Faculty Bibliography

OBJECTIVES/OBJECTIVE:We systematically reviewed evidence to determine lactose intolerance (LI) prevalence, bone health after dairy-exclusion diets, tolerable dose of lactose in subjects with diagnosed LI, and management. DATA SOURCES/METHODS:We searched multiple electronic databases for original studies published in English from 1967-November 2009. REVIEW METHODS/METHODS:We extracted patient and study characteristics using author's definitions of LI and lactose malabsorption. We compared outcomes in relation to diagnostic tests, including lactose challenge, intestinal biopsies of lactase enzyme levels, genetic tests, and symptoms. Fractures, bone mineral content (BMC) and bone mineral density (BMD) were compared in categories of lactose intake. Reported symptoms, lactose dose and formulation, timing of lactose ingestion, and co-ingested food were analyzed in association with tolerability of lactose. Symptoms were compared after administration of probiotics, enzyme replacements, lactose-reduced milk and increasing lactose load. RESULTS:Prevalence was reported in 54 primarily nonpopulation based studies (15 from the United States). Studies did not directly assess LI and subjects were highly selected. LI magnitude was very low in children and remained low into adulthood among individuals of Northern European descent. For African American, Hispanic, Asian, and American Indian populations LI rates may be 50 percent higher in late childhood and adulthood. Small doses of lactose were well tolerated in most populations. Low level evidence from 55 observational studies of 223,336 subjects indicated that low milk consumers may have increased fracture risk. Strength and significance varied depended on exposure definitions. Low level evidence from randomized controlled trials (RCTs) of children (seven RCTs) and adult women (two RCTs) with low lactose intake indicated that dairy interventions may improve BMC in select populations. Most individuals with LI can tolerate up to 12 grams of lactose, though symptoms became more prominent at doses above 12 grams and appreciable after 24 grams of lactose; 50 grams induced symptoms in the vast majority. A daily divided dose of 24 grams was generally tolerated. We found insufficient evidence that use of lactose reduced solution/milk, with lactose content of 0-2 grams, compared to a lactose dose of greater than 12 grams, reduced symptoms of lactose intolerance. Evidence was insufficient for probiotics (eight RCTs), colonic adaptation (two RCTs) or varying lactose doses (three RCTs) or other agents (one RCT). Inclusion criteria, interventions, and outcomes were variable. Yogurt and probiotic types studied were variable and results either showed no difference in symptom scores or small differences in symptoms that may be of low clinical relevance. CONCLUSIONS:There are race and age differences in LI prevalence. Evidence is insufficient to accurately assess U.S. population prevalence of LI. Children with low lactose intake may have beneficial bone outcomes from dairy interventions. There was evidence that most individuals with presumed LI or LM can tolerate 12-15 grams of lactose (approximately 1 cup of milk). There was insufficient evidence regarding effectiveness for all evaluated agents. Additional research is needed to determine LI treatment effectiveness.

BACKGROUND & AIMS/OBJECTIVE:There has been no prospective, community-based study to track changes in adenoma detection by individual physicians over time and to determine the effectiveness of targeted educational interventions. METHODS:We prospectively collected information on 47,253 screening colonoscopies in average-risk individuals 50 years and older performed by a community-based practice in the Twin Cities of Minnesota. During a period of 3 years, 5 specific interventions were implemented; each was designed to improve adenoma detection rates. Controlling for patient-related and procedure-related factors, rates of adenoma detection and 3-year trends for individual physicians were plotted, and intraclass correlation coefficients were calculated. Generalized estimating equations were used to identify factors associated with detection of adenomas and polyps. RESULTS:At least 1 polyp and 1 adenoma were found in 36% and 22% of examinations, respectively. Adenoma detection rates by endoscopists ranged from 10%-39%. There was no significant improvement during the study period despite planned, systematic interventions. Factors associated with adenoma detection included age of the patient (odds ratio [OR], 1.02; 95% confidence interval [CI], 1.02-1.02), male sex (OR, 1.53; 95% CI, 1.34-1.74), and adequate preparation quality (OR, 2.26; 95% CI, 1.64-3.12). CONCLUSIONS:The detection of adenomas by individual physicians during a 3-year period varied and did not appear to change between individual endoscopists, despite planned, systematic interventions. This indicates that other targeted interventions might be required to improve adenoma detection rates among experienced, community gastroenterologists.

BACKGROUND:Left atrial thrombus (LAT) is frequently present in patients with cerebral ischemic events (CIE) who are in atrial fibrillation. The prevalence and predictor of LAT in patients who are in sinus rhythm (SR) is unclear. OBJECTIVE:To determine the prevalence and identify predictors of LAT formation in patients with CIE who are in SR. METHODS:Consecutive patients with CIE who are in SR were evaluated by transesophageal echocardiography (TEE) from July 2000 to August 2001. Patient demographics including cerebrovascular risk factors were recorded. RESULTS:LAT was present in 5.5%. Left ventricular systolic dysfunction (LVSD) was present in 25 (10%). Patients' mean age was 59 +/- 14 years and 119 (50%) were male. In the univariate analysis, LAT was associated with LVSD (odds ratio [OR] 9.24, 95% confidence interval [CI] 2.8; 10.3) and male patients (OR 4.56, 95% CI: 1.6, 12.6) who had coronary artery disease (OR 3.4, 95% CI: 1.3, 8.4). In the multivariate analysis, LVSD (OR 10.6, CI 2.2-51.6) strongly predicted the development of LAT. CONCLUSIONS:LAT is not uncommon in patients CIE, who are in sinus rhythm, especially those with poor left ventricular functions. TEE should be considered in patients with CIE and LVSD for early detection and treatment of LAT.

We systematically reviewed the literature on the extent to which population characteristics or clinical features predict groups of individuals likely to develop advanced liver disease or die from chronic infection with hepatitis B virus (HBV). We searched Medline to include studies with reported cirrhosis, liver failure, liver cancer, or death outcomes after at least 1 year of follow-up from the measurement of predictive factors (age, age at infection, geographic location, race/ethnicity, sex, positive family history, presence of coinfections, HBV viral level, change in hepatitis B e antigen [HBeAg] status, genotype, HBV mutations, nonalcoholic fatty liver disease, alcohol consumption, liver enzymes, and liver biopsy finding). Evidence from 41 included articles suggested that cirrhosis, higher HBV viral level, and male sex were consistently associated with significantly increased risk of death and liver cancer. Evidence about the role of HBV genotype, HBeAg status, age and duration of infection, coinfections with hepatitis C virus, human immunodeficiency virus, hepatitis delta virus, and alanine aminotransferase levels were limited and inconsistent, but were deemed promising to identify patients at higher risk of clinical outcomes. Adults with chronic hepatitis B had increased risk for poorer health outcomes compared to the general population; however, the magnitude of risk varied greatly depending on baseline patient and disease characteristics, and typically clinical outcomes required many years to become manifest. Many adults with chronic hepatitis B had low absolute risks of clinical outcomes and likely would not benefit from immediate treatment. Baseline patient and disease characteristics provide important information about the risk of clinical outcomes and should be incorporated into monitoring or treatment decisions.

OBJECTIVES/OBJECTIVE:The aim of this study was to examine the potential cost-effectiveness of calcium chemoprevention post-polypectomy as a substitute or adjunct for surveillance. METHODS:We constructed a Markov model of post-polypectomy adenoma recurrence and colorectal cancer (CRC) development, calibrated to data from prospective chemoprevention trials of fiber, calcium, antioxidants, and aspirin. We modeled four scenarios for 50-year-old patients immediately after polypectomy: (i) natural history with no further intervention; (ii) elemental calcium 1,200 mg/day from age 50-80; (iii) surveillance colonoscopy from age 50-80 every 5 years, or 3 years for large adenoma; (iv) calcium + surveillance. Patients were followed up until age 100 or death. RESULTS:Calcium was cost-effective compared to natural history ($49,900/life-year gained). However, surveillance was significantly more effective than calcium (18.729 versus 18.654 life-years/patient; 76 percent versus 14 percent reduction in CRC incidence) at an incremental cost of $15,900/life-year gained. Calcium + surveillance yielded a very small benefit (0.0003 incremental life-years/patient) compared with surveillance alone, at a substantial incremental cost of $3,090,000/life-year gained. CONCLUSION/CONCLUSIONS:Post-polypectomy calcium chemoprevention is unlikely to be a reasonable substitute for surveillance. It may be cost-effective in patients unwilling or unable to undergo surveillance.

To further clarify and/or develop calcium and vitamin D as chemopreventive agents against colorectal cancer in humans, understand the mechanisms by which these agents reduce risk for the disease, and develop "treatable" biomarkers of risk for colorectal cancer, we conducted a pilot, randomized, double-blind, placebo-controlled, 2 x 2 factorial clinical trial to test the effects of calcium and vitamin D3, alone and in combination on markers of apoptosis, in the normal colorectal mucosa. Ninety-two men and women with at least one pathology-confirmed colorectal adenoma were treated with 2.0 g/d calcium or 800 IU/d vitamin D3, alone or in combination, versus placebo over 6 months. Overall expression and colorectal crypt distributions of Bcl-2 (an apoptosis inhibitor) and Bax (an apoptosis promoter) in biopsies of normal-appearing rectal mucosa were detected by automated immunohistochemistry and quantified by image analysis. After 6 months of treatment, Bax expression along the full lengths of crypts increased 56% (P = 0.02) in the vitamin D group and 33% in both the calcium (P = 0.31) and calcium plus vitamin D (P = 0.36) groups relative to the placebo group. The vitamin D treatment effect was more pronounced in the upper 40%, or differentiation zone, of crypts (80%; P = 0.01). There were no statistically significant treatment effects on Bcl-2 expression. Overall, these preliminary results suggest that calcium and vitamin D, individually or together, may enhance apoptosis in the normal human colorectal epithelium, and the strongest treatment effects may be vitamin D related and in the upper sections of the colorectal crypts.

BACKGROUND:Chronic hepatitis B infection can lead to liver failure, hepatocellular carcinoma, and death. PURPOSE/OBJECTIVE:To evaluate the effectiveness of antiviral therapy for adults with chronic hepatitis B infection. DATA SOURCES/METHODS:Randomized, controlled trials (RCTs) of interferon (alpha2b and pegylated alpha2a), lamivudine, adefovir, entecavir, and telbivudine published from 1990 to 2008. STUDY SELECTION/METHODS:Randomized, controlled clinical trials of adults with chronic hepatitis B published in English after 1989 that reported death; incidence of hepatocellular carcinoma or liver failure; prevalence and incidence of cirrhosis; presence or seroconversion of hepatitis B e antigen (HBeAg) or surface antigen (HBsAg), viral load of hepatitis B virus DNA; aspartate aminotransferase and alanine aminotransferase (ALT) levels; or fibrosis scores after therapy with interferon-alpha2b, pegylated interferon-alpha2a, lamivudine, adefovir, entecavir, and telbivudine. DATA EXTRACTION/METHODS:Data extracted with standard protocols to calculate risk difference for clinical outcomes, viral load, HBeAg and HBsAg, ALT, histologic scores, and adverse events. DATA SYNTHESIS/RESULTS:In 16 RCTs (4431 patients), drug treatment did not improve clinical outcomes of chronic hepatitis B infection, but the trials were underpowered. In 60 RCTs that examined intermediate outcomes, no single treatment improved all intermediate outcomes. Low-quality evidence suggested HBsAg clearance after interferon-alpha2b (2 RCTs; 211 patients). Moderate-quality evidence suggested ALT normalization at follow-up after treatment with adefovir (2 RCTs; 600 patients) and HBeAg loss with lamivudine (2 RCTs; 318 patients). With interferon-alpha2b, moderate-quality evidence suggested HBeAg loss (3 RCTs; 351 patients), seroconversion (2 RCTs; 304 patients), and ALT normalization (2 RCTs; 131 patients). Pegylated interferon-alpha2a versus lamivudine improved HBeAg seroconversion (1 RCT; 814 patients) and ALT normalization (2 RCTs; 905 patients) off treatment. Pegylated interferon-alpha2a combined with lamivudine versus lamivudine improved HBeAg loss (1 RCT; 543 patients) and ALT normalization (2 RCTs; 905 patients). Adverse events during antiretroviral therapy occurred in more than 50% of patients but were not associated with increased treatment discontinuation. However, most studies excluded patients with hepatic or renal insufficiency or other serious comorbid conditions. LIMITATION/CONCLUSIONS:Marked heterogeneity in study samples, interventions, and measured outcomes preclude definitive conclusions. CONCLUSION/CONCLUSIONS:Evidence was insufficient to assess treatment effect on clinical outcomes or determine whether inconsistent improvements in selected intermediate measures are reliable surrogates. Future research is needed to provide evidence-based recommendations about optimal antiviral therapy in adults with chronic hepatitis B infection.

To investigate the potential efficacy of calcium and vitamin D in reducing risk for colorectal neoplasms and to develop "treatable" phenotypic biomarkers of risk for colorectal neoplasms, we conducted a pilot, randomized, double-blind, placebo-controlled, 2 x 2 factorial clinical trial to test the effects of these agents on cell cycle markers in the normal colorectal mucosa. Ninety-two men and women with at least one pathology-confirmed colorectal adenoma were treated with 2 g/day calcium and/or 800 IU/day vitamin D(3) versus placebo over 6 months. Overall expression and distributions of p21(waf1/cip1) (marker of differentiation), MIB-1 (marker of short-term proliferation), and hTERT (marker of long-term proliferation) in colorectal crypts in the normal-appearing rectal mucosa were detected by automated immunohistochemistry and quantified by image analysis. In the calcium, vitamin D, and calcium plus vitamin D groups relative to the placebo, p21 expression increased by 201% (P = 0.03), 242% (P = 0.005), and 25% (P = 0.47), respectively, along the full lengths of colorectal crypts after 6 months of treatment. There were no statistically significant changes in the expression of either MIB-1 or hTERT in the crypts overall; however, the proportion of hTERT, but not MIB-1, expression that extended into the upper 40% of the crypts was reduced by 15% (P = 0.02) in the vitamin D plus calcium group relative to the placebo. These results indicate that calcium and vitamin D promote colorectal epithelial cell differentiation and may "normalize" the colorectal crypt proliferative zone in sporadic adenoma patients, and support further investigation of calcium and vitamin D as chemopreventive agents against colorectal neoplasms.