Hepatic Encephalopathy - Avid Science · hepatic encephalopathy is difficult to establish because of considerable differences in the etiology and severity of hepatic encephalopathy

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Encephalopathy Encephalopathy

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IntroductionHepatic encephalopathy (HE) may be defined as a

disturbance in central nervous system function because of hepatic insufficiency. This broad definition reflects the ex-istence of a spectrum of neuropsychiatric manifestations related to a range of pathophysiological mechanisms. Present in both acute and chronic liver failure, these neu-ropsychiatric manifestations are potentially reversible. Multiple treatments have been used for HE. However, their efficacy has been infrequently assessed by well-de-signed randomized clinical trials. This handicap reflects the difficulty in evaluating the wide range of neuropsy-chiatric symptomatology. Alteration of consciousness-its most relevant manifestation-undergoes spontaneous fluctuations and will be influenced by concurrent clinical factors, such as infection, hypoxemia, GI hemorrhage, or electrolyte disturbances. Despite these limitations, a criti-cal appraisal of available data renders it possible to deline-ate a rational approach to the treatment of HE [1].

Cirrhosis and chronic liver disease adversely affect neurocognitive functioning [2]. These deficits range from neurological complications such as hepatic myelopathy to cognitive and mental status changes such as hepatic en-cephalopathy (HE) [3]. These neurocognitive difficulties can also severely restrict the patient’s functioning and re-sult in morbidity and mortality [4-7]. The most prominent neurocognitive complication of cirrhosis is HE, which re-flects a spectrum of neuropsychiatric abnormalities seen in patients with liver dysfunction after exclusion of other

Chapter 1

Hepatic Encephalopathy

Parvez S Mantry1 and Ashwini Mehta-Sharma2

1The Liver Institute, Methodist Dallas Medical Center, USA2Plaza Medical Center, USA

*Corresponding Author: Parvez S Mantry, The Liver In-stitute, Methodist Dallas Medical Center, USA, Email: [email protected]

First Published April 16, 2016

Copyright: © 2016 Parvez S Mantry and Ashwini Me-hta-Sharma.

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source.



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known brain disease [8]. The current system for studying HE is based on a subjective clinical classification largely based on mental status changes, the West Haven scale (to be discussed further in the chapter) [3,8-10].

In addition to the mental status changes detected by clinical scales such as the West Haven scale, there are sig-nificant neurocognitive disturbances in those with normal mental status, which is characterized by impaired neu-ropsychological and perceptual motor dysfunction [11]. The current system of HE classification does not take into account the continuum of this neurocognitive dysfunction in HE, which forms a spectrum of neurocognitive impair-ment in cirrhosis (SONIC) [8,12,13]. This spectrum spans a patient’s performance from normal to overt HE to coma. The continuous nature of these impairments is supported by the presence of psychometric and neurophysiological impairments in patients even before they reach overt HE [14]. More specifically, poorer performance on tests in pa-tients with treated overt HE than those without overt HE [2,15], and persistence of psychometric deficits even after adequate resolution of an episode of overt HE [16]. In ad-dition, the worse clinical outcomes in patients with poor psychometric performance as a continuous measure have also been described.

Minimal HE (MHE) may be defined as the presence of measurable cognitive defects in patients with liver dis-ease and/or portalsystemic shunting. Defects in MHE are not identified by detailed clinical history and complete

neurological examination, including interview of close family members, but are detected by abnormalities in neuropsychometric or neurophysiological tests that can be performed at the bedside and in the outpatient setting, in the absence of other known causes of abnormal cogni-tive tests.

Prevalence and EpidemiologyHepatic encephalopathy is an extremely common

complication of liver disease and occurs in approximately 30–45% of patients with cirrhosis and 10–50% of patients with transjugular intrahepatic portosystemic shunt, while minimal hepatic encephalopathy affects approximately 20–60% of patients with liver disease [17].

Epidemiology of liver cirrhosis depends particu-larly on the etiology, and shows a marked geographic dif-ference worldwide, between Western, and Asian coun-tries. While chronic hepatitis C infection and alcoholic consumption account for the majority in Western coun-tries, hepatitis virus infection is the major cause of liver cirrhosis in the eastern hemisphere. 18 In the latter re-gion, hepatitis B virus (HBV) infection prevails on main-land Asia [19], while two thirds of Japanese patients with cirrhosis are positive for hepatitis C virus (HCV) [20]. Parasitic infection and intoxication with aflatoxin [21] in south-eastern Asia, and genetic disorders such as hemo-chromatosis [22] in Australia are also important causes of liver cirrhosis. With the growing pandemic of obesity,



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Cirrhosis from Non alcoholic Steatohepatitis (NASH) is emerging as a very common cause of encephalopathy-this is more so prominent in patients with Diabetes Mellitus. The differences in the etiology of cirrhosis are significant with regard to the incidence of hepatocellular or cholangi-ocellular carcinoma, but no information is currently avail-able on whether the development of hepatic encephalopa-thy depends on the cause of liver cirrhosis [18].

Disease BurdenAlthough the total direct and indirect costs of hepatic

encephalopathy have not been formally quantified, data from the Healthcare Cost and Utilization Project sug-gest that hepatic encephalopathy-related hospitalizations are associated with substantial costs. In 2003, there were over 40,000 patients hospitalized in the United States for a primary diagnosis of hepatic encephalopathy, resulting in total charges of approximately $932 million. Further-more, trends over the past 10 years suggest that the bur-den of hepatic encephalopathy is increasing, as indicated by increases in hospital admissions and higher charges per stay. Because of inconsistencies in coding for hepatic en-cephalopathy, the prevalence and cost data from this data source are believed to significantly underestimate the true burden of hepatic encephalopathy. In addition, expendi-tures for physician fees and out-patient care, as well as in-direct costs attributable to lost work days and decreased

productivity, have not been quantified. Thus, there is need for future studies to more accurately define the burden of hepatic encephalopathy, including minimal hepatic encephalopathy.17 The true incidence and prevalence of hepatic encephalopathy is difficult to establish because of considerable differences in the etiology and severity of hepatic encephalopathy and the complexity in diagnosing minimal hepatic encephalopathy [23]. Therefore, a true representation of the extent of this complication is not fully known [17].

Chronic hepatic encephalopathy (HE) is a common and expensive complication of liver failure, requiring more than 55,000 hospitalizations annually, and costing over $1.2 billion per year in the United States alone [24]. Development of hepatic encephalopathy is associated with a poor prognosis. A retrospective review by Busta-mante et al. [5] examined the survival expectancy of 111 cirrhotic patients who developed a first episode of acute hepatic encephalopathy. During the follow-up period (12 to 17 months), 82 patients (74%) died. The survival prob-ability was 42% at 1 year of follow-up and 23% at 3 years. Surviving patients suffered from diminished health-re-lated quality of life, impaired daily functioning, and de-creased work productivity [25]. An additional 51–62% of cirrhotics had evidence of subclinical HE that interferes with cognition and behavior [26,28], and about 23–30% of these patients ultimately developed overt HE [27,28].



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In addition, patients with HE had increased risks of mo-tor vehicle accidents and other delirium-related injuries because of cognitive dysfunction [29-32]. Male sex, in-creased serum bilirubin, alkaline phosphatase, potas-sium, blood urea nitrogen, decreased serum albumin, and prothrombin activity were independently associated with a poor prognosis [17].

PathogenesisIn the brain of HE patients, neurons appear morpho-

logically normal, but astrocytes show signs of Alzheimer type II degeneration, i.e. nuclear enlargement, peripheral margination of chromatin and prominent nucleoli. Am-monia is generally considered to play a central role in the pathophysiology of HE [33]. In HE, selective altera-tions of blood-brain barrier permeability, changes in cer-ebral energy metabolism, an increased GABA-ergic tone, changes in neurotransmitter systems and alterations of gene expression. e.g. of monoamine oxidase, peripheral-type benzodiazepine receptor (PTBR) and neuronal NO synthase are found [33-42]. The reversibility of HE symp-toms and the reason for its precipitation by a variety of different factors has not been sufficiently explained yet (Table 1). Central insights into the etiology of HE have arisen from recent in vitro work with astrocytes. Astro-cytes are important constituents of the blood-brain bar-rier, and uptake of substances from the blood into the brain is achieved by transastrocytic transport. Astrocytes

communicate directly with neurons [43], regulate neuro-transmitter processing and ionic milieu and provide sub-strates for neurons [44-45]. In brain, astrocytes are the only cells containing glutamine synthetase [46], and rep-resent the major site of cerebral ammonia detoxification. Upon exposure to ammonia, cultured astrocytes develop Alzheimer type II changes. These findings prompted the idea that HE is a disorder of glial cells with a consecutive neuronal dysfunction [39,47,48]. Although the symptoms of HE in acute or chronic liver failure are different, there are good reasons to assume that the pathophysiology of both conditions is similar, but may involve different kinet-ics. In acute liver failure, astrocytes swell and brain edema develops [49].

Table 1: Precipitating Factors of Hepatic Encephalopathy [50].



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HE in chronic liver disease is not accompanied by clinical signs of cerebral edema, but evidence for increased cell hydration has been given. A disturbance of astrocyte hydration is apparently a major pathophysiologic event in both forms [50].

PathophysiologyThe main tenet of all theories of the pathogenesis of HE

is firmly accepted: nitrogenous substances derived from the gut adversely affect brain function. These compounds gain access to the systemic circulation as a result of de-creased hepatic function or portal-systemic shunts. Once in brain tissue, they produce alterations of neurotransmis-sion that affect consciousness and behavior. Abnormalities in glutamatergic, serotoninergic, g-aminobutyric acid– ergic (GABA-ergic), and catecholamine pathways, among others, have been described in experimental HE [51]. The research challenge lies in the dissection of each of these systems and their possible pharmacological manipulation to improve treatment. A large body of work points at am-monia as a key factor in the pathogenesis of HE [52,48]. Ammonia is released from several tissues (kidney, mus-cle), but its highest levels can be found in the portal vein. Portal ammonia is derived from both the urease activity of colonic bacteria and the deamidation of glutamine in the small bowel, and is a key substrate for the synthesis of urea and glutamine in the liver. The hepatic process is efficient, with a first pass extraction of ammonia of approximately

0.8 [53]. In acute and chronic liver disease, increased arte-rial levels of ammonia are commonly seen. In fulminant hepatic failure (FHF), elevated arterial levels (>200 mg/dl) have been associated with an increased risk of cerebral herniation [54]. However, correlation of blood levels with mental state in cirrhosis is inaccurate. The blood-brain barrier permeability to ammonia is increased in patients with HE [55]; as a result, blood levels will correlate weakly with brain values, though recent studies indicate an im-provement of this correlation by correcting the ammonia value to the blood pH [56]. Furthermore, the alterations in neurotransmission induced by ammonia also occur after the metabolism of this toxin into astrocytes , resulting in a series of neurochemical events caused by the functioning alteration of this cell [57]. Other gut-derived toxins have been proposed. Benzodiazepine like substances [58] have been postulated to arise from a specific bacterial popula-tion in the colon [59]. Other products of colonic bacterial metabolism [60], such as neurotoxic short- and medium-chain fatty acids, phenols, and mercaptans, have received less attention in recent years. Manganese may deposit in basal ganglia and induce extrapyramidal symptomatology [61]. All of these compounds may interact with ammo-nia and result in additional neurochemical changes. For example, ammonia activates peripheral- type benzodiaze-pine receptors with subsequent stimulation of the GABA-ergic system, an effect also induced directly by ammonia [1,62].



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Abnormal cerebral blood flow (reflecting abnormal neuronal activity) has also been in functional brain imag-ing studies of patients with liver disease with or without hepatic encephalopathy [63,64]. In a study of eight patients with cirrhosis but with no evidence of hepatic encepha-lopathy at study entry, cerebral perfusion, as measured by single photon emission computerized tomography, was studied after induction of hyperammonemia with an oral amino acid solution intended to mimic the hemo-globin released during an upper gastrointestinal bleed-an established precipitant of hepatic encephalopathy [64]. Hyperammonamia was linked both to abnormalities in cerebral perfusion and to deterioration in performance on neuropsychiatric tests. Test results, 4 h after induction of hyperammonemia, compared with values immediately before its induction showed that venous ammonia con-centration increased from a median of 87 to 105 lM/L; the concentrations of several amino acids increased; cer-ebral perfusion was reduced in the temporal lobes, the left superior frontal gyrus, and right parietal and cingulated gyri; and performance on the immediate and delayed story recall tests declined. The concurrent observations of abnormalities in cerebral perfusion and deterioration in neuropsychiatric performance after induction of hy-perammonaemia are consistent with the possibility that excessive blood ammonia brings about brain changes that result in neuropsychiatric symptoms in liver disease.

Besides causing functional changes such as reduction in cerebral perfusion, ammonia may also be responsible

for structural changes in the brains of patients with hepat-ic encephalopathy. In necropsy studies, brains of cirrhotic patients exhibit Alzheimer type II astrocytosis, character-ized by swollen astrocytes with enlarged nuclei and chro-matin displaced to the perimeter of the cell [65,66]. Type II astrocytosis is hypothesized to be caused in part by the detoxification of ammonia [66]. Astrocytes, the only cells in the brain that can metabolize ammonia, contain glutamine synthetase, which scavenges ammonia in con-verting glutamate to glutamine [40]. The accumulation of glutamine in the presence of excessive concentrations of ammonia is hypothesized to produce osmotic imbalance causing the astrocyte to swell. A causal role of ammonia in Alzheimer type II astrocytosis is supported by the finding that application of ammonia to cells in culture can cause changes consistent with those observed in the postmor-tem brains of patients with hepatic encephalopathy [37].

ClassificationA Working Party on the diagnosis and management

of HE in 1998 considered the need for a standardized no-menclature for characterizing forms/stages of hepatic en-cephalopathy justified in the context of the imprecision of commonly used terms to describe hepatic encephalopa-thy (e.g. ‘portal-systemic encephalopathy’) and inconsist-ent interpretation in clinical research and clinical practice of the meanings of commonly used terms to describe the condition (e.g. ‘acute encephalopathy’, ‘chronic encepha-



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lopathy’).

The Working Party proposed a nomenclature that de-fines hepatic encephalopathy with respect to (i) the nature of hepatic abnormality (ii) the duration and characteristics of neurologic manifestations (Table 2). The nomenclature broadly categorizes hepatic encephalopathy by the nature of hepatic abnormality into three types: type A-hepatic encephalopathy associated with acute liver failure; type B–hepatic encephalopathy associated with portosystemic bypass and no intrinsic hepatocellular disease; and type C–hepatic encephalopathy associated with cirrhosis and portal hypertension or portosystemic shunts (Table 2) [8].

Table 2: Proposed Nomenclature for Hepatic encepha-lopathy [8,68].

Type A hepatic encephalopathy is recognized in the presence of acute liver injury [67]. It often progresses rap-idly–often within hours or days–to coma, seizures, decer-

ebrate rigidity and frequently death [37]. Cerebral edema attributed in part to swelling of astrocytes often accom-panies this form of hepatic encephalopathy. This type of hepatic encephalopathy is associated with a high mortal-ity rate, and death is usually attributed to cerebral hernia-tion and hypoxia caused by increased intracranial pres-sure [40,37,66]. Causes include acetaminophen overdose and viral hepatitis [68]. Type A hepatic encephalopathy is differentiated from the other two types of hepatic en-cephalopathy.

• Type B, is associated with portosystemic bypass and no intrinsic hepatocellular disease,

• Type C, which is associated with cirrhosis [8].

In type B hepatic encephalopathy, toxins bypass the liver because of artificial creation, congenital persistence, or spontaneous development of portosystemic shunts, which connects the portal venous system supplying blood to the liver with the general (systemic) venous circulation. Type B hepatic encephalopathy was separated from Type C for historical reasons and because of its implication for the pathogenesis of HE. Some well known reports of cases of HE in the literature featured patients with HE episodes despite a lack of underlying liver disease [69,70]. They had well documented portosystemic shunts. The mystery as to why the majority of patients with portosystemic shunts and no intrinsic (or at least detectable) liver disease do not experience bouts of overt HE is still unanswered.



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Therefore the consensus panel felt that this setting of HE should be given its own category. Hepatic encephalopathy, Type B (quite rare) and Type C (common) are divided into categories of episodic, persistent and minimal. The main reason for using these new descriptors was the whole scale confusion in the literature as to what constitutes acute on chronic HE. Instead, most of the so called chronic HE re-ported in the old treatment literature was actually individ-ual or recurrent episodes of HE in patients with chronic liver disease [73]. In patients with episodic HE, a distur-bance of consciousness develops over hours to days, but does not persist. This is by far the most common form of HE.

Episodic hepatic encephalopathy is usually marked by episodes of neuropsychiatric impairment precipitated by specific stimuli, such as azotemia, the use of sedatives or tranquilizers, gastrointestinal bleeding, excess dietary protein, metabolic alkalosis, infections and constipation [71,72]. Nearly all of these stimuli can increase blood lev-els of ammonia, which is putatively responsible for neu-ropsychiatric symptoms. An increasingly common pre-cipitant of hepatic encephalopathy the use of transjugular intrahepatic portosystemicshunts to treat portal hyper-tension precipitates or worsens hepatic encephalopathy in at least one in five patients with cirrhosis [40]. The cat-egory of episodic hepatic encephalopathy is divided into subcategories of precipitated, spontaneous and recurrent forms. Precipitated episodic hepatic encephalopathy is

linked to specific causes that exacerbate liver damage (e.g. infection, an alcoholic binge) or increase blood concen-trations of the products of protein metabolism (e.g. exces-sive dietary protein, bleeding in the gastrointestinal tract), whereas spontaneous episodic hepatic encephalopathy has no recognized precipitating factors.

Recurrent hepatic encephalopathy is considered to be present when two bouts of precipitated or spontaneous episodic hepatic encephalopathy occur within a 1-year period [8]. In strictly defined persistent hepatic enceph-alopathy, neuropsychiatric deficits do not remit. While fluctuation in the level of consciousness is seen patients with persistent HE typically do not return to a normal mental status. The decision on how long a bout of HE has to last to be termed persistent was not made by the consensus committee. Many were concerned that this cat-egory might be used to describe patients whose bout of overt HE was not adequately managed. The subcategories of persistent HE are based on the dominant stage of HE exhibited by the patients. Patients with Grade 1 or 2 HE (Table 3) best fit into the mild designation especially as recent reports indicate that Grade II HE can be detected in ambulatory out-patients [73]. Severe persistent HE is used to describe patients predominantly in the advanced grades of HE. Some, but not necessarily all of these patients may exhibit structural damage to the brain on newer imaging techniques. An increasingly recognized group of patients with chronic hepatic dysfunction exhibit prominent neu-



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rological deficits simulating Parkinson’s disease. As some of these patients do not display changes in consciousness they are not currently included in this new nomenclature. This and a number of other areas need to be clarified in fu-ture consensus study group reports. Treatment-dependent hepatic encephalopathy, as mentioned, is mild or severe persistent hepatic encephalopathy that develops upon dis-continuation of medication. There is no reliable data on how common this form of HE is at present [68].

Table 3: West Haven Criteria for Semiquantitive Grading of Mental State [8,68].

Minimal Hepatic EncephalopathyMinimal hepatic encephalopathy (the third and final

category of type C hepatic encephalopathy) is character-ized by slight cognitive abnormalities and may manifest only as subtle changes in reaction times in normal dai-

ly activities, such as driving [8,37,74]. Minimal hepatic encephalopathy, which affects an estimated 50–80% of patients with cirrhosis, is difficult to detect but can be identified with psychometric tests such as the number connection test and the digit symbol test [67,69,74]. An estimated 60% of patients with cirrhosis who have no ab-normal findings by conventional neurologic examination may demonstrate psychometric abnormalities reflecting the presence of minimal hepatic encephalopathy [72]. Despite the subtle nature of its manifestations, minimal hepatic encephalopathy can impact patients’ attention span, psychomotor function, and quality of life, includ-ing the ability to sleep [1]. Recognition of minimal he-patic encephalopathy is important for disease-appropriate intervention to be initiated. The importance of recogniz-ing minimal hepatic encephalopathy notwithstanding, no consensus on diagnostic criteria or diagnostic tests has been established [75]. The development of diagnos-tic criteria and tests is hampered by poor understanding of the nature of minimal hepatic encephalopathy–specifi-cally, regarding whether minimal hepatic encephalopa-thy is phenomenologically distinct from clinical hepatic encephalopathy or whether it constitutes the least severe manifestation of a continuum of a single syndrome that is hepatic encephalopathy. To better understand minimal hepatic encephalopathy relative to the other types, the Working Party proposed a study to assess neuropsychiat-ric abnormalities across the spectrum of hepatic encepha-lopathy. To date, such a study has not been undertaken.



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The term ‘subclinical hepatic encephalopathy’ is often used in the medical literature to designate minimal he-patic encephalopathy [8].

Diagnosis and GradingUsually, HE is due to extensive porto-venous collat-

eral shunting together with a decrease in hepatic function, resulting in increased cerebral ammonia load and dimin-ished ammonia detoxification. Fulminant hepatic failure (FHF) means acute liver failure accompanied by hepatic encephalopathy. Sometimes, HE may be the result of met-astatic liver disease [76], portal vein thrombosis [77], con-gestive heart failure [78], or constrictive pericarditis [79]. Even in the absence of overt liver disease, portosystemic shunting can induce HE [80], reviewed in [81]. Pre-TIPS encephalopathy is an important predictor of death during follow-up after placement of TIPS [82]. The symptoms of encephalopathy in all of these circumstances are charac-teristic, but unspecific. They range from subtle neuropsy-chologic derangements to coma. The diagnosis is made be the recognition of an appropriate hepatic disorder and the presence of encephalopathy in the absence of any other likely nonhepatic causes. Fetor hepaticus and an increased blood ammonia concentration may contribute to the di-agnosis. For study purposes, an exact quantification of HE is required and defined by the West Haven Criteria [83,84].

The PSE index comprises the mental state, asterixis, number connection test results, electroencephalography, and arterial blood ammonia concentrations. Subclinical hepatic encephalopathy (SHE) can only be diagnosed by subtle neuropsychological testing [85]. Preliminary results show that hepatic retinopathy, as detected by neurophysi-ological testing, very sensitively reflects the degree of HE (G. Kircheis and D. H-ussinger, unpublished observation) and responds to HE therapy. At the bedside, HE grade 1 is characterized by disorientation, whereas grade 2 HE shows spontaneous or inducible asterixis. In HE grade 3, the patient is somnolent, grossly disoriented and preco-matose, whereas grade 4 represents coma.

StagingIn patients with cirrhosis and overt encephalopathy,

two staging classifications have been used for patients with HE.

The West Haven criteria of altered mental state in HE [86] (numerous studies have employed variations of these criteria).

• Stage 0. Lack of detectable changes in personality or behavior. Asterixis absent.

• Stage 1. Trivial lack of awareness. Shortened at-tention span. Impaired addition or subtraction. Hypersomnia, insomnia, or inversion of sleep pattern. Euphoria or depression. Asterixis can be



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detected.

• Stage 2. Lethargy or apathy. Disorientation. Inap-propriate behavior. Slurred speech. Obvious as-terixis.

• Stage 3. Gross disorientation. Bizarre behavior. Semistupor to stupor. Asterixis generally absent.

• Stage 4. Coma.

Evaluation of the level of consciousness with the Glasgow Scale87 (Table 4): although the Glasgow coma scale has not been rigorously evaluated in patients with HE, its widespread use in structural and metabolic disor-ders of brain function justifies its application in acute and chronic liver disease.

Table 4: Level of Consciousness with Glasgow Coma Scale [1].

HE-Related Neurocognitive ImpairmentHE is clinically divided into normal or overt HE.

However when psychometric or neurophysiological tests are also used, it can be divided into normal, minimal HE (MHE), and overt HE [8,1]. This is because minimal HE cannot be diagnosed using just the clinical examination without these specialized tests.

Clinical Classification of HE into Normal and Overt HE

The well-known West Haven criteria have been used in several studies, but these criteria suffer from a lack of consistency in their application (Table 3) [1,10]. There is a lack of reproducibility apart from the extremes of con-sciousness [1]. Recent studies have shown that there is good agreement among observers in grading patients who are in a coma and those who are completely alert [8,88]. The Glasgow Coma Scale is used to further classify pa-tients with HE who are in a coma [1,89]. The clinical he-patic encephalopathy staging scale (CHESS) is promising for mental status assessment but is currently undergoing validation trials [90]. Although the clinical scales are easy to apply, there remains a large gray zone in the quantifica-tion of changes between the two extremes of normal and coma (Figure 1) [9,88,91].



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Figure 1: Agreement of clinical scales in HE. There is insufficient agreement between observers in the clinical scales of HE except in the extremes. The large population of HE that exists between coma and appearing clinically normal is prone to misclassification and subjectivity [91].

Differentiation between Stage 0 and Stage 1 of the West Haven Criteria

Stage 0 encompasses patients with normal cognitive function and minimal HE, the only definition being that patients have no current clinical signs and symptoms of overt HE [1]. This differentiation between stage 0 and stage 1 of the West Haven criteria, which is critical for inclusion or exclusion into research trials or therapy, is clouded in uncertainty due to the non specificity of signs

and symptoms of stage 1 HE (Fig. 2) [10]. The problem is this: What profile constitutes symptoms of HE in patients who are otherwise ambulatory? This is a difficult question when using pure clinical scales, as evidenced anecdotally by clinicians and through systematic studies [91].

Figure 2: Characterization of HE using clinical and psy-chometric/neurologic tests. Using clinical and specialized testing patients evaluated for HE are classified as normal, minimal, or overt HE. Depending on the specialized tests used and the availability of population norms, the diag-nosis of MHE versus normal can vary between popula-tions. In addition the important distinction between stage 1 overt HE using West Haven criteria and minimal HE is often blurred due to the inability of the clinical scales to accurately define this stage. This furthers the subjectivity of this categorical approach in the initial stages of HE. The assessment of stage II, when patient begin to exhibit diso-

rientation, is fairly reliable between raters [91].



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Subcategorizing Stage 0 into Normal and MHE

In addition to the difficulties faced in dividing pa-tients into normal (stage 0) and stage 1, there is even more controversy surrounding the division of stage 0 into nor-mal and MHE. MHE is defined as cognitive dysfunction without clinical signs of overt HE [14,92]. The diagnosis of MHE is only possible through specialized psychometric and neurophysiological measures [93]. These methods are sensitive and reproducible to a large extent, but the appli-cations across several populations are limited because of lack of norms and lack of appropriate language forms [93].

Blended Scales for HEBecause the West Haven criteria are of limited sensi-

tivity in evaluating HE, scales that blend psychometric/neurophysiological measures with clinical measures have been developed.10 The portosystemic encephalopathy in-dex developed by Conn et al. [10] includes the clinical as-sessment of mental state, the trail-making test score, EEG, asterixis, and arterial ammonia. However, this index has been criticized because the number connection tests were not controlled for age and education, and some criteria were interdependent [8].

The hepatic encephalopathy scoring algorithm (HESA) is a blended scale consisting of clinical and neu-ropsychological measures [88,94]. The HESA divides pa-

tients with HE into four grades and is a modification of the West Haven criteria. This scale provides an assessment of mental status and neuropsychological state from early overt HE to coma. Experience with HESA in a multicenter trial of hepatic replacement therapy demonstrated its ap-plicability and the need for better criteria than the existing West Haven criteria. Agreements on the HESA were high-est in both extremes, but there remained a significant dif-ference in assessments between sites in the interim. In ad-dition, HESA alone has not been proven to be sensitive for the diagnosis of minimal HE, because the cognitive tests used are relatively simple [94,95]. A simple division of HE into low-grade or high-grade HE has been proposed by Haussinger and colleagues [96]. Although such a meth-od is easy and practical, it has not been adopted widely, because it may be an oversimplification of a multifaceted problem.

Clinical PresentationIn cases that are already known to have liver cirrho-

sis, the diagnosis of hepatic encephalopathy is relatively straight forward since the neurologic and psychiatric symptoms appear with other signs of liver failure, such as ascites and jaundice (Table 5). Otherwise, differential di-agnosis includes any disease that can lead to disturbance of consciousness, including cerebrovascular disorders, central nervous infections, cardiovascular diseases and syncope, metabolic disorders such as hyperglycemia and hypoglycemia, and other organ failures, that is, the kid-



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ney, adrenal glands, and lung. In this context, it is impor-tant to note that the typical clinical sign of flapping tremor (asterixis) also appears in other disorders, such as hypo-glycemia and renal insufficiency [18].

Table 5: Annual rate of occurrence of liver failure and its clinical symptoms in patients with liver cirrhosis, who

have no past history of decompensation.

Diagnosis of Symptomatic HEThe diagnosis of HE is based on a careful neuropsy-

chiatric evaluation. Abnormalities may be evident on the motor examination such as an increase in tone, reduced speed or clumsiness of rapid alternating movements, ataxia, an increase in deep tendon reflexes, or impairment of posture or postural reflexes. Observation is needed for abnormal movements such as tremors and particularly asterixis. Primary sensory modalities are usually normal.

Evidence for a focal abnormality should suggest an alter-nate diagnosis. A comprehensive neurologic examination addressing consciousness, orientation, cognitive func-tion, and sensory and motor function together with the knowledge of the patient’s history is required to make the diagnosis of HE. Concomitant neurologic disease such as subdural hematoma, Wernicke’s disease, intercurrent in-fection (including encephalitis), other metabolic abnor-malities (e.g., water, electrolyte, renal function), and drug intoxications (e.g., alcohol, narcotics,sedatives) must be ruled out [8].

Episodic EncephalopathyThe simplest grading of HE is based on clinical find-

ings. The West Haven criteria (Conn Score) grades HE from I to IV and is widely used [86]; it is based on changes of consciousness, intellectual function, and behavior. The Glasgow coma scale, measuring the response to eye open-ing, verbal behavior, and motor responsiveness, quanti-fies neurologic impairment and is less subject to observer variability than the evaluation of consciousness [97]. In studies of overt manifestations of HE, both grading sys-tems are useful.

Asterixis was assessed according to standard prac-tice, by asking patients to extend their arms with wrists flexed backward and fingers open for 30 seconds or more [99,100]. Asterixis was then graded as follows:



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Table 6: Asterixis Grading.

Approach to a Patient with Cirrhosis Who has Alteration in Mental Status

Although HE is present in most cirrhotic patients with altered mental status, it is definitely not the only rea-son for change in mentation in these patients [68]. There are several other differential diagnoses for the develop-ment of cognitive dysfunction in cirrhotics, especially intra-cranial events, electrolyte abnormalities and sepsis [101]. Therefore, the overall susceptibility of the brain to-wards alteration of higher mental function is present in cirrhosis, and HE should only be diagnosed after the ex-clusion of other potential causes. Physical Examination: A detailed evaluation of the vitals and airway should be performed at the outset and these should be managed ac-cordingly. Once these pressing issues have been managed, it is then important to perform a detailed neurological ex-amination [8].

The physical examination should also concentrate on placing the patient in the West-Haven Criteria [101]. Mo-

tor examination: In most cases, the presence of a previ-ously unknown focal motor deficit is not typical of overt hepatic encehalopathy, which tends to be a global rather than a focal process. If a new focal deficit is found, alter-natives to HE such as a subdural haematoma or ischaemic processes should be considered. Patients with OHE can have hyper-reflexia, positive Babinski’s sign, and in stages 2 and 3, have asterixis [102]. Asterixis is defined as a flap-ping tremor caused by the disturbance in the oscillatory networks in the brain [15]. It can be demonstrated in the tongue, and the upper and lower extremities. Patients who are too obtunded to raise their hands up, ‘as they are stop-ping traffic’, should be instructed to grip the examiner’s hands. The grip in patients with asterixis is never constant and oscillates between tight and loose. Care should be tak-en not to confuse asterixis with tremulousness associated with alcohol abuse or withdrawal. Asterixis is not specific for HE and can also been seen in carbon dioxide intoxi-cation and uraemia. Motor examination in HE patients can also demonstrate Parkinsonian symptoms with the at-tendant rigidity and tremors. In a small subgroup, spinal cord involvement with spastic paraparesis, resulting from hepatic myelopathy, can also occur, but this syndrome is distinct from HE [103].

If the above signs are evident, then the diagnosis of HE is fairly secure clinically and there is no need for fur-ther expensive imaging, and psychometric or neurophysi-ological testing [104].



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Treatment of HETreatment GoalsProvision of Supportive Care [1]Adequate supportive care is critical during all stages of

HE and may involve other professionals in the provision of patient care.

Standard measures for hospitalized patients are appli-cable to subjects with HE. Special considerations include a critical role for the nursing staff in the management of these individuals. The mental state can change rapidly, and disorientation can result in bodily harm. Prevention of falls in disoriented patients at earlier stages of HE may require special measures. In deeper stages of HE, the need for prophylactic tracheal intubations needs to be consid-ered. Adequate nutrition should be provided during the period of altered mental state.

Identification and Removal of Precipitating Factors [1]

A vigorous search to identify and eliminate a precipitat-ing factor or factors should be immediately instituted.

In most cases of cirrhosis with acute or chronic HE, a precipitating factor is found, such as the following:

• GI hemorrhage: Exploration requires stool analy-sis and/or placement of a nasogastric tube.

• Infections. This factor requires culture of all ap-propriate body fluids, especially ascites when pre-sent. Spontaneous bacterial peritonitis and pneu-monia may present with HE.

• Renal and electrolyte disturbances. These include renal failure, metabolic alkalosis, hypokalemia, dehydration, and diuretic effects.

• Use of psychoactive medication. This factor may require a urine screen for benzodiazepines, nar-cotics, and other sedatives.

• Constipation

• Excessive dietary protein. In many cases, an ad-equate clinical history can be best provided by the patient’s relatives.

• Acute deterioration of liver function in cirrhosis. In contrast to the situation in FHF, HE in cirrhosis seldom reflects the acute impact of liver failure.

Exceptions include the presence of superimposed alcoholic hepatitis, the development of an acute circula-tory disturbance (e.g., portal vein thrombosis), and the impairment of liver function seen after surgery in cirrho-sis. Precipitating events should also be sought with the development of encephalopathy after placement of TIPS for control of portal hypertension [105]. Spontaneous encephalopathy (no precipitant factor identified) should raise the suspicion of an abnormal collateral circulation.



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Reduction of Nitrogenous Load from the Gut [1]

Measures to reduce the nitrogenos load from the gut should be implemented.

These include catharsis and the use of nonabsorbable disaccharides and/or antibiotics. Other options include drugs that effect neurotransmission. Surgical exclusion of the colon [106], via ileorectal anastomosis, is rarely per-formed in nontransplant candidates.

Assessment of the Need for Long Term Ther-apy [1]

Patients with cirrhosis are at risk of developing new epi-sodes of encephalopathy.

At discharge, three factors need to be considered:

1. Control of potential precipitating factors. These include avoidance of constipation; prophylaxis of bleeding from gastroesophageal varices, when indicated; prophylaxis of spontaneous bacterial peritonitis, when indicated; judicious use of diu-retics; and avoidance of psychoactive medication.

2. Higher likelihood of recurrent encephalopathy. The development of HE in the absence of a pre-cipitating factor or the development of HE in pa-tients with poor liver function (Child B/C) is such a situation. Prevention of a first episode of HE in

subjects who have undergone a TIPS procedure is done in some centers, though no controlled data are available.

3. Assessment of the need for liver transplantation. The development of overt HE carries a poor prog-nosis [5], with a 1-yr survival of 40%. Appropriate candidates should be referred to transplant cent-ers after the first episode of overt encephalopathy of any type.

Treatment OptionsTreatment of HE is Based on Several, Non–

Mutually Exclusive Options [1]Nutritional ManagementPatients with HE should avoid prolonged periods of

dietary protein restriction and receive the maximum toler-able protein intake, aiming at 1.2 g of protein/kg/day (range 1–1.5).

Restriction of dietary protein at the time of acute en-cephalopathy with subsequent increments to assess clini-cal tolerance is a classic cornerstone of therapy. Protracted nitrogen restriction may contribute to malnutrition and aggravate the prognosis . On the other hand, a positive nitrogen balance will have positive effects on encepha-lopathy by promoting hepatic regeneration and increas-ing the capacity of muscle to detoxify ammonia. Thus, nu-tritional management includes intrinsic effects of dietary



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components as well as long term effects on organs whose dysfunctions contribute to the pathogenesis of HE. The increased catabolic rate of cirrhosis leads to a recommen-dation of 1–1.5 g protein/kg/day [108]. Provision of an adequate nitrogen intake is difficult. Vegetable and dairy sources are preferable to animal protein [109], as they pro-vide a higher calorie to nitrogen ratio and, in the case of vegetable protein, provide nonabsorbable fiber, a substrate for colonic bacteria and subsequent colonic acidification.

Zinc, a cofactor of urea cycle enzymes, may be de-ficient in cirrhotic patients, especially if associated with malnutrition. Zinc supplementation improves the activity of the urea cycle in experimental models of cirrhosis.110 One trial has evaluated the effects of zinc over a short pe-riod (up to a week), without major improvement.111 A positive study administered zinc for 3 months, though the study was not randomized.112 Zinc deficiency precipi-tated encephalopathy in a well-described patient [113]. Patients with zinc deficiency should receive oral zinc sup-plements.

Reduction in the Nitrogenous Load Arising From the Gut

Bowel Cleansing

Bowel cleansing is a standard therapeutic measure in HE [1].

Because the toxins responsible for HE arise from the

gut, bowel cleansing is a mainstay of therapy. In addition, HE itself may result in a slow transit time [115]. Colonic cleansing reduces the luminal content of ammonia, de-creases colonic bacterial counts, and lowers blood am-monia in cirrhotic patients [116]. Various laxatives may be used, but nonabsorbable disaccharides are preferred, as they result in additional effects that potentiate the elimi-nation or reduce the formation of nitrogenous compounds Administration of enemas may be necessary in the patient with a severe impairment of consciousness. Alternatively, bowel cleansing can also be achieved after irrigation of the gut via a p.o. tube. Irrigation with a 5-L isotonic solution of mannitol, 1 g/kg, has been shown in a controlled trial to prevent encephalopathy after a GI hemorrhage [117].

Nonabsorbable Disaccharides

Lactulose is a first-line pharmacological treatment of HE [1].

Careful scrutiny of the clinical trials that are the basis for the use of lactulose (galactosido-fructose) can lead to the conclusion that current standards of evidence-based medicine are not met [67,118]. Pooled analysis of the re-sults of controlled studies is not possible because of meth-odological differences between trials. In fact, a critical reappraisal of the use of lactulose, especially in the man-agement of acute encephalopathy in cirrhosis, would re-quire a new clinical trial. This would be of interest, as in one double-blind study the combination of lactulose and



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neomycin was not better than a placebo in the manage-ment of acute encephalopathy when the precipitant factor was simultaneously corrected [119]. On the other hand, extensive data point at the potential mechanism of action of lactulose [140]. Lactulose is not broken down by intes-tinal disaccharidases and thus reaches the colon, where bacteria will metabolize the sugar to acetic acid and lactic acid. The acidification of the colon may underlie its ca-thartic effect. Passage of ammonia into the colonic lumen results in its incorporation into bacteria with the resulting decrease of portal blood ammonia. As a result, peripheral levels of ammonia are reduced and the total body pool of urea decreases. An excessively sweet taste, flatulence, and abdominal cramping are the most frequent subjec-tive complaints with this drug. If diarrhea develops, the drug should be stopped and reinstituted at a lower dose. Protracted diarrhea may result in hypertonic dehydration with hypernatremia [121]; the resulting hyperosmolarity may aggravate the patient’s mental state.

Antibiotics

Antibiotics are a therapeutic alternative to nonabsorb-able disaccharides for treatment in acute and chronic en-cephalopathy and cirrhosis [1].

Benefits from neomycin, the most widely used drug, are attributed to effects on colonic bacteria. However, neomycin will also affect the small bowel mucosa and may impair the activity of glutaminase in intestinal villi

[122]. Metronidazole, affecting a different bacterial popu-lation than neomycin, will also improve encephalopathy [123]. Infection with Helicobacter pylori was proposed as a mechanism responsible for encephalopathy, in view of the generation of ammonia by this urease-containing organism [124]. A careful assessment of its eradication failed to show a distinct impact on mental states or blood ammonia levels in patients with minimal encephalopathy [125]. At this time, eradication of H. pylori cannot be rec-ommended as a therapeutic strategy. Associated toxicity may hamper the use of antibiotics for a prolonged period. Despite its poor absorption, chronic neomycin, as other aminoglycosides, can cause auditory loss and renal fail-ure. Patients require annual auditory testing if maintained on chronic neomycin. Intestinal malabsorption can result in a spruelike diarrhea. Staphylococcal superinfection can also supervene. Metronidazole neurotoxicity can be se-vere in patients with cirrhosis, where impaired clearance of the drug may be present [126].

Rifaximin is an oral, minimally absorbed antibiotic (<0.4%) with broad-spectrum in vitro activity against en-teric bacteria [127,130]. The tolerability profile of rifaxi-min is comparable to placebo [130], and no clinical drug interactions have been reported [129]. Because of the lack of systemic accumulation with rifaximin [128], no dosing adjustments are required in patients with hepatic insuf-ficiency. Rifaximin was approved in the United States in 2004 for non-dysenteric diarrhea caused by Escherichia



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coli and is licensed in Europe, Latin America, Asia and Africa for several indications, including HE. Multiple published studies have evaluated the safety and efficacy of rifaximin in the treatment of HE [131,146], and rep-resentative data are discussed below. A prospective study was conducted to explore appropriate doses of rifaximin for the treatment of HE [146]. Patients with stage 1–3 HE received rifaximin 600 mg/day (n ¼ 18), 1200 mg/day (n ¼ 19), or 2400 mg/day (n ¼ 17) for 7 days. A significant reduction in the mean PSE index from baseline was ob-served with rifaximin 1200 or 2400 mg/day, but not 600 mg/day . These results suggest that rifaximin ‡1200 mg/day is more beneficial than 600 mg/ day in the treatment of HE. The studies included in this review have all em-ployed a daily dose of 1200 mg. Rifaximin efficacy in HE has been assessed in a randomized, double-blind study [146]. Patients with HE, cirrhosis and lactulose or lactitol intolerance received rifaximin 1200 mg/day (n ¼ 48) or placebo (n ¼ 45) for 14 days. Rifaximin significantly im-proved asterixis compared with placebo (P < 0.01) but did not effectively improve mental state, the primary endpoint of the study. The lack of statistical difference between ri-faximin and placebo may have resulted from the fact that the majority of patients had mild disease at baseline. In this study, the tolerability profile of rifaximin was compa-rable with that of placebo [146] and supported tolerability findings from studies in patients with travelers’ diarrhea [130]. This favorable safety and tolerability profile differ-entiates rifaximin from other antibiotics and non-absorb-

able disaccharides in treatment of HE.

Comparison with other antibiotics Rifaximin has been compared with other antibiotics (e.g. neomycin, paromomycin) in the treatment of HE [131,136-141]. In a randomized, double-blind study, rifaximin 1200 mg/day (n ¼ 15) was compared with neomycin 3 g/day (n ¼ 15) in 30 patients with cirrhosis and stage 1–3 HE [136]. Af-ter 21 days of treatment, neuropsychiatric symptoms and blood ammonia concentrations were significantly reduced vs. baseline in both groups; however, reduction in blood ammonia concentrations was significantly greater with rifaximin treatment vs. neomycin. Although no patient administered rifaximin experienced adverse events, 26% of patients administered neomycin showed increases in blood urea nitrogen and plasma creatinine levels, and 33% reported nausea, abdominal pain and vomiting. In anoth-er randomized trial, patients with cirrhosis and chronic stage 1–2 HE received rifaximin 1200 mg/ day (n ¼ 25) or neomycin 3 g/day (n ¼ 24) for 14 consecutive days per month for 6 months [138]. Both rifaximin and neomycin significantly reduced mean blood ammonia concentra-tions and reduced neuropsychiatric symptoms at end of treatment (Figure 2) [138]. Comparison with non-ab-sorbable disaccharides Rifaximin has also been compared with non-absorbable disaccharides [100,131,133,143,145]. Overall, both rifaximin and disaccharides reduced blood ammonia levels and improved neuropsychiatric symp-toms. However, rifaximin was associated with earlier, more marked improvements and was better tolerated than



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the nonabsorbable disaccharides.

Rifaximin 1200 mg/day (n ¼ 50) was compared with lactitol 60 g/day (n ¼ 53) administered for 5–10 days in patients with HE stage 1 (30%), 2 (49%), or 3 (21%) [5]. Both treatment groups exhibited improvement in neuro-logic parameters and reductions in blood ammonia con-centrations. However, the overall PSE index improved more with rifaximin than with lactitol a finding attributed to greater improvement in EEG results and blood ammo-nia levels with rifaximin. Comparable percentages of pa-tients exhibited clinical improvement at the end of treat-ment (82% for rifaximin and 80% for lactitol). In patients with stage 1, 2 or 3 HE, rifaximin 1200 mg/day (n ¼ 20) significantly improved blood ammonia concentrations, EEG results, overall HE score, asterixis score and mental state compared with lactulose 60 g/day (n ¼ 20) (P < 0.05 for each assessment) [135]. No drug-related adverse events were reported with rifaximin, whereas GI effects, includ-ing nausea (n ¼ 5), flatulence and diarrhea (n ¼ 13), and abdominal cramps (n ¼ 3), were reported with lactulose. Rifaximin also compared favourably with lactulose in a study of patients with mild HE [100]. Patients received rifaximin 1200 mg/day (n ¼ 20) or lactulose 120 mg/day (n ¼ 20) for the first 2 weeks of each month for 90 days. Both treatments improved mental state vs. baseline, and improvements were significantly greater with rifaximin therapy than with lactulose therapy after 60 and 90 days of treatment (P < 0.05 and P < 0.02, respectively). Reduc-tions in PSE index were significantly greater with rifaxi-

min vs. lactulose at 15, 30, 60 and 90 days (P < 0.05). No drug-related adverse effects were reported with rifaximin, whereas GI effects, including abdominal pain (n ¼ 10) and nausea (n ¼ 5), were reported with lactulose. In another study, patients with cirrhosis and HE (n ¼ 58) received rifaximin 1200 mg/day or lactulose 30 g/day for 15 days [134]. Study endpoints included improvement in mental status, asterixis, Reitan number connection test, EEG, and blood ammonia levels and were assessed at baseline and days 3, 6, 9, 12 and 15. Compared with lactulose, rifaxi-min significantly improved all clinical parameters at vari-ous time points (P < 0.05 for each significant time point), excluding the Reitan test and asterixis. Rifaximin exhib-ited a more favorable safety profile than lactulose with no reports of diarrhea, dyspepsia, or anorexia.

Cost effectiveness of treatment; one single-centre, ret-rospective chart review compared the frequency of hos-pitalizations and related outcomes in patients with HE treated with lactulose 60 cc/day for ‡6 months followed by treatment with rifaximin 1200 mg/day for ‡6 months [147]. Rifaximin significantly lowered the mean number of reported hospitalizations (0.5) compared with lactulose (1.6) (P < 0.001). In addition, mean time spent hospital-ized was significantly lower during rifaximin treatment (0.4 weeks) vs. lactulose (1.8 weeks) (P < 0.001). These findings translated into hospitalization charges four times lower with rifaximin ($14 222 per day) than lactulose ($56 635 per day) (charges calculated in 2005 dollars) [147].

In contrast, another study employed decision analysis



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with Markov modeling to determine the cost effectiveness of six treatment strategies (including no treatment, lactu-lose, lactitol, neomycin, rifaximin and rifaximin salvage in patients with intolerance or no response to lactulose) in patients with subclinical to stage 2 HE [148]. Using dis-counted cost per life years gained as the primary outcome, the authors determined that rifaximin was not cost effec-tive as first-line HE therapy. However, they concluded that rifaximin salvage therapy in patients failing lactulose was a highly cost-effective treatment option in mild to moder-ate HE [148].

In summary, multiple clinical studies have demon-strated rifaximin is at least comparable with nonabsorb-able disaccharides in treatment of HE, is more effective in lowering blood ammonia concentrations and demon-strates a favorable tolerability profile. However, these re-sults should be interpreted in the context of the limita-tions imposed by the small sample sizes and unblinded design of many of the studies [164].

Other TherapiesSodium BenzoateSodium benzoate reduces serum ammonia levels by

increasing ammonia excretion in urine; however, limited data support the benefits of sodium benzoate therapy for HE. One prospective study compared the efficacy of so-dium benzoate (n ¼ 38) with lactulose (n ¼ 36) in pa-tients with cirrhosis or surgical portosystemic anastomo-

sis who presented with an HE exacerbation [149]. Sodium benzoate improved symptoms of HE in 80% of patients compared with 81% receiving lactulose (20%). A similar incidence of adverse events was observed between the two groups [149].

Branched-Chain Amino AcidsA primary function of the liver is to regulate amino

acid supply to peripheral tissues. The balance of physi-ologic amino acid concentrations is altered in patients with liver disease with an increased ratio of aromatic to branch-chain amino acids [150,151]. It has been suggest-ed that restoring the appropriate balance of amino acid levels might benefit HE patients [150]. Anecdotal reports have provided some support for this notion [152]; how-ever, results from controlled studies indicate there is no consensus concerning the benefits of branchedchain ami-no acid (BCAA) therapy in HE [150,153-155]. One study compared BCAA therapy with dietary protein supple-mentation in patients with cirrhosis. Oral BCAA supple-ments (n ¼ 17) and dietary protein (n ¼ 20) were equally effective in restoring the nitrogen balance from negative to positive in all patients. A meta-analysis reviewed clini-cal trials evaluating the efficacy of BCAA therapy in pa-tients with cirrhosis and acute HE [154]. Although pooled analysis of five clinical studies demonstrated significant mental recovery from high-grade HE in patients treated with BCAAs, two studies reported an increased mortality risk. A more recent analysis reviewed controlled BCAA studies for the treatment of chronic HE [155]. Only two



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trials could be evaluated, and authors concluded that large, multicentre studies are needed to confirm the use of BCAA therapy in HE.

Dopamine AgonistsAltered dopaminergic transmission has also been im-

plicated in HE pathogenesis [1]. However, there is a pau-city of data on the benefit of dopaminergic agonists in HE therapy. One randomized study compared the efficacy of the dopamine agonist bromocriptine vs. placebo in seven patients with cirrhosis and chronic PSE [156]. In this small study, bromocriptine was not superior to placebo, and three patients experienced constipation during treatment. Benzodiazepine receptor antagonists Benzodiazepines exert depressant effects on the central nervous system by binding to the c-aminobutyric acid (GABA)–benzodiaz-epine receptor complex [118]. It has been suggested that ‘endogenous benzodiazepines’ may cause neuroinhibitory effects in patients with HE [1]. Antagonism of this effect with the benzodiazepine receptor antagonist flumazenil has been evaluated. Intravenous flumazenil (n ¼ 265) im-proved neurologic scores in 18% of patients with stage 3 HE and 15% of patients with stage 4 HE, compared with 4% and 3% of patients, respectively, treated with placebo (n ¼ 262) [157]. Flumazenil also improved EEG record-ings vs. placebo. The authors concluded that flumazenil is beneficial only in patients with cirrhosis and severe HE [157]; further studies are necessary to determine the ben-efits of flumazenil in patients with subclinical, mild, or

moderate HE [164].

Other TherapiesL-ornithine-L-aspartate lowers serum ammonia lev-

els by providing substrates for the intracellular metabolic conversion of ammonia to urea and glutamine [74,1]. Re-sults from controlled trials suggest that ornithine aspar-tate reduces ammonia levels and provides therapeutic benefits in patients with chronic mild to moderate HE [158,159]. One study compared ornithineaspartate 20 g/day for 7 days with placebo in 126 patients with cirrhosis, hyperammonaemia (>50 lmol/L) and chronic HE [158]. Ornithine-aspartate significantly improved venous am-monia concentration (P < 0.01), mental status (P < 0.001) and PSE index (P < 0.01). Adverse events consisted of mild GI disturbances and were reported in 5% of patients administered ornithine-aspartate. A second study evalu-ated the efficacy of oral ornithine-aspartate 18 g/day for 14 days in 66 patients with cirrhosis, hyperammonaemia, and stable, chronic HE [159]. Ornithine-aspartate signifi-cantly improved blood ammonia concentrations, mental state grade and PSE index compared with placebo (P < 0.05 for each comparison), and no adverse events were reported. These findings point to L-ornithine-L-aspartate as a promising HE treatment that deserves further evalu-ation. Levocarnitine has been suggested to lower blood ammonia levels by enhancing metabolic energy produc-tion [74,160]. In 150 patients with mild or moderate HE, levocarnitine significantly reduced serum ammonia levels



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and improved mental status compared with placebo (P < 0.05) [161]. However, in an earlier clinical study, follow-ing rectal ammonium administration in patients with cirrhosis, levocarnitine provided no significant protec-tion against increases in ammonia levels compared with placebo [162]. One controlled study evaluated treatment acarbose in 107 patients with mild or moderate HE [163]. Acarbose 150–300 mg/day significantly decreased blood ammonia levels and improved number connection test scores vs. placebo (P < 0.01). However, acarbose was as-sociated with adverse events including abdominal bloat-ing/ pain, flatulence and increased frequency of bowel movements. The mechanism whereby acarbose improves clinical manifestations of HE is unknown, and its use as a therapeutic agent requires further study [164].

Liver TransplantationThis is the most definitive treatment since HE repre-

sents an irreversible and permanent derangement in liver synthetic function for appropriate candidates. For prob-lematic encephalopathy (nonresponsive to therapy), con-sider imaging of splanchnic vessels to identify large spon-taneous portal-systemic shunts potentially amenable to radiological occlusion. In addition, consider the combina-tion of lactulose and neomycin, addition of oral zinc, and invasive approaches, such as occlusion of TIPS or surgical shunts, if present [1].

Minimal or Subclinical Encephalopa-thy

Treatment can be instituted in selected cases. The most characteristic neuropsychological deficits in patients with cirrhosis are in motor and attentional skills [165]. Although these may impact the ability to perform daily activities, many subjects can compensate for these defects. Recent studies suggest a small but significant impact of these abnormalities on patients’ quality of life [25], includ-ing difficulties with sleep.166 In patients with significant deficits or complaints, a therapeutic program based on di-etary manipulations and/or nonabsorbable disaccharides may be tried. Benzodiazepines should not be used for pa-tients with sleep difficulties [1].

Summary and Challenges for the FutureClinical scales for the diagnosis of HE are fraught with

subjectivity until there is evidence of disorientation. Men-tal status changes and neuropsychological changes are two different planes that need to be tested before decid-ing what strategy is needed to diagnose HE. Mental status changes beyond disorientation (stage 2 or higher) have good interpreter reliability; however, the simple clinical assessment of patients with normal mental status or cog-nitive complaints without disorientation is not objective or adequate. There are several psychometric and neuro-



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physiological tests that can be used to study these patients, which should be performed according to locally available expertise, norms and population.

Therapeutic challenges for Over Hepatic Encepha-lopathy (OHE) depend on the acuity and severity of the clinical condition. At this time, therapy for MHE needs to await long-term trials that focus on clinically relevant outcomes. The overall management consists of properly identifying OHE, gauging its severity, treating potential precipitating factors and using treatments specifically di-rected towards OHE [104].

Out-patient management goals for Hepatic Encepha-lopathy are prevention of recurrence and improvement in daily functioning [104].

At this time, lactulose and rifaximin have emerged as leading therapeutic options for in-patient and out-patient OHE therapy in the US. Liver transplant work-up in these individuals needs to be initiated to ensure a lasting im-provement in mental status. The challenge for the future is to evaluate cognitive function as a continuum with clini-cally important outcomes to increase their relevance and to also develop methods that can be performed in the clin-ic. Therapeutic strategies for MHE need to be developed in the context of clinically relevant outcomes and those for OHE need to be refined to fit the individual patient while minimizing cost and adherence issues [104].

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Hepatic Encephalopathy - Avid Science · hepatic encephalopathy is difficult to establish because of considerable differences in the etiology and severity of hepatic encephalopathy