P.M. Harrison

Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial.

OBJECTIVE--To see whether intravenous acetylcysteine would improve outcome in patients with fulminant hepatic failure after paracetamol overdose. DESIGN--A prospective randomised controlled study. SETTING--The Institute of Liver Studies, Kings College Hospital, London. PATIENTS--50 consecutive patients (21 male) aged 16-60 with fulminant hepatic failure after paracetamol overdose who had not previously received acetylcysteine. INTERVENTIONS--Conventional intensive liver care plus either acetylcysteine (25 patients) in the same dose regimen as used early after a paracetamol overdose, except that the infusion was continued until recovery from encephalopathy or death, or an equivalent volume of 5% dextrose (25 patients). MAIN OUTCOME MEASURES--Survival; incidence of cerebral oedema, renal failure, and hypotension requiring inotropic support; liver function as assessed by prolongation of the prothrombin time; and degree of encephalopathy. RESULTS--The rate of survival was significantly higher in the acetylcysteine treated group than in the controls (48% (12/25 patients) v 20% (5/25); p = 0.037, 95% confidence interval for difference in proportions surviving 3% to 53%). Acetylcysteine treated patients had a lower incidence of cerebral oedema (40% (10/25) v 68% (17/25); p = 0.047, 95% confidence interval for difference in incidence 2% to 54%), and fewer developed hypotension requiring inotropic support (48% (12/25) v 80% (20/25); p = 0.018, 95% confidence interval 7% to 57%). Rates of deterioration and recovery of liver function, however, were similar in the two groups. No adverse reactions to acetylcysteine were seen. CONCLUSIONS--Acetylcysteine is safe and effective in fulminant hepatic failure after paracetamol overdose.

Randomised trial of variceal banding ligation versus injection sclerotherapy for bleeding oesophageal varices

Injection sclerotherapy of bleeding oesophageal varices is undoubtedly beneficial but it is associated with a substantial complication rate, and variceal rebleeding is common during the treatment period before variceal obliteration is achieved. We aimed to find out whether endoscopic variceal banding ligation is safer and more effective. The two methods were compared in a randomised controlled trial of 103 patients (54 assigned to banding ligation, and 49 to injection sclerotherapy) of whom 21 (39%) and 23 (47%), respectively, had active bleeding at index endoscopy. Both treatments were highly effective in controlling active haemorrhage (91% and 92% respectively). Variceal obliteration was not achieved for 22 patients in each group, but among those whose varices were eradicated, banding ligation achieved obliteration more quickly than did sclerotherapy (mean 39 [SD 4] vs 72 [7] days, p = 0.004) and in fewer endoscopy sessions (3.4 [2.2] vs 4.9 [3.5], p = 0.006). Rebleeding was less common in the banding ligation group than in the sclerotherapy group (16 [30%] vs 26 [53%], p < 0.05). There was no difference in outcome between the groups, but 14 sclerotherapy patients were withdrawn from the trial (7 for orthotopic liver transplantation) compared with only 5 (1 for liver transplantation) in the banding ligation group (p < 0.05). Complication rates were similar in the two groups. Variceal banding ligation is a safe and effective technique, which obliterates varices more quickly and with a lower rebleeding rate than injection sclerotherapy.

Improved outcome of paracetamol-induced fulminant hepatic failure by late administration of acetylcysteine

The influence of acetylcysteine, administered at presentation to hospital, on the subsequent clinical course of 100 patients who developed paracetamol-induced fulminant hepatic failure was analysed retrospectively. Mortality was 37% in patients who received acetylcysteine 10-36 h after the overdose, compared with 58% in patients not given the antidote. In patients given acetylcysteine, progression to grade III/IV coma was significantly less common than in those who did not receive the antidote (51% vs 75%), although the median peak prothrombin time was similar for both groups. Whether the beneficial effect is related to replenishment of glutathione stores or a consequence of another hepatic protective mechanism of acetylcysteine requires further study.

Serial prothrombin time as prognostic indicator in paracetamol induced fulminant hepatic failure.

OBJECTIVE--To find out whether changes in the daily prothrombin time are of prognostic importance in patients with paracetamol induced fulminant hepatic failure. DESIGN--Retrospective study. SETTING--The Liver Unit, Kings College Hospital, London. PATIENTS--150 Consecutive patients with paracetamol induced fulminant hepatic failure admitted between October 1986 and February 1989. MAIN OUTCOME MEASURE--Death. RESULTS--Of the 150 patients, 72 (48%) died. In all, 34 of the 37 (92%) patients with a peak prothrombin time of greater than or equal to 180 seconds died as did 20 of the 41 (49%) with a time of 130-179 seconds, nine of the 25 (36%) with a time of 90-129 seconds, and nine of the 47 (19%) with a time of less than 90 seconds. Of the 42 patients with a continuing rise in prothrombin time between days 3 and 4 after overdose, 39 died (93%) compared with 21 of the 96 (22%) in whom the prothrombin time fell. CONCLUSIONS--These data indicate that a continued increase in prothrombin time on day 4 after overdose and a peak prothrombin time of greater than or equal to 180 seconds identify at an early stage those patients with a less than 8% chance of survival. Liver transplantation should be considered in patients meeting either of these criteria.

The relationship between plasma and brain quinolinic acid levels and the severity of hepatic encephalopathy

BACKGROUND/AIMS Quinolinic acid is an endogenous neuroexcitant derived from tryptophan. Brain quinolinic acid concentrations are reportedly elevated in chronic liver failure. The aim of this study was to determine if brain quinolinic acid levels correlate with the severity of hepatic encephalopathy. METHODS Postmortem samples of selected brain regions and plasma samples taken at several stages of encephalopathy were obtained from patients with acute and chronic liver failure. Quinolinic acid levels were measured by mass spectroscopy using [18O]quinolinic acid. RESULTS Plasma quinolinic acid levels were significantly increased by stage I encephalopathy in patients with acute liver failure and by stages II and III in patients with chronic liver failure. Brain quinolinic acid levels were elevated only in patients with acute liver failure and were uniformly distributed at concentrations below those observed in plasma. CONCLUSIONS The uniform distribution of quinolinic acid at subplasma concentrations in the brains of patients with acute liver failure suggests that it is synthesized peripherally and enters the brain across a permeabilized blood-brain barrier. Whereas the elevation of brain quinolinic acid levels in patients who died of acute but not chronic liver failure suggests that the involvement of quinolinic acid in the pathogenesis of hepatic encephalopathy is minimal, it could predispose these patients to seizures.

Hepatic expression of hepatocyte-growth-factor-like/macrophage-stimulating protein mRNA in fulminant hepatic failure

We investigated whether impaired Kupffer cell phagocytosis in fulminant hepatic failure could be due to reduced synthesis of hepatocyte-growth-factor-like/macrophage-stimulating protein (HGFL/MSP), a serum protein synthesised predominantly in hepatocytes and required by tissue macrophages for phagocytosis. Hepatic expression of the 3.0 kb HGFL/MSP mRNA, assessed by northern hybridisation, was lower in nine patients with fulminant hepatic failure undergoing liver transplantation than in three liver grafts as controls (median absorbance units 97 [range 15-1200] versus 1114 [1100-1120], respectively; p < 0.05). Decreased hepatic HGFL/MSP production might cause impaired Kupffer cell phagocytosis in fulminant hepatic failure.

Ischaemic cholangiopathy and sickle cell disease.

We report a case of a 6-year-old girl of Afro-Caribbean origin, known to have sickle cell disease (SCD), with recurrent history of jaundice and abdominal pain. She was extensively investigated, including endoscopic retrograde cholangiopancreatography (ERCP), which revealed diffuse cholangiopathy of both extrahepatic and intrahepatic bile ducts. A pigtail stent was placed and balloon dilatation was performed for stricture of the extrahepatic duct. Since then, she remains well and asymptomatic. We suggest that cholangiopathy is the consequence of sickling in the end arteries of the biliary arterial tree.

New Approaches to Paracetamol Hepatotoxicity

SummaryParacetamol overdose leading to hepatotoxicity remains the most common cause of fulminant hepatic failure in England and Wales. Studies at the Institute of Liver Studies have demonstrated that the continuing mortality is, at least in part, due to an increase in the severity of fulminant hepatic failure secondary to chronic alcohol consumption or the long term use of anticonvulsant drugs.We have also investigated 2 new therapeutic approaches to paracetamol hepatotoxicity. S-adenosyl-L-methionine (SAMe) was shown in 2 mouse models of paracetamol overdose to improve survival and reduce liver damage, an effect almost certainly mediated by repletion of hepatic glutathione. A retrospective analysis of patients with paracetamol-induced fulminant hepatic failure suggested that ‘late’ administration of N-acetylcysteine (NAC) [between 10 and 36 hours after the overdose] exerted a protective effect. The beneficial effect of NAC on survival, cerebral oedema and hypotension in this situation was confirmed by a prospective controlled trial. Later work suggests that part of the benefit of late NAC derives from a reduction in the oxygen debt commonly found in fulminant hepatic failure.New therapies such as SAMe and late NAC merit further study in the management of paracetamol hepatotoxicity. Identification of patients at increased risk of severe liver damage may allow better use of such therapies.