Hepatic Encephalopathy, Hyperammonemia, and Current Treatment

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Hepatic Encephalopathy, Hyperammonemia, and
Current Treatment

• ICU meeting
• April 29, 2002
• Ri ???

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Hepatic Encephalopathy

• Hepatic (portal-systemic) encephalopathy is a
  complex neuropsychiatric syndrome
• disturbances in consciousness and behavior,
• personality changes
• fluctuating neurologic signs, asterixis or
  "flapping tremor,"
• distinctive electroencephalographic changes.

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Hepatic Encephalopathy

• 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
• The diagnosis of hepatic encephalopathy is
  usually one of exclusion

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Hepatic Encephalopathy

• Classifications

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Pathogenesis of HE

• Endogenous Endotoxins
• Increased permeability of brain-blood barrier
• Change in Neurotransmitter and receptors
• Others

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Endotoxins of HE

• Ammonia
• Mercaptans
• Phenols
• Short-chain and Mid-chain fatty acids

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Ammonia

• Healthy individuals equilibrium between the
  production and detoxications
• Main sites of synthesis
• Intestine
• Muscle
• Kidneys

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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

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Ammonia

• Liver detoxified ammonia into urea and glutamine
• Brain can also detoxified ammonia into glutamine
  and glutamate

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Hyperammonemia in Adults
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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

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Toxic Effects in CNS

• Ammonia infusion induced IICP and cerebral edema
  in rats
• Ammonia ? glutamine ? osmotic gradient
• Can be blocked by Methoximine sulphate, a
  glutamine synthase inhibitor
• Increase NO synthase

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Glutamine/Glutamate

• Excitatory toxins
• overstimulation of NMDA receptors
• increased osmotic pressure
• exchange with Tryptophan

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Other Neurotoxins

• Mercaptans
• Degraded from sulfur-containing amino acids
• Inhibit Na/K-ATPase
• Fatty Acids
• Inhibit Na-K-ATPase and Urea synthase
• Phenol neurotoxins
• the delta opioid receptor ligand met-enkephalin

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Increased Permeability

• Permeability of BBB increased in liver failure ?
  cerebral edema
• Increased neutral amino acids uptake
• Decreased glucose, ketones, and basic amino acids
• Astrocytes the main site of Gln production and
  water accumulation

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Transmitter and Receptor

• Increased aromatic amino acids uptake? precursors
  of neurotransmitters
• False transmitters compete with normal
  transmitters
• Tyramine
• Octopamine
• phenylethanolamine

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Transmitters and Receptors

• BZD and Barbiturates bind to GABA receptors in
  CNS
• GABAergic tone increased in HE patients
• Benzodiazepam ? higher activity in HE patients

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Transmitters and Receptors

• Elevated endogenous opioids in brain and plasma
  of rat
• Met-enkephalin was also elevated in HE patients

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Transmitters and Receptors

• Increased serotonin activity in HE patients
• May related to altered sleep-wakeness cycle
• Other trace elements
• Zinc deficiency
• Manganese deposit in globus pallidus --gt
  Dopaminergic dysfunction

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Clinical Staging of HE
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Clinical Spectrum

• Minimal hepatic encephalopathy
• Unawareness of clinical subjective symptoms
• Absent EEG findings
• Psychometric/neurospychological tests can
  disclose deficits
• May account for 60 of cirrhotic patients with
  portosystemic shunts

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Clinical Spectrum

• Stage I
• sleep disturbance,
• general restless,
• mood fluctuation,
• impaired attention

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Clinical Spectrum

• Stage II
• Flapping tremor
• Asterixis inability to sustain muscle tone
• Ataxia
• dysarthria

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Clinical Spectrum

• Stage III
• Somnolence, disorientation
• Increased reflex, clonic spasm
• Pyramidal symptoms
• Stage IV
• Coma
• With/without response to pain

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Precipitating Factors

• Increased nitrogen load
• Gastrointestinal bleeding about 30µg/100ml
• Excess dietary protein
• Azotemia
• Constipation

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Precipitating Factors

• Electrolyte and metabolic imbalance
• Hypokalemia, Alkalosis increased renal
  production of ammonia and free form of NH3
• Hypoxia
• Hyponatremia
• Hypovolemia reduced liver metabolism of ammonia
• Acidosis inhibition of urea synthesis

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Precipitating Factors

• Drugs
• Narcotics CNS depression
• Tranquilizers
• Sedatives CNS depression, prolonged half-life
• Diuretics cause electrolyte imbalance and
  hypovolemia

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Precipitating Factors

• Miscellaneous
• Infection
• Surgery
• Hypothyroidism
• Superimposed acute liver disease
• Progressive liver disease
• Portal-systemic shunts
• Infection with Helicobacter pylori?

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Differential Diagnosis

• Intra-cranial lesions Tumor, infection, stroke,
  bleeding
• Epilepsy
• Metabolic electrolyte, uremia, other
  hyperammonia disease
• Drug/Toxic alcohol, neurodepressant use

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Diagnostic Tools

• Psychometric/neuropsychological tests
• Electrophysiologic studies
• Image techniques
• Clinical laboratory tests

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Psychometric/Neuropsychological Tests

• Bedside simple tests
• Retelling and interpretation a fable
• forward digit span
• backward digital span
• reproduction of simple figures

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Psychometric/Neuropsychological Tests

• WAIS performance IQ
• Line tracing tests LTT
• Number connecting test NCT
• Digital-symbol test DST

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Psychometric/Neuropsychological Tests

• Asymptomatic patients with cirrhosis differ
  significantly from control group
• no significant difference between non-alcoholic
  and alcoholic cirrhosis

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Electrophysiologic Studies

• EEG studies
• from bilateral synchronous alpha waves --gt theta
  waves --gt delta waves --gtflatten to isoelectric
  lines
• inconsistency between EEG findings and clinical
  HE staging
• nonspecific Uremia, CO2 intoxication, vit. B12
  deficiency, hypoxia

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Electrophysiologic Studies

• Visually evoked potentials VEP
• Visual and auditory event-related cerebral
  potentials P300
• BEAM

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Imaging Techniques

• CT only to exclude other intracranial lesions
• PET impaired basal ganglia functions
• MRIT1WI hyperintensive signals in basal
  ganglia poor correlation to clinical
• MRS higher levels of glutamine, glutamate, and
  aspartate

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Clinical Laboratory Tests

• Ammonia not correlate with clinical in all
  patients
• other precipitating factors not direct proof of
  HE
• renal function disorders
• electrolyte imbalance
• acid-base equilibrium
• Liver function
• Inflammatory parameters

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Treatment

• Treatment of precipitating factors
• Diet
• Intestinal cleansing
• Anti-bacterials
• Antipsychotics
• Ammonia metabolism
• Transplantation

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Treatment of Precipitating Factors

• GI bleedings stopped bleeding and avoid anemia
• Infections antimicrobials, esp. SBP
• Acidosis impair urea synthesis
• Diuretics inhibit urea synthesis
• Sedatives discontinued
• hypoglycemia adequate carbohydrate supplement

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Diet Control of HE

• X Severe protein restriction--gtcatabolism of
  protein --gt ammonia formation increased and
  susceptibility to infection
• Cirrhosis patients 0.8 to 1.0g/Kg
• acute episode of HE limited to 20g.day
  initially, then increased as clinical situations
  improves

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Diet Control of HE

• Adequate caloric intake
• Increased vegetable protein
• improved nitrogen balance
• better tolerated
• fibers accelerating GI transit
• May tolerate 30g to 40g daily

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Diet Control of HE

• intolerance to protein intake --gt supplement
  branched-chain amino acids
• improved cerebral performance but not survival
• improved nitrogen balance

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Diet control of HE

• Suggestion of European Society for Parental and
  Enteral Nutrition
• patients tend to be hypermetabolic
• most patients tolerate a normal or even increased
  dietary protein intake
• severely malnourished patients--gtamino acid
  supplements
• patients intolerant to protein intake--gt BCAA
  supplements

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Intestinal Cleansing

• suitable laxatives MgSO4, non-absorbable
  disaccharides
• Disaccharides Lactulose and Lactitol
• dosage30g to 60g daily, based on clinical sign
  and 2 to 4 stools daily
• degraded into short-chain organic acids in colon
• cannot be hydrolyzed or absorbed in small
  intestine

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Lactulose

• pH reduction in colon --gt bacteriostatic effect
  and promote ammonia diffusion from blood
• increased osmotic pressure --gt laxatives
• ehnance barterial ammonia uptake

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Adverse Effects of Disaccharides

• flatulence
• Diarrhea
• pronounced diarrhea may lead to hypovolemia and
  electrolyte imbalance --gt aggravated HE

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Antibacterials

• non-absorbable aminoglycosides Neomycin and
  Paromomycin
• dosage 2 to 4 gm divided to 4 doses
• 3 would be absorbed --gt ototoxicity and
  nephrotoxicity
• should not longer than 1 month
• Rifaximin may be useful as alternative

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Antipsychotics

• to treat the increased GABAergic tone
• Benzodiazepam angatonists ( Flumazenil, Anexate,
  Lanexat, Romazicon)
• HE patients intake benzodiazepam --gt should use
  Flumazenil

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Antipsychotics

• Flumazenil
• no significant effect on recovery or survival
  from hepatic encephalopathy,
• flumazenil had a significant effect on short-term
  improvement. Ex. GCS
• Responders usually improved in initial 6 Hr
• response about 30 with improved neurologic
  score
• flumazenil is beneficial only in a selected
  subset of cirrhotic patients

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Stimulation of Metabolism

• major detoxication mechanism Urea cycle and
  formation of Glutamine
• Urea cycle metabolites
• Ornithine
• Asparate
• Formation of Glutamine
• glutamate
• alpha-ketoglutarate

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Stimulation of Metabolism

• Kircheis et al. L-ornithine-L-aspartate
  improved
• NCT-A performance times,
• postprandial venous ammonia, venous fasting blood
  ammonia concentration
• mental state gradation

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Stimulation of Metabolism

• Benzoate
• to treat congenital defects of ammonia metabolism
• binds to ammonia --gt produce hippurate --gt
  excrete in urine
• Side Effect Odor and taste

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Extracorporeal Detoxication

• Dialysis
• H/D reduced 50 of ammonia level
• CVVHD or CAVHD
• CVVH or CAVH
• PD least effective

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Liver transplantation

• severe and treatment refractory HE dementia,
  spastic paraparesis, cerebellar degeneration,
  extrapyramidal disorders
• acute liver failure with HE candidate for
  transplantation
• other cause of CNS dysfunction should be excluded

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Other Therapeutic Options

• Zinc an essential element in the Urea cycle
• supplement to reverse HE?
• Colectomy or bypass to reduce ammonia production?
• GS inhibitor, methionine sulfoximine reduced
  glutamine production?
• Manganese chelating agents?
• Modification of intestinal flora?

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Conclusion

• Treat precipitating factors first
• lactulose orally or as an enema
• Flumazenil treat BZD induced HE
• Protein restriction in acute stage ( daily lt 20g)
• amino acid solution
• Transplantation treat refractory HE

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Reference

• Hepatic Encephalopathy in Liver Cirrhosis, Drugs
  2000 Dec 60(6) 1353-1370
• Treatment of Hepatic Encephalopathy, NEJM 1997
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• Hepatic Encephalopathy, Eur J Gastroentero
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• Hyperammonemia in Urea Cycle Disorders Role of
  the Nephrologist, A J Kidney Dis. 2001 37(5)
  1069-1080
• Oral L-ornithine-L-asparate therapy of chronic
  hepatic encephalopathy results of a
  placebo-controlled double-blind study. J Hepato.
  1998 28 856-864
• Screening of subclinical hepatic encephalopathy.
  J Hepato. 2000 32 748-753
• Brain electrical activity mapping of EEG for the
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• Neuropsychological characterization of hepatic
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Reference

• Benzodiazepine receptor antagonists for acute and
  chronic hepatic encephalopathy. Cochrane Database
  Syst Rev 2001(4)CD002798
• Flumazenil in the treatment of acute hepatic
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  Liver Dis 2000 May32(4)335-8
• Glutamine as a pathogenic factor in hepatic
  encephalopathy. J Neurosci Res 2001 Jul
  165(1)1-5
• Therapeutic efficacy of L-ornithine-L-aspartate
  infusions in patients with cirrhosis and hepatic
  encephalopathy results of a placebo-controlled,
  double-blind study. Hepatology 1997
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• Oral L-ornithine-L-aspartate therapy of chronic
  hepatic encephalopathy results of a
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• Flumazenil for hepatic coma in patients with
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