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Volume: 3: Issue-2: April-June-2014 Copyrights@2014 ISSN: 2278-0246 Received: 22nd March-2014 Revised: 27th April-2014 Accepted: 28th April-2014

Coden: IJAPBS www.ijapbs.com Research article

H. PYLORI NEGATIVE GASTRITIS: A TIP OF THE ICEBERG

Arathi. C. A1, Arundhathi. S2, Ashwini.S. Ramji3 and Prashanth. B. N4

1,2,3Department of Pathology, Sri Siddhartha Medical College. Agalakote, Tumkur-572107, Karnataka.

4Consultant Gastroenterologist, Vikram- apkon diagnostic centre, Tumkur, Karnataka. Corresponding Author’s email: [email protected] Mobile phone no. : 9449670559

ABSTRACT Introduction: Worldwide common cause of gastritis is H. pylori infection. Treatment of H. pylori infection results in rapid disappearance of polymorphonuclear infiltration, reduction in lymphocytes and gradual normalization of mucosa. Mucosal atrophy and metaplastic changes resolve slowly. A recent study of patients with erosive esophagitis reported that 75 - 90 % of H. pylori- negative subjects had gastritis. Similarly, 56– 69% of H. pylori -negative subjects with dyspepsia or nonerosive gastroesophageal reflux had gastritis. Identifiable risk factors for H. pylori –negative gastritis are alcoholism, smoking, intake of proton pump inhibitors (PPI) and spicy diet. Aims: To find out prevalence and risk factors for non H.pylori gastritis. Materials and methods: Fifty four patients with dyspepsia, were evaluated with endoscopy and biopsy. Biopsies were taken from different areas and were studied for activity in mucosa, chronic inflammation, atrophy of glands, intestinal metaplasia and presence of H.pylori and were graded according to Updated Sydney System. Giemsa stain and Serum IgG anti H.pylori antibodies helped to confirm H. pylori negative gastritis. Results: Out of 54 cases, 33 (61.11%) were H.pylori negative gastritis. All 33 cases presented with dyspepsia and 21 (63.63%) had GERD. On endoscopy, 21 (63.63%) cases showed pangastritis and 2 had ulcer. All patients of GERD were on PPI. On histopathology, 8 (24.24%) cases showed chronic active inflammation, 3(9.09%) had mucosal atrophy and 6 (18.18%) showed intestinal metaplasia. Conclusion: H. pylori- negative gastritis accounted for 61.11%. Common risk factor for H. pylori- negative gastritis is intake of PPI. As H. pylori- negative gastritis incidence is significant, further studies have to be conducted to identify risk factors. Key words: H. pylori- negative, gastritis, proton pump inhibitors, Updated Sydney System, intestinal metaplasia, Giemsa stain, mucosal atrophy INTRODUCTION Gastritis is a histopathological condition characterized by inflammation of the gastric mucosa [1]. The incidence and the natural history of gastritis has been greatly clarified with the use of endoscopic gastric biopsy [2]. A cross-sectional study Worldwide the most common cause of gastritis is H. pylori infection (3). Recent studies reported that majority of the gastritis were H.pylori negative [3]. The unexpected results of these studies led us to question whether the concept that most biopsies could be characterized as either normal or H.pylori infected might be too simple and inadequate for practioners to initiate specific treatment to the patients [3]. Identifiable risk factors for H. pylori –negative gastritis are alcoholism, smoking, intake of proton pump inhibitors (PPI), histamine 2 receptor antagonists and aspirin/ NSAID [3]. Other causes include nonbacterial gastroenteritis caused by Norwalk viruses, haemorrhagic gastritis, collagenous gastritis, allergic gastritis; diffuse eosinophilic gastroenteritis, granulomatous gastroenteritis, syphyllis, malakoplakia, Cryptococcosis, bacilliary anigiomatosis, graft versus host disease [2].

International Journal of Analytical, Pharmaceutical and Biomedical Sciences Page: 26 Available online at www.ijapbs.com

Arundhathi et al IJAPBS ISSN: 2278-0246

H.pylori infection leads to a vast spectrum of diseases including acute and chronic gastritis, chronic active gastritis, follicular, atrophic, lymphocytic, granulomatous, auto-immune, giant fold gastritis, hyperplastic polyps, intestinal and “G” cell metaplasia, gastric adenocarcinoma, gastric MALToma and Menetrier disease. This discovery has resulted in the frequent performance of gastric mucosal biopsies [4]. Hence the evaluating pathologist is expected to comment on whether gastritis was present and, if so, to provide additional details especially in relation to H.pylori infection, to assist the clinician in patient management [3]. Treatment of H. pylori infection results in rapid disappearance of polymorphonuclear infiltration, reduction in lymphocytes and gradual normalization of mucosa. Mucosal atrophy and metaplastic changes resolve slowly if at all [3]. Hence, this study was conducted to investigate the prevalence and risk factors associated with H.pylori negative gastritis.

MATERIALS AND METHODS A cross-sectional study was conducted on fifty four patients with gastritis over a period of one year undergone endoscopy for the same were included in the present study. Patients with dyspepsia, nonerosive reflux disease (NERD) and erosive esophagitis (EE) were included for the study. Detailed clinical history (regarding demographic features, tobacco-smoking status, and alcohol consumption, previous treatment to H. pylori, past and current use of PPI histamine -2 receptor antagonist, aspirin and NSAID use) was collected and these patients were evaluated with endoscopy and biopsy was taken from the representative areas. In patients with pangastritis the biopsies were taken from corpus, fundus and antrum. Patients with past history of cancer of the esophagus, esophageal surgery or surgical resection of the esophagus or stomach, those with active lung, liver, colon, breast or stomach cancer, those on anticoagulant therapy, patients with liver disease with platelets below 70,000/cmm, are excluded from the study.

Histopathological examination All biopsy specimens were routinely processed, followed by hematoxylin and eosin (H & E), Geimsa and Warthin- Starry stains. The sections were studied in detail for the histopathological features and graded according to the updated Sydney system [5, 6]. Serology Serum samples from all study subjects were evaluated for Ig G antibody to the High Molecular weight, cell associated proteins of H.pylori, using ELISA. RESULTS All participants gave informed consent, after which esophagastroduodenoscopy (Fig 1) was carried out. The patients presented with clinical features, heart burn (29/54), abdominal pain (27/54), vomiting (24/54) and dyspepsia (26/54) (Table 1). Males were 35 and 19 were female. Mean age among male was 53.57 ± 12.73 years and females was 55.47 ± 14.66 STD years. Among the clinical feature heart burn accounted for 8/21(38.10%) and 21/33 (63.64%) in H.pylori posititve and negative individuals respectively. Abdominal pain accounted for 7/21(33.33%) and 20/33(60.61%) among H.pylori positive an H.pylori negative individuals.Vomiting accounted for 6/21(28.6%) and 18/33(54.55%) in H.pylori positive and negative individuals respectively. Dyspepsia accounted for 7/21(33.33%) and 19/33 (57.60%) in H.pylori positive and negative individuals respectively. 21 cases of gastritis were H.pylori positive and 33 were H.pylori negative (Fig 2). Among the risk factors PPI intake accounted for 10/21(47.62%) and 19/33(57.58%) in H.pylori positive and negative individuals respectively. NSAID’s intake accounted for 8/21(38.1%) and 17/33(51.52%) in H.pylori gastritis positive and negative individuals respectively. Alcohol consumption accounted for 9/21(42.9%) and 20/33 (60.61%) in H.pylori gastritis positive and negative individuals respectively. The above mentioned risk factors were commonly associated with H.pylori negative gastritis but this association was not statistically significant (table 1). Predominant site of involvement in both H.pylori positive and negative gastritis was antrum. On histopathology most cases of H.pylori negative group showed chronic gastritis (25/33) (Fig 3) accounting for 75.76%, acute on chronic gastritis were seen in 8/33 cases accounting 24.24% which was satistically significant (<0.05) (Fig 4). 3 cases each of H.pylori positive and negative gastritis showed atrophy accounting for 14.29 and 9.09% respectively. There was no satistically significant difference with respect to atrophy and intestinal metaplasia (fig 5) in H.pylori positive and negative patients. (Table 2).



Table 1: Showing the clinical features and the risk factors Clinical features H.pylori negative H.pylori positive P value

Heart Burn 21 (63.64%) 8 (38.1%) 0.067 Abdominal Pain 20(60.61%) 7(33.33%) 0.051

Vomitting 18(54.55%) 6 (28.6%) 0.061 Dyspepsia 19(57.60) 7(33.33%) 0.082

Risk Factors H.pylori negative H.pylori positive PPI 19(57.58%) 10(47.62) 0.474

NSAID’s 17(51.52%) 8(38.1%) 0.335 Alcohol and smoking 20(60.61%) 9(42.9%) 0.202

Table 2: Type and distribution of gastritis in H.pylori negative individuals Site H.pylori negative H.pylori positive P value

Acute antral 0 0 Chronic antral 25 (75.76%) 7 (33.33%) 0.001987

Acute on chronic antral 8 (24.24%) 13 (61.9%) 0.005647 Acute body 0 01 (4.8%)

Chronic body Acute on chronic body

Atrophy 3/33 (9.09%) 3/21 (14.29%) 0.5537 Intestinal metaplasia 6 (18.18%) 5 (23.81%) 0.6167

Fig 1: Endoscopy showing pangastritis

Fig 2: Pie chart showing H.pylori positive and negative gastritis



Fig 3: Chronic gastritis 40x ( H & E)

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

H. Pylori Positive H. Pylori Negative

33.33

75.76

61.9

24.24

Acute‐Chronic

Chronic

Fig 4: Graph showing type of gastritis on histopathology

Fig 5: Intestinal metaplasia 10x (H& E)



DISCUSSION Previous studies of adults with EE, NERD, or FD have primarily focused on a pathogenic role of H.pylori-associated gastritis, allowing the potential to miss gastritis in the absence of infection [1]. There are at least three possible reasons for the higher prevalence of H.pylori negative gastritis in the elderly. First, H.pylori could have been present but, with minimal colonization which might not have been detected by histological examination. Secondly, H.pylori could have been present in the past but was eliminated by treatment. The third possibility is that H.pylori was never present-that the gastritis in these patients had a different eitiology, such as auto-immune gastritis or as a result of ingestion of NSAID’s, both of which might be expected in the elderly population. Other conditions of hypochlorhydria (following partial gastrectomy, or omeprazole treatment) are also associated with a reduced prevalence of H.pylori, suggesting that some degree of acid secretion is necessary for H.pylori to persist in the gastric environment [7]. Studies done by Peura et al showed that 83%, 77%, 83% of EE, NERD & FD respectively had H.Pylori negative gastritis. However the patient populations in these studies were a part of clinical trial under investigation for EE, NERD and FD. The demographic compositions of this population were predominantly females, in contrast to the present study where males predominated [1]. Similar results were obtained in study done by Haber et al which showed that 79.5% of the individuals were H.pylori negative. The demographic composition of this population was predominantly males. This was similar to the present study [8]. In conclusion, H.pylori –negative gastritis was present in 61.11% individuals. Very few cases were classified under the other known causes of gastritis. Non H.pylori gastritis was typically chronic rather than acute on chronic as compared to H.pylori positive cases. The possible risk factors for non- H.pylori gastritis include autoimmune gastritis, infection by organisms other than H. pylori like Mycobacterium avium-intracellulare, Herpes simplex, and Cytomegalovirus, chemical or reactive gastritis caused by bile reflux or NSAID use. Other rare causes include collagenous gastritis, Crohn’s disease-associated gastritis, sarcoidosis, eosinophilic gastritis and lymphocytic gastritis [3]. Autoimmune gastritis is a chronic inflammatory process characterized by chronic atrophic gastritis with parietal and chief cell loss, metaplasia and epithelial remodeling limited to the mucosa of corpus and fundus [3, 9]. In the present study, we had three cases of H.pylori negative gastritis (3/33) with atrophy in the antrum but not in the corpus. Autoimmune gastritis can be ruled out by the absence of serum antiparietal and anti- intrinsic factor antibodies. H.pylori negative gastritis is more common than previously appreciated. It is not clear whether the risk of ulcer in H.pylori negative gastritis getting transformed into malignancy is increased or not. However, it is at least clear that in clinical practice, empirical treatment of H.pylori is not warranted in patients with gastritis without clear evidence of H.pylori infection. The clinical relevance and prognosis of H.pylori –negative gastritis is unknown and need to be further examined as the prevalence of this entity is higher than expected. Though not significant, PPI users seem to be at higher risk for H.pylori gastritis followed by alcohol and NSAID’s consumers.

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