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Can hellicobacter pylori infection increase the risk of variceal bleeding in patients with liver cirrhosis?

Portal hypertension in patients with cirrhosis is the cause of many dangerous complications, such as hepatic encephalopathy, ascites, and gastro-oesophageal variceal bleeding. Gastro-oesophageal variceal bleeding is the cause of more than one-third of deaths in patients with liver cirrhosis.3 H.Pylori infection has a role in some diseases as peptic ulcer4 portal hypertensive gastropathy5 and hepatic encephalopathy.6 However, the role of H.Pylori infection is not well studied in cirrhotic patients with gastro-oesphageal variceal bleeding. The aim of our study was to assess and clarify the effect and the correlation between H.Pylori infection and bleeding from gastro-oesophageal varices in patients with liver cirrhosis and portal hypertension.


Introduction
H.Pylori is a gram-negative bacterium which lives in gastric mucosa, is the main cause of gastritis type B, 1 peptic ulcer disease and Mucosa-associated lymphoid tissue (MALT) lymphoma. 2 Portal hypertension in patients with cirrhosis is the cause of many dangerous complications, such as hepatic encephalopathy, ascites, and gastro-oesophageal variceal bleeding. Gastro-oesophageal variceal bleeding is the cause of more than one-third of deaths in patients with liver cirrhosis. 3 H.Pylori infection has a role in some diseases as peptic ulcer 4 portal hypertensive gastropathy 5 and hepatic encephalopathy. 6 However, the role of H.Pylori infection is not well studied in cirrhotic patients with gastro-oesphageal variceal bleeding. The aim of our study was to assess and clarify the effect and the correlation between H.Pylori infection and bleeding from gastro-oesophageal varices in patients with liver cirrhosis and portal hypertension.

Inclusion criteria
Subjects included in this study were cirrhotic patients, with age group 25-65years old, both males and females.

Exclusion criteria
i. Patients with known peptic ulcer disease.
ii. Those who receiving anti-ulcer treatment in the last three months and still receiving proton pump inhibitors (PPI) or H2 receptor blockers.
iii. Those previously diagnosed to have H.Pylori infection and those who had undergone or were currently undergoing H.Pylori eradication.

Methods
All the included patients will be subjected to the following: Full history taking, full clinical examination, laboratory investigations including: CBC, liver function tests as prothrombin time, serum albumin, Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), total and direct bilirubin, kidney function tests including blood urea and creatinine.

Abdominal ultrasonography, upper gastrointestinal Endoscopy
Endoscopic variceal ligation (EVL) or endoscopic injection sclerotherapy (EIS) with 5% ethanolamine oleate was performed for securing oesophageal varices and injection with histoacryl was performed for securing gastric varices.
A. Child-Pugh classification was done on admission by using parameter of serum bilirubin, serum albumin, prothrombin concentration, hepatic encephalopathy and ascites.
B. Rapid urease test was done for gastric biopsies to diagnose H.Pylori infection by using (rapid urease test kits, Kimberlyclark; Ballard, USA).

Statistical analysis
a) The collected data were computerized and statistically analyzed using SPSS program (Statistical Package for Social Science) version 20. Qualitative data were represented as frequencies and relative percentages.
b) Chi square test (χ 2 ) and Fisher exact was used to calculate difference between qualitative variables as indicated.
Quantitative data were expressed as mean ± SD (Standard deviation). Independent T test was used to calculate difference between quantitative variables in two groups in normally distributed data. The significance Level for all above mentioned statistical tests done. The threshold of significance is fixed at 5% level (P-value) *P value of >0.05 indicates non-significant results. *P value of ≤0.05 indicates significant results.

Results
Two hundred and fifty nine of our cases were males with a percentage of 66% and one hundred and thirty three patients were females with a percentage of 34%. Among of them one hundred and ninety patients presented with upper GIT bleeding with a percentage of 48.4% and two hundred and two patients were non bleeders with percentage of 51.6% (admitted for elective upper endoscopy). According to Child-Pough scoring system: The patients were divided as follow shown in Table 1.

Rapid urease test was done for all biopsies taken for diagnosis of H.Pylori infection and the results were as follow:
H.pylori infection was 60 patients in group A and 112 patients in group B with a total number of 172(43.8%) (Figure 1). Gastrooesphageal variceal bleeding was seen in 31.6%(n=60) of the H.Pylori infected patients and in 68.4%(n=130) of the no infected patients (total number was 190 patients) (P<0.001). Thus, the non-bleeding patients had a higher rate of H.Pylori infection than bleeding patients with a statistically significant difference between the two studied groups as regard infection with H.Pylori (Table 4).

Discussion
Patients with liver cirrhosis and portal hypertension carry high risk of upper GIT bleeding. Many risk factors have been reported for bleeding from esophageal varices .Systemic risk factors such as ascites, hepatic functional reserve, HCC and endotoxemia. 7 Local risk factors include esophagitis, degree of gastropathy, size of the varices, red colour sign, 8 alcohol and the use of an NSAID. The hemodynamic factors as high portal pressure, 9 and high intravariceal pressure with variceal wall tension. 10 Portal hypertensive gastropathy include changes in mucosa of the stomach of patients with liver cirrhosis It is associated with tortuosity and dilation of the submucosal vessels, increased area of the gastric mucosa occupied by vessels and thinning of the vascular wall, and 11 there is activation of growth factors and cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6. 12 TNF-α activates endothelial nitric oxide synthase and endothelin-1 in the gastric mucosa of patients with portal hypertension. 13 Over expressed nitric oxide (NO) synthase produces an excess of NO, which induces peroxynitrite overproduction and hyperdynamic circulation. Over expression of peroxynitrite together with endothelin-1 alters gastric mucosal defense mechanism, which are impaired in portal hypertension so, gastric mucosa becomes weak and tends to be easily injured. 14 H.Pylori is considered a risk factor for peptic ulcer in patients with cirrhosis .There is a significant increase in the production of inducible nitric oxide synthase (iNOS) in patients with portal hypertensive gastropathy. H.Pylori also increases expression of iNOS. 15 Initially we expected that when inflammation from H. Pylori infection is added to the surface mucosa of varices, mucosal breaks can occur easily and become a triggering factor for bleeding varices However, the incidence of gastro-oesphageal variceal bleeding was significantly lower than expected in patients infected with H.Pylori. It may be explained by atrophic gastritis induced by H.Pylori infection which leads to decrease acid production which has harmful effect on variceal wall.
In some studies, it has been reported that the prevalence of H.Pylori infection is significantly lower in patients with gastroesophageal reflux than without. 16 In addition, another report has found that H. Pylori infection inhibits reflux esophagitis by inducing atrophic gastritis. 17 These data confirmed that gastric acid may be involved in esophageal bleeding because of variceal rupture. 18

Conclusion
The results of our study demonstrated that H.Pylori infection was associated with low incidence of bleeding in patients with gastro esophageal varices than without and even may have a protective effect on variceal bleeding through induction of atrophic gastritis and concomitant hypoacidity.