Pharmacotherapy for hyperammonemia.

Review

Pharmacotherapy for hyperammonemia

Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Nyu Medical Center on 12/13/14 For personal use only.

Anna Hadjihambi, Varun Khetan & Rajiv Jalan† 1.

Introduction

UCL Institute for Liver and Digestive Health, UCL Medical School, London, UK

2.

Targets for treatment of hyperammonemia

3.

Treatments

4.

Conclusion

5.

Expert opinion

Introduction: Hepatic encephalopathy (HE) is a serious neuropsychiatric complication that is seen in patients with liver failure. The pathogenesis of HE is not entirely understood, but several hypotheses have emerged and persisted during the years. Despite the many prevalent hypotheses, most of the existing evidence point to ammonia as the main culprit behind primary and secondary symptoms making it the center of potential therapeutic options for the treatment of HE. Most treatments of hyperammonemia target the organs and metabolic processes involved in ammonia detoxification. Areas covered: This article provides a review of the current targets of therapy as well as the drugs used for hyperammonemia treatment. Expert opinion: Lactulose and rifaximin have a proven role as measures to use for secondary prophylaxis and are the mainstay of current therapy. The use of molecular adsorbent recirculating system in patients with severe HE has been proven to be efficacious, but through mechanisms that appear to be independent of ammonia. The main challenge that faces the further development of treatments for HE is finding appropriate end points, and the next step would be to provide evidence of the effectiveness of established treatments and define the role of emerging new treatments. Keywords: acute liver failure, chronic liver failure, hepatic encephalopathy, hyperammonemia, ornithine phenylacetate Expert Opin. Pharmacother. (2014) 15(12):1685-1695

1.

Introduction

Hepatic encephalopathy (HE) is a serious neuropsychiatric complication arising from liver dysfunction [1]. This syndrome is composed of a range of symptoms, including alterations in cognitive, behavioral, fine motor and psychomotor functions, with coma and death occurring in the final stages [2,3]. One characteristic of HE in both acute liver failure (ALF) and chronic liver disease (CLD) is cytotoxic brain edema that affects the astrocytes. In extreme cases, particularly in patients with ALF but rarely in acute-on-chronic liver failure, this can cause an increase in intracranial pressure, brain stem herniation and death [3]. The pathogenesis of HE is not entirely understood, but several hypotheses have emerged and persisted during the last few years. The main factors considered to be responsible for the development and progression of HE are ammonia [4], inflammatory response [5], oxidative stress [6], neurotransmission changes, impaired blood--brain barrier (BBB), neurotoxins, abnormalities in GABA-ergic and benzodiazepine pathways [7], impaired cerebral blood flow and energy metabolism of the brain [8,9]. Despite the many prevalent hypotheses, most of the existing evidence point to ammonia as the main culprit behind primary and secondary symptoms. In ALF patients, the severity of hyperammonemia was shown to correlate with the occurrence of cerebral herniation. Ammonia, therefore, remains at the centre of potential therapeutic options for the treatment of HE [10]. Ammonia is a ubiquitous byproduct of the metabolism of nitrogen-containing compounds and its accumulation has been seen in a number of metabolic disorders [11]. 10.1517/14656566.2014.931372 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted

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Hyperammonemia is believed to be the main culprit behind primary and secondary symptoms of hepatic encephalopathy (HE) although several other factors are also known to be involved. The vast majority of ammonia is detoxified by the liver through the urea cycle. A small amount is then metabolized in peripheral organs; mainly the muscles, kidneys and brain. Most treatments of hyperammonemia target production, absorption or elimination through the organs and metabolic processes involved in detoxification. Drugs such as lactulose and rifaximin have a proven role in the treatment of HE but have limited effect on ammonia levels. Glycerol phenylbutyrate and ornithine phenylacetate provide exciting prospects for new approaches to removing ammonia from the body. The main challenge for the liver community is to take the drugs that are in development and test them in appropriate clinical trials.

This box summarizes key points contained in the article.

The gut is the primary source of ammonia production through the mitochondrial enzyme phosphate-activated glutaminase, which catalyzes deamination of glutamine to glutamate in the enterocytes, as well as by the ammonia-generating activity of intestinal bacteria. The vast majority of ammonia is, in normal physiology, detoxified by the liver through the urea cycle. A small amount is then metabolized in peripheral organs such as the muscles, heart, kidneys and brain [12]. In the presence of liver disease, however, the urea cycle becomes functionally impaired and leads to the development of hyperammonemia in spite of the extended participation of peripheral organs in the ammonia detoxification process. Ammonia then traverses the BBB and causes toxicity in the brain [13]. During liver failure, the enzyme glutamine synthetase (GS) present in the muscles (two types: mitochondrial and cytoplasmic) [14], liver (mitochondrial and cytoplasmic), kidney (cytoplasmic) [15] and brain (cytoplasmic) [16] becomes the primary ammoniadetoxifying pathway. It incorporates ammonia into glutamate and forms glutamine by consuming ATP [10,17]. Astrocytic glutamine production is increased in the presence of high concentrations of ammonia, resulting in an increase in osmotic pressure, which causes fluid accumulation in the astrocytes and leads to cerebral edema [18]. Most treatments of hyperammonemia target the organs and metabolic processes involved in ammonia detoxification. This article will therefore review the current targets of therapy as well as the drugs used for the treatment of hyperammonemia. 2.

Targets for treatment of hyperammonemia

Ammonia metabolism involves five organs: the liver, kidneys, brain, intestines and muscle (Figure 1). All the organs listed 1686

contain the activity of two principle enzymes, GS and glutaminase, which results in a constant metabolic flux of ammonia across each organ. Both enzymes are located in the inner-mitochondrial membrane. Liver In the healthy liver, ammonia is detoxified by urea synthesis in the urea cycle by periportally located hepatocytes as well as through glutamine synthesis in perivenous hepatocytes around the terminal hepatic venules of the liver acini (7% of total hepatocyte population) [19]. Urea cycle enzymes have a low affinity for ammonia but high capacity while, conversely, the enzyme GS has a high affinity but low capacity for ammonia. GS has a beneficial location in the liver, allowing it to scavenge any ammonia that escapes urea cycle detoxification to be metabolized into glutamine by these hepatocytes, thus keeping plasma ammonia levels low [19]. Periportal hepatocytes contain various enzymes such as carbamoyl-phosphate synthetase, aspartate aminotransferase, alanine aminotransferase, urea cycle enzymes and glutaminase [20,21]. Interestingly, the periportal glutaminase (activated by ammonia) and perivenous GS operate simultaneously in a normal liver, resulting in a ‘intracellular glutamine cycle’ [22]. Under physiological conditions, these two enzymes work in equal magnitudes to achieve a glutamine balance across the liver, allowing it to deal with rapid changes in systemic ammonia levels by switching from glutamine uptake to glutamine release [19,23]. In the case of a cirrhotic liver, alterations such as intra/ extrahepatic portosystemic shunts account for up to 70% of portal blood flow (and can reach up to 93% with iatrogenically created portosystemic shunts) [24]. Additionally, in cirrhotic patients, reduced ammonia detoxification capacity has been observed due to diminished urea and glutamine synthesis, which is caused by reduced hepatocyte mass [19]. Under these conditions, the glutamine flux increases by a factor of six, reflecting an increase in the GS activity [25], to compensate for the functional defect of urea cycle enzymes. Furthermore, the perivenous GS activity is not increased, which results in ammonia ions escaping detoxification and therefore being released in the systemic circulation [22] leading to high arterial ammonia concentrations observed in patients with ALF. Depending on the severity of liver dysfunction, the liver is an important target of ammonia detoxification. Current treatments focus on stimulating residual hepatocytic function, increasing urea synthesis and activating glutamine synthetase. 2.1

Kidneys The kidneys are also involved in ammonia detoxification as they contain both GS and glutaminase. This allows them to synthesize and degrade glutamine, which is the main substrate for renal ammoniagenesis in the post-absorptive state [19,26]. Contrary to the liver, kidney-type glutaminase is not activated by ammonia in the kidney but is instead strongly inhibited by glutamate [27]. As shown by the study of McDermott et al. 2.2

Expert Opin. Pharmacother. (2014) 15(12)


• Neurotoxicity

Glutamine

Diet, Blood Glutamine Ammonia passes P-S shunting unfiltered

• Ammonia flux • Glu+NH3 Gln


NH3 • Impaired hepatocyte function • Diminished urea synthesis • Diminished glutamine synthesis

NH3 NH3 Excreted Unhealthy liver • GS activity increased • Net ammonia detoxification by kidney Healthy liver • Glutaminase activity increased • Net ammonia production by kidney

Urea

• Urea cycle (periportal) • Glutamine synthesis (perivenous)

Figure 1. The urea cycle is the main point of ammonia detoxification in normal physiology. With liver disease, however, impaired liver enzyme function and increased portosystemic shunting have been seen to occur. Consequently, peripheral organ systems become the major ammonia-metabolizing pathways.

[28], the kidneys release ammonia into systemic circulation via the renal vein. The ammonia production in the renal vein was estimated to be of a similar magnitude as renal urinary ammonia excretion, thereby maintaining a balanced ammonia flux [19,29]. In the same study, the prolonged administration of ammonium chloride resulted in an increased renal urinary ammonia excretion with no change in renal venous ammonia production. In healthy subjects, it is estimated that ~ 70% of the ammonia generated in the kidneys is released into systemic circulation, while 30% is excreted into the urine [30-32]. These figures reverse however, in a state of chronic acidosis [33]. As a result, the kidney is considered an organ of net ammonia release into the body under normal conditions but can revert to a state of net ammonia removal during acidosis, which is beneficial for the hyperammonemic patients [19]. This may be an attempt by the kidneys to maintain whole-body pH homeostasis. Even though the kidneys typically act as an ammoniareleasing organ in postabsorptive patients in CLD, they are also capable of excreting ammonia [34,35]. It has been indicated that induction of hyperammonemia in healthy volunteers results in net uptake of ammonia by the kidneys from blood plasma [36]. In cirrhotic patients, renal ammonia released in the circulation decreases at elevated ammonia concentrations

while no information exists regarding renal ammonia metabolism in ALF [37]. Experiments of Deutz et al. [38] on rats with ALF and CLD revealed that during these conditions, the increase of arterial ammonia concentrations is mainly determined by portacaval shunting combined with reduced hepatic urea synthesis, and not due to increased ammonia efflux in the arterial pool. Glutamine consumption was seen to be reduced along with the reduced renal ammonia production. Contemporary studies indicate the crucial role of kidneys in the occurrence of hyperammonemia following a stimulated upper gastrointestinal bleed in cirrhotic patients, as well as after feeding in pigs and cirrhotic patients (similar pattern) [39,40]. These studies showed that after either event, there was a net increase in ammonia production by the kidneys, with no change in the ammonia production in the splanchnic area. In conclusion, although kidneys can contribute to hyperammonemia during liver failure by metabolizing glutamine and excreting ammonia into the renal vein, they have also been seen to be highly adaptive to circumstance and are capable of net excretion of ammonia under the right conditions [19]. Brain The brain is an additional organ involved in ammonia metabolism, which attracts a great deal of attention due to its role in 2.3


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HE. It contains both glutaminase, localized in the neurons, as well as GS, which is mostly located in astrocytes [19]. Positronemission tomography studies indicated that, in healthy volunteers, up to 47% of the arterial ammonia was extracted by the brain [41]. As the severity of liver disease increases with resultant hyperammonemia, the astrocytes become an important source of ammonia detoxification via GS [42]. Studies by Dejong et al. [43,44], in rat cerebral cortex during portacaval shunting and acute liver ischemia showed a net consumption of ammonia and production of glutamine. It was calculated in ALF rats that 66% of the ammonia taken up by the brain was metabolized, while leaving the remaining 33% to be stored in a brain ammonia pool. As a result, the contribution of brain in ammonia detoxification (in experimental liver failure) is through ammonia uptake and glutamine release into systemic circulation [19]. Gut The intestines are the primary source of ammonia and are an important therapeutic target in hyperammonemia. Much of the body’s nitrogen source comes from ingested proteins, which are broken down in the small intestines into simple amino acids and ammonia. It was at first hypothesized that the breakdown of nitrogenous materials by gut flora initially supplied the body with ammonia [45]. While true, intestinal breakdown of amino acids, notably glutamine, also plays a large part in the supply of systemic nitrogen [46]. The enterocytes are rich in glutaminase but poor in GS, which results in a net breakdown of glutamine to glutamate and ammonia [47]. Furthermore, large amounts of ammonia are produced not from ingested amino acids, but by the breakdown of blood-borne urea and glutamine in the colonic lumen [48]. Ammonia production by the gut can be exacerbated by pathophysiologic events. Liver failure results in portosystemic shunting, which dumps toxic blood into systemic circulation; and this has been shown to contribute in a major way to systemic hyperammonemia [49,50]. Also, precipitating events, such as gastrointestinal bleeding, result in a release of ammonia from broken down hemoglobin molecules [51]. There are several therapeutic options targeting the gut, which focus on reducing systemic exposure to ammonia. They strive to diminish gut flora, increase transit time of ammonia-rich agents, acidify intestinal contents and reduce protein load. 2.4

Muscle Skeletal muscle contains GS, yet has relatively low GS activity. However, owing to its mass and size, it is the principal glutamine-synthesizing organ in the body [52] and can be a valuable tool in the process of controlling hyperammonemia. Skeletal muscle both takes up and releases ammonia but the glutaminase activity [53] is negligible compared to its skeletal glutamine synthetase activity classifying it as a 2.5

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glutamine-synthesizing organ. In healthy individuals, there is little or no difference between intake and output of ammonia across the muscle [37,54,55]. Furthermore, there is no difference between leg and forearm metabolism of ammonia [55], indicating that the muscle is not a major player in net ammonia removal in healthy individuals. In the presence of liver disease, however, there is substantial data to suggest a change in skeletal muscle ammonia metabolism, and that change is dependent on the levels of arterial ammonia [41]. An increase in ammonia metabolism was seen across the forearm [55] as well as the leg [37]. This change in ammonia uptake was consistently observed in several different models of hyperammonemia, including hepatic coma [41] and gastrointestinal bleeding [37], which were confirmed when a decrease of ammonia metabolism was seen in a muscle wasting scenarios [56]. The rate of change in ammonia metabolism, however, is difficult to quantify. If we look at net arteriovenous differences, a net decrease in plasma ammonia is often observable [57]. Although ammonia is often metabolized into glutamine by skeletal muscle, it can be catabolized in the kidneys and gut to reform free ammonia, which is known as the ‘rebound effect’ [24]. We also cannot conclusively show that all the glutamine produced by the muscles is caused by ammonia metabolism and not by catalysis of other proteins or amino acids [58]. In conclusion, the skeletal muscle potentially plays an enormous role in ammonia detoxification, mainly owing to its size, in both chronic liver failure and ALF. Further studies are required to adequately validate this idea. 3.

Treatments

Current treatments are divided into two rationales: targeting reduction of ammonia production in the body and maximizing the body’s removal of ammonia from the bloodstream. Most therapies that reduce ammonia production focus on the gut’s absorption of nitrogenous products, while therapies involved with maximizing ammonia metabolism focus on stimulating the activity of GS in the liver, kidney, gut and predominantly the muscle (Table 1). 3.1

Reducing ammonia production Nutrition

3.1.1

Restriction of protein intake has been considered a classical approach to control hyperammonemia and HE [59,60]. The idea behind this treatment was that limited intake would result in less ammonia being supplied and absorbed into the blood stream. Despite this, Kondrup et al. [61] found that cirrhotic patients exhibit increased protein requirements in order to maintain balance in nitrogen metabolism. Malnutrition can lead to paradoxical increase in ammonia and decreased survival by influencing protein turnover [62], increasing susceptibility to infections, impairing immunocompetence [63] as well as inducing malabsorption [64,65]. It is believed that maintaining muscle mass in patients is important since it



n/a n/a

See below n/a See below See below See below n/a n/a n/a n/a n/a

LOLA MARS Albumin OP

L-Carnitine

Pos

n/a

n/a n/a Pos Pos n/a

Neg n/a

n/a n/a Phase lI a in progress

n/a

n/a

n/a n/a n/a n/a n/a

Inconclusive Pos in MHE Neg in OHE

Pos Neg Phase lI b in progress

n/a

Pos

Neg n/a Pos Pos Neg

Severity of HE

Neg Neg

n/a Pos n/a

n/a

n/a

n/a n/a Neg Neg Pos

Delayed mortality due to HE

Pos/Neg Pos Pos in open label study Neg Neg

Pos

n/a Pos Pos Pos Possible increase in open label study Pos

Reduction in plasma ammonia

*No prospective randomized controlled data available. LOLA: L-Ornithine L-aspartate; MARS: Molecular adsorbent recirculating system; n/a: No available information; Neg: Negative, drug has not been seen change outcome; OP: Ornithine phenylacetate; Pos: Positive, drug has been seen to improve disorder.

Multiple targets

Muscle glutamine synthetase Liver: Urea cycle Detoxification

LOLA

n/a n/a n/a

n/a

*Embolization of portacaval shunts OP Glycerol phenylbutyrate LOLA OP

Gut glutaminase

n/a Pos n/a n/a n/a

Protein restriction Prebiotics/probiotics Lactulose Rifaximin Branch-chain amino acids

Acute liver disease-treatment of acute HE

Randomized controlled trial results: effects on HE Chronic liver disease-prevention of first recurrent HE

Gut ammonia

Chronic liver disease-prevention of episode of HE

Therapeutic agents

Target

Table 1. Summary of randomized control trials.



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has the ability to remove ammonia from circulation by converting it to its carrier, glutamine, via the enzyme GS. Furthermore, patients administered with enough protein observed an overall beneficial effect in the management of hyperammonemia and HE, an area that requires further study [66]. It is recommended that steps must be taken to limit malnutrition in liver failure patients. However, a clear balance must be established between the type of protein supplied and the amount of protein needed by the patient.

with upper gastrointestinal bleeding and recurrent bouts of HE, providing new information on novel evidence [69]. Side effects of lactulose are limited; however, they can lead to difficulties during liver transplantation and can cause malnutrition in patients [71]. Dehydration can also occur as an adverse effect following long-term treatment [72]. It is therefore suggested that disaccharides such as lactulose be used in accordance with current guidelines. Despite, their limited evidence of efficacy, lactulose is widely used in clinical practice.

Prebiotics and probiotics Prebiotic and probiotic therapies attempt to adapt the gut environment to allow nonurease-producing bacteria to proliferate. This is an attempt to limit the amount of ammonia produced in the colon. Prebiotics, as their name suggests, are the first line of treatment and are responsible for boosting probiotic growth. Lactulose is a potent prebiotic. Patients treated with probiotics often show lowering of blood ammonia and less severe HE, although no significance has been shown [10]. Despite the lack of significance in this data, there seems to be no adverse consequence of using these treatments. Bifidobacteri, Streptococcus thermophiles and Lactobacilli have all been used to different degrees in various studies [10]. Concerns have been raised as to the safety of introducing bacteria into an immunocompromised patient. However, there have been no validating studies to support this idea. In relation to HE, studies have shown prebiotics tend to prevent recurrent lapses when compared to controls [67].

3.1.4


3.1.2

Disaccharides Nonabsorbable disaccharides currently remain the accepted treatment for patients with hyperammonemia and encephalopathy. Lactulose and to a lesser extent lactitol are standardized treatments that are aimed at reducing the amount of ammonia absorbed into the blood stream. Lactulose works in a number of ways. First, it travels undigested to the colon where it is catabolized into lactic acid and acetic acid. This acidification of the colon initiates protonation of ammonia (NH3) to ammonium (NH4+). The gut is then unable to absorb the ammonium ion, allowing it to be excreted harmlessly from the colon [68]. Furthermore, lactulose encourages the growth of nonurease-producing bacteria while inhibiting the growth of urease bacteria, resulting in a net decrease of ammonia produced. Finally, lactulose creates a hyperosmolar environment and acts as a laxative. The increased rate of production of fecal matter prevents efficient absorption of ammonia by the colon. In spite of the numerous mechanisms in which disaccharides may work, there is lack of evidence for the use of lactulose on patients with acute HE [69]. Studies comparing lactulose to control are lacking, and, therefore, no comparative studies exist to validate the use of lactulose for the treatment of hyperammonemia [70]. Some recent studies suggest its usefulness in the treatment of HE as a secondary prophylactic for patients 3.1.3

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Antibiotics The antibiotics used in the treatment of hyperammonemia aim to modify the gut flora, decrease urease-producing bacteria in the colon and subsequently lower blood ammonia levels. These antibiotics are divided into two classes: absorbable and nonabsorbable antibiotics. Certain antibiotics with variable levels of absorption, including vancomycin, neomycin and metronidazole, tend to be not only effective in lowering blood ammonia levels but also produce severe adverse side effects. Examples involve nephrotoxicity and ototoxicity arising from the use of neomycin [71]. In the nonabsorbable antibiotics category, rifaximin is used as a treatment option for diarrhea as well as HE and hyperammonemia. Studies from Wu et al. [73] indicated, through metaanalysis, that rifaximin is as effective and potentially better than nonabsorbable disaccharides at treating HE and hyperammonemia [74]. The data clearly demonstrate that patients tolerate rifaximin better and that best results are achieved when it is coupled with lactulose [75]. A recent, double-blind, randomized study with 120 patients revealed a significant decrease in overt HE when both treatments, lactulose and Rifaximin, were used in combination rather than when lactulose treatment was used alone. Length of hospital stay was also significantly decreased [76]. Moreover, a cohort study of 299 patients revealed a reduced risk of hospitalization involving HE over a 6-month period with the use of Rifaximin [77]. Despite this, further research is required to prove the accurate success of Rifaximin in reducing blood ammonia levels. The only significant complication observed so far with this antibiotic involved two unique cases of Clostridium difficile infection [78]. 3.2

Maximizing ammonia removal and L-aspartate

3.2.1 L-Ornithine L-Ornithine

and L-aspartate (LOLA) are substrates for the urea cycle and can increase urea production through the activation of carbamoyl phosphate synthetase in periportal hepatocytes. They also activate glutamine production by activating GS in perivenous hepatocytes and skeletal muscles [10]. The effect of this enzyme activity stimulation is, even in the end stages of the liver disease, lowered blood ammonia levels [10]. The beneficial effects of LOLA in both overt and minimal HE have been suggested through meta-analysis. There is still debate, however, in the role of these drugs in




reducing ammonia, especially in advanced liver disease [78]. The study of Acharya et al. [79], indicated that LOLA use was ineffective in reducing the ammonia concentration and the severity of HE in ALF patients. However in patients with CLD, patients treated with LOLA were seen to have improvement in recurrent bouts of HE [80,81]. Furthermore, although LOLA initially lowers blood ammonia levels, it has been seen to spike soon after administration of the drug, suggesting it works only temporarily [10]. Overall, LOLA is well tolerated and gives similar results as the effective treatment with lactulose but with fewer side effects. Further research is required in determining amount, duration and dosage of this treatment. 3.2.2 L-carnitine

The biologically active, fatty acid-bound form of L-carnitine is L-acetylcarnitine. Studies by Malaguarnera et al. [82], investigated the suggested idea that L-acetylcarnitine improves blood ammonia and cognitive functions in cirrhotic patients with minimal HE. In this study, a significant clinical improvement in the neuropsychological status of the patient was observed including cognitive function, energy levels and emotional health. Unfortunately, no significant changes were observed by electroencephalography to quantify these findings. It also does not seem to contribute to lowering the ammonia levels in cirrhotic patients. Furthermore, this treatment can exacerbate the illness in cirrhotic patients with advanced HE and therefore further research is required before the routine use of L-carnitine in cirrhotic patients. It is recommend that the use of L-carnitine be withheld in cirrhotic patients until further studies have been established. Branch-chain amino acids There are three branch-chain amino acids (BCAA): valine, leucine and isoleucine. It is believed that the use of BCAA supplements can help maintain muscle mass by forming aketoglutarate from glutamate, which can subsequently metabolize a molecule of ammonia and form glutamine. BCAA also help produce energy by forming keto acids, which are important intermediaries in the tricarboxylic acid cycle. However, there is little evidence to support these hypotheses. BCAA have paradoxically been seen to increase blood ammonia levels. Positron emission tomography scans revealed the metabolism of [13N]-ammonia to make glutamine derived from N-terminal BCAA as opposed to blood ammonia [83]. When glutamine was subsequently catabolized in the kidneys, a net release of ammonia was seen. It is recommended that BCAA be used only by patients who are severely protein intolerant. If given, BCAA should be administered orally, as opposed to intravenous treatment, which may result in lower gut glutaminase activity [84]. 3.2.3

Hemodialysis and filtration devices Hemodialysis is used for the removal of water substances in liver failure. This treatment is known to reduce ammonia 3.2.4

blood levels under the condition that the blood flow rate is maintained and the machine’s exposure area is high [85]. Molecular adsorbent recirculating system (MARS) is also used for the removal of protein-bound and water-soluble toxins with albumin dialysis, enhancing the regeneration of liver cells. Studies have indicated that this method helps to reduce arterial ammonia levels and to delay the onset of HE, but only when used in combination with other standard treatments [86,87]. Overall, data collected from a randomized and controlled MARS trial suggested that, in encephalopathic and cirrhotic patients unresponsive to current therapy, MARS therapy can reduce the severity of HE significantly but its effects on ammonia lowering are not clear [81]. Portacaval shunt embolization Large portosystemic shunts serve to bypass the liver, resulting in hyperammonemia and HE. Embolization of these shunts was indicated to show immediate (~ 100 days) resolving of HE, but it is only effective in the presence of residual liver function. Laleman et al. [88] also suggested that this treatment is less effective or even deleterious in patients with end-stage liver disease and it is probably not possible in patients with multiple portacaval shunts. It is therefore crucial that the severity of liver disease be carefully characterized before embolization of these shunts is attempted. Interestingly, it has been seen to be highly effective in patients with good liver function. 3.2.5

Albumin The study of Simoń-Talero et al. [89] indicated that albumin administration in patients with stage II or higher HE (in addition to existing lactulose and Rifaximin treatment) did not reduce the severity of HE, ammonia levels, oxidative stress markers or cytokines [90]. However, albumin administration was involved in prolonging the survival of these encephalopathic patients after hospitalization, which suggests that this treatment can be beneficial in a subgroup of patients with advanced cirrhosis. It was also found that albumin dialysis in patients with HE were seen to improve more quickly than patients not treated with albumin [91] but further studies are required to come to a definitive conclusion. 3.2.6

Ornithine phenylacetate Drug treatment with ornithine phenylacetate (OP) focuses on the formation of glutamate, and the removal of glutamine. L-Ornithine, as described above, is active in the synthesis of glutamate. OP then stimulates GS activity in peripheral organs, notably the skeletal muscles, as well as residual hepatocytes [92]. The consequent increase in glutamine synthesis results in a net decrease of plasma ammonia. Finally, in order to prevent the ‘rebound effect’ of glutaminase, glutamine is conjugated with phenylacetate to form phenylacetylglutamine, a molecule that cannot be metabolized in vivo and is harmlessly excreted in the urine [93]. 3.2.7


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The first OP study was undertaken by Ytrebo et al. [94] in ALF pigs, suggesting that L-ornithine and phenylacetate act synergistically to successfully prevent increases in arterial ammonia, accompanied by a significant decrease in extracellular brain ammonia as well as prevention of intracranial hypertension. In a small open-label study, the administration of OP was safe and resulted in a marked reduction in ammonia concentration providing proof of concept for its effectiveness as an ammonia-lowering drug [92]. OP is currently in Phase II trials in the United States and has thus far been seen to be safe and efficacious in treatment against hyperammonemia. Glycerol phenylbutyrate (HPN-100) Glycerol phenylbutyrate (GPB) acts similar to OP. GPB is digested by pancreatic lipases to release phenylbutyric acid, which undergoes b-oxidation forming phenylacetic acid. Phenylacetic acid conjugates with glutamine to form phenylacetylglutamine and is excreted by the kidneys, resulting in a net lower glutamine and ammonia concentration in blood plasma [95]. In a recent Phase IIb study, effectiveness of this drug was shown in cirrhotic patients with evidence of reduction of ammonia and a reduction in both the first event of HE and the re-hospitalization admission of patients with HE [95]. This suggests its potential usefulness in secondary prophylaxis of HE. 3.2.8

4.

Conclusion

There have been numerous approaches to treatment of hyperammonemia in patients with liver disease, each taking a different metabolic approach. Overall, limiting ammonia intake has been seen to only provide temporary relief. It is increasing ammonia excretion from the body where the potential lies. There is great promise in extracorporeal devices such as MARS but further testing needs to be done. While old treatments such as rifaximin and lactulose persist as the only accepted therapy regime, it is in new treatments that utilize various metabolic pathways, such as OP and GPB, which have the ability to target ammonia but require large clinical trials. 5.

Expert opinion

The treatment of hyperammonemia is an important field of study as it is central to the pathogenesis of HE, a condition that affects about 50% of patients. Treatment of

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hyperammonemia has the potential to improve a patient’s quality of life and reduce morbidity and mortality of patients with liver failure. In addition to ammonia, inflammation plays an important role in its pathogenesis. Lactulose and rifaximin have a proven role as measures to use for secondary prophylaxis and are the mainstay of current therapy. The recent Phase IIb study of GPB and the Phase IIa study showing substantial reduction in ammonia in cirrhotic patients clearly provide exciting prospects for new approaches to removing ammonia from the body in cirrhotic patients and therefore potential approaches to the treatment of patients with acute episodes. The use of MARS in patients with severe HE has been proven to be efficacious but through mechanisms that appear to be independent of ammonia, indicating an opportunity for combining therapies that may be synergistic. The main challenge that faces the further development of treatments for HE is finding appropriate end points. In patients with acute HE, it is unclear whether the regulators will accept time in HE or reduced admission to intensive care units as appropriate end points or whether they will insist on survival as the defining outcome of efficacy. In patients with minimal HE, the outcomes are also difficult to define because of the lack of a defined marker of the severity of minimal HE. Over the past 10 years, huge progress has been made with new insights into the pathophysiological basis of HE, understanding of ammonia metabolism and in the clinical trials providing evidence of efficacy. The next steps would be to provide evidence of effectiveness of the established treatments and define the role of emerging new treatments.

Acknowledgment A Hadjihambi and V Khetan contributed equally to this work.

Declaration of interest R Jalan is inventor of ornithine phenylacetate a drug that was licensed by University College London Business to Ocera Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.



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aspartate infusions in patients with cirrhosis and hepatic encephalopathy: results of a placebo-controlled, double-blind study. Hepatology 1997;25(6):1351-60

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Stauch S, Kircheis G, Adler G, et al. Oral L-ornithine-L-aspartate therapy of chronic hepatic encephalopathy: results of a placebo-controlled double-blind study. J Hepatol 1998;28(5):856-64 Malaguarnera M, Bella R, Vacante M, et al. Acetyl-L-carnitine reduces depression and improves quality of life in patients with minimal HE. Scand J Gastroenterol 2011;46:750-9 Dam G, Keiding S, Munk OL, et al. Branched-chain amino acids increase arterial blood ammonia in spite of enhanced intrinsic muscle ammonia metabolism in patients with cirrhosis and healthy subjects. Am J Physiol Gastrointest Liver Physiol 2011;301:G269-77 Gluud LL, Dam G, Borre M, et al. Lactulose, rifaximin or branched chain amino acids for HE: what is the evidence? Metab Brain Dis 2013;28:221-5 Cordoba J, Blei AT, Mujais S. Determinants of ammonia clearance by hemodialysis. Artif Organs 1996;20:800-3 Hassanein TI, Tofteng F, Brown RS Jr, et al. Randomized controlled study of extracorporeal albumin dialysis for hepatic encephalopathy in advanced cirrhosis. Hepatology 2007;46(6):1853-62 Demonstrates the effects of albumin perfusion in HE. Karvellas CJ, Gibney N, Kutsogiannis D, et al. Bench-to-bedside review: current evidence for extracorporeal albumin dialysis systems in liver failure. Crit Care 2007;11:215 Laleman W, Simon-Talero M, Maleux G, et al. Embolization of large spontaneous portosystemic shunts for refractory HE: a multicenter survey on safety and efficacy. Hepatology 2013;57:2448-57 Simon-Talero M, Garcia-Martinez R, Torrens M, et al. Effects of intravenous albumin in patients with cirrhosis and episodic HE: a randomized double-blind study. J Hepatol 2013;59:1184-92


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Jover-Cobos M, Noiret L, Lee K, et al. Ornithine phenylacetate targets alterations in the expression and activity of glutamine synthase and glutaminase to reduce ammonia levels in bile duct ligated rats. J Hepatol 2014;60(3):545-53

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Rockey DC, Vierling JM, Mantry P, et al. Randomized, double-blind, controlled study of glycerol phenylbutyrate in HE. Hepatology 2013;56:248A A randomized control trial showing the benefit of glycerol phenylbutyrate and its efficacy in controlling hyperammonemia.

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Affiliation

Anna Hadjihambi, Varun Khetan & Rajiv Jalan† † Author for correspondence UCL Institute for Liver and Digestive Health, UCL Medical School, Upper Third Floor, Royal Free Campus, Pond Street, NW3 2PF, London, UK Tel: +44 207 4332 794; E-mail: [email protected]

1695

Pharmacotherapy for weight loss.

Therapy of hyperammonemia.

Pharmacotherapy for allergic rhinitis.

Hyperammonemia, resolved by chemotherapy.

Pharmacotherapy options for labor induction.

Pharmacotherapy for stimulant-related disorders.

Pharmacotherapy for tonic-clonic seizures.

Pharmacotherapy for Body Dysmorphic Disorder.

The hyperornithinemia-hyperammonemia-homocitrullinuria syndrome.

Pharmacotherapy for hospital-acquired pneumonia.

Essential tools for designing pharmacotherapy.

Pre-hypertension: rationale for pharmacotherapy.

Ongoing challenges for pharmacotherapy for dyslipidemia.

Hyperammonemia in Urinary Tract Infections.

Pharmacotherapy for Severe Obesity in Children.

Pharmacotherapy: a new option for Cushing disease?

Benefits of pharmacotherapy for preventing hip fracture.

Electroconvulsive therapy versus pharmacotherapy for bipolar depression.

Advances in pharmacotherapy for allergic conjunctivitis.

Pharmacotherapy for treatment of retinal vein occlusion.

Pharmacotherapy for post-traumatic stress disorder.

Cognitive therapy and pharmacotherapy for depression.

Pharmacotherapy for lower respiratory tract infections.

Epilepsy and menopause: potential implications for pharmacotherapy.