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Bragg, M.A.; Breaux, W.A.; M’Koma, A.E. Inflammatory Bowel Disease-Associated Colorectal Cancer. Encyclopedia. Available online: (accessed on 29 November 2023).
Bragg MA, Breaux WA, M’Koma AE. Inflammatory Bowel Disease-Associated Colorectal Cancer. Encyclopedia. Available at: Accessed November 29, 2023.
Bragg, Maya A., Williams A. Breaux, Amosy E. M’Koma. "Inflammatory Bowel Disease-Associated Colorectal Cancer" Encyclopedia, (accessed November 29, 2023).
Bragg, M.A., Breaux, W.A., & M’Koma, A.E.(2023, July 12). Inflammatory Bowel Disease-Associated Colorectal Cancer. In Encyclopedia.
Bragg, Maya A., et al. "Inflammatory Bowel Disease-Associated Colorectal Cancer." Encyclopedia. Web. 12 July, 2023.
Inflammatory Bowel Disease-Associated Colorectal Cancer

Colonic inflammatory bowel disease (IBD) encompasses ulcerative colitis (UC) and Crohn’s colitis (CC). Patients with IBD are at increased risk for colitis-associated colorectal cancer (CACRC) compared to the general population. CACRC is preceded by IBD, characterized by highly heterogenous, pharmacologically incurable, pertinacious, worsening, and immune-mediated inflammatory pathologies of the colon and rectum. The molecular and immunological basis of CACRC is highly correlated with the duration and severity of inflammation, which is influenced by the exogenous free hemoglobin alpha chain (HbαC), a byproduct of infiltrating immune cells; extravasated erythrocytes; and macrophage erythrophagocytosis. The exogenous free HbαC prompts oxygen free radical-arbitrated DNA damage (DNAD) through increased cellular reactive oxygen species (ROS), which is exacerbated by decreased tissue antioxidant defenses. Mitigation of the Fenton Reaction via pharmaceutical therapy would attenuate ROS, promote apoptosis and DNAD repair, and subsequently prevent the incidence of CACRC. Three pharmaceutical options that attenuate hemoglobin toxicity include haptoglobin, deferoxamine, and flavonoids (vitamins C/E). Haptoglobin’s clearance rate from plasma is inversely correlated with its size; the smaller the size, the faster the clearance. Thus, the administration of Hp1-1 may prove to be beneficial.

inflammatory bowel disease colitis-associated colorectal cancer exogenous free hemoglobin alpha chain

1. Core Message

Inflammatory bowel disease-associated colorectal cancer (CACRC) is becoming more prevalent worldwide and presents at a younger age. IBD, as well as CACRC, is evolving worldwide, especially in newly industrialized countries. With an aging population, its compound prevalence suggests that CACRC could become an emerging global challenge. Although surveillance and chemoprevention for CACRC exist, sixty percent of patients with CACRC are asymptomatic upon detection and over fifty percent present with advanced disease; this eventually leads to less favorable outcomes compared to sporadic colorectal cancer (SCRC). To understand why, scientists profiled surgical pathology resections of colonic mucosal and submucosal layers from patients with IBD who had undergone pouch surgery, restorative proctocolectomy with ileal pouch–anal anastomosis (RPC-IPAA) [1]. A pool of exogenous/free hemoglobin alpha chains (HbαCs) in areas of active colitis was unexpectedly found. Furthermore, the HbαCs were produced through the action of immune infiltrating cells (macrophages) that promoted reactive oxygen species (ROS) in epithelial cells depleted of colonic tissue homogenate antioxidants (i.e., nuclear factor erythroid 2-related factor 2 (Nrf2), catalase (CAT) superoxide dismutase (SOD), and glutathione peroxide (GPx)). The antioxidants above are significant regulators of cytoprotective responses to oxidative stress and the primary cellular defense against cytotoxic effects of oxidative stress [2][3][4][5][6]. Intestinal mucosal damage in IBD involves reactive oxygen metabolites (ROMs). Endogenous antioxidant enzymes neutralize ROMs in a carefully balanced two-step pathway. First, SOD converts superoxide anion to hydrogen peroxide (H(2)O(2)). Then, hydrogen peroxide is neutralized to water by CAT or glutathione peroxidase (GPO) [1]. This indicates that exogenous/free HbαC has a physiological role in inducing ROS formation and DNAD and, if not attenuated, can trigger carcinogenesis [1].

2. Introduction

Colorectal cancer (CRC) is often described as the “disease no one has to die from”, but approximately 50% of patients with CRC who undergo potentially curative surgery ultimately relapse and die, usually as a consequence of metastatic disease [7][8]. According to GLOBOCAN 2018 data, and the American Cancer Society, for both men and women in the United States of America, colorectal cancer (CRC) is the third main cause of cancer-related mortality in the world [9][10]. CRC is the deadliest cancer [11][12]. IBD is a known risk factor for developing CACRC [13]. IBD patients are at increased risk of CACRC due to long-standing chronic inflammation, genetic alterations, and epigenetic environmental factors [14][15][16]. Additionally, data indicate that CACRC may have evolved through a pathway of tumorigenesis distinct from that of SCRC.
Predominantly colonic IBD, the “colitides”, includes ulcerative colitis (UC) and Crohn’s colitis (CC), which are two heterogeneous, chronic relapsing and remitting gastrointestinal tract disorders in the colon [16][17][18][19][20]. Currently, both diseases affect approximately three million people in the United States. However, the incidence and prevalence of both are increasing worldwide, thus making them global emergent diseases with significant clinical challenges [20]. The global prevalence of IBD is currently evolving, approaching 90 cases/100,000 people [21], though awareness should be assessed in each of the geographical locations of the world [22][23]. North America and Canada have the highest rates of IBD in the world [24][25]. However, over the past three decades, the incidence of IBD in low-income countries has steadily risen. [24][26][27][28][29][30][31]. The burden/implication of IBD is discrete in various countries and locations, especially when contrasted/matched between low-income [32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47] and wealthy nations [48][49]. The estimated data suggest that 25 to 30 percent of cases of CD and 20 percent of patients with UC present during adolescence and young adulthood at the reproductive age [50][51][52][53][54][55][56][57][58][59]. The extent of racial/ethnic and regional differences in the prevalence of IBD in the United States remains largely unknown, warranting additional research [60][61]. However, IBD has predominantly affected white populations, particularly Ashkenazi Jews. But over the last three decades, IBD has “emerged” in minority communities [24][61][62][63][64][65][66]. The genesis of IBD is unknown, but is believed to be multifactorial [16][28][67][68]. It has been hypothesized that intestinal damage in UC and in CC is related both to increased oxygen-derived free radical production, mainly resulting from a respiratory burst of infiltrating phagocyte cells, and to a low concentration of endogenous antioxidant defense mechanisms. Indeed, neutrophils and monocytes in patients with active and/or fulminant IBD exhibit higher concentrations of oxygen-derived free radicals than in normal control samples [68][69][70][71]. Compared to other tissues, the gut is potentially more susceptible to oxidant injury/trauma, which can be exacerbated by the low concentration of antioxidant enzymes in epithelial cells, which contributes to the ROS cytotoxicity observed in the colons of patients with IBD [1][72]. IBD has no curative drug, often resulting in significant long-term comorbidity (1). The development of potential immunosuppressive therapies in IBD aims to achieve long, deep remission, but their effects on subsequent CACRC have yet to be established. However, studies have shown that the longer a person has had IBD, the higher their chance of developing CACRC [73][74][75]. An extensively referenced comprehensive meta-analysis of 19 longitudinal and cross-sectional studies with age-stratified data reported that the cumulative incidence of CACRC in UC is 2% after 10 years, 8% after 20 years, and 18% after 30 years of disease [76]. In contrast, other studies reported lower incidence rates accredited to, among other factors, the benefits of endoscopic monitoring surveillance and anti-inflammatory pharmaceutical chemoprophylaxis [77][78][79].

3. People with Inflammatory Bowel Disease Are at Escalated Risk of Colitis-Associated Colorectal Cancer with a Subsequent Poor Prognosis

People who suffer from colonic IBD are at increased risk for developing CACRC [77][80]. All instances of CACRC are located in segments with colitis [73]. CACRC is one of the most severe complications of IBD, with a mortality rate of 10–15%, and the risk is 1.5–2.4-fold that in the general population [13][81]. The dysplasia of CACRC develops via a different pathway and mechanism in comparison to SCRC [13]. The well-established risk factors for CACRC are time scale and the extent of intestinal inflammatory lesions [13][73][82][83][84]. Genetic factors, coupled with the longevity of the persistent fulminant interdependent inflammatory process in the colonic mucosal layers, are believed to play a remarkable role in CACRC carcinogenesis, and consequently, inflammatory action could decrease this continuous process of inflammation associated with carcinogenesis [85][86][87]. Survivability depends on adherence to colonoscopic surveillance, and early elective colectomy is recommended [73][88][89]. However, some oncologic analyses provide positive results after curative surgeries in patients with CACRC [87][90]. This warrants continuous surveillance to assess postcolectomy safety [73][88][91].
The prevalence of CACRC development is identical for patients with UC and CC [92][93][94][95], as is the quantitative exogenous HbαC between the two colitides [1]. Here was conducted to summarize and determine the efficacy and pharmaceutical safety of Fenton Reaction mitigation as a preventive measure for CACRC.

4. Malfunctioning Tight Junction Protein CALUDIN-1 Is a Source Point of Colitis-Associated Colorectal Cancer Carcinogenesis

The tight junction is an intricate intercellular junction found in epithelial and endothelial cells that is accountable for the genesis of functional epithelial and endothelial barriers that synchronize the passage of cells and solutes through the paracellular space [96]. Patients with IBD are known to have dysfunctional claudin-1, an intestinal epithelial tight junction protein [97][98]. Irregular functions in claudin-1 leads to changes in cell permeability, causing blood capillary extravasation (hemorrhage), macrophage erythrophagocytosis, and the subsequent release of free HbαC exogenously into the interstitial space [1]. Within the interstitial space, HbαC is observed to serve as a biological substrate in the Fenton Reaction, producing hydroxyl radicals, which leads to DNA damage within normal intestinal mucosa and subsequent tumor formation if the damaged DNA is irreparable [99]. This unveiled molecular understanding of chronic inflammation in patients suffering from IBD provides insight into the evolution of CACRC. Inflammation can induce mutagenesis, and the relapsing–remitting nature of this inflammation, coupled with epithelial regeneration, may exert selective pressure, accelerating carcinogenesis [100]. In summary, the sequential molecular pathogenesis of CACRC is due to inflammation, claudin-1 dysfunction, the extravasation of erythrocytes, macrophage erythrophagocytosis, and exogenous HbαC-ROS-DNAD carcinogenesis [11][45]. Within the interstitial space, HbαC acts as a substrate in the Fenton Reaction (Fe2+ + H2O2 → Fe3+ + ·OH + OH-) [46].

5. Pharmacological Mitigation of Fenton Reaction to Prevent Colitis-Associated Colorectal Cancer Oncogenesis

Ex vivo studies demonstrated a pool of free HbαCs (until recently, an unknown tissue by-product) in IBD patient mucosal microenvironments modulated by extravasated microphage erythrophagocytosis [1]. In vitro data show that HbαC induced high levels of ROS production that caused DNAD, which was exacerbated by systemic decreased antioxidant defenses [1][101][102]. The focus is on the fact that if the Fenton Reaction were mitigated via pharmaceutical therapy, then this would reduce ROS and promote DNAD repair and apoptosis, which could prevent the incidence of CACRC [99].

6. Pharmaceutical Approach to Preventing Colitis-Associated Colorectal Cancer

Colonoscopy surveillance serves as the gold standard for prevention, but it has proven relatively inadequate for ascertaining the earliest molecular pathogenic relationship between neoplasia and chronic inflammation (more specifically, Fenton chemistry and its relationship with exogenous/free HbαC, hydroxyl radical (·OH) formation via the Fenton Reaction (Fe2+ + H2O2 → Fe3+ + ·OH + OH), DNA damage (DNAD), and subsequent tumor formation). The Meharry-Vanderbilt alliance focuses on understanding iron chelation therapy for mitigating in vitro Fenton Reactions through a pharmaceutical approach. HbαC removal may be executed and accomplished using chelation therapy with chelating drugs, i.e., deferoxamine (DF), deferiprone (L1), and flavonoids [103][104], to attenuate HbαC toxicity.

6.1. Haptoglobin (Hp)

Free haptoglobin is removed from plasma in 3.5–5 days. On the other hand, the haptoglobin–hemoglobin (Hp-Hb) complex is removed within 20 min. This known fact stresses the importance of Hb removal in the presence of Hp. Haptoglobin is a tetrameric protein, a polymer built of four monomer units that contains two light (α) and two heavy (β) chains covalently bound to each other via disulfide bridges. There are three Hp phenotypes: Hp1-1, Hp2-1, and Hp2-2. Haptoglobin polymorphism occurs due to variations in the α-chain; the α-1 chain carries 83 amino acids and the α-2 chain accommodates 142 amino acids. The β-chain encompasses 245 amino acids and is not polymorphic. Further research has proven that the ability of Hp to avoid damage inflicted by free radicals is largely phenotype-pendent. Various phenotypes have the same binding affinities, but the removal of Hp from the extravascular space is size-dependent and removal of the Hp1-1:Hb complex occurs more rapidly, while the Hp2-2:Hb complex is the largest and its removal occurs more slowly. Thus, when complexed with Hp2-2, Hb-α stays in the circulation predominantly and causes enormous oxidative stress via Fenton chemistry [99][105]. Additionally, the prevalence of Hp2 is higher in IBD patients, thus contributing to reduced anti-inflammatory effects and an increased risk of CACRC development in this population [106][107].

6.2. Deferoxamine (DFO)

Deferoxamine (DFO) is a hydrophilic iron-chelating agent that has been shown to inhibit free radical formation [108][109] and polymeric DFO for enhancing iron chelation cancer therapy. However, its hydrophilic properties limit its ability to cross cell membranes and remain effective in vivo. This feature alone requires higher concentrations and longer incubation periods of DFO in order to yield anti-inflammatory effects (inhibiting the Fe-dependent production of hydroxyl radicals) from the agent. Chelation therapy would remove excess exogenous iron from the body and prevent the production of hydroxyl radicals (−111). Further, antioxidants may also play an important role. Administering antioxidants would neutralize the free radicals and block their harmful effects on intestinal cells. Salicylaldehyde isonicotinoyl hydrazone (SIH) is a lipophilic iron-chelating agent that crosses cell membranes more effectively when compared to DFO, thus requiring lower concentrations and incubation periods to produce similar anti-inflammatory effects when compared to DFO.

6.3. Flavonoids

Flavonoids are free radical scavengers and confer a wide variety of antioxidant and anti-inflammatory activities [110]. Studies have shown that the enteroendocrine system is composed of enteroendocrine cells (EECs) that regulate IBD by monitoring the gut microbiota and controlling the immune response, thus safeguarding the intestines against physical obstacles, as well as modulating gut motility [111]. Flavonoids have an impact on the enteroendocrine system and safeguard it against IBD, which infers that the alleviation of IBD is possibly associated with the regulation of flavonoids in EECs. Presently, over 4000 multifarious flavonoids have been recognized and ascertained in the bright colors of many fruits and vegetables [112][113]. Further, a number of studies have reported the effect of flavonoids on enterohormone secretion; however, there are hardly any studies demonstrating the association between flavonoids, enterohormone secretion, and IBD. The interplay between flavonoids, enterohormones, and IBD is herein illuminated. Furthermore, the conclusion can be drawn that flavonoids may safeguard against IBD by regulating enterohormones, such as glucagon-like peptide 1 (GLP-1), GLP-2, dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors), ghrelin, and cholecystokinin (CCK), a possible mechanism of flavonoids protecting/ shielding against IBD [114].
The most likely way to reduce the incidence of oncological transformation related to IBD is via the clearance of excess exogenous HbαC from the interstitial space. However, this method remains limited until the malfunctioning claudin-1 in the extracellular matrix in the epithelial endothelium and connective tissue is resolved to prevent petechial hemorrhage. This would be the most solid preventive measure to circumvent CACRC development.


  1. Myers, J.N.; Schaffer, M.W.; Korolkova, O.Y.; Williams, A.D.; Gangula, P.R.; M’Koma, A.E. Implications of the Colonic Deposition of Free Hemoglobin-alpha Chain: A Previously Unknown Tissue By-product in Inflammatory Bowel Disease. Inflamm. Bowel Dis. 2014, 20, 1530–1547.
  2. Kruidenier, L.; Verspaget, H.W. Review article: Oxidative stress as a pathogenic factor in inflammatory bowel disease--radicals or ridiculous? Aliment. Pharm. Ther. 2002, 16, 1997–2015.
  3. D’Odorico, A.; Bortolan, S.; Cardin, R.; D’Inca, R.; Martines, D.; Ferronato, A.; Sturniolo, G.C. Reduced plasma antioxidant concentrations and increased oxidative DNA damage in inflammatory bowel disease. Scand. J. Gastroenterol. 2001, 36, 1289–1294.
  4. Krzystek-Korpacka, M.; Neubauer, K.; Berdowska, I.; Boehm, D.; Zielinski, B.; Petryszyn, P.; Terlecki, G.; Paradowski, L.; Gamian, A. Enhanced formation of advanced oxidation protein products in IBD. Inflamm. Bowel Dis. 2008, 14, 794–802.
  5. Boehm, D.; Krzystek-Korpacka, M.; Neubauer, K.; Matusiewicz, M.; Berdowska, I.; Zielinski, B.; Paradowski, L.; Gamian, A. Paraoxonase-1 status in Crohn’s disease and ulcerative colitis. Inflamm. Bowel Dis. 2009, 15, 93–99.
  6. Koutroubakis, I.E.; Malliaraki, N.; Dimoulios, P.D.; Karmiris, K.; Castanas, E.; Kouroumalis, E.A. Decreased total and corrected antioxidant capacity in patients with inflammatory bowel disease. Dig. Dis. Sci. 2004, 49, 1433–1437.
  7. de Lacerda, T.C.; Costa-Silva, B.; Giudice, F.S.; Dias, M.V.; de Oliveira, G.P.; Teixeira, B.L.; dos Santos, T.G.; Martins, V.R. Prion protein binding to HOP modulates the migration and invasion of colorectal cancer cells. Clin. Exp. Metastasis 2016, 33, 441–451.
  8. Nopel-Dunnebacke, S.; Conradi, L.C.; Reinacher-Schick, A.; Ghadimi, M. Influence of molecular markers on oncological surgery of colorectal cancer. Chirurg 2021, 92, 986–995.
  9. Ewing, I.; Hurley, J.J.; Josephides, E.; Millar, A. The molecular genetics of colorectal cancer. Frontline Gastroenterol. 2014, 5, 26–30.
  10. Rawla, P.; Sunkara, T.; Raj, J.P. Role of biologics and biosimilars in inflammatory bowel disease: Current trends and future perspectives. J. Inflamm. Res. 2018, 11, 215–226.
  11. Rawla, P.; Sunkara, T.; Barsouk, A. Epidemiology of colorectal cancer: Incidence, mortality, survival, and risk factors. Prz. Gastroenterol. 2019, 14, 89–103.
  12. M’Koma, A.E.; Moses, H.L.; Adunyah, S.E. Inflammatory bowel disease-associated colorectal cancer: Proctocolectomy andmucosectomy does not necessarily eliminate pouch related cancer incidences. Int. J. Color. Dis. 2011, 26, 533–552.
  13. Marynczak, K.; Wlodarczyk, J.; Sabatowska, Z.; Dziki, A.; Dziki, L.; Wlodarczyk, M. Colitis-Associated Colorectal Cancer in Patients with Inflammatory Bowel Diseases in a Tertiary Referral Center: A Propensity Score Matching Analysis. J. Clin. Med. 2022, 11, 866.
  14. Lucafo, M.; Curci, D.; Franzin, M.; Decorti, G.; Stocco, G. Inflammatory Bowel Disease and Risk of Colorectal Cancer: An Overview From Pathophysiology to Pharmacological Prevention. Front. Pharmacol. 2021, 12, 772101.
  15. Schmitt, M.; Greten, F.R. The inflammatory pathogenesis of colorectal cancer. Nat. Rev. Immunol. 2021, 21, 653–667.
  16. M’Koma, A.E. The Multifactorial Etiopathogeneses Interplay of Inflammatory Bowel Disease: An Overview. Gastrointest. Disord. 2018, 1, 75–105.
  17. Liu, J.Z.; van Sommeren, S.; Huang, H.; Ng, S.C.; Alberts, R.; Takahashi, A.; Ripke, S.; Lee, J.C.; Jostins, L.; Shah, T.; et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat. Genet. 2015, 47, 979–986.
  18. Satsangi, J.; Silverberg, M.S.; Vermeire, S.; Colombel, J.F. The Montreal classification of inflammatory bowel disease: Controversies, consensus, and implications. Gut 2006, 55, 749–753.
  19. Spekhorst, L.M.; Visschedijk, M.C.; Alberts, R.; Festen, E.A.; van der Wouden, E.J.; Dijkstra, G.; Dutch Initiative on Crohn and Colitis. Performance of the Montreal classification for inflammatory bowel diseases. World J. Gastroenterol. 2014, 20, 15374–15381.
  20. Benchimol, E.I.; Fortinsky, K.J.; Gozdyra, P.; Van den Heuvel, M.; Van Limbergen, J.; Griffiths, A.M. Epidemiology of pediatric inflammatory bowel disease: A systematic review of international trends. Inflamm. Bowel Dis. 2011, 17, 423–439.
  21. Kofla-Dlubacz, A.; Pytrus, T.; Akutko, K.; Sputa-Grzegrzolka, P.; Piotrowska, A.; Dziegiel, P. Etiology of IBD-Is It Still a Mystery? Int. J. Mol. Sci. 2022, 23, 12445.
  22. Pena-Sanchez, J.N.; Osei, J.A.; Marques Santos, J.D.; Jennings, D.; Andkhoie, M.; Brass, C.; Bukassa-Kazadi, G.; Lu, X.; Johnson-Jennings, M.; Porter, L.; et al. Increasing Prevalence and Stable Incidence Rates of Inflammatory Bowel Disease Among First Nations: Population-Based Evidence From a Western Canadian Province. Inflamm. Bowel Dis. 2022, 28, 514–522.
  23. Jones, G.R.; Lyons, M.; Plevris, N.; Jenkinson, P.W.; Bisset, C.; Burgess, C.; Din, S.; Fulforth, J.; Henderson, P.; Ho, G.-T.; et al. IBD prevalence in Lothian, Scotland, derived by capture-recapture methodology. Gut 2019, 68, 1953–1960.
  24. M’Koma, A.E. Inflammatory Bowel Disease: An Expanding Global Health Problem. Clin. Med. Insights Gastroenterol. 2013, 6, 33–47.
  25. Benchimol, E.I.; Manuel, D.G.; Guttmann, A.; Nguyen, G.C.; Mojaverian, N.; Quach, P.; Mack, D.R. Changing age demographics of inflammatory bowel disease in Ontario, Canada: A population-based cohort study of epidemiology trends. Inflamm. Bowel Dis. 2014, 20, 1761–1769.
  26. Krzesiek, E.; Kofla-Dlubacz, A.; Akutko, K.; Stawarski, A. The Incidence of Inflammatory Bowel Disease in the Paediatric Population in the District of Lower Silesia, Poland. J. Clin. Med. 2021, 10, 3994.
  27. Cosnes, J.; Gower-Rousseau, C.; Seksik, P.; Cortot, A. Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology 2011, 140, 1785–1794.
  28. Ananthakrishnan, A.N.; Kaplan, G.G.; Ng, S.C. Changing Global Epidemiology of Inflammatory Bowel Diseases: Sustaining Health Care Delivery Into the 21st Century. Clin. Gastroenterol. Hepatol. 2020, 18, 1252–1260.
  29. Ng, S.C.; Shi, H.Y.; Hamidi, N.; Underwood, F.E.; Tang, W.; Benchimol, E.I.; Panaccione, R.; Ghosh, S.; Wu, J.C.Y.; Chan, F.K.L.; et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: A systematic review of population-based studies. Lancet 2017, 390, 2769–2778.
  30. Coward, S.; Clement, F.; Benchimol, E.I.; Bernstein, C.N.; Avina-Zubieta, J.A.; Bitton, A.; Carroll, M.W.; Hazlewood, G.; Jacobson, K.; Jelinski, S.; et al. Past and Future Burden of Inflammatory Bowel Diseases Based on Modeling of Population-Based Data. Gastroenterology 2019, 156, 1345–1353.
  31. Ng, S.C.; Tang, W.; Ching, J.Y.; Wong, M.; Chow, C.M.; Hui, A.J.; Wong, T.C.; Leung, V.K.; Tsang, S.W.; Yu, H.H.; et al. Incidence and phenotype of inflammatory bowel disease based on results from the Asia-pacific Crohn’s and colitis epidemiology study. Gastroenterology 2013, 145, 158–165.e2.
  32. Archampong, T.N.; Nkrumah, K.N. Inflammatory bowel disease in Accra: What new trends. West. Afr. J. Med. 2013, 32, 40–44.
  33. Ukwenya, A.Y.; Ahmed, A.; Odigie, V.I.; Mohammed, A. Inflammatory bowel disease in Nigerians: Still a rare diagnosis? Ann. Afr. Med. 2011, 10, 175–179.
  34. Agoda-Koussema, L.K.; Anoukoum, T.; Djibril, A.M.; Balaka, A.; Folligan, K.; Adjenou, V.; Amouzou, K.; N’dakéna, K.; Redah, R. Ulcerative colitis: A case in Togo. Med. St. Trop. 2012, 22, 79–81.
  35. Mebazaa, A.; Aounallah, A.; Naija, N.; Cheikh Rouhou, R.; Kallel, L.; El Euch, D.; Boubaker, J.; Mokni, M.; Filali, A.; Ben Osman, A. Dermatologic manifestations in inflammatory bowel disease in Tunisia. Tunis. Med. 2012, 90, 252–257.
  36. Senbanjo, I.O.; Oshikoya, K.A.; Onyekwere, C.A.; Abdulkareem, F.B.; Njokanma, O.F. Ulcerative colitis in a Nigerian girl: A case report. BMC Res. Notes 2012, 5, 564.
  37. Bouzid, D.; Fourati, H.; Amouri, A.; Marques, I.; Abida, O.; Haddouk, S.; Ben Ayed, M.; Tahri, N.; Penha-Gonçalves, C.; Masmoudi, H. The CREM gene is involved in genetic predisposition to inflammatory bowel disease in the Tunisian population. Hum. Immunol. 2011, 72, 1204–1209.
  38. O’Keefe, E.A.; Wright, J.P.; Froggatt, J.; Cuming, L.; Elliot, M. Medium-term follow-up of ulcerative colitis in Cape Town. S. Afr. Med. J. 1989, 76, 142–145.
  39. O’Keefe, E.A.; Wright, J.P.; Froggatt, J.; Zabow, D. Medium-term follow-up of Crohn’s disease in Cape Town. S. Afr. Med. J. 1989, 76, 139–141.
  40. Segal, I. Ulcerative colitis in a developing country of Africa: The Baragwanath experience of the first 46 patients. Int. J. Color. Dis. 1988, 3, 222–225.
  41. Segal, I.; Tim, L.O.; Hamilton, D.G.; Walker, A.R. The rarity of ulcerative colitis in South African blacks. Am. J. Gastroenterol. 1980, 74, 332–336.
  42. Wright, J.P.; Marks, I.N.; Jameson, C.; Garisch, J.A.; Burns, D.G.; Kottler, R.E. Inflammatory bowel disease in Cape Town, 1975-1980. Part II. Crohn’s disease. S. Afr. Med. J. 1983, 63, 226–229.
  43. Wright, J.P.; Marks, I.N.; Jameson, C.; Garisch, J.A.; Burns, D.G.; Kottler, R.E. Inflammatory bowel disease in Cape Town, 1975-1980. Part I. Ulcerative colitis. S. Afr. Med. J. 1983, 63, 223–226.
  44. Brom, B.; Bank, S.; Marks, I.N.; Barbezat, G.O.; Raynham, B. Crohn’s disease in the Cape: A follow-up study of 24 cases and a review of the diagnosis and management. S. Afr. Med. J. 1968, 42, 1099–1107.
  45. Novis, B.H.; Marks, I.N.; Bank, S.; Louw, J.H. Incidence of Crohn’s disease at Groote Schuur Hospital during 1970–1974. S. Afr. Med. J. 1975, 49, 693–697.
  46. Sobel, J.D.; Schamroth, L. Ulcerative colitis in the South African Bantu. Gut 1970, 11, 760–763.
  47. Giraud, R.M.; Luke, I.; Schmaman, A. Crohn’s disease in the Transvaal Bantu: A report of 5 cases. S. Afr. Med. J. 1969, 43, 610–613.
  48. Ananthakrishnan, A.N.; Kwon, J.; Raffals, L.; Sands, B.; Stenson, W.F.; McGovern, D.; Kwon, J.H.; Rheaume, R.L.; Sandler, R.S. Variation in treatment of patients with inflammatory bowel diseases at major referral centers in the United States. Clin. Gastroenterol. Hepatol. 2015, 13, 1197–1200.
  49. Kappelman, M.D.; Rifas-Shiman, S.L.; Porter, C.Q.; Ollendorf, D.A.; Sandler, R.S.; Galanko, J.A.; Finkelstein, J.A. Direct health care costs of Crohn’s disease and ulcerative colitis in US children and adults. Gastroenterology 2008, 135, 1907–1913.
  50. Siegmund, B.; Zeitz, M. Inflammatory bowel disease and pregnancy. Z. Gastroenterol. 2009, 47, 1069–1074.
  51. Molodecky, N.A.; Soon, I.S.; Rabi, D.M.; Ghali, W.A.; Ferris, M.; Chernoff, G.; Benchimol, E.I.; Panaccione, R.; Ghosh, S.; Barkema, H.W.; et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 2012, 142, 46–54.e42.
  52. Chouraki, V.; Savoye, G.; Dauchet, L.; Vernier-Massouille, G.; Dupas, J.L.; Merle, V.; Laberenne, J.-E.; Salomez, J.-L.; Lerebours, E.; Turck, D.; et al. The changing pattern of Crohn’s disease incidence in northern France: A continuing increase in the 10- to 19-year-old age bracket (1988–2007). Aliment. Pharm. Ther. 2011, 33, 1133–1142.
  53. Shmidt, E.; Dubinsky, M.C. Inflammatory Bowel Disease and Pregnancy. Am. J. Gastroenterol. 2022, 117, 60–68.
  54. Baiocco, P.J.; Korelitz, B.I. The influence of inflammatory bowel disease and its treatment on pregnancy and fetal outcome. J. Clin. Gastroenterol. 1984, 6, 211–216.
  55. Heetun, Z.S.; Byrnes, C.; Neary, P.; O’Morain, C. Review article: Reproduction in the patient with inflammatory bowel disease. Aliment. Pharm. Ther. 2007, 26, 513–533.
  56. Vermeire, S.; Carbonnel, F.; Coulie, P.G.; Geenen, V.; Hazes, J.M.; Masson, P.L.; De Keyser, F.; Louis, E. Management of inflammatory bowel disease in pregnancy. J. Crohns Colitis 2012, 6, 811–823.
  57. Jakobsen, C.; Paerregaard, A.; Munkholm, P.; Faerk, J.; Lange, A.; Andersen, J.; Jakobsen, M.; Kramer, I.; Czernia-Mazurkiewicz, J.; Wewer, V. Pediatric inflammatory bowel disease: Increasing incidence, decreasing surgery rate, and compromised nutritional status: A prospective population-based cohort study 2007–2009. Inflamm. Bowel Dis. 2011, 17, 2541–2550.
  58. North American Society for Pediatric Gastroenterology; Hepatology, and Nutrition; Colitis Foundation of America; Bousvaros, A.; Antonioli, D.A.; Colletti, R.B.; Dubinsky, M.C.; Glickman, J.N.; Gold, B.D.; Griffiths, A.M. Differentiating ulcerative colitis from Crohn disease in children and young adults: Report of a working group of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the Crohn’s and Colitis Foundation of America. J. Pediatr. Gastroenterol. Nutr. 2007, 44, 653–674.
  59. Griffiths, A.M. Specificities of inflammatory bowel disease in childhood. Best Pract. Res. Clin. Gastroenterol. 2004, 18, 509–523.
  60. Wang, Y.R.; Loftus, E.V.; Jr Cangemi, J.R.; Picco, M.F. Racial/Ethnic and regional differences in the prevalence of inflammatory bowel disease in the United States. Digestion 2013, 88, 20–25.
  61. Afzali, A.; Cross, R.K. Racial and Ethnic Minorities with Inflammatory Bowel Disease in the United States: A Systematic Review of Disease Characteristics and Differences. Inflamm. Bowel Dis. 2016, 22, 2023–2040.
  62. Li, D.; Collins, B.; Velayos, F.S.; Liu, L.; Lewis, J.D.; Allison, J.E.; Flowers, N.T.; Hutfless, S.; Abramson, O.; Herrinton, L.J. Racial and ethnic differences in health care utilization and outcomes among ulcerative colitis patients in an integrated health-care organization. Dig. Dis. Sci. 2014, 59, 287–294.
  63. Castaneda, G.; Liu, B.; Torres, S.; Bhuket, T.; Wong, R.J. Race/Ethnicity-Specific Disparities in the Severity of Disease at Presentation in Adults with Ulcerative Colitis: A Cross-Sectional Study. Dig. Dis. Sci. 2017, 62, 2876–2881.
  64. Avalos, D.J.; Mendoza-Ladd, A.; Zuckerman, M.J.; Bashashati, M.; Alvarado, A.; Dwivedi, A.; Damas, O.M. Hispanic Americans and Non-Hispanic White Americans Have a Similar Inflammatory Bowel Disease Phenotype: A Systematic Review with Meta-Analysis. Dig. Dis. Sci. 2018, 63, 1558–1571.
  65. Hou, J.K.; El-Serag, H.; Thirumurthi, S. Distribution and manifestations of inflammatory bowel disease in Asians, Hispanics, and African Americans: A systematic review. Am. J. Gastroenterol. 2009, 104, 2100–2109.
  66. Ventham, N.T.; Kennedy, N.A.; Nimmo, E.R.; Satsangi, J. Beyond gene discovery in inflammatory bowel disease: The emerging role of epigenetics. Gastroenterology 2013, 145, 293–308.
  67. Price, A.B. Overlap in the spectrum of non-specific inflammatory bowel disease--’colitis indeterminate’. J Clin Pathol. 1978, 31, 567–577.
  68. Farmer, M.; Petras, R.E.; Hunt, L.E.; Janosky, J.E.; Galandiuk, S. The importance of diagnostic accuracy in colonic inflammatory bowel disease. Am. J. Gastroenterol. 2000, 95, 3184–3188.
  69. Kader, H.A.; Tchernev, V.T.; Satyaraj, E.; Lejnine, S.; Kotler, G.; Kingsmore, S.F.; Patel, D.D. Protein microarray analysis of disease activity in pediatric inflammatory bowel disease demonstrates elevated serum PLGF, IL-7, TGF-beta1, and IL-12p40 levels in Crohn’s disease and ulcerative colitis patients in remission versus active disease. Am. J. Gastroenterol. 2005, 100, 414–423.
  70. Burczynski, M.E.; Peterson, R.L.; Twine, N.C.; Zuberek, K.A.; Brodeur, B.J.; Casciotti, L.; Maganti, V.; Reddy, P.S.; Strahs, A.; Immermann, F.; et al. Molecular classification of Crohn’s disease and ulcerative colitis patients using transcriptional profiles in peripheral blood mononuclear cells. J. Mol. Diagn. 2006, 8, 51–61.
  71. Fukushima, K.; Yonezawa, H.; Fiocchi, C. Inflammatory bowel disease-associated gene expression in intestinal epithelial cells by differential cDNA screening and mRNA display. Inflamm. Bowel Dis. 2003, 9, 290–301.
  72. Shkoda, A.; Werner, T.; Daniel, H.; Gunckel, M.; Rogler, G.; Haller, D. Differential protein expression profile in the intestinal epithelium from patients with inflammatory bowel disease. J. Proteome Res. 2007, 6, 1114–1125.
  73. Horio, Y.; Uchino, M.; Babdo, T.; Sasaki, H.; Goto, Y.; Kuwahara, R.; Minagawa, T.; Takesue, Y.; Ikeuchi, H. Incidence, Risk Factors and Outcomes of Cancer of the Anal Transit Zone in Patients with Ulcerative Colitis. J. Crohns Colitis 2020, 14, 1165–1571.
  74. Hardy, R.G.; Meltzer, S.J.; Jankowski, J.A. ABC of colorectal cancer. Molecular basis for risk factors. BMJ 2000, 321, 886–889.
  75. Rubin, D.T.; Parekh, N. Colorectal cancer in inflammatory bowel disease: Molecular and clinical considerations. Curr. Treat. Options Gastroenterol. 2006, 9, 211–220.
  76. Eaden, J.A.; Abrams, K.R.; Mayberry, J.F. The risk of colorectal cancer in ulcerative colitis: A meta-analysis. Gut 2001, 48, 526–535.
  77. Harpaz, N.; Talbot, I.C. Colorectal cancer in idiopathic inflammatory bowel disease. Semin. Diagn. Pathol. 1996, 13, 339–357.
  78. Rubio, C.A.; Befrits, R.; Ljung, T.; Jaramillo, E.; Slezak, P. Colorectal carcinoma in ulcerative colitis is decreasing in Scandinavian countries. Anticancer. Res. 2001, 21, 2921–2924.
  79. Loftus, E.V., Jr. Epidemiology and risk factors for colorectal dysplasia and cancer in ulcerative colitis. Gastroenterol. Clin. N. Am. 2006, 35, 517–531.
  80. Delaunoit, T.; Limburg, P.J.; Goldberg, R.M.; Lymp, J.F.; Loftus, E.V., Jr. Colorectal cancer prognosis among patients with inflammatory bowel disease. Clin. Gastroenterol. Hepatol. 2006, 4, 335–342.
  81. Keller, D.S.; Windsor, A.; Cohen, R.; Chand, M. Colorectal cancer in inflammatory bowel disease: Review of the evidence. Tech. Coloproctol. 2019, 23, 3–13.
  82. Khan, M.A.; Hakeem, A.R.; Scott, N.; Saunders, R.N. Significance of R1 resection margin in colon cancer resections in the modern era. Color. Dis. 2015, 17, 943–953.
  83. Canavan, C.; Abrams, K.R.; Mayberry, J. Meta-analysis: Colorectal and small bowel cancer risk in patients with Crohn’s disease. Aliment. Pharm. Ther. 2006, 23, 1097–1104.
  84. Stidham, R.W.; Higgins, P.D.R. Colorectal Cancer in Inflammatory Bowel Disease. Clin. Colon Rectal Surg. 2018, 31, 168–178.
  85. Munkholm, P. Review article: The incidence and prevalence of colorectal cancer in inflammatory bowel disease. Aliment. Pharm. Ther. 2003, 18 (Suppl. S2), 1–5.
  86. Axelrad, J.E.; Lichtiger, S.; Yajnik, V. Inflammatory bowel disease and cancer: The role of inflammation, immunosuppression, and cancer treatment. World J. Gastroenterol. 2016, 22, 4794–4801.
  87. Baker, A.M.; Cross, W.; Curtius, K.; Al Bakir, I.; Choi, C.R.; Davis, H.L.; Temko, D.; Biswas, S.; Martinez, P.; Williams, M.; et al. Evolutionary history of human colitis-associated colorectal cancer. Gut 2019, 68, 985–995.
  88. Um, J.W.; M’Koma, A.E. Pouch-related dysplasia and adenocarcinoma following restorative proctocolectomy for ulcerative colitis. Tech. Coloproctol. 2011, 15, 7–16.
  89. Gallo, G.; Kotze, P.G.; Spinelli, A. Surgery in ulcerative colitis: When? How? Best Pract. Res. Clin. Gastroenterol. 2018, 32–33, 71–78.
  90. Yashiro, M. Ulcerative colitis-associated colorectal cancer. World J. Gastroenterol. 2014, 20, 16389–16397.
  91. Stjarngrim, J.; Widman, L.; Schmidt, P.T.; Ekbom, A.; Forsberg, A. Post-endoscopy colorectal cancer after colectomy in inflammatory bowel disease patients: A population-based register study. Eur. J. Gastroenterol. Hepatol. 2023, 35, 288–293.
  92. Vleggaar, F.P.; Lutgens, M.W.; Oldenburg, B.; Schipper, M.E.; Samsom, M. British and American screening guidelines inadequate for prevention of colorectal carcinoma in patients with inflammatory bowel disease. Ned. Tijdschr. Geneeskd. 2007, 151, 2787–2791.
  93. M’Koma, A.E.; Seeley, E.H.; Wise, P.E.; Washingtoin, M.K.; Schwartz, D.A.; Herline, A.J.; Muldon, R.L.; Caprioli, R.M. Proteomic analysis of colonic submucosa differentiates Crohn’s and ulcerative colitis. Gastroenterology 2009, 136 (Suppl. S1), A-349.
  94. M’Koma, A.E.; Seeley, E.H.; Washington, M.K.; Schwartz, D.A.; Muldoon, R.L.; Herline, A.J.; Wise, P.E.; Caprioli, R.M. Proteomic profiling of mucosal and submucosal colonic tissues yields protein signatures that differentiate the inflammatory colitides. Inflamm. Bowel Dis. 2011, 17, 875–883.
  95. Seeley, E.H.; Washington, M.K.; Caprioli, R.M.; M’Koma, A.E. Proteomic patterns of colonic mucosal tissues delineate Crohn’s colitis and ulcerative colitis. Proteom. Clin. Appl. 2013, 7, 541–549.
  96. Steed, E.; Balda, M.S.; Matter, K. Dynamics and functions of tight junctions. Trends Cell Biol. 2010, 20, 142–149.
  97. Weber, C.R.; Nalle, S.C.; Tretiakova, M.; Rubin, D.T.; Turner, J.R. Claudin-1 and claudin-2 expression is elevated in inflammatory bowel disease and may contribute to early neoplastic transformation. Lab. Investig. 2008, 88, 1110–1120.
  98. Steed, E.; Rodrigues, N.T.; Balda, M.S.; Matter, K. Identification of MarvelD3 as a tight junction-associated transmembrane protein of the occludin family. BMC Cell Biol. 2009, 10, 95.
  99. Caillet, S.; Yu, H.; Lessard, S.; Lamoureux, G.; Ajdukovic, D.; Lacroix, M. Fenton reaction applied for screening natural antioxidants. Food Chem. 2007, 100, 542–552.
  100. Porter, R.J.; Arends, M.J.; Churchhouse, A.M.D.; Din, S. Inflammatory Bowel Disease-Associated Colorectal Cancer: Translational Risks from Mechanisms to Medicines. J. Crohns Colitis 2021, 15, 2131–2141.
  101. Zielinska, A.K.; Salaga, M.; Siwinski, P.; Wlodarczyk, M.; Dziki, A.; Fichna, J. Oxidative Stress Does Not Influence Subjective Pain Sensation in Inflammatory Bowel Disease Patients. Antioxidants 2021, 10, 1237.
  102. Mrowicka, M.; Mrowicki, J.; Mik, M.; Dziki, L.; Dziki, A.; Majsterek, I. Assessment of DNA damage profile and oxidative /antioxidative biomarker level in patients with inflammatory bowel disease. Pol. Prz. Chir. 2020, 92, 8–15.
  103. Kontoghiorghes, G.J.; Pattichi, K.; Hadjigavriel, M.; Kolnagou, A. Transfusional iron overload and chelation therapy with deferoxamine and deferiprone (L1). Transfus. Sci. 2000, 23, 211–223.
  104. Szymonik, J.; Wala, K.; Gornicki, T.; Saczko, J.; Pencakowski, B.; Kulbacka, J. The Impact of Iron Chelators on the Biology of Cancer Stem Cells. Int. J. Mol. Sci. 2021, 23, 89.
  105. Tayari, M.; Afsharzadeh, D. Amplification of antioxidant activity of haptoglobin(2-2)-hemoglobin at pathologic temperature and presence of antibiotics. Indian J. Clin. Biochem. 2012, 27, 171–177.
  106. Babbs, C.F. Oxygen radicals in ulcerative colitis. Free. Radic. Biol. Med. 1992, 13, 169–181.
  107. Marquez, L.; Shen, C.; Machiels, K.; Perrier, C.; Ballet, V.; Organe, S. Role of Haptoglobin in Susceptibility of IBD and in Triggering Murine Colitis. Gastroenterology 2011, 140, S28.
  108. Meczynska, S.; Lewandowska, H.; Sochanowicz, B.; Sadlo, J.; Kruszewski, M. Variable inhibitory effects on the formation of dinitrosyl iron complexes by deferoxamine and salicylaldehyde isonicotinoyl hydrazone in K562 cells. Hemoglobin 2008, 32, 157–163.
  109. Martino, E.A.; Mendicino, F.; Lucia, E.; Olivito, V.; Bova, C.; Filippelli, G.; Capodanno, I.; Neri, A.; Morabito, F.; Gentile, M.; et al. Iron chelation therapy. Eur. J. Haematol. 2023, 110, 490–497.
  110. Zhao, Q.; Liu, Y.; Wang, X.; Zhu, Y.; Jiao, Y.; Bao, Y.; Shi, W. Cuscuta chinensis flavonoids reducing oxidative stress of the improve sperm damage in 35 bisphenol A exposed mice offspring. Ecotoxicol. Environ. Saf. 2023, 255, 114831.
  111. Yu, Y.; Yang, W.; Li, Y.; Cong, Y. Enteroendocrine Cells: Sensing Gut Microbiota and Regulating Inflammatory Bowel Diseases. Inflamm. Bowel Dis. 2020, 26, 11–20.
  112. Nijveldt, R.J.; van Nood, E.; van Hoorn, D.E.; Boelens, P.G.; van Norren, K.; van Leeuwen, P.A. Flavonoids: A review of probable mechanisms of action and potential applications. Am. J. Clin. Nutr. 2001, 74, 418–425.
  113. Ribeiro, D.; Proenca, C.; Rocha, S.; Lima, J.; Carvalho, F.; Fernandes, E.; Freitas, M. Immunomodulatory Effects of Flavonoids in the Prophylaxis and Treatment of Inflammatory Bowel Diseases: A Comprehensive Review. Curr. Med. Chem. 2018, 25, 3374–3412.
  114. Li, M.; Weigmann, B. A Novel Pathway of Flavonoids Protecting against Inflammatory Bowel Disease: Modulating Enteroendocrine System. Metabolites 2022, 12, 31.
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