- Email: [email protected]
W1407 Amyloidosis in Patients With Gastrointestinal Neuromuscular Disorder of the Gut (GINMD) – Comparison of Serum and Histopathological Diagnostic Techniques
red that displayed apple-green birefringence when viewed under high-intensity crosspolarised light. Positive amyloid tissues were further stained with peroxidise anti-peroxidase immunohistochemical staining technique using monospecific antibodies reactive with serum amyloid A protein(SAA), transthyretin(TTR) and with Kappa and Lambda Immunoglobulin light chains. RESULT Low total protein levels were found in 11 patients , increased free light chains were found in 6 patients (Kappa chains 3, Lambda chains 2 and both Kappa & Lambda chains 1). 3 patients were found to have low Kappa chains. 1 patient had a 2 fold rise of both chains. 2 patients (4%) with >3 fold raised Lambda chains were the only one found to have amyloid lambda deposits in their biopsies . Serum Immunoglobulin levels were normal in 43 patients. CONCLUSION: Our findings confirm that there is a need to exclude amyloidosis in patients with GINMD. In this large series of patients with GINMD a three fold increase in Lambda chains was the only serological marker of intestinal amyloidosis. Histological analysis of full thickness intestinal biopsies remains the most reliable way of diagnosing amyloidosis in these patients. W1408
Legend: GP=Gastroparesis; DM=Diabetes Mellitus; ID=Idiopathic; P-V=Post-Vagotomy; FU= Follow-Up.
Association of Autoimmune Connective Tissue Disorders in Patients With Gastrointestinal Neuromuscular Disorders (GINMD) ATMDilshad H. Chowdhury, David D'Cruz, Graham R. Hughes, Colin Tench, Ana H. Raimundo, Ara Darzi, Joanne E. Martin, David B. Silk
W1406
INTRODUCTION Severe Intestinal dysfunction can occur in patients with systemic sclerosis (>80%) and systemic lupus erythematosus (SLE). These underlying disorders must be therefore be excluded in all patients diagnosed with Gastrointestinal neuromuscular disorders (GINMD). In our early experience with these patients we found evidence of other hitherto undiagnosed connective tissue disorders( CTD). This promted us to undertake a prospective study to determine the incidence of all connective tissue disorders in patients with GINMD. Of a personal series of 116 patients with either manometrically and/or histopathologically proven GINMDrecorded on our database, 62 have been investigated. Serum samples have been analysed for ANA's (anti neuclear antibodies), ENA's (Extractable nuclear antigen ), Anti d-s DNA antibodies ( Double strand DNA) and a wide panel of autoantibodies. RESULTS: 36 patients (58%) presented with extra gastrointestinal symptoms ( Fatigue 14, Dry eyes and dry mouth 11, joint pain 5, Raynauds phenomenon 3 and headache 3). 16 patients (44%) had positive ANAs (speckled 8, Neucleolar 4 and homogeneous 4). ENAs were negative in all patients. 1 patient had positive for Anti - dsDNA antibody. None of our 62 patients have evidence of Systemic Sclerosis. On the basis of clinical and immunological findings 11 of 16 ANA positive patients were diagnosed as having ENAs negative (ScL 70, Ro, La) Sjogrens syndrome and 5 an undifferentiated connective tissue disorders. In the final analysis 25 of 62 GINMD patients (40%) were diagnosed with an underlying autoimmune disorders ( sjogrens 11, MCTD 5, seronegative arthritis 5, anti phospholipid syndrome3 and SLE 1).The majority of these pts. (17,68%) had either normal full thickness jejunal biopsies (5) or α-actin epitope deficiency alone (12) CONCLUSIONS: Our findings thus demonstrate a high incidence of autoimmune and CTDs in patients with GINMD and high light the importance of making the diagnosis, particularly as in our experience treatment of these underlying disorders can lead to improvements in gastrointestinal symptoms. In turn, based on the histopathological findings, GI symptoms in a significant proportion of patients with GINMD with autoimmune disorders could be due to an underlying channelopathy.
DA-9701, a New Prokinetic Agent, Improves Feeding Inhibition by Restraint Stress in Rats -Comparative Study With In Vivo Micro-Animal CT Yong Sung Kim, Moon Young Lee, Eul sik Choi, Jung Taek Oh, Young Woo Sohn, Yong Leol Oh, Han Seung Ryu, Geom Seog Seo, Suck Chei Choi Backgrounds: Stress have a role in pathogenesis of FD and influence food intake in human and animal. Prokinetic drugs used in FD and some drug restores feeding inhibition (FI) induced by acute restraint stress in rat. DA-9701 (DA) is new prokinetic drug (Dong-A Pharm. Korea) formulated from Pharbitis Semen & Corydalis Tuber. We aimed to evaluate the effect of DA on FI induced by acute restraint and to compare the gastric volume using animal CT in rat. Methods: Male S-D rats(300g) were divided into 6 groups; Control(no stress), Stress+vehicle, Stress+DA 1, 3, 10 & 30mg/kg groups(n=6~7). DA or vehicle was administered via gastric gavage 15min before stress. After 60min stress, a chow previously weighed was given and the weight of remaining meal was measured 30 & 60 min later. For measuring gastric volume by animal CT, we used the solid chow that mixed with radiocontrast agent beforehand. After same stress protocol, radiocontrast chow was given to rats. After 1hr, CT scanning was performed with chloral hydrate IP. Results: The restraint stress group significantly decreased food intake than control group. During 30min after stress, there was no statistical difference of food intake between groups(p>0.05). At 60min after stress, vehicle and 30mg/kg of DA group showed significantly decreased food intake compare to control(p<0.05), but 1, 3 & 10 mg/kg of DA-9701 group was not different statistically with control rat (p>0.05). The beneficial effect of 3 mg/kg of DA on FI was completely abolished by WAY 100635. The 3mg/kg of DA could not affect on basal feeding in non-stressed rat. On animal CT, gastric volume in rat with 3mg/kg & 10mg/kg of DA (4.33 & 5.14 cm3) was comparable to control(5.14 cm3), but vehicle rat showed very small volume (1.34 cm3). Conclusions: DA-9701 can improve FI induced by restraint stress in rat and this effect seems to be related with enhanced gastric accommodation by 5HT1A agonism.
W1409 Small Bowel Manometry and Full Thickness Intestinal Biopsies in Patients With Gastrointestinal Neuromuscular Disorders (GINMD) ATMDilshad H. Chowdhury, Ana H. Raimundo, Ara Darzi, Joanne E. Martin, David B. Silk INTRODUCTION: Gastrointestinal neuromuscular disorders (GINMD) are severe disorders in which symptoms arise as a result of neuromuscular dysfunction. Of a personal series of 116 patients recorded on our database, 67 patients ( 12M 55F) mean age 49 years, (abdominal pain 95%,constipation 92%, abdominal distension 78%) had undergone both 24 hour ambulatory study of small bowel motility and laparoscopic full thickness jejunal and colonic biopsies. The aim of the study was to relate the manometric to neuro histopathological findings. METHODS: Prospective qualitative analysis of the small bowel motility tracings was performed , with emphasis on configuration, abnormal propulsion, retrograde contractions( <1cm/min caudad) \and numbers of the phase 3 migrating motor complex (MMC), patterns of contraction and presence or absence of the ‘fed pattern' of motility. All biopsy specimens were examined for the distribution of ganglion cells ( by CD45 staining),myenteric plexus( Haematoxylin eosin staining), Interstitial cells of Cajal(By CD117 staining) and Immunohistochemical localisation of actins and other cytoskeletal proteins were performed. We have previously shown that α-actin epitope deficiency is a biomarker ofChronic idiopathic intestinal pseudoobstruction(1). RESULTS: Of the 67 small bowel motility studies all were abnormal. Abnormalities of the phase ||| MMC were seen in 56(83.6%). 30(44.8%) had evidence of retrograde propulsion. Simultaneous non propagated contractions were seen in 63(94%) and a lack of fed pattern in 22(32.8%). With regard to histology only nine sets of biopsies (14.4%) were normal. In 44(67.7%) the only abnormality was that of α-actin epitope deficiency (1). Reduced ganglion cells in the myenteric plexus(4), ganglionitis(2) and vasculitis (2) were other findings. 5 patients with α-actin epitope deficiency also had reduced ganglion cells (1) ,plexitis(1) and polyglucosan myopathy(3). CONCLUSION: Small bowel manometry is an important investigation in the screening of patients with severe and intractable gastrointestinal symptoms in whom ‘Standard' investigations are normal. As 86% jejunal biopsies were abnormal, patients with abnormal small bowel menometry should undergo laparoscopic full thickness biopsies. We are currently investigating whether the small group of our GINMD patients with normal biopsies and larger numbers with α-actin epitope deficiency alone have an underlying channelopathy. Reference: 1.Knowles et al 2004 GUT 53; 1583-1589
W1407 Amyloidosis in Patients With Gastrointestinal Neuromuscular Disorder of the Gut (GINMD) - Comparison of Serum and Histopathological Diagnostic Techniques ATMDilshad H. Chowdhury, Ana H. Raimundo, Nancy L. Wassef, Ara Darzi, Joanne E. Martin, David B. Silk INTRODUCTION Amyloidosis is a rare and severe disorder and it can cause intestinal dysmotility and pseudoobstruction when it affects the gastrointestinal tract. It is therefore important to exclude this diagnosis in all patients with gastrointestinal neuromuscular disorders (GINMD). In order to determine whether the diagnosis can be made without undertaking fullthickness intestinal biopsies, we have compared the results of serological analyses with those of histopathology in our patients. METHODS Nephelometry was used to analyse serum samples obtained from 43 patients. Serum kappa and Lambda chains were quantitated using manufactured freelite antigen assays. Freelite results were interpreted in conjunction with other laboratory tests and clinical evidence. The standard normal values in our study for Serum Kappa light chains were 3.3-19.4 mg/L and Serum Lambda chains 5.7- 26.3mg/L. Serum albumin, total protein and protein electrophoresis ( IgG, IgM and IgA) were also measured. Full thickness jejunal and colonic biopsies of the 43 patients were analysed for amyloid deposition using the congo red staining method for amyloid. The presence of amyloid was demonstrated by the staining of amorphous material with congo
S-717
AGA Abstracts
AGA Abstracts
related to TSS and GET are presented in the following table: Conclusions: 1) Overall in drug-refractory GP the addition of PP to the Enterra procedure significantly and markedly accelerates gastric emptying, while significantly improving GP symptoms without any adverse events. 2) The Post-vagotomy group of GP is the most responsive to the addition of PP with GET being normalized in 70% of the patients; (<10% retention at 4hrs) while idiopathics are the least improved. 3) Pyloroplasty added to the Enterra GES procedure should be recommended as a routine approach to the refractory GP, since it provides a new benefit without changing morbidity.
Legend: GP=Gastroparesis; DM=Diabetes Mellitus; ID=Idiopathic; P-V=Post-Vagotomy; FU= Follow-Up.
Association of Autoimmune Connective Tissue Disorders in Patients With Gastrointestinal Neuromuscular Disorders (GINMD) ATMDilshad H. Chowdhury, David D'Cruz, Graham R. Hughes, Colin Tench, Ana H. Raimundo, Ara Darzi, Joanne E. Martin, David B. Silk
W1406
INTRODUCTION Severe Intestinal dysfunction can occur in patients with systemic sclerosis (>80%) and systemic lupus erythematosus (SLE). These underlying disorders must be therefore be excluded in all patients diagnosed with Gastrointestinal neuromuscular disorders (GINMD). In our early experience with these patients we found evidence of other hitherto undiagnosed connective tissue disorders( CTD). This promted us to undertake a prospective study to determine the incidence of all connective tissue disorders in patients with GINMD. Of a personal series of 116 patients with either manometrically and/or histopathologically proven GINMDrecorded on our database, 62 have been investigated. Serum samples have been analysed for ANA's (anti neuclear antibodies), ENA's (Extractable nuclear antigen ), Anti d-s DNA antibodies ( Double strand DNA) and a wide panel of autoantibodies. RESULTS: 36 patients (58%) presented with extra gastrointestinal symptoms ( Fatigue 14, Dry eyes and dry mouth 11, joint pain 5, Raynauds phenomenon 3 and headache 3). 16 patients (44%) had positive ANAs (speckled 8, Neucleolar 4 and homogeneous 4). ENAs were negative in all patients. 1 patient had positive for Anti - dsDNA antibody. None of our 62 patients have evidence of Systemic Sclerosis. On the basis of clinical and immunological findings 11 of 16 ANA positive patients were diagnosed as having ENAs negative (ScL 70, Ro, La) Sjogrens syndrome and 5 an undifferentiated connective tissue disorders. In the final analysis 25 of 62 GINMD patients (40%) were diagnosed with an underlying autoimmune disorders ( sjogrens 11, MCTD 5, seronegative arthritis 5, anti phospholipid syndrome3 and SLE 1).The majority of these pts. (17,68%) had either normal full thickness jejunal biopsies (5) or α-actin epitope deficiency alone (12) CONCLUSIONS: Our findings thus demonstrate a high incidence of autoimmune and CTDs in patients with GINMD and high light the importance of making the diagnosis, particularly as in our experience treatment of these underlying disorders can lead to improvements in gastrointestinal symptoms. In turn, based on the histopathological findings, GI symptoms in a significant proportion of patients with GINMD with autoimmune disorders could be due to an underlying channelopathy.
DA-9701, a New Prokinetic Agent, Improves Feeding Inhibition by Restraint Stress in Rats -Comparative Study With In Vivo Micro-Animal CT Yong Sung Kim, Moon Young Lee, Eul sik Choi, Jung Taek Oh, Young Woo Sohn, Yong Leol Oh, Han Seung Ryu, Geom Seog Seo, Suck Chei Choi Backgrounds: Stress have a role in pathogenesis of FD and influence food intake in human and animal. Prokinetic drugs used in FD and some drug restores feeding inhibition (FI) induced by acute restraint stress in rat. DA-9701 (DA) is new prokinetic drug (Dong-A Pharm. Korea) formulated from Pharbitis Semen & Corydalis Tuber. We aimed to evaluate the effect of DA on FI induced by acute restraint and to compare the gastric volume using animal CT in rat. Methods: Male S-D rats(300g) were divided into 6 groups; Control(no stress), Stress+vehicle, Stress+DA 1, 3, 10 & 30mg/kg groups(n=6~7). DA or vehicle was administered via gastric gavage 15min before stress. After 60min stress, a chow previously weighed was given and the weight of remaining meal was measured 30 & 60 min later. For measuring gastric volume by animal CT, we used the solid chow that mixed with radiocontrast agent beforehand. After same stress protocol, radiocontrast chow was given to rats. After 1hr, CT scanning was performed with chloral hydrate IP. Results: The restraint stress group significantly decreased food intake than control group. During 30min after stress, there was no statistical difference of food intake between groups(p>0.05). At 60min after stress, vehicle and 30mg/kg of DA group showed significantly decreased food intake compare to control(p<0.05), but 1, 3 & 10 mg/kg of DA-9701 group was not different statistically with control rat (p>0.05). The beneficial effect of 3 mg/kg of DA on FI was completely abolished by WAY 100635. The 3mg/kg of DA could not affect on basal feeding in non-stressed rat. On animal CT, gastric volume in rat with 3mg/kg & 10mg/kg of DA (4.33 & 5.14 cm3) was comparable to control(5.14 cm3), but vehicle rat showed very small volume (1.34 cm3). Conclusions: DA-9701 can improve FI induced by restraint stress in rat and this effect seems to be related with enhanced gastric accommodation by 5HT1A agonism.
W1409 Small Bowel Manometry and Full Thickness Intestinal Biopsies in Patients With Gastrointestinal Neuromuscular Disorders (GINMD) ATMDilshad H. Chowdhury, Ana H. Raimundo, Ara Darzi, Joanne E. Martin, David B. Silk INTRODUCTION: Gastrointestinal neuromuscular disorders (GINMD) are severe disorders in which symptoms arise as a result of neuromuscular dysfunction. Of a personal series of 116 patients recorded on our database, 67 patients ( 12M 55F) mean age 49 years, (abdominal pain 95%,constipation 92%, abdominal distension 78%) had undergone both 24 hour ambulatory study of small bowel motility and laparoscopic full thickness jejunal and colonic biopsies. The aim of the study was to relate the manometric to neuro histopathological findings. METHODS: Prospective qualitative analysis of the small bowel motility tracings was performed , with emphasis on configuration, abnormal propulsion, retrograde contractions( <1cm/min caudad) \and numbers of the phase 3 migrating motor complex (MMC), patterns of contraction and presence or absence of the ‘fed pattern' of motility. All biopsy specimens were examined for the distribution of ganglion cells ( by CD45 staining),myenteric plexus( Haematoxylin eosin staining), Interstitial cells of Cajal(By CD117 staining) and Immunohistochemical localisation of actins and other cytoskeletal proteins were performed. We have previously shown that α-actin epitope deficiency is a biomarker ofChronic idiopathic intestinal pseudoobstruction(1). RESULTS: Of the 67 small bowel motility studies all were abnormal. Abnormalities of the phase ||| MMC were seen in 56(83.6%). 30(44.8%) had evidence of retrograde propulsion. Simultaneous non propagated contractions were seen in 63(94%) and a lack of fed pattern in 22(32.8%). With regard to histology only nine sets of biopsies (14.4%) were normal. In 44(67.7%) the only abnormality was that of α-actin epitope deficiency (1). Reduced ganglion cells in the myenteric plexus(4), ganglionitis(2) and vasculitis (2) were other findings. 5 patients with α-actin epitope deficiency also had reduced ganglion cells (1) ,plexitis(1) and polyglucosan myopathy(3). CONCLUSION: Small bowel manometry is an important investigation in the screening of patients with severe and intractable gastrointestinal symptoms in whom ‘Standard' investigations are normal. As 86% jejunal biopsies were abnormal, patients with abnormal small bowel menometry should undergo laparoscopic full thickness biopsies. We are currently investigating whether the small group of our GINMD patients with normal biopsies and larger numbers with α-actin epitope deficiency alone have an underlying channelopathy. Reference: 1.Knowles et al 2004 GUT 53; 1583-1589
W1407 Amyloidosis in Patients With Gastrointestinal Neuromuscular Disorder of the Gut (GINMD) - Comparison of Serum and Histopathological Diagnostic Techniques ATMDilshad H. Chowdhury, Ana H. Raimundo, Nancy L. Wassef, Ara Darzi, Joanne E. Martin, David B. Silk INTRODUCTION Amyloidosis is a rare and severe disorder and it can cause intestinal dysmotility and pseudoobstruction when it affects the gastrointestinal tract. It is therefore important to exclude this diagnosis in all patients with gastrointestinal neuromuscular disorders (GINMD). In order to determine whether the diagnosis can be made without undertaking fullthickness intestinal biopsies, we have compared the results of serological analyses with those of histopathology in our patients. METHODS Nephelometry was used to analyse serum samples obtained from 43 patients. Serum kappa and Lambda chains were quantitated using manufactured freelite antigen assays. Freelite results were interpreted in conjunction with other laboratory tests and clinical evidence. The standard normal values in our study for Serum Kappa light chains were 3.3-19.4 mg/L and Serum Lambda chains 5.7- 26.3mg/L. Serum albumin, total protein and protein electrophoresis ( IgG, IgM and IgA) were also measured. Full thickness jejunal and colonic biopsies of the 43 patients were analysed for amyloid deposition using the congo red staining method for amyloid. The presence of amyloid was demonstrated by the staining of amorphous material with congo
S-717
AGA Abstracts
AGA Abstracts
related to TSS and GET are presented in the following table: Conclusions: 1) Overall in drug-refractory GP the addition of PP to the Enterra procedure significantly and markedly accelerates gastric emptying, while significantly improving GP symptoms without any adverse events. 2) The Post-vagotomy group of GP is the most responsive to the addition of PP with GET being normalized in 70% of the patients; (<10% retention at 4hrs) while idiopathics are the least improved. 3) Pyloroplasty added to the Enterra GES procedure should be recommended as a routine approach to the refractory GP, since it provides a new benefit without changing morbidity.