Venanzio Valenza

Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease

The role played by the gut in nonalcoholic fatty liver disease (NAFLD) is still a matter of debate, although animal and human studies suggest that gut‐derived endotoxin may be important. We investigated intestinal permeability in patients with NAFLD and evaluated the correlations between this phenomenon and the stage of the disease, the integrity of tight junctions within the small intestine, and prevalence of small intestinal bacterial overgrowth (SIBO). We examined 35 consecutive patients with biopsy‐proven NAFLD, 27 with untreated celiac disease (as a model of intestinal hyperpermeability) and 24 healthy volunteers. We assessed the presence of SIBO by glucose breath testing (GBT), intestinal permeability by means of urinary excretion of 51Cr‐ethylene diamine tetraacetate (51Cr‐EDTA) test, and the integrity of tight junctions within the gut by immunohistochemical analysis of zona occludens‐1 (ZO‐1) expression in duodenal biopsy specimens. Patients with NAFLD had significantly increased gut permeability (compared with healthy subjects; P < 0.001) and a higher prevalence of SIBO, although both were lower than in the untreated celiac patients. In patients with NAFLD, both gut permeability and the prevalence of SIBO correlated with the severity of steatosis but not with presence of NASH. Conclusions: Our results provide the first evidence that NAFLD in humans is associated with increased gut permeability and that this abnormality is related to the increased prevalence of SIBO in these patients. The increased permeability appears to be caused by disruption of intercellular tight junctions in the intestine, and it may play an important role in the pathogenesis of hepatic fat deposition. (HEPATOLOGY 2009.)

Intestinal permeability in cirrhotic patients with and without spontaneous bacterial peritonitis: is the ring closed?

OBJECTIVES:Impaired intestinal permeability (IP) may have a role in the pathogenesis of ascites and in spontaneous bacterial peritonitis (SBP) in patients with liver cirrhosis (LC). The aim of this study was to assess IP in LC patients with respect to healthy controls.METHODS:IP was evaluated by the 51Cr-ethylenediaminetetraacetic acid (51Cr-EDTA) permeability test in 52 LC patients and in 48 sex- and age-matched controls. The presence of 51Cr-EDTA was also evaluated in ascitic fluid after therapeutic paracentesis in all LC patients with ascites.RESULTS:An altered IP was found in 45% of LC patients compared with 4% of controls (P<0.00001). IP impairment was significantly associated with Child–Pugh status (75% of Child C patients vs. 39% of Child B and 22% of Child A patients), with the presence of ascites (60% in ascitic patients vs. 31% in nonascitic patients), and with a history of SBP (100% of patients with SBP vs. 50% of those without SBP). 51Cr-EDTA was present in all ascitic samples obtained from patients with SBP compared with 22% of patients without SBP.CONCLUSIONS:IP derangement was a common finding in LC, especially in patients with more advanced disease (presence of ascites and history of SBP). The presence of 51Cr-EDTA in ascites in patients with SBP suggests an altered permeability of splancnic vessels and/or peritoneal membranes. Further studies are required to assess 51Cr-EDTA urine and ascite cutoffs to set up SBP preventive strategies.

Anorexia and Serum Leptin Levels in Hemodialysis Patients

Background and Aims: Hyperleptinemia is a common feature in hemodialysis (HD) patients. However, the role of increased serum leptin levels in the pathogenesis of HD-related anorexia is still controversial. The purpose of the present prospective study was to ascertain whether hyperleptinemia is causally implicated in the pathogenesis of HD-related anorexia. Methods: We measured the serum leptin levels and the serum leptin/body mass index (BMI) ratio in 24 healthy subjects and in 49 end-stage renal disease patients on maintenance HD. HD patients were subdivided into anorexic (14/49, 28.5%) and non-anorexic (35/49, 71.5%) according to a questionnaire discriminating for the presence of anorexia-related symptoms. Results: Calorie (kcal/kg/day) and protein (g/ kg/day) intakes were significantly lower in anorexic than in non-anorexic patients (20.1 ± 1.1 vs. 27.9 ± 1.3, p = 0.004, and 0.82 ± 0.05 vs. 1.19 ± 0.05, p = 0.001, respectively). Accordingly, serum albumin, total lymphocyte count, mid-arm muscle circumference, and the protein equivalence of nitrogen appearance (PNA) were significantly lower in anorexic patients. The serum leptin concentration (ng/ml) was significantly higher in HD patients than in controls, in males (15.33 ± 3.4 vs. 3.7 ± 0.3, p = 0.003) and in females (42.3 ± 7.2 vs. 10.5 ± 1.3, p = 0.03). Similarly, serum leptin/BMI ratio was significantly higher in HD patients than in controls, in males (0.56 ± 0.1 vs. 0.16 ± 0.02, p = 0.0028) and in females (1.8 ± 0.2 vs. 0.4 ± 0.04, p < 0.0001). However, serum leptin levels were similar in anorexic and in non-anorexic patients, in males (15.3 ± 5.6 vs. 16.9 ± 4.2, p = 0.85) and in females (46.6 ± 12.9 vs. 47.4 ± 9.4, p = 0.96). No differences were observed between the 2 groups in the serum leptin/BMI ratio, in males (0.59 ± 0.2 vs. 0.58 ± 0.14, p = 0.92) and in females (1.5 ± 0.4 vs. 1.8 ± 0.3, p = 0.94). Similarly, no statistically significant differences in terms of serum leptin levels and leptin/BMI ratio were observed between patients with dietary energy intake of <30 or ≧30 kcal/kg/day and between those with a dietary protein intake of <1.2 or ≧1.2 g/kg/day. No significant correlations were found between serum leptin levels and PNA, albumin, cholesterol, total lymphocytes number, weight change, C-reactive protein, fibrinogen, ferritin, and complement. Conclusion: The present results indicate that mechanisms other than increases in serum leptin levels might be involved in the pathogenesis of HD-related anorexia.

Cardiopulmonary bypass in man: role of the intestine in a self-limiting inflammatory response with demonstrable bacterial translocation

BACKGROUND Cardiopulmonary bypass provokes a systemic inflammatory reaction that, in 1% to 2% of all cases, leads to multiorgan disfunction. The aim of this study was to evaluate the possible role of the intestine in the pathogenesis and development of this reaction. METHODS Eleven selected patients scheduled for elective coronary artery bypass graft surgery were enrolled in a open, prospective clinical study. Gastric tonometry, chromium-labeled test and double sugar intestinal absorption tests, polymerase chain reaction microbial DNA test, and measurement of cytokines and transcriptional factor (nuclear factor kappaB) activation were performed. RESULTS During the postoperative period, gastric pH remained stable (range,7.2 to 7.3). The partial pressure for carbon dioxide gradient between the gastric mucosa and arterial blood increased significantly (from 1 to 23 mm Hg), peaking in the sixth postoperative hour. Interleukin 6 increased significantly over basal levels, peaking 3 hours after cardiopulmonary bypass (96.3 versus 24 pg/mL). Nuclear factor kappaB never reached levels higher than those observed after lipopolysaccharide stimulation. Escherichia coli translocation was documented in 10 patients: in eight cases from removal of aortic cross-clamps and in two cases from the first postoperative hour. With respect to basal value (6.4%), the urine collection revealed a significant increase in excretion of the radioisotope during the first 24 hours after surgery (39.1%), although there were no significant variations with the double sugar test. CONCLUSIONS The results obtained showed a correlation between the damage of the gastrointestinal mucosa, subsequent increased permeability, E coli bacteremia, and the activation of a self-limited inflammatory response in the absence of significant macrocirculatory changes and postoperative complications.

imaging of peritoneal carcinomatosis with FDG PET-CT: diagnostic patterns, case examples and pitfalls

Early diagnosis of peritoneal spread in malignant disease is essential to prevent unnecessary laparotomies and to select the patients in whom complete cytoreduction is feasible. Although anatomic imaging is the mainstay for evaluating peritoneal seeding, small neoplastic implants can be difficult to detect with CT and MR imaging. FDG PET-CT has the potential to improve detection of peritoneal metastases as lesion conspicuity is high at PET due to low background activity and fused PET-CT offers the combined benefits of anatomic and functional imaging. Correlation of uptake modalities with the pathogenesis of intraperitoneal spread of malignancies, provides a rational system of analysis and is essential to define disease. Distinct patterns appear to predict the presence of either nodular or diffuse peritoneal pathology. Main pitfalls are related to normal physiologic activity in bowel loops and blood vessels or focal retained activity in ureters and urinary bladder. PET-CT is most suitable in patients with high tumor markers and negative or uncertain conventional imaging data and in selecting patients for complete cytoreduction. FDG PET-CT adds to conventional imaging in the detection and staging of peritoneal carcinomatosis and is a useful diagnostic tool in monitoring response to therapy and in long term follow-up.

Postoperative dysphagia versus neurogenic dysphagia: scintigraphic assessment.

In order to differentiate the features of dysphagia that occur after supraglottic horizontal laryngectomy from those that occur during neurologic diseases, we divided 38 subjects into 3 groups and submitted them to oropharyngoesophageal scintigraphy. Group 1 (control group) included 15 healthy volunteeers; group 2 comprised 8 patients who had residual dysphagia at least 1 year after supraglottic laryngectomy; and group 3 included 15 patients with various neurologic and neuromuscular disorders. In group 1, the mean values (±2 SD) of selected semiquantitative parameters were consistent with those reported in the literature for normal subjects. In group 2, oral, pharyngeal, and esophageal transit times were not significantly altered, and moderate tracheobronchial postdeglutitive aspiration was present (maximum value, 6.7%; mean value, 2.04%). The pharyngeal retention index was significantly increased (p = .0003) as compared to normal subjects in all cases (maximum value, 40%; mean value, 23%) and was associated in all cases with slight but consistent postdeglutitive aspiration. In group 3, the oral and esophageal phases were significantly prolonged and the retention indices were significantly increased. Statistical analysis documented a significant increase in oral transit time (p = .003), esophageal transit time (p = .01), oral retention index (p = .006), pharyngeal retention index (p = .0007), and esophageal retention index (p = .009) as compared to normal subjects. The swallowing pattern was also altered by 1) an early loss of the bolus from the oral cavity; 2) bolus fragmentation due to double or triple deglutition, reduced lingual propulsion, or the return of a small part of the bolus into the oral cavity during deglutition; and/or 3) double pharyngeal peaks in the activity-time curves. Tracheobronchial aspiration (maximum value, 90%; mean value, 9.70%) was present in some cases, mainly in patients affected by post-stroke dysphagia. On the basis of the obtained results and considering the low doses of radiation delivered to the patient (0.043 Gy), the limited invasiveness, and the excellent patient tolerance, scintigraphy appears to be clinically valid in the functional study of swallowing and in identifying different deglutition disorders.

Vitamin B12 and folic acid plasma levels after ileocecal and ileal neobladder reconstruction

OBJECTIVES To compare the plasma levels of vitamin B12 and folic acid following resection of ileocecal or ileal segments used for orthotopic bladder substitution. METHODS Hemoglobin, hematocrit, and plasma levels of vitamin B12 and folic acid were measured in 34 patients with ileocecourethrostomy (ICUS) and in 16 patients with ileal reservoir (IR), with a mean follow-up of 59.8 +/- 41.9 months. The results were compared with regard to both the type of operation and the length of time since surgery. RESULTS The level of folic acid was normal in all patients. The mean level of vitamin B12 in the ICUS group was 413.67 +/- 160.45 ng/mL compared to 257.63 +/- 121.36 for the IR group. This difference was statistically significant. In the IR group, 18.75% of the patients had a level of vitamin B12 below normal. CONCLUSIONS There is a tendency for vitamin B12 levels to fall in patients in whom the ileum is used. Resection of the ileocecal segment including the junction does not alter the level of vitamin B12.

Long-Term Treatment of Severe SAPHO Syndrome with Adalimumab

SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome defines an association of inflammatory cutaneous disorders with osteoarticular manifestations and represents a clinical and therapeutic challenge. We report a case of severe SAPHO syndrome with acne conglobata and a diffuse involvement of the anterior chest wall and sacroiliac joints that required treatment with isotretinoin and adalimumab, a new fully human anti-tumor necrosis factor (TNF)-α monoclonal antibody. Combination treatment determined a complete clinical remission of cutaneous and osteoarticular manifestations after 48 weeks. Despite maintenance of clinical remission, follow-up imaging studies after 24 months of adalimumab monotherapy revealed osteoarticular disease progression, with features of inflammatory osteitis.TNFα antagonists have been used as third-line therapy for SAPHO syndrome in single case reports or case series, but these lack consistent long-term follow-up. SAPHO syndrome can present an intermittentfavorable course in the majority of cases as well as a chronic-progressive course, the latter requiring aggressive combination treatment with TNFα antagonists and conventional systemic agents.

Small intestinal bacterial overgrowth and intestinal permeability

The gastrointestinal tract is characterized by selective and dynamic permeability allowing the passage of nutrients and fluids and preventing the penetration of intruders such as microorganisms, toxins and other luminal antigens. The gut barrier integrity is essential to maintain human health and homeostasis. A derangement of intestinal permeability (IP) seems to be involved in the pathogenesis of several intestinal and systemic disorders [1]. Several structures including mucous coat, secretory IgA, epithelial layer, intercellular tight junctions, gut immune system and gut microflora contribute to maintain the integrity of such barrier. Small intestinal bacterial overgrowth (SIBO) is a common clinical condition due to an increase in the level of microorganisms to >10 colony forming units/ml of intestinal aspirate and/or of colonictype bacteria within the small intestine. This abnormally high bacterial population could affect intestinal barrier through a direct bacterial injury or an immune system activation resulting in the release of several inflammatory mediators and cytokines [2]. Aim of this study was to assess IP in patients with SIBO and the effect of SIBO decontamination. Twenty patients affected by SIBO as assessed by hydrogen glucose breath test (GBT) (mean age 46.3 ± 7.8 years, M/F 9/11) and 21 controls without SIBO (mean age 45.1 ± 8.1 years, M/F 9/12) were enrolled after written informed consent. The test was considered as an indicative of SIBO when the peak, that is the increase over baseline hydrogen levels, was > 12 parts per million [3]. Exclusion criteria were all factors known to impair IP: gastrointestinal disorders and infections, use of non-steroidal antiinflammatory and immunosuppressive drugs, alcohol consumption, allergic diseases and HIV infection. Chromium ethylene-diamine-tetra-acetate (CrEDTA) absorption test was performed in all patients to assess IP. The test methodology was the same as described in a previous study by our group [4]. The 24-h urinary excretion of Cr-EDTA was expressed as a fraction of the oral administered dose and considered abnormal if ‡ 3% [4]. All patients were treated by rifaximin (Normix 200 mg tablets, Alfa-Wassermann) 1200 mg per day (2 tablets t.i.d.) for 7 days [5] and underwent GBT and Cr-EDTA absorption test 4 weeks after the end of the therapy. An IP derangement was observed in 11 out of 20 SIBO patients (55%, mean Cr-EDTA urinary excretion rate: 3.47 ± 0.30) compared to 1 out of 21 controls (4.8%, mean Cr-EDTA urinary excretion rate: 2.17 ± 0.16; p = 0.002). Among SIBO patients with deranged IP, IP normalized in 6 out of 8 successfully decontaminated (75%) compared to 2 out of 3 non-decontaminated patients (66%, p = ns). The mean Cr-EDTA urinary excretion rate significantly decreased after successful decontamination (2.28 ± 0.38 vs. 3.7 ± 0.58, ANOVA p < 0.005).

Oropharyngoesophageal scintigraphy in the diagnostic algorithm of laryngopharyngeal reflux disease: A useful exam?

OBJECTIVE: To evaluate the role of oropharyngoesophageal scintigraphy in the diagnostic approach to patients with laryngopharyngeal reflux (LPR). STUDY DESIGN: Forty-one patients with chronic laryngopharyngeal symptoms and a control group of 15 healthy volunteers were examined. All subjects underwent standard oropharyngoesophageal scin-tigraphy. The following parameters were considered: activity-time curves, presence of double peaks and reduced slope in oropharyngeal phase, presence of accelerated or slowed esophagogastric transit, persistence of radioactive material on the pharyngeal or esophageal mucosa, and presence of gastroesophageal reflux (GER) under exercise. RESULTS: There were objective signs of laryngeal reflux in 80.5% of the patients. In 82.9%, scintigraphy documented several associated morphofunctional pathologic patterns: positive GER test (61.0%), presence of double peaks (36.6%), indirect signs of pharyngoesophageal inflammation (31.7%), hypotonic lower esophageal sphincter (17.1%), and slowed esophageal clearance (9.8%). CONCLUSIONS: Oropharyngoesophageal scintigraphy may be used as preliminary examination in outpatients with signs and symptoms of LPR. Cases of classic gastroesophageal reflux disease could be separated from those of LPR disease and therefore submitted to more invasive instrumental examinations. (Otolaryngol Head Neck Surg 2005;132: 717-21.)