Intern Emerg Med DOI 10.1007/s11739-014-1055-x

IM - ORIGINAL

Are clinical features able to predict Helicobacter pylori gastritis patterns? Evidence from tertiary centers Marilia Carabotti • Edith Lahner • Barbara Porowska Enzo Colacci • Paolo Trentino • Bruno Annibale • Carola Severi



Received: 23 December 2013 / Accepted: 29 January 2014 Ó SIMI 2014

Abstract Outcome of Helicobacter pylori infection is different according to gastritis extension (i.e. antrumrestricted gastritis or pangastritis). The aim of this study is to evaluate whether different gastritis patterns are associated with specific gastrointestinal symptoms or clinical signs that could be suggestive of the topography of gastritis. 236 consecutive symptomatic outpatients were recruited in two tertiary centers. They filled in a validated and self-administered Rome III modular symptomatic questionnaire, and underwent gastroscopy with histological sampling. 154 patients with Helicobacter pylori infection were included. Clinical presentation did not differ between antrum-restricted gastritis and pangastritis, gastro-esophageal reflux disease being present in 48.2 and 54.1 % of patients and dyspepsia in 51.8 and 45.9 %, respectively. However, pangastritis statistically differed from antrumrestricted gastritis in that the presence of clinical signs (p \ 0.0001) was observed in 33.7 % of the patients, consisting of iron deficiency (31.6 %), iron deficiency-

B. Annibale and C. Severi are the principal investigators. M. Carabotti (&)  E. Colacci  C. Severi Department of Internal Medicine and Medical Specialties, University ‘‘Sapienza’’ of Rome, Viale del Policlinico 155, 00161 Rome, Italy e-mail: [email protected] E. Lahner  B. Annibale Department of Digestive and Liver Disease, Sant’Andrea Hospital, University ‘‘Sapienza’’ of Rome, Via di Grottarossa 1035-1039, 00189 Rome, Italy B. Porowska  P. Trentino Department of General and Special Surgery ‘‘Paride Stefanini’’, University ‘‘Sapienza’’ of Rome, Viale del Policlinico 155, 00161 Rome, Italy

anemia (20.4 %) and levothyroxine malabsorption (3.1 %). Symptoms are not helpful in suggesting gastritis pattern whereas their association with signs, accurately detected, is indicative for the presence of pangastritis. Keywords Pangastritis  Topography of gastritis  Gastro-esophageal reflux disease  Dyspepsia

Introduction Helicobacter pylori (H. pylori) is one of the most common human infections, and it is estimated that more than half of the world population is infected [1]. H. pylori is an ancient colonizer of the human stomach and represents the main etiological factor in the development of gastritis, benign peptic ulcer and gastric cancer. For this reason, H. pylori is a WHO type I carcinogen for gastric cancer [2]. Gastritis patterns associated with H. pylori infection strongly influence its clinical outcomes. In accordance with the extension of the gastritis, it is possible to distinguish antrum-restricted gastritis, where the infection and related inflammation are limited to the antrum, from pangastritis where inflammation extends proximally in the stomach with the involvement of both body and fundus. Antrumrestricted gastritis is generally associated with increased acid secretion with increased risk of peptic disease while pangastritis is associated with hypochlorhydria, contributing to gastric carcinogenesis [1]. For this reason, the corpus-predominant gastritis index has been recently proposed as an early marker to identify the H. pylori-infected patients at a higher risk of gastric cancer [3]. The clinical presentation of H. pylori-related gastritis is variable, ranging from absence of symptoms to gastro-esophageal reflux disease (GERD) or dyspepsia.

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Furthermore, controversies exist as to the contribution of H. pylori-related gastritis in the pathogenesis of these syndromes whose associations are mainly derived from studies evaluating the clinical outcomes of eradication treatments [4, 5]. Concerning GERD, the Maastricht consensus on management of H. pylori infection concludes that H. pylori status has no effect on symptom severity, symptom recurrence, and treatment efficacy [1]. On the other hand, concerning dyspepsia, data on the contribution of H. pylori infection on the development of symptoms have not been clarified since the number needed to treat to cure one case of dyspepsia is of 14 patients [4]. Besides, pangastritis represents a risk factor for noneradication in lean and obese patients [6, 7] that requires repeated eradication regimens that favor the development of antibiotic resistance. In fact, in pangastritis patients, H. pylori infection is considered peculiar because the bacteria is able to colonize a stomach with reduced acid secretion and then, as already suggested, virulence and persistence mechanisms may be different in respect to patients with normal acid secretion [6]. Furthermore, the gradual reduction in acid secretion might progressively lead to hypochlorhydria-related alterations, such as iron deficiency, iron deficiency-anemia and drugs malabsorption [8–11]. Prior to the present time, the definition of H. pylori gastritis extension requires invasive endoscopy with multiple mucosa sampling and histological examination, and no data are available on the possibility of identifying H. pylori-related gastritis patterns through their clinical presentation. The aim of this study was to evaluate whether antrum-restricted gastritis and pangastritis are associated with specific upper gastrointestinal (GI) symptoms or clinical signs that could be indicative of the topography of gastritis.

Methods Patients 236 consecutive outpatients referred to tertiary level reference centers (Departments of Internal Medicine and Medical Specialties and Digestive and Liver Disease, University ‘‘Sapienza’’, Rome) for dyspeptic or GERD symptoms were included. Each patient underwent gastroscopy with multiple mucosa sampling, with at least two biopsies on the greater and lesser curvature of the gastric antrum and body, and one from the incisura angularis, according to the updated Sydney System [12]. Out of 236 patients, 82 were excluded from the study, 64 for the absence of H. pylori infection and 18 for the presence of organic lesions (Fig. 1). No patients presented with

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Fig. 1 Flow-chart of the study

dysplasia or cancer. All patients filled out the validated and self-administered Rome III modular symptomatic questionnaire, [13] and symptoms were analyzed either separately or altogether to classify patients in defined syndromes: (1) GERD, the typical reflux syndrome defined by the presence of troublesome heartburn or regurgitation [14]; (2) DYSPEPSIA, defined by the presence of symptoms thought to originate in the gastroduodenal region. This was further subdivided into Postprandial Distress and Epigastric Pain Syndromes (PDS and EPS) in the presence of postprandial fullness or early satiation, or pain or burning localized to the epigastrium not associated with other abdominal or chest-related symptoms, respectively [13]. At enrolment, to evaluate the presence of clinical signs, all patients had performed a blood examination with determination of complete blood count, ferritin and vitamin B12. Cut-off values of hemoglobin for the diagnosis of anemia were 12 g/dl in females and 13 g/dl in males, whereas that of ferritin for the diagnosis of iron deficiency was B15 lg/L [15]. Previous intake of proton pump inhibitors (PPI) has been evaluated; moreover, levothyroxine malabsorption was suspected in patients who presented with altered thyroid homeostasis despite adequate daily drug dose as reported [11]. In case of iron deficiency, a complete diagnostic algorithm was undertaken to exclude any possible cause of bleeding or extragastric malabsorption, including fecal occult blood, colonoscopy and Higham score for a semiquantitative menstrual flow evaluation [16]. Finally abdominal ultrasound was performed to exclude other possible causes of dyspepsia. Histological examination On the basis of histological examination, two groups were identified: antritis when gastric infection was restricted to the antrum, and pangastritis when infection involved body

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and fundus. According to the updated Sydney System, [6] pangastritis were further divided into: 1.

2.

3.

Antral-predominant when inflammation score in the antrum was greater than one grade more than inflammation in the corpus; Corpus-predominant when inflammation score in the corpus was greater than one grade more than that in the antrum; Equal-score pangastritis when the difference in the inflammation score between antrum and corpus was one or lesser than one grade.

Diagnosis of H. pylori infection was assessed on the basis of histological examination (Giemsa stain) when the bacteria was present in at least 2 out of 5 samples. Statistical analysis Differences between the groups were evaluated using the Chi-squared test (MedCalc software). A p value \0.05 was considered statistically significant. Results Helicobacter pylori infection was found in 72.9 % (172/ 236) of the patients, 18 with organic lesions. Of the 154 patients included in the study, 68.8 % (106/154) were women, and 31.2 % (48/154) men, with a median age of 55 years (range 20–83). 48 % (74/154) of the patients had been previously treated for H. pylori infection, and 31.2 % (48/154) have had previously performed at least one gastroscopy without a validated histological sampling. At time of the patients’ enrolment, 31.8 % (49/154) were taking PPI, self prescribed or recommended by a general practitioner, and 10.4 % (16/154) were taking levothyroxine. All patients were symptomatic, 52 % (80/154) presenting GERD and 48 % (74/154) dyspepsia. 36.4 % (56/154) presented antrum-restricted gastritis and 63.6 % (98/154) pangastritis (87.7 % equal score, 11.2 % antrum-predominant and only one corpus-predominant). The median ages of patients with antrum-restricted gastritis and pangastritis were not different, being respectively 60 years (range 24–83) and 54 years (range 20–82). The same overlap exists concerning gender, being male tofemale ratios 1:1.15 in antrum-restricted gastritis and 1:3.45 in pangastritis. The clinical presentation did not differ between antrumrestricted gastritis and pangastritis, being GERD present in 48.2 % (27/56) and 54.1 % (53/98) (p = 0.59) and dyspepsia in 51.8 % (29/56) and 45.9 % (45/98) (p = 0.59) of the patients, respectively (Fig. 2). Furthermore, in dyspeptic patients, EPS and PDS were almost equally distributed

Fig. 2 Prevalence of gastro-esophageal reflux disease (GERD) and dyspepsia according to the presence of antrum-restricted gastritis (antritis, gray columns) and pangastritis (black columns)

independent from the gastritis patterns, being present, respectively, in 25.0 and 23.2 % of antrum-restricted gastritis and 20.4 and 21.4 % of pangastritis. Pangastritis statistically differed from antrum-restricted gastritis for the presence of clinical signs (p \ 0.0001) that were observed in 33.7 % (33/98) of the patients with pangastritis. No biochemical alterations and clinical signs were observed in antritis patients. Between pangastritis patients, the predominant sign was iron deficiency (p \ 0.0001), observed in 31.6 % (31/98) of the patients, with a median ferritin of 9.7 lg/L (range 4–15). In 20 out of the 31 patients, an iron deficiency was associated with anemia with a median hemoglobin of 11.3 g/dl (range 6.1–12) and ferritin of 5.7 lg/L (range 2–15). No macrocytic anemia was observed and a median of vitamin B12 level was 477 ng/ml (range 300–676). Between patients with signs, GERD and dyspepsia were again equally distributed, being present in 50 % (17/34) and 50 % (17/34) of the patients, respectively. Between the 16 patients taking levothyroxine, 14 had pangastritis and 2 antritis. Drug malabsorption was found in 3 patients, all of whom had pangastritis.

Discussion The present study shows that symptomatic presentation of H. pylori-related gastritis overlaps between pangastritis and antrum-restricted gastritis suggesting that symptoms do not assist the clinician in the prediction of gastritis’s topography. However, the presence of pangastritis is strongly supported by the association of symptoms and signs, such as iron deficiency, with or without anemia, or levothyroxine malabsorption. Up to now, the available studies have only focused on the relationship between pattern of gastritis and the presence of clinical signs [10, 11], but data on symptomatic outcomes are lacking.

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The pattern of colonization within the stomach appears to be an important determinant of H. pylori disease manifestations, being that the infection is an important determinant for gastric acid secretion. Several studies have demonstrated that pangastritis leads to decreased acid secretion, which results from an injury to the gastric glands, with a consequent increased intragastric pH [17]. The subsequent hypo/achlorhydria mainly influences absorption of micronutrients in that gastric acid plays a key role in iron absorption, facilitating the dissociation and reduction of non-heme iron from food and its binding to ascorbic acid required for iron solubilization until its duodenal absorption [18]. Furthermore, acid is required for many different drug absorptions [11]. In fact, it has been demonstrated that, patients with impaired acid secretion require an increased dose of thyroxine, suggesting that normal gastric acid secretion is necessary for effective absorption of oral thyroxine [9]. The present study confirms the close relationship between pangastritis and signs. The association of signs and symptoms in pangastritis may then represent an indication to address the gastroscopy investigation with appropriate biopsy sampling. It has to be noted however that, even if anemia should be considered an ‘‘alarm’’ sign, since due to the frequent lack of endoscopic findings, an accurate biopsy mapping is usually not performed. In fact, it has been recently reported that accurate biopsy mapping according to Sydney System recommendations is followed only in 4 % of gastroscopies, causing an important drop of diagnosis [19], with pangastritis remaining often under-diagnosed. [20]. The present results in turn highlight the lack of association between specific upper GI syndromes and gastritis patterns. In the present study, GERD and dyspepsia are equally distributed not only between the two patterns of gastritis, but also between patients with hypochlorhydriarelated signs. It appears then that gastric acid secretion, that likely contributes to the genesis of signs, poorly influences the onset of symptoms. However, the high selected population investigated tertiary level centers, which included one-fourth patients who have failed in H. pylori eradication regimen, does not allow extension of the present results to the general population. In fact the prevalence of H. pylori infection observed, is higher than that previously reported [1], with a low incidence of macroscopic lesions and an high prevalence of functional GI syndromes. Nevertheless, the high prevalence of pangastritis found in our sample, is in accordance with previous studies [19], indicating that our selected population may well be representative of the usual distribution of gastritis patterns. In conclusion, upper GI syndromes, either GERD or dyspepsia, are not helpful in predicting H. pylori-related gastritis patterns. Nevertheless, their association with signs is indicative for the presence of pangastritis that require for

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its diagnosis an accurate gastric biopsy sampling, even in the absence of macroscopic findings. Acknowledgments This study was in part supported by Grants of the University of Rome Sapienza (Grant Numbers B8SE10002 290005). Conflict of interest

None.

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Are clinical features able to predict Helicobacter pylori gastritis patterns? Evidence from tertiary centers.

Outcome of Helicobacter pylori infection is different according to gastritis extension (i.e. antrum-restricted gastritis or pangastritis). The aim of ...
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