Treatment of hepatic encephalopathy

  TREATMENTS BASED UPON THE AMMONIA HYPOTHESIS
    • Reduction in ammoniagenic substrates
      - Enemas
      - Dietary protein reduction
    • Inhibition of intestinal ammonia production and absorption
      - Oral antibiotics
      - Lactulose and lactitol
      - Modification of colonic flora
    • Stimulation of metabolic ammonia metabolism
      - Ornithine-aspartate
      - Sodium benzoate

  TREATMENTS BASED UPON THE FALSE NEUROTRANSMITTER HYPOTHESIS
    • BCAA infusions
    • Oral BCAA supplements

  TREATMENTS BASED UPON THE GABA HYPOTHESIS

  MISCELLANEOUS TREATMENTS
    • Zinc
    • Melatonin

  EXPERIMENTAL TREATMENTS
    • L-Carnitine
    • Glutamatergic antagonists
    • Serotonin antagonists
    • Opioid antagonists

  RECOMMENDATIONS
    • Chronic therapy

 

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Hepatic encephalopathy or portosystemic encephalopathy (PSE) represents a reversible decline in neurologic 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 ammonia is clearly 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 as well. (See "Pathogenesis of hepatic encephalopathy";).

Currently available therapies for hepatic encephalopathy are based upon these hypotheses (show 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 [1]. There are a number of problems which interfere with the interpretation of data from these studies (show table 2).

  • A common problem is the variety of clinical conditions which 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 quantitate treatment effects and treatment endpoints are highly variable. (See "Clinical manifestations and diagnosis of hepatic encephalopathy";).

  • It is not known if data obtained in patients with overt hepatic encephalopathy can be extrapolated to subclinical hepatic encephalopathy and vice versa. However, many studies include patients both with overt and subclinical hepatic encephalopathy.

  • Another important variable is the treatment of control groups. Very few studies use a placebo; in most cases, a new drug is compared to "standard treatment" (which by itself may be highly effective) or to lactulose (the efficacy of which has never been tested in a prospective placebo-controlled trial) as "gold standard".

  • The sample size of most published studies is not sufficient.

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 (show 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 these precipitating events is typically associated with a prompt and permanent improvement of hepatic encephalopathy. As a result, every attempt should be made to identify such precipitating events while instituting therapy with specific agents described below. More recently, insertion of a transjugular intrahepatic portosystemic shunt (TIPS) has emerged as another cause of hepatic encephalopathy [3]. These patients also should be treated with medical therapy.

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 (show table 1). 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].

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. Nasogastric lavage should be performed in patients with upper gastrointestinal bleeding while limiting protein intake and treating constipation may be effective in patients with chronic encephalopathy. Both cleansing enemas and dietary protein restriction are effective in patients with acute hepatic encephalopathy.

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. The efficacy of enemas of one to three liters of 20 percent lactulose or lactitol solutions was proven in a randomized control trial; a favorable response was noted in 78 to 86 percent of patients [5]. Interestingly, enemas with tap water were ineffective, raising the possibility that colonic acidification rather than bowel cleansing was the effective therapeutic mechanism.

Dietary protein reduction — Patients with grade III to IV hepatic encephalopathy usually do not receive oral nutrition. As soon as they improve, individual protein tolerance can be titrated by gradually increasing oral protein intake from a baseline of 40 g/day every three to five days. Oral protein intake should not exceed 70 g/day in a patient with a history of hepatic encephalopathy; a level below 70 g/day is rarely necessary and minimum intake should not be lower than 40 g/day to avoid negative nitrogen balance [6]. A preliminary controlled trial found that a moderate intake of protein (0.8 g/kg/d) may be sufficient to satisfy protein requirements without worsening the course of hepatic encephalopathy [7].

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 — Antibiotics of several types can be used to inhibit ammonia production. The drugs of choice are aminoglycosides (neomycin or paromomycin); alternatives include metronidazole, vancomycin, and rifaximin [8, 9, 10]. The daily dose of neomycin is 2 to 8 g given in four doses. Approximately 70 to 80 percent of patients with hepatic encephalopathy treated with neomycin improve, a response rate similar to that seen with lactulose [11]. However, ototoxicity and nephrotoxicity limit long-term treatment with neomycin. In addition, alterations in gut flora can contribute to bacterial overgrowth syndromes. For these reasons, neomycin should be reserved for patients who cannot tolerate or are resistant to disaccharides.

Lactulose and lactitol — Synthetic disaccharides (lactulose and lactitol) are currently the mainstay of therapy of hepatic encephalopathy. Although a properly conducted placebo-controlled trial has not been performed, their efficacy is considered beyond doubt [11, 12]. The therapeutic effects are 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 NH3 in the colon and effectively reducing plasma ammonia concentrations.

Other effects which may contribute to the clinical effectiveness of lactulose and lactitol include [12]:

  • Increased incorporation of ammonia by bacteria for synthesis of nitrogenous compounds
  • Modification of colonic flora, resulting in displacement of urease-containing bacteria with Lactobacillus [13]
  • Cathartic effects of a hyperosmolar load in the colon which improves the slow gastrointestinal transit in patients with subclinical hepatic encephalopathy
  • Increased fecal nitrogen excretion of up to fourfold due to the increase in stool volume [14]
  • Reduced formation of potentially toxic short-chain fatty acids (eg, propionate, butyrate, valerate) [15]

The dose of lactulose (45 to 90 g/day) should be titrated in every patient 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, 12]. Treatment is usually well tolerated, and the principal toxicity is abdominal cramping, diarrhea, and flatulence.

Lactitol has been evaluated in a number of clinical trials and several meta-analyses. It appears to be as effective as lactulose, is more palatable, and may have fewer side effects [16, 17, 18]. 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 [19].

Modification of colonic flora — Modification of the colonic flora to increase the number of saccharolytic bacteria can be produced by repeated oral administration of another bacterium. Enterococcus faecium SF68, a fermentative lactic acid producing, urease-negative bacterium inhibits the replication of other intestinal bacteria. One controlled study randomized 40 patients to treatment with SF68 and lactulose for alternating three week periods [20]. SF68 was at least as effective as lactulose in lowering arterial blood ammonia for long-term treatment of chronic hepatic encephalopathy. It had no adverse effects, and in contrast to lactulose, treatment can be interrupted for two weeks without losing the beneficial effects.

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 carbamylphosphate 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 — The only compound tested in randomized controlled trials is ornithine-aspartate. In periportal hepatocytes, ornithine serves both as an activator of carbamylphosphate synthetase and ornithine-carbamyltransferase, and as a substrate for ureagenesis. Ornithine (via alpha-ketoglutarate) and aspartate increase ammonia removal by these cells via stimulation of glutamine synthesis.

The potential value of this approach can be illustrated by the following observations:

  • In one report of patients with cirrhosis, ornithine-aspartate infusions prevented hyperammonemia after an oral protein load in a dose-dependent fashion, but had no effect on fasting plasma ammonia concentrations [21].

  • In a controlled trial of patients with hepatic encephalopathy, the administration of ornithine-aspartate (20 g/day give intravenously over four hours for seven days) improved fasting and postprandial blood ammonia levels compared to placebo-treated patients [22]. There was also symptomatic improvement (assessed by psychometric tests and the PSE index) in patients with hepatic encephalopathy grade I or II, but no effect in those with subclinical hepatic encephalopathy.

  • Another controlled trial evaluated the efficacy of oral ornithine-aspartate (18 g/day in three divided doses) compared to placebo in 66 patients with chronic hepatic encephalopathy [23]. After 14 days, active therapy was associated with improvement in the portosystemic encephalopathy index, mental state grade, and psychometric testing.

  • In contrast to the studies discussed above, preliminary results from a placebo-controlled randomized trial comparing long-term oral administration of ornithine-aspartate with placebo failed to show a significant difference between the two groups [24]. A possible contributing factor to the negative results was that it included only patients with subclinical or mild hepatic encephalopathy.

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. In a prospective, randomized double-blind study of 74 patients with acute hepatic encephalopathy, sodium benzoate (5 gm BID) was compared with lactulose (dose adjusted for two or three semiformed stools per day day) [25]. Treatment effects were evaluated using the PSE index, visual, auditory, and somatosensory evoked potentials, and a battery of psychometric tests for intelligence and memory. The improvement in encephalopathy parameters and the incidence of side effects were similar In both treatment groups. The cost of lactulose was 30 times that of sodium benzoate.

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 — A number of randomized controlled studies have evaluated the use of modified amino acid solutions with a high content of BCAA and a low content of AAA [26]. These studies differ with respect to the amino acid solutions used, the study protocols, patient selection, and the duration of treatment, and therefore cannot be compared with each other. The results have been conflicting; most studies found no significant improvement in hepatic encephalopathy or reduction in mortality in patients treated with BCAA [26]. However, a meta-analysis revealed a significant trend toward improvement in both parameters, and concluded that further randomized controlled trials are needed [27]. At present, infusions of modified amino acid solutions or of BCAA should not be used in the standard treatment of patients with hepatic encephalopathy.

Oral BCAA supplements — Supplementation of the diet by BCAA or by protein hydrolysates enriched with BCAA may be of value for the long-term treatment of hepatic encephalopathy. Six out of nine controlled trials observed no beneficial effect with this regimen, but most studies included only a few patients [26]. Significant improvement in chronic hepatic encephalopathy was seen in three studies. One was a double blind study of 64 patients in whom 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) [28]. 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 [29]. 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.

At present, 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 [30, 31]. GABA-ergic transmission may interact with ammonia in the pathogenesis of hepatic encephalopathy [32]. (See "Pathogenesis of hepatic encephalopathy";).

The benzodiazepine receptor antagonist flumazenil has been used for treatment of hepatic encephalopathy in a number of clinical uncontrolled studies and in several controlled trials with limited success. 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 [33, 34, 35, 36, 37]. Four were crossover trials and one was a placebo-controlled double-blind trial; flumazenil was superior to placebo in three studies.

The results can be viewed according to the severity of the encephalopathy:

  • Flumazenil appeared to have little or no benefit in a study of patients with subclinical or mild hepatic encephalopathy due to either acute or chronic liver disease [36]. There was a tendency toward a more frequent response to flumazenil than placebo, but most patients treated with flumazenil did not respond.

  • An international multicenter trial sponsored by Hoffmann-La Roche which evaluated the effects of flumazenil in noncomatose in patients with mild to moderate encephalopathy [33]. An uncommon PSE score heavily based upon neurologic signs was used to document drug effects. Furthermore, 24 of 49 randomized patients had to be excluded from the final analysis, mostly due to inadequate benzodiazepine screening. Treatment included three bolus doses each followed by a one-hour observation period and then a continuous infusion over three hours. Flumazenil was superior to placebo whether the data were evaluated by standard analysis or an intent to treat analysis; among the 25 patients not excluded, clinically relevant improvement was seen in 35 percent compared to 0 percent in those given placebo.

  • A double-blind, placebo-controlled, crossover Italian multicenter trial evaluated 527 patients with cirrhosis and severe encephalopathy (grade III or IVa) [37]. Improvements in neurologic score (16.1 versus 3.3 percent with placebo) and EEG tracings (24.7 versus 4.2 percent) were infrequent but more common with flumazenil.

  • The Canadian multicenter trial evaluated patients in hepatic coma and had very strict exclusion criteria, which resulted in the rejection of 56 of 77 potential patients [35]. Improvement in neurologic symptoms was observed in 6 of 11 treated patients compared to 0 of 10 receiving placebo; a few patients in both groups showed improvement in the EEG. The beneficial effect of flumazenil was not related to the presence of identifiable benzodiazepines in the blood.

The available data were summarized in a systematic review of 12 controlled trials that included a total of 765 patients [38]. The authors concluded that treatment with flumazenil was associated with a significant improvement in hepatic encephalopathy compared to placebo at the end of treatment (30 versus 7 percent, risk difference 0.23). 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. Thus, it does not appear to have a significant role outside of clinical trials. A later meta-analysis that included six of the controlled trials reached similar estimates of efficacy [39].

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 [40]. Zinc is contained in vesicles in presynaptic terminals of a class of neurons, many of which are a subclass of the glutamatergic neurons [41]. Stimulated release may modulate ion channel function and neurotransmission [42]. Zinc may also enhance the hepatic conversion of amino acids into urea [43].

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 [44]. 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 double-blind crossover trial [45].

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 cirrhotic patients without encephalopathy, as found in 48 percent of patients in one study [46].

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." . 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 [47]. Furthermore, plasma melatonin levels in cirrhotics 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 [48]. Orally administered melatonin therefore could be a treatment option in cirrhotic patients with altered sleep/wake cycles. The hypnotic effect of melatonin could also improve sleep quality, thereby decreasing the need for sedatives.

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. Data in portacaval-shunted rats suggest that L-carnitine is protective against ammonia neurotoxicity [49, 50].

The available clinical data are insufficient to assess the role of L-carnitine in human disease. In cirrhotic patients subjected to a rectal ammonium overload test, intravenous L-carnitine improved psychometric tests significantly after 30 minutes, whereas circulating ammonia levels were not influenced [51]. 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 [52].

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 [53].

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 [54].

RECOMMENDATIONS — The initial management of acute hepatic encephalopathy involves two steps (show figure 1). 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 (show table 3):

  • Hypovolemia
  • Gastrointestinal bleeding
  • Hypokalemia and/or metabolic alkalosis
  • Hypoxia
  • Sedatives or tranquilizers
  • Hypoglycemia
  • Infection (including SBP)
  • Rarely, hepatoma and/or vascular occlusion (hepatic vein or portal vein thrombosis)

The second step is initiation of measures to lower blood ammonia concentrations (whether or not the values are frankly elevated) (show figure 1). This involves use of the following modalities:

  • Nasogastric lavage in the patient with upper gastrointestinal bleeding
  • Oral lactulose or lactitol; lactulose enemas can be give if the patient cannot take lactulose orally
  • Limitation of dietary protein intake
  • Oral neomycin if the patient has not responded to lactulose after 48 hours.
  • Flumazenil if the patient has been given benzodiazepines

Chronic therapy — Chronic management of the patient with recurrent encephalopathy or subclinical encephalopathy requires continuous administration of lactulose and careful attention to diet. Limitation of protein intake (to 70 g/day) is reasonable in patients with hepatic encephalopathy, but protein restriction should be avoided as it will lead to negative nitrogen balance [5]. The titration of individual protein tolerance after an episode of acute hepatic encephalopathy should permit the design of an individual diet for each patient. In protein-intolerant patients, vegetable proteins are superior to proteins derived from fish, milk, or meat, and they improve nitrogen balance [55].

Another alternative for patients intolerant to protein is the addition of branched chain amino acids to a low protein diet.

 

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References

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