Carla Venturi

Intestinal Permeability Test as a Predictor of Clinical Course in Crohn's Disease

Objective:The clinical course of Crohns disease is often unpredictable. The aim of this study was to select the most useful parameters able to predict clinical relapses.Methods:One hundred-thirty Crohns disease patients in clinical remission were followed every 4 months for 2 yr or until clinical relapse. Demographic and clinical data were recorded and intestinal permeability (lactulose/mannitol [L/M] test) and biochemical tests (white blood cell count, erythrocyte sedimentation rate, C-reactive protein, α1 acid glycoprotein, and serum iron) were performed at study entry. A subgroup of 54 patients had clinical follow-up and repeated tests every 4 months.Results:Fifty-two patients (40%) relapsed during the 2-yr follow-up. A significant correlation was found between relapse and gender (p= 0.030) but not between relapse and age, extent and type of disease, previous surgery, or therapy. Increased L/M test (p= 0.0001) and decreased serum iron level (p= 0.0057) were associated with clinical relapse. Time-dependent analysis, performed on patients receiving serial evaluation, showed that L/M test alteration was the only variable that could predict a relapse (RR 8.84, 95% confidence interval [CI] 1.41–53.37; p < 0.05).Conclusion:The L/M test identifies Crohns disease patients in apparent remission, but with a high risk of clinical relapse, better than clinical and biochemical indices. Different treatment strategies might be suggested for this subgroup of patients.

HLA class II alleles, genotypes, haplotypes, and amino acids in primary biliary cirrhosis: A large-scale study†

Twin and family studies suggest there is a significant genetic component to primary biliary cirrhosis (PBC). However, the inability to replicate reported associations has been a recurring problem, with the only consistently reported genetic association that between PBC and HLA‐DRB1*0801. However, recently even this has been questioned, and a number of novel associations have also been reported. We reinvestigated HLA class II DRB1, DQA1, and DQB1 alleles and haplotypes in a total of 492 well‐characterized PBC patients, 412 from the United Kingdom and an additional 80 patients from northern Italy. There was a clear and significant association with HLA‐DRB1*0801 in both groups of patients compared to population‐specific healthy controls (12% versus 4% in the UK patients, P = .00087, OR = 3.05; and 18% versus 6% in the Italian patients, P = .021, OR = 3.15). There were also significant protective associations with DRB1*11 in the Italian patients (28% versus 47%, P = .0071, OR = 0.42), but not in the UK patients (8% versus 8%) and a protective association with DRB1*13 in both series (14% versus 20%, P = .042, OR = 0.65 in the UK patients; and 10% versus 31%, P = .00092, OR = 0.25 in the Italian patients). In conclusion, a complex relationship exists between HLA and PBC, and some genetic associations may be population specific. (HEPATOLOGY 2006;44:667–674.)

Prevalence of coeliac disease in primary biliary cirrhosis and of antimitochondrial antibodies in adult coeliac disease patients in Italy

BACKGROUND Although an association between primary biliary cirrhosis and coeliac disease has recently been reported in Northern Europe, there are still conflicting data concerning this issue. AIM To evaluate both the prevalence of coeliac disease in a series of primary biliary cirrhosis patients and that of antimitochondrial antibodies in a series of adult biopsy proven coeliac disease patients from Northern Italy. PATIENTS AND METHODS A total of 87 primary biliary cirrhosis patients (79 female, 8 male) were screened for both IgA-transglutaminase antibodies and antiendomysium antibodies and, in those with either IgA-transglutaminase antibodies or antiendomysium antibodies positivity, upper endoscopy with distal duodenum biopsy was offered. In those who refused upper endoscopy, the intestinal permeability test with lactulose/mannitol excretion was performed. RESULTS Antiendomysium antibodies positivity was detected in 3 subjects (3.4%), all of whom had serum IgA-transglutaminase antibodies above the normal range, and fulfilled the diagnosis of coeliac disease. Of 21 other patients with serum IgA-transglutaminase antibodies above the normal range, 17 underwent upper endoscopy which revealed normal duodenum architecture. The remaining 4 patients underwent the lactulose/mannitol excretion test which was within the normal range. Sera from 108 adult coeliac disease patients were tested for antimitochondrial antibodies and positivity was found in 4 patients (3.7%): all had normal liver biochemistry tests, whereas 2 of them also presented thyroid disease. Antibodies directed to the 74-kDa polypeptide of antimitochondrial antibodies were found in 3 out of 4 antimitochondrial antibodies+ve patients. CONCLUSIONS These results suggest an association between primary biliary cirrhosis and coeliac disease similar to that observed in the Northern European series. In conclusion, screening for coeliac disease with antiendomysium antibodies in primary biliary cirrhosis is justified, and screening for antimitochondrial antibodies is advisable in adult coeliac disease patients.

Lactulose/mannitol test has high efficacy for excluding organic causes of chronic diarrhea

Abstract Objectives Diagnosis in chronic diarrhea in the absence of a distinctive clinical pattern is often challenging, as biochemical tests prescribed at the first evaluation do not show enough sensitivity and specificity to tailor further investigation. Intestinal permeability to sugars is an accurate test for detecting intestinal damage. The aim of this study was to evaluate the diagnostic value of the lactulose/mannitol (L/M) test in patients with chronic diarrhea. Methods We conducted a prospective cohort study to evaluate the diagnostic value of the L/M test in chronic diarrhea. The test was administered to 261 consecutive patients presenting with three or more bowel movements daily for at least 3 wk. Biochemical tests including complete blood cell count, acute phase reactive proteins, serum albumin and iron, and stool cultures for bacteria, ova, and parasites were assessed at the same time. Additional diagnostic investigations were directed by clinical features as well as first-line test results. Results Over 3 yr, 120 (46%) of our patients were found to have an organic cause for chronic diarrhea, whereas in 141 (54%) a functional condition was diagnosed. Multivariate logistic regression analysis revealed that the L/M test and C-reactive protein were independent predictors for the final diagnosis of organic cause of chronic diarrhea, with odds ratios of 1.5 (95% CI = 1.29–1.78) and 5.2 (95% CI = 1.90–14.12), respectively. The area under the receiver operating characteristic (ROC) curve of the adjusted model was 0.82, with positive predictive value of 80.4% and negative predictive value of 77.7%. Conclusions The L/M test is a powerful tool for workup in patients with chronic diarrhea. Introducing the L/M test as first-level test effectively improves the selection of patients who need further evaluation.

Chemokine receptor 5 and primary biliary cirrhosis: a two-centre genetic association study.

Abstract: Background: Chemokines and their receptors are important mediators of leucocyte trafficking and are suggested to be critical for establishment of inflammatory autoimmune processes. CC chemokine receptor 5 (CCR5) is expressed preferentially by CD4+ T cells. We hypothesised that the CCR5delta(Δ)32 genotype, which impairs surface expression of CCR5 in heterozygotes and is linked to a functional polymorphism of CD45RA expressed on suppressor‐inducer‐like ‘naïve’ CD4+ T cells, may modulate the inflammatory process in primary biliary cirrhosis (PBC).

Lack of higher frequency of the chemokine receptor 5-delta32/delta32 genotype in hepatitis C.

PURPOSE An elevated frequency of the CCR5-Delta32 mutation in German patients with hepatitis C with viremia has been reported. The aim of the present study was to verify whether this mutation occurs in an Italian population with hepatitis C and whether it is an adverse host factor indicative of severity of liver disease and response to antiviral therapy. STUDY The authors amplified 189-bp (wild-type) and 157-bp (Delta32 deletion) fragments of the CCR5 gene by polymerase chain reaction in 130 patients with chronic hepatitis C. Comparisons were drawn with 110 blood donors and 135 patients with primary biliary cirrhosis. RESULTS Four (3.1%) patients with chronic hepatitis C and 1 blood donor (0.9%) were CCR5-Delta32 homozygous, whereas there was no CCR5-Delta32 homozygosity among primary biliary cirrhosis patients; the wild-type gene was present in a similar percentage in the 3 groups of patients without any significant difference (83.1% vs 90.4% vs 83.6%, respectively). Among the patients with chronic hepatitis C, no significant correlation was found between CCR5-Delta32 homozygosity and the following parameters: histologic grade/stage, hepatitis C virus genotype, viral load, serum aspartate aminotransferase, serum alanine aminotransferase, and serum gamma-glutamyltransferase. Ninety-five patients received a standard antiviral protocol with pegylated interferon (PEG Intron)+ribavirin; a sustained response was achieved in 59 patients (62.1%), and the remainder did not respond or experienced a relapse. Response to treatment was not influenced by CCR5-Delta32 deletion. CONCLUSION No greater frequency of CCR5-Delta32 homozygosity was seen in an Italian population of patients with chronic hepatitis C. This mutation does not seem to influence either the overall severity of liver disease or the response to viral therapy.

Tumour necrosis factor-alpha behaviour in serum during recombinant-alpha-2b-interferon treatment of chronic viral hepatitis

Objective: To investigate the behaviour of serum tumour necrosis factor-alpha (TNF-alpha) during alpha-interferon (alpha-IFN) treatment in patients with chronic viral hepatitis. Design: The study included 31 patients with chronic active hepatitis: five positive for hepatitis B surface antigen (HBsAg) and hepatitis B early antigen (HBeAg), and six positive for HBsAg, anti-HBe and hepatitis B virus (HBV) DNA; the remaining 20 were anti-hepatitis C virus (HCV) positive. All patients received 3 million units recombinant-alpha-2b-interferon three times weekly and were followed up for at least 3 months. Serum samples were collected at 0 and 24 h, and on days 1 15, 30 and 90. Responders were those patients whose transaminase levels returned to normal during alpha-IFN treatment

Lactulose/mannitol test has high efficacy for identifying organic causes of chronic diarrhea

OBJECTIVES: Diagnosis in chronic diarrhea in the absence of a distinctive clinical pattern is often challenging, as biochemical tests prescribed at the first evaluation do not show enough sensitivity and specificity to tailor further investigation. Intestinal permeability to sugars is an accurate test for detecting intestinal damage. The aim of this study was to evaluate the diagnostic value of the lactulose/mannitol (L/M) test in patients with chronic diarrhea. METHODS: We conducted a prospective cohort study to evaluate the diagnostic value of the L/M test in chronic diarrhea. The test was administered to 261 consecutive patients presenting with three or more bowel movements daily for at least 3 wk. Biochemical tests including complete blood cell count, acute phase reactive proteins, serum albumin and iron, and stool cultures for bacteria, ova, and parasites were assessed at the same time. Additional diagnostic investigations were directed by clinical features as well as first-line test results. RESULTS: Over 3 yr, 120 (46%) of our patients were found to have an organic cause for chronic diarrhea, whereas in 141 (54%) a functional condition was diagnosed. Multivariate logistic regression analysis revealed that the L/M test and C-reactive protein were independent predictors for the final diagnosis of organic cause of chronic diarrhea, with odds ratios of 1.5 (95% CI 1.29 ‐1.78) and 5.2 (95% CI 1.90 ‐14.12), respectively. The area under the receiver operating characteristic (ROC) curve of the adjusted model was 0.82, with positive predictive value of 80.4% and negative predictive value of 77.7%. CONCLUSIONS: The L/M test is a powerful tool for workup in patients with chronic diarrhea. Introducing the L/M test as first-level test effectively improves the selection of patients who need further evaluation. (Am J Gastroenterol 2003;98: 2245‐2252.

Hepatocellular proliferation, TNFα and inflammation in primary biliary cirrhosis (PBC)

The aims of this study were to investigate the rate of hepatocellular proliferation in PBC and its correlation with the site of inflammation and serum TNFα levels. Hepatic proliferation was evaluated in liver sections from 11 patients with PBC (two histological stage II, eight stage III, one stage IV) using the indirect immunoperoxidase technique with a monoclonal antibody against proliferating cell nuclear antigen (PCNA). Counter-staining with hematoxylin was performed and at least 500 nuclei were counted by two observers who blindly calculated the site of positive cells (perivenular, periportal/periseptal). The percentage of hepatocytes expressing PCNA was significantly higher in the periportal/periseptal regions than in the perivenular area (70 ± 5.8% vs. 36 ± 6.9%, P < 0.002). Hepatocellular PCNA expression in the periportal/periseptal (portal area) correlated with TNFα serum levels (r = 0.8, P < 0.03). In conclusion, hepatocellular proliferation in PBC significantly correlates with the site of inflammation and serum levels of TNFα. This data seems to confirm that inflammation and cytokines may stimulate hepatocyte DNA synthesis.