Crohn's disease
http://www.100md.com
《美国医学杂志》
Kanchi Kamakata CHILDS Trust Hospital and Sundaram Medical Foundation Hospitals, Chennai, India
Abstract
Crohn's disease is a chronic inflammatory disease of the gastrointestinal tract and is an important cause of morbidity in children and adolescents. In India Crohn's disease (CD) was considered a rare disease, however, during the last 10 years CD in adults is being reported from several centers especially in Southern India. CD is characterized by transmural granulomatous inflammation involving any part of the gastrointestinal tract in a discontinuous manner. The peak incidence of Crohn's disease occurs during the adolescent and young adult years. The clinical presentation and complications are varied and several extraintestinal manifestations have been recognized. The understanding of the pathophysiology has opened new avenues in the management. The recognition of this problem in children and adolescents by pediatricians is necessary for proper diagnosis and management.
Keywords: Crohn′s disease; Ulcerative colitis; Inflammatory bowel disease; Children
Crohn's disease is an idiopathic, relapsing chronic inflammatory disease of the gastrointestinal tract categorized as Inflammatory Bowel Disease (IBD) and is an important cause of morbidity in children and adolescents. IBD comprises of two important entities CD and Ulcerative Colitis (UC) based on clinical, laboratory, radiologic, endoscopic and histologic features. In 10% of cases the findings are non-specific and therefore termed as indeterminate colitis (IC).[1] This subset of IBD has a propensity to progress to CD rather than to UC. Approximately 25-30% of CD present before the age of 20 years and therefore pediatricians need to recognize the varied presentations of this disorder[2].
Epidemiology
The incidence of CD in children is much less than that seen in adults.[3] It is more prevalent in Western countries compared to Asia and Africa. The incidence of pediatric CD range from 0.2 to 8.5 per 100,000.[3] Recently there have been reports of CD from Africa, China and Japan. In Singapore the incidence of CD in adults is 3.6 per 100,000.[4] The incidence of CD is on the rise in children similar to the trend seen in adults whereas UC has shown a more stable pattern. In India, recently there have been several reports of CD in adults[5] whereas data on pediatric CD is sparse. This change in frequency of CD could be due to increased awareness and availability of better diagnostic facility. Some authors believe that the recent increase of CD in India is not apparent but real and consider the improved sanitation- hygiene hypothesis as an important etiological factor.[5]
CD can occur in all age groups and follows the same bimodal pattern of age distribution as IBD. The proportion of patients with CD below the age of 20 years varies between 25-40% with around 10% being less than 10 years of age.[3] The mean age of presentation is about 12.1 years.[6] Early onset IBD (EOIBD) i.e. presentation before the age of 5 years, is a unique subgroup constituting 4% of pediatric IBD.[2] In this subset it is difficult to differentiate between UC and CD. In South India the youngest age of CD was 4.6 yrs and in their series 90% were more than 9yrs of age.[7] CD is seen in both sexes. In US there seems to be a preponderance of CD in boys[3] whereas in South India it was more prevalent in girls.[7] The effect of breastfeeding and cigarette smoking remains controversial. CD occurs with a higher frequency in patients with Turner's syndrome, Hermansky-Pudlak syndrome More Details, cystic fibrosis and glycogen storage disease type 1B.[8]
Crohn's disease could represent a persistent infection with a fastidious organism or an abnormal and prolonged response to a common pathogen. Various organisms have been linked with CD but none of them are evident in the etiopathogenesis. In genetically susceptible individuals the microvascular injury caused by these infections could result in a granulomatous vasculitis of the mesenteric vessels, leading to microvascular thrombosis, multifocal gastrointestinal infarction, and finally gross pathologic sequelae such as ulcerations, fistulas, fibrosis, and strictures.
Genetics
A single well accepted risk factor for the development of CD is having a first-degree relative with the disease. The age-adjusted risk of developing CD during lifetime for a first-degree relative of a proband is about 4%, which is more than for UC. Familial IBD is particularly common with EOIBD and the incidence of IBD among first-degree relatives may be as high as 56%.[2]
The CD susceptible gene NOD2/CARD 15 (Cathapse Activation Recruitment Domain) has been identified on chromosome 16. The NOD2/CARD 15 encodes the protein recognizing lipopolysaccharides of the bacterial cell wall membrane. Mutations of this gene predisposes to CD by exhibiting inappropriate response to bacterial components and thereby altering the signaling pathways of the innate immune system leading to the development and persistence of intestinal inflammation. This genetic make up is associated more with ileal disease, early onset CD or stricturing disease.[9]
Immunologic Factors
CD may represent an aberration in the normal balance between physiologic inflammation and pro-inflammatory cytokines. This imbalance results in the conversion of physiological inflammation to a pathologic one and leads to tissue destruction. The defect may be at several sites including increased antigen uptake through a leaky gut epithelium, defective antigen processing, abnormal vascular endothelial cell function, and abnormalities in the production of interleukins and eicosanoids.
Pathophysiology
The prevailing hypothesis regarding the pathogenesis of CD is an interaction between environmental factors and an altered immune response in genetically predisposed children, leading to chronic inflammation of the gastrointestinal tract. Figure1 In CD there is a disordered regulation of mucosal and systemic immune response resulting in the perpetuation of the inflammatory cascade. A dysregulated TH1 response (T helper 1) seems to be crucial in the conversion of physiologic to pathologic inflammation. The immunological profile in CD is predominantly a cell-mediated response. Active mucosal inflammation of the small and large intestine results in diarrhea, protein-losing enteropathy, bleeding, abdominal pain and stricture formation. Proinflammatory cytokines and eicosanoids increase vascular permeability and cause electrolyte secretion, and augment smooth muscle contraction. Many cytokines promote the recruitment and activity of collagen forming cells leading to fibrous tissue proliferation and thereby resulting in bowel wall thickening and stricture formation. The causal role of TNF-a in the etiopathogenesis of CD has gained importance.
Pathology and distribution
The transmural inflammation and discontinuous involvement are the characteristic features of CD differentiating it from UC where the inflammation is continuous and restricted to the mucosa. The distribution of the lesions in CD though discontinuous may involve any part of gastrointestinal tract from the oral cavity to the colon. In the West isolated colonic involvement is seen in 10-20 %, ileo-colonic disease in 50-70% and diffuse small bowel disease in 10-15 %[10]. Isolated gastroduodenal disease may be seen in less than 5% whereas endoscopic and histologic gastroduodenal disease may be as high as 30-40% of children.[2] The involvement of the small intestine differentiates CD from UC and is a pointer for diagnosis. Perirectal disease is seen in 20% of patients and is associated with recto sigmoid inflammation. Noncaseating granuloma is the hallmark of CD.[2]
Clinical presentation
The clinical presentation in CD depends upon the site of involvement of the gastrointestinal tract. Abdominal pain and systemic symptoms are generally more severe in CD than in UC. A dyspeptic-type of epigastric pain is seen in children with gastro duodenal involvement. Diarrhea occurs in two-third of affected children. In children with predominantly ileal involvement, constipation may be a rare presentation. Gross blood in the stools is unusual with isolated small bowel disease and more common when the colon is involved. Fever occurs in approximately 50%. Fatigue, anorexia, weight loss and diminution in growth velocity are other presenting symptoms in children. Perirectal involvement fistulae, fissure and skin tags are important clues to the diagnosis. CD is subcategorized as predominantly inflammatory, fistulizing or stricturing disease based on the clinical phenotype. The clinical profile of the patients seen in South India is shown in table1.
Complications
Hemorrhage, obstruction, perforation, abscess and fistula formation are well known in CD. Perianal disease may present with abscess formation, perirectal and perianal fistulization and can precede the intestinal manifestation by years. Perforation with internal fistulae is another serious complication. Carcinoma of the colon is a long-term complication of inflammatory bowel disease. The two well accepted risk factors for cancer are duration and severity of the disease. Complications such as perianal and rectovaginal fistula, esophageal stricture and small bowel obstruction necessitating resection were also seen in children from South India
Extra Intestinal Manifestations
Several extra intestinal manifestations which may have some prognostic significance are seen in 25-30%[2] of patients with CD. The important skin manifestations include erythema nodosum and pyoderma gangrenosum. Apthous ulcerations are the most common oral manifestation of CD. The oral manifestations may occur along with intestinal disease or precede it. Oral ulcerations was the primary presentation documented in two children from South India.[7] Ocular manifestations such as episcleritis and anterior uveitis are less common in children than in adults and occur when the disease is active. Arthritis is the most common extraintestinal manifestation in children and occurs in 7-25 % of pediatric IBD and may occur years before the intestinal symptoms.[11] Hepatobiliary complications such as chronic hepatitis, sclerosing cholangitis, cholelithiasis and elevated aminotransferase may precede the active disease.[12] The renal manifestations of IBD include nephrolithiasis, hydronephrosis and enterovesical fistula. Other extraintestinal manifestations are thromboembolic manifestations, vasculitis, pancreatitis, interstitial pneumonitis and pericarditis.
Weight loss is seen in more than 50% of children with CD and is a clue in the evaluation of children with abdominal pain.[8] Failure to thrive is therefore an important presentation of CD. Malnutrition can be due to suboptimal dietary intake, increased gastrointestinal losses, malabsorption, delayed gastric emptying and increased requirements associated with marked inflammatory activity. The severe mucosal inflammation leads to the loss of cellular constituents and hematochezia and results in protein-losing enteropathy, iron-deficiency anemia, vitamin deficiencies, increased fecal loss of calcium, zinc and magnesium.
Growth failure and decrease in growth velocity may precede gastrointestinal symptoms and an absolute height deficiency may be present in 30% at the time of diagnosis.[2] Permanent growth failure can also occur. The probable reasons for growth failure are chronic under nutrition, administration of corticosteroids, low levels of insulin-like growth factor (IGF 1), and alteration of cytokine profiles.
The delay in sexual maturation seen in some children with CD may have a significant effect on self-esteem and socialization. There is irreversible loss of growth potential in those who develop secondary sexual characters before attaining remission whereas if they attain remission before puberty there is good catch up growth and height velocity.
Bone disease is a common problem in children with CD. The causative factors include malnutrition, various effects of cytokines and glucocorticoid therapy. Despite the potential for children with CD to develop osteoporosis, the bone mineral density in adulthood is normal if they are managed appropriately.
Diagnosis
The initial evaluation of a child with suspected CD includes a detailed elicitation of clinical, family and treatment history by the pediatrician. Any child or adolescent with recurrent abdominal pain associated with or without fever, diarrhoea and growth failure is a possible candidate for CD and requires complete examination. A careful assessment of the growth and development of the child is essential. The abdominal examination may not be contributory however if a mass is palpable especially in the right iliac fossa one may consider CD or tuberculosis in the Indian setting. A perianal and rectal examination is necessary to detect skin tags, fissures and fistulae. Laboratory tests such as complete blood count, C reactive protein, motion for occult blood and total protein albumin/globulin ratio should be included.
An ultrasound (US) examination of the abdomen may detect thickened bowel loops, pseudo kidney sign and enlarged lymph nodes in CD. The US findings of free fluid, lymph nodes, thickened mesentery or omentum are more diagnostic of abdominal tuberculosis than CD. The child should then be referred to the pediatric gastroenterologist for a more complete work up. The diagnosis of CD in children is made by a combination of clinical observations and confirmed by laboratory, radiologic, endoscopic, and histologic findings. CD can be classified as mild, moderate and severe based on the clinical presentation.. The popular scoring system for pediatric CD is the Pediatric Crohn's Disease Activity Index (PCDAI) [13] which helps in assessing the severity of the disease.
The differential diagnosis depends on the age and clinical presentation and includes ulcerative colitis, HIV enteropathy, yersenia enterocolitis, allergic enterocolitis, tuberculosis, lymphoma, intestinal polyps and diarrhoea predominant IBS. In India it is a dictum though difficult to differentiate CD from TB.
Endoscopic Evaluation
In CD the characteristic lesions on ileo-colonoscopy are the skip lesions, cobble stoning of mucosa, apthous ulcers or deep irregular ulcers of varying sizes with normal intervening mucosa Figure2. Rectal sparing and terminal ileal involvement are features of CD rather than UC. Histopathologically the presence of noncaseating granuloma is diagnostic of CD but often difficult to differentiate from TB. The inflammatory cells have a transmural distribution and the fissuring ulcers extend to the muscularis propria. Normal appearing colonic mucosa should always be biopsied since microscopic inflammation is a feature of CD Gastric antral biopsy and identification of focal active gastritis or microgranuloma also increases the diagnostic yield.[14]
Radiologic Evaluation
Barium Meal Series is useful to identify small bowel involvement and lesions such as strictures, fistulae, and ulcerations may be identified. This contrast study has largely been replaced by contrast enhanced computerized tomography.
Contrast Enhanced Computerized Tomography (CECT) is more sensitive than barium studies to identify bowel wall thickening and assess the length and site of strictures in small bowel CD. Ultrasound abdomen is done as a primary modality of investigation and may be used as screening test.
Serological markers
Perinuclear anti-neutrophil cytoplasmic antibody (pANCA) and anti sacchromyces cerevisiae antibody (ASCA) are potentially important addition to the diagnostic panel of IBD. Combination of these markers has shown a specificity of 95% and sensitivity of 55% in children with CD.[15] They are not considered as a screening test for CD. The detection of ASCA antibodies in individuals with CD may depend on the duration of exposure to sacchromyces cerevesiae.
Newer Investigation Modalities
Isolated small bowel CD may be diagnosed using a double balloon enteroscope that helps to directly visualize and biopsy the lesions. The wireless capsule endoscopy has been used as a diagnostic tool in adults with isolated small bowel CD[16]. Gandolium enhanced Magnetic Resonance Imaging (MRI) Scan has been beneficial in some cases of IBD to differentiate between CD and UC.
CD VS Uc
The distinction between CD from UC though essential may be difficult in some circumstances. Some of the differentiating clinical and endoscopic features are shown in table2.
CD VS TB
It is crucial to differentiate CD from TB for administrating appropriate therapy. Tuberculosis has always been considered a possible differential diagnosis in the evaluation of granulomatous colitis resulting in patients with CD being treated as tuberculosis. There are some differentiating features between CD and intestinal TB. The ulcer in CD are longitudinal whereas it is more transverse in TB. Perianal involvement is a feature of CD and not TB. The granulomas are smaller, ill formed, numerous and non-caseating in CD whereas they are larger, well formed confluent and caseating in TB[17]. Isolated lymphnode involvement can occur without bowel involvement in CD but not in TB.
Therapy
The general goals of treatment are to achieve best clinical and laboratory control of inflammatory disease with least possible side effects from medication, promote growth through adequate nutrition and permit the child to function as normal as possible.[3] 5-Aminosalicylates like sulfasalazine or 5-ASA remain the cornerstone of treatment for CD. The 5 ASA drugs (mesalamine, balsalazide) exert local anti-inflammatory effects through a number of mechanisms, which includes inhibition of 5 -lipoxygenase with a result in decreased production of leukotriene B4, scavenging of reactive oxygen metabolites, prevention of the upregulation of leucocyte adhesion molecules and inhibition of interleukin 1 synthesis. 5 ASA is rapidly absorbed from the upper intestinal tract and various drug delivery systems have been employed so that it reaches the distal small bowel or colon. Mesalamine is coated with Eudragit, a pH sensitive acrylic resin or ethyl cellulose to release the drug at the appropriate site. Uncoated mesalamine is also available as enema for use in left sided lesions. Mesalamine is used in the dose of 40-60mg/kg/day as the first line drug in mild CD and also as maintenance drug.
Steroids
Corticosteroids are used in acute stages of moderate to severe CD or when aminosalicylates are ineffective Prednisolone is started at a dose of 1-2 mg/kg day in moderate CD. Once clinical remission is reached attempts are made to wean the medication to alternate day therapy and then tapered before stopping within 6-8 weeks. Newer corticosteroids such as oral budesonide at a dose of 6-9mg/day may be prescribed to avoid the systemic side effects of steroids.
Immunomodulators
The recognition of the central role played by the immune system in the pathogenesis of IBD has increased the use of immunomodulators.
6 Mercaptopurine (1-1.5mg/kg/day) and azathioprine (2-2.5mg/kg/day) are effective in patients with active disease when added on to corticosteroid therapy. They facilitate the development of remission and promote tapering of the corticosteroids. These drugs usually require three to six months to exhibit efficacy, and are not effective as primary therapy. Methotrexate has been used in children with CD with beneficial results.
Antibiotics
Though no infective agent has been implicated in the etiology, Ciprofloxacin and metronidazole have shown some efficacy in active CD especially those associated with perirectal disease, perianal fistulae and even small bowel CD.
Biological therapy
Several novel therapies have been investigated in the treatment of IBD. They may be biologic agents such as infliximab, natalizumab, Interleukin 10 or non-biologic agents such as thalidomide, granulocyte colony stimulating factor.[18] Anti-Tumour Necrosis Factor, infliximab has been evaluated in pediatric CD and has proved effective as a short-term therapy in moderate to severe CD and in children with active draining external fistulae.[19]
Nutritional Therapy
Children with CD should be supported with proper nutrition to ensure better results from therapy. Caloric supplementation is essential in children with growth- delay or under-nutrition. It is evident that enteral nutrition with an oligopeptide formula or amino acid based formula has fewer relapses. Patients who attain remission with exclusive enteral nutrition have prolonged remission and improved linear growth.[20] Calcium supplementation is an important adjuvant to prevent bone disease.
Psychological Therapy
CD is a chronic condition that may have a profound influence on the lives of affected children and their family members. Adolescents have a difficult time in handling the disease. Every effort should be made to facilitate normal age appropriate activities and early intervention by psychologists or psychiatrists should be sought if problems develop.
Surgical Therapy
The indications for surgery in CD include intractability, uncontrolled hemorrhage, perforation, obstruction, fistulae, growth retardation, and carcinoma.
Multidisciplinary Approach
The care of the child with CD involves a multidisciplinary approach involving the pediatrician, pediatric gastroenterologist, nutritionist, psychologist, pediatric surgeon, social worker and nurse. The team should also include parents, siblings and teachers who should be well informed about the child's problem. This concept in care ensures an ideal, comprehensive management of the CD patient and helps in achieving appropriate levels of physical, mental and social well being. The transition of the adolescent from the child centered health care systems to the adult oriented health care system should be done with utmost care.
Conclusion
Crohn's disease is an emerging chronic gastrointestinal disease of childhood and adolescence which affects a very vulnerable period in the life of the individual characterized by remissions and relapses and continues through adulthood. Indian children are not spared from this problem and it is essential that pediatricians are aware of this disease to enable proper diagnosis and prompt referral.
References
1. Kirschner BS. Inflammatory Bowel Disease in Children. Pediatr Clin North Am 1988; 1:189-208.
2. Baldassano RN, Piccoli DA. Inflammatory bowel disease in Pediatric and Adolescent patients. Gastroenterol Clin North Am 1999; 28: 445-455.
3. Mamula P, Markowitz JE, Baldassano RN. Inflammatory bowel disease in early childhood and adolescence: special considerations. Gastroenterol Clin North Am 2003; 32 : 967-995.
4. Law NM, Lim CC, Chong R, Ng HS. Crohn's disease in the Singapore Chinese population. J Clin Gastroenterol 1998; 26 : 27-29.
5. Desai HG, Guptae PA. Increasing incidence of Crohn's disease in India; Is it related to improved sanitation Indian J Gastroenterol 2005; 24 : 23-24.
6. Cosgrove M, Al-Atia RF, Jenkins HR. The epidemiology of pediatric inflammatory bowel disease. Arch Dis Child 1996; 74: 460-461.
7. Sathiyasekaran M, Raju BB, Shivbalan S, Rajarajan K. Pediatric Crohn's disease in South India. Indian Pediatr 2005; 42 : 459-463.
8. Cuffari C, Darbari A. Inflammatory Bowel disease in the pediatric and adolescent patients. Gastroenterol Clin N Am 2002; 31 : 275-291.
9. Bonen DK, Cho JK. The genetics of Inflammatory Bowel Disease. Gastroenterol 2003; 124 : 521-530.
10. Hyams JS. Crohn's disease. In Wyllie R, Hyams JS, Eds. Pediatric Gastrointestinal Disease: Pathophysiology, Diagnosis, Management. WBSaunders. Philadelphia 1999: 401-418.
11. Burbrige EJ, Huang S, Bayless TM. Clinical manifestations of Crohn's disease in children and adolescents. Pediatrics 1975; 55 : 866-871.
12. Hyams JF. Extraintestinal manifestation of Inflammatory bowel disease in children. J Pediatr Gastroenterol Nutr 1994; 19 : 7-21.
13. Hyams JS, Ferry GD, Mandel FS, Gryboski JD, Kibort PM, Kirschner BS, Griffiths AM, Katz AJ, Grand RJ, Boyle JT et al. Development and validation of a pediatric Crohn's disease activity index. J Pediatr Gastroenterol Nutr 1991; 12 : 439-447.
14. Abdullah BA, Gupta SK, Croffie JM, Pfefferkorn MD, Molleston JP, Corkins MR, Fitzgerald JF. The role of oesophagoduodenoscopy in the initial evaluation of childhood inflammatory bowel disease: A 7-year study. J Pediatr Gastroenterol 2002; 35 : 636-640.
15. Ruemmele FM, Targan SR, Levy G, Dubinsky M, Braun J, Seidman EG. Diagnostic accuracy of Serological assays in pediatric Inflammatory bowel disease. Gastroenterology 1998; 115 : 822-829.
16. Reddy DN, Kaffes AJ, Sriram PVJ, Venkat Rao G. Capsule endoscopic features of crohns disease. Digestive Endoscopy 2004; 16 : 138.
17. Pulimood AB, Ramakrishna BS, Kurian G, Peter S, Patra S, Mathan VI. Endoscopic mucosal biopsies are useful in distinguishing granulomatous colitis due to crohns disease from tuberculosis. Gut 1999; 45 : 537-541.
18. Mamula P, Mascarenhas MR, Baldassano RN. Biological and novel therapies for inflammatory bowel disease in children. Pediatr Clin North Am 2002; 49 : 1-25.
19. Baldassano R, Braegger CP, Escher JC, DeWoody K, Hendricks DF, Keenan GF, Winter HS. Infliximab (REMICADE) therapy in the treatment of pediatric Crohn's disease. Am J Gastroenterol 2003; 98 : 833-838.
20. Griffiths AN, Ohlsson A, Sherman PN, Sutherland LR. Meta analysis of enteral nutrition as primary treatment of active Crohn's disease. Gastroenterology 1995; 108 : 1056-1067.(Sathiyasekaran Malathi, S)
Abstract
Crohn's disease is a chronic inflammatory disease of the gastrointestinal tract and is an important cause of morbidity in children and adolescents. In India Crohn's disease (CD) was considered a rare disease, however, during the last 10 years CD in adults is being reported from several centers especially in Southern India. CD is characterized by transmural granulomatous inflammation involving any part of the gastrointestinal tract in a discontinuous manner. The peak incidence of Crohn's disease occurs during the adolescent and young adult years. The clinical presentation and complications are varied and several extraintestinal manifestations have been recognized. The understanding of the pathophysiology has opened new avenues in the management. The recognition of this problem in children and adolescents by pediatricians is necessary for proper diagnosis and management.
Keywords: Crohn′s disease; Ulcerative colitis; Inflammatory bowel disease; Children
Crohn's disease is an idiopathic, relapsing chronic inflammatory disease of the gastrointestinal tract categorized as Inflammatory Bowel Disease (IBD) and is an important cause of morbidity in children and adolescents. IBD comprises of two important entities CD and Ulcerative Colitis (UC) based on clinical, laboratory, radiologic, endoscopic and histologic features. In 10% of cases the findings are non-specific and therefore termed as indeterminate colitis (IC).[1] This subset of IBD has a propensity to progress to CD rather than to UC. Approximately 25-30% of CD present before the age of 20 years and therefore pediatricians need to recognize the varied presentations of this disorder[2].
Epidemiology
The incidence of CD in children is much less than that seen in adults.[3] It is more prevalent in Western countries compared to Asia and Africa. The incidence of pediatric CD range from 0.2 to 8.5 per 100,000.[3] Recently there have been reports of CD from Africa, China and Japan. In Singapore the incidence of CD in adults is 3.6 per 100,000.[4] The incidence of CD is on the rise in children similar to the trend seen in adults whereas UC has shown a more stable pattern. In India, recently there have been several reports of CD in adults[5] whereas data on pediatric CD is sparse. This change in frequency of CD could be due to increased awareness and availability of better diagnostic facility. Some authors believe that the recent increase of CD in India is not apparent but real and consider the improved sanitation- hygiene hypothesis as an important etiological factor.[5]
CD can occur in all age groups and follows the same bimodal pattern of age distribution as IBD. The proportion of patients with CD below the age of 20 years varies between 25-40% with around 10% being less than 10 years of age.[3] The mean age of presentation is about 12.1 years.[6] Early onset IBD (EOIBD) i.e. presentation before the age of 5 years, is a unique subgroup constituting 4% of pediatric IBD.[2] In this subset it is difficult to differentiate between UC and CD. In South India the youngest age of CD was 4.6 yrs and in their series 90% were more than 9yrs of age.[7] CD is seen in both sexes. In US there seems to be a preponderance of CD in boys[3] whereas in South India it was more prevalent in girls.[7] The effect of breastfeeding and cigarette smoking remains controversial. CD occurs with a higher frequency in patients with Turner's syndrome, Hermansky-Pudlak syndrome More Details, cystic fibrosis and glycogen storage disease type 1B.[8]
Crohn's disease could represent a persistent infection with a fastidious organism or an abnormal and prolonged response to a common pathogen. Various organisms have been linked with CD but none of them are evident in the etiopathogenesis. In genetically susceptible individuals the microvascular injury caused by these infections could result in a granulomatous vasculitis of the mesenteric vessels, leading to microvascular thrombosis, multifocal gastrointestinal infarction, and finally gross pathologic sequelae such as ulcerations, fistulas, fibrosis, and strictures.
Genetics
A single well accepted risk factor for the development of CD is having a first-degree relative with the disease. The age-adjusted risk of developing CD during lifetime for a first-degree relative of a proband is about 4%, which is more than for UC. Familial IBD is particularly common with EOIBD and the incidence of IBD among first-degree relatives may be as high as 56%.[2]
The CD susceptible gene NOD2/CARD 15 (Cathapse Activation Recruitment Domain) has been identified on chromosome 16. The NOD2/CARD 15 encodes the protein recognizing lipopolysaccharides of the bacterial cell wall membrane. Mutations of this gene predisposes to CD by exhibiting inappropriate response to bacterial components and thereby altering the signaling pathways of the innate immune system leading to the development and persistence of intestinal inflammation. This genetic make up is associated more with ileal disease, early onset CD or stricturing disease.[9]
Immunologic Factors
CD may represent an aberration in the normal balance between physiologic inflammation and pro-inflammatory cytokines. This imbalance results in the conversion of physiological inflammation to a pathologic one and leads to tissue destruction. The defect may be at several sites including increased antigen uptake through a leaky gut epithelium, defective antigen processing, abnormal vascular endothelial cell function, and abnormalities in the production of interleukins and eicosanoids.
Pathophysiology
The prevailing hypothesis regarding the pathogenesis of CD is an interaction between environmental factors and an altered immune response in genetically predisposed children, leading to chronic inflammation of the gastrointestinal tract. Figure1 In CD there is a disordered regulation of mucosal and systemic immune response resulting in the perpetuation of the inflammatory cascade. A dysregulated TH1 response (T helper 1) seems to be crucial in the conversion of physiologic to pathologic inflammation. The immunological profile in CD is predominantly a cell-mediated response. Active mucosal inflammation of the small and large intestine results in diarrhea, protein-losing enteropathy, bleeding, abdominal pain and stricture formation. Proinflammatory cytokines and eicosanoids increase vascular permeability and cause electrolyte secretion, and augment smooth muscle contraction. Many cytokines promote the recruitment and activity of collagen forming cells leading to fibrous tissue proliferation and thereby resulting in bowel wall thickening and stricture formation. The causal role of TNF-a in the etiopathogenesis of CD has gained importance.
Pathology and distribution
The transmural inflammation and discontinuous involvement are the characteristic features of CD differentiating it from UC where the inflammation is continuous and restricted to the mucosa. The distribution of the lesions in CD though discontinuous may involve any part of gastrointestinal tract from the oral cavity to the colon. In the West isolated colonic involvement is seen in 10-20 %, ileo-colonic disease in 50-70% and diffuse small bowel disease in 10-15 %[10]. Isolated gastroduodenal disease may be seen in less than 5% whereas endoscopic and histologic gastroduodenal disease may be as high as 30-40% of children.[2] The involvement of the small intestine differentiates CD from UC and is a pointer for diagnosis. Perirectal disease is seen in 20% of patients and is associated with recto sigmoid inflammation. Noncaseating granuloma is the hallmark of CD.[2]
Clinical presentation
The clinical presentation in CD depends upon the site of involvement of the gastrointestinal tract. Abdominal pain and systemic symptoms are generally more severe in CD than in UC. A dyspeptic-type of epigastric pain is seen in children with gastro duodenal involvement. Diarrhea occurs in two-third of affected children. In children with predominantly ileal involvement, constipation may be a rare presentation. Gross blood in the stools is unusual with isolated small bowel disease and more common when the colon is involved. Fever occurs in approximately 50%. Fatigue, anorexia, weight loss and diminution in growth velocity are other presenting symptoms in children. Perirectal involvement fistulae, fissure and skin tags are important clues to the diagnosis. CD is subcategorized as predominantly inflammatory, fistulizing or stricturing disease based on the clinical phenotype. The clinical profile of the patients seen in South India is shown in table1.
Complications
Hemorrhage, obstruction, perforation, abscess and fistula formation are well known in CD. Perianal disease may present with abscess formation, perirectal and perianal fistulization and can precede the intestinal manifestation by years. Perforation with internal fistulae is another serious complication. Carcinoma of the colon is a long-term complication of inflammatory bowel disease. The two well accepted risk factors for cancer are duration and severity of the disease. Complications such as perianal and rectovaginal fistula, esophageal stricture and small bowel obstruction necessitating resection were also seen in children from South India
Extra Intestinal Manifestations
Several extra intestinal manifestations which may have some prognostic significance are seen in 25-30%[2] of patients with CD. The important skin manifestations include erythema nodosum and pyoderma gangrenosum. Apthous ulcerations are the most common oral manifestation of CD. The oral manifestations may occur along with intestinal disease or precede it. Oral ulcerations was the primary presentation documented in two children from South India.[7] Ocular manifestations such as episcleritis and anterior uveitis are less common in children than in adults and occur when the disease is active. Arthritis is the most common extraintestinal manifestation in children and occurs in 7-25 % of pediatric IBD and may occur years before the intestinal symptoms.[11] Hepatobiliary complications such as chronic hepatitis, sclerosing cholangitis, cholelithiasis and elevated aminotransferase may precede the active disease.[12] The renal manifestations of IBD include nephrolithiasis, hydronephrosis and enterovesical fistula. Other extraintestinal manifestations are thromboembolic manifestations, vasculitis, pancreatitis, interstitial pneumonitis and pericarditis.
Weight loss is seen in more than 50% of children with CD and is a clue in the evaluation of children with abdominal pain.[8] Failure to thrive is therefore an important presentation of CD. Malnutrition can be due to suboptimal dietary intake, increased gastrointestinal losses, malabsorption, delayed gastric emptying and increased requirements associated with marked inflammatory activity. The severe mucosal inflammation leads to the loss of cellular constituents and hematochezia and results in protein-losing enteropathy, iron-deficiency anemia, vitamin deficiencies, increased fecal loss of calcium, zinc and magnesium.
Growth failure and decrease in growth velocity may precede gastrointestinal symptoms and an absolute height deficiency may be present in 30% at the time of diagnosis.[2] Permanent growth failure can also occur. The probable reasons for growth failure are chronic under nutrition, administration of corticosteroids, low levels of insulin-like growth factor (IGF 1), and alteration of cytokine profiles.
The delay in sexual maturation seen in some children with CD may have a significant effect on self-esteem and socialization. There is irreversible loss of growth potential in those who develop secondary sexual characters before attaining remission whereas if they attain remission before puberty there is good catch up growth and height velocity.
Bone disease is a common problem in children with CD. The causative factors include malnutrition, various effects of cytokines and glucocorticoid therapy. Despite the potential for children with CD to develop osteoporosis, the bone mineral density in adulthood is normal if they are managed appropriately.
Diagnosis
The initial evaluation of a child with suspected CD includes a detailed elicitation of clinical, family and treatment history by the pediatrician. Any child or adolescent with recurrent abdominal pain associated with or without fever, diarrhoea and growth failure is a possible candidate for CD and requires complete examination. A careful assessment of the growth and development of the child is essential. The abdominal examination may not be contributory however if a mass is palpable especially in the right iliac fossa one may consider CD or tuberculosis in the Indian setting. A perianal and rectal examination is necessary to detect skin tags, fissures and fistulae. Laboratory tests such as complete blood count, C reactive protein, motion for occult blood and total protein albumin/globulin ratio should be included.
An ultrasound (US) examination of the abdomen may detect thickened bowel loops, pseudo kidney sign and enlarged lymph nodes in CD. The US findings of free fluid, lymph nodes, thickened mesentery or omentum are more diagnostic of abdominal tuberculosis than CD. The child should then be referred to the pediatric gastroenterologist for a more complete work up. The diagnosis of CD in children is made by a combination of clinical observations and confirmed by laboratory, radiologic, endoscopic, and histologic findings. CD can be classified as mild, moderate and severe based on the clinical presentation.. The popular scoring system for pediatric CD is the Pediatric Crohn's Disease Activity Index (PCDAI) [13] which helps in assessing the severity of the disease.
The differential diagnosis depends on the age and clinical presentation and includes ulcerative colitis, HIV enteropathy, yersenia enterocolitis, allergic enterocolitis, tuberculosis, lymphoma, intestinal polyps and diarrhoea predominant IBS. In India it is a dictum though difficult to differentiate CD from TB.
Endoscopic Evaluation
In CD the characteristic lesions on ileo-colonoscopy are the skip lesions, cobble stoning of mucosa, apthous ulcers or deep irregular ulcers of varying sizes with normal intervening mucosa Figure2. Rectal sparing and terminal ileal involvement are features of CD rather than UC. Histopathologically the presence of noncaseating granuloma is diagnostic of CD but often difficult to differentiate from TB. The inflammatory cells have a transmural distribution and the fissuring ulcers extend to the muscularis propria. Normal appearing colonic mucosa should always be biopsied since microscopic inflammation is a feature of CD Gastric antral biopsy and identification of focal active gastritis or microgranuloma also increases the diagnostic yield.[14]
Radiologic Evaluation
Barium Meal Series is useful to identify small bowel involvement and lesions such as strictures, fistulae, and ulcerations may be identified. This contrast study has largely been replaced by contrast enhanced computerized tomography.
Contrast Enhanced Computerized Tomography (CECT) is more sensitive than barium studies to identify bowel wall thickening and assess the length and site of strictures in small bowel CD. Ultrasound abdomen is done as a primary modality of investigation and may be used as screening test.
Serological markers
Perinuclear anti-neutrophil cytoplasmic antibody (pANCA) and anti sacchromyces cerevisiae antibody (ASCA) are potentially important addition to the diagnostic panel of IBD. Combination of these markers has shown a specificity of 95% and sensitivity of 55% in children with CD.[15] They are not considered as a screening test for CD. The detection of ASCA antibodies in individuals with CD may depend on the duration of exposure to sacchromyces cerevesiae.
Newer Investigation Modalities
Isolated small bowel CD may be diagnosed using a double balloon enteroscope that helps to directly visualize and biopsy the lesions. The wireless capsule endoscopy has been used as a diagnostic tool in adults with isolated small bowel CD[16]. Gandolium enhanced Magnetic Resonance Imaging (MRI) Scan has been beneficial in some cases of IBD to differentiate between CD and UC.
CD VS Uc
The distinction between CD from UC though essential may be difficult in some circumstances. Some of the differentiating clinical and endoscopic features are shown in table2.
CD VS TB
It is crucial to differentiate CD from TB for administrating appropriate therapy. Tuberculosis has always been considered a possible differential diagnosis in the evaluation of granulomatous colitis resulting in patients with CD being treated as tuberculosis. There are some differentiating features between CD and intestinal TB. The ulcer in CD are longitudinal whereas it is more transverse in TB. Perianal involvement is a feature of CD and not TB. The granulomas are smaller, ill formed, numerous and non-caseating in CD whereas they are larger, well formed confluent and caseating in TB[17]. Isolated lymphnode involvement can occur without bowel involvement in CD but not in TB.
Therapy
The general goals of treatment are to achieve best clinical and laboratory control of inflammatory disease with least possible side effects from medication, promote growth through adequate nutrition and permit the child to function as normal as possible.[3] 5-Aminosalicylates like sulfasalazine or 5-ASA remain the cornerstone of treatment for CD. The 5 ASA drugs (mesalamine, balsalazide) exert local anti-inflammatory effects through a number of mechanisms, which includes inhibition of 5 -lipoxygenase with a result in decreased production of leukotriene B4, scavenging of reactive oxygen metabolites, prevention of the upregulation of leucocyte adhesion molecules and inhibition of interleukin 1 synthesis. 5 ASA is rapidly absorbed from the upper intestinal tract and various drug delivery systems have been employed so that it reaches the distal small bowel or colon. Mesalamine is coated with Eudragit, a pH sensitive acrylic resin or ethyl cellulose to release the drug at the appropriate site. Uncoated mesalamine is also available as enema for use in left sided lesions. Mesalamine is used in the dose of 40-60mg/kg/day as the first line drug in mild CD and also as maintenance drug.
Steroids
Corticosteroids are used in acute stages of moderate to severe CD or when aminosalicylates are ineffective Prednisolone is started at a dose of 1-2 mg/kg day in moderate CD. Once clinical remission is reached attempts are made to wean the medication to alternate day therapy and then tapered before stopping within 6-8 weeks. Newer corticosteroids such as oral budesonide at a dose of 6-9mg/day may be prescribed to avoid the systemic side effects of steroids.
Immunomodulators
The recognition of the central role played by the immune system in the pathogenesis of IBD has increased the use of immunomodulators.
6 Mercaptopurine (1-1.5mg/kg/day) and azathioprine (2-2.5mg/kg/day) are effective in patients with active disease when added on to corticosteroid therapy. They facilitate the development of remission and promote tapering of the corticosteroids. These drugs usually require three to six months to exhibit efficacy, and are not effective as primary therapy. Methotrexate has been used in children with CD with beneficial results.
Antibiotics
Though no infective agent has been implicated in the etiology, Ciprofloxacin and metronidazole have shown some efficacy in active CD especially those associated with perirectal disease, perianal fistulae and even small bowel CD.
Biological therapy
Several novel therapies have been investigated in the treatment of IBD. They may be biologic agents such as infliximab, natalizumab, Interleukin 10 or non-biologic agents such as thalidomide, granulocyte colony stimulating factor.[18] Anti-Tumour Necrosis Factor, infliximab has been evaluated in pediatric CD and has proved effective as a short-term therapy in moderate to severe CD and in children with active draining external fistulae.[19]
Nutritional Therapy
Children with CD should be supported with proper nutrition to ensure better results from therapy. Caloric supplementation is essential in children with growth- delay or under-nutrition. It is evident that enteral nutrition with an oligopeptide formula or amino acid based formula has fewer relapses. Patients who attain remission with exclusive enteral nutrition have prolonged remission and improved linear growth.[20] Calcium supplementation is an important adjuvant to prevent bone disease.
Psychological Therapy
CD is a chronic condition that may have a profound influence on the lives of affected children and their family members. Adolescents have a difficult time in handling the disease. Every effort should be made to facilitate normal age appropriate activities and early intervention by psychologists or psychiatrists should be sought if problems develop.
Surgical Therapy
The indications for surgery in CD include intractability, uncontrolled hemorrhage, perforation, obstruction, fistulae, growth retardation, and carcinoma.
Multidisciplinary Approach
The care of the child with CD involves a multidisciplinary approach involving the pediatrician, pediatric gastroenterologist, nutritionist, psychologist, pediatric surgeon, social worker and nurse. The team should also include parents, siblings and teachers who should be well informed about the child's problem. This concept in care ensures an ideal, comprehensive management of the CD patient and helps in achieving appropriate levels of physical, mental and social well being. The transition of the adolescent from the child centered health care systems to the adult oriented health care system should be done with utmost care.
Conclusion
Crohn's disease is an emerging chronic gastrointestinal disease of childhood and adolescence which affects a very vulnerable period in the life of the individual characterized by remissions and relapses and continues through adulthood. Indian children are not spared from this problem and it is essential that pediatricians are aware of this disease to enable proper diagnosis and prompt referral.
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