M E TA A N A LY S I S A N D S Y S T E M AT I C R E V I E W
Effect of L-carnitine on liver enzymes and biochemical factors in hepatic encephalopathy: A systematic review and
meta-analysis
Amir Abbasnezhad,* Razieh Choghakhori,†Sara Kashkooli,¶Meysam Alipour,‡Omid Asbaghi¶and Rasool Mohammadi§
*Nutritional Health Research Center,†Razi Herbal Medicines Research Center, Faculty of Medicine,§Department of Epidemiology and Biostatistics, School of Public Health and Nutrition,¶Student Research Committee, Lorestan University of Medical Sciences, Khorramabad, and‡Nutrition and Metabolic Diseases Researcher Center, Department of Nutrition, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
Key words
albumin, ammonia, bilirubin, hepatic encephalopathy, L-carnitine, meta-analysis.
Accepted for publication 15 June 2019.
Correspondence
Razieh Choghakhori, Razi Herbal Medicines Research Center, Faculty of Medicine, Lorestan University of Medical Sciences, Goledasht Blvd, PO Box 6813833946, Khorramabad, Iran.
Email: [email protected]
Declaration of conflict of interest:The authors declare that no conflict of interest exists.
Author contribution:A. A. and R. C. designed the study. S. K. and O. A. reviewed and selected the articles. S. K. and M. A. extracted needed data from articles. A. A. and R. M.
performed data analysis and interpretation.
R. C. drafted the manuscript.
Financial support:There are nofinancial or other competing interests for principal investigators, patients included, or any member of the trial.
Abstract
Background and Aims:We aimed to investigate the effect of L-carnitine on biochemical factors including ammonia, bilirubin, albumin, alanine aminotransferase, aspartate amino- transferase (AST), blood urea nitrogen (BUN), and creatinine (Cr) in patients with hepatic encephalopathy (HE).
Methods:A systematic search was carried out in Web of Science, PubMed, Scopus, and Cochrane Library databases tofind articles related to the effect of L-carnitine supplemen- tation in patients with HE, up to 7 February 2019. There was no language and time limita- tion. Meta-analyses were carried out using both the random andfixed effects models where appropriate, andI2index was used to evaluate the heterogeneity.
Results: Search yielded 3462 publications. Nine randomized clinical trials with 779 patients were eligible. L-carnitine supplementation significantly reduced blood levels of ammonia. Furthermore, our results indicated that L-carnitine supplementation significantly reduced blood levels of bilirubin, AST, BUN, and Cr in patients with HE. Subgroup analysis demonstrated that L-carnitine significantly reduced ammonia in patients with all the ages, long and short duration of the supplementation, doses less or higher than 4000 mg/day, any route of treatment (intravenous or oral), and in patients with any grade of the symptoms of HE. Moreover, we found that L-carnitine significantly increased circulating levels of albumin in HE patients.
Conclusions: Present systematic review and meta-analysis revealed that L-carnitine supplementation significantly reduced blood levels of ammonia, bilirubin, AST, BUN, and Cr in HE patients. Moreover, we found that L-carnitine significantly increased circulat- ing levels of albumin. However, further large-scale randomized clinical trials are needed.
Introduction
Hepatic encephalopathy (HE) is a neuropsychiatric complication with various symptoms including lethargy, confusion, and behav- ioral abnormalities that occurs commonly in acute liver failure or chronic liver disease.1 Recent studies have indicated that over 30% of patient with hepatic cirrhosis will eventually develop HE and even a higher percentage of them are at risk of developing minimal degrees of HE.2Severity of the symptoms of HE ranges from minimal HE with no detectable alterations in personality or behavior to severe HE with marked confusion, amnesia, and coma.3In hepatic failure, gut neurotoxins, which enter the sys- temic circulation, cause neurological damages.4One of the neuro- toxins whose levels increase in the blood is ammonia, which directly and indirectly changes the neuronal function.4Moreover, most hepatic failure cases have abnormal circulating levels of
alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, and albumin that indicate the presence of con- comitant coagulopathy, inflammation, and infection.5In addition, it has been reported that kidney disease occurs approximately in 25% of the patients with liver diseases,6and thus, assessment of kidney function is important in these patients.
Carnitine is an essential nutrient that plays a vital role in energy metabolism.7It is synthesized from two essential amino acids, ly- sine and methionine.8Carnitine transports long-chain fatty acids into the inner mitochondrial compartment and thus is essential for beta-oxidation.8It has been reported that carnitine deficiency occurs in various disorders, such as renal disease treated by hemo- dialysis, diabetes mellitus, malnutrition, cirrhosis, and endocrine disorders.6,7Therefore, recently, the supplementation of carnitine has become the subject of many investigations. Numerous studies have assessed the effect of L-carnitine supplementation in HE. A doi:10.1111/jgh.14765
systematic review and meta-analysis, which includedfive random- ized clinical trials (RCTs), demonstrated that L-carnitine supple- mentation had no significant effect on quality of life, fatigue, and non-serious adverse events, whereas it significantly reduced am- monia.9 Results of the studies assessed the effect of L-carnitine supplementation on biochemical factors in HE were inconsistent.
A study by Mariano Malaguarnera et al.10 indicated that L- carnitine supplementation could improve circulating levels of am- monium, albumin, and AST and has no significant effect on biliru- bin and ALT. However, Michele Malaguarneraet al.11indicated that carnitine supplementation had no significant effect on bio- chemical factors including albumin, bilirubin, and AST, whereas it significantly reduced ammonium and ALT. Due to the inconsis- tent results found in the literature, we carried out a systematic re- view and meta-analysis of RCTs to assess the effect of L- carnitine supplementation on biochemical variables in patients with HE.
Methods
Present systematic review and meta-analysis was performed ac- cording to the guidelines of the 2009 preferred reporting items for systematic reviews and meta-analysis statement.12
Search strategy. We systematically searched Web of Sci- ence, PubMed, Scopus, and Cochrane Library databases tofind ar- ticles related to the effect of L-carnitine supplementation in patients with HE, up to 7 February 2019. There was no language and time limitation. To include patients with HE, irrespective of etiology, we searched the following search keywords in the titles, abstracts, and keywords:“hepatic encephalopathy,” “liver enceph- alopathy,” “Non-alcoholic Fatty Liver Disease,” “Nonalcoholic Steatohepatitis,” “Alcoholic Fatty Liver,”Hepatitis,“Human Viral Hepatitides,” “Liver Cirrhoses,” “Hepatic Cirrhosis,” “Liver Fi- broses,” “Liver Fibrosis,” “Liver Neoplasm,” “Hepatic Neo- plasms,” “Cancer of Liver,” “Hepatocellular Cancer,”and “liver disease” in combination with levocarnitine, “Vitamin BT,” l- carnitine,“L Carnitine,”and carnitine (Data S1, search strategy).
Moreover, a manual search and reference lists check of all in- cluded studies and related reviews were performed to identify fur- ther relevant articles. Initially, 3462 studies were identified, of which,finally, nine unique studies meeting inclusion criteria were selected for inclusion in this meta-analysis. The process of study selection is shown in theflow diagram (Fig. 1). Reference manage- ment was carried out using EndNote X7.5.
Study selection. Articles were eligible for inclusion in this meta-analysis if they fulfilled the following criteria: (i) RCTs of L-carnitine supplementation with any route of administration in patients with HE; (ii) trials with any duration of treatment; and (iii) reported mean or median values in baseline and at the end of supplementation in intervention and control groups with stan- dard deviation (SD), standard error of the mean (SEM), or 95%
confidence interval (CI). The exclusion criteria were as follows:
(i) studies with no placebo or control group; (ii) case–control, cross-sectional, cohort design, and review studies; (iii) studies that used a combination of other vitamins and minerals; (iv) animal studies; and (v) studies in which the data were not available.
Data extraction. After removing duplicates, titles and ab- stracts of all studies were assessed independently by two reviewers (S. K. and O. A.) tofind potentially relevant studies for reading the full text. Finally, full text of selected articles was reviewed to de- termine whether the article is qualified for inclusion. Any disagree- ment in study inclusion was consulted with a third author (A. A.).
Major demographic and clinical data of included trials, containing the first author’s name, publication year, country in which the study was conducted, study design, dosage and duration of L- carnitine supplementation, and sample size, in both intervention and control groups, were extracted. Moreover, baseline andfinal values of blood biochemical variables, including ammonia, biliru- bin, albumin, ALT, AST, blood urea nitrogen (BUN), and creati- nine (Cr) were etracted.
Quality assessment. Quality of each included study was assessed using the 5-point scale Jadad score.13This scale assesses the quality of RCTs and includes random allocation (up to two points), double blinding (up to two points), and description of withdrawals and dropouts (up to one point). Studies with the scores of 3 and higher are generally considered as a high quality study.
Data synthesis and statistical analysis. All analyses were conducted using the STATA v.12 (Stata Corporation, Col- lege Station, TX, USA). In this meta-analysis, we used mean change and SD of the change of the variables between baseline and post-intervention. When SD of change was not reported, it was calculated using the following formula: s.d. = square root [(s.d. pre-intervention)2 + (s.d. post-intervention)2 (2R × s.d.
pre-intervention × s.d. post-intervention)]. A correlation coeffi- cient of 0.8 was assumed asR-value of the above-mentioned for- mula. If the studies reported the median and range (or 95% CI) of the variables, we estimated the mean and SD according to the method by Hozoet al.14 We used the GetData Graph Digitizer software 2.2415to extract the data of the studies that reported the data in the graphic form. First, we used the fixed effect model for assessment of the pooled effect size. The random effect model was used when the heterogeneity was presented. We performed subgroup analysis based on age, route and dose of the treatment, quality of the included studies, grade of the symptoms of HE, and duration of the treatment, to detect possible sources of the het- erogeneity. Publication bias was evaluated using visual assessment of funnel plots, Beg test and Egger’s regression asymmetry test.
To estimate the impact of each trial on the pooled effect size, the sensitivity analysis (metaninf analysis) was performed (one-study remove (leave-one-out) approach). Between-study heterogeneity was examined usingQtest andI-square (I2) test.16
Results
Study selection. Thefirst step of searching yielded 689, 97, 947, and 1729 citations in PubMed, Cochrane Library, Web of Science, and Scopus, respectively. Of these, 1296 articles were ex- cluded due to the duplication. The titles and abstracts of 2166 ar- ticles were reviewed. Of these, 2138 studies were excluded due to the following reasons: animal studies, reviews, supplementation
with other ingredients, no placebo or control group, and not related studies. Therefore, full text of 28 studies assessed for the eligibil- ity. Eventually, nine articles were included in this meta-analysis.
Study characteristics. All nine studies10,11,17–23were dou- ble blinded and placebo-controlled studies. The intervention dura- tions were from 12 h to 90 days. Data are pooled from studies with 779 participants in the intervention arm and 741 participants in the control arm. Age range of the participants was 37 to 74 years old.
Except one study that was conducted in Japan,17other studies have been conducted in Italy. All the included studies were parallel in design. All the studies were conducted on both genders. Basis on the jaded scale, seven studies had good quality (≥3) and quality score of two studies was lower than 3 (Table 1). The
supplementation doses also varied between studies. Supplementa- tion dose of L-carnitine was ranged from 1000 to 6000 mg/day.
Route of the treatment in three studies was intravenous, and other studies have given oral L-carnitine. Characteristics of the included studies are summarized in Table 1.
Publication bias and sensitivity analyses. Evaluation of the publication bias by funnel plots demonstrated no evidence of publication bias within the studies (Figure S5). Results of the metaninf analysis indicated that the elimination of any studies did not alter thefinal results (Figure S6).
Meta-analysis. Results of the meta-analysis of nine trials indi- cate that L-carnitine supplementation significantly reduced blood Figure 1 Flowchart of study selection for inclusion trials in the systematic review.
Table1Characteristicsoftheselectedstudiesincludedinthismeta-analysis AuthorYearCountryParticipantsSexAge intervention/ control StudydesignSamplesizein intervention/placebo group Treatment/controlDoseof carnitine(mg) Duration (day) Jaded score
Outcome KazutoTajiri2018JapanPatientswithadvanced livercirrhosis
F/M74/73R/DB/CO18/16L-carnitine+BCAA/BCAA100031Ammonia Bothgroupsreceivedlactulose KazutoTajiri2018JapanPatientswithadvanced livercirrhosis F/M74/73R/DB/CO18/25L-carnitine+BCAA/BCAA100071Ammonia Bothgroupsreceivedlactulose MicheleMalaguarnera2011ItalySeverehepatic encephalopathy
F/M37–64/35–65R/DB/PL30/30L-carnitine/placebo4000905Ammonia,bilirubin, albumin,ALT,andASTBothgroupsreceivedneomycin, lactulose,lactitol,andBCAA MicheleMalaguarnera2011ItalyMildhepatic encephalopathy F/M40–66/41–67R/DB/PL30/30L-carnitine/placebo4000905Ammonia,bilirubin, albumin,ALT,andASTBothgroupsreceivedneomycin, lactulose,lactitol,andBCAA MicheleMalaguarnera2011ItalyModeratehepatic encephalopathy
F/M40–66/41–67R/DB/PL30/30L-carnitine/placebo4000905Ammonia,bilirubin, albumin,ALT,andASTBothgroupsreceivedneomycin, lactulose,lactitol,andBCAA MarianoMalaguarnera2009ItalyCirrhoticpatientswith hepaticcoma F/M51.6/52.1R/DB/CO24/24L-carnitine+BCAA/BCAA400012h4Ammonia,BUN,andCr Bothgroupsreceivedlactulose MarianoMalaguarnera2009ItalyCirrhoticpatientswith hepaticcoma
F/M51.6/52.1R/DB/CO24/24L-carnitine+BCAA/BCAA400014Ammonia,BUN,andCr Bothgroupsreceivedlactulose MarianoMalaguarnera2008ItalyCirrhoticpatients withminimalhepatic encephalopathy F/M48/45R/DB/PL60/55L-carnitine/placebo4000304Ammonia,bilirubin, albumin,ALT,andAST MarianoMalaguarnera2008ItalyCirrhoticpatients withminimalhepatic encephalopathy
F/M48/45R/DB/PL60/55L-carnitine/placebo4000604Ammonia,bilirubin, albumin,ALT,andAST MarianoMalaguarnera2008ItalyCirrhoticpatients withminimalhepatic encephalopathy F/M48/45R/DB/PL60/55L-carnitine/placebo4000904Ammonia,bilirubin, albumin,ALT,andAST MarianoMalaguarnera2006ItalyCirrhoticpatientswith hepaticcoma
F/M51.4/50.2R/DB/PL13/11L-carnitine/placebo400035AmmoniaandBUN Bothgroupsreceivedlactulose MarianoMalaguarnera2005ItalyHepaticcomaF/M51.7/53.2R/DB/PL21/19L-carnitine/placebo4000303Ammonia MarianoMalaguarnera2005ItalyPatientswithhepatic encephalopathy F/M51.7/53.2R/DB/PL21/19L-carnitine/placebo4000603Ammonia MarianoMalaguarnera2005ItalyPatientswithhepatic encephalopathy
F/M51.7/53.2R/DB/PL21/19L-carnitine/placebo4000903Ammonia MarianoMalaguarnera2005ItalyPatientswithhepatic encephalopathy F/M51.7/53.2R/DB/PL30/30L-carnitine/placebo4000303Ammonia MarianoMalaguarnera2005ItalyPatientswithhepatic encephalopathy
F/M51.7/53.2R/DB/PL30/30L-carnitine/placebo4000603Ammonia MarianoMalaguarnera2005ItalyPatientswithhepatic encephalopathy F/M51.7/53.2R/DB/PL30/30L-carnitine/placebo4000903Ammonia (Continues)
Table1.(Continued) AuthorYearCountryParticipantsSexAge intervention/ control StudydesignSamplesizein intervention/placebo group Treatment/controlDoseof carnitine(mg) Duration (day) Jaded score
Outcome MarianoMalaguarnera2005ItalyPatientswithhepatic encephalopathy
F/M51.7/53.2R/DB/PL25/25L-carnitine/placebo4000303Ammonia MarianoMalaguarnera2005ItalyPatientswithhepatic encephalopathy F/M51.7/53.2R/DB/PL25/25L-carnitine/placebo4000603Ammonia MarianoMalaguarnera2005ItalyPatientswithhepatic encephalopathy
F/M51.7/53.2R/DB/PL25/25L-carnitine/placebo4000903Ammonia MarianoMalaguarnera2003ItalyPatientwithmild hepaticencephalopathy F/M51.7/52.4R/DB/PL35/33L-carnitine/placebo4000305Ammonia MarianoMalaguarnera2003ItalyPatientwithmild hepaticencephalopathy
F/M51.7/52.4R/DB/PL35/33L-carnitine/placebo4000605Ammonia MarianoMalaguarnera2003ItalyPatientwithmoderate hepaticencephalopathy F/M51.7/52.4R/DB/PL25/27L-carnitine/placebo4000305Ammonia MarianoMalaguarnera2003ItalyPatientwithmoderate hepaticencephalopathy
F/M51.7/52.4R/DB/PL25/27L-carnitine/placebo4000605Ammonia AngeloCecere2002ItalyPatientswithsubclinical hepaticencephalopathy F/M64.3/67.4R/DB/PL16/11L-carnitine/notreatmentin controlgroup 600072Ammonia Bothgroupsreceivedlactulose AngeloCecere2002ItalyPatientswithsubclinical hepaticencephalopathy
F/M64.3/67.4R/DB/PL16/11L-carnitine/notreatmentin controlgroup 6000142Ammonia Bothgroupsreceivedlactulose AngeloCecere2002ItalyPatientswithsubclinical hepaticencephalopathy
F/M64.3/67.4R/DB/PL16/11L-carnitine/notreatmentin controlgroup 6000212Ammonia Bothgroupsreceivedlactulose AngeloCecere2002ItalyPatientswithsubclinical hepaticencephalopathy
F/M64.3/67.4R/DB/PL16/11L-carnitine/notreatmentin controlgroup
6000282Ammonia Bothgroupsreceivedlactulose ALT,alanineaminotransferase;AST,aspartateaminotransferase;B,blinded;BCAA,branchedchainaminoacids;BUN,bloodureanitrogen;Cr,creatinine;DB,doubleblinded;NR,notreported;PC, placebo-controlled;R,randomized.
levels of ammonia (weighted mean difference [WMD] and 95%
CI: 27.92 mg/dL [ 33.21, 22.63],P<0.001) (Fig. 2). There was a moderate-to-high level of heterogeneity between included studies (I2= 85.3%,P<0.001). Thus, we conducted the subgroup analyses tofind the sources of heterogeneity. As Table 2 shows, in all the subgroups including age, route and dose of the treatment, quality of the included studies, grade of the symptoms of HE, and duration of the treatment, L-carnitine supplementation signif- icantly decreased ammonia. Furthermore, our results indicated that L-carnitine significantly reduced circulating levels of bilirubin (WMD [95% CI]: 0.17 mg/dL [ 0.25, 0.09],P<0.001) (Fig- ure S1). This meta-analysis indicated that L-carnitine significantly decreased blood concentrations of AST, whereas it had no signif- icant effect on ALT (WMD [95% CI]: 4.34 IU/L [ 6.81, 1.88],P= 0.001; 2.42 IU/L [ 5.35, 0.51],P= 0.11, respec- tively) (Figs 3,4). In addition, L-carnitine had a significant increas- ing effect on albumin (WMD [95% CI]: 0.25 g/dL [0.15, 0.36], P= 0.001) (Fig. 2). We found that L-carnitine significantly de- creased both BUN and Cr (WMD [95% CI]: 1.14 mmol/L [ 1.58, 0.71], P < 0.001; 5.73 μmol/L [ 10.76, 0.71], P= 0.02, respectively) (Figures S3 and S4).
Discussion
This systematic review and meta-analysis indicated that L- carnitine supplementation significantly reduced blood levels of ammonia, bilirubin, AST, BUN, and Cr in patients with HE. The reducing effect of L-carnitine on ammonia was found in patients with all the ages, long and short duration of the supplementation, doses less or higher than 4000 mg/day, any route of treatment
(intravenous or oral), and in any grade of the symptoms of HE.
Moreover, we found that L-carnitine had a significant increasing effect on circulating levels of albumin in HE patients.
Hepatic encephalopathy is a neuropsychiatric syndrome with a wide range of symptoms and functional disorders of the brain.3 Its exact mechanisms have not yet been known and is still unclear.
Several factors have contributed to the pathophysiology of HE, such as astrocytes swelling, and increased levels of biochemical like short-chain fatty acids, serotonin, and ammonia.5,24 Liver has a major detoxifying role in body. Thus, liver damages lead to increased levels of toxins in blood that can disturb brain func- tion.5Increased blood concentration of ammonia is one of the clas- sic laboratory abnormalities in patients with HE.5 Evaluating blood ammonia can help diagnose liver cirrhosis patients with al- tered mental status.4Chronic increase in the blood levels of ammo- nia resulting from chronic liver failure can lead to a change in the metabolism of brain cells. On the other hand, acute increase in the blood levels of ammonia increases cerebral bloodflow and accu- mulation of lactate.3 Measuring the ammonia concentration in blood is one of the important factors in assessing the therapeutic efficacy of a treatment in HE.4 Furthermore, it has long been known that in patients with liver damages, the abnormal levels of liver function enzymes, albumin, and bilirubin were common.5 In addition to the abnormal circulating levels of the biochemical factors related to the liver function, abnormal levels of biomarkers related to the kidney function such as BUN and Cr were also re- ported.6Elevated levels of the toxic chemicals in blood can cause a concomitant liver and kidney disease.6
Current therapy for patients with HE is the decrease of ammo- nia production and absorption from the gut; however, newer
Figure 2 Forest plot of the random effects meta-analysis of the effect of L-carnitine on ammonia. WMD, weighted mean difference.
methods such as modifying gutflora and blocking benzodiazepine receptors might be effective.3Most of the previous studies have reported a beneficial effect of L-carnitine in HE, and they reported that L-carnitine supplementation could reduce concentration of blood and brain ammonia.10,11In 2013, a systematic review and
meta-analysis indicated that L-carnitine supplementation could re- duce circulating levels of ammonia in these patients.25 Further- more, in 2019, a systematic review and meta-analysis indicated that L-carnitine supplementation had a significant reducing effect on ammonia, whereas it had no significant effect on quality of Figure 3 Forest plot of thefixed effects meta-analysis of the effect of L-carnitine on aspartate aminotransferase. WMD, weighted mean difference.
Figure 4 Forest plot of thefixed effects meta-analysis of the effect of L-carnitine on alanine aminotransferase. WMD, weighted mean difference.
Table 2 Subgroup analysis of the effect of L-carnitine supplementation on ammonia levels
No WMD (95% CI) Pwithin group Pheterogeneity I2(%)
Route of treatment
Intravenous 5 18.81 ( 21.9, 15.73) <0.001 0.809 0.0
Oral 23 31.66 ( 38.59, 24.74) <0.001 <0.001 87.8
Trial duration (day)
≤1 month 15 29.06 ( 36.78, 21.33) <0.001 <0.001 84.7
1 month 13 27.42 ( 35.43, 19.42) <0.001 <0.001 86.9
L-carnitine dose (mg)
≤4000 14 26.67 ( 31.98, 21.36) <0.001 <0.001 86.6
4000 4 54.49 ( 74.63, 34.35) <0.001 0.693 0.0
Age (year)
≤50 6 16.82 ( 24.42, 9.22) <0.001 <0.001 78.8
50 22 32.68 ( 39.38, 25.98) <0.001 <0.001 86.2
Grade of the symptoms of hepatic encephalopathy
Minimal hepatic encephalopathy 10 27.97 ( 37.33, 18.61) <0.001 <0.001 77.7
Mild hepatic encephalopathy 8 43.86 ( 64.49, 23.22) <0.001 <0.001 94.2
Moderate hepatic encephalopathy 4 21.79 ( 30.47, 13.11) <0.001 0.002 79.2
Severe hepatic encephalopathy 3 19.07 ( 26.54, 11.59) <0.001 0.373 0.0
Hepatic coma 3 19.25 ( 22.49, 16.01) <0.001 0.749 0.0
Jaded score
<3 6 30.31 ( 49.44, 11.16) 0.002 0.017 63.7
≥3 22 27.82 ( 33.45, 22.19) <0.001 <0.001 87.6
CI, confidence interval; WMD, weighted mean differences.
life, fatigue, and non-serious adverse events in HE patients.9 Our systematic review and meta-analysis demonstrated that L-carnitine had a significant reducing effect on ammonia levels.
Moreover, we found that L-carnitine also had beneficial effects on other biochemical factors. Our results indicated that L-carnitine supplementation reduced circulating levels of biliru- bin, AST, BUN, and Cr and enhanced albumin levels. Carnitine is essential for the transfer of fatty acids across the inner mito- chondrial membrane.26The liver is the central organ for carnitine distribution and metabolism; therefore, any liver disorders can af- fect carnitine metabolism.27Based on previous studies, patients with liver disease have lower blood carnitine concentrations.28 Carnitine stimulates the expression of urea cycle enzyme and in- creases the urea genesis thatfinally leads to a decreased ammonia level in blood and brain.7In addition, it has been shown that the carnitine administration had the protective effect against ammo- nium toxicity and consequently against glutamate neurotoxicity.7 The excess of extracellular glutamate under ammonium ion exposure leads to mitochondrial dysfunctions, alteration in nitric oxide metabolism, ATP shortage, free radical accumulation, and oxidative stress.7Moreover, ammonia exposure of the brain tissue leads to alteration of other neurotransmission systems like the activation of GABA or benzodiazepine receptors. Carnitine may have a beneficial effect by enhancing the energy dynamics of the cell and also inhibiting the hyperexcitability of the cell mem- brane.7Although the beneficial effect of L-carnitine administra- tion on biochemical factors and metabolism of brain cells in patients with HE have been reported, there is a lack of studies re- garding the effect of L-carnitine to improve the clinical symptom of such patients, and further studies in this area are needed to reveal more facts.
Our meta-analysis was different from the meta-analysis of Martí-Carvajalet al.,9in many ways. They searched different da- tabases and found less studies. Theirfirst step of searching yielded 744 records, while ourfirst step of searching yielded 3462 record.
Finally, they includedfive studies, while we included nine studies.
They searched the medical literature up to 10 September 2018, and we searched literature up to 7 February 2019. Furthermore, we aimed to assess the effect of L-carnitine supplementation on bio- chemical variables including ammonia, bilirubin, albumin, ALT, AST, BUN, and Cr in HE patients. While the primary outcomes of the study by Martí-Carvajalet al.9were the effect of L-carnitine on all-cause mortality, quality of life and serious adverse events in HE patients, and the secondary outcomes were non-serious ad- verse events, fatigue, days of hospitalization, and blood ammo- nium levels. Present systematic review and meta-analysis has several strengths. We included RCTs that examined complemen- tary endpoints, providing a comprehensive review on this topic.
This review is based on an up-to-date literature search from a large number of databases and included nine studies. To our best knowl- edge, this is the first systematic review and meta-analysis that assessed the effect of L-carnitine supplementation on most of the important biochemical factors such as AST, ALT, BUN, Cr, albu- min, and bilirubin in HE patients, whereas previous meta-analysis evaluated the effect of L-carnitine only on ammonia. Present study has also several limitations. Although we conducted a comprehen- sive search of the electronic literature, there might be studies that have not been included. Finally, the small sample size of the indi- vidual studies limits the strength of the conclusion of the present
meta-analysis; however, we hope this study will be helpful for fu- ture studies.
In conclusion, our systematic review and meta-analysis indi- cated that L-carnitine supplementation could improve circulating levels of the most of the biochemical factors in HE. We found that L-carnitine supplementation significantly reduced blood levels of ammonia, bilirubin, AST, BUN, and Cr. Moreover, we found that L-carnitine significantly increased circulating levels of albumin in HE patients. However, further large-scale RCTs are needed to fully determine the beneficial effects of L-carnitine in HE.
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Supporting information
Additional supporting information may be found online in the Supporting Information section at the end of the article.
Figure S1.Forest plot of thefixed-effects meta-analysis of the ef- fect of L-carnitine on bilirubin.
Figure S2.Forest plot of the random-effects meta-analysis of the effect of L-carnitine on albumin.
Figure S3.Forest plot of thefixed-effects meta-analysis of the ef- fect of L-carnitine on Blood urea nitrogen (BUN).
Figure S4.Forest plot of thefixed-effects meta-analysis of the ef- fect of L-carnitine on creatinine.
Figure S5.Funnel plot of the included studies.
Figure S6.Plot of the sensitivity analysis results for the meta-anal- yses across all studies.
Data S1.Supporting Information.