General appearance

The disease most often appears before the age of 40 with nonspecific symptoms of inflammation. Thus, the patient presents with fever, fatigue, abdominal pain and tenderness (often in the right lower quadrant), and diarrhea. In children, retarded growth and development often occur before any other manifestation. As the disease progresses, sequelae such as strictures and fistulae start arising [1] [2], which may result in bowel obstruction.

Intestinal manifestations

The most commonly affected sites in Crohn's disease are the distal small intestine and the proximal colon, although the disease can occur throughout the whole gastrointestinal (GI) tract. Vomiting becomes a frequent symptom in gastroduodenal involvement [3]. Excessive pain, oozing fistulae, and scars characterize a perianal disease. If the colon is affected, there may be the blood in the stool [4].

Extraintestinal manifestations

Numerous extraintestinal manifestations can exist in Crohn's disease [5]. Arthritic and musculoskeletal pain is the most common [6]. Aphthous ulceration of the mouth is also frequent, as is erythema nodosum of the skin. Episcleritis and uveitis are the principal eye presentations. Hepatobiliary problems such as primary sclerosing cholangitis, which also happens in ulcerative colitis, are also common. Gallstones and kidney stones arise presumably because of malabsorption of fats and bile salts. Apart from kidney stones, the urologic complications include enterovesical fistulae and hydronephrosis. Crohn's disease is also characterized by a hypercoagulable state, osteopenia and osteoporosis, and deficiencies in iron, vitamin B12, and folate, which lead to anemia. Other anemic states are also possible, for example owing to gastrointestinal bleeding.

The standard laboratory tests do not show results specific for Crohn's disease. Anemia and hypoalbuminemia are common. C-reactive protein (CRP) levels and erythrocyte sedimentation rate (ESR) may be of use since there is an association with the presence of complications of Chron's disease [7]. Fecal calprotectin may serve as a marker for intestinal inflammation.

There are two serological tests of significant importance, one indicating the presence of anti-Saccharomyces cerevisiae antibodies (ASCA) which are mainly seen in Crohn's disease, the other showing positive results in patients with ulcerative colitis for perinuclear antineutrophil cytoplasmic antibodies (p-ANCA). These tests may help to distinguish these two diseases.

A number of imaging techniques are available for diagnosis. Whereas barium contrast imaging has been used for a long time, it is being replaced by ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), and capsule endoscopy methods. These modalities have been extensively evaluated for accuracy in detecting various pathological aspects of Chron's disease [8], such as the extent of the disease at different locations within the GI tract, the severity of the lesions, the detection of intraabdominal fistulae and abscesses, and other features. Ultrasonography is a widely used and affordable technique that does not involve ionizing radiation, but its accuracy for diagnosing Crohn's disease depends on the location of the lesions, whereas the precision of MRI diagnosis is less depended on the position of the pathologic changes. All three methods (ultrasound, CT, and MRI) are highly accurate in identifying stenosis, fistulae, and abscesses. Barium studies can also detect fistulae. CT scans efficiently reveal extramural and hepatobiliary complications [9], as well as bowel wall thickening and edema. The advantage of MRI is the absence of radiation. Other imaging modalities include esophagogastroduodenoscopy (EGD), endoscopic retrograde cholangiopancreatography (ERCP), ileocolonoscopy, and balloon enteroscopy.

In Chron's disease lesions of the intestine often alternate with unaffected areas, which is the reason why they are called skip lesions. The histology may show the presence of non-caseating granulomas.

Mild Crohn's disease patients are usually initially prescribed 5-aminosalicylic acid preparations. If no improvement is noted, corticosteroids, 6-mercaptopurine/azathioprine or methotrexate are indicated, while biological agents are considered last resort before surgery. Moderate and severe cases benefit from the top-down approach, that uses a combination of biologic agents and steroids from the beginning. 6-mercaptopurine combined with a biologic agent efficiently induces remission [10].

5-aminosalicylic acid preparations include sulfasalazine and mesalazine. Mesalazine better prevents relapse than its peer. Corticosteroids effectively relieve severe systemic symptoms but are reserved for situations where obvious infection signs are absent. They should be administered for short periods of time and if withdrawal proves difficult, immunosuppressants should be considered. This therapy category is not without side effects, so patients need careful monitoring.

Biologic therapy includes agents such as infliximab, a chimeric mouse-human monoclonal antibody against tumor necrosis factor alpha (TNF-α), adalimumab and certolizumab pegol. The latter agents are less immunogenic, but seemingly equally effective. Natalizumab and vedolizumab are integrin antagonists, while ustekinumab inhibits interleukins 12 and 23. Other therapeutic agents that may prove beneficial include tacrolimus and mycophenolate mofetil. Surgical treatment is required for fistulae, abscesses, toxic megacolon, perforation, intractable hemorrhage, and strictures.

Crohn's disease has an overall favorable prognosis, but the course of the disease is marked by remissions and relapses. The risk of a fatal outcome is very small if the patient follows appropriate treatment. New therapeutic agents have improved survival even in individuals classically considered having increased risk, such as females with long disease duration [11]. The classical course of the disease included complications like chronic obstructive pulmonary disease and gastrointestinal malignancies, but their incidence has diminished in the current era. Relapses are more frequently encountered in the first year after diagnosis and may be as high as 50% of cases. Surgery is required in up to 39% of cases 10 years after diagnosis and sometimes more than on operation is needed [12]. The most common reason for surgery is stricture removal. The younger the patient is at the time of diagnosis, the higher the probability for multiple surgical interventions is. Crohn's disease of the proximal small bowel implies a higher risk of mortality than an ileal or ileocecal disease. The risk for colorectal cancer is also diminished by modern therapy. Life quality is near- normal in cases that are not very severe.

The etiology of Crohn's disease is at this time unknown, but several genetic, vascular, immunologic, microbial, environmental and psychosocial factors are thought to be involved. Oral contraceptive use and smoking also seem to play a role in disease etiology, as do nonsteroidal anti-inflammatory agents. These risk factors may cause Crohn's disease in individuals that are susceptible to develop an aberrant immunologic response [13]. Several abnormal genes thought to regulate mucosal immunity have been described. Despite this fact, Crohn's disease is not considered to be a genetic disease and Mendelian inheritance is absent. The first gene ever to be demonstrated to be involved in Crohn's disease susceptibility is CARD15, located on chromosome 16. It can be affected by over 60 mutations, but 3 are most frequent [14]. IL23R, PTPN22, CCR6, JAK2, IL12B, STAT3, CDKAL1 and LRRK2 gene mutations are other possibilities [15]. Most of these translate as immune function abnormalities, whereas the ATG16L1gene impairs the autophagosome pathway, with important implications in disease pathogenesis.

Inflammation caused by Listeria species, Pseudomonas species, and Mycobacterium paratuberculosis is considered dysfunctional in Crohn's disease cases [13]. This condition is believed to be also caused by increased production of TNF-α by macrophages [16]. Smoking increases the risk of Crohn's disease twice [17]. Fat rich diet is also involved in the etiology of this condition [18]. The disease is not caused by the measles vaccine, as once thought [19].

Therefore, there is no single etiology for Crohn's disease. This condition is caused by environmental factors that disrupt gut microbiota balance and abnormally stimulate the intestinal immune response in genetically susceptible individuals.

Crohn's disease is more frequent in urban areas than rural ones [20]. 43 children in 100.000 and 201 adults in 100.000 are estimated to suffer from this condition in America [21], whereas Europeans have a 5.6 per 100,000 inhabitants incidence [22]. Asian incidence of the disease ranges between 0.5 and 4.2%. Individuals belonging to the upper socioeconomic class are more frequently affected [23], as are individuals living in temperate climates and industrialized areas.

Disease incidence has two peaks, one between 15 and 30 years of age and one between the ages of 60 and 70 years. Most individuals are diagnosed before turning 30 years old. The female sex is slightly more prone to developing this condition, with a 1.1-1.8 times higher incidence than men [24]. However, during childhood, this ratio is reversed, with a male-to-female ratio of 1.6:1.

T lymphocytes play a key role in Crohn's disease pathogenesis. They respond in an unrestrained manner due to their defective regulation and secrete proinflammatory cytokines that recruit other inflammatory cells that, in turn, release more inflammatory substances, leading to unwanted process escalation and intestinal injury. These phenomena are more severe in cases with defective epithelial barrier integrity and abnormal autophagy [25]. The inflammatory infiltrate initially located around a crypt, after forming a crypt abscess progresses to mucosal ulceration and invasion of the deeper layers. The process ends with noncaseating granulomas formation, that extends to the entire intestine and possibly the adjacent structures, such as regional lymph nodes and the mesentery. The granuloma is the pathognomonic lesion of Crohn's disease [13]. The colon becomes atrophic and ulcerated, but lesions are interpolated with normal areas of mucosa.

The pathophysiology of bowel obstruction in Crohn's disease is explained by mucosal edema that narrows the intestinal lumen. Deep ulcers may transform into enterocutaneous, enteroenteral, enterovaginal or enterovesical fistulae. Frank intestinal perforation is rarer in Crohn's disease than other bowel inflammatory diseases because of the presence of multiple adhesions.

Crohn's disease cannot be prevented because its etiology remains unclear. Several nonspecific preventive measures have, however, been advanced. These include avoiding or stopping smoking, stress management, good hydration, optimizing vitamin D levels and having a well-balanced diet, rich in fibers, saturated fats, fruits, vegetables and omega-3 fatty acid. Processed food, preservatives, artificial flavors and colors, raw nuts and dairy consumption should be limited.

Crohn's disease is a chronic condition, part of the intestinal bowel diseases cluster, that extends throughout the entire gastrointestinal system, from the mouth to the anus. It is characterized by periods of relapse and remission. Patients complain about abdominal pain and diarrhea or about more severe symptoms that accompany intestinal obstruction and fistulization. The disease causes malnutrition, anorexia, nausea, vomiting, weight loss and fatigability. Acute periods are accompanied by fever and rectal bleeding. Children experience growth failure, that may precede gastrointestinal symptoms by a ling time. Bone loss and coping difficulties are not uncommon.

Clinical examination may reveal signs of anemia such as tachycardia and paleness. Jaundice is another possibility. The abdomen is more or less painful on palpation and evidence of hematochezia may be present. Skin lesions that may be encountered include ulcerations, pyoderma gangrenosum, and erythema nodosum. Puberty signs may be delayed and visual impairment may be due to episcleritis or uveitis. Arthritis associated with Crohn's disease predominantly affects large joints.

Diagnosis relies on laboratory and imaging tests. The first category includes anti-Saccharomyces cerevisiae antibodies and perinuclear antineutrophil cytoplasmic antibodies, in addition to fecal calprotectin and other standard tests. Computer tomography enterography or magnetic resonance enterography are slowly replacing more simple radiological tests and offer relevant information, such as the existence of strictures and fistulae. Superior digestive endoscopy and ileocolonoscopy must be performed in every case because they not only fully characterize mucosal aspect, but allow biopsy specimens to be obtained and investigated.

Treatment relies on several therapeutic classes: 5-aminosalicylic acid derivates, corticosteroids, immunosuppressive agents and monoclonal antibodies. Discomfort may be alleviated by antidiarrheal agents and anticholinergic and antibiotics are sometimes needed. Surgery is not curative in Crohn's disease, but it is often necessary in order to resolve disease complications like strictures, abscesses, and fistulae.

Crohn's disease causes inflammation throughout the entire digestive system, leading to abdominal pain, malnutrition, weight loss, mouth sores, fatigability, bloody stools, and diarrhea. The inflammatory process can be confined, however, to a single segment of the digestive tract. Symptoms install suddenly, but the patient may also have periods of remission, with no complaints. Affected individuals also complain about eyes and joints inflammation. In children growth and puberty are delayed.

The diagnosis is established using blood tests and imaging methods, but an upper intestinal endoscopy and colonoscopy are usually compulsory. These techniques allow direct visualization of the mucosa and pieces of the diseased tissue can be obtained and analyzed. With treatment, many achieve a good life quality. If complications such as fistulae, abscesses and bowel obstruction arise, surgery is needed.

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