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Hepatic Encephalopathy - Effective Treatments Available Once Acute Precipitants Have Been Eliminated

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  • claudine intexas
    This is a pretty good article. It stages degrees of enchphalopathy although it does seem to imply that it occurs only in more advanced liver disease. But
    Message 1 of 1 , Aug 16, 2001
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      This is a pretty good article. It 'stages' degrees of
      enchphalopathy although it does seem to imply that it
      occurs only in more advanced liver disease. But those
      stage 1 symptoms sound like a list of my 'mental'
      complaints and I don't even have any fibrosis any

      NOTE: To view the article with Web enhancements, go

      Hepatic Encephalopathy - Effective Treatments
      Available Once Acute Precipitants Have Been Eliminated
      [Drug & Ther Perspect 17(15):8-11, 2001. � 2001 Adis
      International Limited]

      Hepatic encephalopathy is a clinical syndrome of
      unknown pathogenesis. The diagnosis is appropriate
      whenever a patient with liver disease has neurological
      and psychological symptoms that cannot be attributed
      to other pathologies. The disease may arise from a
      variety of hepatic disorders, exhibit a wide range of
      severities(ranging from minimal cerebral dysfunction
      to coma),follows a fluctuating course, and is
      reversible. The first line of therapy in hepatic
      encephalopathy should always be elimination of known
      precipitating factors.Subsequent therapeutic options
      depend on the severity and duration of disease.

      Pathogenesis Obscure
      A number of pathogenetic models for hepatic
      encephalopathy have been proposed, but the
      pathogenesis of this condition remains obscure.

      Neurotoxins Possibly to Blame
      Elevated blood ammonia levels may cause hepatic
      encephalopathy. In patients with cirrhosis of the
      liver,increased portal vein pressure can lead to the
      formation of collateral vessels which allow intestinal
      ammonia to bypass the liver. Liver disease itself also
      reduces the capacity of the organ to metabolise
      ammonia. The resultant elevation in blood ammonia
      levels may increase energy consumption in the brain
      and lead to swelling of astroglial cells.
      Hyperammonaemia does not fully explain hepatic
      encephalopathy, however, because 10%of affected
      patients have normal blood ammonia levels.[1]Other
      possible endogenous neurotoxins include mercaptans,
      phenols, and short- and medium-chain fatty acids.[1]

      Faulty Blood-brain Barrier Suspected
      Changes in the blood-brain barrier have been observed
      in patients with acute or chronic liver disease.This
      can result in absorption of more neutral amino acids
      and less glucose, ketone bodies and basic amino acids
      by the brain.[1]

      Neurotransmitter Abnormalities Offer Clues
      Disturbances in amino acid metabolism in patients with
      liver disease may result in the formation of 'false
      neurotransmitters' which compete with normal
      transmitters for receptors in the brain. Other changes
      in neurotransmitter systems that may contribute to
      hepatic encephalopathy include elevated
      ��-aminobutyric acid(GABA) activity and increased
      cerebral formation of serotonin.[1]

      Hepatic Encephalopathy Takes Many Forms
      The clinical course of hepatic encephalopathy can be
      extremely variable (e.g. clinically undetectable,
      acute remitting, chronic remitting, chronic persisting
      or chronic progressive).[1]

      Subclinical Disease Often Goes Unnoticed
      Minimal hepatic encephalopathy has no clinical
      symptoms. Nevertheless, 60% of those affected show
      impairments in psychometric tests used to evaluate
      driving ability. It affects up to 60% of patients who
      have liver cirrhosis and portocaval collaterals but no
      clinically detectable cerebral function deficits.[1]
      50% of patients with minimal hepatic encephalopathy
      will develop clinically apparent disease within 6

      Overt Disease Can Be Staged
      According to a somewhat arbitrary system, there are
      4stages of clinically apparent hepatic

      stage I: sleep disturbances, restlessness, mood
      fluctuations, loquacity (talkativeness), impaired
      attention/concentration, often slight finger tremor
      stage II: detectable neuromuscular disturbances
      (e.g.flapping tremor or asterixis), ataxia, changes in
      reflexes (usually diminution), dysarthria
      stage III: increased impairment of
      consciousness,aggressive behaviour, monotonous
      voice,perseverations, increased reflexes, clonic
      spasm,pyramidal symptoms, increased muscle tone
      stage IV: coma.

      Diagnosis May Require Psychometric Testing
      The main features of clinically overt hepatic
      encephalopathy have been described in the previous
      section. Minimal hepatic encephalopathy, in contrast,
      can be diagnosed only by
      psychometric/neuropsychological testing; in affected
      patients, impairments in psychomotor speed,
      visual-spatial orientation and visual-constructive
      ability are typically seen. While EEG abnormalities
      may also be detected, these are inconsistent,
      nonspecific and often overlap with normal findings.
      Measurement of visual and auditory event-related
      cerebral potentials may prove more sensitive than
      psychometric tests. Clinical laboratory tests provide
      information about hepatic function and possible
      precipitating factors without directly proving the
      presence of hepatic encephalopathy.[1]

      Base Treatment on the Stage of Disease
      Therapy recommendations for patients with hepatic
      encephalopathy vary according to the severity
      (stage)of disease (see table 1 and Patient care

      Patient Care Guidelines. Management options for
      patients with hepatic encephalopathy in liver
      Treat Precipitating Factors First
      Diagnosis and treatment of precipitating factors(table
      2), which are responsible for 80% of relapse or
      deterioration of hepatic encephalopathy in patients
      with cirrhosis of the liver, is the first step in the
      treatment of hepatic encephalopathy. Common
      precipitating factors include gastrointestinal
      bleeding, infection, and use of sedatives or

      Keep Dietary Protein Levels up
      Because the usual source of suspected neurotoxins(e.g.
      ammonia) is often the intestine, diet is of prime
      importance in the management of hepatic
      encephalopathy. Unfortunately, patients often find
      dietary modifications difficult to implement.[1]
      Protein restriction/abstinence is no longer advocated
      as a long term treatment of hepatic encephalopathy
      because it counter productively leads to increased
      formation of ammonia (as a result of protein
      catabolism)and increased susceptibility to infection.
      Rather, patients with cirrhosis of the liver require a
      daily protein intake of between 0.8 and 1.2 g/kg,[3,1]
      except when acute encephalopathic episodes necessitate
      temporary restrictions (to about 20 g/day). Such
      restrictions should be gradually lifted (by 10g every
      3 to 5 days) once improvement in hepatic
      encephalopathy has occurred.Dietary carbohydrate
      intake should be increased during periods of protein
      restriction to ensure the patient is obtaining an
      adequate caloric intake.[1]

      Vegetable proteins are preferred to fish, meat or milk
      proteins because they are believed to improve nitrogen
      balance without aggravating hepatic encephalopathy. In
      the small group of patients who are
      protein-intolerant(i.e. their cerebral function
      deteriorates as protein intake is increased), addition
      of orally administered branched-chain amino acid (up
      to 0.25 g/kg bodyweight)has been shown to improve
      psychometric test performance.[4]

      Clean out the Intestine
      Intestinal cleansing removes nitrogen-containing
      substances, a potential source of ammonia, from the
      gut.This approach is particularly important in
      patients with constipation and gastrointestinal
      bleeding. Oral laxatives and enemas are used.[1]
      While saline laxative products (e.g. MgSO4) are useful
      in this setting, synthetic non-absorbable
      disaccharides are the agents of choice.[5,6] Examples
      of the latter include lactulose and lactilol, which
      are degraded by colonic bacterial flora to lactic acid
      and other organic acids. The resultant reduction in pH
      inhibits the activities of ammonia-producing bacteria
      and enhances net movement of ammonia into the
      intestine,thus reducing systemic ammonia burden. The
      increase in osmotic pressure in the lumen caused by
      non-absorbable dissacharides also has a laxative
      effect which enhances intestinal cleansing.[1]

      The dosage of lactulose should be titrated such that
      the patient passes 2 to 4 soft stools daily; usually
      30 to 60 g/day is appropriate. Rectal administration
      is also effective. Lactilol (30 to 45 g/day)[7] and,
      in lactose-intolerant patients, lactose (up to 100
      mg/day)[8]are effective alternatives. Possible adverse
      effects of synthetic disaccharides include flatulence,
      abdominal pain and diarrhoea (the latter, if severe,
      can cause electrolyte imbalances, hypovolaemia and
      aggravation of encephalopathy).

      Antibiotics Are as Effective as Laxatives
      Antibacterial agents reduce levels of ammonia in the
      blood by influencing ammonia-producing flora and/or
      enterocytes in the large intestine. The efficacy of
      non-absorbable aminoglycosides such as neomycin(2 to 4
      g/day in divided doses) and paromomycin(1 to 2 g/day)
      is equal to that of disaccharide therapy.[9]However,
      treatment should not be continued for more than 1
      month[10] because 3% of the dose may be absorbed,
      resulting in cumulative ototoxicity and
      nephrotoxicity. These drugs should also be used
      cautiously in patients with renal
      insufficiency.Alternatives to aminoglycosides include
      metronidazole 500mg twice daily, aminopenicillins 2 to
      4 g/day, and vancomycin 1 to 2 g/day.[1]

      Flumazenil Is Effective in Some Patients
      Benzodiazepine receptor antagonists (e.g.
      flumazenil)which reduce GABAergic tone have been shown
      to produce benefits in some patients with hepatic
      encephalopathy but currently can only be recommended
      for patients with liver cirrhosis when there is a
      strong suspicion of intake of benzodiazepines.[11]

      Stimulating Ammonia Metabolism May Help
      A number of compounds may be administered with the aim
      of increasing ammonia metabolism by enhancing
      glutamine or urea synthesis. Those which have been
      reported to improve hepatic encephalopathy include
      ornithine, benzoate and zinc (the latter

      A New Liver Is the Answer for Some Patients
      Liver transplantation is indicated for a small group
      of patients with liver cirrhosis and
      severe,treatment-refractory encephalopathy. Candidates
      should also be free of other diseases, e.g. chronic
      alcoholic abuse or degenerative brain disease, which
      will adversely affect post-transplantation
      outcomes.Successful liver transplantation has been
      shown to improve hepatic encephalopathy on
      psychometric testing.[1]

      Table 1. Therapy Recommendations for Patients With
      Hepatic Encephalopathy (HE)[1]
      Disease stage Diet/protein intake Disaccharides
      Purgation (enemas) Antibiotics Branched-chain amino
      acids Flumazenil Stimulation of ammonia metabolism
      Minimal HE No restriction ++ + 0 ++ 0 ++
      Stage I As tolerated ++ ++ (+) ++ (+) ++
      Stage II As tolerated ++ ++ (+) ++ (+) ++
      Stage III 0 ++ ++ ++ ? (+) ?
      Stage IV 0 ++ ++ ++ ? (+) ?
      Chronic, persistent HE No restriction ++ + 0 ? (+) ?
      0 = not recommended; + = consider; (+) = might be
      useful in some cases; ++ = recommended; ? = usefulness
      Table 2. Precipitating Factors for Hepatic
      Excessive protein intake
      Blood transfusion
      Dehydration (e.g. diuretics, fluid restriction)
      Arterial hypotension/hypovolaemia (e.g.
      gastrointestinal bleeding)
      Psychotropic medications
      Portosystemic shunts

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      therapy of hepatic encephalopathy. Ann Intern Med
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      Barbaro G, Di Lorenzo G, Soldini M, et al. Flumazenil
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