Hepatic Encephalopathy, Hyperammonemia, and Current Treatment - PowerPoint PPT Presentation

Loading...

PPT – Hepatic Encephalopathy, Hyperammonemia, and Current Treatment PowerPoint presentation | free to view - id: 33e5f-NGY4M



Loading


The Adobe Flash plugin is needed to view this content

Get the plugin now

View by Category
About This Presentation
Title:

Hepatic Encephalopathy, Hyperammonemia, and Current Treatment

Description:

Intestinal Cleansing. suitable laxatives: MgSO4, non-absorbable disaccharides ... degraded into short-chain organic acids in colon ... – PowerPoint PPT presentation

Number of Views:6052
Avg rating:5.0/5.0
Slides: 61
Provided by: ntuhSi
Category:

less

Write a Comment
User Comments (0)
Transcript and Presenter's Notes

Title: Hepatic Encephalopathy, Hyperammonemia, and Current Treatment


1
Hepatic Encephalopathy, Hyperammonemia, and
Current Treatment
  • ICU meeting
  • April 29, 2002
  • Ri ???

2
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.

3
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

4
Hepatic Encephalopathy
  • Classifications

5
Pathogenesis of HE
  • Endogenous Endotoxins
  • Increased permeability of brain-blood barrier
  • Change in Neurotransmitter and receptors
  • Others

6
Endotoxins of HE
  • Ammonia
  • Mercaptans
  • Phenols
  • Short-chain and Mid-chain fatty acids

7
Ammonia
  • Healthy individuals equilibrium between the
    production and detoxications
  • Main sites of synthesis
  • Intestine
  • Muscle
  • Kidneys

8
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

9
Ammonia
  • Liver detoxified ammonia into urea and glutamine
  • Brain can also detoxified ammonia into glutamine
    and glutamate

10
(No Transcript)
11
Hyperammonemia in Adults
12
(No Transcript)
13
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

14
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

15
Glutamine/Glutamate
  • Excitatory toxins
  • overstimulation of NMDA receptors
  • increased osmotic pressure
  • exchange with Tryptophan

16
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

17
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

18
Transmitter and Receptor
  • Increased aromatic amino acids uptake? precursors
    of neurotransmitters
  • False transmitters compete with normal
    transmitters
  • Tyramine
  • Octopamine
  • phenylethanolamine

19
Transmitters and Receptors
  • BZD and Barbiturates bind to GABA receptors in
    CNS
  • GABAergic tone increased in HE patients
  • Benzodiazepam ? higher activity in HE patients

20
Transmitters and Receptors
  • Elevated endogenous opioids in brain and plasma
    of rat
  • Met-enkephalin was also elevated in HE patients

21
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

22
Clinical Staging of HE
23
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

24
Clinical Spectrum
  • Stage I
  • sleep disturbance,
  • general restless,
  • mood fluctuation,
  • impaired attention

25
Clinical Spectrum
  • Stage II
  • Flapping tremor
  • Asterixis inability to sustain muscle tone
  • Ataxia
  • dysarthria

26
Clinical Spectrum
  • Stage III
  • Somnolence, disorientation
  • Increased reflex, clonic spasm
  • Pyramidal symptoms
  • Stage IV
  • Coma
  • With/without response to pain

27
Precipitating Factors
  • Increased nitrogen load
  • Gastrointestinal bleeding about 30µg/100ml
  • Excess dietary protein
  • Azotemia
  • Constipation

28
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

29
Precipitating Factors
  • Drugs
  • Narcotics CNS depression
  • Tranquilizers
  • Sedatives CNS depression, prolonged half-life
  • Diuretics cause electrolyte imbalance and
    hypovolemia

30
Precipitating Factors
  • Miscellaneous
  • Infection
  • Surgery
  • Hypothyroidism
  • Superimposed acute liver disease
  • Progressive liver disease
  • Portal-systemic shunts
  • Infection with Helicobacter pylori?

31
Differential Diagnosis
  • Intra-cranial lesions Tumor, infection, stroke,
    bleeding
  • Epilepsy
  • Metabolic electrolyte, uremia, other
    hyperammonia disease
  • Drug/Toxic alcohol, neurodepressant use

32
Diagnostic Tools
  • Psychometric/neuropsychological tests
  • Electrophysiologic studies
  • Image techniques
  • Clinical laboratory tests

33
Psychometric/Neuropsychological Tests
  • Bedside simple tests
  • Retelling and interpretation a fable
  • forward digit span
  • backward digital span
  • reproduction of simple figures

34
Psychometric/Neuropsychological Tests
  • WAIS performance IQ
  • Line tracing tests LTT
  • Number connecting test NCT
  • Digital-symbol test DST

35
Psychometric/Neuropsychological Tests
  • Asymptomatic patients with cirrhosis differ
    significantly from control group
  • no significant difference between non-alcoholic
    and alcoholic cirrhosis

36
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

37
Electrophysiologic Studies
  • Visually evoked potentials VEP
  • Visual and auditory event-related cerebral
    potentials P300
  • BEAM

38
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

39
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

40
Treatment
  • Treatment of precipitating factors
  • Diet
  • Intestinal cleansing
  • Anti-bacterials
  • Antipsychotics
  • Ammonia metabolism
  • Transplantation

41
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

42
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

43
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

44
Diet Control of HE
  • intolerance to protein intake --gt supplement
    branched-chain amino acids
  • improved cerebral performance but not survival
  • improved nitrogen balance

45
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

46
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

47
Lactulose
  • pH reduction in colon --gt bacteriostatic effect
    and promote ammonia diffusion from blood
  • increased osmotic pressure --gt laxatives
  • ehnance barterial ammonia uptake

48
Adverse Effects of Disaccharides
  • flatulence
  • Diarrhea
  • pronounced diarrhea may lead to hypovolemia and
    electrolyte imbalance --gt aggravated HE

49
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

50
Antipsychotics
  • to treat the increased GABAergic tone
  • Benzodiazepam angatonists ( Flumazenil, Anexate,
    Lanexat, Romazicon)
  • HE patients intake benzodiazepam --gt should use
    Flumazenil

51
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

52
Stimulation of Metabolism
  • major detoxication mechanism Urea cycle and
    formation of Glutamine
  • Urea cycle metabolites
  • Ornithine
  • Asparate
  • Formation of Glutamine
  • glutamate
  • alpha-ketoglutarate

53
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

54
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

55
Extracorporeal Detoxication
  • Dialysis
  • H/D reduced 50 of ammonia level
  • CVVHD or CAVHD
  • CVVH or CAVH
  • PD least effective

56
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

57
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?

58
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

59
Reference
  • Hepatic Encephalopathy in Liver Cirrhosis, Drugs
    2000 Dec 60(6) 1353-1370
  • Treatment of Hepatic Encephalopathy, NEJM 1997
    337(7) 473-479
  • Hepatic Encephalopathy, Eur J Gastroentero
    Hepatol 2001 13 325-334
  • 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
    diagnosos of subclinical hepatic encephalopathy
    in chronic liver disease. Eur J of Gasteroentero
    Hepatol 2001, 13 513-552
  • Hepatic Encephalopathy. A J Gastroentero. 2001
    96(7) 1968-1975
  • Neuropsychological characterization of hepatic
    encephalopathy J Hepatol. 2001 34 768-773

60
Reference
  • Benzodiazepine receptor antagonists for acute and
    chronic hepatic encephalopathy. Cochrane Database
    Syst Rev 2001(4)CD002798
  • Flumazenil in the treatment of acute hepatic
    encephalopathy in cirrhotic patients a double
    blind randomized placebo controlled study. Dig
    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
    Jun25(6)1351-60
  • Oral L-ornithine-L-aspartate therapy of chronic
    hepatic encephalopathy results of a
    placebo-controlled double-blind study. J Hepatol
    1998 May28(5)856-64
  • Flumazenil for hepatic coma in patients with
    liver cirrhosis an Italian multicentre
    double-blind, placebo-controlled, crossover
    study. Eur J Emerg Med 1998 Jun5(2)213-8
  • Nutritional treatment with branched-chain amino
    acids in advanced liver cirrhosis. J
    Gastroenterol 200035 Suppl 127-12
About PowerShow.com