Symptoms and signs in individuals with serology positive for celiac disease but normal mucosa

<p>Abstract</p> <p>Background</p> <p>Antibody serology is an important tool in the investigation of celiac disease (CD), but does not always correlate with mucosal appearance in the small intestine. Patients with positive CD serology but normal mucosa (Marsh 0) are at increased risk of future CD. In this study we describe a model for identifying and characterizing individuals with normal mucosa but positive CD serology. Such individuals are sometimes referred to as having latent CD.</p> <p>Methods</p> <p>The records of ten Swedish pathology departments were used to identify individuals with biopsies indicating normal duodenal/jejunal mucosa. Using the national personal identification number, these data were linked with CD serology data (antigliadin, antiendomysial and tissue transglutaminase antibodies); and we thereby identified 3,736 individuals with normal mucosa but positive CD serology. Two independent reviewers then manually reviewed their biopsy reports to estimate comorbidity. We also randomly selected 112 individuals for validation through patient chart review.</p> <p>Results</p> <p>The majority of the 3,736 individuals were females (62%). Children (0–15 years) made up 21.4%. The median number of biopsy specimen was 3. Our review of biopsy reports found that other gastrointestinal comorbidity was rare (inflammatory bowel disease: 0.4%; helicobacter pylori infection: 0.2%). Some 22% individuals selected for patient chart review had a relative with CD. The most common symptoms among these individuals were diarrhea (46%) and abdominal pain (45%), while 26% had anemia. Although 27% of the individuals selected for validation had been informed about gluten-free diet, only 13% were adhering to a gluten-free diet at the end of follow-up.</p> <p>Conclusion</p> <p>Individuals with positive CD serology but normal mucosa often have CD-like symptoms and a family history of CD.</p

Hepatic profile analyses of tipranavir in Phase II and III clinical trials

<p>Abstract</p> <p>Background</p> <p>The risk and course of serum transaminase elevations (TEs) and clinical hepatic serious adverse event (SAE) development in ritonavir-boosted tipranavir (TPV/r) 500/200 mg BID recipients, who also received additional combination antiretroviral treatment agents in clinical trials (TPV/r-based cART), was determined.</p> <p>Methods</p> <p>Aggregated transaminase and hepatic SAE data through 96 weeks of TPV/r-based cART from five Phase IIb/III trials were analyzed. Patients were categorized by the presence or absence of underlying liver disease (+LD or -LD). Kaplan-Meier (K-M) probability estimates for time-to-first US National Institutes of Health, Division of AIDS (DAIDS) Grade 3/4 TE and clinical hepatic SAE were determined and clinical actions/outcomes evaluated. Risk factors for DAIDS Grade 3/4 TE were identified through multivariate Cox regression statistical modeling.</p> <p>Results</p> <p>Grade 3/4 TEs occurred in 144/1299 (11.1%) patients; 123/144 (85%) of these were asymptomatic; 84% of these patients only temporarily interrupted treatment or continued, with transaminase levels returning to Grade ≤ 2. At 96 weeks of study treatment, the incidence of Grade 3/4 TEs was higher among the +LD (16.8%) than among the -LD (10.1%) patients. K-M analysis revealed an incremental risk for developing DAIDS Grade 3/4 TEs; risk was greatest through 24 weeks (6.1%), and decreasing thereafter (>24-48 weeks: 3.4%, >48 weeks-72 weeks: 2.0%, >72-96 weeks: 2.2%), and higher in +LD than -LD patients at each 24-week interval. Treatment with TPV/r, co-infection with hepatitis B and/or C, DAIDS grade >1 TE and CD4⁺> 200 cells/mm³at baseline were found to be independent risk factors for development of DAIDS Grade 3/4 TE; the hazard ratios (HR) were 2.8, 2.0, 2.1 and 1.5, respectively. Four of the 144 (2.7%) patients with Grade 3/4 TEs developed hepatic SAEs; overall, 14/1299 (1.1%) patients had hepatic SAEs including six with hepatic failure (0.5%). The K-M risk of developing hepatic SAEs through 96 weeks was 1.4%; highest risk was observed during the first 24 weeks and decreased thereafter; the risk was similar between +LD and -LD patients for the first 24 weeks (0.6% and 0.5%, respectively) and was higher for +LD patients, thereafter.</p> <p>Conclusion</p> <p>Through 96 weeks of TPV/r-based cART, DAIDS Grade 3/4 TEs and hepatic SAEs occurred in approximately 11% and 1% of TPV/r patients, respectively; most (84%) had no significant clinical implications and were managed without permanent treatment discontinuation. Among the 14 patients with hepatic SAE, 6 experienced hepatic failure (0.5%); these patients had profound immunosuppression and the rate appears higher among hepatitis co-infected patients. The overall probability of experiencing a hepatic SAE in this patient cohort was 1.4% through 96 weeks of treatment. Independent risk factors for DAIDS Grade 3/4 TEs include TPV/r treatment, co-infection with hepatitis B and/or C, DAIDS grade >1 TE and CD4⁺> 200 cells/mm³at baseline.</p> <p>Trial registration</p> <p>US-NIH Trial registration number: NCT00144170</p