Current Concepts. Review Article T REATMENT OF HEPATIC ENCEPHALOPATHY

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1 C U R R E N T C O N C E P T S Review Article Current Concepts T REATMENT OF HEPATIC ENCEPHALOPATHY STEPHEN M. RIORDAN, M.D., AND ROGER WILLIAMS, M.D. HEPATIC encephalopathy is a complex neuropsychiatric syndrome that may occur in such diverse clinical situations as inherited errors of the urea cycle, acute or chronic liver disease, and spontaneous or iatrogenic portosystemic venous shunting, including that following procedures to establish a transjugular intrahepatic portosystemic shunt. The clinical manifestations of this syndrome range from subtle abnormalities detectable only by psychometric testing to deep coma. Several grading systems have been proposed; one based on clinical and electroencephalographic abnormalities is shown in Table 1. 1 Hepatic encephalopathy may be present in 50 to 70 percent of all patients with cirrhosis, including those with abnormalities demonstrable only by psychometric testing. 2,3 Most manifestations of hepatic encephalopathy are reversible with medical treatment. Some patients with hepatic encephalopathy have progressive, debilitating syndromes, such as dementia, spastic paraparesis, cerebellar degeneration, and extrapyramidal movement disorders, associated with structural abnormalities of the central nervous system. 1,4 These syndromes were formerly regarded as irreversible, but there may be gradual improvement after successful orthotopic liver transplantation. 5 The accumulation of unmetabolized ammonia, predominantly as a result of poor hepatic function and portosystemic shunting, has traditionally been considered to have an important role in the pathogenesis of hepatic encephalopathy. In addition, a number of other possible mechanisms have recently been proposed, including production of false neurotransmitters, activation of central g-aminobutyric acid benzodiazepine receptors by ligands of endogenous origin, altered cerebral metabolism, and dis- From the Institute of Hepatology, University College London Medical School, Chenies Mews, London WC1E 6HX, United Kingdom, where reprint requests should be addressed to Dr. Williams. 1997, Massachusetts Medical Society. turbed activity of Na /K ATPase. Decreased activity of urea-cycle enzymes due to zinc deficiency and the deposition of manganese in the basal ganglia may also contribute to hepatic encephalopathy. 1,6-11 These pathogenetic mechanisms are not necessarily exclusive. Most treatment measures of proved value are based on the ammonia hypothesis. APPROACH TO MANAGEMENT None of the manifestations of hepatic encephalopathy are specific to this disorder, and it is essential to exclude alternative diagnoses (Table 2). 12 Although the level of ammonia in the arterial blood tends to be elevated in patients with more advanced hepatocellular dysfunction, especially when substantial portosystemic shunting is present, it is only poorly correlated with the grade of hepatic encephalopathy. 13 Consequently, this measurement is of little clinical value in establishing the diagnosis or following the progress of patients with hepatic encephalopathy. Conversely, practical bedside tests, such as the number-connection and other trail-making tests, 14,15 are easily administered and, in this era of cost-effective medicine, provide useful information, especially in patients with subclinical hepatic encephalopathy that would otherwise be overlooked. The treatment of hepatic encephalopathy in patients with the rare condition of acute liver failure and in those with the much more common chronic liver disease should be considered separately. Hepatic encephalopathy in patients with acute liver failure is rapid in onset and progression and is almost always complicated by cerebral edema in the later stages. It is of paramount importance to consider orthotopic liver transplantation for such patients on the basis of the prognosis. 16,17 Patients with acute liver failure and grade 3 or 4 hepatic encephalopathy should undergo elective ventilation, sedation with fentanyl, and paralysis with atracurium both to protect the airway and to facilitate the management of cerebral edema by preventing surges in intracranial pressure related to psychomotor agitation. Monitoring of extradural pressure is of value in these patients but carries some risk. 18 Mannitol given by repeated bolus injections (0.5 g per kilogram of body weight over a period of 10 minutes) remains the main pharmacologic treatment of cerebral edema in this setting. Acetylcysteine given by continuous infusion to patients with grade 4 hepatic encephalopathy has been reported to improve the cerebral blood flow and the cerebral metabolic rate for oxygen. Epoprostenol (prostaglandin I 2 ) also improves the cerebral metabolic rate for oxygen. 19 Hypoglycemia can be a lethal complication of Volume 337 Number 7 473

2 The New England Journal of Medicine TABLE 1. A GRADING SYSTEM FOR HEPATIC ENCEPHALOPATHY.* GRADE LEVEL OF CONSCIOUSNESS PERSONALITY AND INTELLECT NEUROLOGIC SIGNS E LECTROENCEPHALOGRAPHIC A BNORMALITIES 0 Normal Normal None None Subclinical Normal Normal Abnormalities only on psychometric None analysis 1 Inverted sleep pattern, restlessness Forgetfulness, mild confusion, agitation, irritability Tremor, apraxia, incoordination, impaired handwriting Triphasic waves (5 cycles/sec) 2 Lethargy, slow responses Disorientation as regards time, amnesia, decreased inhibitions, inappropriate behavior 3 Somnolence but rousability, confusion Disorientation as regards place, aggressive behavior Asterixis, dysarthria, ataxia, hypoactive reflexes Asterixis, hyperactive reflexes, Babinski signs, muscle rigidity 4 Coma None Decerebration Delta activity *The system is based on clinical and electroencephalographic features suggested by Gitlin. 1 Triphasic waves (5 cycles/sec) Triphasic waves (5 cycles/sec) DISORDER TABLE 2. DIFFERENTIAL DIAGNOSIS OF HEPATIC ENCEPHALOPATHY.* Metabolic encephalopathies Hypoglycemia Electrolyte imbalance Hypoxia Carbon dioxide narcosis Azotemia Ketoacidosis Toxic encephalopathies Alcohol Acute intoxication Withdrawal syndrome Wernicke Korsakoff syndrome Psychoactive drugs Salicylates Heavy metals Intracranial lesions Subarachnoid, subdural, or intracerebral hemorrhage Cerebral infarction Cerebral tumor Cerebral abscess Meningitis Encephalitis Epilepsy or postseizure encephalopathy Neuropsychiatric disorders *Data are adapted from Ferenci. 12 DIAGNOSTIC TEST Blood chemical analysis This diagnosis is especially pertinent to patients with liver disease. Measurement of blood alcohol level, erythrocyte transketolase activity, therapeutic response to thiamine, toxicologic screening Computed tomography, lumbar puncture, arteriography, electroencephalography, virologic testing Tests for organic brain syndromes acute liver failure, and monitoring of blood glucose at least every four hours is mandatory. The further treatment of patients with acute liver failure is beyond the scope of this review, which focuses on the treatment options for patients with hepatic encephalopathy as a complication of chronic liver disease, in whom cerebral edema is much less frequent. Most episodes of hepatic encephalopathy in patients with chronic liver disease are due to a clinically apparent precipitating event or to the spontaneous development of portosystemic shunting (Table 3). Several factors may be operative in a given patient at the same time. For example, septicemia or bacterial peritonitis, typically with gram-negative, colonic-type flora, develops within 48 hours in about half of patients with Child Pugh class C cirrhosis who have an acute gastrointestinal hemorrhage. 20 Hypokalemia and systemic alkalosis, complicating the use of diuretic agents to treat the ascites, in turn lead to increased renal production of ammonia and increased diffusion of ammonia across the blood brain barrier, respectively. 21 Older age is generally considered to be an important influence on the prevalence and severity of hepatic encephalopathy complicating surgical creation of a portosystemic shunt. 22 The number of patients referred for surgical creation of a shunt has fallen with the advent of the transjugular intrahepatic portosystemic shunt, the establishment of which has become a standard procedure in the treatment of recurrent variceal hemorrhage in many centers. This procedure is associated with a 25 percent overall incidence of chronic hepatic encephalopathy, 23 which is more likely to occur in women, patients over the age of 60 years, and patients with marked hypoalbuminemia. 23,24 Every effort should be made to identify the precipitating factor and, if possible, correct it. Other therapeutic measures are described below 474 August 14, 1997

3 C U R R E N T C O N C E P T S T A B L E 3. FACTORS PRECIPITATING HEPATIC ENCEPHALOPATHY IN PATIENTS WITH CHRONIC LIVER DISEASE. PRECIPITANT Excess dietary protein* Constipation* Anorexia Fluid restriction Gastrointestinal hemorrhage* Infection (including bacterial peritonitis)* Blood transfusion Azotemia* Hypokalemia* Systemic alkalosis* Dehydration Fluid restriction Diuretic effect Excessive paracentesis Diarrhea due to osmotic laxatives Arterial hypotension Gastrointestinal hemorrhage Peripheral vascular dilatation Arterial hypoxemia Anemia Use of benzodiazepines Use of other psychoactive drugs Portosystemic shunts* Spontaneous Surgical Transjugular intrahepatic Progressive hepatic parenchymal damage* Development of hepatoma* POSSIBLE MECHANISM Increased ammonia production Increased diffusion of ammonia across blood brain barrier Reduced metabolism of toxins because of hepatic hypoxia Activation of central g-aminobutyric acid benzodiazepine receptors Compounding of central nervous system depressant effect Reduced hepatic metabolism of toxins because of diversion of portal blood Reduced hepatic metabolism of toxins because of decreased functional reserve *This is one of the more common precipitants. T A B L E 4. RESULTS OF CONTROLLED TRIALS OF TREATMENTS FOR HEPATIC ENCEPHALOPATHY AS A COMPLICATION OF CHRONIC LIVER DISEASE.* Ammonia hypothesis Reduced ammonia production Dietary protein restriction ( ) Vegetable-protein diet ( ) Carbohydrate enemas ( ) Water enemas ( ) Oral lactulose ( ) Oral lactitol ( ) Oral lactose in lactase deficiency ( ) Oral antibiotics Neomycin ( ) Metronidazole ( ) Rifaximin ( ) Enterococcus faecium ( ) Lactobacillus acidophilus Alone ( ) With neomycin ( ) Helicobacter pylori eradication (NP) Increased ammonia metabolism Ornithine a-ketoglutarate ( ) Ornithine aspartate ( ) Sodium benzoate ( ) Phenylacetate ( ) Zinc supplementation ( ) False-neurotransmitter hypothesis Branched-chain amino acids Enteral ( ) Parenteral ( ) Keto analogues ( ) Levodopa ( ) Bromocriptine ( ) g-aminobutyric acid benzodiazepine receptor ligand hypothesis Flumazenil ( ) Manganese hypothesis Edetate calcium disodium (NP) Sodium para-aminosalicylic acid (NP) *A plus sign indicates that controlled trials support the treatment; a plus minus sign that results of controlled trials are conflicting; a minus sign that controlled trials do not support the treatment; and NP that controlled trials have not been performed. according to the various hypotheses relating to the pathogenesis of hepatic encephalopathy. The use of these measures is not in every case currently supported by the results of controlled clinical trials (Table 4). Hepatic encephalopathy as a complication of spontaneous or surgically created portosystemic anastomoses or transjugular intrahepatic portosystemic shunts is usually successfully managed along conventional lines. Transhepatic embolization or surgical ligation of portosystemic shunts is occasionally of benefit when hepatic encephalopathy is refractory to other treatments. 25,26 Refractory hepatic encephalopathy as a complication of transjugular intrahepatic portosystemic shunts can be successfully managed by implanting a reducing stent. 27 REDUCTION OF PRODUCTION AND ABSORPTION OF AMMONIA The intestinal production of ammonia can be reduced by restricting the intake of dietary protein and inhibiting urease-producing colonic bacteria. Although the restriction of dietary protein has long been recognized as an effective treatment, 12,28 patients with cirrhosis often require minimal daily protein intakes of 0.8 to 1.0 g per kilogram to maintain nitrogen balance. 29 Long-term restriction to values below this range should be avoided if possible. After dietary protein has been initially limited to 20 g a day, the intake should be increased by 10 g every three to five days until the patient s protein tolerance has been established. Volume 337 Number 7 475

4 The New England Journal of Medicine Supplementation with vegetable, rather than animal, protein may be advantageous in patients whose total daily dietary protein tolerance is less than 1 g per kilogram, since controlled studies have suggested that supplementation with vegetable protein may result in a substantial improvement in nitrogen balance without precipitating or worsening hepatic encephalopathy. 30 This beneficial effect may be due to the higher content of fiber in a vegetable diet than in an animal diet with an equal amount of nitrogen. The fiber increases the rate of transit of food through the intestine and lowers the ph of the colonic lumen as a result of its fermentation by colonic bacteria. 29 Most patients will accept a diet containing 30 to 40 g of vegetable protein, although restriction of sodium will render such a diet unpalatable. The physiologic shedding of gut epithelial cells provides additional luminal protein to be metabolized to ammonia by bacteria. Both dietary and endogenous ammoniagenic substrates are removed from the intestinal lumen by the osmotic cathartic action of nonabsorbable disaccharides such as lactulose (b-galactosidofructose) and lactitol (b-galactosidosorbitol). These compounds are currently the main therapeutic agents for chronic hepatic encephalopathy. The efficacy of oral lactulose for the treatment of hepatic encephalopathy has been established in controlled trials. 31 The daily dose of lactulose should be titrated to result in two to four soft, acidic (ph less than 6) stools daily. For most patients the daily dose is between 30 and 60 g. As well as having a cathartic effect, lactulose lowers the colonic ph as a result of the production of organic acids by bacterial fermentation. The decrease in ph creates an environment that is hostile to the survival of urease-producing intestinal bacteria and may promote the growth of non urease-producing lactobacilli, resulting in reduced production of ammonia in the colonic lumen. In addition, acidification of the colonic secretions not only reduces the absorption of ammonia by nonionic diffusion, but also results in the net movement of ammonia from the blood into the bowel lumen. 21 Enemas containing lactulose or other carbohydrates may be used if oral or nasogastric administration of the carbohydrate is impossible. Conversely, water enemas are ineffective, suggesting that acidification of the colonic lumen, rather than bowel cleansing alone, is responsible for the therapeutic effect. 32 Although it is not licensed for use in the United States at present, oral lactitol at a dose of 30 to 45 g daily is as effective as lactulose for treating hepatic encephalopathy and has the advantage of being more palatable and associated with a lower incidence of side effects, such as flatulence. 33,34 Oral lactose at a dose of 100 g daily is another proved alternative in lactase-deficient patients. 35 Antibiotics with activity against urease-producing bacteria, such as neomycin or metronidazole, also reduce the production of intestinal ammonia and have proved value. 31,36,37 The efficacy of neomycin (6 g daily) is similar to that of lactulose. 37 A small percentage of this drug is absorbed from the gastrointestinal tract and may cause ototoxic and nephrotoxic effects, especially with continuous use over several months. 38 This drug should be used with particular caution by patients with renal insufficiency. The efficacy of metronidazole (800 mg daily) for one week is similar to that of neomycin, 36 although the possibility of gastrointestinal disturbance and other systemic side effects limits the use of this agent for longer periods. Rifaximin, a nonabsorbed derivative of rifamycin, is a proved alternative at a dose of 1200 mg daily. 39 Since the therapeutic effects of nonabsorbable disaccharides depend on their metabolism by colonic flora, a question of considerable clinical relevance is whether combined treatment with lactulose and antibiotics is effective in patients with hepatic encephalopathy refractory to either agent alone. The effectiveness of combined therapy depends on whether the lactulose can be metabolized by a population of intestinal bacteria resistant to the antibiotic. The limited data available suggest that lactulose and neomycin may have an additive effect in reducing the intestinal production of ammonia, accompanied by an enhanced clinical response, in the majority of patients who have an inadequate response to lactulose alone. 40,41 However, an increase in stool ph after the addition of an antibiotic suggests that disaccharidemetabolizing intestinal bacteria have been eradicated; combination therapy should then be discontinued. 41 The idea of populating the colonic lumen with non urease-producing bacteria as a treatment for hepatic encephalopathy was first raised more than 30 years ago, when an uncontrolled study suggested that high oral doses of Lactobacillus acidophilus might have a beneficial effect in patients with cirrhosis and hepatic encephalopathy. 42 Few controlled data are available, although one small study showed that the addition of L. acidophilus supplements for one to four weeks produced clinical improvement in 71 percent of patients with hepatic encephalopathy refractory to neomycin alone. The results of a crossover study in three patients suggested that treatment with L. acidophilus alone was ineffective. 43 Conversely, oral administration of Enterococcus faecium for three periods of four weeks, separated by two-week drugfree intervals, reduced systemic ammonia levels and was at least as effective as lactulose in patients already on a restricted diet of 1 g of protein per kilogram. In contrast to the effect of lactulose, the therapeutic effect of E. faecium was sustained during treatment-free intervals. No adverse effects have been reported. 44 Surgical approaches to reducing the intestinal production of ammonia, such as colectomy or colonic- 476 August 14, 1997

5 CURRENT C O N C E P T S exclusion procedures, were used in the past for patients with hepatic encephalopathy refractory to other measures. 25 The operative morbidity and mortality were high, and today such patients should be considered for orthotopic liver transplantation. In addition to ammonia produced in the intestinal lumen, ammonia generated in the stomach by urease-producing Helicobacter pylori has recently been suggested to contribute substantially to blood ammonia levels, especially in the presence of gastric hypochlorhydria, and to precipitate or exacerbate hepatic encephalopathy in patients with cirrhosis. 45,46 Although the importance of H. pylori as a risk factor for hepatic encephalopathy remains unclear and the efficacy of eradication therapy has not been proved in controlled trials, our current practice is to eradicate this organism in patients with cirrhosis and a history of hepatic encephalopathy. INCREASED METABOLISM OF AMMONIA IN THE TISSUES Ornithine and aspartate are important substrates in the metabolic conversion of ammonia to urea and glutamine, respectively. Ornithine aspartate thus provides substrates for both of these ammonia-detoxification pathways. Controlled trials suggest that both enteral and parenteral formulations of ornithine aspartate, but not ornithine a-ketoglutarate, significantly reduce ammonia levels and have useful therapeutic effects in patients with cirrhosis and mild hepatic encephalopathy In one study, an oral dose of 9 g three times daily had an efficacy similar to that of lactulose. 48 Treatment with benzoate or phenylacetate, which react with glycine to form hippurate and with glutamine to form phenacetylglutamine, respectively, is also of proved value 51,52 ; there is evidence that sodium benzoate at a dose of 10 g daily may be as effective as lactulose. 52 Two of the five enzymes responsible for the metabolism of ammonia to urea in the urea cycle are zinc-dependent. Zinc deficiency is common in patients with cirrhosis and is caused predominantly by increased loss of zinc in the urine. 53 There are reports of overt hepatic encephalopathy precipitated by zinc deficiency and reversed by supplementation with oral zinc. 54 In a recent controlled trial, the rate of formation of urea from amino acids and ammonia was increased in eight patients with cirrhosis, zinc deficiency, and mild hepatic encephalopathy who were given 600 mg of oral zinc sulfate per day for three months. A significant improvement in psychometric test scores accompanied the resultant restoration of plasma zinc levels and reduction in systemic ammonia levels. 10 Similar beneficial effects of zinc supplementation for periods ranging from seven days to three months have also been reported in other controlled studies, 55,56 as well as some negative results. 57,58 Although further studies are required, zinc-deficient patients with cirrhosis should receive supplementation in view of the widespread importance of this trace element for the synthesis of DNA and protein and the function of metalloenzymes. REDUCTION OF FALSE NEUROTRANSMITTERS Treatment with formulas rich in branched-chain amino acids but low in aromatic amino acids is based on the hypothesis that reduced concentrations of branched-chain amino acids (leucine, isoleucine, and valine) and increased concentrations of aromatic amino acids (phenylalanine, tyrosine, and tryptophan) may promote hepatic encephalopathy by causing the production of false neurotransmitters. 1,8,12 Randomized, controlled trials involving the parenteral administration of formulas enriched with branched-chain amino acids demonstrated no benefit, improvement in hepatic encephalopathy but not in mortality rates, or improvement in both. 59 Differences in the control treatments, duration of therapy, selection of patients, precipitating events, and exclusion criteria make the interpretation of these conflicting results difficult. Similar problems confound the interpretation of the efficacy of enteral supplementation with formulas enriched with branched-chain amino acids. 60 Ornithine salts of branched-chain keto acids may be more effective than branched-chain amino acids themselves. 30 Although current results do not support the general use of branched-chain amino acids as a treatment for hepatic encephalopathy, they have a specific role in improving nitrogen balance without precipitating hepatic encephalopathy in malnourished patients with cirrhosis who are intolerant of protein supplementation. 61 However, most patients with cirrhosis who require parenteral feeding tolerate standard synthetic amino acid preparations. 62 Decreased activity of dopaminergic neurotransmission has also been suggested to have a role in the pathogenesis of hepatic encephalopathy. 1,8,12 However, controlled trials in patients with cirrhosis and hepatic encephalopathy failed to demonstrate any beneficial effect of treatment with levodopa or bromocriptine. 63,64 INHIBITION OF g-aminobutyric ACID BENZODIAZEPINE RECEPTORS Benzodiazepines exert their depressant effects on the central nervous system by interacting with highaffinity binding sites on the g-aminobutyric acid benzodiazepine receptor complex. Binding to this receptor by a benzodiazepine-like ligand not present in the normal brain has been proposed as an important factor in the pathogenesis of hepatic encephalopathy. 1,7,12 However, controlled trials of the efficacy of treatment with the benzodiazepine-receptor antagonist flumazenil in small numbers of patients demonstrated typically incomplete improvement in the Volume 337 Number 7 477

6 The New England Journal of Medicine clinical grade of hepatic encephalopathy in 18 to 78 percent, which included only 50 percent of the patients who had recently received benzodiazepines CORRECTION OF MANGANESE DEPOSITION IN THE BASAL GANGLIA Clinical observations suggest that manganese may accumulate in the basal ganglia of patients with cirrhosis, as shown by hyperintensity of the globus pallidus on T 1 -weighted magnetic resonance images. 11 It has been suggested that the deposition of manganese in the basal ganglia may contribute to the pathogenesis of hepatic encephalopathy. 11 This suggestion is based on similarities between aspects of chronic hepatic encephalopathy and manganese intoxication 68 and reports of the reversibility of hepatic encephalopathy and this magnetic resonance imaging abnormality after liver transplantation. 69 However, reports conflict as to whether the intensity of the T 1 -weighted signal in the globus pallidus correlates with either neuropsychiatric test scores or the clinical grade of hepatic encephalopathy. 70,71 Longitudinal studies are needed to investigate the possible therapeutic effects of chelation of manganese with edetate calcium disodium or treatment with sodium para-aminosalicylic acid, which has been reported to be of value in chronic manganese poisoning from occupational exposure. 72 ORTHOTOPIC LIVER TRANSPLANTATION Orthotopic liver transplantation is increasingly being used in the treatment of patients with end-stage cirrhosis, even older patients, many of whom have hepatic encephalopathy along with other manifestations of severe hepatic decompensation. Liver transplantation is also indicated in the small group of patients with severe, refractory hepatic encephalopathy, including such syndromes as dementia, spastic paraparesis, cerebellar degeneration, and extrapyramidal disorders, even when hepatic encephalopathy is the sole manifestation of hepatic decompensation. In practice, therefore, medical management of hepatic encephalopathy is mainly used for patients who do not yet meet the criteria for liver transplantation and in whom hepatic encephalopathy is likely to be mild, and for those in whom transplantation is contraindicated because of other medical or social problems. The latter group represents a substantial number of patients, because of the increasing life expectancy of patients with cirrhosis and the comorbidity associated with advancing age. There is some divergence of opinion as to whether treatment is warranted for patients with subclinical hepatic encephalopathy. 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