Familial Mediterranean Fever: a review for clinical management.

Familial Mediterranean Fever (FMF) is a hereditary autosomal recessive, autoinflammatory disorder characterized by recurrent, self-limiting episodes of short duration (mean 24-72 h) of fever and serositis. FMF is the most frequent periodic febrile syndrome among the autoinflammatory syndromes (AS), a heterogeneous group of recently identified diseases clinically characterized by recurrent febrile attacks, in the absence of autoantibodies and antigen-specific T lymphocytes. In FMF, periodic attacks show inter- and intra-individual variability in terms of frequency and severity. Usually, they are triggered by apparently innocuous stimuli and may be preceded by a prodromal period. The Mediterranean FeVer gene (MEFV) responsible gene maps on chromosome 16 (16p13) encoding the pyrin-marenostrin protein. The precise pathologic mechanism is still to be definitively elucidated; however a new macromolecular complex, called inflammasome, seems to play a major role in the control of inflammation and it might be involved in the pathogenesis of FMF. The most severe long-term complication is type AA amyloidosis, principally affecting the kidney and the cause of chronic renal failure. Two types of risk factors, genetic and non-genetic, have been identified for this complication. Currently, the only effective treatment of Familial Mediterranean Fever is the colchicine. New drugs in a few colchicine resistant patients have been tried, but additional studies on larger series are necessary to draw definitive conclusions.

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.

Efficacy of etanercept in the treatment of a patient with Behçet's disease.

Behçet's disease is a systemic inflammatory disorder without a specific treatment that is chosen on the basis of the type and severity of manifestation in the organ involved. More recently, biological agents like etanercept have emerged as possible therapeutic alternatives in patients resistant to conventional therapy. We describe the successful treatment for 1 year of resistant Behçet's disease with etanercept. After the administration of this drug, a resolution of the clinical, laboratory and instrumental picture was achieved with a suspension of immunosuppressive treatments and a reduction of steroid dependency (5 mg/day). No side effects were observed.

Gastrointestinal involvement in a case of hereditary angioedema: could the early weaning have had a role?

Hereditary angioedema (HAE) is a noninflammatory disorder due to reduced C1-inhibitor level and/or function and characterized by recurrent, circumscribed, and self-limiting episodes of cutaneous and mucous membrane swellings involving different organs. A heterogeneous group of mutations in the C1-inhibitor gene have been found. HAE might present with diverse clinical pictures, even within families with the same mutation, but the cause of this variability is not known yet. We describe the case of type II HAE in a young adult presenting with recurrent abdominal pain for many years, occasionally associated with ascites. We suppose that an early weaning might have influenced his phenotype, making his gastrointestinal tract a "vulnerable organ," in which hereditary angioedema could express itself.

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.

Fecal calprotectin in first-degree relatives of patients with ulcerative colitis.

OBJECTIVES: The pathogenesis of inflammatory bowel disease seems to depend on the combination of genetic and environmental factors. To evaluate genetic susceptibility, one approach is to search for specific markers in apparently unaffected family members of patients. Our aim was to evaluate fecal calprotectin concentrations (FCCs) in first-degree relatives of patients with ulcerative colitis (UC). PATIENTS: Fifty-five patients with UC and 167 healthy first-degree relatives were recruited; 38 of the patients' spouses were also enrolled. One hundred fifty healthy subjects participated as the control group. METHODS: FCCs were determined by ELISA. FCCs were compared among the groups by Kruskal-Wallis analysis of variance (ANOVA) test followed by Mann-Whitney U test. RESULTS: Significantly greater FCCs were found in first-degree relatives of patients with UC (76.0 [34.7-129.6] microg/g) as compared with controls (31.6 [17.0-45.0]) (P < 0.0001). Fecal calprotectin levels in patients with UC (256.0 [153.0-356.0] microg/g) were significantly higher as compared with first-degree relatives, spouses (43.8 [18.6-89.0] microg/g), and controls (P < 0.0001 for all comparisons). FCC of relatives was significantly higher than FCC of spouses (P = 0.01). FCC of spouses had a significantly higher FCC with respect to controls (P = 0.01). CONCLUSIONS: First-degree relatives of patients with UC had greater FCC values and could have a subclinical intestinal inflammation. It needs to be clarified if this finding is the consequence of genetic predisposition, of environmental factors, or the interaction of both, and if relatives with high FCC have a greater risk of developing the disease.

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.

Management and treatment of lactose malabsorption.

Lactose malabsorption is a very common condition characterized by intestinal lactase deficiency. Primary lactose malabsorption is an inherited deficit present in the majority of the world's population, while secondary hypolactasia can be the consequence of an intestinal disease. The presence of malabsorbed lactose in the colonic lumen causes gastrointestinal symptoms. The condition is known as lactose intolerance. In patients with lactase nonpersistence, treatment should be considered exclusively if intolerance symptoms are present. In the absence of guidelines, the common therapeutic approach tends to exclude milk and dairy products from the diet. However, this strategy may have serious nutritional disadvantages. Several studies have been carried out to find alternative approaches, such as exogenous beta-galactosidase, yogurt and probiotics for their bacterial lactase activity, pharmacological and non pharmacological strategies that can prolong contact time between enzyme and substrate delaying gastrointestinal transit time, and chronic lactose ingestion to enhance colonic adaptation. In this review the usefulness of these approaches is discussed and a therapeutic management with a flow chart is proposed.

[Functional dyspepsia: definition, classification, clinical and therapeutic management]. / Dispepsia funzionale: definizione, classificazione, approccio clinico e terapeutico.

Dyspepsia is a very common syndrome characterized by pain and/or discomfort of the upper abdomen. Sometimes, an organic disease causes this syndrome (organic dyspepsia); more frequently, there are no known diseases (functional dyspepsia). These latter conditions are identified by exclusion. The pathogenesis of this syndrome is yet to be clarified. Currently, functional dyspepsia is classified in ulcer-like dyspepsia, dysmotility-like dyspepsia and nonspecific dyspepsia, in which symptoms do not clearly fit into any of the above categories. The current guidelines for the management of "uninvestigated dyspepsia" suggest testing for Helicobacter pylori infection and relative treatment if positive. A gastroscopy should be performed in case of persistence of symptoms to discriminate between the organic and functional forms. In the latter, to optimize patient management, it is necessary to find the exact subgroup. Antacids, H2-receptor antagonists and proton pump inhibitors have been demonstrated to be useful in ulcer-like dyspepsia. Prokinetic agents are more effective in the dysmotility-like dyspepsia. Further studies will be necessary to confirm the efficacy of emerging therapeutic strategies.

Lactobacillus acidophilus protects tight junctions from aspirin damage in HT-29 cells.

BACKGROUND/AIMS: Non-steroidal anti-inflammatory drugs cause enterocyte damage inducing an increase of intestinal permeability. Tight junctions are the key structures in the permeability of the intestinal mucosa. ZO-1 is a tight junction associated protein considered a good marker of their integrity. It has been suggested that probiotics could play a protective role in the intestinal barrier function. We determined, in vitro, whether the heat-killed Lactobacillus acidophilus strain LB (LaLB) with its spent culture supernatant protects tight junctions of HT-29 cells from aspirin (ASA) damage. METHODS: HT-29 cells were treated with ASA alone or ASA and LaLB with its spent culture supernatant together. Morphological alterations of tight junctions were evaluated by immunofluorescence using an anti-ZO-1 antibody. Moreover, a semiquantitative assay for ZO-1 was performed by Western blot. RESULTS: Immunofluorescence analysis showed a fragmented and granulous ZO-1 staining, after ASA treatment. Using both ASA and LaLB with its spent culture supernatant together, we found a fine continuous linear web at cell-cell contacts similarly to control. Western blot revealed that ASA inhibited ZO-1 expression and LaLB with its spent culture supernatant counteracted this effect. CONCLUSIONS: This pilot study shows, for the first time, the protective effect of LaLB with its spent culture supernatant on tight junctions from ASA damage. These results suggest that probiotics could play a role in the prevention of ASA-induced alterations of intestinal permeability.

Systemic inflammatory diseases and silicone breast prostheses: report of a case of adult still disease and review of the literature.

There has been a debate about the possibility of a link between silicone breast implants and the onset of systemic connective tissue diseases (eg, scleroderma, systemic lupus erythematosus, rheumatoid arthritis) and other inflammatory pathologies, such as silicone implant associated syndrome and adult Still disease. We report a case of adult Still disease in a patient with a silicone gel breast implant. The disease regressed with steroidal treatment, and the patient is now no longer steroid-dependent, although the implant is still in place.

[Probiotics: history, definition, requirements and possible therapeutic applications]. / I probiotici: storia, definizione, requisiti e possibili applicazioni terapeutiche.

The ingestion of probiotics is associated with various beneficial effects on human health and modifies the physiological homeostasis of the intestinal flora. Probiotics are microorganisms with some particular characteristics: human origin, safety in human use, bile and acid resistance, survival in the intestine, at least temporary colonization of the human gut, adhesion to the mucosa and bacteriocine production. Thanks to these characteristics, probiotics block the invasion of human intestinal cells by the enteroinvasive bacteria. Furthermore, they should be able to stimulate and modulate the intestinal immune response, and to protect and stabilize the mucosal barrier. Finally, the efficacy of probiotics should be evident and documented with valid studies. All their properties should be maintained during processing and storage. Probiotics are usually used to protect the host from pathogens. With regard to this, they are useful in the prevention of antibiotic and traveler's diarrhea and they may play a role in the management of gastric Helicobacter pylori infection. Furthermore, their efficacy in the treatment of infectious diarrhea, in inflammatory bowel diseases, in pouchitis and in food allergy has been shown. Probiotics can improve the symptoms of irritable bowel syndrome and of lactose malabsorption. Finally, it has been suggested that such microorganisms may play a role in the prevention of carcinogenesis and of tumor growth.