- Email: [email protected]
The relevance of luminal release is doubtful
July 1998
defined as alanine aminotransferase level normalization while on IFN therapy and during the first 6 months of posttreatment follow-up, together with serum HCV RNA negativity. Pretreatment viremia was assessed by branched DNA (Chiron Corp., Emeryville, CA), genotype by LiPA (Innogenetics, Gent, Belgium), and DNA sequencing by the chain termination method, directly from double-stranded Taqamplified fragments. In group I, we have already shown that absence of cirrhosis and low pretreatment viremia were associated with sustained response.5 In group II, low pretreatment viremia and genotype 2 and 3 were associated with sustained response. NS5A region (amino acid position 2209–2248) was sequenced in pretreatment serum samples from 14 patients (7 sustained responders and 7 nonresponders to IFN) infected by genotype 1b. Among the 7 sustained responders, the number of mutations were: eight in 2 patients, six in 1 patient, five in 1 patient, four in 1 patient, three in 1 patient, and two in 1 patient (total, 36 in 7 patients). Among the 7 nonresponders, the number of mutations were: four in 1 patient, two in 2 patients, and one in 4 patients (total, 12 in 7 patients). Median pretreatment viremia was lower among the 7 sustained responders (,200,000 Eq/mL) than among nonresponders (1,300,000 Eq/mL). Finally, among the 7 sustained responders, liver histology showed chronic active hepatitis in 4 patients and chronic persistent hepatitis in 3 patients, whereas among the 7 nonresponders, 2 patients were cirrhotic and 5 had chronic active hepatitis. Notably, the 2 sustained responders with less than four mutations had low pretreatment viremia (640,000 and ,200,000 Eq/mL) and very mild liver disease (both chronic persistent hepatitis), whereas the single nonresponder with four mutations was cirrhotic. In an article recently published in GASTROENTEROLOGY,4 only 1 of 7 sustained responders had four or more NS5A amino acid mutations, whereas in our study 5 of the 7 sustained responders had four or more mutations, the other 2 sustained responders showing classical predictors of favorable response (low pretreatment viremia and histologically mild liver disease). In our study, the number of amino acid mutations was inversely related to pretreatment viremia, as also shown among Japanese patients,2 again in contrast with the study by Squadrito et al.4 The degree of liver fibrosis is not reported, and level of pretreatment viremia is not shown in detail4; thus, the above discrepancies could be caused by different virological and/or histological features of the patients studied. In conclusion, our results suggest that NS5A amino acid mutations are associated with IFN responsiveness in patients infected by genotype 1b, independently from their geographic origin, but they represent only one of the predictors of favorable response, with absence of cirrhosis, low pretreatment viremia, and genotype 2 and 3 being the other most important ones. SILVIO MAGRIN, M.D. CARMELO FABIANO, Ph.D. Divisione di Medicina Interna Azienda Ospedaliera V. Cervello FABRIZIO GIANGUZZA, Ph.D. MASSIMO CUTRERA, Ph.D. Dipartimento di Biologia Cellulare e dello Sviluppo GIUSEPPE ALAIMO, M.D. LUIGI PAGLIARO, M.D. Istituto di Medicina Generale e Pneumologia University of Palermo Palermo, Italy
CORRESPONDENCE
245
1. Enomoto N, Sakuma I, Asahina Y, et al. Mutations in the nonstructural protein 5A gene and response to interferon in patients with chronic hepatitis C virus 1b infection. N Engl J Med 1996;334: 77–81. 2. Chayama K, Tsubota A, Kobayashi M, et al. Pretreatment virus load and multiple amino acid substitutions in the interferon sensitivitydetermining region predict the outcome of interferon treatment in patients with chronic genotype 1b hepatitis C virus infection. Hepatology 1997;25:745–749. 3. Zeuzem S, Lee J-H, Roth WK. Mutations in the nonstructural 5A gene of European hepatitis C virus isolates and response to interferon alfa. Hepatology 1997;25:740–744. 4. Squadrito G, Leone F, Sartori M, et al. Mutations in the nonstructural 5A region of hepatitis C virus and response of chronic hepatitis C to interferon alfa. Gastroenterology 1997;113:567– 572. 5. Magrin S, Craxı` A, Fabiano C, et al. HCV viraemia is more important than genotype as a predictor of response to interferon in Sicily (Southern Italy). J Hepatol 1996;25:583–590.
The Relevance of Luminal Release Is Doubtful Dear Sir: We read with interest the article by Vuyyuru and Schubert on the role of histamine in the regulation of oxyntic mucosal somatostatin release with resulting effects on acid secretion in the isolated perfused mouse stomach.1 In this work, the assessment of histamine and somatostatin release is based solely on the release of those substances to the gastric lumen. A previous study from our laboratory2 shows that histamine secretion to the gastric lumen is largely a passive ‘‘washout’’ phenomenon. Thus, we feel that one should be quite conservative in the interpretation of data such as those obtained by Vuyyuru and Schubert. Another problem with the isolated mouse stomach is that it does not differentiate between antral and oxyntic mucosal somatostatin, whose regulation may be different. HELGE L. WALDUM, M.D., Ph.D. ARNE K. SANDVIK, M.D., Ph.D. Section of Gastroenterology Trondheim University Hospital Trondheim, Norway 1. Vuyyuru L, Schubert ML. Histamine, acting via H3 receptors, inhibits somatostain and stimulates acid secretion in isolated mouse stomach. Gastroenterology 1997;113:1545–1552. 2. Sandvik AK, Waldum HL, Kleveland PM, et al. Gastrin produces an immediate and dose-dependent histamine release preceding acid secretion in the totally isolated, vascularly perfused rat stomach. Scand J Gastroenterol 1987;22:803–808.
Histamine H3 Receptors and Gastric Acid Secretion Dear Sir: We read with great interest the article by Vuyyuru and Schubert1 concerning the stimulatory effects mediated by histamine H3 receptors in the isolated mouse stomach. The authors provided convincing evidence that in this species, histamine H3 receptors are mainly located on D cells with the function of reducing somatostatin secretion and consequently increasing histamine release and acid secretion. This effect seems to be more relevant than the H3-mediated inhibition of histamine release from enterochromaffin-like (ECL) cells, with consequent reduction of acid secretion. These results obtained in the mouse
defined as alanine aminotransferase level normalization while on IFN therapy and during the first 6 months of posttreatment follow-up, together with serum HCV RNA negativity. Pretreatment viremia was assessed by branched DNA (Chiron Corp., Emeryville, CA), genotype by LiPA (Innogenetics, Gent, Belgium), and DNA sequencing by the chain termination method, directly from double-stranded Taqamplified fragments. In group I, we have already shown that absence of cirrhosis and low pretreatment viremia were associated with sustained response.5 In group II, low pretreatment viremia and genotype 2 and 3 were associated with sustained response. NS5A region (amino acid position 2209–2248) was sequenced in pretreatment serum samples from 14 patients (7 sustained responders and 7 nonresponders to IFN) infected by genotype 1b. Among the 7 sustained responders, the number of mutations were: eight in 2 patients, six in 1 patient, five in 1 patient, four in 1 patient, three in 1 patient, and two in 1 patient (total, 36 in 7 patients). Among the 7 nonresponders, the number of mutations were: four in 1 patient, two in 2 patients, and one in 4 patients (total, 12 in 7 patients). Median pretreatment viremia was lower among the 7 sustained responders (,200,000 Eq/mL) than among nonresponders (1,300,000 Eq/mL). Finally, among the 7 sustained responders, liver histology showed chronic active hepatitis in 4 patients and chronic persistent hepatitis in 3 patients, whereas among the 7 nonresponders, 2 patients were cirrhotic and 5 had chronic active hepatitis. Notably, the 2 sustained responders with less than four mutations had low pretreatment viremia (640,000 and ,200,000 Eq/mL) and very mild liver disease (both chronic persistent hepatitis), whereas the single nonresponder with four mutations was cirrhotic. In an article recently published in GASTROENTEROLOGY,4 only 1 of 7 sustained responders had four or more NS5A amino acid mutations, whereas in our study 5 of the 7 sustained responders had four or more mutations, the other 2 sustained responders showing classical predictors of favorable response (low pretreatment viremia and histologically mild liver disease). In our study, the number of amino acid mutations was inversely related to pretreatment viremia, as also shown among Japanese patients,2 again in contrast with the study by Squadrito et al.4 The degree of liver fibrosis is not reported, and level of pretreatment viremia is not shown in detail4; thus, the above discrepancies could be caused by different virological and/or histological features of the patients studied. In conclusion, our results suggest that NS5A amino acid mutations are associated with IFN responsiveness in patients infected by genotype 1b, independently from their geographic origin, but they represent only one of the predictors of favorable response, with absence of cirrhosis, low pretreatment viremia, and genotype 2 and 3 being the other most important ones. SILVIO MAGRIN, M.D. CARMELO FABIANO, Ph.D. Divisione di Medicina Interna Azienda Ospedaliera V. Cervello FABRIZIO GIANGUZZA, Ph.D. MASSIMO CUTRERA, Ph.D. Dipartimento di Biologia Cellulare e dello Sviluppo GIUSEPPE ALAIMO, M.D. LUIGI PAGLIARO, M.D. Istituto di Medicina Generale e Pneumologia University of Palermo Palermo, Italy
CORRESPONDENCE
245
1. Enomoto N, Sakuma I, Asahina Y, et al. Mutations in the nonstructural protein 5A gene and response to interferon in patients with chronic hepatitis C virus 1b infection. N Engl J Med 1996;334: 77–81. 2. Chayama K, Tsubota A, Kobayashi M, et al. Pretreatment virus load and multiple amino acid substitutions in the interferon sensitivitydetermining region predict the outcome of interferon treatment in patients with chronic genotype 1b hepatitis C virus infection. Hepatology 1997;25:745–749. 3. Zeuzem S, Lee J-H, Roth WK. Mutations in the nonstructural 5A gene of European hepatitis C virus isolates and response to interferon alfa. Hepatology 1997;25:740–744. 4. Squadrito G, Leone F, Sartori M, et al. Mutations in the nonstructural 5A region of hepatitis C virus and response of chronic hepatitis C to interferon alfa. Gastroenterology 1997;113:567– 572. 5. Magrin S, Craxı` A, Fabiano C, et al. HCV viraemia is more important than genotype as a predictor of response to interferon in Sicily (Southern Italy). J Hepatol 1996;25:583–590.
The Relevance of Luminal Release Is Doubtful Dear Sir: We read with interest the article by Vuyyuru and Schubert on the role of histamine in the regulation of oxyntic mucosal somatostatin release with resulting effects on acid secretion in the isolated perfused mouse stomach.1 In this work, the assessment of histamine and somatostatin release is based solely on the release of those substances to the gastric lumen. A previous study from our laboratory2 shows that histamine secretion to the gastric lumen is largely a passive ‘‘washout’’ phenomenon. Thus, we feel that one should be quite conservative in the interpretation of data such as those obtained by Vuyyuru and Schubert. Another problem with the isolated mouse stomach is that it does not differentiate between antral and oxyntic mucosal somatostatin, whose regulation may be different. HELGE L. WALDUM, M.D., Ph.D. ARNE K. SANDVIK, M.D., Ph.D. Section of Gastroenterology Trondheim University Hospital Trondheim, Norway 1. Vuyyuru L, Schubert ML. Histamine, acting via H3 receptors, inhibits somatostain and stimulates acid secretion in isolated mouse stomach. Gastroenterology 1997;113:1545–1552. 2. Sandvik AK, Waldum HL, Kleveland PM, et al. Gastrin produces an immediate and dose-dependent histamine release preceding acid secretion in the totally isolated, vascularly perfused rat stomach. Scand J Gastroenterol 1987;22:803–808.
Histamine H3 Receptors and Gastric Acid Secretion Dear Sir: We read with great interest the article by Vuyyuru and Schubert1 concerning the stimulatory effects mediated by histamine H3 receptors in the isolated mouse stomach. The authors provided convincing evidence that in this species, histamine H3 receptors are mainly located on D cells with the function of reducing somatostatin secretion and consequently increasing histamine release and acid secretion. This effect seems to be more relevant than the H3-mediated inhibition of histamine release from enterochromaffin-like (ECL) cells, with consequent reduction of acid secretion. These results obtained in the mouse