of particular concern are the 12 patients (18%) who had adenomatous colonic and rectal polyps, an established risk factor for colorectal cancer. Although the precise risk of colon cancer in patients with Cowden disease has not been firmly established, all patients should receive a thorough initial GI workup with follow-up care as appropriate. Cronkhite-Canada syndrome This tetrad of diffuse macular hyperpigmentation, alopecia, nail atrophy, and GI polyposis initially was described in 2 patients by Cronkhite and Canada in 1952. This extremely rarely identified syndrome has been further defined with the collection of more than 50 cases from the literature. The average age of onset is 59, with a range of ages of 31-86 years. The hyperpigmented macules and plaques (85% of patients) most often occur on the upper extremities but may be diffusely distributed. Nail dystrophy (affecting 90% of patients) is seen in all fingers and toes and is characterized by onycholysis and a unique pattern of normal nail in the shape of an inverted triangle that borders up against dystrophic nail. The alopecia (>95% of patients) described with this disease is of rapid onset, with progression from patchy hair loss to eventual complete loss of hair. GI symptoms include diarrhea, significant weight loss, and abdominal pain. The presence of hamartomatous polyps is quite common, with transformation to malignancy occurring in some cases. Cronkhite-Canada syndrome is fatal in about one half of patients, usually as a result of malnutrition or persistent diarrhea. Therapy involves nutritional support and careful observation for metabolic derangements over the course of the illness. A recent case report noted a temporal association with the initiation of ranitidine therapy and resolution of clinical symptoms in one patient, although the mechanism of response to therapy in this patient is unclear. Bannayan-Riley-Ruvalcaba syndrome This is a rare autosomal dominant genodermatosis with classic triad of macrocephaly, genital lentiginosis, and intestinal polyposis. Given overlap with Cowden syndrome with phenotypic expression and similar allelic syndromes (both with identical PTEN mutations), both diseases are collectively referred to as PTEN hamartoma-tumor syndrome. Mucocutaneous findings include vascular malformations, lipomatosis, speckled lentigines of the penis and vulva, facial acanthosis nigricanslike lesions, and multiple acrochordons. Similarly to Cowden disease, patients can have prominent diffuse hamartomatous polyposis and vascular lipomatous hamartomas manifesting as tender or painful, rapidly enlarging, aggressive subcutaneous and/or visceral lesions. Prominent hamartomatous polyposis occurs in 35-45% of cases of Bannayan-Riley-Ruvalcaba syndrome but is not associated with an increased risk of malignancy. Polyps can located anywhere along the GI tract, with a preference for colonic or rectal localization. Presentation of polyposis may not manifest until middle age, requiring routine follow-up visits with a yearly hemoglobin test and fecal occult blood test. During childhood, symptoms include massive watery diarrhea, abdominal pain, painless rectal bleeding, and chronic anemia. The size of the polyps can be quite large, leading to intussusception and intestinal obstruction. Inflammatory bowel disease Both Crohn disease (CD) and ulcerative colitis (UC) bring with them a considerable host of dermatologic findings. Since there is a large amount of overlap in these findings, the diseases will be considered together in this discussion. CD is characterized clinically by symptoms of fever, abdominal pain, fatigability, and diarrhea that may or may not be bloody. The disease most often is diagnosed in patients aged 15-35 years, although it has been described in people of all ages. Histologically, the inflammatory lesions of CD extend through all layers of the gut lining and may extend into the mesentery or local lymphatics. The disease may appear in all areas of the GI tract from the mouth to the anus and often is characterized by skip lesions, areas of the bowel that are completely free of inflammation. Although UC affects patients in similar age groups, this disease is more likely to result in bloody diarrhea and abdominal distension. The pathologic appearance of this disease demonstrates continuous colonic involvement from the rectum to the junction with the terminal ileum, with the inflammation confined to the mucosal layer. Diagnosis of both diseases generally is made easily with a combination of sigmoidoscopy and barium-assisted radiologic studies. Cutaneous manifestations of inflammatory bowel disease are quite common, with various studies suggesting skin involvement in 9-19% of patients with UC and 9-40% in patients with CD. The most common skin findings are described below.
ACKNOWLEDGMENTSSection 9 of 11
We are indebted to Jan V. Hirschmann, MD, for his critical reading of this manuscript and to Richard A. Willson, MD, for his helpful suggestions during the creation of this article. MULTIMEDIASection 10 of 11
REFERENCESSection 11 of 11
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