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CME Released: 08/10/2010; Valid for credit through 08/10/2011

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Target Audience
This activity is intended for primary care clinicians, hepatologists, gastroenterologists, infectious disease specialists, psychiatrists, and other specialists who care for patients with hepatic encephalopathy.

Goal
The goal of this activity is to review mechanisms of hepatic encephalopathy, diagnosis, and optimal management.

Learning Objectives
Upon completion of this activity, participants will be able to: . !escribe the types and patterns of hepatic encephalopathy "#E$ and ris% factors for the development of both minimal and overt #E &. Construct an appropriate diagnostic assessment for patients with suspected #E that addresses a valid differential diagnosis '. !evelop treatment strategies for #E that incorporate pharmacologic and nonpharmacologic therapies

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Aut or(s)
&avi Pra*as + M,

Metro#ealth Medical Center, Case >estern 6eserve University, Cleveland, 8hio !isclosure: 6avi +ra%ash, M!, has disclosed no relevant financial relationships.
-evin ,. Mullen+ M,

+rofessor in Medicine, Case >estern 6eserve University4 /astroenterology !ivision4 0ellowship !irector, Metro#ealth Medical Center, Cleveland, 8hio !isclosure: ?evin !. Mullen, M!, has disclosed the following relevant financial relationships: 7erved as an advisor or consultant for: 8cera Therapeutics, <nc.4 7alix +harmaceuticals, <nc. and has received honoraria, but not for this manuscript 7erved as a spea%er or a member of a spea%ers bureau for: 7alix +harmaceuticals, <nc.

Editor(s)
/atalie 0ood

Chief Editor, Nature Reviews Gastroenterology & Hepatology !isclosure: .atalie >ood has disclosed no relevant financial relationships.

CME Aut or(s)


,1sir1e Lie+ M,+ MSEd

Clinical +rofessor4 !irector, 6esearch and 0aculty !evelopment, University of California, <rvine !isclosure: !@sir@e -ie, M!, M7Ed, has disclosed the following relevant financial relationship: 7erved as a nonproduct spea%er for: ;Topics in #ealth; for Merc% 7pea%er 7ervices

CME &evie$er(s)
Sara Fleisc man

CME +rogram Manager, Medscape, --C !isclosure: 7arah 0leischman has disclosed no relevant financial relationships.
Laurie E. Scudder+ ,/P+ /P

CME *ccreditation Coordinator, Medscape, --C !isclosure: -aurie E. 7cudder, !.+, .+, has disclosed no relevant financial relationships.

Mechanisms, Diagnosis and Management of Hepatic Encephalopathy


6avi +ra%ash, M!4 ?evin !. Mullen, M!
CME 6eleased: )A2 )2&) )4 Balid for credit through )A2 )2&)

Abstract
#epatic encephalopathy "#E$ is a serious neuropsychiatric complication of both acute and chronic liver disease. 7ymptoms of #E can include confusion, disorientation and poor coordination. * general consensus exists that the synergistic effects of excess ammonia and inflammation cause astrocyte swelling and cerebral edema4 however, the precise molecular mechanisms that lead to these morphological changes in the brain are unclear. Cerebral edema occurs to some degree in all patients with #E, regardless of its grade, and could underlie the pathogenesis of this disorder. The different grades of #E can be diagnosed by a number of investigations, including neuropsychometric tests "such as the psychometric hepatic encephalopathy score$, brain imaging and clinical scales "such as the >est #aven criteria$. #E is best managed by excluding other possible causes of encephalopathy alongside identifying and the precipitating cause, and confirming the diagnosis by a positive response to empiric treatment. Empiric therapy for #E is largely based on the principle of reducing the production and absorption of ammonia in the gut through administration of pharmacological agents such as rifaximin and lactulose, which are approved by the 0!* for the treatment of #E.

Introduction
#epatic encephalopathy "#E$ is a serious neuropsychiatric complication of both acute and chronic liver disease.C D This disease encompasses a broad range of neuropsychiatric abnormalities of varying severity: affected patients exhibit alterations in psychomotor, intellectual, cognitive, emotional, behavioral and fine motor functions. #E can be classified as either EovertE or EminimalE. 8vert #E "8#E$ is a syndrome of neurological and neuropsychiatric abnormalities that can be detected by bedside clinical tests. Fy contrast, patients with minimal #E "M#E$ present with normal mental and neurological status upon clinical examination but specific psychometric tests yield abnormal results. * classification system for #E disorders was devised by the >or%ing +arty at the GGA >orld Congress of /astroenterology in Bienna, *ustria "0igure .$C D This classification has helped to standardi=e the nomenclature used in #E diagnosis and research worldwide, and has been used throughout this article.

$igure 1! Classification of #epatic Encephalopathy "#E$ +roposed by the >or%ing +arty at the GGA >orld Congress of /astroenterology, Bienna, *ustria. The >or%ing +arty proposed a classification system for #E to standardi=e the nomenclature used in #E diagnosis. #E can be graded into three types: type * #E is associated with acute liver failure4 type F #E is found in patients with portosystemic bypass and no intrinsic hepatocellular disease4 type C #E is associated with cirrhosis or portal hypertension or portosystemic shunts. Type C #E can be further divided into three categories: episodic #E "precipitated4 spontaneous4 recurrent$4 persistent #E "mild4 severe4 treatment( dependent$4 minimal #E.

#istorically, the role of ammonia accumulation has dominated explanations of the pathogenesis of #E. 8ver the past decade, however, evidence has emerged for a role of other concurrent factors "such as inflammation and hyponatremia$ in the development of #E. C&( :D 7ome degree of cerebral edema occurs in all patients with #E, including those with M#E, and astrocyte swelling is thought to have a %ey role in the disease. The precise molecular mechanisms that cause these changes in the brain of patients with #E are, however, yet to be elucidated. The burden of disease for cirrhosis is increasing, especially with regard to the rise in the number of patients with hepatitis C or nonalcoholic steatohepatitis. 0or this reason, recognition of the complications of cirrhosis "including #E$ and the need for improved management of patients affected by this disease is imperative. CH(GD #E has a substantial negative effect on 1uality of life, even in patients with minimal disease. C )D +rasad et al.C D were the first group to show that treatment of M#E improves patientsE 1uality of life. Moreover, patients with #E have poor navigational s%ills and an impaired ability to drive. C &( ID This impairment places these individuals at an increased ris% of road traffic violations and accidents.C I, :D *part from these negative effects on 1uality of life and daily functioning, patients with #E also have increased mortality.CG, HD 0urthermore, diagnosis of M#E has a prognostic implication with regard to the ris% of progression to 8#E. C HD >ith increased awareness and improved diagnostic methods, the burden of #E is li%ely to attain epidemic proportions. This 6eview therefore considers the pathogenesis, diagnosis and management of #E. The

therapies that are effective in the treatment of #E are also discussed along with the available options for long(term management of this disorder.

The athoge#esis of #E has not been clearly defined. The general consensus is that
elevated levels of ammonia and an inflammatory response wor% in synergy to cause astrocytes to swell and fluid to accumulate in the brain "cerebral edema$, which is thought to explain the symptoms of #E. The precise molecular mechanisms that result in these morphological changes in the brain are yet to be identified.

Ammonia
*mmonia is a byproduct of the metabolism of nitrogen(containing compounds and is involved in a number of metabolic reactions. #owever, ammonia is toxic at elevated concentrations and must be removed from the body.C A, GD <n mammals, ammonia is most commonly eliminated through the formation of urea in the liver. This nontoxic metabolite is water soluble and can be excreted by the %idneys. <n patients with acute liver failure, however, brain and muscle cells are involved in the metabolism of ammonia to a greater extent than normal. C GD These Eammonia sin%sE utili=e the amino acid glutamate to detoxify ammonia by converting it to glutamine. C&),& D *ccumulation of ammonia has received considerable attention as an explanation for the pathogenesis of #E. <n the early Athcentury, .enc%i, +avlov and Jales%i demonstrated the development of neuropsychiatric changes in dogs after experimental portacaval fistula surgery "termed Ec% fistula$ induced the symptoms of #E. C&&D The neuropsychiatric symptoms worsened if the dogs were fed meat, which led to the term Emeat intoxication syndromeE. C&'D Fehavioral alterations in patients with liver dysfunction were formally described later in the &) th century by +hillips and colleagues.C&KD <n GG , -oc%wood and colleagues demonstrated direct evidence for the role of ammonia in the pathogenesis of #E by using radiolabeled nitrogen in +ET imaging studies of patients with severe liver disease and M#E. C&ID *strocytes are the o#ly cells i# the %rai# that can metaboli=e ammonia.C GD The en=yme gluta&i#e sy#thetase "present in the endoplasmic reticulum of astrocytes$ is responsible for the conversion of e1uimolar concentrations of glutamate and ammonia to glutamine. C& D <ntracellular levels of glutamine, therefore, increase enormously as the ambient ammonia concentrations rise owing to liver failure.C&:D 's gluta&i#e is a# os&olyte, water moves inside the astrocyte causing it to swell. This swelling leads to cere%ral ede&a and intra(cranial hypertension.C&H,&AD *dministration of methionine sulfoximine "an inhibitor of glutamine synthase$ prevents astrocyte swelling in experiments in animals. C&G,')D 7udden exposure of astrocytes to high concentrations of ammonia in vitro "e1uivalent to the levels of ammonia in the brain observed during acute liver failure and thereby, type * #E$ results in glutamate release. C' ( ''D This release is thought to contribute to increased neuronal activity because glutamate is an excitatory neurotransmitter and is believed to be responsible for the clinical changes observed in patients with type * #E, including agitation, confusion, sei=ures and coma. -ow(grade cerebral edema and a predominantly neuroinhibitory state "that is, slowing of mental processes$ is pathognomonic of type C #E, which is associated with chronic liver disease "0igure $.C'K(':D <n astrocytes, prolonged exposure to increased concentrations of ammonia induces a number of changes. *strocyte swelling is, in part, compensated for by release of the osmolytes myoinositol and taurine from inside the cell. C'KD This homeostatic mechanism results in depletion of intracellular myoinositol stores4 low intracellular myoinositol levels are associated with an increased ris% of sudden deterioration of #E. C'HDThe activity of glutamate receptors in the postsynaptic plate are downregulated and glutamate transporters on the astrocyte cell membrane are inactivated. C'AD 8ver time, some of these cells change in

shape and form and become E*l=heimer type <<E astrocytes, as observed in both in vitro studies and in human autopsy specimens.C'G,K)D

Inflammation
*mmonia dysmetabolism cannot single(handedly explain all the neurological changes that are seen in patients with #E.CK D (e sis is a )ell*+#o)# reci itati#g factor for deco& e#satio# of liver disease i# a reviously sta%le atie#t )ith cirrhosis ,a rocess #o) ter&ed acute*o#*chro#ic liver failure-! 7hawcross et al.C'D studied the effect of induced hyperammonemia in a group of patients with cirrhosis who were admitted to hospital with systemic inflammatory response syndrome "7<67$.C'D+atients with 7<67 who were given an oral amino acid solution to induce hyperammonemia achieved worse psychometric test results. #owever, once 7<67 "and the infection$ had been successfully treated, and patientEs levels of the inflammatory mar%ers tumor necrosis factor "T.0$, interleu%in "<-$( and <-(: had returned to normal, their psychometric test results did not deteriorate after hyperammonemia was induced. C'D 7imilar results were obtained when a large population of patients with cirrhosis underwent blood tests "to measure levels of ammonia and inflammatory mar%ers$ and psychometric assessment. C&D The presence and severity of M#E were independent of both serum levels of ammonia and the severity of liver disease4 however, serum levels of inflammatory mar%ers "such as C( reactive protein, white blood cell count, <-(:$ were much higher in patients with M#E than in patients without M#E.C&D The eri heral i&&u#e syste& co&&u#icates )ith the %rai# i# res o#se to i#fectio# a#d i#fla&&atio#! 'strocytes a#d &icrogial cells release cyto+i#es i# res o#se to i#.ury or i#fla&&atio#.CK&D 0indings from studies in rats have indicated that the rise i# %lood levels of T/$ that occurs duri#g i#fla&&atio# sti&ulates glial cells to secrete the cyto+i#es 01*1 a#d 01*2!3K'D T.0 also co& ro&ises the e#dothelial %lood*%rai# %arrier a#d 01*14 affects the i#tegrity of the glial side of the %lood*%rai# %arrier! 3KK,KID Foth T.0 and <-( : e#ha#ce fluid* hase er&ea%ility of isolated brain endothelial cells in vitro, and T.0 also i#creases the diffusio# of a&&o#ia i#to astrocytes! 3526

/eurosteroids
<n patients with #E, expression of the A %!a translocator protein "also %nown as the eri heral*ty e %e#7odia7e i#e rece tor$ is thought to be upregulated in microglial cells that are activated by inflammation. 0#creased ex ressio# of this rece tor results in increased mitochondrial synthesis of neuroactive steroids, which are also %nown as neurosteroids.CKHD Evidence suggests that neurosteroids are involved in the pathogenesis of #E. CKAD These compounds are synthesi=ed in the central and peripheral nervous system, either from cholesterol or from steroid precursors "metabolites of steroid hormones produced in the gonads and adrenals$. <n the brain, neurosteroids are mainly produced by myelinating glial cells "such as astrocytes$.CKGD /eurosteroid sy#thesis occurs i# the &itocho#drial e#do las&ic reticulu& of astroglial cells. Translocator proteins are situated on the mitochondrial membrane in astrocytes and regulate neurosteroid synthesis. CI),I D '&&o#ia a#d &a#ga#ese, which accumulate in patients with liver failure, are thought to e#ha#ce neurosteroid synthesis by activating these translocator proteins. C:D 0indings from brain autopsies have shown an increased density of expression of this protein in patients with cirrhosis.CI&,I'D <n addition, Cagnin et al.CKHD demonstrated increased densities of translocated protein expression in the brains of patients with M#E by using a specific ligand that binds to this protein in +ET imaging studies.CKHD.eurosteroids are positive allosteric modulators of the

8'9'' rece tor4 they increase influx of chloride ions and thereby enhance /*F*ergic tone. These effects are responsible for some clinical se1uelae in patients with type C #E. CIKD

O2idative and /itrosative Stress


Enhanced production of reactive nitrogen species "6.7$ and reactive oxygen species "687$ occurs in cultured astrocytes "isolated from rats$ that are exposed to ammonia, inflammatory cyto%ines, hyponatremia or ben=odia=epines.CI,IID This process is dependent on levels of calcium and occurs through .(methyl(!(aspartate receptor pathways.CI:D #ilgier et al. CIHD demonstrated overstimulation of .(methyl(!(aspartate receptors in the rat brain after intravenous administration of ammonium chloride. 'cute s)elli#g of astrocytes has also %ee# o%served )he# these cells are ex osed to R:( or R/( in vitro.CIAD <n &)):, *lbrecht and .orenberg proposed a ETro,an horseE hypothesis to account for the toxic effect of glutamine in astrocytes.CIGD These researchers suggested that glutamine formed in the cytoplasm enters the mitochondrial matrix and is cleaved to release ammonia while still inside the mitochondria. This i#tra&itocho#drial a&&o#ia is the# thought to &ediate release of R:( a#d R/( through calcium(dependent pathways.CIGD Evidence indicating a close association and interplay between astrocyte swelling and 687 is now growing. CID *part from astrocyte swelling, 687 are also involved in nitration of tyrosine residues in intracellular proteins.CII,IAD Tyrosi#e #itratio# affects tra#sastrocytic su%strate tra#s ort a#d selective degradatio# of the er&ea%ility of the %lood*%rai# %arrier; )hich ulti&ately ro&otes astrocyte s)elli#g a#d cere%ral ede&a.C&GD

Manganese
Manganese is a #eurotoxi# that preferentially accu&ulates i# the %asal ga#glia. Manganese deposition has been detected by M6< in the basal ganglia of patients with cirrhosis and in rats with an extensive portacaval shuntC: (:'D and has been shown to resolve with normali=ation of liver function.C:K,:ID Manganese is thought to induce changes in astrocytes of the basal ganglia that ro&ote the for&atio# of 'l7hei&er ty e 00 astrocytes . This neurotoxin is also involved in stimulation of translocator proteins on astrocytes, which further enhances neurosteroid synthesis and /*F*ergic tone. CAD +referential deposition of manganese in the basal ganglia might explain the +ar%insonian symptoms "such as tremors$ seen in some patients with #E.C::D

The a

roach to <E comprises

exclusion of other causes of encephalopathy, identification of the precipitating cause and a trial of empiric treatment for #E "0igure &$. * rapid response to this empiric treatment confirms a diagnosis of #E, whereas lac% of response within H& h indicates that further treatment options should be considered "as discussed below$.

$igure 2! Management of +atients with #epatic Encephalopathy "#E$. * tripartite strategy is useful in the management of patients with #E. 8ther potential causes of encephalopathy, such as C.7 sepsis, cerebral edema and hypoxia, must be excluded and the precipitating cause of #E identified before a firm diagnosis of #E can be made. in patients with cirrhosis, factors such as sepsis, drugs and dietary protein overload can precipitate #E. >hen #E is suspected, simultaneous, empiric treatment for #E should be initiated to improve the patientLs symptoms. *ny improvement in #E symptoms after initiation of therapy indicates that the diagnosis of #E is correct. * lac% of improvement indicates that another explanation for the symptoms should be sought. 5+redominantly observed in patients with acute liver failure.

,ifferential ,iagnosis and 3nderl!ing Causes

7everal conditions have similar symptoms to #E "0igure &$ and exclusion of these causes of encephalopathy is imperative for the correct management of patients with #E. <f patients show evidence of changes in mental status, exclusion of subdural hematoma is vital as patients with cirrhosis have coagulopathies and an increased ris% of falls. C:HD Cirrhosis is associated with an increased ris% of sepsis, sepsis(related organ failure and death. C:AD Medication(induced adverse effects are very common in patients with cirrhosis, as the liver is the site of first(pass metabolism for most drugs and this organ is dysfunctional in these patients. *s well as excluding conditions that can mimic #E, diagnosis of this disease involves the identification of potential precipitating causes. These two processes are a %ey aspect of the management of patients with suspected #E. Most patients with chronic liver disease have at least one "and often multiple, coexisting$ simultaneous precipitating factors capable of inducing an episode of #E. Many different assessments, including brain imaging and neuropsychometric tests, can be used to diagnose #E " Table $. 8#E is conventionally graded by clinical scales such as the >est #aven criteria.C:GD M#E, by contrast, can only be diagnosed by specific neuropsychometric tests.C D * wide spectrum of neurological and neuropsychological abnormalities exists in patients with cirrhosis, which stretches from no #E at one end to severe #E and coma at the other.CH)D
Table 4.

*dvantages and !isadvantages of !iagnostic Tests for #epatic Encephalopathy

Clinical Scales for Grading #E


* number of scales have been devised for the diagnosis of #E4 the first of its %ind was proposed by +arson(7mith and colleagues in GIH.CH D 0or patients with moderate to severe #E, the /lasgow Coma 7cale can also be employed.CH&D =est <ave# Criteria! <n GHH, Conn et al.C:GD developed the >est #aven criteria " Table $, which have been used in a number of studies of #E. C:GD This scale semi1uantitatively grades a patientEs mental state by means of sub,ective assessments of behavior, intellectual function, alteration of consciousness and neuromuscular function. The original version of the >est #aven criteria comprised four grades, ranging from grade "which includes symptoms such as a trivial lac% of awareness$ through to grade K "which implies an unresponsive patient in a coma$. #owever, the findings of studies utili=ing this scale demonstrated substantial variability between observers in their assessments of low grades of #E. <n &))K, *modio and colleagues, therefore, proposed a modification to the >est #aven criteria that introduced ob,ective scales for the assessment of the individual components of the criteria in patients with #E.CH',HKD 0urther studies are needed to determine whether this version of the >est #aven criteria should be implemented for general use in patients with suspected #E.
Table 4.

*dvantages and !isadvantages of !iagnostic Tests for #epatic Encephalopathy <e atic E#ce halo athy (cori#g 'lgorith&! Characteri=ation of the different grades of #E is especially important in the design of therapeutic trials. The #E 7coring *lgorithm "#E7*$ was originally devised by #assanein et al.CHID for use in a multicenter study that assessed the utility of extracorporeal albumin dialysis in the treatment of patients with #E. CHID This algorithm is particularly useful for assessing patients with low grades of #E, as minimal variability was evident between the scores given at the different sites participating in the study " Table $. CHID
Table 4.

*dvantages and !isadvantages of !iagnostic Tests for #epatic Encephalopathy

/euro"s!c ometric Tests


.europsychometric tests "including Epaper and pencilE tests and computeri=ed tests$ are employed to identify impairments in domains such as visuospatia functioning, attention, processing speed and response inhibition. 8ver time, these tests have proven to be sensitive to the changes associated with M#E. #owever, these tests are not without their limitations " Table $.
Table 4.

*dvantages and !isadvantages of !iagnostic Tests for #epatic Encephalopathy "<E(! The psychometric #E 7core "+#E7$ is a battery of neuropsychometric tests that was specifically designed to diagnose the subtle cognitive changes that characteri=e M#E in patients with cirrhosis " Table and Fox $. CH:,HHD .ormative data for comparison were initially obtained in /ermany, followed by <taly and 7pain. CH',H:,HAD *bnormal test results are strongly correlated with changes found on functional brain neuroimaging scans. The >or%ing +arty of the GGA >orld Congress of /astroenterology, Bienna, *ustria, endorsed this test as the official Egold standardE for the diagnosis of M#E. .otably, apart from the +#E7, no other psychometric tests for #E have been validated by comparisons with normative data. This lac% of validation remains an important area for further research in the field of M#E. The +#E7 has failed to gain popularity in the U7*, however, owing to the lac% of U7(specific normative data and limited availability of the testing system.
Table 4.

*dvantages and !isadvantages of !iagnostic Tests for #epatic Encephalopathy


5o2 4.

The +sychometric #epatic Encephalopathy 7core R9'/(! The 6epeatable Fattery for the *ssessment of .eurological 7tatus "6F*.7$ was issued to diagnose neurocognitive disorders such as dementia, traumatic brain in,ury, stro%e,

multiple sclerosis and bipolar disorder in the U7*. * subset of the 6F*.7 tests is used in the U7* instead of the +#E7. This modified version of the 6F*.7 was designed to focus specifically on the cognitive changes that occur in patients with 8#E. CHHD The modified 6F*.7 test has now been used in multiple studies in the U7* and has proven to be effective in screening patients for M#E.CHG,A)D -i%e the +#E7, the 6F*.7 is a paper and pencil test that ta%es about &)(&I min to administer. <n addition to the domains assessed in the +#E7, the 6F*.7 test scores patientsE visual, verbal and wor%ing memory.

Com"uteri6ed Ps!c ometric Tests


* number of computeri=ed psychometric tests have been developed in the past I years that, once approved by a large consensus group, have the potential to revolutioni=e the assessment of patients with #E. 0#hi%itory Co#trol Test! The inhibitory control test seems to be the most popular of the currently available computeri=ed tests for #E. This test assesses two different cognitive domains that are affected in patients with M#EMresponse inhibition and attention. CA ,A&D The principle of this test is based on EtargetsE and EluresE. +atients are shown a series of different alphabet se1uences that flash on the computer screen one after another, and are expected to respond when ENE is followed by E9E and vice versaMa so(called Etarget. #owever, patients are told not to respond to a ElureEMwhen ENE followed by ENE or E9E is followed by E9E. * lure response greater than five "out of K) attempts$ detects M#E with high sensitivity. CA ,A&D This test has been validated against conventional standard psychometric tests and, in a trial of probiotic therapy for #E, has shown close correlations with other #E scores and improvements in test results in patients who responded to therapy.CA&D #owever, most studies that used the inhibitory control test have been published by a single group of investigators and have been conducted only in either >isconsin or Birginia, U7*. .onetheless, this test shows promise and might ultimately be approved for the diagnosis of M#E. C>R Co& uteri7ed 'ssess&e#t (yste&! The eponymous computeri=ed assessment system from Cognitive !rug 6esearch -td "C!6$, /oring(on(Thames, U?, was devised specifically for neuropsychiatric profiling of patients with cirrhosis and M#E. CA'D This battery consists of seven tests that comprise over I) parallel forms of each tas% and comprehensively measure power of attention, continuity of attention, 1uality of episodic memory, 1uality of continuous memory and speed of memory. This test has shown good correlation with the gold( standard +#E7 test and is popular in the U?.CA'D

Electro" !siological Assessments


Critical $lic+er $re?ue#cy Test! The critical flic%er fre1uency test was validated for the assessment of patients with #E in &))&CAKD and for the assessment of patients with #E who were undergoing trans,ugular intrahepatic portosystemic shunt "T<+7$ placement in &))G. CAID The principle of this test is based on the fact that retinal glial cells in patients with #E undergo similar changes "that is, swelling$ to those seen in cerebral glial cells, termed hepatic retinopathy. The test involves showing the patient light pulses, initially at a fre1uency of :) #=, which is gradually reduced in ). #= decrements, once per second. The critical flic%er fre1uency represents the fre1uency at which discrete light pulses are first perceived. The test results are not influenced by sex, occupation or education level, and are only slightly dependent on age. 0urthermore, the test results correlate positively with those of paper and pencil neuropsychometric tests.CAK,AID Moreover, a critical flic%er fre1uency of below 'G #= diagnoses M#E with high sensitivity and specificity. This tool has been widely used to assess #E in therapeutic trials. Electroe#ce halogra hy! Electroencephalography is an excellent tool for diagnosing #E in the research setting. #E is associated with a decreased mean fre1uency of electrical activity in

the brain, and the diagnostic sensitivity for #E of this finding ranges between K'O and ))O in published studies.CH'D .ew advances in electroencephalography, such as artificial neural networ% expert system software and short epoch, dominant activity and cluster analysis, could prove useful for the diagnosis of #E, although they re1uire further validation in clinical trials. CA:D

5rain Imaging
Cerebral edema in patients with #E is increasingly being detected by M6<. C':D Many M6< techni1ues can identify low(grade cerebral edema " Table & $. * CT scan of the head is useful to identify conditions that could either mimic or exacerbate #E, such as subdural hematoma or a cerebrovascular event " Table & $.
Table 7.

Frain <maging Modalities for !iagnosis of #epatic Encephalopathy


Table 7.

Frain <maging Modalities for !iagnosis of #epatic Encephalopathy

Measurement of Serum Ammonia Levels


-evels of arterial and venous ammonia correlate positively with the severity of #E. CAHD #owever, routine measurement of ammonia levels in the blood is not recommended, as the results of the test would not change either the approach to diagnosis or management of a patient with suspected #E. *dditionally, this test can be challenging to perform in the clinic, as the blood

sample should be collected from a stasis(free vein "that is, without using a tourni1uet and ta%ing care not to cause turbulence or hemolysis$ and must be immediately transported on ice to the laboratory to be analy=ed within &) min. Many treatment options are available for patients with 8#E "as described below$, but no evidence currently supports the treatment of M#E. Most patients show clinical signs of improvement in the symptoms of #E within &K(KA h of initiation of treatment "both empiric therapy and treatment of the underlying causes$. 7erum levels of ammonia might lag behind the clinical response. #owever, if #E persists after H& h of treatment, the following possibilities must be explored: other causes of encephalopathy might have been missed or inade1uately treated4 a precipitating factor might have been missed, treated inade1uately or remain uncorrected4 effective empiric therapy has not been instituted or has been given to excess "in the case of lactulose, as discussed below$.

P armacological T era"!
Correction of the underlying factors that precipitate #E might in itself help to resolve the disease, but predicting a patientEs response to treatment is difficult. <nade1uate response to treatment can be due to a combination of factors. *ll patients should, therefore, receive empiric therapy for #E as other possible diagnoses are being excluded. Empiric therapy is based on the principle of reducing the production and absorption of ammonia in the gutMa number of agents are beneficial for this purpose " Fox & $.
5o2 7.

8ptions for -ong(term Treatment of #epatic Encephalopathy /o#a%sor%a%le >isaccharides! .onabsorbable disaccharides include lactulose and lactitol "an analog of lactulose that is not available in U7*$. CAA(G)D <n addition to having a laxative effect, lactulose and lactitol reduce the colonic p# and interfere with mucosal upta%e of glutamine in the gut, thereby reducing the synthesis and absorption of ammonia. CG D -actulose is considered the first(line therapy for #E. This agent can be administered orally through a nasogastric tube to a comatose or unresponsive patient or rectally through enemas. The usual oral dose of lactulose is about I(') ml given twice a day to induce &(' soft bowel movements daily. *bdominal bloating and a sweet taste in the mouth are the principal adverse effects associated with normal doses of lactulose.CG&D 8vertreatment with lactulose, however, results in the serious adverse effects of severe dehydration, hyponatremia and worsening of #E, especially in patients treated in the intensive care unit. CG'D Clinicians must be mindful of the adverse effects of lactulose overtreatment in patients with #E. '#ti%iotics! 7everal antibiotics can be used as empiric treatment for #E "0igure & and Fox & $. 6ifaximin is a minimally absorbed oral antibiotic with few adverse effects and no reported

drug(drug interactions. * large, multicenter study, published in &) ), demonstrated that remission of #E was prolonged in patients treated with rifaximin compared with those who did not receive this antibiotic.CGKD 6ifaximin received 0!* approval in March &) ) for the treatment of #E "at an oral dose of II) mg twice daily$.
5o2 7.

8ptions for -ong(term Treatment of #epatic Encephalopathy .eomycin was one of the first antibiotics to be investigated as a potential treatment for #E. This drug mainly wor%s by inhibiting mucosal glutaminase in the intestine, which reduces ammonia production in the gut.C:GD .eomycin inhibits ammoniagenic coliform bacteria that produce urease "an en=yme that converts urea into ammonia$ and are prevalent in the gut. The main adverse effects of neomycin sulfate administration include ototoxic and nephrotoxic effects and intestinal malabsorption. The use of this antibiotic has declined over the past few years, owing to the availability of safer antibiotics such as rifaximin.

/utritional Interventions
7%eletal muscle metaboli=es ammonia in patients with chronic liver disease. C G(& D -oss of lean body mass depletes this Eammonia sin%E and increases the ammonia load to the brain, thereby worsening #E. * strong consensus, therefore, exists that patients with cirrhosis should receive a high(protein diet. The European 7ociety for +arenteral and Enteral .utrition recommended, in &)):, that patients with cirrhosis must eat at least .& g2%g of protein daily. CGI,G:D They also recommended that the diet of patients with cirrhosis should be supplemented with branched( chain amino acids "FC**s$ and vegetable protein once #E has developed. 9ra#ched*chai# '&i#o 'cids! FC**s have been studied extensively and a recent meta( analysis has shown that patients with cirrhosis who receive FC**s are more li%ely to recover from #E than those who do not receive this supplement. CGHDFC**s improve levels of serum albumin, increase progression(free survival and reduce both the number of hospitali=ations and the length of hospital stays in patients with cirrhosis. CGH(GGD These amino acids can be administered orally as well as intravenously4 however, their use can be limited by poor availability and high costs. Vegeta%le*%ased "rotei#! Begetable(based protein is better tolerated by patients with cirrhosis than meat(based protein. Begetable(based protein foods have a high fiber content, which increases intestinal transit time and colonic motility and enhances intestinal nitrogen clearance.CGGD Begetable protein also reduces colonic p#, which prevents ammonia from being absorbed in the gut. The adverse effects of a predominantly vegetarian diet include abdominal bloating and flatulence. To reduce these effects and increase a patientEs protein inta%e vegetable protein can be combined with dairy products, such as mil% and cheese.

Long8term Management
:ut atie#t Ma#age&e#t of <E! *fter an episode of #E has resolved, patients with cirrhosis tend to remain on empiric therapy for an indefinite period of time or until they undergo liver transplantation. The goals of therapy at this stage are to prevent recurrent episodes of #E and to ensure a reasonable 1uality of life.C ))D -actulose and rifaximin are popular choices for ongoing therapy in patients who have experienced an episode of #E " Fox & $. *dherence of patients to lactulose therapy on a long( term basis is limited by its gastrointestinal adverse effects. +atients must also be educated with regard to the need to monitor the consistency of their bowel movements and use appropriate dose titration when being treated with lactulose. 6ifaximin, by contrast, has emerged as an effective treatment strategy to prevent recurrence of #E in a multicenter study published in &) ).CGKD +atients who had previously experienced at least two episodes of #E and were in remission were randomly assigned to receive either rifaximin or placebo and were followed up for : months. More than G)O of participants in this study were treated with lactulose in addition to rifaximin or placebo. The patients in the rifaximin group maintained their remission from #E more effectively than did patients in the placebo group, and rifaximin was associated with improved tolerability and decreased adverse effects compared with placebo. CGKD 6ifaximin is, therefore, li%ely to dominate treatment strategy for #E in the future.
5o2 7.

8ptions for -ong(term Treatment of #epatic Encephalopathy "ersiste#t <E! 8rthotopic liver transplantation is the ultimate solution for patients affected by #E. #owever, #E has lost ground as an indication for liver transplantation in the era of the Model for End(stage -iver !isease "ME-!$ score. 7tewart et al.C ) D reported that the severity of #E before liver transplantation is inversely correlated with the duration of survival after transplantation, and that the prognosis of patients who undergo transplantation for #E is worse than that indicated by their ME-! score.C ) D * crucial issue, therefore, is that the wor%(up of a patient who is eligible for liver transplantation should be initiated at the earliest opportunity after an acute episode of #E. 7urgical portosystemic shunting or T<+7 placement worsens #E because ammonia in the gut circulation can then bypass first(pass metabolism in the liver and go directly to the brain. C )&D 7ymptoms of #E that result from portosystemic shunting are amenable to shunt closure or a reduction in stent diameter, but these procedures are indicated only if the patient is not a candidate for transplantation. *lternative treatments for the underlying condition that prompted shunt placement "that is, recurrent variceal bleeding or refractory ascites$ should be considered to prevent the development of #E.

#E is a neuropsychiatric complication of cirrhosis. *mmonia is recogni=ed as a crucial component in the pathogenesis of #E, but other factors such as inflammation, neurosteroids and manganese are also implicated in the development of the disease. 8#E can be diagnosed clinically and mild to moderate grades of the disease might be present in a considerable proportion of ambulatory patients with cirrhosis. +atients with M#E have normal findings on clinical examination, but abnormal psychometric test results. 7everal computeri=ed psychometric tests are being developed to aid the clinical diagnosis of #E and enable clinicians to screen patients with cirrhosis for this condition in an outpatient setting. 7erum levels of ammonia have limited value in the diagnosis of #E, despite being an indicator of disease severity. Empiric treatment should be started in all patients with 8#E. The main goals of outpatient management of patients who have previously experienced an episode of #E is focused on the maintenance of remission and on ensuring that they have a reasonable 1uality of life. 6ifaximin and lactulose have both received 0!* approval for the maintenance of remission in patients who have previously been affected by #E. *n early wor%( up for liver transplantation is beneficial for the management of patients with #E who are candidates for this procedure. *pproval of computeri=ed psychometric tests by the #epatic Encephalopathy Consensus group for the diagnosis of M#E is on the hori=on. This approval will facilitate widespread implementation of screening of patients with cirrhosis for #E in an outpatient setting. 0urthermore, cyclic /M+ and related molecules hold promise as biomar%ers of M#E, which could revolutioni=e the future diagnosis and management of these patients. C )', )KD Translational research that involves advanced M6< techni1ues and proton spectroscopy might resolve controversial issues in the pathogenesis of #E. *lthough preliminary studies have shown that patients with M#E derive benefit from treatment, results of large multicenter trials in this setting are awaited. <dentification of a cost(effective and well(tolerated agent for the treatment of #E remains a challenge.

#epatic encephalopathy "#E$ is a serious neuropsychiatric complication of acute and chronic liver disease <nflammation and raised levels of ammonia in the blood "owing to diminished clearance of ammonia by the liver$ underlie the pathogenesis of #E 7ome degree of cerebral edema is observed in all grades of #E The occurrence of any neuropsychiatric manifestation in patients with liver disease should be treated as #E unless proven otherwise *n acute episode of #E is managed by a tripartite strategy: ruling out other causes of encephalopathy, identifying the precipitating cause and initiating empiric therapy 6ifaximin and lactulose are the only two medications approved by 0!* for long(term treatment of #E >or%(up for liver transplantation must be initiated as early as possible

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&H.#Russinger, !., ?ircheis, /., 0ischer, 6., 7chiliess, 0. P vom !ahl, 7. #epatic encephalopathy in chronic liver disease: a clinical manifestation of astrocyte swelling and low(grade cerebral edemaT $! Hepatol! @2; )'I( )'A "&)))$. &A. Cooper, *. Q., Mc!onald, Q. M., /elbard, *. 7., /ledhill, 6. 0. P !uffy, T. E. The metabolic fate of '.(labeled ammonia in rat brain. $! "iol! C%e&! 2A5; KGA&(KGG& " GHG$. &G.#Russinger, !. P 7chliess, 0. +athogenetic mechanisms of hepatic encephalopathy. Gut AB; I:( :I "&))A$. ').Tanigami, #. et al. Effect of glutamine synthetase inhibition on astrocyte swelling and altered astroglial protein expression during hyperammonemia in rats. Neuros'ien'e 1@1; K'H(KKG "&))I$. ' .6ose, C., ?resse, >. P ?ettenmann, #. *cute insult of ammonia leads to calcium( dependent glutamate release from cultured astrocytes, an effect of p#. $! "iol! C%e&! 280; &)G'H(&)GKK "&))I$. '&.6ose, C. Effect of ammonia on astrocytic glutamate upta%e2release mechanisms. $! Neuro'%e&! CB "7uppl. $, ( I "&)):$. ''.#ert=, -., Murthy, C. 6., -ai, Q. C., 0it=patric%, 7. M. P Cooper, *. Q. 7ome metabolic effects of ammonia on astrocytes and neurons in primary cultures. Neuro'%e&! Pat%ol! 2; GH( &G " GAH$. 'K. CVrdoba, Q., 7anpedro, 0., *lonso, Q. P 6ovira, *. # magnetic resonance in the study of hepatic encephalopathy in humans. Meta ! "rain #is! 1B; K I(K&G "&))&$. 'I.#Russinger, !. -ow grade cerebral edema and the pathogenesis of hepatic encephalopathy in cirrhosis. Hepatology 5@; AH( G) "&)):$. ':.6ovira, *., *lonso, Q. P Cordoba, Q. M6 imaging findings in hepatic encephalopathy. A$NR A&! $! Neuroradiol! 2C; : &( :& "&))A$. 'H.7hawcross, !. -. et al. -ow myo(inositol and high glutamine levels in brain are associated with neuropsychological deterioration after induced hyperammonemia. A&! $! P%ysiol! Gastrointest! )iver P%ysiol! 28B; /I)'(/I)G "&))K$. 'A.Futterworth, 6. 0. +athophysiology of hepatic encephalopathy: The concept of synergism. Hepatol! Res! @8; 7 :(7 & "&))A$. 'G./regorios, Q. F., Mo=es, -. >. P .orenberg, M. !. Morphologic effects of ammonia on primary astrocyte cultures. <<. Electron microscopic studies. $! Neuropat%ol! *+p! Neurol! 55; K)K(K K " GAI$. K)..orenberg, M. !. The role of astrocytes in hepatic encephalopathy. Neuro'%e&! Pat%ol! 2; '('' " GAH$. K .7hawcross, !. P Qalan, 6. The pathophysiologic basis of hepatic encephalopathy: central role for ammonia and inflammation. Cell! Mol! )i-e .'i! 22; &&GI(&')K "&))I$. K&.#Russinger, !. P 7chliess, 0. *strocyte swelling and protein tyrosine nitration in hepatic encephalopathy. Neuro'%e&! /nt! 5B; :K(H) "&))I$. K'.Moldawer, -. -. et al. Cachectin2tumor necrosis factor(W alters red blood cell %inetics and induces anemia in vivo! ,A.*" $! @; :'H( :K' " GAG$. KK.de Bries, #. E. et al. The influence of cyto%ines on the integrity of the blood(brain barrier in vitro! $! Neuroi&&unol! 25;'H(K' " GG:$. KI.!idier, .. et al. 7ecretion of interleu%in(X by astrocytes mediates endothelin( and tumour necrosis factor(W effects on human brain microvascular endothelial cell permeability. $! Neuro'%e&! 82; &K:(&IK "&))'$. K:.!uchini, *. Effects of tumor necrosis factor(W and interleu%in(: on fluid(phase permeability and ammonia diffusion in C.7(derived endothelial cells. $! /nvestig! Med! 55; KHK(KA& " GG:$. KH.Cagnin, *., Taylor(6obinson, 7. !., 0orton, !. M. P Fanati, 6. F. /n vivo imaging of cerebral ;peripheral ben=odia=epine binding sites; in patients with hepatic encephalopathy. Gut AA; IKH(II' "&)):$.

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?. !. Mullen %evin.mullen3case.edu 'uthor Co#tri%utio#s 6. +ra%ash and ?. !. Mullen contributed e1ually to researching data for the article, to substantial discussion of the content, to writing the article, and to reviewing and2or editing the manuscript before submission. Y &) ) .ature +ublishing /roup

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