Hepatic encephalopathy in adults: Clinical manifestations and diagnosis

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 (ISHEN) 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 previously known as subclinical hepatic encephalopathy. ISHEN suggested using the term covert hepatic encephalopathy to refer to subclinical and grade I overt hepatic encephalopathy because the distinction between these stages is difficult. [4-6].

Covert hepatic encephalopathy is seen in up to 80 percent of patients with cirrhosis, depending on the diagnostic tests utilized and the severity of the underlying disease [7-13]. Among patients with cirrhosis due to metabolic dysfunction-associated steatohepatitis (MASH), hepatic encephalopathy is the most common initial decompensating event [14].

Hepatic encephalopathy is often easy to detect in patients presenting with overt neuropsychiatric symptoms. It may be more difficult to detect in patients with cirrhosis 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 alcohol-associated liver disease or Wilson disease) or the patient has comorbid illness with neuropsychologic dysfunction (eg, depression, sleep apnea, or polypharmacy).

This topic will review the clinical manifestations and diagnosis of hepatic encephalopathy in adults with cirrhosis. The pathogenesis and treatment of hepatic encephalopathy are discussed elsewhere. (See "Hepatic encephalopathy in adults: Treatment".)

CATEGORIZATION AND GRADING — 

Hepatic encephalopathy is categorized based on several factors: the severity of manifestations, the time course, and whether precipitating factors are present [15].

●Severity of manifestations – The severity of hepatic encephalopathy is graded based on the clinical manifestations (table 1 and figure 1) [15] (see 'Clinical manifestations' below):

•Covert hepatic encephalopathy includes minimal hepatic encephalopathy (abnormal results on psychometric or neurophysiologic testing without clinical manifestations) (see 'Psychometric tests' below) and Grade I (changes in behavior, mild confusion, disordered sleep, slow speech)

•Grade II: Lethargy, moderate confusion, asterixis

•Grade III: Marked confusion (stupor), incoherent speech, sleeping but arousable

•Grade IV: Coma, unresponsive to pain

Asterixis is most pronounced in patients with grade II or III encephalopathy [16]. Asterixis is typically absent in patients with grade IV encephalopathy, who instead may demonstrate decorticate or decerebrate posturing.

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 may be useful 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 non-precipitated or precipitated. If precipitated, the precipitating factors should be specified (table 2). (See 'Evaluation for precipitating causes' below.)

PATHOGENESIS — 

The mechanisms causing hepatic encephalopathy in patients with decompensated cirrhosis remain incompletely understood. However, factors that have been implicated in the pathogenesis of hepatic encephalopathy include [17]:

●Inflammation – Systemic inflammation contributes to the development of hepatic encephalopathy by triggering a cascade of events that affect the central nervous system [18]. In patients with cirrhosis, the impaired liver fails to clear gut-derived toxins and inflammatory mediators from the bloodstream, which are then shunted from the portal to the systemic circulation through collateral vessels. Consequently, these substances accumulate and cross the blood-brain barrier, leading to neuroinflammation. This neuroinflammation increases the toxicity of ammonia and may disrupt neurotransmitter balance.  Ultimately, these processes culminate in cognitive impairment, altered consciousness, and the characteristic symptoms of hepatic encephalopathy. Therefore, interventions that reduce systemic inflammation may help manage and prevent the progression of this condition [19-21].  

●Elevated ammonia concentration – Ammonia is a known neurotoxin that precipitates hepatic encephalopathy. The gastrointestinal tract is the primary source of ammonia, which enters the circulation via the portal vein and is shunted around the liver via portosystemic collaterals. Ammonia is produced by enterocytes from glutamine and by colonic bacterial catabolism of nitrogenous sources, such as ingested protein and secreted urea. The normal liver clears almost all portal vein ammonia, converting it into glutamine and preventing entry into the systemic circulation. However, glutamine is metabolized in mitochondria yielding glutamate and ammonia, and glutamine-derived ammonia may interfere with mitochondrial function leading to astrocyte dysfunction [22].

Sarcopenia is a syndrome of decreased muscle mass, strength, and function that has been identified as a risk factor for hepatic encephalopathy [23]. Muscle wasting may also contribute to the risk of hepatic encephalopathy because muscle is an important site for extrahepatic ammonia removal. Ammonia metabolism by muscle consumes branch-chain amino acids. Thus, hyperammonemia both contributes to and is caused by sarcopenia. In addition, other muscle alterations such as myosteatosis have been associated with an increased risk of developing hepatic encephalopathy [24-26].

Finally, kidney ammoniagenesis can be a potent source of ammonia in response to volume depletion, hypokalemia, and increased kidney delivery of glutamine in the setting of gastrointestinal bleeding.

The kidneys play a crucial role in detoxifying ammonia in patients with cirrhosis. When the liver's capacity to convert ammonia into urea is impaired, the kidneys compensate by excreting ammonia directly into the urine. This kidney adaptation helps to reduce the levels of toxic ammonia in the bloodstream, thus mitigating the risk of hepatic encephalopathy. Additionally, the kidneys may increase the production of glutamine, which further aids in ammonia detoxification. However, in decompensated cirrhosis, kidney function often deteriorates, compromising this compensatory mechanism and exacerbating hyperammonemia.

●Glutaminase gene – Some patients appear to be predisposed to hepatic encephalopathy to a greater degree than others with similar severity of cirrhosis. The reasons for these differences in susceptibility are incompletely understood. One study suggested that variation in the glutaminase gene may be responsible [27]. Patients who had a variant of the promoter region of the glutaminase gene that was associated with increased enzyme activity appeared to have an increased risk of hepatic encephalopathy.

CLINICAL MANIFESTATIONS — 

Hepatic encephalopathy is characterized by cognitive deficits and impaired neuromuscular function (figure 1 and figure 2). 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 cirrhosis.

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 1 and figure 2) [28]. 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.

Patients with hepatic encephalopathy usually have decompensated cirrhosis and thus have many of the physical stigmata associated with severe liver 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 liver failure since their development requires a relatively longer period of liver 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".)

Laboratory abnormalities — Laboratory studies in some patients with hepatic encephalopathy may be normal, whereas other patients have elevated arterial and venous ammonia concentrations. However, the upper limits of normal for ammonia levels vary widely between laboratories.

Patients often have abnormal liver biochemical tests (such as higher bilirubin and lower albumin levels). Patients may also have electrolyte disturbances (such as hyponatremia and hypokalemia). (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:

•For patients with covert hepatic encephalopathy, similar manifestations may be seen with sleep apnea, depression, dementia, or sedating medication use (see 'Differential diagnosis' below)

•Serum laboratory testing to rule out metabolic abnormalities

•For patients with evidence of or a history of trauma (eg, a fall), for patients who were found down without a clear history, and for patients with focal neurologic signs, we obtain a noncontrast computed tomography (CT) scan of the brain to evaluate for intracranial hemorrhage (see "Acute toxic-metabolic encephalopathy in adults", section on 'Hepatic encephalopathy')

●Evaluation for precipitating causes of the hepatic encephalopathy (see 'Evaluation for precipitating causes' below)

While arterial and venous ammonia concentrations may be elevated in patients with hepatic encephalopathy, an elevated ammonia level is not required to make the diagnosis. In addition, patients with hepatic encephalopathy may have normal ammonia levels, and elevated ammonia levels may be seen in patients who do not have hepatic encephalopathy (table 3).

A diagnosis of covert hepatic encephalopathy is supported by abnormal psychometric testing, but it requires clinical assessment in addition to excluding alternative causes of mental status changes. In such patients, our initial approach is to ask about subtle signs of impaired mental status, and if signs point to suspected covert hepatic encephalopathy, we perform psychometric testing. (See 'Psychometric 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 covert 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 working memory) leading to difficulties with normal daily activities [29]. 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 was 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 cirrhosis 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 alcohol ingestion) and to look for conditions that may have precipitated the hepatic encephalopathy. (See 'Differential diagnosis' below and 'Evaluation for precipitating causes' below.)

Ammonia — The increase in blood ammonia levels in patients with cirrhosis is a consequence of impaired liver function and of shunting of blood around the liver. Muscle wasting may contribute since muscle is an important site for extrahepatic ammonia removal. The kidney can produce large amounts of ammonia in the setting of gastrointestinal bleeding, volume depletion, and hypokalemia.

Whether to measure the serum ammonia concentration in patients suspected of having hepatic encephalopathy remains controversial because ammonia levels are inconsistently elevated [30,31]. Measuring serum ammonia levels is not required to establish the diagnosis of hepatic encephalopathy or for the long-term follow-up of patients with cirrhosis. Ammonia levels also do not improve the pre-test probability of overt hepatic encephalopathy. Furthermore, ammonia levels can be elevated in a variety of non-hepatic conditions (table 3).

Neither arterial or venous ammonia concentration is useful in screening for hepatic encephalopathy [32]. However, patients with cirrhosis and coma who have low ammonia values should be evaluated to exclude other causes of mental status changes.

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 [4,33-36]. These tests (eg, Psychometric Hepatic Encephalopathy Score [PHES]) may be more useful for detecting minor deficits of mental function than conventional clinical assessment [33]. Several psychometric tests have been developed, but none is performed routinely in clinical practice.

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 [37,38]. 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) [39].

Specific psychometric tests for evaluating patients with suspected hepatic encephalopathy include:

●Psychometric Hepatic Encephalopathy Score – PHES is regarded as the gold-standard psychometric test in research studies, but it is rarely performed in clinical practice [40,41]. PHES is a collection of five timed paper-pencil tests. Performance is graded by a trained observer who also assesses for mistakes and then compares the patient's results to population-based normal values. Encephalopathy is defined by performance that is multiple standard deviations below population-based normal values.

●EncephalApp – EncephalApp is a smartphone application that includes a timed test of attention based on the Stroop effect [42]. Its results are compared with population-based normal values. EncephalApp cannot be performed in patients with color blindness. It is sensitive but not specific for detecting covert hepatic encephalopathy.

●Animal Naming Test – The Animal Naming Test (ANT) is a timed (one minute) test that records the number of unique animals identified by the patient. The optimal cutoff is uncertain, but one study reported <15 animals as diagnostic [43].  

Radiologic imaging — Radiologic imaging is primarily used to exclude other causes of mental status changes when a history of trauma is provided (or cannot be excluded) or when there are focal neurologic changes. We typically obtain a noncontrast CT scan of the head when the clinical findings suggest another cause for the patient's mental status changes (such as a subdural hematoma from trauma).

Investigational tests — Electrophysiologic tests to detect hepatic encephalopathy include electroencephalogram (EEG) monitoring, evoked potentials, and critical flicker frequency testing [44-47]. However, use of these tests is mainly limited to research settings.

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 [44].

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 [45].

Evaluation for precipitating causes — There are several conditions that may precipitate an episode of hepatic encephalopathy in patients with cirrhosis or a portal-systemic shunt (table 2). These include [28,48-51]:

●Gastrointestinal bleeding

●Infection (including spontaneous bacterial peritonitis and urinary tract infections)

●Hypokalemia and/or metabolic alkalosis

●Kidney failure

●Hypovolemia

●Hypoxia

●Sedative or benzodiazepine use

●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 includes:

●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.

●Urine drug screen. Some patients covertly use medications (eg, sedatives) that may precipitate hepatic encephalopathy requiring hospital admission.  

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 liver failure, cirrhosis, or a portal-systemic shunt, other causes for the patient's confusion should be considered, such as a subdural hematoma, kidney failure, or mental status changes associated with the patient's underlying liver disease (eg, Wilson disease).

The evaluation of patients with delirium and confusional states is discussed elsewhere. (See "Diagnosis of delirium and confusional states".)

CAPACITY TO DRIVE — 

We advise patients to avoid driving following an episode of overt hepatic encephalopathy. For patients who want to resume driving, we advise them to contact their local department of motor vehicles for a driving assessment based on local regulations. We agree with guidance from professional societies that assessing the ability to drive should be done according to local regulations because psychometric tests cannot reliably determine if the patient is a safe driver [52].

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 5^th to 6^th 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 10^th to 12^th 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 cirrhosis. (See 'Introduction' above.)

●Clinical manifestations – Hepatic encephalopathy is characterized by cognitive deficits and impaired neuromuscular function (figure 1 and figure 2). Cognitive findings in patients with hepatic encephalopathy vary from subtle deficits that are not apparent without specialized testing (covert 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 (see 'Diagnosis' above):

•A history and physical examination to detect the cognitive and neuromuscular impairments that characterize hepatic encephalopathy.

•Psychometric testing if covert hepatic encephalopathy is suspected. (See 'Psychometric tests' above.)

•Exclusion of other causes of mental status changes: Serum laboratory testing to rule out metabolic abnormalities, a noncontrast computed tomography scan of the brain if the clinical findings (such as history of trauma or focal neurologic signs) suggest another cause for the patient's findings (such as a subdural hematoma).

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

•Urine drug screen

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Peter Ferenci, MD (deceased), who contributed to earlier versions of this topic review.