HEPATIC ENCEPHALOPATHYThe term hepatic encephalopathy (HE) encompasses a widearray of transient and reversible neurologic and psychiatricmanifestations usually found in patients with chronic liverdisease and portal hypertension, but also seen in patientswith acute liver failure. HE develops in 50% to 70% ofpatients with cirrhosis, and its occurrence is a poor prognosticindicator, with projected one- and three-year survivalrates of 42% and 23%, respectively, without liver transplantation.1 Symptoms may range from mild neurologic disturbancesto overt coma.2,3 HE is often triggered by an incitingevent that results in a rise in the serum ammonia level. Theprecise underlying pathophysiologic mechanisms are not well understood, and the mainstay of therapy is the eliminationof the precipitating event and excess ammonia.4 Livertransplantation generally reverses HE.

PATHOPHYSIOLOGYA number of factors, occurring alone or in combination,have been implicated in the development of HE. Thesefactors may differ in acute and chronic liver disease andinclude the production of neurotoxins, altered permeabilityof the blood-brain barrier, and abnormal neurotransmission(Fig. 92-1). The best-described neurotoxin involved in HEis ammonia, which is produced primarily in the colon,

where bacteria metabolize proteins and other nitrogenbasedproducts into ammonia. Enterocytes synthesizeammonia from glutamine.4-6 Once produced, ammoniaenters the portal circulation and, under normal conditions,is metabolized and cleared by hepatocytes. In cirrhosis andportal hypertension, reduced hepatocyte function and portosystemicshunting contribute to increased circulatingammonia levels. Arterial hyperammonemia is observed inup to 90% of patients with HE, although serum levels areneither sensitive nor specific indicators of its presence.Increased permeability of the blood-brain barrier increasesthe uptake and extraction of ammonia by the cerebellumand basal ganglia.7-9 Acute hyperammonemia appears tohave a direct effect on brain edema, astrocyte swelling, andthe transport of neurally active compounds such as myoinositol,and thereby contributes to HE.10-12Other alterations in HE affect neuronal membranefluidity, central nervous system (CNS) neurotransmitterexpression, and neurotransmitter receptor expression andactivation.13,14 The γ-aminobutyric acid (GABA)–benzodiazepinesystem has been the most well studied. AlthoughCNS benzodiazepine levels and GABA receptor concentrationsare unchanged in animal models of HE, increasedsensitivity of the astrocyte (peripheral-type) benzodiazepinereceptor enhances activation of the GABA-benzodiazepinesystem.15,16 This activation occurs in part through afeed-forward system in which production of neurosteroids(allopregnanolone and tetrahydrodeoxycorticosterone) by astrocytes further activates the GABAA-benzodiazepinereceptor system.17,18 Other factors that influence CNS neurotransmission,including serotonin (5-hydroxytryptamine,5-HT),19-21 nitric oxide (NO), circulating opioid peptides,manganese, and increased oxygen free radical production,have also been postulated to contribute to HE.4Finally, hyperammonemia, particularly in acute liverfailure, also increases astrocyte glutamine production viaglutamine synthetase. The rise in astrocyte glutamine andglutamate concentrations contributes to factors associatedwith CNS dysfunction.5,22,23

CLINICAL FEATURES AND DIAGNOSISHE may present as a spectrum of reversible neuropsychiatricsymptoms and signs, ranging from mild changes in cognitionto profound coma, in patients with acute or chronicliver disease. It is often precipitated by an inciting event(e.g., gastrointestinal bleeding, electrolyte abnormalities,infections, medications, dehydration). The diagnosis of HE,therefore, requires careful consideration in the appropriateclinical situation. Occasionally, HE may be the initial presentation

of chronic liver disease. Subtle findings in HEmay include forgetfulness, alterations in handwriting, difficultywith driving, and reversal of the sleep-wake cycle.24,25Overt findings may include asterixis, agitation, disinhibitedbehavior, seizures, and coma. Other causes of altered mentalstatus, particularly hypoglycemia, hyponatremia, medicationingestion, and structural intracranial abnormalitiesresulting from coagulopathy or trauma, should be consideredand rapidly excluded in patients suspected ofhaving HE.No specific laboratory findings indicate the presence ofHE definitively. The most commonly used test to assess apatient with possible HE is the blood ammonia level. Anelevation in the blood ammonia level in a patient with cirrhosisand altered mental status supports a diagnosis of HE.Blood ammonia levels may be elevated in the absence ofHE, however, because of gastrointestinal bleeding or theingestion of certain medications (e.g., diuretics, alcohol,narcotics,valproic acid).15,26,27 In addition, blood ammonialevels may be elevated in the presence of HE, even in theabsence of cirrhosis and portal hypertension, in patientswith metabolic disorders that influence ammonia generationor metabolism,such as urea cycle disorders (see Chapter76) and disordersof proline metabolism (Table 92-1).28,29Use of a tourniquet when blood is drawn and delayed processingand cooling of a blood sample may raise the bloodammonia level.15 Measurement of arterial ammonia offersno advantage over measurement of venous ammonia levelsin patients with chronic liver disease.30 In patients with acuteliver failure, however, elevated arterial ammonia levels (150to 200 mg/dL or higher) may be predictive of the presence ofbrain edema and herniation (see Chapter 93).12,31,32Of the scoring systems used to grade the severity ofHE, the West Haven system, based on a scale of 0 to 4, isthe most widely used in clinical practice (Table 92-2).25Although clinically useful, the West Haven criteria areinsensitive and have led to the development of standardizedpsychometric tests and rapid bedside mental status assessmentsto aid in the diagnosis of HE and facilitate research.33-37One simple paper and pencil test, the portosystemic encephalopathysyndrome test (PSET), evaluates the patient’sattention, concentration, fine motor skills, and orientationand has been shown to be highly specific for the diagnosisof HE.33,38 The development of these tests has led to recognitionof the syndrome of minimal HE, in which abnormalitiesare observed on testing but clinically recognizable alterations

of HE are minimal or not detected. The presence of minimal HE is common in patients with cirrhosis, appearsto influence the patient’s quality of life and driving ability,and confers an increased risk that overt HE will develop inthe patient. Whether treatment of minimal HE confers anybenefit is an area of active investigation.24,39-41A number of novel imaging and functional tests have beenstudied in the diagnosis of HE. Magnetic resonance spectroscopy(MRS) has been used to measure brain concentrationsof choline and glutamine noninvasively.42 Magneticresonance (MR) T1 mapping with partial inversion recovery(TAPIR) has been investigated as a means to measurechanges in the brain quantitatively over clinically relevantmeasurement times.33 Whether MR-based techniques can bestandardized and become practical diagnostic tests is uncertain.The critical flicker frequency test, a simple light-basedtest that has been used to assess cerebral cortex function ina number of disorders, has been shown to be a reliablemarker of minimal HE and may become a clinically usefulscreening test.34-36TREATMENTCurrent treatments for HE are directed primarily towardthe elimination or correction of precipitating factors (ebleeding, infection, hypokalemia, medications, dehydration),reduction in elevated blood ammonia levels, andavoidance of the toxic effects of ammonia in the CNS. In thepast, dietary protein restriction was considered an importantcomponent of the treatment of HE. Subsequent work,however, has suggested that limiting protein-calorie intakeis not beneficial in patients with HE.43-45 Vegetable and dairyproteins are preferred to animal proteins because of a morefavorable calorie-to-nitrogen ratio. Although branchedchainamino acid supplementation may improve symptomsmodestly, the benefits of such supplementation are not sufficientto justify its routine use.4Nonabsorbable disaccharides have been the cornerstoneof the treatment of HE. Oral lactulose or lactitol (the latteris not available in the United States) are metabolized bycolonic bacteria to byproducts that appear to have beneficialeffects by causing catharsis and reducing intestinal pH,thereby inhibiting ammonia absorption.46 These agentsimprove symptoms in patients with acute and chronic HEwhen compared with placebo but do not improve psychometrictest performance or mortality. The most commonside effects experienced by patients who take lactulose areabdominal cramping, flatulence, diarrhea, and electrolyteimbalance. Lactulose may also be administered per rectum(as an enema) to patients who are at increased risk of aspiration,although the efficacy of enema administration has notbeen evaluated.

Oral antibiotics also have been used to treat HE, with theaim of modifying the intestinal flora and lowering stool pHto enhance the excretion of ammonia. Antibiotics are generallyused as second-line agents after lactulose or in patientswho are intolerant of nonabsorbable disaccharides. Neomycinhas been approved by the U.S. Food and Drug Administration(FDA) for use in acute HE in a dose of 1 to 3 gorally every six hours for up to six days but has been usedmore commonly off-label to treat chronic HE in doses of 0.5to 1 g every 12 hours, in addition to lactulose. The efficacyof neomycin in acute or chronic HE, however, is not clearlyestablished,47 and ototoxicity and nephrotoxicity caused byneomycin have been reported, particularly in patients withpreexisting renal dysfunction.4 Rifaximin has been studiedand approved by the FDA for the treatment of chronic HEon the basis of the results of a multicentered, randomized,controlled trial in which the overall clinical efficacy andrate of side effects were similar in patients treated withlactitol and those treated with rifaximin.48 The usual doseis 400 mg orally three times daily. Two systematic reviewsof randomized controlled trials that compared rifaximin with other therapies (nonabsorbable disaccharides andother antibiotics) for the treatment of acute or chronic HEhave confirmed that the efficacy and side effect profiles arecomparable.49,50 Other antibiotics, including metronidazoleand vancomycin, have been reported to be effective in smalltrials and case series, but the data to support their use areinsufficient.In addition to antibiotics, several other agents that maymodify intestinal flora and modulate ammonia generationor absorption have been evaluated as potential treatmentsfor HE. Acarbose, an intestinal α-glucosidase inhibitorused to treat type 2 diabetes mellitus, inhibits the intestinalabsorption of carbohydrates and glucose and results intheir enhanced delivery to the colon. As a result, the ratioof saccharolytic to proteolytic bacterial flora is increased,and blood ammonia levels are decreased. A randomized,controlled, double-blind, crossover trial has demonstratedthat acarbose improves mild HE in patients with cirrhosisand adult-onset diabetes mellitus.51 Similarly, probioticregimens have been used to modify intestinal flora anddiminish ammonia generation. Four small studies havesuggested that these agents may be beneficial in humanswith mild HE.40,52-55 These agents merit further evaluationand may be alternatives for patients who do not toleratelactulose.Strategies to enhance ammonia clearance may also beuseful in the treatment of HE. Sodium benzoate, sodiumphenylbutyrate, and sodium phenylacetate, all of whichincrease ammonia excretion in urine, are approved by

the FDA for the treatment of hyperammonemia resultingfrom urea cycle enzyme defects and may improve HE incirrhosis (see Chapter 76). Administration of sodium benzoate,however, results in a high sodium load, and the efficacyof this agent is not clearly established.4,56 The combinationof intravenous sodium phenylacetate and sodium benzoate(Ammonul, Ucyclyd Pharma, Scottsdale, Ariz) in HE isbeing studied. Administration of zinc, which has been usedbecause zinc deficiency is common in patients with cirrhosis57-59 and because zinc increases the activity of ornithinetranscarbamylase, an enzyme in the urea cycle, may alsoimprove HE; however, clear efficacy has not been established.Extracorporeal albumin dialysis using the molecularadsorbent recirculating system (MARS) has resulted in areduction in blood ammonia levels and improvement insevere HE in patients with acute-on-chronic liver failure(see Chapter 93).60 Further studies are needed to clarifywhether albumin dialysis has a role in treatment of HE.Finally, l-ornithine–l-aspartate (LOLA), a salt of the aminoacids ornithine and aspartic acid that activates the ureacycle and enhances ammonia clearance, has been shown inseveral randomized controlled studies to improve HE comparedwith lactulose61-63; however, this agent is not availablein the United States.Flumazenil is a specific benzodiazepine (GABAA receptor)antagonist that has been used in patients with HE. Itimproves the degree of encephalopathy and electrophysiologicfindings in approximately one fourth of patients withgrade 3 or 4 HE. It has a short half-life and a number ofpotential side effects, including seizures, arrhythmias, andwithdrawal symptoms, that limit its clinical usefulness

Table 92-1 Differential Diagnosis of HyperammonemiaAcute liver failureChronic kidney diseaseCigarette smokingCirrhosisGastrointestinal bleedingInborn errors of metabolismProline metabolism disordersUrea cycle disorders (e.g., carbamyl phosphate synthetase Ideficiency, ornithine transcarbamylase deficiency,argininosuccinate lyase deficiency, N-acetyl glutamate synthetasedeficiency)MedicationsAlcoholDiuretics (e.g., acetazolamide)NarcoticsValproic acidMuscle exertion and ischemia

Portosystemic shuntsTechnique and conditions of blood samplingHigh body temperatureHigh-protein dietTourniquet use

GRADEImpairmentINTELLECTUAL FUNCTION NEUROMUSCULAR FUNCTION0 Normal NormalMinimal, subclinical Normal examination findings. Subtle changes in work ordrivingMinor abnormalities of visual perception or on psychometricor number tests1 Personality changes, attention deficits, irritability,depressed stateTremor and incoordination2 Changes in sleep-wake cycle, lethargy, mood andbehavioral changes, cognitive dysfunctionAsterixis, ataxic gait, speech abnormalities (slow and slurred)3 Altered level of consciousness (somnolence), confusion,disorientation, and amnesiaMuscular rigidity, nystagmus, clonus, Babinski sign,hyporeflexia4 Stupor and coma Oculocephalic reflex, unresponsiveness to noxious stimuliModified from the West Haven Criteria; in Ferenci P, Lockwood A, Mullen K, et al. Hepatic encephalopathy—definition, nomenclature, diagnosis, and quantification:Final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology 2002; 35:716-21.

4 Stupor and coma Oculocephalic reflex, unresponsiveness to noxious stimuli