Morphology of the Gastric Mucosa in Patients with Ulcer Diseases JERRY S. TRIER, MD
NORMAL ANATOMY
ACUTE EROSIVE GASTRITIS
The normal morphology of the gastric mucosa has been described clearly (1, 2). The structure of the mucosal lining of the stomach is not uniform but differs with its location. Acid-secreting fundal gland mucosa normally is found in the gastric fundus and body while non-acid-secreting pyloric or antral gland mucosa is found in the antrum. Both fundal and pyloric gland mucosa have similar mucous-secreting gastric surface cells which line the gastric pits and surface. These are rapidly renewed as new cells are formed at the base of the pits maintaining the integrity of the gastric mucosal lining as old cells are exfoliated from the surface. This rapid renewal rate of surface epithelium (4 to 5 days in humans) helps to explain the rapid healing which may follow injury to the superficial layer of the gastric mucosa. While the superficial layers of the fundal and antral mucosae appear identical in structure, the deeper or glandular layers of the mucosae differ. Fundal mucosa normally contains many acid-secreting parietal cells and pepsin-secreting chief cells, wherea~ antral mucosa contains primarily mucous-secreting glandular cells. Both fundal and antral mucosae contain endocrine epithelial cells; however, the endocrine cell populations are distinctive in each type of mucosa. For example, the endocrine cells which produce gastrin are confined primarily to antral mucosa (3). The cell renewal rates of the glandular layer of both antral and fundal mucosa are much slower than the surface cell renewal rate, hence the glandular cells are relatively stable cell populations.
Acute erosive gastritis is associated with shock, stress, and with the exposure of gastric mucosa to agents known to break the mucosal barrier to hydrogen ion (alcohol, hypertonic solutions, un-ionized weak organic acids including aspirin and bile acids). At times, acute erosive gastritis occurs in the absence of obvious predisposing causes. The histopathology of the multiple lesions seen in this condition is characteristic in that erosions are superficial, fail to penetrate the muscularis mucosa, and thus are usually confined to the mucosa itself. There is no fibrosis associated with the ulcerations and there is only a mild to moderate inflammatory response in the mucosa (4). The superficial ulcers can be distributed throughout the stomach and may be seen in both fundal- and pyloric-type mucosae. Healing is often rapid and generally complete without residual scarring unless one or more of the superficial erosions penetrate the muscularis mucosa and progress to chronic ulcer formation.
From the Department of Medicine, Peter Bent Brigham Hospital and Harvard Medical School, Boston, Massachusetts. Address for reprint requests: Dr. Jerry S. Trier, Department of Medicine, Peter Bent Brigham Hospital and Harvard Medical School, Boston, Massachusetts 02115.
138
CHRONIC PEPTIC GASTRIC ULCERS The histopathological features of chronic peptic gastric ulcers have been known for years and there has been relatively little recent progress in our understanding of the histogenesis of these lesions. The mucosa, muscularis mucosa, and a variable amount of submucosa and even muscularis propria, are destroyed by the ulcer itself. In typical chronic peptic ulcers, the ulcer bed contains four distinct layers (4). The luminal aspect of the crater is characterized by an acute inflammatory exudate with polymorphonuclear leukocytes and mononuclear cells enmeshed in a network of fibrin. Beneath this is a Digestive Diseases, VoL 21, No. 2 (February 1976)
MORPHOLOGY OF GASTRIC MUCOSA layer of relatively homogeneous eosinophilic-staining necrotic material. Still deeper is a layer of granulation tissue containing proliferating capillaries, connective tissue elements, and inflammatory cells. The deepest layer in a well-developed chronic ulcer consists of dense fibrous tissue which may extend deeply into the muscularis propria. The localization of chronic peptic gastric ulcers to specific regions of the stomach is of great interest. The vast majority of gastric ulcers occur in antral-type mucosa and most occur within 2 cm of the junction of antral- and fundal-type mucosae (5, 6). Since the antral mucosa occupies a variable percentage of total gastric mucosal surface, gastric ulcers can appear at widely differing distances from the pylorus in specific patients and still lie within this junctional zone. For example, it has been well documented that in humans, with advancing age, the fundic-antral border moves proximally, especially along the lesser curvature (7). The reason for the striking predilection for the development of gastric ulcers in antral mucosajust distal to the junction of fundal and antral mucosae is unknown, but must provide some as yet unrecognized clues regarding the pathogenesis and histogenesis of chronic peptic gastric ulcer disease. Another important and now thoroughly documented observation is that chronic peptic gastric ulcers are commonly associated with antral gastritis (usually nonerosive gastritis)(8). The histological features of the gastritis seen in association with gastric ulcer disease include infiltration of the lamina between gastric pits and glands with plasma cells, lymphocytes, and polymorphonuclear leukocytes. This infiltrate spreads apart adjacent gastric pits and glands. When gastritis is severe, microabcesses of the gastric pits and reduced height of the overlying gastric surface cells may be seen. It is not known for certain whether the gastritis precedes or follows development of the ulcer. In one careful study, gastritis was found to persist or worsen after ulcer healing had taken place, suggesting that antral gastritis may be a primary rather than a secondary phenomenon (9). It is also of interest that among alcoholics, a population with a high incidence of peptic ulcer disease, the incidence of antral gastritis has been reported to be as high as 84% (10). The cause of the antral gastritis associated with chronic peptic gastric ulcer disease is not known but it has been suggested that reflux of duodenal contents containing barrier-breaking bile acids or ingestion of barrier breakers such as alcohol or aspirin may be involved. Digestive Diseases, Vol. 21, No. 2 (February 1976)
The association of gastritis of the body and fundus with chronic gastric ulcer disease is less clearcut. However, inflammation of the lamina propria of the acid-secreting mucosa seems increased, though not as often or as severely as inflammation of the antrum.
AREAS FOR F U T U R E INVESTIGATION
Where do we go from here to increase our understanding of the histogenesis of gastritis, and gastric ulcer disease? One area of research which appears promising is the careful examination of morphological changes induced by substances which break the gastric mucosal barrier to hydrogen ion backdiffusion. Initial studies suggest that not all barrier breakers produce the same lesion; aspirin (11), alcohol (12), and bile salts (13) all appear to disrupt initially the gastric surface cell cytoplasm without obvious damage to intercellular junctions. In contrast, hypertonic urea appears to damage intercellular junctions without producing extensive cytoplasmic damage (12). Extension of these provocative morphological studies and their careful correlation with physiological changes induced by specific barrier! breakers may help clarify the mechanisms by which the "barrier" manages to maintain the tremendous hydrogen ion gradient between gastric lumen and gastric tissue under normal circumstances. It would also seem worthwhile to examine the pattern and rate of epithelial cell proliferation in the gastric antrum of gastric ulcer and gastritis patients and to compare these values to cell proliferation in similar locations in ulcer-free individuals. Such studies are now feasible with the development of in vitro methods which permit measurement of cell renewal in cultured human enteric mucosa obtained by peroral suction biopsy techniques (14). In addition, direct examination of protein, glycoprotein, pepsin, and gastrin synthesis by gastric mucosae in normal subjects and in patients with gastritis and ulcer disease would be of interest. Again, recent studies using in vitro organ culture methods have demonstrated that such studies are now feasible (15, 16, 17). Documentationofalteredcellproliferation and/or mucosal synthetic and secretory functions, if present, might provide leads to help explain altered mucosal resistance to acid-peptic digestion in patients with gastritis and gastric ulcer disease.
] 39
TRIER
REFERENCES 1. Fawcett DW: The esophagus, stomach, and intestines. A Textbook of Histology. W Bloom, DW Fawcett (eds). Philadelphia, 1968, W.B. Saunders, pp 544-581 2. Ito S: Anatomic structure of the gastric mucosa. Handbook of Physiology; Alimentary Canal. C Code (ed). Washington, D.C., 1967, American Physiology Society, pp 705-758 3. McGuigan ]E, Greider MH: Correlative immunochemical and light microscopic studies of the gastrin cell of the antral mucosa. Gastroenterology 60:223-236, 1971 4. Eigenbrodt EH: The pathology of peptic ulcer. Gastrointestinal Disease. MH Sleisenger, JS Fordtran (eds). Philadelphia, 1973, W.B. Saunders, pp 621-627 5. Oi M, Ito S, Kumagai F, Yoshida K, Tanaka Y, Yoshikawa K, Miho 0 , Ki Jimi M: A possible dual control mechanism in origin of peptic ulcer. Gastroenterology 57:280-293, 1969 6. Morson BC, Dawson IMP: Gastrointestinal Pathology, Oxford, England, 1972, Blackwell Scientific Publications, p 114 7. Kimura K: Chronological transition of the fundic-pyloric border determined by stepwise biopsy of the lesser and greater curvatures of the stomach. Gastroenterology 63:584-592, 1972 8. Hebbel R: Chronic gastritis: Its relation to gastric and duodenal ulcer and to gastric cancer. Am J Pathol 19:43-71, 1943 9. Gear MWL, Truelove SC, Whitehead R: Gastric ulcer and gastritis. Gut 12:639-645, 1971
140
10. Dinoso VP, Chey WY, Braverman SP, Rosen AP, Ottenberg D, Lorber SH: Gastric secretion and gastric mucosal morphology in chronic alcoholics. Arch Int Med 130:715719, 1972 11. Hingson DJ, Ito D: Effect of aspirin and related compounds on the fine structure of mouse gastric mucosa. Gastroenterology 61:156-177, 1971 12. Eastwood GL, Kirchner JP: Changes in the fine structure of mouse gastric epithelium produced by ethanol and urea. Gastroenterology 67:71-84, 1974 13. Eastwood GL: Effects of sodium tautocholate on the fine structure of mouse gastric mucosa. Clin Research 21:962, 1973 14. Browning TH, Trier JS: Organ culture of mucosal biopsies of human small intestine. J Clin Invest 48:1423-1432, 1969 15. Kagnoff MF, Donaldson RM, Trier JS: Organ culture of rabbit small intestine: Prolonged in vitro steady state protein synthesis and secretion and secretory IgA secretion. Gastroenterology 63:541-551, 1972 16. MacDermott RP, Donaldson RM, Trier JS: Glycoprotein synthesis and secretion by mucosal biopsies of rabbit colon and human rectum. J Clin Invest 54:545-554, 1974 17. Sutton D, Donaldson RM: In vitro biosynthesis and secretion of pepsinogen by rabbit gastric mucosa. Gastroenterology 66:786, 1974
Digestive Diseases, Vol. 21, No. 2 (February 1976)
NORMAL ANATOMY
ACUTE EROSIVE GASTRITIS
The normal morphology of the gastric mucosa has been described clearly (1, 2). The structure of the mucosal lining of the stomach is not uniform but differs with its location. Acid-secreting fundal gland mucosa normally is found in the gastric fundus and body while non-acid-secreting pyloric or antral gland mucosa is found in the antrum. Both fundal and pyloric gland mucosa have similar mucous-secreting gastric surface cells which line the gastric pits and surface. These are rapidly renewed as new cells are formed at the base of the pits maintaining the integrity of the gastric mucosal lining as old cells are exfoliated from the surface. This rapid renewal rate of surface epithelium (4 to 5 days in humans) helps to explain the rapid healing which may follow injury to the superficial layer of the gastric mucosa. While the superficial layers of the fundal and antral mucosae appear identical in structure, the deeper or glandular layers of the mucosae differ. Fundal mucosa normally contains many acid-secreting parietal cells and pepsin-secreting chief cells, wherea~ antral mucosa contains primarily mucous-secreting glandular cells. Both fundal and antral mucosae contain endocrine epithelial cells; however, the endocrine cell populations are distinctive in each type of mucosa. For example, the endocrine cells which produce gastrin are confined primarily to antral mucosa (3). The cell renewal rates of the glandular layer of both antral and fundal mucosa are much slower than the surface cell renewal rate, hence the glandular cells are relatively stable cell populations.
Acute erosive gastritis is associated with shock, stress, and with the exposure of gastric mucosa to agents known to break the mucosal barrier to hydrogen ion (alcohol, hypertonic solutions, un-ionized weak organic acids including aspirin and bile acids). At times, acute erosive gastritis occurs in the absence of obvious predisposing causes. The histopathology of the multiple lesions seen in this condition is characteristic in that erosions are superficial, fail to penetrate the muscularis mucosa, and thus are usually confined to the mucosa itself. There is no fibrosis associated with the ulcerations and there is only a mild to moderate inflammatory response in the mucosa (4). The superficial ulcers can be distributed throughout the stomach and may be seen in both fundal- and pyloric-type mucosae. Healing is often rapid and generally complete without residual scarring unless one or more of the superficial erosions penetrate the muscularis mucosa and progress to chronic ulcer formation.
From the Department of Medicine, Peter Bent Brigham Hospital and Harvard Medical School, Boston, Massachusetts. Address for reprint requests: Dr. Jerry S. Trier, Department of Medicine, Peter Bent Brigham Hospital and Harvard Medical School, Boston, Massachusetts 02115.
138
CHRONIC PEPTIC GASTRIC ULCERS The histopathological features of chronic peptic gastric ulcers have been known for years and there has been relatively little recent progress in our understanding of the histogenesis of these lesions. The mucosa, muscularis mucosa, and a variable amount of submucosa and even muscularis propria, are destroyed by the ulcer itself. In typical chronic peptic ulcers, the ulcer bed contains four distinct layers (4). The luminal aspect of the crater is characterized by an acute inflammatory exudate with polymorphonuclear leukocytes and mononuclear cells enmeshed in a network of fibrin. Beneath this is a Digestive Diseases, VoL 21, No. 2 (February 1976)
MORPHOLOGY OF GASTRIC MUCOSA layer of relatively homogeneous eosinophilic-staining necrotic material. Still deeper is a layer of granulation tissue containing proliferating capillaries, connective tissue elements, and inflammatory cells. The deepest layer in a well-developed chronic ulcer consists of dense fibrous tissue which may extend deeply into the muscularis propria. The localization of chronic peptic gastric ulcers to specific regions of the stomach is of great interest. The vast majority of gastric ulcers occur in antral-type mucosa and most occur within 2 cm of the junction of antral- and fundal-type mucosae (5, 6). Since the antral mucosa occupies a variable percentage of total gastric mucosal surface, gastric ulcers can appear at widely differing distances from the pylorus in specific patients and still lie within this junctional zone. For example, it has been well documented that in humans, with advancing age, the fundic-antral border moves proximally, especially along the lesser curvature (7). The reason for the striking predilection for the development of gastric ulcers in antral mucosajust distal to the junction of fundal and antral mucosae is unknown, but must provide some as yet unrecognized clues regarding the pathogenesis and histogenesis of chronic peptic gastric ulcer disease. Another important and now thoroughly documented observation is that chronic peptic gastric ulcers are commonly associated with antral gastritis (usually nonerosive gastritis)(8). The histological features of the gastritis seen in association with gastric ulcer disease include infiltration of the lamina between gastric pits and glands with plasma cells, lymphocytes, and polymorphonuclear leukocytes. This infiltrate spreads apart adjacent gastric pits and glands. When gastritis is severe, microabcesses of the gastric pits and reduced height of the overlying gastric surface cells may be seen. It is not known for certain whether the gastritis precedes or follows development of the ulcer. In one careful study, gastritis was found to persist or worsen after ulcer healing had taken place, suggesting that antral gastritis may be a primary rather than a secondary phenomenon (9). It is also of interest that among alcoholics, a population with a high incidence of peptic ulcer disease, the incidence of antral gastritis has been reported to be as high as 84% (10). The cause of the antral gastritis associated with chronic peptic gastric ulcer disease is not known but it has been suggested that reflux of duodenal contents containing barrier-breaking bile acids or ingestion of barrier breakers such as alcohol or aspirin may be involved. Digestive Diseases, Vol. 21, No. 2 (February 1976)
The association of gastritis of the body and fundus with chronic gastric ulcer disease is less clearcut. However, inflammation of the lamina propria of the acid-secreting mucosa seems increased, though not as often or as severely as inflammation of the antrum.
AREAS FOR F U T U R E INVESTIGATION
Where do we go from here to increase our understanding of the histogenesis of gastritis, and gastric ulcer disease? One area of research which appears promising is the careful examination of morphological changes induced by substances which break the gastric mucosal barrier to hydrogen ion backdiffusion. Initial studies suggest that not all barrier breakers produce the same lesion; aspirin (11), alcohol (12), and bile salts (13) all appear to disrupt initially the gastric surface cell cytoplasm without obvious damage to intercellular junctions. In contrast, hypertonic urea appears to damage intercellular junctions without producing extensive cytoplasmic damage (12). Extension of these provocative morphological studies and their careful correlation with physiological changes induced by specific barrier! breakers may help clarify the mechanisms by which the "barrier" manages to maintain the tremendous hydrogen ion gradient between gastric lumen and gastric tissue under normal circumstances. It would also seem worthwhile to examine the pattern and rate of epithelial cell proliferation in the gastric antrum of gastric ulcer and gastritis patients and to compare these values to cell proliferation in similar locations in ulcer-free individuals. Such studies are now feasible with the development of in vitro methods which permit measurement of cell renewal in cultured human enteric mucosa obtained by peroral suction biopsy techniques (14). In addition, direct examination of protein, glycoprotein, pepsin, and gastrin synthesis by gastric mucosae in normal subjects and in patients with gastritis and ulcer disease would be of interest. Again, recent studies using in vitro organ culture methods have demonstrated that such studies are now feasible (15, 16, 17). Documentationofalteredcellproliferation and/or mucosal synthetic and secretory functions, if present, might provide leads to help explain altered mucosal resistance to acid-peptic digestion in patients with gastritis and gastric ulcer disease.
] 39
TRIER
REFERENCES 1. Fawcett DW: The esophagus, stomach, and intestines. A Textbook of Histology. W Bloom, DW Fawcett (eds). Philadelphia, 1968, W.B. Saunders, pp 544-581 2. Ito S: Anatomic structure of the gastric mucosa. Handbook of Physiology; Alimentary Canal. C Code (ed). Washington, D.C., 1967, American Physiology Society, pp 705-758 3. McGuigan ]E, Greider MH: Correlative immunochemical and light microscopic studies of the gastrin cell of the antral mucosa. Gastroenterology 60:223-236, 1971 4. Eigenbrodt EH: The pathology of peptic ulcer. Gastrointestinal Disease. MH Sleisenger, JS Fordtran (eds). Philadelphia, 1973, W.B. Saunders, pp 621-627 5. Oi M, Ito S, Kumagai F, Yoshida K, Tanaka Y, Yoshikawa K, Miho 0 , Ki Jimi M: A possible dual control mechanism in origin of peptic ulcer. Gastroenterology 57:280-293, 1969 6. Morson BC, Dawson IMP: Gastrointestinal Pathology, Oxford, England, 1972, Blackwell Scientific Publications, p 114 7. Kimura K: Chronological transition of the fundic-pyloric border determined by stepwise biopsy of the lesser and greater curvatures of the stomach. Gastroenterology 63:584-592, 1972 8. Hebbel R: Chronic gastritis: Its relation to gastric and duodenal ulcer and to gastric cancer. Am J Pathol 19:43-71, 1943 9. Gear MWL, Truelove SC, Whitehead R: Gastric ulcer and gastritis. Gut 12:639-645, 1971
140
10. Dinoso VP, Chey WY, Braverman SP, Rosen AP, Ottenberg D, Lorber SH: Gastric secretion and gastric mucosal morphology in chronic alcoholics. Arch Int Med 130:715719, 1972 11. Hingson DJ, Ito D: Effect of aspirin and related compounds on the fine structure of mouse gastric mucosa. Gastroenterology 61:156-177, 1971 12. Eastwood GL, Kirchner JP: Changes in the fine structure of mouse gastric epithelium produced by ethanol and urea. Gastroenterology 67:71-84, 1974 13. Eastwood GL: Effects of sodium tautocholate on the fine structure of mouse gastric mucosa. Clin Research 21:962, 1973 14. Browning TH, Trier JS: Organ culture of mucosal biopsies of human small intestine. J Clin Invest 48:1423-1432, 1969 15. Kagnoff MF, Donaldson RM, Trier JS: Organ culture of rabbit small intestine: Prolonged in vitro steady state protein synthesis and secretion and secretory IgA secretion. Gastroenterology 63:541-551, 1972 16. MacDermott RP, Donaldson RM, Trier JS: Glycoprotein synthesis and secretion by mucosal biopsies of rabbit colon and human rectum. J Clin Invest 54:545-554, 1974 17. Sutton D, Donaldson RM: In vitro biosynthesis and secretion of pepsinogen by rabbit gastric mucosa. Gastroenterology 66:786, 1974
Digestive Diseases, Vol. 21, No. 2 (February 1976)
