Pathogenesis And Clinical Management Of Two Disorders Of The Gastrointestinal Tract

Colon cancer (CC) and ulcerative colitis (UC) are two disorders of the gastrointestinal tract that are responsible for much personal suffering and impose a significant impact on healthcare resources. In spite of the wealth of revolutionary advances in the understanding of the pathogenesis and thus the improving medical care for both CC and UC respectively, there still remains a lot to be determined. These two gastrointestinal (GI) diseases, despite both manifesting at the colon, and presenting with common symptoms, have largely different pathophysiology. In terms of clinical management, despite the disease-specific treatments, there are various overlaps, particularly in terms of general wellbeing/dietary management. Interestingly, there is a well-recognised association between the increased risk of CC in individuals with UC (Eaden, 2001).

UC is a chronic, relapsing inflammatory disease of the colon. A simple, exact cause of the disease does not however seem likely. Instead, UC appears to be a condition related to an interaction between genetic predisposing factors, environmental influences and endogenous modifiers (Hawkey et al., 2012). Overall, these contributory elements to the pathogenesis of UC result in the activation of the intestinal immune system and a continual cycle of inflammation and repair.

The colonic mucosa is an epithelial barrier, providing the first-line defence mechanism of the mucosal immune system (Ordàs et al., 2012). Antigenic presence maintains this immune system as described earlier. Enhanced permeability of this barrier is implicated in UC. Tissue injury and colitis are a result of the breakdown of mucosal immunoregualation (Hawkey et al., 2012). A Th2 response is thought to characterize UC (i.e. increased mucosal interleukin IL-5, IL-10 and IL-13). This could be observed in the characteristic UC-induced lesions in animal models of colitis (Dohi et al., 2000). Moreover, the colon damage is thought to be the direct result of an exaggerated T-cell response (Kathleen and Jurenka, 2003).

Genetic associations are important in both UC and CC respectively. The known genetic associations for UC are thought to account for only about 20% susceptibility (Matricon et al., 2010). Moreover, the low concordance rates for UC observed in a study of monozygotic twins (6-14%) (Matricon et al., 2010) confirm the importance of non-genetic influence. In support of this view, epidemiological studies have shown that changing lifestyle and environmental linked with socio-economic development may indeed contribute to an increased incidence of UC (Hawkey et al., 2012). Recognised hereditary conditions account for approximately 5-10% of CC (Hawkey, 2012). The two major ones, strongly predisposing to CC are familial adenomatous polyposis (FAP) and Lynch syndrome (HNPCC). Both of these syndromes follow an autosomal dominant inheritance pattern. Moreover, a further 20% of CC cases are a result of an increased risk to disease due to a family history.

FAP is caused by a germline mutation in the adenomatous polyposis coli (APC) gene. APC is a tumour suppressor gene, which inhibits cell proliferation when normally expressed (Hawkey et al., 2012). Inactivation of APC results in the colonic epithelial cell to continually proliferate, leading to clonal expansion. This mutation thus underlies the development of a large number of adenomas (>100) at a relatively young age. Ongoing proliferation of the epithelial cells at the top of the colonic crypt leads to the formation of adenomatous polyps. In FAP, a very large number of adenomatous polyps develop. Since additional mutations can accrue in this expanding clone, the cancer eventually manifests.

HPNCC is also caused by germline mutations in one of the DNA mismatch repair (MMR) genes. The most commonly mutated DNA MMRs are hMSH2, hMLH1, hMSH6 or hPMS2 (Peltomaki and Vasen., 1997; Clendenning et al., 2008). However the majority, approximately 70%, of mutations is found in hMLH1 and MSH2 (Jang and Chung, 2010). These genes play a key role in proof-reading DNA during replication and are thus important for maintaining genomic stability. Their mutation thus results in genomic instability and increases potential for the occurrence of pro-cancerous mutations. Interestingly, recent evidence has shown that a polymorphism in hMLH1 MMR, is associated with susceptibility to refractory ulcerative colitis (Bagnoli et al., 2004).

A vast number of genes are implicated in colorectoral carcinogenesis (i.e. tumour suppressor genes and oncogenes). In addition to the genetic factors, epigenetic changes have also been observed in colon tumours (Brenner, 2004). Increasingly the well-documented impact of various environmental factors of UC (Quigley, 2012) has triggered interest into the role of epigenetic events in UC. This field of research is only newly emerging for UC, however much has already been documented in the incidence of CC.

For example, DNA methylation at the promoter region is one way that colon cancer can be promoted. This mechanism is able to terminate and silence gene expression without DNA mutation (Brenner, 2004). In particular, genes responsible for the prevention of the development of cancer can be inactivated (Myohanen et al., 1998). The methylation and inactivation of p14, usually an upstream inducer of the p53 tumor suppressor pathway, is often associated with 25% of colon cancers (Burri et al., 2001). This inactivation results in the same cancer phenotype as mutation of p53 (Brenner, 2004). Approximately 35% of colon cancers occur as a result of the methylation of tumour suppresser gene p16 (CDKN2A).

Exposure to environmental microbes may indeed be the most important exogenous factor related to the pathogenesis of UC (Hawkey et al., 2012). This is particularly important early on in life when development of the mucosal immune system is still underway. It is thus proposed that immune education requires appropriate exposure (i.e. indigenous flora) and episodic infections to prime and condition the immune response (Bernstein et al., 2008). Animal models of colitis have demonstrated persuasive evidence to implicate this. Regardless of the underlying genetic defect in the animal models, the colitis does not occur in a germ-fee environment, and only progresses upon colonization with commensal bacterial flora (Strober et al., 2002). Although many observations are suggestive of a causal relation between UC and direct exposure to alimentary bacteria and other antigens, other observations would not conform. For example, Froese et al., (2001) showed occurrence of UC in an autotransplanted colonic neovagina where there is indeed no exposure to alimentary antigens.

Approximately 11% of CC have been attributed to excess body weight (Bardou M, 2013). As in the case of CC, there exists a relationship between obesity and the progression of disease in UC. Excess energy intake is now known to increase pathogenic microbial populations (Mi-Kyung Sung and Mi-Young Park, 2013). Mechanistic explanations with regards to the relationship between obesity and intestinal inflammation have not yet been identified in humans. Nonetheless, various rodent model studies have provided an insight into how intestinal inflammation is mediated through obesity-related factors. Leptin-deficient mice (ob/ob) showed resistance to chemically-induced colitis indicating the role of leptin as a critical mediator in colitis progression (Siegmund et el., 2002).

Other environmental factors, including changes in dietary habits, have been suggested to be involved in the onset of both CC and UC. A recent systematic review of 19 studies reported that meat intake, among other foods, was positively associated with increased UC risk (Hou et al., 2011). Similarly a substantial amount of data has shown an association between meat and CC. For example, of sixteen cohort studies investigating red meat, almost all reported an increased risk of CC with higher intake (World Cancer Research Fund, 2011).

In both UC and CC, providing the patient with information and support surrounding their condition is a priority in clinical management. For example, stress may exacerbate both conditions and thus necessitate psychosocial support from a counselor. The counselor's advice may help the individual to cope with the uncertainties of their disease (Hawkey et al., 2012) Specialist multidisciplinary care, taking into account the age of the patient, should be available (NICE, 2013). The treatment path chosen for both UC and CC is likely to depend on a combination of their clinical severity, the extent of disease and the person`s individual priorities.

There is no specific, curative treatment for UC. The main objectives of therapy are thus to treat the active disease through addressing its associated symptoms (i.e. abdominal pain, poor appetite etc.), improve quality of life (QoL), reduce the risk of complications and to avoid the need for surgical intervention (Hawkey et al., 2012). Whereby surgery is largely viewed as a last resort intervention in UC, it is indeed the primary form of treatment in CC (NICE, 2011) and is particularly important in the treatment of metastatic disease. Surgery for UC may be considered in emergency cases where severe UC is not responding to drug treatment. In CC, surgery with curative intent is aimed at removing the tumour and corresponding lymphatic drainage. Moreover, radiotherapy is used as an adjuvant treatment to CC surgery (NICE, 2011). In both UC and CC, emphasis is placed on the importance of maintaining an adequate intake of calories and preventing weight loss and malnutrition. This may be challenging in the face of symptoms (both of the disease and medical treatment) that may discourage an adequate intake. The unique role of the dietitian would be required in this area. A recent systematic review of randomized controlled trials (RCT's) has investigated the role of fiber in the treatment and maintenance of UC (Wedlake et al., 2013). The rationale behind the potential use of fiber in treatment is related to its physiological properties that may impact on GI inflammation. Only three of 10 studies in UC showed positive between group effects of fiber on disease activity thus providing limited weak evidence for the efficacy of fiber in improving UC outcomes. The studies used a variety of supplements or dietary advice. The benefits were more commonly seen for supplements rather than dietary advice. A potential confounding factor in that individuals may be more likely to comply with supplements than make dietary modifications, which require much more effort, may have been introduced into the results of this study. Further studies are needed to reach a conclusion on whether the results are indeed represented by a true lack of impact of fiber. Conventional drugs for both the induction and maintenance of UC include: aminosalicylates, corticosteroids, antibiotics, and immunomodulators (Kathleen and Jerenka, 2003). These drugs can be oral or topical and corticosteroids may be administered intravenously in people with acute severe disease (NHS, 2011). Aminosalicylates are most commonly used for maintaining remission. Drugs in this class have anti-inflammatory effects by inhibition of IL-1, IL-2 and NF-kB (Cipolla et al., 2002). Additionally, Jani and Regueiro (2002) have shown that they are involved in the impairment of monocyte and lymphocyte function and provide antioxidant activity. Some individuals taking this drug will be faced with its associated side effects, such as nausea and vomiting. This will need to be taken into account when considering a patient's individualised medical management (NICE, 2011). Corticosteroids are using during acute episodes of UC. Their potent immunosuppressive effects include inhibition of the arachadonic acid cascade, IFN-y and IL-1, -2, -4, -5, -6, and -8 (Kathleen and Jerenka, 2003). Again, it is important to consider the associated symptoms with this type of drug (i.e. weight gain).

A therapeutic strategy is to target the microbial environment within the colon (Shahanan, 2005). Probiotics are thought to be effective through their impact on host GI microbiota and promotion of mucosal immunoregulation (Whelan and Quigley, 2013). A recent systematic review of controlled trials (Jonkers et al., 2012) has suggested positive implications with regards to the use of probiotics in the treatment of UC. Namely, nonpathogenic E. coli, S, boulardii, Lactobillus reuteri (by enema) (Olivi et al, 2012) and VSL#3 (Tursi et al., 2010) are some of the effective probiotics (Whelan and Quigley, 2013). They are involved in maintaining remission in UC as well as in its treatment while the disease is still mild-moderately active. A strength of the systematic review was that only data from the same probiotics were meta-analysed. This is important as probiotics may have differing efficacies. Thus, the avoidance of heterogenetic analysis of probiotics allowed for specific and more reliable conclusions. Nevertheless, other studies have not been as favourable and larger, longer-term studies are required shed light on optimal doses and treatment periods (Jonkers et al., 2012).

The medical management of cancer is individualized, taking into account the specific risks and benefits to the treatment of cancer. Many members of the MDT team are thus involved in the care of CC patients, for example, an oncologist (a radiotherapy and chemotherapy specialist), and a specialist nurse. Clinical guidelines (NICE, 2011) state that the combination and sequence of chemotherapy treatment should be individualized, consider the associated side effects and take into account the patient's preferences. Chemotherapy administered in the advanced disease state works to palliate symptoms or to prolong life, with no expectation to cure (Hawkey et al., 2012). In order to weigh up the benefits and risks in this scenario, it is useful to look at some of the evidence. A randomized control trial in patients with metastatic CC established that chemotherapy with 5-fluroouracil (5-FU)-based regimens contributed to an improved QoL. 5-FU was able to improve median survival rate from 5 to 10 months compared to best supportive care (Hawkey et al., 2012).

When administered in the adjuvant setting, often after the patient has undergone potentially curative surgery, the goal of chemotherapy is to disease the risk of recurrence and death from the disease (Hawkey et al., 2012).

Although a less conventional treatment for UC, epidemiological data have found that smoking may confer some level of protection. Patients with UC often relate the cessation of smoking to the onset of UC. The mechanism of this effect is unclear though and these observed effects of smoking are paradoxical to the implications of smoking in CC. A meta-analysis conducted by Botteri et al. (2008) on CC and smoking and found that smoking is significantly associated with colorectal cancer incidence and mortality.

Animal studies have showed that non-steroidal anti-inflammatory drugs (NSAIDs) are able to cause colitis as well as exacerbate the disease (Freneaux et al., 1990). However, in contrast, the use of NSAIDs such as sulindac and celecoxib can induce regression of adenomas in FAP (Cruz-Correa et al., 2002; Thun et al., 2002) and are thus beneficial in the treatment of CC (Giardiello et al., 1993). Cruz-Correa and colleagues conducted a prospective cohort study to investigate the efficacy of sulindac in 12 patients with ileorectal anastomosis for a follow-up period of 77 months. The overall outcome showed that sulindac was beneficial (significant regression of polyp number was observed in all patients at 12 months with p= 0.039). However, it is worth noting that the sample size of this cohort was very small with 5 of the 12 participants dropping out. The lack of information as to why participants dropped out, is a drawback of this study. Such information could be important for example be useful in exploring whether dropout was due to harsh side effects of the drug. There is still yet much to be discovered about the pathophysiology of both UC and CC. A continued improvement in understanding of the pathogenesis' of these disorders will expand and enhance the provision of medical management.