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ASA-induced Erosions of the Gastric Mucosa Be Identified at Histology?
PATHOLOGY RESEARCH AND PRACTICE
© Urban & Fischer Verlag http://www.urbanfischer.de/journalslprp
Can NSAIDIASA-induced Erosions of the Gastric Mucosa Be Identified at Histology? M. Stolte,
s. Panayiotou and J. Schmitz
Institute of Pathology, Bayreuth Hospital, Bayreuth, Germany
Summary Studies in animals have shown that NSAID/ASA-induced erosions have an ischaemic pathogenesis. We therefore studied the question of whether such erosions in human gastric biopsy material can be identified on the basis of the ischaemic necrosis. Histological sections prepared from forceps biopsy material obtained from 122 patients with erosions (at least three biopsy specimens from the erosion and two from antrum and corpus each) were classified by a pathologist blinded to the endoscopic findings and the medication used by the patients. NSAIDIASA erosions were diagnosed when a homogeneous eosinophilic ischaemic necrosis blending into the adjoining lamina propria presented. Helicobacter pylori (Hp)-induced erosions were diagnosed when, in the presence of Hp gastritis, erosive defects were covered with a non-homogeneous fibrinoid necrosis containing granulocytes and cell debris. Finally, the histological classification was compared with data on medication usage. The histological diagnosis was Hp-induced erosions in 59 patients, NSAID/ASA-induced erosions with no Hp gastritis in 23, and NSAID/ASA-induced erosions with concomitant Hp gastritis in 40. A comparison of this histological classification with the data provided by the referring physicians on patient medication revealed that 70% of the patients with histological diagnosis of NSAID/ASA-induced erosions in the absence of Hp gastritis, and 65% of those diagnosed to have NSAIDI ASA-induced erosions and concomitant Hp gastritis, had been taking such drugs. Among the erosions diagnosed as H. pylori-induced, 81% of the patients were reported not to take such medication. The sensitivity of the diagnosis of NSAID/ASA-induced erosions was 72.9%, and specificity 79.6%. The results of the present study show that a high percentage of the NSAID/ASA-induced erosions of the gastric mucosa can indeed be correctly diagnosed at histology. Pathol. Res. Pract. 195: 137-142 (1999)
Key words: Gastric mucosa - NSAID/ASA-induced erosions - Helicobacter pylori
Introduction Erosions of the gastric mucosa may have numerous different causes. Thus, for example, Helicobacter pylori can give rise to erosions located predominantly in the antrum [10, 12, 31]. In the rare form of lymphocytic gastritis, a multitude of erosions with central depression may occur in the corpus [9, 15J. Rare causes of erosions are mini-early carcinomas and early lymphomas [32J, severe general illnesses leading to shock [11, 17J, rare infections of the gastric mucosa [18, 25J, Crohn's disease [3J, the use of iron-containing preparations [20J, and duodenogastric reflux of pathological bile acids [21]. Apart from infection with Helicobacter pylori, the most common cause of erosions in the gastric mucosa is the use of medication capable of injuring the gastric mucosa of the NSAID/ASA type [6, 14, 15, 30J. Numerous investigations into the pathogenesis of these NSAID/ASA-induced erosions have been carried out in recent years and have shown that apart from prostaglandin synthesis and oxidative phosphorylation [4J, the underlying aetiological factors also include disturbances of local microcirculation caused by these substances, resulting in ischaemic necrosis [19]. In the pathogenesis of these microcirculatory disturbances, roles are played by reactive oxygen metabolites, neutrophil granulocytes ("free radicals"), leukotrienes, proteases, platelet thrombi and local spasms of the tiny blood vessels in the submucosa [16,22,23,24, 35].
Address for correspondence: Prof. Dr. M. Stolte,Institute of Pathology, Klinikum Bayreuth, Preuschwitzer StraBe 101, D95445 Bayreuth, Germany. Tel.: 0921/400 5600, Fax: 0921/400-5609 0344-0338/99/195/3-137 $12.00/0
138 . M. Stolte et al.
On the basis of this new information, gained mainly from animal experimental research into the pathogenesis of NSAIDIASA erosions, we carried out a study to determine whether these facts can be utilized in the field of diagnostic endoscopy/biopsy, that is, whether NSAID/ASA-induced erosions can also be diagnosed on the basis of ischaemic necrosis in patients.
Material and Methods We sent a special questionnaire dealing specifically with the classification of erosions of the gastric mucosa to physicians submitting material to our institute (Table 1). The items concerned the use of medication, the nature of the drugs employed, the location of the erosions, their number, size, appearance, surface configuration, marginal structures and possible associated lesions. Biopsy requirements
In patients undergoing endoscopy for dyspepsia and found to have erosions at endoscopy, at least three forceps biopsies from the erosions, and two forceps biopsies each from endoscopically normal antrum and corpus mucosa, were requested. Histological methods
The biopsy material was fixed in 4% formalin, dehydrated in a graded series of alcohol, embedded in paraffin, microtomed into 4 urn step sections, and stained with haematoxylin-eosin and the Warthin-Starry silver stain.
Histological classification of the erosions
The formal pathomorphological classification of the erosions was carried out in accordance with the recommendations of the Working Group for Gastroenterological Pathology of the German Society of Pathology [5]. The aetiopathic classification into NSAID/ASA-induced or Hp-induced erosions was based on animal experimental data on the pathogenesis of NSAIDI ASA erosions and on our earlier investigations on Hp-induced erosions {3l] in accordance with the following hypothetical criteria:
1. NSAID/ASA erosions were diagnosed by histology whenever, within the area of the erosion, a homogeneous eosinophilic ischaemic necrosis blending into the adjacent lamina propria was found (Fig. 1). Depending on the status of the gastric mucosa in the margin of the erosion and in endoscopically normal antrum and corpus mucosa, this type of erosion was subdivided into: a) NSAID/ASA erosions in normal mucosa or in a chemically-induced gastritis, and b) NSAID/ASAerosion in Hp gastritis. 2. Hp-induced erosions were diagnosed whenever, within an Hp gastritis, erosive defects covered with inhomogeneous fibrinoid necrosis that did not blend into the adjacent lamina propria were found. Such necrosis also contained cell debris and granulocytes (Fig. 2). The hypothetical aetiopathic classification of the erosions was carried out by one and the same pathologist (MS), who was completely blind to all clinical data and endoscopic findings. The results of the histological investigation were then compared with the clinical data on medication usage and the endoscopic appearance of the erosions.
Table 1 H. pylori induced
NSAR-ASS induced
NSAR-ASS induced with concomitant Hp-Gastritis
Number of patients
59
23
40
Male:female
22:37
8:15
p
20:20
n.s.
60
n.s.
Av. age (years)
55
54
Site pylorus prepyloric antrum rest of antrum corpus antrum and corpus
8.5% 55.9% 25.4% 3.4% 6.8%
17.4% 47.8% 17.4% 8.7% 8.7%
7.5% 45.0% 30.0% 2.5% 15.0%
n.s.
Size of erosion lentil-sized pea-sized bean-sized
55.9% 37.3% 6.8%
47.8% 26.1% 26.1%
27.5% 37.5% 35.0%
p=0.0042
Formal typing acute subacute chronic
5.1% 11.9% 85.0%
21.7% 56.6% 21.7%
17.5% 70.0% 12.5%
P < 0.0001
NSAID/ASA-induced erosions· 139
Results The histological slides obtained from 122 patients in whom erosions were unambiguously confirmed by histology were evaluated. On the basis of the given histological criteria, a Helicobacter pylori-induced erosion was diagnosed in 59 patients (48.4%), and an NSAID/ASA-induced erosion in the absence of Helicobacter pylori gastritis in 23 patients (18.8%), while an NSAID/ASA-induced erosion in the presence of Hp gastritis was diagnosed in 40 patients (32.8%). The average age and sex distribution of the patients, site distribution, size and formal histological typing of the erosions are seen in Table 1. Statistically significant differences were found with regard to size and formal histological typing of the erosions: the NSAID-ASA-induced erosions were larger and more frequently acute or subacute. With regard to number, configuration, endoscopic appearance of the margins, and the endoscopically diagnosed surface appearance, as well as to the histological depth of the lesion and the nature and frequency of associated lesions, no statistically significant differences were observed between the three histological diagnostic Table 2. Endoscopic features of the erosion (n = 122)
2 Fig. 1 (upper). NSAID/ASS-induced erosion of the gastric mucosa: homogeneous eosinophilic ischaemic necrosis blending into the adjacent lamina propria. Fig. 2 (below). Helicobacter pylori gastritis-induced erosion: erosive defect covered with inhomogeneous fibrinoid necrosis with cell debris and granulocytes.
Classification and grading of the gastritis in antrum and corpus were done in accordance with the principles laid down in the updated Sydney System [26], with minor modifications [33]. Patients with Crohn's disease or gastric carcinoma or MALT lymphoma were excluded from the study.
Statistical methods The morphological, anamnestic and histological data were presented in tabular form, broken down in accordance with the histological classification of the erosions. The nominal data in the resulting tables were checked for uniformity using the Chi square test. The siginificance level was set at 0.05. The sensitivity and specificity of the histological diagnosis (NSAID/ASA-induced or Hp-induced) were also calculated.
No. solitary 2-5 5-10 more than 10
18.0% 47.5% 23.0% 11.5%
Form flat raised in part flat, in part raised
32.0% 50.8% 17.2%
Margin sharply delimited unsharply delimited
72.9% 27.1%
Surface - actively bleeding - haemorrhagic - non-haemorrhagic
0.8% 34.4% 64.8%
Histological depth of penetration - superficial - base of foveolae - body of glands - muscularis mucosae
14.3% 81.4% 13.4% 0.9%
Associated lesions erosions in descending pt. of duodenum erosions in the duodenal bulb ulcer in the duodenal bulb pyloric ulcer gastric ulcer reflux oesophagitis
0.8% 23.8% 20.5% 8.2% 1.6% 14.7%
140 . M. Stolte et al.
Table 3. Admitted medication usage in patients with erosions N medication Medication containing acetyl salicylic acid NSAIDs "Painkillers" Iron preparations Others
57.3 % 28.2% 6.5 % 3.2% 0.8% 4.0%
Table 4. Comparison of histological classification of erosions with patient information on medication usage Histological erosion classification Admitted medication usage
HP-induced
NSAID/ASS- NSAID/ASSinduced in HPinduced gastritis
No drug use
48 (81 %)
7 (30 %)
14 (35%)
NSAID/ASS
II (19%)
16 (70%)
26 (65 %)
groups. In view of this uniformity, the results of the analysis are summarized in Table 2. The data provided by the endoscopists on the use of medication of the 122 patients with histologically confirmed erosions (see Table 3) show that 38.7% of the patients had been using drugs capable of inducing erosions of the gastric mucosa. A comparison of the histological classification of the erosions and the data on drug usage (see Table 4) shows that 81% of the erosions histologically diagnosed as H. pylori-induced lesions were not associated with medication usage. In contrast, the drug history of 70% of the patients with histologically diagnosed NSAID/ASA-induced erosions in the absence of Helicobacter pylori gastritis, and of 65% of the patients with histologically diagnosed NSAIDI ASA-induced erosions with concomitant Hp gastritis actually showed prior use of NSAIDIASA preparations. In the group of 23 patients with histologically diagnosed NSAID/ASA erosions, but no H. pylori gastritis, the histological work-up of the antrum and corpus mucosa revealed no pathological findings in 13% of the cases, but a chemically-induced antral gastritis in 87%. On pooling the two groups with the histological diagnosis of NSAID/ASA-induced erosions, this histological diagnosis was found to have a sensitivity of79.24% and a specificity of 69.56%.
Discussion Although our results show that a high percentage of NSAID/ASA-induced erosions of the gastric mucosa
can be correctly diagnosed at the histological work-up, the specificity and sensitivity of this histological diagnosis are only 69% and 79%, respectively. However, if we take into account the fact that some of these patients will probably have made false statements on drug usage, or have deliberately concealed their use of ASAcontaining pain killers, it is very probable that the histological suspicion of NSAID/ASA-induced erosions is correct in a higher percentage of the cases than indicated above. This assessment is indirectly supported by an analysis of the data on medication usage and the classification of gastritis in those patients with a histological diagnosis of NSAID/ASA-induced erosions in the absence of Hp-induced gastritis, for although 30% of these patients denied taking medication, and 87% of the same patients were found to have chemically-induced gastritis, thus providing indirect evidence for the use of NSAIDIASA preparations [29 J. In the presence of Helicobacter pylori gastritis, we expected to find a large uncertainty in the histological classification of the erosions. Apparently, however, the criterion ischaemic necrosis we selected as an indicator for NSAID/ASA-induced erosions is so accurate that 65% of the erosions so diagnosed were compatible with medication usage. In this study on the differentiation of the pathogenesis of erosions of the gastric mucosa, the endoscopic findings were not particularly helpful. The presumably NSAID/ASA-induced erosions were statistically significantly more frequently acute or subacute, and also larger than the Hp-induced lesions. We expected to find that the NSAID/ASA-induced erosions are more frequently unsharply delimited, multiple and haemorrhagic as compared with the Hp-induced erosions; however, no statistically significant differences were found in respect of these parameters. The results of our analysis provide indirect confirmation of numerous experimental animal studies which aimed to clarify the pathogenesis of NSAIDIASA-induced lesions of the gastric mucosa. The inhibition of prostaglandin synthesis and oxidative phosphorylation by these substances [4, 7, 8J alone probably does not suffice to explain the development of erosions. Of greater importance for the generation of ischaemic necrosis is the NSAIDIASA-induced swelling of the endothelium lining the capillaries in the mucosa [37 J, granulocyte adhesion in the capillaries [2, 18J, sludge phenomena involving the granulocytes leading to the formation of so-called white thrombi and platelet thrombi [7, 27, 36J, gradual slowing of the bloodflow [37 J, and spastic vasoconstriction [8, 28]. The neutrophil granulocytes seem to play a key role in the pathogenesis of NSAID/ASA-induced erosions, because in animal experiments injury to the mucosa does not occur when the function of the neutrophil granulo-
NSAID/ASA-induced erosions· 141
cytes is blocked or the animals are rendered "granulocyte-free" [34J. This pathomechanism underlying the damage to the mucosa applies not only to the stomach, but also to the small bowel [I] and large bowel [4J, where, as our experience shows, the NSAID/ASA-induced injury can also be relatively readily identified by the ischaemic necrosis. Since, of course, ischaemic necrosis of the mucosa of the gastrointestinal tract can have numerous other causes (shock, vascular disease, amyloidosis, cardiac insufficiency, and many more), the finding of such a necrosis at histology can only lead to a tentative diagnosis. However, the fact that the pathologist's report indicates the possibility that the lesion may be due to the use of NSAIDIASA preparations can prompt the careproviding physician to take a careful drug history - if he has not already done so - to exclude other causes of ischaemic necrosis and thus provide a better basis for the diagnosis of NSAID/ASA-induced erosion or ulceration than would be possible without the histological findings. In summary, we believe the results of our study show that the histological diagnosis of suspected NSAIDI ASA-induced erosions of the gastric mucosa is correct in a large percentage of cases. This suspected diagnosis can help the physician to identify previously unknown use of these drugs, to weigh up the risks and benefits to the particular patient of taking such medication, and to counsel him/her accordingly. The aetiopathic diagnosis of the erosions can also be improved by the biopsybased investigation of an underlying disease of the gastric mucosa (Hp gastritis?, C-gastritis?) that might be present. Whether the criterion of histologically detected ischaemic necrosis may serve not only for the clarification of erosions, but also for the aetiopathic classification of ulcerations, needs to be investigated in further studies.
References 1. Aaabakken L, Osnes M (1989) Non-steroidal anti-inflammatory drug-induced disease in the distal ileum and large bowel. Scand J Gastroenterol, Supp1163: 48-55 2. Appleyard CB, McCafferty, Tigley AC, Swain MG, Wallace JL (1996) Tumor necrosis factor mediation of NSAID-induced gastric damage: role of leukeocyte adherence. Am J Physiol270: G42-48 3. Arigama J, Weklin L, Lindstrom CJ, Wenkert A, Roberts GM (1980) Gastroduodenal erosions in Crohn's disease. Gastrointest Radiol 5: 121-125 4. Bjamason J, Hayllar J, MacPherson AJ, Russel AS (1993) Side effects of nonsteroidal anti-inflammatory drugs on the small and large bowel in humans. Gastroenterology
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P, Stolte M (1992) Klassifikation der Erosionen des Magens. Pathologe 13: 249-251 Davenport HW (1964) Gastric mucosa injury by gastric and acetylsalicylic acid. Gastroenterology 46: 245 Davies NM (1995) Toxicity of nonsteroidal anti-inflammatory drugs in the large intestine. Dis Colon Rectum 38: 1311-1321 Davies NM, Wallace JW (1997) Nonsteroidal anti-inflammatory drug-induced gastrointestinal toxicity: New insights into an old problem. J Gastroenterol22: 1-4 Dixon MF, Wyatt 11, Burke DA, Rathbone BJ (1988) Lymphocytic gastritis - relationship to Campylobacter pylori infection. J Pathol154: 125-132 Elta GH, Fewaz KA, Dayal Y, et al (1983) Chronic erosive gastritis - a recently recognized disorder. Dig Dis Sci 28:7-12 Franzin G, Manfrin C, Musola R, Rodella S, Fratton A (1984) Chronic erosions of the stomach - clinical evaluation. Endoscopy 16: 1-5 Green PHR, Gold RP, Marboe CC, Weinberg LM, Goldfarb JP, Brasitius TA (1982) Chronic erosive gastritis: clinical, diagnostic and pathological features in nine patients. Am J Gastroenterol77: 542-547 Haot J, Jouret A, Willete M, Gossin A, Mainguet P (1990) Lymphocytic gastritis - prospective study of its relationship with varioliform gastritis. Gut 31: 282-285 Hawkey CJ, Karrasch JA, Szczepanski L, Walker DG, BarkumA, SwannellA, Yeomans ND (1998) Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs. N Engl J Med 338: 727-734 Hazlman BL (1989) Incidence of gastropathy in destructive arthropathies. Scand J Rheumatol Suppl 78: 1-4 Ito M, Guth PH (1985) Role of oxygen derived free radicals in hemorrhagic shock-induced gastric lesions in the rat. Gastroenterology 88: 1162-1167 Karvonen AL, Sipponen P, Lehtola J, Ruokonpn A (1983) Gastric mucosal erosions. An endoscopic, histological and functional study. Scand J Gastroenterol 18: 1051-1056 Karvonen AL, Lehtola J (1983) Gastric mucosa erosions, a clinical history and findings. The possible role of herpes simplex infection in etiology. Ann Clin Res 15: 137-141 Kathora T, Guth PH (1987) Effect of aspirin plus hydrochloric acid on the gastric mucosal microcirculation. Gastroenterology 93: 810-817 Laine LA, Bentley C, Chandrasoma P (1988) Effect of oral iron therapy on the upper gastrointestinal tract. A prospective evaluation. Dig Dis Sci 33: 172-177 Mann NS (1976) Bile induced acute erosive gastritis. Am J Dig Dis 21: 89-92 Oates PJ, Hakkinen JP (1988) Indices on the mechanism of theanol-induced gastric damage in rats. Gastroenterology 94: 10-21 Pihan G, Regillo C, Szabo S (1987) Free radicals and lipid peroxidation in ethanol- or aspirin-induced gastric mucosa injury. Dig Dis Sci 32: 1395-1401 Pihan G, Rogers C, Szabo (1988) Vascular injury in acute gastric mucosal damage. Mediatory role of leukotrienes. Dig Dis Sci 33: 625-632 Plein K, Zimmer J, Jacobi H, Stolte M, Hotz J (1977) Symptomatik, Differentialdiagnostik, Therapie und Prog-
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nose der nicht-neoplastischen Riesenfaltenbildungen im Magen (Hypertrophe Gastropathie vom Bild des Morbus Menetrier). Leber Magen Darm 27: 271-277 Price AB (1991) The Sydney-System: Histological division. J Gastroenterol Hepatol 6: 209-222 Rampton DS (1987) Non-steroidal antiinflammatory drugs and the lower gastrointestinal tract. Scand J Gastroenterol22: 1--4 Rothlein R, Czaijkow ski M, Kishimoto T (1994) Intercellular adhesion molecule-1 in inflammatory response. Chem Immunol50: 135-142 Sobala GM, King RFG, Axon ATR, Dixon MF (1990) Refluxgastriti s in the intact stomach. J Clin Pathol 43: 303-306 Soli AH, Weinstein WM, Kurata J, McCarthy D (1991) Nonsteroidal-antiinflammatory drugs and peptid disease (UCLA conference ). Ann Int Med 1/4: 307-319 Stolte M, Eidt S (1992) Chronic erosions of the antral mucosa: a sequela of Helicobacter pyloris-induced gastritis. Z Gastroenterol 30: 846--850 Stolte M, Malfertheiner P, Borchard F (1993) Ordnung im Chaos der Klassifikationen der Erosionen der Magenschleimhaut. Leber Magen Darm 23: 59-66 Stolte M, Stadelmann P, Bethke B, Burkhard G (1995) Relationships between the degree of Helicobacter pylori
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37.
colonisation and the degree and activity of gastritis, surface epithelial degeneration and mucus secretion. Z Gastroenterol33: 89-93 Wallace JL, Keenan CM, Granger DN (1990) Gastric ulceration induced by nonsteroidal antiinflammatory drugs is a neutrophile dependent process. Am J Physiol 259:; G462-G467 Wallace JC, MgKnight GW, Keenan CM, Yles NIA, MacNaughton WK (1990) Effects of leukotrienes on susceptibility of the rat stomach to damage and investigation of the mechanism of action. Gastroenterology 98: 1l78-1186 Wallace JL, Arvors KE (1991) A monoclonal antibody against the CK 19 leukocyte adhesion molecule prevents indomethacin-induced gastric damage in the rabbit. Gastroenterology 100: 878-883 Wallace JL, Granger DN (1992) The pathogenesis of NSAID-gastropathy - are neutrophils the culprits? TIPA 13: 129-131
Received: November 26, 1998 Accepted: December 15, 1998
© Urban & Fischer Verlag http://www.urbanfischer.de/journalslprp
Can NSAIDIASA-induced Erosions of the Gastric Mucosa Be Identified at Histology? M. Stolte,
s. Panayiotou and J. Schmitz
Institute of Pathology, Bayreuth Hospital, Bayreuth, Germany
Summary Studies in animals have shown that NSAID/ASA-induced erosions have an ischaemic pathogenesis. We therefore studied the question of whether such erosions in human gastric biopsy material can be identified on the basis of the ischaemic necrosis. Histological sections prepared from forceps biopsy material obtained from 122 patients with erosions (at least three biopsy specimens from the erosion and two from antrum and corpus each) were classified by a pathologist blinded to the endoscopic findings and the medication used by the patients. NSAIDIASA erosions were diagnosed when a homogeneous eosinophilic ischaemic necrosis blending into the adjoining lamina propria presented. Helicobacter pylori (Hp)-induced erosions were diagnosed when, in the presence of Hp gastritis, erosive defects were covered with a non-homogeneous fibrinoid necrosis containing granulocytes and cell debris. Finally, the histological classification was compared with data on medication usage. The histological diagnosis was Hp-induced erosions in 59 patients, NSAID/ASA-induced erosions with no Hp gastritis in 23, and NSAID/ASA-induced erosions with concomitant Hp gastritis in 40. A comparison of this histological classification with the data provided by the referring physicians on patient medication revealed that 70% of the patients with histological diagnosis of NSAID/ASA-induced erosions in the absence of Hp gastritis, and 65% of those diagnosed to have NSAIDI ASA-induced erosions and concomitant Hp gastritis, had been taking such drugs. Among the erosions diagnosed as H. pylori-induced, 81% of the patients were reported not to take such medication. The sensitivity of the diagnosis of NSAID/ASA-induced erosions was 72.9%, and specificity 79.6%. The results of the present study show that a high percentage of the NSAID/ASA-induced erosions of the gastric mucosa can indeed be correctly diagnosed at histology. Pathol. Res. Pract. 195: 137-142 (1999)
Key words: Gastric mucosa - NSAID/ASA-induced erosions - Helicobacter pylori
Introduction Erosions of the gastric mucosa may have numerous different causes. Thus, for example, Helicobacter pylori can give rise to erosions located predominantly in the antrum [10, 12, 31]. In the rare form of lymphocytic gastritis, a multitude of erosions with central depression may occur in the corpus [9, 15J. Rare causes of erosions are mini-early carcinomas and early lymphomas [32J, severe general illnesses leading to shock [11, 17J, rare infections of the gastric mucosa [18, 25J, Crohn's disease [3J, the use of iron-containing preparations [20J, and duodenogastric reflux of pathological bile acids [21]. Apart from infection with Helicobacter pylori, the most common cause of erosions in the gastric mucosa is the use of medication capable of injuring the gastric mucosa of the NSAID/ASA type [6, 14, 15, 30J. Numerous investigations into the pathogenesis of these NSAID/ASA-induced erosions have been carried out in recent years and have shown that apart from prostaglandin synthesis and oxidative phosphorylation [4J, the underlying aetiological factors also include disturbances of local microcirculation caused by these substances, resulting in ischaemic necrosis [19]. In the pathogenesis of these microcirculatory disturbances, roles are played by reactive oxygen metabolites, neutrophil granulocytes ("free radicals"), leukotrienes, proteases, platelet thrombi and local spasms of the tiny blood vessels in the submucosa [16,22,23,24, 35].
Address for correspondence: Prof. Dr. M. Stolte,Institute of Pathology, Klinikum Bayreuth, Preuschwitzer StraBe 101, D95445 Bayreuth, Germany. Tel.: 0921/400 5600, Fax: 0921/400-5609 0344-0338/99/195/3-137 $12.00/0
138 . M. Stolte et al.
On the basis of this new information, gained mainly from animal experimental research into the pathogenesis of NSAIDIASA erosions, we carried out a study to determine whether these facts can be utilized in the field of diagnostic endoscopy/biopsy, that is, whether NSAID/ASA-induced erosions can also be diagnosed on the basis of ischaemic necrosis in patients.
Material and Methods We sent a special questionnaire dealing specifically with the classification of erosions of the gastric mucosa to physicians submitting material to our institute (Table 1). The items concerned the use of medication, the nature of the drugs employed, the location of the erosions, their number, size, appearance, surface configuration, marginal structures and possible associated lesions. Biopsy requirements
In patients undergoing endoscopy for dyspepsia and found to have erosions at endoscopy, at least three forceps biopsies from the erosions, and two forceps biopsies each from endoscopically normal antrum and corpus mucosa, were requested. Histological methods
The biopsy material was fixed in 4% formalin, dehydrated in a graded series of alcohol, embedded in paraffin, microtomed into 4 urn step sections, and stained with haematoxylin-eosin and the Warthin-Starry silver stain.
Histological classification of the erosions
The formal pathomorphological classification of the erosions was carried out in accordance with the recommendations of the Working Group for Gastroenterological Pathology of the German Society of Pathology [5]. The aetiopathic classification into NSAID/ASA-induced or Hp-induced erosions was based on animal experimental data on the pathogenesis of NSAIDI ASA erosions and on our earlier investigations on Hp-induced erosions {3l] in accordance with the following hypothetical criteria:
1. NSAID/ASA erosions were diagnosed by histology whenever, within the area of the erosion, a homogeneous eosinophilic ischaemic necrosis blending into the adjacent lamina propria was found (Fig. 1). Depending on the status of the gastric mucosa in the margin of the erosion and in endoscopically normal antrum and corpus mucosa, this type of erosion was subdivided into: a) NSAID/ASA erosions in normal mucosa or in a chemically-induced gastritis, and b) NSAID/ASAerosion in Hp gastritis. 2. Hp-induced erosions were diagnosed whenever, within an Hp gastritis, erosive defects covered with inhomogeneous fibrinoid necrosis that did not blend into the adjacent lamina propria were found. Such necrosis also contained cell debris and granulocytes (Fig. 2). The hypothetical aetiopathic classification of the erosions was carried out by one and the same pathologist (MS), who was completely blind to all clinical data and endoscopic findings. The results of the histological investigation were then compared with the clinical data on medication usage and the endoscopic appearance of the erosions.
Table 1 H. pylori induced
NSAR-ASS induced
NSAR-ASS induced with concomitant Hp-Gastritis
Number of patients
59
23
40
Male:female
22:37
8:15
p
20:20
n.s.
60
n.s.
Av. age (years)
55
54
Site pylorus prepyloric antrum rest of antrum corpus antrum and corpus
8.5% 55.9% 25.4% 3.4% 6.8%
17.4% 47.8% 17.4% 8.7% 8.7%
7.5% 45.0% 30.0% 2.5% 15.0%
n.s.
Size of erosion lentil-sized pea-sized bean-sized
55.9% 37.3% 6.8%
47.8% 26.1% 26.1%
27.5% 37.5% 35.0%
p=0.0042
Formal typing acute subacute chronic
5.1% 11.9% 85.0%
21.7% 56.6% 21.7%
17.5% 70.0% 12.5%
P < 0.0001
NSAID/ASA-induced erosions· 139
Results The histological slides obtained from 122 patients in whom erosions were unambiguously confirmed by histology were evaluated. On the basis of the given histological criteria, a Helicobacter pylori-induced erosion was diagnosed in 59 patients (48.4%), and an NSAID/ASA-induced erosion in the absence of Helicobacter pylori gastritis in 23 patients (18.8%), while an NSAID/ASA-induced erosion in the presence of Hp gastritis was diagnosed in 40 patients (32.8%). The average age and sex distribution of the patients, site distribution, size and formal histological typing of the erosions are seen in Table 1. Statistically significant differences were found with regard to size and formal histological typing of the erosions: the NSAID-ASA-induced erosions were larger and more frequently acute or subacute. With regard to number, configuration, endoscopic appearance of the margins, and the endoscopically diagnosed surface appearance, as well as to the histological depth of the lesion and the nature and frequency of associated lesions, no statistically significant differences were observed between the three histological diagnostic Table 2. Endoscopic features of the erosion (n = 122)
2 Fig. 1 (upper). NSAID/ASS-induced erosion of the gastric mucosa: homogeneous eosinophilic ischaemic necrosis blending into the adjacent lamina propria. Fig. 2 (below). Helicobacter pylori gastritis-induced erosion: erosive defect covered with inhomogeneous fibrinoid necrosis with cell debris and granulocytes.
Classification and grading of the gastritis in antrum and corpus were done in accordance with the principles laid down in the updated Sydney System [26], with minor modifications [33]. Patients with Crohn's disease or gastric carcinoma or MALT lymphoma were excluded from the study.
Statistical methods The morphological, anamnestic and histological data were presented in tabular form, broken down in accordance with the histological classification of the erosions. The nominal data in the resulting tables were checked for uniformity using the Chi square test. The siginificance level was set at 0.05. The sensitivity and specificity of the histological diagnosis (NSAID/ASA-induced or Hp-induced) were also calculated.
No. solitary 2-5 5-10 more than 10
18.0% 47.5% 23.0% 11.5%
Form flat raised in part flat, in part raised
32.0% 50.8% 17.2%
Margin sharply delimited unsharply delimited
72.9% 27.1%
Surface - actively bleeding - haemorrhagic - non-haemorrhagic
0.8% 34.4% 64.8%
Histological depth of penetration - superficial - base of foveolae - body of glands - muscularis mucosae
14.3% 81.4% 13.4% 0.9%
Associated lesions erosions in descending pt. of duodenum erosions in the duodenal bulb ulcer in the duodenal bulb pyloric ulcer gastric ulcer reflux oesophagitis
0.8% 23.8% 20.5% 8.2% 1.6% 14.7%
140 . M. Stolte et al.
Table 3. Admitted medication usage in patients with erosions N medication Medication containing acetyl salicylic acid NSAIDs "Painkillers" Iron preparations Others
57.3 % 28.2% 6.5 % 3.2% 0.8% 4.0%
Table 4. Comparison of histological classification of erosions with patient information on medication usage Histological erosion classification Admitted medication usage
HP-induced
NSAID/ASS- NSAID/ASSinduced in HPinduced gastritis
No drug use
48 (81 %)
7 (30 %)
14 (35%)
NSAID/ASS
II (19%)
16 (70%)
26 (65 %)
groups. In view of this uniformity, the results of the analysis are summarized in Table 2. The data provided by the endoscopists on the use of medication of the 122 patients with histologically confirmed erosions (see Table 3) show that 38.7% of the patients had been using drugs capable of inducing erosions of the gastric mucosa. A comparison of the histological classification of the erosions and the data on drug usage (see Table 4) shows that 81% of the erosions histologically diagnosed as H. pylori-induced lesions were not associated with medication usage. In contrast, the drug history of 70% of the patients with histologically diagnosed NSAID/ASA-induced erosions in the absence of Helicobacter pylori gastritis, and of 65% of the patients with histologically diagnosed NSAIDI ASA-induced erosions with concomitant Hp gastritis actually showed prior use of NSAIDIASA preparations. In the group of 23 patients with histologically diagnosed NSAID/ASA erosions, but no H. pylori gastritis, the histological work-up of the antrum and corpus mucosa revealed no pathological findings in 13% of the cases, but a chemically-induced antral gastritis in 87%. On pooling the two groups with the histological diagnosis of NSAID/ASA-induced erosions, this histological diagnosis was found to have a sensitivity of79.24% and a specificity of 69.56%.
Discussion Although our results show that a high percentage of NSAID/ASA-induced erosions of the gastric mucosa
can be correctly diagnosed at the histological work-up, the specificity and sensitivity of this histological diagnosis are only 69% and 79%, respectively. However, if we take into account the fact that some of these patients will probably have made false statements on drug usage, or have deliberately concealed their use of ASAcontaining pain killers, it is very probable that the histological suspicion of NSAID/ASA-induced erosions is correct in a higher percentage of the cases than indicated above. This assessment is indirectly supported by an analysis of the data on medication usage and the classification of gastritis in those patients with a histological diagnosis of NSAID/ASA-induced erosions in the absence of Hp-induced gastritis, for although 30% of these patients denied taking medication, and 87% of the same patients were found to have chemically-induced gastritis, thus providing indirect evidence for the use of NSAIDIASA preparations [29 J. In the presence of Helicobacter pylori gastritis, we expected to find a large uncertainty in the histological classification of the erosions. Apparently, however, the criterion ischaemic necrosis we selected as an indicator for NSAID/ASA-induced erosions is so accurate that 65% of the erosions so diagnosed were compatible with medication usage. In this study on the differentiation of the pathogenesis of erosions of the gastric mucosa, the endoscopic findings were not particularly helpful. The presumably NSAID/ASA-induced erosions were statistically significantly more frequently acute or subacute, and also larger than the Hp-induced lesions. We expected to find that the NSAID/ASA-induced erosions are more frequently unsharply delimited, multiple and haemorrhagic as compared with the Hp-induced erosions; however, no statistically significant differences were found in respect of these parameters. The results of our analysis provide indirect confirmation of numerous experimental animal studies which aimed to clarify the pathogenesis of NSAIDIASA-induced lesions of the gastric mucosa. The inhibition of prostaglandin synthesis and oxidative phosphorylation by these substances [4, 7, 8J alone probably does not suffice to explain the development of erosions. Of greater importance for the generation of ischaemic necrosis is the NSAIDIASA-induced swelling of the endothelium lining the capillaries in the mucosa [37 J, granulocyte adhesion in the capillaries [2, 18J, sludge phenomena involving the granulocytes leading to the formation of so-called white thrombi and platelet thrombi [7, 27, 36J, gradual slowing of the bloodflow [37 J, and spastic vasoconstriction [8, 28]. The neutrophil granulocytes seem to play a key role in the pathogenesis of NSAID/ASA-induced erosions, because in animal experiments injury to the mucosa does not occur when the function of the neutrophil granulo-
NSAID/ASA-induced erosions· 141
cytes is blocked or the animals are rendered "granulocyte-free" [34J. This pathomechanism underlying the damage to the mucosa applies not only to the stomach, but also to the small bowel [I] and large bowel [4J, where, as our experience shows, the NSAID/ASA-induced injury can also be relatively readily identified by the ischaemic necrosis. Since, of course, ischaemic necrosis of the mucosa of the gastrointestinal tract can have numerous other causes (shock, vascular disease, amyloidosis, cardiac insufficiency, and many more), the finding of such a necrosis at histology can only lead to a tentative diagnosis. However, the fact that the pathologist's report indicates the possibility that the lesion may be due to the use of NSAIDIASA preparations can prompt the careproviding physician to take a careful drug history - if he has not already done so - to exclude other causes of ischaemic necrosis and thus provide a better basis for the diagnosis of NSAID/ASA-induced erosion or ulceration than would be possible without the histological findings. In summary, we believe the results of our study show that the histological diagnosis of suspected NSAIDI ASA-induced erosions of the gastric mucosa is correct in a large percentage of cases. This suspected diagnosis can help the physician to identify previously unknown use of these drugs, to weigh up the risks and benefits to the particular patient of taking such medication, and to counsel him/her accordingly. The aetiopathic diagnosis of the erosions can also be improved by the biopsybased investigation of an underlying disease of the gastric mucosa (Hp gastritis?, C-gastritis?) that might be present. Whether the criterion of histologically detected ischaemic necrosis may serve not only for the clarification of erosions, but also for the aetiopathic classification of ulcerations, needs to be investigated in further studies.
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Received: November 26, 1998 Accepted: December 15, 1998