Bacterial infections are frequently associated with upper gastrointestinal bleeding in cirrhotic patients,4,31
developing in up to 66% (20% within the first 48 hours, 35–66% within two weeks).4
About two thirds of these infections are present at hospital admission while the remaining third develop during admission.1
Moreover, bacterial infections are more common in cirrhotic patients with acute variceal bleeding than in those admitted to hospital with other forms of decompensation, such as encephalopathy (see box 2
Box 2. Clinical evidence linking infection to variceal bleeding in cirrhotics
- Bacterial infections are common in cirrhotic patients with variceal haemorrhage
- Infection is independently associated with gastrointestinal haemorrhage in cirrhotics
- Infection is associated with failure to control variceal bleeding and early variceal rebleeding in these patients
- Prophylactic antibiotics prevent early rebleeding after acute variceal haemorrhage
Our group showed that proven bacterial infection, or a surrogate of its presence (use of antibiotics), had the strongest independent association with failure to control bleeding in cirrhotic patients with variceal bleeding, even stronger than active bleeding at endoscopy and severity of liver disease.4
Recently, a prospective survey of 1037 cirrhotics reported that the 297 patients with proven infection had a fourfold increase in the incidence of gastrointestinal bleeding (8% v
2%; p<0.001) compared with 346 known not to have bacterial infection, and that infection was independently associated with the occurrence of gastrointestinal haemorrhage.82
The strong association between infection and variceal bleeding in cirrhotics has been confirmed in several studies: association with failure to control bleeding,4,83
A recent meta-analysis confirmed that antibiotic prophylaxis prevented infections in cirrhotic patients with gastrointestinal bleeding and significantly increased the short term survival rate.31
The improvement in mortality was equivalent to that seen with terlipressin. In a very recent randomised study of 120 patients, prophylactic ofloxacin compared with on demand antibiotics was shown to prevent early rebleeding (24% v
64%; p<0.01) and to decrease the amount of blood transfused (1.40 (0.89) v
2.81 (2.29) units; p<0.05), in addition to preventing bacterial infections.5
Therefore, since our hypothesis was published,23
there are now a number of publications strongly suggesting a causal link between the presence of an infection and initiation of acute variceal bleeding and its associated early rebleeding, supporting our hypothesis.
Worsening of liver function is a recognised risk factor for first variceal bleeding84
so that infection may contribute to this risk, or indeed be a trigger for variceal haemorrhage, particularly as the liver damage occurring in sepsis may itself contribute to an acute increase in portal hypertension. The risk of portal hypertensive related bleeding in cirrhotic patients is related to the degree of portal hypertension, liver dysfunction, and to the size and endoscopic appearance of varices.84
However, trigger factors are not known. In the setting of portal vein thrombosis in non-cirrhotic patients, where often there are oesophageal varices of the largest size with red signs, the incidence of bleeding is much lower than in cirrhotics with similar varices. Thus the bleeding rate in portal vein thrombosis has been documented as 12.5 episodes per 100 patient years85
whereas the risk of first bleeding with Child grade A cirrhotics with large varices and moderate red signs is 24% in one year and in Child grade C with small varices and no red signs, 20%.84
The difference probably lies in the presence of liver disease (although the thrombophilic conditions often associated with portal vein thrombosis cannot be discounted). Cirrhosis predisposes to risk of infection which is not reported in non-cirrhotic portal hypertension.
This increased release of endotoxin and viable bacteria into the portal and systemic circulation is closely related to liver cirrhosis, with portal hypertension and liver dysfunction influencing increased intestinal permeability and altered small bowel motility on the one hand and bacterial overgrowth on the other (fig 1). Low grade endotoxaemia leads to priming of monomacrophages and an increase in NO and TNF-α. Bacterial translocation causes a further increase in NO and TNF-α, a reduced response to vasoconstrictors, and an increased risk of bacterial infection, with the associated risk of variceal bleeding, renal failure, hepatocellular injury, hepatic encephalopathy, and mortality (fig 2).
Figure 1 Damage to the intestinal barrier leads to bacterial translocation and endotoxaemia and thus to impairment of liver function and increase in portal pressure, possibly causing further damage to the gut: a vicious circle.
Figure 2 Endotoxaemia, bacterial translocation, and bacterial infection may be different expressions of the same process at different degrees of severity, and are associated with increasingly severe complications. NO, nitric oxide; TNF-α, (more ...)
The possible causative role of bacterial infection in variceal haemorrhage is less easily understood but nevertheless is most intriguing.23
Indeed, the known risk factors for variceal bleeding (HVPG, liver function, size of varices, and presence of red signs) do not readily explain why bleeding and early rebleeding occur unpredictably in patients with cirrhosis. Portal pressure rises significantly with daily meals as well as exercise, yet despite these marked daily changes, bleeding episodes are relatively infrequent. Thus a merely mechanical understanding of variceal bleeding as a consequence of portal pressure and tension on the variceal wall does not in our view explain the pattern of variceal bleeding. Endotoxaemia secondary to bacterial infection may indeed be the critical trigger for variceal haemorrhage23
as it produces a wide series of effects that may predispose the cirrhotic patient to bleeding: impairment of primary and secondary haemostasis, increase in portal pressure, and worsening of liver function (fig 3).
Figure 3 Possible pathophysiological pathways through which bacterial infection can trigger variceal haemorrhage. Summary
- Endotoxaemia and infections are common in cirrhotic patients
- Endotoxaemia and infections derange systemic and splanchnic haemodynamics in cirrhotics
- Infections impair coagulation in cirrhotics
- Infections worsen liver function in cirrhotics
- Infections may trigger variceal bleeding
- Infections are a causative factor in early variceal rebleeding