Henry J. Binder

Diagnostic utility of contrast echocardiography and lung perfusion scan in patients with hepatopulmonary syndrome

BACKGROUND & AIMS Two modalities, contrast echocardiography and lung perfusion scan, are used to identify intrapulmonary vascular dilatation and diagnose hepatopulmonary syndrome (HPS), but a comparison of these two procedures has not been performed. The aim of this study was to compare the use of these diagnostic modalities in detecting intrapulmonary vascular dilatation and diagnosing HPS. METHODS Forty consecutive outpatients with biopsy-proven cirrhosis had contrast echocardiography, a lung perfusion scan, and arterial blood gases analyzed. RESULTS Fifteen of 40 cirrhotics (38%) had positive contrast echocardiogram results. Seven patients with positive echocardiogram results had gas exchange abnormalities and could be considered to have HPS (7 of 40 [17.5%]). Three of these patients were hypoxemic and had no concurrent cardiopulmonary disease, and each had positive contrast echocardiogram and lung perfusion scan results and were readily diagnosed as having HPS. The other 4 patients (3 hypoxemic and 1 normoxemic with an elevated alveolar-arterial gradient) had coexisting intrinsic lung disease and/or chest radiograph abnormalities complicating the diagnosis of HPS, and each had positive echocardiogram and negative lung scan results. The remaining 8 patients with positive echocardiogram results had normal lung scan and normal gas exchange results. No patient had positive lung scan and negative contrast echocardiogram results. CONCLUSIONS Contrast echocardiography is the most useful screening test for intrapulmonary vasodilatation and may be positive more frequently than lung perfusion scans in patients with HPS.

Enteric infections, diarrhea, and their impact on function and development

Enteric infections, with or without overt diarrhea, have profound effects on intestinal absorption, nutrition, and childhood development as well as on global mortality. Oral rehydration therapy has reduced the number of deaths from dehydration caused by infection with an enteric pathogen, but it has not changed the morbidity caused by such infections. This Review focuses on the interactions between enteric pathogens and human genetic determinants that alter intestinal function and inflammation and profoundly impair human health and development. We also discuss specific implications for novel approaches to interventions that are now opened by our rapidly growing molecular understanding.

Short-chain fatty acids stimulate active sodium and chloride absorption in vitro in the rat distal colon

Studies were performed to determine the mechanism by which short-chain fatty acids increase colonic Na and Cl absorption by determining unidirectional 22Na and 36Cl fluxes across isolated stripped mucosa from the rat distal colon under voltage clamp conditions. Mucosal butyrate (25 mM, in the absence of bicarbonate) significantly enhanced both net Na and net Cl absorption by 7.0 +/- 1.3 and 6.9 +/- 1.0 microEq/h.cm2, respectively, without increasing the short-circuit current. Net Na and Cl absorption in butyrate-Ringers solution and HCO3-Ringers solution were identical. Butyrate stimulation of Na (and Cl) absorption was Cl-dependent and prevented by 1 mM mucosal amiloride, an inhibitor of Na-H exchange, but was HCO3-independent and not inhibited by acetazolamide, a carbonic anhydrase inhibitor. In contrast, bicarbonate-stimulated Na (and Cl) absorption was also Cl-dependent and amiloride-sensitive, but was significantly inhibited by acetazolamide. The effect of mucosal butyrate on net Na and Cl absorption was substantially greater than serosal butyrate, which in the presence of bicarbonate did not alter ion transport. The stimulation of Na and Cl absorption by mucosal butyrate was significantly greater than by propionate and acetate, whereas mucosal formate did not alter Na transport. The results of this study permit the following model: short-chain fatty acid stimulation of active Na and Cl absorption involves uptake of the nonionized form of butyrate and the coupling of Na-H and Cl-butyrate exchanges.

Calcium oxalate urolithiasis in mice lacking anion transporter Slc26a6

Urolithiasis is one of the most common urologic diseases in industrialized societies. Calcium oxalate is the predominant component in 70–80% of kidney stones, and small changes in urinary oxalate concentration affect the risk of stone formation. SLC26A6 is an anion exchanger expressed on the apical membrane in many epithelial tissues, including kidney and intestine. Among its transport activities, SLC26A6 mediates Cl−-oxalate exchange. Here we show that mutant mice lacking Slc26a6 develop a high incidence of calcium oxalate urolithiasis. Slc26a6-null mice have significant hyperoxaluria and elevation in plasma oxalate concentration that is greatly attenuated by dietary oxalate restriction. In vitro flux studies indicated that mice lacking Slc26a6 have a defect in intestinal oxalate secretion resulting in enhanced net absorption of oxalate. We conclude that the anion exchanger SLC26A6 has a major constitutive role in limiting net intestinal absorption of oxalate, thereby preventing hyperoxaluria and calcium oxalate urolithiasis.

Amylase-Resistant Starch plus Oral Rehydration Solution for Cholera

BACKGROUND Although standard glucose-based oral rehydration therapy corrects the dehydration caused by cholera, it does not reduce the diarrhea. Short-chain fatty acids, which are produced in the colon from nonabsorbed carbohydrates, enhance sodium absorption. We conducted a study to determine the effects of an orally administered, nonabsorbed starch (i.e., one resistant to digestion by amylase) on fecal fluid loss and the duration of diarrhea in patients with cholera. METHODS We randomly assigned 48 adolescents and adults with cholera to treatment with standard oral rehydration therapy (16 patients), standard therapy and 50 g of rice flour per liter of oral rehydration solution (16 patients), or standard therapy and 50 g of high-amylose maize starch, an amylase-resistant starch, per liter of oral rehydration solution (16 patients). The primary end points were fecal weight (for every 12-hour period during the first 48 hours after enrollment) and the length of time to the first formed stool. RESULTS The mean (+/-SD) fecal weights in the periods 12 to 24 hours, 24 to 36 hours, and 36 to 48 hours after enrollment were significantly lower in the resistant-starch group (2206+/-1158 g, 1810+/-1018 g, and 985+/-668 g) than in the standard-therapy group (3251+/-766 g, 2621+/-1149 g, and 2498+/-1080 g; P=0.01, P= 0.04, and P=0.001, respectively). From 36 to 48 hours after enrollment, fecal weight was also significantly lower with the resistant-starch therapy than with the rice-flour therapy (985+/-668 g vs. 1790+/-866 g, P=0.01). The mean duration of diarrhea was significantly shorter with the resistant-starch therapy (56.7+/-18.6 hours) than with standard therapy alone (90.9+/-29.8 hours, P=0.001) or the rice-flour therapy (70.8+/-20.2 hours, P=0.05). Fecal excretion of starch was higher with the resistant-starch therapy (32.6+/-30.4) than with the standard therapy (11.7+/-4.1 g, P=0.002) or the rice-flour therapy (15.1+/-8.4 g, P=0.01). CONCLUSIONS The addition of a resistant starch to oral rehydration solution reduces fecal fluid loss and shortens the duration of diarrhea in adolescents and adults with cholera.

Effect of Bile Salts and Fatty Acids on the Colonic Absorption of Oxalate

These studies were designed to evaluate the effect of bile salts and fatty acids on colonic oxalate absorption. Five millimolar deoxycholate significantly increased oxalate absorption from 34.2 +/- 9.4 nmoles per min per g dry weight to 330.4 +/- 47.3 (P less than 0.001) and changed water absorption to water secretion. Deoxycholate also increased the absorption of urea, decreased the electrical potential difference, and increased colonic clearance of oxalate, observations which are consistent with an increase in colonic mucosal permeability. In contrast, taurocholate did not increase oxalate absorption. Ricinoleic acid also significantly increased the absorption. These results suggest that bile salts and fatty acids increase colonic absorption of oxalate. Oleic acid had similar effects on oxalate absorption but was less effective than ricinoleic acid. Octanoic acid, a medium chain fatty acid, did not alter oxalate absorption of oxalate by a nonspecific alteration of mucosal permeability. These observations may further explain many of the clinical phenomena associated with enteric hyperoxaluria.

Importance of the Colon in Enteric Hyperoxaluria

To investigate the role of the colon in increased oxalate absorption, we measured urinary oxalate and fecal fat excretion in 26 patients with gastrointestinal disease. Eight patients with steatorrhea of various causes (Crohns disease [two], chronic pancreatitis [four], jejunoileal bypass [one] and extrahepatic biliary obstruction [one]) had hyperoxaluria (greater than 45 mg per 24 hours). All these patients had intact colons. In contrast, none of five patients with ileostomies and steatorrhea secondary to ileal resection had hyperoxaluria. Absorption of 14C-oxalate was increased in three patients with steatorrhea and intact colons but not in three patients with steatorrhea and an ileostomy. Thus, the colon is both the site of and required for increased oxalate absorption in enteric hyperoxaluria. The lack of a direct relation between fecal fat excretion and urinary oxalate excretion in the patients with hyperoxaluria and steatorrhea suggests that steatorrhea, although important, is not the only determinant in the pathogenesis of hyperoxaluria.

Stimulation of Colonic Secretion of Water and Electrolytes by Hydroxy Fatty Acids

Recent reports have suggested that the diarrhea that accompanies steatorrhea may be related to fecal hydroxy fatty acids. Therefore, the effect of hydroxy fatty acids on colonic water and electrolyte movement was studied in the in vivo rat colon using a continuous perfusion technique. Perfusion with 2 mm ricinoleic acid resulted in net secretion of water, sodium, and chloride and is accompanied by a marked increase in mucosal permeability, as determined by inulin clearance, and a decrease in electrical potential difference. Oleic acid (2 mm), which did not cause secretion but did inhibit net absorption, induced similar alterations in electrical potential difference and inulin clearance. These results suggest that hydroxy fatty acids may be a mediator of the diarrhea of steatorrhea.

Bile salt alteration of colonic electrolyte transport: role of cyclic adenosine monophosphate.

Previous studies of the mechanism of bile salt stimulation of electrolyte secretion in the colon resulted in the suggestion that cyclic AMP may be the intracellular mediator of bile salt-induced secretion. In these studies, cyclic AMP levels were measured and the effect of dibutyryl cyclic AMP on sodium transport was determined. Colonic mucosal cyclic AMP levels in the rat increased by 54% after in vivo incubations with taurochenodeoxycholic acid. Taurocholic acid, which neither induces fluid secretion nor increases short circuit current at concentrations at which taurochenodeoxycholic acid will increase both fluid secretion and short circuit current, does not alter mucosal cyclic AMP. Dibutyryl cyclic AMP decreased net sodium absorption and increased short circuit current; findings which were qualitatively identical to those produced by taurochenodeoxycholic acid. These studies support the proposal that bile salts stimulate colonic electrolyte secretion by increasing mucosal cyclic AMP.

Treatment of Crohn's disease with azathioprine: a controlled evaluation.

To determine whether azathioprine is an effective drug in the treatment of Crohns disease a double-blind study was performed. Twenty-seven patients with involvement of either small or large intestine or both were randomized to either a treatment group (azathioprine 3 mg per kg of body weight) or a placebo group for 4 months. During the subsequent 4-month period, the treatment schedule of the two groups was reversed. Although some patients improved dramatically on azathioprine, others improved during the placebo period. This study does not provide evidence to support the effectiveness of azathioprine in the treatment of Crohns disease.