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Allergic Predisposition, Histamine and Histamine Receptor Expression (H1R, H2R) Are Associated with Complicated Courses of Sigmoid Diverticulitis

  • 2011 SSAT Plenary Presentation
  • Published:
Journal of Gastrointestinal Surgery

Abstract

Background

We aimed to evaluate our hypothesis that allergic predisposition and expression of histamine receptors might contribute to complicated courses of sigmoid diverticulitis.

Methods

Expression of histamine and histamine receptors (H1R, H2R) was analysed on protein level (immunohistochemistry/immunofluorescence (IF)) as well as mRNA level (reverse transcription–PCR (RT-PCR) in surgical specimen of patients (n = 101) having undergone resection for sigmoid diverticulits (n = 57 complicated diverticulitis/n = 44 non-complicated diverticulitis).

Results

The mean number of comorbid diseases per patient was 1.76 ± 1.25. Thirty-nine of 101 patients (38.6%) exhibited allergic predisposition (grass poll, food, drug, pets, etc.). Comorbid diseases were significantly associated with complicated diverticulitis (p = 0.027). Complicated sigmoid diverticulitis was significantly associated with high H1R and H2R expression (p < 0.001). Furthermore, an association of complicated diverticulitis with allergic predisposition was found (odds ratio = 3.2, p = 0.0097). IF double-labelling experiments showed a strong correlation of increased histamine expression with expression of H1R and H2R on intestinal enterocytes (histamine/H1R, rho = 0.841, p < 0.0001 and histamine/H2R, rho = 0.806, p < 0.0001). The results of increased H1R and H2R expression in complicated sigmoid diverticulitis were also detected on mRNA level in a subset of patients (RT-PCR, p = 0.009).

Conclusions

Our findings suggest that allergic predisposition might be another important risk factor for complicated courses of acute sigmoid diverticulitis and linked with histamine receptor expression. Supportive therapies with antihistaminic drugs might become an option. Allergic predisposition might be worth considering when indicating surgery for sigmoid diverticulitis.

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Acknowledgements

The authors thank the assistance of Mrs. Manuela Schneider and Mrs. Sabine Gahn for their technical support. We thank the excellent academy of the chairmen of the Deutsche Gesellschaft für Allgemein- und Visceralchirurgie (DGAV) for the financial support. For S.K., the work was supported by the Wilhelm Sander Foundation (grant 2007.068.1).

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Authors and Affiliations

  1. Department of General-, Visceral-, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Wuerzburg, Germany

    Burkhard H. A. von Rahden, Christian Jurowich, Matthias Jung, Christoph-Thomas Germer & Martin Grimm

  2. Department of Pathology, University Hospital Wuerzburg, Wuerzburg, Germany

    Stefan Kircher

  3. Department of Cardiac and Thoracic Surgery, University of Wuerzburg Hospital, Oberduerrbacher Strasse 6, 97080, Wuerzburg, Germany

    Maria Lazariotou

  4. Department of Craniomaxillofacial and Oral Surgery, Plastic Operations, General Hospital Nuremberg, Nuremberg, Germany

    Martin Grimm

  5. Klinik und Poliklinik für Allgemein-, Viszeral-, Gefäss- und Kinderchirurgie, Universitätsklinikum Würzburg, Oberdürrbacherstr. 6, 97080, Würzburg, Germany

    Burkhard H. A. von Rahden

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Correspondence to Burkhard H. A. von Rahden.

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Discussant

Dr. Kirk A. Ludwig (Milwaukee, WI): First, let me say thank you for trying to bring some science to the study of diverticular disease. The clinical and basic science literature is generally not very good, and there are far too many knowledge gaps for what is such a common condition.

Diverticulitis is a disease of Western society with an increase in incidence seen as the first cohort of children raised on white flour and refined sugar came of age about 40 years after the start of the Industrial Revolution. Clearly, there is a dietary relationship, and there may also be an environmental relationship that may coincide with the two- to threefold increase in environmental allergies seen in the last 40 years. Perhaps, there is some common mechanism at work here.

My major concern with this study is whether what we see in terms of the strong H1R and H2R expression in the complicated diverticulitis patients by both IHC and RT-PCR is not simply a result of the intense inflammation seen in this group of patients as opposed to the cause of the intense inflammation.

Is it not possible that the patients in the non-complicated group might at some point have been part of the complicated group, and given sufficient treatment, they simply recovered and became part of the chronic symptom, but not terribly inflamed non-complicated group? If so, then finding high histamine receptor levels in the complicated group may simply be a result of the inflammation, not the cause of the inflammation.

Finally, how exactly was “allergic predisposition” defined and how was it determined? This assessment could be biassed if it was made retrospectively. How does one define and document what many people would not think twice about… an environmental allergy? These are just so common, as to barely warrant mentioning as part of a medical history? Also, were the investigators blinded as to the group designation when examining the IHC slides so that bias was avoided?

Closing Discussant

Dr. Burkhard H. A. von Rahden: Thank you very much for your kind acknowledgement of our efforts regarding sigmoid diverticulitis. We totally agree with you that diverticulitis is somehow a “neglected disease”—and an incoming congress scheduled for autumn in Cologne/Germany is going to cover this interesting topic subsumed under this title: “Diverticulitis—a fresh approach to a neglected disease”. Many questions are open regarding the appropriate conservative and surgical treatment and about the underlying molecular mechanisms of the inflammatory process and its implications for clinical practice. Initiating this work about histamine metabolism in this context, we found it rather astonishing that there are no data regarding this issue in diverticulitis—although the histamine story is already ongoing for some time.

Regarding your question concerning the cause-and-effect chain and whether histamine receptor expression seen on enterocytes in complicated diverticulitis might be merely epiphenomenalistic, actually, we cannot exclude this from our current data. Larger and preferably prospectively arranged investigations should answer this question. However, our results of H1R and H2R expression on protein and mRNA level suggest that it is definitely worth to take a closer look and initiate more research. The reason why this is appealing is the vast variety of potential treatment options in the modulation of histamine metabolism—e.g. with antihistaminics, supplementation of DAO, probiotics, vitamins A and D, etc.). Even if histamine receptors might merely be a bystander, it could nevertheless be that targeting might have some effect in the modulation of the disease process.

The current data suggest that complicated diverticulitis and chronically recurrent diverticulitis are different types of the disease and explicitly not different stages of the disease. This view seems well supported by what we see in clinical practice and what can be derived from current literature. I would like to refer to the work by Jennifer Chapman from the Mayo Clinic, who published two important papers, one about complicated diverticulitis (Ann Surg 242(4):576–81) and one about chronically recurrent diverticulitis (Ann Surg 2006, 243(6):876–830). The major findings in these studies were that complicated diverticulitis occurs mostly during the first episode, whereas a chronically recurrent course of the disease is usually not associated with an increased risk of complicated courses. We have addressed diverticulitis as a complicated type when a covered or free perforation is proven and also when there is a severe inflammatory infiltrate, which did not disappear even after antibiotic pretreatment. The latter is addressed as phlegmonous diverticulitis. Chronically recurrent diverticulitis types—by contrast—are characterized by their clinical course, and on histology, one can see evidence of chronic scarring, but no severe inflammatory infiltrate.

Concerning the definition of “allergic predisposition” and the mode of acquisition of these data, the data regarding prevalence of allergies in these patients were actually gathered prospectively. We exploited several sources of prospectively documented data—by the anaesthesiologist (during premedication vistit)—by the nurses (during preclinical preparation of the patient and during admission to the ward)—and by the surgeon (during history taking and physical examination). We did not stratify our results regarding different types of allergies. We did not think that the number of patients in our study would allow us to go deeper into subgroup analysis. Investigators were indeed blinded during the analysis of the IHC slides, and correlation analyses were performed during work-up of the database.

This paper has been chosen for presentation at the Digestive Disease Week 2011, Chicago during the SSAT plenary session and at the SSAT Residents and Fellows Conference 2011.

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von Rahden, B.H.A., Jurowich, C., Kircher, S. et al. Allergic Predisposition, Histamine and Histamine Receptor Expression (H1R, H2R) Are Associated with Complicated Courses of Sigmoid Diverticulitis. J Gastrointest Surg 16, 173–182 (2012). https://doi.org/10.1007/s11605-011-1702-8

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