Continuing Education Activity

Hepatic encephalopathy (HE) is a reversible syndrome observed in patients with advanced liver dysfunction. This syndrome is characterized by a wide spectrum of neuropsychiatric abnormalities resulting from the accumulation of neurotoxic substances in the brain. This activity describes the evaluation and management of hepatic encephalopathy in patients. It highlights the role of the interprofessional team in evaluating and treating patients with this condition.

Objectives:

• Outline the typical presentation of a patient with hepatic encephalopathy.
• Explain the common physical exam findings associated with hepatic encephalopathy.
• Review the risk factors for developing hepatic encephalopathy.
• Explain the importance of improving care coordination amongst the interprofessional team to enhance the delivery of care for patients with hepatic encephalopathy.

Introduction

Hepatic encephalopathy (HE) is a reversible syndrome observed in patients with advanced liver dysfunction. The syndrome is characterized by a spectrum of neuropsychiatric abnormalities resulting from the accumulation of neurotoxic substances in the bloodstream (and ultimately in the brain).  Symptoms typically include confusion, personality changes, disorientation, and a depressed level of consciousness.  The earliest stage is often characterized by an inverted sleep-wake pattern wherein patients are found to be sleeping during the day and awake throughout the night.  Throughout the intermediate stages, patients tend to experience worsening levels of confusion, lethargy, and personality changes. In the advanced stages, hepatic encephalopathy may eventually lead to coma (e.g., hepatic coma or coma hepaticum) and ultimately to death.[1][2][3]

Etiology

Triggers of HE include renal failure, gastrointestinal bleeding (e.g., esophageal varices), constipation, infection, medication non-compliance, excessive dietary protein intake, dehydration (e.g., fluid restriction, diuretics, diarrhea, vomiting, excessive paracentesis), electrolyte imbalance, consumption of alcohol, or consumption of certain sedatives, analgesics or diuretics all in the setting of chronic liver disease. In some cases, hepatic encephalopathy may occur following the creation of a transjugular intrahepatic portosystemic shunt (TIPS).[4][5]

Epidemiology

HE occurs as a complication of advanced liver disease (e.g., 30-45% of patients with cirrhosis, 24 to 53% of patients with TIPS) - which may be acute or chronic.[6]  In the case of chronic liver disease, as it tends to have an insidious onset, most patients do not seek treatment until late in the course of the disease - once complications develop. There are approximately 7-11 million cases of HE prevalent in the United States, with approximately 150,000 patients newly diagnosed each year. Of the newly diagnosed patients, approximately 20% present with cirrhosis. Almost 60% of cases occur in the presence of chronic hepatitis C either alone or in combination with alcohol-related liver disease.  [7]

Pathophysiology

Putative neurotoxins include ammonia, short-chain fatty acids, mercaptans, false neurotransmitters (e.g., tyramine, octopamine, beta-phenylethanolamines), manganese, and GABA - though ammonia is the most widely recognized. [8]

Under normal conditions, ammonia is produced by bacteria in the gastrointestinal tract (e.g., breakdown product of amines, amino acids, purines, and urea) followed by metabolism and clearance by the liver. In the case of cirrhosis or advanced liver dysfunction, however, there is either a decrease in the number of functioning hepatocytes, portosystemic shunting, or both, resulting in decreased ammonia clearance and hyperammonemia.

Once ammonia crosses the blood-brain barrier, it has multiple neurotoxic effects. These include alterations in molecular transport (e.g., amino acids, electrolytes, water) in astrocytes and neurons, increased synthesis of glutamine from glutamate by astrocytes, inhibition of excitatory and inhibitory postsynaptic potential generation, impaired amino acid metabolism, and impaired energy utilization as a result of increased GABA activity.

History and Physical

In order to make a diagnosis of HE, there must be confirmed the presence of liver disease (e.g., abnormal liver function tests, ultrasound or liver biopsy demonstrating liver disease) or a portosystemic shunt, and exclusion of other potential etiologies (e.g., intracranial lesions, masses, hemorrhage or stroke; seizure activity; post-seizure encephalopathy; intracranial infections; or toxic encephalopathy from other causes). 

During the intermediate stages of HE, a characteristic jerking movement of the limbs is often observed (e.g., asterixis) when the patient attempts to hold arms outstretched with hands bent upward at the wrist.  Other physical signs may include hyperreflexia, a positive Babinski’s sign, or Parkinsonian symptoms (e.g., rigidity or tremors).

Evaluation

A diagnosis of HE should involve a thorough evaluation of the patient’s vital signs and airway followed by classification of the symptoms according to the West-Haven Criteria.  Also, it is important to properly differentiate between the presence of asterixis and tremulousness that may, in fact, be associated with alcohol withdrawal or abuse.[9][10][11]

Elevated blood ammonia levels are often seen in patients with hepatic encephalopathy.  It is more useful, however, to assess the clinical improvement or deterioration of a patient undergoing treatment rather than monitor serial arterial blood ammonia measurements.

Although electroencephalogram(EEG) changes (e.g., high-amplitude low-frequency waves and triphasic waves) may be observed in hepatic encephalopathy, these findings are not specific for the syndrome. An EEG may, however, be useful in ruling out seizure activity during the initial workup. Computed tomography (CT) or magnetic resonance imaging (MRI) may be employed to rule out the presence of intracranial lesions, masses, or hemorrhage. MRI may additionally be useful in demonstrating a common finding in hepatic failure and encephalopathy – basal ganglia T1 hyperintensity.

Treatment / Management

Treatment for HE involves proper identification and treatment of the underlying cause.  Antibiotics (e.g., rifaximin, neomycin/paromomycin/metronidazole, or vancomycin) are often given empirically due to the frequency of infection as an underlying cause.  Additional treatment measures include lactulose/lactitol (a non-absorbable osmotic laxative that also helps convert ammonia to non-absorbable ammonium in the gastrointestinal tract), LOLA (L-ornithine and L-aspartate preparation - increases the use of ammonia in the urea cycle to produce urea), zinc (to correct underlying deficiency common in cirrhotic patients) either alone or in combination with each other and/or antibiotics.

Patients at risk for aspiration or respiratory compromise should be prophylactically intubated and monitored in the ICU.  In the case of patients with concomitant alcohol withdrawal, medications that depress the central nervous system (e.g., benzodiazepines) should be avoided.[12][13][7]

Differential Diagnosis

• Intracranial lesions: subdural hematoma, intracranial hemorrhage, tumor, stroke, abscess
• CNS infections: meningitis
• Metabolic encephalopathy: hypoglycemia, anoxia
• Wernicke encephalopathy
• Post-seizure encephalopathy
• Drug-related- antipsychotics, sedatives, antidepressants

Complications

Even patients who show clinical improvement had residual cognitive impairment compared with patients with cirrhosis with either minimal hepatic encephalopathy or no encephalopathy.[14]

Postoperative and Rehabilitation Care

Patients with hepatic encephalopathy are at risk for recurrent episodes of encephalopathy.

Protein restriction is only of use in patients with acute flare-ups and is not justified in chronic cases. These patients need nutrition as they have a high catabolic rate and severe wasting.

Vegetable protein is better tolerated compared to animal protein.

Medications should be used with caution; one should avoid constipation, blood thinners and use prophylaxis against spontaneous bacterial peritonitis.

Consultations

• Transplant surgeon
• Interventional radiologist for TIPS
• Gastroenterologist

Pearls and Other Issues

Hepatic Encephalopathy may be classified according to the West Haven Criteria (a semi-quantitative grading of mental state - based on the level of dependence on therapy and the impairment in autonomy, behavior, consciousness, intellectual function) or the World Health Congress of Gastroenterology Criteria (based on the underlying cause of HE and associated conditions).[15]

West Haven Criteria

Grade 1

• Trivial lack of awareness
• Euphoria or anxiety
• Shortened attention span; impaired performance of addition or subtraction

Grade 2

• Lethargy or apathy
• Minimal disorientation for time or place
• Subtle personality change
• 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

Type A (acute)

• HE associated with acute liver failure, typically with cerebral edema

Type B (bypass)

• HE caused by portal-systemic shunting (without associated intrinsic liver disease)

Type C (cirrhosis)

• HE in patients with cirrhosis - subdivided into episodic, persistent, and minimal encephalopathy

Minimal Hepatic Encephalopathy

Minimal encephalopathy (MHE) is a form of HE that is not associated with any grossly evident signs of cognitive dysfunction but with cognitive deficits that can be demonstrated with neuropsychological testing. MHE has been shown to impair overall quality of life and ability to work and has been associated with a higher risk of motor vehicle accidents. Patients with MHE are also more prone to falls and have an increased risk of their condition progressing to overt HE. Psychometric testing remains the standard for diagnosis of MHE - these include the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and PSE-Syndrome-Test - which incorporate a number of neuropsychological tests aimed at measuring multiple domains of cognitive function (which tend to be more reliable than older tests focused on assessing single domains of cognitive function). Treatment with rifaximin or lactulose has also been shown to improve the quality of life in patients with MHE. Rifaximin has furthermore been shown to improve driving performance in simulated experiments. The combination of both Rifaximin and lactulose has been shown to prevent the recurrence of episodic HE over a period of 6 months follow-up.[16]

Enhancing Healthcare Team Outcomes

Once hepatic encephalopathy has been diagnosed, it carries a poor prognosis. Close to 40% of patients are dead within 12 months. in view of this high mortality an interprofessional team that closely monitors and manages the patient is vital to improve the quality of life. At the onset of the diagnosis, the patient should be referred to a liver transplant surgeon to determine his or her eligibility.

The pharmacist plays a critical role in monitoring the medications, which cannot only exacerbate the condition but can remain in the body for prolonged periods because they are not broken down by the liver. All the doses of drugs have to be decreased, and one should avoid potentially liver-toxic drugs.

The nurse should educate the patient and the family on the disorder, its progression and potential complications. The mental status changes have to be closely monitored because they impart a very poor quality of life. Further, most patients have very little insight into their disease and may not be able to perform any daily living activities- hence a consult with a social worker, home care nurse, and a physical therapist are recommended. Finally, a dietitian should be consulted to ensure that the patient is receiving adequate calories. [17][18](Level V)

Outcomes

With or without treatment, the prognosis for most patients with hepatic encephalopathy is poor. None of the current treatments are curative, and liver transplant is not readily available for most patients. The current day treatments are to ease symptoms and improve the quality of life. Because of the enormous burden of the disease, an interprofessional approach is highly recommended.[19][15] (Level V)