INTRODUCTION — Hepatic encephalopathy describes a spectrum of potentially reversible neuropsychiatric abnormalities seen in patients with liver dysfunction and/or portosystemic shunting. Overt hepatic encephalopathy develops in 30 to 45 percent of patients with cirrhosis and in 10 to 50 percent of patients with transjugular intrahepatic portal-systemic shunts [1,2]. The International Society for Hepatic Encephalopathy and Nitrogen Metabolism consensus defines the onset of disorientation or asterixis as the onset of overt hepatic encephalopathy [3]. Some patients with hepatic encephalopathy have subtle findings that may only be detected using specialized tests, a condition known as minimal hepatic encephalopathy [4-6]. Minimal hepatic encephalopathy is seen in up to 80 percent of patients with cirrhosis [7-13].
Hepatic encephalopathy is often easy to detect in patients presenting with overt neuropsychiatric symptoms. It may be more difficult to detect in patients with chronic liver diseases who have mild signs of altered brain function, particularly if the underlying cause of the liver disease may be associated with neurologic manifestations (such as alcoholic liver disease or Wilson disease).
This topic will review the clinical manifestations and diagnosis of hepatic encephalopathy in adults. The pathogenesis and treatment of hepatic encephalopathy are discussed elsewhere. (See "Hepatic encephalopathy: Pathogenesis" and "Hepatic encephalopathy in adults: Treatment".)
CATEGORIZATION AND GRADING — Hepatic encephalopathy is categorized based on four factors: the underlying disease, the severity of manifestations, the time course, and whether precipitating factors are present (figure 1) [14-16].
●Underlying disease: A classification scheme based on the underlying disease has been proposed [14,15]:
•Type A: hepatic encephalopathy occurring in the setting of acute liver failure
•Type B: hepatic encephalopathy occurring in the setting of portal-systemic bypass with no intrinsic hepatocellular disease
•Type C: hepatic encephalopathy occurring in the setting of cirrhosis with portal hypertension or systemic shunting
●Severity of manifestations: The severity of hepatic encephalopathy is graded based on the clinical manifestations (table 1 and figure 2) [16] (see 'Clinical manifestations' below):
•Minimal: Abnormal results on psychometric or neurophysiological testing without clinical manifestations (see 'Psychometric tests' below)
•Grade I: Changes in behavior, mild confusion, slurred speech, disordered sleep
•Grade II: Lethargy, moderate confusion
•Grade III: Marked confusion (stupor), incoherent speech, sleeping but arousable
•Grade IV: Coma, unresponsive to pain
Patients with grade I encephalopathy may have mild asterixis, whereas pronounced asterixis is seen in patients with grade II or III encephalopathy [17]. Asterixis is typically absent in patients with grade IV encephalopathy, who instead may demonstrate decorticate or decerebrate posturing.
Patients with minimal or grade I hepatic encephalopathy are described as having covert hepatic encephalopathy, whereas patients with grade II to IV hepatic encephalopathy are described as having overt hepatic encephalopathy. The separation of minimal hepatic encephalopathy from grade I hepatic encephalopathy is important for clinical studies.
●Time course: The time course for hepatic encephalopathy can be episodic, recurrent (bouts of hepatic encephalopathy that occur within a time interval of six months or less), or persistent (a pattern of behavioral alterations that are always present, interspersed with episodes of overt hepatic encephalopathy).
●Precipitating factors: Episodes of hepatic encephalopathy are described as being either nonprecipitated or precipitated. If precipitated, the precipitating factors should be specified (table 2). (See 'Evaluation for precipitating causes' below.)
CLINICAL MANIFESTATIONS — Hepatic encephalopathy is characterized by cognitive deficits and impaired neuromuscular function (figure 2 and figure 3). Patients with minimal hepatic encephalopathy have subtle cognitive deficits, often appear to be asymptomatic, and may only be detected with psychomotor or electrophysiologic testing. Patients with overt hepatic encephalopathy have signs and symptoms that can be detected clinically, without the use of psychomotor testing (though psychomotor testing may be helpful in evaluating patients with mild encephalopathy).
In addition to the clinical manifestations of hepatic encephalopathy, patients frequently have clinical manifestations of chronic liver disease.
Signs and symptoms — Cognitive findings in patients with hepatic encephalopathy vary from subtle deficits that are not apparent without specialized testing (minimal hepatic encephalopathy), to more overt findings, with impairments in attention, reaction time, and working memory (figure 2 and figure 3) [18]. Patients with severe hepatic encephalopathy may progress to hepatic coma.
Disturbances in the diurnal sleep pattern (insomnia and hypersomnia) are common initial manifestations of hepatic encephalopathy and typically precede other mental status changes or neuromuscular symptoms. As hepatic encephalopathy progresses, patients may develop mood changes (euphoria or depression), disorientation, inappropriate behavior, somnolence, confusion, and unconsciousness.
Neuromuscular impairment in patients with overt hepatic encephalopathy includes bradykinesia, asterixis (flapping motions of outstretched, dorsiflexed hands), slurred speech, ataxia, hyperactive deep tendon reflexes, and nystagmus. Less commonly, patients develop loss of reflexes, transient decerebrate posturing, and coma.
Focal neurologic deficits may also be present. In a report of 32 patients who had 46 episodes of hepatic encephalopathy, a focal neurologic sign was detected in eight patients (17 percent of the episodes) [19]. The most common was hemiplegia. None of the patients with focal neurologic signs had abnormal findings on computed tomography scan or cerebrospinal fluid examination. Cerebral magnetic resonance imaging was performed in five of the eight patients and was normal in all five. Similarly, five patients with focal neurologic signs underwent Doppler ultrasound of the neck and vessels. In all five, the Doppler imaging was normal. The focal neurologic deficits resolved completely in seven of eight surviving patients after six months of follow-up.
Patients with hepatic encephalopathy usually have advanced chronic liver disease and thus have many of the physical stigmata associated with severe hepatic dysfunction. Physical findings may include muscle wasting, jaundice, ascites, palmar erythema, edema, spider telangiectasias, and fetor hepaticus. Some of these findings (such as muscle wasting, spider telangiectasias, and palmar erythema) are usually absent in previously healthy patients with acute hepatic failure since their development requires a relatively longer period of hepatic dysfunction. (See "Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis", section on 'Clinical manifestations' and "Acute liver failure in adults: Etiology, clinical manifestations, and diagnosis".)
Sarcopenia is a syndrome of decreased muscle mass, strength, and function that has been identified as a risk factor for hepatic encephalopathy, and this is possibly related to impaired detoxification of ammonia [20]. In a meta-analysis of five studies including 1713 patients with cirrhosis, sarcopenia was associated with higher risk of mild and overt hepatic encephalopathy compared with no sarcopenia (pooled odds ratio [OR] 3.34, 95% CI 1.68-6.67 and OR 2.05, 95% CI 1.28-3.29, respectively) [21].
Laboratory abnormalities — Laboratory abnormalities in patients with hepatic encephalopathy may include elevated arterial and venous ammonia concentrations. In addition, patients typically have abnormal liver biochemical and synthetic function tests due to underlying liver disease. Patients may also have electrolyte disturbances (such as hyponatremia and hypokalemia) related to hepatic dysfunction and/or diuretic use. (See 'Ammonia' below and "Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis", section on 'Laboratory findings'.)
DIAGNOSIS — The approach to the diagnosis of hepatic encephalopathy includes:
●A history and physical examination to detect the cognitive and neuromuscular impairments that characterize hepatic encephalopathy.
●Exclusion of other causes of mental status changes (see 'Differential diagnosis' below).
•Serum laboratory testing to rule out metabolic abnormalities.
•A computed tomography (CT) scan of the brain if the clinical findings suggest another cause for the patient's findings may be present (such as a subdural hematoma from trauma); a CT scan may also demonstrate cerebral edema (found in 80 percent of patients with acute hepatic encephalopathy) (see "Acute toxic-metabolic encephalopathy in adults", section on 'Hepatic encephalopathy').
●Evaluation for possible precipitating causes of the hepatic encephalopathy (see 'Evaluation for precipitating causes' below).
While arterial and venous ammonia concentrations are often elevated in patients with hepatic encephalopathy, an elevated ammonia level is not required to make the diagnosis. In addition, elevated ammonia levels may be seen in patients who do not have hepatic encephalopathy (table 3).
For patients with mild degrees of hepatic encephalopathy (minimal hepatic encephalopathy or grade I encephalopathy) in whom the diagnosis is unclear, psychometric and electrophysiologic tests may be helpful. In such patients, our approach is to first to ask about subtle signs of impaired mental status, and if signs point to the possible presence of minimal hepatic encephalopathy to perform psychometric testing (typically the number connection test) (algorithm 1). An alternative but less sensitive test is the Mini-Mental State Examination (MMSE). (See "The mental status examination in adults", section on 'Cognitive screening tests'.)
For patients with more severe hepatic encephalopathy (grades III and IV), the Glasgow Coma Scale may be useful for further stratifying the severity of neurologic impairment (figure 2) [22]. (See 'Psychometric tests' below and 'Electrophysiologic tests' below and 'Clinical manifestations' above.)
History and physical examination — The evaluation should start by inquiring about mental status changes, keeping in mind that in patients with minimal hepatic encephalopathy the signs may be subtle. Patients should be asked about changes in their sleep patterns and in cognitive capacity (decreased attention span, impaired short term memory) leading to difficulties with normal daily activities. Patients should also be asked about impaired work performance and work- or driving-related accidents. Patients should also be examined for signs of neuromuscular dysfunction. (See 'Clinical manifestations' above.)
Laboratory tests — Ammonia is the best characterized neurotoxin that precipitates hepatic encephalopathy. However, an elevated serum ammonia concentration is not required to make the diagnosis and is not specific for hepatic encephalopathy. In addition, ammonia levels are influenced by factors such as how the blood sample is obtained and handled. Serum ammonia levels should not be used to screen for hepatic encephalopathy in patients who are asymptomatic or who have mental status changes in the absence of liver disease or a portal-systemic shunt.
Other routine laboratory tests should be obtained to exclude other causes of mental status changes (eg, hypoglycemia, uremia, electrolyte disturbances, and intoxication) and to look for conditions that may have precipitated the hepatic encephalopathy. (See 'Differential diagnosis' below and 'Evaluation for precipitating causes' below.)
Ammonia — The gastrointestinal tract is the primary source of ammonia, which enters the circulation via the portal vein. Ammonia is produced by enterocytes from glutamine and by colonic bacterial catabolism of nitrogenous sources, such as ingested protein and secreted urea. The intact liver clears almost all of the portal vein ammonia, converting it into urea or glutamine and preventing entry into the systemic circulation. The increase in blood ammonia levels in advanced liver disease is a consequence of impaired liver function and of shunting of blood around the liver. Muscle wasting, a common occurrence in these patients, also may contribute since muscle is an important site for extrahepatic ammonia removal.
Whether to measure the serum ammonia concentration in patients suspected of having hepatic encephalopathy remains controversial. While the venous and arterial ammonia levels correlate with the severity of hepatic encephalopathy, levels are inconsistently elevated [23,24]. Measuring serum ammonia levels may be useful under certain conditions (eg, monitoring efficacy of ammonia lowering therapy), but is not required to make the diagnosis of hepatic encephalopathy or for the long-term follow-up of patients with advanced liver disease. The accuracy of ammonia determination is influenced by many factors (such as fist clenching, use of a tourniquet, and whether the sample was placed on ice). These factors should be considered when interpreting results. Furthermore, ammonia levels can be elevated in a variety of nonhepatic conditions (table 3).
Venous ammonia concentration is not useful for screening for hepatic encephalopathy since levels vary [25]. In addition, hepatic encephalopathy is only directly related to ammonia levels up to about a twofold increase above normal. Any further increase of ammonia concentration does not contribute to the further evolution of hepatic encephalopathy [26].
As with the venous ammonia concentration, hepatic encephalopathy is only directly related to arterial ammonia concentration up to about a twofold increase above normal. Furthermore, the grade of hepatic encephalopathy is more closely related to the partial pressure of gaseous ammonia (pNH3) than the total arterial ammonia concentration, since gaseous ammonia readily enters the brain [26]. The pNH3 can be calculated from the total ammonia and pH [27], though this is rarely done outside of clinical studies. (See "Hepatic encephalopathy: Pathogenesis".)
Postprandial ammonia levels may be more closely related to minimal hepatic encephalopathy than fasting levels. Thus, in clinical trials, ammonia is often measured after a standard meal (or glutamine load) [28]. In one study, induced hyperammonemia was associated with a significant increase in daytime subjective sleepiness and changes in the electroencephalogram (EEG) architecture of a subsequent sleep episode in patients with cirrhosis [29].
Other potential markers — Serum levels of 3-nitrotyrosine may be elevated in patients with minimal hepatic encephalopathy. One study found that using a cutoff of 14 nM, 3-nitrotyrosine was 93 percent sensitive and 89 percent specific for detecting minimal hepatic encephalopathy [30].
Psychometric tests — Commonly performed bedside tests are insufficiently sensitive to detect subtle changes in mental function. As a result, several psychometric tests have been evaluated that quantify the impairment of mental function in patients with mild stages of hepatic encephalopathy [4,31-34]. These tests are more sensitive for the detection of minor deficits of mental function than conventional clinical assessment or an EEG [31]. Several psychometric tests have been developed, but none is used routinely in clinical practice. Our approach is to use the number connection test if signs point to the possible presence of minimal hepatic encephalopathy.
The use of psychometric tests is limited because many are cumbersome and time consuming (up to two hours per session), their reliability is decreased by a learning effect when they are applied repeatedly, and there is poor correlation among the tests [35,36]. Another issue with psychometric tests is that they are nonspecific (ie, they cannot differentiate among multiple underlying conditions that may lead to similar test results) [37]. This is a particular problem in patients with alcoholic liver disease or Wilson disease since both are associated with central nervous system abnormalities.
Number connection test (Reitan Test) — The most frequently used psychometric test is the number connection test (NCT or Reitan Test), which is easily administered and interpreted (figure 4 and figure 5) [32,33,38]. The NCT is a timed connect-the-numbers test. Patients without hepatic encephalopathy should finish the test in a number of seconds less than or equal to their age in years. In other words, if a patient is 50 years old, he should be able to finish the test in ≤50 seconds.
The test traditionally has two parts, but often only the first part of the test (figure 4) is used because the second part (figure 5) can be confusing and often does not add additional clinical information.
Psychometric Hepatic Encephalopathy Score (PHES) — In an attempt to improve the performance of testing for minimal hepatic encephalopathy, a battery of five paper and pencil tests were combined into a new instrument, the Psychometric Hepatic Encephalopathy Score (PHES) [39]. The PHES includes a line tracing test, digit symbol test, serial dotting test, and both parts of the NCT. It examines visual perception, visuospatial orientation, visual construction, motor speed and accuracy, concentration, attention, and memory. The test can be performed in 10 to 20 minutes at the bedside. Possible scores range from -18 to +6 points.
In one study, when a cutoff of ≤-4 points was used, the test had a high sensitivity and specificity for detecting mild hepatic encephalopathy [39]. A simplified version of the test consisting only of the digit symbol, serial dotting, and line tracing tests was found to be as accurate as the full PHES test [40]. However, a study comparing the PHES test with an EEG in 100 patients with cirrhosis found agreement in detection of minimal hepatic encephalopathy in only 73 percent of patients [41]. The poor correlation may reflect differences in how these tests detect various features of minimal hepatic encephalopathy.
The PHES test has been recommended by a panel of international experts for the neuropsychological assessment of early hepatic encephalopathy, though in practice it is rarely used [14].
Other psychometric tests — More complex tests continue to be used for clinical studies, which often include multiple tests that measure different brain functions (such as memory, motor performance, attention, etc). The interpretation of the tests often requires a trained psychologist and sophisticated statistical methods [42].
●The Inhibitory Control Test (ICT) is a computerized test of attention and response inhibition that has been used to characterize attention deficit disorder, schizophrenia, and traumatic brain injury. The subject is instructed only to respond to two alternating letters (X/Y) (called "targets") and not to respond when they are not alternating (called "lures"). Lower lure responses, higher target responses, and shorter lure and target reaction times indicate good psychometric performance.
A study comparing ICT to a psychometric battery of tests in 136 patients estimated its sensitivity for minimal hepatic encephalopathy to be 88 percent [43]. Patients with minimal hepatic encephalopathy had significantly higher ICT lures and lower targets compared with patients without minimal hepatic encephalopathy. Another study comparing ICT with other diagnostic standards found that ICT was not useful for diagnosis of minimal hepatic encephalopathy unless results were adjusted by target accuracy (a measure reflecting the total number of correct responses from a set of presented targets, such as specific letters in a string of other letters) [44].
●Computerized testing that measures neurocognitive functions (eg, the Cognitive Drug Research [CDR] battery) is an alternative to paper and pencil based testing (such at the PHES). It does not rely as heavily on the motor function of the patient for completion. The CDR battery was compared with the PHES in 89 patients with cirrhosis [45]. There was a high correlation between the two assessment methods. The Model for End-stage Liver Disease score correlated with PHES, whereas venous ammonia concentrations correlated with the CDR domains of Continuity of Attention and Quality of Episodic Memory. There were marked deteriorations in the CDR composite scores representing Accuracy of Working and Episodic Memory after amino acid challenge to increase blood ammonia concentrations. Both PHES and CDR returned to the control range after liver transplantation.
●The Stroop task is a test of psychomotor speed and cognitive flexibility that evaluates the functioning of the anterior attention system and is sensitive for the detection of cognitive impairment in minimal hepatic encephalopathy [46]. The task has two components: "off" and "on" states depending on the discordance or concordance of stimuli. This test is available as an application for smart phones (EncephalApp Stroop) and can be administered in a few minutes.
●The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) measures a wide range of neurocognitive functions relevant to minimal hepatic encephalopathy. The test has been used in multiple clinical trials in the United States for a variety of neurologic disorders and in patients with advanced cirrhosis [47]. The RBANS has not yet been compared directly with the PHES, and its responsiveness to hepatic encephalopathy treatment is unknown.
●Another useful test is the measurement of reaction times to auditory and visual stimuli [48,49]. The equipment is inexpensive, and the time to perform it is reasonably short. It can be applied repeatedly since it is not affected by learning effects.
●Other emerging diagnostic strategies concentrate on computerized tests and batteries such as the Scan test, a three-level-difficulty computerized reaction time test [50], central nervous system (CNS) vital signs [51], and Immediate Post-concussion Assessment and Cognitive Testing (ImPACT) [52]. A simple test using a smartphone-based application may be a useful tool for repeated assessment of minimal hepatic encephalopathy [46].
Electrophysiologic tests — Electrophysiologic tests to detect minimal hepatic encephalopathy include EEG monitoring, evoked potentials, and critical flicker frequency testing. However, none of these tests is widely used.
Electroencephalogram activity — The evolving EEG changes associated with increasingly severe hepatic encephalopathy consist initially of a bilaterally synchronous decrease in wave frequency and an increase in wave amplitude, associated with the disappearance of a readily discernible normal alpha-rhythm (8 to 13 cps). The simplest EEG assessment of hepatic encephalopathy is grading the degree of abnormality of the conventional EEG tracing. A more refined assessment can be accomplished with computer-assisted spectral analysis of the EEG, which permits variables in the EEG (such as the mean dominant EEG frequency and the power of a particular EEG rhythm) to be quantified. Minor changes in the dominant EEG frequency occur in mild hepatic encephalopathy. Spectral EEG analysis may improve the assessment of mild hepatic encephalopathy by decreasing inter-operator variability and providing reliable parameters correlated with mental status [53].
The bispectral index (BIS) monitor is a rapid bedside tool to monitor EEG activity. In a prospective study, BIS monitoring was useful for grading and monitoring the degree of involvement of the central nervous system in patients with chronic liver disease and to classify the degree and progression of hepatic encephalopathy [54].
Evoked potentials — Evoked potentials are externally recorded electrical signals that reflect synchronous volleys of discharges through neuronal networks in response to various afferent stimuli. They are categorized as visual, somatosensory, or acoustic, depending on the type of stimulus [55]. A more sophisticated form of evoked responses is event-related responses, which require some form of intellectual function. A typical event-related response is the P300 peak after auditory stimuli. The P300 is extremely sensitive for detecting subtle changes of brain function and can be used to diagnose minimal hepatic encephalopathy [56].
Critical flicker frequency — Retinal glial cells are involved in ammonia detoxification by glutamine synthesis. In patients with liver failure, they exhibit morphological changes similar to those observed in brain astrocytes, suggesting that retinal gliopathy could serve as a marker of cerebral gliopathy in patients with hepatic encephalopathy. These observations provided the rationale for the development of a visual test (the critical flicker/fusion frequency) for determining whether hepatic encephalopathy is present. Advantages of the test are that it is objective and it is not affected by the patient's age or education/literacy level [57-59]. However, a meta-analysis suggests that it is only moderately sensitive for detecting minimal hepatic encephalopathy. The meta-analysis included nine studies with 622 patients and found that critical flicker frequency had a sensitivity for detecting minimal hepatic encephalopathy of 61 percent and a specificity of 79 percent [60].
In an analysis of patients with cirrhosis and controls, critical flicker frequency differentiated patients with overt hepatic encephalopathy from those without hepatic encephalopathy. PHES testing, critical flicker frequency, and a combination of PHES and critical flicker frequency could not reliably distinguish patients with minimal hepatic encephalopathy from controls or those with overt hepatic encephalopathy [61].
Radiologic imaging — Radiologic imaging is primarily used to exclude other causes of mental status changes. We typically obtain a noncontrast head CT scan when the clinical findings suggest that another cause for the patient's mental status changes may be present (such as a subdural hematoma from trauma).
Computed tomography and magnetic resonance imaging of the brain — A noncontrast CT scan is indicated in patients with overt hepatic encephalopathy in whom the diagnosis is uncertain, to exclude other diseases associated with coma or confusion. A CT scan may also reveal generalized or localized cerebral edema, suggesting a diagnosis of hepatic encephalopathy.
Magnetic resonance imaging — Magnetic resonance imaging (MRI) is superior to CT for the diagnosis of brain edema in liver failure, but it is not an established method for diagnosing hepatic encephalopathy. Changes have been observed on T1-weighted images with a strong signal in the basal ganglia in patients with hepatic encephalopathy, possibly due to manganese accumulation [62]. However, these changes are neither sensitive nor specific indicators of hepatic encephalopathy [63,64].
Magnetic resonance spectroscopy and positron emission tomography — In vivo magnetic resonance spectroscopy (MRS) is a noninvasive method that is being studied but is not yet in routine clinical use. It permits serial measurement of various neurometabolites in the brain using a variety of isotopes, such as (1)H, (32)P, and (12)C. Proton (1H) MRS assesses regional brain concentrations of choline, creatine (Cr), glutamine/glutamate (Glx), myoinositol, and N-acetyl aspartate, depending on the spectral sequence used. (1H) MRS has tremendous potential for the future, particularly for documenting treatment effects [65].
Patients with hepatic encephalopathy should display an increase in Glx resonance since ammonia is detoxified in astrocytes to glutamine by glutamine synthetase. Several studies have assessed changes in Glx/Cr in patients with different stages of hepatic encephalopathy [66-69]. Some have shown significant direct correlation between the severity of hepatic encephalopathy and Glx/Cr [66,67], whereas others have not [68,69]. In other studies, findings on MRI and MRS correlated with abnormalities in the basal ganglia and presence of Parkinsonian signs in patients with cirrhosis [70].
Another pertinent observation is that the increase in brain glutamine during hepatic encephalopathy (represented in MRS by increased Glx) increases intracellular osmolality. To maintain osmotic equilibrium, the astrocytes lose osmolytes such as myoinositol (mI). The mI/Cr ratio is significantly reduced in patients with hepatic encephalopathy, suggesting that an imbalance in the astrocytic osmotic equilibrium may contribute to the pathogenesis of hepatic encephalopathy [68,69]. (See "Hepatic encephalopathy: Pathogenesis".)
Microstructural white matter changes in the brain can be detected using voxel-based diffusion tensor imaging analysis during MRS. The test is based upon calculating indices for an apparent diffusion coefficient (ADC) and fractional anisotropy (FA). One study showed widespread brain regions with increased brain mean diffusion values, indicating enhanced water content and decreased FA in patients with hepatic encephalopathy [71]. The brain mean ADC and FA values from selected regions correlated with the neuropsychological scores.
The variability among the results of proton MRS studies may be due to differences in the patient populations studied (eg, sample size, severity of hepatic encephalopathy, age, and cause of liver failure), differences in techniques, and the methods used in the diagnosis of hepatic encephalopathy.
Another method, T1 mapping with partial inversion recovery (TAPIR), has been used to obtain a series of T1-weighted images to produce T1 maps. In one report using this technique, imaging of 15 control subjects and 11 patients was performed on a 1.5T MRI scanner [72]. The measurement time per patient with this technique, including adjustments, was approximately five minutes. T1 changes in the brains of patients with hepatic encephalopathy were determined quantitatively with TAPIR in short, clinically relevant measurement times. Significant correlations between the change in T1 and hepatic encephalopathy severity were shown in the globus pallidus, the caudate nucleus, and the posterior limb of the internal capsule.
Cerebral glucose metabolism is considered to be a marker for brain function and thus should correlate with cerebral ammonia metabolism in patients with hepatic encephalopathy. A study evaluated this hypothesis by correlating plasma and cerebral ammonia metabolism with the results of (13)N-ammonia and (18)F-fluorodeoxyglucose positron emission tomography in 21 patients with cirrhosis and no hepatic encephalopathy or grade I hepatic encephalopathy [73]. A correlation between MRS with plasma and cerebral ammonia metabolism could be demonstrated only in white matter. By contrast, MRS alterations correlated with glucose utilization in several brain regions. These data suggest that cerebral ammonia metabolism is important but not the only causal factor related to development of hepatic encephalopathy.
Evaluation for precipitating causes — There are several conditions that may precipitate an episode of hepatic encephalopathy in patients with liver disease or a portal-systemic shunt (table 2). These include [18,74-77]:
●Gastrointestinal bleeding
●Infection (including spontaneous bacterial peritonitis and urinary tract infections)
●Hypokalemia and/or metabolic alkalosis
●Renal failure
●Hypovolemia
●Hypoxia
●Sedatives or tranquilizers
●Hypoglycemia
●Constipation
●Rarely, hepatocellular carcinoma and/or vascular occlusion (hepatic vein or portal vein thrombosis)
Patients with hepatic encephalopathy should be evaluated for potential precipitating causes. This evaluation should include:
●A history to determine if the patient has been exposed to any medications or toxins (including alcohol)
●Physical examination to look for signs of gastrointestinal bleeding or hypovolemia (see "Approach to acute upper gastrointestinal bleeding in adults", section on 'Bleeding manifestations' and "Etiology, clinical manifestations, and diagnosis of volume depletion in adults", section on 'Clinical manifestations')
●A search for sources of infection with blood and urine cultures, as well as paracentesis for patients with ascites (see "Spontaneous bacterial peritonitis in adults: Diagnosis")
●Routine serum chemistries to look for metabolic and electrolyte abnormalities
●Serum alpha-fetoprotein (see "Clinical features and diagnosis of hepatocellular carcinoma", section on 'Alpha-fetoprotein')
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of patients presenting with mental status changes is long (table 4). While hepatic encephalopathy should be considered in patients with acute or chronic liver disease or a portal-systemic shunt, particularly those with a history of hepatic encephalopathy, other causes for the patient's confusion should be considered, such as a subdural hematoma, renal failure, or mental status changes associated with the patient's underlying liver disease (eg, Wilson disease).
A general approach to the evaluation of patients with delirium and confusional status is discussed elsewhere. (See "Diagnosis of delirium and confusional states".)
CAPACITY TO DRIVE — A concern in patients with minimal hepatic encephalopathy is whether they are at increased risk for driving accidents since declines in cognitive function in other populations (such as those with dementia) have been associated with such a risk [78]. Studies evaluating this question have reached disparate conclusions. The majority suggest that patients with minimal hepatic encephalopathy are at increased risk for accidents [4,79-83], though a pilot study of stable individuals with cirrhosis found that while 66 percent of the subjects had minimal hepatic encephalopathy, they did not exhibit major impairments in their fitness to drive [84].
Deciding when and how to evaluate the driving capacity of patients with cirrhosis is complex. Psychometric tests alone do not appear to be useful for assessing driving fitness. Several factors have to be considered [83]:
●The available data suggest that most patients with cirrhosis do not have minimal hepatic encephalopathy at any given time and do not have impaired driving capacity when measured under real life conditions.
●Optimal means to identify patients at risk for driving remain unclear.
●Legislation regarding reporting of individuals with impaired driving capacity varies by state in the United States, and by country elsewhere. Thus, it may not be possible to restrict driving based on the results of specific testing in all regions.
●How often patients should be reassessed for driving capacity is unclear.
The legal ramifications related to driving and hepatic encephalopathy remain poorly defined [85]. Until further data are available, we use the following approach [86]:
●It may be reasonable to restrict driving in patients with persistent hepatic encephalopathy associated with cirrhosis, particularly in those in whom their clinical course, physical examination, and reports from relatives suggest that they may be at increased risk of accidents.
●Neuropsychiatric testing to detect minimal hepatic encephalopathy is reasonable in centers where it is available, particularly in patients at increased risk, such as those with advanced cirrhosis (Child-Pugh Class B or C), large portal-systemic shunts (eg, transjugular intrahepatic portal-systemic shunt or surgery), alcoholic liver disease, or prior episodes of hepatic encephalopathy. However, the cost-effectiveness of this approach is unknown. Another option would be to have such patients undergo a driving test conducted by a trained examiner, but how such driving tests should be performed has not been standardized.
●A graded approach (such as restricting driving to short distances during daytime hours) may be adequate for patients with only mild neuropsychiatric impairment and good driving reports from relatives.
●Reassessment of patients at risk for progressive liver disease should be made on an individual basis.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cirrhosis" and "Society guideline links: Adult with altered mental status in the emergency department".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Hepatic encephalopathy (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Definition – Hepatic encephalopathy describes the spectrum of potentially reversible neuropsychiatric abnormalities seen in patients with liver dysfunction. (See 'Introduction' above.)
●Clinical manifestations – Hepatic encephalopathy is characterized by cognitive deficits and impaired neuromuscular function (figure 2 and figure 3). Cognitive findings in patients with hepatic encephalopathy vary from subtle deficits that are not apparent without specialized testing (minimal hepatic encephalopathy) to more overt findings, with impairments in attention, reaction time, and working memory. Patients with severe hepatic encephalopathy may progress to hepatic coma. Neuromuscular impairments include bradykinesia, hyperreflexia, rigidity, myoclonus, and asterixis. Disturbances in the diurnal sleep pattern (insomnia and hypersomnia) are common initial manifestations of hepatic encephalopathy and typically precede other mental status changes or neuromuscular symptoms. (See 'Clinical manifestations' above and 'Categorization and grading' above.)
●Diagnosis – The approach to the diagnosis of hepatic encephalopathy includes (algorithm 1) (see 'Diagnosis' above):
•A history and physical examination to detect the cognitive and neuromuscular impairments that characterize hepatic encephalopathy.
•Psychometric testing if minimal hepatic encephalopathy is suspected.
•Exclusion of other causes of mental status changes: Serum laboratory testing to rule out metabolic abnormalities, a computed tomography scan of the brain if the clinical findings suggest another cause for the patient's findings may be present (such as a subdural hematoma from trauma).
While arterial and venous ammonia concentrations are often elevated in patients with hepatic encephalopathy, an elevated ammonia level is not required to make the diagnosis. In addition, elevated ammonia levels may be seen in patients who do not have hepatic encephalopathy (table 3).
●Evaluation for precipitating causes – Patients with hepatic encephalopathy should be evaluated for potential precipitating causes (table 2). This evaluation should include (see 'Evaluation for precipitating causes' above):
•A history to determine if the patients have been exposed to any medications or toxins (including alcohol)
•Physical examination to look for signs of gastrointestinal bleeding or hypovolemia
•A search for sources of infection with blood and urine cultures, as well as paracentesis for patients with ascites
•Routine serum chemistries to look for metabolic and electrolyte abnormalities
•Serum alpha-fetoprotein
