'Double-hit' pegylated interferon-alpha successfully treats Hepatitis B and Hepatitis D co-infection.

Hepatitis delta (HDV) infection is either acquired simultaneously with, or as a superinfection to, existing Hepatitis B (HBV). It leads to a serious form of chronic viral hepatitis and accelerated liver-related morbidity and mortality including hepatocellular carcinoma. Current treatment regimes propose Pegylated interferon-alpha for 48 weeks however sustained virological response (SVR) rates remain low. We report a patient who initially responded to Pegylated interferon treatment for HBV-HDV co-infection. Although initial improvement in viraemia from both virsues was seen, SVR was not achieved with ongoing progression of liver injury biochemically. However, the summative effect of a second course of Pegylated interferon 2 years later led to HDV cure (SVR 12 months post-treatment), very low level HBV carrier status (with persistently undetectable viral load) and ongoing biochemical normalization. This case illustrates a successful treatment strategy for persistent HBV-HDV co-infection where proposed treatment regimes elicit an initial response but SVR is not achieved.

Reduced circulating BMP10 and BMP9 and elevated endoglin are associated with disease severity, decompensation and pulmonary vascular syndromes in patients with cirrhosis.

BACKGROUND: BMP9, originating from the liver, and BMP10 are circulating BMPs that preserve vascular endothelial integrity. We assessed BMP9, BMP10 and soluble endoglin (sEng) levels and their relationships to liver disease severity and associated pulmonary vascular syndromes in a cohort of well-characterised liver disease patients. METHODS: Plasma samples from patients with liver disease (n = 83) and non-disease controls (n = 21) were assayed for BMP9, BMP10 and sEng. Levels were also assessed in a separate cohort of controls (n = 27) and PoPH patients (n = 8). Expression of mRNA and immunohistochemical staining was undertaken in liver biopsy specimens. Plasma BMP activity was assessed using an endothelial cell bioassay. FINDINGS: Plasma BMP9 and BMP10 levels were normal in patients with compensated cirrhosis or fibrosis without cirrhosis, but markedly reduced in patients with decompensated cirrhosis, including those with hepatopulmonary syndrome (HPS) or portopulmonary hypertension (PoPH). Liver biopsy specimens revealed reduced mRNA expression and immunostaining for these ligands. Patient plasma samples with reduced BMP9 and BMP10 levels exhibited low BMP activity that was restored with exogenous BMP9. Endoglin mRNA expression was increased in cirrhotic livers and elevated circulating sEng levels in PoPH and HPS patients suggested increased endothelial sEng shedding in these syndromes. INTERPRETATION: Plasma BMP9 and BMP10 levels are reduced in decompensated cirrhosis, leading to reduced circulating BMP activity on the vascular endothelium. The pulmonary complications of cirrhosis, PoPH and HPS, are associated with markedly reduced BMP9 and BMP10 and increased sEng levels, suggesting that supplementation with exogenous ligands might be a therapeutic approach for PoPH and HPS.

Giant Cell Hepatitis - A Rare Association with Connective Tissue Disease.

A 68-year-old gentleman presented to hepatology department with asymptomatic year-long history of stably deranged liver function tests. His peak alkaline phosphatase (ALP), was 828 with alanine transaminase (ALT) of 141. Full liver workup was negative; hence, a liver biopsy was organised, which confirmed giant cell hepatitis (GCH). A computed tomography (CT) scan revealed non-specific interstitial pneumonitis (NSIP) pattern interstitial lung disease supported by lung function tests. Antibody testing showed strongly positive antinuclear antibody (ANA) with anti-polymyositis/scleroderma (anti-PM-SCL) antibody. Clinical picture was in keeping with likely undifferentiated connective tissue disease (UCTD) with polyarthralgia, early morning stiffness, Raynaud's and nailfold infarcts with capillaritis on nail bed examination. Further testing confirmed triple-positive antiphospholipid antibodies twice 12 weeks apart (immunoglobulin M [IgM] anti beta-2 glycoprotein antibodies, lupus anticoagulant and IgM anticardiolipin antibody). He was treated with mycophenolate and hydroxychloroquine with resolution of symptoms. Giant cell hepatitis is uncommon, with only 100 cases reported worldwide. To our knowledge, this is the only report of GCH in the context of UCTD, highlighting the significance of careful evaluation of liver disease overlap and the successful role of mycophenolate mofetil (MMF) in this setting.

Pulmonary vascular clearance of harmful endogenous macromolecules in a porcine model of acute liver failure.

BACKGROUND: Pulmonary complications are common in acute liver failure (ALF). The role of the lungs in the uptake of harmful soluble endogenous macromolecules was evaluated in a porcine model of ALF induced by hepatic devascularization (n = 8) vs. controls (n = 8). In additional experiments, pulmonary uptake was investigated in healthy pigs. Fluorochrome-labeled modified albumin (MA) was applied to investigate the cellular uptake. RESULTS: As compared to controls, the ALF group displayed a 4-fold net increased lung uptake of hyaluronan, and 5-fold net increased uptake of both tissue plasminogen activator and lysosomal enzymes. Anatomical distribution experiments in healthy animals revealed that radiolabeled MA uptake (taken up by the same receptor as hyaluronan) was 53% by the liver, and 24% by the lungs. The lung uptake of LPS was 14% whereas 60% remained in the blood. Both fluorescence and electron microscopy revealed initial uptake of MA by pulmonary endothelial cells (PECs) with later translocation to pulmonary intravascular macrophages (PIMs). Moreover, the presence of PIMs was evident 10 min after injection. Systemic inflammatory markers such as leukopenia and increased serum TNF-α levels were evident after 20 min in the MA and LPS groups. CONCLUSION: Significant lung uptake of harmful soluble macromolecules compensated for the defect liver scavenger function in the ALF-group. Infusion of MA induced increased TNF-α serum levels and leukopenia, similar to the effect of the known inflammatory mediator LPS. These observations suggest a potential mechanism that may contribute to lung damage secondary to liver disease.

Albumin infusion improves renal blood flow autoregulation in patients with acute decompensation of cirrhosis and acute kidney injury.

BACKGROUND & AIMS: In cirrhotic patients with renal failure, renal blood flow autoregulation curve is shifted to the right, which is consequent upon sympathetic nervous system activation and endothelial dysfunction. Albumin infusion improves renal function in cirrhosis by mechanisms that are incompletely understood. We aimed to determine the effect of albumin infusion on systemic haemodynamics, renal blood flow, renal function and endothelial function in patients with acute decompensation of cirrhosis and acute kidney injury. METHODS: Twelve patients with refractory ascites and 10 patients with acute decompensation of cirrhosis and acute kidney injury were studied. Both groups were treated with intravenous albumin infusion, 40-60 g/days over 3-4 days. Cardiac and renal haemodynamics were measured. Endothelial activation/dysfunction was assessed using von Willebrand factor and serum nitrite levels. F2α Isoprostanes, resting neutrophil burst and noradrenaline levels were quantified as markers of oxidative stress, endotoxemia and sympathetic activation respectively. RESULTS: Albumin infusion leads to a shift in the renal blood flow autoregulation curve towards normalization, which resulted in a significant increase in renal blood flow. Accordingly, improvement of renal function was observed. In parallel, a significant decrease in sympathetic activation, inflammation/oxidative stress and endothelial activation/dysfunction was documented. Improvement of renal blood flow correlated with improvement in endothelial activation (r = 0.741, P < 0.001). CONCLUSIONS: The data suggest that albumin infusion improves renal function in acutely decompensated cirrhotic patients with acute kidney injury by impacting on renal blood flow autoregulation. This is possibly achieved through endothelial stabilization and a reduction in the sympathetic tone, endotoxemia and oxidative stress.

Glucose-6-phosphate dehydrogenase deficiency: an unusual cause of acute jaundice after paracetamol overdose.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the commonest human enzyme defect causing haemolytic anaemia after exposure to specific triggers. Paracetamol-induced haemolysis in G6PD deficiency is a rare complication and mostly reported in children. We report the first case (to the best of our knowledge) of acute jaundice without overt clinical features of a haemolytic crisis, in an otherwise healthy adult female following paracetamol overdose, due to previously undiagnosed G6PD deficiency. It is important that clinicians consider this condition when a patient presents following a paracetamol overdose with significant and disproportionate jaundice, without transaminitis or coagulopathy.

Extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute-on-chronic liver failure: the RELIEF trial.

UNLABELLED: Acute-on-chronic liver failure (ACLF) is a frequent cause of death in cirrhosis. Albumin dialysis with the molecular adsorbent recirculating system (MARS) decreases retained substances and improves hemodynamics and hepatic encephalopathy (HE). However, its survival impact is unknown. In all, 189 patients with ACLF were randomized either to MARS (n=95) or to standard therapy (SMT) (n=94). Ten patients (five per group) were excluded due to protocol violations. In addition, 23 patients (MARS: 19; SMT: 4) were excluded from per-protocol (PP) analysis (PP population n=156). Up to 10 6-8-hour MARS sessions were scheduled. The main endpoint was 28-day ITT and PP survival. There were no significant differences at inclusion, although the proportion of patients with Model for Endstage Liver Disease (MELD) score over 20 points and with spontaneous bacterial peritonitis (SBP) as a precipitating event was almost significantly greater in the MARS group. The 28-day survival was similar in the two groups in the ITT and PP populations (60.7% versus 58.9%; 60% versus 59.2% respectively). After adjusting for confounders, a significant beneficial effect of MARS on survival was not observed (odds ratio [OR]: 0.87, 95% confidence interval [CI] 0.44-1.72). MELD score and HE at admission and the increase in serum bilirubin at day 4 were independent predictors of death. At day 4, a greater decrease in serum creatinine (P=0.02) and bilirubin (P=0.001) and a more frequent improvement in HE (from grade II-IV to grade 0-I; 62.5% versus 38.2%; P=0.07) was observed in the MARS group. Severe adverse events were similar. CONCLUSION: At scheduled doses, a beneficial effect on survival of MARS therapy in patients with ACLF could not be demonstrated. However, MARS has an acceptable safety profile, has significant dialysis effect, and nonsignificantly improves severe HE.

Role of predisposition, injury, response and organ failure in the prognosis of patients with acute-on-chronic liver failure: a prospective cohort study.

INTRODUCTION: Acute deterioration of cirrhosis is associated with high mortality rates particularly in the patients who develop organ failure (OF), a condition that is referred to as acute-on-chronic liver failure (ACLF), which is currently not completely defined. This study aimed to determine the role of predisposing factors, the nature of the precipitating illness and inflammatory response in the progression to OF according to the PIRO (predisposition, injury, response, organ failure) concept to define the risk of in-hospital mortality. METHODS: A total of 477 patients admitted with acute deterioration of cirrhosis following a defined precipitant over a 5.5-year period were prospectively studied. Baseline clinical, demographic and biochemical data were recorded for all patients and extended serial data from the group that progressed to OF were analysed to define the role of PIRO in determining in-hospital mortality. RESULTS: One hundred and fifty-nine (33%) patients developed OF, of whom 93 patients died (58%) compared with 25/318 (8%) deaths in the non-OF group (P < 0.0001). Progression to OF was associated with more severe underlying liver disease and inflammation. In the OF group, previous hospitalisation (P of PIRO); severity of inflammation and lack of its resolution (R of PIRO); and severity of organ failure (O of PIRO) were associated with significantly greater risk of death. In the patients who recovered from OF, mortality at three years was almost universal. CONCLUSIONS: The results of this prospective study shows that the occurrence of OF alters the natural history of cirrhosis. A classification based on the PIRO concept may allow categorization of patients into distinct pathophysiologic and prognostic groups and allow a multidimensional definition of ACLF.

Nitric oxide and L-arginine metabolism in a devascularized porcine model of acute liver failure.

In acute liver failure (ALF), the hyperdynamic circulation is believed to be the result of overproduction of nitric oxide (NO) in the splanchnic circulation. However, it has been suggested that arginine concentrations (the substrate for NO) are believed to be decreased, limiting substrate availability for NO production. To characterize the metabolic fate of arginine in early-phase ALF, we systematically assessed its interorgan transport and metabolism and measured the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) in a porcine model of ALF. Female adult pigs (23-30 kg) were randomized to sham (N = 8) or hepatic devascularization ALF (N = 8) procedure for 6 h. We measured plasma arginine, citrulline, ornithine levels; arginase activity, NO, and ADMA. Whole body metabolic rates and interorgan flux measurements were calculated using stable isotope-labeled amino acids. Plasma arginine decreased >85% of the basal level at t = 6 h (P < 0.001), whereas citrulline and ornithine progressively increased in ALF (P < 0.001 and P < 0.001, vs. sham respectively). No difference was found between the groups in the whole body rate of appearance of arginine or NO. However, ALF showed a significant increase in de novo arginine synthesis (P < 0.05). Interorgan data showed citrulline net intestinal production and renal consumption that was related to net renal production of arginine and ornithine. Both plasma arginase activity and plasma ADMA levels significantly increased in ALF (P < 0.001). In this model of early-phase ALF, arginine deficiency or higher ADMA levels do not limit whole body NO production. Arginine deficiency is caused by arginase-related arginine clearance in which arginine production is stimulated de novo.

Biliary atresia and survival into adulthood without transplantation: a collaborative multicentre clinic review.

BACKGROUND: Biliary atresia is a progressive biliary injury which occurs only in infants. AIMS: To review the experience of patients surviving into adulthood without the need for liver transplantation in childhood. METHODS: A multicentre review of patients with biliary atresia treated surgically who survived into adulthood without the need for transplantation. RESULTS: Twenty-two patients were identified across four centres. Median age at the last follow-up was 25 years (range: 18-46), and 21 patients had clinical features of portal hypertension. At last follow-up values of liver enzymes varied from normal to 15 × the upper limit of normal (ULN) for ALT (median 2.11 × ULN) and 9 × the ULN for ALP (median 2.02 × ULN). Six patients had a serum bilirubin > 50 µmol/l. Pruritus and jaundice were noted in 8 of 20 patients (40%) and 11 of 22 patients (50%) respectively. Thirteen patients (59.1%) were shown to have imaging features of sclerosing cholangitis, with strictures of intrahepatic bile duct(s) (IHBD), dilatation of IHBD (n = 8), or stone(s) within the IHBD (n = 5). A history of presumed bacterial cholangitis was present in 11 patients (50%). Successful pregnancies were recorded in three of fourteen female patients. Four patients underwent transplant between the ages of 20-27 years. Twenty-one patients (95.5%) were alive, including 18 (81.8%) with their native liver at the time of last follow-up. CONCLUSIONS: Some patients treated for biliary atresia will survive into adulthood with their native liver, but commonly with secondary biliary disease including cholangitis and portal hypertension.

Alterations in the functional capacity of albumin in patients with decompensated cirrhosis is associated with increased mortality.

UNLABELLED: Albumin concentration is diminished in patients with liver failure. Albumin infusion improves survival of cirrhotic patients with spontaneous bacterial peritonitis, and it is hypothesized that this may be due in part to its detoxifying capabilities. The aim of this study was to perform detailed quantitative and qualitative assessment of albumin function in patients with cirrhosis. Healthy controls and patients with acute deterioration of cirrhosis requiring hospital admission (n = 34) were included. Albumin function was assessed using affinity of the fatty acid binding sites using a spin label (16 doxyl-stearate) titration and electron paramagnetic resonance spectroscopy and ischemia-modified albumin (IMA) was measured. Twenty-two patients developed acute-on-chronic liver failure. Twelve were treated with the Molecular Adsorbents Recirculating System (MARS) and 10 with standard medical therapy. For each parameter measured, the patients' albumin had reduced functional ability, which worsened with disease severity. Fifteen patients died, and IMA, expressed as an albumin ratio (IMAR), was significantly higher in nonsurvivors compared with survivors (P < 0.001; area under the receiver operating curve = 0.8). No change in the patients' albumin function was observed following MARS therapy. A significant negative correlation between IMAR and the fatty acid binding coefficients for sites 1 and 2 (P < 0.001 for both) was observed, indicating possible sites of association on the protein. CONCLUSION: The results of this study suggests marked dysfunction of albumin function in advanced cirrhosis and provide further evidence for damage to the circulating albumin, which is not reversed by MARS therapy. IMAR correlates with disease severity and may have prognostic use in acute-on-chronic liver failure.

Pulmonary complications in liver disease.

Pulmonary complications of liver disease are poorly understood and often identified late. Abnormalities of the pulmonary vasculature lead to two distinct complications, hepatopulmonary syndrome and portopulmonary hypertension, which differ in their clinical features and management. This article focuses on these two entities.

Non-invasive prediction of oesophageal varices in cirrhosis.

Non-invasive predictors of varices in cirrhosis would reduce the need for screening endoscopies. Platelet count and spleen size have been shown to be useful parameters, in mixed groups of cirrhotics with different aetiologies. We evaluated this in two homogeneous groups with cirrhosis due to hepatitis C and alcohol. Non-invasive predictors appear promising in the former group, but less so in the latter group.

Artificial liver support systems in the management of complications of cirrhosis.

Acute-on-chronic liver failure (ACLF) is associated with multiorgan dysfunction requiring intensive care support and carries an exceptionally high risk of mortality. Decompensation of liver cirrhosis is triggered by different precipitating events but the final common pathway is hypothesized to be unregulated systemic inflammation. The concept of an artificial liver that may impact favorably upon the inflammatory response and provide liver function to prevent complications seems to be promising. This article aims to describe the currently available artificial and bioartificial systems and reviews their effect on different complications of cirrhosis, such as liver function and hepatic hemodynamics, renal function and systemic hemodynamics, hepatic encephalopathy, inflammation/infection, and coagulation. Due to the difficulties in studying large patient numbers with ACLF and the heterogeneity of this patient group, only limited data on survival are available. The currently available studies indicate that there is a survival benefit for artificial and bioartificial liver support in certain subgroups of patients; however, further studies are warranted. At present several studies in this field are under way. In this review several of the companies interested in the manufacture of the respective devices provide an up-to-date report of ongoing trials. In summary, artificial and bioartificial liver support are already playing important roles in the treatment of complications of ACLF. Better understanding of the pathophysiology of ACLF, further development of the current systems, and their evaluation in appropriately controlled clinical studies are necessary to translate their application to improvement in outcome of patients with ACLF.

Association of reduced extracellular brain ammonia, lactate, and intracranial pressure in pigs with acute liver failure.

UNLABELLED: We previously demonstrated in pigs with acute liver failure (ALF) that albumin dialysis using the molecular adsorbents recirculating system (MARS) attenuated a rise in intracranial pressure (ICP). This was independent of changes in arterial ammonia, cerebral blood flow and inflammation, allowing alternative hypotheses to be tested. The aims of the present study were to determine whether changes in cerebral extracellular ammonia, lactate, glutamine, glutamate, and energy metabolites were associated with the beneficial effects of MARS on ICP. Three randomized groups [sham, ALF (induced by portacaval anastomosis and hepatic artery ligation), and ALF+MARS] were studied over a 6-hour period with a 4-hour MARS treatment given beginning 2 hours after devascularization. Using cerebral microdialysis, the ALF-induced increase in extracellular brain ammonia, lactate, and glutamate was significantly attenuated in the ALF+MARS group as well as the increases in extracellular lactate/pyruvate and lactate/glucose ratios. The percent change in extracellular brain ammonia correlated with the percent change in ICP (r(2) = 0.511). Increases in brain lactate dehydrogenase activity and mitochondrial complex activity for complex IV were found in ALF compared with those in the sham, which was unaffected by MARS treatment. Brain oxygen consumption did not differ among the study groups. CONCLUSION: The observation that brain oxygen consumption and mitochondrial complex enzyme activity changed in parallel in both ALF- and MARS-treated animals indicates that the attenuation of increased extracellular brain ammonia (and extracellular brain glutamate) in the MARS-treated animals reduces energy demand and increases supply, resulting in attenuation of increased extracellular brain lactate. The mechanism of how MARS reduces extracellular brain ammonia requires further investigation.

Increased gene and protein expression of the novel eNOS regulatory protein NOSTRIN and a variant in alcoholic hepatitis.

BACKGROUND & AIMS: Increased intrahepatic resistance in cirrhosis is associated with reduced endothelial NO synthase (eNOS) activity and exacerbated by superimposed inflammation. NOSTRIN induces intracellular translocation of eNOS and reduces NO generation. Our aims were to quantify and compare hepatic expression of eNOS, NOSTRIN, NOSIP, and caveolin-1 in alcoholic cirrhosis with or without superimposed alcoholic hepatitis and in normal livers. METHODS: Biopsy specimens from 20 decompensated alcoholic cirrhotic patients with portal hypertension (10 with alcoholic hepatitis) and 6 normal livers were analyzed: real-time polymerase chain reaction for quantification of messenger RNA; Western blotting; and enzyme assays of eNOS in normal and diseased liver were performed. Localization and interaction of eNOS and NOSTRIN in liver was assessed by immunohistochemistry and co-immunoprecipitation. RESULTS: eNOS mRNA was significantly increased and eNOS activity decreased in alcoholic hepatitis patients, despite no differences in eNOS protein expression among the patients. Patients with alcoholic hepatitis had significantly higher hepatic levels of NOSTRIN and caveolin-1 mRNA compared with cirrhosis alone or normal biopsy specimens. A NOSTRIN splice variant, not present in normal tissue, was detected on mRNA and protein levels in all alcoholic patients. Coimmunoprecipitation demonstrated association among NOSTRIN, eNOS, and caveolin-1. CONCLUSIONS: An increase in mRNA and protein of NOSTRIN and its shortened variant in alcoholic hepatitis may partly account for the paradox of increased mRNA levels and normal protein expression but decreased enzymatic activity of eNOS in diseased liver. Such intracellular regulators of NO production may be important in the development of increased intrahepatic resistance in alcoholic hepatitis patients.

Increasing dimethylarginine levels are associated with adverse clinical outcome in severe alcoholic hepatitis.

UNLABELLED: Previous studies suggest reduced hepatic endothelial nitric oxide synthase activity contributes to increased intrahepatic resistance. Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, undergoes hepatic metabolism via dimethylarginine-dimethylamino-hydrolase, and is derived by the action of protein-arginine-methyltransferases. Our study assessed whether ADMA, and its stereo-isomer symmetric dimethylarginine (SDMA), are increased in alcoholic hepatitis patients, and determined any relationship with severity of portal hypertension (hepatic venous pressure gradient measurement) and outcome. Fifty-two patients with decompensated alcoholic cirrhosis were studied, 27 with acute alcoholic hepatitis and cirrhosis, in whom hepatic venous pressure gradient was higher (P = 0.001) than cirrhosis alone, and correlated with ADMA measurement. Plasma ADMA and SDMA were significantly higher in alcoholic hepatitis patients and in nonsurvivors. Dimethylarginine-dimethylamino-hydrolase protein expression was reduced and protein-arginine-methyltransferase-1 increased in alcoholic hepatitis livers. ADMA, SDMA and their combined sum, which we termed a dimethylarginine score, were better predictors of outcome compared with Pugh score, MELD and Maddrey's discriminant-function. CONCLUSION: Alcoholic hepatitis patients have higher portal pressures associated with increased ADMA, which may result from both decreased breakdown (decreased hepatic dimethylarginine-dimethylamino-hydrolase) and/or increased production. Elevated dimethylarginines may serve as important biological markers of deleterious outcome in alcoholic hepatitis.

Systemic and regional hemodynamics in pigs with acute liver failure and the effect of albumin dialysis.

OBJECTIVE: Acute liver failure (ALF) is haemodynamically characterized by a hyperdynamic circulation. The aims of this study were to investigate the systemic and regional haemodynamics in ALF, to measure changes in nitric oxide metabolites (NOx) and to evaluate whether these haemodynamic disturbances could be attenuated with albumin dialysis. MATERIAL AND METHODS: Norwegian Landrace pigs (23-30 kg) were randomly allocated to groups as controls (sham-operation, n = 8), ALF (hepatic devascularization, n = 8) and ALF + albumin dialysis (n = 8). Albumin dialysis was started 2 h after ALF induction and continued for 4 h. Systemic and regional haemodynamics were monitored. Creatinine clearance, nitrite/nitrate and catecholamines were measured. A repeated measures ANOVA was used to analyse the data. RESULTS: In the ALF group, the cardiac index increased (PGT < 0.0001), while mean arterial pressure (PG = 0.02) and systemic vascular resistance decreased (PGT < 0.0001). Renal resistance (PG = 0.04) and hind-leg resistance (PGT = 0.003) decreased in ALF. There was no difference in jejunal blood flow between the groups. ALF pigs developed renal dysfunction with increased serum creatinine (PGT = 0.002) and decreased creatinine clearance (P = 0.02). Catecholamines were significantly higher in ALF, but NOx levels were not different. Albumin dialysis did not attenuate these haemodynamic or renal disturbances. CONCLUSIONS: The haemodynamic disturbances during the early phase of ALF are characterized by progressive systemic vasodilatation with no associated changes in metabolites of NO. Renal vascular resistance decreased and renal dysfunction developed independently of changes in renal blood flow. After 4 h of albumin dialysis there was no attenuation of the haemodynamic or renal disturbances.