Barbara Zanini

Mortality for liver disease in patients with HIV infection : A cohort study

We undertook this study to assess the association between the various potential causes of liver disease in HIV-seropositive patients and mortality due to liver failure. Three hundred and eight in-hospital deaths were observed from 1987 to December 1995 in a prospectively followed cohort of 1894 HIV-seropositive patients. For each study subject, clinical data were evaluated to assess whether liver failure had substantially contributed to mortality. A case control study nested in the cohort was then performed, which compared demographic and clinical variables observed at enrollment and during follow-up between patients who died for liver disease as the main or concurrent cause of death (cases) and those who died as a result of illness related to AIDS or other causes (controls). Among 308 in-hospital deaths, liver failure was found the cause of death in 35 patients (12%); in 16 cases, it was the primary cause and in 19 cases it was concurrent. Multivariate analysis showed that in-hospital liver-disease-related mortality was independently associated with hepatitis B surface antigen reactivity (odds ratio [OR], 9; 95% confidence interval [CI], 3.8-21.7) and history of alcohol abuse (OR, 2.3; 95% CI, 1-5.2). Prevention and treatment of hepatitis B virus infection and alcohol intake are management priorities in HIV-seropositive patients.

Severe hepatotoxicity during combination antiretroviral treatment: Incidence, liver histology, and outcome

Objectives: To assess incidence, risk factors, histology, and outcome of severe hepatotoxicity (SH) during antiretroviral treatment (ART). Methods: Seven hundred fifty‐five HIV‐seropositive patients consecutively prescribed new ART were selected. Liver function tests were assessed at baseline, after 1 month, and every 4 months thereafter. Liver biopsy was recommended in case of SH (i.e., increase in liver enzymes ≥10 times the upper limit of normal or 5 times baseline if markedly abnormal). Results: Twenty‐six cases of SH were observed with an incidence of 4.2% personyears. Liver failure (LF) was rarely seen (1.1 per 100 person‐years). Liver damage was invariably observed in patients with chronic viral hepatitis. Liver histology showed exacerbation of viral hepatitis in all 16 patients for whom a liver biopsy was available at the time of SH. A direct correlation was found between alanine aminotransferase increase and increase in CD4+ T‐cell count in patients with SH (r = 0.53, p < .001). Death occurred during follow‐up in 7 of 26 (27%) patients, all of whom showed LF and baseline CD4+ count less than 200 cells/mm3 (7/7 patients = 100% vs. 8/19 patients without LF; p < .01). Relapse of SH was observed after ART was recommenced in 7 of 17 (41%) patients. Five of these 7 patients did not show further SH relapse after treatment with interferon. Conclusions: This study provides estimates of SH and LF in a large populationbased setting where hepatitis C virus coinfection is highly prevalent and provides indications that liver damage may be caused by immune reconstitution and related exacerbation of viral hepatitis. A strict follow‐up for hepatotoxicity is mandatory when ART is initiated in patients with <200 CD4+ T cells/mm3. Antihepatitis pre‐ or comedication could be an effective preventive or curative measure.

Incidence of Post-Infectious Irritable Bowel Syndrome and Functional Intestinal Disorders Following a Water-Borne Viral Gastroenteritis Outbreak

OBJECTIVES:Post-infectious irritable bowel syndrome (PI-IBS) may develop in 4–31% of affected patients following bacterial gastroenteritis (GE), but limited information is available on long-term outcome of viral GE. During summer 2009, a massive outbreak of viral GE associated with contamination of municipal drinking water (Norovirus) occurred in San Felice del Benaco (Lake Garda, Italy). To investigate the natural history of a community outbreak of viral GE, and to assess the incidence of PI-IBS and functional gastrointestinal disorders, we carried out a prospective population-based cohort study with a control group.METHODS:Baseline questionnaires were administered to the resident community within 1 month of the outbreak. Follow-up questionnaires of the Italian version of Gastrointestinal Symptom Rating Scale (GSRS, a 15-item survey scored according to a 7-point Likert scale) were mailed to all patients responding to baseline questionnaire at 3 and 6 months, and to a cohort of unaffected controls, living in the same geographical area, at 6 months after the outbreak. The GSRS item were grouped in five dimensions: abdominal pain, reflux, indigestion, diarrhea, and constipation. At month 12, all patients and controls were interviewed by a health assistant to verify Rome III criteria of IBS. Students t-test and χ2- or Fishers exact test were used as appropriate.RESULTS:Baseline questionnaires were returned by 348 patients: mean age±s.d. 45±22 years, 53% female. At outbreak, nausea (scored ≥4), vomiting, and diarrhea lasting 2–3 days or more were reported by 66, 60, and 77% of patients, respectively. A total of 50% reported fever and 19% reported weight loss (mean 3 kg). Follow-up surveys were returned at month 6 by 186 patients and 198 controls: mean GSRS score was significantly higher in patients than in controls for abdominal pain, diarrhea, and constipation. At month 12, we identified 40 patients with a new diagnosis of IBS (Rome III criteria), in comparison with 3 subjects in the control cohort (P<0.0001; odds ratio 11.40; 95% confidence intervals 3.44–37.82). The 40 cases of PI-IBS were subtyped according to the predominant stool pattern as follows: 4 IBS with constipation, 7 IBS with diarrhea, 16 with mixed IBS, and 13 with unsubtyped IBS.CONCLUSIONS:Our study provides evidence that Norovirus GE leads to the development of PI-IBS in a substantial proportion of patients (13%), similar to that reported after bacterial GE.

Liver Damage and Kinetics of Hepatitis C Virus and Human Immunodeficiency Virus Replication during the Early Phases of Combination Antiretroviral Treatment

In order to assess the relationship between human immunodeficiency virus (HIV) RNA, hepatitis C virus (HCV) RNA, CD4, CD8, and liver enzymes during combination antiretroviral therapy, these parameters were measured in 12 HIV-HCV-coinfected patients (who were naive for antiretrovirals) on the day before and 3, 7, 14, 28, 56, and 84 days after initiating the following treatments: stavudine and lamivudine in all patients, indinavir in 6 patients, and nevirapine in 6 patients. HIV RNA declined rapidly, CD4 cells increased slowly, and CD8 cells and liver enzymes were stable. HCV RNA showed a transient significant increase at days 14 and 21 (7.33+/-0.16 [mean +/- SE] and 7.29+/-0.2 log copies/mL vs. 7+/-0.2 log copies/mL at baseline; P<.05). These changes were similar in both treatment groups. A 2-fold alanine aminotransferase increase was observed in 4 of 12 patients; 4 of 4 patients showed increased HCV RNA. The relationship between HCV RNA increase and HIV RNA decrease indicates virus-virus interference. An HCV RNA increase may cause significant liver damage only in a minority of patients.

Celiac Disease With Mild Enteropathy Is Not Mild Disease

BACKGROUND & AIMS Patients with celiac disease have varying degrees of damage to the small intestinal mucosa, ranging from lymphocytic duodenosis with normal villous structure to severe villous atrophy. We assessed whether the severity of mucosal lesions was associated with clinical and laboratory features of celiac disease. METHODS We compared demographic, clinical, and laboratory characteristics among patients with celiac disease who were classified based on the severity of duodenal lesions. We analyzed data from 1408 adult patients seen consecutively at a tertiary referral center since 1990. Patients were classified as having villous atrophy (n = 1249) or as having mild enteropathy (n = 159) in the presence or absence of villous atrophy. RESULTS Similar percentages of patients with villous atrophy, vs mild enteropathy, experienced weight loss (17% vs 17%), gastrointestinal manifestations (70% vs 70%), extraintestinal manifestations (66% vs 57%), and other associated conditions (19% vs 23%). More patients with villous atrophy than patients with mild enteropathy developed osteopenia or osteoporosis (22% vs 5%; P = .0005). Greater percentages of patients with villous atrophy than those with mild enteropathy also had anemia (42% vs 29%; P = .002), folate deficiency (75% vs 64%; P = .02), hypocholesterolemia (7% vs 2%; P = .02), hypocalcemia (26% vs 13%; P = .004), or hyperparathyroidism (45% vs 29%; P = .004). CONCLUSIONS Although osteopenia, osteoporosis, and alterations in laboratory parameters are prevalent among patients with celiac disease with mild enteropathy, they are more prevalent and severe in those with villous atrophy. The prevalence of associated conditions is similar between these groups. These results indicate that celiac disease with mild enteropathy is not mild disease, but requires treatment with a gluten-free diet.

High tissue-transglutaminase antibody level predicts small intestinal villous atrophy in adult patients at high risk of celiac disease

BACKGROUND Duodenal biopsy may be unnecessary to confirm celiac disease in patients with high tissue-transglutaminase antibody level. AIMS To define a cut-off value of tissue-transglutaminase antibody with high positive likelihood ratio for duodenal atrophy in patients with suspected celiac disease. METHODS We retrospectively identified 945 patients with suspected celiac disease and classified according to the method used for tissue-transglutaminase antibody assay: Group A (n=393, Eu-tTG® Eurospital), Group B (n=263; Eu-tTG® Eurospital) and Group C (n=289; Celikey® Phadia). Duodenal histology was graded according to Marsh. Sensitivity, specificity, and positive likelihood ratio were used to evaluate cut-off points of tissue-transglutaminase antibody as predictor of villous atrophy. RESULTS 100% specificity and ∞ positive likelihood ratio for duodenal atrophy was observed at a cut-off value of tissue-transglutaminase antibody 5 times higher than the upper limit of normal. CD diagnosis was confirmed by concordance with antiendomysial antibodies, and by reduction of t-TG titre in all patients and improvement of duodenal histology in 80% during gluten-free diet. CONCLUSIONS Tissue-transglutaminase antibody level 5-folds the upper limit of normal is 100% specific for duodenal atrophy and using this cut-off biopsy could by avoided in 1/3 of patients. Diagnostic criteria of celiac disease in adults need revision.

Celiac disease in elderly adults: clinical, serological, and histological characteristics and the effect of a gluten-free diet.

To compare celiac disease (CD) in older and younger adults and to assess the effects of a gluten‐free diet (GFD).

Effectiveness and Tolerability of Combination Treatment of Chronic Hepatitis C in Illicit Drug Users: Meta-Analysis of Prospective Studies

BACKGROUND Hepatitis C virus (HCV) infection is a global health problem. In Western countries, illicit drug users (IDUs) constitute the largest proportion of HCV patients. International guidelines no longer regard ongoing illicit drug use as a contraindication to antiviral therapy for chronic hepatitis C (CHC). Nonetheless, in clinical practice, few IDUs have access to HCV treatment, likely because many physicians believe these patients will have poor adherence or a lack of treatment efficacy. OBJECTIVE The aim of this study was to assess effectiveness and tolerability of combination treatment with ribavirin plus recombinant or pegylated interferon-α in the treatment of CHC in IDUs. METHODS MEDLINE, EMBASE, and the Cochrane Library were searched for relevant studies published in English between 2000 and December 2008. The following terms were searched: chronic hepatitis C, interferons, antiviral agents, methadone, and substance-related disorders. Full-text articles and abstracts were searched using predefined criteria. A manual search of abstracts from 8 international meetings of hepatologists was also conducted. Only prospective studies with a sample size >15 and a homogeneous treatment schedule were included. Articles were extracted independently by 2 of the authors using an electronic standardized form including study quality indicators. RESULTS Sixteen prospective studies were included, and data from a cohort of 953 IDUs were analyzed. The estimated overall sustained virologic response (SVR) and dropout (DO) rates in IDUs were 52% (95% CI, 44%-60%) and 26% (18%-35%, 95% CI), respectively. The rate of psychiatric severe adverse events (SAEs) that led to treatment discontinuation was 2% (95% CI, 1%-3%). These prevalences were not significantly different from those reported in registration trials of treatment of CHC that excluded IDUs from the study population (SVR, 50% [95% CI, 39%-61%]; DO, 26% [95% CI, 12%-41%]; and psychiatric SAEs, 2% [95% CI, 0%-6%]). By subgroup analysis, active ongoing drug use negatively affected the rate of treatment success (39% [95% CI, 30%-49%] vs 55% [95% CI, 45%-64%]; P = 0.02). CONCLUSION Based on data from 16 prospective clinical studies of CHC treatment in IDUs published in the past 10 years, findings on effectiveness and tolerability are comparable to those in the general population.

Factors That Contribute to Hypertransaminasemia in Patients With Celiac Disease or Functional Gastrointestinal Syndromes

BACKGROUND & AIMS Transaminasemia develops via different pathways in patients with celiac disease; no information is available on risk factors specifically attributable to celiac disease. METHODS We analyzed data collected from consecutive patients referred from January 1997 through December 2009 to the celiac disease clinic at the Spedali Civili of Brescia, Italy. We assessed the factors affecting hypertransaminasemia in 683 patients with celiac disease (based on serologic and biopsy analysis, cohort A; 34 ± 14 years of age) and 304 with functional syndromes (cohort B; 37 ± 13 years of age). RESULTS Hypertransaminasemia was detected in 138 patients in cohort A (20%). It was associated with malabsorption (odds ratio [OR], 2.22; P = .004), diarrhea (OR, 1.72; P = .005), and increasing severity of mucosal lesion (Marsh-Oberhuber class; OR, 1.46; P = .001) but not with body mass index (BMI) or the serum level of tissue-transglutaminase antibodies (tTG). Hypertransaminasemia was detected in 22 patients in cohort B (7%) and was associated with the World Health Organizations BMI categories (OR, 7.9; P < .001). In subsets of patients studied with the same analytical method (313 of cohort A and 188 of cohort B), the level of tTG was significantly higher in cohort A at baseline (25.2 ± 16.9 U/L aspartate aminotransferase [AST]) than in cohort B (20.6 ± 9.9 U/L AST, P < .0001) and was related to BMI in cohort B (P = .0012) but not cohort A. When patients were placed on gluten-free diets, the levels of AST decreased from 25.2 ± 16.9 U/L to 19.9 ± 6.6 U/L (P < .0001), independently of the changes of duodenal histology and tTG and correlated with BMI (P = .0007); the prevalence of hypertransaminasemia decreased from 13% to 4%. CONCLUSIONS Patients with celiac disease have a higher prevalence of hypertransaminasemia than controls (patients with functional syndromes). Hypertransaminasemia is related to the severity of the duodenal lesion and malabsorption but not BMI. By contrast, there was a positive correlation between the levels of AST and BMI in controls; this relationship was restored when patients with celiac disease were placed on gluten-free diets.

Pilot dose-finding trial on interferon alpha in combination with ribavirin for the treatment of chronic hepatitis C in patients not responding to interferon alone.

BACKGROUND Effectiveness of combination therapy with standard interferon alpha doses and ribavirin is far from being demonstrated in patients with hepatitis C non responders to interferon alpha monotherapy. Recent kinetic studies revealed that these doses may be suboptimal. AIMS To find the criteria for optimisation of the interferon dose, to be used in combination with ribavirin in patients with hepatitis C non responders to interferon alpha monotherapy. PATIENTS Sixty-three patients enrolled in a pilot controlled trial were treated for 6 months with ribavirin ([1000-1200 mg daily) and were randomised to concurrently receive interferon alpha 2b for 6 months at: 3 Million Units thrice weekly [group A (21 patients)], 5 MU thrice weekly [group B (21 patients)] and 5 million units daily [group C (21 patients)]. RESULTS A sustained virological response was observed in: 1 patient from group A (5%), 2 patients from group B (9%) and 8 patients from group C (38%; p=0.02 vs group A; p=0.03 vs group B). Side-effects were not significantly different between the 3 groups. Multivariate analysis showed that infection by hepatitis C virus genotypes 2 or 3 and interferon alpha dosage of 5 million units daily were independent predictors of sustained response. CONCLUSIONS These results suggest that higher interferon doses administered daily in combination with ribavirin could be more effective in those patients with hepatitis C who had not responded to interferon alone.