R. Jalan

Tumour necrosis factor α is an important mediator of portal and systemic haemodynamic derangements in alcoholic hepatitis

Background: The role of proinflammatory cytokines in the pathogenesis of portal hypertension is unclear. Aims and methods: This study tests the hypothesis that tumour necrosis factor α (TNF-α) is an important mediator of the circulatory disturbances in alcoholic hepatitis (AH) and evaluates the acute and short term effect of a single infusion of the monoclonal chimeric anti-TNF-α antibody (Infliximab) on portal and systemic haemodynamics in 10 patients with severe biopsy proven AH. Cardiovascular haemodynamics, hepatic venous pressure gradient (HVPG), and hepatic and renal blood flow were measured before, 24 hours after Infliximab, and prior to hospital discharge. Results: Serum bilirubin (p<0.05), C reactive protein (p<0.001), and white cell count (p<0.01) were reduced significantly, as were plasma levels of interleukin (IL)-6 and IL-8 after treatment. Of the 10 patients, nine were alive at 28 days. Mean HVPG decreased significantly at 24 hours (23.4 (2.8) to 14.3 (1.9) mm Hg; p<0.001) with a sustained reduction prior to discharge (12.8 (1.9) mm Hg; p<0.001). Mean arterial pressure and systemic vascular resistance increased significantly (p<0.001and p<0.01, respectively), mirrored by a reduction in cardiac index (5.9 (0.5) to 4.7 (0.5) l/min/m2; p<0.05) prior to discharge. Hepatic and renal blood flow also increased significantly (506.2 (42.9) to 646.3 (49.2) ml/min (p=0.001) and 424.3 (65.12) to 506.3 (85.7) ml/min (p=0.001), respectively) prior to discharge. Conclusion: The results of this study illustrate that anti-TNF-α treatment in AH patients produces a highly significant, early, and sustained reduction in HVPG, possibly through a combination of a reduction in cardiac output and intrahepatic resistance. In addition, there was a reduction in hepatic inflammation and improved organ blood flow, suggesting an important role for TNF-α in mediating the circulatory disturbances in AH.

Reduction in renal blood flow following acute increase in the portal pressure: evidence for the existence of a hepatorenal reflex in man?

BACKGROUND: To investigate the relation between changes in portal haemodynamics and renal blood flow (RBF) in patients with cirrhosis. PATIENTS/METHODS: Twenty patients with cirrhosis and transjugular intrahepatic portosystemic stent-shunts were divided into two groups which were well matched. At routine portography, either changes in unilateral RBF (group I) or changes in cardiac output (group II) before and after shunt occlusion were studied. Blood was obtained from the renal and systemic circulations for the measurement of neurohumoral factors before and after shunt occlusion in group I patients. RESULTS: After shunt occlusion, there was a progressive reduction in unilateral RBF from a mean (SD) of 289 (32) to 155 (25) (-43.5%) (p < 0.001). These changes correlated significantly with the changes in the portal atrial gradient (p < 0.001). There was no significant change in heart rate, mean arterial pressure and right atrial pressure. No significant changes were found in the concentrations of the various neurohumoral factors measured. There was a less notable but significant reduction in the cardiac output (-10.9%) (p = 0.02) unaccompanied by significant reduction in the pulmonary capillary wedge pressure or mean arterial pressure. CONCLUSIONS: These results suggest the existence of hepatorenal reflex in man which is important in the regulation of RBF, although other mechanisms may also be contributory.

Longterm follow up of transjugular intrahepatic portosystemic stent shunt (TIPSS) for the treatment of portal hypertension: results in 130 patients.

BACKGROUND: Transjugular intrahepatic portosystemic stent shunts (TIPSS) are increasingly being used to manage the complications of portal hypertension. This study reports on the follow up on 130 patients who have undergone TIPSS. PATIENTS AND METHODS: One hundred and thirty patients (81 male), mean (SD) age 54.7 (12.5) years underwent TIPSS. The majority (64.6%) had alcoholic cirrhosis and 53.2% had Childs C disease. Indications were: variceal haemorrhage (76.2%), refractory ascites (13.1%), portal hypertensive gastropathy (4.6%), others (6.1%). Shunt function was assessed by Doppler ultrasonography and two then six monthly portography and mean follow up for survivors was 18.0 months (range 2-43.5). RESULTS: The procedure was successful in 119 (91.5%). Sixty three episodes of shunt dysfunction were observed in 45 (37.8%) patients. Variceal rebleeding occurred in 16 (13.4%) patients and was always associated with shunt dysfunction. Twenty (16.8%) patients had new or worse spontaneous encephalopathy after TIPSS and 11 (64.7%) patients had an improvement in resistant ascites. Thirty day mortality was 21.8% and one year survival 62.5%. CONCLUSION: TIPSS is an effective treatment for variceal bleeding, resistant ascites, and portal hypertensive gastropathy. Rebleeding is invariably associated with shunt dysfunction, the frequency of which increases with time, therefore regular and longterm shunt surveillance is required.

PROSPECTS FOR EXTRACORPOREAL LIVER SUPPORT

This present review is timely with the increasing use of the molecular adsorbents recirculating system (MARS) for the management of liver failure, with over 3000 patients having been treated with this device worldwide. In the UK, MARS is being used for the treatment of individual patients both in the National Health Service and also in the private sector. In order to investigate the latest position with respect to bioartificial liver devices, a meeting was held at University College London Hospital in September 2003 and this article is based on the most up to date data presented there. Liver failure, whether of the acute variety with no pre-existing liver disease (acute liver failure (ALF)) or an acute episode of decompensation superimposed on a chronic liver disorder (acute on chronic liver failure (ACLF)), carries a high mortality. In patients with ALF, lack of detoxification, metabolic, and regulatory functions of the liver leads to life threatening complications, including kidney failure, encephalopathy, cerebral oedema, severe hypotension, and susceptibility to infections culminating in multiorgan failure.1 The only established therapy for such patients is liver transplantation (LTx) but currently one third of these patients die while waiting for a transplant and the organ shortage is increasing (fig 1).2 However, liver failure, whether of the acute or acute on chronic variety, is potentially reversible, and considerable work has been carried out over many years to develop effective liver support devices. Figure 1 Annual death rates on the waiting list for liver transplantation between 1997 and 2001 in UNOS categories 1 (acute/fulminant liver failure), 2a (decompensated chronic liver disease urgently requiring transplant), and 2b (decompensated chronic liver disease requiring transplant less urgently). (Source: OPTN/SRTR data, as of 1 August 2002.) The development of these devices has been approached in two very different ways. The biological devices, which aim …

A comparison between gastric and oesophageal variceal haemorrhage treated with transjugular intrahepatic portosystemic stent shunt (TIPSS)

Background: Transjugular intrahepatic portosystemic stent‐shunts (TIPSS) are becoming widely used in the management of oesophageal variceal haemorrhage (OVH). Their place in the treatment of gastric variceal haemorrhage (GVH), a condition with a traditionally poor prognosis, remains unclear. The aims of our study were to compare portal haemodynamics and patient outcome in patients undergoing TIPSS for either GVH or OVH.

The treatment of hepatic encephalopathy

Current recommendations for the treatment of hepatic encephalopathy are based, to a large extent, on open or uncontrolled trials, undertaken in very small numbers of patients. In consequence, there is ongoing discussion as to whether the classical approach to the treatment of this condition, which aims at reducing ammonia production and absorption using either non-absorbable disaccharides and/or antibiotics, should be revisited, modified or even abandoned. Pros and cons of present therapeutic strategies and possible future developments were discussed at the fourth International Hannover Conference on Hepatic Encephalopathy held in Dresden in June 2006. The content of this discussion is summarized.

Ammonia and Hepatic Encephalopathy: The More Things Change, the More They Remain the Same

Ammonia is thought to be central in the pathogenesis of hepatic encephalopathy and has been of importance to generations dating back to the early Egyptians. Hippocrates 2500 years ago described ‘encephalopathy’ simply translated as ‘inside head suffering.’ Over 1500 papers have been written on hepatic encephalopathy since 1966, but only a minority of these actually refer to the original observation of hepatic encephalopathy and the link with ammonia made by Marcel Nencki and Ivan Pavlov in 1893 with very little acknowledgement being made to the early landmark studies which described the importance of the muscle and kidneys in maintaining ammonia homeostasis as well as the liver and gut. Furthermore, infection was recognized as being an important modulator of brain function by the ancient Greek physicians and philosophers. This review focuses upon the original experiments of Nencki and Pavlov and describes how they fit into what we understand about the pathophysiology and treatment of hepatic encephalopathy today.

Enhanced vasodilatation to endothelin antagonism in patients with compensated cirrhosis and the role of nitric oxide

Background and aims: Patients with advanced cirrhosis have systemic vasodilatation and increased nitric oxide (NO) production despite activated vasopressor systems, including the endothelin system. The aims of this study were to assess the contribution of endogenous endothelin 1 (ET-1) and NO to the maintenance of basal forearm vascular tone in patients with preascitic cirrhosis (n=7) and in age and sex matched healthy controls (n=7). Methods: Using venous occlusion plethysmography, forearm blood flow (FBF) responses to subsystemic locally active intra-arterial infusion of BQ-123 (a selective endothelin type A receptor (ETA) receptor antagonist; 10 nmol/min) were measured before and during application of an “NO clamp”: a balanced co-infusion of l-NG-monomethyl-arginine (a selective NO synthase inhibitor) and sodium nitroprusside (an exogenous NO donor) to block endogenous NO production and restore NO mediated basal FBF, respectively. Results:l-NMMA infusion produced a reduction in FBF (p<0.001) which was similar in both groups. Before applying the “NO clamp”, BQ-123 caused an increase in FBF in both groups (p<0.001) that was greater in patients with cirrhosis (p<0.01). During the “NO clamp”, BQ-123 induced vasodilatation was abolished in controls and attenuated in patients (p<0.001) but remained significantly greater in patients with cirrhosis (p<0.01). Conclusions: These findings indicate a greater ETA mediated contribution of endogenous ET-1 to the maintenance of basal forearm vascular tone in patients with preascitic cirrhosis. In addition, enhanced vasodilatation to ETA receptor antagonism in cirrhosis cannot be entirely attributed to NO release but is likely to be related to reversal of direct ET-1 mediated tone.

Oral Amino Acid Load Mimicking Hemoglobin Results in Reduced Regional Cerebral Perfusion and Deterioration in Memory Tests in Patients with Cirrhosis of the Liver

This study tests the hypothesis that administration of an oral amino acid load mimicking hemoglobin in patients with cirrhosis of the liver causes deterioration in neuropsychological function and a reduction in regional cerebral perfusion. Eight overnight fasted, metabolically stable cirrhotic patients with no evidence of overt hepatic encephalopathy were studied prior to and 4 h after simulating an upper gastrointestinal bleed by oral administration of 75 g of a solution mimicking the amino acid composition of hemoglobin. Neuropsychological function was measured using a test battery. Peripheral venous blood was collected for the measurement of ammonia and amino acid concentrations. Regional cerebral perfusion was measured using a head SPECT scanner following intravenous administration of technetium-99m hexamethyl propylamineoxime. The amino acid solution resulted in significant deterioration in the immediate and delayed story recall tests. Ammonia concentration increased from a median of 87 (range 67–94) μmol/L to 105 (98–112) μmol/L at 4 h after the simulated bleed (p < 0.01). The concentration of almost all amino acids increased; only isoleucine levels decreased following the upper gastrointestinal bleed. SPECT analysis showed a significant reduction in cerebral perfusion after the simulated bleed in both temporal lobes, left superior frontal gyrus, and right parietal and cingulate gyrus. An oral amino acid load mimicking hemoglobin in cirrhotic patients produces hyperammonemia and hypoisoleucinemia and causes a significant deterioration in memory tests, probably due to a reduction in regional cerebral perfusion. The model of simulating the metabolic effects of an upper gastrointestinal bleed in patients with cirrhosis of the liver seems to be useful in studying the metabolism of hepatic encephalopathy.

Dogs with congenital porto-systemic shunting (cPSS) and hepatic encephalopathy have higher serum concentrations of C-reactive protein than asymptomatic dogs with cPSS

Hepatic encephalopathy (HE) is a cause of significant morbidity and mortality in patients with liver disorders and a wide range of rodent models of HE have been described to facilitate studies into the pathogenesis and treatment of HE. However, it is widely acknowledged that no individual model perfectly mimics human HE and there is a particular need for spontaneous, larger animal models. One common congenital abnormality in dogs is the portosystemic shunt (cPSS) which causes clinical signs that are similar to human HE such as ataxia, disorientation, lethargy and occasionally coma. As inflammation has recently been shown to be associated with HE in humans, we hypothesised that inflammation would similarly be associated with HE in dogs with cPSS. To examine this hypothesis we measured C-reactive protein (CRP) in 30 healthy dogs, 19 dogs with a cPSS and no HE and 27 dogs with a cPSS and overt HE. There was a significant difference in CRP concentration between healthy dogs and dogs with HE (p < 0.001) and between dogs with HE and without HE (p < 0.05). The novel finding that there is an association between inflammation and canine HE strengthens the concept that HE in dogs with cPSS shares a similar pathogenesis to humans with HE. Consequently, dogs with a cPSS may be a good spontaneous model of human HE in which to further examine the role of inflammation and development of HE.