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y Definition y Etiology y Pathophysiology y Existing treatments y Newer and experimental agents y Conclusion
y Complex neuropsychiatric syndrome
characterised by disturbances in consciousness and behaviour , personality changes, flapping tremors and electroencephalographic changes.
y May be acute and reversible or chronic and
y Exact data regarding incidence and prevalence is lacking y 70% of patients with liver cirrhosis. y Approximately 50% of patients with liver cirrhosis develop HE after surgical portosystemic bypass procedures. y After placement of a TIPS (transjuglar intrahepatic porto systemic shunt) nearly one third of patients develop HE. while clinically unremarkable have pathologic changes on EEG. .
Etiology y y y Fulminant hepatic failure Acute severe viral hepatitis /drugs/toxins Acute fatty liver of pregnancy Acute hepatocellular necrosis. Chronic liver disease Cirrhosis of all types (70%) Primary liver cancer Surgically induced porto-caval shunts. y y y .
Common precipitants y Increased nitrogen load gastrointestinal bleeding excess dietary protein azotemia constipation y Electrolyte and metabolic imbalance hypokalemia alkalosis hypoxia y Drugs narcotics diuretics y Miscellaneous infection surgery acute liver disease progressive liver disease .
Pathogenesis Postulated factors/mechanisms y Ammonia neurotoxicity y -Aminobutyric acid hypothesis y Plasma amino acid imbalance hypothesis y Excitatory inhibitory neurotransmitter imbalance y Synergistic neurotoxins .
AMMONIA THEORY Ammonia production y Degradation of urea or protein y Primary site: gut y Other sites: kidney and skeletal muscles y Gut-generating ammonia: 4g/day y Equilibrium of ammonia and ammonium: .
kidney : synthesize glutamic acid and glutamine Excreted in the urine y . liver.Ammonia elimination y y y Transferred to the liver Metabolized by series of urea cycle enzymes Utilized by brain.
aspartic acid and ATP y Depressed cerebral blood flow and oxygen consumption y Direct neuronal toxicity .Ammonia intoxication y Interferes with cerebral metabolism: depletion of glutamic acid.
Role of GABA y amino butyric acid (GABA) y Principle inhibitory neurotransmitter y Generated in the gut by bacteria y Bypasses the diseased or shunted liver. .
.tryptophan Due to the failure of hepatic deamination Decreased branched-chain amino acids (BCAAs): valine . leucine.Amino acid imbalance y Increased aromatic amino acids (AAAs): tyrosine. Phenylalanine . Isoleucine Due to increased metabolism by skeletal muscle and kidneys Imbalance of plasma amino acids More AAAs enter into blood-brain barrier and CNS Cerebral tryptophan increases synthesis of serotonin (depressant action) y y y y Phenylalanine inhibits tyrosine 3-hydroxylase ( key enzyme for catecholaminergic neurotransmitters) y Tyrosine increases synthesis of tyramine .octapamine which compete with catecholaminergic neurotransmitters for the same receptor site.
Neurotransmitters y Decreased synthesis of normal neurotransmitters L-Dopa Dopamine Noradrenaline y Enhanced synthesis of false neurotransmitters Octopamine Tyramine .
Synergistic neurotoxins y y Mercaptans and short chain fatty acids Mecaptans : generated from the degradation of methionine in gut. cause fetor hepaticus y Both mercaptans and short-chain fatty acids have direct neuronal cytotoxicity and also inhibit enzymes of urea cycle. . y Individually. failed to induce HE but displayed synergism .
incoherent speech. sleeping but arosable coma.initially responsive to noxious stimuli later unresponsive + 4 - . mild confusion. slurred speech. moderate confusion +/Usually normal 2 + Abnormal (triphasic slow waves) Abnormal (triphasic slow waves) Abnormal (delta waves) 3 Marked confusion.Clinical staging stage mental status asterixis EEG 1 Euphoria or depression. disordered sleep Lethargy.
Targets for treatment .
Treatment of precipitating factors y Constipation y Electrolyte and acid base balance y Infection y Gastro intestinal bleeds y Portosystemic shunts .
Current therapies y Non absorbable disaccharides lactulose and lactitol y Antibiotics vancomycin metronidazole rifaximin .
diarrhoea. flatulence .Lactulose y Metabolised to lactic acid and acetic acid y Hostile environment for intestinal bacteria y Reduces ammonia production y Cause 2~4 soft stool/d y Side-effects: abdominal cramps.
Antibiotics y Neomycin Alters gut flora. impairs ammonia absorption Impaired hearing or deafness (in long term use) Long term use (>1 month) is not advisable y Metronidazole Active against bacteroids and other organisms As effective as neomycin Neurotoxic y Rifaximin Relatively safer Adverse effects: flatulence. constipation . nausea . abdominal pain .
Effects transient . BCAAs Provide safe and well-tolerated source of nutrition in patients with cirrhosis Achieve positive nitrogen balance Improved mental status Efficacy not established y y y y . role as adjunctive therapy.associated with higher rate of symptomatic improvement than placebo.Alternative therapies y y GABA/BZ receptor antagonists Flumazenil .
L-Dopa and Bromocriptine y Decreased dopaminergic neurotransmission is a component of false neurotransmitter theory y Improvement in chronic portosystemic encephalopathy y Constipation and increased prolactin concentration are side effects. .
y Development of cost effective treatment. y Minimise the side effects of existing treatment.Need for newer agents y Current pharmacotherapy limited due to complex pathophysiology of the disease. . y Improve morbidity associated with HE.
y Decrease inflammation and oxidative stress in hepatocyte hepatic clearance of ammonia y Studies show improved neuropsychological testing.Newer agents Probiotics y Multiple beneficial effects in treatment of minimal HE y Decrease total ammonia in portal blood by: a) bacterial urease activity b) ammonia absorption by decreasing pH c) intestinal permeability d) improving nutritional status of gut epithelium. .
Ornithine L. .L.aspartate (LOLA) L(LOLA y Substrate for urea synthesis y Reinforce glutamine synthesis which serves to detoxify ammonia y Studies show decrease in ammonia concentration and symptomatic improvement in mild to moderate hepatic encephalopathy.
Sodium benzoate y Interacts with glycine to form hippurate y Excreted renally with loss of ammonia ions y Prospective double blind trial reported similar symptomatic improvement and incidence of adverse effects as lactulose y Use limited by potential salt overload and unpleasent taste. .
.y Acarbose glycosidase inhibitor y Facilitates reduction of bacterial flora in addition to inhibiting conversion of carbohydrates into monosaccharides. y Significant reduction in serum ammonia concentration and symptomatic improvement in encephalopathy y Side effects : abdominal bloating . flatulence. increased frequency of bowel movements.
.Zinc y Cofactor of urea cycle enzymes. enhances hepatic conversion of amino acids to urea y Found in vesicles of glutaminergic presynaptic terminals effecting neurotransmission y Zn deficiency common in cirrhosis and hepatic encephalopathy y Replacement should be considered if the patient is deficient.
.Exprimental agents Levocarnitine y Metabolite of lysine degradation. y Evaluated in patients in 2 studies and currently under trials. y Carrier of short chain fatty acids across mitochondrial membrane. y Demonstrated decrease in serum ammonia levels and improved mental status.
combines with glutamine to form phenylacetylglutamine.Sodium phenylbutyrate y Converted to phenylacetate. y Currently undergoing clinical trials in patients with cirrhosis and HE(HALT-HE) . y Excreted renally with the loss of ammonia ions. y It`s combination with sodium benzoate is currently approved for hyperammonemia in urea cycle disorders.
y Significant improvement in clinical grading and other markers of encephalopathy. y Currently in pre clinical trials. .Memantine y Studies demonstrate overactivity of NMDA receptors in HE. y Memantine is a NMDA receptor antagonist approved for alzheimers.
y Gut 23:801.Refrences y Harrison`s principles of internal medicine 17th edition.806. y Drugs 2010. y Hepatology4 :279-287 .9.no. vol 70.
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