China, Louise; (2020) The role of human albumin solution in preventing infection in patients with acute decompensation of liver cirrhosis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Liver disease is the only major cause of mortality currently increasing in the UK and is the fifth most common cause of death. Patients with symptoms of liver failure secondary to cirrhosis are described as acute decompensation (AD) patients. They are highly prone to bacterial infection secondary to immune dysfunction. Elevated circulating Prostaglandin E2 (PGE2) levels contribute to immune suppression in AD patients. The plasma protein albumin can bind and catalyse inactivation of PGE2. Albumin is synthesised in the liver and levels fall as the synthetic function of the liver declines in AD and binding capacity becomes defective, making PGE2 more bioavailable. Previous work has shown a serum albumin of < 30g/L predicted immune dysfunction in a small cohort of AD patients and low serum albumin is associated with increased risk of nosocomial infection. Finally, a pilot study suggested that albumin infusions to raise levels above 30g/L may improve immune function in AD. There is a widespread belief in Hepatology that albumin holds additional therapeutic benefit, other than volume resuscitation. However, there are no randomised clinical studies to support this. My thesis examined whether prophylactic intravenous human albumin infusions to increase serum albumin >30g/L would prevent AD patients from developing infection. A new IV 20% Human Albumin Solution (HAS) treatment regimen was tested in a 79 patient single-arm feasibility study in busy healthcare settings. Clinical data collected during this study allowed for the modification and improvement of the protocol and outcomes to move to a multicenter randomised control trial of >800 patients. I developed a plasma bioassay to explore the impact of IV albumin on plasma mediated macrophage dysfunction that was feasible in a large trial setting to investigate possible underlying mechanisms of any effect. Samples from this feasibility study supported a beneficial effect of albumin infusions on immune function by binding plasma PGE2. Subsequent analyses from patients randomised to IV 20% HAS treatment versus standard care showed IV HAS decreased plasma PGE2 and improved the functional ability of plasma albumin to bind PGE2. However, there was no improvement in macrophage TNFα production nor any markers of systemic inflammation. This was despite patients in the treatment arm receiving 1000 mLs (700-1500) (median (interquartile range); Med(IQR) compared to 100 mLs (0-600) in standard care (P<0.0001, adjusted mean difference 710.4 (95% CI 631.9 to 788.8)). This was consistent with no clinical impact of IV albumin on infection with no differences in incidence of new infection, nor outcome in patients admitted with infection or receiving antibiotics at enrolment. In addition, no improvement in renal dysfunction nor mortality was observed. In summary albumin infusions to raise and maintain serum albumin >30g/L have no effect on immune function nor markers of systemic inflammation and do not decrease incidence of infection in AD patients. It should not be used for this purpose and perhaps the widespread use of albumin over other fluids in cirrhosis might be reconsidered.

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