Treatment of HE has evolved slowly over the last 50 years, with several breakthroughs occurring during this time. However, clinicians currently operate in somewhat of a vacuum regarding formal treatment guidelines, as the most recent sanctioned clinical guidelines for overt HE were published a decade ago; updated guidelines from the American Association for the Study of Liver Diseases are expected soon.66
Nonetheless, treatment can be structured around several key management principles that parallel the pathophysiology of the disease: management of precipitating factors, reduction of ammonia (and perhaps additional toxins), modulation of fecal fora, modulation of neurotransmission, correction of nutritional deficiencies, and reduction of inflammation. Additional management strategies for less common clinical scenarios will also be discussed.
Management of Precipitating Factors
The majority of HE episodes are precipitated by an event rather than spontaneous, with infection being the most common, although its frequency appears to be declining.67
Often, precipitants are overt and obvious, but a careful history and physical examination are required in order to identify other, less dramatic contributing causes. Gastrointestinal bleeding commonly precipitates HE, even after it is successfully abated; occult chronic gastrointestinal blood loss can also lead to HE and should be evaluated and treated if possible.71
Dehydration, often in the setting of aggressive diuresis with volume contraction alkalosis and electrolyte disturbances, is a particularly common cause of HE in patients with ascites and edema. Individuals who have undergone TIPS insertion for fluid overload are particularly susceptible to dehydration or excessive diuresis if medications are not appropriately tapered after the TIPS procedure. Such dehydration-induced HE usually responds to fluid resuscitation and electrolyte repletion.32
Clinicians should note that albumin seems to play a significant role in treatment of such patients, while other colloids may be less helpful.72
Unfortunately, a mainstay of treatment for chronic persistent HE, lactulose, can lead to severe volume depletion and hypokalemia due to excessive stooling, paradoxically exacerbating the disease that the well-meaning clinician intended to ameliorate. Treatment of HE should include repletion of electrolytes (often lost with overzealous use of diuretics and disaccharides [DS]), particularly potassium, as potassium deficiency can exacerbate hyperammonemia by upregulating renal glutaminase and ammoniagenesis. Constipation is also believed to be a frequent cause of HE, presumably because it increases the amount of time that ammonia and other toxins can be absorbed from the gastrointestinal tract; simple osmotic stool softeners and avoidance of dehydration can help to prevent constipation. Possible noncompliance with lactulose should also be suspected.
Electrolyte derangements commonly precipitate HE events, particularly in the setting of hypokalemia and hyponatremia. Hyponatremia itself can cause neurologic dysfunction, which may be difficult to differentiate from the manifestations of HE. Cerebral edema appears to be a commonality between these 2 neurologic syndromes. Treatment of hyponatremia requires saline resuscitation for patients with hypovolemia and water restriction or vasopressin antagonists for patients with euvolemic or hypervolemic hyponatremia. Whether treatment of hyponatremia with a vasopressin antagonist will also be effective for treatment or prevention of HE remains an intriguing question.
Finally, many patients with advanced liver disease also suffer from anxiety, depression, chronic pain, or sleep disorders; as a result, these patients commonly take sedating medications intended to improve their quality of life. Because these sedatives, particularly those in the benzodiazepine and opiate classes, often trigger or exacerbate underlying HE, they should be removed from the regimen of HE patients as quickly as possible.
Reduction of Ammonia and Other Toxins
Although clinical trials have produced inconsistent evidence of overall clinical improvement associated with ammonia reduction, this intervention has nonetheless been a main goal of HE treatment for the past 4 decades, and decreased ammonia is often cited as a significant endpoint of clinical trials assessing HE treatments. While hyperammonemia alone is insufficient to explain the spectrum of symptoms seen in HE, a significant correlation is seen between the degree of ammonia elevation and the stage of HE.31
The clinical significance of hyperammonemia is more pronounced in the setting of type A HE, where cerebral edema and death have been significantly correlated with the degree of hyperammonemia.74
The mainstay of ammonia reduction for type C HE over the past 40 years has been nonabsorbable DS such as lactulose (β-galactosidofructose) in the United States and lactitol (β-galactosidosorbitol) in Europe. However, the efficacy of these agents has been called into question by a widely cited meta-analysis that examined DS versus placebo or antibiotics for the treatment of HE.75
The authors of this study concluded that the body of evidence for the use of DS in HE is limited and of poor quality; they also found that DS appears to be no better than placebo and worse than antibiotics for treatment of this disease. However, more recent data regarding the use of lactulose for prevention of HE recurrence appears more promising.76
Despite the questionable benefit of lactulose in well-designed trials, most clinicians still believe in the efficacy of DS, and lactulose continues to be widely prescribed for HE.
The mechanism of action through which DS works is multifaceted. While intestinal “hurry” is their best-known mechanism for eliminating fecal waste products, including ammonia, DS are much more than simple cathartics. Upon entering the colon, DS are cleaved into monosaccharides by the bacterial fora, some of which (eg, Lactobacilli and Bifidobacteria) can then incorporate these monosaccharides into subsequent generations of bacteria, thereby gaining a growth advantage. The unincorporated monosaccharides are also utilized as fuel for the bacteria. This fermentation process generates lactic acid and hydrogen ions, thereby acidifying the fecal stream within the colon and causing subsequent protonation of ammonia molecules (NH3) into ammonium ions (NH4+). Because the charged NH4+ is poorly absorbed across the colonocyte, the ion remains trapped within the colonic lumen. In addition, this protonation reaction can allow for movement of NH3 from the bloodstream back into the colonic lumen in a classic example of stoichiometry (NH3 + H+→ NH4+). Another mechanism of action that has been postulated for DS involves transformation of the fecal fora: reduction of urease-producing bacteria (which are not given a growth advantage with DS) in favor of the proteolytic species (eg, Lactobacilli and Bifidobacteria). In this regard, DS can be considered a prebiotic—ie, a “meal” for the bacterial biomass.
Another mechanism for reducing ammonia involves the use of so-called ammonia scavengers, such as intra-venous sodium benzoate and sodium phenylacetate (Ammonul, Ucyclyd Pharma) or a prodrug of phenylacetate, oral sodium phenylbutyrate (Buphenyl, Medicis); both of these scavengers are approved for use in patients with urea cycle disorders and hyperammonemia (mostly children). Oral sodium benzoate (Ucephan, B Braun) is also sometimes used off-label for ammonia scavenging. It is available as a powder and can be obtained from specialty pharmacies. These compounds work by combining with glycine (in the case of benzoate) or glutamine (in the case of phenylacetate) to form water-soluble and renally excretable compounds (benzoylglycine or hippurate and phenylacetylglutamine, respectively) that eliminate ammonia through the urine.
The use of these drugs is a way to bypass the saturated urea cycle, but these agents still require intact renal function for elimination of ammonia. Also, while these products are available in the United States, they are not approved for HE. One downside to their use is their large therapeutic dose (measured in grams per day)— which leads to a significant sodium load (1–2 g/day at therapeutic doses) that may contribute to fluid retention in cirrhotic patients—as well as poor palatability. A new compound, glycerol phenylbutyrate (HPN-100, Hyperion Therapeutics), is a prodrug of sodium phenylbutyrate with a much lower anticipated therapeutic dose requirement and improved palatability. Glycerol phenylbutyrate is currently being evaluated for type C HE and recently met the primary endpoint in a phase III trial of urea cycle disorders.
A newer avenue being explored for reduction of ammonia is the use of orally ingested, activated charcoal. A compound called AST-120 (Ocera Therapeutics), a spherical carbon adsorbent, has been studied in patients with mild HE and cirrhotic patients with pruritus. This compound's known capability for adsorbing small molecules—not only ammonia, but also lipopolysaccharides and cytokines—makes it an attractive therapeutic option for HE. A pilot study showed that AST-120 had efficacy equivalent with lactulose and fewer adverse events.78
Other data have noted a reduction in ammonia and cerebral edema following treatment with AST-120 in animal models of cirrhosis. A larger trial of AST-120 in patients with mild type C HE, the ASTUTE trial, has recently been completed, and results are anticipated soon.
For patients with severe HE who do not respond to traditional therapies, clinicians may consider the use of an extracorporeal device for “liver dialysis.” Currently, the only such system that is clinically available in the United States is the molecular adsorbent recirculating system (MARS, Gambro), also known as albumin dialysis, which is indicated for acute poisoning. A large randomized controlled study was conducted in the United States for patients with severe HE not responding to standard care. Patients receiving MARS demonstrated more rapid and significant improvements in HE, but no benefit in mortality was found in this group of patients with terminal liver failure.79
Other devices, including bioartificial machines with hepatocytes, have been studied for treatment of HE, but none are currently approved in the United States.80
Finally, certain patients with ongoing hyperammonemia and persistent HE despite removal of precipitating factors and optimal therapeutic management will be recognized as having large or extensive spontaneous portosystemic shunting. These shunts may be amenable to embolization via percutaneous catheterization, but experience in the United States remains limited.
Modulation of Fecal Flora
The gut microbiome's influence is becoming increasingly recognized across many diverse disease states, including inflammatory bowel disease, irritable bowel syndrome, and obesity. Bacterial fora also appear to play a significant role in the pathogenesis of HE, and modification of this flora—either through antibiotics, probiotics, or prebiotics—is important for the successful treatment of this disease. Prebiotics (of which lactulose and fermentable fibers are examples) may directly enhance the growth of bacterial strains that are potentially beneficial to the host (ie, Bifidobacteria
), thereby indirectly reducing the influence of potentially more harmful resident fora (ie, urease-producing species). Prebiotics also come in the form of indigestible fibers and have shown benefit for the management of HE, particularly MHE, both when used alone and when used in combination with probiotics (in which case they are termed “synbiotics”).82
Probiotics have also been studied (either alone or as synbiotics) for the treatment of HE and have shown some benefit, mostly in the setting of minimal disease.84
The bacterial species that appear to be most successful include Lactobacilli
. Investigators in Belgium have also demonstrated improvements in both acute and chronic animal models of HE when these animals were treated with genetically enhanced species of Lactobacilli
that had augmented ammonia-consumption capabilities.89
Probiotics may also improve overall liver function, perhaps by reducing translocation and subsequent endotoxemia and by ameliorating the hyperdynamic circulation.84
On the other side of the treatment spectrum, antibiotics have been clearly proven to treat HE, particularly when used to prevent recurrent exacerbations. Rifaximin (Xifaxan, Salix) is a poorly absorbed relative of rifamycin that has broad antibacterial activity against both aerobes and anaerobes. Rifaximin has a preferential site of action in the small bowel (presumably due to its enhanced solubility in bile) where it typically lowers the bacterial load 100–1,000-fold; however, it stops short of obliterating all fora and is less effective in the colon.90
A large randomized controlled study investigating rifaximin versus placebo in patients who were already using lactulose (91% of both arms) showed a highly statistically significant benefit for rifaximin in preventing recurrences of HE and decreasing hospitalizations related to HE over a 6-month period.91
In an exploratory analysis, the trial also demonstrated an improvement in quality of life in patients receiving rifaximin, as assessed by the Chronic Liver Disease Questionnaire.92
Other antibiotics used to treat HE include neomycin (an aminoglycoside), metronidazole (for anaerobes only), paromomycin, and oral vancomycin. These antibiotics all have considerable limitations either related to safety (ie, ototoxicity and nephrotoxcity with neomycin; neurologic toxicity with metronidazole) or resistance (oral vancomycin); for these reasons, these agents have largely been replaced by rifaximin, which is now approved by the US Food and Drug Administration for treatment of HE. The mechanism of action for antibiotics in HE is assumed to be related to modulation of bacterial flora, but this hypothesis has not been proven. One postulated mechanism of action is the correction of small intestinal bacterial overgrowth, which is frequently identified in cirrhotic patients, although this explanation remains controversial.93
Studies evaluating antibiotics for the treatment of HE have shown reductions in ammonia levels, but some researchers have speculated that the benefit of antibiotics also arises from an anti-inflammatory effect or downregulation of intestinal glutaminase activity. Studies are still needed to examine the effects of chronic antibiotic administration on fecal fora, as well as their effect on cytokines and other markers of inflammation in HE.
Finally, acarbose, an α-glucosidase inhibitor used in the management of diabetes, has also been studied for the treatment of HE. By reducing glucose absorption from the intestine, this drug may promote the survival of primarily saccharolytic (rather than proteolytic) bacteria, thereby reducing the generation of ammonia. A randomized, double-blind, crossover trial of acarbose in diabetic patients with mild HE demonstrated reductions in ammonia concentrations and improvements in number connection tests and HE grades.94
Further clinical trial data are needed before this drug can become more widely used for this indication.
Modulation of Neurotransmission
The final common pathway for the pathophysiology of HE appears to be altered neurotransmission, manifested as upregulation of both GABA neuroinhibitory receptors and N-methyl-D-aspartic acid–glutamate excitatory receptors, resulting in a clash of combined inhibitory and excitatory signals. Targeting this derangement has long been an avenue for HE management, and trials have been conducted with flumazenil, naloxone, bromocriptine, levodopa, and AChE inhibitors, many of which have met with minimal clinical success. When faced with a comatose patient with HE, a therapeutic trial of flumazenil or naloxone is certainly appropriate if benzodiazepine or opiate ingestion has been identified or suspected. However, the effect of these drugs is short-lived, and minimal evidence exists to support their use.95
More recently, a pilot study of the AChE inhibitor rivastigmine in patients with moderate HE showed a benefit in psychometric testing.59
Correction of Nutritional Deficiencies
Patients with advanced liver disease often face tremendous difficulties in maintaining proper nutritional balance. Many factors are involved in their poor nutrition, including poor dietary absorption (particularly of fat-soluble vitamins), poor intake (due to confusion, weakness, or ascites), and a baseline hypercatabolic state. This imbalance often leads to a wasting syndrome due to protein-calorie malnutrition. Since skeletal muscle appears to play some role in controlling the flux of ammonia in the body, muscle mass depletion may lead to worsening of HE, although this effect has not been consistently demonstrated.
Zinc is another potentially important factor in terms of nutritional deficiencies. Zinc serves as a cofactor for several of the enzymes involved in the urea cycle; thus, zinc deficiency, which is common in cirrhotic patients, may decrease the efficiency of the urea cycle. A recent randomized, open-label trial suggests that zinc supplementation may provide a benefit in patients with HE.97
A product that is frequently used for treatment of HE outside of the United States is L-ornithine L-aspartate (LOLA), which is believed to act by supplying substrates for the urea cycle and glutamine synthesis that may otherwise become depleted in cirrhotic patients with generalized protein malnutrition and amino acid deficiencies. The data regarding LOLA's use in HE were published in a meta-analysis of 3 trials and demonstrated a significant benefit in patients with grade I–II HE, but not with minimal HE.98
However, this product is not currently available in the United States.
A new compound that is similar to LOLA, L-ornithine phenylacetate (LOPA), also known as OCR-002 (Ocera Therapeutics), has been developed and is currently being tested as a treatment for HE. This agent may work by increasing the supply of ornithine to the urea cycle, thereby enhancing the incorporation of ammonia into glutamine. Ammonia is then scavenged by subsequently conjugating phenylacetate with glutamine to form phenylacetylglutamine, which is then excreted in urine. Results are eagerly awaited from a recently completed phase I trial of LOPA in patients with HE, and the company has announced plans for a phase II trial to begin in 2011.99
Another approach to addressing nutritional deficiencies in cirrhotic patients with HE focuses on correcting the Fischer ratio: the balance between branched-chain amino acids (BCAA) and aromatic amino acids (AAA). This ratio is typically 3:1 in the healthy population, but it becomes inverted in cirrhotic patients. The benefits of BCAA (valine, leucine, and isoleucine) are believed to be 2-fold: They are essential for protein production, and they are critical for the prevention of catabolism, which can worsen HE. AAA, on the other hand, appear to be precursors of “false” neurotransmitters such as octopamine or phenylethylamine. These have been implicated in the pathogenesis of HE because of their potential to inhibit neurotransmission via nonfunctional competitive blockade of receptors. A surplus of AAA can also cause problems related to the production of neurotoxic phenols and downregulation of the synthesis of excitatory neurotransmitters, such as norepinephrine and dopamine, thus further contributing to neurologic dysfunction.52
By supplementing diets with BCAA, patients are able to continue adequate protein intake, reduce catabolism and muscle breakdown (which helps to maintain the ammonia clearance provided by muscle), and prevent the synthesis of false neurotransmitters. A meta-analysis of BCAA supplementation supported its use for improving the rate of recovery from episodic HE but did not demonstrate a survival advantage.100
BCAA supplements are limited in clinical practice due to poor palatability and higher costs.
The most important recent development in nutritional supplementation for HE is reversal of the long-held belief that protein restriction is beneficial for patients with episodic or persistent HE. A study evaluating low-protein versus normal-protein diets for patients with episodic HE demonstrated that both groups showed similar rates of improvement; however, the protein-restricted group suffered from accelerated protein catabolism.101
Finally, some evidence from an Italian center supports supplementation with carnitine, either L-carnitine or its acetylated form, for treatment of HE.102
Confirmation of these positive results in other centers is needed.
Reduction of Inflammation
Patients with cirrhosis have a significantly increased risk of infection related to their relative immunosuppression and dysfunctional reticuloendothelial system. This risk is almost 5 times that of noncirrhotic patients hospitalized for other indications. Indeed, infection, a prototypical inflammatory state, is a common precipitant of HE because these infections often manifest without typical signs and symptoms. Clinicians must aggressively search for and treat these infections in patients presenting with HE. Many practitioners assume an infectious process is involved in the presentation of more severe cases of HE and begin empiric antimicrobial therapy while body fluid analyses and cultures are performed. In addition, standard-of-care treatment demands the systematic performance of diagnostic paracentesis for any patient with ascites who is admitted to the hospital with decompensation. Antibiotics are clearly indicated in the treatment of infections in patients with HE, and many of these HE events will improve with conservative management alone—intravenous fluids, antibiotics, drainage of abscesses, and rest.
Even in the absence of an active infection, patients with cirrhosis are in a relatively proinflammatory state, marked by elevated levels of endotoxin, tumor necrosis factor (TNF)-α, and other proinflammatory cytokines, as well as upregulation of certain toll-like receptors.105
This inflammatory state may be related to bowel wall edema due to portal hypertension or delayed transit time with subsequent translocation of bacteria and/or endotoxin into the bloodstream. Whether antibiotics given to HE patients without active infection have an impact on the relative inflammatory state of cirrhosis is unclear, but antibiotics do appear to improve the hyperdynamic circulation of cirrhosis and reduce both the risk of hepatorenal syndrome and death.106
Other potential HE therapies that have an anti-inflammatory role include pentoxifylline and the activated charcoal product AST-120. A recent large randomized controlled trial of pentoxifylline versus placebo in patients with Child-Pugh class C cirrhosis showed no benefit in overall mortality, but the study authors did demonstrate a significant reduction in complications of cirrhosis, including development of HE, in patients treated with pentoxifylline. Pentoxifylline is thought to work in these patients because of its anti–TNF-α activity, as TNF-α is typically elevated in patients with cirrhosis. A study comparing pentoxifylline with placebo or another agent for the treatment or prevention of HE is needed before pentoxifylline can become accepted as therapy for HE.
Other potential anti-inflammatory therapies for HE should also be explored. With its distinct mechanism of action, AST-120 may be able to bind very small molecules in the gut—such as TNF-α, lipopolysaccharide, or endotoxin—and thereby block their absorption. AST-120 is currently being evaluated for use in patients with mild HE.