Evaluating spleen volume in inflammatory bowel disease

Introduction

Inflammatory bowel disease (IBD), encompassing Crohn’s disease (CD) and ulcerative colitis (UC), refers to a group of chronic, relapsing inflammatory diseases of the gastrointestinal tract [1]. CD can affect any part of the digestive system, from the mouth to the anus, whereas UC affects the colon [2,3]. Over the past 2 decades, the global incidence and prevalence of IBD have risen significantly, reflecting its growing impact on public health [4,5].

UC and CD are immune-mediated diseases that arise from a complex interplay of genetic, environmental, microbial and immunological factors [6-9]. Although the intestine remains the primary site of pathology, IBD is increasingly recognized as a systemic disease with a wide range of extraintestinal manifestations, highlighting the broader immune dysregulation that characterizes IBD [10,11]. Among the organs involved in immune function, the spleen holds a primary role in modulating systemic inflammation and immune responses in various autoimmune diseases [12]. Secondary spleen involvement and/or splenomegaly in patients with IBD have been described in cases of portal hypertension, myeloproliferative diseases, cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections, amyloidosis, splenic abscesses, and splenic granulomas [13-20].

However, data regarding the direct relationship between IBD and spleen volume (SV) remain scarce. Recent advances in imaging and immunological techniques have increased scientific interest in the spleen’s role as an immune system modulator in IBD [21]. Changes in SV can may offer valuable insights into disease activity, severity, and response to current biologic therapies [20-23].

This present review aims to summarize the current evidence on splenic volumetric changes in IBD patients and explore potential associations with clinical outcomes, as outlined in the existing literature.

Materials and methods

We performed an in-depth review of the literature in ResearchGate, Google Scholar PubMed, EMBASE, Cochrane Library, Clinicaltrials.gov and Scopus up to March 2025. Keywords and phrases used included “spleen”, “spleen volume”, “splenic size”, “spleen enlargement”, “spleen features”, “splenomegaly”, “inflammatory bowel disease”, “Crohn’s disease” and “Ulcerative colitis”. Inclusion criteria in the final review were: a) articles investigating the direct relationship between SV and IBD; and b) full articles, as well as articles in research letter form. Exclusion criteria were: a) articles that included animal models; and b) articles in abstract form.

Results

Nine studies met the inclusion criteria and were included in the final literature review [22-30]. Five studies were retrospective [22-26], while 2 studies were prospective [27,28]. It is important to note that 6 of the 7 aforementioned studies excluded patients with causes of SV alterations other than IBD [22-24,26-28]. Additionally, 2 studies included Mendelian randomization analyses [29,30]. The 9 included studies described various imaging techniques—such as computed tomography (CT) scans, abdominal ultrasound and magnetic resonance imaging—as well as genetic data from genome-wide association studies (GWAS) to assess the SV in correlation with IBD presence, activity, clinical outcomes and response to biologic treatment. Pereira et al conducted a prospective study involving 115 IBD patients undergoing laparotomy, where spleen size was measured during surgery [27]. They found no correlation between spleen size and disease site, extent or recurrence, but patients with CD were more likely to have enlarged spleens compared to those with UC. Smaller spleen sizes in both CD and UC were linked to more severe disease complications [27]. Muller et al also performed a prospective study using ultrasound in 50 IBD patients [28]. Although they did not define a specific cutoff for spleen size, they observed that patients with relapsing UC tended to have smaller spleens than those with controlled disease (P<0.01) [28]. Balaban et al conducted a retrospective study of 52 IBD patients, defining small spleens as less than 95 mm in length [24]. They found small spleens in 10% of CD patients and 21.9% of UC patients [24]. Kawashima et al carried out a single-center retrospective case–control study using CT scans [22]. They reported significantly larger SVs in CD patients (3.6±1.7 cm³/kg) compared to controls (2.2±1.0 cm³/kg; P=0.01), while no significant difference was seen in UC patients [22]. They also found a significant correlation between SV and CD disease activity (P<0.01) [22]. Khasper et al used CT imaging in a retrospective study of 90 CD patients [25]. While SV did not differ between active and inactive CD, the ratio of SV to body mass index (BMI) was significantly higher in active disease (15.26 vs. 11.69; P=0.004) [25]. Shi et al analyzed CT data from 49 CD patients treated with infliximab [23]. Responders showed significant reductions in SV (P<0.001) and SV/BMI ratio (P<0.001) [23]. In contrast, non-responders had increases in both SV and SV/BMI [23]. Additionally, SV/BMI was positively correlated with C-reactive protein (CRP) and tumor necrosis factor-alpha (TNF-α) levels [23]. Azam et al performed a retrospective study on 100 CD patients using CT scans [26]. They found that the SV/BMI ratio correlated with perianal disease severity (P=0.009) and disease duration (P=0.014) [26]. Elevated SV was also linked to worsen clinical outcomes, such as higher risk of bowel resection (odds ratio [OR] 1.184, P=0.03) and frequent flares (OR 1.089, P=0.05) [26]. Song et al conducted a 2-sample Mendelian randomization study using large GWAS datasets [29]. They found that a greater genetically predicted SV was associated with a higher risk of developing CD (OR 1.237, 95%CI 1.056-1.417; P=0.021 in the Integrative Epidemiology Unit dataset; OR 1.292, 95%CI 1.120-1.463; P=0.003 in the European Bioinformatics Institute dataset) [29]. They also showed that CD mildly increases SV (OR 1.009, 95%CI 1.000-1.018; P=0.047) [29]. Finally, Su et al performed a Mendelian randomization meta-analysis [30]. Their results indicated that increased SV is genetically associated with a higher risk of both UC and CD [30]. Each standard unit increase in SV raised the risk for UC by 11.5% (OR 1.115, 95%CI 1.014-1.227; P=0.025) and for CD by 27.2% (OR 1.272, 95%CI 1.133-1.428; P<0.001) [30]. Table 1 presents the characteristics of the observational (non-Mendelian) studies evaluating SV alterations in IBD patients, Table 2 displays the Mendelian randomization analyses exploring the bidirectional association between SV and IBD, and Table 3 presents studies that examined the correlation between SV disease activity in UC and CD.

Table 1 Characteristics of observational (non-Mendelian) studies evaluating spleen volume alterations in patients with IBD

Table 2 Mendelian randomization analyses investigating the bidirectional association between spleen volume and IBD

Table 3 Correlation between spleen volume and disease activity in CD and UC

Discussion

Splenic function and volume can be significantly altered in gastrointestinal diseases that have a strong immunological substrate, such as celiac disease and IBD [24,31]. Both CD and UC have been associated with hyposplenism, as demonstrated by elevated pitted erythrocyte counts under differential interference contrast microscopy and reductions in immunoglobulin M levels [21,32,33]. Hyposplenism observed in IBD is reversible after successful treatment with biologics [21]. Splenic function impairment often corresponds with a reduction in spleen size [24,27,28]. Several pathogenic mechanisms have been proposed to explain splenic atrophy and dysfunction in IBD [27]. These include intense chronic immune activation—particularly in cases of pancolitis—as well as the systemic effects of absorbed bowel toxins [27]. In both CD and UC, small SV is associated with complications such as abscesses, fistulas, perforation, bleeding and toxic megacolon [27]. In CD, small spleens are further associated with a higher risk of perioperative and postoperative infections and complications [27]. In UC, smaller SVs are more frequently observed in patients with relapsing pancolitis, possibly due to circulating immune complexes that impair the function of the splenic reticuloendothelial system [28]. Given the increased susceptibility to infections in patients with reduced splenic function, it is reasonable that patients with IBD and small SV—possibly indicative of hyposplenism—should receive vaccinations and prophylactic antibiotics, following protocols similar to those accredited for post-splenectomy patients [28].

Interestingly, no significant correlation has been established between a small spleen size and the anatomical extent of CD [27,28]. This may be partly due to the fact that most studies investigating SV in CD have described splenomegaly rather than splenic atrophy [20,22,24-27,29]. Patients with CD present larger spleens than those with UC, as CD can affect a more extensive part of the gastrointestinal tract and deeper intestinal layers compared to UC [22,34]. It should be noted that studies addressing SV in UC predominantly report a reduction in spleen size [24,27,28]. In addition, there are data that indicate no substantial change in SV in UC patients compared to healthy controls [22]. Table 4 summarizes the studies that investigated differences in SV between CD and UC.

Table 4 Differences in spleen volume between Crohn’s disease (CD) and ulcerative colitis (UC)

One major limitation in early studies by Pereira and Muller et al, is the lack of adjustment of SV for patients’ body weight or BMI, both of which are important factors influencing spleen size [27,28,35]. The first study that adjusted SV for the body weight was reported by Kawashima et al, and revealed a positive correlation between SV and CD activity [22]. Nevertheless, the study’s retrospective, single-center design and small sample size were major limitations [22]. Subsequently, Khasper et al introduced the SV/BMI ratio, proposing that values above 14 may serve as a potential marker of active CD [25]. In their study, the average SV did not differ significantly between patients with active and inactive CD (Table 3) [25]. This lack of statistical significance may be attributed to the small sample size, as well as the potential influence of non-cirrhotic portal hypertension, which affects up to 1% of patients with IBD and can contribute to spleen enlargement [25]. However, when SV was adjusted for BMI, a significant difference emerged: patients with active CD had a markedly higher SV/BMI ratio (15.26±4.86) compared to those with inactive disease (11.69±5.19, P=0.004) (Table 3) [25]. The recent work by Azam et al further correlated the elevated SV/BMI ratio with complicated phenotypes of CD, such as structuring and penetrating disease [26]. The utility of SV as a functional biomarker for monitoring CD activity and treatment response has been also investigated in a recent therapeutic study [23]. Treatment with infliximab, a TNF-α inhibitor, has been shown to significantly reduce SV/BMI and SV/weight ratios, with a parallel decrease in CRP and TNF-α levels, which are both established markers of CD activity [23,36,37]. Thus, according to Shi et al, a decrease in the baseline SV/BMI ratio may serve as a promising early indicator of therapeutic response to infliximab in CD patients [23].

It should be emphasized that splenomegaly in patients with CD is not linked to functional hypersplenism, as no decrease in platelet count is observed, a common laboratory finding in patients with splenomegaly and portal hypertension [22,38]. Additionally, in CD, the immune response can contribute to spleen enlargement and increased platelet counts, possibly due to splenic edema resulting in impaired splenic function—the exact underlying mechanism remains unclear [22,39]. However, in a study by Kawashima et al, despite the increased platelet counts seen in IBD patients, no correlation was found between platelet count and SV [22]. Furthermore, a study by Shi et al did not show a correlation between SV/BMI ratio and platelet count [23]. Therefore, splenomegaly in CD is probably driven by more complex immune processes, rather than simple hemodynamic changes [22]. The potential pathophysiology of splenomegaly in patients with CD is also thought to reflect the intense immune activation occurring in the intestinal mucosa, which disrupts the gut barrier and allows inflammatory cytokines such as TNF-α to enter the systemic circulation and affect the spleen [22,40,41]. Additionally, the presence of mesenteric lymphadenopathy in both UC and CD underscores the involvement of lymphatic tissue in IBD [42,43]. Given that splenomegaly can be observed in other autoimmune conditions, such as Felty’s syndrome in patients with rheumatoid arthritis, further research into the underlying pathogenic mechanisms of spleen enlargement in CD is considered imperative [44,45].

New important insights into the causal relationship between SV and CD and UC have been established by recent Mendelian randomized studies [29,30]. These studies demonstrated a strong correlation between a genetically predicted increase in SV and the appearance of CD and UC [29,30]. Notably, a study conducted by Song et al reported that increased SV can be related with increased susceptibility to CD, while CD can also lead to spleen enlargement [29]. These observations suggest the existence of a potential bidirectional causal relation between increased spleen size and CD, which further highlights the complex interplay between immune system regulation and intestinal inflammation [29]. T-regulatory cells, which are trafficked between the spleen and the intestine, may play a crucial role in the shared pathogenic mechanisms underlying both the splenic and intestinal immune dysfunction [46,47]. This bidirectional movement of T-regulatory cells could represent a key component of the immune response in inflammatory diseases like IBD, where immune system dysregulation in one organ may influence and exacerbate dysfunction in the other [29,39]. The connection between splenic and intestinal immune dysfunction, facilitated by T-regulatory cells, emphasizes the need for further investigation into how immune regulation at these sites may influence disease progression and severity [29]. Thus, targeting spleen function and T-regulatory cells through anti-inflammatory therapies could present novel strategies for the management of IBD [30]. The pathogenetic mechanisms that may contribute to changes in spleen size in patients with IBD are summarized in Table 5.

Table 5 Pathogenetic mechanisms likely contributing to spleen size changes in patients with IBD

Despite the advantages of Mendelian randomization in reducing confounding factors, compared to traditional observational studies, further research is needed to clarify the precise molecular pathways linking SV to IBD [29,30]. Additionally, future studies should include subgroup analyses based on age, sex and ethnicity, factors that may biologically influence SV, in order to provide a more comprehensive understanding of the complex relationship between spleen size and IBD [48-51]. Moreover, given the significant heterogeneity among existing studies evaluating the correlation between SV and IBD, future research should adopt standardized outcome measures, definitions and inclusion criteria, in order to reduce heterogeneity and enable meaningful comparisons and robust meta-analyses.

References

1. Fakhoury M, Negrulj R, Mooranian A, Al-Salami H. Inflammatory bowel disease:clinical aspects and treatments. J Inflamm Res 2014;7:113-120.

2. Ranasinghe I R, Tian C, Hsu R. Crohn disease. In:StatPearls. StatPearls Publishing, Treasure Island, 2024, Available from:https://www.ncbi.nlm.nih.gov/books/NBK436021/[Accessed 17 July 2025].

3. Gros B, Kaplan GG. Ulcerative colitis in adults:a review. JAMA 2023;330:951-965.

4. Sarter H, Crétin T, Savoye G, et al;EPIMAD study Group. Incidence, prevalence and clinical presentation of inflammatory bowel diseases in Northern France:a 30-year population-based study. Lancet Reg Health Eur 2024;47:101097.

5. Kontola K, Oksanen P, Huhtala H, Jussila A. Increasing incidence of inflammatory bowel disease, with greatest change among the elderly:a nationwide study in Finland, 2000-2020. J Crohns Colitis 2023;17:706-711.

6. Molodecky NA, Kaplan GG. Environmental risk factors for inflammatory bowel disease. Gastroenterol Hepatol (N Y) 2010;6:339-346.

7. Loddo I, Romano C. Inflammatory bowel disease:genetics, epigenetics, and pathogenesis. Front Immunol 2015;6:551.

8. Lin Z, Luo W, Zhang K, Dai S. Environmental and microbial factors in inflammatory bowel disease model establishment:a review partly through Mendelian randomization. Gut Liver 2024;18:370-390.

9. Lu Q, Yang MF, Liang YJ, et al. Immunology of inflammatory bowel disease:molecular mechanisms and therapeutics. J Inflamm Res 2022;15:1825-1844.

10. Levine JS, Burakoff R. Extraintestinal manifestations of inflammatory bowel disease. Gastroenterol Hepatol (N Y) 2011;7:235-241.

11. Xu XR, Liu CQ, Feng BS, Liu ZJ. Dysregulation of mucosal immune response in pathogenesis of inflammatory bowel disease. World J Gastroenterol 2014;20:3255-3264.

12. Bronte V, Pittet MJ. The spleen in local and systemic regulation of immunity. Immunity 2013;39:806-818.

13. Navarro JT, Ribera JM, Mate JL, et al. Hepatosplenic T-gammadelta lymphoma in a patient with Crohn's disease treated with azathioprine. Leuk Lymphoma 2003;44:531-533.

14. Jiang H, He S, Wang H. A rare complication of people with inflammatory bowel disease after ileostomy:a case report. Medicine (Baltimore) 2023;102:e35098.

15. Puli SR, Presti ME, Alpert MA. Splenic granulomas in Crohn disease. Am J Med Sci 2003;326:141-144.

16. AndréMFJ, Piette JC, Kémény JL, et al;and the French Study Group on Aseptic Abscesses. Aseptic abscesses:a study of 30 patients with or without inflammatory bowel disease and review of the literature. Medicine (Baltimore) 2007;86:145-161.

17. Sangineto M, Luglio CV, Suppressa P, SabbàC, Napoli N. A case of sarcoidosis with isolated hepatosplenic onset and development of inflammatory bowel disease during recovery stage. Auto Immun Highlights 2017;8:6.

18. Jentzer A, Veyrard P, Roblin X, et al. Cytomegalovirus and inflammatory bowel diseases (IBD) with a special focus on the link with ulcerative colitis (UC). Microorganisms 2020;8:1078.

19. Zhang H, Zhao S, Cao Z. Impact of Epstein-Barr virus infection in patients with inflammatory bowel disease. Front Immunol 2022;13:1001055.

20. Rozen P, Flatau E, Schujman E, Gefel A. Variability of splenomegaly in Crohn's disease. Am J Gastroenterol 1977;67:489-493.

21. Di Sabatino A, Rosado MM, Cazzola P, et al. Splenic function and IgM-memory B cells in Crohn's disease patients treated with infliximab. Inflamm Bowel Dis 2008;14:591-596.

22. Kawashima K, Onizawa M, Fujiwara T, et al. Evaluation of the relationship between the spleen volume and the disease activity in ulcerative colitis and Crohn disease. Medicine (Baltimore) 2022;101:e28515.

23. Shi X, Wang JH, Rao SX, Liu TT, Wu H. A novel role of the splenic volume in Crohn's disease:evaluating the efficacy of infliximab. Front Pharmacol 2023;14:1246657.

24. Balaban DV, Popp A, Lungu AM, Costache RS, Anca IA, Jinga M. Ratio of spleen diameter to red blood cell distribution width:a novel indicator for celiac disease. Medicine (Baltimore) 2015;94:e726.

25. Khashper A, Shwartz D, Taragin BH, Shalmon T. Splenic size as a marker for active inflammation in Crohn's disease. Clin Imaging 2022;84:164-167.

26. Azam MB, Senthamizhselvan K, Mohan P, Ramkumar G. Utility of spleen volume to body mass index ratio in Crohn's disease:a retrospective cohort study. Indian J Gastroenterol 2024 Nov 7 [Epub ahead of print]. doi:10.1007/s12664-024-01704-0

27. Pereira JL, Hughes LE, Young HL. Spleen size in patients with inflammatory bowel disease. Does it have any clinical significance?Dis Colon Rectum 1987;30:403-409.

28. Muller AF, Cornford E, Toghill PJ. Splenic function in inflammatory bowel disease:assessment by differential interference microscopy and splenic ultrasound. Q J Med 1993;86:333-340.

29. Song HH, Zhang HR, Hu XR, Jiang XC. A bidirectional Mendelian randomization study of spleen volume and Crohn disease. Medicine (Baltimore) 2024;103:e40515.

30. Su Q, Li J, Lu Y, et al. Spleen volume in relation to ulcerative colitis and Crohn's disease:a Mendelian randomization study. Sci Rep 2025;15:6588.

31. Mathur A, McLean MH, Cao H, Vickers MA. Hyposplenism and gastrointestinal diseases:significance and mechanisms. Dig Dis 2022;40:290-298.

32. Di Sabatino A, Carsetti R, Rosado MM, et al. Immunoglobulin M memory B cell decrease in inflammatory bowel disease. Eur Rev Med Pharmacol Sci 2004;8:199-203.

33. Di Sabatino A, Rosado MM, Ciccocioppo R, et al. Depletion of immunoglobulin M memory B cells is associated with splenic hypofunction in inflammatory bowel disease. Am J Gastroenterol 2005;100:1788-1795.

34. Freeman HJ. Natural history and long-term clinical course of Crohn's disease. World J Gastroenterol 2014;20:31-36.

35. Harris A, Kamishima T, Hao HY, et al. Splenic volume measurements on computed tomography utilizing automatically contouring software and its relationship with age, gender, and anthropometric parameters. Eur J Radiol 2010;75:e97-e101.

36. Pagnini C, Cominelli F. Tumor necrosis factor's pathway in Crohn's disease:potential for intervention. Int J Mol Sci 2021;22:10273.

37. Yang DH, Yang SK, Park SH, et al. Usefulness of C-reactive protein as a disease activity marker in Crohn's disease according to the location of disease. Gut Liver 2015;9:80-86.

38. Yoshida H, Shimizu T, Yoshioka M, et al. The role of the spleen in portal hypertension. J Nippon Med Sch 2023;90:20-25.

39. Di Sabatino A, Biancheri P, Rovedatti L, MacDonald TT, Corazza GR. New pathogenic paradigms in inflammatory bowel disease. Inflamm Bowel Dis 2012;18:368-371.

40. Lima ES, Andrade ZA, Andrade SG. TNF-alpha is expressed at sites of parasite and tissue destruction in the spleen of mice acutely infected with Trypanosoma cruzi. Int J Exp Pathol 2001;82:327-336.

41. Engwerda CR, Ato M, Cotterell SE, et al. A role for tumor necrosis factor-alpha in remodeling the splenic marginal zone during Leishmania donovani infection. Am J Pathol 2002;161:429-437.

42. Sahin A, Artas H, Eroglu Y, et al. A neglected issue in ulcerative colitis:mesenteric lymph nodes. J Clin Med 2018;7:142.

43. Maconi G, Sorin V, Kopylov U, et al. Diagnostic significance of mesenteric lymph node involvement in proximal small bowel Crohn's disease. Therap Adv Gastroenterol 2022;15:1756284822111⇘.

44. Wegscheider C, Ferincz V, Schöls K, Maieron A. Felty's syndrome. Front Med (Lausanne) 2023;10:1238405.

45. de Porto AP, Lammers AJ, Bennink RJ, ten Berge IJ, Speelman P, Hoekstra JB. Assessment of splenic function. Eur J Clin Microbiol Infect Dis 2010;29:1465-1473.

46. Yamada A, Arakaki R, Saito M, Tsunematsu T, Kudo Y, Ishimaru N. Role of regulatory T cell in the pathogenesis of inflammatory bowel disease. World J Gastroenterol 2016;22:2195-2205.

47. Miragaia RJ, Gomes T, Chomka A, et al. Single-cell transcriptomics of regulatory T cells reveals trajectories of tissue adaptation. Immunity 2019;50:493-504.

48. Chow KU, Luxembourg B, Seifried E, Bonig H. Spleen size is significantly influenced by body height and sex:establishment of normal values for spleen size at US with a cohort of 1200 healthy individuals. Radiology 2016;279:306-313.

49. Mustapha Z, Tahir A, Tukur M, Bukar M, Lee WK. Sonographic determination of normal spleen size in an adult African population. Eur J Radiol 2010;75:e133-e135.

50. Fateh SM, Mohammed NA, Mahmood KA, et al. Sonographic measurement of splenic size and its correlation with body parameters. Med Int (Lond) 2023;3:7.

51. Palmer KR, Sherriff SB, Holdsworth CD, Ryan FP. Further experience of hyposplenism in inflammatory bowel disease. Q J Med 1981;50:463-471.