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“familial hyperpepsinogenemia” and Helicobacter pylori infection
THE AMERICAN JOURNAL OF GASTROENTEROLOGY © 2000 by Am. Coll. of Gastroenterology Published by Elsevier Science Inc.
Vol. 95, No. 4, 2000 ISSN 0002-9270/00/$20.00 PII S0002-9270(00)00726-7
“Familial Hyperpepsinogenemia” and Helicobacter pylori Infection Howard R. Mertz, M.D., Walter L. Peterson, M.D., and John H. Walsh, M.D. Vanderbilt University, Department of Medicine, Nashville, Tennessee; Department of Internal Medicine, University of Texas Southwestern Medical School at Dallas and Medical Service, Dallas VA Medical Center, Dallas, Texas; and CURE Neuroenteric Biology Center UCLA/West LA VAMC, Los Angeles, California
OBJECTIVE: Pepsinogen 1 (PG1) is a proenzyme precursor to pepsin, a protease secreted by the gastric chief cell. PG1 levels correlate with maximal gastric acid output. In 1979, Rotter et al. reported two pedigrees in which elevated PG1 levels and duodenal ulcers were prevalent. They proposed autosomal dominant inheritance of elevated PG1 and suggested that it was a risk factor for duodenal ulcer disease. In 1982, Helicobacter pylori (Hp) was discovered and was shown to be an important factor in peptic ulcer disease. Hp infection is also associated with increased PGI levels. We tested serum from one of the original pedigrees for Hp antibodies to determine whether Hp infection could explain the ulcers and elevated PG1 levels. METHODS: ELISA tests were performed using the urease fraction of a crushed Hp extract. Banked serum from one of the original families was thawed and tested. RESULTS: Of the subjects, 90% (nine of 10) with elevated PG1 were seropositive for Hp, compared to only 31% (17 of 55) of those with normal PG1 levels (p ⬍ 0.001). The mean PG1 level was higher in the seropositive (94.1 ⫾ 13.3 ng/ml) than the seronegative subjects (54.8 ⫾ 3.6, p ⬍ 0.05). Three of the four subjects with ulcers were Hpseropositive. The prevalence of Hp-seropositivity and elevated PG1 declined in parallel in each successive generation. When neither parent was seropositive, children were seronegative. CONCLUSIONS: The etiology of elevated PG1 levels in this pedigree is more likely due to Helicobacter pylori infection than to a genetic predisposition. (Am J Gastroenterol 2000; 95:943–946. © 2000 by Am. Coll. of Gastroenterology)
INTRODUCTION Pepsinogen I (PG1) is a proenzyme contained within and secreted by gastric chief cells. Once secreted into the acidic gastric lumen, PG1 is cleaved into pepsin, a protease that aids in digestion of proteins. Serum PG1 levels correlate with maximal acid output (MAO) and, therefore, presumably with parietal cell mass (1, 2). In 1979, Rotter et al. reported PG1 levels in two family pedigrees in which several family members had been diagnosed with duodenal
ulcers (3). They found elevated PG1 levels in 10 of 11 subjects with ulcers and proposed an autosomal dominant inheritance pattern for elevated PG1. It was thought that increased PG1 was a marker for increased acid secretion and duodenal ulcer disease in some families. In 1982, Helicobacter pylori (Hp) was discovered and was soon found to be an important factor in peptic ulcer disease (4). Hp infection is associated with increased PG1 levels, independent of MAO. It is possible that Hp infection, rather than an inherited trait, explained the elevated PG1 and ulcer tendency in the families described by Rotter et al. Banked sera from one of the original hyperpepsinogen families was available for Hp testing. We performed Hp ELISA tests on the sera to determine whether elevated PG1 levels in that kindred were associated with Hp infection.
MATERIALS AND METHODS The original family (no. 2 from Rotter et al.) was identified when the index ulcer patient in generation III reported ulcer disease in his deceased father (generation II) and paternal grandfather (generation I). Two of his children and one nephew had also been diagnosed with ulcer. Three generations comprising 75 blood relatives from this family donated blood for PG1 measurement. Blood samples from 65 of these subjects were available for Hp testing. Sera from the other family in the original study were unavailable for testing. The ELISA test was performed as previously described in detail (5). In summary, a crushed Hp extract was separated on a sephacryl column, and the urease fraction was used to coat 96-well ELISA plates (Costar, Owens Corning, Toledo, OH). The human serum was diluted 1:1000 in PBS buffer and was incubated in the coated wells in duplicate. After lavage, horseradish peroxidase-conjugated rabbit antihuman IgG (Sigma) was incubated in the wells and washed again. Color indicator (o-phenylenediamine dihydrochloride in citrate buffer, pH 5.0) and peroxide were added. After 30 min, the reaction was stopped with 10% H2SO4. Absorbance at 492 nm was determined with an ELISA reader (Titertech MkII; Flow Laboratories, McClean, VA). Positive serology was determined using a cutoff established by 16 control-
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AJG – Vol. 95, No. 4, 2000
Figure 1. Pepsinogen 1 and Helicobacter pylori. Family members who were seropositive for H. pylori had higher pepsinogen 1 levels than those who were seronegative (p ⬍ 0.005; means and SEM are displayed). Subjects with a history of ulcer are indicated by solid triangles. The cutoff for normal PG1 is 100 ng/ml, as indicated by the horizontal line.
positive and 12 control-negative sera from patients with Hp status as established by biopsy, histology, and culture. Pepsinogen 1 levels had been determined by Dr. M. Samloff, as previously described (1, 6). Elevated pepsinogen 1 has been defined as ⱖ100 pg/ml, based on measurement of 300 normal subjects in Dr. Samloff’s laboratory (6). Statistical analysis was performed using the 2 analysis for nonparametric data, and a Student’s t test for parametric data. Significance was defined as p ⬍ 0.05.
RESULTS In this pedigree from three generations, 26 of 65 subjects were seropositive for Hp. In all, 90% (nine of 10) of family members with elevated PG1 were seropositive for Hp, compared with only 31% (17 of 55) of those with normal PG1 levels (p ⬍ 0.001). The mean PG1 level was higher in those seropositive for Hp than those seronegative (Fig. 1). Of the four subjects with documented duodenal ulcers, three were Helicobacter seropositive. Hp seropositivity decreased in each successive generation: III, 50%; IV, 25%; and V, 3%. This was in parallel with the decreasing prevalence of elevated PG1 in each generation: III, 83%; IV, 54%; and V, 23% (Fig. 2). Subject age correlated with PG1 level (r2 ⫽ 0.22, p ⬍ 0.0005) and Hp-positivity (40.5 ⫾ 3.8 yr for Hp-positive vs 24.6 ⫾ 2.2 for Hp-negative, p ⬍ 0.005). Review of the PG1 levels in the pedigree reveals that three of six subjects in generation III had elevated PG1 levels, and all three were Hp-seropositive. In generation IV,
six of 13 offspring of members with elevated PG1also had elevated PG1. Five of the six were Hp-seropositive. In generation V, none of the 13 offspring of members with elevated PG1 had elevated levels. Ten were tested for Hp, and all 10 were seronegative. Correlation of Hp-seropositivity between parents and offspring was performed. Serum was available from 16 spouses of members of the lineage, 11 of whom were Hp-seropositive. When one or more parent was Hp seropositive, 16 of 32 offspring were also Hp-seropositive. When neither parent was Hp seropositive, none of 6 offspring were seropositive (p ⬍ 0.05).
Figure 2. Helicobacter pylori infection and increased PG1 levels by generation. The prevalence of elevated PG1 levels and H. pylori serum antibodies is lower in each of three successive generations (III, IV, V) of this pedigree.
AJG – April, 2000
DISCUSSION The concept of autosomal dominant inheritance of elevated PG1 was based on pedigree analysis of two families in which duodenal ulcers were prevalent. Because Hp infection is known to be associated with elevated PG1 levels and to be a risk factor for duodenal ulcers, we postulated that Hp may be the cause of elevated PG1 in this pedigree. The larger of the two families had serum tested for Hp. All but one subject (90%) with elevated PG1 was seropositive for Hp, compared with only 30% of those with normal PG1. There also was a significant elevation in mean PG1 levels in this family when Hp antibodies were present in the serum. It is established that the seroprevalence for Hp antibodies increases with age (7, 8). In this pedigree, generational and agerelated prevalence of Hp seropositivity and elevated PG1 run in parallel. Review of the pedigree shows that elevated PG1 was present in none of 13 of the last generation who were children of members of the lineage with elevated PG1. If analysis is limited to those ⬎14 yr (an age when PG1 levels should have reached the adult maximum (6), none of five had elevated PG1. None of these 13 were Hp-seropositive. These findings suggest that Hp infection was the etiology of the elevated PG1 levels in this family. Several investigators have demonstrated that eradication of Hp with antibiotics in patients with dyspepsia or ulcer disease leads to a significant drop in serum PG1 levels, often from levels ⬎100 ng/ml to normal levels (9 –12). The mechanisms by which Hp infection elevates PG1 levels is not known; however, it may relate to increased production of PG1. Pepsinogen gene expression in rats has been shown to be inducible by Helicobacter felis gastric infection (13). Alternatively, inflammation induced by the organism may allow more PG1 to diffuse through injured chief cell walls into the serum. Isolated guinea pig chief cells express TNF receptors and undergo cell death with pepsinogen release after exposure to TNF (14). In humans, Helicobacter strains that are positive for the Cag-A protein are associated with greater gastric inflammation and higher PGI levels than Cag-A–negative strains, supporting the link between gastric inflammation and serum PGI elevation (15). Other factors that may influence serum pepsinogen levels include cigarette smoking, vagal tone and psychological distress (16, 17). The influence of cigarette smoking on PGI elevation is somewhat controversial, with some studies showing higher PGI levels in smokers (17) and others not (16, 18). This association is complicated by an increased prevalence of HP infection among smokers (19, 20). We did not have access to information about smoking or psychological states of the subjects and, therefore, could not address these issues. An inherited increase in PG1 levels is unlikely to be the explanation for the elevated levels seen in this pedigree, although genetic susceptibility to Hp-induced PG1 elevation is conceivable. As well, there may be genetic determinants of parietal cell mass associated with higher PG1 levels.
Familial Hyperpepsinogenemia and H. pylori
945
However, any analysis of PG1 level inheritance must take Hp infection into account. Evaluation of the families within this pedigree also suggests that the Hp status of parents influences the Hp status of the offspring. Drum et al. have also demonstrated intrafamilial clusters of Hp infection (21). Vertical transmission is possible. Alternatively parents, and children share behaviors and household exposures that promote Hp infection. Reprint requests and correspondence: Howard Mertz, M.D., Assistant Professor of Medicine, 1501 TVC, Vanderbilt University Medical Center, Nashville, TN 37232–5280. Received May 3, 1999; accepted Dec. 29, 1999.
REFERENCES 1. Samloff IM, Secrist DM, Passaro E Jr. A study of the relationship between serum group I pepsinogen levels and gastric acid secretion. Gastroenterology 1975;69:1198 –2000. 2. Waldum HL, Burhol PG, Straume BK. Serum group I pepsinogens and gastrin in relation to gastric H⫹ and pepsin outputs before and after subcutaneous injection of pentagastrin. Scand J Gastroenterol 1978;13:943– 6. 3. Rotter JI, Sones JQ, Samloff IM, et al. Duodenal-ulcer disease associated with elevated serum pepsinogen I: An inherited autosomal disorder. N Engl J Med 1979;300:63– 6. 4. Marshall BJ, Goodwin CS, Warren JR, et al. Prospective double-blind trial of duodenal ulcer relapse after eradication of Campylobacter pylori. Lancet 1988;2:1437– 42. 5. Karnes WE Jr, Ohning GV, Stynik BV, et al. Elevation of meal-stimulated gastrin release in subjects with Helicobacter pylori infection: Reversal by low intragastric pH. Rev Infect Dis 1991;13:S665–70. 6. Samloff IM, Liebman WM, Panitch NM. Serum group I pepsinogens by radioimmunoassay in control subjects and patients with peptic ulcer. Gastroenterology 1975;69:83–90. 7. Jones DM, Eldridge J, Fox AJ, et al. Antibody to the gastric campylobacter-like organism (Campylobacter pylori-dis)– Clinical correlations and distribution in the normal population. J Med Microbiol 1986;22:57– 62. 8. Perez-Perez GI, Sworkin BM, Chodos JE, et al. Campylobacter pylori antibodies in humans. Ann Intern Med 1988; 109:11–7. 9. Oderda G, Holton J, Altare F, et al. Amoxycillin plus tinidazole Campylobacter pylori gastritis in children: Assessment by serum IgG antibody, pepsinogen I, and gastrin levels. Lancet 1989;1:690 –2. 10. Parente F, Maconi G, Sangaletti O, et al. Behavior of acid secretion, gastrin release serum pepsinogen I, and gastric emptying of liquids over six months from eradication of Helicobacter pylori in duodenal ulcer patients. A controlled study. Gut 1995;37:210 –5. 11. Maconi G, Lazzaroni M, Sangaletti O, et al. Effect of Helicobactor pylori eradication on gastric histology, serum gastrin and pepsinogen I levels and gastric emptying in patients with gastric ulcer. Am J Gastroenterol 1997;92:1844 – 8. 12. Perez-Paramo M, Albillos A, Calleja J, et al. Changes in gastrin and serum pepsinogens in monitoring of Helicobacter pylori response to therapy. Dig Dis Sci 1997;42:1734 – 40. 13. Kishi K, Kinoshita Y, Matsushima Y, et al. Pepsinogen C gene product is a possible growth factor during gastric mucosal healing. Biochem Biophys Res Comm 1997;238:17–20. 14. Fiorucci S, Santucci L, Migliorati G, et al. Isolated guinea
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pig gastric chief cells express tumor necrosis factor receptors coupled with the spingomyelin pathway. Gut 1996;38: 182–9. 15. Parente F, Imbesi V, Maconi G, et al. Influence of bacterial CagA status on gastritis, gastric function indices, and pattern of symptoms in H. pylori-positive dyspeptic symptoms. Am J Gastroenterol 1998;93:1073–9. 16. Walker P, Luther J, Samloff M, et al. Life events stress and psychological factors in men with peptic ulcer disease. Gastroenterology 1988;94:323–30. 17. Parente F, Lazzaroni M, Sangaletti O, et al. Cigarette smoking, gastric acid secretion and serum pepsinogen I concentrations in duodenal ulcer patients. Gut 1985;26:1327–32.
AJG – Vol. 95, No. 4, 2000
18. Sumii K, Kimura M, Morikawa A, et al. Recurrence of duodenal ulcer and elevated serum pepsinogen I levels in smokers and nonsmokers. Am J Gastroenterol 1990;85:1493–7. 19. Lin SK, Lambert JR, Nicholson L, et al. Prevalence of Helicobacter pylori in a representative Anglo-Celtic population of urban Melbourne. J Gastroenterol Hepatol 1998; 13:505–10. 20. Gohl KL. Prevalence of risk factors for Helicobacter pylori infection in a multi-racial dyspeptic Malaysian population undergoing endoscopy. J Gastroenterol Hepatol 1997;12:29 –35. 21. Drumm B, Perez-Perez G, Blaser M, et al. Intrafamilial clustering of Helicobacter pylori infection. N Engl J Med 1990; 322:359 – 63.
Vol. 95, No. 4, 2000 ISSN 0002-9270/00/$20.00 PII S0002-9270(00)00726-7
“Familial Hyperpepsinogenemia” and Helicobacter pylori Infection Howard R. Mertz, M.D., Walter L. Peterson, M.D., and John H. Walsh, M.D. Vanderbilt University, Department of Medicine, Nashville, Tennessee; Department of Internal Medicine, University of Texas Southwestern Medical School at Dallas and Medical Service, Dallas VA Medical Center, Dallas, Texas; and CURE Neuroenteric Biology Center UCLA/West LA VAMC, Los Angeles, California
OBJECTIVE: Pepsinogen 1 (PG1) is a proenzyme precursor to pepsin, a protease secreted by the gastric chief cell. PG1 levels correlate with maximal gastric acid output. In 1979, Rotter et al. reported two pedigrees in which elevated PG1 levels and duodenal ulcers were prevalent. They proposed autosomal dominant inheritance of elevated PG1 and suggested that it was a risk factor for duodenal ulcer disease. In 1982, Helicobacter pylori (Hp) was discovered and was shown to be an important factor in peptic ulcer disease. Hp infection is also associated with increased PGI levels. We tested serum from one of the original pedigrees for Hp antibodies to determine whether Hp infection could explain the ulcers and elevated PG1 levels. METHODS: ELISA tests were performed using the urease fraction of a crushed Hp extract. Banked serum from one of the original families was thawed and tested. RESULTS: Of the subjects, 90% (nine of 10) with elevated PG1 were seropositive for Hp, compared to only 31% (17 of 55) of those with normal PG1 levels (p ⬍ 0.001). The mean PG1 level was higher in the seropositive (94.1 ⫾ 13.3 ng/ml) than the seronegative subjects (54.8 ⫾ 3.6, p ⬍ 0.05). Three of the four subjects with ulcers were Hpseropositive. The prevalence of Hp-seropositivity and elevated PG1 declined in parallel in each successive generation. When neither parent was seropositive, children were seronegative. CONCLUSIONS: The etiology of elevated PG1 levels in this pedigree is more likely due to Helicobacter pylori infection than to a genetic predisposition. (Am J Gastroenterol 2000; 95:943–946. © 2000 by Am. Coll. of Gastroenterology)
INTRODUCTION Pepsinogen I (PG1) is a proenzyme contained within and secreted by gastric chief cells. Once secreted into the acidic gastric lumen, PG1 is cleaved into pepsin, a protease that aids in digestion of proteins. Serum PG1 levels correlate with maximal acid output (MAO) and, therefore, presumably with parietal cell mass (1, 2). In 1979, Rotter et al. reported PG1 levels in two family pedigrees in which several family members had been diagnosed with duodenal
ulcers (3). They found elevated PG1 levels in 10 of 11 subjects with ulcers and proposed an autosomal dominant inheritance pattern for elevated PG1. It was thought that increased PG1 was a marker for increased acid secretion and duodenal ulcer disease in some families. In 1982, Helicobacter pylori (Hp) was discovered and was soon found to be an important factor in peptic ulcer disease (4). Hp infection is associated with increased PG1 levels, independent of MAO. It is possible that Hp infection, rather than an inherited trait, explained the elevated PG1 and ulcer tendency in the families described by Rotter et al. Banked sera from one of the original hyperpepsinogen families was available for Hp testing. We performed Hp ELISA tests on the sera to determine whether elevated PG1 levels in that kindred were associated with Hp infection.
MATERIALS AND METHODS The original family (no. 2 from Rotter et al.) was identified when the index ulcer patient in generation III reported ulcer disease in his deceased father (generation II) and paternal grandfather (generation I). Two of his children and one nephew had also been diagnosed with ulcer. Three generations comprising 75 blood relatives from this family donated blood for PG1 measurement. Blood samples from 65 of these subjects were available for Hp testing. Sera from the other family in the original study were unavailable for testing. The ELISA test was performed as previously described in detail (5). In summary, a crushed Hp extract was separated on a sephacryl column, and the urease fraction was used to coat 96-well ELISA plates (Costar, Owens Corning, Toledo, OH). The human serum was diluted 1:1000 in PBS buffer and was incubated in the coated wells in duplicate. After lavage, horseradish peroxidase-conjugated rabbit antihuman IgG (Sigma) was incubated in the wells and washed again. Color indicator (o-phenylenediamine dihydrochloride in citrate buffer, pH 5.0) and peroxide were added. After 30 min, the reaction was stopped with 10% H2SO4. Absorbance at 492 nm was determined with an ELISA reader (Titertech MkII; Flow Laboratories, McClean, VA). Positive serology was determined using a cutoff established by 16 control-
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AJG – Vol. 95, No. 4, 2000
Figure 1. Pepsinogen 1 and Helicobacter pylori. Family members who were seropositive for H. pylori had higher pepsinogen 1 levels than those who were seronegative (p ⬍ 0.005; means and SEM are displayed). Subjects with a history of ulcer are indicated by solid triangles. The cutoff for normal PG1 is 100 ng/ml, as indicated by the horizontal line.
positive and 12 control-negative sera from patients with Hp status as established by biopsy, histology, and culture. Pepsinogen 1 levels had been determined by Dr. M. Samloff, as previously described (1, 6). Elevated pepsinogen 1 has been defined as ⱖ100 pg/ml, based on measurement of 300 normal subjects in Dr. Samloff’s laboratory (6). Statistical analysis was performed using the 2 analysis for nonparametric data, and a Student’s t test for parametric data. Significance was defined as p ⬍ 0.05.
RESULTS In this pedigree from three generations, 26 of 65 subjects were seropositive for Hp. In all, 90% (nine of 10) of family members with elevated PG1 were seropositive for Hp, compared with only 31% (17 of 55) of those with normal PG1 levels (p ⬍ 0.001). The mean PG1 level was higher in those seropositive for Hp than those seronegative (Fig. 1). Of the four subjects with documented duodenal ulcers, three were Helicobacter seropositive. Hp seropositivity decreased in each successive generation: III, 50%; IV, 25%; and V, 3%. This was in parallel with the decreasing prevalence of elevated PG1 in each generation: III, 83%; IV, 54%; and V, 23% (Fig. 2). Subject age correlated with PG1 level (r2 ⫽ 0.22, p ⬍ 0.0005) and Hp-positivity (40.5 ⫾ 3.8 yr for Hp-positive vs 24.6 ⫾ 2.2 for Hp-negative, p ⬍ 0.005). Review of the PG1 levels in the pedigree reveals that three of six subjects in generation III had elevated PG1 levels, and all three were Hp-seropositive. In generation IV,
six of 13 offspring of members with elevated PG1also had elevated PG1. Five of the six were Hp-seropositive. In generation V, none of the 13 offspring of members with elevated PG1 had elevated levels. Ten were tested for Hp, and all 10 were seronegative. Correlation of Hp-seropositivity between parents and offspring was performed. Serum was available from 16 spouses of members of the lineage, 11 of whom were Hp-seropositive. When one or more parent was Hp seropositive, 16 of 32 offspring were also Hp-seropositive. When neither parent was Hp seropositive, none of 6 offspring were seropositive (p ⬍ 0.05).
Figure 2. Helicobacter pylori infection and increased PG1 levels by generation. The prevalence of elevated PG1 levels and H. pylori serum antibodies is lower in each of three successive generations (III, IV, V) of this pedigree.
AJG – April, 2000
DISCUSSION The concept of autosomal dominant inheritance of elevated PG1 was based on pedigree analysis of two families in which duodenal ulcers were prevalent. Because Hp infection is known to be associated with elevated PG1 levels and to be a risk factor for duodenal ulcers, we postulated that Hp may be the cause of elevated PG1 in this pedigree. The larger of the two families had serum tested for Hp. All but one subject (90%) with elevated PG1 was seropositive for Hp, compared with only 30% of those with normal PG1. There also was a significant elevation in mean PG1 levels in this family when Hp antibodies were present in the serum. It is established that the seroprevalence for Hp antibodies increases with age (7, 8). In this pedigree, generational and agerelated prevalence of Hp seropositivity and elevated PG1 run in parallel. Review of the pedigree shows that elevated PG1 was present in none of 13 of the last generation who were children of members of the lineage with elevated PG1. If analysis is limited to those ⬎14 yr (an age when PG1 levels should have reached the adult maximum (6), none of five had elevated PG1. None of these 13 were Hp-seropositive. These findings suggest that Hp infection was the etiology of the elevated PG1 levels in this family. Several investigators have demonstrated that eradication of Hp with antibiotics in patients with dyspepsia or ulcer disease leads to a significant drop in serum PG1 levels, often from levels ⬎100 ng/ml to normal levels (9 –12). The mechanisms by which Hp infection elevates PG1 levels is not known; however, it may relate to increased production of PG1. Pepsinogen gene expression in rats has been shown to be inducible by Helicobacter felis gastric infection (13). Alternatively, inflammation induced by the organism may allow more PG1 to diffuse through injured chief cell walls into the serum. Isolated guinea pig chief cells express TNF receptors and undergo cell death with pepsinogen release after exposure to TNF (14). In humans, Helicobacter strains that are positive for the Cag-A protein are associated with greater gastric inflammation and higher PGI levels than Cag-A–negative strains, supporting the link between gastric inflammation and serum PGI elevation (15). Other factors that may influence serum pepsinogen levels include cigarette smoking, vagal tone and psychological distress (16, 17). The influence of cigarette smoking on PGI elevation is somewhat controversial, with some studies showing higher PGI levels in smokers (17) and others not (16, 18). This association is complicated by an increased prevalence of HP infection among smokers (19, 20). We did not have access to information about smoking or psychological states of the subjects and, therefore, could not address these issues. An inherited increase in PG1 levels is unlikely to be the explanation for the elevated levels seen in this pedigree, although genetic susceptibility to Hp-induced PG1 elevation is conceivable. As well, there may be genetic determinants of parietal cell mass associated with higher PG1 levels.
Familial Hyperpepsinogenemia and H. pylori
945
However, any analysis of PG1 level inheritance must take Hp infection into account. Evaluation of the families within this pedigree also suggests that the Hp status of parents influences the Hp status of the offspring. Drum et al. have also demonstrated intrafamilial clusters of Hp infection (21). Vertical transmission is possible. Alternatively parents, and children share behaviors and household exposures that promote Hp infection. Reprint requests and correspondence: Howard Mertz, M.D., Assistant Professor of Medicine, 1501 TVC, Vanderbilt University Medical Center, Nashville, TN 37232–5280. Received May 3, 1999; accepted Dec. 29, 1999.
REFERENCES 1. Samloff IM, Secrist DM, Passaro E Jr. A study of the relationship between serum group I pepsinogen levels and gastric acid secretion. Gastroenterology 1975;69:1198 –2000. 2. Waldum HL, Burhol PG, Straume BK. Serum group I pepsinogens and gastrin in relation to gastric H⫹ and pepsin outputs before and after subcutaneous injection of pentagastrin. Scand J Gastroenterol 1978;13:943– 6. 3. Rotter JI, Sones JQ, Samloff IM, et al. Duodenal-ulcer disease associated with elevated serum pepsinogen I: An inherited autosomal disorder. N Engl J Med 1979;300:63– 6. 4. Marshall BJ, Goodwin CS, Warren JR, et al. Prospective double-blind trial of duodenal ulcer relapse after eradication of Campylobacter pylori. Lancet 1988;2:1437– 42. 5. Karnes WE Jr, Ohning GV, Stynik BV, et al. Elevation of meal-stimulated gastrin release in subjects with Helicobacter pylori infection: Reversal by low intragastric pH. Rev Infect Dis 1991;13:S665–70. 6. Samloff IM, Liebman WM, Panitch NM. Serum group I pepsinogens by radioimmunoassay in control subjects and patients with peptic ulcer. Gastroenterology 1975;69:83–90. 7. Jones DM, Eldridge J, Fox AJ, et al. Antibody to the gastric campylobacter-like organism (Campylobacter pylori-dis)– Clinical correlations and distribution in the normal population. J Med Microbiol 1986;22:57– 62. 8. Perez-Perez GI, Sworkin BM, Chodos JE, et al. Campylobacter pylori antibodies in humans. Ann Intern Med 1988; 109:11–7. 9. Oderda G, Holton J, Altare F, et al. Amoxycillin plus tinidazole Campylobacter pylori gastritis in children: Assessment by serum IgG antibody, pepsinogen I, and gastrin levels. Lancet 1989;1:690 –2. 10. Parente F, Maconi G, Sangaletti O, et al. Behavior of acid secretion, gastrin release serum pepsinogen I, and gastric emptying of liquids over six months from eradication of Helicobacter pylori in duodenal ulcer patients. A controlled study. Gut 1995;37:210 –5. 11. Maconi G, Lazzaroni M, Sangaletti O, et al. Effect of Helicobactor pylori eradication on gastric histology, serum gastrin and pepsinogen I levels and gastric emptying in patients with gastric ulcer. Am J Gastroenterol 1997;92:1844 – 8. 12. Perez-Paramo M, Albillos A, Calleja J, et al. Changes in gastrin and serum pepsinogens in monitoring of Helicobacter pylori response to therapy. Dig Dis Sci 1997;42:1734 – 40. 13. Kishi K, Kinoshita Y, Matsushima Y, et al. Pepsinogen C gene product is a possible growth factor during gastric mucosal healing. Biochem Biophys Res Comm 1997;238:17–20. 14. Fiorucci S, Santucci L, Migliorati G, et al. Isolated guinea
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pig gastric chief cells express tumor necrosis factor receptors coupled with the spingomyelin pathway. Gut 1996;38: 182–9. 15. Parente F, Imbesi V, Maconi G, et al. Influence of bacterial CagA status on gastritis, gastric function indices, and pattern of symptoms in H. pylori-positive dyspeptic symptoms. Am J Gastroenterol 1998;93:1073–9. 16. Walker P, Luther J, Samloff M, et al. Life events stress and psychological factors in men with peptic ulcer disease. Gastroenterology 1988;94:323–30. 17. Parente F, Lazzaroni M, Sangaletti O, et al. Cigarette smoking, gastric acid secretion and serum pepsinogen I concentrations in duodenal ulcer patients. Gut 1985;26:1327–32.
AJG – Vol. 95, No. 4, 2000
18. Sumii K, Kimura M, Morikawa A, et al. Recurrence of duodenal ulcer and elevated serum pepsinogen I levels in smokers and nonsmokers. Am J Gastroenterol 1990;85:1493–7. 19. Lin SK, Lambert JR, Nicholson L, et al. Prevalence of Helicobacter pylori in a representative Anglo-Celtic population of urban Melbourne. J Gastroenterol Hepatol 1998; 13:505–10. 20. Gohl KL. Prevalence of risk factors for Helicobacter pylori infection in a multi-racial dyspeptic Malaysian population undergoing endoscopy. J Gastroenterol Hepatol 1997;12:29 –35. 21. Drumm B, Perez-Perez G, Blaser M, et al. Intrafamilial clustering of Helicobacter pylori infection. N Engl J Med 1990; 322:359 – 63.