Oral Pathology in Digestive Diseases

Correlations between alterations in the oral cavity and systemic conditions have been widely reported. A considerable number of gastrointestinal (GI) diseases of varied nature may produce lesions in the hard and soft oral tissues. Among the different types of manifestations of GI, oral lesions represent an important, if not a major component of the manifestation of these diseases. As a consequence, recognition and management of oral lesions accompanying the GI conditions, is mandatory for all clinicians, either gastroenterologists or dentists. The aim of this article is to underline useful data about the most common GI conditions (intestinal bowel diseases (IBD), gastroesophageal reflux, genetic diseases, malabsorption conditions, infections, metastatic tumors) and their link to oral pathology.


INTRODUCTION
Correlations between alterations in the oral cavity and systemic conditions have been widely reported [1][2][3][4][5][6] . Oral cavity can act as a mirror, which has the potential to refl ect the human body's internal condition 7 . A considerable number of gastrointestinal (GI) diseases of varied nature (infl ammatory, infectious, genetic and other etiology) may produce alterations in the hard and soft oral tissues [2][3][4] . Many GI diseases can give rise to diff erent oral lesions. Sometimes, the oral lesions are similar and subepithelial abscesses) with white-yellow content and with an erythematous and edematous base [8][9][10][11][12][13] . Th ese lesions look like a snail. Th e lesions are found on the tongue, lips, gums, tonsils, mouth, soft and hard palate.

Linear ulcerations:
Th ese lesions are usually located in the buccal sulci and may be accompanied by hyperplastic mucosa at their borders.

Angular cheilitis:
Th e commissural and adjacent skin may have recurrent fi ssures and indurated erythematous plaques not necessarily related with Candida infection.

Atrophic Glossitis
Th e fi liform papilla and sometimes the fungiform papilla of the dorsum of the tongue undergo atrophy, leaving a bald, red tongue.

Caries 11. Herpetiform dermatitis
Dermatitis herpetiformis is an uncommon chronic skin disease that rarely aff ects the oral cavity. Oral manifestations include erythematous-purple macules, erosions, ulcers and blisters, which can aff ect the tongue, buccal mucosa and alveolar ridge. Clinically, it is diffi cult to make a diff erential diagnosis between diseases that produce vesicles, such as pemphigus or pemphigoid, celiac disease, so the histological and immunofl uorescence studies are needed 6,7,14 . 12. Other non-specifi c oral fi ndings reported in literature include submandibular lymphadenopathy, sicca syndrome and hyposialia, dental caries, halitosis, candidiasis, dysphagia, odynophagia, lichen planus, dysgeusia, glossitis, mucosal discoloration, periodontal involvement, perioral erythema with scaling and minor salivary gland enlargement.

Idiopathic inflammatory bowel disease (IBD)
Th e term infl ammatory bowel disease (IBD) involves a group of chronic infl ammatory disorders of not well-fi c, these disorders may precede the underlying disease and therefore can facilitate an early diagnosis [1][2][3][4][5][6][7] . Th e oral tissues may also off er an easy biopsy site for conditions such as infl ammatory bowel diseases or digestive metastatic tumors. Careful and repeated assessment of the oral cavity is essential for a proper diagnosis 6-8 .

Recurrent aphthous stomatitis (RAS)
It is a common disease of the oral mucosa, which occurs more frequently in children and young people, with an average incidence of between 20% and 60% over a lifetime [1][2][3] . RAS often begins in the second decade of life and reaches the highest frequency in the third decade. Th ere are many variations in clinical patterns, such as frequency, duration, number and size of lesions. Usually the lesions are round or ovoid ulcerations with wellcircumscribed margins, reddish halo, and yellow or gray bottom. Pain is the main symptom of RAS and often aff ects the quality of life of the patient and causes anxiety. Although trauma, stress, microorganisms, family history, food hypersensitivity, immunological factors, hormonal factors and genetic predisposition have been proposed as potential causal factors, the etiology of RAS is still unknown. It is reported that sleep disorder is also linked to immunological disorder [7][8][9][10] . Other predisposing factors include celiac disease and nutritional defi ciencies: low levels of iron, vitamins B3 and B12, vitamin C and folic acid 10,11 .

Labial swelling and fi ssuring:
It consists in a chronic enlargement of the lips with perpendicular fi ssures, cracks or crusts along the vermilion.

Cobblestoning:
Th e jugal mucosa exhibits normal color plaques separated by mild depressions or fi ssures, giving the appearance of cobblestones.

Mucogingivitis:
Th e gingival tissues may become hyperplasic and granular, not only the free gingiva but also the attached gingiva, and in certain cases this lesion can be extended up to the mucogingival margin.

Pyostomatitis vegetans (PV):
PV is described as a chronic muco-cutaneous pathology consisting of the formation of numerous pustules (intra known etiology that aff ects diff erent segments of the gastrointestinal tract, mainly the bowel. Th e two main forms of IBD are Crohn's disease (CD) and Ulcerative Colitis (UC). Th e signs and symptoms are related to the damage in the bowel, but in some cases the patient can exhibit extra intestinal manifestations, also in the oral cavity, even before the intestinal manifestations are found. Th e clinical diff erences between the oral manifestations of CD and UD may be blurred with overlapping clinical features. Nonspecifi c clinical changes such as dry mouth, halitosis and gastric refl ux are found and these changes are neither diagnostic nor helpful in the diff erentiation of the two conditions. Th e microscopic fi ndings of granulomas are considered diagnostic of oral Crohn's disease, whereas micro-abscesses, containing neutrophils and eosinophils, without granulomas are considered typical for ulcerative colitis 8,9,12,13 .

1.a. Crohn's disease (CD)
Patients with Crohn´s disease develop chronic infl ammation and non-caseating granulomas in diff erent parts of the gastrointestinal tract, especially in the distal ileum and colon. Th e most common signs and symptoms include diarrhea and abdominal pain, but some patients could experience extra-intestinal manifestations of the disease, involving eyes, joints, skin and mouth 10,11 .

Epidemiology
CD usually aff ects males in their third decade of life; however, it can appear in a wide range of ages including young children. Its incidence varies depending on the age of the group studied, being higher in pediatric patients. Regarding to its prevalence, there are geographical diff erences, but it has been estimated between 319 and 322 cases per 100,000 habitants 10 .

Etiopathogenesis
Th e exact cause and pathogenesis of CD are still not known. It has been postulated that genetically predisposed individuals would present an imbalance or deregulation of their immune response when exposed to diff erent agents, such as environmental (stress, tobacco and diet) and microbiological (bacterial species) agents leading to the pro-infl ammatory environment and tissue damage seen in this disease 7,11 .

Oral manifestations
Oral lesions in CD are more frequent in young male patients and their prevalence can range from 20 to 50%. Th e predominant clinical presentation includes ulcers, papules and edema, while the most common si-tes aff ected are lips, gingiva and the vestibular sulci. It has been reported that oral lesions are of help in the diagnosis of systemic Crohn's disease. Some papers reported that only 0.5% of the patients with Crohn's disease have also oral manifestations. Th ese patients were more likely to have also anal and esophageal lesions. Th ere is a predilection for males and onset in youth. Patients with active CD have been reported to have a higher degree of oral lesions, but apparently, the type of them has no relationship with the disease activity and type of treatment. Diff erent types can coexist in the same patient, and according to the absence or presence of granulomas formation in the histopathological study, these are classifi ed into specifi c and non-specifi c lesions respectively. Th e specifi c oral lesions are labial swelling and fi ssuring, mucosal tags, cobblestoning, mucogingivitis, linear ulcerations. Th e nonspecifi c lesions are: recurrent aphthous stomatitis (RAS) like ulcerations, angular cheilitis, lichen planus, submandibular lymphadenopathy, sicca syndrome. Despite most of the oral manifestations of CD are not severe and their symptoms are mild or absent, some patients may experience facial distortion and disabling pain, originating emotional stress and deteriorating quality of life 1-3,10,11 .

1.b Ulcerative colitis (UC)
It has clinical and histopathological features that diff erentiate it from CD: chronic infl ammation of the gastrointestinal tract is mostly limited to the lining of the colon; there is no granuloma, the disease usually progresses with repeated periods of remissions and exacerbations and, in severe cases, can aff ect the entire thickness of the intestinal wall, which can cause signifi cant bleeding 7,8,10 .

Epidemiology
Ulcerative colitis is a favorite among men and is twice as common as CD. Unlike CD, UC is commonly diagnosed in patients with an average age of 30 years. Th e emergence of UC follows a bimodal model, with peaks in early adulthood and between the sixth and seventh decade of life. Europe is the continent with the highest incidence, with 24.3 new cases per 100,000 people every year 10 .

Etiopathogenesis
Similar to CD, it is postulated that the development of UC would be infl uenced by diff erent factors, including microbiological, genetic and environmental components that would interact with each other triggering the pathology. on as the supernumerary teeth. Osteomas, which cause focal expansion of the surface of the maxillary bone, may be felt through the skin or buccal mucosa and may be large enough to be clinically visible 14-17 .

2.b. Peutz-Jeghers syndrome
It is due to a mutation in the LKB1 gene. Th is condition, which is associated with hamartomatous polyposis, in most of the small intestine, is autosomal dominant or results from spontaneous mutation. Th e most signifi cant oral manifestation is perioral and / or oral pigmentation, which develops from childhood. Oral lesions are usually fl at, painless, brown, pigmented spots on the tongue or lip lining. Microscopically, these lesions show a slight acanthosis, with elongation of rete peg, and increased pigmentation of the adjacent melanocytes and keratinocytes, without an increase in the number of melanocytes. As with Gardner's syndrome, oral manifestations can help diagnose this condition at an early age and allow screening for intestinal disease 18 .

HYPERSENSITIVITY Celiac disease (CD) or "celiac sprue"
It is an autoimmune disease in which individuals who are genetically predisposed, show impairment of small bowel villi as a result of an abnormal immune response as a consequence of gluten ingestion. Th e diagnosis of CD is made clinically and histologically, which also allows the classifi cation of this disease into four main types; classic, atypical, silent and latent. Th e diagnosis of CD can be sometimes diffi cult, mostly because patients may exhibit a wide spectrum of signs and symptoms. It is important to identify this disease process early because aff ected individuals have an increased risk for developing diff erent malabsorption syndromes and lymphoma of the gut.

Etiopathogenesis
Gluten (present in most cereals) is partially degraded by the action of gastrointestinal enzymes in peptides that pass into the intestinal chorion due to increased permeability of the epithelial barrier. Once they reach the lamina propria, the peptides are cleaved by tissue transglutaminase, which increases their affinity for antigen presenting cells (APCs) and thus their immunogenicity. Th e presentation of these peptides to CD4+ lymphocytes triggers an adaptive immune response with infl ammation and tissue damage due to the release of cytokines and matrix metalloproteinases 19 .

Oral manifestations
Pyostomatitis vegetans (PV): is the oral counterpart of Pyoderma gangrenosum and is very commonly associated with UC and, unlike most oral lesions, is considered to be a specifi c marker of disease activity [8][9][10][11][12][13] . Th e patient may have fever, submandibular adenopathy and pain, extremely variable symptoms that are not necessarily related to the extent and size of the ulcers. Occasionally, oral manifestations may be the fi rst indication that a patient has IBD10. Oral lesions should be routinely analyzed also by special histochemical investigations to rule out infectious etiology (e.g. fungal infections or tuberculosis). Because microscopic granulomatous lesions are observed in other diseases of the oral cavity, including orofacial granulomatosis and sarcoidosis, the positive diagnosis of Crohn's disease cannot be ruled solely by oral biopsy. However, oral biopsy can guide the specialist to investigate the GI tract for IBD [8][9][10] . Th e microscopic aspect itself is not diagnostic, because neutrophil or eosinophilic intraepithelial abscesses can be seen in other conditions, such as candidiasis, benign migratory glossitis, stomatitis areata migrans and pemphigus vegetans. Also, the clinical appearance and the anamnestic information should be correlated with the microscopic results. When present, the severity of the oral disease usually refl ects the severity of the intestinal disease [11][12][13] . Furthermore, the gastroenterologist may use oral manifestations to determine the severity of bowel disease and / or response to treatment 1,11-13 .

2.a. Gardner syndrome
It is a genetic defect of chromosome 5 that leads to the disease by autosomal dominant or sporadic mutation characterized by intestinal polyposis with a very high risk of malignant transformation into colonic adenocarcinoma. It is associated with a number of extracolonic changes, including skin, skeleton and soft tissue. Th e potential manifestations of oral cavity are represented by: multiple enostoses of the jaws; supernumerary teeth and / or unerupted teeth; increased risk of odontomas; osteomas of the jaws and the paranasal sinuses. Enostoses are frequently observed radiographically in the alveolar portions of the jaws. Th ey are completely asymptomatic. Supernumerary teeth appear in the region of the incisors, while the molar areas are rarely aff ected. Th e odontomas appear in the same distributi-the etiological factors in the pathogenesis of RAS, this association is debatable. Hp might have a role in the pathogenesis of oral lesions, e.g. ulcers, carcinomas and lymphomas. Also, a dark erythematous tongue with slimy yellowish coating could be a sign of peptic ulcer due to Hp infection. On the other hand, it has been speculated that the oral cavity could be a second reservoir for Hp, and that is why the eradication treatment for Hp does not respond always properly. Hp can be found within the oral epithelium, such as buccal mucosa and the tongue. Hp was also found in normal or ulcerated/ infl ammatory tonsils and in adenoid tissues 25-30 .

OTHER PATHOLOGY Gastroesophageal reflux disease (GERD)
It is a chronic digestive disorder caused by the return of gastric content to the esophagus and up or out of the oral cavity, with symptoms and, potentially, esophageal lesions. Gastric refl ux is a normal process that occurs occasionally in children and adults. Most episodes are short and do not cause symptoms or complications. In contrast, people with gastroesophageal refl ux disease have disturbing symptoms as a result of refl ux. It is considered that at least 40% of the general population presents complaints, at least once a month. Th ese are burns in the chest, which can extend to the neck and mouth, the regurgitation of ingested foods, sour or bitter taste, diffi culties or pain when swallowed, vomiting, bloating, which occur more frequently after meals, with a duration of up to at 2 hours, being aggravated by the lying position and improved when standing up. It is important to note that atypical symptoms, such as dry cough, wheezing, hoarseness, can be confused with other airway diseases. Th e main cause for refl ux disease is weakening of the lower esophageal sphincter. Th e most frequent oral lesions are: dental erosions, dysgeusia, sour taste, halitosis, mucositis, xerostomia, buccal epithelial atrophy, hyperesthesia, burning mouth, RAS like ulcerations. In patients with GERD, chronic or recurrent exposure to acidic gastric juice on tooth enamel can be recognized by the presence of dental erosion, the severity of which depends on the duration of the disease, the amount and quality of refl ux and the individual resistance [31][32][33][34] .

Plummer Vinson syndrome (PVS)
It is a rare clinical condition, characterized by a triad of dysphagia, iron defi ciency anemia and esophageal web Epidemiology CD has been estimated to aff ect about 1% of the world's population, being increasing in recent years. Celiac disease is more common in European countries as well as in developing regions such as South America, South Asia and South Africa. Despite the typical occurrence in childhood, recent studies have reported an increase in adult involvement. Women are more aff ected than men (7: 1) 1,9,20,21 .

Oral manifestations
Multiple oral manifestations were described. It is considered that 50% of patients with CD have no digestive symptoms at the time of diagnosis [19][20][21][22][23][24] . Moreover, oral lesions would be useful in the early detection of atypical CD, which corresponds to the most common form of this disease. Th ese patients have an increased risk of enamel development abnormalities, especially enamel hypoplasia. In the temporal dentition, the most aff ected teeth are the second molar, while in the permanent teeth the central incisors are most commonly aff ected. In general, enamel hypoplasia is distributed bilaterally and symmetrically on both dental arches. Although lingual depapilation and burning sensation of the tongue have been described as typical oral manifestations of CD, these manifestations are less frequent. Often these manifestations are observed in patients with CD, secondary to anemia and not as a manifestation caused by the disease itself. It was found that in the active phase of the disease there was a decrease in salivary fl ow, which leads to dry mouth and burning sensation of the tongue. A higher rate of caries has been described in celiac patients. Th is cariogenic risk would be explained by the increased sensitivity of the hypoplastic enamel and the aforementioned changes in salivary fl ow rates and saliva composition observed in patients with CD. Th ere is no consensus on the relationship between CD and mouth ulcers. RAS ulcers are likely to be secondary to anemia. Herpetiform dermatitis corresponds to a dermatological condition strongly associated with CD14.

Helicobacter pylori (Hp)
It is a Gram-negative aerophilic bacterium, which colonizes the gastric mucosa and its infection is associated with the development of gastric and duodenal ulcer, MALT lymphoma and gastric cancer. Although it has been suggested that H. pylori infection may be one of oral cavity, most commonly in the posterior mandible and usually through the blood stream. Th e veins of the vertebral plexus are considered the primary path. Patients with mandibular metastases may be asymptomatic, or may complain of jaw or tooth pain, paresthesia, or loosening of teeth. Initially, the tumor is sometimes found in an unhealed extraction socket, after an unexplained loosen tooth has been extracted. Radiographs are necessary and show irregular, poorly circumscribed and often multifocal opacities. Less commonly, metastases may involve the maxilla or oral soft tissues 38,[41][42] .

CONCLUSIONS
Among the diff erent types of manifestations of gastrointestinal diseases, oral lesions represent an important, if not a major component of the manifestation of these diseases.
Although the frequency of oral manifestations, linked to gastrointestinal diseases, is variable and in most cases is non-specifi c (such as RAS like ulceration, stomatitis, burning sensation), these alterations may precede the underlying disease and therefore can facilitate an early diagnosis 2,3,7,43 . During the inspection of oral cavity, one can observe the persistent localized or generalized pain, halitosis, ptialism, xerostomia, the existence of ulcers (their type, frequency, recurrence, numbers, mass, or bleeding) 1,2,8 . Th is may increase the possibility of existing IBD, neoplasia, nutritional causes, infection, chronic infl ammation, or gastroesofageal refl ux 44 . According to the relationship between oral and digestive diseases the importance of recognition of oral signs and symptoms is a necessity. In many GI diseases oral lesions may be the only signs of the underlying disease and, therefore, the diagnosis can be confi rmed only by recognizing the oral pathology 45 . Th e oral tissues off er a biopsy site for serious GI conditions such as IBD, or digestive metastatic tumors 46 .
Compliance with ethics requirements: Th e authors declare no confl ict of interest regarding this article. Th e authors declare that all the procedures and experiments of this study respect the ethical standards in the Helsinki Declaration of 1975, as revised in 2008(5), as well as the national law. Informed consent was obtained from all the patients included in the study.
in the post-cricoid region. Dysphagia is a common symptom. Th e dataon its prevalence and incidence are limited to a single population-based study (in South Wales in 1960). Th e oral lesions often found in PVS are related to iron defi ciency anemia. Stomatitis, RAS likes ulcerations, angular cheilitis, pallor of the mucosa and atrophic glossitis are the most typical oral lesions 2,3,35 .

Malabsorption syndrome
Th e malabsorption syndrome includes numerous clinical entities accompanied by chronic diarrhea, abdominal distension and failure to grow 2,7 . Th is may appear due to congenital defects in the membranous transport system of the small intestine epithelium or due to acquired defects of the surface of the absorption epithelium. GI diseases related to protein-caloric malnutrition, or micronutrient malabsorption may have an eff ect on the oral tissues. Th e iron malabsorption, inducing iron defi ciency anemia, or the vitamin B12 malabsorption in pernicious anemia, are two of the most frequent example of malabsorption syndrome. When the malabsorption is suffi ciently severe, the fi rst oral manifestation is atrophic glossitis 36,37 . In milder cases, the atrophy is patchy. Th e more severe cases show involvement of the entire dorsum. In very severe cases, there may be shallow, round to oval-shaped, persistent ulcers with bright red borders, clinically resembling to the aphthous ulcers. Overt tongue lesions are usually sore, but a more common complaint is a burning sensation (glossopyrosis) that may precede clinically detectable oral lesions. Other involvements of the oral mucosal can show atrophic zones, with or without aphthouslike ulcers causing burning sensation, but these lesions are not as dramatic as the bald tongue. Th ey often go unnoticed. Aff ected patients are predisposed also to angular cheilitis 36,37 .

Metastatic tumors
Th e oral cavity is a rare but occasional target for metastases. Oral metastatic lesions from distant tumors are uncommon, accounting for only 1% of all oral malignancies [38][39][40] . Th e primary tumors are mainly lung, breast, kidney and colon tumors, which represent about 70% of the cases, reported in the literature [38][39][40] . Neoplasms of the gastrointestinal tract occasionally metastasize to the