Appendectomy and Parkinson's Disease Risk: A Meta-Analysis
Khalid Alhazmi1*, Salah Alghamdi2
1Department of Pathology, Faculty of Medicine, University of Tabuk, Kingdom of Saudi Arabia.
2Department of Surgery, Faculty of Medicine, University of Tabuk, Kingdom of Saudi Arabia.
Abstract
The emergence of alternative methods of treating appendicitis and the fact that the gut lymphoid tissue is active (in terms of immune modulation and gut microbiota replenishment) increased the concern about the association of appendectomy with systemic diseases. The literature on the association between appendectomy and Parkinson's disease (PD) lacks the current meta-analysis aimed to assess the association between appendectomy and PD. We systematically searched PubMed, Cochrane Library, and Google Scholar for relevant articles published in the English language, the searching engine was limited to the period from January 2010 to January 2021. Studies on humans were eligible, while animal and experimental studies were excluded, the keywords used were Parkinson's disease, appendicitis, Parkinsonism, appendectomy, gut lymphoid tissue, and movement disorders with protean "AND" or "OR". Out of the 263 references found, 39 full texts were screened, and only five studies fulfilled the inclusion and exclusion criteria, the studies included 8210081 patients and showed that no association between appendectomy and PD, odd ratio, 1.16, 95% CI, 0.92-1.46, and P-value, 0.20. Significant heterogeneity was observed between the studies included (three from the United States of America and two from Europe) and no relationship was evident between appendectomy and PD, further studies controlling for the causes of appendectomy and temporal profile of both PD and appendectomy are recommended.
Keywords: Appendectomy, Parkinson's disease, Gut lymphoid tissue, Disease Risk
Introduction
The caecal appendix was previously thought of as a redundant organ of revolution, however, the rare malformation and being highly conserved suggested a role, the appendix is rich in lymphoid tissue and a primary source of immunoglobulin A. Studying the lymphoid system in the appendix is relevant due to the increasing population age, and the parallel substantial lymphoid changes with that. The light center of the appendix is lost in the elderly (in some a complete closure was noted) affecting lymphoid transformation and lymphocyte migration (Aminova, 2018; Girard-Madoux et al., 2018). Furthermore, due to its position and shape, it could be a primary niche for the gut microbiota (the intestinal flora). Indeed, the appendix is continuously shedding microbiota to replenish especially after a diarrheal episode. Thus, it is suggested to play a major role in systemic diseases (including Parkinson's disease) by controlling the immune system, the number and diversity of gut flora, and keeping the integrity of the intestinal barrier (Holzer & Farzi, 2014; Kooij et al., 2016).
There is an increasing awareness that Parkinson's disease is a systemic disease (Ahmad, et al., 2017; AlJohani & AlZahrani 2017). The observations of a reduced rate of PD after vagotomy and the high concentration of alpha-synuclein in the appendix relative to other parts in the gastrointestinal tract suggested a role in the pathology of PD (Holmqvist et al., 2014; Svensson et al., 2015; Borghammer & Hamani, 2017). The hypothesis is that: the synthesis of α-synuclein in the appendix is modulated by the gut microbiota and reaches the brain by retrograde axonal transport (Palacios et al., 2018).
The association between Parkinson's disease (PD) and the accumulation of misfolded α-synuclein is established. However, the association with gut α-synuclein has been discussed controversially. Importantly, α-synuclein was suggested as an interventional and diagnostic measure for PD (Bu et al., 2019). There is increasing evidence of treating uncomplicated appendicitis less invasively (antibiotic or conservative) (Rollins et al., 2016). Investigating the association of gut lymphoid tissue removal with systemic diseases might support either approach. Thus, we conducted this review and meta-analysis to assess the relationship between appendectomy and Parkinson's disease.
MATERIALS and Methods
Eligibility criteria according to PICOS
We included retrospective, prospective cohorts, and case-control studies investigating the relationship between appendectomies and Parkinson's disease in adults and published in English. Case reports, case series, experimental, and animal studies were excluded, not including randomized trials is obvious due to the difficulty in conducting such methodologies.
Intervention and outcomes measures
Appendectomy conducted at any age and confirmed by records and the development of Parkinson's disease confirmed by a physician were considered, the self-reported diagnosis was not. No specification for the follow-up period.
The search strategy
The PubMed, Cochrane library, and Google Scholar databases were systematically searched for relevant articles; Two Authors (S. A. and K. A) Independently screened the titles and abstracts. Also, the references of the retrieved articles were screened for inclusion or exclusion and discrepancies were solved by agreement. The keywords used were Parkinson's disease, appendicitis, Parkinsonism, appendectomy, gut lymphoid tissue, and movement disorders with protean "AND" or "OR". Studies published from January 2010 up to January 2021 were eligible. Out of the 263 references found, 39 full texts were screened, and only five studies fulfilled the inclusion and exclusion criteria. We used the Ottawa Newcastle scale for non-randomized studies (Cook & Reed, 2015) (Figure 1, Table 1).
Statistical analysis
The most recent RevMan version 5.4 was used for data analysis, the data were entered manually at 95% CI a P-value of <0.05 was considered significant. The fixed effect was used unless significant heterogeneity was observed (>50%). The funnel plot was used to test for sensitivity (lateralization).
|
|
|
Figure 1. Trials included in the association between appendectomy and Parkinson's disease. |
Results and Discussion
Out of the 263 references found, 39 full texts were screened, and only five studies (three from the United States of America and two from Europe) fulfilled the inclusion and exclusion criteria. Two studies (Svensson et al., 2016; Yilmaz et al., 2017) showed the association of appendectomy and Parkinson's disease, another two studies were on the side that appendectomy might be protective (Palacios et al., 2018; Liu et al., 2020), while one study was neutral (Killinger et al., 2018). The studies included 8210081 patients (1339594 cases and 6870487 controls) without appendectomy. The random effect was applied due to the significant heterogeneity observed (I2=92%, P-value<0.001). The diamond showed no protective effect of appendectomy against Parkinson's disease, odd ratio, 1.16, 95% CI, 0.92-1.46, and P-value, 0.20 (Figure 2, Table 2).
Table 1. Ottawa Newcastle assessment for the included studies
|
Author |
Selection |
Compatibility |
Outcome |
Score |
|
Killinger et al. (2018) |
3 |
2 |
4 |
9 |
|
Liu et al. (2020) |
3 |
2 |
4 |
9 |
|
Palacios et al. (2018) |
3 |
2 |
4 |
9 |
|
Svensson et al. (2016) |
3 |
2 |
4 |
9 |
|
Yilmaz et al. (2017) |
3 |
2 |
4 |
9 |
Table 2. The relationship between gut lymphoid tissue removal and Parkinson's disease.
|
Author |
Year |
Country |
Type of study |
No of patients |
result |
|
Killinger et al. |
2018 |
USA |
Case-control |
644/551,647 vs. 1608/1146353 |
Lower risk |
|
Liu et al. |
2020 |
Sweden |
Case-control, nested |
1908/78,650 vs. 78120/3,146,000 |
Risk reduction |
|
Palacios et al. |
2018 |
USA |
Prospective |
177/ 442700 vs. 406/ 1249191 |
No relationship |
|
Svensson et al. |
2016 |
USA |
A case-control |
19/265,758 vs. 15/1,328,790 |
Small increase |
|
Yilmaz et al. |
2017 |
Germany |
Retrospective |
69/839 vs. 12/153 |
No relationship |
|
|
|
a) |
|
|
|
b) |
Figure 2. The relationship between gut lymphoid tissue removal and Parkinson's disease.
The pathogenesis of Parkinson's disease (the commonest neurodegenerative movement disorder) is the accumulation of misfolded α-synuclein, in Lewy bodies with a loss of dopaminergic neurons in the substantia nigra. Currently, no available treatment that modifies the course of this disabling disease (Balestrino & Schapira, 2020). The high concentration of alpha-synuclein in the appendix relative to other parts of the gastrointestinal tract may be targeted as a therapeutic intervention. The present data showed a higher rate of PD (no amounting to statistical significance) among those without appendectomy compared to their counterparts' odd ratio, 1.16, 95% CI, 0.92-1.46, and P-value, 0.20. The present findings were similar to a previous study (Lu et al., 2019). However, the results were limited with significant heterogeneity (RR 1.02, 95% CI 0.87-1.20, I2 = 83.1%, P = 0.789). The discrepancy observed between different studies might be explained by the temporal profile, Mendes et al. (2015) found a protective effect of appendectomy in middle age and late-onset PD and an effect that was not observed among the young age group. While Marras and colleagues (2016) who assessed PD incidence among adults (who underwent an appendectomy in late and middle) found a higher rate of the disease during the first five years following appendectomy but no thereafter. The underlying cause of appendectomy including secondary appendicitis, appendicitis within a hernia, and intraluminal foreign bodies are further confounders (Hines et al., 2016). Besides, alteration of the gut lymphoid expression is a great player on chronic inflammation and cancer development (Yuksel et al., 2019).
The gut lymphoid tissue and PD pathology
PD is a multisystem disorder with both motor and nonmotor components. Both central and peripheral neurons are affected. The pathology is the accumulation of misfolded α-Synuclein in enteric neurons and Lewy bodies of substantia nigra. The gut accumulation and nonmotor symptoms in the gastrointestinal tract precede the brain pathology by more than 20 years and during the prodromal phase of the disease (Stokholm et al., 2016; Killinger et al., 2018).
The high α-synuclein concentration in the appendix, the mucosa rich in immune cells, and the lack of a blood-tissue barrier suggested a role in PD development. In addition to its role in detecting and destroying pathogenic organisms. Besides, experimental studies found that α-synuclein migrates from cell to cell in a prion-like fashion and might ascend the vagus nerve to reach the brain. Furthermore, vagotomy was shown to reduce PD risk in some epidemiological studies (Volpicelli-Daley et al., 2011; Tysnes et al., 2015; Liu et al., 2017).
The study was limited by the significant heterogeneity observed between the included studies and the fact that studies were published only in the United States and Europe. The literature in other parts of the World and the searched databases was not found.
Conclusion
No relationship was found between appendectomy and PD, the marked heterogeneity observed might affect the current results. Nevertheless, the association between the two common diseases was not documented. Further studies controlling for the causes of appendectomy and temporal profile of both PD and appendectomy are recommended.
ACKNOWLEDGMENTS: We would like to acknowledge the Saudi Digital Library for accessing the data.
CONFLICT OF INTEREST: None
FINANCIAL SUPPORT: None
ETHICAL CONSIDERATIONS: The authors did not include any study published by them in this meta-analysis.
Ahmad, R., Naqvi, A., Ahmad, N., Baraka, M., Mastour, M., Al Sharedah, S., Al Ghamdi, S., Al Rabae, G. & Al Ghamdi, M. (2017). Awareness, perception, attitude, and knowledge regarding complementary and alternative medicines (CAMs) among the pharmacy and medical students of a public university in Saudi Arabia. Archives of Pharmacy Practice, 8(2), 51-63.
AlJohani, K., & AlZahrani, A. S. (2017). Awareness among Medical and Dental Students Regarding the Relationship between Periodontal and Systemic Conditions. International Journal of Pharmaceutical Research & Allied Sciences, 6(4), 61-72.
Aminova, G. G. (2018). Structure and cytoarchitectonic of the lymphoid tissue of the Appendix of man in elderly and senile ages. Advances in gerontology= Uspekhi Gerontologii, 31(2), 273-279.
Balestrino, R., & Schapira, A. H. V. (2020). Parkinson disease. European Journal of Neurology, 27(1), 27-42. doi:10.1111/ene.14108.
Borghammer, P., & Hamani, C. (2017). Preventing Parkinson disease by vagotomy: Fact or fiction? Neurology. 88(21), 1982-1983. doi:10.1212/WNL.0000000000003969.
Bu, J., Liu, J., Liu, K., & Wang, Z. (2019). Diagnostic utility of gut α-synuclein in Parkinson’s disease: a systematic review and meta-analysis. Behavioural Brain Research, 364, 340-347. doi:10.1016/j.bbr.2019.02.039.
Cook, D. A., & Reed, D. A. (2015). Appraising the quality of medical education research methods: the medical education research study quality instrument and the Newcastle–Ottawa scale-education. Academic Medicine, 90(8), 1067-1076. doi:10.1097/ACM.0000000000000786.
Girard-Madoux, M. J., de Agüero, M. G., Ganal-Vonarburg, S. C., Mooser, C., Belz, G. T., Macpherson, A. J., & Vivier, E. (2018, April). The immunological functions of the appendix: an example of redundancy?. In Seminars in Immunology, 36, 31-44. Academic Press. doi:10.1016/j.smim.2018.02.005.
Hines, J. J., Paek, G. K., Lee, P., Wu, L., & Katz, D. S. (2016). Beyond appendicitis; radiologic review of unusual and rare pathology of the appendix. Abdominal Radiology, 41(3), 568-581. doi:10.1007/s00261-015-0600-z. PMID: 27039327.
Holmqvist, S., Chutna, O., Bousset, L., Aldrin-Kirk, P., Li, W., Björklund, T., Wang, Z.Y., Roybon, L., Melki, R. & Li, J.Y., (2014). Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathologica, 128(6), 805-820. doi:10.1007/s00401-014-1343-1346
Holzer, P., & Farzi, A. (2014). Neuropeptides and the microbiota-gut-brain axis. Microbial Endocrinology: the Microbiota-Gut-Brain Axis in Health and Disease, 817, 195-219. doi:10.1007/978-1-4939-0897-4_9.
Killinger, B. A., Madaj, Z., Sikora, J. W., Rey, N., Haas, A. J., Vepa, Y., Lindqvist, D., Chen, H., Thomas, P. M., Brundin, P., et al. (2018). The vermiform appendix impacts the risk of developing Parkinson’s disease. Science Translational Medicine, 10(465), 5280-5295. doi:10.1126/scitranslmed.aar5280.
Kooij, I. A., Sahami, S., Meijer, S. L., Buskens, C. J., & Te Velde, A. A. (2016). The immunology of the vermiform appendix: a review of the literature. Clinical & Experimental Immunology, 186(1), 1-9. doi:10.1111/cei.12821.
Liu, B., Fang, F., Pedersen, N. L., Tillander, A., Ludvigsson, J. F., Ekbom, A., Svenningsson, P., Chen, H. & Wirdefeldt, K. (2017). Vagotomy and Parkinson disease: A Swedish register–based matched-cohort study. Neurology, 88(21), 1996-2002. doi:10.1212/WNL.0000000000003961.
Liu, B., Fang, F., Ye, W., & Wirdefeldt, K. (2020). Appendectomy, Tonsillectomy and Parkinson's Disease Risk: A Swedish Register-Based Study. Frontiers in Neurology, 11, 510. doi:10.3389/fneur.2020.00510.
Lu, H. T., Shen, Q. Y., Xie, D., Zhao, Q. Z., & Xu, Y. M. (2019). Lack of association between appendectomy and Parkinson’s disease: a systematic review and meta-analysis. Aging Clinical and Experimental Research, 32(11), 2201-2209. doi:10.1007/s40520-019-01354-9.
Marras, C., Lang, A. E., Austin, P. C., Lau, C., & Urbach, D. R. (2016). Appendectomy in mid and later life and risk of Parkinson's disease: A population‐based study. Movement Disorders, 31(8), 1243-1247. doi:10.1002/mds.26670.
Mendes, A., Gonçalves, A., Vila‐Chã, N., Moreira, I., Fernandes, J., Damásio, J., Teixeira‐Pinto, A., Taipa, R., Lima, A. B. & Cavaco, S. (2015). Appendectomy may delay P arkinson's disease Onset. Movement Disorders, 30(10), 1404-1407. doi:10.1002/mds.26311
Palacios, N., Hughes, K. C., Cereda, E., Schwarzschild, M. A., & Ascherio, A. (2018). Appendectomy and risk of Parkinson's disease in two large prospective cohorts of men and women. Movement Disorders, 33(9), 1492-1496.. doi:10.1002/mds.109.
Palacios, N., Hughes, K. C., Cereda, E., Schwarzschild, M. A., & Ascherio, A. (2018). Appendectomy and risk of Parkinson's disease in two large prospective cohorts of men and women. Movement Disorders, 33(9), 1492-1496. doi:10.1002/mds.109.
Rollins, K. E., Varadhan, K. K., Neal, K. R., & Lobo, D. N. (2016). Antibiotics versus appendicectomy for the treatment of uncomplicated acute appendicitis: an updated meta-analysis of randomised controlled trials. World Journal of Surgery, 40(10), 2305-2318. doi:10.1007/s00268-016-3561-7.
Stokholm, M. G., Danielsen, E. H., Hamilton‐Dutoit, S. J., & Borghammer, P. (2016). Pathological α‐synuclein in gastrointestinal tissues from prodromal P arkinson disease patients. Annals of Neurology, 79(6), 940-949. doi:10.1002/ana.24648.
Svensson, E., Horváth‐Puhó, E., Stokholm, M. G., Sørensen, H. T., Henderson, V. W., & Borghammer, P. (2016). Appendectomy and risk of Parkinson's disease: a nationwide cohort study with more than 10 years of follow‐up. Movement Disorders, 31(12), 1918-1922. doi:10.1002/mds.26761
Svensson, E., Horváth‐Puhó, E., Thomsen, R. W., Djurhuus, J. C., Pedersen, L., Borghammer, P., & Sørensen, H. T. (2015). Vagotomy and subsequent risk of P arkinson's disease. Annals of Neurology, 78(4), 522-529. doi:10.1002/ana.24448
Tysnes, O. B., Kenborg, L., Herlofson, K., Steding‐Jessen, M., Horn, A., Olsen, J. H., & Reichmann, H. (2015). Does vagotomy reduce the risk of Parkinson's disease?. Annals of Neurology, 78(6), 1011-1012. doi:10.1002/ana.24531.
Volpicelli-Daley, L. A., Luk, K. C., Patel, T. P., Tanik, S. A., Riddle, D. M., Stieber, A., Meaney, D. F., Trojanowski, J. Q. & Lee, V. M. Y. (2011). Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron, 72(1), 57-71. doi:10.1016/j.neuron.2011.08.033.
Yilmaz, R., Bayram, E., Ulukan, Ç., Altınok, M. K., & Akbostancı, M. C. (2017). Appendectomy history is not related to Parkinson’s disease. Journal of Parkinson's Disease, 7(2), 347-352. doi:10.3233/JPD-171071.
Yuksel, E. S., Topal, F., Gür, Ö., Topal, F., Karahanlý, C., & Uran, B. (2019). IL-17 and IL-22 in colitis associated colorectal cancer in mice. Medical Science, 23, 375-380.
