Portosystemic Encephalopathy Treatment & Management

Updated: Sep 17, 2019
  • Author: Gagan K Sood, MD; Chief Editor: BS Anand, MD  more...
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Treatment

Approach Considerations

Consultation with a neurologist is of value, especially if doubts exist regarding the etiology of the encephalopathy.

Alcohol rehabilitation is a requirement for acceptance for listing for orthotopic liver transplantation. Regardless of whether the patient is a candidate for orthotopic liver transplantation or not, the development of portosystemic encephalopathy is a potential revelation that permits progress toward achieving and maintaining abstinence. This is a critical step for increasing the probability of survival and is often best approached initially by taking advantage of the inpatient status.

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Medical Care

Nonabsorbable disaccharides

Despite the availability of multiple approaches, treatment with nonabsorbed disaccharides remains the mainstay of therapy for hepatic encephalopathy. These agents act by at least three mechanisms, as follows:

  • The luminal bacteria metabolize lactulose and lactitol (beta galactoside-sorbitol). The consequent acidification of the gut lumen leads to ammonia being protonated to the ammonium ion (NH4+), which is relatively membrane impermeable; therefore, less ammonia is absorbed from the colon.

  • The second benefit to gut luminal acidification is a reduction in the number of bacteria present, which reduces the presence of bacterial urease and consequent ammoniagenesis.

  • The osmotic effect of nonabsorbed disaccharides enhances gastrointestinal transit.

A typical starting dose for the treatment of chronic hepatic encephalopathy is 20 g of oral (PO) lactulose twice daily with the goal of producing two to three soft bowel movements daily. Dose increases or reductions may be necessary based on the patient's response.

In the acute setting, hepatic encephalopathy may be treated with 20 g lactulose every few hours until a satisfactory result is achieved, but care must be taken to avoid diarrhea that leads to electrolyte depletion and dehydration. Lactulose enemas may be of benefit when a paralytic ileus precludes PO or nasoenteral tube administration. Note:  Because the bacterial metabolism of lactulose results in the production of hydrogen, this agent should not be used as a lavage preparation for colonoscopy, as electrocautery under these circumstances may produce explosive results.

Clinical evaluations regarding the efficacy of nonabsorbed disaccharides are limited, especially when their widespread use and the potential for adverse reactions are considered. The toxicity of lactulose and lactitol includes gastrointestinal bloating due to bacterial gas production, dehydration, and electrolyte disturbances. The latter may result in paralytic ileus and, therefore, must be carefully distinguished from the more common bloating. Indeed, these complications of lactulose therapy may paradoxically worsen hepatic encephalopathy. Gastrointestinal upset infrequently leads to a requirement for dose reduction or, ultimately, discontinuance. It may be less problematic with lactitol.

Antibiotics

Treatment with nonabsorbable antibiotics also is advocated as a treatment of hepatic encephalopathy, and it may be of particular value in a patient intolerant of lactulose. This may be relevant for a patient with intestinal ileus, in whom the administration of lactulose may generate large volumes of hydrogen gas upon bacterial fermentation. Similarly, patients with multiple electrolyte disturbances or dehydration may benefit from this antibiotic approach rather than from the use of lactulose.

Neomycin at 1 g PO three or four times daily may be used, but it is not recommended for prolonged use. As much as 3% of a PO dose of neomycin may be absorbed systemically, and nephrotoxicity may result. The efficacy of neomycin has been questioned when no clinical benefit could be demonstrated when it was compared with placebo in the treatment of acute hepatic encephalopathy.

Oral metronidazole is used with success, but long-term therapy may result in toxicity, including peripheral neuropathy.

Rifaximin is a relatively newer nonabsorbable antibiotic for the treatment of hepatic encephalopathy. Its efficacy in hepatic encephalopathy has been studied in more than 20 studies, including 14 randomized controlled studies. In seven studies, rifaximin was compared to lactulose or lactilol. Results of Cochrane meta-analysis from these studies suggested rifaximin to be significantly more effective than nonabsorbable disaccharides (lactulose or lactilol) in the treatment of hepatic encephalopathy.

In March 2010, rifaximin was approved by the Food and Drug Administration (FDA) to reduce recurrence of hepatic encephalopathy. The approval was based on a phase 3 clinical trial conducted by Bass et al that evaluated rifaximin’s ability to reduce the risk of recurrent hepatic encephalopathy. [1] In this trial, 299 patients received either rifaximin 550 mg or placebo twice daily. Each group also received lactulose. The primary endpoint—the risk of a recurrent episode of hepatic encephalopathy—was reduced by 58% in the rifaximin group compared to the placebo group (<  0.0001). [1] The key secondary endpoint, risk of experiencing hepatic encephalopathy-related hospitalization, was reduced by 50% in patients who received rifaximin compared to those who received placebo (= 0.0129).

An open-label maintenance extension of the phase 3 trial of rifaximin in hepatic encephalopathy reported benefits of long-term treatment with rifaximin in maintenance of remission from overt encephalopathy. [2] This study reported results of long-term efficacy and survival of 152 rollover patients from the registration trial and 128 new patients treated with rifaximin. The rollover patients were rifaximin (n = 70) or placebo (n = 82) patients who completed or withdrew from the registration trial with a Conn Score of 2 of less.

Sixty of the 70 rifaximin-treated patients from the registration trial who enrolled in the long-term follow-up remained in remission at study completion or withdrawal, and 43 (72%) of these patients did not experience breakthrough overt encephalopathy. [2] The risk of experiencing breakthrough encephalopathy was decreased by 79% compared to their prior 6-month placebo treatment. Changes in the Model for End-Stage Liver Disease (MELD) score were minimal in both the registration trial and the open-label extension, regardless of the treatment (see the MELD Score calculator). The authors concluded that longer therapy with rifaximin is associated with continued protection from breakthrough hepatic encephalopathy, with no adverse effect on expected mortality. [2]

Altering gut flora

The presence of urease-expressing bacterial organisms in the gut microflora forms the basis for efforts to repopulate the gut with nonureolytic organisms, such as Lactobacillus acidophilus and Enterococcus faecium. In theory, this should result in a reduction in colonic ammoniagenesis, but few well-designed studies exist to support the routine clinical application of this approach. Results of small trials with Lactobacillus species have been mixed. The use of orally administered Enterococcus species resulted in sustained protection from hepatic encephalopathy in one study and appeared to be safe. Further evaluation of this approach is justified and needed.

The presence of Helicobacter pylori in the gastric mucosa represents another potential source of ammonia because this organism produces urease. Helicobacter ammoniagenesis may be most significant when accompanied by achlorhydria, in part due to increased absorption of nonprotonated ammonia across the gastric mucosa and, possibly, from increased numbers of bacteria. The role of H pylori in the pathogenesis of hepatic encephalopathy remains contentious; some investigators have identified it as an independent risk factor for the development of hepatic encephalopathy, whereas others have not.

One possible explanation for improvement in hepatic encephalopathy following eradication therapy for H pylori is that the antibiotics decreased the gut's colonic population of urease-expressing organisms and those of the gastric mucosa. It appears reasonable to treat patients for H pylori when dictated by routine clinical circumstances (eg, in the treatment of peptic ulcer disease) but not as prophylaxis for hepatic encephalopathy.

Probiotics

Probiotics are not as useful in overt hepatic encephalopathy but have been used with some success in minimal HE. The species that are most efficacious are lactobacilli and bifidobacteria. Probiotics may also reduce bacterial translocation and subsequent endotoxemia and ameliorate the hyperdynamic circulation.

Although probiotics appear to reduce plasma ammonia concentration when compared with placebo or no intervention, a Cochrane meta-analysis concluded that probiotics are efficacious in altering clinically relevant outcomes, [3] but further randomized clinical trials are needed. Another study showed lactulose and probiotics are effective for secondary prophylaxis of hepatic encephalopathy in patients with cirrhosis. [4]

Ammonia scavengers and activated charcoal

Intravenous sodium benzoate and sodium phenylacetate or the phenylacetate prodrug oral sodium phenylbutyrate can combine with glycine or glutamine to form water-soluble compounds excreted through the kidneys. These agents are not yet approved by the FDA for use in hepatic encephalopathy; they depend on normal renal function for ammonia excretion, and the large therapeutic doses confer a significant sodium load, which can increase fluid retention.

Newer ammonia scavengers and orally ingested activated charcoal are being studied for the treatment of hepatic encephalopathy.

Glycerol phenylbutyrate (HPN-100) is a compound that is a prodrug of sodium phenylbutyrate with much lower therapeutic doses needed. It has been used for urea cycle disorders and continues to undergo clinical trials for chronic hepatic encephalopathy. [5, 6, 7]

With regard to orally ingested activated charcoal, AST-120 is a spherical carbon adsorbent of small molecules (ammonia, lipopolysaccharides, and cytokines) that has been used to improve symptoms of hepatic encephalopathy. [6] A pilot study showed equal efficacy as lactulose and fewer adverse events. [8]

Increasing ammonia metabolism

Another treatment approach is to increase the metabolism of ammonia with the administration of substrates that permit its incorporation.

Ornithine is a substrate for urea, and aspartate is a substrate for glutamine. Both enteral and intravenous administration of ornithine aspartate (a mixture of the two amino acids) in some controlled trials have been shown to lower serum ammonia levels and improve mild hepatic encephalopathy by increasing the conversion of ammonia to urea. Trials using ornithine alpha-glutarate did not demonstrate a benefit. In part, this may be because it only supplies one substrate for incorporation of ammonia. Relatively large doses of amino acids (18 g/day PO) appear to be necessary for any clinical benefit.

The mechanism of action of L-ornithine L-aspartate may extend beyond the urea cycle. Administration of ornithine aspartate to portal hypertensive rats results in high concentrations of glutamate in the plasma and cerebrospinal fluid (CSF) and an associated reduction in plasma ammonia. The elevated glutamate concentrations facilitate synthesis of glutamine by glutamine synthase, which is expressed at high levels in the liver, brain, and skeletal muscle. This mechanism may permit further significant reductions in ammonia levels within both the central nervous system and the systemic circulation. Indeed, increased glutamine synthase expression is induced in the skeletal muscle by portocaval shunting.

An increase in plasma concentrations of BCAAs also is an anticipated metabolic consequence of increased glutamate availability. It remains of uncertain significance and does not necessarily contribute to the improvement in hepatic encephalopathy documented in this experimental model.

Sodium benzoate has also been shown to be efficacious in reducing serum ammonia. It is conjugated to glycine to form hippuric acid, which is excreted in the urine. Similarly, phenylacetate is conjugated with glutamine to form phenacetylglutamine. Both of these organic acids have been used successfully to treat hepatic encephalopathy in some clinical trials.

Zinc supplementation

The urea cycle allows the conversion of ammonia to urea. Because two of the enzymes in this metabolic pathway require zinc as a cofactor and because reduced plasma zinc levels from increased urinary zinc losses are documented in hepatic encephalopathy, oral zinc supplementation is proposed as a treatment of this condition.

The measurement of serum zinc levels may not accurately reflect whole-body zinc status, but it would appear reasonable to supplement patients found to have low serum zinc levels with zinc gluconate.

Flumazenil

Treatment efforts with flumazenil, a competitive antagonist of BZPs, are based on the GABA hypothesis; however, results of the small clinical trials performed to date are variable.

In two well-designed studies, flumazenil was found to be of value in a limited number of patients but clear factors that might permit their identification were not proposed; therefore, because of the difficulty in establishing a more generalized improvement in the patient's condition and the relatively short duration of action of the drug, it is not of convincing benefit.

Dopamine agonists

Parkinsonian or extrapyramidal symptoms may manifest with hepatic encephalopathy. Treatment with levodopa or bromocriptine is shown to result in improvement in clinical and electroencephalographic findings in anecdotal reports and small studies.

Although the use of bromocriptine is advocated for cases of refractory hepatic encephalopathy, well-designed prospective controlled trials have not been conducted.

Albumin

Simón-Talero et al found evidence that a subgroup of patients with advanced cirrhosis and episodic hepatic encephalopathy may benefit from treatment with albumin. In a randomized, prospective, double-blind, controlled trial, 56 cirrhotic patients with an acute episode of hepatic encephalopathy received albumin (n = 26) or saline (n = 30), in addition to commonly administered therapy consisting of laxatives and 1200 mg of rifaximin per day. [9]

The investigators determined that albumin did not aid in reducing the percentage of patients with encephalopathy during the hospitalization period, with no significant difference found between the albumin and saline groups with regard to the percentage of patients at day 4 whose encephalopathy had resolved. At day 90, however, the survival rate in the albumin and saline groups did differ significantly (69.2% vs 40.0%, respectively). The investigators suggested that the development of encephalopathy possibly signals which patients with advanced cirrhosis may benefit from albumin therapy. [9]

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Surgical Care

The definitive approach to management of portosystemic encephalopathy is orthotopic liver transplantation (OLT). Portosystemic encephalopathy as a complication of end-stage liver disease may warrant discussion of OLT. Indeed, even central nervous system structural changes evident on magnetic resonance imaging may be reversed slowly following OLT; however, a detailed discussion of OLT is beyond the scope of this article (see Liver Transplantation).

A retrospective cohort study by Laleman et al indicated that embolization can be used safely and effectively to treat hepatic encephalopathy in patients with large spontaneous portosystemic shunts (SPSSs). [10] The study involved 37 patients with refractory hepatic encephalopathy and a single large SPSS who underwent embolization. Within 100 days following the procedure, 22 patients (59.4%) were free of the encephalopathy, with 18 of them remaining free of it over a mean follow-up period of 697 days. One major, albeit nonlethal, procedure-associated complication occurred in the study. [10]

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Diet

Nutritional therapy includes the following:

  • Therapy with branched-chain amino acids (BCAA) has been evaluated extensively as a treatment for hepatic encephalopathy. They are of suggested benefit in lowering the production of false neurotransmitters. Vegetable protein–based diets that exclude meat are relatively high in BCAAs and low in aromatic amino acid content. Clinical trials performed to date with vegetable protein–based diets or BCAAs have not demonstrated any consistent or convincing benefit with respect to the clinical manifestations of hepatic encephalopathy and do not support their widespread use for the treatment or prevention of hepatic encephalopathy.

  • Vegetable protein, however, may have other benefits. In patients with subclinical hepatic encephalopathy, one study demonstrated computer-analyzed electroencephalographic (EEG) findings improved with vegetable protein–based diets, despite the lack of any change in ammonia levels. Urinary 3-methyl-histidine excretion was increased with the use of an animal-protein diet, and the vegetable diet was associated with a decrease in urinary nitrogen excretion; thus, the nitrogen balance tended to be more positive with the vegetable-protein diet.

  • Patients with advanced liver disease often present with poor nutritional status and may develop a negative nitrogen balance exacerbated by acute or recurrent efforts to restrict dietary protein. Although the practice of strictly limiting dietary protein in these patients was advocated until relatively recently, adverse nutritional consequences now appear to outweigh any potential benefit for the prevention of hepatic encephalopathy. In general, patients with chronic liver disease should be advised to eat approximately 1 g of dietary protein per kilogram body weight per day. In this context, BCAAs may be a useful dietary supplement to help preserve skeletal muscle mass via protein sparing, with little risk of precipitating hepatic encephalopathy.

  • With a well-tolerated exogenous source of amino acids, the catabolic metabolism that otherwise results in negative nitrogen balance therefore may be offset. This is of particular importance in patients awaiting orthotopic liver transplantation, in whom a protracted nutritional decline may occur during the long wait for a suitable donor liver.

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Activity

Consider restricting patients with encephalopathy from driving motor vehicles or operating potentially dangerous machinery. This may be difficult to justify to patients and their families in the absence of formal psychometric testing. Reaction times and judgment are typically impaired. Similarly, a patient may need to perform different job duties in order to avoid physical or, possibly, financial harm. Clearly, these issues may settle themselves because mental status changes resolve completely with therapy. These difficult issues need review on an individual basis and require periodic reassessment.

Patients need adequate rest, and their goal should be to sleep at least 8 hours at night. Strenuous activity should be avoided, but regular mild exercise is distinctly advantageous for maintaining bone mass and cardiovascular conditioning in anticipation of the long wait for a donor organ required for an orthotopic liver transplantation.

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