Hepatic encephalopathy (HE) is a complex syndrome that results in neuropsychiatric disturbances in patients with cirrhosis or acute liver failure. Symptoms can range from subtle abnormalities, detectable only through specialized neuropsychological testing, to overt coma. The various stages of encephalopathy are based on level of consciousness, cognitive function, behavioral disturbances, and neuromuscular features (Table 159-6). Mild symptoms such as sleep pattern reversal, confusion, irritability, or altered personality may be apparent only to close contacts. For this reason, it is often helpful to evaluate a cirrhotic patient in the presence of family members.
A classification system for HE was established by the World Congress of Gastroenterology in 1998 (Table 159-7). This system is based on the nature of the underlying liver disease and the persistence and severity of symptoms. HE can be associated with acute liver failure, porto-systemic shunting without intrinsic liver disease, and cirrhosis. HE encephalopathy associated with cirrhosis can be further characterized as episodic, persistent, or minimal. Episodic HE develops over a short period of time and fluctuates in severity. Patients with persistent HE exhibit continuous overt neurologic or behavioral abnormalities. Minimal hepatic encephalopathy (MHE) is a milder form of HE in which impairment in cognitive function is only detectable through neuropsychological testing. The etiology and management of each of these forms of HE varies.
Pathophysiology of Hepatic Encephalopathy
Multiple factors contribute to the development of hepatic encephalopathy, but the exact pathogenesis remains unclear. Most theories postulate that the brain is exposed to toxic substances that are produced by bacterial flora. These substances are generated through processing of nitrogenous dietary compounds and are incompletely cleared from the blood by the compromised liver. Ammonia was the first neurotoxic substance identified and has been extensively studied. The majority of patients with overt HE have elevated plasma levels of ammonia. However, the level of hyperammonemia does not necessarily correlate with degree of hepatic encephalopathy.
There are several mechanisms by which ammonia affects central nervous system (CNS) function. Patients with HE have increased ammonia diffusion across the blood-brain barrier. Ammonia enters CNS astrocytes and combines with the neurotransmitter glutamate to form glutamine. Glutamine is converted back to ammonia and glutamate within astrocyte mitochondria. Mitochondrial ammonia stimulates production of reactive oxygen species and aquaporin 4, which results in astrocyte swelling and histologic changes known as Alzheimer type II astrocytosis. Ammonia also has deleterious effects on cerebral perfusion and glucose metabolism, which contribute to CNS impairment.
Gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the CNS, may also play an important role in the pathogenesis of HE. Increased GABA levels have been associated with liver injury and hyperammonemia. The proposed mechanism of increased GABA activity is through increased production of endogenous benzodiazepine ligands by gut bacteria that bind the benzodiazepine site of GABA receptors and upregulates GABA-ergic transmission. The best supporting evidence for this theory is the observation of improvement in mental status in some patients with HE after administration of the benzodiazepine antagonist flumazenil even in the absence of exposure to exogenous benzodiazepines.
Other substances, such as mercaptans, neurosteroids, and manganese may also contribute to HE through neuronal and astrocytic injury. Most likely, all of these factors have varying influences in individual patients with HE depending on the etiology, acuity, and severity of the underlying liver disease.
Diagnosis of Hepatic Encephalopathy
The diagnosis of HE remains largely clinical. There are no specific signs, symptoms, or laboratory tests that are diagnostic of the disorder. Patients with HE may exhibit a range of altered levels of consciousness and cognitive-behavioral changes. Symptoms commonly associated with HE, however, are nonspecific and can be associated with other conditions such as hypoglycemia, intracranial pathology, uremia, or intoxication. Other causes of altered mental status therefore must be excluded before making the diagnosis of HE. Asterixis, a flapping tremor of the outstretched hands, is a common feature of HE but may also be seen in other metabolic encephalopathies, such as uremia. Focal neurologic deficits such as hemiplegia or hemiparesis, and seizures are rarely observed in patients with HE and should prompt further CNS evaluation, including imaging, to exclude structural lesions. Laboratory abnormalities such as elevated plasma levels of ammonia are commonly seen in HE but are not universal. Routine ordering of plasma ammonia levels in cirrhotic patients with delirium is not recommended to evaluate for or follow the course of HE. Ordering of ammonia levels should be reserved for patients in whom another etiology for encephalopathy is reasonably likely to help evaluate the likelihood of HE. Patients with levels above 150 μmol/L are more likely to have hepatic encephalopathy, but elevated levels below that threshold may or may not have hepatic encephalopathy. EEG testing is always abnormal in overt HE, but observed changes, such as triphasic waves, are not specific.
- The diagnosis of hepatic encephalopathy (HE) remains largely clinical, based on history and physical examination, while ruling out other potential etiologies of encephalopathy. There are no specific signs, symptoms, or laboratory tests that are diagnostic of the disorder. Ammonia levels should not be ordered routinely to evaluate for or follow the course of hepatic encephalopathy.
Management of Hepatic Encephalopathy
Management of patients with HE associated with acute and chronic liver disease is detailed below. Encephalopathy associated with portal-systemic shunting without intrinsic liver disease will not be discussed.
Hepatic Encephalopathy Associated with Cirrhosis: Episodic
In most patients with episodic HE associated with cirrhosis, a precipitating factor can be identified (Table 159-8). In general, precipitants alter CNS function by increasing toxin generation, by impairing liver function and enhancing portosystemic shunting of toxins to the brain, by decreasing clearance of toxins, or by enhancing the effects of toxins on the CNS. Common precipitants include gastrointestinal bleeding, infection, hypokalemia, azotemia, acute hepatitis, and drug side effects. A thorough evaluation for precipitating factors is indicated for all hospitalized patients with HE. Identified precipitants must be treated.
Table 159-8 Common Precipitants of Episodic Hepatic Encephalopathy Associated with Cirrhosis |Favorite Table|Download (.pdf)
Table 159-8 Common Precipitants of Episodic Hepatic Encephalopathy Associated with Cirrhosis
- Gastrointestinal bleeding
- Drug side effects
- Excessive protein ingestion
Gastrointestinal bleeding is the most common precipitant of episodic HE in patients with cirrhosis. This occurs through a combination of impaired hepatic function from decreased hepatic perfusion and increased production of nitrogenous byproducts from digestion of blood proteins. Evaluation of gastrointestinal blood loss and control of active bleeding must be performed in all patients with episodic HE.
- Gastrointestinal bleeding is the most common precipitant of episodic hepatic encephalopathy (HE) in patients with cirrhosis. Evaluation of gastrointestinal blood loss and control of active bleeding must be performed in all patients with episodic HE. All patients with HE and ascites should undergo a diagnostic paracentesis to exclude SBP, the most common bacterial infection in hospitalized patients with cirrhosis.
A high prevalence of infection occurs in patients with HE, and a careful assessment for occult infection is indicated in all patients with HE. All patients with HE and ascites should undergo a diagnostic paracentesis to exclude SBP, the most common bacterial infection in hospitalized patients with cirrhosis. If there is a high index of suspicion for infection, empiric antibiotic therapy should be started after cultures have been drawn and before results are known. Cirrhotic patients frequently have baseline neutropenia from hypersplenism and may not exhibit leukocytosis in response to bacterial infections. Patients with advanced liver disease are also often hypothermic and do not mount a fever in response to infection. The mechanism by which infection causes HE in patients with cirrhosis is believed to be cytokine-mediated. Activation of cytokines exacerbates astrocyte swelling, and bacterial cell wall compounds augment the effects of ammonia on cerebral blood flow.
Azotemia and electrolyte disturbances can also cause HE in patients with cirrhosis. Cirrhotic patients, particularly those with ascites, are often exposed to potent diuretics. Intravascular volume depletion from vigorous diuresis can reduce renal perfusion and result in azotemia and increased ammonia production. A hypoklalemic alkalosis can enhance both renal ammonia production and ammonia transport across the blood brain barrier by favoring ammonia over ammonium ion. In these patients, reestablishing intravascular volume and correcting electrolyte imbalances can often reverse encephalopathy without any other specific therapy.
A careful review of medications and diet is also important when evaluating patients with cirrhosis and HE. Exposure to sedatives and analgesics, especially benzodiazepines, can potentiate the effects of putative neurotoxins in HE and should be avoided. In a minority of patients, increased dietary protein intake can precipitate an episode of encephalopathy by increasing the nitrogen load in the gastrointestinal tract. This can often be reversed with simple dietary modifications; however, protein restrictions should not be applied routinely for all patients with cirrhosis or hepatic encephalopathy.
Hepatic Encephalopathy Associated with Cirrhosis: Persistent
In patients with cirrhosis and persistent encephalopathy, or those with episodic encephalopathy whose symptoms continue after treatment of underlying precipitating factors, specific therapy directed toward encephalopathy is indicated. All proposed therapies reduce gut bacterial production of toxins derived from intraluminal nitrogenous substances. Although commonly used, the efficacy of most of these therapies remains equivocal based on data from clinical trials and meta-analyses.
The nonabsorbable disaccharides (lactulose and lactitol) have remained the mainstay of therapy for HE. Theoretically, lactulose increases ammonia clearance through its cathartic action and decreases intestinal ammonia absorption by “trapping” it in the acidic colonic lumen that results from the accumulation of short-chain fatty acids. Patients often show improvement in symptoms of HE within hours of lactulose administration. However, a Cochrane review concluded that “there is insufficient evidence to determine whether non-absorbable disaccharides are of benefit in patients with HE” and “nonabsorbable dissacharides should not be used as the comparator in randomized trials of HE.”
Despite the absence of compelling evidence to support its use, lactulose remains the most commonly used agent for the treatment of HE. It may have the greatest efficacy in patients with HE precipitated by gastrointestinal bleeding, since its cathartic action rapidly evacuates the colon of blood, thereby reducing bacterial protein load. Lactulose is titrated to a goal of producing 3–5 soft bowel movements per day. In most patients, 30 cc administered twice a day is sufficient. Higher or more frequent dosing may cause bloating and excessive diarrhea. For patients who are not able to take oral medications, lactulose can be administered per rectum (300 cc lactulose with 700 cc water). There are few adverse side effects from lactulose other than occasional hypernatremia.
High dietary protein intake may be associated with hepatic encephalopathy. In theory, dietary protein intake stimulates nitrogenous toxin production in the gut. While dietary protein restriction may improve HE in certain individuals, this benefit has been difficult to establish in controlled trials. Many studies of severe acute alcoholic hepatitis even observed that administration of high protein/high calorie diets improved, rather than exacerbated, encephalopathy. Furthermore, protein restriction to less than 40 g per day can accelerate catabolism and contribute to malnutrition. During episodes of severe encephalopathy, dietary protein intake is negligible during the first few days in the hospital. After this initial period, it is reasonable to modestly restrict dietary protein to 1.0 g/kg/day and to observe the patient for clinical improvements. Protein from vegetable sources may be better tolerated than animal-derived protein.
Orally administered poorly absorbed antibiotics may improve HE by decreasing toxin production by gut flora. Several clinical trials have assessed the efficacy of various antibiotics in patients with different classes of HE. Studies of oral metronidazole and oral vancomycin have yielded equivocal results. Rifaximin, a derivative of rifamycin, has broad spectrum activity against Gram-negative rods and Gram-positive cocci. Several studies suggest that rifaximin is superior to disaccharides in patients with both overt and minimal encephalopathy. One recent study showed no increased risk for bacterial overgrowth or fungal colonization with rifaximin therapy for prolonged periods. The recommended dose of rifaximin is 400 mg three times daily. Its use may be limited by cost ($1200–$2000 per month), and FDA approval is still pending. Neomycin, an aminoglycoside, is contraindicated in patients with HE due to the risk of ototoxicity and renal failure.
Therapies that enhance ammonia clearance include sodium benzoate, zinc, and L-ornithine L-asparate (LOLA). Sodium benzoate combines with ammonia to produce hippurate, which is renally excreted. It has been used extensively in children with urea cycle deficits and compares favorably with lactulose in patients with HE in limited trials. LOLA increases hepatic conversion of ammonia and performs better than placebo at lowering plasma ammonia and improving encephalopathy grade. Zinc lowers plasma ammonia by increasing ornithine transcarbamylase activity, but its benefits in HE have been inconsistent. Flumazenil, a benzodiazepine receptor antagonist, has been shown to improve HE grade but is not currently FDA-approved for treatment of HE. Branched chain amino acids in several different formulations improve symptoms but not survival and are relatively expensive. Probiotics reduce substrate for other gut bacteria; early trials suggest a possible benefit in minimal encephalopathy.
Hepatic Encephalopathy Associated with Cirrhosis: Minimal
Minimal hepatic encephalopathy (MHE) is a milder form of HE in which impairment in cognitive function is only detectable through neuropsychological testing such as the number connection test and block design test. The deficits in MHE are primarily related to visual-spacial orientation, attention deficits, and impaired short-term memory. Oral and written skills are grossly intact. Neuroimaging studies have shown changes in cerebral blood flow and abnormalities on neuropsychological testing. While patients with MHE have no overt symptoms of encephalopathy, they may have a diminished capacity to work or drive. One study comparing physical requirements of employment with concurrent psychomotor and motor deficits concluded that more than half of “blue-collar” workers and one quarter of “white collar” workers with MHE were unfit to work. Studies assessing the effect of MHE on driving through simulator and on-road testing have yielded inconsistent results. Some studies observe no impairment in ability to drive. Other studies have shown that patients with MHE have more collisions and have difficulty following traffic rules and road signs. At present, there is no consensus on driving restrictions for patients with MHE. Several recent controlled trials have suggested that both lactulose and rifaximin improve neuropsychological testing and quality of life in patients with MHE.
Hepatic Encephalopathy Associated with Acute Liver Failure
The clinical presentation and management of HE associated with acute liver failure differs from HE in cirrhosis and portal hypertension. Cerebral edema and intracranial hypertension is common in HE associated with acute liver failure but rare in chronic liver disease. The risk of cerebral edema correlates with encephalopathic grade. The risk is very low in grades 1 and 2 but progresses to 35% in grade 3 and 75% in grade 4. The reason for the association between cerebral edema and acute liver failure is not known. HE associated with both acute and chronic liver disease can present with marked hyperammonemia and consequences of ammonia on cerebral function should be similar in both types of liver disease. It is possible that markers of systemic inflammation commonly seen in acute liver failure, but not chronic liver disease, may be a contributing factor. Excess free water with hyponatremia may exacerbate ammonia-induced cerebral edema.
- Cerebral edema and intracranial hypertension is common in hepatic encephalopathy (HE) associated with acute liver failure but rare in chronic liver disease. The risk of cerebral edema correlates with encephalopathic grade, low risk in HE grades 1 and 2 but progresses to 35% in HE grade 3 and 75% in HE grade 4. Patients with acute liver failure who develop grade 2 HE should be admitted to an intensive care unit with integrated monitoring and multiorgan support. Patients with grade 3 HE should be ventilated for airway protection and the head should be elevated to 30 degrees.
Accurately assessing intracranial pressure (ICP) on clinical grounds is difficult. Physical findings such as papillary changes, abnormalities in the oculovestibular reflex, and decerebrate posturing are indicators of intracranial hypertension but often become apparent at an irreversible stage of HE. Some medical centers advocate the use of invasive monitoring devices to accurately measure ICP. However, one retrospective report from the U.S. Acute Liver Failure Study reported a 10% complication rate associated with invasive ICP monitoring, of which 5% could have contributed to death. There was also no significant improvement in outcomes in patients with invasive monitoring. Therefore, while ICP monitoring generally provides important information, particularly in patients with high grade HE, risks and benefits of its usage are largely dependent on local expertise on placement and interpretation of the devices.
Patients with acute liver failure who develop grade 2 HE should be admitted to an intensive care unit with integrated monitoring and multiorgan support. Patients with grade 3 HE should be ventilated for airway protection, and the head should be elevated to 30 degrees. Intravenous hypotonic solutions should be avoided because of the risk of hyponatremia-induced cerebral edema. Bolus infusions of mannitol (0.5 to 1.0 g/kg) or hypertonic saline should be given to patients with objective evidence of increased ICP. Temporary hyperventilation with a goal PaCO2 of 25 mm Hg may be helpful if the ICP cannot be adequately lowered with mannitol. Most patients require renal replacement therapy (RRT) to lower ammonia levels since lactulose is ineffective in acute liver failure. Intracranial hypertension refractory to medical management should prompt consideration for liver transplantation. More detailed instructions for the management of patients with acute liver failure can be found in recommendations published by the U.S. Acute Liver Failure Study Group (Table 159-9).
Table 159-9 Evidence-Based Medicine: Key References for Complications of Cirrhosis |Favorite Table|Download (.pdf)
Table 159-9 Evidence-Based Medicine: Key References for Complications of Cirrhosis
|Runyon B. Hepatology. 2009;49:2087–2107.||Review article||Discusses diagnosis and management of ascites, SBP, and HRS.||Review||AASLD Practice guidelines for management of adult patients with ascites from cirrhosis|
|Runyon BA, et al. Ann Intern Med. 1992;117:215–220.||Prospective observational||SAAG is superior to exudates/transudate concept in establishing cause of ascites||Heterogeneous patient population||The study provides guidelines for the use of the SAAG from ascitic fluid analysis to determine whether ascites is due to cirrhosis|
|Stanley MM, et al. N Engl J Med. 1989;321:1632–1638.||Randomized controlled trial||Used a combination of sodium restriction, spironolactone, and furosemide to treat ascites||Multicenter trial comparing diuretic therapy with peritoneovenous shunt||Ascites can be controlled with medical therapy in 90% of patients|
|Gines P, et al. Gastroentrology. 1987;93:234–241.||Randomized controlled trial||Compared paracentesis with diuretics in the treatment of ascites||Evaluated tense ascites||Large volume paracentesis can be safely performed for control of tense ascites in cirrhosis|
|Haynes GR, et al. Eur J Anaesth. 2003; 20:771–793.||Meta-analysis||79 randomized trials in multiple settings showed albumin infusion reduces rises in creatinine, but no effect on mortality||Included only 10 trials in patients with ascites||No consensus statement as to value of albumin after paracentesis|
|Salerno F, et al. Gastroenterology. 2007;133:825–834.||Meta-analysis||Evaluated TIPS for refractory ascites; included individual patient data; significant improvement in survival (p = 0.035) with TIPS and similar likelihood of encephalopathy||Systematic review||Shows improved survival with TIPS compared to medical therapy in patients with refractory ascites|
|Hoefs JC, et al. Hepatology. 1982; 2:399–407.||Observational study||Establishes criteria for diagnosis of SBP as positive culture with PMN count > 250 cells/mm3||Small study N, limited follow-up time||Established criteria for empiric therapy for SBP|
|Felisart J, et al. Hepatology. 1985;5:457–462.||Randomized controlled trial||Cefotaxime covers 95% of SBP flora||Treatment effectiveness compared to ampicillin-tobramycin only||Suggests Cefotaxime as preferred therapy for suspected SBP|
|Salerno F. Gut. 2007;56: 1310–1318.||Review||Established criteria for diagnosis of 2 types of hepatorenal syndrome||Review||Report of a consensus group on criteria for the diagnosis of hepatorenal syndrome|
|Esrailian E, et al. Dig Dis Sci. 2007;52:742–748.||Retrospective nonrandomized controls||Midodrine/octreotide reduced mortality 43% versus 71% compared to albumin treated controls||Retrospective nonrandomized control||Suggests potential benefit of midodrine/octreotide in type 1 HRS|
|Ferenci P, et al. Hepatology; 2002;35:719.||Review article||Discusses definition and criteria for diagnosis of hepatic encephalopathy||Review article||Defines the three types of encephalopathy|
|Sundaram V, et al. Med Clin North Am. 2009;93:819–836.||Review article||Discussion of pathophysiology, clinical features, and treatment of encephalopathy||Review article||Comprehensive review of the management of hepatic encephalopathy|
|Als-Nielsen B, et al. BMJ. 2004;328:1046.||Meta analysis||Disaccharides compared to placebo or no intervention showed modest but statistically significant benefit||Review article||Nonabsorbable disaccharides improve symptoms in about 75% of patients with overt encephalopathy|
|Bass N, et al. N Engl J Med. 2010;362:1071–1081.||Randomized placebo controlled trial||Rifaximin 550 mg twice a day maintained remission from hepatic encephalopathy more effectively than placebo and reduced risk of hospitalization||6 month study 90% received concomitant lactulose||Over a short interval rifaximin reduced episodes of overt encephalopathy compared to placebo in patients also receiving lactulose|
|Prasad S, et al. Hepatology. 2007;45:549–549.||Randomized trial||Lactulose improved cognitive function and quality of life in patients with minimal hepatic encephalopathy||Short duration||Lactulose was beneficial in patients with minimal encephalopathy|
|Stravitz RT, et al. Crit Care Med. 2007 Nov;35(11): 2498–2508.||Guideline||ICP monitoring recommended in advanced hepatic encephalopathy awaiting liver transplantation. For high ICP, use osmotic therapy with IV mannitol to maintain mildly hyperosmotic state and high normal serum sodium to minimize cerebral edema.||Divergent practices exist for some areas of management, and some recommendations supported by limited evidence or expert opinion.||Concensus guidleines direct ICU management of acute liver failure and may direct future studies.|