Intestinal Malabsorption and Skin Diseases

Dig Dis 2008;26:167–174 DOI: 10.1159/000116775

Intestinal Malabsorption and Skin Diseases Ludovico Abenavoli a Ilaria Proietti b Luisa Vonghia a Lorenzo Leggio a Anna Ferrulli a Rodolfo Capizzi b Antonio Mirijello a Silvia Cardone a Noemi Malandrino a Veruska Leso a Maurizio Rotoli b Pier Luigi Amerio b Giovanni Gasbarrini a Giovanni Addolorato a Institutes of a Internal Medicine and b Dermatology, Catholic University, Rome, Italy

Key Words Skin ⴢ Malabsorption ⴢ Small intestine ⴢ Celiac disease ⴢ Inflammatory bowel disease

Abstract Several skin manifestations were described in patients affected by intestinal disorders. The development of skin diseases in these patients could be related to the impairment of intestinal absorption and motility, other than to immunological and hormonal changes. The growing evidence of the association between skin disorders and intestinal diseases suggests that the skin could be considered the ‘mirror of the gut’. Copyright © 2008 S. Karger AG, Basel

Introduction

Intestinal malabsorption can be accompanied by skin manifestations [1]. In 1973, Jones [2] described the skin as a ‘mirror of the gut’, underlining the close connection between these two sites. The author identified four subtypes of association between skin and gut: (i) a primary alimentary disease associated with skin changes; (ii) a primary skin disorder associated with small intestinal dysfunction; (iii) a specific skin disease associated with a particular gut disorder, and (iv) a generalized disorder © 2008 S. Karger AG, Basel 0257–2753/08/0262–0167$24.50/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

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associated with both changes in the skin and in the gut. This association reflects the pathogenic link between the ‘gut-skin axis’ [3] and should be considered in the clinical management of an intestinal and/or skin disease. In the following the cutaneous diseases associated with intestinal malabsorption are briefly described.

Epidemiology

The correlation between skin and intestinal disorders is heterogeneous and involves several diseases. An important correlation between gut and skin occurs in celiac disease (CD). In CD the most common cutaneous presentation is dermatitis herpetiformis, that affects 15–25% of CD patients [4, 5]. However, CD is associated with several skin alterations: 5% of patients with idiopathic aphthous stomatitis, 1–2% of patients with alopecia areata and 4.34% of patients with psoriasis have been found affected by CD [5]. Other conditions frequently associated with skin manifestations include inflammatory bowel disease (IBD). The incidence of cutaneous manifestations comprises between 1 and 15%, with a higher incidence when the colon is involved [6, 7]. The most common and specific skin manifestations are erythema nodosum and pyoderma gangrenosum. Erythema nodosum in particular has been reported in 15% of patients with Crohn’s disLudovico Abenavoli, MD Institute of Internal Medicine, Catholic University Largo A. Gemelli, 8 IT–00168 Rome (Italy) Tel. +39 06 3015 4334, Fax +39 06 3550 2775, E-Mail [email protected]

ease and in about 10% of patients with ulcerative colitis [7]; pyoderma gangrenosum has been described in 1–20% of IBD patients [8]. In addiction, aphthous stomatitis occurs in up to 11% of patients and psoriasis has been reported in 7–11% of the IBD population [9]. Other rare skin disorders include Sweet’s syndrome, acrodermatitis enteropathica, vitiligo, polymyositis, lupus erythematosus and scleroderma [6]. Moreover, perianal disease is very frequent occurring in about 50% of Crohn’s disease patients [10], and it varies from perianal erythema to abscesses and perianal complex fistulae. Metastatic Crohn’s disease is rare [6]. Regarding Whipple disease, hyperpigmentation, which is its most common skin finding, has a frequency of 45–54% [11], while the other forms of skin involvement are very rare. Skin manifestations of gastrointestinal polyposis are extremely frequent. In Peutz-Jeghers syndrome, pigmentation of the lips occurs in 96% of the cases and oral mucosa pigmentation occurs in 83%, while other locations are less frequently involved: areas around the nose and eyes in 36% of the cases, the extremities are involved in 32%, occasionally the pigmentation is also seen on the external genitals or the intestinal mucosa [12]. In Cowden syndrome, mucocutaneous lesions have been found in over 90% of patients [13]. In the small bowel, carcinoid cutaneous manifestations can be present and are generally related to a carcinoid syndrome, which occurs in 10% of these tumors. However, when a carcinoid syndrome occurs, the most common symptoms are the cutaneous manifestations (80%) [14]. Other correlations between skin and intestinal disorders are present, however they are rare and heterogeneous.

Pathogenesis

The small bowel is a complex organ that has four important functions [5]: (1) motility, that is necessary for transport and mixing of food and intestinal, hepatic and pancreatic secretions; (2) absorption, necessary for assimilating nutritive substances, vitamins, minerals, water, bile salts and drugs; (3) immunologic function, as it has a role as a lymphoid organ, by immunoglobulin and other immunomediators with local and systemic actions, and (4) hormonal secretion, by the synthesis of endocrine and neuroendocrine substances secreted by paracrine or autocrine pathways. In the bowel a selective ‘barrier’ separates the external and internal compartments, and 168

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blocks the free passage of potentially antigenic, toxic and carcinogen substances. The alteration of one or more of these functions may also affect the cutaneous surface and generate skin manifestations. In the following the principal skin manifestations associated with intestinal diseases are described.

Specific Disorders

Celiac Disease Gluten sensitivity is relatively associated with several skin alterations [5] (table 1). The most common presentation of CD is a chronic itch associated with the presence of several symmetrical papulovesicular rashes that evolve to crusting lesions broadly distributed over the body, but especially on the forearms, knees, buttocks, wrists and scalp. It is well known as dermatitis herpetiformis (DH) (fig. 1). Skin biopsy shows the characteristic lineal, granular deposits of IgA in the dermal papillae [15]. All patients with DH have some degree of CD, and these patients are very likely to reflect the entire spectrum of histologic and clinical CD in adults. Gluten must be present in the diet for the development of DH, however a genetic susceptibility to gluten has been proposed as an etiological mechanism [5, 16]. The skin disease and intestinal abnormality respond within weeks to 1–2 years to a gluten-free diet (GFD). Both the skin disease and the intestinal disease recur with reinstitution of diet containing gluten [17]. This strongly supports the belief that DH is an intestinal manifestation of CD. Clinically, one finds that 10–20% of patients with DH have classic symptoms of malabsorption and another 20% are estimated to have atypical symptoms, but at least 60% of patients have silent CD [18]. Complications of malabsorption, such as iron deficiency, occur in 10% of patients with DH [18]. Antigluten, antiendomysium, antigliadin and tissue transglutaminase antibodies have been detected in patients with DH [19]. These gluten-specific cells migrate to the gut mucosa where they mediate cytotoxic reactions involving epithelial cells [20]. IgA endomysial antibodies have been found in 70–90% of patients with DH on a diet containing gluten. This means that 10–30% of patients with DH are IgA endomysial antibody negative and IgA tissue transglutaminase negative [21]. Because 10–30% of cases of DH would be missed on serologic screening, it seems likely that a similar percentage of the population of patients with CD would be likewise missed. This makes it likely that the true prevalence of CD is significantly higher than currently indicated by serologic Abenavoli et al.

testing. With the exception of the finding of granular IgA in dermal papillae of patients with DH, no consistent serologic or immunologic difference between patients with DH and patients with CD has ever been identified. Recently, Sardy et al. [22] identified epidermal transglutaminase as the antigen in DH skin. The same investigators have evaluated serum of patients with DH and CD for the presence of epidermal transglutaminase antibodies. They found that the epidermal transglutaminase antibodies in serum of patients with DH had a higher avidity for the transglutaminase antigen than did serum of patients with CD. The significance of this finding has not yet been determined. Some immune-mediated skin diseases other than DH have been reported to reverse with GFD, in particular alopecia areata (AA), psoriasis, and aphthous stomatitis [5, 16]. It is likely that chronic stimulation of the immune system by gluten may be a cause of these immune disorders. AA is a chronic autoimmune disease characterized by non-scarring alopecia. In the general population the prevalence of CD is 1 in 305 and of AA 1 in 819 [5]. Corazza et al. [23] found that the prevalence of CD in patients with AA was 1 in 85. Although remission and recurrence may be observed during the clinical course of AA, many patients on GFD showed complete regrowth of scalp hair and other body hair and no further recurrence of AA at follow-up [23]. The positive effects of GFD on the pattern of autoimmune conditions, such as AA, associated with CD have been attributed to a normalization of the immune response. This study suggests that AA patients constitute a novel risk group of CD. Psoriasis is a chronic, relapsing dermatosis characterized by scaling, erythema, and, less commonly, postulation. Recent studies have showed an association between CD and psoriasis [5, 24] and an improvement of skin lesions after 3–6 months of GFD, without other pharmacological approaches, was described. In an open study, Michaelsson et al. [24] evaluated the effect of GFD in 33 antigliadin antibodies (AGA)-positive patients and 6 AGA-negative patients with psoriasis. Of the 33 AGApositive patients, 2 had IgA antiendomysial antibodies, and at the duodenal biopsy 15 showed an increased number of lymphocytes in the epithelium, but in some this increase was only slight. GFD was started for 3 months. 30 out of 33 patients strictly complied with GFD, after which they showed a significant decrease of psoriatic lesions. This included a significant decrease in the 16 AGApositive patients with normal routine histology in duodenal biopsy. The AGA-negative patients did not improve. Intestinal Malabsorption and Skin Diseases

Fig. 1. Typical lesions of DH in a celiac patient.

Table 1. Cutaneous diseases associated with CD reported in the

literature Dermatitis herpetiformis Psoriasis Alopecia areata Aphthous stomatitis Urticaria Hereditary angioneurotic edema Cutaneous vasculitis Linear IgA bullous dermatosis Erythema nodosum Erythema elevatum ditium Necrolytic migratory erythema Vitiligo

Behçet’s disease Dermatomyositis Porphyria Acquired hypertrichosis lanuginosa Pyoderma gangrenosum Ichthyosiform dermatoses Pellagra Generalized acquired cutis laxa Atypical mole syndrome Blue rubber bleb nevus syndrome

There was also a significant decrease in serum of eosinophil cation protein in patients with elevated AGA. The positive effects of GFD were observed not only in patients with an increased number of lymphocytes in the duodenal epithelium, but also in some patients with seemingly normal epithelium [24]. Our group reported a case of severe psoriasis in a CD patient not responding to specific therapies for psoriasis and in whom the regression of skin lesions after GFD was very rapid [25]. The association between psoriasis and CD was subsequently confirmed by Ojetti et al. [26]. The authors evaluated the prevalence of CD in patients affected by psoriasis, showing a high frequency of CD (4.34%) in psoriatic patients. Moreover, the same group has evaluated the prevalence of malabsorpDig Dis 2008;26:167–174

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Table 2. Common skin manifestations of IBD

Granulomatous lesions Perianal and peristomal ulcers and fistulas Metastatic Crohn’s disease Oral granulomatous ulcers (cobblestoning) Reactive lesions Aphthous stomatitis Erythema nodosum Pyoderma gangrenosum Sweet’s syndrome Lesions secondary to nutritional deficiency Acrodermatitis enteropathica (zinc) Stomatitis-glossitis-angular cheilitis (vitamin B) Scurvy (vitamin C) Purpura (vitamins C and K) Pellagra (niacin) Abnormal hair and nails (protein) Non-specific eczema (essential fatty acids) Autoimmune cutaneous disease Psoriasis Vitiligo Polymyositis Lupus erythematosus Scleroderma

tion in 55 psoriatic patients [27]. The authors found that malabsorption was more prevalent among psoriatic patients than among controls and hypothesized that CD and other diseases associated with psoriasis, as for example bacterial overgrowth, parasitic infestations and eosinophilic gastroenteritis, could be possible causes of malabsorption in these patients. Approximately 5% of patients with aphthous stomatitis have been found to have positive endomysial antibody tests and CD on small bowel biopsy [28]. Patients with aphthous stomatitis should be asked about a history of gastrointestinal complaints and screened for markers of CD, since recurrent aphthous stomatitis may in some cases respond to GFD. Inflammatory Bowel Disease Skin manifestations of IBD are relatively common [6]. In IBD in a genetically predisposed patient, a modified immune response to bacterial or other local factors may act as a trigger for activation of T cells, secretion of cytokine and production of autoantibodies against shared antigens (‘antigen mimicry’) [7]. The presence of these antigens also in extraintestinal organs, as skin, leads to an immune attack of these sites. In this connection a colonic epithelial protein and the human tropomyosin isoform 170

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5, which are shared by different extraintestinal sites including the skin, seem to be the most important targets of the autoimmune attack of extraintestinal organs [29]. Moreover, matrix metalloproteinases (MMPs), which are expressed in the intestine and in the skin, are involved [4]. In particular, MMPs are implicated in the mucosal damage of the intestine caused by excessive T-cell activation and secretion of pro-inflammatory cytokines and the imbalance between expression of MMPs and their inhibitors has been implicated in ulcer formation [30]. As to genetic susceptibility, particularly polymorphism – 1031C TNF-␣ has been associated with erythema nodosum in IBD patients [31]. Skin lesions can be classified into three principal classes: granulomatous, reactive and secondary to nutritional deficiency (table 2). Granulomatous cutaneous lesions have the same histological features of the bowel disease and include: perianal and peristomal ulcers and fistulas, metastatic Crohn’s disease, oral granulomatous ulcers. Perianal disease is very frequent occurring in about 50% of Crohn’s disease patients during their clinical history, and it varies from perianal erythema to abscesses and perianal complex fistulae [32]. Other fistulae can be internal or enterocutaneous, but rarely develop on the abdominal scar after laparotomy or at the umbilicus. Metastatic Crohn’s disease is a rare complication defined as the occurrence of specific granulomatous cutaneous lesions remote from the intestinal disease [33]. It manifests as subcutaneous nodules or ulcers mainly at the lower extremities with rare cases of genital localizations. It seems unrelated to the bowel activity. Mucosal nodularity (cobblestoning) is the presence of mucosal colored papules, forming firm plaques on the buccal mucosa and palate. These lesions are specific for Crohn’s disease. The group of reactive skin manifestations of IBD includes aphthous stomatitis, erythema nodosum (EN), pyoderma gangrenosum (PG), and the rare Sweet’s syndrome. Aphthous stomatitis is observed in about 10% of patients (fig. 2) [6] and generally occurs during active intestinal disease. Aphthae are shallow round ulcers with a central fibrinous membrane and erythematous halo. EN is the most common skin manifestation occurring in up to 15% of patients with Crohn’s disease and in about 10% of patients with ulcerative colitis [34]. Characteristic lesions are raised, erythematous, warm, round, tender nodules, occurring on the anterior tibial surface. Histological examination shows a lymphohistiocytic infiltrate of the lower derma. The etiology is thought to be hypersensitivity response involving immune complex deposition to venules in septa of connective tissue in subcutaAbenavoli et al.

neous fat [35]. Eruption of EN is associated with exacerbations of IBD but not with severity or extent. PG is a very debilitating ulcerating chronic skin disorder occurring in about 1–20% of IBD patients [35]. It occurs equally in both sexes [36]. The lesions are often on the extensor surface of the legs and particularly coincide with exacerbation of intestinal disease, and are associated with other extraintestinal manifestations. They are distinguishable from other ulcers by the presence of craterlike holes, pustules, and purulent drainage. The cause is not clear and it is thought to involve impaired cellular immunity and abnormal neutrophil function. Another rare cutaneous manifestation associated with IBD is Sweet’s syndrome [37], which is a neutrophilic dermatosis probably related to PG consistent with painful erythematous plaques or nodules often associated with fever and leukocytosis. The more frequent nutritional-deficient cutaneous manifestation is acrodermatitis enteropathica, which is caused by zinc deficiency and manifests as a psoriasis form of erythema [38]. Furthermore, an association between autoimmune cutaneous disease and IBD has been reported. The most frequent disease is psoriasis (7–11% of the IBD population vs. 1–2% of the general population), followed by vitiligo and, more rarely, polymyositis, lupus erythematosus and scleroderma [39]. Whipple’s Disease Whipple’s disease (WD) is a rare, multisystemic, chronic disease of the small bowel characterized by fever, arthritis and malabsorption. It is secondary to Tropheryma whippelii infection [40]. Cutaneous involvement has rarely been observed. The most common skin finding is hyperpigmentation, particularly of light-exposed areas. It has a frequency of 45–54% and is often erroneously diagnosed as Addison’s disease. Its pathogenesis is probably related to malabsorption [40]. Other forms of skin involvement are very rare and non-specific and include subcutaneous nodules, erythroderma, purpura, vasculitis, panniculitis, hyperkeratosis, erythematous and urticarial lesions, dermatomyositis, eczematous dermatitis and lichenoid lesions with sarcoid granulomas in dermis [41]. An intestinal and/or cutaneous biopsy is necessary for diagnosis because it can show PAS-positive inclusion corresponding to T. whippelii infection [42]. Peutz-Jegher Syndrome It is a dominantly transmitted disorder related to the STK11 gene located on chromosome 19 characterized by multiple gastric, tenual and colic polyps. Skin features Intestinal Malabsorption and Skin Diseases

Fig. 2. Aphthous stomatitis in the course of Crohn’s disease.

include melanin pigmentation of skin and mucous membranes. In particular, periorificial, oral, periocular, palmar, and digital lentigines are characteristic [43]. Pigmentation of the lips occurs most consistently in 96% of the cases, followed by pigmentation of the oral mucosa in 83%. The areas around the nose and eyes are involved in 36% [44]. The extremities are involved in 32%, when pigmentation occurs on the palms, soles, and volar aspects of the fingers and toes. Occasionally the pigmentation is also seen on the external genitals or intestinal mucosa. A cutaneous variant in expression of pigmentation in this syndrome exists, both among and within affected families. The pigmentation may vary from scattered intense dark freckling to solitary faint pigment spots. Moreover, the occurrence of pigmentation is age-specific. Mucocutaneous pigmentation is not present at birth, but starts to appear in infancy or early childhood, reaching a maximum at puberty. Histologically, Peutz-Jegher syndrome pigment macules resemble lentigines. An accumulation of pigment-laden macrophages is present in the upper dermis, with increased numbers of normal-appearing melanocytes in the basal layer. The mucocutaneous pigmentation is benign; no malignant degeneration of these spots has been described.

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Cowden Disease Cowden disease is an autosomal dominant disorder in which gastrointestinal polyps develop along with numerous skin lesions [13]. Pathognomonic features of CD patients are mucocutaneous lesions found in 99% of patients before the age of 30 years. These comprise facial trichilemmomas, acral and palmoplantar keratoses, papillomatous papules and mucosal lesions. Mucocutaneous lesions appear most commonly in the second and third decades. Facial papules are the most frequent finding. Coalescing mucosal lesions with a predilection for buccal and gingival mucosae lead to the characteristic cobblestone-like pattern that is found in 40% of patients. Hemangiomas and lipomas can occur. A distinctive nodule of the scalp known as Cowden fibroma has been described [13]. Small Bowel Carcinoid Tumors The small bowel, in particular ileum, represents the second most frequent localization of carcinoid tumors. Clinical manifestations include e.g. occlusion, pain, hemorrhage, carcinoid syndrome [45]. In carcinoid syndrome the hypersecretion of vasoactive substances as serotonin, histamine and bradykinin are responsible to cutaneous manifestations [45]. This tumor, especially in case of hepatic metastasis, causes a vasomotor crisis located principally on the face (‘blue island’ in ‘red sea’ or Björk syndrome), firstly paroxystic, and then intermittent and finally subsequent with telangiectasias, erythrocyanosis and pigmentation. Cutaneous metastasis presents as deep nodules. A pellagra-like erythema related to a deviation of tryptophan metabolism can occur; a sclerodrema-like status is rare. In bronchial carcinoid tumors, periorbital edema, sialorrhea and tearing associated with flushes have been reported [46]. A dermatological diagnosis is generally easy, as cutaneous symptoms are concomitant with metastatic tumors and increased levels of serotonin and 5-hydroxyindolacetaldehyde. Metastases to the skin seem to be a late manifestation of advanced disease, but data in the literature are scant and limited to single case reports only [45]. These metastases may present as painless subcutaneous nodules, but sometimes they are extremely painful. The pathogenesis of the severe pain encountered in these often tiny metastatic deposits remains difficult, as neural involvement is not a consistent finding. Intestinal Overgrowth The small bowel normally contains a bacterial flora which is crucial for proper bowel functioning [47]. The 172

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distal ileum is colonized by obligate or facultative anaerobic bacteria, most significantly Bacteroides species, while aerobes and facultative anaerobes are dominant in the more proximal small bowel [47, 48]. Any alteration of this condition in the small bowel may result in diarrhea and malabsorption [49]. A concentration of 1 ! 105 organisms/ml aspirate fluid is diagnostic for bacterial overgrowth syndrome [47]. This condition is often associated with EN and abdominal pain and sometimes to Sweet’s syndrome [50]. Moreover, a case of skin eruption associated with bacterial overgrowth has been described [51]. The initial skin lesions were ‘target’ lesions, while older lesions showed a psoriasiform scale and a tendency to central clearing. These manifestations were associated with raised levels of IgM and IgG containing circulating immune complexes and deposition of IgM and IgG in the dermis and were suppressed by antibiotic therapy [51]. In another case report [52], an association between bacterial overgrowth and skin eruptions, myalgia and arthralgia has been reported. In this case the pathological features and the response to therapy were typical of the dermatosis-arthritis syndrome [52]. Lactose Intolerance Lactose intolerance is defined as gut pain and distension, borborygmi, flatus and diarrhea, induced by lactose [53]. Generally, extraintestinal manifestations are uncommon, however an association between lactose intolerance and cutaneous manifestations has been described [54], namely a severe chronic eczema has been described in a patient with lactose intolerance. Corticosteroid treatment was required for a long period of time and the introduction of a lactose-free diet led to a complete disappearance of the skin lesions and permitted the discontinuation of the pharmacological treatment. Moreover, oral ulcers can occur in patients affected by lactose intolerance and can be removed by a lactose-free diet [53]. Intestinal Lymphangiectasia Intestinal lymphangiectasia (IL) is a rare disease characterized by abnormally dilated lymphatics in the small intestinal wall and/or the mesentery, often associated with systemic disorders of the lymphatic system, or with a process specifically located in the gastrointestinal tract [55]. This condition causes extreme leakage of lymph into the gastrointestinal tract causing loss of proteins, immunoglobulins and lymphocytes, which in turn leads to depression of the humoral and cellular immune systems [56]. An association between IL and skin diseases has been described only in case reports and in particular in Abenavoli et al.

children. Behçet’s disease [57], viral warts [55], aplasia cutis congenita [58], alopecia [59], cutis marmorata telangectasia congenita syndrome [60], and yellow nail syndrome [61] are skin diseases which are reported in the literature and associated with IL. It is possible that the onset of cutaneous lesions in patients affected by IL was likely triggered by a generalized depression of the immune system. Enteropathic Acrodermatitis Enteropathic acrodermatitis is a rare hereditary recessive autosomic disorder caused by zinc malabsorption [62]. This deficiency leads to diarrhea, growing delay and acral and periorificial cutaneous alterations that generally occur several days after birth and weaning. The typical lesion is an erythematous speck, with net margins, eroded, covered centrally by crusts and with vesicles or pustules on the periphery. The chronic and variegated eruption is often psoriasis-like. Initially the perioral and perianal lesions are often interpreted as Candida albicans infections and the immunological state of the patient

turns out to be weakened. Nearly all the children show a diffuse alopecia and paronychias that provoke nail dystrophies. In some cases, striped hairs, with clear and dark bands, glossitides and stomatitis can be observed [63].

Conclusions

Intestinal malabsorption, such as celiac disease, Whipple’s disease, Peutz-Jeghers-Touraine syndrome, small bowel carcinoid tumor, Crohn’s disease, intestinal overgrowth, intestinal lymphangioectasias and enteropathic acrodermatitis, is often associated with various skin and nail diseases, and several hypotheses have been proposed regarding the possible mechanisms involved. At present, it is difficult to come to a conclusion regarding the association between gastrointestinal diseases and skin disorders because data are not definitive. Future studies are needed to verify the real involvement of cutaneous areas in gastrointestinal diseases because it can result in early diagnosis and treatment.

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