Me Dc Linna Encephalopathy 2008

8/13/2019 Me Dc Linna Encephalopathy 2008

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Hepatic Encephalopathy

Santiago J. Munoz, MDa,b,*aDivision of Hepatology, Department of Medicine, Albert Einstein Medical Center,

Philadelphia, PA 19141, USAbJefferson Medical College, Philadelphia, PA 19107, USA

Hepatic encephalopathy (HE) is a syndrome of neuropsychiatric dysfunc-

tion caused by portosystemic venous shunting, with or without intrinsic liver

disease [1]. Patients with HE often present with the onset of mental status

changes ranging from subtle psychologic abnormalities to profound coma.

Several hypotheses have been proposed to explain the mental impairment

associated with portosystemic shunting and liver disease. Clinicians diagnos-

ing HE frequently have the opportunity to intervene and reverse severe HE,

even hepatic coma. The recent advances in understanding and managementof HE are the subject of this article.

Epidemiology and clinical significance

HE is a common complication of advanced cirrhosis. Between one third

to one half of hospitalizations for cirrhosis are related to HE [2]. The fre-

quency of hospitalization for HE has nearly doubled over the last decade,

with lengths of stay between 5 and 7 days[2]. Patients with HE often have

other manifestations of end-stage liver disease, such as ascites, jaundice, or

gastrointestinal variceal bleeding. HE can also develop as an isolated man-

ifestation of decompensated cirrhosis. HE usually signals advanced liver

failure, and is often considered a clinical indication for evaluation for liver

transplantation[3]. HE may disable the patient from employment, driving,

and self-care, and require involvement of family or household members in

the care of affected patients. The clinical importance of HE is underscored

by the frequent reversibility of the precipitating factors.

* P.O. Box 403, Moorestown, NJ 08057.

E-mail address: [email protected]

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doi:10.1016/j.mcna.2008.03.009 medical.theclinics.com

Med Clin N Am 92 (2008) 795812
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Risk factors

Severe, acute, or chronic liver disease and portosystemic venous shunting

are the sine qua non for the development of HE. The more advanced the

liver disease, the more likely the development of HE. Patients with cirrhosis

who have minimal HE (formerly known as subclinical HE) are at risk of

developing overt HE[4]. Placement of a transjugular intrahepatic portosys-

temic shunt (TIPS) is also a risk factor. Patients who have diabetes mellitus

or malnutrition seem to develop HE more frequently with cirrhosis[5]. HE

is an essential component of acute liver failure[6]. Severe hyperammonemia

(O150200 mmol/L) with acute liver failure can cause cerebral edema that

contributes to HE [7]. Patients with portal vein thrombosis and extensive

portosystemic shunting without significant parenchymal liver disease occa-

sionally develop HE. Other risk factors can precipitate HE (Box 1).

Types of hepatic encephalopathy

HE is clinically classified into three major categories, according to the

underlying hepatic condition (Table 1) [8]. Type A occurs in patients with

acute liver failure. Type B occurs in patients without intrinsic liver disease

but with large, noncirrhotic, portosystemic shunting. Type C is related tounderlying cirrhosis with portosystemic shunting. Type C is the most com-

mon form. It can be episodic or persistent. Episodic HE can lead to repeated

hospitalizations, often caused by precipitating factors (seeBox 1). The HE

Box 1. Precipitating factors for hepatic encephalopathy

Dehydration

Gastrointestinal bleeding

Infections (especially spontaneous bacterial peritonitis, urinarytract, skin, or pulmonary)

Constipation

Excessive dietary protein

Central nervous system acting drugs

Hypokalemia

Renal failure

Urinary obstruction

Hyponatremia

SurgeryTransjugular intrahepatic portal-systemic shunt

Superimposed liver injury (acute hepatitis, drug-induced liver

injury)

Hepatocellular carcinoma

Terminal liver disease

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episode can be treated by correction of precipitating factors (see later).

Sometimes an episode of HE may not have recognizable precipitating

factors (spontaneous episodic HE). Some patients develop recurrent HE.If the HE lasts beyond 4 weeks or is recurrent, type C HE is considered

persistent. Both episodic and persistent HE can be adequately suppressed

by therapy, but may reappear after therapy discontinuation.

Clinical presentation

HE presents with a broad spectrum of clinical manifestations (Table 2).

The patient or household contacts may describe changes in mentation,

such as a decrease in memory and concentration ability, mental fogginess,or mild confusion. With severe manifestations, a patient may rapidly

Table 1

Types of hepatic encephalopathy

Type A Encephalopathy from acute liver failureType B Encephalopathy caused by portosystemic shunting, without

intrinsic liver disease

Type C Encephalopathy of cirrhosis associated with portosystemic shunting:

Episodic: precipitated, spontaneous, or recurrent

Resistant: mild, severe, treatment-dependent

Minimal: previously known as subclinical

Table 2

Clinical manifestations and severity of hepatic encephalopathy

Encephalopathy Consciousness

Intellectual

function

Personality

behavior

Neuromuscular

abnormalities

Stage I (mild) Abnormal sleep

pattern

Shortened

attention span,

mildly impaired

computations

Euphoria,

depression,

irritability

Metabolic tremor,

muscular

incoordination,

impaired

handwriting

Stage II

(moderate)

Lethargy, mild

disorientation

Amnesia, grossly

impaired

computations

Overt change in

personality,

inappropriate

behavior

Slurred speech,

asterixis

(flapping),

hypoactive

reflexes,

ataxia

Stage III

(severe)

Somnolence,

semistupor

Inability to

compute

Paranoia, bizarre

behavior

Hyperactive

reflexes,

nystagmus,Babinskis sign,

clonus, rigidity

Stage IV

(coma)

Stupor,

unconscious

None None Dilated pupils,

opisthotonus,

coma

Data from Conn H, Lieberthal M. The hepatic coma syndromes and lactulose. Baltimore:

Williams & Wilkins; 1979.

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develop overt mental changes, such as grossly inappropriate behavior,

slurred speech, and marked personality changes that can progressively dete-

riorate into a stuporous, comatose state. This can lead to urgent hospitali-zation for evaluation of suspected stroke or drug overdose. Seizures are

an uncommon manifestation of HE. The patient developing HE is typically

unaware of the changes in behavior, personality, and consciousness. An en-

cephalopathic patient may resist evaluation and have to be managed in ac-

cordance to his or her lack of competency if grossly confused, inappropriate,

or agitated. Conn and Lieberthal [1] proposed a thorough clinical assess-

ment of HE (see Table 2). Ortiz and colleagues [9] recently evaluated

a nine-item linear scale to assess HE severity, but this scale is relatively com-

plex and contains components that often develop asynchronously. A prac-tical and simple gradation of HE is commonly used clinically, but entails

significant subjective observer bias (Table 3)[1]. The presence of a flapping

tremor (asterixis) signifies stage II. The flapping often weakens as HE prog-

resses to stage III and disappears in stage IV. The complex portosystemic

encephalopathy index is an arbitrary composite score designed to assess

HE severity[1]. This index grades the level of abnormality of arterial blood

ammonia level, electroencephalogram, asterixis, mental state, and trail-mak-

ing test time. It is a valuable research tool for clinical trials, particularly to

evaluate therapeutic agents, but is too complex for standard clinicalpractice. An objective, relatively simple, specific, and sensitive method to di-

agnose and assess the severity of HE has not yet been devised. The patient

history often yields clues of underlying liver disease, whether chronic viral

hepatitis C or B, autoimmune liver disease, fatty liver, or alcoholic liver

disease. In any patient presenting with mental changes and prior liver

disease, HE is a major element in the differential diagnosis that requires

investigation. The patient with HE may have had a recent precipitating

event, such as gastrointestinal bleeding, spontaneous bacterial peritonitis,

other infections, dehydration, constipation, excessive dietary protein intake,excessive alcohol intake, urinary obstruction, and electrolytic derangements

(see Box 1). Physical examination may reveal a disheveled appearance or

Table 3

Clinical grades of hepatic encephalopathy

Grade Findings

0 No abnormality detected

1 Shortened attention span, impaired addition and subtraction skills,

mild euphoria or anxiety2 Lethargy, apathy, disoriented to time, personality change,

inappropriate behavior

3 Somnolence, semistupor, responsive to stimuli, confused when awake,

gross disorientation

4 Coma, little or no response to stimuli, mental state not testable

Data from Conn H, Lieberthal M. The hepatic coma syndromes and lactulose. Baltimore:

Williams & Wilkins; 1979. p. 7.

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other signs of inadequate self-care. The mental status examination discloses

signs ranging from confusion and disorientation (stage II); to somnolence

(stage III); to unresponsive coma (stage IV) (seeTable 3). Physical findingscan help grade the severity of encephalopathy. Asterixis is absent in stage I,

and present in stage II, but may become difficult to elicit and weak in stage

III. The asterixis and other signs can be intermittent, wax and wane, or

inconsistently occur in patients with a given stage of HE. Generally, the

neurologic examination in HE demonstrates nonlocalizing signs of diffuse

neuropsychologic dysfunction, as in other metabolic encephalopathies. Fo-

cal neurologic signs are occasionally present, such as nystagmus, Babinskis

sign, clonus, opisthotonus, and even decerebrate and decorticate posturing

in stage IV. In a prospective study, 17.4% of HE episodes exhibited focalneurologic signs [10]. Hemiplegia and hemiparesis were the most common

focal neurologic signs, but hemiagnosia and monoplegia were also observed

[10]. Seizures were more common in patients with focal neurologic signs.

The focal neurologic deficits resolved, without sequelae, in parallel with

the resolution of the HE[3]. The development of focal neurologic signs or

seizures in a patient with encephalopathy should lead to appropriate brain

imaging, however, because structural brain lesions, such as subdural hema-

tomas, can cause the focal neurologic signs.

Differential diagnosis and evaluation

HE may clinically mimic other entities, including other metabolic toxic-

encephalopathies, transient ischemic attack, stroke, intracranial hemor-

rhage, brain tumors, and brain abscesses (Box 2). A thorough diagnostic

evaluation is required to exclude these alternative diagnoses to establish

Box 2. Major differential diagnoses in hepatic encephalopathy

Metabolic encephalopathies caused by uremia, sepsis,

hypoxia, hypoglycemia, ketoacidosis, hypercapnea, thyroid

dysfunction, or cerebral edema

Intracranial bleeding: subdural hematoma, intracranial

hemorrhage

Ischemic brain disease: transient ischemic attack, ischemic

stroke

Central nervous system abscess, encephalitis, meningitis(bacterial, viral, fungal)

Central nervous system neoplasm

Delirium tremens

Alcoholism

Postictal state



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the diagnosis of HE. An evaluation for other causes of abnormal mental sta-

tus is necessary even in patients with recurrent episodes of severe HE (stage

RII). Multiple causes of encephalopathy may be identified, such as HE anduremic encephalopathy in a patient with liver failure and hepatorenal

syndrome. Cerebral edema or even fatal uncal herniation have rarely been

described in cirrhotic patients with HE[1113].

History and physical examination are key tools in diagnosing overt HE.

An elevated blood ammonia level and absence of structural lesions on brain

imaging support the diagnosis. The previously reported discrepancy between

blood ammonia levels and HE severity was related to problems with the

biochemical assay for ammonia. Ammonia is a labile compound. Spontane-

ous deamination and evaporation at room temperature during storage mayoccur. These factors can cause errors in blood ammonia results. If properly

processed, blood ammonia levels correlate well with the severity of HE[14

17]. Furthermore, venous blood ammonia level, when properly assayed, cor-

relates well with arterial ammonia level[13]. When evaluating a patient with

mental status changes, blood ammonia levels should be drawn in a nonhe-

parinized container, immediately placed on ice, and assayed within 30 min-

utes. Normal blood ammonia levels in a patient with severe mental status

changes do not support the diagnosis of HE. Conversely, an elevated ammo-

nia level in a comatose patient does not exclude coexistent conditions con-tributing to the abnormal mental status (see Box 2). Markedly elevated

ammonia levels in a comatose patient (O150200 mmol/l), however, are

strongly suspicious of HE, provided there is no history of recent seizures.

Blood ammonia levels may be moderately elevated in patients with cirrhosis

without HE.

Head CT or MRI is important to exclude structural lesions as causes of

an abnormal mental status. Even though the electroencephalogram may

demonstrate the triphasic spikes frequently seen in HE, the test is not rou-

tinely used to diagnose HE. Electroencephalogram is useful when the diag-nosis is uncertain, such as in the presence of focal neurologic signs or seizure

activity, or in a comatose patient. Psychometric tests, such as the Number

Connection Test or other variants of simple computational chores, can

help document the clinical course of HE and assess response to therapy of

patients with stage I or II HE. These tests lack specificity because they

can reflect other forms of toxic-metabolic encephalopathy. More complex

neurophysiologic and neuropsychologic tests used to diagnose minimal

(subclinical) forms of HE are unnecessary to evaluate patients with overt

HE. Minimal HE frequently precedes the development of overt HE.

Pathogenesis

Ultimately, HE results from functional disturbances of cells involved in

neurotransmission. The neurologic impairment in HE is believed to be

caused by multiple factors (Fig. 1). Previous hypotheses had attempted to

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explain HE by individual neurotoxic mediators or disruption of single

neurotransmitters [1725]. Several mechanisms, however, likely induce the

observed abnormalities of neuronal and astrocytic function. Potential path-

ogenic factors include a direct neurotoxic effect of ammonia, oxidative stress

caused by generation of reactive oxygen species, endogenous benzodiaze-

pine-like ligands, subclinical intracellular astrocytic edema,g-aminobutyric

acidlike molecules that act as g-aminobutyric acid agonists, abnormal

histamine and serotonin neurotransmission, endogenous opiates, neuroste-

roids, inflammatory cytokines, and potential manganese toxicity[17,18,26].

Hyperammonemia is directly neurotoxic and may also sensitize astrocytes

and neurons to injury by other pathways and mediators [27]. Further re-

search is needed to ascertain the therapeutic implications of these multiple

pathways for HE.

Precipitating factors

Precipitating factors are critically important in the diagnosis and manage-

ment of HE. They are responsible for most episodes of HE. They should bediligently sought in patients with liver disease presenting with mental status

changes. HE without apparent precipitating factors from terminal cirrhosis

is uncommon. Episodic HE should be attributed to liver failure only after

systematically excluding all the precipitating factors (seeBox 1).

The mechanisms by which precipitating factors induce HE are diverse

and incompletely understood. When encephalopathy is associated with

gastrointestinal bleeding or dietary protein overload, excessive ammonia pre-

cursors (amino acids, peptides, and proteins) cause increased ammonia

production[28,29]. This may lead to neuronal and astrocyte dysfunction. In-creased intake of dietary protein may not be readily apparent or volunteered

by the encephalopathic patient. This information should be sought from

household members. Other precipitating factors (hypoxia, hypovolemia,

excessive amounts of central nervous systemacting drugs, antidepressants,

sedatives, analgesics, and severe hyponatremia) likely operate by direct neu-

ronal inhibition. Even at standard dosages, central nervous systemacting

Hepatic

Encephalopathy

ammonia oxidative stress cytokines

GABAbenzodiazepine-likeopiates

astrocyte

edema

serotonine

histamine

Fig. 1. Neurologic impairment factors in HE.



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agents may accumulate in patients with advanced cirrhosis because of de-

creased hepatic clearance. Elevated serum drug levels can cause mental status

changes. Hypokalemic alkalosis potently stimulates renal ammoniagenesis.Renal dysfunction, including the hepatorenal syndrome, may decrease renal

ammonia excretion. A hypercatabolic state induced by septic complications,

such as spontaneous bacterial peritonitis or other infections, provides

increased precursors for ammonia synthesis that may directly inhibit neuro-

nal function by cytokines or endotoxins. Finally, increased portosystemic

venous blood shunting caused by hepatocellular carcinoma or intercurrent

portal vein thrombosis may increase the delivery of ammonia and other

neurotoxins to the central nervous system.

Treatment

Proper management of HE requires identification and treatment of the

precipitating factors (see Box 1). This treatment is probably more potent

than any pharmacotherapy. Multiple precipitating factors are often present.

An episode of HE should be attributed to end-stage cirrhosis only after care-

ful exclusion of the known precipitating factors. Similarly, the diagnosis of

HE in a patient with underlying liver disease is established only after exclud-

ing other etiologies for mental status changes.

Correction of precipitating factors

Dehydration, from excessive diuresis, diarrhea, or vomiting, is a common

and easily correctable precipitating factor. Patients with severe ascites may

be intravascularly depleted and dehydrated. Clinical signs of dehydration,

and elevated serum creatinine and other laboratory tests consistent with

hemoconcentration, establish the diagnosis. Dehydration is reversed by dis-continuation of diuretics, intravenous infusion of physiologic saline, and

therapy for the underlying cause of increased fluid and electrolyte losses.

Gastrointestinal bleeding is identified and treated appropriately. Microor-

ganisms cultured from infected sites (spontaneous bacterial peritonitis, uri-

nary tract infection, pneumonia, cellulitis, and so forth) should be diagnosed

and treated with appropriate antibiotics. Broad-spectrum antibiotics should

be initiated after obtaining pancultures when infection is suspected in pa-

tients with stage III or IV HE, such as in patients with fever or unexplained

leukocytosis. The onset of HE requires diagnostic paracentesis in a patientwith ascites, for analysis of cell type, cell count, Gram stain, and culture.

Hypokalemia should be vigorously corrected with parenteral potassium in

HE. Severe hyponatremia (serum sodium !125 mEq/L) can contribute to

HE, particularly when the sodium level is less than 120 mEq/L. Discontinu-

ation of diuretics and appropriate free-water restriction are required. Limited

infusions of hypertonic saline (3% NaCl, 150 mL intravenous) may be

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needed for very severe hyponatremia. The new vasopressin receptor antago-

nists have shown promising results in treating severe hyponatremia with cir-

rhosis. They can be considered for patients with severe HE and severehyponatremia [3032]. HE precipitated by excessive dietary protein intake

or use of sedatives often gradually resolves provided that the patient receives

general supportive care and specific pharmacologic therapy for HE (see next).

Urinary obstruction by prostatic processes, genitourinary stones, or renal in-

sufficiency, including the hepatorenal syndrome, should be treated. Pulmo-

nary infections, acute respiratory distress syndrome, large pleural effusions,

sleep apnea, and other forms of respiratory insufficiency causing hypoxemia

should be appropriately treated in the setting of HE. Pharmacologic therapy

with lactulose or nonabsorbable antibiotics should be undertaken or intensi-fied in patients with HE who are being weaned from mechanical ventilation.

Pharmacologic therapy

Agents that induce diarrhea or modulate intestinal bacterial flora can

decrease ammonia production and increase ammonia excretion. The com-

monly used agents include lactulose, lactitol, neomycin, rifaximin, and met-

ronidazole[17,18,3336].

Lactulose

For many years, lactulose was the only pharmacologic agent available to

treat HE [1,35,3750]. This nonabsorbable dissacharide is administered

orally at initial dosages of 30 mL two to four times daily. This therapy

should induce mild diarrhea, with three to five semisolid bowel movements

daily. Some patients achieve this goal with small dosages, whereas others re-

quire large amounts of lactulose. Oral lactulose is helpful for the outpatient

who requires maintenance therapy for chronic or recurrent HE, and forthe inpatient with episodic HE. In this latter instance, lactulose is used in

conjunction with correction of the precipitating factors. Lactulose is admin-

istered orally to patients with stage I or II encephalopathy. Oral administra-

tion may be hazardous in patients with stage III or IV HE because of the

risk of pulmonary aspiration. In patients with severely depressed conscious-

ness, lactulose is administered by a nasogastric tube. Lactulose cannot be

given orally in patients with suspected ileus, and is inadvisable in patients

with tense ascites. Patients with advanced HE are preferably administered

lactulose by colonic retention enemas (300 mL of lactulose plus 700 mLof tap water) [45]. The amount of lactulose administered by enemas is

much greater than that administered orally or by nasogastric tube. Admin-

istration by enemas causes less abdominal distention because of avoidance

of lactulose passage through the small bowel. Lactulose enemas may be

preferable for the patient who has stage III or IV encephalopathy, severe

ascites, spontaneous bacterial peritonitis, or is otherwise unable to have



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a nasogastric tube inserted. Some patients cannot retain the enemas for a suf-

ficient time because of incontinence.

Lactulose therapy has significant limitations, including a very sweet taste,increased intestinal gas production, abdominal distention and cramping,

and diarrhea [48,49]. These adverse events are common and often lead to

poor compliance in outpatients. Patients may skip dosages or take lactulose

sporadically. Inadequate compliance is the major limitation of lactulose

therapy.

Oral antibiotics

Inhibition of production of ammonia or other neurotoxins by intestinal

bacteria has promoted the use of antibiotics, such as neomycin, metronida-

zole, vancomycin, and rifaximin [37,40,41,5056]. The evidence for efficacy

of neomycin is ambiguous[50], however, and it entails some toxicity. Met-

ronidazole and oral vancomycin have been studied to a very limited extent.

Rifaximin, a nonabsorbable rifamycin antibiotic derivative, has been found

to be effective therapy in numerous clinical trials [52,54,55,5764]. It lacks

significant toxicity and side effects because of minimal gastrointestinal

absorption. Rifaximin has gained rapid acceptance as either first-line or as

adjunct therapy to lactulose. It has been evaluated primarily in comparison

with lactulose, but is often clinically used in combination with lactulose. The

number and length of hospitalizations for HE was significantly reduced after

treatment with rifaximin, compared with lactulose-treated patients in two

retrospective American studies [54,55]. A dose-effect study suggested that

1200 mg/day of rifaximin was superior to lower doses, but the difference

was marginal [61]. Rifaximin at somewhat lower doses is currently under

prospective evaluation in a large United States multicenter trial.

Dietary protein

Restriction of dietary protein to 40 g/day or less used to be advocated for

patients with HE because excessive dietary protein can precipitate HE. Pro-

longed protein restriction in HE, however, can exacerbate the catabolic state

of cirrhosis and cause release of amino acids and other nitrogenated by-

products from muscles. The current recommended protein diet for patients

with a history of HE is 0.8 to 1.5 g/kg/d. Patients admitted for a bout of

stage IIIIV HE often have low protein intake for the first several days of

hospitalization, primarily related to an inability to ingest meals. As soonas possible, they should resume a normal protein content in their diet by ei-

ther oral or enteral feedings[65]. Patients with chronic HE occasionally do

not tolerate normal amounts of dietary protein. A switch to vegetable pro-

tein[66]or supplementation with branched-chain amino acids may be con-

sidered in this situation[16,17]. Branched-chain amino acid preparations are

relatively expensive.

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Artificial liver support

Devices to temporarily replace critical hepatic functions could be useful

for HE. In irreversible acute or chronic liver failure, a liver-assist device

could stabilize the patient until a suitable liver donor becomes available

for urgent liver transplantation. The device could sustain a patient with

HE while correcting the precipitating factors. Several devices have been

analyzed during the last few decades. A bioartificial liver, consisting of car-

tridges packed with porcine hepatocytes, was recently evaluated for acute

liver failure [67]. This trial demonstrated no benefits in survival or in the

neurologic status [67]. A large, multicenter, randomized controlled trial

compared the molecular absorbent recirculating system (MARS), a variant

of extracorporeal albumin dialysis, plus standard medical therapy (lactulose

plus neomycin or metronidazole) for 5 days versus standard medical therapy

alone in patients with stage III or IV HE[68]. MARS therapy produced sig-

nificantly more rapid and frequent improvement in HE, but the study was

not blinded [68]. Other trials have shown discrepant effects of MARS on

survival in acute-on-chronic liver disease. Given the complexity and cost

of MARS, more evaluation is necessary before this modality can be clini-

cally advocated. New artificial support systems, such as the selective plasma

hemofiltration, have shown promising preliminary results in HE and are un-

dergoing large clinical trials[69].

Chronic therapy

Patients with persistent or chronic HE should be carefully evaluated for

persistent or intermittent, low-grade gastrointestinal bleeding, including

bleeding from portal hypertensive gastropathy or colopathy. Frequent die-

tary ingestion of more than 1.5 g/kg of protein per day may cause persistent

or chronic HE. Consultation with a dietician for dietary evaluation andcounseling concerning the limits and types of dietary protein intake, is nec-

essary in HE patients. Without identifiable precipitating factors, persistent

HE related to deteriorating liver function or after TIPS may require chronic

therapy with lactulose or the nonabsorbable antibiotic rifaximin to suppress

HE. The modest effects of lactulose therapy on HE were first described sev-

eral decades ago[1,35,3750]. Long-term compliance with lactulose is poor,

and patients often take it intermittently. Lactulose and nonabsorbable anti-

biotics act synergistically, and the combination may permit reducing the

dosages of each agent. Chronic antibiotic administration can lead to bacte-rial resistance, bacterial overgrowth, and fungal colonization. It is unknown

whether chronic therapy with nonabsorbable antibiotics for persistent or

chronic HE should be continuous or cyclic to minimize the potential for re-

sistance or fungal overgrowth [59]. Chronic neomycin administration can

cause otovestibular toxicity because of the small, but significant, gastrointes-

tinal absorption of this aminoglycoside.



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Hepatic encephalopathy, cerebral edema, and increased intracranial

pressure in liver failure

Patients with cirrhosis and HE rarely develop cerebral edema that leads

to elevated intracranial pressure. A few case reports have described cerebral

edema in cirrhosis[11,12], but a review of the data suggests that other causes

for cerebral edema, such as hypoxic injury or seizures, had not been com-

pletely excluded. Autopsy studies in patients who expired from complica-

tions of cirrhosis, including HE, rarely show significant cerebral edema.

Conversely, cerebral edema is a common finding at autopsy of patients

who died from acute liver failure (formerly known as fulminant hepatitis).

Nevertheless, studies using sensitive techniques, such as MRI spectroscopy,

have reported increased water content in the cirrhotic brain[13]. This find-

ing suggests that subclinical neuronal or astrocytic edema could have a path-

ogenic role in chronic HE. The current evidence does not support placement

of intracranial pressure transducers in cirrhotic patients who develop HE.

The situation is different in patients with acute (fulminant) liver failure

who develop stage III or IV HE. Given the high frequency of significant

cerebral edema in this setting, with an attendant risk of uncal herniation,

these patients are candidates for the placement of an intracranial pressure

transducer[6]. An intracranial pressure transducer is often required to diag-

nose intracranial hypertension because a head CT scan is relatively insensi-

tive to detection of early cerebral edema in acute liver failure[70].

If the initial intracranial pressure reading is normal, the encephalopathy

could be ascribed to metabolic encephalopathy of liver failure (HE), and

therapy should be directed at lowering the serum ammonia level. If, how-

ever, the opening intracranial pressure is greater than 10 mm Hg, the hepatic

coma may be caused by the cerebral edema. In this situation, the therapy

consists primarily of mannitol, mild hypothermia, and barbiturate infusion

in refractory cases [6]. Ammonia seems to play a role in swelling of astro-

cytes by incorporation into glutamine [17,18,20], but vascular reactivity,

cerebral perfusion, and other humoral factors are also important in

the pathogenesis of intracranial hypertension in fulminant hepatitis.

The identification of the role of hyperammonemia in the intracranial hyper-

tension of acute liver failure has provided a rationale for administration of

ammonia-lowering therapy, including lactulose or nonabsorbable antibi-

otics in this setting. The latter agents are preferred because lactulose may

produce large amounts of gas in the small bowel, which can cause difficulties

with abdominal closure during liver transplantation.

Hepatic encephalopathy after transjugular intrahepatic

porto-systemic shunt

The introduction of TIPS represented a major advance in the manage-

ment of refractory ascites or esophagogastric variceal hemorrhage

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unresponsive to pharmacologic or endoscopic therapy [7173]. From 20%

to 77% of patients receiving TIPS develop HE, with the rate of HE depen-

dent on the patients residual liver function [7173]. The severity of HEafter TIPS is variable and ranges from HE easily controlled with antibiotics

or dissacharides to chronic HE that is refractory to combination therapy.

In general, stage II or higher HE is a contraindication to TIPS therapy. Oc-

casionally, however, TIPS must be performed as life-saving therapy for in-

dications, such as uncontrollable variceal bleeding, regardless of a history

of HE.

TIPS is also increasingly performed for ascites refractory to diuretics

[71,72]. A recent large meta-analysis found that TIPS may, in fact, be supe-

rior to large-volume paracentesis[74]. TIPS is certainly not urgent for asci-tes, and paracentesis often offers a reasonable alternative therapy. A history

of stage II or higher HE constitutes a relative contraindication for TIPS

therapy for ascites. Insertion of TIPS in patients with Child-Pugh class C

cirrhosis can lead to further hepatic decompensation, resulting in acute liver

failure, severe HE, and even cerebral swelling[12]. Clinical trials of TIPS for

ascites generally excluded patients with Child-Pugh class C with total serum

bilirubin level O 5 mg/dL, or with stage II or higher HE. These criteria

should also be used in clinical practice. Salerno and colleagues[74]recently

showed that the following features independently predicted onset of HE af-ter TIPS: age greater than 60 years; low mean arterial blood pressure; high

MELD score; and a low post-TIPS porto-systemic pressure gradient (from

a widely open stent). These factors must, therefore, be considered when con-

templating TIPS installation for refractory ascites.

Prophylactic therapy with lactulose or antibiotics after insertion of TIPS

is not recommended except for a patient prone to HE who has been rescued

from uncontrollable variceal hemorrhage by urgent TIPS[75]. Patients may

experience a few episodes of HE within the first few months after TIPS.

Standard therapy with nonabsorbable antibiotics (with or without lactulose)often produces a satisfactory outcome. Intentional narrowing or therapeutic

occlusion of the TIPS stent rarely becomes necessary when patients develop

severe and intractable HE after TIPS[76].

Liver transplantation

Episodic or persistent HE in a patient who has cirrhosis constitutes a clin-

ical indication for liver transplant evaluation based on the lower survival

associated with the onset of HE [3]. When the precipitating factor is fullytreated and the underlying liver function is well preserved (ie, Childs-Pugh

class A patients), the option of liver transplantation may be deferred and

the patient can be expectantly monitored. Some patients may develop dis-

abling and recurrent HE, however, even with a low MELD score. The

low probability of receiving a liver donor for transplantation is problematic

for this patient. Although the MELD score prediction of 3-month survival



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was not affected by the presence or absence of HE[77], this model was tested

using crude, single-center data from a transplant database [77]. Detailed

analysis of the effect of the subtypes of HE (severe, disabling, chronic, orrecurrent versus precipitated, self-limited, and episodic) on the predictive

accuracy of MELD score for survival is necessary because cirrhotic patients

who develop severe HE have poor survival, even with a fairly low MELD

score[78,79].

Other therapies

Other agents are potentially useful for HE. The ketoanalogues of the

branched-chain amino acids (ketoleucine, ketoisocaproate, and ketovaline)could reduce the ammonia pool by amination to the corresponding amino

acids, while increasing precursors for protein synthesis and inhibiting

protein breakdown [80,81]. Following amination, the ketoanalogues can

be effectively incorporated into biologically important proteins [81]. Some

clinical studies have indeed shown benefit for HE, but these molecules

have not been further developed because of poor palatability[82]. Supple-

ments with branched-chain amino acids have been extensively investigated

as potential therapy for HE without proof of efficacy, and branched-chain

amino acid is currently rarely used[17,18]. Benzoate may be useful as an am-monia scavenger to treat HE[83,84]. It is approved as an ammonia-reducing

agent for urea cycle enzyme deficiency syndromes. It is currently under eval-

uation as therapy for HE. Opioid and benzodiazepine antagonists, such as

naloxone and flumazenil, have been proposed as potential therapies for

HE, but have too short-lived effects to be clinically useful[85].

Summary

HE is a common and severe complication of chronic or acute liver failure.

Identification and correction of precipitating factors remains the corner-

stone of HE therapy. Adjuvant use of nonabsorbable antibiotics and disac-

charides, such as rifaximin and lactulose, alone or in combination, help

expedite recovery from HE. Liver transplantation is often the most success-

ful long-term therapy for HE.

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