Biology of Hepatic Encephalopathy. School of Medicine Division of Transplantation Immunology & Mucosal Biology MRC Centre for Transplantation

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1 Biology of Hepatic Encephalopathy School of Medicine Division of Transplantation Immunology & Mucosal Biology MRC Centre for Transplantation

2 Pavlov s Physiology Factory 1904: Nobel Prize for developing the concept of the conditional reflex in which he trained a dog to salivate to the sound of a bell. Hepatic Encephalopathy was first described by Ivan Pavlov and Marcel Nencki over 120 years ago at the Imperial Institute of Experimental Medicine in Russia.

3 Serendipity Surgically created a portacaval shunt in a dog (Eck-Pavlov Shunt) Diverting blood away from the portal vein to the IVC Developed behavioural symptoms 10 days 6 weeks following surgery Nencki M, Pawlow J & Zaleski J (1896). Ueber den ammoniakgehalt des blutes under der organe und die harnstoffbildung bei den saugethieren. Archiv fuer experimentelle pathologie und pharmakologie 37,

4 Meat Intoxication Syndrome Aggression Irritability Ataxia Convulsions Coma This was exacerbated by eating red meat but not by milk or bread. Nencki M, Pawlow J & Zaleski J (1896). Archiv fuer experimentelle pathologie und pharmakologie 37,

5 Nitrogen Balance Studies Increased ammonium salts in urine. Arterial ammonia rose x 3-4 approaching that normally found in the portal vein following a protein meal. Increased urinary excretion of ammonia following a protein meal. Brain ammonia content was x4 that of normal. Ammonia administration orally or iv Developed behavioural symptoms Coma & Death

6 Ammonia is central in the pathogenesis of Hepatic Encephalopathy µmol/l Olde Damink et al. Neurochem. Int. 2001

7 Almost all organs are involved in ammonia metabolism Urea Ammonia Glutamine Urea

8 Ammonia metabolism in cirrhosis Urea Ammonia Glutamine Urea Muscle plays an important role in ammonia metabolism in cirrhosis

9 How does the ammonia affect the brain? Patients with liver dysfunction have impaired urea synthesis. The brain acts as an alternative ammonia detoxification pathway. Astrocytes are star-shaped cells that provide physical and nutritional support for neurons. Converting ammonia to glutamine.

10 Ammonia-glutamine-brain swelling hypothesis ASTROCYTE GLUTAMATE NH 3 GLUTAMINE Ammonia H 2 0 H 2 0 GLUTAMINE H 2 0 H 2 0 H 2 0 Astrocyte swelling & increased brain water

11 Myo-inositol is an important osmotic regulator within the astrocyte Ammonia H 2 0 Myo-inositol Glutamine Low myo-inositol levels in the brain are associated with neuropsychological deterioration Shawcross et al. Am J Physiol 2004

12 Pathogenesis of Cerebral Oedema NH 3 Hepatocellular necrosis and apoptosis Inflammatory Mediators (e.g. NO) Astrocyte swelling ICP Cerebral Blood Flow

13 Acute Liver Failure Cerebral Oedema and Intracranial Hypertension.. the most feared complication of ALF.. Blei, Hepatology 2000;32:

14 Cerebral Ammonia and Risk of Cerebral Herniation Clemmeson et al. Hepatology 1999

15 Incidence of Intracranial Hypertension in 3300 patients at King s over 35 years Clinical Evidence of Intracranial Hypertension. All ALF, n= % Developing ICH Bernal et al. J Hepatol Error bars are 95% CI. p<

16 In cirrhosis, hepatic encephalopathy is a neuropsychiatric syndrome associated with low grade brain oedema Poor concentration Psychomotor dysfunction Impaired memory Sensory abnormalities Increased reaction time Cordoba et al. The development of low-grade cerebral oedema in cirrhosis is supported by the evolution of 1H-magnetic resonance abnormalities which reverse after liver transplantation. J of Hepatol. 2001

17 More than just ammonia? In practice the correlation between the arterial ammonia concentration and the clinical manifestation of encephalopathy in cirrhosis is often poor. We now recognise infection as being a common precipitant of encephalopathy.

18 Delirium: Hepatic versus Septic Encephalopathy Recognition of the association between systemic infection and impaired brain function dates back to Hippocrates >2500 years ago. Hepatic Septic Sepsis-related encephalopathy arises from the action of inflammatory mediators on the brain or a cytotoxic response by brain cells to these mediators.

19 Astrocytes are part of the macrophage lineage Astrocytes have a huge repertoire of cytokine responses. Nitric oxide, free radicals, prostanoids & proinflammatory cytokines. Inflammation may modulate the effects of ammonia on the brain.

20 Evidence for the role of inflammation in Hepatic Encephalopathy: ALF Mortality SIRS Score Rolando observed a rapid progression in the severity of HE in those patients with ALF that have more marked inflammation (SIRS). (Rolando et al. Hepatology 2000). In a study from the US ALF group, progression of HE from mild to deeper stages was temporally associated with the development of infection, especially in those with acetaminophen-induced ALF. (Vaquero et al. Gastroenterology 2003).

21 In patients with cirrhosis, there is mounting evidence for the role of SIRS in exacerbating the symptoms of HE Minimal Grade 1-4 Coma Clinical Studies Shawcross et al. J. Hepatol Shawcross et al. Metabolic Brain Dis Shawcross & Sharifi J. Hepatol Montoliu et al. Am. J of Gastroenterol Animal Studies Willard et al. Exp. Brain Res Tanaka et al. J Neurosci Res Marini & Broussard. Mol. Genet. Metab Jover et al. Hepatology 2006 Cauli et al. Hepatology 2007 Wright et al. Hepatology 2007

22 Endotoxemia produces coma & brain oedema in BDL rats HD (ammonia fed) rats had significantly raised frontal brain water compared to: Sham p=0.001 BDL p= Significant increase in brain water in all groups treated with LPS. Wright G, Davies N et al. Hepatology 2007

23 Significant increase in brain nitrotyrosine was seen in the BDL rats treated with LPS only Ammonia and LPS cause nitrosation of proteins in the brain and act as an important pathway in producing alteration in the mental state. Nitrotyrosine is formed from the reaction between ammonia and peroxynitrite; peroxynitrite being formed from the interaction of increased astroglial NO with superoxide. Wright G, Davies N et al. Hepatology 2007

24 Systemic Inflammation, Ammonia and the Blood Brain Barrier LPS NH 3 Neutrophil Cytokine Cerebral Blood Flow Granules (Myeloperoxidase) Microbial Pathogen Microglia Shawcross et al. Hepatology 2010

25 Rajiv Jalan Gut Liver Brain Axis

26 Precipitating Factors Overt Hepatic Encephalopathy Normal Ammonia Load (TIPSS; constipation; GI bleeding) Infection Endotoxemia (Bacterial translocation) Hyponatremia Dehydration/Diarrhoea Renal Dysfunction Metabolic Alkalosis Sedative Drugs e.g. benzodiazepines

27 Therapeutic Overview Strategies of Therapies in HE L-Ornithine L- Aspartate Ornithine Phenylacetate Glycerol Phenylbutyrate Flumazenil Dopamine Agonists Minocycline Anti-cholinesterases Hypothermia NSAIDs Anti-TNFα Lactulose Rifaximin [Neomycin/Vancomycin] Norfloxacin Probiotics AST 120 beads [Protein Restriction] Hemodialysis Hemofiltration Fluid Expansion

28 Encephalopathy and the Kidney

29 Summary Ammonia is central in the pathogenesis of hepatic encephalopathy. The understanding of inter-organ ammonia metabolism is key in the design of ammonialowering therapies. Inflammation and infection modulate the cerebral effects of ammonia. Future therapies are likely to target the generation of systemic and cerebral inflammation in the development of encephalopathy.

30 THANK YOU Dr Debbie Shawcross Senior Lecturer and Honorary Consultant in Hepatology Institute of Liver Studies King s College London