1. Introduction

Hepatic Encephalopathy (HE) is a complication of cirrhosis. It manifests in the form of neurological and psychiatric symptoms. In early symptoms of HE, patients experience deficits of attention and visuospatial construction, as well as impaired motor speed and accuracy. Overt Hepatic Encephalopathy (OHE) is characterized by asterixis, stupor and can lead to coma. Coma is associated with poor prognosis and high mortality. Minimal Hepatic Encephalopathy (MHE) is the mildest form of HE. It is characterized by low-grade alterations of mental status generally diagnosed by psychometric testing [1]. 20% of patients with decompensated cirrhosis, present with overt hepatic encephalopathy. In patients with cirrhosis who have no evidence of neuropsychiatric impairment, the chance of developing an episode of HE within five years of presentation is about 5% to 25%. The presence of hepatic encephalopathy is associated with significant impairment in the performance of complex tasks, such as driving, and lays a detrimental effect on the quality of life, and safety [2]. Treatment for HE is based on measures to reduce the production and passage to the bloodstream of intestinal nitrogenous compounds such as ammonia. Traditionally, the first choice therapeutic option has been non-absorbable antibiotics such as neomycin, kanamycin sulfate, and paromomycin. These antibiotics decrease the number of bacteria responsible for producing nitrogenous compounds. Such antibiotic therapy has proved to be effective, but absorption of even a small fraction of these antibiotics can cause ototoxic and nephrotoxic side effects, hence this treatment is not common anymore. Recently, metronidazole, L-Ornithine L-aspartate (LOLA), and rifaximin use are advocated and their results are quite impressive [3].

L-Ornithine L-aspartate (LOLA), a stable salt of two endogenous amino acids, has ammonia-lowering properties. L-ornithine and L-aspartate are readily absorbed, distributed, and metabolized. L-ornithine acts as an important mediator in the urea cycle that takes place in periportal hepatocytes. It also acts as an activator of carbamoyl phosphate synthetase. L-ornithine as well as L-aspartate both are involved in transamination to glutamate via glutamine synthetase in perivenous hepatocytes. Furthermore, both these amino acids play a crucial role in metabolic pathways where ammonia molecule is incorporated into urea and glutamine. It is the cellular and biological location of these pathways that confirms the application of LOLA as an effective ammonia-lowering strategy that can be used for the management and treatment of hepatic encephalopathy. These metabolic pathways were interpreted by experimental studies performed on animals and were confirmed by RCT trials performed on patients with severe liver diseases. More recent studies have indicated that LOLA may have a direct hepatoprotective effect as well [4]. In the current AASLD-EASL Guidelines [4], recommendations relating to the use of LOLA for the treatment of HE in cirrhosis were based upon the results of a single RCT with intravenous LOLA while the oral formulation was pointed out to be ineffective. The objectives of the present review are to provide an up-to-date evidence base for the efficacy of LOLA for the treatment of OHE and MHE in cirrhosis and to analyze where LOLA stands in terms of lowering ammonia levels.

2. Methods

A search of PubMed was performed to identify relevant research articles. Mesh keywords used included " Hepatic Encephalopathy" AND "Ornithylaspartate". The search was restricted to human studies, Randomized Control Trials, and those done in the last 15 years. Articles written in the English language were included. The pediatric population was not included and a filter of >18 years was applied. The exclusion criteria were animal studies.

3. Results

The total number of studies retrieved was 13 initially. After the primary and secondary screening, a total of 7 studies were retrieved and these studies are included in the review. The total number of subjects in our study was 847.

4. Discussion

Several randomized controlled trials have been done in the last 2 decades to explore the efficacy of LOLA in HE. Some studies explored its use in OHE, while others studied its role in MHE. These analyses were focused on comparing the effectiveness of LOLA to other treatments, and also compared oral versus intravenous formulation of LOLA. In this review, we sought to dig deeper to understand the role of LOLA in HE. Table 1 summarizes the characteristics of the studies which are included in our review article.

4.1 LOLA for prophylaxis

Aside from understanding the role of LOLA in HE patients for treatment, its role as an effective drug for prophylaxis is yet to be understood. It has been previously used for primary as well as secondary prophylaxis. Prophylactic management of patients to prevent the development of the first episode of HE is known as primary prophylaxis while preventing recurrence of HE in patients who had the previous episode of HE is classified as secondary prophylaxis [12]. In 2001, Mittal W et al. [9] made an effort to understand the role of LOLA in MHE. He selected patients with two or more abnormal psychometric tests. The patients in the experimental group were given LOLA 6 g three times per day. The duration of the study was 3 months. Interestingly, only 5% of the patients in the experimental group developed HE, while about 10% of the patients in the placebo went on to develop HE. The study concluded that LOLA can prevent the development of HE. Sharma K et al. [7] in 2014, performed an RCT to find out the effect of rifaximin, probiotics, and LOLA individually in the reversal of MHE. The patients were diagnosed to have MHE based on a critical flicker frequency (CFF) test and three neuropsychometric tests (NPTs). Results supported the evidence that LOLA can have a role in the reversal of MHE. In 2018, Varakanahalli et al. [5] studied the role of LOLA as secondary prophylaxis in patients with previous episodes of HE. Primary endpoint was the development of HE. The RCT concluded that LOLA is effective in the secondary prophylaxis of HE and is associated with significant improvements in CFF scores, psychometric hepatic encephalopathy score, ammonia levels, and health-related quality of life. Table 2 further elaborates on these RCTs.

4.2 LOLA as a treatment for HE

Several different drugs can be used for the treatment of HE. The main goal of treatment is to reduce the levels of ammonia in the blood which can decrease its levels in the brain leading to the reversal of the condition. Antibiotics are often given empirically due to the frequency of infection as an underlying cause. Additional treatment measures include lactulose/lactitol (a non-absorbable osmotic laxative that helps convert ammonia to non-absorbable ammonium in the gastrointestinal tract), and zinc (to correct underlying deficiency common in cirrhotic patients) [14]. In 2018, Sidhu SS  et al. [6] performed an RCT study on 193 patients having episodic OHE (grades 2–4). Intravenous LOLA, 30 g daily in three divided doses, was given to 98 patients in the treatment group (placebo=95). Meantime taken for recovery from OHE, venous ammonia levels and length of hospital stay in LOLA-treated patients were significantly reduced. It is important to note that in this trial, all patients, both LOLA and placebo-treated, received lactulose. However, despite receiving lactulose, patients in the placebo arm of the trial remained overtly encephalopathic and hyperammonemic. These lactulose-resistant features were shown to be significantly improved following intravenous LOLA. Abid S et al. [8] and Ahmad I et al. [10] also studied the role of LOLA in HE and demonstrated that LOLA could be used effectively for HE. Poo JL et al. [11] compared lactulose and LOLA and concluded that oral administration of lactulose or L-ornithine - L-aspartate to Mexican patients with cirrhosis and hyperammonemic encephalopathy significantly reduced serum ammonia levels in study groups and additionally improved mental status parameters, number connection test, asterixis scores, and EEG activity in the group receiving L-ornithine-L-aspartate. Table 3 further elaborates the role of LOLA in HE treatment.

Table 1: Characteristics of studies included in the review.

Table 2: Illustrates the possible use of LOLA in primary prophylaxis and MHE.

Table 3: Findings of RCT studies done to evaluate the role of LOLA in HE.

5. Conclusion

To summarize, LOLA can be effective for the treatment of hepatic encephalopathy and minimal hepatic encephalopathy. The studies have found it an effective strategy to lower ammonia levels, which can help to reduce the grade of HE or in the case of MHE, help to improve the psychometric hepatic encephalopathy score, and health-related quality of life. It has also been shown to be effective for secondary prophylaxis. Having said that, there is a still need for large-scale RCTs to understand the role of LOLA as an effective drug for hepatic encephalopathy.

References

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