**5. Factors influencing the development of portal hypertensive gastropathy**

Many factors related to portal hypertension affect the presence and the severity of PHG. As the commonest cause of portal hypertension is liver cirrhosis, the presence or absence of cirrhosis, and its severity, may also affect the PHG.

#### **5.1. Factors related to portal hypertension**

• **Severity of portal hypertension:** The frequency of PHG is strongly correlated with the severity of portal hypertension, as indicated by hepatic venous pressure gradient (HVPG), esophageal intra‐variceal pressure, and/or presence of esophageal varices and its size [12]. It was also found that portal hypertension associates with severe PHG, but not mild PHG, this was evident in patients with severe PHG, which were discovered to have elevated HVPG, high hepatic sinusoidal resistance, and low hepatic blood flow, all markers of se‐ vere portal hypertension [12].

On the other hand, PHG as a marker of portal hypertension has conflicting results among the studies. Its sensitivity, positive predictive value (PPV) and negative predictive value (NPV), vary considerably between the studies, but its specificity has been reported to be above 95%.

The pathogenesis of PHG is still poorly understood. Portal hypertension is essential in the presence of PHG, due to the mechanical effect of the increased pressure in the portal vein which leads to hyper‐dynamic congestion with a net increase in the gastric blood flow, this increase occurs in the submucosal, muscle, and serosal layers, while decreasing in the muco‐ sal layer due to congestion and stasis. These hemodynamic changes impair gastric muco‐ sal defense mechanisms, which lead to release of pro‐inflammatory mediators, and alter the growth factors which render gastric mucosa more susceptible to injury, and impair mucosal healing. This defenseless mucosa may explain the increase in the rate of bleeding from PHG, additionally this abnormal gastric microcirculation, may render gastric mucosa more vulnera‐ ble to hypoxia, and more susceptible to noxious gastric factors, such as aspirin and ethanol [4]. Many other factors have also been implicated in the pathogenesis of PHG such as increased pro‐ duction of nitric oxide (NO), oxygen free radicals, endothelin‐1, tumor necrosis factor‐α, and prostaglandins. The most important factor, NO, is a potent vasodilator secreted by endothelial cells which may underlie the gastric vascular dilation and hyper‐dynamic circulation in PHG. Furthermore, the expression of transforming growth factor α (TGF‐α) and the epidermal growth factor (EGF) receptors in the gastric mucosa were reported to be highly elevated in areas of spon‐ taneous gastric injury. Recently, studies found other factors, like p53‐upregulated modulator of apoptosis (PUMA), to be markedly induced in the gastric mucosa of PHG patients [11]. Increased gastric mucosal apoptosis and decreased mucosal proliferation, were also noted in rats with PGH.

**5. Factors influencing the development of portal hypertensive gastropathy**

Many factors related to portal hypertension affect the presence and the severity of PHG. As the commonest cause of portal hypertension is liver cirrhosis, the presence or absence of

• **Severity of portal hypertension:** The frequency of PHG is strongly correlated with the severity of portal hypertension, as indicated by hepatic venous pressure gradient (HVPG), esophageal intra‐variceal pressure, and/or presence of esophageal varices and its size [12]. It was also found that portal hypertension associates with severe PHG, but not mild PHG,

cirrhosis, and its severity, may also affect the PHG.

**5.1. Factors related to portal hypertension**

Snake‐skin pattern has higher specificity (93–100%) for the diagnosis of PHG [10].

PHG can present at any age, including pediatric or adult patients [7].

**4. Pathophysiology**

60 Stomach Disorders

This leads us to the conclusion that not all patients with portal hypertension exhibit evi‐ dence of, or develop PHG. On the other hand, resolution of PHG, which occurs after inter‐ vention to decrease portal hypertension (by pharmacotherapy, trans‐jugular intrahepatic portosystemic shunt (TIPS), or liver transplantation), may suggest an association between PHG and portal hypertension [13].

Thus, although PHG cannot be diagnosed without portal hypertension, it is however not the only factor that evokes PHG.


Other techniques are also used for obliteration of the esophageal varices including angio‐ graphic variceal obliteration (which increases the PHG frequency), and percutaneous trans‐ hepatic variceal embolization; after which 38% of the patients develop *De‐novo* PHG. The development of PHG for the first time or its increase in frequency and/or its severity is attributed to increased gastric mucosal congestion due to a decrease in the blood flow in the esophageal varices, which leads to an increase in the portal blood flow.

This phenomenon can be explained by obliteration of the blood flow after eradication of esophageal varices, this can lead to increased portal pressure and redistribution of residual blood flow that had passed through the previously patent varices. This mechanism is sup‐ ported by the finding that gastric mucosal blood flow increases after variceal ligation [4].

Some investigators believe that the higher rate of PHG in patients undergoing endoscopic variceal eradication (sclerotherapy or banding) merely reflects other factors rather than the procedures *per se*, factors like; increased duration of portal hypertension, advanced liver disease, or severe portal hypertension in patients selected to undergo variceal eradication, must be evaluated in patients who developed PHG or showed an increase in its severity [18]. Nevertheless, higher frequency of PHG in patients undergoing sclerotherapy, suggest that portal hypertension is still the main underlying cause of PHG

#### **5.2. Factors related to liver cirrhosis**

• **Cirrhotic vs non‐cirrhotic portal hypertension:** Primary liver disease usually occurs in PHG, but is not essential for PHG, provided another cause of portal hypertension exists. Consequently, PHG can occur in patients with other causes of portal hypertension; non‐ cirrhotic portal fibrosis, pre‐hepatic or post‐hepatic portal hypertension [19].

Portal pressure is not the only factor that is determinant of PHG, other factors, like cirrhosis, may be implicated in the development of the mucosal lesions, which are characteristic of PHG. PHG was found to occur more commonly in patients with cirrhotic liver than in non‐cirrhotic portal hypertension patients, also the patients with cirrhosis have a more aggressive course of PHG with faster progression to more severe PHG as time advances [19].

Taking this in consideration, other factors may also be involved in the pathogenesis of PHG. For example, in patients with portal hypertension and cirrhosis, there is an increase in the level of many vasodilator substances in systemic circulation e.g. gastrin, secretin, and VIP, this increase in the level of vasodilator or the decrease in the sensitivity to vasoconstrictor substance may have a role in the underlying mechanism of PHG [10]. However, these changes were also found in cirrhotic patients not suffering from PHG, thus the exact picture of the pathogenesis is not yet fully understood.


with severe PHG (especially those without esophageal varices) had more frequent CTP stage C than patients with mild PHG [7].

Model for end‐stage liver disease (MELD) is another important scoring system for assessing liver disease severity, which was found to significantly correlate with PHG severity [20].

On the other hand, the severity of PHG was correlated to markers of advanced liver disease (like hypoalbuminemia and hyperbilirubinemia) which are biochemical markers of advanced liver disease. Markers of portal hypertension (thrombocytopenia) and of insulin resistance (hyperglycemia), were also significant independent predictors of PHG [21].

#### **5.3. Other factors**

Other techniques are also used for obliteration of the esophageal varices including angio‐ graphic variceal obliteration (which increases the PHG frequency), and percutaneous trans‐ hepatic variceal embolization; after which 38% of the patients develop *De‐novo* PHG. The development of PHG for the first time or its increase in frequency and/or its severity is attributed to increased gastric mucosal congestion due to a decrease in the blood flow in the

This phenomenon can be explained by obliteration of the blood flow after eradication of esophageal varices, this can lead to increased portal pressure and redistribution of residual blood flow that had passed through the previously patent varices. This mechanism is sup‐ ported by the finding that gastric mucosal blood flow increases after variceal ligation [4].

Some investigators believe that the higher rate of PHG in patients undergoing endoscopic variceal eradication (sclerotherapy or banding) merely reflects other factors rather than the procedures *per se*, factors like; increased duration of portal hypertension, advanced liver disease, or severe portal hypertension in patients selected to undergo variceal eradication, must be evaluated in patients who developed PHG or showed an increase in its severity [18]. Nevertheless, higher frequency of PHG in patients undergoing sclerotherapy, suggest

• **Cirrhotic vs non‐cirrhotic portal hypertension:** Primary liver disease usually occurs in PHG, but is not essential for PHG, provided another cause of portal hypertension exists. Consequently, PHG can occur in patients with other causes of portal hypertension; non‐

Portal pressure is not the only factor that is determinant of PHG, other factors, like cirrhosis, may be implicated in the development of the mucosal lesions, which are characteristic of PHG. PHG was found to occur more commonly in patients with cirrhotic liver than in non‐cirrhotic portal hypertension patients, also the patients with cirrhosis have a more aggressive course of

Taking this in consideration, other factors may also be involved in the pathogenesis of PHG. For example, in patients with portal hypertension and cirrhosis, there is an increase in the level of many vasodilator substances in systemic circulation e.g. gastrin, secretin, and VIP, this increase in the level of vasodilator or the decrease in the sensitivity to vasoconstrictor substance may have a role in the underlying mechanism of PHG [10]. However, these changes were also found in cirrhotic patients not suffering from PHG, thus the exact picture of the

• **Duration of liver disease:** The duration of liver disease positively correlates with develop‐ ment of PHG, with average cumulative incidence of 3% at 1 year, 10% at 2 years, and 24%

• **Liver disease severity:** PHG is correlated with liver disease severity, as measured by Child‐ Turcotte‐Pugh score (CTP score) (**Table 2**), Child‐Pugh stage C cirrhosis is associated with more frequent and faster progression of PHG. Also, it was found that cirrhotic patients

cirrhotic portal fibrosis, pre‐hepatic or post‐hepatic portal hypertension [19].

PHG with faster progression to more severe PHG as time advances [19].

esophageal varices, which leads to an increase in the portal blood flow.

that portal hypertension is still the main underlying cause of PHG

**5.2. Factors related to liver cirrhosis**

62 Stomach Disorders

pathogenesis is not yet fully understood.

at 3 years [7].

Many other factors may be involved in the pathogenesis of PHG, this includes thrombocyto‐ penia or splenomegaly which are associated with the severity of PHG. Additional factors like an increase in the thickness of the lesser omentum and the presence of a splenorenal shunt were found to correlate with PHG in patients with chronic liver disease [22].

#### *5.3.1. Factors that do not affect the risk of PHG*

Although, portal hypertension is essential for PHG diagnosis, there is still no association between the etiology of portal hypertension and PHG. Similarly, as cirrhosis is the common cause of portal hypertension, there is no correlation between the underlying causes of cirrho‐ sis and PHG. Moreover, in cirrhotic patients, the role of Helicobacter pylori (H. pylori) in the pathogenesis of PHG is not fully understood. Some contributed that Helicobacter has no role in the pathogenesis of PHG in these patients [23]. However, there is evidence of association between H. pylori infection and PHG in cirrhotic patients, in these patients, Helicobacter infection may be related to the severity of PHG. This was strengthened by the fact that there was mild improvement of PHG after H. pylori eradication. Therefore, we can conclude that there may be a minor role for H. pylori in the pathogenesis of PHG in cirrhotic patients [23]. Further studies on large number of patients are conducted to show the effect of H. pylori eradication in the treatment of PHG, especially severe portal gastropathy in cirrhosis.


A total Child‐Turcotte‐Pugh score of 5–6 considered class A, 7–9 is class B, and 10– 15 is class C. INR, international normalized ratio.

**Table 2.** Child‐Turcotte‐Pugh score.

Also, there is no evidence that there is any increase in the prevalence or severity of PHG with the use of either nonsteroidal anti‐inflammatory drugs (NSAIDs), or COX‐(cyclooxygenase)‐2 inhibitor [24]. Another negative correlation was found between alcohol and smoking along‐ side PHG, thus there is no benefit from abstinence or quitting smoking [25]. Likewise, the presence of PHG was independent of patient's age, or sex.
