Journal of Hepatology
Volume 41, Issue 1 , Pages 152-155, July 2004

Acute liver failure: avoidance of deleterious cofactors and early specific medical therapy for the liver are better than late intensive care for the brain

  • Jacques Bernuau

      Affiliations

    • Corresponding Author InformationCorresponding author. Tel.: +33-1-40-875746; fax: +33-1-47-309440

Fédération d'Hépatogastroentérologie, INSERM U-481, Hôpital Beaujon, F-92118 Clichy, France

See Article, pages 89–96

Article Outline

 

Acute liver failure (ALF) is a complex syndrome reflecting a rapidly progressing, life-threatening but potentially reversible, deterioration of liver function in patients recently free of any overt chronic liver disease. Since the early 1990s, a changing epidemiology of ALF has emerged. In Western countries, the incidence of viral ALF decreased [1] whereas that of drug-induced, especially acetaminophen-induced, ALF increased [1], [2]. In Asian countries, although widespread use of vaccination against hepatitis B virus (HBV) was associated with a highly significant decrease in HBV-induced ALF in children [3], ‘flares’ in adults with chronic HBV infection [4] and acute hepatitis E, especially in India [5], are the main causes of ALF. According to the cause, the overall mortality rate ranges from 40 to 100% [1] and, thus, prevention of ALF [2], [3], [6], so often an iatrogenic complication [1], [2], should become a key preoccupation of the medical community.

In the last 20 years, emergency liver transplantation (ELT) emerged as the ‘only therapeutic intervention of proven benefit for patients with advanced ALF’ [7]. However, without any doubt, some patients underwent unnecessary transplantation [6], [7] and survival after ELT—55% after 10 years in Europe [8]—is much more pejorative than spontaneous survival. So, optimized efficacy of the medical management, both cause specific and not specific, of patients with, or—even better—threatened by, ALF is clearly beneficial when it allows to save the patient's liver.

Supportive, non-specific, medical management of patients with established ALF (i.e. with clinical encephalopathy) was frequently reviewed [2], [9], [10], [11]. This highly complex management includes treatment and, when possible, prevention of multiple organ failure and bacterial and fungal superinfections, but its most critical target at late stages of encephalopathy is the life-threatening intracranial hypertension due to brain edema [12], [13]. A recent controlled trial suggested that phenytoin may be effective as a prophylaxis of subclinical seizure activity [14]. In this issue of the Journal, Bhatia et al. report the results of a controlled trial of phenytoin as prophylaxis of seizures in patients with ALF and stage III–IV encephalopathy [15]. A controlled trial in the field of ALF, where so few are available [2], [9], is always a noteworthy achievement. Experienced hepatologists from New Delhi, after having stratified patients with established ALF according to their clinical severity at inclusion, demonstrated that IV phenytoin used at recommended dosages for preventing clinical seizures was ineffective: rates of seizures and severe cerebral edema as well as fatality rates were similar in patients receiving the antiepileptic drug and in those who did not [15].

Since liver transplantation is not yet available in India, Bhatia et al.'s study offers the opportunity to reconsider many aspects, and pitfalls, of medical supportive care of patients with established ALF in order to optimize their survival. Several features of special interest of the Bhatia et al.'s study deserve further comments. First, the question could be raised whether the results of the Indian trial may be applied worldwide. Although etiology of ALF in the 42 patients included in the study was dominated by hepatitis E, a major cause of ALF in India [5], I confidently hypothesize that results would have been similar had the study been performed in a Western country where drug-induced hepatotoxicity is currently the leading cause of ALF [1]. Indeed, in patients with ALF and late stages of encephalopathy, the latter more than the cause of the acute liver disease is the main prognostic factor of short term outcome [1]. So, in my view, results of the Indian study may be applied worldwide in patients with ALF and stage III–IV encephalopathy.

Second, among the 42 patients with a 74% rate of clinically significant cerebral edema, the overall rate of clinical seizures was 24% [15]. The uncommon occurrence of seizures in patients with ALF, previously pointed out [12], fits well our own clinical experience. The 24% rate in the Bhatia et al.'s study shows that severe cerebral edema by itself is not the only requirement for the occurrence of seizures. The latter could simply reflect the intrinsic aggravation of cerebral edema due to the continuing downhill course of ALF. However, since specificity of symptoms is always very low in patients with ALF, it is not unjustified to question whether seizures could be, at least in part, related to additional factors concomitant to ALF, namely acute renal failure and the use of potentially neurotoxic drugs. Bhatia et al. adequately defined number of expressions and variables used in their study but, on the only basis of a normal result, 0.7 mg/dl, of serum creatinine, concluded that ‘no patient developed renal failure’ [15]. Several arguments make me reluctant to support this statement. Normal serum creatinine may coexist with acute renal failure. In patients with well defined ALF, the incidence of acute renal failure (a) is higher in those with, than in those without, severe cerebral edema, (b) was 30% in cases not due to acetaminophen hepatotoxicity in United Kingdom [2] and (c) 38% among 50 consecutive Indian patients with an increased frequency in those with jaundice [16]. Finally, in patients managed by Bhatia et al., mean serum bilirubin level was 16.5 mg/dl (i.e. 280μmol/l) [15]. This key result must lead to be extremely cautious regarding a normal value of serum creatinine because of the negative interference between bilirubin-derived biliverdin and serum creatinine when the latter is assayed, at high pH, by a Jaffé reaction derived technic [17], [18]. This methodological drawback was confirmed by a recent study using enzymatic creatinine [19]. Therefore, I hypothesize that a significant number of patients included in the Bhatia et al.'s study did actually develop acute renal failure. Thus, according to this hypothesis, it results that using ranitidine, a potentially neurotoxic anti-H2 receptor antagonist with delayed clearance in patients with severe cirrhosis [20], exposes patients with ALF complicated by severe cerebral edema and acute renal failure—a condition comparable to severe cirrhosis—to an unpredictable risk of neurotoxicity with seizures. This, admittedly controversial, hypothesis could have been confirmed, or denied, by plasma drug assays but can hardly be denied only on clinical grounds in so critically ill patients. Pharmacokinetics of drugs is profoundly altered in patients with both severe hepatic and renal dysfunction [21] and cerebral aggravation in patients with ALF may be due to drugs associated with fitting [10] and also to terlipressin [22].

Third, Bhatia et al. provided three other critical data which may share some relationship with the occurrence of cerebral edema and seizures among their 42 patients with ALF. Mean arterial pressure (MAP) was low (<60 mmHg). Since, in patients with stage III–IV encephalopathy, cerebral blood flow closely depends on systemic arterial pressure, this low level of MAP suggests that, at least in those of the Indian patients with the lowest values, some degree of cerebral hypoperfusion might have been a cofactor of seizures. Half the patients of the trial had significant hyponatremia, ranging between 115 and 135μmol/l. Although natremia levels of patients who developed seizures and those of patients who did not were not compared, hyponatremia could have been another cofactor of seizures in these patients. Hyponatremia may contribute to the development, or the aggravation, of cerebral edema and a recent, noteworthy, controlled trial at King's (London) showed that hypertonic sodium chloride administration allows a significant decrease in intracranial pressure [23]. Finally, the high mean hyperglycemia, 243 mg/dl, in addition to its unfavourable prognostic value in critically ill patients [24], may also result in increased intracranial pressure [25].

Despite so many possible cofactors of seizures, the overall 31% survival rate reported by Bhatia et al. is within the expected range [18]. The 42 patients are mainly younger than 30, but none of them had ALF due to acetaminophen, a cause frequently associated with increased survival rates [1], [2].

Finally, what is the most important message delivered by Bhatia et al. regarding patients with ALF? In my view, it is not the recommendation for not using phenytoin in patients with stage III–IV encephalopathy, but the vigorous emphasis that their patients ‘presented too late to the hospital’ [15]. Although repeatedly denounced for decades, the ‘too late’ referal to liver units, or at least to a hepatogastroenterologist (even by a phone call), of patients affected by acute liver disease and severe coagulopathy (prothrombin ratio <50% of normal) remains a key factor of the development of established ALF [2], [18]. This universal message, unfortunately, is still true all around the world including countries where ELT is available [1].

It is crucial to understand why delayed hepatologic evaluation of these patients may be so deleterious. At least three processes may be involved. First, the etiological diagnosis of the acute liver disease, especially that of the cases with an unusual clinical profile (such as non-intentional acetaminophen-induced hepatotoxicity) or due to a relatively uncommon cause, is too often delayed. Second, and consequently, specific treatments targeting the liver—the key organ to be preserved and supported in patients with acute liver disease still without clinical encephalopathy but with severe coagulopathy and thus threatened by ALF—may also be delayed. Whereas these specific treatments have their full efficacy when liver tissue lesions are still (relatively) limited, their delayed application allows the spread of liver destruction. Classical examples of this issue include all the treatable acute liver diseases [2], [18] such as acetaminophen-induced hepatotoxicity [1], [2], herpes simplex hepatitis, acute fatty liver of pregnancy, auto-immune hepatitis, hypoxic hepatitis, Budd-Chiari syndrome and the acute form of Wilson's disease [26]. Third, and most important, there is a risk of unappreciated aggravation of either the destruction of liver tissue or the patient's condition. A key factor of such an aggravation, often associated with both delayed diagnosis and the lack of specific treatment, is the undiscriminating use of various hepatotoxic, nephrotoxic or neurotoxic substances when the first therapeutic law in patients with acute liver diseases, ‘stop any drug’, is not followed [18]. For many years, this concept of deleterious ‘aggravating cofactors’ is consistent with the clinical experience of the author in many patients with ALF associated with acute viral hepatitis due to hepatitis A, or B (or B and D), or C, and also with dengue fever, herpes simplex hepatitis, varicella and isoniazid-induced hepatitis. The hypothesis is now supported by recent reports of recent (prior to encephalopathy) ingestion of acetaminophen in patients with ALF complicating acute viral hepatitis type B in the United States [27], [28] or type A in France [29]. Inadequate consumption of acetaminophen could also explain life-threatening cases of ALF having complicated parvovirus B19 infection, a febrile illness, in Belgian children [30]. Aggravating cofactors may be extra-hepatic as well. As an example, admission hyponatremia, a frequent finding in patients with ALF in New Delhi [15], but also in London [23] and Clichy (personal experience), usually attests the previously unappreciated development of acute renal failure associated with inadequate low sodium rehydratation. So it is quite likely that early referal to hepatologists of patients with acute liver disease and severe coagulopathy (prothrombin ratio <50%) could actually reduce, even eliminate, the sometimes multiple aggravating cofactors that precipitate the patient in the life-threatening condition of established ALF.

So the final question is: why referal to liver units (or at least an early phone call to a hepatologist) is delayed in so many patients with acute liver disease, severe coagulopathy and no clinical encephalopathy? This issue is fully pertinent in this editorial since, as mentioned above, Bhatia et al. clearly stressed that their patients ‘presented too late to the hospital’ [15]. My view is that hepatologists, and still more non-hepatologists, are confined within the classical, but too rigid, Trey and Davidson's definition of ALF in which clinical encephalopathy is both an absolute requirement for the diagnosis of ALF and a marker of the catastrophic prognosis most often associated to it [31]. For many years, Benhamou and the Beaujon's group do think that ‘the liver fails before encephalopathy’ [32] as attested by the early deterioration in coagulation factors activities and, often but inconstantly, by early jaundice. Encephalopathy should be considered as a late symptom of ALF (J. Wendon, personal communication) and the concept of ALF without encephalopathy was used by several authors [26], [33], [34], [35], [36]. So, practically speaking, hepatologists should teach repeatedly to non-hepatologists not to wait for even ‘early symptoms’ of encephalopathy prior to refer patients with acute liver disease and severe coagulopathy to a hepatologist: waiting for encephalopathy would lead to unacceptably delayed referal, as prospectively observed by Bhatia et al. [15]! Any physician will agree that, in these patients who are threatened by established ALF, both avoidance of deleterious cofactors and early specific medical therapy for the liver must be prefered to late intensive care for the brain.

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PII: S0168-8278(04)00219-3

doi:10.1016/j.jhep.2004.05.007

Journal of Hepatology
Volume 41, Issue 1 , Pages 152-155, July 2004

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