Langley Pg

CHARCOAL HÆMOPERFUSION IN THE TREATMENT OF FULMINANT HEPATIC FAILURE

Abstract Twenty-two patients with fulminant hepatic failure who deteriorated to grade-IV coma despite full supportive therapy were treated by repeated periods of haemoperfusion through columns containing activated charcoal. The procedure was well tolerated clinically. Eleven of the patients regained consciousness and ten left hospital. Follow-up liver biopsies in the first three patients at around six months after discharge from hospital showed restitution of the normal lobular architecture. Of the eleven treatment failures, haemorrhage was responsible for death in three, and in six brain herniation secondary to cerebral œdema was an important contributory factor. The column extracted most aminoacids from plasma, and during perfusion arterial concentrations of phenylalanine, tyrosine, and methionine-aminoacids known to be involved in the pathogenesis of the encephalopathy—fell significantly. The charcoal was coated with a biocompatible polymer, and there was no evidence for removal of coagulation factors. The extraction of platelets was below 30% in most instances, and in only two patients was there evidence that bleeding may have been precipitated by the haemoperfusion. These survival figures are to be compared with a previous survival figure of 10% in a series of ninety-two cases with fulminant hepatic failure and grade III or IV encephalopathy treated by full supportive measures.

TREATMENT OF FULMINANT HEPATIC FAILURE BY POLYACRYLONITRILE-MEMBRANE HÆMODIALYSIS

24 patients with fulminant hepatic failure who had deteriorated to grade-IV coma were treated by repeated periods of haemodialysis with a polyacrylonitrile membrane. 9 patients fully recovered consciousness, and 8 (33%) survived to leave hospitals. These results are to be compared with those of conservative management alone (15% survival in 53 cases) and those obtained initially with charcoal haemo-perfusion (38%). Of the 16 treatment failures, cerebral oedema was found at necropsy in 13 (18%). Whether this would have been less of problem if treatment had been started earlier in the course of the illness remains to be determined.

Evaluation of the BioLogic-DT sorbent-suspension dialyser in patients with fulminant hepatic failure.

The BioLogic-DT sorbent suspension dialyser was developed to remove toxic substances from the blood of patients with liver failure. In the present study a randomised controlled trial was carried out in 10 patients with fulminant hepatic failure who had developed grade 4 encephalopathy to evaluate the safety and biocompatibility of the dialyser in such severely ill patients. A total of 18 treatments were performed in 5 patients. Haemodynamic stability was maintained throughout. There was a significant loss of platelets (163 ± 34 to 101 ± 13 x 109/l) and decrease in plasma fibrinogen (0.53 ± 0.09 to 0.31 ± 0.08 g/l) with a rise in blood activated clotting time (190 ± 17 to 223 ± 22 sec) — not seen in the controls —, which was a result of the dialysis being carried out without the use of heparin as anticoagulant. Removal of metabolites by treatment was limited, with no significant effect on blood ammonia level and further developments of the system will be needed for this very sick group of patients.

PROSTACYCLIN TO PREVENT PLATELET ACTIVATION DURING CHARCOAL HÆMOPERFUSION IN FULMINANT HEPATIC FAILURE

Adverse effects associated with hypotension and the appearance of platelet aggregates in the circulation complicate charcoal haemoperfusion of patients with fulminant hepatic failure. In an attempt to avoid these difficulties the platelet protective effect of prostacyclin (PGI2) given intravenously before and continuously during haemoperfusion was evaluated with an improved charcoal column design. Two of the six patients who underwent haemoperfusion without PGI2 had hypotension, which in one was associated with a striking rise in Swank screen filtration pressure necessitating discontinuation of haemoperfusion after an hour. No platelet losses were observed in the six patients treated with haemoperfusion and PGI2 infusion, and there was significant protection from platelet activation, as assessed by the prevention of release into plasma of the platelet-specific protein beta-thromboglobulin.

Thiopurine methyltransferase phenotype and genotype in relation to azathioprine therapy in autoimmune hepatitis

BACKGROUND/AIMS Toxicity and efficacy of azathioprine is governed partly by the activity of thiopurine methyltransferase (TPMT). Azathioprine has been used for many years, with corticosteroids or alone, for the treatment of autoimmune hepatitis (AIH) but no studies of TPMT phenotype and genotype in relation to response to the drug in AIH have been published. METHODS Erythrocyte TPMT activities were measured by a radioincorporation assay in 72 consecutive outpatients with AIH, 53 of whom were genotyped for the commonest defective alleles in Europeans (TPMT*3A, *3B and *3C) by restriction fragment length polymorphism analysis. RESULTS TPMT activities were significantly lower in patients intolerant of azathioprine (group I, n=15) than in those who sustained remission on azathioprine alone (group II, n=28; P=0.003) and those who tolerated azathioprine but continued to require corticosteroids (group III, n=29; P<0.0001), and were higher in group III than in group II (P=0.034). Ten patients with defective alleles (all heterozygotes) had significantly lower TPMT activities (P=0.002). However, in 25% there was discordance between phenotype and/or genotype and response to azathioprine. CONCLUSIONS TPMT phenotyping or genotyping may be advisable before institution of azathioprine therapy in AIH but neither approach invariably predicts response to the drug.

TEMPORARY EXTRACORPOREAL LIVER SUPPORT FOR SEVERE ACUTE ALCOHOLIC HEPATITIS USING THE BIOLOGIC-DT

Patients with severe acute alcoholic hepatitis develop multiple organ failure which is associated with production of inflammatory cytokines and a poor prognosis. The aim of the present pilot study was to evaluate the effects of the BioLogic-DT sorption-suspension dialyser in patients with severe acute alcoholic hepatitis. Ten patients with encephalopathy (grade II-IV) were entered into the study, 5 received treatment with the BioLogic-DT for 6 hours daily for 3 days and 5 received conventional treatment as controls. The system was biocompatible with no adverse effects on blood pressure or platelet counts, factor V, fibrinogen or antithrombin III. No bleeding episodes were observed even with the use of small doses of heparin. After 3 days, blood ammonia was lower in the BioLogic-DT treated patients than in the controls, although blood lactate was higher. There were slight increases in plasma TNF and IL-8 during treatment over and above the higher levels present initially, possibly as a result of activation of white cells in the extracorporeal circuit. The further development of the BioLogic-DT dialyser with the addition of a plasma treatment module capable of removing cytokines would be worth evaluating in acute alcoholic hepatitis.

Platelet function in chronic liver disease

Abnormalities of platelet aggregation in response to adenosine diphosphate in 56 patients with chronic liver disease correlated with impairment of hepatocellular function but not with the etiology of the liver disease. Platelet-poor plasma from some patients appeared to contain an inhibitor since, in cross-over studies, it reduced the degree of aggregation of control subjects. However, platelet-poor plasma from some other patients enhanced aggregation in controls, and this was thought to be due to the presence of fibrin monomer. In the majority of patients with severe liver disease, platelet function still appeared defective, even after exclusion of the effects of plasma, and was independent of the platelet count in peripheral venous blood. Since patient platelet volumes were smaller than those of controls, these findings might be explained by deficiency of the larger hemostatically active type of platelet as a consequence of either bone marrow failure or splenic sequestration.

Effects of serial resin hemoperfusion in fulminant hepatic failure.

Resin hemoperfusion using an albumin coated Amberlite XAD-7 column was performed in 19 patients in coma due to fulminant hepatic failure. The procedure was clinically well tolerated, with good blood compatibility, platelet and white cell levels being 97.3 ± SE 3.2% and 105 ± 3.8% of the respective initial values after four hours hemoperfusion. No significant changes were observed in β-thromboglobulin, screen filtration pressure, plasma electrolytes, calcium, protein or albumin. The total plasma bilirubin fell by a mean of 24 μmol/l, with a reduction in 21 of the 25 perfusions studied of up to 104 μmol/l during perfusion. Mean plasma levels of total bile acids were 137 ± 19 μmol/l and 115 ± 16 μmol/l respectively before and after four hours hemoperfusion. The amount of bile acids recovered by elution of the resin column was over three times greater than that apparent from the change in plasma levels. Column chromatography on Sephadex G-25 of material eluted from the resin column showed various peaks to be removed, including substances in the middle molecular weight range (1000-5000 daltons). Of the patients treated, eight (42%) survived to leave hospital.

Plasma levels and hepatic mRNA expression of transforming growth factor-β1 in patients with fulminant hepatic failure

Abstract Background/Aims: Transforming growth factor-β 1 is an important cytokine involved in cell growth and inflammation which has been shown to be inhibitory to hepatic DNA synthesis. The aim of this study was to investigate the plasma levels and hepatic mRNA expression of transforming growth factor-β 1 ni patients with fulminant hepatic failure in whom liver regeneration may be impaired. Methods: Plasma levels of transforming growth factor-β 1 and human hepatocyte growth factor were measured in 57 fulminant hepatic failure patients and 20 healthy volunteers by ELISA. Northern blot analysis of transforming growth factor-β 1 and H3 histone, a marker for liver proliferation, was performed in liver tissue of 14 fulminant hepatic failure patients. Results: The plasma levels of total transforming growth factor-β 1 in fulminant hepatic failure patients on admission (median 38.8 ng/ml, range 8.4–108 ng/ml) were significantly higher than those in control subjects (23.0 ng/ml, 8.5–34.9 ng/ml, p n =10, p n =47). In contrast, the plasma levels of free transforming growth factor β 1 were greater in paracetamol overdose (623 pg/ml, 46.7–1241 pg/ml, n =21) than in non-A, non-B hepatitis (131 pg/ml, 77.2–254 pg/ml, n =9), with both being higher than control (72.3 pg/ml, 28.7–108, n =7, p p 1 in paracetamol-overdose patients ( n =8, p n =6), compared to controls ( n =4). Conclusions: The increased circulating plasma TGF-β 1 in FHF may be part of the tissue repair process in fulminant hepatic failure. In patients with non-A, non-B hepatitis, the increased total transforming growth factor-β 1 together with a less elevated hepatocyte growth factor could be related to impaired liver regeneration in this group.

Controlled trial of antithrombin III supplementation in fulminant hepatic failure

Patients with fulminant hepatic failure have severe circulatory disturbances which may be due to fibrin and cellular plugs in micro-vessels which are a consequence of intravascular coagulation and which can lead to multiorgan failure. Since antithrombin III supplementation has been shown to be beneficial in animal models of septic shock with disseminated intravascular coagulation, a controlled study was performed to investigate the effect of antithrombin III supplementation in fulminant hepatic failure. Twenty-five patients in grade III or IV coma were selected on the basis of evidence of sepsis, intravascular coagulation and a high risk of developing multiorgan failure. Thirteen patients received 3000 units of antithrombin III (Kybernin P; Behringwerke), followed by a further 1000 units every 6 h. Antithrombin III activity increased from 0.26 +/- 0.04 SE U/ml to 0.82 +/- 0.07 U/ml at 3 h post infusion (normal range 0.80-1.20 U/ml) and remained greater than 0.80 U/ml throughout the study without any apparent increase in the frequency of bleeding. However, survival was not improved and markers of intravascular coagulation remained similar between the two groups. Thus, although the antithrombin III deficiency in fulminant hepatic failure can be corrected by supplementation with antithrombin III concentrate, its use in the prevention of intravascular coagulation and to avoid microvessel plugging needs to be studied at an earlier stage in the disease.