Acute hepatic failure : University of Toronto experience

GA LEVY. Acute hepatic failure: University of Toronto experience. Can J GastroenteroJ 1993;7(7):542-544, Fulminant hepatic failure (FHF) is a serious disorder of the liver that is associated with a mortality of 80 to 90%. Admission of patients to specialized liver intensive care units has resulted in an improvement of survival from 10 co 30%. To date, however, no specific medical therapy has proven to be effective, and liver transplantation is the main form of therapy for these patients. Previously, the author demonstrated that prostaglandins could alter the course of FHF in an experimental animal model caused by the coronavirus, murine hepatitis virus strain 3. Furthermore, in an uncontrolled trial in patients with this disorder, overall survival was 71 % in patients treated with intravenous prostaglandins. Based upon these initial results, a prospective randomized controlled trial of intravenous prostaglandin Ei compared with placebo was performed in 41 patients. The overall results showed no improvement in survival of the prostaglandin-created patients (40%) compared with the controls who were treated with placebo (38%). However, in the patients with FHF caused by acetaminophen, survival was higher in the prostaglandin-rreaced group (54.5%) compared with the placebo-created patients (37.5%). Furthermore, if treatment with prostaglandin Et was initiated within 10 days of first symptoms, survival was 73%, compared with 16% survival if treatment was delayed for more than four days. These results suggest a potential role for prostaglandins in the early management of patients with Fl lF, especially due to acetaminophen toxicity.

Insuffisance hepatique aigue: experience menee a l'Universite de Toronto RESUME: L'insuffisance hepatique fulminante est une maladie grave du foie qui est associee a un rnux de mortalite de l'ordre de 80 % a 90 %.L'aJmission des patients clans les unites Je soins incensifs specialises pour le foie a donne lieu a une amelioration du laux de survie de 10 % a 30 %. Jusqu'a present, cependanr, aucune therapeutique medicate specifique ne s'est revelee efficace et la transplantation hcpatique demeure la principale forme de traitement pour ces patients.Auparavant, les auteurs ont demontre que !es prostaglandines pouvaient alterer la is defined as the development of severe impairment of hepatocellular function in an individual who has no evidence of previous liver disease.It has been recently subdivided into three subgroups: hyperacute, acute and subacute.Hyperacute FHF is defined as the onset of FHF less than 48 co 72 h after initial symptoms, acute is defined as the onset of illness less than eight weeks from the onset of symptoms and subacute is defined as the onset of liver failure within eight to 28 weeks from the onset of initial symptoms.The mortality of FHF of all etiologies can be as high as 80% as the patient develops grade III to IV hepatic encephalopathy (1).
Since the recognition of this disease entity in 1970 by Trey and Davidson, there have been a number of developments which have resulted in new treatments for these patients.The group at King's College, London, United Kingdom, headed by Roger Williams established the principle of admission of such patients to a defined liver unit.Based upon this, advances in treatment -including charcoal hemoperfusion, introduction of intra.cranialpressure monitors, infusion of glucose and insulin, prostacycl ins and a n ticoagulants -have advanced our understanding of this disease entity and, in some cases, improved survival (2).In progression de l'insuffisance hepatique fulminante clans le cadre d'un modele animal experimental provoque par le coronavirus et la souche 3 du virus de l'hepatite murine.De plus, clans un essai non controle chez des patients atteints de cette maladie, le taux de survie global a ete de 71 % chez les patients traites avec des prostaglandines intraveineuses.Sur la base de ces resultats initiaux, une etude controlee randomisee prospective portant sur la prostaglandine Et comparee a du placebo a ete effectuee aupres de 41 patients.Les resultats globaux n'ont revele aucune amelioration du taux de survie chez les patients traites avec la prostaglandine (40 %) en comparaison avec les controles qui ont ete traites avec du placebo (38 %).Cependant, chez les patients atteints d'une insuffisance hepatique fulminante causee par l'acetaminophene, le taux de survie s'est revele plus haut chez les sujets traites avec la prostaglandine (54,5 %) que chez les patients qui recevaient du placebo (37,5 %).En outre, si le traitement avec la prostaglandine Et avait ete amorce clans les 10 jours suivant les premiers symptomes, le taux de survie etait de 73 %, contre 16 % si le traitement etait retarde de plus de 4 jours.Ces resultats donnent a penser que les prostaglandines auraient un role potentiel clans le traitement precoce des patients atteints d'insuffisance hepatique fulminante, particulierement attribuable a une intoxication a l'acetaminophene.1980, Benhamou (3) defined the importance of measurements of coagulation factors V and VII as discriminants of survival.O'Grady ( 4) used a multivariate analysis in 1989 to determine prognostic indicators for patients with severe forms of FHF.
In the 1980s it became apparent that liver transplantation could be effective for treatment of patients with FHF, and this has become the main form of therapy for severe FHF (5).

THERAPY AT THE UNIVERSITY OF TORONTO
Liver transplantation: With the establishment of a liver transplant program in 1985 at the University of Toronto, patients with FHF became candidates for liver transplantation.Early transplant experience of the author's group was patients with FHF constituted 28% of total liver transplantation.As of 1991, this group has transplanted 26 patients with FHF; the survival rate, 48%, is in keeping with the races reported by other institutions.On further analysis of these data, however, it has become apparent that patients with status II and Ill hepatic encephalopathy do well following liver transplantation (78% survival) whereas patients with deep stage IV hepatic encephalopathy do poorly (26% survival).
With these rates in mind, the University of Toronto looked for other forms of treatment to help patients with FHF.

PROSTAGLANDINS AND FHF
Animal experiments: The author's group (6) has previously reported that 16, 16 dimethyl prostaglandin Ez (dmPGE2), a known cytoprotective agent, was able to alter the course of FHF in an experimental model of fulminant viral hepatitis, a murine hepatitis virus type 3. Whereas fully susceptible animals infected with the virus develop histological and biochemical evidence of fulminant hepatic hepatitis -as evidenced by massive hepatic necrosis with hypoglycemia and metabolic acidosis -animals treated with dmPGEi, either before or after infection, demonstrated a marked reduction in both histological and biochemical evidence of liver damage, as characterized by normal blood glucose, total carbon dioxide and alanine aminotransferase determinations.The effect of dmPGEi was specific as another prostaglandin, PGF2a, demonstrated no such cytoprotective effects.Clinical experience: The results of animal experiments led Sinclair et al ( 7) to an open trial to study the effect of prostaglandins on patients with ful[(\.inantand subfulminant viral hepatitis.Seventeen patients presented with FHF secondary to hepatitis A, Band C. Fourteen of these patients had stage Ill or IV hepatic encephalopathy.All patients had high levels of aspartate transaminase and bilirubin, and markedly abnormal prothrombin times and partial CAN J GASTROENTEROL VOL 7 No 7 SEPTEMBER/0crOBER 1993 Acute hepatic failure thromboplastin times.Intravenous PGEt was initiated within 24 to 48 h of presentation and a marked improvement in hepatic synthetic function was noted in the vast majority of patients.Overall survival was 71 % in this series.None of the patients with hepatitis B or A virus infection flared upon tapering of therapy; however, a relapse was noted in patients with hepatitis C, necessitating further therapy.Two of the patients required prolonged oral prostaglandins, but are free from disease six months later.These initial results suggest that treatment with prostaglandins of the E series may be beneficial in patients with fulminant and subfulminant hepatitis. Based upon these initial results, Sheiner and colleagues (8) performed a prospective randomized control trial of intravenous PGE1 compared with placebo at the University of Toronto.Although it was calculated that 52 patients would be required if the expected mortality was reduced from 80 to 40%, after three years with recruitment declining the trial was stopped with an enrolment of 41 patients.The patients ranged in age from three to 66 years; 16 patients were male and 25 were female.The etiology was viral (20 patients), drugs/toxins (19) and ischemia (two).Stages of hepatic encephalopathy on admission were stage I and II, (n=25), stage III (n=lO), stage IV (n=6).Ac initiation of therapy, 73% of the patients had deteriorated to stage IV.Failure of treatment was defined as continued deterioration on therapy, and open-Label PGEt was initiated and patients were listed for transplantation.
The overall results showed that eight of 20 PGE1-treated patients ( 40%) versus eight of 21 placebotreated patients (38%) survived (not statistically different).Based on initial presentation of hepatic encephalopathy in grades I and II, 50% survival was seen in the PGE1 group, whereas only 38% was seen in the placebo group.The mortality rates for viral hepatitis were similar in the placebo and prostaglandin groups, but survival in the drug/toxin hepatitis group was significantly higher than in the placebo group (54.5% versus 37.5%).Furthermore, regardless of the initial randomi-zation, if treatment with PGE1 was initiated within l O days of first symptoms, survival was 73% (eight of 11) compared with 16% (three of 18) if treatment was delayed for more than 14 days (P<0.001).
Although this trial failed to show an overall benefit for PGE1 therapy in FHF, the results support the facts that PGE1 may be of benefit if started early (less than 10 days) in the course ofFHF and appears to be more useful in drug-/ toxin-induced FHF.

CONCLUSIONS
There have been several significant advances in the understanding of the pathogenesis and treatment of FHF.Early recognition of these patients in transfer to a liver unit has resulted in a marked improvement in survival.Fur-thermore, liver transplantation can be successful in these patients even when the patients lapse into deep coma.Finally, recent data suggest a role for prostaglandins and prostacyclins in the therapy of patients with FHF, especially when started early.