Fulminant Hepatic Failure

I was pleased when Paul Berk asked me to do this issue of Seminars, for it will be the third one that I have done on fulminant hepatic failure for this journal, and how many authors can match that! The first issue[1] was in May 1986 and the second[2] in November 1996. In looking back over the contents, it is interesting to see how far we have progressed in our knowledge of this very rare syndrome of liver failure. In the use of terminology, however, habits have proved difficult to break and the use of the term fulminant hepatic failure continues, although the categorization into hyperacute, acute, and subacute liver failure that we put forward much more accurately reflects the differing clinical pattern and course of these subgroups, which correlate also with etiology and survival. The finding that the more rapid onset the greater the chance of spontaneous recovery is now well-accepted. To compare findings and the results of treatments from centers around the world, it is essential to compare like with like.

To date most of the research in acute liver failure (ALF) has been directed toward the study of the effects of liver failure on the brain, such as encephalopathy and the associated dysfunction of other organs, which are so characteristic of the syndrome. Knowledge of the process underlying the development of such severe liver damage-indeed complete hepatic necrosis in some instances-and how spontaneous recovery and regeneration to a normal structure can occur has lagged behind. More is becoming known, however, as is evident from Stephen Riordan's masterly review in the first article of the response to injury and of factors influencing the regeneration process. Perhaps with better understanding, the possibility of being able to block the progression of harmful processes by specific ligands or receptor antagonists early on in the disease may not be so distant. Riordan's article also gives an up-to-date account of the selection criteria for liver transplantation and the increasing shortage of organs that, despite all the difficulties, is the only therapy at present that can afford a prospect of survival for the most severely affected cases.

Whether to transplant in an individual case is one of the most difficult decisions in management, although a high percentage of the patients fulfilling criteria are likely to die if a transplant is not performed (high positive predictive value). Experience has shown that in the group not fulfilling criteria the survival is not as high as was originally thought. How to pick out those patients in this group who are going to deteriorate has not been answered satisfactorily, and it is in this group of patients that effective liver support devices to provide more time for assessment or even spontaneous recovery could have a real place.

The next three articles are concerned with the etiology and clinical course of the disease in various parts of the world, including describing the very different pattern of illness seen in the Far East and Japan. For the first time, substantial data on the causes of ALF in the United States are included, thanks to the establishment of the ALF Group under Will Lee's direction and with support from the National Institutes of Health. One of the recurring topics in all three Seminars issues has been the extraordinary number of ALF cases from acetaminophen overdose taken with suicidal intent that we have had in the United Kingdom, so much so that it is often referred to as “the English disease.” Now, however, as reported by Lee, acetaminophen hepatotoxicity has been seen increasingly in the United States, although more frequently in association with therapeutic or misadventure use than with suicidal intent. I thought it would be of interest to compare the latest data from the United States with those from the United Kingdom, which Bernal has done in his article. He also analyzes the effects of recent legislation in the United Kingdom restricting availability of the drug through smaller pack sizes in supermarkets and pharmacists on the number of cases of acetaminophen overdose. This approach is also likely to have an effect in France and is one that the United States, in my opinion, should certainly be encouraged to follow. For comparison with these accounts from the West, we have the quite different picture of ALF described from Asia and the Far East by Cheng and colleagues. Viral hepatitis continues to be the major cause in these areas, with the very interesting spontaneous reactivation of hepatitis B virus infection as well as dual infections. Each of these contributors has included aspects of management that he considers to be of particular importance in their particular cases, including the use of liver transplantation. There is no single article on management, because I felt so much of the intensive care management for ALF is now well-established. Nevertheless, in these clinical contributions and in the subsequent section on encephalopathy, the reader should find guidance with respect to the more controversial aspects of management, including the use of n-acetyl cysteine, intracranial bolts, and so on.

In this issue, I was particularly keen to try to bring together all the new experimental studies coming through on the pathophysiological disturbances in the brain that underlie encephalopathy, the cardinal defining feature of the syndrome. Encephalopathy in its later stages is associated with dysfunction of other organs, including most importantly the kidney and making up the multiorgan failure that is so important in determining the outcome of liver failure. we have the real leaders of research in this area contributing-Butterworth, Blei (Vaquero et al), and Rajiv Jalan-and they write fascinating accounts. Inevitably there is some overlap among the three contributions, but I felt this was to the good, reflecting also the different emphasis on the many different pathophysiological disturbances involved in the brain and the other body organs affected sequentially or in parallel. The comparison with the encephalopathy of chronic liver disease by Vaquero et al is particularly relevant in view of recent reports that cerebral edema can also develop in some cases of chronic liver disease. Not surprisingly, Jalan is very concerned with the hemodynamic aspects of ALF and the changes in the splanchnic and cerebral circulations and makes a strong case for the use of intracranial bolts in managing the elevation in intracranial pressure.

The susceptibility of ALF patients to infection from the early stages of the disease was well-documented in the earlier issues of Seminars, and previous issues have included detailed descriptions of the pattern of infections in relation to impairment in host defense mechanisms. The need for early detection and treatment of systemic and local infections remains paramount. What is new in this issue is the important influence of infection on the progression and deterioration in encephalopathy. The article by Rolando et al[3] showing a correlation between the severity of the systemic inflammatory response syndrome (SIRS) and the likelihood of progressive encephalopathy and cerebral edema, I believe, represened a landmark in new thinking on ALF syndrome.

The other area that Paul Berk felt we should critically evaluate was the burgeoning number of extracorporeal liver support devices. There have been so many reports in recent years on new bioreactors and on improved cell cultures, both pig and human derived. An efficient temporary liver support system for ALF to provide more time for spontaneous recovery to occur has long been considered the Holy Grail of liver disease, and it remains as elusive as ever. In the final article, Sen presents new information on albumin dialysis in an artificial liver support system. The removal of protein-bound toxins that accumulate in ALF by albumin dialysis is undoubtedly effective. The cost of such a device is much less than that of the more complicated bioartificial ones that include components of functioning liver cells, either pig or human, to provide additional synthetic and biotransformatory functions. The efficacy of albumin dialysis should give us a better understanding of the role of protein-bound toxins in the development of the clinical syndrome of ALF and in the ultimate outcome. In any event, I hope that the critical appraisal of the results so far obtained with the various devices currently under clinical trial will be informative and at the same time give some idea of our own thoughts on how further trials should be designed to answer the important questions posed.

What is fascinating to me is the possible interaction of the liver failure toxins and improvement-or prevention of further deterioration-in the liver damage, whether determined initially by raised toxin, viruses, acetaminophen overdose, or drug idiosyncrasy. If the deteriorating metabolic and biotransformatory processes in the liver can be influenced by removal of toxins, does this translate into an improved hepatocyte function and recovery rate? If so, what else is needed from the synthetic functions that may be provided by living hepatocytes in the bioartificial systems, bearing in mind that deficiencies in circulating proteins are not in fact critical because they can easily be replaced by intravenous infusion. In addition, does toxin removal reverse the processes underlying the characteristic dysfunction of other organs in ALF already referred to? The dependence of such multiorgan failure on the liver damage is shown by its temporary improvement that follows the carrying out of a hepatectomy. The critical question therefore is whether toxin removal alone can interrupt the vicious cycle of liver damage and multiorgan dysfunction or is an additional function, as may be provided by living hepatocytes, required?

Finally, a warm thank you to all the contributors for their inspiring accounts, to Paul Berk for his guidance throughout, and to Enda O'Sullivan, editorial assistant at the Institute for much assistance in getting it all together.

REFERENCES

• 1 Fulminant Hepatic Failure.  Semin Liver Dis 1986 6: 97-164
• 2 Fulminant Hepatic Failure. Semin Liver Dis 1996 16: 341-435
• 3 Rolando N, Wade J, Davalos M. et al . The systemic inflammatory response syndrome in acute liver failure.  Hepatology . 2000;  32 734-739