The Management of Hepatic Encephalopathy
OVERVIEW Hepatic encephalopathy (HE) is a complex, potentially reversible, neuropsychiatric syndrome observed in patients with cirrhosis or acute liver failure. Patients with HE may have symptoms ranging from subtle abnormalities, detectable only through specialized psychological testing, to frank coma. Generally accepted stages for the broad spectrum of clinical manifestations of encephalopathy are based on level of consciousness, cognitive function, behavioral disturbances, and neuromuscular features (Table 1). In milder cases, the encephalopathic patient may be unaware of any deficits, and symptoms such as sleep pattern reversal, mild confusion, irritability, or personality changes may be apparent only to close contacts. Consequently, it is often helpful to obtain a history from a cirrhotic patient in the presence of family members. HE remains largely a clinical diagnosis; no specific signs, symptoms, or laboratory test results are diagnostic of this disorder. The symptoms commonly associated with HE also occur in other conditions, such as hypoglycemia, head trauma, and intoxication. Asterixis, a flapping tremor of the outstretched hands, is a common feature of HE but also occurs in other metabolic encephalopathies. Elevated plasma levels of ammonia are common but not universal in HE, and the level of blood ammonia concentration is not always correlated with the severity of encephalopathy. Electroencephalography testing results are always abnormal in overt HE, but observed changes, such as triphasic waves, are not specific. Focal neurologic deficits such as hemiplegia or hemiparesis are observed in fewer than 20% of patients with HE, and seizures are rarely observed. Consequently, other causes of altered mental status must be ruled out before the diagnosis of HE is confirmed, and any focal neurologic deficiency should prompt central nervous system (CNS) imaging to rule out structural lesions. PATHOPHYSIOLOGY The pathogenesis of HE is multifactorial, and despite extensive research in both humans and animals, it remains unclear. The basic tenet of most hypotheses is that the brain is exposed to toxic substances produced in the gut by the actions of bacteria on nitrogenous compounds, which are incompletely cleared from the blood by the compromised liver. Ammonia was the first such substance described and has been the most extensively studied. There is compelling evidence that ammonia is an important pathogenetic factor in HE. Most patients with overt HE exhibit elevated plasma levels of ammonia, and children with urea cycle enzyme deficits and otherwise normally functioning livers develop profound hyperammonemia and symptoms indistinguishable from those of HE. Ammonia can affect CNS function through several mechanisms. After crossing the blood–brain barrier, ammonia enters CNS astrocytes and combines with the neurotransmitter glutamate to form glutamine through the action of glutamine synthetase. Astrocytic glutamine enters mitochondria, in which it is converted back to ammonia and glutamate. Mitochondrial ammonia contributes to the production of reactive oxygen species and upregulates aquaporin 4. This results in astrocytic swelling that causes histologic changes known as Alzheimer type II astrocytosis. Adverse effects of ammonia on cerebral perfusion and glucose metabolism additionally contribute to CNS impairment. There is evidence that γ-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. Increased production of endogenous benzodiazepine ligands by gut bacteria can result in increased GABAergic transmission and altered CNS function. This explains why some patients with HE respond to the benzodiazepine antagonist flumazenil even in the absence of exposure to exogenous benzodiazepines. Other substances, such as mercaptans and neurosteroids, and manganese toxicity may also contribute to neuronal and astrocytic injury in HE. In all likelihood, these factors have varying influences in individual patients, depending on the cause, acuity, and severity of the liver disease and hence the variable manifestations of HE.
TABLE 1:â•‡ Clinical manifestations and severity of hepatic encephalopathy Encephalopathy stage Level of consciousness Cognitive function Behavioral disturbance Neuromuscular feature I (mild) Abnormal sleep pattern Shortened attention span, mildly impaired computations Euphoria, depression, irritability Tremor, muscular incoordination, impaired handwriting II (moderate) Lethargy, mild disorientation Amnesia, grossly impaired computations Overt change in personality, inappropriate behavior Slurred speech, asterixis (flapping), hypoactive reflexes, ataxia III (severe) Somnolence, semistupor Inability to compute Paranoia, bizarre behavior Hyperactive reflexes, nystagmus, Babinski sign, clonus, rigidity IV (coma) Stupor, unconsciousness None None Dilated pupils, opisthotonus, coma Modified from Conn H, Lieberthal M: The hepatic coma syndromes and lactulose, Baltimore, 1979, Williams & Wilkins.
BOX 1:â•‡ Precipitating factors in hepatic encephalopathy Gastrointestinal bleeding Sedatives or analgesics Dehydration Renal failure Hypokalemia Metabolic alkalosis Infection (spontaneous bacterial peritonitis, pneumonia, urinary tract infection) Excessive dietary protein Constipation
CLASSIFICATION AND MANAGEMENTOF HEPATIC ENCEPHALOPATHY HE can be classified according to the underlying disorder that leads to it. It is associated with cirrhosis and portal hypertension, the presence of shunts, and, more ominously, acute liver failure. In practice, HE is classified as overt encephalopathy, minimal HE, and encephalopathy associated with acute liver failure. Overt Encephalopathy HE is a common complication of cirrhosis and can be episodic, developing over a short period of time with fluctuations in severity, or it can be persistent, with continuous overt neurologic or behavioral abnormalities. In most patients with episodic encephalopathy, a precipitating factor other than liver disease can be identified (Box 1). Gastrointestinal bleeding is a very common precipitant of HE. This occurs through a combination of decreasing hepatic and renal perfusion and a large protein load to the gut, which results in increased production of nitrogenous byproducts. Evaluation of gastrointestinal blood loss and control of active bleeding must be performed in all patients with episodic HE. Infection is also a common precipitating factor for HE. The clinician must search for a source of infection. Cirrhosis can make the signs of infection less apparent. The baseline neutropenia and impaired response to infection can obscure the source of infection. The authors recommend a basic workup for infectious disease and that patients with overt HE and ascites undergo a diagnostic paracentesis to rule out spontaneous bacterial peritonitis. If there is a high index of suspicion for infection, empiric antibiotic therapy should be started after culture samples have been obtained. Many cirrhotic patients take diuretics; intravascular volume depletion from vigorous diuresis can reduce renal perfusion and result in azotemia and increased ammonia production. A hypokalemic alkalosis can enhance renal ammonia production, thereby precipitating HE. Reestablishing intravascular volume and correcting electrolyte imbalances often reverses encephalopathy. Exposure to sedatives and analgesics, especially benzodiazepines, can potentiate the effects of putative neurotoxins in HE and should be avoided. In postoperative or critical care settings, HE is often blamed for the prolonged effects of sedation in patients with cirrhosis. In such patients, use of sedatives should be minimized as much as possible, and clinicians must be aware that these drugs may have prolonged effects. Treatment for overt HE is designed to treat the inciting factors. If this is insufficient, then modulating the gut bacteria with medication is the mainstay of treatment. The medications used reduce the gut production of ammonia through a variety of mechanisms. Despite maximal medical therapy, HE is refractory in some patients. The medications used for treatment of overt HE are used for all types of HE but are best understood in the context of overt HE. Oral Disaccharides For many years, the nonabsorbable disaccharides lactulose and lactitol have been the mainstay of therapy for HE. Theoretically, lactulose increases ammonia clearance through its cathartic action and decreases ammonia absorption by increasing the stool pH. Many affected patients have an improvement in symptoms of HE within hours of lactulose administration. These agents improve symptoms of encephalopathy, but they do not reduce the mortality rate. Despite the limitations, these treatments are the “gold standard” of therapy for HE. Lactulose is typically administered orally and in multiple doses each day. The dosing schedule should be individualized for the patient to achieve three to five bowel movements per day. Excess bowel movements as a result of these agents can actually precipitate episodes of HE, probably through dehydration and electrolyte abnormalities. The side effects of these agents (bloating, nausea, flatus, diarrhea, abdominal pain) dramatically limit their use in many patients. In view of the transient changes in the gut from these medications, noncompliance with the therapy results in return of HE symptoms. When these drugs are used, patient education and monitoring are paramount in trying to ensure compliance. In a patient with acute or worsened overt HE, administration of these agents should be carefully monitored because excessive administration can lead to significant bloating if the patient is not having bowel moments. This results from the consumption of the compound by the gut bacteria, which leads to bloating and further stasis of the gut. For patients unable to take lactulose orally, it can be administered per rectum as a retention enema (300â•¯mL of lactulose with 700â•¯mL of water). Dietary Protein Restriction The potential association between dietary protein intake and encephalopathy was first described decades ago. In theory, reducing dietary protein intake should reduce nitrogenous toxin production. Although improvement may occur in individual encephalopathic patients with dietary protein restriction, this benefit has been difficult to demonstrate in controlled trials. In fact, in several studies of severe acute alcoholic hepatitis, the administration of high-protein/high-calorie diets improved rather than exacerbated encephalopathy. In addition, protein restriction to less than 40â•¯g/day can accelerate catabolism and contribute to malnutrition. In practice, monitoring for changes in HE is best in patients on a regular-protein diet. Low-Absorbable Antibiotics Suppression of toxin production by gut bacteria is the basis for the use of poorly absorbed antibiotics. In numerous clinical trials, researchers have assessed the efficacy of various antibiotics in patients with different classes of encephalopathy. Neomycin and metronidazole were classically used to treat HE; however, the side effects of these medications have limited their use. Limited effectiveness is noted with oral vancomycin. Rifaximin, a derivate of rifamycin, was originally developed to treat traveler’s diarrhea and has broad-spectrum activity against gram-negative rods and gram-positive cocci. Several studies show that rifaximin is equal to if not better than oral disaccharides in patients with both overt and minimal encephalopathy. Concerns about possible bacterial overgrowth or fungal colonization are unfounded. Rifaximin has been shown effective in long-term treatment of HE with minimal side effects. There is a theoretical risk of bacterial overgrowth and associated infections with long-term use of rifaximin, but this has not been confirmed in studies. In patients with intolerance to oral disaccharides, it is the medication of choice, and for some patients, its lower side effect profile makes it the primary medication for treatment of HE. The U.S. Food and Drug Administration approved the use of rifaximin for the reduction in the risk of the recurrence of overt HE in patients with advanced liver disease. The recommended dosage is 550â•¯mg by mouth twice per day. The medication is effective in treating acute HE and maintaining a response to prevent overt HE. Rifaximin remains expensive, however, and patients are often unable to afford the medication in the long term. In practice, the combination of lactulose and rifaximin is known to be additive in its effect in some patients. Other Therapies Sodium benzoate combines with ammonia to produce hippurate, which is renally excreted. In limited trials, it compares favorably with lactulose. L-ornithine L-aspartate increases hepatic conversion of ammonia and is better than placebo at lowering plasma ammonia levels and improving encephalopathy grade. Flumazenil, a benzodiazepine antagonist, showed improvement in encephalopathy grade but is not approved for this indication by the U.S. Food and Drug Administration. Zinc lowers plasma ammonia by increasing ornithine transcarbamylase activity, but its benefits in HE have been inconsistent. Branched-chain amino acids in several different formulations improve symptoms but not length of survival, and they are relatively expensive. Trials of probiotics, which are live organisms that confer a benefit on health, have yielded mixed results for benefit in treating encephalopathy. A meta-analysis suggested that probiotics might be beneficial in the treatment of HE. The evidence remains limited as to their effectiveness. Hepatic Encephalopathy Associated With Acute Liver Failure HE is a prominent and ominous component of acute liver failure, but it differs from that observed in cirrhosis and portal hypertension. Although marked hyperammonemia can occur in both disorders, cerebral edema with intracranial hypertension is common in acute liver failure but rarely occurs in chronic liver disease. The risk of cerebral edema is correlated with the encephalopathic grade in acute liver failure. It is very low in grades 1 and 2 HE but progresses to 35% in grade 3 HE and 75% in grade 4 HE. The reason for this association with acute liver failure is not entirely clear, because the consequences of hyperammonemia on cerebral function should be similar in acute and chronic liver disease. Some authorities have proposed that markers of systemic inflammation commonly observed in acute liver failure may be a contributing factor. Excess free water with hyponatremia may exacerbate ammonia-induced cerebral edema. 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 are apparent only at an irreversible stage. Consequently, some medical centers advocate the use of invasive monitoring devices, which accurately measure ICP. However, there is significant risk in monitoring in patients with acute liver failure and related coagulopathy. 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 encephalopathy 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 1â•¯g/kg) or hypertonic saline should be given to patients with objective evidence of increased ICP. Temporary hyperventilation, with a goal Paco2 of 25â•¯mmâ•¯Hg, may be helpful if the ICP cannot be adequately lowered with mannitol. Most patients require renal replacement therapy to lower ammonia levels because 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 and by the American Association for the Study of Liver Diseases practice guidelines. Minimal Hepatic Encephalopathy Minimal HE is a milder form of HE in which impairment in cognitive function is detectable only through neuropsychological testing. It affects 20% to 70% of patients with cirrhosis. The numberconnection test and block-design test have reasonable specificities for minimal HE and are easy to administer. The deficits in minimal HE are primarily related to visuospatial orientation, attention problems, and impaired short-term memory. Oral and written skills show little impairment. Neuroimaging studies have shown a correlation between minimal HE and changes in cerebral blood flow and abnormalities on neuropsychological testing. Although patients with minimal HE have no overt symptoms of encephalopathy, their capacity to work or drive may be diminished. When tested on a driving simulator, patients with minimal HE both overestimate their abilities to drive and show impaired performance. Other studies have shown that patients with minimal HE have more collisions and have difficulty with traffic rules and road signs. At present, there is no consensus as to whether driving restrictions should be mandated. Treatment with both lactulose and rifaximin improve neuropsychological testing and quality of life in patients with minimal HE. These therapies also show some benefit in driving performance as well. S u g g e s t e d R e a d i n g s Bass NM, Mullen KD, Sanyal A, et al: Rifaximin treatment in hepatic encephalopathy, N Engl J Med 362(12):1071–1081, 2010. Holte K, Krag A, Gluud LL: Systematic review and meta-analysis of randomized trials on probiotics for hepatic encephalopathy, Hepatol Res 42(10): 1008–1015, 2012. Polson J, Lee WM: American Association for the Study of Liver Disease. AASLD position paper: the management of acute liver failure, Hepatology 41(5):1179–1197, 2005. Sanyal AJ, Mullen KD, Bass NM: The treatment of hepatic encephalopathy in the cirrhotic patient, Gastroenterol Hepatol (N Y) 6(4 Suppl 8):1–12, 2010.