Factors influencing pulmonary methane excretion in man. An indirect method of studying the in situ metabolism of the methane-producing colonic bacteria.

Measurements of pulmonary excretion of methane (CH(4)) were used to obtain information on the CH(4)-producing bacteria in man. Preliminary studies indicated that (a) all CH(4) excreted by man is produced by colonic bacteria, (b) there is no appreciable utilization of CH(4) by man, and (c) breath CH(4) can serve as a relatively accurate indicator of CH(4) production in the intestine. The rate of pulmonary CH(4) excretion varied enormously, ranging from undetectable (<5 x 10(-6) ml/min) to 0.66 ml/minute. In general, the CH(4) excretion rate for subjects was consistently very low (nonproducers) or relatively large (producers). 33.6% of the adult population were producers of CH(4). Whereas diet, age over 10 yr, and sex did not influence the rate of CH(4) production, some familial factor appeared to play an important role. 84% of siblings of CH(4) producers also were producers, while only 18% of the siblings of nonproducers were found to be CH(4) producers. This familial tendency appeared to be determined by early environmental rather than genetic factors. These studies of CH(4) excretion demonstrate that the exposure of individuals to intestinal bacterial metabolites may differ markedly and that these differences may be chronic and determined by familial factors.

Risk factors for severe delayed postpolypectomy bleeding.

BACKGROUND AND STUDY AIMS: Postpolypectomy bleeding is a rare but serious adverse event. The aim of this study was to identify factors associated with the risk of severe delayed postpolypectomy bleeding. PATIENTS AND METHODS: This was a case-control study, comparing cases who developed hematochezia and required medical evaluation 6 hours to 14 days after colonoscopic polypectomy, and control patients who underwent polypectomy without delayed bleeding, and who were selected in approximately a 3 : 1 ratio. The following risk factors were specified a priori: resuming anticoagulation (within 1 week following polypectomy), aspirin use, hypertension, and polyp diameter. RESULTS: Of the 4592 patients who underwent colonoscopy with polypectomy, 41 patients (0.9 %) developed delayed postpolypectomy bleeding (cases), and 132 patients were selected as controls. The mean age was 64.3 years for cases and 65.4 years for controls. Cases presented on average 6 days after polypectomy (range 1 - 14 days), and 48 % required blood transfusion (average 4.2 units, range 0 - 17). Two patients required surgery. Anticoagulation was resumed following polypectomy in 34 % of cases compared with 9 % of controls (OR 5.2; 95 % CI 2.2 - 12.5; P < 0.001). For every 1 mm increase in polyp diameter, the risk of hemorrhage increased by 9 % (OR 1.09; 95 % CI 1.0 - 1.2; P = 0.008). Hypertension (OR 1.1) and aspirin use (OR 1.1) did not increase the risk of postpolypectomy bleeding. In exploratory analysis, diabetes (OR 2.5) and coronary artery disease (OR 3.0) were associated with postpolypectomy hemorrhage, but the association was no longer statistically significant once adjusted for the use of anticoagulation. CONCLUSIONS: Resuming anticoagulation following polypectomy and polyp diameter were strongly associated with increased risk of severe delayed postpolypectomy bleeding.

Use of pulmonary hydrogen (H 2 ) measurements to quantitate carbohydrate absorption. Study of partially gastrectomized patients.

A technique was developed to quantitate the absorption of ingested carbohydrate by means of continuous measurements of pulmonary H(2) excretion. This technique is based on the observation that H(2) is produced in the colon when carbohydrate is fermented by colonic bacteria, and this H(2) is then excreted by the lungs. The quantitative relationship of pulmonary H(2) excretion to unabsorbed carbohydrate was studied in nine subjects. After ingestion of 6.5, 13, and 26 g of lactulose (a nonabsorbable disaccharide), H(2) excretion increased linearly, averaging (+/-1 SEM) 13+/-3.5, 23+/-7.2, and 49+/-7 ml per 2 hr. Because of consistent individual differences in H(2) excretion per gram of lactulose, the variability of this linear response was less in a given subject, with the H(2) excretion after 6.5 g and 26 g lactulose dosages averaging 55+/-4.2% and 214+/-16% of that observed after the 13 g dose. It was further demonstrated with fecal homogenates, as well as in rats after direct intracecal instillation of carbohydrate, that there was no significant difference in the rate of H(2) formation from lactulose as compared with the normally ingested sugars. Thus, a subject's H(2) excretion after a 13 g dose of lactulose can be used as a standard to convert H(2) excretion after ingestion of other carbohydrates into grams of carbohydrate not absorbed. Application of this technique to seven partially gastrectomized patients indicated all subjects malabsorbed a portion of a 100 g dose of glucose whereas six of seven completely absorbed a 25 g dose. Malabsorption of physiologic quantities of various carbohydrates was clearly demonstrated in one subject. This technique appears to provide quantitative information on carbohydrate malabsorption not readily obtained by presently available techniques.

Fate of soluble carbohydrate in the colon of rats and man.

The fate of glucose in the colon of rats and man was investigated by measuring breath 14CO2 and fecal 14C after direct instillation of 14C-labeled glucose, acetate, and lactate into the cecum. For the 6 h after administration of as much as 400 mg of [U-14C]-glucose to the rat and 12.5 g to man, 14CO2 excretion was as rapid after intracecal as after intragastric instillation. Less than 20% of 14C instilled into the cecum as glucose was recovered in feces and only about 15% of this fecal 14C was in a dialyzable form. The conversion of intracecally administered glucose to CO2 was dependent upon the presence of the colonic flora, as evidenced by the minimal excretion of 14CO2 after administration of [14C]glucose to germ-free rats. In contrast, acetate and lactate, fermentation products of glucose, were converted to CO2 as rapidly in germ-free rats as in their conventional counterparts. Measurement of O2 availability in the colonic lumen indicated that insufficient O2 was available for the aerobic metabolism of glucose by the colonic bacteria. These experiments suggest that the colon bacteria anaerobically metabolize most of the glucose to short-chain fatty acids, which are absorbed and oxidized by the host. Most of the remaining fecal glucose is converted to a larger molecular form that has limited osmotic activity. Thus, the colonic flora benefits the host by reducing the osmotic load of nonabsorbed carbohydrate and by making possible the salvage of a large percentage of the calories of carbohydrate, which is not absorbed in the small bowel.

Use of inert gases and carbon monoxide to study the possible influence of countercurrent exchange on passive absorption from the small bowel.

The purpose of the present study was to quantitate the influence of countercurrent exchange on passive absorption of highly diffusible substances from the small intestine of the rabbit. The absorption of carbon monoxide, which is tightly bound to hemoglobin and therefore cannot exchange, was compared to the absorption of four unbound gases (H(2), He, CH(4), and (133)Xe), which should exchange freely. The degree to which the observed absorption of the unbound gases falls below that predicted from CO absorption should provide a quantitative measure of countercurrent exchange.CO uptake at high luminal Pco is flow-limited and, assuming that villus and central hemoglobin concentrations are equal, the flow that equilibrates with CO (F(co)) was calculated to equal 7.24 ml/min/100 g. The observed absorption rate of the unbound gases was from two to four times greater than would have been predicted had their entire uptake been accounted for by equilibration with F(co). This is the opposite of what would occur if countercurrent exchange retarded absorption of the unbound gases. The unbound gases have both flow- and diffusion-limited components, and F(co) should account for only the fraction of absorption that is flow limited. A simple model of perfusion and diffusion made it possible to calculate the fraction of the total uptake of unbound gases that was flow limited. This fraction of the total observed absorption rate was still about 1.8 times greater than predicted by CO absorption. A possible explanation for this discrepancy is that plasma skimming reduces the hemoglobin of villus blood to about 60% of that of central blood. Thus, F(co) is actually about 1.7 times greater than initially calculated, and with this correction, there is close agreement between the predicted and observed rates of absorption of each of the unbound gases. We conclude that countercurrent exchange does not influence passive absorption under the conditions of this study.

Quantitation of countercurrent exchange during passive absorption from the dog small intestine: evidence for marked species differences in the efficiency of exchange.

The present investigation was designed to quantitatively assess the possible influence of countercurrent exchange on passive absorption from the small intestine of the dog. Villus blood flow was measured with a modification of the microsphere method. Simultaneously, the absorption from the gut lumen of five diffusible gases (H2, He, CH4, 133Xe, and CO) was determined. Villus blood flow averaged 0.247 +/- 0.03 (SEM) ml/min per g. The observed absorption of H2, He, CH4, and 133Xe was only 16.2 +/- 1.8, 12.8 +/- 2.3, 12.0 +/- 1.8, and 15.8 +/- 1.4 %, respectively, of what this villus blood flow could carry away if it reached perfect equilibrium with the luminal gases. This low absorption rate could result from diffusion limitation to absorption or countercurrent exchange. The diffusive permeability of the barrier seperating the luminal gases and villus blood flow was assessed by measuring the absorption rate of CO. Because absorbed CO binds tightly to hemoglobin, it cannot exchange, and when present in low concentrations its uptake is entirely diffusion limited. Knowledge of the diffusion rate through tissue of the unbound gases relative to that of CO made it possible to calculate the degree to which each of the unbound gases should equilibrate with villus tip blood. The percentage equilibration between lumen and blood at the villus tip for H2, He, CH4, and 133Xe was 99.7, 99.9, 75.6, and 36.0% , respectively. Each of these values greatly exceeded the percentage equilibration of blood leaving the villus (calculated from the observed absorption rate and villus blood flow) and indicated an exchange of 83.8, 87.2, 84.1, and 56.1% of initially absorbed H2, He, CH4, and 133Xe. This result is in accord with theoretical calculations which suggest that countercurrent exchange should be exceedingly efficient in the dog. The striking effect of countercurrent exchange on passive absorption in the dog differs from our previous studies in the rabbit where no exchange was demonstrated. This marked species difference may result from anatomical differences in villus architecture. The dog has long, densely packed villi while the rabbit has broad, widely spaced villi. In the dog, only the villus tips may equilibrate with the lumen, hence a countercurrent gradient may be established in the villus. The entire villus of the rabbit may equilibrate with the lumen and no gradient for countercurrent exchange can therefore be established.

Use of carbon monoxide to measure luminal stirring in the rat gut.

We used carbon monoxide (CO) as a probe to quantitatively measure intestinal unstirred water layers in vivo. CO has several features that make it uniquely well suited to measure the unstirred layer in that its tight binding to hemoglobin makes uptake diffusion limited, and its relatively high lipid solubility renders membrane resistance negligible relative to the water barriers of the unstirred layer and epithelial cell. The unique application of CO was the measurement of the absorption rate of CO both from the gas phase as well as a solute dissolved in saline. Several lines of evidence showed that a gut stripped free of saline and then filled with gas contained a negligible unstirred layer. Thus, absorption of CO from the gas phase measured resistance of just the epithelial cell. Subtraction of this value from the resistance of CO absorption from saline provided a direct measure of unstirred layer resistance. Studies in the rat showed for a 3-min absorption period that the conventionally calculated apparent unstirred layer for the jejunum was 411 micron and for the colon was 240 micron. However, this conventionally calculated unstirred layer resistance did not truly depict the situation in the rat gut, since there was a continuing depletion of CO from outer surfaces of luminal contents throughout the experiment period. This produced a continually increasing diffusion barrier with time. Calculation of expected absorption rate from unstirred cylinders with the dimensions of the rat gut indicated that there was virtually no stirring in the small intestine and minimal stirring in the colon. The technique described in this paper appears to be simpler and to require fewer assumptions for validity than other techniques previously used to measure unstirred layers in vivo.

Colorectal cancer mortality: effectiveness of biennial screening for fecal occult blood.

BACKGROUND: In 1993, a randomized controlled trial in Minnesota showed, after 13 years of follow-up, that annual fecal occult blood testing was effective in reducing colorectal cancer mortality by at least 33%. Biennial screening (i.e., every 2 years) resulted in only a 6% mortality reduction. Two European trials (in England and in Denmark) subsequently showed statistically significant 15% and 18% mortality reductions with biennial screening. Herein, we provide updated results-through 18 years of follow-up--from the Minnesota trial that address the apparent inconsistent findings among the trials regarding biennial screening. METHODS: From 1976 through 1977, a total of 46551 study subjects, aged 50-80 years, were recruited and randomly assigned to an annual screen, a biennial screen, or a control group. A screen consisted of six guaiac-impregnated fecal occult blood tests (Hemoccult) prepared in pairs from each of three consecutive fecal samples. Participants with at least one of the six tests that were positive were invited for a diagnostic examination that included colonoscopy. All participants were followed annually to ascertain incident colorectal cancers and deaths. RESULTS: The numbers of deaths from all causes were similar among the three study groups. Cumulative 18-year colorectal cancer mortality was 33% lower in the annual group than in the control group (rate ratio, 0.67; 95% confidence interval [CI] = 0.51-0.83). The biennial group had a 21% lower colorectal cancer mortality rate than the control group (rate ratio, 0.79; 95% CI = 0.62-0.97). A marked reduction was also noted in the incidence of Dukes' stage D cancers in both screened groups in comparison with the control group. CONCLUSION: The results from this study, together with the other two published randomized trials of fecal occult blood screening, are consistent in demonstrating a substantial, statistically significant reduction in colorectal cancer mortality from biennial screening.

Fecal occult blood screening for colorectal cancer.

We critically analyzed the current literature on fecal occult blood testing as it pertains to colorectal cancer screening. We used articles published or referenced in the major English-language medical and gastroenterology journals for the last 10 years. Large, randomized controlled trials, case-control and cohort studies, and other sources containing information pertinent to the application of fecal occult blood testing for colorectal cancer screening were selected. Although the fecal occult blood test results are capable of predicting the presence of colorectal cancers and polyps, the sensitivity is variable in different studies and low for the latter. Nevertheless, most reports of its use emphasize that a relatively high percentage of the cancers detected are early-stage lesions. Currently available methods for colorectal cancer screening are imperfect, thereby increasing the cost-effectiveness ratio. The fecal occult blood test remains a workable approach to reducing the mortality from colorectal cancer provided it is carried out with attention to important variables such as the need for compliance, including the compliance of physicians.

Effect of dietary fiber on intestinal gas production and small bowel transit time in man.

The influence of dietary fiber on intestinal gas production and on small bowel transit time was studied in eight healthy subjects using breath H2 excretion as an indicator of colonic gas production. Hydrogen excretion following ingestion of bran was substantially less than that following ingestion of lactulose, a nonabsorbable fermentable sugar. Likewise, human fecal homogenates produced only about 10% as much H2 and CO2 during incubation with bran as with glucose or lactulose. Thus, the polysaccharides in bran appear to be relatively poor substrate for colonic bacterial gas production, and reported gas-related symptoms after bran ingestion may be due to some other mechanism. The small bowel transit time of bran was greater than that of lactulose; however, addition of bran to lactulose did not slow lactulose transit.

Milk intolerance in Manitoba Indian school children.

The breath H2 test was used to determine the prevalence of milk intolerance in Indian schoolchildren, 5 to 19 years old. One hundred four children were randomly assigned to one of six groups: 1) reconstituted skimmed milk powder (SMP); 2) SMP and sandwich; 3) SMP and lactase; 4) diluted (1:1) evaporated whole milk (EM); 5) EM and sandwich; and 6) EM and lactase. Samples of expired air were collected 2 hr after ingestion of 245 ml of milk. Five children had H2 levels suggestive of appreciable lactose malabsorption; two had symptoms. The mean H2 excretion levels of the subjects on SMP were significantly higher than those on EM. The group on SMP alone excreted significantly more H2 than any other group except those receiving SMP and a sandwich. The relatively low prevalence of milk intolerance in this populatin group should not preclude continuation and promotion of milk programs in their schools. However, preference should be given to the use of EM rather than SMP. The needs of children who cannot hydrolyze lactose must also be considered in the planning of food supplement programs.

Follow-up after polypectomy: consensus?

Patients who have had a colorectal adenoma resected have an increased risk of subsequent cancer and may benefit from follow-up surveillance. Surveillance strategies should be tailored to the assessed risk of each individual patient. A number of long-term follow-up studies indicate that the risk of metachronous neoplasia is higher if on index colonoscopy there were multiple (> or = 2) adenomas, or if any adenoma was large (> or = 1 cm), contained villous tissue or severe dysplasia, or if the patient had a family history of colorectal neoplasia. Data from the U.S. National Polyp Study indicate that polyp resection and follow-up surveillance greatly reduces the incidence of metachronous cancer, and that the first follow-up colonoscopy does not need to be performed for 3 years. Current data have been incorporated into a comprehensive consensus practice guideline.

Interference with the adenoma-carcinoma sequence.

Epidemiological, pathological, and genetic studies indicate that most colorectal cancers arise in benign neoplastic polyps (adenomas). The likelihood of malignant change increases with adenoma size and volume of villous tissue. Adenomas are monoclonal products of a single stem cell mutation. Acquired genetic mutations and chromosomal deletions that occur late in the polyp-cancer sequence have been well described, although the initiating events leading to micro-adenoma formation are still unknown. Both inherited and environmental factors are implicated. Although the evidence in support of the adenoma-carcinoma sequence is indirect, it is compelling. Chemoprevention trials have not yet identified effective methods of primary prevention. Colonoscopic resection of adenomas (secondary prevention) plus post-polypectomy surveillance markedly decreases the incidence of colorectal cancer.

Screening guidelines for colorectal cancer.

Evidence-based guidelines recommend that all asymptomatic, average-risk U.S. citizens >50 years of age be encouraged to undergo screening for colorectal cancer. Those at higher risk should be offered more intensive screening and follow-up surveillance. It is estimated that widespread adoption of these recommendations could reduce mortality from colorectal cancer by >50%. The only screening methods that have been evaluated directly are the fecal occult blood test and flexible sigmoidoscopy. Current guidelines now recommend annual screening for fecal occult blood plus flexible sigmoidoscopy every 5 years for asymptomatic, average-risk men and women >50 years of age. Indirect evidence supports the options of colonoscopy or barium enema x-ray screening for highly motivated individuals, but these methods have not yet been tested in prospective trials. In the future, gene-based screening tests may be developed, and computed tomography of the colon ("virtual colonoscopy") may prove effective and feasible.

Calcium supplements and colorectal adenomas. Polyp Prevention Study Group.

Experimental and observational findings suggest that calcium intake may protect against colorectal neoplasia. To investigate this hypothesis, we conducted a randomized, double-blind trial of colorectal adenoma recurrence. Nine hundred thirty patients with a recent history of colorectal adenomas were randomly given calcium carbonate (3 gm daily; 1200 mg elemental calcium) or placebo, with follow-up colonoscopies one and four years after the qualifying examination. The main analysis focused on new adenomas found after the first follow-up endoscopy, up to (and including) the second follow-up examination. Risk ratios of at least one recurrent adenoma and ratios of the average numbers of adenomas were calculated as measures of calcium effect. There was a lower risk of recurrent adenomas in subjects assigned calcium. Eight hundred thirty-two patients had two follow-up examinations and were included in the main analysis; the adjusted risk ratio of one or more adenomas was 0.81 (95% CI 0.67 to 0.99); the adjusted ratio of the average numbers of adenomas was 0.76 (95% CI 0.60 to 0.96). Among subjects who had at least one follow-up colonoscopy, the adjusted risk ratio of one or more recurrent adenomas was 0.85 (95% CI 0.74 to 0.98). The effect of calcium seemed independent of initial dietary fat and calcium intake. No toxicity was associated with supplementation. These findings indicate that calcium supplementation has a modest protective effect against colorectal adenomas, precursors of most colorectal cancers.

The effect of anesthesia and laparotomy on blood flow to the stomach, small bowel, and colon of the dog.

The effect of anesthesia and laparotomy on the distribution of blood flow to the different tissue layers of the stomach, small bowel, and colon of the dog was studied using a double-isotope, microsphere technique. In conscious dogs total jejunal flow significantly exceeded both ileal and colonic flow. Mucosal flow comprised about two thirds of total gastric and small bowel flow, but less than half of colonic flow. Fifteen minutes after induction of anesthesia, there was a marked increase in flow to all levels of the alimentary tract, as well as to each tissue layer. This increase was transient, since by 1 hour flow to all gut levels had decreased nearly to baseline levels. Laparotomy per se did not significantly alter blood flow to the full thickness or mucosal layer of either stomach, small bowel, or colon. These findings indicate that future studies of gut function or blood flow should be performed in conscious animals or in anesthetized animals only after complete cardiovascular stabilization. Neither laparotomy nor anesthesia caused a redistrubtion of flow away from the mucosal layers, and hence the observation that patients have often stopped bleeding at the time of operation for uncontrolled hemorrhage is unexplained.

Colorectal cancer update. Prevention, screening, treatment, and surveillance for high-risk groups.

Great advances have been made in understanding the cause and molecular genesis of colorectal cancer. The disease can be prevented by a healthful diet and lifestyle or by resecting the precursor of most of these cancers, the advanced adenomatous polyp. Screening the average-risk population plus special surveillance for high-risk groups now is recommended by evidence-based guidelines. Surgery is highly curative for patients without distant metastases, and adjuvant therapy improves survival in selected patients with advanced cancers.

Evaluation of trainee competence.

The ongoing evaluation of endoscopic competence is an essential element of every medical and surgical endoscopic training program. The primary goal of this evaluation is to assure the greatest benefit for patients with digestive diseases. Observational methods to assess competence plus current guideline recommendations for certification and proctoring are discussed in this article.

Failure to demonstrate degradation of (4-14C) cholesterol to volatile hydrocarbons in rats and in human fecal homogenates.

The inability of previous workers to recover completely the radioactivity from ingested [4-14C] cholesterol has led to the hypothesis that the colonic flora of some individuals degrade the sterol nucleus to volatile hydrocarbons, particularly CH4. In the present investigation, the production of radioactive volatiles was measured following incubation of [4-14C] cholesterol with 8 human fecal homogenates or after instillation of the labeled sterol into the cecum of 3 rats housed in a closed rebreathing system. Three of the 8 homogenates and each of the 3 rats produced copious CH4. However, analysis by combustion demonstrated no radioactivity above background in the volatile headspace of the homogenates or the gas space of the closed system housing the rats, indicating that less than 0.001% of the number 4 carbon of [4-14C] cholesterol could have been converted to volatile hydrocarbons. This study, therefore, provides no support for the concept that volatile products account for the incomplete recovery of ingested sterols observed in certain subjects. However, this hypothesis can not be excluded entirely until similar results are obtained with subjects who can be shown to degrade cholesterol.

Office-based management of diarrhea.

Diarrhea of unknown cause is a particularly challenging diagnostic problem as it may be trivial and self-limiting or the presenting symptom of a life-threatening disorder. Antibiotic-associated diarrhea is a frequent complication of antimicrobial therapy, especially in the elderly. The more severe form, pseudomembranous colitis, is now known to be caused by a toxin produced in the colon by Clostridium difficile.