Oral Disease and Oral-Cutaneous Manifestations of Gastrointestinal and Liver Disease

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CHAPTER 22 Oral Disease and Oral-Cutaneous Manifestations of Gastrointestinal and Liver Disease

DISORDERS OF THE MOUTH AND TONGUE

Xerostomia (dry mouth) is a common complaint with destruction or atrophy of the salivary glands as a result of autoimmune disease (Sjögren’s syndrome), after radiation therapy, or as a consequence of a variety of medications, such as anticholinergics, H1 antihistamines, tricyclic antidepressants, hypnotics, sedatives, antihypertensives, antipsychotics, antiparkinson agents, and diuretics.1

Sjögren’s syndrome is an autoimmune disease that is classified by the triad of xerostomia, keratoconjunctivitis sicca (dry eyes), and arthritis.2,3 It may be characterized as primary when no other disorders are diagnosed or secondary when connective tissue disease, such as rheumatoid arthritis or systemic lupus erythematosus, is present. The oral manifestations of Sjögren’s syndrome are caused by the irreversible destruction of the salivary glands by a lymphocytic infiltrate that results in diminished or absent saliva. The lack of saliva is associated with difficulty chewing, odynophagia, and diminished taste and smell, as well as mucosal erythema, increased incidence of dental caries, oral candidiasis, and salivary gland calculi. Sucking mints and chewing gum may help by increasing salivary flow, which assists in the the removal of debris. Patients with xerostomia should avoid sweets and acidic foods and beverages and be encouraged to sip water and suck ice chips frequently. Preparations containing 1% sodium carboxymethyl cellulose may be used to moisten the oral cavity. Salivary stimulants such as cevimeline (Evoxac), 30 mg three times daily, or pilocarpine (Salagen), 5 mg four times daily, are effective sialogogues.

Glossitis, inflammation of the tongue, occurs in a heterogeneous group of disorders that includes nutritional deficiencies, chemical irritants, drug reactions, iron deficiency, pernicious anemia, amyloidosis, sarcoidosis, infections, and vesiculoerosive diseases. Sometimes, no underlying cause can be detected.3 Patients may complain of lingual pain (glossodynia) or burning sensation (glossopyrosis). Loss of filiform papillae results in a spectrum of changes, from patchy erythema with or without erosive changes to a completely smooth, atrophic, erythematous surface (Fig. 22-1). Atrophic glossitis is a sign of protein-calorie malnutrition and muscle atrophy and is commonly found in older adults. Median rhomboid glossitis manifests as an asymptomatic, well-defined erythematous patch in the midposterior dorsum of the tongue.4

Glossodynia (burning sensation or pain in tongue) in the absence of clinical or histologic evidence of glossitis may be associated with anxiety or depression. Although it is found most commonly in postmenopausal women, hormonal therapy is of no value.5 Hypnosis has been found to improve glossodynia when a psychogenic component or when organic disease is present.6 Serologic evaluation for hypomagnesemia and for vitamin B12 or folate deficiency, as well as a complete medication history, may occasionally yield a correctable cause.7

Hypogeusia (diminished sense of taste) and dysgeusia (distortion of normal taste) are other complaints that are sometimes associated with glossitis. Hypogeusia and dysgeusia have been attributed to various neurologic, nutritional, and metabolic disorders and to a large number of medications. The evidence supporting these associations is tenuous.8,9 How taste buds are affected by aging is not understood. Tobacco smokers, denture wearers, and patients with anxiety or other psychiatric disorders commonly complain of hypogeusia and dysgeusia. Radiation therapy to the head and neck may result in altered taste. The therapy is empirical and includes identifying and correcting any associated condition. Patients may be treated with zinc supplementation, a low-dose anxiolytic, or an antidepressant medication such as a selective serotonin reuptake inhibitor (SSRI).10 Paradoxically, tricyclic antidepressant medications block responses to a wide range of taste stimuli and may contribute to clinical reports of hypogeusia and dysgeusia.11,12

Geographic tongue (benign migratory glossitis) is characterized by patchy loss of filiform papillae forming irregular, moving configurations that resemble geographic landmarks on a map. Geographic tongue is reported to occur in up to 4% of the population. Patients may complain of pain or difficulty in eating acidic, spicy, or salty foods. Recurrent episodes are common and may represent pustular psoriasis. Some patients may present with an exfoliative cheilitis and/or migratory annular plaques and papules on any of the oral mucosal surfaces, representing geographic mucositis in ectopic locations. Histologically, spongiosus and neutrophilic microabscesses are found in the epithelium, with no evidence of candidiasis. Treatment consists of topical anesthetics, benzocaine (Orabase) or aluminium hydroxide and magnesium hydroxide (Maalox) protective coatings, and topical glucocorticoids, along with control of the underlying cutaneous psoriasis if present.13 Geographic tongue has no known associations with malignancy.14

Black hairy tongue is another common entity. The dorsal surface of the tongue may appear yellow, green, brown, or black because of exogenous pigment trapped within elongated keratin strands of filiform papillae.15 Acquired black hairy tongue is seen most commonly in chronic smokers and often follows a course of systemic antibiotics, the use of hydrogen peroxide, or drinking coffee or tea.14 Off-label treatment consists of 25% podophyllum or topical tretinoin (Retin-A) gel.15 Chronic débridement with a tongue scraper may also be helpful.

MUCOCUTANEOUS DISORDERS

CANDIDIASIS

Candida spp. (chiefly Candida albicans) are part of the normal flora in almost half of the population. Oral candidiasis or candidosis (moniliasis, thrush) typically appears as white curd-like patches or as red (atrophic) or white and red friable lesions on any mucosal surface (Fig. 22-2). Many newborns experience initial overgrowth of Candida before colonization of the gastrointestinal (GI) tract. Candidiasis often occurs during or after antibiotic or glucocorticoid therapy, in denture wearers, pregnant women, and older adults, and in patients with anemia, diabetes mellitus, Hashimoto’s thyroiditis, Cushing’s disease, or familial hypoparathyroidism. Immunosuppression caused by human immunodeficiency virus (HIV; see later), other debilitating illnesses, or cancer chemotherapy may lead to candidiasis (see Chapter 33). Candida albicans remains the predominant species cultured. However, C. glabrata, C. krusei, and other azole-resistant species must be considered in resistant cases. Oral candidiasis is also associated with xerostomia, whatever the cause. Topical therapy is most effective in patients with no underlying chronic conditions (see Chapter 45) and may entail the use of the following: (1) nystatin (Mycostatin), 100,000-U vaginal tablet dissolved orally three to five times daily; (2) clotrimazole (Mycelex), 10-mg troche to be dissolved orally five times daily; or (3) clotrimazole, 500-mg vaginal tablet, to be dissolved orally at bedtime.

Topical agents are effective in the absence of immunosuppression, whereas oral antifungal agents are needed in immunocompromised patients (see Chapters 33 and 34). In denture wearers, adjunctive measures, including regular denture cleaning, soaking in a dilute bleach solution, and taking the dentures out overnight, are important for clearing. When dysphagia and/or upper GI bleeding accompany oral thrush, concurrent candidal esophagitis should be considered (see Chapter 45). Systemic candidiasis may result when normal barriers to infection are lost. Microthrombi, resulting from obstruction of cutaneous and systemic vessels, lead to local necrosis and manifest as small necrotic papules and ulcerations that are easily visible on the skin and mucosa.

HUMAN IMMUNODEFICIENCY VIRUS INFECTION

Oral and cutaneous complications are common in patients with HIV infection (see Chapter 33).16 These manifestations cause significant morbidity and can provide valuable diagnostic and prognostic information. Frequently, the first and most common HIV-associated infection of the mouth is candidiasis. The history and physical findings usually establish the diagnosis. The presence of spores, pseudohyphae, or hyphal forms on a smear (potassium hydroxide, periodic acid–Schiff, Papanicolaou), culture, or biopsy confirms the diagnosis. Oral candidiasis in HIV should be treated systemically. Systemic therapy involves the use of oral azole preparations (fluconazole or itraconazole). Amphotericin B given intravenously is also effective, but usually not necessary. Treatment for one to two weeks is usually effective, even in the late stages of HIV infection. Frequent recurrences may require chronic or repeated treatment. The likelihood of clinical relapse is dependent on the degree of immunosuppression and the duration of therapy. As adjunctive measures, mouth rinses with chlorhexidine gluconate (Peridex), Listerine, or hydrogen peroxide–saline may be of some benefit.17,18

Periodontal disease and alveolar bone loss occur commonly in the general population, as well as in individuals with or at risk for AIDS. The association of cardiovascular disease, diabetes mellitus, low birth weight, other systemic diseases, and periodontal disease is a growing field of investigation.

Hairy leukoplakia (oral hairy leukoplakia, HL) appears as corrugated white lesions on the lateral borders of the tongue (Fig. 22-3). HL is usually asymptomatic and may be an early sign of HIV infection. The epithelium in patients with HL is infected with Epstein-Barr virus.19 The severity of HL does not correlate with the stage of HIV disease. However, the presence of HL in an HIV-infected person has prognostic implication. Analysis of 198 cases of HL has demonstrated that the median time to onset of AIDS is 24 months, and the median time to death in the era prior to highly active antiretroviral therapy (HAART) was 41 months.20 Other mucosal white lesions, such as oral leukoplakia (Fig. 22-4), can resemble HL lesions; biopsy confirmation should be considered if the diagnosis of HL is in doubt. HL may be confused with candidiasis (which coexists in about half of cases). A prudent first step in management is the administration of anticandidal therapy. The suspicion of HL justifies a discussion of its implications and suggestion of HIV testing. Although HL occurs predominantly in HIV-infected homosexual and bisexual men, it also has been found in renal and other organ transplant recipients. Because HL is usually asymptomatic, treatment is elective. HL responds to oral acyclovir, topical retinoic acid, and podophyllum. When treatment is discontinued, HL usually returns.

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Figure 22-3. Hairy leukoplakia involving the tongue in a patient with AIDS.

(Courtesy of Dr. Sol Silverman, Jr, DDS, and Dr. Victor Newcomer.)

Kaposi’s sarcoma (KS) is a common consequence of HIV infection and is associated with human herpesvirus 8. A significant decline in the incidence of KS occurred during 1996 and 1997, which corresponded to the introduction of HAART. Although KS is usually found on the skin, more than half of patients also have intraoral lesions.21 The first sign of KS occurred in the mouth in 22% of patients and, in another 45%, KS occurred in the mouth and skin simultaneously.20,21 The cutaneous lesions of KS appear as asymptomatic red to purple, oval macules that develop into papules, plaques, or nodules. They rarely ulcerate, except on the lower extremities and genitalia. Edema often accompanies cutaneous lesions, especially on the lower extremities or on the face. Oral lesions may vary in appearance from minimal, asymptomatic, flat, purple or red macules to large nodules. The hard palate is the most frequent location, followed by the gingiva and tongue (Fig. 22-5).22 The differential diagnosis of KS includes purpura, hemangioma, coagulation defects, and bacillary angiomatosis. Diagnosis is established by biopsy. Treatment approaches are mainly palliative but include topical alitretinoin (9cis-retinoic acid) gel, imiquimod, radiation therapy, chemotherapy (including intralesional injections), and surgery.23 Patients with cutaneous KS may have asymptomatic visceral lesions (see Chapter 33).

image

Figure 22-5. Kaposi’s sarcoma involving the palate.

(Courtesy of Dr. Sol Silverman, Jr, DDS, and Dr. Victor Newcomer.)

Lymphoma may involve the oral cavity and skin in HIV patients and, rarely, may be the first sign of HIV or lymphoma.

Other conditions associated with HIV infection include the following: extensive oral, genital, or cutaneous warts; recurrent aphthae; chronic mucocutaneous herpes simplex virus (HSV) infections; lymphocytic infiltrates of major salivary glands, leading to secondary Sjögren’s syndrome; drug reactions, including drug-induced Stevens-Johnson syndrome; Bartonella infections (bacillary angiomatosis and its associated peliosis hepatis); premature and progressive periodontal disease; and acute necrotizing ulcerative gingivitis.24

ULCERATIVE DISEASES

Aphthous ulcers (canker sores, recurrent aphthous ulcers [RAUs]) are painful shallow ulcers, often covered with a grayish-white or yellow exudate and surrounded by an erythematous margin. They appear almost exclusively on unkeratinized oral mucosal surfaces (Table 22-1). Rarely, RAUs may occur in the esophagus, upper and lower GI tracts, and anorectal epithelium. RAUs develop at some time in 25% of individuals in the general population and recur at irregular intervals. Three clinical forms of aphthous ulcers are recognized—minor aphthae (most common), major aphthae (less common), and herpetiform aphthae (least common). Minor aphthae typically are smaller than 5 mm and heal in one to three weeks (Fig. 22-6A). Major aphthae may exceed 6 mm (see Fig. 22-6B) and require months to heal, often leaving scars. Herpetiform aphthae are 1 to 3 mm in diameter, occur in clusters of 10 to hundreds of ulcers, and resolve quickly.42

Table 22-1 Distinctions between Aphthous and Herpetic Oral Ulcers

CONDITION MUCOSA LOCATION
Aphthous ulcers Unkeratinized Lateral tongue, floor of the mouth, labial and buccal mucosa, soft palate, pharynx
Herpes simplex virus ulcers Keratinized Gingiva, hard palate, dorsal tongue

The cause of RAU is thought to be multifactorial, with precipitating factors including the following: (1) immunologic abnormalities such as celiac disease and increased allergen presentation caused by decreased constitutive oral barriers (putatively from sodium lauryl sulfate use in dental products); (2) chronic trauma, such as from ill-fitting dentures; (3) vitamin or mineral deficiencies, such as iron, folate, and vitamin B12; (4) genetic predisposition; (5) stress and anxiety; (6) allergies to food or medication, such as to cyclooxygenase 2 (COX-2) inhibitors or sertraline; and (7) xerostomia.25 Helicobacter pylori infection may be associated with RAUs as eradication of H. pylori appears to be associated with a reduction of recurrences, as well as a decrease in the number of ulcers and days of symptoms.26 Morphologically identical aphthous lesions may be seen in inflammatory bowel disease (IBD; see later) and Behçet’s syndrome. The workup for recurrent aphthous ulcers includes a complete blood count (CBC), erythrocyte sedimentation rate, serum iron, ferritin, folate, and B12 levels, potassium hydroxide (KOH) stain, Tzanck smear, viral culture, biopsy of coexisting skin lesions to exclude HSV, and colonoscopy to address the possibility of inflammatory bowel disease (IBD). Histologically, lesional tissue shows ulcerated mucosa with chronic mixed inflammatory cells.

Management of aphthous ulcers includes palliative and curative measures. First, vitamin deficiencies, if found, should be treated. Otherwise, patients should be advised to use multivitamins with iron and avoid crusty, salty, or spicy foods to minimize irritation of oral lesions. Soft toothbrushes, repair of dentition, and other measures to avoid unnecessary oral trauma should be instituted. Analgesics and topical anesthetics such as 2% viscous lidocaine may be helpful, along with bismuth subsalicylate (Kaopectate) and sucralfate to protect lesions and accelerate healing. Aphthous ulcers can be treated effectively with a potent topical glucocorticoid, such as fluocinonide (Lidex) or clobetasol (Temovate) gel or ointment. Second-line therapy includes colchicine, 0.6 mg three times daily; cimetidine, 400 to 800 mg/day; azathioprine, 50 mg/day; or thalidomide, 200 mg/day (U.S. Food And Drug Administration [FDA]–approved for HIV patients). Short courses of systemic prednisone (20 to 60 mg/day) are reproducibly effective when more conservative approaches are not satisfactory. An elimination diet may be helpful for patients with allergic reactions to certain foods or medications, including a trial of sodium lauryl sulfate–free dental products.27 A gluten-free diet is recommended for patients with gluten-sensitive enteropathy (see Chapter 104).

Infection with HSV commonly produces painful vesicles and ulcers on the genitalia, eyes, lips, mouth, and skin. Primary herpetic gingivostomatitis is caused by HSV type 1 (or, occasionally, type 2). Primary infection occurs in up to 90% of the population before puberty. The illness is often mild and mistaken for a routine upper respiratory tract infection; it may include varying degrees of fever, malaise, and adenopathy, together with oral and gingival ulcers. Lesions may appear on the lips. They generally heal in one to two weeks. Management is palliative, but acyclovir, 400 mg three times a day, may shorten the course and reduce severity. Secondary bacterial infection is common and can be treated topically.

Recurrent orolabial herpes simplex is caused by reactivation of HSV that has been dormant in regional ganglia, with no associated increase in HSV antibody titers. Episodes may be precipitated by fever, sunlight, and physical or emotional stress. Recurrences vary in frequency and severity. Typically, the lesions involve the lips (cold sores) and are preceded by several hours of prodromal symptoms such as burning sensation, tingling, or pruritus. Vesicles then appear but soon rupture, leaving small, irregular, painful ulcers. Coalescence of ulcers, crusting, and weeping of lesions are common. Intraoral recurrent herpetic ulcers occur on keratinized mucosa (i.e., hard palate or gingiva; see Table 22-1). They appear as shallow, irregular, small ulcerations and may coalesce. Labial and oral herpetic ulcers normally heal in less than two weeks. Recurrent HSV is the most common cause of recurrent erythema multiforme.

In immunocompromised patients, HSV can affect any mucocutaneous surface and can appear as large, irregular, pseudomembrane-covered ulcers. This is especially true in HIV-infected persons, in whom all perineal and orolabial ulcerations should be considered manifestations of HSV until proven otherwise (see Chapters 33 and 125). Care should be taken to avoid ocular autoinoculation.

Herpes simplex is usually diagnosed from the history and clinical findings. A history of a prodrome or of vesicles, the site of lesions, and the reappearance of lesions in the same location help differentiate herpes from other ulcerative disorders. A cytologic smear (Tzanck) showing multinucleate giant cells is suggestive, although viral cultures and monoclonal antibody staining of smears are more sensitive and specific tests for diagnosing HSV infection. Topical acyclovir is of little benefit in recurrent labial herpes and is of limited benefit in recurrent genital HSV. Systemic acyclovir is regularly used for treatment of primary or recurrent attacks in immunosuppressed patients (2 g orally in divided doses, or 5 mg/kg intravenously three times daily until lesions heal). Famciclovir, 125 mg twice daily, or valacyclovir, 500 mg twice daily, are also available in the United States. Oral treatment should optimally begin within the first few hours of the prodrome. Suppression of recurrences may be accomplished with acyclovir, 200 mg orally three times daily or 400 mg twice daily. Acyclovir is used for the prevention of recurrent oral and genital herpes associated with bone marrow transplantation (see Chapter 34). Antivirals are also used to prevent recurrent herpes infections in other immunocompromised patients such as those with leukemia or HIV infection, or after solid organ transplantation.

Herpes zoster is caused by a reactivation of the varicella virus. The oral lesions can resemble the ulcers of aphthous stomatitis, except for the following features: the ulcers are unilateral; lip and/or skin lesions may coexist; and the onset is sudden, acutely painful, and often associated with fever. High dosages of acyclovir (4 g/day orally), famciclovir, 500 mg every 8 hours, or valacyclovir, 1 g every 8 hours, at the onset may be helpful in accelerating healing.

Cytomegalovirus (CMV) affects 40% to 80% of adults, as evidenced by serologic studies. However, symptomatic disease occurs mainly after solid organ or bone marrow transplantation or in HIV-infected persons. Other than retinitis, mucosal ulcers are the main consequence of CMV infection. Skin is rarely affected. Characteristic features of biopsy specimens include intranuclear and intracytoplasmic inclusions. Treatment includes use of ganciclovir, valganciclovir, cidofovir, or foscarnet and treatment of any underlying immunodeficiency.

Acute necrotizing ulcerative gingivitis is an acute inflammatory and necrotic infection affecting the interdental papillae, and commonly affects healthy young adults. Treatment consists of surgical débridement, oral rinses, and systemic antibiotics.

Cutaneous amebiasis is a rare complication of amebic dysentery. Undermined ulcers of the perineum and genitalia may result from direct inoculation from the colon and rectum to the anus after contact with contaminated stool or from external inoculation after intercourse or hand (scratching) contact. Dissemination may result from invasion of the colonic mucosa, with hematogenous spread to the liver and then to the lungs or chest wall. In long-standing disease, the ulcer borders may become vegetative and proliferative and resemble a squamous cell carcinoma. Because primary carcinomas of the rectum, colon, and cervix may be secondarily colonized with Entamoeba histolytica, it is important that either possibility be ruled out.

VESICULOBULLOUS DISEASES

Pemphigoid is a general term for heterogeneous blistering disorders characterized by bullae and ulcers affecting the mucosa of the oral cavity, pharynx, esophagus, anus, conjunctiva, and skin. Oral findings appear as highly inflamed (erythematous) mucosa on the buccal mucosa and gingival mucosa. Two types of pemphigoid have been identified, bullous pemphigoid and cicatricial (mucous membrane) pemphigoid. Patients with bullous pemphigoid typically have skin lesions, and about one third also have mucous membrane lesions. All patients with cicatricial pemphigoid have mucosal lesions, and about one third also have skin lesions (tense bullae). Ocular symblepharon (i.e., adhesion between the tarsal and bulbar conjunctiva) commonly occurs with cicatricial pemphigoid. Potentially fatal upper GI bleeds because of esophageal involvement by pemphigoid has been reported.28 Immunofluorescent staining of involved mucosa and skin shows linear deposition of antibody and complement in the basement membrane zone. Serum antibodies against 230- and 180-kd antigens located at the squamous epithelial basement membrane have been documented. Patients with serum IgG and IgA antibodies are more likely to respond to systemic medications. Treatment ranges from low-dose to high-dose prednisone for patients without contraindications to glucocorticoid use. Alternative therapies for patients with contraindications or systemic toxicities to glucocorticoids include dapsone, tetracycline and nicotinamide in combination, azathioprine, chlorambucil, plasma exchange, intravenous immune globulin (IVIG), cyclosporine, cyclophosphamide given orally or in a pulse-dosing format, methotrexate, and infliximab.29

Pemphigus vulgaris differs from pemphigoid in that bullous skin lesions, which are often flaccid, are more severe (and can be life-threatening if untreated) and oral involvement can be extensive. Mucosal involvement can cause poor nutrition and severe pain. Half of patients with pemphigus vulgaris present with oral lesions, and oral lesions occur in almost 100% of patients during the illness. Autoantibodies mediate a loss of cell to cell adhesion. IgG antibodies and complement on the surface of squamous epithelial cells are diagnostic. Indirect immunofluorescence detects circulating IgG antibodies in most patients with pemphigus vulgaris. Treatment consists of various regimens of topical or systemic prednisone, sometimes supplemented with cytotoxic or immunosuppressive drugs.

Paraneoplastic pemphigus shares features of pemphigus vulgaris and erythema multiforme.30 It is associated with various malignancies, including GI malignancies, lymphomas and leukemias, thymomas, and soft tissue sarcomas. Five features characterize paraneoplastic pemphigus: (1) painful mucosal erosions and a polymorphous skin eruption; (2) intraepidermal acantholysis, keratinocyte necrosis, and vacuolar interface reaction; (3) deposition of IgG and C3 intercellularly and along the epidermal basement membrane zone; (4) serum autoantibodies that bind to skin and mucosa epithelium in a pattern characteristic of pemphigus, as well as binding to simple, columnar, and transitional epithelia; and (5) immunoprecipitation of a complex of four proteins (250, 230, 210, and 190 kd) from keratinocytes by the autoantibodies. The prognosis of paraneoplastic pemphigus depends on the associated underlying malignancy, and successful treatment is predicated on successful elimination of the underlying malignancy.

Epidermolysis bullosa (EB) is a heterogeneous group of rare inherited disorders of skin fragility (Fig. 22-7). They are characterized by the formation of blisters with minimal trauma and are divided into dystrophic (scarring), junctional, and simplex forms. Oral erosions, premature caries, and gingival involvement, as well as GI disease, are common in the dystrophic form but also occur in some patients with the junctional form. In addition to oral erosions, esophageal strictures are the most common GI complication in dystrophic EB.31 They may be narrow or broad and most commonly occur in the upper third of the esophagus, but also may be found in the lower third. The esophageal strictures are probably induced by repeated trauma from food and/or refluxed gastric contents; therefore, strict adherence to a soft food diet remains a mainstay of management. Although dilations with bougienage historically have been shunned because of an unacceptable risk of increasing esophageal stenosis over the long term, evidence supports the use of balloon dilation as a safe and efficacious method of palliating esophageal strictures without this risk. Surgical excision, feeding gastrostomy, and colonic interpositioning have been effectively used in dystrophic EB patients with severe esophageal strictures. Esophageal webs in the postcricoid area have also been described. Anal stenosis and constipation (with or without stenosis) are frequent in patients with dystrophic EB. Junctional EB has been uniquely associated with pyloric atresia. Anemia and growth retardation frequently develop in patients with severe dystrophic and junctional EB, partly because of GI and oral complications.

Patients with clinical lesions identical to the dystrophic forms of EB but with no family history and an adult onset have been identified; their condition is called acquired EB or EB acquisita (EBA). EBA, like pemphigus and pemphigoid, is an autoimmune disease. The autoantibodies in EBA are directed against type VII collagen.32 The diagnosis of EBA is established by routine histology and direct immunofluorescence examination of skin biopsy specimens. Patients may have significant mucosal involvement, like patients with cicatricial pemphigoid, especially oral and esophageal disease. Coexistent Crohn’s disease has been reported in a number of patients with EBA. Treatment is with immunosuppressive agents.

Erythema multiforme (EM) is an acute, benign mucocutaneous eruption associated with underlying infections (especially HSV). It is often preceded or accompanied by low-grade fever, malaise, and symptoms suggesting an upper respiratory tract infection. The eruption consists of alternating pink and red target lesions on the elbows, knees, palms, and soles and of shallow, broad oral erosions. Patients with EM may only have oral involvement. Variable degrees of nonspecific erythema are found, with or without ulcers. Crusting, hemorrhagic, and moist lip ulcers may be present. Severe oral and pharyngeal pain, secondary bacterial and fungal infections, and bleeding are common complications. The diagnosis is made by clinical characteristics, ruling out other specifically diagnosable diseases, and by response to treatment. The biopsy reveals a nonspecific interface reaction. Oral EM can be self-limited or chronic, and often the inciting process goes unidentified. Management includes palliative measures and elimination of any offending agent. Often, glucocorticoids and/or other immunosuppressive drugs are needed. Recurrences and flares have variable patterns. Herpes-associated erythema multiforme lesions are treated with episodic or suppressive antiviral therapy with acyclovir, valacyclovir, famciclovir, or foscarnet.33

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