Hepatic Encephalopathy, Hyperammonemia, and Current Treatment in ICU Room Assoc.Prof. Chan Sovandy Chairman by : Prof.So Saphy and Assoc Prof, Kim chhoung
Hepatic Encephalopathy Hepatic (portal systemic ) encephalopathy is a complex neuropsychiatric syndrome May be acute and reversible or chronic and progressive In severe cases,irreversible coma and death may occur. Acute episodes may recur with variable frequency
Hepatic Encephalopathy Classifications Table A : HE associated with acute liver failure Type B : HE associated with portosystem bypass Type C : HE associated with chronic liver disease/cirrhosis - Episodic HE single or recurrent - Persistent HE mild or severe - Subclinical HE alteratirely minimal HE
Pathogenesis of HE Endogenous Endotoxins Increased permeability of brain blood barrier Change in neurotransmitter and receptors Others
Endotoxins of HE Ammonia Mercaptans Phenols Short-chain and Mid-chain fatty acids
Ammonia Healthy individuals : equilibrium between the production and detoxications Main sites of synthesis - Intestine - Muscle - kidneys
Ammonia Production Small intestine -> The degradation of glutamine produced ammonia Large intestine -> Breakdown of urea and proteins by normal flora Muscles : Proportion to muscle work Kidney : increased production when hypokalemia and diuretic therapy
Ammonia Liver : detoxified ammonia into urea and glutamine Brain : can also detoxified ammonia into glutamine and glutamate
Hyperammonemia in Adults Reye s syndrom (postviral, Aspirine induced) Liver failure. Acute or Chronic Hepatitis. Wilson s disease. Alpha 1 Antitrypsin deficiency. Alcohol Cirrhosis.Drug induced (antiseizure medication)
Hyperammonemia in Adults High dose Chemotherapy Later onset urea cycle defects Infection
Toxic Effects in CNS Brain : detoxification is ATP dependent Hyperammonemia -> more energy consumption Swelling of Astroyctes No linear correlation between ammonia level and CNS dysfunction
Toxic Effects in CNS Ammonia infusion : cerebral edema in rats Ammonia -> glutamine -> osmotic gradient Can be blocked by Methoximine sulphate, a glutamine synthase inhibitor Increase NO synthase
Clinical Staging of HE Stage 1 : - sleep disturbance - general restless - mood fluctuation - impaired attension
Clinical Staging of HE Stage 2 : - Flapping tremor - Asterixis : inability to sustain muscle tone - Ataxia - dysarthria
Clinical Staging of HE Stage 3 : - Somnolence, disorientation - Increased reflex, clonic spasm - Pyramidal symptoms Stage 4 : - Coma - with /without response to pain
Precipitation Factors Increased nitrogen load - GI bleeding : about 30 Microgram /100ml -Excess dietary protein - Azotemia - Constipation Electrolyte and Metabolic imbalance Hypokalemia,alkalosis,hypoxia,hyponatremia,hyp ovolemia,acidosis
Precipitating Factors Drugs : narcotics,tranquilizers,sedatives,diuretics Miscellaneous : infection,surgery,hypothyroidism,superimpose d acute liver disease, progressive liver disease, portal-systemic shunts, infection with Helicobacter pylori?
Differential Diagnosis Intra-cranial lesion (tumor, infection,stroke, bleeding ) Epilepsy Metabolic (electrolyte, uremia, other hyperammonemia disease ) Drugs /Toxic : alcohol, neurodepressant use
Diagnosis Tool Psychometric /neuropsychological tests Electrophysiologic studies Image techniques Clinical laboratory tests
Treatment Treatment of precipitation factors Diet Intestinal cleansing Anti-bacterials Antipsychotics Ammonia metabolism Transplantation
Treatment of Precipitation Factors GI bleeding : stopped and avoid anemia Infections : antimicrobials Acidosis : impair urea synthesis Diuretic : inhibit urea synthesis Sedatives : discontinued Hypoglycemia : adequate carbohydrate supplement
Diet Control of HE X : severe protein restriction -> catabolism of protein -> ammonia formation increased and susceptibility to infection Cirrhosis patients : 0.8 to 1.0 g /kg Acute episode of HE : limited to 20g. Day initially,then increased as clinical situations improves
Diet Control of HE Adequate caloric intake Increased vegetable protein -improved nitrogen balance - better tolerated - fibers accelerating GI transit - may tolerate 30g to 40 g daily
Intestinal Cleansing Lactulose Disaccharides -dosage :30 g to 60 g daily, based on clinical signs and 2 to 4 stools daily
Antibacterials Non absorbable aminoglycosides : Neomycin and Paromomycin Dosage : 2 to 4 g divided to 4 doses Should not longer than 1 month Rifaximin may be useful as alternative
Antipsychotics Benzodiazepam antagonists : - Flumazenil - Anexate - Lanexat - Romazicon HE patients intake benzodiazepam -> should use Flumazenil
Stimulation of Metabolism Major detoxication mechanism : Urea cycle and formation of Glutamine Urea cycle metabolites : - Ornithine - Asparate Formation of Glutamine - glutamate - alpha-ketoglutarate
Extracorporeal Detoxication Dialysis : can reduced 50% of ammonia level Liver transplanbtation
Conclusion Treat precipitation factors first Lactulose orally or as an enema Flumazenil : treat BZD induced HE Protein restriction in acute stage (daily <20 g) Amino acid solution Transplantation : treat refractory HE
Sen Sok International university Hospital Ammonemia level 25 20 21 15 10 10 9 9 5 5 3 0 >1000µmol/l >700µmol/l >400µmol/l >100µmol/l >200µmol/l >300µmol/l
Cause to Hyperammonemia 16 15 14 12 10 8 10 9 8 9 6 4 2 5 2 4 0
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