Systemic and local collagen turnover in hernia patients.

BACKGROUND

Hernia formation is a multifactorial disease involving important endogenous factors possibly affected by exogenous factors. Alterations in collagen composition seem to contribute to abdominal wall hernia formation, possibly related to increased collagen breakdown. The collagen composition appears altered in fascial tissue but also in skin biopsies, suggesting that the collagen alterations are systemic. More pronounced collagen alterations are found in patients with hernia recurrences. Hypothetically, primary inguinal hernias are formed due to a systemic predisposition to altered connective tissue, whereas impaired healing influences on the development of incisional hernias and hernia recurrences. The overall objective of this thesis was to investigate the collagen turnover systemically and locally in patients with primary inguinal hernia, multiple hernias and incisional hernia.

METHODS AND RESULTS

In a systematic literature review, a total of 55 original articles were reviewed evaluating connective tissue alterations in patients with abdominal wall hernias. Patients with inguinal and incisional hernias exhibit a decreased type I to III collagen ratio in fascia and skin biopsies with the most pronounced alterations found in patients with direct inguinal hernia and hernia recurrence. An increased level of MMP-2 was reported in patients with inguinal hernias. In a nationwide study from the Danish Hernia Database, 92,283 patients with an inguinal hernia repair were identified from January 1998 until June 2010. A total of 843 patients were also registered with a ventral hernia repair. Direct (OR = 1.28 [95% C.I. 1.08-1.51]) and recurrent (OR = 1.76 [95% C.I. 1.39-2.23]) inguinal hernia repairs were significantly associated with ventral hernia repair compared to indirect inguinal hernia repair after adjustment for gender, age and surgical approach. In a multivariable subgroup analysis, direct and recurrent inguinal hernia repair were associated with primary ventral hernia surgery, whereas only recurrent inguinal hernia repair was associated with secondary ventral hernia surgery. In a cohort of 305 patients followed up a median of 3.7 years after emergency or elective laparotomy, a total of 79 patients were identified with an incisional hernia. Patients were subgrouped based on the identified risk factors male gender and smoking in eight groups with nine patients in each. Pooled serum samples were screened for MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-12, MMP-13, TIMP-1, TIMP-2, and TIMP-4 with a multiarray and zymography. The screening indicated differences in MMP-9 and TIMP-1, which were measured in serum samples of the whole patient cohort with ELISA. There were no differences in systemic MMP-9 and TIMP-1 levels between patients with and without incisional hernia. Patients were enrolled consecutively in four groups: 1) patients undergoing elective laparoscopic cholecystectomy without hernias (N = 18), patients operated on for 2) primary unilateral inguinal hernia (N = 17), 3) multiple hernias defined as three or more primary hernias (N = 21) and 4) incisional hernia (N = 25). Venous blood was collected preoperatively. Pro-MMP-2 and pro-MMP-9 were measured in serum by gelatine zymography, and there were no significant differences between hernia patients and controls. Furthermore, serological biomarkers for type I, III, IV and V collagen turnover were measured in serum by solid-phase competitive immunoassays. In patients with inguinal hernia, type III and V collagen turnover were significantly decreased, whereas type IV collagen turnover was significantly increased. In incisional hernia patients, type V collagen turnover was significantly decreased, whereas type IV collagen turnover was significantly increased. Type IV collagen turnover seem to predict the presence of both inguinal and incisional hernia. An ePTFE tube was implanted perioperatively in all four patient groups and explanted on the tenth post-operative day. Newly synthesized granulation tissue in the ePFTE tube represents the patients' wound healing potential. Hydroxyproline levels were measured as a marker for total collagen deposition and were unaltered in hernia patients compared to controls. Pro-MMP-2 and pro-MMP-9 levels in the PTFE tubes did not differ between hernia patients and controls. A fascia transversalis biopsy was excised perioperatively in all four patient groups. There were no significant differences between hernia patients and controls in total collagen concentration or morphology of the fascia transversalis.

CONCLUSIONS

Direct and recurrent inguinal hernia repair are associated with ventral hernia repair, suggesting a systemic predisposition to the hernia disease. MMPs are not suitable as serum biomarkers for inguinal or incisional hernia disease. Serum biomarkers for collagen turnover are altered in both inguinal and incisional hernia patients; specifically markers for type IV collagen turnover seem to predict the presence of hernias.  A systemic biomarker predicting hernia disease would be useful to plan a tailored surgical strategy for the individual patient.