Endometriosis and atherosclerosis: what we already know and what we have yet to discover.

The possible association between endometriosis and atherosclerosis represents an emerging topic in the field of women's health. In this Clinical Opinion paper, we analyze this theme focusing on the pathogenetic mechanisms of both diseases, deeply discussing about what is already known about this association and producing starting points about what we consider suitable to research in the near future with regard to cardiovascular involvement in women affected by endometriosis. We have identified 5 reports specifically carried out to investigate the relationship between atherosclerosis and endometriosis; these studies show the presence of subclinical atherosclerosis in women affected by endometriosis, susceptible of regression after surgical removal of endometriosis, with a possible prognostic relevance for variations of cardiovascular risk in these women. However, to date, no studies in literature have been carried out to investigate the real incidence of cardiovascular events in women with endometriosis.

Looking for celiac disease in Italian women with endometriosis: a case control study.

In the last years, a potential link between endometriosis and celiac disease has been hypothesized since these disorders share some similarities, specifically concerning a potential role of oxidative stress, inflammation, and immunological dysfunctions. We investigated the prevalence of celiac disease among Italian women with endometriosis with respect to general population. Consecutive women with a laparoscopic and histological confirmed diagnosis of endometriosis were enrolled; female nurses of our institution, without a known history of endometriosis, were enrolled as controls. IgA endomysial and tissue transglutaminase antibodies measurement and serum total IgA dosage were performed in both groups. An upper digestive endoscopy with an intestinal biopsy was performed in case of antibodies positivity. Presence of infertility, miscarriage, coexistence of other autoimmune diseases, and family history of autoimmune diseases was also investigated in all subjects. Celiac disease was diagnosed in 5 of 223 women with endometriosis and in 2 of 246 controls (2.2% versus 0.8%; P = 0.265). Patients with endometriosis showed a largely higher rate of infertility compared to control group (27.4% versus 2.4%; P < 0.001). Our results confirm that also in Italian population an increased prevalence of celiac disease among patients with endometriosis is found, although this trend does not reach the statistical significance.

Regression of endothelial dysfunction in patients with endometriosis after surgical treatment: a 2-year follow-up study.

STUDY QUESTION: How does endothelial function change in women with endometriosis after surgical treatment? SUMMARY ANSWER: Surgical treatment of endometriosis leads to endothelial function improvement, resulting in reduction of cardiovascular risk. WHAT IS KNOWN ALREADY: Some recent studies have demonstrated that in young women with endometriosis, even if structural alterations are absent, endothelial dysfunction, expressed as flow-mediated dilation (FMD) impairment, can nevertheless occur. However, there are no data about changes of endothelial function in women with endometriosis after surgical treatment of endometriosis. STUDY DESIGN, SIZE, DURATION: This is a follow-up study carried out in 68 women enrolled in a previous study. Endothelial function was evaluated 2 years after surgical procedure and compared with baseline values. PARTICIPANTS/MATERIALS, SETTING, METHODS: Twenty-two patients who had undergone surgical treatment of endometriosis (named as patients with STE) and 10 control subjects without endometriosis, from the original study sample participated in this follow-up study. Assessment of endothelial function by FMD evaluation and measurements of serum markers of endothelial activation and inflammation were done in all these subjects. MAIN RESULTS AND THE ROLE OF CHANCE: After a 2-year follow-up period, FMD increased significantly with respect to baseline values among patients with STE [average pre- to post-difference: 5.07%, 95% confidence intervals (CI) 3.50, 6.63%; P < 0.001] but not among controls (average pre- to post-difference: 1.56%, 95% CI -0.55, 3.67%; P = 0.13). Follow-up FMD values were not significantly different between patients with STE and controls (average difference 1.50%, 95% CI -1.24, 4.23%; P = 0.27). Follow-up markers of inflammation and endothelial cells activation were similar among patients with STE and controls. LIMITATIONS, REASONS FOR CAUTION: Although this study represents the first in the literature assessing endothelial function after surgical treatment of endometriosis, further longitudinal studies are desirable to define better the real risk that women with a history of endometriosis will develop cardiovascular events. WIDER IMPLICATIONS OF THE FINDINGS: Endothelial dysfunction may be a better predictor of future cardiovascular events than traditional risk factors and the improvement in endothelial function we observed in patients after STE may have significant implications for their future cardiovascular risk. STUDY FUNDING/COMPETING INTEREST(S): No external funding has been either sought or obtained for this study. There are no conflicts of interest to declare.

Endothelial dysfunction but not increased carotid intima-media thickness in young European women with endometriosis.

BACKGROUND: Atherosclerosis is a chronic and degenerative disease developing typically in the elderly; nonetheless, a condition of accelerated atherosclerosis can be observed precociously in the presence of some diseases. Endometriosis, a chronic benign gynecological disorder, shows some characteristics, such as oxidative stress, systemic inflammation and a pro-atherogenic lipid profile, which could increase the risk of developing accelerated atherosclerosis. The aim of our study was to evaluate markers of subclinical atherosclerosis in young European women with endometriosis. METHODS: This cross-sectional study included 37 women with endometriosis and 31 control subjects. The presence of subclinical atherosclerosis was investigated by ultrasound evaluation of common carotid intima-media thickness (ccIMT) and flow-mediated dilation (FMD); in addition, serum levels of lipids, inflammatory and coagulation parameters, as well as markers of endothelial inflammation and activation, were determined. RESULTS: Women with endometriosis showed significantly lower values of FMD compared with controls [mean difference: -4.62, 95% confidence interval (CI): -6.52, -2.73; P < 0.001], whereas no significant differences in ccIMT values were found between the two groups. As regards markers of endothelial inflammation and activation, women with endometriosis had significantly higher values of inter-cellular adhesion molecule 1 (P < 0.001), vascular cell adhesion molecule 1 (P < 0.001), E-selectin (P < 0.001), von Willebrand factor (P = 0.004) and ristocetin cofactor (P = 0.001) compared with controls. CONCLUSIONS: Our study suggests that women with endometriosis have more subclinical atherosclerosis, resulting in a higher risk of developing cardiovascular disorders. Moreover, our findings demonstrate that endothelial dysfunction can occur in the absence of structural atherosclerotic changes; its evaluation might be helpful in young women with endometriosis.

Fecal calprotectin concentrations in alcoholic patients: a longitudinal study.

OBJECTIVES: Excessive alcohol consumption often results in intestinal damage, mediated by inflammatory processes, mainly characterized by an increased influx of leukocytes. Fecal calprotectin is a granulocyte cytosolic protein, representing as a promising marker of subclinical intestinal inflammation. In this study, we assessed fecal calprotectin concentrations (FCCs) in current drinking alcoholics, both at the baseline, and then during a subsequent 84-day period. Moreover, FCCs in the alcoholics were compared with the FCCs in healthy controls. METHODS: Twenty-eight, active-drinking alcoholics were enrolled in this study and compared with 40 healthy volunteers as the control group. In alcoholics, FCCs were determined at the beginning of the study (baseline; T0) and then every 2 weeks (T1-T6) during the following 84-day period. Potential differences in FCCs were analyzed between alcoholics and healthy controls, and during the 84-day period within the group of alcoholics. In addition, an analysis of FCCs was conducted in three subgroups of alcoholics, considering their drinking status during the 84-day period (abstinent, relapsed, and active). RESULTS: At baseline, no significant differences in median FCCs were found between alcoholics and controls. No significant changes of median FCCs were found, comparing baseline FCCs and FCCs during the 84-day period (T1-T6) in the whole group of alcoholics, nor in the three subgroups of alcoholics. CONCLUSION: FCCs in active-drinking alcoholics are not significantly different, compared with the healthy controls. Moreover, FCCs do not significantly differ according to the alcohol drinking status. These results may suggest the absence of a subclinal intestinal inflammation involving neutrophils in the alcoholics.

Can chronic gastritis cause an increase in fecal calprotectin concentrations?

AIM: To evaluate fecal calprotectin concentrations (FCCs) in subjects with chronic gastritis and the correlation between FCCs and gastritis activity score. METHODS: FCCs were measured in 61 patients with histological diagnosis of gastritis and in 74 healthy volunteers. Histological grading of gastritis was performed according to the updated Sydney gastritis classification. Patients were subdivided into 2 groups according to the presence/absence of an active gastritis. Patients with chronic active gastritis were divided into 3 subgroups on the basis of the activity score (mild, moderate, marked). FFCs in relation to Helicobacter pylori (H. pylori) infection and proton pump inhibitor (PPI) use were also evaluated. RESULTS: FCCs in patients with chronic active gastritis were not significantly different to FCCs either in subjects with non active gastritis or in healthy controls. Among patients with chronic active gastritis (even marked), FCCs did not significantly differ according to activity score. No significant differences in FCCs were found when considering H. pylori, as well as when considering PPI chronic use. CONCLUSION: FCCs were not significantly increased in subjects with chronic gastritis, even in those patients with a marked neutrophil infiltration.

Endometriosis, need for a multidisciplinary clinical setting: the internist's point of view.

Endometriosis is a common condition characterized by proliferation of endometrial tissue outside the uterus, both in the pelvis and in other extra-pelvic sites. The clinical picture of endometriosis is widely heterogeneous. A correct diagnostic work-up of these patients can sometimes be very difficult, since there are a number of gynecological, intestinal and systemic diseases mimicking endometriosis, as well as other conditions that could be associated with or are a consequence of this disorder. Therefore, multidisciplinary care should be encouraged to ensure correct evaluation and improve the management of these patients.

Autoimmune enteropathy in children and adults.

Autoimmune enteropathy is a rare disorder characterized by severe and protracted diarrhea, weight loss from malabsorption and immune-mediated damage to the intestinal mucosa, generally occurring in infants and young children, although some cases of adult onset have been reported in the literature. Pathogenetic mechanisms involve immunological disorders, in which the presence of antienterocyte autoantibodies, although detected since first description, seems now to be secondary. As occurs frequently in autoimmunity, subjects with autoimmune enteropathy may be affected by other autoimmune disorders, sometimes leading to particular forms, i.e. the IPEX syndrome and the APECED syndrome. The prognosis of autoimmune enteropathy patients depends on the severity of digestive symptoms (including fecal output), on the severity and extension of histological lesions along the gastrointestinal apparatus, and on the presence of extra-intestinal involvement. Management of autoimmune enteropathy patients is based on nutritional support and adequate hydration to ensure optimal growth and development, together with immunosuppressive therapy. Recently, biological agents have been introduced, with apparent beneficial effects.

Intestine: organ or apparatus?

It is well known that human intestine is involved in different important functions. First of all, it is responsible for digestion and absorption of nutrients, electrolytes, water, bile salts and drugs, but it also has immunologic, endocrine and motor functions. Moreover, intestinal microflora, composed by a large diversity of bacterial cells, provides several beneficial functions for the host and is, nowadays, defined by many authors as an organ itself. In consideration of intestine complexity, we tried to understand if it can be considered only an organ or if it is an apparatus itself. We have analyzed the different components and their relationships, showing that a continuous collaboration is required among enterocytes, endocrine intestinal cells, gut immune system and microflora to assure an efficient mechanism of defense. In consideration of the complexity of intestinal components, together with the emergent role of microflora, we think that we could start to consider gut as a real apparatus, and not only as an organ.

Adverse reactions to food: allergies and intolerances.

All the anomalous reactions secondary to food ingestion are defined as 'adverse reactions to food'. In 1995 the European Academy of Allergology and Clinical Immunology suggested a classification on the basis of the responsible pathogenetic mechanism; according to this classification, non-toxic reactions can be divided into 'food allergies' when they recognize immunological mechanisms, and 'food intolerances' when there are no immunological implications. The diagnostic approach to adverse reactions to food is based on accurate clinical history and objective examination, and further execution of specific tests when allergy or intolerance is suspected. The therapy for food allergies is the elimination of the food to which hypersensibility has been found; this strategy can lead, especially in pediatric age, to tolerance. If elimination diets cannot be completely performed, or if it is not possible to identify the food to eliminate, some drugs (e.g. antihistaminics, steroids, etc.) can be administered. Specific allergen immunotherapy has been recently introduced. Fundamental is food allergy prevention, especially in high-risk subjects. The therapeutic approach to secondary food intolerances is based principally on primitive disease resolution; on the other hand, some specific treatments (e.g. beta-galactosidases in lactose malabsorption) are available in case of primary intolerance.

Classification of malabsorption syndromes.

Malabsorption syndrome is usually defined as the complex of symptoms secondary to maldigestion and/or malabsorption, realizing when the extension of the disease exceeds the ability of intestine compensation. Several conditions have been recognized as being responsible for this syndrome. Up to now, different criteria have been used to order them, but a definitive classification is still not available because of the complexity of the absorption process, the involvement of different organs and structures, and the coexistence of different mechanisms in some diseases causing malabsorption. We propose a new classification of diseases causing malabsorption syndrome according to the responsible etiopathogenetic mechanisms: (a) alteration of digestive processes; (b) alteration of uptake and transport caused by damage or reduction of absorption surface, and (c) miscellaneous. A comment about the mechanisms responsible for malabsorption is given for all the cited diseases.

Fecal calprotectin concentrations in patients with small intestinal bacterial overgrowth.

BACKGROUND/AIMS: Small intestinal bacterial overgrowth (SIBO) is defined by any condition in which the proximal part of the small bowel harbors for a long time > 10(5) bacteria/ml of the intestinal juice. No data are currently available about direct or indirect parameters indicating the presence of leukocytes in the gut wall and mucosal neutrophil turnover in patients with SIBO. In our pilot study we evaluate fecal calprotectin concentrations (FCC) in patients with SIBO in order to identify a possible presence of subclinical intestinal inflammation. METHODS: 40 consecutive patients with SIBO resulting positive to hydrogen glucose breath test, and 40 adult healthy volunteers were included in the study. FCC were determined by ELISA. Mean FCC were compared by means of the t-test for independent samples. RESULTS: FCC in patients with SIBO were not significantly different compared to controls (p = 0.907). CONCLUSION: Our study shows for the first time that FCC in patients with SIBO do not significantly differ from controls, suggesting that in SIBO there are no intestinal subclinical inflammatory changes involving principally the neutrophils.

Faecal calprotectin concentrations in untreated coeliac patients.

OBJECTIVE: Calprotectin is a granulocyte cytosolic protein that is considered to be a promising marker of subclinical inflammation. High faecal calprotectin concentrations (FCCs) have been found in several intestinal diseases, but no data are currently available on patients with coeliac disease. The purpose of this pilot study was to evaluate FCCs in untreated coeliac patients and to correlate them with clinical score and histological characteristics. MATERIAL AND METHODS: Twenty-eight consecutive coeliac patients were recruited. Thirty healthy adult volunteers participated as the control group. FCCs were determined by ELISA. Clinical assessment was carried out in all patients. The histological severity of lesions and the infiltration of neutrophil polymorphs in the intestinal mucosa were also evaluated. Mean FCCs in patients and the control group were compared by means of the t-test for independent samples. In coeliac patients, differences in FCCs in subgroups identified by clinical score, lesion severity and neutrophil infiltration were evaluated by the Kruskal-Wallis non-parametric test. RESULTS: FCCs in untreated coeliac patients were not significantly different from those in controls (p=0.163). Among coeliac patients, FCCs were not significantly different in relation to the level of clinical score, lesion severity or neutrophil infiltration (p=0.92, p=0.96 and p=0.74, respectively). CONCLUSIONS: This study shows, for the first time, that FCCs in untreated coeliac patients do not differ significantly from those in controls.

Prophylactic aspirin therapy does not increase faecal calprotectin concentrations.

OBJECTIVE: Non-steroidal anti-inflammatory drugs (NSAID) can induce enteropathy. Aspirin ingestion is associated with a lower small-intestinal inflammation than other NSAID. Faecal calprotectin concentrations have recently been proposed as a simple non-invasive test to identify NSAID enteropathy. The aim of our pilot study was to evaluate calprotectin concentrations in patients on treatment with low-dose aspirin. METHODS: Twenty-two patients on prophylactic treatment with aspirin were recruited. Twenty-five healthy volunteers were enrolled as a control group. Faecal calprotectin concentrations were determined by enzyme-linked immunosorbent assay. Statistical analysis was performed by t-test for unpaired data. RESULTS: The mean faecal calprotectin concentration in patients (57.95+/-44.28 microg/g) did not show significant differences compared with controls (45.76+/-26.45 microg/g; P=0.251). CONCLUSIONS: We found that low-dose aspirin does not induce an increase in faecal calprotectin increase.