Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.429602
Title: Albumin dialysis in liver failure
Author: Sen, Sambit
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2006
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Abstract:
Albumin-bound toxins accumulating due to hepatic dysfunction are believed to lead to multi-organ dysfunction in liver failure, contributing to a poor prognosis. Thus, liver support devices utilising albumin dialysis have been developed, and the Molecular Adsorbents Recirculating System (MARS) is the one being investigated most thoroughly. This series of studies was designed to systematically investigate its role in liver disease. The initial studies evaluated its clinical impact in patients with severe alcoholic hepatitis. MARS therapy was safe and feasible. Improvement of hyperbilirubinaemia and hepatic encephalopathy were the most consistent findings. Effects on systemic haemodynamics or renal function were insignificant. A rapid and sustained portal hypotensive effect was observed, suggesting that albumin dialysis may be a useful adjunctive therapy for variceal bleeding in patients with liver failure. An apparent reduction in mortality was observed, though the studies were not powered to evaluate survival. The next study investigated the pathophysiological basis of these changes in acute- on-chronic liver failure. Albumin dialysis improved encephalopathy, accompanied by reduced oxidative stress, without significant changes in arterial ammonia or cytokines. The improvement in encephalopathy independent of ammonia highlights the importance of other mediators such as oxidative stress in its pathogenesis. A porcine model of acute liver failure (ALF) was used to study the effect of MARS on the cerebral changes. Attenuation of intracranial hypertension was observed, as was a reduction of cerebral oedema (in white matter), without alterations of arterial ammonia, cerebral blood flow, cytokines or oxidative stress. Thus, while hyperammonaemia is probably essential for the initial development of cerebral oedema and intracranial hypertension in ALF, cerebral hyperaemia and inflammation are not. Regional differences exist for brain oedema, perhaps with therapeutic indications. Factors in addition to hyperammonaemia are also important. Finally, the effect of albumin dialysis on protein-bound drugs was studied. MARS efficiently removed both albumin-bound (phenytoin, midazolam) and non-albumin-bound (fentanyl) substances. The mechanism is probably by uptake of free drug, with constant re-equilibration of free and bound components. Albumin dialysis may be important in treating non-dialysable protein-bound substance intoxications. Therefore, albumin dialysis does bring about measurable biochemical and pathophysiological changes, translating to clinical improvements. Ongoing randomized controlled trials will provide a definitive answer regarding impact on mortality.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.429602  DOI: Not available
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