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Absorptive. Testing following small intestinal transplantation
April 1998
Intestinal Disorders A361
G1472 BLEEDING FROM ANORECTAL VARICES, A RARE BUT FREQUENTLY LETHAL COMPLICATION OF LIVER CIRRHOSIS. G. Coremans, E. De Goede, H. Piessevaux, F. Nevens, A. Wilmer, J. Fevery, A. Geubel. Departments of Gastroenterology of the University Hospital Gasthuisberg Leuven and Saint-Luc Brussels.
• G1474 PLASMA CITRULLINE: A BIOCHEMICAL MARKER OF ENTEROCYTE MASS IN VILLOUS ATROPHY. P. Cmnn (1), K. Vahedi (1), C. Coudray-Lucas (2), A. Lavergne (3), L. Cynober (2), C. Matuchansky (1), B. Messing (1). (1) Saint-Lazare, (2) Saint-Antoine and (3) Lariboisi~re Hospital. Paris, France.
Introduction: Esophageal varices are a frequent complication of cirrhosis and the characteristics of variceal bleeding are well known. In contrast, anorectal varices have a much lower prevalence and acute bleeding from such lesions in cirrhotic patients have rarely been described. The aim of the study was to assess the prevalence and characteristics of acute bleeding from anorectal varices and to determine factors influencing their occurrence and outcome. Patients and Methods: Patients with cirrhosis admitted in our institutions between May 1992 and May 1997 were studied retrospectively. Results: The mean annual incidence of bleeding from gastroesophageal varices in patients admitted with cirrhosis was 30%. The incidence of bleeding from anorectal varices was much lower 1.2%. During this period 5 patients, 1 female (mean age: 53 -+ 19 yrs) presented with this condition. All had esophageal varices, three with Child's grade 3 and two with grade 2. The causal varicous vein was demonstrated in the 2 patients in whom arteriography was performed. Mean Hb, albumin, platelets, PT and venous ammonia were 7.7 -+0.8 (g/dl), 3.1 __.0.8 (g/dl), 99 -+ 61 (109/1), 32.7 -+ 5.7% and 73 -+39 (microg/dl) resp. at onset of the bleeding. Two patients developed their bleeding at home and 3 in the hospital while treated with lactulose enemas for encephalopathy in the intensive care unit. Temperature was measured rectally. Massive bleeding from a spurting protruding varicous vein was observed in the 5 patients: 3 at the ventral site of the distal rectum, 1 at the anal verge and 1 in a perianal erosion. The first bleeding episode was stopped in all patients by coagulation and/or suture in 4, and rubber band ligation in 1. The n° of hemostatic procedures per patient varied from 1 to 10. Three patients, of whom one was treated in extremis with TIPPS died within 2,7 and 52 d after the initial bleeding. Death was directly related to recurrence of massive bleeding from varicous veins in hemostatic ulcers. In conclusion: Bleeding from anorectal varices in cirrhotic patients is a rare condition. The mortality rate however is extremely high. Persistent portal hypertension and poor coagulation and hemostatic ulcers are clear predispositions for recurrence after initial hemostasis. Enemas and rectal thermometers should be avoided in these patients. Early porto-systemic shunting for the overall control of portal hypertension should be considered in an early stage.
Circulating citrulline, an amino acid non included into protein and produced by enterocytes from glutamine, was shown to be a biochemical marker of enterocyte mass after intestinal resection (Gastroenterology 1996; 110: A796). We have prospectively tested this marker in adult patients with enteropathies potentially associated with villous atrophy (VA). Methods: All consecutive patients with enteropathy and without previous intestinal resection, 20 coeliac disease (CD) uncomplicated, 5 small bowel T lymphoma including 4 complicating CD and 2 other enteropathies, were included. They were investigated the same day as following: 1) a plasma citrulline determination (ion exchange chromatography), 2) multiples intestinal biopsies: all 27 patients had proximal duodeoo-jejunal biopsies with grading of VA and 10 patients had ileal biopsies due to clinical indication, 3) a search of biological deficiencies and serum antiendomysium antibody of IgA class. Results: Citrullinemia was significantly lower in patients in comparison to controls (22+ 14 vs 41-+ 10 ~mol/l, p<0.001) and in patients with a proximal total or subtotal VA (n=15) vs patients without VA or with a partial VA (n=12) (17 + 12 vs 28 + 8 [amol/1, p < 0.02); in these two last subgroups citrullinemia was lower than in controls (p < 0.01). In patients with extension of VA to ileum (n=4) plasma citrulline level was indetectable in case of total VA (n=2) and severely decreased (7-+ 1 lamol/1) in case of subtotal duodenojejunoileal VA. Hypocitrullinemia was also correlated (p < 0.05) to biochemical deficiency i.e. albuminemia and calcemia but not to creatinine clearance or body mass index. In CD without lymphoma after 6 months of gluten free diet, the presence of antiendomysium antibody was not associated with a further decrease in citrullinemia (22-+ 13 vs 28-+8 ~mol/1). Conclusion: Plasma citrulline is a biological marker which can assess both the degree and aboral extension of VA. This study confirms the value of citrullinemia in assessing the human enterocyte mass.
G1473 ABSORPTIVE. TESTING FOLLOWING SMALL INTESTINAL TRANSPLANTATION. RM Craig,, J Fryer, Northwestern University Medical Center, Chicago IL. Background and purpose: We are currently following our patients with small intestinal transplantation with serial absorptive tests to assess absorptive capacity with time, and to see if absorptive findings correlate with clinical observations. Methods: The first patient in our institution who underwent a small intestinal transplantation has been followed over the ensuing year with serial testing. The patient had two episodes of moderately severe graft rejection which responded to augmentation of her immunosuppression. At the end of her first year following her transplantation, she developed post transplant lymphoproliferative disease (PTLD) that showed resolution when immunosuppressive medication was decreased. Multiple enteroscopic examinations with histology; D-xylose kinetics, Schilling's tests; fecal fat; and radiolabeled urinary DTPA, a measure of permeability, were performed throughout her year post-transplantation, and pharmacokinetics of cyclosporin A(CSA) were determined on one occasion. Results: CSA levels remained low when CSA was delivered orally or by jejunal tube. Bioavailability of CSA was very low (6%) on the occasion that it was tested. In spite of that, D-xylose and Schilling's tests remained normal throughout the year, regardless of the clinical status of the patient. Fecal fat levels were slightly elevated whenever they were checked, but had marginal predictive value, due to too much variation in fat ingestion. Endoscopic biopsies were more reliable indicators of rejection than the endoscopic appearance. Urinary DTPA rose during the second episode of rejection to 11.2% (N < 4%), but returned to normal with resolution of rejection (1.5%-3.8%) and remained normal during the development of PTLD. Conclusions: 1. DTPA permeability studies may be the best non-invasive test for graft rejection. 2. In spite of diminished CSA bioavailability, D-xylose and Schilling's tests remained normal whenever they were determined. It is unclear whether the diminished CSA bioavailability is related to poor drug absorption or increased metabolism in the gut or liver. 3. Endoscopic biopsies were the most reliable tests indicating graft rejection and the development of PTLD. This study was not supported by any pharmaceutical concern.
G1475 TACHYKININ RECEPTOR ANTAGONISTS PREVENT SENKTIDE, CASTOR OIL, OR E. C O L I ENDOTOXIN-INDUCED INCREASE OF FECAL MASS OUTPUT IN GUINEA PIGS. 1T. Croci. IE. Ottolina, 2X. Emonds-Alt, 1L. Manara, 3G. Le Fur and 4j_p. Maffrand, SANOFI-Midy Research Center, Via G.B. Piranesi 38, 20137 Milan (Italy), 2SANOFI Recherche, 371, Rue du Pr. J. Blayac, 34184 Montpellier, 332/34 rue Marbeuf, 75374 Paris and 4195 R.te d'Espagne, 31036 Toulouse (France). We investigated the influence of the potent and selective tachykinin NK~_, NK2, NI~ receptor antagonists, SR 140333, SR 48968 (1) and SR 142801 (2) on guinea-pig fecal mass output stimulated by senktide, castor oil and E. coli endotoxin (LPS). Methods: Output was assessed in fed male guinea-pigs (HsdPoc:DH, 350-400 g) whose feces were collected for 8h (senktide) or 10h (castor oil, LPS) starting immediately after the stimulants. On the day of the experiment, animals were placed individually in grid-floor cages, with water ad libitum but no food, and randomly allocated to different treatments (n=9-18 per group). Dry weight of feces and pellet number were recorded. Antagonists were dissolved in 2% dimethylsulfoxide and injected sc in 2 ml/kg, lh before stimulants. Drug-free animals received only vehicle. Experiments were done by personnel unaware of the treatment code. Senktide (30 ~tg/kg every 2h, four injections) and LPS (5 mg/kg) were given ip, castor oil (10 ml/kg) by gavage. Results: The tachykinin NK~, NK~, NI~ receptor antagonists, SR 140333, SR 48968, SR 142801 (1 to 1000 lag/kg, sc), had no effect on their own but dosedependently reduced the increase in defecation induced by stimulants and, at 1 mg/kg, completely prevented LPS mortality (100%, 9/9 animals) 24h after the toxin. Fecal mass output (fecal dry weight, g-+SE; number of pellets -+ SE) was similar for senktide, 3.3 -+0.5, 50 -+ 5; castor oil, 2.7 -+0.3, 44 -+4 and LPS, 3.0 -+3.3, 46 -+ 3 (control drug-free animals, 0.4 -+0.2, 5 -+ 2). The IDso of SR 140333, SR 48968 and SR 142801, lag/kg sc, (in parentheses 95% confidence limits) were: senktide, -9, -5, -6; castor oil, 3 (1-6), 6 (2-12), -151; LPS, ~20, -18, ~23. Conclusions: We suggest that endogenous tachykinins account for LPS-toxicity and fecal mass output induced by senktide, castor oil and LPS. [1] Croci T., Emonds-Alt X., Le Fur G. and Manara L. (1995) Life Sci. 56, 267-275. [2] Croci T., Landi M., Emonds-Alt X., Le Fur G. and Manara L. (1995) Life Sci. 57, PL361-366.
Intestinal Disorders A361
G1472 BLEEDING FROM ANORECTAL VARICES, A RARE BUT FREQUENTLY LETHAL COMPLICATION OF LIVER CIRRHOSIS. G. Coremans, E. De Goede, H. Piessevaux, F. Nevens, A. Wilmer, J. Fevery, A. Geubel. Departments of Gastroenterology of the University Hospital Gasthuisberg Leuven and Saint-Luc Brussels.
• G1474 PLASMA CITRULLINE: A BIOCHEMICAL MARKER OF ENTEROCYTE MASS IN VILLOUS ATROPHY. P. Cmnn (1), K. Vahedi (1), C. Coudray-Lucas (2), A. Lavergne (3), L. Cynober (2), C. Matuchansky (1), B. Messing (1). (1) Saint-Lazare, (2) Saint-Antoine and (3) Lariboisi~re Hospital. Paris, France.
Introduction: Esophageal varices are a frequent complication of cirrhosis and the characteristics of variceal bleeding are well known. In contrast, anorectal varices have a much lower prevalence and acute bleeding from such lesions in cirrhotic patients have rarely been described. The aim of the study was to assess the prevalence and characteristics of acute bleeding from anorectal varices and to determine factors influencing their occurrence and outcome. Patients and Methods: Patients with cirrhosis admitted in our institutions between May 1992 and May 1997 were studied retrospectively. Results: The mean annual incidence of bleeding from gastroesophageal varices in patients admitted with cirrhosis was 30%. The incidence of bleeding from anorectal varices was much lower 1.2%. During this period 5 patients, 1 female (mean age: 53 -+ 19 yrs) presented with this condition. All had esophageal varices, three with Child's grade 3 and two with grade 2. The causal varicous vein was demonstrated in the 2 patients in whom arteriography was performed. Mean Hb, albumin, platelets, PT and venous ammonia were 7.7 -+0.8 (g/dl), 3.1 __.0.8 (g/dl), 99 -+ 61 (109/1), 32.7 -+ 5.7% and 73 -+39 (microg/dl) resp. at onset of the bleeding. Two patients developed their bleeding at home and 3 in the hospital while treated with lactulose enemas for encephalopathy in the intensive care unit. Temperature was measured rectally. Massive bleeding from a spurting protruding varicous vein was observed in the 5 patients: 3 at the ventral site of the distal rectum, 1 at the anal verge and 1 in a perianal erosion. The first bleeding episode was stopped in all patients by coagulation and/or suture in 4, and rubber band ligation in 1. The n° of hemostatic procedures per patient varied from 1 to 10. Three patients, of whom one was treated in extremis with TIPPS died within 2,7 and 52 d after the initial bleeding. Death was directly related to recurrence of massive bleeding from varicous veins in hemostatic ulcers. In conclusion: Bleeding from anorectal varices in cirrhotic patients is a rare condition. The mortality rate however is extremely high. Persistent portal hypertension and poor coagulation and hemostatic ulcers are clear predispositions for recurrence after initial hemostasis. Enemas and rectal thermometers should be avoided in these patients. Early porto-systemic shunting for the overall control of portal hypertension should be considered in an early stage.
Circulating citrulline, an amino acid non included into protein and produced by enterocytes from glutamine, was shown to be a biochemical marker of enterocyte mass after intestinal resection (Gastroenterology 1996; 110: A796). We have prospectively tested this marker in adult patients with enteropathies potentially associated with villous atrophy (VA). Methods: All consecutive patients with enteropathy and without previous intestinal resection, 20 coeliac disease (CD) uncomplicated, 5 small bowel T lymphoma including 4 complicating CD and 2 other enteropathies, were included. They were investigated the same day as following: 1) a plasma citrulline determination (ion exchange chromatography), 2) multiples intestinal biopsies: all 27 patients had proximal duodeoo-jejunal biopsies with grading of VA and 10 patients had ileal biopsies due to clinical indication, 3) a search of biological deficiencies and serum antiendomysium antibody of IgA class. Results: Citrullinemia was significantly lower in patients in comparison to controls (22+ 14 vs 41-+ 10 ~mol/l, p<0.001) and in patients with a proximal total or subtotal VA (n=15) vs patients without VA or with a partial VA (n=12) (17 + 12 vs 28 + 8 [amol/1, p < 0.02); in these two last subgroups citrullinemia was lower than in controls (p < 0.01). In patients with extension of VA to ileum (n=4) plasma citrulline level was indetectable in case of total VA (n=2) and severely decreased (7-+ 1 lamol/1) in case of subtotal duodenojejunoileal VA. Hypocitrullinemia was also correlated (p < 0.05) to biochemical deficiency i.e. albuminemia and calcemia but not to creatinine clearance or body mass index. In CD without lymphoma after 6 months of gluten free diet, the presence of antiendomysium antibody was not associated with a further decrease in citrullinemia (22-+ 13 vs 28-+8 ~mol/1). Conclusion: Plasma citrulline is a biological marker which can assess both the degree and aboral extension of VA. This study confirms the value of citrullinemia in assessing the human enterocyte mass.
G1473 ABSORPTIVE. TESTING FOLLOWING SMALL INTESTINAL TRANSPLANTATION. RM Craig,, J Fryer, Northwestern University Medical Center, Chicago IL. Background and purpose: We are currently following our patients with small intestinal transplantation with serial absorptive tests to assess absorptive capacity with time, and to see if absorptive findings correlate with clinical observations. Methods: The first patient in our institution who underwent a small intestinal transplantation has been followed over the ensuing year with serial testing. The patient had two episodes of moderately severe graft rejection which responded to augmentation of her immunosuppression. At the end of her first year following her transplantation, she developed post transplant lymphoproliferative disease (PTLD) that showed resolution when immunosuppressive medication was decreased. Multiple enteroscopic examinations with histology; D-xylose kinetics, Schilling's tests; fecal fat; and radiolabeled urinary DTPA, a measure of permeability, were performed throughout her year post-transplantation, and pharmacokinetics of cyclosporin A(CSA) were determined on one occasion. Results: CSA levels remained low when CSA was delivered orally or by jejunal tube. Bioavailability of CSA was very low (6%) on the occasion that it was tested. In spite of that, D-xylose and Schilling's tests remained normal throughout the year, regardless of the clinical status of the patient. Fecal fat levels were slightly elevated whenever they were checked, but had marginal predictive value, due to too much variation in fat ingestion. Endoscopic biopsies were more reliable indicators of rejection than the endoscopic appearance. Urinary DTPA rose during the second episode of rejection to 11.2% (N < 4%), but returned to normal with resolution of rejection (1.5%-3.8%) and remained normal during the development of PTLD. Conclusions: 1. DTPA permeability studies may be the best non-invasive test for graft rejection. 2. In spite of diminished CSA bioavailability, D-xylose and Schilling's tests remained normal whenever they were determined. It is unclear whether the diminished CSA bioavailability is related to poor drug absorption or increased metabolism in the gut or liver. 3. Endoscopic biopsies were the most reliable tests indicating graft rejection and the development of PTLD. This study was not supported by any pharmaceutical concern.
G1475 TACHYKININ RECEPTOR ANTAGONISTS PREVENT SENKTIDE, CASTOR OIL, OR E. C O L I ENDOTOXIN-INDUCED INCREASE OF FECAL MASS OUTPUT IN GUINEA PIGS. 1T. Croci. IE. Ottolina, 2X. Emonds-Alt, 1L. Manara, 3G. Le Fur and 4j_p. Maffrand, SANOFI-Midy Research Center, Via G.B. Piranesi 38, 20137 Milan (Italy), 2SANOFI Recherche, 371, Rue du Pr. J. Blayac, 34184 Montpellier, 332/34 rue Marbeuf, 75374 Paris and 4195 R.te d'Espagne, 31036 Toulouse (France). We investigated the influence of the potent and selective tachykinin NK~_, NK2, NI~ receptor antagonists, SR 140333, SR 48968 (1) and SR 142801 (2) on guinea-pig fecal mass output stimulated by senktide, castor oil and E. coli endotoxin (LPS). Methods: Output was assessed in fed male guinea-pigs (HsdPoc:DH, 350-400 g) whose feces were collected for 8h (senktide) or 10h (castor oil, LPS) starting immediately after the stimulants. On the day of the experiment, animals were placed individually in grid-floor cages, with water ad libitum but no food, and randomly allocated to different treatments (n=9-18 per group). Dry weight of feces and pellet number were recorded. Antagonists were dissolved in 2% dimethylsulfoxide and injected sc in 2 ml/kg, lh before stimulants. Drug-free animals received only vehicle. Experiments were done by personnel unaware of the treatment code. Senktide (30 ~tg/kg every 2h, four injections) and LPS (5 mg/kg) were given ip, castor oil (10 ml/kg) by gavage. Results: The tachykinin NK~, NK~, NI~ receptor antagonists, SR 140333, SR 48968, SR 142801 (1 to 1000 lag/kg, sc), had no effect on their own but dosedependently reduced the increase in defecation induced by stimulants and, at 1 mg/kg, completely prevented LPS mortality (100%, 9/9 animals) 24h after the toxin. Fecal mass output (fecal dry weight, g-+SE; number of pellets -+ SE) was similar for senktide, 3.3 -+0.5, 50 -+ 5; castor oil, 2.7 -+0.3, 44 -+4 and LPS, 3.0 -+3.3, 46 -+ 3 (control drug-free animals, 0.4 -+0.2, 5 -+ 2). The IDso of SR 140333, SR 48968 and SR 142801, lag/kg sc, (in parentheses 95% confidence limits) were: senktide, -9, -5, -6; castor oil, 3 (1-6), 6 (2-12), -151; LPS, ~20, -18, ~23. Conclusions: We suggest that endogenous tachykinins account for LPS-toxicity and fecal mass output induced by senktide, castor oil and LPS. [1] Croci T., Emonds-Alt X., Le Fur G. and Manara L. (1995) Life Sci. 56, 267-275. [2] Croci T., Landi M., Emonds-Alt X., Le Fur G. and Manara L. (1995) Life Sci. 57, PL361-366.