α1-Antitrypsin and fibromyalgia: new data in favour of the inflammatory hypothesis of fibromyalgia

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Summary

α1-Antitrypsin (AAT) circulates in high serum concentrations, and impregnates most body tissues. AAT has a broad anti-inflammatory spectrum, and modulates most inflammatory reactions occurring in human body. Recently, a possible relationship between AAT deficiency (AAT-D) and fibromyalgia (FM) has been raised, with the finding that intravenous infusions of purified human AAT efficiently controlled FM symptoms in two patients with severe hereditary AAT-D. On the other hand, functional magnetic resonance imaging has detected a significant greater activity in pain sensitive areas of the brain in patients with FM, in response to cutaneous stimuli, providing further evidence for a physiological explanation for FM pain. In recent studies abnormal profiles of inflammation markers in serum and biopsies have been found in FM patients. Since most of these inflammation mediators can be inhibited by AAT, these observations would suggest that at least a subset of the FM syndrome could be related to an inflammatory process, possibly due to an imbalance between inflammatory and anti-inflammatory substances, in the soft body tissues. Future directions of research would be: (1) to develop epidemiological studies to determine the gene frequency of AAT deficiency alleles in FM patients; (2) implementation of a double-blind placebo-controlled clinical trial to determine the specific role of AAT augmentation therapy in AAT-D patients with FM; (3) identification of specific laboratory markers for diagnostic and clinical evaluation purposes in FM; (4) application of the newest medical imaging techniques for diagnosis; and (5) identification of genetic, familial, and environmental risk factors suspected to participate in the FM syndrome development.

Introduction

While scientific advances on the α1-antitrypsin (AAT) field have been both rapid and relevant since the first description of AAT deficiency (AAT-D) about 40 years ago [1], [2], fibromyalgia (FM) remains being an enigmatic and worldwide prevalent syndrome with unknown aetiology and pathogenesis, and without any effective treatment to date [3]. Several studies have shown that AAT is a natural molecule with a broad anti-inflammatory spectrum, which modulates most inflammatory reactions occurring in the human body [4], [5]. Recently, a case report has raised a possible relationship between AAT-D and FM, based on the observation that AAT replacement therapy efficiently controlled long-term FM symptoms in a pair of female with AAT-D [6]. Although such a case report has the weakest level of Evidence Based Medicine, sometimes an unusual case may become an “index case”, and may lead to the formulation of new hypothesis on diagnostic and therapeutic options [7]. On the other hand, recent studies have found abnormal profiles of inflammation markers and pro-inflammatory cytokynes both in serum [8], [9], [10], [11], [12], [13], [14], [15] and biopsy samples [16], [17], [18], [19], [20] of some FM patients, that do not exist in normal subjects. All these data would suggest that at least a subset of FM could be related to an abnormal inflammatory process, probably located at subcutaneous connective tissue, due to a possible imbalance between inflammatory and anti-inflammatory biological substances [6].

The objectives of the present study are: (1) to update recent data on anti-inflammatory properties of AAT; (2) to perform a critical review (following the Evidence Based Medicine rules) of the published studies on FM and inflammation; (3) to formulate an hypothesis about the possible inflammatory pathogenesis of FM; and (4) to promote the development of future studies focusing on AAT-D, FM and inflammation.

Section snippets

Methods

Data for this review were identified by searches on Medline, PubMed, from 1960 to 2004, and references from relevant articles using the search terms: “alpha 1-Antitrypsin”, “alpha 1-Protease inhibitor”, “alpha 1-Proteinase inhibitor”; “alpha 1-Antitrypsin deficiency”, “fibromyalgia”, “inflammation mediators”, and “cytokines”, according to the medical subject headings (Mesh) terminology of United States National Library of Medicine. In addition, some relevant articles were provided by experts in

α1-Antitrypsin a concept in progress: from an acute phase reactant to a broad spectrum anti-inflammatory biological molecule

AAT is a 52 kD globular glucoprotein, with a unique chain of 394 aminoacids and 3 lateral chains of carbohydrates linked by 3 residues of asparagine. The AAT gene is located on the long arm of the 14th chromosome, in 14q31-32.3 position. The gene is organized into 3 non-coding exons (Ia, Ib, Ic) and 4 coding (II, III, IV and V) exons. Hepatocytes are the primary source of AAT, but other cells, including monocytes, macrophages, and lung and intestinal epithelial cells may also synthesise low

Acknowledgement

We wish to thank to Ms. Jlmena Blanco-Fueyo for the final English revision of the manuscript.

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