Hepatic Encephalopathy

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Hepatic Encephalopathy

FromDrugs & Therapy Perspectives [TM]Hepatic Encephalopathy - Effective Treatments Available Once AcutePrecipitants Have Been Eliminated[Drug & There Perspect 17(15):8-11, 2001. © 2001 Adis International Limited]----------------------------------------------------------AbstractHepatic encephalopathy is a clinical syndrome of unknown pathogenesis. TheDiagnosis is appropriate whenever a patient with liver disease hasNeurological and psychological symptoms that cannot be attributed to otherPathologies. The disease may arise from a variety of hepatic disorders,Exhibit a wide range of severities(ranging from minimal cerebral dysfunctionTo coma),follows a fluctuating course, and is reversible. The first line ofTherapy in hepatic encephalopathy should always be elimination of knownPrecipitating factors.Subsequent therapeutic options depend on the severityAnd duration of disease.Hepatic Encephalopathy continued...[Drug & There Perspect 17(15):8-11, 2001. © 2001 Adis International Limited]------------------------------------------------------Pathogenesis ObscureA number of pathogenetic models for hepatic encephalopathy have beenProposed, but the pathogenesis of this condition remains obscure.Neurotoxins Possibly to BlameElevated blood ammonia levels may cause hepatic encephalopathy. In patientsWith cirrhosis of the liver,increased portal vein pressure can lead to theFormation of collateral vessels which allow intestinal ammonia to bypass theLiver. Liver disease itself also reduces the capacity of the organ toMetabolise ammonia. The resultant elevation in blood ammonia levels mayIncrease energy consumption in the brain and lead to swelling of astroglialCells. Hyperammonaemia does not fully explain hepatic encephalopathy,However, because 10%of affected patients have normal blood ammoniaLevels.[1]Other possible endogenous neurotoxins include mercaptans, phenols,And short- and medium-chain fatty acids.[1]Faulty Blood-brain Barrier SuspectedChanges in the blood-brain barrier have been observed in patients with acuteOr chronic liver disease.This can result in absorption of more neutral aminoAcids and less glucose, ketone bodies and basic amino acids by the brain.[1]Neurotransmitter Abnormalities Offer CluesDisturbances in amino acid metabolism in patients with liver disease mayResult in the formation of 'false neurotransmitters' which compete withNormal transmitters for receptors in the brain. Other changes inNeurotransmitter systems that may contribute to hepatic encephalopathyInclude elevated É¡-aminobutyric acid(GABA) activity and increased cerebralFormation of serotonin.[1]Hepatic Encephalopathy Takes Many FormsThe clinical course of hepatic encephalopathy can be extremely variable(e.g. Clinically undetectable, acute remitting, chronic remitting, chronicPersisting or chronic progressive).[1]Subclinical Disease Often Goes UnnoticedMinimal hepatic encephalopathy has no clinical symptoms. Nevertheless, 60%Of those affected show impairments in psychometric tests used to evaluateDriving ability. It affects up to 60% of patients who have liver cirrhosisAnd portocaval collaterals but no clinically detectable cerebral functionDeficits.[1] 50% of patients with minimal hepatic encephalopathy willDevelop clinically apparent disease within 6 months.[2]Overt Disease Can Be StagedAccording to a somewhat arbitrary system, there are 4 stages of clinicallyApparent hepatic encephalopathy:[1]Stage I: sleep disturbances, restlessness, mood fluctuations, loquacity(talkativeness), impaired attention/concentration, often slight fingerTremorStage II: detectable neuromuscular disturbances (e.g.flapping tremor orAsterixis), ataxia, changes in reflexes (usually diminution), dysarthriaStage III: increased impairment of consciousness,aggressive behaviour,Monotonous voice,perseverations, increased reflexes, clonic spasm, pyramidalSymptoms, increased muscle toneStage IV: coma.Diagnosis May Require Psychometric TestingThe main features of clinically overt hepatic encephalopathy have beenDescribed in the previous section. Minimal hepatic encephalopathy, inContrast, can be diagnosed only by psychometric/neuropsychological testing;In affected patients, impairments in psychomotor speed, visual-spatialOrientation and visual-constructive ability are typically seen. While EEGAbnormalities may also be detected, these are inconsistent, nonspecific andOften overlap with normal findings. Measurement of visual and auditoryEvent-related cerebral potentials may prove more sensitive than psychometricTests. Clinical laboratory tests provide information about hepatic functionAnd possible precipitating factors without directly proving the presence ofHepatic encephalopathy.[1]Base Treatment on the Stage of DiseaseTherapy recommendations for patients with hepatic encephalopathy varyAccording to the severity (stage) of disease (see Table 1 and Patient careGuidelines).[1]Patient Care Guidelines. (click image to zoom) Management options forPatients with hepatic encephalopathy in liver cirrhosis[1]Treat Precipitating Factors FirstDiagnosis and treatment of precipitating factors (Table 2), which areResponsible for 80% of relapse or deterioration of hepatic encephalopathy inPatients with cirrhosis of the liver, is the first step in the treatment ofHepatic encephalopathy. Common precipitating factors includeGastrointestinal bleeding, infection, and use of sedatives or diuretics.[1]Keep Dietary Protein Levels upBecause the usual source of suspected neurotoxins (e.g. ammonia) is oftenthe intestine, diet is of prime importance in the management of hepaticencephalopathy. Unfortunately, patients often find dietary modificationsdifficult to implement.[1]Protein restriction/abstinence is no longer advocated as a long termtreatment of hepatic encephalopathy because it counter productively leads toincreased formation of ammonia (as a result of protein catabolism) andincreased susceptibility to infection. Rather, patients with cirrhosis ofthe liver require a daily protein intake of between 0.8 and 1.2 g/kg,[3,1]except when acute encephalopathic episodes necessitate temporaryrestrictions (to about 20 g/day). Such restrictions should be graduallylifted (by 10g every 3 to 5 days) once improvement in hepatic encephalopathyhas occurred. Dietary carbohydrate intake should be increased during periodsof protein restriction to ensure the patient is obtaining an adequatecaloric intake.[1]Vegetable proteins are preferred to fish, meat or milk proteins because theyare believed to improve nitrogen balance without aggravating hepaticencephalopathy. In the small group of patients who areprotein-intolerant(i.e. their cerebral function deteriorates as proteinintake is increased), addition of orally administered branched-chain aminoacid (up to 0.25 g/kg bodyweight)has been shown to improve psychometric testperformance.[4]Clean out the IntestineIntestinal cleansing removes nitrogen-containing substances, a potentialsource of ammonia, from the gut.This approach is particularly important inpatients with constipation and gastrointestinal bleeding. Oral laxatives andenemas 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 bycolonic bacterial flora to lactic acid and other organic acids. Theresultant reduction in pH inhibits the activities of ammonia-producingbacteria and enhances net movement of ammonia into the intestine, thusreducing systemic ammonia burden. The increase in osmotic pressure in thelumen caused by non-absorbable dissacharides also has a laxative effectwhich enhances intestinal cleansing.[1]The dosage of lactulose should be titrated such that the patient passes 2 to4 soft stools daily; usually 30 to 60 g/day is appropriate. Rectaladministration is also effective. Lactilol (30 to 45 g/day)[7] and, inlactose-intolerant patients, lactose (up to 100 mg/day)[8]are effectivealternatives. Possible adverse effects of synthetic disaccharides includeflatulence, abdominal pain and diarrhoea (the latter, if severe, can causeelectrolyte imbalances, hypovolaemia and aggravation of encephalopathy).Antibiotics Are as Effective as LaxativesAntibacterial agents reduce levels of ammonia in the blood by influencingammonia-producing flora and/or enterocytes in the large intestine. Theefficacy of non-absorbable aminoglycosides such as neomycin(2 to 4 g/day individed doses) and paromomycin (1 to 2 g/day) is equal to that ofdisaccharide therapy.[9] However, treatment should not be continued for morethan 1 month[10] because 3% of the dose may be absorbed, resulting incumulative ototoxicity and nephrotoxicity. These drugs should also be usedcautiously in patients with renal insufficiency.Alternatives toaminoglycosides include metronidazole 500mg twice daily, aminopenicillins 2to 4 g/day, and vancomycin 1 to 2 g/day.[1]Flumazenil Is Effective in Some PatientsBenzodiazepine receptor antagonists (e.g. flumazenil) which reduce GABAergictone have been shown to produce benefits in some patients with hepaticencephalopathy but currently can only be recommended for patients with livercirrhosis when there is a strong suspicion of intake of benzodiazepines.[11]Stimulating Ammonia Metabolism May HelpA number of compounds may be administered with the aim of increasing ammoniametabolism by enhancing glutamine or urea synthesis. Those which have beenreported to improve hepatic encephalopathy include ornithine, benzoate andzinc (the latter inconsistently).[1]A New Liver Is the Answer for Some PatientsLiver transplantation is indicated for a small group of patients with livercirrhosis and severe, treatment-refractory encephalopathy. Candidates shouldalso be free of other diseases, e.g. chronic alcoholic abuse or degenerativebrain disease, which will adversely affect post-transplantation outcomes.Successful liver transplantation has been shown to improve hepaticencephalopathy on psychometric testing.[1]