NAD(P)H oxidase modulates angiogenesis and the development of portosystemic collaterals and splanchnic hyperaemia in portal hypertensive rats.

Then, the expression of angiogenesis markers (western blotting), the formation of portosystemic collaterals (radioactive microspheres) and the production of superoxide anion (lucigenin-enhanced chemiluminescence) were determined. Mean arterial pressure, portal pressure, and superior mesenteric arterial blood flow and resistance were also measured.Results: In portal hypertensive rats, NAD(P)H oxidase blockade significantly decreased portosystemic collateral formation, and superior mesenteric arterial flow. It also reduced the splanchnic expression of VEGF, VEGF receptor-2 and CD31, and attenuated the increased production of superoxide, compared with vehicle.Conclusions: NAD(P)H oxidase plays an important role in experimental portal hypertension, modulating splanchnic angiogenesis, the formation of portosystemic collaterals and the development of splanchnic hyperdynamic circulation. These results suggest that NAD(P)H oxidase may represent a new target in the treatment of portal hypertension.

Assessment of therapeutic benefit of antiviral therapy in chronic hepatitis C: is hepatic venous pressure gradient a better end point?

Chronic hepatitis C is a major healthcare problem. The response to antiviral therapy for patients with chronic hepatitis C has previously been defined biochemically and by PCR. However, changes in the hepatic venous pressure gradient (HVPG) may be considered as an adjunctive end point for the therapeutic evaluation of antiviral therapy in chronic hepatitis C. It is a validated technique which is safe, well tolerated, well established, and reproducible. Serial HVPG measurements may be the best way to evaluate response to therapy in chronic hepatitis C.

CO2 wedged hepatic venography in the evaluation of portal hypertension.

BACKGROUND/AIMS/METHODS During hepatic vein catheterisation, in addition to measurement of hepatic venous pressure gradient (HVPG), iodine wedged retrograde portography can be easily obtained. However, it rarely allows correct visualisation of the portal vein. Recently, CO2 has been suggested to allow better angiographic demonstration of the portal vein than iodine. In this study we investigated the efficacy of CO2 compared with iodinated contrast medium for portal vein imaging and its role in the evaluation of portal hypertension in a series of 100 patients undergoing hepatic vein catheterisation, 71 of whom had liver cirrhosis. RESULTS In the overall series, CO2 venography was markedly superior to iodine, allowing correct visualisation of the different segments of the portal venous system. In addition, CO2, but not iodine, visualised portal-systemic collaterals in 34 patients. In cirrhosis, non-visualisation of the portal vein on CO2 venography occurred in 11 cases; four had portal vein thrombosis and five had communications between different hepatic veins. Among non-cirrhotics, lack of portal vein visualisation had a 90% sensitivity, 88% specificity, 94% negative predictive value, and 83% positive predictive value in the diagnosis of pre-sinusoidal portal hypertension. CONCLUSIONS Visualisation of the venous portal system by CO2 venography is markedly superior to iodine. The use of CO2 wedged portography is a useful and safe complementary procedure during hepatic vein catheterisation which may help to detect portal thrombosis. Also, lack of demonstration of the portal vein in non-cirrhotic patients strongly suggests the presence of pre-sinusoidal portal hypertension.

Magnesium hydrogen breath test using end-expiratory sampling to assess achlorhydria in pernicious anaemia patients

A modified magnesium hydrogen breath test, using end expiratory breath sampling, is described to investigate achlorhydria. The efficacy of this test in the diagnostic investigation of pernicious anaemia was compared with that of serum pepsinogen I. Twenty one patients with pernicious anaemia--that is, patients with achlorhydria--and 22 with healed duodenal ulcer and normal chlorhydria were studied. Magnesium hydrogen breath test, serum pepsinogen I, serum gastrin, and standard gastric acid secretory tests were performed in all subjects. The mean (SEM) hydrogen peak value was lower in patients with pernicious anaemia than in the duodenal ulcer group (21.7 (1.9) v 71.3 (5.2) ppm; p = 0.00005). The hydrogen peak value had a 95.2% sensitivity and a 100% specificity to detect pentagastrin resistant achlorhydria. Mean serum pepsinogen I concentrations were also significantly lower in patients with pernicious anaemia than in the duodenal ulcer group (10.7 (2.7) v 123.6 (11.8) micrograms/l p = 0.00005). Sensitivity and specificity to detect pernicious anaemia were both 100% for pepsinogen I. It is concluded that this modified magnesium hydrogen breath test is a simple, noninvasive, cost effective, and accurate method to assess achlorhydria and may be useful in the diagnostic investigation of patients with suspected pernicious anaemia.

Dexamethasone inhibition of leucocyte adhesion to rat mesenteric postcapillary venules: role of intercellular adhesion molecule 1 and KC

BACKGROUND A previous study showed that the glucocorticoid dexamethasone, at doses of 100 ¿g/kg and above, inhibited leucocyte adhesion to rat mesenteric postcapillary venules activated with interleukin 1ß (IL-1ß), as assessed by videomicroscopy. AIMS To identify whether the adhesion molecule, intercellular adhesion molecule 1 (ICAM-1), or the chemokine KC could be targeted by the steroid to mediate its antiadhesive effect. METHODS Rat mesenteries were treated with IL-1ß (20 ng intraperitoneally) and the extent of leucocyte adhesion measured at two and four hours using intravital microscopy. Rats were treated with dexamethasone, and passively immunised against ICAM-1 or KC. Endogenous expression of these two mediators was validated by immunohistochemistry, ELISA, and the injection of specific radiolabelled antibodies. RESULTS Dexamethasone greatly reduced IL-1ß induced leucocyte adhesion, endothelial expression of ICAM-1 in the postcapillary venule, and release of the mast cell derived chemokine KC. Injection of specific antibodies to the latter mediators was also extremely effective in downregulating (>80%) IL-1ß induced leucocyte adhesion. CONCLUSIONS Induction by IL-1ß of endogenous ICAM-1 and KC contributes to leucocyte adhesion to inflamed mesenteric vessels. Without excluding other possible mediators, these data clearly show that dexamethasone interferes with ICAM-1 expression and KC release from mast cells, resulting in suppression of leucocyte accumulation in the bowel wall, which is a prominent feature of several gastrointestinal pathologies.

Nadolol plus isosorbide mononitrate alone or associated with band ligation in the prevention of recurrent bleeding: A multicenter randomized controlled trial.

Background and aims: Previous clinical trials suggest that adding non-selective beta-blockers improves the efficacy of endoscopic band ligation (EBL) in the prevention of recurrent bleeding, but no study has evaluated whether EBL improves the efficacy of beta-blockers + isosorbide-5-mononitrate. The present study was aimed at evaluating this issue in a multicentre randomised controlled trial (RCT) and to correlate changes in hepatic venous pressure gradient (HVPG) during treatment with clinical outcomes. Methods: 158 patients with cirrhosis, admitted because of variceal bleeding, were randomised to receive nadolol+isosorbide-5-mononitrate alone (Drug: n=78) or combined with EBL (Drug+EBL; n=80). HVPG measurements were performed at randomisation and after 4¿6 weeks on medical therapy. Results: Median follow-up was 15 months. One-year probability of recurrent bleeding was similar in both groups (33% vs 26%: p=0.3). There were no significant differences in survival or need of rescue shunts. Overall adverse events or those requiring hospital admission were significantly more frequent in the Drug+EBL group. Recurrent bleeding was significantly more frequent in HVPG non-responders than in responders (HVPG reduction ¿20% or ¿12 mm Hg). Among non-responders recurrent bleeding was similar in patients treated with Drugs or Drugs+EBL. Conclusions: Adding EBL to pharmacological treatment did not reduce recurrent bleeding, the need for rescue therapy, or mortality, and was associated with more adverse events. Furthermore, associating EBL to drug therapy did not reduce the high rebleeding risk of HVPG non-responders.

The extent of the collateral circulation influences the postprandial increase in portal pressure in patients with cirrhosis.

Background: In cirrhosis, repeated flares of portal pressure and collateral blood flow provoked by postprandial hyperaemia may contribute to variceal dilation and rupture. Aim: To examine the effect of the extent of the collateral circulation on the postprandial increase in portal pressure observed in cirrhosis. Patients and methods: The hepatic venous pressure gradient (HVPG), hepatic blood flow and azygos blood flow were measured in 64 patients with cirrhosis before and after a standard liquid meal. Results: Peak increases in HVPG (median+14.9%), hepatic blood flow (median+25.4%), and azygos blood flow (median+32.2%) occurred at 30 min after the meal. Compared with patients with marked postprandial increase in HVPG (above the median, n¿=¿32), those showing mild (<15%, n¿=¿32) increase in HVPG had a higher baseline azygos flow (p<0.01) and underwent a greater postprandial increase in azygos flow (p<0.02). Hepatic blood flow increased similarly in both groups. Postprandial increases in HVPG were inversely correlated (p<0.001) with both baseline azygos flow (r¿=¿¿0.69) and its postprandial increase (r¿=¿¿0.72). Food intake increased nitric oxide products in the azygos (p<0.01), but not in the hepatic vein. Large varices (p<0.01) and previous variceal bleeding (p<0.001) were more frequent in patients with mild increase in HVPG. Conclusions: Postprandial hyperaemia simultaneously increases HVPG and collateral flow. The extent of the collateral circulation determines the HVPG response to food intake. Patients with extensive collateralisation show less pronounced postprandial increases in HVPG, but associated with marked flares in collateral flow. Collateral vessels preserve their ability to dilate in response to increased blood flow.

Enteral nutrition as primary therapy in Crohn's disease

The developments in enteral feeding for Crohn's disease in the past decade are critically reviewed. The advent of amino acid based chemically defined elemental diets signalled the end of 'total bowel rest' in the management of these patients. Subsequently, controlled clinical trials showed that elemental diets were as effective as corticosteroids in inducing clinical remission in patients with acute exacerbations of Crohn's disease. The later use of peptide based elemental diets, in Crohn's disease produced somewhat conflicting results. The initial uncontrolled studies suggest that polymeric whole protein diets might also be effective in the management of acute exacerbations of the disease, casting in turn doubts concerning the role of dietary antigens in the pathogenesis of Crohn's disease. Results of controlled studies comparing the use of elemental and polymeric diets as primary therapy in Crohn's disease have, however, also produced conflicting results. The results of one recent controlled trial in which