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Crohn's DiseaseReview of G enetic Pathways, N ew Treatments, and Tim ing of

SurgeryM ark E. Martin11/20/10

Dr. Mark BrackenPathophysiology 4400Utah Valley U niversity


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There have been m any identified pathways for the onset of Crohn's Disease. Recently,with the advent of new technologies we have been able to explore deeper into the human genomeand uncover, what were hidden pathways of many different types of disease. The thirteen-yearstudy of the human genome ended in 2003. Init ial ly headed by Dr. James W atson and completedby Dr. Francis Collins, the Human Genome Project completed the mapping of the humangenome and spurred a m yriad of new research fronts. Not only did the m apping of the hum angenome give rise to new possibilities in medicine but it also allowed for the reclassification ofexisting diseases. In this paper I will be reviewing symptoms, risk factors and new methods fordiscovering genetic etiologies of Crohn's Disease. Additionally, I have also decided to reviewthe consensus among professionals regarding the time that surgical intervention is necessary.

Even thoug h the etiology of CD has b een ra the r elusive in recent years the risk factorsand symptoms have becom e well identified and accepted. Currently North A m eric a's prev alencerate is 170/100,000 [ ] ] . This represents approximately half a million children and adults [ i j .Interestingly, the incidence of CD is higher in well-developed countries than in underdevelopedcountries. This has led to the hypothesis that improved hygiene lim its antigen exposure early inchildhood and a resulting im mu ne response to later developing bacterial flora is responsible fo rthe onset f i j . Some risk factors of contracting CD includ e being an Ashkenazi Jew. This isprimarily due to the aristocratic inbreeding that took place and the subsequent weaker imm une

-X Wsystems that dev eloped . Also having ajlrst-degree relative with CD an^of coursestress andsmoking.

Some of the m ajor sy m ptom s associated with CD are abdominal pa in, vom iting, diarrhea(which can somet imes be bloody), c onstipation,and we ight loss. O ne m ajor difference in theclinical patholog y of CD from that of U C is the affected area of the gastrointestinal tract.


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genes corresponded to these pathways. Secondly, a bound ary needed to be defined around theplausible genes. Thirdly, a statistical method was needed to be able to compute the measure ofassociation to the disease status [ 2 \ . The resulting measure of association was termed "GeneScore" [ 2 ] . While a number of different statistical methods were used to determine gene scores,PCA regression was found to be the most powerful to determine varying allele frequencies [ 2 ] .Among the findings, IL23R was the first gene identified and replicated, and is the highest knownranking gene in the datasets. Other genes sharing com mo n pathways with IL23R w ere isolatedand analyzed. IL23R w as then removed from the list of genes and analysis of the rem aininggenes was rerun with the decease status conditioned on IL23R [ 2 j . This enabled exp loration ofother genes implicated in the disease pathway. Interestingly enough, after th e IL23R variationwas removed and gene scores were recalculated, the top ten genes remained consistent [2]. So far,twenty-one of the 32 genes represent sign ificant Croh n's disease pathways. These identifiedgenes are primary in interle uk in signaling, B cell, and cytokine signaling pathways [ 2 j .

Once identified and diagnosed the qu estion becomes what is the m ost appropriatetreatment. Probiotics may be an answer fo r many suffering from gastrointestinal disease. Onlyrecently has extensive research been conducted into this highly variable field. In 2004, th e WorldHealth Organization estimated there to be more than four billion episodes of diarrheal disease,from which 2.2 m illion fatalities resulted, mak ing it the fi


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at some point in their life and an estimated 10% of patients with affected proximal areas of thesmall intestine and the duodenum will also require surgery (5] . Overall, it is estimated that 74% ofpatients wil l require surgery within the first 13 years of diagnoses and 50% of relapses willrequire surgery within the first 10 years after the first operation [ s j .

The timing of surgery for CD patients depends on the evaluation of a number of differentfactors. These factors are listed as such: (a) a failure of medical treatment, (b) the onset ofspecific complications related to the disease or to pharmacological treatment, (c) dysplasia orcancer and (d) stagnated or retarded growth in children [ 5 j . In some cases, the timing for surgeryis relatively straightforward, as in a case with an abdominal fistula. Most of the time, the variouscomplications and the clinical heterogeneity of the disease produce so many diverse possibilitiesthat a general systematic approach is nearly impossible [ 5 j . The demand for multidisciplinaryteams to be involved is paramount due to the need of each case to be assessed individually.Collaboration between teams and the sharing of common goals, namely to establish an idealmoment for surgery, avoid diagnostic delays, and attaining the best pre-operative conditions tooptimize surgical outcomes is crucial [ 5 ] .

Factors that point to a "general failure in medical treatment" are difficult to define. Aconsensus as what is meant by a failure of medical treatment is as follows:(a) Worsening or persistence of symptoms despite correct treatment [5]. Recognizing a failure in

medical treatment on these grounds takes experience and proper medical judgment [ 5 ] .Patients must be monitored closely to identify if any partial clinical improvement occurs andto see if tolerance to residual symptoms has declined.


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Bibliography1.) Nathan, D . G., & Orkin, S. H. (2009). M usings on genome m edic ine: Crohn's disease.Genome Medicine, 1:1032.) Ballard, D., Abraham, C, Cho, 3., & Zhao, H. (2010 ). Pathway analysis compa rison usingCrohn 's disease genome wide association studies. BM C M edical Genomics. 3:253.) Hume, G. E., Fowler, V. E.,Lincoln, D ., Eri, R., Tem pleton, D., Florin, T. H ., Cavanaugh, J.A., & Radford-Smith, G. L. (2006). Angiotensinogen and transform ing growth factor ( 3 1 :novel genes in the pathogenesis of Crohn's disease. LMed Genet, 43:e51.doi:10.1136/jmg.2005.0404774. ) Culligan, E. P., Hill, C., & Sleator, D. (2009). Probiotics and ga stroninal disease: successes,problems and future prospects. GirtPathogens, 1:19. doi:10.1186/1757-4749-l-195.) Alos, R., & Hinojosa, J. (2008). Timing of surgery in Crohn's disease: A key issue in themanagement. World lonrnal of Gastroenterology, 14(36), 553 2-5539.doi:http://dx.doi.org/10.3748/wjg.!4.5532


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