Phillip P. Toskes

Small Intestine Bacterial Overgrowth

The gastrointestinal tract proximal to the distal ileum is usually sparsely populated with bacteria. When overgrowth of bacteria in the small intestine is accompanied by nutrient malabsorption and clinical manifestations of weight loss and malnutrition, the setting has been called the stasis, stagnant loop, or blind loop syndrome. Since the publication of a number of excellent general reviews of the subject several years ago, 1–4 there has been an increased understanding of some of the pathophysiologic events accompanying overgrowth of bacteria in the small intestine. In particular attention has been drawn to the potential addition of mucosal injury to disturbances of the intraluminal environment in the altered handling of various nutrients. In addition, clinical recognition of the entity has increased with the use of noninvasive screening tests, with improvement in culture technique, and with increased recognition of several types of disordered intestinal motility predisposing to overgrowth. The purpose of this review will be to (a) analyze recent developments in the understanding of this syndrome, putting them into perspective with the previously reviewed material; (b) point out the clinical ramifications of the recent information, especially with the perspective that most conditions predisposing to bacterial overgrowth are lifelong, once present; and (c) suggest several areas where future investigation might prove fruitful in furthering our understanding of the pathophysiology and management of small intestine bacterial overgrowth.

Clinically significant vitamin B12 deficiency secondary to malabsorption of protein-bound vitamin B12

Protein- (chicken serum) bound [57Co]cyanocobalamin absorption was evaluated in five hypochlorhydric patients who had developed B12 deficiency despite having normal absorption of unbound crystalline vitamin B12. All five patients had decreased urinary excretion of protein-bound B12 (0.06–0.34%) as compared to twelve normal controls (0.61–5.6%), P<.001. Improvement in protein-bound B12 absorption in four of the five patients occurred with the exogenous administration of hydrochloric acid, pepsin, gastric intrinsic factor, or a combination thereof. Vitamin B12 deficiency developing in the setting of hypochlorhydria may result from deficiency of acid-peptic digestion of B12 bound to protein and/or a relative deficiency of intrinsic factor. This digestive defect is not detected with tests which measure the absorption of unbound crystalline B12 but is detected by a simple test which employs B12 bound to chicken serum as the form of protein-bound B12.

American Pancreatic Association Practice Guidelines in Chronic Pancreatitis: evidence-based report on diagnostic guidelines.

Abstract The diagnosis of chronic pancreatitis remains challenging in early stages of the disease. This report defines the diagnostic criteria useful in the assessment of patients with suspected and established chronic pancreatitis. All current diagnostic procedures are reviewed, and evidence-based statements are provided about their utility and limitations. Diagnostic criteria for chronic pancreatitis are classified as definitive, probable, or insufficient evidence. A diagnostic (STEP-wise; survey, tomography, endoscopy, and pancreas function testing) algorithm is proposed that proceeds from a noninvasive to a more invasive approach. This algorithm maximizes specificity (low false-positive rate) in subjects with chronic abdominal pain and equivocal imaging changes. Furthermore, a nomenclature is suggested to further characterize patients with established chronic pancreatitis based on TIGAR-O (toxic, idiopathic, genetic, autoimmune, recurrent, and obstructive) etiology, gland morphology (Cambridge criteria), and physiologic state (exocrine, endocrine function) for uniformity across future multicenter research collaborations. This guideline will serve as a baseline manuscript that will be modified as new evidence becomes available and our knowledge of chronic pancreatitis improves.

Malabsorption of protein-bound cobalamin but not unbound cobalamin during cimetidine administration

The suppressive effects of cimetidine on acid, pepsin, and intrinsic factor secretion have been well documented; however, the effect of cimetidine on cobalamin absorption has not been assessed. The absorption of both unbound [57Co] cyanocobalamin and protein-bound [57Co] cyanocobalamin was evaluated in 12 patients with duodenal ulcer disease during and after discontinuation of cimetidine therapy. Cimetidine administration did not lead to malabsorption of unbounds cobalamin but caused malabsorption of protein-bound cobalamin (0.22±0.08%, [mean±1sem] versus 2.3±0.10% in control subjects,P<0.01). This malabsorption was reversible upon discontinuation of cimetidine. Patients on cimetidine therapy malabsorb protein-bound cobalamin and, during long-term treatment, are at risk for developing cobalamin deficiency. This malabsorption of protein-bound cobalamin is not detectable by the usual tests of cobalamin absorption which employ unbound cobalamin.

Trypsin-like immunoreactivity as a test for pancreatic insufficiency.

AT present, the clinician has several tests available for the assessment of pancreatic function. However, many of these tests lack sensitivity or specificity or both, or are difficult to perform. R...

Small Bowel Bacterial Overgrowth: Presentation, Diagnosis, and Treatment.

Opinion statementSmall bowel bacterial overgrowth (SBBO) syndrome is associated with excessive numbers of bacteria in the proximal small intestine. The pathology of this condition involves competition between the bacteria and the human host for ingested nutrients. This competition leads to intraluminal bacterial catabolism of nutrients, often with production of toxic metabolites and injury to the enterocyte. A complex array of clinical symptoms ensues, resulting in chronic diarrhea, steatorrhea, macrocytic anemia, weight loss, and less commonly, protein-losing enteropathy. Therapy is targeted at correction of underlying small bowel abnormalities that predispose to SBBO and appropriate antibiotic therapy. The symptoms and signs of SBBO can be reversed with this approach.

Fecal Pancreatic Elastase 1 Is Inaccurate in the Diagnosis of Chronic Pancreatitis

Many tests are available to assess pancreatic function. The ideal test would be simple and have adequate sensitivity in mild to moderate chronic pancreatitis (MCP) and severe CP (SCP). Fecal pancreatic elastase 1 (FPE1) assay (ScheBo Tech) has been proposed as a reliable test to evaluate pancreatic exocrine function, with sensitivities of up to 100% in diagnosing CP. Cutoff values (microgram/g stool) of < 100 have been suggested as SCP, 100-200 as MCP, and > 200 as normal. The tests ability to detect MCP distinguished by the absence of steatorrhea, and its specificity among various etiologies of malabsorption, has not been fully evaluated. The aim of this study was to evaluate this assay in subjects including patients with SCP with steatorrhea, patients with MCP with no steatorrhea, healthy controls, and diseased controls with nonpancreatic malabsorption. Thirty-six subjects [15 healthy controls, 7 malabsorption controls, and 14 subjects with CP (7 MCP, 7 SCP)] had FPE1 assays. One hundred fifty-four assays for FPE1 were run for analysis. The intraassay and interassay intraclass correlation coefficients were 0.93 and 0.90, respectively. All SCP had values of < 100 micrograms/g but more than half of the MCP subjects had FPE1 levels within the normal range. The subjects with nonpancreatic malabsorption had FPE1 values ranging from 55 to > 500 micrograms/g of stool. Although the assay detected SCP with steatorrhea, it did not consistently separate the MCP patients from normals. The majority of those with nonpancreatic malabsorption had false-positive values. These results may differ from previously described data because of the purposeful inclusion of MCP subjects, documented by the lack of steatorrhea, and the inclusion of disease controls with nonpancreatic malabsorption. Although PE1 concentrates in the stool and is not significantly degraded, subtle changes in this enzyme, as in MCP, do not seem to be detectable by this assay. This group continues to be the most difficult group to diagnose clinically.

Predictive Value of Gastric Parietal Cell Autoantibodies as a Marker for Gastric and Hematologic Abnormalities Associated with Insulin-dependent Diabetes

The frequency and significance of gastric parietal cell autoimmunity was assessed in 771 patients with insulin-dependent diabetes (IDD) of onset before 30 yr of age. Gastric parietal autoantibodies (PCA) were found 4 times more frequently in the patients with IDD (9%) than among 600 matched nondiabetic controls (2%). Caucasian female patients with IDD had PCA twice as frequently as male patients. Thyroid microsomal autoantibodies were more frequent in patients with IDD and PCA, than in those with IDD alone (Caucasian 46% versus 18%, black 25% versus 2.5%). A history of pernicious anemia and/or PCA was found in 25 of 40 families of IDD probands with PCA. Achlorhydria was demonstrated in 6 of 11 patients (54%) with PCA but in none of seven IDD patients without PCA. The six patients with achlorhydria had significantly lower uptakes of oral radiolabeled co-balamin, lower serum cobalamin levels, lower intrinsic factor-R protein ratios in their gastric aspirates, and lower plasma ferritin levels than patients with IDD but without PCA. None of the study group had IF antibodies in their serum or gastric juice. Overt pernicious anemia and neuropathy were found in one patient with PCA. Young patients with IDD at risk for atrophie gastritis and cobalamin deficiency can initially be identified by screening for PCA. Many of these young patients with PCA already have achlorhydria and evidence of decreased absorption of cobalamin. These patients can then be followed with cobalamin levels and/or with complete blood counts to identify those requiring therapy.

Comparative analysis of direct pancreatic function testing versus morphological assessment by endoscopic ultrasonography for the evaluation of chronic unexplained abdominal pain of presumed pancreatic origin

Objectives: The diagnosis of “minimal change” chronic pancreatitis (MCCP) is often considered when conventional imaging studies are unrevealing in a patient population with abdominal pain of presumed pancreatic origin. Direct pancreatic function testing using secretin as a secretagogue (ST) has been considered the most sensitive method to diagnose MCCP but is not widely available to clinicians. Endoscopic ultrasound (EUS) allows detailed imaging of pancreatic architecture, but the sensitivity and specificity for MCCP remain to be determined. We sought to compare the accuracy of EUS and ST in patients with presumed MCCP. Methods: Seventy-four patients referred to our pancreas clinic with unexplained abdominal pain and previously negative imaging studies underwent an ST for evaluation of possible MCCP. Twenty-one of these also underwent EUS. EUS images were read by 1 of 2 experts blinded to ST results. Results: Using ST as the “gold standard,” EUS had a maximum sensitivity of 71% when the cut-off for diagnosis was set at at least 3 EUS features. Conversely, maximum specificity (92%) was seen when the cut-off value was set at at least 6 EUS criteria. Diagnostic certainty was only 50% (positive predictive value = 0.5) when at least 6 criteria were used as the cut-off. MCCP was excluded with greater than 70% certainty when less than 3 criteria were present. At the best cut-off value of at least 4 features, EUS had a sensitivity of 57% and a specificity of 64%. Conclusions: In this patient population with abdominal pain of presumed pancreatic origin, EUS and standard pancreatic function testing are often discordant. If ST is assumed to be the reference against which other tests are compared, EUS is less accurate than ST in diagnosing MCCP.

Bentiromide as a test of exocrine pancreatic function in adult patients with pancreatic exocrine insufficiency: Determination of appropriate dose and urinary collection interval

A dose-ranging crossover study of orally administered bentiromide was conducted in 47 patients with chronic pancreatic disease and 61 healthy volunteers. Four doses (100 mg, 500 mg, 1 g, and 5 g) and postdosing urine collection periods (0-3, 0-6, 0-12, and 0-24 h) were studied. Of these, the 500-mg dose and 0-6-h urine collection period afforded maximal separation of urinary arylamine excretion rates between the two populations. At this dose and collection period, the lower limit of normal (mean - 2 SD) for the control group was 57%; none of the healthy volunteers had 6-h arylamine excretion rates less than 50%. The agent was well tolerated except at the 5-g dose level, where nausea, vomiting, and diarrhea were common. Bentiromide appears to be a useful agent in the assessment of exocrine pancreatic function.