S. W. M. Olde Damink

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.

Review article: surgical, neo-adjuvant and adjuvant management strategies in biliary tract cancer

Aliment Pharmacol Ther 2011; 34: 1063–1078

Acute endotoxemia following transjugular intrahepatic stent-shunt insertion is associated with systemic and cerebral vasodilatation with increased whole body nitric oxide production in critically ill cirrhotic patients

BACKGROUND & AIMS Transjugular intrahepatic stent-shunt (TIPSS) insertion, in patients with uncontrolled gastro-intestinal bleeding, often results in worsening of the systemic hemodynamics which can be associated with intracranial hypertension but the underlying mechanisms are unclear. This study explored the hypothesis that TIPSS insertion results in acute endotoxemia which is associated with increased nitric oxide production resulting in systemic and cerebral vasodilatation. METHODS Twelve patients with cirrhosis who were undergoing TIPSS for uncontrolled variceal bleeding were studied prior to and 1-h after TIPSS insertion. Changes in cardiac output (CO) and cerebral blood flow (CBF) were measured. NO production was measured using stable isotopes using l-[guanidino-(15)N(2)] arginine and l-[ureido-(13)C;5,5-(2)H(2)] citrulline infusion. The effect of pre- and post-TIPSS plasma on nitric oxide synthase (NOS) activity on human endothelial cell-line (HUVEC) was measured. RESULTS TIPSS insertion resulted in a significant increase in CO and CBF. Endotoxin and induced neutrophil oxidative burst increased significantly without any significant changes in cytokines. Whole body NO production increased significantly and this was associated with increased iNOS activity in the HUVEC lines. The change in NO production correlated with the changes in CO and CBF. Brain flux of ammonia increased without significant changes in arterial ammonia. CONCLUSIONS In conclusion, the insertion of TIPSS results in acute endotoxemia which is associated with increased nitric oxide production possibly through an iNOS dependent mechanism which may have important pathophysiological and therapeutic relevance to understanding the basis of circulatory failure in the critically ill cirrhotic patient.

Feasibility of randomized controlled trials in liver surgery using surgery-related mortality or morbidity as endpoint

There is a shortage of randomized controlled trials (RCTs) on which to base guidelines in liver surgery. The feasibility of conducting an adequately powered RCT in liver surgery using the dichotomous endpoints surgery‐related mortality or morbidity was examined.

Development of a composite endpoint for randomized controlled trials in liver surgery

The feasibility of randomized controlled trials (RCTs) in liver surgery using a single‐component clinical endpoint is low as such endpoints require large sample sizes owing to their low incidence. A liver surgery‐specific composite endpoint (CEP) could solve this problem. The aim of this study was to develop a liver surgery‐specific CEP with well‐defined components.

New insights in intestinal ischemia-reperfusion injury: implications for intestinal transplantation.

Purpose of reviewIschemia–reperfusion injury is inevitable during intestinal transplantation and can negatively affect the transplant outcome. Here, an overview is provided of the recent advances in the pathophysiological mechanisms of intestinal ischemia–reperfusion injury and how this may impact graft survival. Recent findingsThe intestine hosts a wide range of microorganisms and its mucosa is heavily populated by immune cells. Intestinal ischemia–reperfusion results in the disruption of the epithelial lining, affecting also protective Paneth cells (antimicrobials) and goblet cells (mucus), and creates a more hostile intraluminal microenvironment. Consequently, both damage-associated molecular patterns as well as pathogen-associated molecular patterns are released from injured tissue and exogenous microorganisms, respectively. These ‘danger’ signals may synergistically activate the innate immune system. Exaggerated innate immune responses, involving neutrophils, mast cells, platelets, dendritic cells, as well as Toll-like receptors and complement proteins, may shape the adaptive T-cell response, thereby triggering the destructive alloimmune response toward the graft and resulting in transplant rejection. SummaryInnate immune activation as a consequence of ischemia–reperfusion injury may compromise engraftment of the intestine. More dedicated research is required to further establish this concept in man and to design more effective therapeutic strategies to better tolerize intestinal grafts.

The gut-liver axis.

Purpose of reviewThe liver adaptively responds to extra-intestinal and intestinal inflammation. In recent years, the role of the autonomic nervous system, intestinal failure and gut microbiota has been investigated in the development of hepatic, intestinal and extra-intestinal disease. Recent findingsThe autonomic nervous system can be stimulated via enteral fat leading to cholecystokinin release, stimulating receptors in the gut and in the brain. This promotes bowel integrity, dampening the inflammatory response to food antigens. Consensus exists that intravenously administered long-chain fatty acids can cause liver damage but randomized-controlled trials are lacking. Disruption of the enterohepatic circulation of bile salts can give rise to cholestasis and nonalcoholic fatty liver disease, which may progress to fibrosis and cirrhosis. Reduced intestinal availability of bile salts reduces stimulation of the farnesoid X receptor. This may induce hepatic bile salt overload and associated hepatotoxicity through reduced action of intestinal fibroblast growth factor 19. Evidence is put forward to suggest that the intestinal microbiota is associated with liver abnormalities. SummaryEnteral lipids reduce inflammation and liver damage during stress or systemic inflammation, whereas parenteral lipid is associated with liver damage. Maintaining the enterohepatic circulation of bile salts limits hepatic cholestasis through an farnesoid X receptor feedback pathway. Changes in gut microbiota composition may induce liver disease.

Review article: pancreatic renin-angiotensin systems in health and disease

Aliment Pharmacol Ther 2011; 34: 840–852

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.

Positive End-Expiratory Pressure Induces Liver Congestion in Living Donor Liver Transplant Patients : Myth or Fact

Living-donated liver transplant (LDLT) patients may develop lung edema during reperfusion, requiring higher positive end-expiratory pressure (PEEP) levels, which may impair liver outflow. The aim of the study was to assess the effect of increased PEEP levels on venous liver outflow and systemic hemodynamics in patients after LDLT. Thirty-nine LDLT recipients were enrolled in this study. All patients were postoperatively pressure-controlled ventilated and three different PEEP levels (0, 5 and 10 mbar) were randomly set. Systemic hemodynamic parameters and flow velocities of the hepatic artery, portal vein, and right hepatic vein were recorded at each PEEP level. PEEP of 10 mbar increased significantly central venous and pulmonary capillary pressure. Flow velocities in the right hepatic vein, the portal vein, the hepatic artery, mean arterial pressure, pulmonary arterial pressure, and cardiac index were not influenced by PEEP. Our study demonstrated that PEEP up to 10 mbar did not impair liver outflow in LDLT recipients.