• Zarko Spasovski City General Hospital 8th September, Skopje, Department of General and Emergency Surgery, Skopje, Republic of North Macedonia
  • Meri Kirjas Institute of Immunobiology and Human Genetics, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, Republic of North Macedonia
  • Biljana Novevska Petrovska City General Hospital 8th September, Skopje, Department of Pathology, Skopje, Republic of North Macedonia
  • Sashko Stojanoski City General Hospital 8th September, Skopje, Department of General and Emergency Surgery, Skopje, Republic of North Macedonia
  • Stefan Krstevski City General Hospital 8th September, Skopje, Department of General and Emergency Surgery, Skopje, Republic of North Macedonia


cholecystitis, inflammation, cytokines, interleukins, immunoglobulins


Introduction: Cholecystitis is an inflammatory response of the body triggered by a number of mutually supporting biological mechanisms, which by creating and releasing inflammatory mediators - cytokines activate the innate or acquired immune system.

Material and methods: The study was conducted at the General City Hospital (GCH) "8th September" in Skopje and the Institute of Immunology and Human Genetics in Skopje, in the period of 2020-2022. Statistical analysis of the data was performed with the statistical package SPSS for Windows 26.0.

Results: The study included 165 subjects with gallbladder inflammation divided into 3 groups: mild, moderate and severe inflammation grade. Patients with mild, moderate, and severe inflammatory processes differed significantly in IgG levels (p = 0.049), IgA (p = 0.021), and IgM (p = 0.016) and insignificantly in IgE1 levels (p = 0.16). Patients with a severe inflammatory process had a higher prevalence of IL-2R and IL-8 than patients with a mild grade (p = 0.035; p = 0.26, respectively). The intensity of inflammatory process had a non-significant effect on the levels ​​of TNF-alpha (p = 0.078), and a significant effect on the levels ​​of fibrinogen (p = 0.001), with significantly higher levels ​​of fibrinogen in the group of patients with severe inflammatory process compared to the group with mild grade (p = 0.0009).

Conclusion: The intensity of inflammatory process affects the serum levels ​​of inflammatory cytokines with presence of strong correlation between the severe form of cholecystitis and elevated serum levels ​​of certain inflammatory cytokines.


Doherty G, Manktelow M, Skelly B, Gilespie P, Bjourson Aj, Watterson S. The Need for Standardizing Diagnosis, Treatment and Clinical Care of Cholecystitis and Biliary Colic in Gallbladder Disease. MDPI 2022; 58(3): 388. doi: 10.3390/medicina58030388.

Ambe PC, Weber AS, Wassenberg D. Is gallbladder inflammation more severe in male patients presenting with acute cholecystitis? BMC Surg 2015; 15: 48. doi: 10.1186/s 12893-015-0034-0.

Shabanzadeh DM, Holmboe SA, Sørensen LT, Linneberg A, Andersson AM, Jørgensen T. Are incident gallstones associated to sex-dependent changes with age? A cohort study. Andrology 2017; 5(5): 931-938. doi: 10.1111/andr.12391.

Thesbjerg SE, Harboe KM, Bardram L, Rosenberg J. Sex differences in laparoscopic cholecystectomy. Surg Endosc 2010; 24(12): 3068-72. doi: 10.1007/s00464-010-1091-1.

Gomes CA, Soares C, Di Saverio S, Sartelli M, de Souza Silva PG, Orlandi AS, et al. Gangrenous cholecystitis in male patients: A study of prevalence and predictive risk factors. Ann Hepatobiliary Pancreat Surg 2019; 23(1): 34-40. doi: 10.14701/ahbps. 2019.23.1.34.

Nikfarjam M, Harnaen E, Tufail F, Muralidharan V, Fink MA, Starkey G, Jones RM, Christophi C. Sex differences and outcomes of management of acute cholecystitis. Surg Laparosc Endosc Percutan Tech 2013; 23(1): 61-65. doi: 10.1097/SLE. 0b013e31 82773 e52.

Nadkarni S, Cooper D, Brancaleone V, Bena S, Perretti M. Activation of the annexin A1 pathway underlies the protective effects exerted by estrogen in polymorphonuclear leukocytes. Arterioscler Thromb Vasc Biol 2011; 31(11): 2749-2759. doi: 10.1161/ ATVBAHA.111.235176.

Vodo S, Bechi N, Petroni A, Carolina Muscoli C, Aloisi AM. Testosterone-Induced Effects on Lipids and Inflammation. Mediators Inflam 2013; ID 183041.

Fehrenbacher JC, Bingener J, Aho JM, Wasky PR, Locke EE, Schwesinger WH, et al. Men with acute cholecystitis have higher tissue-based cytokine levels than women: a cross-sectional study Sickle. Chirurgia 2015; 28: 49-53. 9729.

Ferrero-Miliani L, Nielsen OH, Andersen PS, Girardin SE. Chronic inflammation: importance of NOD2 and NALP3 in interleukin-1beta generation. Clin Exp Immunol. 2007; 147(2): 227-235. doi: 10.1111/j.1365-2249.2006.03261.x.

Davalos D, Akassoglou K. Fibrinogen as a key regulator of inflammation in disease. Semin Immunopathol 2012; 34(1): 43-62. doi: 10.1007/s00281-011-0290-8.

Malkin CJ, Pugh PJ, Jones RD, Kapoor D, Channer KS, Jones TH. The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men. J Clin Endocrinol Metab 2004; 89(7): 3313-3318. doi: 10.1210/jc. 2003-031069.

Cotton JA, Platnich JM, Muruve DA, Jijon H, Buret AG, Beck PL. Interleukin-8 in gastrointestinal inflammation and malignancy: induction and clinical consequences. IJICMR 2016; 8: 13-34.

Kasprzak A, Szmyt M, Malkowski W, Przybyszewska W, Helak-Łapaj C, Seraszek-Jaros A, et al. Analysis of immunohistochemical expression of proinflammatory cytokines (IL-1α, IL-6, and TNF-α) in gallbladder mucosa: comparative study in acute and chronic calculous cholecystitis. Folia Morphol (Warsz) 2015; 74(1): 65-72. doi: 10.5603/FM.2015.0011.

Gulati K, Guhathakurta S, Joshi J, Rai N, Ray A (2016) Cytokines and their Role in Health and Disease: A Brief Overview. MOJ Immunol 2016; 4(2): 00121. DOI: 10.15406/moji.2016.04.00121

Mahmood F, Akingboye A, Malam Y, Thakkar M, Jambulingam P. Complicated Acute Cholecystitis: The Role of C-Reactive Protein and Neutrophil-Lymphocyte Ratio as Predictive Markers of Severity. Cureus 2021; 13(2): e13592. doi: 10.7759/cureus.13592.

Kumar K, Abbas AK, Robbins N, Fausto N, Aster JC. Pathologic Basis of Disease. 8th ed. Philadelphia:Saunders; 2008.

Sakuramoto S, Sato S, Okuri T, Sato K, Hiki Y, Kakita A. Preoperative evaluation to predict technical difficulties of laparoscopic cholecystectomy on the basis of histological inflammation findings on resected gallbladder. Am J Surg 2000; 179(2): 114-121. doi: 10.1016/s0002-9610(00)00248-8.

Singh A, Singh G, Kaur K, Goyal G, Saini G, Sharma D. Histopathological Changes in Gallbladder Mucosa Associated with Cholelithiasis: A Prospective Study. Niger J Surg 2019; 25(1): 21-25. doi: 10.4103/njs.NJS_15_18.

Kiriyama S, Kozaka K, Takada T, Strasberg SM, Pitt HA, Gabata T, et al. Tokyo Guidelines 2018: diagnostic criteria and severity grading of acute cholangitis (with videos). J Hepatobiliary Pancreat Sci 2018; 25(1): 17-30. doi: 10.1002/jhbp.512.

Chong JU, Lee JH, Yoon YC, Kwon KH, Cho JY, Kim SJ, et al. Influencing factors on postoperative hospital stay after laparoscopic cholecystectomy. Korean J Hepatobiliary Pancreat Surg 2016; 20(1): 12-16. DOI:

Di Buono G, Romano G, Galia M, Amato G, Maienza E, Vernuccio F, et al. Difficult laparoscopic cholecystectomy and preoperative predictive factors. Sci Rep 2021; 11: 2559.

Real-Noval H, Fernández-Fernández J, Soler-Dorda G. Predicting factors for the diagnosis of gangrene acute cholecystitis. Cir Cir 2019; 87(4): 443-449. doi: 10.24875/ CIRU.19000706.

Yuksekdag S, Bas G, Okan I, Karakelleoglu A, Alimoglu O, Akcakaya A, et al. Timing of laparoscopic cholecystectomy in acute cholecystitis. Niger J Clin Pract 2021; 24(2): 156-160. doi: 10.4103/njcp.njcp_138_20.

Liu Z, Kemp TJ, Gao YT, Corbel A, McGee EE, Wang B, et al. Association of circulating inflammation proteins and gallstone disease. J Gastroenterol Hepatol 2018; 33(11): 1920-1924. doi: 10.1111/jgh.14265.






Original Articles