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Blood pepsinogen as a subclinical marker for duodenal ulcer
CURRENT THERAPEUTIC RESEARCH VOL. 54, NO. 2, AUGUST1993
BLOOD P E P S I N O G E N AS A SUBCLINICAL MARKER FOR DUODENAL U L C E R P. DOTTO, 1 F. VIANELLO, 1 T. DEL BIANCO, 1 G. LAINO, 1 G. BATTAGLIA,2 M. GION, 3 S. KUSSTATSCHER, 1 G. DEL FAVER0,1 M. PLEBANI,4 AND F. DI MARIO 1
~Gastroenterology Department, University of Padua, Padua, 2Gastroenterology and 3Radioimmunology Departments, Venice General Hospital, Venice, and 4Clinical Chemistry Department, University of Padua, Padua, Italy
ABSTRACT Genetic factors, p a r t i c u l a r l y group A pepsinogen (PGA) a n d c e r t a i n blood groups, seem to play a considerable part in the heterogeneity of ulcer disease, especially with regard to d u o d e n a l ulcer. The a i m of this study was to evaluate s e r u m PGA levels both in patients with duodenal ulcer a n d in various family members, thereby c o n f i r m i n g possible corr e l a t i o n s between duodenal ulcer and m e m b e r s h i p in a given blood group. Serum PGA levels were found to be higher in duodenal ulcer p a t i e n t s t h a n in control subjects, whereas relatives of ulcer carriers had i n t e r m e d i a t e levels. B e l o n g i n g to a n y given blood group did n o t i n f l u e n c e PGA levels in the three groups considered. Blood groups and PGA m a y therefore be considered separate subclinical m a r k e r s for peptic ulcer, a l t h o u g h f u r t h e r prospective studies are w a r r a n t e d before P G A is to be considered as a prognostic m a r k e r for the onset of ulcer disease in h e a l t h y individuals. INTRODUCTION
Genetic factors play a considerable role in the heterogeneity of ulcer disease, particularly of duodenal ulcer (DU). Certain genetic markers for DU have been proposed, especially group A pepsinogen (PGA). 1 A high family predisposition for ulcer disease has also been reported, 2 with close relatives showing a frequency of ulcer development two to three times higher than in the population at large. 3'4 Other genetic risk factors include belonging to a particular h u m a n leukocyte antigen (HLA) system 5'6 or to the blood group 0 7's and an association with the Lewis [Le(a-b-)] blood group system. 9 The aim of this study was to measure serum PGA levels in DU patients and their relatives, contrasting these with levels found in a group of healthy control individuals, and to evaluate any correlation with membership in one or another particular blood group. Address correspondenceto: FrancescoDi Mario, M.D., Cattedra Malattie Apparato Digerente,VI Piano Monoblocco,Via Giustiniani, 2, 35128 Padua, Italy. Received for publication on August 10, 1992. Printed in the U.S.A. Reproductionin whole or part is not permitted. 172
0011-393X/93/$3.50
P. DOTTOET AL.
MATERIALS AND METHODS
Serum PGA (radioimmunoassay method, ~g/L) and blood groups (Ortho Diagnostic Systems Inc., Raritan, New Jersey) were verified in 34 DU patients (19 male, 15 female; age range, 28 to 84 years), in 81 first- and second-degree relatives of these patients (50 male, 31 female; age range, 7 to 79 years), and in a control group of 150 individuals (68 male, 82 female; age range, 16 to 78 years) with no history of any gastrointestinal pathology and yielding normal results on routine laboratory blood testing. Results were reported as mean +- one standard deviation; statistical analysis was performed by Student's t test. Informed consent was provided by all study participants. RESULTS
Serum PGA levels proved significantly higher in the DU patients than in the control group (Table I); levels of the ulcer patients' relatives were intermediate values, lower than those of the patients themselves but higher than control levels (Table I). These differences persisted when the groups were further divided according to sex. This trend was not influenced by age, remaining similar among control subjects and family members in the various age brackets (as shown in Figure 1). Table II illustrates the distribution of blood groups among DU patients, their relatives, and the control group. Belonging to different blood groups was not found to correlate with variation in PGA levels of either control subjects or family members. PGA concentrations were always higher in patients' relatives than in control subjects, regardless of their respective blood groups (Figure 2). DISCUSSION
Numerous studies have confirmed clinically a genetic pathogenesis for ulcer disease, particularly for duodenal ulcer. ~'7 In homozygous twins, conTable I. Mean (-+SE) serum PGA levels (~g/L) in patients with duodenal ulcer (DU), in patients' family members (F), and in healthy controls (C).
DU F C *P i P $P §P
< < < <
Total
Males
Females
107.2 -+ 59.5*'§ 75.8 + 27.6"§ 48.5 -+ 21.9"
108.2 _+ 58.3* 86,3 +- 30.41" 51.5 - 20,8""i"
105.9 -+ 56,3* 64.2 -+ 24.6:~ 52.0 +- 23.4",$
0.0005 versus control individuals. 0.025 versus control individuals. 0.01 versus control individuals. 0.01 versus relatives.
173
BLOOD PEPSINOGEN AS SUBCLINICAL MARKER FOR DU
100
==Control ,c..... 1~ Patients' 80 ._1 :d_
60
,< L.~ 40 (2_
20
0
/
<10
F
11-20
21-30
31-40
41-50
51-60
Age Brackets (yr)
61-70
>70
Figure 1. Levels of serum pepsinogen A (PGA) in control group and in family members of patients with duodenal ulcer in the various age brackets.
cordance for ulcer is less than 100% but is nonetheless higher than in dizygotic twins. 3'4 It has also been shown that belonging to blood group O and having nonsecretory status, 7,s as well as the presence of urinary pepsinogen isoenzyme 51°'11 or of the histocompatibility antigens HLA B5, B22, or BW355'6'12 are associated with a relatively higher risk of ulcer. Analyses of the genetic origin of certain physiologic anomalies typical of ulcer patients (subclinical markers), such as high serum PGA, 18'14 have also been reported. In fact, the Rotter group has shown that ulcer patients may feature either high (in 50% of the cases studied) or normal PGA levels, the former phenotype inherited as a dominant autosomal characteristic. 15'16 A similar study 17 that measured total serum pepsinogen demonstrated that about 80% of DU patients had high blood pepsinogen levels and about 60% of their relatives had similarly high levels of the zymogen.
Table II. Blood group distribution among duodenal ulcer patients, their relatives, and healthy controls. Blood Group
Patients (%)
Relatives (%)
Controls (%)
A B 0 AB
31.7 21.1 44.7 2.5
28 14 53 5
4O 11.1 45 3.9
174
P. DOTTOET AL.
100
• Control group D,~
I.; ,-, ~, I.~, ~ #..~ v~
; I ;~
80
._I "O3 60-
::t.
<
0
4o-
n
20-
A
B
0
AB
Blood Groups Figure 2. Levels of s e r u m pepsinogen A (PGA) in control group and in family members of patients with duodenal ulcer in relation to blood groups.
The same investigators 17 also reported a relationship between belonging to blood group O and high PGA levels. Like other works in the literature, 13'14 our study confirms that DU patients have high mean levels of PGA; however, the most interesting point raised herein is confirmation of a PGA secretion gradient, with higher levels in ulcer patients than in their relatives, and in turn, higher levels in those relatives than in control subjects. This clearly demonstrates the importance of genetic factors in the pathogenesis of duodenal ulcer. Unlike certain other reports, 17 our study found no association between PGA levels and blood group O. As for the influence of the blood group, an association between blood group O and DU has been reported, s b u t there are no reports of this trend in ulcer patients' families. Our own findings suggest that (1) family members have the same blood group distribution found in DU patients, with group O as most common; and that (2) there is no correlation between blood group and PGA. Thus blood groups and PGA may be independent subclinical markers for ulcer. These findings lead us to conclude that it would be useful to study PGA separately as a subclinical marker for ulcer disease. There is need for further prospective studies to evaluate PGA as a potential prognostic m a r k e r for the onset of ulcer lesions in healthy individuals. References: 1. Rotter JI, Rimoin DL, Samloff IM. Genetic heterogeneity in peptic ulcer. Lancet 1979; 1:1088-1089. 175
BLOODPEPSINOGENASSUBCLINICALMARKERFORDU
2. Rotter JI, Grossman MI. Genetic aspects of ulcer disease. In: Holtermuller KH, Malagelada JR, eds. Advances in ulcer disease. Amsterdam: Excerpta Medica, 1980:7-26. 3. Rotter JI. Peptic ulcer. In: Emeri AEH, Rimoin DL, eds. The principles and practice of medical genetics. Edinburgh: Churchill Livingstone, 1983:863-878. 4. Gotlieb-Jensen K. Peptic ulcer: Genetic and epidemiologic aspects based on twin studies. Copenhagen: Munksgard, 1972. 5. Rotter JI, Rimoin DL, Gursky JM, et al. HLA B5 associated with duodenal ulcer. Gastroenterology 1977; 73:438-440. 6. Venturi C, Bortolami M, Di Mario F, et al. Serum pepsinogen I levels and HLA B22: A genetic association in a subgroup of duodenal ulcer patients. Ital J Gastroenterol 1986; 18:77-78. 7. McConnell RB. Gastric and duodenal ulcer. In: The genetics of gastrointestinal disorders. London: Oxford University Press, 1966:76-105. 8. Clarke CA, Wyn Edwards J, Haddock DRW, et al. ABO blood and secretor character in duodenal ulcer. BMJ 1956; 2:725-727. 9. Battaglia G, Di Mario F, Farini R, et al. Blood groups in gastric and duodenal ulcer: Distribution and correlation with gastric functional parameters. IRCS Med Sci 1984; 12:354-355. 10. Samloff IM, Townes PL. Pepsinogens. Genetic polymorphism in man. Science 1970; 168: 144-145. 11. Samloff IM, Cole D. Pepsinogens, phenotypes, and ABO blood groups in controls and patients with duodenal ulcer. (Abstract) Gastroenterology 1975; 68:980/A123. 12. Gough MJ, Giles GR. HLA antigens in duodenal ulceration. Gut 1979; 20:1919-1920. 13. Samloff IM, Liebman WM, Panitch NM. Serum group I pepsinogens by radio-immunoassay in control subjects and patients with peptic ulcer. Gastroenterology 1975; 69:83-90. 14. Di Mario F, Plebani M, Vianello F, et al. Total serum pepsinogen: A reliable gastric secretory parameter? A study in peptic ulcer patients and normal subjects. Ital J Gastroenterol 1982; 14:71-75. 15. Rotter JI, Sones JQ, Samloff IM, et al. Duodenal ulcer disease associated with elevated serum pepsinogen I. An inherited autosomal dominant disorder. New Engl J Med 1979; 300:63-66. 16. Rotter JI, Petersen GN, Samloff IM, et al. Genetic heterogeneity of familial hyperpepsinogenemic I and normopepsinogenemic I duodenal ulcer disease. Ann Intern Med 1979; 91:372-377. 17. Habibullah CM, Mujahid AM, Ishaq M, et al. Study of duodenal ulcer disease in 100 families using total serum pepsinogen as a genetic marker. Gut 1984; 25:1380-1383.
176
BLOOD P E P S I N O G E N AS A SUBCLINICAL MARKER FOR DUODENAL U L C E R P. DOTTO, 1 F. VIANELLO, 1 T. DEL BIANCO, 1 G. LAINO, 1 G. BATTAGLIA,2 M. GION, 3 S. KUSSTATSCHER, 1 G. DEL FAVER0,1 M. PLEBANI,4 AND F. DI MARIO 1
~Gastroenterology Department, University of Padua, Padua, 2Gastroenterology and 3Radioimmunology Departments, Venice General Hospital, Venice, and 4Clinical Chemistry Department, University of Padua, Padua, Italy
ABSTRACT Genetic factors, p a r t i c u l a r l y group A pepsinogen (PGA) a n d c e r t a i n blood groups, seem to play a considerable part in the heterogeneity of ulcer disease, especially with regard to d u o d e n a l ulcer. The a i m of this study was to evaluate s e r u m PGA levels both in patients with duodenal ulcer a n d in various family members, thereby c o n f i r m i n g possible corr e l a t i o n s between duodenal ulcer and m e m b e r s h i p in a given blood group. Serum PGA levels were found to be higher in duodenal ulcer p a t i e n t s t h a n in control subjects, whereas relatives of ulcer carriers had i n t e r m e d i a t e levels. B e l o n g i n g to a n y given blood group did n o t i n f l u e n c e PGA levels in the three groups considered. Blood groups and PGA m a y therefore be considered separate subclinical m a r k e r s for peptic ulcer, a l t h o u g h f u r t h e r prospective studies are w a r r a n t e d before P G A is to be considered as a prognostic m a r k e r for the onset of ulcer disease in h e a l t h y individuals. INTRODUCTION
Genetic factors play a considerable role in the heterogeneity of ulcer disease, particularly of duodenal ulcer (DU). Certain genetic markers for DU have been proposed, especially group A pepsinogen (PGA). 1 A high family predisposition for ulcer disease has also been reported, 2 with close relatives showing a frequency of ulcer development two to three times higher than in the population at large. 3'4 Other genetic risk factors include belonging to a particular h u m a n leukocyte antigen (HLA) system 5'6 or to the blood group 0 7's and an association with the Lewis [Le(a-b-)] blood group system. 9 The aim of this study was to measure serum PGA levels in DU patients and their relatives, contrasting these with levels found in a group of healthy control individuals, and to evaluate any correlation with membership in one or another particular blood group. Address correspondenceto: FrancescoDi Mario, M.D., Cattedra Malattie Apparato Digerente,VI Piano Monoblocco,Via Giustiniani, 2, 35128 Padua, Italy. Received for publication on August 10, 1992. Printed in the U.S.A. Reproductionin whole or part is not permitted. 172
0011-393X/93/$3.50
P. DOTTOET AL.
MATERIALS AND METHODS
Serum PGA (radioimmunoassay method, ~g/L) and blood groups (Ortho Diagnostic Systems Inc., Raritan, New Jersey) were verified in 34 DU patients (19 male, 15 female; age range, 28 to 84 years), in 81 first- and second-degree relatives of these patients (50 male, 31 female; age range, 7 to 79 years), and in a control group of 150 individuals (68 male, 82 female; age range, 16 to 78 years) with no history of any gastrointestinal pathology and yielding normal results on routine laboratory blood testing. Results were reported as mean +- one standard deviation; statistical analysis was performed by Student's t test. Informed consent was provided by all study participants. RESULTS
Serum PGA levels proved significantly higher in the DU patients than in the control group (Table I); levels of the ulcer patients' relatives were intermediate values, lower than those of the patients themselves but higher than control levels (Table I). These differences persisted when the groups were further divided according to sex. This trend was not influenced by age, remaining similar among control subjects and family members in the various age brackets (as shown in Figure 1). Table II illustrates the distribution of blood groups among DU patients, their relatives, and the control group. Belonging to different blood groups was not found to correlate with variation in PGA levels of either control subjects or family members. PGA concentrations were always higher in patients' relatives than in control subjects, regardless of their respective blood groups (Figure 2). DISCUSSION
Numerous studies have confirmed clinically a genetic pathogenesis for ulcer disease, particularly for duodenal ulcer. ~'7 In homozygous twins, conTable I. Mean (-+SE) serum PGA levels (~g/L) in patients with duodenal ulcer (DU), in patients' family members (F), and in healthy controls (C).
DU F C *P i P $P §P
< < < <
Total
Males
Females
107.2 -+ 59.5*'§ 75.8 + 27.6"§ 48.5 -+ 21.9"
108.2 _+ 58.3* 86,3 +- 30.41" 51.5 - 20,8""i"
105.9 -+ 56,3* 64.2 -+ 24.6:~ 52.0 +- 23.4",$
0.0005 versus control individuals. 0.025 versus control individuals. 0.01 versus control individuals. 0.01 versus relatives.
173
BLOOD PEPSINOGEN AS SUBCLINICAL MARKER FOR DU
100
==Control ,c..... 1~ Patients' 80 ._1 :d_
60
,< L.~ 40 (2_
20
0
/
<10
F
11-20
21-30
31-40
41-50
51-60
Age Brackets (yr)
61-70
>70
Figure 1. Levels of serum pepsinogen A (PGA) in control group and in family members of patients with duodenal ulcer in the various age brackets.
cordance for ulcer is less than 100% but is nonetheless higher than in dizygotic twins. 3'4 It has also been shown that belonging to blood group O and having nonsecretory status, 7,s as well as the presence of urinary pepsinogen isoenzyme 51°'11 or of the histocompatibility antigens HLA B5, B22, or BW355'6'12 are associated with a relatively higher risk of ulcer. Analyses of the genetic origin of certain physiologic anomalies typical of ulcer patients (subclinical markers), such as high serum PGA, 18'14 have also been reported. In fact, the Rotter group has shown that ulcer patients may feature either high (in 50% of the cases studied) or normal PGA levels, the former phenotype inherited as a dominant autosomal characteristic. 15'16 A similar study 17 that measured total serum pepsinogen demonstrated that about 80% of DU patients had high blood pepsinogen levels and about 60% of their relatives had similarly high levels of the zymogen.
Table II. Blood group distribution among duodenal ulcer patients, their relatives, and healthy controls. Blood Group
Patients (%)
Relatives (%)
Controls (%)
A B 0 AB
31.7 21.1 44.7 2.5
28 14 53 5
4O 11.1 45 3.9
174
P. DOTTOET AL.
100
• Control group D,~
I.; ,-, ~, I.~, ~ #..~ v~
; I ;~
80
._I "O3 60-
::t.
<
0
4o-
n
20-
A
B
0
AB
Blood Groups Figure 2. Levels of s e r u m pepsinogen A (PGA) in control group and in family members of patients with duodenal ulcer in relation to blood groups.
The same investigators 17 also reported a relationship between belonging to blood group O and high PGA levels. Like other works in the literature, 13'14 our study confirms that DU patients have high mean levels of PGA; however, the most interesting point raised herein is confirmation of a PGA secretion gradient, with higher levels in ulcer patients than in their relatives, and in turn, higher levels in those relatives than in control subjects. This clearly demonstrates the importance of genetic factors in the pathogenesis of duodenal ulcer. Unlike certain other reports, 17 our study found no association between PGA levels and blood group O. As for the influence of the blood group, an association between blood group O and DU has been reported, s b u t there are no reports of this trend in ulcer patients' families. Our own findings suggest that (1) family members have the same blood group distribution found in DU patients, with group O as most common; and that (2) there is no correlation between blood group and PGA. Thus blood groups and PGA may be independent subclinical markers for ulcer. These findings lead us to conclude that it would be useful to study PGA separately as a subclinical marker for ulcer disease. There is need for further prospective studies to evaluate PGA as a potential prognostic m a r k e r for the onset of ulcer lesions in healthy individuals. References: 1. Rotter JI, Rimoin DL, Samloff IM. Genetic heterogeneity in peptic ulcer. Lancet 1979; 1:1088-1089. 175
BLOODPEPSINOGENASSUBCLINICALMARKERFORDU
2. Rotter JI, Grossman MI. Genetic aspects of ulcer disease. In: Holtermuller KH, Malagelada JR, eds. Advances in ulcer disease. Amsterdam: Excerpta Medica, 1980:7-26. 3. Rotter JI. Peptic ulcer. In: Emeri AEH, Rimoin DL, eds. The principles and practice of medical genetics. Edinburgh: Churchill Livingstone, 1983:863-878. 4. Gotlieb-Jensen K. Peptic ulcer: Genetic and epidemiologic aspects based on twin studies. Copenhagen: Munksgard, 1972. 5. Rotter JI, Rimoin DL, Gursky JM, et al. HLA B5 associated with duodenal ulcer. Gastroenterology 1977; 73:438-440. 6. Venturi C, Bortolami M, Di Mario F, et al. Serum pepsinogen I levels and HLA B22: A genetic association in a subgroup of duodenal ulcer patients. Ital J Gastroenterol 1986; 18:77-78. 7. McConnell RB. Gastric and duodenal ulcer. In: The genetics of gastrointestinal disorders. London: Oxford University Press, 1966:76-105. 8. Clarke CA, Wyn Edwards J, Haddock DRW, et al. ABO blood and secretor character in duodenal ulcer. BMJ 1956; 2:725-727. 9. Battaglia G, Di Mario F, Farini R, et al. Blood groups in gastric and duodenal ulcer: Distribution and correlation with gastric functional parameters. IRCS Med Sci 1984; 12:354-355. 10. Samloff IM, Townes PL. Pepsinogens. Genetic polymorphism in man. Science 1970; 168: 144-145. 11. Samloff IM, Cole D. Pepsinogens, phenotypes, and ABO blood groups in controls and patients with duodenal ulcer. (Abstract) Gastroenterology 1975; 68:980/A123. 12. Gough MJ, Giles GR. HLA antigens in duodenal ulceration. Gut 1979; 20:1919-1920. 13. Samloff IM, Liebman WM, Panitch NM. Serum group I pepsinogens by radio-immunoassay in control subjects and patients with peptic ulcer. Gastroenterology 1975; 69:83-90. 14. Di Mario F, Plebani M, Vianello F, et al. Total serum pepsinogen: A reliable gastric secretory parameter? A study in peptic ulcer patients and normal subjects. Ital J Gastroenterol 1982; 14:71-75. 15. Rotter JI, Sones JQ, Samloff IM, et al. Duodenal ulcer disease associated with elevated serum pepsinogen I. An inherited autosomal dominant disorder. New Engl J Med 1979; 300:63-66. 16. Rotter JI, Petersen GN, Samloff IM, et al. Genetic heterogeneity of familial hyperpepsinogenemic I and normopepsinogenemic I duodenal ulcer disease. Ann Intern Med 1979; 91:372-377. 17. Habibullah CM, Mujahid AM, Ishaq M, et al. Study of duodenal ulcer disease in 100 families using total serum pepsinogen as a genetic marker. Gut 1984; 25:1380-1383.
176