Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome marked by disturbances in consciousness, personality, intellect, and neuromuscular coordination and control; a diminishing level of consciousness; and electroencephalographic changes. End-stage cirrhosis and extensive hepatic metastases are the common underlying diseases that lead to this condition. Fulminant hepatic failure, characterized by the development of acute liver failure over several weeks, may be followed by hepatic encephalopathy. In reversible liver disease, the encephalopathy may be acute and reversible with early intervention; however, in end-stage liver disease, it has a grave prognosis.
The complete physiology of hepatic encephalopathy is not precisely known. It is thought to involve a combination of shunted liver circulation and biochemical alterations that ultimately alter neurotransmission. In liver dysfunction, collateral blood vessels form and shunt blood from the portal circulation to the systemic circulation, allowing neurotoxins absorbed from the gastrointestinal (GI) tract to bypass the liver and circulate to the brain. (A transjugular intrahepatic portosystemic stent shunt procedure can also alter the portal circulation.) The gastrointestinal (GI) tract normally absorbs toxic substances, which are broken down or detoxified by the liver before being released into the central circulatory system. If the process of detoxification is eliminated because of shunting, these toxic substances are released directly into the general circulation and may cross the blood-brain barrier. In liver failure, the permeability of the blood-brain barrier may also be increased.
The best known hazardous substance is ammonia, the end product of intestinal protein digestion or digestion of blood from GI bleeding. Bacteria in the colon also form ammonia, which contributes to raising the ammonia level, resulting in hyperammonemia. When ammonia comes in contact with the central nervous system, it interferes with neurotransmitters, alters cerebral energy, and causes cerebral edema. Massive cerebral edema may cause brain herniation and death (Huether, 2006). Ammonia also inhibits cellular chloride channels, additionally contributing to depression of the central nervous system (Haussinger et al., 2002). The correlation between the level of ammonia and the severity of encephalopathy is not definitively understood.
An accumulation of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, may be responsible for the decreased level of consciousness. Endogenous benzodiazepine substances in the central nervous system of individuals with liver failure may increase GABA’s inhibitory transmission function, ultimately causing a decrease in neurotransmission (Jones et al., 1993). Benzodiazepine levels are higher in hepatic encephalopathy, but they show only a weak correlation with the stage of encephalopathy (Basile et al., 1993).
Glutamine, which is synthesized from glutamate and ammonia, is an excitatory neurotransmitter. In hepatic encephalopathy, the reuptake of glutamate into cells may be inhibited, because brain tissue levels of glutamate are decreased, whereas extracellular levels are increased. The reason for these shifts is thought to be the hyperammonemia. The main center for the synthesis of glutamine from glutamate and ammonia is the astrocytes, and it may be that the hyperammonemia causes swelling of the astrocytes, preventing this process (Norenberg, 1998).
Other toxins that alter neuropsychiatric functioning include false neurotransmitters, accumulation of short-chain fatty acids, elevated manganese, hypokalemia, and alkalosis. False neurotransmitters are molecules similar to neurotransmitters which can inhibit the transmission of neural messages. In liver failure, branched-chain amino acids (BCAAs) are decreased and aromatic amino acids (AAAs) are increased. The AAAs travel to the brain, where they are metabolized into false neurotransmitters. Hyperammonemia may increase the breakdown of BCAAs. However, not enough is known yet about this pathway to use BCAAs to guide treatment (Als-Nielson et al., 2003).
Manganese may play a role in the pathogenesis of HE, because 80% of patients with cirrhosis in hepatic coma have increased concentrations of manganese. Prolonged exposure to manganese results in extrapyramidal symptoms and Alzheimer type II astrocytosis. Manganese and ammonia may act synergistically in causing HE symptoms (Weissenborn et al., 1995).
Other factors can aggravate HE, include vomiting and diarrhea, which can lead to hypokalemia and alkalosis. Alkalosis may increase the amount of the gaseous form of ammonia in the blood (Yurdaydin, 2003). Renal impairment may contribute to alkalosis, and if urea synthesis is impaired, more ammonia is formed. GI bleeding, transfusions, and an excessive protein intake may potentially cause hyperammonemia. Infection may worsen encephalopathy in individuals with acute liver failure (Rolando et al., 2000). Certain medications, especially sedatives, also can contribute to worsening symptoms.
The pathogenesis of hepatic encephalopathy is multifactorial, with ammonia being the predominant causative agent. Astrocytic changes in the brain and decreased glucose utilization in the cerebral cortex, with increased glucose utilization in the thalamus, caudate lobe, and cerebellum, suggest that hypometabolism explains the neuropsychiatric abnormalities seen in hepatic encephalopathy.
There are many variants of HE. The acute form is caused by fulminant liver failure with rapid progression to coma, seizures, and decerebrate rigidity; this form is associated with a high mortality rate from cerebral herniation and hypoxia. The slower onset form has milder symptoms and a longer duration and is reversible if the precipitating factors can be treated. The chronic form of HE is characterized by persistence of neuropsychiatric symptoms that do not resolve with adequate treatment. In rare cases, progressive, irreversible neurologic changes occur, including dementia, extrapyramidal manifestations, cerebellar degeneration, transverse cordal myelopathy, and peripheral neuropathy. The subclinical form of HE does not produce overt neuropsychiatric symptoms, but subtle changes can be detected with psychomotor testing; this form usually is reversible with treatment (Abou-Assi & Vlahcevic, 2001).
EPIDEMIOLOGY AND ETIOLOGY
Because the clinical manifestations of HE can range from subtle abnormalities to coma, the epidemiology is difficult to estimate. HE is seen most often with cirrhosis, the excessive scarring of the liver caused by a chronic. irreversible reaction to hepatic inflammation and necrosis. In the United States, the most common causes of cirrhosis are alcoholic liver disease and hepatitis C, whereas worldwide, hepatitis B is the leading cause of cirrhosis (Murphy, 2006). Estimates of the incidence of HE in cirrhosis run as high as 50% to 70%. Subclinical HE occurs in 50% to 80% of patients with cirrhosis; the most common symptoms are difficulty sleeping and altered concentration and hand-eye coordination (Friedman & Schiano, 2004). All patients with fulminant hepatic failure have HE (Gitlin et al., 1986). HE also occurs in patients with extensive hepatic metastasis.
RISK PROFILE
• Acute or chronic liver disease
• Cirrhosis
• Hepatitis
• Primary malignant liver tumors
• Cholangiocarcinoma
• Metastasis of GI malignancies. GI malignancies are prone to spread to the liver because of the portal venous drainage. Metastasis can reach the liver from any organ, but the passage of blood from the GI tract to the liver via the portal circulation explains the high rate of metastasis from GI primary tumors. Fifteen percent of colorectal cancers present with liver metastasis, and 60% develop liver metastasis (Kemeny et al., 2004).
• Breast cancer, lung cancer, and melanoma with liver metastasis, or any malignancy with widespread hepatic metastasis
• Inherited errors of the urea cycle
• Spontaneous or iatrogenic portosystemic venous shunting
• Precipitating factors (Box 22-1)
BOX 22-1
PRECIPITATING CONDITIONS IN HEPATIC ENCEPHALOPATHY
• Alkalosis
• Anemia
• Azotemia/uremia
• Constipation
• Dehydration
• Excessive protein intake
• Gastrointestinal bleeding
• Hepatocellular cancer
• Hypoglycemia
• Hypokalemia
• Hyponatremia
• Hypothyroidism
• Hypovolemia
• Hypoxia
• Infection (Helicobacter pylori infection in the stomach)
• Liver metastasis (widespread)
• Medications (opioids, benzodiazepines, sedatives)
• Noncompliance with treatment
• Portosystemic shunts
• Surgery
• Transjugular intrahepatic portosystemic shunt (TIPS)
• Vascular occlusion
PROGNOSIS
The 1-year survival rate for hepatic encephalopathy in cirrhosis is 40% (Friedman & Schiano, 2004). The prognosis for HE in patients with cancer depends on the extent of liver metastasis and the patient’s response to cancer treatment. In gastric and pancreatic cancer, metastasis to the liver correlates with a short survival. In colorectal cancer, if the liver is the sole site of metastatic disease and treatment is effective, survival may be extended (Kemeny et al., 2004). Extensive liver metastasis may cause malabsorption, electrolyte disturbances, hepatic encephalopathy, and liver failure progressing to death. HE in individuals with massive liver metastasis, disseminated disease, and poor response to treatment has a limited prognosis.
PROFESSIONAL ASSESSMENT CRITERIA (PAC)
1. The clinical features of hepatic encephalopathy tend to vary, because all parts of the brain may be affected, and the condition may manifest differently in the acute and chronic forms of liver failure. The acute form of HE is associated with fulminant liver failure characterized by rapid progression to profound coma, seizures, and decerebrate rigidity. Chronic HE is characterized by persistence of neuropsychiatric symptoms. Subclinical HE involves subtle changes detectable by psychomotor testing and is usually reversible. Box 22-2 presents the four stages of portosystemic encephalopathy.
BOX 22-2
STAGES OF PORTOSYSTEMIC ENCEPHALOPATHY
Stage 1: Prodromal
• Subtle manifestations that may not be recognized immediately
• Personality changes
• Behavior changes (agitation, belligerence)
• Emotional lability (euphoria, depression)
• Impaired thinking
• Inability to concentrate
• Fatigue, drowsiness
• Slurred or slowed speech
• Sleep pattern disturbances
Stage II: Impending
• Continuing mental changes
• Mental confusion
• Disorientation to time, place, or person
• Asterixis
Stage III: Stuporous
• Progressive deterioration
• Marked mental confusion
• Stuporous, drowsy, but arousable
• Abnormal electroencephalogram tracing
• Muscle twitching
• Hyperreflexia
• Asterixis
Stage IV: Comatose
• Unresponsiveness, leading to death in 85% of patients progressing to this stage
• Unarousable, obtunded
• Response to painful stimulus
• No asterixis
• Positive Babinski’s sign
• Muscle rigidity
• Fetor hepaticus (characteristic liver breath; musty, sweet odor)
• Seizures
From Ignatavicius, D. D., & Workman, M. L. (2006). Medical-surgical nursing: Critical thinking for collaborative care. (5th ed.). Philadelphia: W. B. Saunders.
2. Assess airway.
3. Neurologic status: Level of consciousness (ranges from slightly altered to coma), pupils, and ability to follow commands. In acute liver failure, seizures and lateralizing signs may be observed.
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