Solving doubts about L‐ornithine L‐aspartate for overt hepatic encephalopathy: Whom and how to treat
Authors: Piero Amodio, Javier Ampuero
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. See Article On Page 700 Bouts of overt hepatic encephalopathy (OHE)—i.e., hepatic encephalopathy (HE) causing at least clear disorientation in time or asterixis1—severely hamper autonomy and quality of life, causing a heavy burden on caregivers and health systems.2 Hyperammonemia plays a crucial role in the pathophysiology of HE, so reducing ammonia levels is currently the primary therapeutic target. However, the link between HE and ammonia is not strict because other factors intervene to alter brain function, principally infection.3 Thus, to select the appropriate therapy could be challenging because of the multiple factors involved.1 A notable increase in the secondary prevention of bouts of OHE has been reached in recent years. It was proved that the risk for episodes of OHE increases after a previous one,4 and evidence exists that individuals who underwent more than one bout in the last 6 months have a higher risk than those who had only one bout.5 Disaccharides, particularly lactulose, were proven to reduce the risk for episodes of OHE by about 50% in a year.6 Rifaximin in addition to lactulose further halves the risk for bouts of OHE in the following 6 months in patients who had suffered from more than one bout of OHE in the previous 6 months.5 With lower accuracy than that reached for lactulose and rifaximin, oral branched chain amino acid supplementation has also been proved to be effective.7 Proper nutrition might also be useful in HE: some evidence of beneficial effects of a diet intervention (about halving the risk for OHE in the follow‐up of subjects with minimal HE) was recently published.8 In contrast to the studies about OHE prophylaxis, evidence about proper management of a single bout of OHE is poor. This depends mainly on two factors: (1) the variety of the events that can precipitate OHE and (2) the outcome that should be taken into account. There is consensus that treatment of the precipitant event is mandatory.1 On the contrary, how to measure the outcome is unclear. A too short interval between the beginning of treatment and the evaluation of outcome may bias the results toward the ineffectiveness of any therapy; in contrast, a too long interval may prove the identity of the efficacy of any treatment because a bout of OHE will resolve, as per definition of the term “bout.” In addition, pooling together OHE of any degree from time disorientation (i.e., the so‐called grade 2) to coma (i.e., the so‐called grade 4) might be misleading. The article by Sidhu et al.9 is an example of a good approach to the problem: it takes into account the daily dynamics of HE over 5 days, which represents a reasonable time interval to assess the treatment. Further, the outcome of OHE may depend on its severity, so categorizing the OHE grade not only provides information about the clinical status but might also help in the selection of the most appropriate therapy.10 Of note, Sidhu et al.9 assessed the global effect of L‐ornithine L‐aspartate (LOLA), taking into account the OHE grade. LOLA was found more effective in lower (particularly grade 2) than higher (3/4) OHE grades in comparison with placebo, confirming previous results.5 Also, the dose (usually 20 g) and the length (3‐8 days) of intravenous LOLA treatment are not homogeneous between randomized controlled trials.5 This study made a day‐to‐day evaluation for HE improvement up to 5 days, finding that the first 4 days of treatment were enough to observe the beneficial effects of 30 g of intravenous LOLA. HE occurring in acute‐on‐chronic liver failure was not considered in this randomized controlled trial, a condition in which the treatment would probably be unsuccessful because of the simultaneous presence of inflammation‐related triggers, very poor liver function, and the occurrence of other complications. Notably, some precipitating factors for OHE, including oxidative stress and inflammation, are not covered by the usual treatments. In fact, LOLA did not reduce proinflammatory cytokines compared to placebo in this study (in contrast to the reduction of ammonia plasma levels).9 Consequently, this drug could be suboptimal in some scenarios where inflammation is the main driver for the bout of OHE, which makes necessary to identify the main trigger before selecting and initiating the therapy. Another interesting point is whether LOLA could be used as monotherapy or together with other drugs, such as nonabsorbable disaccharides or antibiotics. Currently, the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver guidelines indicate that intravenous LOLA can be used as an alternative or additional agent to treat patients nonresponsive to conventional therapy.1 Sidhu et al.9 considered as basal treatment the association of LOLA with nonabsorbable disaccharides plus ceftriaxone. This can provide a reasonable baseline treatment in a study evaluating a metabolic drug, such as LOLA, because this kind of treatment does not interact with LOLA and can homogenize bouts of OHE that might require mainly disaccharides (e.g., OHE precipitated by constipation) or antibiotics (e.g., OHE precipitated by infection). Therefore, the results of this study reinforce the message that LOLA should be used as an add‐on therapy rather than as monotherapy. A limit of the study is the significant number of subjects who were excluded. While this is reasonable in a trial, the efficacy of LOLA is doubtful in real practice in about half of the patients with OHE. Also, the impact of LOLA probably should have been stratified according to the trigger, depending on the presence of ammonia‐related (e.g., constipation, bleeding) or inflammation‐related (e.g., infections) factors that can influence its efficacy. Another severe limitation is the selection of placebo. Indeed, 30 g of LOLA is a 30‐g mixture of two amino acids. This might also reduce the ammonia output from muscles, reducing amino acid muscle catabolism because of an unspecific nutritional effect. Would the effect be found if placebo had had the same nitrogen content as LOLA? In other words, is the effect of LOLA specific, or is it a class effect of intravenous amino acids? The absence of any effect in previous studies on intravenous branched chain amino acids7 cannot be invoked as proof that the infusion of an amino acid mixture per se is not effective as an add‐on treatment for OHE because all these studies were designed using branched chain amino acids as an alternative treatment in comparison with standard treatment. In the era of personalized medicine, known drugs for OHE must be adapted and selective therapies developed, taking into account the severity of the bout and the main triggers. Despite its limits, the study performed by Sidhu et al.9 clarifies the role of LOLA to treat a bout of OHE, especially in patients with relevant hyperammonemia, regarding the adequate dose (30 g) and length of the therapy (up to 4 days), as well as the target population (low HE grades) and the concomitant treatment (at least, lactulose). In addition, this study provides new opportunities for treatment and suggests further studies with an add‐on design to improve the speed of recovery for bouts of OHE.