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Treatment of hepatic encephalopathy
Author
Peter Ferenci, MD Section Editor
Bruce A Runyon, MD Deputy Editor
Peter A L Bonis, MD
Last literature review version 19.1: January 2011 | This topic last updated: February 9, 2011 (More)
INTRODUCTION — Hepatic encephalopathy or portosystemic encephalopathy (PSE) represents a reversible impairment of neuropsychiatric function associated with impaired hepatic function. Despite the frequency of the condition, we still lack a clear understanding of pathogenesis. Nevertheless, decades of experience have suggested that an increase in ammonia concentration is implicated and that there may be a role for inhibitory neurotransmission through gamma-aminobutyric acid (GABA) receptors in the central nervous system (CNS) and changes in central neurotransmitters and circulating amino acids. (See "Pathogenesis of hepatic encephalopathy".)
Currently available therapies for hepatic encephalopathy are based upon these hypotheses (table 1). Some treatments are based upon clinical observations, some upon extrapolation of experimental data obtained in animal models of hepatic encephalopathy, and a smaller number upon controlled, randomized clinical trials. There are a number of problems that interfere with the interpretation of data from these studies (table 2).
A common problem is the variety of clinical conditions that are summarized under the term "hepatic encephalopathy." The clinical features of hepatic encephalopathy include a wide range of neuropsychiatric symptoms ranging from minor, not readily discernible signs of altered brain function to overt psychiatric and/or neurologic symptoms to deep coma. As a result, the methods to quantify treatment effects and endpoints are highly variable. (See "Clinical manifestations and diagnosis of hepatic encephalopathy".)It is not known if data regarding treatment in patients with overt hepatic encephalopathy can be extrapolated to minimal hepatic encephalopathy and vice versa. However, many studies included patients both with overt and minimal hepatic encephalopathy.Another important variable is the treatment of control groups. Very few studies use a placebo; in most cases, the new drug was compared to "standard treatment" (which by itself may be highly effective) or to lactulose (the efficacy of which has only been tested in a prospective placebo-controlled trial recently [1]) as "gold standard."The sample size of most published studies was small.
TREATMENT OF PRECIPITATING CAUSES — It is important to recognize that hepatic encephalopathy, acute and chronic, is reversible and that a precipitating cause rather than worsening of hepatocellular function can be identified in the majority of patients. In one classic study, over 80 percent of 100 cases were attributable to such factors as gastrointestinal bleeding, increased protein intake, hypokalemic alkalosis, infection, and constipation (all of which increase arterial ammonia levels), or to hypoxia and the use of sedatives and tranquilizers (table 3) [2]. Patients with advanced cirrhosis may be particularly sensitive to benzodiazepines because of an increased concentration of benzodiazepine receptor ligands in the brain. (See 'Treatments based upon the GABA hypothesis' below.)
Treatment of precipitating events is typically associated with a prompt improvement of hepatic encephalopathy. As a result, every attempt should be made to identify such precipitating events while instituting therapy with the specific agents described below (table 3).
AGITATION — Patients hospitalized with HE may be agitated. Agitation often resolves upon treatment of the HE; however, patients may represent a hazard to themselves and their caregivers until treatment takes effect. Management may include judicious use of restraints, which may be a safer option than pharmacologic treatment since patients with advanced liver disease and HE may be particularly vulnerable to oversedation with medications. Should medications be required, haloperidol is a safer option than benzodiazepines based mainly on clinical experience and some limited data [3].
TREATMENTS BASED UPON THE AMMONIA HYPOTHESIS — The gastrointestinal tract is the primary source of ammonia, which enters the circulation via the portal vein. Ammonia is produced by enterocytes from glutamine and by colonic bacterial catabolism of nitrogenous sources such as ingested protein and secreted urea. The intact liver clears almost all of the portal vein ammonia, converting it into glutamine and preventing entry into the systemic circulation. Elevations of ammonia are detected in 60 to 80 percent of patients with hepatic encephalopathy, and therapy aimed at reduction of the circulating ammonia level usually results in resolution of the encephalopathy. (See "Pathogenesis of hepatic encephalopathy".) Treatment is aimed at either reducing or inhibiting intestinal ammonia production or increasing the removal of ammonia (table 1).
Correction of hypokalemia — Correction of hypokalemia, if present, is an essential component of therapy since hypokalemia increases renal ammonia production. The often concurrent metabolic alkalosis may contribute by promoting ammonia entry into the brain by promoting the conversion of ammonium (NH4+), a charged particle which cannot cross the blood-brain barrier, into ammonia (NH3), which can [4]. (See "Hypokalemia-induced renal dysfunction", section on 'Increased ammonia production'.)
Reduction in ammoniagenic substrates — Removing the source of the ammonia from the gastrointestinal tract can be an important step in certain patients. The modalities used vary with the clinical setting.
Lactulose and lactitol — Synthetic disaccharides (lactulose and lactitol) are currently a mainstay of therapy of hepatic encephalopathy, albeit there is limited evidence from well-designed randomized, controlled trials to demonstrate their efficacy. A systematic review found that lactulose or lactitol (which is not available in the US) were more effective than placebo in improving hepatic encephalopathy (RR of no improvement 0.62, 95% CI 0.46 to 0.84) but had no significant benefit on mortality [5]. However, the benefit on encephalopathy no longer reached statistical significance when the analysis was confined to studies with the highest methodologic quality. The authors also found that antibiotics appeared to be relatively more effective. At least two meta-analyses suggested that lactitol was at least as effective as lactulose, was more palatable, and may have fewer side effects [6-8]. In patients with lactase deficiency, the nonmetabolized lactose has most of the same effects as the synthetic disaccharides in the colon and is much cheaper [9].
Most of the controlled trials included patients with overt hepatic encephalopathy. However, at least one controlled trial published (61 patients) suggested a benefit in patients with minimal hepatic encephalopathy [10]. Treatment with lactulose was associated with improvement in health-related quality of life and cognitive function. These results are striking because the benefit of treating patients with minimal hepatic encephalopathy had not been previously demonstrated, but whether treatment should be routine in such patients is unclear. These findings need to be confirmed in a large, placebo controlled trial.
Lactulose may also help prevent recurrent hepatic encephalopathy. In a placebo-controlled trial involving 140 patients who recovered from hepatic encephalopathy, patients randomized to lactulose (30 to 60 mL in two to three divided doses so that patients passed two to three soft stools per day) had significantly fewer episodes of recurrent overt hepatic encephalopathy (20 versus 47 percent) during 14 months of follow-up [1]. However, there were no significant differences in deaths or rates of readmission for causes other than hepatic encephalopathy.
The basis for treatment with lactulose or lactitol is due to the absence of a specific disaccharidase on the microvillus membrane of enterocytes in the human small bowel, thereby permitting entry into the colon. In the colon, lactulose (beta-galactosidofructose) and lactitol (beta-galactosidosorbitol) are catabolized by the bacterial flora to short chain fatty acids (eg, lactic acid and acetic acid) which lower the colonic pH about 5.0. The reduction in pH favors the formation of the nonabsorbable NH4+ from NH3, trapping NH4+ in the colon and effectively reducing plasma ammonia concentrations.
Other effects that may contribute to the clinical effectiveness of lactulose and lactitol include [11]:
Increased incorporation of ammonia by bacteria for synthesis of nitrogenous compoundsModification of colonic flora, resulting in displacement of urease-containing bacteria with Lactobacillus [12]Cathartic effects of a hyperosmolar load in the colon which improves the slow gastrointestinal transit in patients with subclinical hepatic encephalopathyIncreased fecal nitrogen excretion of up to fourfold due to the increase in stool volume [13]Reduced formation of potentially toxic short-chain fatty acids (eg, propionate, butyrate, valerate) [14]
The dose of lactulose (45 to 90 g/day) should be titrated to achieve two to three soft stools per day with a pH below 6. Approximately 70 to 80 percent of patients with hepatic encephalopathy improve on lactulose treatment [11,15]. Treatment is usually well tolerated, and the principal toxicity is abdominal cramping, diarrhea, and flatulence.
Enemas — Cleansing of the colon is a rapid and effective method to remove ammoniagenic substrates. It can be achieved either by cathartics or by enemas. A randomized trial involving 20 patients suggested that 1 to 3 L of 20 percent lactulose or lactitol solution enemas were more effective than tap water enemas [16]. A possible explanation is that colonic acidification rather than bowel cleansing was the effective therapeutic mechanism.
As part of the study, the investigators also randomized a total of 33 patients to lactulose or lactitol solutions and noted "a favorable response" in 78 and 86 percent of patients, respectively [16]. The efficacy of oral versus enema administration of lactulose or lactitol is unclear. Its convenience suggests oral administration is the preferred route of administration.
Dietary protein reduction — There is no good clinical evidence supporting protein restriction in patients with acute hepatic encephalopathy. A randomized trial found no difference between moderate (0.8 g/kg per day) and more aggressive protein restriction [17]. A retrospective analysis of prospectively collected data demonstrated that "higher protein intake was associated with improved hepatic encephalopathy" in patients with alcoholic hepatitis [18].
Patients with grade III to IV hepatic encephalopathy usually do not receive oral nutrition. As soon as they improve, a general diet can be given.
A randomized cross-over trial in eight patients suggested that vegetable proteins were superior to proteins derived from fish, milk, or meat with regard to nitrogen balance [19]. As a general rule, only patients who have had a TIPS or surgical portosystemic shunt have hepatic encephalopathy severe enough to warrant use of vegetable protein or protein restriction.
Inhibition of intestinal ammonia production and absorption — Lowering of blood ammonia levels can be effectively achieved by reducing ammonia production and absorption with antibiotics, synthetic disaccharides (such as lactulose), or the administration of a non-urease-producing bacterium.
Oral antibiotics — Although neomycin has been used for many years to treat hepatic encephalopathy, no controlled studies have found it to be effective compared with standard treatment alone. A 1977 study found neomycin to be as effective as lactulose in 33 patients [15], but a more recent randomized trial of 39 patients comparing neomycin at a dose of 6 g per day to placebo reported no difference in outcomes between the two treatment groups [20]. In addition, neomycin is associated with ototoxicity and nephrotoxicity, limiting long-term use.
Other antibiotics, such as metronidazole, oral vancomycin, and rifaximin, have been found effective in limited clinical trials and are better tolerated than neomycin [21-23]. Metronidazole and oral vancomycin are not used commonly. A meta-analysis of five controlled trials of rifaximin found that it had similar efficacy as nonabsorbable disaccharides for acute and chronic hepatic encephalopathy, but was perhaps somewhat better tolerated [24]. A randomized controlled trial published after the meta-analysis found that rifaximin was more effective than a placebo in preventing recurrent episodes of hepatic encephalopathy during six months follow-up [25]. Later placebo-controlled trials found that rifaximin improved quality of life [26] and performance on a simulated driving test in patients with minimal hepatic encephalopathy [27]. Rifaximin has received approval from the United States Food and Drug Administration for reducing the risk of overt hepatic encephalopathy recurrence.
Thus, antibiotics may be an acceptable choice, but they can all cause alterations in gut flora, and some are substantially more costly than nonabsorbed disaccharides. As a result, they may be best suited for patients who cannot tolerate or are resistant to disaccharides.
Modification of colonic flora (probiotics and prebiotics) — Alteration of gut flora (either with probiotics or with prebiotics such as fermentable fiber) has been associated with improvement in hepatic encephalopathy in pilot studies [28-32]. Such therapy appears to lower blood ammonia concentrations possibly by favoring colonization with acid-resistant, non-urease producing bacteria [28]. The role for this approach is still being elucidated. (See "Probiotics for gastrointestinal diseases".)
Acarbose — Acarbose (an inhibitor of alpha glycosidase that is approved for treatment of diabetes mellitus) inhibits the upper gastrointestinal enzymes (alpha-glucosidases) that convert carbohydrates into monosaccharides. (See "Alpha-glucosidase inhibitors and lipase inhibitors for treatment of diabetes mellitus".) It also promotes the proliferation of intestinal saccharolytic bacterial flora while reducing proteolytic flora that produce mercaptans, benzodiazepine-like substances, and ammonia. Their reduction could improve hepatic encephalopathy. This hypothesis appeared to be confirmed by a randomized, controlled crossover trial involving 107 cirrhotic patients with diabetes mellitus and grade 1 to 2 hepatic encephalopathy [33]. Treatment was associated with a significant reduction in blood ammonia levels and improvement in encephalopathy.
Stimulation of metabolic ammonia metabolism — Ammonia is removed by formation of urea in periportal hepatocytes and/or by synthesis of glutamine from glutamate in perivenous hepatocytes. In cirrhosis, the activities of carbamyl phosphate synthetase and of glutamine synthetase (the key enzymes for urea and glutamine synthesis) are impaired and the glutaminase flux is increased in a compensatory fashion, resulting in hyperammonemia. As a result, ornithine-aspartate and benzoate have been used to lower plasma ammonia concentrations by enhancing the metabolism of ammonia to glutamine and hippurate, respectively.
Ornithine-aspartate — Ornithine serves both as an activator of carbamyl phosphate synthetase and ornithine-carbamyl transferase in periportal hepatocytes, and as a substrate for ureagenesis. Ornithine (via alpha-ketoglutarate) and aspartate increase ammonia removal by these cells via stimulation of glutamine synthesis.
Several controlled trials have suggested a benefit of ornithine-aspartate in patients with mild hepatic encephalopathy [34-37]. As an example, one study of 126 patients with cirrhosis, hyperammonemia, and chronic hepatic encephalopathy were randomly assigned to treatment with ornithine-aspartate (20 g infusion over four hours for seven days) or placebo [35]. Patients with mildly symptomatic hepatic encephalopathy in the active treatment group had significant improvements in fasting and postprandial blood ammonia concentrations compared with placebo, as well as improvement in clinical measures. There was no effect in patients with subclinical hepatic encephalopathy. A smaller placebo-controlled study also found benefits of oral ornithine-aspartate (18 g/day) with no adverse effects [36]. In an open label prospective observational study, treatment of HE with oral L-ornithine-L-aspartate in patients with cirrhosis markedly improved HR-QOL and was well tolerated [38].
Thus, the available data are mixed but suggest that in patients with mild hepatic encephalopathy and cirrhosis, ornithine-aspartate may be somewhat more effective than placebo, but further studies are needed. Ornithine-aspartate has not been compared directly with lactulose or lactitol and experience in patients with more severe hepatic encephalopathy is limited.
By contrast, discordant data have been published in patients with acute liver failure. In aggregate, they suggest that ornithine aspartate is ineffective in such patients. An illustrative study included 201 patients with acute liver failure who were randomly assigned to either placebo or ornithine-aspartate infusions (30 g daily) for three days. Active treatment had no effect on the improvement in encephalopathy grade, consciousness recovery time, survival time, or complications such as seizures and renal failure.
Sodium benzoate — An entirely different approach to eliminate ammonia is the use of benzoate. Benzoate reacts with glycine to form hippurate. For each mole of benzoate used, one mole of waste nitrogen is excreted into the urine.
A prospective, randomized, double-blind study of 74 patients with acute hepatic encephalopathy found that treatment with sodium benzoate (5 gm twice daily) resulted in similar improvements in encephalopathy as lactulose [39]. There was no placebo group. The cost of lactulose was 30 times that of sodium benzoate.
While this study is encouraging, we are reluctant to recommend sodium benzoate as first line therapy prior to a trial of lactulose until the results are confirmed in a placebo-controlled study, given the much broader experience with lactulose.
TREATMENTS BASED UPON THE FALSE NEUROTRANSMITTER HYPOTHESIS — It has been suggested that increases in the ratio of plasma aromatic amino acids (AAA) to branched-chain amino acids (BCAA) as a consequence of hepatic insufficiency could contribute to encephalopathy. The altered ratio could then increase brain levels of aromatic amino acid precursors for monoamine neurotransmitters and contribute to altered neuronal excitability. As a result, a number of studies have evaluated the effects of the provision of BCAA, given either intravenously or orally.
BCAA infusions — Several randomized, controlled studies have evaluated the use of parenteral nutrition with modified amino acid solutions with a high content of BCAA and a low content of AAA [40,41]. A meta-analysis suggested that mental recovery was consistently more rapid in treated patients [41]. Three studies suggested lower mortality in treated patients while two others suggested that treatment increased mortality [41]. The studies included in this meta-analysis differed with respect to the amino acid solutions used, the study protocols, patient selection, and the duration of treatment, and therefore cannot be compared directly with each other. In addition, all studies were of relatively short duration. We do not presently consider infusions of modified amino acid solutions or BCAA as standard treatment of patients with hepatic encephalopathy.
Oral BCAA supplements — The benefit of oral branched chain amino acid supplements (BCAA) is unclear. A systematic review of 11 randomized trials (with a total of 556 patients) found no convincing evidence of a benefit [42]. However, significant improvement in chronic hepatic encephalopathy has been described in some of the trials suggesting a potential benefit in some patients. As an example, a double-blind trial of 64 patients found that long-term supplementation of oral BCAA to a low protein diet was more likely to improve mental performance at three months than supplementation with casein (80 versus 35 percent) [43]. In addition, some patients who did not improve on casein rapidly improved when switched to BCAA. Another report evaluated 37 hospitalized protein-intolerant patients with cirrhosis [44]. Addition of BCAA to the diet enabled the daily protein intake to be increased to up to 80 g without worsening of cerebral function; in comparison, many control patients (receiving a casein as protein source) deteriorated after increasing dietary protein intake. No benefit of BCAA supplementation was observed in protein-tolerant patients. Based upon these results, we feel that dietary BCAA supplementation is indicated only in severely protein-intolerant patients.
TREATMENTS BASED UPON THE GABA HYPOTHESIS — The GABA-receptor complex appears to be a contributor to neuronal inhibition in hepatic encephalopathy. This complex, in the postsynaptic membrane, is the principal inhibitory network in the central nervous system. It consists of a GABA-binding site, a chloride channel, and barbiturate and benzodiazepine receptor sites. Increases in transmission could be caused by increases in ligands for any of the three receptors. Since there is evidence for an increase in benzodiazepine receptor ligands in patients with hepatic encephalopathy, the effects of benzodiazepine receptor antagonists have been studied [45,46]. GABA-ergic transmission may interact with ammonia in the pathogenesis of hepatic encephalopathy [47]. (See "Pathogenesis of hepatic encephalopathy".)
The benzodiazepine receptor antagonist flumazenil has been used for treatment of hepatic encephalopathy in a number of uncontrolled studies and in several controlled trials with limited success [48-52]. Response to treatment, when it occurred, was seen within a few minutes after intravenous administration in most patients; however, two-thirds of the patients who responded deteriorated two to four hours later. The controlled trials varied in design and exclusion criteria, and are therefore not directly comparable.
The available data were summarized in a systematic review of 12 controlled trials that included a total of 765 patients [53]. The authors concluded that treatment with flumazenil was associated with a significant improvement in hepatic encephalopathy compared with placebo at the end of treatment (30 versus 7 percent, absolute improvement of 23 percent (95% CI 18 to 28 percent)). The benefit was short-term, and appeared to be confined to patients who otherwise had a favorable prognosis. No significant benefit on recovery or survival was demonstrated. A second meta-analysis that included six of the controlled trials reached similar estimates of efficacy [54].
These findings suggest that while some patients with hepatic encephalopathy may benefit from flumazenil, it cannot be recommended as routine therapy. Flumazenil may be helpful, however, in patients who have received benzodiazepines. (See "Benzodiazepine poisoning and withdrawal".)
MISCELLANEOUS TREATMENTS — Zinc and melatonin have been suggested as having potential value in some patients with chronic or recurring hepatic encephalopathy, although little evidence exists to document their effectiveness.
Zinc — Zinc deficiency is common in patients with cirrhosis and in those with hepatic encephalopathy [55]. Zinc is contained in vesicles in presynaptic terminals of a class of neurons, many of which are a subclass of the glutamatergic neurons [56]. Stimulated release may modulate ion channel function and neurotransmission [57]. Zinc may also enhance the hepatic conversion of amino acids into urea [58].
Little information is available on the clinical effects of zinc supplementation in overt hepatic encephalopathy. A patient has been described who exhibited a relationship between zinc deficiency and severe recurrent hepatic encephalopathy [59]. The study included a period in which zinc deficiency was artificially induced by oral histidine. An episode of overt encephalopathy occurred that was identical to earlier episodes and responded to oral zinc. Long-term zinc supplementation significantly improved severe recurrent hepatic encephalopathy which had been refractory to protein restriction, lactulose, and neomycin.
However, this anecdotal report has not been confirmed in larger studies. As an example, short-term zinc supplementation had no clinically significant effect in 15 patients with chronic hepatic encephalopathy studied in a blinded crossover trial [60]. As a result, we do not recommend zinc supplementation for treatment of hepatic encephalopathy.
Melatonin — One of the most frequently described, sometimes disabling symptoms of subclinical forms of hepatic encephalopathy are sleep disturbances or, more generally, alterations in the sleep/wake cycle. Unsatisfactory sleep is also characteristic of patients with cirrhosis who do not have encephalopathy (48 percent of patients in one study [61]).
The abnormalities in sleep may be due in part to alterations in the 24-hour rhythm of the hormone melatonin, which is considered to be the output signal of the biological "clock." (See "Physiology and clinical use of melatonin".) In one series of patients with cirrhosis, the onset of the rise in plasma concentrations of melatonin and the melatonin peak during the night were displaced to later hours [62]. Furthermore, plasma melatonin levels in patients with cirrhosis were significantly higher during daylight hours, at a time when melatonin is normally very low or absent.
These findings support the hypothesis that an alteration of circadian rhythmicity is responsible for the disruption in the sleep/wake cycle frequently seen in cirrhosis. Melatonin can influence its own rhythm when administered at defined time points of the day, shifting the curve forward or backward [63]. Some authorities have tried orally administered melatonin in patients with cirrhosis who have an altered sleep/wake cycles. However, our clinical experience with this drug has not revealed a benefit in patients with cirrhosis. (See "Physiology and clinical use of melatonin".)
EXPERIMENTAL TREATMENTS — A number of experimental approaches are being evaluated in animal models for the treatment of hepatic encephalopathy. Few have received any testing in clinical trials.
L-Carnitine — Carnitine is a metabolite in the degradation pathway of the essential amino acid Iysine and is synthesized by oxidation of E-amino-trimethyl-lysine. It serves as a carrier for short chain fatty acids across the mitochondrial membrane. (See "Carnitine metabolism in renal disease and dialysis", section on 'Role of carnitine in intermediary metabolism'.) Data in portacaval-shunted rats suggest that L-carnitine is protective against ammonia neurotoxicity [64,65].
The available clinical data are insufficient to assess the role of L-carnitine in human disease. In patients with cirrhosis who were subjected to a rectal ammonium overload test, intravenous L-carnitine improved psychometric tests significantly after 30 minutes, whereas circulating ammonia levels were not influenced [66]. However, the increase in plasma ammonia after rectal ammonia overload was significantly lower in treated patients with evidence of portal hypertension than in patients without these signs.
Glutamatergic antagonists — There is good evidence that the glutamatergic neurotransmitter system is involved in the pathogenesis of hepatic encephalopathy. The N-methyl-D-aspartate (NMDA) receptor is one of three known central glutamate receptors. NMDA overactivity has been observed in two different experimental rat models of encephalopathy. The administration of the NMDA receptor antagonist memantine resulted in a significant improvement in clinical grading and less slowing of EEG activity, smaller increases in CSF glutamate concentrations, and lower intracranial pressure and brain water content than in untreated control rats [67].
Serotonin antagonists — Accumulated neurochemical data in different animal models of fulminant hepatic failure and in humans with hepatic encephalopathy suggest that serotoninergic tone is increased in the brain in hepatic encephalopathy. The nonselective serotonin receptor antagonist methysergide had no effect in control rats, but increased motor activity in rats with stage II to III hepatic encephalopathy stage in a dose-dependent manner; in contrast, the 5-HT2 receptor antagonist seganserin had no effect [68].
Opioid antagonists — Plasma levels of Met-enkephalin and beta-endorphin are elevated in patients and in experimental animals suffering from liver failure. Administration of (+/-)-naltrexone, but not (+)-naloxone, significantly increased the motor activity of rats with stage III hepatic encephalopathy [69].
PROGNOSIS AFTER RECOVERY — Patients with overt hepatic encephalopathy may have persistent and cumulative neurologic deficits despite an apparent normalization of mental status after treatment. In a study that summarized the results of two cohorts of patients with cirrhosis, overt hepatic encephalopathy was associated with persistent deficits in working memory, response inhibition, and learning when assessed by psychometric testing [70]. The number of episodes of overt hepatic encephalopathy correlated with the severity of residual impairment.
SUMMARY AND RECOMMENDATIONS
Acute therapy — The initial management of overt hepatic encephalopathy type C (ie, caused by cirrhosis and portal hypertension /or systemic shunts) involves two steps:
Identification and correction of precipitating causesMeasures to lower the blood ammonia concentration
Correction of precipitating causes — The first step is the identification and correction of precipitating causes. Careful evaluation should be performed to determine the presence of any of the following (table 3):
HypovolemiaGastrointestinal bleedingHypokalemia and/or metabolic alkalosisHypoxiaSedatives or tranquilizersHypoglycemiaInfection (including SBP)Vascular occlusion (hepatic vein or portal vein thrombosis)
Approximately 70 to 80 percent of patients with hepatic encephalopathy improve after correction of precipitating factors.
Lower blood ammonia — The second step is initiation of measures to lower the blood ammonia concentrations (whether or not the values are frankly elevated). Correction of hypokalemia is also an essential component of therapy since hypokalemia increases renal ammonia production. We do not recommend dietary protein restriction in patients with acute hepatic encephalopathy.
Drug therapy is the mainstay of treatment to lower the blood ammonia concentration. There are no large comparative trials to determine whether disaccharides, ornithine-aspartate, or benzoate are more effective for initial treatment of HE. Our approach to drug therapy is as follows:
We suggest initiating drug therapy for acute hepatic encephalopathy with lactulose or lactitol (in countries in which it is available; lactitol is not available in the US) (Grade 2C). While a well-performed, placebo-controlled study of lactulose therapy has not been performed, there is extensive clinical experience supporting its efficacy. The dose of lactulose (45 to 90 g/day) should be titrated to achieve two to three soft stools per day with a pH below 6. Lactulose enemas can be given if the patient cannot take lactulose orally. (See 'Lactulose and lactitol' above.)
An acceptable alternative is infusion of ornithine-aspartate (20 g infusion per day given over four hours). The drug is not available in the United States. (See 'Ornithine-aspartate' above.)
For those who have not improved within 48 hours, we suggest second-line therapy with non-absorbed antibiotics (Grade 2C). As a general rule, antibiotics are added to rather than substituted for lactulose. Whether a combination of lactulose with antibiotics provides a benefit for the patient is unknown.
Neomycin has been used as a second-line therapy in patients who have not responded to disaccharides, but we are concerned about its lack of efficacy in a placebo-controlled trial and its theoretical potential for ototoxicity and nephrotoxicity. Various doses have been used but we generally use 500 mg three times a day or 1 gram twice daily. (See 'Oral antibiotics' above.) With regard to the nephrotoxicity, only a few cases have been described and thus the risk (although unknown) is probably very low. In patients with deep hepatic encephalopathy (coma), some authorities prefer to give lactulose by enema for several days, reserving neomycin for those who do not respond.
An alternative is rifaximin (400 mg taken orally three times daily or 550 mg taken orally two times a day).
A further alternative is sodium benzoate (5 g twice daily). Sodium benzoate is not available as a pharmaceutical in the United States or the European Union. (See 'Oral antibiotics' above and 'Stimulation of metabolic ammonia metabolism' above.)
Chronic therapy — In patients with recurrent type C encephalopathy (ie, caused by cirrhosis and portal hypertension /or systemic shunts), we suggest continuous administration of lactulose (Grade 2B). Protein restriction is not needed unless encephalopathy is resistant to lactulose. In patients whose symptoms worsen with protein intake, substitution of proteins from fish, milk, or meat with vegetable proteins may improve nitrogen balance. (See 'Dietary protein reduction' above.) Another alternative for patients intolerant to protein is the addition of branched-chain amino acids to a low protein diet. BCAA supplementation is indicated only in severely protein-intolerant patients.
Minimal hepatic encephalopathy — Patients with minimal hepatic encephalopathy may benefit from treatment with lactulose, but the decision for treatment should be individualized based upon the results of psychometric testing and the degree to which the encephalopathy has an impact on quality of life.
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