874 Original article
Intestinal metaplasia in portal hypertensive gastropathy: a frequent pathology Duygu ˙Ibrisim ¸ a, Ug˘ur C ¸ evikbas¸ b, Filiz Akyu¨za, S¸ule Poturog˘lua, Emel Ahıshalıa, ¨ zdila, Mine Gu¨llu¨og˘lub, Kadir Demira, Fatih Besı¸ sık ¸ a, Gu¨ngo¨r Boztas¸ a, Sadakat O ¨ ktena and Sabahattin Kaymakog˘lua Yılmaz C ¸ akalog˘lua, Zeynel Mungana, Atilla O Objective To compare the frequency of intestinal metaplasia (IM) in patients with portal hypertensive gastropathy (PHG) to the control group with functional dyspepsia. Methods Two-hundred and eighty-nine cases were prospectively evaluated in three groups (controls:group I – 123 patients; cirrhotics: group II – 135 patients; noncirrhotic portal hypertensives: group III – 31 patients). Mucosal biopsies (three antrum, one angulus, two corpus) were taken and examined for atrophy, IM, dysplasia, Helicobacter pylori (Hp) and histologic PHG.
significantly higher than in patients with PHG (P < 0.05) and there was a positive correlation between Hp and atrophy (P < 0.05). In multivariate analysis, PHG and age were found as independent predictors for IM; PHG, age and Hp for atrophy. Conclusion Frequencies of atrophy and IM are higher in patients with PHG. PHG is a reliable marker for IM and atrophy in gastric mucosa. Eur J Gastroenterol Hepatol c 2008 Wolters Kluwer Health | Lippincott 20:874–880 Williams & Wilkins. European Journal of Gastroenterology & Hepatology 2008, 20:874–880
Results Frequencies of IM in groups I, II and III were 17.1% (type I, 3.3%; type II, 10.6%; type III, 3.3%), 34.3% (type I, 9.6%; type II, 17%; type III, 6.7%) and 33.3% (type I, 9.7%; type II, 12.9%; type III, 9.7%), respectively. In patients with PHG, frequency of IM was significantly higher than in control group (P < 0.05) and correlated with the severity of PHG (P < 0.05). The frequency of type III IM was not statistically different among the three groups. Frequency of atrophy in cirrhotic patients was higher than in control group (17.9% in group I, 32.6% in group II, 25.8% in group III; P < 0.05). In the control group, Hp prevalence was
Introduction Portal hypertensive gastropathy (PHG) is a common complication of portal hypertension (PHT), occurring in approximately 50–80% of patients. It is the term used to describe the endoscopic appearance of gastric mucosa with a characteristic mosaic-like pattern (MP) with or without red marks (cherry red spots and black-brown spots), seen in patients with cirrhotic and noncirrhotic PHT [1]. The exact pathogenesis of PHG is unknown. Among the pathogenetic factors, local haemodynamic disturbances, imbalance among microcirculatory mediators in gastric mucosa, as well as PHT per se were claimed [2]. The aetiology of characteristic lesions of PHG is not clear; it does not seem to be related to Helicobacter pylori (Hp) infection, and acid secretion does not play an important role. In patients with cirrhosis, prevalence of Hp infection is lower than in the general population [3]. The weakness c 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins 0954-691X
Keywords: intestinal metaplasia, portal hypertension, portal hypertensive gastropathy Departments of aGastroenterohepatology and bPathology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey Correspondence to Duygu ˙Ibrisim, ¸ Sahrayicedit Mah. Halk Sk. 14/7 Kadikoy, 34734 Istanbul, Turkey Tel: + 90 532 377 2139; fax: + 90 216 325 5664; e-mail:
[email protected] Received 18 November 2007 Accepted 8 February 2008
of the gastric mucosal barrier (reduced epithelial cell integration and a thinner gastric mucous layer) and in some patients, hypergastrinemia-induced acid load are considered to facilitate development of mucosal lesions [4,5]. Intestinal metaplasia (IM) is defined as a potentially reversible change in which a fully differentiated cell type is replaced by another differentiated cell type, and usually represents a change to cells better able to withstand an adverse environment. Thus, IM represents a change from gastric epithelial phenotype to a small intestinal or large intestinal phenotype [6]. As PHG is also a chronic cause of mucosal irritation, it is not surprising that IM develops in the base of PHG. In this study, we aimed to compare the frequency of IM in patients with PHG to a control group with functional dyspepsia. DOI: 10.1097/MEG.0b013e3282fc7380
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Portal hypertensive gastropathy and intestinal metaplasia ˙Ibrisim ¸ et al. 875
Materials and methods Patient selection
Two-hundred and eighty-nine patients [154 (53.3%) female and 135 (46.7%) male with mean age 46.36 ± 11.404 years)] who were admitted to Gastroenterohepatology Department of Istanbul University, Istanbul Medical Faculty between December 2002 and October 2005 were prospectively evaluated. This study was approved by the local ethics committee, and all participants signed an informed consent. One-hundred and twenty-three participants [mean age: 46.04 ± 10.789 years, 64 (52%) female] were enrolled in the control group (group I). One-hundred and thirty-five cirrhotic patients [mean age: 46.9 ± 11.006 years, 71 female (52.6%)] and 31 noncirrhotic patients with PHT [mean age: 45.19 ± 15.167 years, 19 female (61.3%)] comprised group II and group III, respectively. All groups were similar for age and sex characteristics (P > 0.05). Inclusion criteria were as follows. (i) Patients who were diagnosed with functional dyspepsia with normal laboratory tests and without any organic lesion in the upper gastrointestinal system endoscopy were enrolled in the control group (group I). (ii) Cirrhotic patients with PHG and noncirrhotic portal hypertensive patients with PHG were established in groups II and III, respectively. Diagnosis of liver cirrhosis or noncirrhotic PHT was based on clinical and laboratory findings, imaging techniques [upper gastrointestinal system endoscopy, ultrasonography and/or computerized tomography (CT)/MRI] and/or liver biopsy. The patients were excluded if they met any of the following criteria: patients without PHT and endoscopically detected gastric or duodenal erosions/ ulcers, patients who have PHT but not PHG, patients who have hepatocellular carcinoma or any other malignancy, patients who were previously administered Hp eradication therapy, patients who were treated with antisecretory or antibiotic therapy in the last 2 weeks, and patients with prominent coagulopathy [prothrombine time (PT) > 25 s and/or platelet counts < 25000/mm3]. Methods
For all participants, detailed clinical history, aetiology and duration of illness, b-blocker administration, history of upper and/or lower gastrointestinal system bleeding and history of endoscopic variceal therapy were evaluated. Biochemical indices, viral serological tests, autoimmune markers and liver biopsy for indicated patients were performed. The Child–Pugh classification was used for grading liver functional reserve [7]. All participants underwent upper gastrointestinal system endoscopy. Patients who had normal endoscopic findings or gastritis with erythema were enrolled in control group (group I). In cirrhotic (group II) and noncirrhotic (group III) patients with PHG, presence of mucosal edema, MP
and red marks (cherry red spots and/or black-brown spots) were endoscopically defined as PHG [1]. ‘The New Italian Endoscopy Club’ criteria were used for grading of PHG. Mucosal erythema and MP indicated mild disease, whereas red marks (cherry red spots and/or black-brown spots) were indicative of severe PHG [8]. According to endoscopic localization, PHG was classified as fundus-dominant, antral-dominant and diffuse type [9]. The size of oesophageal varices (OEV) was graded into grades 1–3 endoscopically. Gastroesophageal varices (GEV) were subclassified into two groups, type 1 GEV (GEV1) and type 2 GEV (GEV2) varices. Isolated gastric varices (IGV) occurring in the absence of EV were also subclassified into two groups, type 1 IGV (IGV1) and type 2 IGV (IGV2) varices [10]. For each participant, six mucosal biopsy specimens [five for histopathological evaluation (two antrum, one angulus and two corpus) and one for rapid urease test] were taken. Hp infection was evaluated with both microscopic examination of biopsy specimens and rapid urease test. Positivity in either histopathological examination or rapid urease test established a positive Hp status. Histopathological examination
Endoscopic biopsies were embedded in paraffin after standard tissue processing. Three-micrometer-thick serial sections were cut and the consecutive sections were stained with hematoxylin and eosin , modified giemsa , periodic acid Schiff/Alcian blue pH 2.5 (PAS/AB pH 2.5) and high iron diamine/Alcian blue pH 2,5 (HID/AB pH 2.5). All microscopic examinations were done by two pathologists (M.G.G., U.C.) who were blind to the clinical and endoscopic findings. The mucosal biopsies were evaluated according to the ‘Updated Sydney System’ [11] for chronic inflammation, active inflammation, glandular atrophy, IM, dysplasia and the presence of Hp microorganisms. The findings were graded as mild, moderate and severe except for dysplasia, which was graded as mild and severe. Histologic evaluation for portal hypertensive gastropathy
The mucosal areas displaying edema and dilated capillaries, which were filled with erythrocytes in the superficial lamina propria, were considered PHG positive [12]. Histologic evaluation for intestinal metaplasia
The presence of IM was investigated on the sections stained with hematoxylin and eosin, PAS/AB pH 2.5 and HID/AB pH 2.5. Biopsies displaying IM were grouped as type I (complete), type II (incomplete) and type III (incomplete) IM. The IM areas containing goblet cells
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876 European Journal of Gastroenterology & Hepatology 2008, Vol 20 No 9
and columnar cells with brush border were considered as IM type I. The acidic mucin (sialomucin) contained in the cytoplasma of goblet cells was stained purple with AB pH 2.5. The biopsies displaying IM with columnar cells without brush border were included in the incomplete IM group. The ones with goblet and columnar cells secreting sialomucin, which stained purple with AB pH 2.5 and blue with HID were considered type II IM and those with goblet and columnar cells secreting sulfomucin, which stains brown-black with HID were considered type III IM (Fig. 1) [13]. Statistical analysis
The SPSS 11.0 pocket program (SPSS Inc., Chicago, USA) was used. Histological findings were analyzed by ‘multicolumned w2 test’ and ‘analysis of variance’. Correlation analysis was tested with ‘Pearson correlation’ and ‘Kendall’s i_b correlation test’. Factors affecting atrophy and IM were evaluated with ‘multivariate analysis’. A ‘P’ value of less than 0.05 was considered significant.
Results Of the cirrhotic patients, 34 were in Child A, 55 in Child B and 46 in Child C stage. The most common aetiology was HBV (hepatitis B virus) (54 patients). Other aetiologies were HCV (hepatitis C virus) (21), cryptogenic (30), alcohol (14), autoimmune hepatitis (8), primary biliary cirrhosis (5), Budd–Chiary syndrome (1), Wilson’s disease (1) and haemochromatosis (1). Of the
noncirrhotic patients with PHT, 20 had idiopathic PHT; other aetiologies were congenital hepatic fibrosis (3) and portal vein thrombosis (8). All groups were compared for the frequencies of gastritis, histological PHG, IM, atrophy, dysplasia and Hp infection. Gastric inflammation was more prominent in the control group than in the cirrhotic and noncirrhotic portal hypertensive groups (P < 0.05). Ninety-nine percent of patients with endoscopically diagnosed PHG, also had histological PHG. In endoscopical examination of the cirrhotic group, 89 (65.9%) patients had mild and 46 (34.1%) had severe PHG. Only in three cirrhotic patients was antral-dominant PHG detected; others had fundusdominant PHG. Although 16 (51.6%) of noncirrhotic patients had mild PHG, 15 (48.4%) of them had severe PHG. Localization of PHG was fundus-dominant in all noncirrhotic patients. Frequency of IM was significantly higher in patients with PHG (P < 0.05). When the control group was compared with the cirrhotic group, the frequency of IM was significantly higher in the cirrhotic group (P < 0.05). There was no significant difference between cirrhotic and noncirrhotic portal hypertensive patients and between control and noncirrhotic portal hypertensive groups (P > 0.05). Frequencies of type III IM were similar in all groups (P > 0.05). The frequency of gastric atrophy was significantly higher in patients with PHG than in the control group (P < 0.05). No significant difference was
Fig. 1
(a)
(b)
(d)
(c)
(e)
Histological evaluation of portal hypertensive gastropathy (PHG) and intestinal metaplasia (IM). (a) PHG and IM. Edema in the lamina propria and capillary dilatation and congestion as features of PHG and type I IM with columnar cells having brush border and goblet cells among them (hematoxylin and eosin , original magnification 200 ). (b) An area of type I IM in atrophic mucosa (PAS/AB pH 2,5, original magnification 100 ). (c) Incomplete IM with goblet cells and columnar cells secreting blue-purple asidic mucin (sialomucin). (PAS/AB pH 2,5, original magnification 400 ). (d) Type II IM with goblet cells and columnar cells secreting blue acidic mucin (sialomucin) (HID/AB pH 2,5, original magnification 400 ) and (e) type III IM with goblet cells and columnar cells secreting brown-black sulfomucin (HID/AB pH 2,5, original magnification 400 ).
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Portal hypertensive gastropathy and intestinal metaplasia ˙Ibrisim ¸ et al. 877
shown between cirrhotic and noncirrhotic group and control and noncirrhotic group (P > 0.05). Frequency of dysplasia was similar in all groups (P > 0.05). Frequency of Hp infection was significantly higher in the control group than in the cirrhotic and noncirrhotic portal hypertensive groups (P < 0.05). Cirrhotic and noncirrhotic groups with PHT were similar for frequency of Hp infection (P > 0.05). The frequencies of IM, atrophy and dysplasia and Hp in all groups are shown in Fig. 2. In all groups, atrophy, IM and dysplasia showed a positive correlation with age. The control group revealed positive correlations between atrophy and age (r = 0.17, P < 0.05), IM and age (r = 0.18, P < 0.05) and dysplasia and age (r = 0.15, P < 0.05). In the noncirrhotic portal hypertensive group, there were positive correlations between atrophy and age (r = 0.32, P < 0.05), IM and age (r = 0.44, P < 0.05) and dysplasia and age (r = 0.15, P < 0.05). The cirrhotic group showed a negative correlation between Hp and Child–Pugh score (r = – 0.44, P < 0.05). In the control group, there was a positive correlation between rates of Hp and atrophy (r = 0.3, P < 0.05). In patients with PHG, rates of IM and severity of PHG showed a positive correlation (r = 0.38, P < 0.05). There was also a positive correlation between frequency of
atrophy and severity of PHG in these groups (r = 0.22, P < 0.05). In cirrhotic patients, severity of PHG and grade of Child–Pugh score were positively correlated (r = 0.32, P < 0.05). OEVs were seen in all patients with PHG. In the cirrhotic group, whereas 25 (18.5%) patients had grade I varices, 77 (57%) patients had grade II, 12 (8.9%) patients had grade III and 21 (15.6%) patients had grade III – with red signs varices. Of the patients with noncirrhotic PHT, three (9.7%) had grade I, 21 (67.7%) had grade II, five (16.1%) had grade III and two (6.5%) had grade III – with red signs varices. Gastric varices were found in 23 (13.9%) of the patients with PHG (groups II and III). In the cirrhotic group, seven (5.4%) patients had type 1 GEV (GEV1) and 10 (7.4%) patients had type 2 GEV (GEV2). In the noncirrhotic group with PHT, two (6.5%) patients had GEV1, two (6.5%) patients had GEV2 and two (6.5%) patients had IGV (IGV1). In all patients with PHG and in the cirrhotic group, the grade of OEV and the presence of gastric varices showed a positive correlation with the severity of PHG (P < 0.05). Moreover, the grade of OEV and the presence of gastric varices also showed a positive correlation with the rates
Fig. 2
(b) 34.30%
17.10%
Control (c)
Dysplasia
Cirrhotic
5.00%
4.90%
4.00% 3.00%
2.20%
2.00% 1.00% 0.00% Control
Cirrhotic
35.00% 30.00% 25.00% 20.00% 15.00% 10.00% 5.00% 0.00%
Noncirrhotic 6.50%
7.00% 6.00%
33.30% Atrophy
40.00% 35.00% 30.00% 25.00% 20.00% 15.00% 10.00% 5.00% 0.00%
Noncirrhotic
32.60% 25.80% 17.90%
Control
Cirrhotic
Noncirrhotic
(d) 60.00% Helicobacter pylori (Hp)
Intestinal metaplasia
(a)
49.60% 50.00% 40.00%
31.90%
30.00%
29.00%
20.00% 10.00% 0.00% Control
Cirrhotic
Noncirrhotic
Frequencies of intestinal metaplasia (IM), atrophy, dysplasia and Helicobacter pylori (Hp) in all groups. (a) In group I, 21 (17.1%) cases had IM [4 (3.3%) type I, 13 (10.6%) type II and 4 (3.3%) type III]. In group II, 45 (34.3%) patients had IM [13 (9.6%) type I, 23 (17%) type II and 9 (6.7%) type III]. In group III, IM was detected in 10 (33.3%) patients [3 (9.7%) type I, 4 (12.9%) type II, 3 (9.7%) type III]. (b) Gastric atrophy was found in 22 (17.9%) cases of control group, 44 (32.6%) of cirrhotic group and eight (25.8%) of noncirrhotic portal hypertensive group. (c) Six (4.9%) cases in control group, three (2.2%) in cirrhotic and two (6.5%) in noncirrhotic portal hypertensive group had dysplasia. (d) Hp infection was detected in 61 (49.6%) patients in control group, 43 (31.9%) in cirrhotic and nine (29%) in noncirrhotic portal hypertensive groups.
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878 European Journal of Gastroenterology & Hepatology 2008, Vol 20 No 9
of IM and atrophy (P < 0.05). Thirty-four (25.4%) patients in the cirrhotic group and 10 (33.3%) patients in the noncirrhotic PHG (26.8% of all patients with PHG) had a history of upper gastrointestinal system bleeding. The history of upper gastrointestinal system bleeding and the severity of PHG were positively correlated (P < 0.05). Patients with PHG who had been administered b-blocker therapy for any period, had a significantly lower rate of atrophy (P < 0.05). In multivariate analysis; the effects of PHG, older age, sex and Hp infection on the development of IM and atrophy were evaluated. Independent variables were PHG and older age for IM, and PHG, older age and Hp for atrophy.
Discussion PHG, the second most important cause of upper gastrointestinal system bleeding in PHT, is defined as the mucosal changes detected in the upper gastrointestinal system endoscopy [14]. In the congestive base of PHG, the gastric mucosal barrier is defective, microvascular permeability increases and the mucosa becomes more susceptible to the irritant effects of luminal factors [4,5]. IM is the replacement of gastric mucous cells with an epithelium similar to that of the small intestine. It is common in chronic gastritis of all causes and increases in prevalence with disease duration. Metaplastic epithelium can be recognized morphologically by the presence of goblet cells, absorptive cells and cells resembling colonocytes or by its enzyme or mucin content. IM is generally regarded as a condition that predisposes to malignancy. Type I IM poses no increased risk of carcinoma, whereas type III is considered to represent an early dysplastic lesion. Atrophy of the gastric mucosa is defined as loss of glandular tissue. IM is almost always present as a component of atrophic gastritis [11,15]. Chronic inflammation of gastric mucosa may be caused by Hp infection, autoimmune gastritis, bile reflux gastritis, nonsteroidal anti-inflammatory drugs and other gastric irritants such as a high salt diet and possibly cigarette smoking. This inflammatory process may trigger a sequence of events, which begin with gastritis, continue with atrophy and IM and lead to the development of intestinal type gastric cancer [6,16,17]. PHG is a cause of chronic mucosal irritation and may be followed by the development of IM. There are no data about the frequencies of IM and gastric cancer in patients with PHG. In this study, the frequency of IM was evaluated in patients with PHG and found significantly higher than in the control group. The prevalence of IM in patients with gastritis was reported as 16–20% in
different studies [18,19]. In our study, the frequency of IM was 17.1% in patients with functional dyspepsia and was consistent with the literature. These rates were 34.3 and 33.3% in cirrhotic and noncirrhotic portal hypertensive groups, respectively. This insignificant difference between two groups supports the theory that the liver disease is not the real mechanism, and PHT causing the haemodynamic changes in gastric mucosa is responsible for PHG. IM is generally associated with atrophy and correlated with age [20,21] In our study, the frequency of atrophy in patients with PHG was also higher than in the control group. In all groups, atrophy, IM and dysplasia were correlated with age. Although the frequencies of IM and atrophy were significantly higher in all patients with PHG and in the cirrhotic group than in the control group, in the noncirrhotic group a frequency similar with cirrhotic patients was statistically insignificant compared with the control group. This condition may be owing to relatively lower patient numbers in the noncirrhotic group. From three types of IM, type III IM is the least common and was reported as 6.7% in cases with IM [22]. In our study, rates of type III IM were 3.3, 6.7 and 9.7% in the control, cirrhotic and noncirrhotic groups, respectively, and were not statistically different. An increased frequency of gastric cancer in patients with PHG has not been reported. In a retrospective evaluation of upper gastrointestinal system endoscopy results of 14,960 cases between 1995 and 2005 in our department, gastric cancer was found in 186 (1.2%) cases. Endoscopically detected gastric cancer was shown in 180 (1.4%) of the 12,960 cases without PHT and six (0.3%) of 2,000 cases with PHT. The frequency of gastric cancer was statistically higher in patients without PHT (P = 0.001). In our study, the frequency of dysplasia in patients with PHG was not different from the control group (P > 0.05). We believe that the risk of gastric malignancy does not increase in patients with PHG, because rates of type III IM and dysplasia, which have malign potential, are not higher in this group. Because PHG causes IM by changing the microenvironment in gastric mucosa, an adaptive process leads to type I and type II IM. Type III IM is thought to develop in genetically susceptible patients with the addition of environmental factors and arise from the somatic mutations in stem cells. In many cases, the areas of dysplasia are found to be adjacent to gastric cancers [6,23]. Zhang et al. [24] reported that rate of Hp colonization changed in different ages (lower rates under 30 years and over 60 years) and ranged between 33 and 57% in patients with chronic gastritis. In our study, Hp prevalence was 49.6% in the control group and significantly higher than
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Portal hypertensive gastropathy and intestinal metaplasia ˙Ibrisim ¸ et al. 879
other groups. Although Hp prevalence was lower in groups with PHG, higher IM and atrophy rates in these groups support the theory that these cellular changes are not related to Hp infection and are directly correlated with PHG. In addition, although there was a strong correlation (P = 0.001) between rates of Hp and atrophy in the control group, no significant relation was shown in the groups with PHG. The positive correlation betweeen Hp and atrophy rates in the evaluation of all cases, is a result of prominent significance in the control group. A positive correlation between Child–Pugh score and severity of PHG may be explained by the longer duration of PHG in patients with advanced liver disease. Lower Hp rates in patients with higher Child–Pugh score may be related to cellular changes in gastric mucosa with longterm PHG. Although atrophy, IM and dysplasia are correlated with age in all groups, no correlation between age and Hp was shown. This may be because of an increase in IM frequency in years and inappropriate changes in Hp in the gastric microenvironment. The grade of OEVs and the presence of gastric varices were correlated with the severity of PHG in all patients. This correlation indicates that PHT reflects similarly to the upper gastrointestinal system collaterals and gastric mucosa. Moreover, a positive correlation between varices and gastric atrophy and IM implies that presence and grade of varices are parallel with the grade of PHG. The frequency of severe PHG was significantly higher in patients with previous upper gastrointestinal bleeding.
investigated and compared with a control group with functional dyspepsia. The frequency of IM is higher in PHG, but type III IM, which is clinically important and primarily associated with genetic factors, has a similar frequency to the control group. The frequency of atrophy is also higher in PHG. PHG is a reliable marker for IM and atrophy in gastric mucosa. Long-term studies in which patients with PHG were followed up with clinical, laboratory and endoscopical findings are needed to better understand the clinical meaning of these results.
Acknowledgement Conflict of interest: none declared.
References 1 2
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In multivariate analysis, independent predictors were PHG and age for IM, and PHG, age and Hp for atrophy. In patients who were given b-blocker therapy, the frequency of atrophy was significantly lower. This effect seems to be related to the improvement of congestion in gastric mucosa with these agents. As a criticism of our study, it would be nice to have a control group of portal hypertensive patients without PHG. But the rates of the abnormalities in PHG, such as IM and atrophy, were needed to be compared with an index group. This index group is the group with dyspepsia, which is the most frequent in the population. In this way, it would be possible to say that if PHG increases IM, compared with the rates in normal population, comparing two groups with PHT with and without PHG would be more reliable to detect the direct effect of PHG. But to find enough patients for the group of PHT without PHG was difficult, so it could not be performed.
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In conclusion, in our study, for the first time in the literature, the frequency of IM in patients with PHG was
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