Επιπολασμός ανευρύσματος κοιλιακής αορτής σε ασθενείς με βουβωνοκήλη. Διερεύνηση κοινών αιτιοπαθογενετικών μηχανισμών διαταραχής του συνδετικού ιστού

Abstract

Abdominal aortic aneurysms and abdominal wall hernias constitute significant health problems creating substantial social and financial burdens for health and surgical services in several countries. Similar epidemiological features for aortic aneurysms and inguinal hernias have been described, with both conditions largely affecting males of increasing age with a history of smoking and/or chronic obstructive pulmonary disease. The clinical association between the two disease states has been extensively investigated in observational studies, which have demonstrated an increased incidence of incisional and inguinal hernia in patients undergoing abdominal aortic aneurysm repair compared to patients with aorto-iliac occlusive disease. However, limited evidence exists regarding whether inguinal hernia represents an independent risk factor for aortic aneurysm development. Even though these clinical conditions have a multifactorial aetiology, a dysregulation in connective tissue metabolism appears to constitute underlying pathophysiological mechanisms of aneurysm and hernia formation. Extracellular matrix components of the aortic and abdominal wall are under a dynamic balance of synthesis and degradation. Matrix metalloproteinases (MMPs) appear to play crucial role in both the connective tissue degradation and the modulation of inflammatory and immune responses, and have implicated as the main culprits of the degenerative process of aneurysm and hernia. Nevertheless, it is unknown whether a systemic disorder of connective tissue metabolism exists to explain the clinical correlation of these conditions. Furthermore, even though the relationship between congenital connective tissue disorders, such as Ehlers-Danlos syndrome and Marfan’s disease, and arterial aneurysms and abdominal wall hernias is well documented, no gene association studies investigating gene polymorphic sites of the components participating in extracellular degrading processes and inflammatory responses in aneurysm and hernia populations exist.Objective.The objective of the present study was:1. To assess whether patients with inguinal hernia are more likely to have abdominal aortic aneurysm than patients without hernia receiving aneurysm screening. 2. To investigate whether a potential systemic collagen metabolism defect in patients with aneurysm and hernia may be demonstrated by estimating the levels of selected MMPs and TIMPs in the systemic circulation.3. To determine whether the angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is associated with aneurysm and hernia.Methods.Clinical-epidemiological study Male patients over the age of 55 undergoing primary inguinal hernia repair were screened with ultrasonography of the abdominal aorta for aneurysm. A reference group was selected from male individuals without clinical evidence of inguinal hernia participating in an aneurysm screening program. Prevalence and odds ratios of abdominal aortic aneurysm in the two groups were calculated.Biochemical study.Plasma concentrations of MMP-9, MMP-2, TIMP-1 and TIMP-2 were quantified using ELISA in 33 male patients with abdominal aortic aneurysm and 91 male patients with inguinal hernia. The same substances were measured in 35 healthy male controls.Genetic study.A case-control study was conducted in 264 subjects: 65 patients with abdominal aortic aneurysm, 91 patients with inguinal hernia, 19 patients with both aortic aneurysm and inguinal hernia, and 89 healthy controls were investigated for the ACE I/D and the MTHFR C677T polymorphisms. DNA was extracted from whole blood and genotype analysis was performed using a two stage polymerase chain reaction technique.Results.Clinical-epidemiological study The clinical study cohort consisted of 235 patients with inguinal hernia and 203 controls. The aortic diameter in patients with inguinal hernia was 22 ± 9 mm (mean ± 1SD), and was significantly higher than that of control individuals 20 ± 6 mm (p = 0.045). The prevalence of abdominal aortic aneurysm in the hernia and control group was 8.1% and 3.9%, respectively (adjusted odds ratio 3.9, 95% CI 1.6-9.5, p = 0.039). For aneurysms larger than 4 cm, the prevalence in those with and without inguinal hernia was 5.1% and 1.5%, respectively (adjusted odds ratio 4.7, 95% CI 1.2-18.5, p = 0.025).Biochemical study.MMP-9 and MMP-2 concentrations were lower in the plasma of patients with inguinal hernia and abdominal aortic aneurysm than controls, with hernia patients having the lowest circulating levels. The levels of TIMP-2 were significantly elevated in patients with inguinal hernia and significantly reduced in patients with aortic aneurysm, whereas opposite correlations were found for circulating TIMP-1.Genetic study.The genotype distribution for the ACE I/D polymorphism was similar within patient groups (aneurysm vs. aneurysm plus hernia vs. hernia). Differences in genotype distribution were identified between patient groups and controls, with the ACE I/D genotype being associated with aneurysm, hernia and coexistent aneurysm plus hernia (aneurysm vs. control, OR 3.7, 95% CI 1.8-7.2, p = 0.000; aneurysm plus hernia vs.control, OR 3.9, 95% CI 1.4-11.1, p = 0.007; hernia vs. control, OR 2.5, 95% CI 1.3-4.5, p = 0.004). No significant differences in the frequencies of the alleles among the study populations were detected. There were no significant differences in the frequency of the MTHFR C677T variant between any of the groups examined.Conclusions.Several factors have been found to be associated with increased prevalence of abdominal aortic aneurysm. Of these, older age, male gender and smoking have been documented to have the greatest association with aortic aneurysm, and have been used as inclusion criteria upon which implementation of abdominal aortic aneurysm screening programs is based. In the present study, an independent association between inguinal hernia and abdominal aortic aneurysm has been demonstrated, and it was found that male patients with inguinal hernia have increased prevalence of abdominal aortic aneurysm compared to male subjects without hernia. Entry into a screening program for aortic aneurysm with abdominal ultrasonography of male patients over the age of 55 admitted for inguinal hernia repair should be considered.As far as a potential systemic connective tissue disorder responsible for the clinical manifestations of aneurysm and hernia is concerned, the present study showed that such a disorder is not reflected in the blood levels of MMPs. Different patterns of circulating MMP and TIMP levels were found in patients with aneurysm and hernia compared with controls. Further research, with tissue analyses and measurement of other collagen and elastin specific MMPs/TIMPs and markers of ECM synthesis, is needed to further investigate a potential pathologenic link between the two conditions.Lastly, the genetic association of abdominal aortic aneurysm and inguinal hernia has not been previously investigated, despite their strong genetic background and significant clinical correlations. A heterozygote ACE I/D state was found to be associated with increased risk for the presence of aneurysm and/or hernia, whereas the MTHFR C677T polymorphism was not found to be correlated with either abdominal aortic aneurysm or inguinal hernia. Further gene association studies might give further insight into the genetic basis of the disease states