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Lower esophageal sphincter: How to quantitate?
346
SELECTED SUMMARIES
GASTROENTEROLOGY Vol. 103. No. 1
tries, and HCV-K2a and HCV-K2b were found commonly in Oriental countries. These results suggest that HCV-PT may be the Western type and HCV-K2 may be the Oriental type. The prevalence of HCV-Kl was highest in every country except for the United States, suggesting that this type may be the major or wild type of HCV [Takada N et al., J Hepatol (submitted)]. In the classification of Houghton et al., differences between HCV-K2a and HCV-K2b were not recognized. This may be mainly due to very low prevalence or almost absence of HCV-K2 in Western countries. The distributions of HCV genotypes among countries are somewhat similar to those of HBV subtypes of adr and ayr or adw and ayw. However, subtypes of HBV are not related to the clinical features of patients with type B hepatitis. On the other hand, the initial response to interferon treatment was significantly better in patients with HCV-K2 than in patients with HCV-Kl. Significantly better effects of interferon in patients having HCV-K2 than in patients having HCV-Kl were confirmed by the longer-term observations in larger numbers of patients. Disappearance of HCV RNA encoding the NS5 region was not different between HCV-K1 and HCV-K2. The comments of Dr. Davis concerning this point may be misunderstood. In the paper, we described that HCV RNA became negative also in patients showing the partial response. Difference of the prevalence of HCV-Kl in patients with hepatocellular carcinoma (HCC) between Japanese alcoholics and nonalcoholics was significant in an analysis of larger numbers of patients. In seven Spanish patients and two Chinese patients with HCC, the genotype was all HCV-Kl. These results suggest a possibility that genotypes may be related to the oncogenicity of HCV. Other facts suggesting that genotypes of HCV may also be related to clinical problems are now accumulating. For example, the detection rate of HCV RNA by the two-stage PCR using the primers for the 5’noncoding region was low in HCV-K2, and detection rate of antibodies to C-100-3 protein was clearly lower in Chinese patients with HCV-K2 than those with HCV-K1. These results indicate that genomic variations of HCV are clearly related to the clinical differences. However, the mechanisms are not known. As suggested by Dr. Davis, changes in the envelope proteins resulting from nucleotide variations should be considered as the possible causes for clinical difference. In Japan, HCV-PT is not present naturally or is very rare. Therefore, we know very little about HCV-PT. In a Japanese study of Shoji et al. (Jpn J Gastroenterol 1991;88:706-713, in Japanese] which was cited by Dr. Davis, the relapse rate after discontinuation of interferon treatment was very low compared with many other reports from Japan. The dose of interferon used in that study was different from that used in the studies from the United States and Europe. Genotypes were not determined in that study. Therefore, the study did not represent the difference between HCV-I (PT) and HCV-II (Kl), as suggested by Dr. Davis. These facts indicate the need of further studies on HCV-PT in Western countries to clarify the relation between genomic variation and clinical difference. All HCV RNA (NS5) in the samples from Japanese and Chinese patients reacted with one of the specific probes for the four types, indicating that genotypes of HCV in the Orient may be limited to the four types. Some HCV RNAs (NS5) from patients of Western countries did not react with any probes for the four types, indicating presence of other unknown subtypes in the West. Some of these samples reacted very weakly with the 401-bp HCV-Kl-PT probe, suggesting that these samples may be families of HCV-PT and that there may be subtypes in HCV-PT as seen in HCV-K2. Clear clinical difference was not found between patients having HCV-K2a and HCV-KZb, suggesting that differentiation of HCVK2a and HCV-K2b has no clinical meaning. N. TAKADA,
M.D.
S. TAKASE,
M.D.
A. TAKADA.
M.D.
LOWER ESOPHAGEAL TO QUANTITATE?
SPHINCTER:
HOW
Stein HJ, DeMeester TR, Naspetti R, et al. (Department of Surgery, University of Southern California School of Medicine, Los Angeles, California). Three dimensional imaging of the lower esophageal sphincter in gastroesophageal reflux disease. Ann Surg 1991;214:374-384. This study reports the usefulness of lower esophageal sphincter (LES) pressure vector volume (SPVV) in differentiating normal subjects from patients with reflux esophagitis. SPVV is a composite measure of LES pressure, LES length, and radial asymmetry of the LES. SPVV was measured by recording LES pressure with a catheter that had either four or eight radially oriented pressure sensors. Three-dimensional images of the LES were constructed by a computer program that interpreted the data from the radially placed manometric ports. The three-dimensional images could be rotated on the computer screen. The computer integrated the sum of the area under the curve from these radially oriented LES pressure waveforms and generated a number which was called SPVV. The total SPVV was divided into its intrathoracic and intra-abdominal components based on how much of the SPVV was located above or below the respiratory inversion point. The study was performed in two parts: part one, the validation studies, and part two, the comparison of normal subjects and patients with gastroesophageal reflux (GER) disease. Validation studies were performed in I5 normal subjects and 27 symptomatic patients with GER using a catheter that had four or eight radially oriented pressure sensors at the same level and a catheter with four radially placed pressure sensors spaced at s-cm intervals. Pressures were measured with either a rapid motorized or station pullthrough technique. The goal of the validation studies was to determine if a manometric catheter and the technique used in regular clinical practice can be used for SPVV measurements. There was a strong correlation between the SPVV measured by rapid pull-through recorded by eight vs. four radially placed pressure sensors at the same level on the catheter. Similarly, there was a strong correlation between the rapid and slow pull-throughs, recorded by eight and four pressure sensors. Slow pull-through recorded by eight pressure sensors located at the same radial level vs. four sensors placed radially at s-cm intervals on the catheter also showed a strong correlation. Based on these observations, investigators used a slow pull-through technique and a catheter that had four radially oriented pressure sensors located at s-cm intervals and studied two groups of subjects, 50 normal subjects and 150 consecutive patients with abnormal 24-hour esophageal pH study. The patients were categorized into the following four groups based on endoscopy: (a) normal esophageal mucosa, (b) esophagitis, (c) esophageal stricture, and(d) Barrett’s esophagus. In addition, 32 patients had follow-up studies l-10 years after either a Nissen or Belsey fundoplication. The results show that the mean SPVV was significantly lower in all of the four groups of patients, i.e., patients with normal mucosa, esophagitis, stricture, and Barrett’s esophagus, compared with the normal control population. The
July 1992
difference in the SPVV between normals and patients was seen in the total as well as intra-abdominal SPVV. Eighty percent of the patients with esophagitis, stricture, and Barrett’s esophagus were below the 5% confidence limit of the normals. However, only 55% of the patients with normal esophageal mucosa were below the fifth percentile of controls. When compared with the traditional manometric criteria of a defective LES, the SPVV was a better parameter only in an additional 18% of patients with no mucosal injury. There was no difference in the traditional criteria and SPVV criteria in the remaining three groups. SPVV was restored to normal following fundoplication procedures and correlated well with the symptom relief. Comment. The pathogenesis of gastroesophageal reflux disease is multifactorial. The sphincteric mechanism at the lower end of the esophagus, luminal clearance, acid neutralization mechanism, and esophageal mucosal defense factors are the protective factors and gastric refluxate is the major aggressive factor in the causation of esophagitis (Ann Intern Med 1982;97:203-210). The sphincteric mechanism at the lower end of the esophagus constitutes the major factor that prevents reflux of gastric contents into the esophagus. The smooth muscle of the LES is an important constituent of the sphincteric mechanism. The other sphincteric mechanism is contributed by the crural diaphragm (J Clin Invest 1988;81:1182-1189). Because the significance of the crural diaphragm in reflux disease is currently not known, the literature during the last 25 years has focused on the role of smooth muscle LES in gastroesophageal reflux disease. A number of early investigators equated low intraluminal LES pressures with an incompetent sphincter. However, improvements in the techniques of LES pressure measurement and more studies in this area pointed out that a significant number of patients with reflux esophagitis have normal LES pressures (Gastroenterology 1986;91:897-904). The pressure in the LES is radially as well as axially asymmetric. Furthermore, there is variability in the length of the LES among different subjects. Earlier studies by DeMeester et al. suggested that a shorter length of the LES makes it more susceptible to incompetency. Furthermore, the length of the LES in the abdomen has also been equated with competence of the antireflux barrier. Therefore, based on these observations, a parameter that combines LES pressure, its axial and radial asymmetry, and its length could provide a useful number that may equate with competency of the antireflux barrier. However, there are two major problems with the proposed hypothesis: (a] although the role of LES pressure as a barrier against the flow of gastric contents into the esophagus is well accepted, the role of LES length and axial as well as radial asymmetry is not totally clear; (b) the hypothesis assumes that
SELECTED SUMMARIES
347
gastroesophageal reflux occurs as a passive process due to abnormalities of basal LES pressure, LES length, and axial asymmetry. On the contrary, long-term esophageal manometry and pH recordings suggest that transient relaxations of the LES rather than the poor LES tone is the major mechanism of gastroesophageal reflux (N Engl J Med 1982;307:1547-1522). In other words, there is an active inhibition of the LES, which is mediated through the central nervous system that brings about gastroesophageal reflux (Gastroenterology 1986;91:133-140). Another methodological and conceptual problem with this work of Stein et al. is the use of respiratory inversion point to determine the location of the diaphragm and the intra-abdominal length of the LES. Studies by Dodds et al. (Gastroenterology 1974:67:592-600) pointed out that the relative movement between the pressure sensor and the LES during inspiration and expiration may cause respiratory reversal in the LES pressure recordings. In support of their theory is the observation that respiratory reversal can be present in LES pressure recordings of patients with hiatal hernia in whom the entire LES is intrathoracic. If we leave these above issues aside, the data shown by Stein et al. are, indeed, impressive. The SPVV can clearly differentiate patients with esophagitis. esophageal strictures, and Barrett’s esophagus from normal controls. Furthermore, SPVV becomes normal after Nissen or Belsey repairs. Improvement in symptoms of gastroesophageal reflux correlates strongly with improvements in SPVV scores. However, patients with symptomatic reflux disease who have no mucosal injury or esophagitis do not consistently show abnormal SPVV. This is an important group of patients and may constitute SO%-70% of the patient population seen by gastroenterologists. About 50% of these patients fell in the normal SPVV range. When comparing SPVV with the traditional parameters, i.e., LES pressure. total length, and intra-abdominal length, considered independently as normal or abnormal, SPVV was not a better measure in patients with esophagitis. esophageal stricture, and Barrett’s esophagus. However, in patients with normal esophageal mucosa. an additional 18% of patients were found to have abnormalities by SPVV compared with traditional criteria. Three-dimensional imaging of the LES and calculations of the SPVV seem to advance our diagnostic armamentarium in that it better identifies patients with no evidence of esophagitis. Should SPVV replace the traditional criteria of sphincter competence analysis? Definitely, if these findings are confirmed by other investigators and keeping in mind that calculations of SPVV requires time-consuming analysis. Furthermore, data need to be plotted and calculated using a computer and a specialized software program. K. J. HEINE, M.D. R. K. MITTAL, M.D.
SELECTED SUMMARIES
GASTROENTEROLOGY Vol. 103. No. 1
tries, and HCV-K2a and HCV-K2b were found commonly in Oriental countries. These results suggest that HCV-PT may be the Western type and HCV-K2 may be the Oriental type. The prevalence of HCV-Kl was highest in every country except for the United States, suggesting that this type may be the major or wild type of HCV [Takada N et al., J Hepatol (submitted)]. In the classification of Houghton et al., differences between HCV-K2a and HCV-K2b were not recognized. This may be mainly due to very low prevalence or almost absence of HCV-K2 in Western countries. The distributions of HCV genotypes among countries are somewhat similar to those of HBV subtypes of adr and ayr or adw and ayw. However, subtypes of HBV are not related to the clinical features of patients with type B hepatitis. On the other hand, the initial response to interferon treatment was significantly better in patients with HCV-K2 than in patients with HCV-Kl. Significantly better effects of interferon in patients having HCV-K2 than in patients having HCV-Kl were confirmed by the longer-term observations in larger numbers of patients. Disappearance of HCV RNA encoding the NS5 region was not different between HCV-K1 and HCV-K2. The comments of Dr. Davis concerning this point may be misunderstood. In the paper, we described that HCV RNA became negative also in patients showing the partial response. Difference of the prevalence of HCV-Kl in patients with hepatocellular carcinoma (HCC) between Japanese alcoholics and nonalcoholics was significant in an analysis of larger numbers of patients. In seven Spanish patients and two Chinese patients with HCC, the genotype was all HCV-Kl. These results suggest a possibility that genotypes may be related to the oncogenicity of HCV. Other facts suggesting that genotypes of HCV may also be related to clinical problems are now accumulating. For example, the detection rate of HCV RNA by the two-stage PCR using the primers for the 5’noncoding region was low in HCV-K2, and detection rate of antibodies to C-100-3 protein was clearly lower in Chinese patients with HCV-K2 than those with HCV-K1. These results indicate that genomic variations of HCV are clearly related to the clinical differences. However, the mechanisms are not known. As suggested by Dr. Davis, changes in the envelope proteins resulting from nucleotide variations should be considered as the possible causes for clinical difference. In Japan, HCV-PT is not present naturally or is very rare. Therefore, we know very little about HCV-PT. In a Japanese study of Shoji et al. (Jpn J Gastroenterol 1991;88:706-713, in Japanese] which was cited by Dr. Davis, the relapse rate after discontinuation of interferon treatment was very low compared with many other reports from Japan. The dose of interferon used in that study was different from that used in the studies from the United States and Europe. Genotypes were not determined in that study. Therefore, the study did not represent the difference between HCV-I (PT) and HCV-II (Kl), as suggested by Dr. Davis. These facts indicate the need of further studies on HCV-PT in Western countries to clarify the relation between genomic variation and clinical difference. All HCV RNA (NS5) in the samples from Japanese and Chinese patients reacted with one of the specific probes for the four types, indicating that genotypes of HCV in the Orient may be limited to the four types. Some HCV RNAs (NS5) from patients of Western countries did not react with any probes for the four types, indicating presence of other unknown subtypes in the West. Some of these samples reacted very weakly with the 401-bp HCV-Kl-PT probe, suggesting that these samples may be families of HCV-PT and that there may be subtypes in HCV-PT as seen in HCV-K2. Clear clinical difference was not found between patients having HCV-K2a and HCV-KZb, suggesting that differentiation of HCVK2a and HCV-K2b has no clinical meaning. N. TAKADA,
M.D.
S. TAKASE,
M.D.
A. TAKADA.
M.D.
LOWER ESOPHAGEAL TO QUANTITATE?
SPHINCTER:
HOW
Stein HJ, DeMeester TR, Naspetti R, et al. (Department of Surgery, University of Southern California School of Medicine, Los Angeles, California). Three dimensional imaging of the lower esophageal sphincter in gastroesophageal reflux disease. Ann Surg 1991;214:374-384. This study reports the usefulness of lower esophageal sphincter (LES) pressure vector volume (SPVV) in differentiating normal subjects from patients with reflux esophagitis. SPVV is a composite measure of LES pressure, LES length, and radial asymmetry of the LES. SPVV was measured by recording LES pressure with a catheter that had either four or eight radially oriented pressure sensors. Three-dimensional images of the LES were constructed by a computer program that interpreted the data from the radially placed manometric ports. The three-dimensional images could be rotated on the computer screen. The computer integrated the sum of the area under the curve from these radially oriented LES pressure waveforms and generated a number which was called SPVV. The total SPVV was divided into its intrathoracic and intra-abdominal components based on how much of the SPVV was located above or below the respiratory inversion point. The study was performed in two parts: part one, the validation studies, and part two, the comparison of normal subjects and patients with gastroesophageal reflux (GER) disease. Validation studies were performed in I5 normal subjects and 27 symptomatic patients with GER using a catheter that had four or eight radially oriented pressure sensors at the same level and a catheter with four radially placed pressure sensors spaced at s-cm intervals. Pressures were measured with either a rapid motorized or station pullthrough technique. The goal of the validation studies was to determine if a manometric catheter and the technique used in regular clinical practice can be used for SPVV measurements. There was a strong correlation between the SPVV measured by rapid pull-through recorded by eight vs. four radially placed pressure sensors at the same level on the catheter. Similarly, there was a strong correlation between the rapid and slow pull-throughs, recorded by eight and four pressure sensors. Slow pull-through recorded by eight pressure sensors located at the same radial level vs. four sensors placed radially at s-cm intervals on the catheter also showed a strong correlation. Based on these observations, investigators used a slow pull-through technique and a catheter that had four radially oriented pressure sensors located at s-cm intervals and studied two groups of subjects, 50 normal subjects and 150 consecutive patients with abnormal 24-hour esophageal pH study. The patients were categorized into the following four groups based on endoscopy: (a) normal esophageal mucosa, (b) esophagitis, (c) esophageal stricture, and(d) Barrett’s esophagus. In addition, 32 patients had follow-up studies l-10 years after either a Nissen or Belsey fundoplication. The results show that the mean SPVV was significantly lower in all of the four groups of patients, i.e., patients with normal mucosa, esophagitis, stricture, and Barrett’s esophagus, compared with the normal control population. The
July 1992
difference in the SPVV between normals and patients was seen in the total as well as intra-abdominal SPVV. Eighty percent of the patients with esophagitis, stricture, and Barrett’s esophagus were below the 5% confidence limit of the normals. However, only 55% of the patients with normal esophageal mucosa were below the fifth percentile of controls. When compared with the traditional manometric criteria of a defective LES, the SPVV was a better parameter only in an additional 18% of patients with no mucosal injury. There was no difference in the traditional criteria and SPVV criteria in the remaining three groups. SPVV was restored to normal following fundoplication procedures and correlated well with the symptom relief. Comment. The pathogenesis of gastroesophageal reflux disease is multifactorial. The sphincteric mechanism at the lower end of the esophagus, luminal clearance, acid neutralization mechanism, and esophageal mucosal defense factors are the protective factors and gastric refluxate is the major aggressive factor in the causation of esophagitis (Ann Intern Med 1982;97:203-210). The sphincteric mechanism at the lower end of the esophagus constitutes the major factor that prevents reflux of gastric contents into the esophagus. The smooth muscle of the LES is an important constituent of the sphincteric mechanism. The other sphincteric mechanism is contributed by the crural diaphragm (J Clin Invest 1988;81:1182-1189). Because the significance of the crural diaphragm in reflux disease is currently not known, the literature during the last 25 years has focused on the role of smooth muscle LES in gastroesophageal reflux disease. A number of early investigators equated low intraluminal LES pressures with an incompetent sphincter. However, improvements in the techniques of LES pressure measurement and more studies in this area pointed out that a significant number of patients with reflux esophagitis have normal LES pressures (Gastroenterology 1986;91:897-904). The pressure in the LES is radially as well as axially asymmetric. Furthermore, there is variability in the length of the LES among different subjects. Earlier studies by DeMeester et al. suggested that a shorter length of the LES makes it more susceptible to incompetency. Furthermore, the length of the LES in the abdomen has also been equated with competence of the antireflux barrier. Therefore, based on these observations, a parameter that combines LES pressure, its axial and radial asymmetry, and its length could provide a useful number that may equate with competency of the antireflux barrier. However, there are two major problems with the proposed hypothesis: (a] although the role of LES pressure as a barrier against the flow of gastric contents into the esophagus is well accepted, the role of LES length and axial as well as radial asymmetry is not totally clear; (b) the hypothesis assumes that
SELECTED SUMMARIES
347
gastroesophageal reflux occurs as a passive process due to abnormalities of basal LES pressure, LES length, and axial asymmetry. On the contrary, long-term esophageal manometry and pH recordings suggest that transient relaxations of the LES rather than the poor LES tone is the major mechanism of gastroesophageal reflux (N Engl J Med 1982;307:1547-1522). In other words, there is an active inhibition of the LES, which is mediated through the central nervous system that brings about gastroesophageal reflux (Gastroenterology 1986;91:133-140). Another methodological and conceptual problem with this work of Stein et al. is the use of respiratory inversion point to determine the location of the diaphragm and the intra-abdominal length of the LES. Studies by Dodds et al. (Gastroenterology 1974:67:592-600) pointed out that the relative movement between the pressure sensor and the LES during inspiration and expiration may cause respiratory reversal in the LES pressure recordings. In support of their theory is the observation that respiratory reversal can be present in LES pressure recordings of patients with hiatal hernia in whom the entire LES is intrathoracic. If we leave these above issues aside, the data shown by Stein et al. are, indeed, impressive. The SPVV can clearly differentiate patients with esophagitis. esophageal strictures, and Barrett’s esophagus from normal controls. Furthermore, SPVV becomes normal after Nissen or Belsey repairs. Improvement in symptoms of gastroesophageal reflux correlates strongly with improvements in SPVV scores. However, patients with symptomatic reflux disease who have no mucosal injury or esophagitis do not consistently show abnormal SPVV. This is an important group of patients and may constitute SO%-70% of the patient population seen by gastroenterologists. About 50% of these patients fell in the normal SPVV range. When comparing SPVV with the traditional parameters, i.e., LES pressure. total length, and intra-abdominal length, considered independently as normal or abnormal, SPVV was not a better measure in patients with esophagitis. esophageal stricture, and Barrett’s esophagus. However, in patients with normal esophageal mucosa. an additional 18% of patients were found to have abnormalities by SPVV compared with traditional criteria. Three-dimensional imaging of the LES and calculations of the SPVV seem to advance our diagnostic armamentarium in that it better identifies patients with no evidence of esophagitis. Should SPVV replace the traditional criteria of sphincter competence analysis? Definitely, if these findings are confirmed by other investigators and keeping in mind that calculations of SPVV requires time-consuming analysis. Furthermore, data need to be plotted and calculated using a computer and a specialized software program. K. J. HEINE, M.D. R. K. MITTAL, M.D.