Biomedical subjects
Publications and source records attributed to Michael Emmett.
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BACKGROUND: Surreptitious ingestion of laxatives can lead to serious factitious diseases that are difficult to diagnose. Most cases involve ingestion of bisacodyl or senna. Thin layer chromatography (TLC) of urine or stool is the only commercially available test for these laxatives. Such testing is considered highly reliable, but its accuracy in clinical practice is unknown. Our aim was to evaluate the reliability of TLC laxative testing by a clinical reference laboratory in the United States. METHODS: Diarrhea was induced in healthy volunteers by ingestion of bisacodyl, senna, or a control laxative (n = 11 for each laxative group). Samples of urine and diarrheal stool were sent in blinded fashion to the clinical reference laboratory for bisacodyl and senna analysis. RESULTS: TLC testing for bisacodyl-induced diarrhea revealed a sensitivity of 73% and specificity of 91% when urine was tested and sensitivity and specificity of 91% and 96%, respectively, when stool was analyzed. When diarrhea was induced by senna, the TLC assay for senna failed to identify even a single urine or stool specimen as positive (zero% sensitivity). CONCLUSIONS: Considering the expected prevalence of surreptitious laxative abuse in patients with chronic idiopathic diarrhea (2.4%-25%, depending on the clinical setting), TLC of urine or stool for bisacodyl by this reference laboratory would often produce misleading results, and testing for senna would have no clinical value. The major problems are false-positive tests for bisacodyl and false-negative tests for senna.
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BACKGROUND & AIMS: In normal intestine, cyclic nucleotides (adenosine 3',5'-cyclic monophosphate [cAMP], guanosine 3',5'-cyclic monophosphate) and Ca(2+) inhibit neutral sodium absorption. In contrast, in the jejunum of a knockout mouse model of cystic fibrosis (CF), agents that elevate intracellular cAMP levels did not inhibit neutral sodium absorption, suggesting that the antiabsorptive effect of cAMP is dependent on the cystic fibrosis transmembrane conductance regulator (CFTR). The aim of the present study was to determine if a prostaglandin E(1) analogue, which causes elevation of intracellular cAMP and Ca(2+) levels, inhibits neutral sodium absorption in patients with CF in vivo. METHODS: Electrolyte and water absorption/secretion was measured during steady state perfusion of the jejunum with a balanced electrolyte solution. Patients with CF and healthy subjects were studied under basal conditions and during intraluminal infusion of a prostaglandin E(1) analogue (misoprostol). RESULTS: The rate of neutral sodium absorption in the basal state was similar in healthy subjects and patients with CF. Prostaglandin infusion markedly reduced neutral sodium absorption in both healthy subjects and patients with CF. Prostaglandin caused high rates of electrolyte and water secretion in healthy subjects but only trivial rates of secretion in patients with CF. CONCLUSIONS: CFTR mutations causing CF in humans do not prevent prostaglandin E(1) inhibition of neutral sodium absorption, even though these mutations produce a severe defect in prostaglandin-stimulated electrolyte secretion. These findings suggest that an intact antiabsorptive response to either cAMP or Ca(2+) may contribute to the relatively low level of intestinal disease in patients with CF.
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A comparison of clinically useful phosphorus binders for patients with chronic kidney failure. Over the past 30 years it has become apparent that hyperphosphatemia plays a major causative role across the entire spectrum of morbidity associated with advancing kidney dysfunction and failure. A large fraction (60% to 70%) of dietary phosphorus is absorbed and normally excreted by the kidneys. Ideally, as kidney function deteriorates, the net quantity of phosphorus absorbed from the GI tract should be proportionally reduced to match the decrease in kidney function. After initiation of chronic dialysis therapy, the absorbed phosphorus load should match the amount of phosphorus removed via dialysis plus any excreted by residual kidney function. Because it is very difficult to reduce dietary phosphorus to these levels, a variety of oral phosphorus binders have been employed. Currently available binders include alkaline aluminum, magnesium, and calcium salts (primarily calcium carbonate and calcium acetate), various iron salts, and the binding resin sevelamer hydrochloride. Lanthanum carbonate is the newest agent and will probably be released shortly. This review compares the theoretic and in vitro chemistry of these drugs with in vivo data obtained in both normal patients, and in patients with kidney failure. The clinical potency and potential toxicity of the binding agents are compared, and optimal drug administration strategies are also reviewed.
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Quantitation of fecal bile acid excretion can help elucidate the cause of diarrhea or steatorrhea. Fecal bile acids can be measured with gas chromatography-mass spectrometry, but this is time-consuming, expensive, and not available for clinical use. Relatively simple enzymatic methods have been described for the measurement of fecal 3alpha-hydroxy bile acids, but these have not been validated in patients with gastrointestinal disease. We found that an enzymatic method yielded falsely low results in patients with malabsorption syndromes for two reasons: First, the preliminary hydrolysis step did not completely deconjugate bile acids, precluding their extraction into diethyl ether for enzymatic assay. Second, long-chain fatty acids inhibited 3alpha-hydroxysteroid dehydrogenase activity. By increasing the duration of hydrolysis and the concentration of enzyme, we developed a simple, accurate, and reproducible method for measuring fecal 3alpha-hydroxy bile acids that agreed well with values obtained with the use of gas chromatography-mass spectrometry (R =.95), both in normal subjects and in patients with malabsorption syndromes.
BACKGROUND: Patients with short bowel syndrome (SBS) have steatorrhea, in part because of bile acid malabsorption that causes decreased bile acid secretion into the duodenum and consequent fat maldigestion. In SBS patients with colon in continuity, luminal calcium forms calcium fatty acid soaps rather than precipitating as insoluble calcium oxalate. Soluble oxalate is hyperabsorbed by the colon leading to hyperoxaluria and an increased risk for renal calcium oxalate stones and deposits. The authors hypothesized that oral ingestion of conjugated bile acids would increase fat absorption and thereby decrease calcium fatty acid soap formation and oxalate hyperabsorption. METHODS: The effect of conjugated bile acid replacement therapy (9 g/d) on fecal fat excretion and urine oxalate excretion was measured in an appropriate patient, utilizing the metabolic balance technique. The effects of chronic bile acid replacement therapy on oxalate excretion and nutritional status also were measured in a 3-month outpatient study. RESULTS: Natural conjugated bile acid replacement therapy reduced fecal fat excretion from 119 to 79 g/d (Delta40 g/d), and urinary oxalate excretion from 87 to 64 mg/d (966 to 710 micromol/d; Delta23 mg/d). Cholylsarcosine, a synthetic conjugated bile acid, had similar but less powerful effects. During a 3-month outpatient trial of natural conjugated bile acids (9 g/d), urine oxalate decreased to normal levels (27 mg/d) in association with weight gain, decreased hunger, and decreased hyperphagia. CONCLUSION: Conjugated bile acid replacement therapy reduced fecal fat excretion, reduced urinary oxalate excretion, and improved nutritional status in a patient with SBS with colon in continuity, hyperoxaluria, and oxalate nephrolithiasis.
Due to genetic defects in apical membrane chloride channels, the cystic fibrosis (CF) intestine does not secrete chloride normally. Depressed chloride secretion leaves CF intestinal absorptive processes unopposed, which results in net fluid hyperabsorption, dehydration of intestinal contents, and a propensity to inspissated intestinal obstruction. This theory is based primarily on in vitro studies of jejunal mucosa. To determine if CF patients actually hyperabsorb fluid in vivo, we measured electrolyte and water absorption during steady-state perfusion of the jejunum. As expected, chloride secretion was abnormally low in CF, but surprisingly, there was no net hyperabsorption of sodium or water during perfusion of a balanced electrolyte solution. This suggested that fluid absorption processes are reduced in CF jejunum, and further studies revealed that this was due to a marked depression of passive chloride absorption. Although Na+-glucose cotransport was normal in the CF jejunum, absence of passive chloride absorption completely blocked glucose-stimulated net sodium absorption and reduced glucose-stimulated water absorption 66%. This chloride absorptive abnormality acts in physiological opposition to the classic chloride secretory defect in the CF intestine. By increasing the fluidity of intraluminal contents, absence of passive chloride absorption may reduce the incidence and severity of intestinal disease in patients with CF.