Investigations into the pathophysiology, prognosis and clinical management of acute liver failure

Murphy, Nicholas D. ORCID: 0000-0001-8074-1447 (2022). Investigations into the pathophysiology, prognosis and clinical management of acute liver failure. University of Birmingham. Ph.D.

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In this thesis I will describe how my work has contributed to the understanding and management of acute liver failure (ALF). There are three main themes of my work:

1. Understanding the pathophysiological mechanisms in ALF
2. Defining prognosis in ALF.
3. Management of ALF, in particular focusing on the prevention of intracranial hypertension (ICH).

Acute liver failure (ALF) is a rare syndrome, estimated to result in less than 10 cases per million in the West (1). In severe form it results in critical illness with multiple organ failure. It occurs in all age groups and usually presents in young adults without any previous liver disease. It has a high mortality and for those with a severe presentation the only treatment option is liver transplantation, however, the shortage of donor organs means that is only an option for selected cases (2).

The ability to predict outcome early in the course of the illness is of critical importance when considering transplantation; there is only a short window of clinical opportunity during which liver transplantation is a viable option before the condition of the patient deteriorates to the point where transplantation becomes futile (3). Like other forms of critical illness, the progression to multiple organ failure dictates outcome. Additionally, patients with ALF can develop intracranial hypertension (ICH) due to cerebral oedema which has a further, significant, impact on morbidity and mortality. Management strategies to reduce the incidence and impact of ICH are, alongside accurate prognostication, an essential part of intensive care unit management of patients with ALF (4).

Furthermore, performing clinical research in patients with ALF is very difficult for a number of reasons. It is a rare condition thus studies take a long time to recruit sufficient numbers. Patients are also extremely sick with the illness following a fulminating course and so often die early or are transplanted, confounding trial outcomes. Consequently, the number of randomised clinical trials in ALF is very small internationally and collaborations of liver centres have been developed with only varying degrees of success. The US ALF study group has produced 68 papers over its 22-year history. To this end, I was a founding member of the European ALF initiative in 2010, which initiated a number of surveys in clinical practice across Europe (5,6).

The work that I authored with colleagues has had a significant impact on the understanding and management of ALF. It has directly influenced international management guidelines (7,8) in both Europe and the USA through the national hepatology associations (EASL & AASLD). My works covers the following principal themes:

\( \underline{\textbf{1. Pathophysiology}}\)

Lactic acidosis was recognised as a prominent feature of ALF during the 1960s and the importance of it as a prognostic marker was elucidated during the late 1980s (9,10). The metabolic acidosis seen in ALF is due to a combination of lactic acidosis and acute kidney injury, both of which contribute to prognostic indices. I have directly contributed to the understanding of lactate metabolism in ALF through innovative work revealing the changes in lactate metabolism that occur during and following liver transplantation. The liver becomes a net producer of lactate in ALF instead of a consumer and I demonstrated that splanchnic lactate production comes from both the gut and the liver in ALF. The accompanying editorial noted that due to the design of the study which enabled sampling of portal vein lactate we were uniquely placed to distinguish between splanchnic and liver metabolism (11). The net production of lactate from the liver reverses following emergency liver transplantation, contributing to the rapid fall in serum lactate seen (12,13). This is significant as it helps to explain why a high lactate has prognostic value. The lactate produced within the liver represents the activation of inflammatory cells which use glycolysis aerobically and is a marker for the inflammatory burden. This inflammatory burden contributes to liver damage and to the systemic inflammatory response and organ failure seen (11).

As well as work into lactate metabolism in ALF I have worked with colleagues in the Centre for Liver and GI Research in Birmingham to delineate the immunological mechanisms perpetuating liver damage. In particular, we demonstrated T-cell recruitment and activation within the liver during ALF (14). This work adds to the understanding of how the migration to and activation of inflammatory cells, stimulates the lactate production within the liver and result in systemic inflammation and organ failure.

\( \underline{\textbf{2. Prognosis in ALF}}\)

Bernal and colleagues showed that serum lactate, which contributes to the metabolic acidosis in ALF, was also a prognostic marker in ALF due to paracetamol toxicity. I led work with colleagues in Birmingham, extending this work and demonstrated that it held true for non-paracetamol causes of ALF as well (15,16). This study confirmed and supports the use of lactate as a prognostic marker in a different cohort of patients with ALF, strengthening the evidence for its use. In our centre lactate levels at 12 hours following admission was shown, on multivariate analysis, to be a significant differentiator for survival. The 12 hour interval is important as it differentiates those patients in whom arterial lactate falls following initial resuscitation from those with persistent hyperlactataemia.

I have continued to maintain an interest in prognostic models in ALF and contributed data and was an author on a recent publication examining dynamic models of predicting outcome in paracetamol induced ALF (17). The dynamic models look at both day one and day 2 markers. The lead time effect of early critical care intervention on organ failure increases the fidelity of the model and increases confidence in predication.

\( \underline{\textbf{3. Management of ALF}}\)

Cerebral ischaemia and herniation related to cerebral swelling remains a significant cause of death in ALF (18).

The recognition that cerebral oedema was a significant cause of death in ALF led to the introduction of intracranial pressure (ICP) monitoring and strategies to reduce it in patients with established intracranial hypertension (19,20). The use of osmotherapy with mannitol became the main therapy for cerebral oedema complicating ALF. Once established ICH is difficult to treat and tends to recure despite therapy.

In novel work I initiated and studied, I looked at alternative types of osmotherapy in ALF by considering the use of hypertonic saline. It can increase blood osmolality and as sodium does not cross the blood brain barrier it serves to reduce brain water. In fact, because of the active nature of the barrier, sodium is actively pumped out, making its reflection coefficient (the tendency to not cross the blood brain barrier) higher than that of mannitol (21). ICH has a very poor prognosis and so prevention is a logical approach.

In a landmark study I, together with colleagues investigated the prophylactic use of hypertonic saline infusions in patients with ALF in a randomised controlled trial. We demonstrated that maintaining serum sodium at approximately 150 mmol/l, prevented the increase in intracranial pressure seen in the control group. This study has now been cited over 340 times and has been adopted as standard therapy internationally (22).

I have had a long-standing interest in the use of extracorporeal liver support in ALF, with the concept of liver dialysis being particularly appealing. Many systems have been investigated including the use of albumin dialysis via the molecular absorbent recirculating system (MARS). Together with colleagues I investigated the effects of the MARS extracorporeal liver support on physiological parameters in a series of patients with ALF (23). The study demonstrated that MARS therapy improved haemodynamic stability and decreased jugular bulb oxygen saturation reflecting an increase in cerebrovascular tone during the sessions. Notably, intracranial pressure did not change significantly over the treatment period suggesting that factors, not cleared via MARS, are important in the pathology.

More recently, I helped develop the concept and design of an international collaboration, with colleagues in King’s College London and the Rigshospitalet (Copenhagen), to investigate the effects of prophylactic hypothermia on intracranial pressure in ALF (24). This international, multicentre, randomised controlled clinical trial compared moderate hypothermia with standard of care in patients with ALF at risk of cerebral oedema. Whilst the study was unable to show any difference in the rates of ICH the accompanying editorial noted that this “landmark study” highlighted the need to determine the correct target temperature to manage patients with ALF and how further experimental research is needed (25).

1. Bernal W, Wendon J. Acute Liver Failure. N Engl J Med. 2013 Dec 26;369(26):2525–34.
2. Reuben A, Tillman H, Fontana RJ, Davern T, McGuire B, Stravitz RT, et al. Outcomes in Adults With Acute Liver Failure Between 1998 and 2013. Ann Intern Med. 2016 Jun 7;164(11):724–32.
3. O’Grady J. Timing and benefit of liver transplantation in acute liver failure. J Hepatol. 2014 Mar;60(3):663–70.
4. Murphy ND. The pathology and management of intracranial hypertension in acute liver failure. 2007;678–90.
5. Bernal W, Han Y, Laterre PF, Lee A, Mas A, Murphy N, et al. 912 CLINICAL MANAGEMENT OF ACUTE LIVER FAILURE 2010: RESULTS OF A PAN-EUROPEAN SURVEY. J Hepatol. 2011 Mar;54:S364.
6. Wendon J, Bernal W, Laterre P, Nevens F, Hudson M, Aldersly M, et al. Acute liver failure: a European perspective. Crit Care. 2010;14(Suppl 1):P541.
7. Lee WM, Stravitz RT, Larson AM. Introduction to the Revised American Association for the Study of Liver Diseases Position Paper on Acute Liver Failure 2011. Hepatol Baltim Md. 2012 Mar;55(3):965–7.
8. Wendon J, Cordoba J, Dhawan A, Larsen FS, Manns M, Nevens F, et al. EASL Clinical Practical Guidelines on the management of acute (fulminant) liver failure. J Hepatol. 2017;66(5):1047–81.
9. Colombi A, Tholen H. Haemodialysis in the treatment of lactic acidosis associated with acute hepatic and renal failure. Postgrad Med J. 1971 Sep 1;47(551):628–31.
10. O’Grady JG, Alexander GJM, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology. 1989 Aug;97(2):439–45.
11. Chang D-M. Hyperlactatemia in acute liver failure: Decreased clearance versus increased production: Crit Care Med. 2001 Nov;29(11):2225–6.
12. Murphy ND, Kodakat SK, Wendon JA, Jooste CA, Muiesan P, Rela M, et al. Liver and intestinal lactate metabolism in patients with acute hepatic failure undergoing liver transplantation. Crit Care Med. 2001 Nov;29(11):2111–8.
13. Walsh TS, McLellan S, Mackenzie SJ, Lee A. Hyperlactatemia and pulmonary lactate production in patients with fulminant hepatic failure. Chest. 1999 Aug;116(2):471–6.
14. Tuncer C, Oo YH, Murphy N, Adams DH, Lalor PF. The regulation of T-cell recruitment to the human liver during acute liver failure. Liver Int. 2013 Jul;33(6):852–63.
15. Bernal W, Donaldson N, Wyncoll D, Wendon JA. Blood lactate as an early predictor of outcome in paracetamol-induced acute liver failure: a cohort study. Lancet. 2002 Feb;359(9306):558–63.
16. Macquillan GC, Seyam MS, Nightingale P, Neuberger JM, Murphy ND. Blood lactate but not serum phosphate levels can predict patient outcome in fulminant hepatic failure. Liver Transplant Off Publ Am Assoc Study Liver Dis Int Liver Transplant Soc. 2005 Sep;11(9):1073–9.
17. Bernal W, Wang Y, Maggs J, Willars C, Sizer E, Auzinger G, et al. Development and validation of a dynamic outcome prediction model for paracetamol-induced acute liver failure: a cohort study. Lancet Gastroenterol Hepatol. 2016 Nov;1(3):217–25.
18. Boeckx NK, Haydon G, Rusli F, Murphy N. Multiorgan failure is the commonest cause of death in fulminant hepatic failure: a single centre experience. Liver Int. 2004;24(6):702–3.
19. Braude S, Gimson AES, Williams R. Progress in the management of fulminant hepatic failure. Intensive Care Med. 1981 May;7(3):101–3.
20. Hanid MA, Mackenzie RL, Jenner RE, Chase RA, Mellon PJ, Trewby PN, et al. Intracranial pressure in pigs with surgically induced acute liver failure. Gastroenterology. 1979 Jan;76(1):123–31.
21. Qureshi AI, Suarez JI. Use of hypertonic saline solutions in treatment of cerebral edema and intracranial hypertension: Crit Care Med. 2000 Sep;28(9):3301–13.
22. Murphy ND, Auzinger G, Bernel W, Wendon JA. The effect of hypertonic sodium chloride on intracranial pressure in patients with acute liver failure. Hepatol Baltim Md. 2004 Feb;39(2):464–70.
23. Lai WK, Haydon G, Mutimer D, Murphy ND. The effect of molecular adsorbent recirculating system on pathophysiological parameters in patients with acute liver failure. Intensive Care Med. 2005 Nov;31(11):1544–9.
24. Bernal W, Murphy ND, Brown S, Whitehouse T, Bjerring PN, Hauerberg J, et al. A multicentre randomized controlled trial of moderate hypothermia to prevent intracranial hypertension in acute liver failure. J Hepatol. 2016 Aug;65(2):273–9.
25. Porcher R, Vaquero J. Hypothermia in acute liver failure: What got lost in translation? J Hepatol. 2016 Aug;65(2):240–2.

Type of Work: Thesis (Doctorates > Ph.D.)
Award Type: Doctorates > Ph.D.
Licence: All rights reserved
College/Faculty: Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department: Institute of Immunology and Immunotherapy
Funders: None/not applicable
Subjects: R Medicine > R Medicine (General)


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