Latest Treatment of Crohns Disease
Genetic variation in the genes encoding NOD proteins in humans has been associated with inflammatory diseases such as Crohn's disease 76, 77 , and recently, an infectious phenotype (susceptibility to enteric L. monocytogenes infection) has been observed in Nod2 knockout mice 75 . This subject is discussed further in the chapter by Fukata et al. in this book.
Latory factor-1 (IRF1), colony-stimulating factor-2 (CSF2), and T-cell transcription factor-7 (TCF7) (Fig. 4b). Initially, the association between RA and SNPs in SLC22A4 was reported 10 , and a report on Crohn's disease-associated SNPs in SLC22A4 or SLC22A5 followed 46 . In addition, SLC22A4 was reported to have a functional variant associated with RA 14 . These reports indicated that SLC22A4 A5 locus has susceptible variants to multiple autoimmune inflammatory disorders and behaves in an ethnic-specific manner. Identification of RA Crohn's-associated polymorphisms in SLC22A4 and SLC22A5 The whole genome linkage study identified IBD5 as a IBD-linked locus 50 and subsequent hierarchical strategy analysing trios using denser microsatellites narrowed the locus down to 1 cM with 2 loci. Then, the region was further closely evaluated with a dense SNP map that identified haplotypes consisting of two SNPs in SLC22A4 and SLC22A5 genes (OR 1.6). The one SNP substitutes 503rd L to F with...
In observational studies, say a comparison in outcome between patients with Crohn's disease and ulcerative colitis, there may be no 'intervention' involved and so the requirement for randomisation to groups is not pertinent. Nevertheless, as we illustrated in Table 4.2, different observers may be involved in the study in which case we can regard these as the 'interventions' and so randomise the patients to observers.
At least 3 months reserve of vitamin B12 is usually stored in the liver. Vitamin B12 is mainly derived from meat, eggs and milk, with little in vegetarian foods. Vegans are therefore particularly at risk of deficiency. Vitamin B12 deficiency may also be caused by gastric pathology, such as atrophic gastritis, where IF is not synthesized, or terminal ileal disease, such as Crohn's disease, where the absorptive surface is damaged. The Schilling test can distinguish between these causes (see Chapter 46).
Gastrointestinal disease inevitably interferes with nutrition. Reduced intake may be due to nausea and vomiting, poor dentition, or dysphagia secondary to oesophageal disease. Pancreatic, biliary and intestinal diseases cause malabsorption. Coeliac disease and Crohn's disease in particular are associated with multiple deficiencies, including calcium and vitamin D deficiency leading to osteoporosis.
I am always struck by the variety of illnesses the students have experienced and the depth of their reflections. Among the illnesses they have personally had are diabetes, hyperthyroidism, traumatic rupture of a kidney, ulcerative colitis, Crohn's disease (an inflammatory disease of the intestine, also called ileitis), depression, Hodgkin's disease (amalignancy), seizures, Bell's palsy (paralysis of a facial nerve), and appendicitis. Their family members have had strokes, heart disease, pneumonia, emphysema, and cancer. One student even told of her dog's malignancy and its impact on her and her family. Of her illness, Crohn's disease, a junior wrote of complex feelings and her disappointment with some of her physicians' actions.
IBD is thought to result in the genetically-susceptible host following a triggering event. Genetic factors play a more dominant role in Crohn's disease than ulcerative colitis based on accumulated data from identical twin studies and familial clustering 58 . Polymorphisms in the NOD2 CARD15 gene (R702W, G908R and 1007fs) have been identified in patients with Crohn's disease 59, 60 . Nucleotide oligomer-ization domain (Nod) proteins are PRRs with homology to plant disease resistance proteins 61, 62 , which confer responsiveness to peptidoglycan through Rip2 RICK kinase, a mediator of NF-kB activation 63-65 . Approximately a third of patients with Crohn's disease carry one of three allelic variants of NOD2 CARD15 compared with 10-15 of the normal population or ulcerative colitis patients 66-69 . Homozygosity increases the relative risk of developing Crohn's disease by as much as 40-fold as compared to simple heterozygosity 59, 70, 71 . Clinical phenotypic associations with NOD2 CARD15...
NOD 2 (CARD15) genotypes which are located on chromosome 16 have been found to be significantly associated with Crohn's disease. NOD2 is expressed in intestinal epithelial cells and may serve as a key component of innate mucosal responses to luminal bacteria as an antibacterial factor. While in a large study no association between the NOD2 variants Pro269Ser, Arg702Trp, Gly908Arg, Leu1007fsinsC and primary AS was found, an association was identified between Gly908Arg and ulcerative spondyloarthritis and an inverse association between Pro268Ser and ulcerative spondyloarthritis with only non-significant trends for spondylarthritis associated with Crohn's disease 69 . The frequency of these variants was higher in patients with Crohn's disease with radiographic sacroiliitis compared to Crohn's disease without radiographic sacroiliitis 70 . The major CARD15 polymorphisms were found not to be associated with primary AS in two other studies 71, 72 . Overall, primary AS seems not be...
Inflammatory bowel disease (IBD) The general name for diseases that cause inflammation of the bowels, including ulcerative colitis and Crohn's disease. Although these two diseases are similar, there are also some important distinctions. Ulcerative colitis is an inflammatory disease of the inner lining of the large intestine, which becomes inflamed and ulcerates. Ulcerative colitis is often most severe in the rectal area and can cause frequent bloody diarrhea. Crohn's disease, on the other hand, affects the last part of the small intestine, although it can also affect any part of the digestive tract. Moreover, Crohn's disease tends to Scientists do not yet know what causes inflammatory bowel disease, although they suspect that a number of factors may be involved, including the environment, diet, and heredity. Smoking appears to increase the likelihood of developing Crohn's disease. A new theory suggests that Crohn's disease may be caused by infection (similar to cat scratch disease).
Crohn's disease IBD1 Inflammatory bowel disease that seems to have both genetic and environmental causes not well understood but generally considered likely to be autoimmune. Mutations in the CARD15 gene (caspase recruitment domain-containing protein 15) are associated with susceptibility to Crohn's disease in some families.
IBD is not caused by a discrete intestinal infection, although both ulcerative colitis (UC) and Crohn's are triggered by environmental factors that are almost certainly enteric microbes or their products. Antibiotics are generally ineffective in UC, but do improve some forms of Crohn's disease, and administering probiotics, which are live commensal bacteria, ameliorates some forms of IBD. Intestinal infection with Mycobacterium tuberculosis and Yersinia species can strikingly resemble ileocaecal Crohn's disease. Similarly, bacterial and amoebic dysentery, cytomegalovirus and herpes simplex virus infection can cause bloody diarrhoea, abdominal pain and intestinal ulceration that can be confused with UC.
Crohn's disease can affect any part of the intestinal tract, although three patterns predominate terminal ileal inflammation, colitis and anorectal inflammation. An individual patient could have one, two or three of these areas affected, in any combination. Furthermore, while inflammation in UC is contiguous, extending for a variable distance from the rectum, in CD there may be normal areas interspersed between inflamed segments 'skip lesions'.
In the classic presentation of CD, the differential diagnosis of malabsorption includes distinguishing between the following diseases tropical sprue, celiac disease, Whipple's disease, irritable bowel syndrome, and inflammatory bowel disease (Crohn's disease and ulcerative colitis). Steatorrhea is often present in malabsorption syndromes and seldom assists in the differential diagnosis.
A large population of macrophages reside in the normal intestinal mucosa where they represent a major APC population. Various studies suggest that intestinal macrophages cannot easily be induced to mediate acute inflammatory responses. In inflammatory bowel disease, however, there is an increase in the mucosal macrophage population where the recruited macrophages are phenotypically disparate from the resident macrophages (Mahida, 2000). These recruited macrophages appear to perform a major role in mediating the chronic mucosal inflammation seen in patients with ulcerative colitis and Crohn's disease. There is evidence that the recruited macrophages release reactive metabolites of oxygen and nitrogen and proteases which degrade the extracellular matrix. There is also evidence that the recruited macrophages may be primarily responsible for the secretion of cytokines which are important in the pro-inflammatory process, including TNF-a, IL-1, IL-6, IL-8, IL-12 and IL-18.
Anoderm, which inhibits healing (42). The pain associated with a fissure may cause the patient to ignore the urge to defecate, resulting in the passage of a large hard bowel movement, which further traumatizes the area, leading to a vicious cycle of pain, constipation, and re-injury. The majority of primary anal fissures are painful and may be associated with streaking of the stool with blood or blood on the toilet paper. Secondary anal fissures result from other underlying causes, such as Crohn's disease, anal cancer, HIV, tuberculosis, abscess or fistula, and sexually transmitted diseases. Depending on the cause, some of these may be painless, especially Crohn's disease and anal cancer, and may present as a non-healing ulcer and or recurrent bleeding. They may also be located away from the midline unlike primary anal fissures. Any suspicion of a secondary cause for a fissure should prompt the physician to get a biopsy to diagnose the above-mentioned secondary causes.
A 32-year-old Caucasian male presented to the emergency department with complaints of bloody diarrhea 20 times per day and dehydration. A CBC was notable for anemia with normal white blood cell and platelet counts. Past medical history was significant for Crohn's disease diagnosed at age 20 involving the small and large intestines. He underwent ileocecal resection, and had been asymptomatic and required no therapy for the past 5 years. During his 2-day hospital course, anemia and dehydration were corrected, the diarrhea resolved, and immunosuppression with prednisone and azathioprine was started to treat a flare of inflammatory bowel disease.
Crohn's disease and ulcerative colitis are the two major forms of IBD characterized by acute and chronic inflammation in the absence of a known pathogen. These inflammatory disorders are distinguished by the depth and location of inflammation with ulcerative colitis being limited to the mucosa of the colon and Crohn's disease involving both the small intestine and the colon in a transmural fashion. The patho-genesis of Crohn's disease and ulcerative colitis is multifactorial, resulting from the interplay of genetic predisposition, environmental and immunological factors 21 . Initiation and perpetuation of the intestinal inflammation in this chronic disorder has been thought to result from dysregulated immune response to commensal bacteria in the genetically-susceptible host. For instance, the efficacy of fecal diversion and the recurrence when the fecal stream is restored 22, 23 , the existence of subpopulations who can be improved by antibiotics or probiotic treatment 24 , and the...
The great promise of polygenics has yet to be fulfilled. However, there are signs of life. Thus, a frameshift mutation in an immune signalling protein, NOD2, has recently been found in 6 of patients with Crohn's disease versus 2 of controls12. Presumably such subjects will now be studied intensively for differences in their natural history and response to treatment compared to Crohn's patients who do not have this mutation. An intronic polymorphism in the calpain 10 gene has been hailed as the first type 2 diabetes polygene13. However, the situation is complex, with inconsistent findings in other studies14 and no clear mechanism of action as yet being defined. A common polymorphism in PPAR7 appears to reduce the risk of type 2 diabetes15. The search is continuing and more polymorphic variants contributing susceptibility to type 2 diabetes will undoubtedly be found.
Dysregulation of the mucosal immune response is critical to the pathogenesis of numerous intestinal diseases. For example, Crohn's is a Th1 (see later) inflammatory condition associated with T cell and macrophage infiltration of the lamina propria and expression of the proinflammatory cytokines IL-12,IL-18, IFN-y and TNF-a (Garside, 2000) that can induce villous atrophy and crypt hyperplasia. Indeed, treatment of Crohn's with anti-TNF monoclonal antibodies can be a highly effective therapy. Interestingly, C. parvum infection increases susceptibility of mice to develop
However, an accurate diagnosis of ulcerative colitis may require an examination of the colon by inserting a colonoscope, which allows doctors to see the degree of damage. A biopsy of the colon may help confirm the diagnosis. To diagnose Crohn's disease, barium X rays can reveal characteristic signs of inflammation in the lining of the intestine. An upper gastrointestinal endo-scopy and colonoscopy may be performed to check for evidence of bowel damage caused by inflammation. If a child with IBD does not respond to these medicines, surgery may be considered, although the recurrent nature of Crohn's disease makes surgery a last-ditch effort. An aggressive surgical approach to Crohn's disease also can cause other complications, such as short bowel syndrome (which reduces the ability to absorb nutrients and also may cause growth failure).
Granulomatous lesions without vasculitis or central necrosis may be observed in systemic vascu-litis, mainly in WG. Their clinical aspects are highly variable, ranging from papules, nodules, subcutaneous infiltration or pseudotumor to chronic ulcers. Any site of the body may be involved breasts, scrotum, face, gingivae, etc. Other granulomatous diseases have to be considered in the differential diagnosis including sarcoidosis, Crohn's disease, mycobacterial infections and foreign body granulomas. 4.7.5. Superficial thrombophlebitis Sometimes, the clinical aspect of thrombophlebitis of superficial veins is non-specific and diagnosis can only be confirmed by histological examination of a deep skin biopsy. However, such lesions are more often found in thromboangiitis obliterans, Behcet's disease, Crohn's disease and relapsing polychondritis.
Superficial inflammation of the rectal mucosa, causing bleeding, diarrhoea, urgency of defecation and mucus discharge, may be caused by ulcerative colitis or Crohn's disease. In many cases, inflammation remains confined to the rectum and never extends proximally. Rectal steroids and 5-aminosalicylic acid (5ASA, mesalazine) are usually effective and long-term treatment with oral 5ASA may be initiated.
Crohn's disease can affect any part of the intestine, but in about 60 of cases it preferentially affects the terminal ileum, causing mucosal ulceration and transmural granulomatous inflammation. An inflammatory mass and fistulae between the small intestine and adjacent structures, such as the bladder, may occur. Crohn's disease of the terminal ileum has been shown to be associated with mutations in the NOD2 gene, which may determine how monocytes and Paneth cells interact with enteric bacteria (see Chapter 34). Ileocaecal tuberculosis and Yersinia enterocolitica infection can appear clinically identical to ileal Crohn's disease.
As a key mediator controlling the viability of the GI colonic mucosa, KGF might be beneficial in diseases of the GI tract other than mucositis. Consistent with this notion, it was discovered that KGF expression was markedly increased in surgical specimens from patients with ulcerative colitis or Crohn's disease (17-19). Subsequent studies demonstrated that rHuKGF ameliorated mucosal damage in several colitis models (69-71). A specific role of KGF in colon mucosal protection and repair was demonstrated by a study using KGF-null mice, which were more susceptible to dextran sulfate-mediated colonic injury than their wild-type counterparts (72). In rats that had undergone large bowel surgery, rHuKGF promoted healing of colonic anastomoses, possibly by accelerating reparative processes and enhancing protection of the anastomotic wound bed by increasing epithelial proliferation and mucus production (73,74). KGF also reduced the extent of intestinal atrophy in animals maintained on total...
Increased B-cell reactivity a autoantibodies, is not part of BS. This is also true for ANCA (Tunc et al., 2001) and anticardiolipin antibodies (Tokay et al., 2001). However antibodies to Saccharo-myces cerevisiae, usually seen in Crohn's disease have also been reported in BS (Krause et al., 2002 Fresko et al., in print). Antibodies to alpha-tropomysin with an animal model for uveitis has also been described (Mahesh et al., 2005). Finally, the target antigen for the endothelial antibodies found in some patients has been described as alpha-enolase (Lee et al., 2003).
Genital ulcerations can result from other infective organisms such as syphilis and Coxsackie virus. Ulcerations can occur from dermatoses, such as aphthous ulcers, Behcet's syndrome, severe contact dermatitis, pyoderma gangrenosum, or benign familial pemphigus (Hailey-Hailey' s disease). Vulvar ulcerations also can be caused by malignancy, such as with basal cell carcinoma or squamous cell carcinomas of the vulva, and can arise in relation to systemic diseases processes, such as Crohn's disease. Finally, vulvovaginal ulcerations may result from traumatic causes such as immobility, with the development of decubitus ulcers, or from foreign bodies, such as a pessary used to treat pelvic organ prolapse and incontinence.