Altered Serum Gastrin Levels in Achlorhydric States William D. TurnIpseed, MD, Madison, Wisconsin Luther M. Keith, Jr, MD, Columbus, Ohio
There is an ever burgeoning interest in the significance of serum gastrin levels of patients with gastrointestinal disease. Hypergastrinemia, most commonly associated with the Zollinger-Ellison syndrome, paradoxically occurs in certain achlorhydric states, particularly pernicious anemia and atrophic gastritis. Moreover, calcium challenge elicits a dramatic elevation in already high basal gastrin levels found in untreated patients vitith Zollinger-Ellison syndrome or those with residual or metastatic non-beta cell gastrin-producing tumors. Also, transient brisk elevations in gastrin levels consistently accompany secretin infusion in these patients. Because the response of basal hypergastrinemia to calcium and secretin infusion in patients with achlorhydria and the relationship of gastrin levels to antral pH have not been previously reported, this investigation was designed to study the effect of calcium and secretin infusion on serum gastrin concentrations in achlorhydric patients and to confirm the relationship between altered gastric pH and hypergastrinemia in achlorhydric states. Material and Methods Fifteen patients with histamine-fast achlorhydria (six with pernicious anemia and nine with atrophic gastritis) were compared with fifteen control patients free of upper gastrointestinal disease who had normal gastric acid secretion and pH. The Squibb” immunoassay technic was used to determine mean fasting gastrin concentrations by triplicate analysis of serum from each patient in the achlorhydric and control study groups. Mean age-group gastrin determinations were made in fifty patients selected at random who had no known gastrointestinal disease. The ten males and five females with achlorhydria had a mean age of 60 years. The following procedures were used: upper gastrointestinal and small bowel radiography, gastric endoscopy, determination of serum folate and vitamin Bi2 levels, immunoelectrophoresis, and
serum anti-intrinsic factor antibody titers. Calcium and secretin infusions were performed to determine serum gastrin response in eight achlorhydric patients and in eight normal controls. Under fasting conditions, each patient was given a 500 cc solution of intravenous calcium (elemental Ca++, 15 mg per kg of body weight) as calcium gluconate over a 4 hour period and serum samples were obtained each hour. Jorpes secretin (1 clinical unit per kg) was infused during a 1 hour period and blood samples were obtained every 15 minutes during the infusion and for 1 hour after. Achlorhydric patients were sorted into the following subgroups according to the presence or absence of antral gastritis: group I, pernicious anemia without antral gastritis (4); group II, pernicious anemia with antral gastritis (2); group III, atrophic gastritis without antral involvement (6); group IV, atrophic gastritis with antral involvement (1). Fasting serum gastrin levels and gastrin response to calcium and secretin infusion were determined in each group. Statistical group comparisons were made by means oft test analysis.
Results The six achlorhydric patients with pernicious anemia and seven of the nine patients with atrophic gastritis had normal upper gastrointestinal and small bowel series. In the remaining two patients with atrophic gastritis, large antral polyps were demonstrated by x-ray film. Endoscopic examination demonstrated atrophic mucosal changes in the fundus and body of the stomach in all patients with both pernicious anemia and atrophic gastritis. Severe degenerative mucosal changes were observed in the antral portion of the stomach in two of six patients with pernicious anemia and in three of nine patients with atrophic gastritis. All patients with pernicious anemia had abnormal Shillings test results (less than 10 per cent), megaloblastic marrow changes, and positive anti-intrinsic factor antibody titers. Gastric pH in the achlorhydric group ranged from 6.0 to 8.1 with a mean of 7.1 f 0.2, whereas the mean
From ths Department of Surgery, The Chii State University College of Medkii, Columbus, Chio. Reprint requests should be addressed to Luther M. Keith, Jr, MD. The Chii State University Hospital. 410 West Tenth Avenue, Columbus, Ohio 43210.
Vofums 131, February 1976
pH for the control
group
was 1.9 f 0.1.
Basal gastrin levels in achlorhydric patients were significantly higher than in patients with normal gastric
acid production
pg/ml
f
8). (Figure
(891 pg/ml 1.) Basal
f 282 versus 84
gastriri
levels in pa-
175
Turnipseed and Keith
Gastrin
T
pg/ml
BASAL GASTRIN Antrum Normal
Achlor I hydria
1000
BASAL
Gastrin
GASTRIN
pg/mkrnicious Anemia Atrophic Gastritis NormlAnt Antritis Norm Ant Antritis 2000 1000
500
500 150
150
L
Figure 1. In the presence of a normal antrum, achforhydr& patients have higher gastrin levels than the controls.
tients with antral gastritis (groups II and IV) averaged 197 pg/ml f 19, whereas patients without antral gastritis (groups I and III) averaged 1,509 pg/ml f 426. The difference is significant. (Figure 2.) In the absence of antral gastritis, mean basal gastrin values were 1,825 pg/ml f 63 for patients with pernicious anemia and 1,192 pg/ml f 620 in those with atrophic gastritis. The gastrin concentration in the sixth-decadeage control group was 49 pg/ml f 6, which was comparable to determined gastrin levels in the other age groups. There was no evidence that gastrin levels increase with progressing age. Eight achlorhydric patients-group I (3); group II (2); group III (1); group IV (2)-and eight normal controls were challenged with an intravenous calcium stimulus. A dramatic response in gastrin levels (greater than 200 per cent increase) to calcium infusion was noted in group I but not in the other study groups or controls. (Figures 3 and 4.) Stimulation ratios-maximal gastrin level (MGL)
PERNICIOUS ANEMIA Calcium Infusion 1 4 hrs 1
Gastrin pg/ml
Antritis
Figure 2. Achiorhydric patients with pernicious anemia or atrophic gastritis do not have high gastrin ieveis when antrai gastritis is present.
divided by basal gastrin level (BGL)-determined for each group confirmed an impressive difference in response to calcium: group I, 2.1; group II, 1.1; group III, 1.2; group IV, 1.0; controls, 1.1. Gastrin levels were depressed 25 to 35 per cent by secretin infusion in both achlorhydric patients and normal controls [I].
Comments Most patients with achlorhydria have basal gastrin levels which are elevated in relation to intragastric pH and are inversely related to the acid secretory capacity of the stomach [2-51. Gastric achlorhydria, however, is not invariably associated with hypergastrinemia and substantial evidence now exists to suggest that gastrin production is related to the degree of antral gastritis present [2,6-81. Data from this study clearly support the observation by earlier investigators that gastric pH directly influences production and/or release of
Gastrin pg/ml 1500
ATROPIIIC GASTRITIS Calcium Infusion ( 4 hrs 1 Normal Antrum
Inflamed Antrum
1000 500 150
t... I
12345
12345
Figure 3. Calcium infusion elicits a hypergastrinemia response in patients with pernicious anemia in the absence of antrai gastritis.
176
II
______________________.____ _L._.__?%sErb
12345
12345
Figure 4. Calcium infusion elicits a slight gastrin response in patients with atrophic gastritis if the antrum is spared.
The American Journal of Surgery
Attered Serum Gastrin Levels
gastrin and tend to support the concept that the existence of severe antral disease suppresses gastrin levels. In the absence of antral gastritis there is no significant difference in basal gastrin levels between achlorhydric patients with pernicious anemia and those with atrophic gastritis (1,825 pg/ml f 630 versus 1,192 pg/ml f 620). However, when antral gastritis is present in achlorhydric patients with either disease, much lower gastrin levels are consistently observed (174 pg/ml f 22 versus 205 pg/ml f 38). Although autoregulation of the antral-gastrin axis is impaired in achlorhydric states, reflex mechanisms for control of gastrin release are apparently still present. It has been shown, for example, that in pernicious anemia, reacidification of the gastric antrum (pH < 4) produces gastrin levels that are depressed but not to normal levels [3]. Intravenous secretin given to the same patients induces a fail in serum gastrin below basal levels [3,5]. Other investigators have demonstrated that feeding is only a mild stimulus for gastrin response in pernicious anemia [S]. In this study, calcium challenge caused a dramatic elevation in serum gastrin levels of patients with pernicious anemia and a spared antrum. Patients with atrophic gastritis and a spared antrum showed a less impressive gastrin response to calcium stimulation. Although other investigators have suggested that cells with “endocrinelike” function exist in pernicious anemia, the only evidence contained in this study which supports that concept was the magnitude of the gastrin response to calcium stimulation [3]. In contrast to reactions observed in the Zollinger-Ellison syndrome, secretin challenge in achlorhydric patients with atrophic gastritis or pernicious anemia suppressed serum gastrin below basal levels. In conclusion, severe basal hypergastrinemia is not confined to the Zollinger-Ellison syndrome but frequently occurs in achlorhydric patients with pernicious anemia or atrophic gastritis. When the antrum is affected by gastritis, gastrin levels are
Volume 131, February 1976
much lower. The precise mechanism is unknown, but impairment of the acid inhibition reflex appears to play an important role. The dramatic response to calcium stimulation in patients with pernicious anemia also suggests the possibility that cells with endocrinelike autonomy may exist in the gastric mucosa. Indeed, calcium infusion may prove to be a useful method to confirm the diagnosis of pernicious anemia. Summary Hypergastrinemia occurs in achlorhydric states if the antrum is not diseased, and evidence has been presented that suggests that antral gastritis diminishes gastrin levels in achlorhydric patients. There is a dramatic gastrin response to calcium challenge in patients with pernicious anemia. Only minimal response was observed in patients with atrophic gastritis. Unlike the response observed in the Zollinger-Ellison syndrome, secretin challenge suppresses gastrin in achlorhydric states. These findings add a new dimension to the utility of serum gastrin determinations. References 1. TurnipseedWD, Kefth LM Jr, Takeuchi 0: Gastrin response to calcium and secretin infusion in achlorhydric patients. Surg Forum October 1976. 2. Cullen DR. Ganguli PC, Irvine WJ: Plasma gastrin concentration in pernicious anaemia and in achlorhydria without pernicious anaemia. C/in Sci 40: 3, 1971. 3. Hansky J, Korman MG, Soveny C, St. John DJB: Radioimmunoassay of gastrin: studies in pernicious anaemia. Gut 12: 97, 1971. 4. Korman MG, St. John DJB, Hansky J: Studies on serum gastrin levels in pernicious anaemia. Gut 11: 98 1, 1970. 5. McGuigan JE, Trudeau WL: Serum gastrin concentrations in pernicious anemia. N&g/J w 282: 358, 1970. 6. Ganguli PC, Henderson JT, Shearman DJC: Plasma gastrin concentration and antral histology in patients with achlorhydria. Br Sot Gestroenteroll2: 320, 1971. 7. Hughes WS, Brooks FP, Conn HO: Serum gastrin levels in primary hypogammaglobulinemia and pernicious anemia. Ann lnt Med 77: 746, 1972. 8. Strickland RG, Bhathal PS, Korman MG, Hansky J: Serum gastrin and the antral mucosa in atrophic gastriiis. Br MedJ 4: 451, 1971.
177
There is an ever burgeoning interest in the significance of serum gastrin levels of patients with gastrointestinal disease. Hypergastrinemia, most commonly associated with the Zollinger-Ellison syndrome, paradoxically occurs in certain achlorhydric states, particularly pernicious anemia and atrophic gastritis. Moreover, calcium challenge elicits a dramatic elevation in already high basal gastrin levels found in untreated patients vitith Zollinger-Ellison syndrome or those with residual or metastatic non-beta cell gastrin-producing tumors. Also, transient brisk elevations in gastrin levels consistently accompany secretin infusion in these patients. Because the response of basal hypergastrinemia to calcium and secretin infusion in patients with achlorhydria and the relationship of gastrin levels to antral pH have not been previously reported, this investigation was designed to study the effect of calcium and secretin infusion on serum gastrin concentrations in achlorhydric patients and to confirm the relationship between altered gastric pH and hypergastrinemia in achlorhydric states. Material and Methods Fifteen patients with histamine-fast achlorhydria (six with pernicious anemia and nine with atrophic gastritis) were compared with fifteen control patients free of upper gastrointestinal disease who had normal gastric acid secretion and pH. The Squibb” immunoassay technic was used to determine mean fasting gastrin concentrations by triplicate analysis of serum from each patient in the achlorhydric and control study groups. Mean age-group gastrin determinations were made in fifty patients selected at random who had no known gastrointestinal disease. The ten males and five females with achlorhydria had a mean age of 60 years. The following procedures were used: upper gastrointestinal and small bowel radiography, gastric endoscopy, determination of serum folate and vitamin Bi2 levels, immunoelectrophoresis, and
serum anti-intrinsic factor antibody titers. Calcium and secretin infusions were performed to determine serum gastrin response in eight achlorhydric patients and in eight normal controls. Under fasting conditions, each patient was given a 500 cc solution of intravenous calcium (elemental Ca++, 15 mg per kg of body weight) as calcium gluconate over a 4 hour period and serum samples were obtained each hour. Jorpes secretin (1 clinical unit per kg) was infused during a 1 hour period and blood samples were obtained every 15 minutes during the infusion and for 1 hour after. Achlorhydric patients were sorted into the following subgroups according to the presence or absence of antral gastritis: group I, pernicious anemia without antral gastritis (4); group II, pernicious anemia with antral gastritis (2); group III, atrophic gastritis without antral involvement (6); group IV, atrophic gastritis with antral involvement (1). Fasting serum gastrin levels and gastrin response to calcium and secretin infusion were determined in each group. Statistical group comparisons were made by means oft test analysis.
Results The six achlorhydric patients with pernicious anemia and seven of the nine patients with atrophic gastritis had normal upper gastrointestinal and small bowel series. In the remaining two patients with atrophic gastritis, large antral polyps were demonstrated by x-ray film. Endoscopic examination demonstrated atrophic mucosal changes in the fundus and body of the stomach in all patients with both pernicious anemia and atrophic gastritis. Severe degenerative mucosal changes were observed in the antral portion of the stomach in two of six patients with pernicious anemia and in three of nine patients with atrophic gastritis. All patients with pernicious anemia had abnormal Shillings test results (less than 10 per cent), megaloblastic marrow changes, and positive anti-intrinsic factor antibody titers. Gastric pH in the achlorhydric group ranged from 6.0 to 8.1 with a mean of 7.1 f 0.2, whereas the mean
From ths Department of Surgery, The Chii State University College of Medkii, Columbus, Chio. Reprint requests should be addressed to Luther M. Keith, Jr, MD. The Chii State University Hospital. 410 West Tenth Avenue, Columbus, Ohio 43210.
Vofums 131, February 1976
pH for the control
group
was 1.9 f 0.1.
Basal gastrin levels in achlorhydric patients were significantly higher than in patients with normal gastric
acid production
pg/ml
f
8). (Figure
(891 pg/ml 1.) Basal
f 282 versus 84
gastriri
levels in pa-
175
Turnipseed and Keith
Gastrin
T
pg/ml
BASAL GASTRIN Antrum Normal
Achlor I hydria
1000
BASAL
Gastrin
GASTRIN
pg/mkrnicious Anemia Atrophic Gastritis NormlAnt Antritis Norm Ant Antritis 2000 1000
500
500 150
150
L
Figure 1. In the presence of a normal antrum, achforhydr& patients have higher gastrin levels than the controls.
tients with antral gastritis (groups II and IV) averaged 197 pg/ml f 19, whereas patients without antral gastritis (groups I and III) averaged 1,509 pg/ml f 426. The difference is significant. (Figure 2.) In the absence of antral gastritis, mean basal gastrin values were 1,825 pg/ml f 63 for patients with pernicious anemia and 1,192 pg/ml f 620 in those with atrophic gastritis. The gastrin concentration in the sixth-decadeage control group was 49 pg/ml f 6, which was comparable to determined gastrin levels in the other age groups. There was no evidence that gastrin levels increase with progressing age. Eight achlorhydric patients-group I (3); group II (2); group III (1); group IV (2)-and eight normal controls were challenged with an intravenous calcium stimulus. A dramatic response in gastrin levels (greater than 200 per cent increase) to calcium infusion was noted in group I but not in the other study groups or controls. (Figures 3 and 4.) Stimulation ratios-maximal gastrin level (MGL)
PERNICIOUS ANEMIA Calcium Infusion 1 4 hrs 1
Gastrin pg/ml
Antritis
Figure 2. Achiorhydric patients with pernicious anemia or atrophic gastritis do not have high gastrin ieveis when antrai gastritis is present.
divided by basal gastrin level (BGL)-determined for each group confirmed an impressive difference in response to calcium: group I, 2.1; group II, 1.1; group III, 1.2; group IV, 1.0; controls, 1.1. Gastrin levels were depressed 25 to 35 per cent by secretin infusion in both achlorhydric patients and normal controls [I].
Comments Most patients with achlorhydria have basal gastrin levels which are elevated in relation to intragastric pH and are inversely related to the acid secretory capacity of the stomach [2-51. Gastric achlorhydria, however, is not invariably associated with hypergastrinemia and substantial evidence now exists to suggest that gastrin production is related to the degree of antral gastritis present [2,6-81. Data from this study clearly support the observation by earlier investigators that gastric pH directly influences production and/or release of
Gastrin pg/ml 1500
ATROPIIIC GASTRITIS Calcium Infusion ( 4 hrs 1 Normal Antrum
Inflamed Antrum
1000 500 150
t... I
12345
12345
Figure 3. Calcium infusion elicits a hypergastrinemia response in patients with pernicious anemia in the absence of antrai gastritis.
176
II
______________________.____ _L._.__?%sErb
12345
12345
Figure 4. Calcium infusion elicits a slight gastrin response in patients with atrophic gastritis if the antrum is spared.
The American Journal of Surgery
Attered Serum Gastrin Levels
gastrin and tend to support the concept that the existence of severe antral disease suppresses gastrin levels. In the absence of antral gastritis there is no significant difference in basal gastrin levels between achlorhydric patients with pernicious anemia and those with atrophic gastritis (1,825 pg/ml f 630 versus 1,192 pg/ml f 620). However, when antral gastritis is present in achlorhydric patients with either disease, much lower gastrin levels are consistently observed (174 pg/ml f 22 versus 205 pg/ml f 38). Although autoregulation of the antral-gastrin axis is impaired in achlorhydric states, reflex mechanisms for control of gastrin release are apparently still present. It has been shown, for example, that in pernicious anemia, reacidification of the gastric antrum (pH < 4) produces gastrin levels that are depressed but not to normal levels [3]. Intravenous secretin given to the same patients induces a fail in serum gastrin below basal levels [3,5]. Other investigators have demonstrated that feeding is only a mild stimulus for gastrin response in pernicious anemia [S]. In this study, calcium challenge caused a dramatic elevation in serum gastrin levels of patients with pernicious anemia and a spared antrum. Patients with atrophic gastritis and a spared antrum showed a less impressive gastrin response to calcium stimulation. Although other investigators have suggested that cells with “endocrinelike” function exist in pernicious anemia, the only evidence contained in this study which supports that concept was the magnitude of the gastrin response to calcium stimulation [3]. In contrast to reactions observed in the Zollinger-Ellison syndrome, secretin challenge in achlorhydric patients with atrophic gastritis or pernicious anemia suppressed serum gastrin below basal levels. In conclusion, severe basal hypergastrinemia is not confined to the Zollinger-Ellison syndrome but frequently occurs in achlorhydric patients with pernicious anemia or atrophic gastritis. When the antrum is affected by gastritis, gastrin levels are
Volume 131, February 1976
much lower. The precise mechanism is unknown, but impairment of the acid inhibition reflex appears to play an important role. The dramatic response to calcium stimulation in patients with pernicious anemia also suggests the possibility that cells with endocrinelike autonomy may exist in the gastric mucosa. Indeed, calcium infusion may prove to be a useful method to confirm the diagnosis of pernicious anemia. Summary Hypergastrinemia occurs in achlorhydric states if the antrum is not diseased, and evidence has been presented that suggests that antral gastritis diminishes gastrin levels in achlorhydric patients. There is a dramatic gastrin response to calcium challenge in patients with pernicious anemia. Only minimal response was observed in patients with atrophic gastritis. Unlike the response observed in the Zollinger-Ellison syndrome, secretin challenge suppresses gastrin in achlorhydric states. These findings add a new dimension to the utility of serum gastrin determinations. References 1. TurnipseedWD, Kefth LM Jr, Takeuchi 0: Gastrin response to calcium and secretin infusion in achlorhydric patients. Surg Forum October 1976. 2. Cullen DR. Ganguli PC, Irvine WJ: Plasma gastrin concentration in pernicious anaemia and in achlorhydria without pernicious anaemia. C/in Sci 40: 3, 1971. 3. Hansky J, Korman MG, Soveny C, St. John DJB: Radioimmunoassay of gastrin: studies in pernicious anaemia. Gut 12: 97, 1971. 4. Korman MG, St. John DJB, Hansky J: Studies on serum gastrin levels in pernicious anaemia. Gut 11: 98 1, 1970. 5. McGuigan JE, Trudeau WL: Serum gastrin concentrations in pernicious anemia. N&g/J w 282: 358, 1970. 6. Ganguli PC, Henderson JT, Shearman DJC: Plasma gastrin concentration and antral histology in patients with achlorhydria. Br Sot Gestroenteroll2: 320, 1971. 7. Hughes WS, Brooks FP, Conn HO: Serum gastrin levels in primary hypogammaglobulinemia and pernicious anemia. Ann lnt Med 77: 746, 1972. 8. Strickland RG, Bhathal PS, Korman MG, Hansky J: Serum gastrin and the antral mucosa in atrophic gastriiis. Br MedJ 4: 451, 1971.
177
