Oral manifestations may be the first sign of a systemic disease, or represent lesions associated with an established or recurrent disease. Oral health care providers are often the first to recognize these signs. Some lesions have characteristic features that allow for early detection and intervention. On the contrary, clinical manifestations may be diverse and require a comprehensive evaluation to establish a definitive diagnosis. This article reviews the oral manifestations of select systemic diseases to help clinicians develop a differential diagnosis that leads to early diagnosis and timely intervention.
Key points
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Oral manifestations may be the first, and sometimes the only, sign of a systemic disease.
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Some conditions have characteristic features that allow for early detection, whereas others require a comprehensive dental and medical evaluation to establish a definitive diagnosis.
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Identification of oral manifestations can allow for early diagnosis and intervention in patients with systemic diseases.
Introduction
Many systemic diseases are accompanied by oral manifestations. Several studies have documented an association between periodontal disease and systemic conditions, such as cardiovascular disease and diabetes mellitus. Oral manifestations may be the first sign of a systemic disease or may represent a recurrent or refractory disease. Many diseases present with clinically similar oral lesions and require an extensive workup to establish a diagnosis. Oral ulceration, for example, may be a sign of lupus erythematosus, pemphigus vulgaris, Behçet disease, Crohn’s disease (CD), and many syndromic conditions. Generalized gingival enlargement should prompt investigation for conditions like hyperplastic gingivitis, drug-related gingival hyperplasia, gingival fibromatosis, leukemia, Wegener granulomatosis, and nutritional deficiencies like scurvy. Severe gingival inflammation may be seen in diabetes mellitus, human immunodeficiency virus infection, leukemia, and thrombocytopenia. Therefore, a comprehensive examination of the oral cavity and a thorough history taking can aid in determining the underlying etiology of oral lesions and allow for early diagnosis and intervention. The present article provides a succinct review of oral manifestations of select systemic diseases.
Amyloidosis
Description
Amyloidosis is a rare condition characterized by the extracellular deposition of insoluble amyloid fibrils, a material formed from protein misfolding. There are 30 human fibrillary proteins and each type of amyloidosis is associated with a specific protein. The common forms include: AL, which can occur alone or in association with multiple myeloma and is caused by deposition of monoclonal immunoglobulin light chains; AA, which develops as a result of chronic diseases such as rheumatoid arthritis, tuberculosis, sarcoidosis; Aβ 2 M is associated with long-term renal dialysis. Some forms are inherited and known as heredofamilial amyloidosis.
Clinical Features
Deposition of amyloid may be localized or diffuse. Any site in the head and neck region can be affected, however, the larynx is the most common site for amyloid deposition. The most frequently reported intraoral location is the tongue, and amyloid deposition may result in macroglossia. Amyloidosis of the head and neck sites, excluding the larynx, is usually associated with an underlying condition. As amyloidosis is often associated with nonspecific signs and symptoms, such as fatigue, and weight loss, the diagnosis is often rendered after a biopsy is performed. Patients may exhibit yellowish, red, or purplish papules, individual nodules or diffuse swelling, submucosal hemorrhage, or ulcerations of the oral mucosa. The tongue is often enlarged, firm to rubbery on palpation, and typically shows scalloping of the lateral borders due to indentations from the teeth ( Fig. 1 A). Amyloid deposits in the upper aerodigestive tract can cause hoarseness and dysphagia. Systemic manifestations arise from the deposition of amyloid in various tissues that results in heart failure, nephrotic syndrome, hepatomegaly, and peripheral or autonomic neuropathy. Infiltration of the salivary and lacrimal glands may cause xerostomia and dry eyes. Skin lesions manifest as subcutaneous plaques or nodules. Amyloid infiltration of the blood vessels increases vessel fragility resulting in submucosal hemorrhage that manifests as purpura, petechiae, and ecchymosis in the periorbital areas ( Fig. 1 B).
Histopathology
Amyloid seems as an amorphous, acellular, eosinophilic material in the submucosal connective tissue that may be either diffusely distributed or arranged in a perivascular manner. Amyloid stains with Congo-red and under polarized light shows an apple-green birefringence.
Diagnosis and Management
Biopsy of rectal mucosa and subcutaneous abdominal fat tissue is typically used to confirm the diagnosis. Gingiva and labial salivary glands are potential sites for intraoral biopsy. After confirmation of diagnosis, it is important to identify the type of amyloidosis because different forms of amyloid proteins lead to substantially different prognoses and outcomes. Patients should be referred to a hematologist, and a comprehensive workup should be performed for the evaluation of systemic disorders. Treatment is focused on managing the underlying condition. The prognosis of systemic amyloidosis is typically poor. The severity of organ involvement, especially cardiac, is the most important prognostic factor. Prognosis of a single organ or localized amyloidosis is good and may be treated symptomatically or by surgical intervention when there is a functional or esthetic deficit.
Lipoid proteinosis
Description
Lipoid proteinosis (LP) is a rare genodermatosis also known as hyalinosis cutis et mucosae or Urbach-Wiethe disease. It is caused by loss of function mutations in the ECM1 gene that results in the deposition of an amorphous hyaline material in the skin and mucosal membranes. LP is more common in areas where consanguineous marriages take place.
Clinical Features
Disease onset is usually in early infancy or, rarely, after a few years. Hoarseness is often the first sign and one of the most striking clinical manifestations. A pathognomonic sign for LP is the presence of multiple firm, beaded papules along the eyelid margins, termed moniliform blepharosis .
Accumulation of amorphous material may result in nodular, diffusely enlarged, and thickened labial and buccal mucosa ( Fig. 2 ), and tongue. The patient may develop waxy yellow-white submucosal plaques and nodules, thickening of the sublingual frenum and epiglottis, and gingival enlargement ( Fig. 3 A). The oropharyngeal mucosa may seem pale, and indurated resulting in restriction of mouth opening and tongue movement, and difficulty in swallowing. The tongue may become firm and have a “wooden hard” consistency. Ductal stenosis may cause recurrent salivary gland swelling.
Most patients, in the early disease, present with recurrent blistering and subsequent acneiform scarring, predominantly on the face and extremities. Over time, the lesions may vary from waxy yellow papules and nodules to hyperkeratotic plaques in areas exposed to mechanical friction, to generalized skin thickening ( Fig. 3 B). Scalp involvement may lead to scarred alopecia. Bilateral intracranial calcifications develop in the late stage of the disease. Seizures are, thus, an important neurologic sequela. Other neurologic manifestations include social and behavioral changes, memory deficits, and mental retardation.
Histopathology
A tissue biopsy of the affected site will show deposition of an acellular, eosinophilic hyaline material in the connective tissue, largely around the blood vessels, nerves, sweat glands, and hair follicles. This material is diastase-resistant and stains with periodic acid-Schiff (PAS).
Differential Diagnosis
LP may have overlapping clinical-histopathological features with systemic amyloidosis, plasminogen deficiency, and erythropoietic protoporphyria. Amyloidosis and plasminogen deficiency can be excluded with Congo-red and Fraser-Lendrum stains, respectively. Erythropoietic protoporphyria usually does not cause similar oral lesions. The skin lesions may resemble dermatologic conditions like xanthomas and lesions of leprosy. ,
Diagnosis and Management
Diagnosis is confirmed by histopathological findings on biopsy of mucosal and skin lesions. The presence of comma or bean-shaped intracranial calcifications in the temporal lobes or hippocampi is the most common radiographic finding. In addition, genetic testing for the ECM1 gene can confirm the disease. There is no evidence-based treatment of LP and the disease runs a stable, chronic course. Surgical excision or debulking of the mucosal lesions, especially of the laryngeal mucosa to avoid breathing difficulty, may be required in some cases. A tracheostomy may be necessary for improving the airway. Gingivectomy is effective for facilitating oral hygiene. Oral application of dimethyl sulfoxide, acitretin, and corticosteroids has been reported to improve the symptoms but the efficacy of these treatments remains controversial. Most patients with LP have a normal life expectancy.
Pyostomatitis vegetans
Description
Pyostomatitis vegetans (PV) is a rare inflammatory disorder that is considered an oral manifestation of inflammatory bowel disease (IBD). The most common association of PV is with ulcerative colitis and is often described as a specific marker of the disease. , PV exhibits a male predilection and is most common in young and middle-aged adults.
Clinical Features
Oral lesions may precede or appear with intestinal symptoms. Patients exhibit multiple slightly elevated, serpentine yellowish pustules on an erythematous base ( Fig. 4 ). The pustules rupture to form widespread shallow ulcerations resembling “snail track” ulcers. Rarely, tiny nodular lesions and hemorrhagic crusting may also be present. As lesions progress they develop verrucous folds. Any area of the oral mucosa may be affected, although the most commonly affected sites are the buccal and labial mucosa, hard and soft palate ( Fig. 5 ), and gingiva. Tongue and floor of the mouth are the least affected areas. , Most patients complain of mild tenderness or discomfort. The severity of PV may coincide with exacerbation of the underlying gastrointestinal disease.
Histopathology
PV is usually characterized by the presence of intraepithelial and subepithelial eosinophilic abscesses. Marked edema may cause an acantholytic appearance of the involved epithelium.
Differential Diagnosis
The differential diagnosis includes ulcerative and blistering conditions, such as pemphigus vulgaris, bullous pemphigoid, dermatitis herpetiformis, herpes simplex infections, syphilis, erythema multiforme, epidermolysis bullosa acquisita, bullous drug reaction, and Behçet disease. ,
Diagnosis and Management
Diagnosis of PV is based on the combination of clinical features, association with IBD, peripheral eosinophilia, and characteristic histologic findings. Identification of PV should facilitate investigation for IBD. The mainstay of management is primarily to treat the underlying gastrointestinal disease which usually results in the improvement of oral and skin lesions. Diet modulations, the use of corticosteroids, antispasmodic agents, and psychotherapy are the commonly used therapies. Oral lesions can be managed with local therapy such as topical corticosteroids. In the past, severe and recalcitrant lesions were treated with systemic corticosteroids, , dapsone, and sulfasalazine. More recently, newer disease-altering drugs, such as tumor necrosis factor-alpha (TNF-α) blockers, have been used to treat moderate to severe ulcerative colitis. Janus kinase (JAK) inhibitors, such as tofacitinib (Xeljanz) and upadacitinib (Rinvoq), are used in cases where TNF blockers do not work well or are not tolerated.
Crohn’s disease
Description
CD is an inflammatory disorder of the gastrointestinal tract (GIT) that has oral and intestinal manifestations. Lesions can involve any part of GIT but predominantly affect the terminal ileum and colon. The underlying etiology likely involves an inappropriate mucosal inflammatory response to intestinal bacteria. CD has a bimodal age distribution, the first peak is seen in early adulthood and the second at 50 to 70 years of age.
Clinical Features
The disease is characterized by periods of exacerbation and remission. The most common systemic manifestations include abdominal pain and prolonged diarrhea associated with rectal blood loss, fever, perianal fissure, arthralgia, and weight loss. Extraintestinal manifestations may affect the skin, eyes, and joints. Oral manifestations are reported in approximately 0.5% to 37% of cases and may precede systemic manifestations. Intraoral findings include mucogingivitis (linear ulcerations in the vestibule), gingival erythema ( Fig. 6 ), diffuse persistent swelling of labial and buccal mucosa, cobblestone appearance of the mucosa ( Fig. 7 ), soft tissue tags in the mucobuccal fold, and nodules in the vestibular retromolar area. Nonspecific manifestations include angular cheilitis, glossitis, and aphthous ulcers.
