Acetyl-L-carnitine for patients with hepatic encephalopathy

What is hepatic encephalopathy?
Hepatic encephalopathy is a common and devastating neuropsychiatric complication of acute liver failure or chronic liver disease. The liver in people with hepatic encephalopathy cannot clear the portal venous blood (the big pipeline that leads blood from the small intestine into the liver). Due to this, blood ammonium levels and levels of other toxic substances are increased, which leads to brain damage. Hepatic encephalopathy is associated with significantly increased mortality among patients with liver disease, including those awaiting liver transplantation.

What is acetyl-L-carnitine?
Acetyl-L-carnitine is a substance that reduces blood and brain ammonium levels and may act as a brain-protective agent.

The purpose of this review
This Cochrane systematic review assessed the benefits and harms of treating people with hepatic encephalopathy with acetyl-L-carnitine in addition to providing standard care (lactulose, antibiotics, etc.) compared with placebo or no acetyl-L-carnitine intervention in addition to standard care.

Findings of this review
Review authors searched the medical literature up to 10 September 2018, and identified five relevant randomised clinical trials, including a total of 398 participants. All trials were performed in Italy by only one team of investigators. All were considered at high risk of bias and included small numbers of participants, which makes potential overestimation of benefits and underestimation of harms likely. The pharmaceutical industry did not sponsor any trial. Trials tested acetyl-L-carnitine given orally or intravenously versus placebo. The drug did not seem to have effects on quality of life, fatigue, or non-serious adverse events when compared with placebo (inactive sham drug).

Shortcomings of the trials included in this review
None of the included trials reported data on participants’ all-cause mortality, serious adverse events, or days of hospitalisation. Researchers poorly reported harms caused by acetyl-L-carnitine, so the harms profile remains unclear. Risks of bias, imprecision, and outcome reporting bias all make the certainty of evidence low or very low. A reduction in blood ammonium levels favoured participants receiving acetyl-L-carnitine, but study authors observed no clinical benefits.

It is clear that additional randomised clinical trials are required to assess the benefits and harms of acetyl-L-carnitine compared with placebo in the treatment of people with hepatic encephalopathy. These trials should be well designed, conducted by independent researchers, and collaborative, and should include large numbers of participants.

Authors' conclusions: 

This Cochrane systematic review analysed a heterogeneous group of five trials at high risk of bias and with high risk of random errors conducted by only one research team. We assessed acetyl-L-carnitine versus placebo in participants with cirrhosis with covert or overt hepatic encephalopathy. Hence, we have no data on the drug for hepatic encephalopathy in acute liver failure. We found no information about all-cause mortality, serious adverse events, or days of hospitalisation. We found no clear differences in effect between acetyl-L-carnitine and placebo regarding quality of life, fatigue, and non-serious adverse events. Acetyl-L-carnitine reduces blood ammonium levels compared with placebo. We rated all evidence as of very low quality due to pitfalls in design and execution, inconsistency, small sample sizes, and very few events. The harms profile for acetyl-L-carnitine is presently unclear. Accordingly, we need further randomised clinical trials to assess acetyl-L-carnitine versus placebo conducted according to the SPIRIT statements and reported according to the CONSORT statements.

Read the full abstract...
Background: 

Hepatic encephalopathy is a common and devastating neuropsychiatric complication of acute liver failure or chronic liver disease. Ammonia content in the blood seems to play a role in the development of hepatic encephalopathy. Treatment for hepatic encephalopathy is complex. Acetyl-L-carnitine is a substance that may reduce ammonia toxicity. This review assessed the benefits and harms of acetyl-L-carnitine for patients with hepatic encephalopathy.

Objectives: 

To assess the benefits and harms of acetyl-L-carnitine for patients with hepatic encephalopathy.

Search strategy: 

We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE Ovid, Embase Ovid, LILACS, and Science Citation Index Expanded for randomised clinical trials. We sought additional randomised clinical trials from the World Health Organization Clinical Trials Search Portal and ClinicalTrials.gov. We performed all electronic searches until 10 September 2018. We looked through the reference lists of retrieved publications and review articles, and we searched the FDA and EMA websites.

Selection criteria: 

We searched for randomised clinical trials in any setting, recruiting people with hepatic encephalopathy. Trials were eligible for inclusion if they compared acetyl-L-carnitine plus standard care (e.g. antibiotics, lactulose) versus placebo or no acetyl-L-carnitine plus standard care. We are well aware that by selecting randomised clinical trials, we placed greater focus on potential benefits than on potential harms.

Data collection and analysis: 

We selected randomised clinical trials, assessed risk of bias in eight domains, and extracted data in a duplicate and independent fashion. We estimated risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes. We measured statistical heterogeneity using I² and D² statistics. We subjected our analyses to fixed-effect and random-effects model meta-analyses. We assessed bias risk domains to control systematic errors. We assessed overall quality of the data for each individual outcome by using the GRADE approach.

Main results: 

We identified five randomised clinical trials involving 398 participants. All trials included only participants with cirrhosis as the underlying cause of hepatic encephalopathy. Trials included participants with covert or overt hepatic encephalopathy. All trials were conducted in Italy by a single team and assessed acetyl-L-carnitine compared with placebo. Oral intervention was the most frequent route of administration. All trials were at high risk of bias and were underpowered. None of the trials were sponsored by the pharmaceutical industry.

None of the identified trials reported information on all-cause mortality, serious adverse events, or days of hospitalisation. Only one trial assessed quality of life using the Short Form (SF)-36 scale (67 participants; very low-quality evidence). The effects of acetyl-L-carnitine compared with placebo on general health at 90 days are uncertain (MD -6.20 points, 95% confidence interval (CI) -9.51 to -2.89). Results for additional domains of the SF-36 are also uncertain. One trial assessed fatigue using the Wessely and Powell test (121 participants; very low-quality evidence). The effects are uncertain in people with moderate-grade hepatic encephalopathy (mental fatigue: MD 0.40 points, 95% CI -0.21 to 1.01; physical fatigue: MD -0.20 points, 95% CI -0.92 to 0.52) and mild-grade hepatic encephalopathy (mental fatigue: -0.80 points, 95% CI -1.48 to -0.12; physical fatigue: 0.20 points, 95% CI -0.72 to 1.12). Meta-analysis showed a reduction in blood ammonium levels favouring acetyl-L-carnitine versus placebo (MD -13.06 mg/dL, 95% CI -17.24 to -8.99; 387 participants; 5 trials; very low-quality evidence). It is unclear whether acetyl-L-carnitine versus placebo increases the risk of non-serious adverse events (8/126 (6.34%) vs 3/120 (2.50%); RR 2.51, 95% CI 0.68 to 9.22; 2 trials; very low-quality evidence). Overall, adverse events data were poorly reported and harms may have been underestimated.

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