Hepatic Encephalopathy

Etiology

Hepatic encephalopathy can develop due to underlying liver disease or portosystemic shunts, such as transjugular intrahepatic portosystemic shunt (TIPS) or spontaneous shunts. The former is associated with liver disease, while the latter results from portal circulation being redirected to the systemic circulation, bypassing the liver and leading to the accumulation of toxic metabolites.[8] Acute liver failure may be triggered by viral hepatitis, exposure to hepatotoxins (eg, acetaminophen), or ischemic liver injury (eg, septic shock). Chronic liver failure with cirrhosis can result from various causes, including alcoholic cirrhosis, chronic viral hepatitis B or C, nonalcoholic fatty liver disease, hemochromatosis, Wilson disease, and alpha-1 antitrypsin deficiency. Consequently, depending on the underlying etiology, hepatic encephalopathy may develop in diverse scenarios.

In some cases, hepatic encephalopathy occurs without liver dysfunction, such as in congenital portosystemic shunts or extrahepatic portal vein obstruction with shunting, where systemic circulation bypasses the liver, resulting in hyperammonemia and neurological symptoms. Acute liver failure is characterized by a sudden loss of liver function, typically without portosystemic shunting, and is associated with markedly elevated ammonia levels and severe cerebral edema. In cirrhosis, hepatic encephalopathy may develop with or without significant portosystemic shunting, often linked to hyperammonemia, although ammonia levels do not always correlate with symptom severity. The etiological classification is outlined below.

In the context of cirrhosis, hepatic encephalopathy can be triggered by various factors, including: 

• Gastrointestinal bleeding (eg, acute variceal bleeding)
• Constipation
• Infections
• Dehydration (due to factors such as fluid restriction, diuretics, diarrhea, vomiting, or excessive paracentesis)
• electrolyte imbalances (eg, hyponatremia and hypokalemia)
• Alcohol use disorder
• Medications (eg, benzodiazepines, opioids, and nonsteroidal anti-inflammatory drugs [NSAIDs])
• Kidney dysfunction and azotemia 

Furthermore, hepatic encephalopathy can complicate 30% to 50% of cirrhosis patients who undergo TIPS. However, the use of smaller stents and better patient selection can reduce this incidence.[8][9][10] Spontaneous portosystemic shunts, which occur when fetal shunt pathways between the portal and systemic circulation reopen due to cirrhosis, may also contribute significantly to hepatic encephalopathy. Over time, the volume of the systemic shunt increases, portal circulation declines, and liver failure worsens.[11]

Epidemiology

A population-based study estimated that approximately 44% of individuals with cirrhosis may develop hepatic encephalopathy within a 5-year period.[12] In another study involving over 9000 newly diagnosed cirrhosis patients, about one-third had decompensated cirrhosis, and of these, 51% experienced hepatic encephalopathy.[13]

Chronic liver disease often presents with subtle, gradual symptoms, leading many patients to delay seeking treatment until complications arise. A study based on the commercial medical claims database estimated the prevalence of hepatic encephalopathy in the United States in 2018 at 202,000 cases.[14] However, it is noteworthy that this study may not have accounted for cases of minimal hepatic encephalopathy, which can affect up to 80% of patients with cirrhosis and is characterized by subtle features that require specialized testing for detection.[5] 

Pathophysiology

The neuropathology of hepatic encephalopathy was first described in 1949, but our understanding of its exact causes and mechanisms remains incomplete.[1] A central factor in the pathogenesis of hepatic encephalopathy is the role of elevated serum ammonia levels. Colonic bacteria and mucosal enzymes break down dietary proteins, releasing ammonia in the gastrointestinal tract. This ammonia is normally absorbed into the portal circulation, where the liver converts it into urea through the urea cycle. However, in cases of hepatic failure or systemic shunting, ammonia can accumulate and bypass the liver, entering the systemic circulation. This buildup of ammonia, known as hyperammonemia, disrupts neuronal function and contributes to encephalopathy. Ammonia is one of several neurotoxic substances that impair excitatory neurotransmission.[15] 

Individuals With Chronic Liver Failure or Cirrhosis

Elevated ammonia levels cause astrocyte swelling, oxidative stress, and neurotransmitter imbalances, all of which contribute to hepatic encephalopathy. Other contributing factors include systemic inflammation and changes to the blood-brain barrier. Additionally, alterations in the gut microbiome have a significant role in ammonia production and the development of hepatic encephalopathy. In patients with long-standing cirrhosis, manganese toxicity is another potential contributor, which can be detected using magnetic resonance imaging (MRI), especially T1-weighted imaging, where abnormalities in the globus pallidus may be evident.[16] Several other substances and factors have also been implicated in the development of hepatic encephalopathy, including mercaptans, short-chain fatty acids, reduced glutamatergic synaptic function, lactate, and dopamine metabolites.[17]

Individuals With Acute Liver Failure Without Preexisting Liver Disease

Hepatic encephalopathy secondary to acute liver failure involves a presentation with distinct differences—primarily attributable to the development of rapid brain swelling and the relatively rapid deterioration of the condition. This section highlights some of the key aspects of hepatic encephalopathy in acute liver failure.

Ammonia can cross the blood-brain barrier and enter the brain, where astrocytic glutamine synthetase converts it along with glutamate into glutamine. Glutamine acts as an osmolyte, leading to an increase in cerebral volume. This causes brain edema and intracranial hypertension, as well as increases the risk of brain herniation.[18]

Serum ammonia levels directly influence the severity of hepatic encephalopathy in cirrhosis patients, though the correlation is not linear or exponential. The relationship is more pronounced in patients with fulminant hepatic failure. In these cases, the risk of cerebral edema increases when arterial ammonia levels exceed 200 μmol/L (340 μg/dL).[1]

Hepatic Encephalopathy in Acute Liver Failure

Acute liver failure is characterized by severe acute liver injury accompanied by impaired synthetic function (international normalized ratio [INR] of ≥1.5) and altered mental status. This typically occurs in patients without preexisting liver disease or cirrhosis.[19]

Acute liver failure can result from various causes, as listed below.

• Acetaminophen (paracetamol) toxicity
• Viral hepatitis
• Autoimmune hepatitis
• Ischemic hepatopathy
• Veno-occlusive disease
• Acute fatty liver of pregnancy
• Toxin exposure, including mushroom poisoning
• Sepsis

Evaluation and Management of Hepatic Encephalopathy Secondary to Acute Liver Failure

The classification of hepatic encephalopathy stages is consistent for both acute liver failure and cirrhosis. In patients with acute liver failure and hepatic encephalopathy, cerebral edema is relatively rare in those with West Haven grade 1 or 2 encephalopathy. However, it is observed in approximately 25% to 35% of patients with grade 3 encephalopathy and about 75% of those with grade 4 encephalopathy.[20][21]

Increased intracranial pressure can result in manifestations such as systemic hypertension, bradycardia, respiratory depression (known as Cushing triad), seizures, and abnormal brainstem reflexes. The optimal management approach for increased intracranial pressure in acute liver failure or fulminant hepatic failure remains uncertain.

Potential treatments to consider in this situation include:

• Elevating the head end of the bed by 30 degrees.
• Cautiously administering short-term sedatives in ventilated patients to prevent patient-ventilator dyssynchrony.
• Administering a bolus of mannitol or hypertonic saline.

Histopathology

Significant morphological changes primarily affect astrocytes and microglia within the brain in cirrhosis.[22] These alterations in astrocytes are commonly referred to as "Alzheimer type II astrocytosis" and are consistently observed in brain tissue sections of individuals who succumbed to grade 4 hepatic encephalopathy. Microscopic examination reveals that hyperammonemia can cause astrocytes to enlarge and appear pale due to reduced chromatin content.

Notably, these changes typically arise after prolonged exposure to hyperammonemia and are not commonly seen in fulminant hepatic failure. As the most prominent neuropathological changes in individuals with cirrhosis and hepatic encephalopathy involve glial cells rather than neurons, this condition has been described as a "primary gliopathy."[22]

History and Physical

Liver disease should be confirmed through abnormal liver function tests, radiologic imaging, or liver biopsy to diagnose hepatic encephalopathy. Alternatively, the presence of a portosystemic shunt may be identified. Ruling out other potential causes that could mimic hepatic encephalopathy, such as intracranial lesions, masses, stroke, seizure activity, post-seizure encephalopathy, intracranial infections, or toxic encephalopathy, from other etiologies is also essential.

History

Obtaining the patient's medical history is crucial for identifying the likely causes of liver failure and guiding appropriate interventions. If the patient is unable to communicate, it is important to interview close family members, caretakers, or friends who can provide relevant information.

When gathering a patient's medical history, it is important to inquire about the following:

• Symptoms related to liver failure and its complications, such as jaundice, pruritus, gastrointestinal bleeding, coagulopathy, increased abdominal girth, renal failure, and changes in mental status.
• Alterations in sleep patterns and cognitive function, including decreased attention span and impaired short-term memory, which may affect daily activities.
• History of exposure to hepatotoxins, such as alcohol, medications, herbal supplements, mushrooms, organic solvents, or phosphorus-containing substances (eg, those found in fireworks).
• Risk factors for viral hepatitis, including travel, blood transfusions, sexual contacts, or occupation.
• Family history of liver disease, including Wilson disease or alpha-1 antitrypsin deficiency.
• Potential precipitating causes for encephalopathy, such as constipation, infection, sedative use, gastrointestinal bleeding, or conditions leading to hypovolemia (eg, diarrhea or vomiting).

Physical Examination

Signs of chronic liver failure: During a physical examination, patients with hepatic encephalopathy often present with signs of advanced chronic liver disease, commonly referred to as decompensated cirrhosis. These physical findings may include:

• Muscle wasting and sarcopenia
• Jaundice
• Ascites 
• Palmar erythema (reddening of the palms)
• Edema (swelling)
• Spider telangiectasias (small, dilated blood vessels near the skin's surface)
• A distinctive odor—"fetor hepaticus"

However, in patients with acute fulminant hepatitis without a history of chronic liver disease, some of these findings—such as muscle wasting, spider telangiectasias, and palmar erythema—are typically absent, as these physical signs require a longer duration of hepatic dysfunction to develop. Notably, decreased muscle mass, strength, and function, a condition known as sarcopenia, is commonly observed in patients with cirrhosis and is associated with an increased risk of hepatic encephalopathy.[23][24]

Neurocognitive and neuromuscular signs: Hepatic encephalopathy is characterized by alterations in neurocognitive function and impaired neuromuscular performance. The neurocognitive manifestations are variable, with initial signs often involving a reduced awareness of one's surroundings and stimuli, accompanied by behaviors such as yawning and episodes of dozing off. Disturbances in the diurnal sleep pattern, such as insomnia or hypersomnia, are common and often precede other mental status changes or neuromuscular symptoms.[25]

Neuromuscular manifestations of hepatic encephalopathy include a variety of signs, such as bradykinesia (slowness of movement), asterixis (flapping motions of outstretched, dorsiflexed hands), slurred speech, ataxia (lack of coordination), hyperactive deep tendon reflexes, and nystagmus. Asterixis is typically observed during the intermediate stages of hepatic encephalopathy.

Patients may exhibit restless tossing or muscle or limb twitching as hepatic encephalopathy progresses, which can evolve into multifocal myoclonus. Additional physical signs may include hyperreflexia, a positive Babinski sign, or symptoms resembling Parkinsonian features, such as rigidity or tremors. Less frequently, patients may experience loss of reflexes, transient decerebrate posturing, or progression to a comatose state. In some cases, individuals may present with focal neurological deficits, despite negative findings on computed tomography (CT) or MRI of the brain.[26]

Evaluation

Diagnosing hepatic encephalopathy begins with a comprehensive assessment of the patient’s vital signs and airway. A detailed clinical evaluation, including a thorough history and physical examination, is essential for identifying potential precipitating factors. Understanding the context of liver disease, previous episodes, and associated triggers is crucial to accurate diagnosis and management. Hepatic encephalopathy is a diagnosis of exclusion, and neuroimaging should be performed in cases where alternative diagnoses are suspected, such as in patients with compensated cirrhosis experiencing their first episode of hepatic encephalopathy or individuals with alcohol use disorder and relapse. Notably, it is also important to differentiate hepatic encephalopathy from conditions such as alcohol withdrawal, as both can present with tremors and asterixis. A tremor is a fine rhythmic movement, while asterixis is a coarse, non-rhythmic flapping of the hands.

Diagnostic Tests for Hepatic Encephalopathy

Initial investigations: Initial evaluations for hepatic encephalopathy should include arterial blood gas (ABG) analysis, particularly in higher grades of the condition. ABG analysis can help detect electrolyte imbalances, dehydration, or signs of variceal bleeding. Blood glucose levels should also be assessed, as hypoglycemia may occur in patients with liver dysfunction and compromised nutritional status.

Ammonia levels: Ammonia levels are generally elevated in both arterial and venous blood in patients with hepatic encephalopathy. However, assessing the patient’s clinical improvement or deterioration during treatment is more valuable than relying solely on serial ammonia measurements. Neither elevated arterial nor venous ammonia concentrations are definitive for diagnosing hepatic encephalopathy.[27] However, a normal ammonia level has a high negative predictive value. Ammonia levels should be tested within 1 hour of collection and stored at cool temperatures to ensure accuracy. Other biomarkers, such as elevated serum 3-nitrotyrosine levels, may be present in patients with mild hepatic encephalopathy. Research indicates that a cutoff value of 14 nM for 3-nitrotyrosine has a sensitivity of 93% and a specificity of 89% for detecting minimal hepatic encephalopathy.[28]

Liver function tests and electrolytes: Liver function tests and electrolyte levels are often abnormal in the presence of underlying liver disease. Common findings include elevated levels of bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, prothrombin time, and INR. Additionally, patients may experience electrolyte imbalances such as hyponatremia and hypokalemia, which are known triggers for hepatic encephalopathy.

Additional Tests for Hepatic Encephalopathy

Additional tests for diagnosing hepatic encephalopathy may include a complete blood count, kidney function tests (as kidney injury is a common precipitant of hepatic encephalopathy), and thyroid-stimulating hormone levels. When sepsis is suspected as a trigger, investigations for infection, such as blood cultures, procalcitonin, and C-reactive protein, are essential. These tests also help rule out septic encephalopathy in relevant cases. 

Psychometric tests: Psychometric tests have been developed to assess the degree of cognitive impairment in individuals with mild hepatic encephalopathy.[29][30][31] These tests have demonstrated greater sensitivity than electroencephalograms (EEG) in detecting subtle cognitive deficits.[29] However, many psychometric tests are complex, time-consuming, and not widely used in routine clinical practice. Critical Flicker Frequency (CFF), which measures visual discrimination, has proven valuable for detecting minimal hepatic encephalopathy. The Number Connection Test (NCT), also known as the Reitan Test, is one of the most commonly used psychometric assessments.[30][32][33] This test is favored for its ease of administration and interpretation. The NCT requires patients to connect numbers in a sequential order within a set time. Patients without hepatic encephalopathy typically complete the test in a duration equal to or less than their age in years. For example, a patient aged 50 or older should be able to complete the test in 50 seconds or less.

Electroencephalogram: EEG activity activity can reveal changes such as high-amplitude low-frequency waves and triphasic waves, which may be seen in hepatic encephalopathy. However, these findings are not specific to the condition. An EEG can be helpful during the initial evaluation to rule out seizure activity.

Radiologic imaging: Radiologic imaging, such as CT or MRI, may be used to rule out alternative causes of encephalopathy, including intracranial lesions, masses, or hemorrhage. In some cases, a CT scan during hepatic encephalopathy may show cerebral edema, particularly in acute liver failure and certain cases of post-TIPS hepatic encephalopathy. Although MRI is considered superior to CT for detecting brain edema in liver failure, it is not an established method for diagnosing hepatic encephalopathy. In certain instances, changes have been observed on T1-weighted MRI images, which may reveal a strong signal in the basal ganglia in patients with hepatic encephalopathy, potentially due to manganese accumulation.[34] However, these changes are neither highly sensitive nor specific indicators.[35][36] Contrast-enhanced CT of the abdomen can be useful for evaluating portosystemic shunts, providing insight into their presence and helping to guide therapeutic interventions, as discussed below. 

Grading

Following diagnosis, hepatic encephalopathy should be graded according to detailed classifications outlined in subsequent sections. Traditionally, the West Haven system has been used to assess the severity of hepatic encephalopathy, grading it from 0 to 4. However, the milder stages—particularly grade 0 (minimal hepatic encephalopathy) and grade 1 (subtle confusion or mood changes)—pose challenges for clinical diagnosis due to the difficulty in recognizing these subtle changes. To address this, the concepts of covert and overt hepatic encephalopathy were introduced. Covert hepatic encephalopathy includes both minimal hepatic encephalopathy and grade 1, detectable only through specialized tests. Overt hepatic encephalopathy refers to more noticeable symptoms, starting from grade 2 onward. Additionally, hepatic encephalopathy is classified by its clinical course into episodic, recurrent, and persistent forms.

Treatment / Management

The management of hepatic encephalopathy generally involves supportive care and ammonia-lowering therapy. Supportive care is a critical component of treatment, which addresses several key aspects, such as maintaining adequate nutrition, preventing dehydration and electrolyte imbalances, and ensuring a safe environment to reduce the risk of accidents or falls. Disaccharides, such as lactulose and lactitol, and antibiotics, such as rifaximin, are key components of ammonia-lowering therapy.

Nutritional Support

Patients with hepatic encephalopathy should not have their protein intake restricted. Instead, they should receive nutritional support with an appropriate energy intake of approximately 35 to 40 kcal/kg/d. This dietary plan should maintain protein intake at around 1.2 to 1.5 gm/kg/d. Notably, it is important to encourage the consumption of small meals throughout the day to prevent fasting, which can increase ammonia production. For patients who experience worsening symptoms with protein intake, vegetable protein can be considered an alternative. Additionally, adding branched-chain amino acids (BCAAs) to a low-protein diet may be considered for individuals intolerant to protein. This approach is especially beneficial for patients undergoing procedures such as TIPS or surgical portosystemic shunts who are also experiencing hepatic encephalopathy.

Hydration and Electrolyte Correction

Supportive care includes ensuring proper hydration and correcting electrolyte imbalances. This involves providing adequate oral fluids and, when necessary, administering intravenous hydration to prevent dehydration. Additionally, any electrolyte abnormalities should be corrected by replenishing essential electrolytes as needed.

Safe Environment

Establishing a safe environment for patients with overt symptoms is crucial, as these individuals may experience agitation, posing a risk to themselves and their caregivers. While addressing a patient's agitation, it is crucial to note that sedative medications, such as benzodiazepines, can potentially exacerbate encephalopathy and impede recovery. Therefore, their use should be carefully considered, and, in some instances, temporary restraint may be required until the patient's agitation resolves.

Treatment of Precipitating Factors

Promptly identifying and addressing the precipitating causes of hepatic encephalopathy is crucial. These triggers may include constipation, infections (such as spontaneous bacterial peritonitis or urinary tract infections), electrolyte and metabolic imbalances (eg, hypokalemia or hypoglycemia), hypovolemia, and the use of benzodiazepines or other sedatives. Timely intervention to correct these factors is essential for effective management.

Ammonia Levels Management

In most cases of hepatic encephalopathy, ammonia levels are elevated, though this is not always the case. Regardless of ammonia levels, steps should be taken to reduce ammonia levels once the diagnosis is confirmed. However, if serum ammonia levels are elevated without corresponding clinical signs of hepatic encephalopathy, it is noteworthy that this alone does not justify ammonia-lowering therapy. The decision to initiate treatment should be based on a thorough clinical assessment and the presence of symptoms rather than on ammonia levels alone.

Common medications used in the management of hepatic encephalopathy include disaccharides such as lactulose and lactitol, along with the antibiotic rifaximin.

• Lactulose: Lactulose works through multiple mechanisms to reduce blood ammonia levels. When bacteria in the gut break down lactulose, it creates an acidic environment that promotes the conversion of ammonia (NH₃) to ammonium (NH₄⁺), reducing the diffusion of NH₃ into the bloodstream. Additionally, lactulose promotes the diffusion of NH₃ from the bloodstream into the gut, where it is converted to NH₄⁺. Furthermore, lactulose also exerts an osmotic effect in the colon, promoting distention and peristalsis, which facilitates the excretion of NH₃. Through these combined mechanisms, lactulose effectively reduces blood ammonia levels of NH₃. Typically, lactulose is administered at a dose of 20 to 30 grams, 2 to 4 times per day, to achieve at least 2 to 3 soft stools daily. In cases where oral administration is not possible, lactulose can be administered as an enema. About 70% to 80% of patients with hepatic encephalopathy show improvement with lactulose treatment.[37][38][39] While lactitol is available in certain countries, it is not approved for use in the United States.
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• Rifaximin: Rifaximin is an antibiotic with minimal absorption in the gastrointestinal tract, resulting in high concentrations within the intestines. This drug is believed to reduce ammonia production by targeting and eliminating ammonia-producing bacteria in the colon. Rifaximin works by binding to bacterial DNA-dependent RNA polymerase, inhibiting bacterial RNA synthesis. This drug is often considered for patients who do not respond to lactulose or lactitol or those who experience intolerance to these medications. Rifaximin is typically prescribed at a dosage of 550 mg orally twice daily or 400 mg orally 3 times daily.

• L-ornithine-L-aspartate: L-ornithine-L-aspartate (LOLA) is a compound that stimulates ammonia metabolism and enhances its conversion in the urea cycle to produce urea. This compound serves as an alternative treatment for hepatic encephalopathy; however, its clinical availability may be limited.[40]
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Closure of Portosystemic Shunts

Balloon-occluded retrograde transvenous obliteration (BRTO) or plug-assisted retrograde transvenous obliteration (PARTO) procedures can be effective for patients with refractory hepatic encephalopathy caused by portosystemic shunts. These interventions close the shunts, restore portal circulation to the liver, and reduce ammonia accumulation.

Extracorporeal Albumin Dialysis

Techniques such as DIALIVE might be effective for severe hepatic encephalopathy.[41] Several systems are available, but the long-term survival benefit of these machines has not been definitively proven.[42] Although DIALIVE has been shown to reduce ammonia levels in patients with ACLF, the effect was not statistically significant. These extracorporeal therapies are believed to utilize albumin's binding properties to remove toxins, including ammonia, cytokines, and bile acids, thereby reducing the severity of hepatic encephalopathy. While studies indicate improvement in encephalopathy symptoms, the survival benefits remain unclear.[41](A1)

Liver Transplantation

Liver transplantation is typically considered for patients with cirrhosis when there is a major complication (such as ascites, hepatic encephalopathy, or variceal bleeding) or when the Model for End-Stage Liver Disease (MELD) score exceeds 15.[43] A single episode of overt hepatic encephalopathy increases mortality risk independently of other organ failures, and referral to a liver transplantation center for evaluation should be considered.[44] In patients who are candidates for and undergo liver transplantation, cognitive impairment associated with hepatic encephalopathy often reverses within 5 years after the transplantation.[45] This highlights the potential for significant improvement in cognitive function and quality of life following successful liver transplantation.(A1)

Chronic Management

Identifying and managing potential precipitating factors is essential for individuals at risk of recurrent hepatic encephalopathy. If precipitating factors cannot be identified or effectively controlled, ongoing therapy with disaccharides such as lactulose or lactitol, in combination with rifaximin, can be beneficial.

Prevention of Hepatic Encephalopathy

Lactulose is recommended for patients with cirrhosis after the first episode of covert hepatic encephalopathy to prevent further episodes. If the patient is already on lactulose, rifaximin may be added after another episode. Management of sarcopenia requires a comprehensive approach, including proper nutritional support and a structured exercise plan. While BCAAs show potential in addressing sarcopenia, further studies are needed to confirm their efficacy.

Differential Diagnosis

The differential diagnoses of hepatic encephalopathy include the below-mentioned categories.

• Metabolic causes: Hypoglycemia, hypoxia, and alcohol withdrawal.
• Intracranial lesions: Subdural hematoma, intracranial hemorrhage, tumor, stroke, and abscess.
• Other primary central nervous system processes: Meningitis, Wernicke encephalopathy, and post-seizure encephalopathy.
• Sepsis and septic encephalopathy 
• Uremic encephalopathy
• Drug-related effects: Antipsychotics, sedatives, antidepressants, and valproate can cause hyperammonemia without liver dysfunction.

Pertinent Studies and Ongoing Trials

Several treatment strategies have been explored for managing hepatic encephalopathy, with some showing promising results.

BCAA Infusions

Various randomized trials have investigated the use of parenteral nutrition with modified amino acid solutions that contain a high concentration of BCAAs and a low concentration of aromatic amino acids. Patients with cirrhosis often have a higher depletion of BCAA compared to aromatic amino acids. However, the evidence regarding the effect on mortality remains conflicting, and the studies conducted thus far have involved small sample sizes and short follow-up periods. As a result, BCAA infusions are not routinely recommended for the management of hepatic encephalopathy.[46]

Oral BCAA Supplements

Several trials have investigated the effects of oral BCAA supplements, showing beneficial effects on hepatic encephalopathy, though no clear mortality benefits have been observed. Patients with hyperammonemia are often depleted of amino acids, and BCAAs, in particular, serve as building blocks for neurotransmitter production and muscle synthesis, which may explain their potential effectiveness in managing the condition.[40][47][48]

Polyethylene Glycol

Polyethylene glycol (PEG) solution, a cathartic agent, can enhance ammonia excretion through the stool. Several studies have shown that patients treated with PEG experienced more significant improvements in their hepatic encephalopathy scoring algorithm (HESA) scores compared to those receiving lactulose. These findings suggest that PEG could be a viable option for managing hepatic encephalopathy.[49][50]

Sodium Benzoate

Sodium benzoate reduces ammonia levels through a chemical reaction with glycine, forming hippurate, which is then excreted via the kidneys. A trial demonstrated that sodium benzoate improved hepatic encephalopathy, similar to those achieved with lactulose.[51] Although these results are promising, additional research is needed to establish the role of sodium benzoate as a first- or second-line therapy.

Probiotics

Probiotic therapy has demonstrated the potential to reduce blood ammonia concentrations by promoting the colonization of acid-resistant, non-urease–producing bacteria. Lactobacillus and Bifidobacterium are the most effective species for managing hepatic encephalopathy. While probiotics are often used empirically due to the perceived safety of the intervention, rigorous and supportive data are lacking to firmly establish their effectiveness.[25][52]

Flumazenil

Flumazenil, a benzodiazepine receptor antagonist, may provide temporary improvement in patients with hepatic encephalopathy. However, a large meta-analysis found that it did not affect all-cause mortality. Although some evidence suggests short-term benefits, flumazenil is not a recommended treatment for hepatic encephalopathy.[53] 

Zinc

Zinc deficiency is prevalent in patients with cirrhosis and hepatic encephalopathy.[54] Studies on zinc supplementation have produced inconsistent results; therefore, routine recommendations for zinc supplementation in these patients have not been established.

Other agents under exploration include fecal microbiota transplant, L-carnitine, serotonin antagonists, and opioid antagonists. Further research is necessary to comprehensively assess their effectiveness.

Staging

Hepatic encephalopathy can be classified using the West Haven criteria, which provides a semi-quantitative grading of mental state based on the degree of dependence on therapy and impairments in autonomy, behavior, consciousness, and intellectual function. Alternatively, the World Health Congress of Gastroenterology criteria can be used to classify hepatic encephalopathy based on the underlying etiology and associated conditions.[55]

West Haven Criteria

The West Haven criteria provide a structured framework for assessing the severity of hepatic encephalopathy, ranging from subtle cognitive changes to profound coma.

• Grade 1
  • Trivial lack of awareness
  • Euphoria or anxiety
  • Shortened attention span and impaired ability to perform simple calculations (addition or subtraction)
• Grade 2
  • Lethargy or apathy
  • Minimal disorientation to time or place
  • Subtle personality changes
  • Inappropriate behavior
• Grade 3
  • Somnolence to semi-stupor, but responsive to verbal stimuli
  • Confusion
  • Gross disorientation
• Grade 4
  • Coma

World Health Congress of Gastroenterology Criteria

The World Health Congress of Gastroenterology criteria categorize hepatic encephalopathy into distinct types based on its underlying etiology, offering a comprehensive approach to the management of hepatic encephalopathy.

• Type A (acute): Hepatic encephalopathy associated with acute liver failure, typically with cerebral edema.
• Type B (bypass): Hepatic encephalopathy caused by portal-systemic shunting, without associated intrinsic liver disease.
• Type C (cirrhosis): Hepatic encephalopathy in patients with cirrhosis, which is further subdivided into episodic, persistent, and minimal encephalopathy.

Minimal Hepatic Encephalopathy 

Minimal hepatic encephalopathy is not characterized by overt signs of cognitive dysfunction but by subtle cognitive deficits detectable through neuropsychological testing.[5] This form of hepatic encephalopathy has been shown to impair the overall quality of life and workability, as well as increase the risk of motor vehicle accidents. Psychometric testing, including the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the PSE-Syndrome test, remains the standard for diagnosis. Both tests incorporate a range of neuropsychological assessments that measure multiple cognitive domains, providing a more reliable evaluation than tests focused on individual cognitive functions.

Treatment with rifaximin or lactulose has demonstrated improvements in the quality of life for patients with minimal hepatic encephalopathy. Rifaximin has also been shown to enhance driving performance in simulated experiments. Additionally, the combination of rifaximin and lactulose has proven effective in preventing the recurrence of episodic hepatic encephalopathy.

General Classification

Hepatic encephalopathy is broadly categorized into 2 main types—overt and covert. While exact statistics on the prevalence of each form are unavailable, these categories represent a spectrum of disease severity. Covert hepatic encephalopathy includes minimal hepatic encephalopathy and West Haven grade 1, whereas overt hepatic encephalopathy encompasses grades 2 through 4 of the West Haven criteria.[56]

Prognosis

Patients with chronic liver disease who develop hepatic encephalopathy are at risk of recurrence. Even after treatment, neurological deficits may persist despite an apparent return to normal mental status. The severity of these residual impairments is typically greater in individuals who have had multiple overt episodes. Additionally, hepatic encephalopathy is also associated with a poor prognosis in individuals with liver failure.[57] A study involving hospitalized patients with hepatic encephalopathy reported a 44% survival probability at 12 months and 35% at 24 months.[58]

Complications

Complications associated with hepatic encephalopathy include:

• Agitation, which may pose a potential risk of harm to both patients and their caregivers.
• Seizures.
• Residual cognitive impairment, even in patients who show clinical improvement.
• Decreased likelihood of survival within 12 to 24 months for patients with recurrent episodes.
• Cerebral edema, seizures, and brain herniation in patients with acute fulminant hepatic failure.