Patients with cirrhosis can develop multiple complications as a consequence of portal hypertension and liver decompensation . Gastrointestinal (GI) bleeding is a life-threatening event observed frequently in cirrhosis and is commonly attributed to variceal bleeding . Since non-bleeding varices are asymptomatic, screening upper GI endoscopy is mandatory for cirrhotic patients in order to assess the indication for prophylactic treatment . However, upper GI bleeding (UGIB) in cirrhosis is not synonymous with variceal bleeding. Several studies have reported that peptic ulcer can be the cause of bleeding in almost 10% of cirrhotics who present with UGIB [2,4].
Previous studies have pointed out the high prevalence of peptic ulcer disease in patients with cirrhosis [5-8]. Furthermore, it has been shown that such patients have a significantly higher risk of peptic ulcer bleeding compared with the general population . Moreover, there are data underlining that any episode of UGIB due to peptic ulcer worsens the prognosis of cirrhotic patients [10,11]. In a recent study, the 90-day mortality of cirrhotic patients after peptic ulcer bleeding was 25%, significantly higher than that of non-cirrhotic patients . More recently, in a multicenter study, the authors concluded that patients with cirrhosis and acute peptic ulcer bleeding have a 45-day mortality risk similar to that of patients who bleed from varices, further emphasizing the importance of peptic ulcer disease in this setting . However, the existing data have limitations, as many of the published studies were retrospective and did not assess the presence of Helicobacter pylori (H. pylori) infection. Moreover, most of the studies included only patients with symptomatic GI bleeding.
The exact pathophysiology of ulcerogenesis in cirrhotic patients has not been fully elucidated, as there are conflicting data concerning the contribution of H. pylori infection and the potential role of portal hypertension [5,7,8,14,15]. In the present study, we prospectively evaluated the prevalence and risk factors of peptic ulcer in asymptomatic cirrhotic patients who underwent screening upper GI endoscopy.
Patients and methods
Consecutive patients with cirrhosis who attended the outpatient liver clinics of our Department during a 12-month period were invited to participate in the study. Patients were considered eligible if they were over 18 years of age and fulfilled the criteria for screening upper GI endoscopy, either on the basis of an initial diagnosis of cirrhosis or during follow up for gastroesophageal varices and within the guidelines established by the Baveno VI consensus workshop . We excluded patients with acute on chronic liver failure (ACLF), fulminant hepatic failure, known hepatocellular carcinoma (HCC) or other extrahepatic malignancies, transjugular intrahepatic portosystemic shunts (TIPS), previous surgical treatment for portal hypertension, and a history of gastric surgery or known peptic ulcer disease. We also excluded patients who had received antacids, H2-receptor antagonists, proton pump inhibitors, or antiplatelet, anticoagulation or anti-inflammatory agents during the last month before upper GI endoscopy.
The study protocol conformed to the principles outlined in the Declaration of Helsinki and was approved by the Ethics Committee of the hospital. All participants gave written informed consent.
The diagnosis of cirrhosis was based on histological and/or elastographic findings for patients with compensated liver disease and on clinical and/or radiological findings for patients with decompensated liver disease. Based on reliable liver elastography, patients with compensated liver disease were considered to have cirrhosis if they were found to have liver stiffness >14 kPa. The clinical and/or radiological diagnosis of cirrhosis with decompensated liver disease was made in cases with chronic liver disease of any cause and current or history of ascites, variceal bleeding, encephalopathy, and/or non-obstructive jaundice. The severity of cirrhosis was assessed using the Child-Pugh classification . Adopting the Baveno VI consensus workshop statements, supported by more recently published data, patients with liver stiffness by elastography <20 kPa and platelet (PLT) counts >150,000/mm3 were considered to be most unlikely to have clinically significant portal hypertension (CSPH) [3,17,18].
All patients included in the study underwent upper GI endoscopy. Gastroduodenal lesions were classified as gastric ulcer, duodenal ulcer, portal hypertensive gastropathy (PHG), esophageal varices, gastric varices, or no abnormal findings. Active ulcer was defined as a fibrin-covered mucosal lesion with a minimal size of 5 mm. The presence and severity of PHG were defined according to the North Italian Endoscopic Club classification , while varices identified endoscopically were classified as either small or medium/large, with the cutoff diameter being 5 mm . Varices were further classified as having a low (LRV) or high risk (HRV) for bleeding. LRV included small varices, while HRV represented small varices with red color signs or medium/large varices .
At each endoscopy, a total of 5 biopsy specimens were taken with sterilized biopsy forceps (3 from the antral mucosa proximal to the pylorus and 2 from the greater curvature of the corpus). Two samples from the antrum and 2 samples from the body of the stomach were fixed in 10% formalin and sent for histopathologic examination (Giemsa staining). The remaining specimen from the antrum was used for the rapid urease analysis (CLO-test, Delta West Ltd., Australia). Patients were considered to have H. pylori infection if H. pylori was detected by either the histopathologic examination or the rapid urease test.
All endoscopies were performed by 2 endoscopists (JV, GP) with more than 3 years’ experience. On the day of endoscopy, a complete medical history was obtained from each patient and all recent (within the previous 3 months) liver-related laboratory tests, imaging, and elastography results were recorded.
Values are expressed as mean±SD or median (range). Quantitative variables were compared between patients with or without peptic ulcer using the sample Student’ s t-test or the Mann-Whitney U test. Categorical data were analyzed using the χ2-test with Yate’s correction or the 2-sided Fisher’s exact test as appropriate. All statistical analyses were performed using SPSS 22.0 for Windows (SPSS, Chicago, IL, USA). A P-value <0.05 was considered statistically significant.
From March 2017 to February 2018, 105 consecutive cirrhotic patients underwent screening upper GI endoscopy and were invited to participate in the study. Of these, 5 were excluded because of ACLF (n=1), HCC (n=3), or TIPS (n=1). Finally, a total of 100 cirrhotic patients were included in this study. Viral hepatitis and alcohol abuse were the most common causes of chronic liver disease. The majority of patients were Child class A. However, half of them had a history of liver decompensation. Using the Baveno VI criteria as a discriminative tool for identifying cases without CSPH, 12/87 patients (14%) had both liver stiffness <20 kPa and PLT counts >150,000/mm3. The clinical and laboratory baseline characteristics of the patients are presented in Table 1.
Table 1 Baseline characteristics of 100 asymptomatic patients with cirrhosis
Esophageal varices were found in 59/100 (59%) patients. Of these, 39 (39%) were considered to have a high risk for bleeding. Gastric varices were found in only 3 (3%) patients. The majority of patients (81%) had PHG, while severe PHG was present in 33% (33/100).
Peptic ulcer was detected in 19% (19/100) of patients. Gastric ulcers were more common than duodenal ulcers (14% or 14/100 vs. 5% or 5/100, P=0.033). All gastric ulcers were observed in the antrum. Peptic ulcer was diagnosed in 14% (7/50) of patients with decompensated cirrhosis compared to 24% (12/50) of patients with compensated disease (P=0.202). In addition, peptic ulcer was detected in 23% (14/60) of patients with Child class A, 11% (4/35) of patients with Child class B, and 20% (1/5) of patients with Child class C (P=0.361).
Liver disease etiology was not associated with the presence of peptic ulcer. Patients with alcohol-related liver disease tended to have a greater prevalence of gastric ulcers compared to all other etiologies of cirrhosis, but the difference did not reach statistical significance (27.3% or 6/22 vs. 10.4% or 8/78, P=0.076). The prevalence of peptic ulcer was not associated with the presence and severity of varices, PHG, or the possibility of CSPH according to the Baveno VI criteria. However, there was a trend for a higher prevalence of gastric ulcer in patients with severe rather than mild/moderate PHG (21.0% or 7/33 vs. 8.3% or 4/48, P=0.112). Furthermore, the presence of peptic ulcer was not associated with age, sex, Child-Pugh score, model for end-stage liver disease (MELD) score, or with the complications of cirrhosis (hepatic encephalopathy, ascites), levels of liver stiffness or liver function tests (Table 2).
Table 2 Association of peptic ulcer disease with clinical, laboratory and endoscopic findings
Finally, the prevalence of peptic ulcer disease was 25% (3/12) in patients most likely not to have CSPH (Baveno VI criteria), and 20% (15/75) in the remainder of our patient population (P=0.707).
H. pylori infection
Fifty-four percent of our patients were found to be positive for H. pylori infection. The presence of H. pylori infection was not correlated with the presence of peptic ulcer disease: H. pylori positive: 52.6% (9/19) of patients with and 54.3% (44/81) of patients without peptic ulcer (P=0.998). In contrast, patients with decompensated compared to those with compensated liver disease were more commonly infected with H. pylori (66% or 33/50 vs. 42% or 21/50, P=0.027). H. pylori infection was not associated with the presence of PHG (H. pylori positive: 54.5% [44/81] of patients with and 45.5% [9/19] of patients without PHG, P=0.633) or the presence of gastroesophageal varices (H. pylori positive: 52.5% [31/59] of patients with and 56.1% [23/41] of patients without varices, P=0.839).
In our prospective study, a relatively high (~20%) prevalence of peptic ulcer was found in asymptomatic patients with cirrhosis who underwent upper GI endoscopy for screening purposes. Previous studies have also reported equally high prevalences of peptic ulcer in cirrhotic patients, with rates ranging from 15-20% [5,6,8,21-23]; however, most of those studies had specific limitations, mostly involving patients with additional risk factors for peptic ulcer. In particular, Bang et al revealed an ulcer prevalence of 18% among cirrhotics, but their population consisted specifically of alcoholics and 4.9% were either on non-steroidal anti-inflammatory drugs (NSAIDs) or on antiplatelet medication . In an Italian study, Siringo et al found a point prevalence of peptic ulcer of 15%, but 30% of their patients underwent upper GI endoscopy because of symptoms . Likewise, in another Greek study by Tzathas et al, the prevalence of peptic ulcer among cirrhotics was 18%, but they also included both symptomatic and asymptomatic patients as well as patients receiving NSAIDs or antiplatelet drugs . In contrast, we established a high incidence of peptic ulcer in patients with cirrhosis encompassing all etiologies of liver disease and without any symptom, while we excluded all patients receiving drugs that predispose to peptic ulcer.
The majority of peptic ulcers observed in our study were located in the stomach, in agreement with previous reports [5,7]. Although drugs are considered the main predisposing factor for the development of gastric ulcers, obviously this was not the case in our study. Our findings are supported by those of Luo et al, who reported that the risk of developing peptic ulcer disease and/or bleeding remains higher after adjustments for ulcerogenic medications (e.g., NSAIDs, antiplatelets, anticoagulants) .
The fact that in all patients with gastric ulcer the ulcer was observed in the antrum and not in the body, apart from the ulcer’s size, also distinguishes them from the gastric erosions commonly observed in portal gastropathy. As is well known, portal gastropathy affects mainly the body of the stomach and not the antrum . Consequently, severe portal gastropathy that can lead to gastric erosions is possibly not the main pathophysiology factor that could to some extent explain the high incidence of gastric ulcers in cirrhotic patients.
H. pylori infection is an established cause of peptic ulcer in non-cirrhotic patients; hence, many studies have tried, though not successfully, to establish an association between peptic ulcer and H. pylori infection in cirrhotics [6,8,25]. We were also not able to demonstrate such an association, as the prevalence of H. pylori infection was not statistically different in our cirrhotic patients with or without a peptic ulcer. Only Calvet et al reported a positive correlation between H. pylori infection and peptic ulcer in cirrhotics , but the diagnosis of H. pylori infection was made by serological methods, which have been shown to be suboptimal in patients with cirrhosis . In previous studies, the prevalence of H. pylori infection in cirrhotics ranged from 20-60% [8,25-27]. We also observed a high prevalence of H. pylori infection among cirrhotics (54%), probably reflecting the high prevalence of H. pylori infection in the general Greek population . We did not detect any association between H. pylori infection and the presence of gastroesophageal varices and/or PHG, reinforcing the impression that other mechanisms are involved in the pathogenesis of such complications of portal hypertension [27,29].
We did not find a significant association between the prevalence of peptic ulcer and the severity of cirrhosis, as expressed by Child-Pugh and MELD score or liver decompensation. Similar findings have also been demonstrated in most previous studies [5,22,30], while only Siringo et al reported a significant association between ascites and the presence of asymptomatic peptic ulcer .
The association between hepatic venous pressure gradient (HVPG) and peptic ulcer in cirrhotic patients has been controversial. Chen et al reported a significant association between HVPG levels higher than 12 mmHg and the presence of peptic ulcer . However, in another study by Bang et al such an association was not clearly documented . In the most recent trial by Ardevol et al, 93% of patients with peptic ulcer had HVPG >10 mmHg, but HVPG was not measured in the entire study population . We did not measure HVPG, but we tried to indirectly assess portal hypertension by liver elastography. According to our results, liver stiffness values were not associated with the presence of peptic ulcer. On the other hand, our cirrhotic patients, expected to have minimal probability for high-risk esophageal varices, based on low liver stiffness (<20 kPa) and high platelet counts (>150,000/mm3), and therefore no need for upper GI screening endoscopy according to the Baveno VI consensus meeting, were found to have an increased prevalence (23%) of peptic ulcer. Thus, the exclusion of the latter patient subgroup from screening upper GI endoscopy carries the risk of non-diagnosis of the usually asymptomatic peptic ulcer, precludes the early onset of treatment and eventually increases the risk of peptic ulcer complications such as bleeding. The exact pathophysiological basis of peptic ulcer development in cirrhosis has not been fully elucidated. H. pylori infection does not seem to be a driving factor, while, even if medications such as NSAIDs or antiplatelets strongly increase the risk of peptic ulcer in cirrhotic patients, their absence is not associated with a low risk of ulcerogenesis. Several pathogenetic factors have been implicated, such as impaired defensive mechanisms, decreased levels of the cytoprotective prostaglandin E or structural changes in the gastric mucosa . Additionally, experimental studies have demonstrated increased gastric submucosal shunting of blood away from the gastric mucosa, leading to reduced oxygen supply, poor perfusion, and a lack of reactive response to toxic injury [5,31].
We did not observe a significant difference in the prevalence of peptic ulcer between sexes. This is in agreement with most studies, except for the study by Calvet et al which reported a male predominance among patients with peptic ulcer . Unsurprisingly, most studies have shown that peptic ulcers are commonly observed in cirrhotic patients in the sixth decade of life [6,7,23]. Nevertheless, in accordance with our results, most studies did not find a difference in the mean age of cirrhotics with or without peptic ulcer. Finally, no difference across etiologies of liver disease was observed in our population. Similar findings have also been reported by most other studies, except for the study by Siringo et al, which found a higher prevalence of peptic ulcer in patients with cirrhosis due to chronic hepatitis B but provided no explanation .
In conclusion, our prospective study shows that the prevalence of peptic ulcer is high in asymptomatic patients with cirrhosis of various etiologies who undergo screening upper GI endoscopy. This is an interesting and potentially clinically relevant finding, as a prompt diagnosis of peptic ulcer will lead to appropriate management and potential prevention of serious complications in such a susceptible setting. One of the most interesting findings of our study was that the prevalence of peptic ulcer was higher in cirrhotic patients who may not be currently advised to have screening upper GI endoscopy, as they are considered to have a minimal probability of high-risk esophageal varices. These findings, of course, need to be investigated in larger prospective studies, as their confirmation could question the current recommendations for endoscopic screening in subgroups of cirrhotic patients and could support the need for endoscopic screening in the whole cirrhotic population. Finally, more studies are required to further clarify the underlying pathophysiologic mechanisms of ulcerogenesis in cirrhosis, the critical time point of its occurrence, the rate of possible recurrence, and the optimal prophylaxis for the elimination or minimization of the possibility of complications.
What is already known:
Several studies have pointed out a higher prevalence of peptic ulcer disease in cirrhotics compared to non-cirrhotic patients
Any episode of upper gastrointestinal (GI) bleeding due to peptic ulcer worsens the prognosis of cirrhotic patients
The existing data have limitations, as many of the published studies were retrospective
There are conflicting data concerning the contribution of Helicobacter pylori (H. pylori) infection and the potential role of portal hypertension severity
What the new findings are:
We have documented a relatively high prevalence of peptic ulcer in asymptomatic patients with cirrhosis who underwent upper GI endoscopy for screening purposes
H. pylori infection does not seem to play an important role in the pathophysiology of ulcerogenicity in patients with liver cirrhosis
The prevalence of peptic ulcer was higher in patients who may not be currently advised to have screening upper GI endoscopy, as they are considered to have a minimal probability of high-risk esophageal varices