Perspectives on Liver Failure: Past and Future

• ABSTRACT
• APPROACHES TO LIVER SUPPORT
• IMPROVING INTENSIVE CARE
• CURRENT STATUS AND FUTURE CHALLENGES
• ABBREVIATIONS
• REFERENCES

ABSTRACT

Acute liver failure (ALF) remains a potentially devastating syndrome with a high mortality rate. Much interest continues to center upon the possibility of providing effective liver support through various artificial and bioartificial extracorporeal devices. The development of purpose-designed intensive care units for the treatment of ALF allowed a better understanding of the clinical syndrome and its best management, through the ability to conduct detailed clinical observation and clinical trials of new interventions. Survival rates are substantially improved today compared with the mortality rate that approximated 100% when the syndrome was first described nearly five decades ago. Nonetheless, these have plateaued in recent years, prompting one to consider whether major new advances in disease understanding are needed to further improve the overall outcome. A major challenge to a broader understanding of disease pathogenesis and the ability to direct appropriate therapy remains the substantial number of cases of ALF for which no specific etiology can be identified. Much is now known about the basic molecular mechanisms underlying hepatocyte cell death in ALF and an important issue is whether these cell death pathways can, in the future, be interrupted for therapeutic gain. Such considerations would seem most relevant in the early stages of the clinical course, when damage to the liver is not so severe but perhaps programmed to so evolve. A particular challenge will be to reduce hepatocellular death without inhibiting the liver's regenerative potential, given the pleiotropic functions of some of the molecules involved in both processes.

Acute liver failure (ALF) is a potentially devastating syndrome with an ongoing high mortality rate, which may include as components cerebral edema, hemodynamic instability, coagulopathy, profound metabolic disturbances, a particular susceptibility to bacterial and fungal infection, and multiorgan failure. The original description of ALF by Trey and Davidson in 1959 was based on the occurrence of hepatic encephalopathy as the consequence of severe liver injury developing within 8 weeks of the onset of often nonspecific symptoms in patients without pre-existing liver disease.[1] More recent terminologies proposed in the late 1980s and early 1990s take into account the interval between the onset of jaundice and the development of encephalopathy, in recognition of the fact that the jaundice-to-encephalopathy time is an important prognostic index.[2] [3] [4] In contrast to the original description, these later classifications allow for the inclusion of cases with previously asymptomatic chronic liver conditions, such as fulminant presentations of Wilson's disease and reactivation of underlying chronic hepatitis B viral infection.

APPROACHES TO LIVER SUPPORT

Historically, much interest has centered upon the possibility of providing effective liver support through various artificial and bioartificial extracorporeal devices (not incorporating and incorporating viable hepatocytes, respectively), with the aim of removing putative toxins and either allowing time for or even actively promoting liver regeneration, upon which spontaneous survival ultimately depends, or to act as a bridge to liver transplantation in those most severely affected patients in whom the liver is judged to be irreversibly damaged. Limited controlled clinical trial data are available for any of these extracorporeal approaches, past or present.

Early attempts at providing liver support in the late 1950s through the early 1970s initially focused on the possible value of hemodialysis, using a variety of membranes, based on the known dialyzability of ammonia. While improvement in encephalopathy grade was often documented,[5] [6] this was generally not associated with increased patient survival rates, a pattern sadly true of many studies of liver support strategies. Recognition of the possible need for a more aggressive approach toward the removal of protein-bound molecules led to the subsequent use of exchange transfusion and, later still, plasmapheresis, including a more recent high-volume approach, with instances of neurological benefit reported in various case series.[7] [8] [9] Alternative approaches, again uncontrolled, included the extracorporeal perfusion of patients' blood through porcine, baboon, or cadaveric human livers and human-to-human cross-circulation, based on the perception that a biological component providing a full range of liver functions might be necessary to optimize outcomes.[10] [11] However, whether the additional synthetic and biotransformatory processes provided by exposure of patients' blood to functioning hepatocytes are necessarily required above and beyond an efficient excretory function for facilitating or enhancing recovery of the damaged liver was never established, and, in fact, remains unclear to this day.

The introduction of charcoal hemoperfusion to clinical practice in 1972[12] was viewed as a potential major advance in liver support, based on the demonstration that activated charcoal is a potent adsorbent for several putative toxins that accumulate in the serum of patients with ALF, including mercaptans, γ-aminobutyric acid, aromatic amino acids, and fatty acids.[13] Several experimental studies performed in both small and large animal models of ALF reporting a survival benefit with charcoal hemoperfusion, especially with earlier intervention,[14] [15] [16] [17] led to initial clinical assessment in patients with ALF and advanced encephalopathy grade.[18] [19] [20] These studies found improved metabolic profiles, including an increased branched chain amino acid to aromatic amino acid ratio, and at least a transient recovery of consciousness in the majority of treated patients. However, no clinical benefit could be demonstrated in the only randomized controlled clinical trial performed, even when potentially confounding influences such as etiology of ALF and the jaundice-to-encephalopathy time were taken into account.[21] While methodological issues may have confounded the interpretation of these findings, in particular such that a type II statistical error could not be excluded, the negative results nonetheless halted the further development of charcoal hemoperfusion as a “stand-alone” therapy for ALF. However, it has not been lost to clinical application, given its incorporation into several existing artificial and bioartificial liver support devices.

The development of bioartificial devices marked the next phase in the history of liver support for ALF, based on a return to the notion, although still unproven, that functioning hepatocytes might be necessary if full clinical benefit of any extracorporeal perfusion therapy were to be attained. Controlled data from a multicenter analysis performed in the United States and Europe were reported in 2004 for one such system, namely the HepatAssist bioartificial liver support device (Arbios Systems, Inc., Los Angeles, CA), which contains porcine hepatocytes as the cellular component, the number approximating 2% of the normal adult hepatocyte mass, along with a charcoal hemoperfusion column.[22] One hundred seventy-one patients with ALF were randomized to treatment with the device or standard medical therapy. Thirty-day survival in the two groups was not significantly different. However, over 50% of enrolled patients underwent liver transplantation during the study and when the effect of transplantation was excluded, a modest survival benefit was suggested in the HepatAssist-treated group, highlighting the difficulties in properly evaluating the efficacy of any nontransplant-based therapies in the transplant era.

In the only other controlled experience with a bioartificial liver device so far reported, a pilot but controlled clinical trial of the Extracorporeal Liver Assist Device (ELAD) (Vital Therapies, Inc., La Jolla, CA), which contains a human hepatoblastoma cell line in numbers in the order of 15% of the normal adult hepatocyte mass,[23] in 1996 demonstrated no statistically significant clinical or metabolic effect in treated patients. Several alternative designs to the HepatAssist and ELAD have been developed over the past decade and at least preliminarily assessed clinically.[13] No controlled data are available. Only one device currently undergoing assessment incorporates scarcely available primary human hepatocytes as the cellular component. The suitability or otherwise of immortalized or reversibly immortalized human hepatocytes for use in bioartificial liver support devices, as an alternative to primary human or porcine cells, represents one of the most challenging areas of continued investigation.

While interest in bioartificial liver support devices continues, issues pertaining to their costs and complexity have led some to reconsider the certainly less complicated concepts of artificial liver support, in particular those based on albumin dialysis techniques. Clinical data concerning use in ALF of one such module, the molecular adsorbent recirculating system (MARS) (Gambro Lundia AB, Lund, Sweden), developed at the University of Rostock in the early 1990s, are currently available in only a small number of patients.[24] [25] Data are similarly limited with regard to efficacy of another recently developed device, based on a form of plasma fractionation and named after the Greek god, Prometheus.[26] Both systems include columns of charcoal and anion exchange resins for the final adsorption of toxins. There is no doubt that the stimulus of these new techniques will lead to a better understanding of the functionality of albumin in relation to the binding of toxic substances and its true role in the management of patients with ALF.

IMPROVING INTENSIVE CARE

The establishment of the first purpose-designed intensive care unit for the treatment of liver failure at King's College Hospital, London, in 1973 represented an important advance in the management of patients with ALF. The referral of significant numbers of patients with this rare disease to this and other similarly highly specialized units elsewhere in the world has allowed a better understanding of the clinical syndrome and its best management, through the ability to conduct detailed clinical observations and clinical trials of new interventions. Etiologies and natural histories for the various causative factors could be delineated and prognostic criteria developed.[13] [21] [27] [28] [29] The latter have formed the basis of selection criteria for emergency liver transplantation. While such criteria undoubtedly represent a great advance, there remains some difficulty in accurately predicting at an early stage, in particular, exactly which individual patients can confidently be managed with medical care alone.

Survival rates are substantially improved nowadays compared with the mortality rate that approximated 100% when the syndrome was first described nearly five decades ago. Two large, recent series from the United Kingdom and the United States showed that 50% and 43% of patients, respectively, survived with medical therapy alone,[30] [31] while an additional 23% and 29% of patients survived to undergo liver transplantation. The immediate cause of death in those that die of ALF has also changed over the years, with recent data from King's College indicating that intracranial hypertension was responsible in only 22% of patients, very different from early accounts where cerebral edema with uncontrolled elevation in intracranial pressure was the single most common cause. Such a difference is but one example of just how much has been achieved in the field of liver intensive care over the years. Not only has the management of encephalopathy improved, but a better understanding of the pathophysiology underlying other aspects of the clinical syndrome has led to evidence-based regimens for the intensive care management of its other components, as will be detailed later in this issue.

CURRENT STATUS AND FUTURE CHALLENGES

Nonetheless, survival rates are plateauing, prompting one to consider whether major new advances in disease understanding, leading to new treatments, could further improve the overall outcome. One important recent observation is that the severity of the systemic inflammatory response syndrome (SIRS) influences the pathogenesis of intracranial hypertension in the ALF setting. In particular, an analysis of 887 ALF patients admitted to a single center over an 11-year period found significant associations between infection, severity of the SIRS, and progressive encephalopathy, resulting in a poor prognosis.[32] Mechanisms responsible for this association between the SIRS and encephalopathy are currently uncertain, but SIRS-mediated glycolysis, leading to increased lactate production and the potential for cerebral edema,[33] may be at least partly responsible. Increased cerebral blood flow mediated by proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), important mediators of the SIRS, may also be contributory.[34]

A major challenge to a broader understanding of disease pathogenesis and the ability to direct appropriate therapy remains the substantial and increasing number of cases of ALF for which no specific etiology can be identified.[35] This group has a poor overall outcome and currently represents the single most common indication for super-urgent liver transplantation in the United Kingdom.[35] [36] Undetected idiosyncratic drug reactions undoubtedly account for at least some cases, with recent descriptions of ALF due to the green tea extract, Camellia sinensis, demonstrating for just how long rare toxicities of over-the-counter-type dietary supplements may remain undetected.[37] [38] [39] The existence of another hepatitis virus responsible for ALF has, to date, eluded the best efforts of virologists and it is notable that the characteristic high levels of IgM evident in known cases of virus-mediated ALF are not evident in the indeterminate group.[40] Conversely, autoantibodies were evident in 44% of such cryptogenic cases in a recent analysis,[40] raising the possibility of an immune-mediated etiology, although titers were not associated with the severity of liver injury and responsiveness to corticosteroids is rare. It remains unacceptable at present that in around 25% of cases a specific cause cannot be identified, precluding any likelihood that specific therapy can be applied.

Much is now known about the basic molecular mechanisms underlying the two forms of hepatocyte cell death in ALF, namely apoptosis and necrosis, the magnitude of which, along with the degree to which regeneration occurs, ultimately dictates the severity of the clinical syndrome. It is apparent that TNF-α and the Fas ligand are the two key initiating molecules, independently mediating hepatocellular death through interaction with their cell membrane receptors, namely TNF-receptor 1 (TNF-R1) and Fas receptor, respectively, with the subsequent activation of caspases. Pathways by which several etiologies of ALF induce liver cell death have been defined. For example, necrosis of the hepatocyte is a feature of acetaminophen hepatotoxicity. Conversely, apoptosis, as a result of activation of the TNF-α/TNF-R1 pathway, is typical of ischemia-reperfusion liver injury, while Fas/Fas ligand-mediated apoptotic cell death is a feature of fulminant hepatitis B and fulminant Wilson's disease. Nonetheless, it is apparent that any insult capable of inducing apoptosis may alternately cause cell death by necrosis if the degree of associated mitochondrial injury is sufficient to exhaust adenosine triphosphate stores. It has also been established that a myriad of other molecules and cellular processes, including oxidative stress, can influence the activity of these cell death pathways.[41]

An important issue is whether these cell death pathways can, in the future, be interrupted for therapeutic gain, ideally leading to improved survival rates without the need to resort to liver transplantation. With the power of modern technology in drug design, it may not be too far-fetched to speculate that specific antagonists may one day be used to block key signaling steps and thereby alter the course of the disease. Such considerations would seem most relevant to the early stages of the clinical course, when damage to the liver is not so severe but perhaps programmed to so evolve. A particular challenge will be to reduce hepatocellular death without inhibiting the liver's regenerative potential, given the pleiotropic functions of some of the molecules involved in both processes, such as TNF-α.

At least until further understanding of pathogenesis evolves and new approaches to management are explored, emergency liver transplantation will continue to play a fundamental role in the management of patients with the most severe form of ALF. Nonetheless, the rapidity with which the clinical syndrome often progresses, along with a worldwide shortage of donor organs, such that many patients die or develop contraindications to transplantation before a donor liver becomes available, even with priority listing, limits the number that can be treated in this way. The ability to cryopreserve cells for storage in banks without loss of differentiated function, such that that cell-based therapy could be ready for clinical application “on demand,” raises the possibility that there may be an important role for hepatocyte transplantation in this setting. Only a small number of patients treated by hepatocyte transplantation have been reported to date.[13] The feasibility and clinical value of transplantation of adult stem cells with increased regenerative potential is also a matter of conjecture, bearing in mind that in experimental animal models, repopulation of the whole liver can be obtained with infusion of relatively small numbers of purified hepatic stem cells.[42] [43] The possibility of a bone marrow-derived stem cell repopulating the liver with mature hepatocytes following hepatic injury has also been described experimentally,[44] although if extrapolated from the animal to the human situation, the time required for engraftment and cell differentiation would be problematic in the acute setting. On the premise that the fetal liver would contain an increased proportion of cells exhibiting the full regenerative potential of stem cells, transplantation of fetal hepatocytes has also been suggested,[45] but clinical data so far are limited and the range of ethical issues pertaining to the use of fetal cells is currently the subject of much debate. As with other proposed therapies, controlled trials on a multicenter basis in well-defined patient groups and with standardized outcome measures will be essential if the clinical value of hepatocyte or any type of stem cell transplantation in ALF is to be properly evaluated.

ABBREVIATIONS

• ALF acute liver failure

• ELAD Extracorporeal Liver Assist Device

• MARS molecular adsorbent recirculating system

• SIRS systemic inflammatory response syndrome

• TNF-α tumor necrosis factor-α

• TNF-R1 TNF-receptor 1

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Professor Roger WilliamsM.D. 

Director, The Institute of Hepatology, Royal Free and University College Medical School

69-75 Chenies Mews, London WC1E 6HX, United Kingdom

Email: roger.williams@ucl.ac.uk

REFERENCES

• 1 Trey C, Davidson C S. The management of fulminant hepatic failure. In: Popper H, Schaffner F Progress in Liver Failure. New York; Grune and Stratton 1970: 282-298
  Search in Google Scholar
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  Thieme ConnectPubMedSearch in Google Scholar
• 3 O'Grady J G, Schalm S W, Williams R. Acute liver failure: redefining the syndromes.  Lancet. 1993;  342 273-275
  CrossrefPubMedSearch in Google Scholar
• 4 O'Grady J G, Alexander G JM, Hayllar K M et al.. Early indicators of prognosis in fulminant hepatic failure.  Gastroenterology. 1989;  97 439-445
  PubMedSearch in Google Scholar
• 5 Kiley J E, Pender J C, Welch H F, Welch C S. Ammonia intoxication treated by haemodialysis.  N Engl J Med. 1958;  259 1156-1161
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• 6 Opolon P, Rapin J R, Huguet C et al.. Hepatic failure coma (HFC) treated by polyacrylnitrile membrane (PAN) haemodialysis (HD).  Trans Am Soc Artif Intern Organs. 1976;  22 701-710
  PubMedSearch in Google Scholar
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• 8 Trey C, Burns D G, Saunders S J. Treatment of hepatic coma by exchange blood transfusion.  N Engl J Med. 1966;  274 473-481
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• 9 Larsen F S, Hansen B A, Ejlersen E et al.. Cerebral blood flow, oxygen metabolism and transcranial Doppler sonography during high-volume plasmapheresis in fulminant liver failure.  Eur J Gastroenterol Hepatol. 1996;  8 261-265
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  Search in Google Scholar
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  PubMedSearch in Google Scholar
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  Search in Google Scholar
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  PubMedSearch in Google Scholar
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  PubMedSearch in Google Scholar
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Professor Roger WilliamsM.D. 

Director, The Institute of Hepatology, Royal Free and University College Medical School

69-75 Chenies Mews, London WC1E 6HX, United Kingdom

Email: roger.williams@ucl.ac.uk