Pathophysiology & Heal

The exact cause of Crohn disease remains unknown. Current theories implicate the role of genetic, microbial, immunologic, environmental, dietary, vascular, and even psychosocial factors as potential causative agents. It has been suggested that patients have an inherited susceptibility for an aberrant immunologic response to one or more of these provoking factors. Microscopically, the initial lesion starts as a focal inflammatory infiltrate around the crypts, followed by ulceration of superficial mucosa. Later, inflammatory cells invade deep layers and, in that process, begin to organize into noncaseating granulomas.

The granulomas extend through all layers of the intestinal wall and into the mesentery and the regional lymph nodes. Although granuloma formation is pathognomonic of Crohn disease, absence does not exclude the diagnosis. Macroscopically, the initial abnormality is hyperemia and edema of the involved mucosa. Later, discrete superficial ulcers form, which become deep serpiginous ulcers located transversely and longitudinally over an inflamed mucosa, giving the mucosa a cobblestone appearance. The lesions are often segmental, being separated by healthy areas, and are often referred to as skip lesions.

Transmural inflammation results in thickening of the bowel wall and narrowing of the lumen. As the disease progresses, it is complicated by obstruction, fistulization by way of the sinus tracts penetrating the serosa, microperforation, abscess formation, adhesions, and malabsorption. Obstruction is initially caused by significant edema of the mucosa and associated spasm of the bowel. Obstruction is intermittent and is often reversible with conservative measures and anti-inflammatory agents. With further progression, the obstruction becomes chronic because of scarring, luminal narrowing, and stricture formation.

Fistulae may be enteroenteral, enterovesical, enterovaginal, or enterocutaneous. Serosal inflammation causes adhesions; thus, free perforations are less common in this disease. Malabsorption occurs as result of loss of functional mucosal absorptive surface. This phenomenon can lead to protein-calorie malnutrition, dehydration, and multiple nutrient deficiencies. Involvement of the terminal ileum may result in malabsorption of bile acids, which leads to steatorrhea, fat-soluble vitamin deficiency, and gallstone formation.

Fat malabsorption, by trapping calcium, may result in increased oxalate excretion (normally complexed by calcium), causing kidney stone formation. Nearly 30% patients with either large- or small-bowel disease develop perianal complications. The latter may precede development of intestinal symptoms and manifests as anal fissure, perianal fistula, or abscess. Although any area of the GI system may be affected, the most common site of disease is the ileocecal region, followed by the colon, the small intestine alone, the stomach (rarely), and the mouth.

The esophagus is involved very rarely. In addition to local complications, a variety of extraintestinal manifestations may be associated with Crohn disease. The usual sites are skin, joints, mouth, eyes, liver, and bile ducts. Skin manifestations (eg, erythema nodosum, pyoderma gangrenosum) and peripheral arthritis (eg, asymmetric involvement of larger joints) are probably more common with colitis than with enteritis. Aphthous ulcers are the most common mouth lesions. Ocular manifestations (eg, episcleritis, recurrent iritis, uveitis) are other manifestations of the disease.

These manifestations often parallel the course of bowel disease and usually subside when the disease is brought under control. Ankylosing spondylitis and sacroiliitis, which cause hip and back pain, may antedate the bowel disease by several years and may persist after surgical or medical remission of the disease. Amyloidosis and thromboembolic manifestations may also occur. Involvement of the liver varies from simple elevation of enzyme levels to benign pericholangitis, sclerosing cholangitis, autoimmune chronic active hepatitis, and cirrhosis. Cholangiocarcinoma is a rare late complication of primary sclerosing cholangitis.

Sometimes, a hepatic abscess manifests as fever of unexplained origin. Frequency United States The prevalence of Crohn disease is approximately 7 cases per 100,000 population. The incidence and the prevalence of Crohn disease (especially colonic) seem to have steadily increased over the last 5 decades, mainly in northern climates. International The prevalence of Crohn disease is reportedly lower in southern European countries, South Africa, and Australia (approximately 0. 9-3. 1 cases per 100,000 population) and is even lower in Asian and South American countries (approximately 0. 5-0. 08 cases per 100,000 population).

Urban areas may have a higher prevalence of inflammatory bowel disease (IBD) than rural areas. Upper socioeconomic classes are thought to have a higher prevalence than lower socioeconomic classes. Mortality/Morbidity Crohn disease usually has a chronic, indolent course regardless of the site of involvement. Studies have estimated ranges from no increased risk to up to a 5-fold increased risk of death. • The chance of death and complications increases with the duration of the illness. • • As the disease progresses, medical therapy becomes less effective, and most patients develop complications requiring surgery (approximately 80%).

• • The disease frequently recurs after surgery. Race Data on racial incidence seem to show that the condition is uncommon in nonwhites in underdeveloped regions; however, this is not applicable to nonwhites in urban settings, where the rate may even exceed that of whites. • This condition is seemingly more common in whites than in blacks or Asians. • • A 2- to 4-fold increase in the prevalence of Crohn disease has been found among the Jewish population in the United States, Europe, and South Africa compared to other ethnic groups. Sex The male-to-female ratio is 1. 1-1. 8:1.

Age The onset of Crohn disease has a bimodal distribution. The first peak occurs between the ages of 15-30 years, and the second peak occurs between the ages of 60-80 years. However, most cases begin before age 30 years. History • Patients with Crohn disease most commonly present with symptoms related to a chronic inflammatory process involving the ileocolic region. • o Low-grade fever, prolonged diarrhea with abdominal pain, weight loss, and generalized fatigability are usually reported. o o The patients may develop crampy or steady right lower quadrant or periumbilical pain.

The pain precedes and may be partially relieved by defecation. Diarrhea is usually nonbloody and often intermittent. o o If the colon is involved, patients may report diffuse abdominal pain accompanied by mucus, blood, and pus in the stool. o • Patients may also present with complaints suggestive of intestinal obstruction. • o Initially, the obstruction is secondary to inflammatory edema and spasm of the bowel and manifests as postprandial bloating, cramping pains, and loud borborygmi. Once the bowel lumen becomes chronically narrowed, patients may complain of constipation and obstipation.

Complete obstruction may sometimes be caused by impaction of undigested foods. o o Perianal fissures or fistulae are common. o o Cologastric fistulae may manifest as feculent vomiting, enterovesical fistulae as recurrent urinary tract infections and pneumaturia, enterovaginal fistulae as feculent vaginal discharge, and enterocutaneous fistulae as feculent soiling of the skin. o o Development of fistulae into the mesentery may result in intra-abdominal or retroperitoneal abscess formation. o o Patients may also have perianal disease, including perianal fissures, abscesses, and fistulae. o

• Patients may have problems related to extraintestinal manifestations of the disease, which may involve the skin, joints, mouth, eyes, liver, and bile ducts. • • Young people with Crohn disease commonly experience unexplained growth failure and delayed puberty. • Physical Physical examination should focus on the patient’s temperature, weight, nutritional status, presence of abdominal tenderness or a mass, perianal and rectal examination findings, and extraintestinal manifestations. • Physical findings may typically reveal right lower quadrant tenderness. A mass can sometimes be felt secondary to thickened or matted loops of inflamed bowel.

• • Perianal involvement manifests as skin tags, fistulae, abscesses, and scarring. • • Extraintestinal manifestations of the skin include erythema nodosum and pyoderma gangrenosum. • • Eye involvement is usually manifested as uveitis or episcleritis. • • A peripheral arthritis involving the large joints may also be present. • Causes Genetic, environmental, microbial, immunologic, dietary, vascular, and psychosocial factors have been implicated in the pathogenesis of Crohn disease. • Recent studies have shown compelling evidence for an inheritable risk for the development of the disease.

Several genes are thought to contribute to the complex phenotype; however, mutations within the NOD2 gene (or the IBD1 gene) have been shown to confer susceptibility to Crohn disease. • • Interleukins and tumor necrosis factor-alpha (TNF-alpha) have also been implicated in the disease process. Crohn disease is characterized by a T-helper type 1 cellular immune response pattern that leads to production of interleukin 12 (IL-12), TNF, and interferon gamma (IFN-gamma). TNF has been shown to play a critical role in the inflammation in this disease.

Increased production of TNF by macrophages in patients with Crohn disease results in increased concentrations of TNF in the stool, blood, and mucosa. • • Most of the genes thought to be involved in the development of the disease play a role in mucosal immunity and are found on the mucosal barrier epith Lab Studies • Laboratory study findings may indicate the presence of inflammatory activity or nutritional deficiencies. • o Anemia may be due to multiple causes, including chronic inflammation, iron malabsorption, chronic blood loss, and malabsorption of vitamin B-12 or folate.

o o Leukocytosis may be due to chronic inflammation, abscess, or steroid treatment. o o Hypoalbuminemia, hypocholesterolemia, hypocalcemia, hypomagnesemia, and hypoprothrombinemia may reflect malabsorption. o o Acute inflammatory markers, such as C-reactive protein and orosomucoid, correlate closely with disease activity. The erythrocyte sedimentation rate is thought to be more helpful in assessing the disease activity of Crohn colitis than ileitis. o o Stool samples should be tested for routine pathogens, ova, parasites, and Clostridium difficile toxin. o

• Two serologic tests are available to attempt to differentiate ulcerative colitis (UC) from Crohn disease. • o Perinuclear antineutrophil cytoplasmic antibody (p-ANCA), a myeloperoxidase antigen, is more commonly found in UC, whereas antibodies to the yeast Saccharomyces cerevisiae (ie, anti-S cerevisiae antibodies [ASCA]) are more commonly found in Crohn disease. o o Therefore, a test result positive for p-ANCA antigen and negative for ASCA suggests the diagnosis of UC; conversely, a test result positive for ASCA and negative for p-ANCA antigen suggests the presence of Crohn disease. o

o However, these tests are only recommended as an adjunct to clinical diagnosis, as the test results are not specific and have been found to be positive in other bowel diseases. o Imaging Studies • Barium contrast studies • o These studies are very useful in defining the nature, distribution, and severity of the disease. An experienced radiologist should perform these studies to obtain the most information. o o An upper GI series, together with a small-bowel follow-through and spot films of the terminal ileum is the initial diagnostic procedure of choice in most patients presenting with typical symptoms of Crohn disease.

o o Barium enema may help evaluate colonic lesions once the patient can tolerate the procedure. Barium contrast studies are useful in evaluating features such as rigidity, pseudodiverticula, fistulization, and submucosal edema. These studies are noninvasive and usually well tolerated. In patients with ileitis, the terminal ileum may not be visualized, possibly because of spasm of the ileocecal valve. o o Radiographic findings in both the small and large bowel parallel the clinical pattern. o o Edema and ulceration of the mucosa in the small bowel may appear as thickening and distortion of valvulae conniventes.

Edema of the deep layers of the bowel wall results in separation of the barium-filled bowel loops. o o Tracking of deep ulcerations, both transversely and longitudinally, results in a cobblestone appearance. o o Ileitis can also manifest as a sting sign on barium study secondary to spasm or, rarely, because of fibrotic stricturing. o o Fistulae can also be detected by barium studies of the digestive tract or through injection into the opening of the suspected fistula. o • CT scan is helpful in assessing extramural complications such as fistulae, abscesses, and hepatobiliary and renal complications. •

• MRI can be superior to CT scanning in demonstrating pelvic lesions. • • Ultrasound is helpful in differentiating tubo-ovarian pathology. • • Radionucleotide scans may be helpful in assessing the severity and extent of the disease in patients who are too ill to undergo colonoscopy or barium studies. • Procedures • Colonoscopy • o Consider colonoscopy if a single-contrast barium enema has proved to be less informative in evaluating a colonic lesion. o o Colonoscopy is useful in obtaining biopsy tissue, which helps in differentiation of other diseases, in evaluation of mass lesions, and in performance of cancer surveillance.

o o Colonoscopy also enables dilatation of fibrotic strictures in patients with long-standing disease. Colonoscopy may also be used in the postoperative period to evaluate surgical anastomoses to predict the likelihood of clinical relapse as well as the response to postoperative therapy. o • Upper endoscopy • o Upper endoscopy with biopsy is helpful in differentiating Crohn disease from peptic ulcer disease in patients with upper GI tract symptoms. o o Endoscopic retrograde cholangiopancreatography is helpful as both a diagnostic tool and a therapeutic tool in patients with sclerosing cholangitis and stricture formation.

o o Endoscopic ultrasonography (EUS) and magnetic resonance cholangiopancreatography (MRCP) may provide equally valuable information without invasive complications. o Histologic Findings Transmural involvement with noncaseating granulomas is seen in about 50% of cases as well as patchy skip lesions. Lymphoid aggregates may also be seen throughout the bowel wall. Medical Care • Diarrhea o Chronic diarrhea responds well to antidiarrheal agents such as loperamide (2-4 mg), diphenoxylate with atropine (1 tab), and tincture of opium (8-15 gtt).

Such agents may be administered up to 4 times daily but should not be given to patients with active colitis because of the risk of developing toxic megacolon. o Patients with terminal ileal disease cannot absorb bile acids, which can lead to secretory diarrhea in the colon. These patients benefit from bile acid sequestrants (eg, cholestyramine [2-4 g], colestipol [5 g] bid/tid ac). Those who have extensive ileal disease or resection of more than 100 cm of ileum have defective bile salt absorption and develop steatorrhea. These patients benefit from a low-fat diet and medium-chain triglyceride preparations.

Bile sequestrants exacerbate this type of diarrhea. o Diarrhea may also develop because of bacterial overgrowth, short-bowel syndrome, and lactase deficiency. o Abdominal cramps may be reduced with propantheline (0. 125 mg), dicyclomine (10-20 mg), or hyoscyamine (0. 125 mg). These drugs should not be used if a bowel obstruction is considered possible. • For colon and small-bowel inflammation, anti-inflammatory drugs or antibiotics are helpful. o Sulfasalazine is mainly useful in colonic disease because the active compound, 5-aminosalicylic acid (5-ASA), is released in the large bowel by bacterial degradation of the parent compound.

Sulfasalazine does not alleviate small-bowel disease. Products such as mesalamine (Asacol) that release 5-ASA in the distal small bowel secondary to pH changes are more useful in patients with small intestinal Crohn disease. Long-term maintenance with mesalamine (800 mg tid) may delay clinical relapse. Sulfasalazine does not have an additive effect or a steroid-sparing effect when used in conjunction with corticosteroids. In contrast to its action in UC, it does not seem to maintain remission in Crohn disease.

o A short course of steroid therapy is indicated in patients with severe systemic symptoms (eg, fever, nausea, weight loss) and in those who do not respond to anti-inflammatory agents. Prednisone (40-60 mg/d) is generally helpful in acute inflammation. Once remission is achieved, slowly taper steroids (5-10 mg q1-2wk). o In patients who relapse after withdrawal of steroids, other treatment options are required. Steroids are not indicated for maintenance therapy because of serious complications such as aseptic necrosis of the hip, osteoporosis, cataract, diabetes, and hypertension.

o In patients with a tender palpable mass, exclude an underlying abscess before starting steroids. Adding antibiotics is always beneficial if coexisting infection is considered likely. o Consider immunosuppressants such as azathioprine (2 mg/kg/d) or its active metabolite, 6-mercaptopurine (6-MP), if steroid withdrawal proves difficult. Response is usually observed within 3-6 months. Careful supervision is needed because of the risk of bone marrow suppression. o If medical therapy fails, surgical resection of the inflamed bowel, with restoration of continuity, is indicated.

Urgent surgery may be required in rare cases of sustained or recurrent hemorrhage and toxic megacolon. Partial small bowel obstruction may sometimes be treated conservatively with intravenous hydration, nasogastric suction, and parenteral nutrition if there is no evidence of adhesion or strangulation. • Fistulae o Fistulae between bowel loops (eg, ileoileal, ileocecal, ileosigmoid) are usually benign and may not produce any major problems. o Enterovesicular, enterocutaneous, cologastric, and coloduodenal fistulae are more serious.

Surgical intervention is rarely required unless fistulae are complicated by progressive obstruction or abscess formation or a large segment of bowel is bypassed, leading to severe diarrhea and malabsorption. Otherwise, medical management is used to treat underlying infections and symptoms with oral metronidazole (1 g/d) for at least 1-2 months. Ciprofloxacin confers additional benefit if no improvement occurs o Antimetabolites are beneficial in reducing drainage and closing fistulae in 30-40% of patients. Total parenteral nutrition (TPN) and bowel rest may promote fistula healing during medical therapy.

• New medical therapies o Anti–tumor necrosis factor (TNF) antibody ? TNF, a key inflammatory cytokine and mediator of intestinal inflammation, is expressed prominently in IBD. Infliximab is a chimeric mouse-human monoclonal antibody against TNF and shows promise in Crohn disease. It blocks TNF in the serum and at the cell surface, leading to the lysis of TNF-producing macrophages and T cells. ? In one study, nearly 65% of refractory cases of Crohn disease responded well to treatment with infliximab (5 mg/kg), and a third went into complete remission.

Patients who relapsed after initial response responded again to further infusions. Infliximab is also effective in patients who have refractory perianal and enterocutaneous fistulae. On average, the effect lasts for 12 weeks. Important adverse effects include the development of a lupuslike syndrome and an increased incidence of tuberculosis. Anti–double-stranded DNA is not always associated with clinical lupus. An added benefit of infliximab treatment is the ability to possibly taper the prednisone dose, which will decrease further adverse effects.

Unfortunately, infliximab is immunogenic, and repeated administration may result in the development of antibodies to infliximab that lead to infusion reactions, loss of efficacy, and delayed hypersensitivity reactions. ? Two anti-TNF agents, adalimumab and certolizumab, may be less immunogenic than infliximab and have shown efficacy in the treatment of Crohn disease that is refractory to standard medical treatment of corticosteroids and immunomodulatory agents. ? Adalimumab is a recombinant human IgG1 monoclonal antibody that binds with high affinity and specificity to human soluble TNF-alpha but not to lymphotoxin (TNF-beta).

Results have shown that the immunogenicity of adalimumab is low compared to the chimeric mouse-human monoclonal antibody infliximab. ? Two placebo-controlled trials, CLASSIC I and CLASSIC II, showed that adalimumab was effective for both induction and maintenance of remission in patients who were previously naive to anti-TNF therapy. The CHARM trial demonstrated the same effect in a mixed population of patients who either were naive to infliximab therapy or had previously been on infliximab therapy.

In patients who had lost response or become intolerant of infliximab, the GAIN trial results showed a benefit from adalimumab therapy induction with remission at 4 weeks. Furthermore, an open label study conducted in France that assessed the long-term efficacy and safety of adalimumab maintenance therapy in this population showed that it was well tolerated and effective in maintaining clinical remission in patients with Crohn disease with lost response or intolerance to infliximab.

? Certolizumab pegol, a humanized Fab’antibody fragment conjugated to polyethylene glycol, has also demonstrated efficacy in maintaining remission in patients with moderately to severely active Crohn disease who previously responded to induction therapy with the same agent (PRECISE trial). However, data only covered a 6-month period. o Immunosuppressive agents: Tacrolimus may be effective in treating Crohn disease. o Mycophenolate mofetil acts by inhibiting a de novo pathway of purine synthesis in lymphocytes, leading to intracellular depletion of guanosine monophosphate.

This results in the suppression of cytotoxic T cells and formation of antibodies by activated B cells. A dose of 500 mg twice a day in 2 divided doses is well tolerated by patients and can be used to reduce the steroid dose. o Anti-inflammatory cytokines: Interleukin 10 (IL-10) and interleukin 11 (IL-11) are anti-inflammatory cytokines and have been found by some researchers to elicit a moderate response in Crohn disease; however, more trials are needed. Surgical Care • Fibrostenotic obstruction may require surgical correction; in some cases, endoscopic dilatation is effective. •

• Patients with perianal fistulae usually respond well to medical treatment (eg, metronidazole, 6-MP, cyclosporin [in refractory cases]). Surgical treatment is indicated if medical treatment fails or if an abscess is present. • • The recommended guidelines for those requiring surgery include persistent symptoms despite high-dose corticosteroids, treatment-related complications, intolerable adverse effects, detection of dysplasia, or suspicion of a malignant stricture or abscess. • • The recurrence rate postoperatively remains high despite medical management in the postoperative period.

The recurrence rate for patients undergoing total colectomy and ileostomy appears to be lower than for those undergoing segmental procedures. • Diet The diet should be balanced. Fiber supplementation is said to be beneficial for patients with colonic disease, whereas a low-roughage diet is usually indicated for patients with obstructive symptoms. • Patients with Crohn disease of the small intestine often have lactose intolerance; therefore, avoidance of dairy products may be indicated. •

• Patients who undergo extensive resection of the terminal portion of the ileum may benefit from a low-fat diet with the addition of medium-chain triglyceride preparations. • • Enteral therapy with an elemental diet has been suggested to induce remission in acute disease, but patients have frequently relapsed after initiation of a normal diet. • • Indications for TPN • o Short-term use – Patients with active inflammation and severe malnutrition and those with fistulae (given preoperatively) o o Long-term use – Patients who have had extensive intestinal resection

o Complications • In the initial stages, obstruction is caused by bowel edema and spasm, which is intermittent and reversible. Treatment involves conservative measures, such as nasogastric decompression, intravenous fluids, anti-inflammatory agents, and steroids (if required). If medical therapy fails, then surgical resection is necessary. • Fistulae occur because of the penetration of a sinus tract through the bowel wall to adjacent viscera. • o Most fistulae are enteroenteric and enteromesenteric. They usually cause no symptoms and require no treatment. o

o Coloenteric fistulae and cologastric fistulae may result in bacterial overgrowth, diarrhea, and weight loss. o o Enterovesical fistulae and enterovaginal fistulae are often complicated by infection. o o Enterocutaneous fistulae usually occur at a previous surgical site, tracking the path of least resistance. o o Many fistulae close with the use of TPN, but they recur when oral feeding resumes. o • A tender abdominal mass, fever, and leukocytosis indicate a possible underlying abscess. A CT scan helps confirm the diagnosis. Abscesses are treated with surgical drainage and broad-spectrum antibiotics.

• • Severe hemorrhage is unusual in patients with Crohn disease. • • Malabsorption may occur for multiple reasons, such as bacterial overgrowth in an enterocolic fistula, strictures and stasis, extensive disease of the small bowel, and resection of large portions of the small intestine. Bile acid malabsorption may occur with extensive ileal disease, further exacerbating the malabsorption process. The steatorrhea that develops may lead to further complications, such as malnutrition, clotting abnormalities, calcium deficiency, and osteomalacia, which may progress to osteoporosis.

Vitamin B-12 deficiency may also occur with ileal resection or long-standing disease. • • Patients with colonic disease have an increased risk of colon cancer, which has been shown to be correlated with the extent and duration of the disease and the patient’s age at onset. The role of colonoscopy as a screening tool in such cases is unclear. The risk of lymphoma secondary to medical therapy is still being investigated. • Prognosis • Although Crohn disease is chronic with recurrent relapses, appropriate medical and surgical therapy helps patients to have a reasonable quality of life.

•  Medical therapy becomes less effective with time, and surgery for underlying complications is required in nearly two thirds of patients at some point in their disease. • • The mortality rate increases with the duration of the disease, and GI tract cancer is the leading cause of disease-related death. • • Acute regional enteritis, which is often discovered during laparotomy for suspected appendicitis, has an excellent prognosis. The acute episode is treated conservatively, and two thirds of patients may not have subsequent evidence of regional enteritis. •