Efficacy and safety of carnitine supplementation on NAFLD: a systematic review and meta-analysis

doi:10.21203/rs.3.rs-2465125/v1

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Efficacy and safety of carnitine supplementation on NAFLD: a systematic review and meta-analysis

https://doi.org/10.21203/rs.3.rs-2465125/v1

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published 29 Apr, 2023

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Background & Objective: The efficacy and safety of L-carnitine supplementation on Non-alcoholic fatty liver disease (NAFLD) is unclear. This systematic review and meta-analysis aimed to assess the efficacy and safety of L-carnitine supplementation on NAFLD.

Methods: We searched in four databases (PubMed, Embase, Cochrane Library, and Web of Science) from inception to 1 November 2022 for potentially relevant records without language restrictions. We collected information on first author, publication year, country, setting, study design, population characteristics, duration of follow-up, outcome variables of interest, and sources of funding. We using a modified Cochrane risk of bias tool assessed the risk of bias, and using GRADE assessed the certainly of evidence, and using the Credibility of Effect Modification Analyses (ICEMAN) tool assessed the credibility of any apparent subgroup effect.

Results:This systematic review and meta-analysis included eight eligible randomised controlled trials (RCTs). Low certainty evidence show that L-carnitine supplementation significantly changes (reduced) in the AST levels and ALT levels (MD: -26.38, 95%CI: -45.46 to -7.30). Moderate certainty evidence show that L-carnitine supplementation significantly changes in the HDL-cholesterol levels (MD: 1.14, 95%CI: 0.21 to 2.07) and the Triglyceride levels (MD: -6.92, 95%CI: -13.82 to -0.03). Moderate credibility of ICEMAN result show that L-carnitine supplementation no difference on changes of AST and ALT levels in younger (MD: 0.5, 95%CI: -0.70 to 1.70), but have significantly changes (reduced) in the adults (MD: -20.3, 95%CI: -28.62 to -12.28).

Conclusion: L-carnitine supplementation may improve liver function and regulates triglyceride metabolism in patients with NAFLD, and with no significant adverse effects.

L-carnitine

Non-alcoholic fatty liver disease

Efficacy

Systematic review

Meta-analysis

Non-alcoholic fatty liver disease (NAFLD) is a condition where the accumulation of lipids exceeds 5% of hepatocytes when no other causes (eg., heavy alcohol consumption, drug consumption)[1]. There are various stages in the progression of NALFD, the initial stages of non-alcoholic fatty liver (NAFL) can progress to non-alcoholic steatohepatitis (NASH) characterized by persistent inflammatory processes, which in turn can progress to NASH fibrosis[2]. In NASH, hepatic steatosis is associated with hepatic inflammation that may be histologically indistinguishable from alcoholic steatohepatitis. Worldwide, NAFLD has a reported prevalence of 6 to 35 percent (median 20%). The pathogenesis of NAFLD has not been fully elucidated, but the most widely supported theory implicates steatohepatitis as the key mechanism leading to hepatic steatosis[3, 4]. Therefore, for NAFLD that cannot be controlled by weight loss or lifestyle interventions, any treatments that can stop hepatocellular steatosis or inflammatory lesions can be used for treatment[5-7].

Carnitine or L-b-hydroxy-c-N-trimethylaminobutyric acid is synthesized in the liver and kidneys. It was report that f carnitine can facilitates the transfer of long-chain fatty acids across the mitochondrial inner membrane as acylcarnitine esters and acts as an obligatory cofactor for β-oxidation of fatty acids[8]. Carnitine present in almost all animal species, as well as in several microorganisms and in some higher plants[9]. L-carnitine in humans is both endogenously synthesized and obtained through food ingestion, and also used as a drug. For example, the US Food and Drug Administration (FDA) approved the use specifically of the intravenous (IV) formulation of L-carnitine in dialysis patients[10]. As an obligatory cofactor for the oxidation of fatty acids or other mechanism, L-carnitine can be used to treat NAFLD[11]. Some evidence suggests that L L-carnitine treatment for NAFDLA is effective[11, 12], but some studies have concluded the opposite[13]. These gaps suggest that a higher level of evidence is needed to address this issue[14].

A meta-analysis published in 2020 shows that L-carnitine supplementation for patients with nonalcoholic fatty liver disease demonstrates a reduction in AST, ALT, TG levels and HOMA-IR[15]. However, this study did not use Grading of Recommendations Assessment, Development and Evaluation (GRADE) to assess the level of evidence, creating some resistance to clinical dissemination. In addition, this meta-analysis included few trials and had a low sample size, and had high risk of bias. Coinciding with the publication of new clinical trial[16-18], it is necessary to update this evidence. Therefore, our systematic review and meta-analysis aimed to assess the efficacy and safety of L-carnitine supplementation on NAFLD.

We completed this systematic review and meta-analysis according to the Cochrane handbook for Systematic Reviews of Interventions[19] and the GRADE guidance[20]. We reported it following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidance[21]. We registered this study prospectively in Open Science Framework, https://osf.io/8xtcp.

Search strategy and study eligibility

We searched in four databases (PubMed, Embase, Cochrane Library, and Web of Science) from inception to 1 November 2022 for potentially relevant records without language restrictions (for search terms used, see the appendix text S1). The search was updated on 24 December 2022. We also hand searched reference lists of relevant articles, and searched for relevant studies from the abstract of conference. Search strategies for all databases were completed under the guidance of a literature search specialist (JH T).

In this systematic review and meta-analysis, we considered studies eligible for included if they: (1) randomised controlled trials (RCTs); (2) patients of all ages with nonalcoholic fatty liver disease (NAFLD); (3) intervention group received carnitine supplement or carnitine supplement plus other nutrients; (4) comparison group received the same treatment as the intervention group with the exception of carnitine; (5) reported at least one outcomes we interest, included liver function tests (AST, ALT, γ-GT), lipid profile tests (HDL-cholesterol, LDL-cholesterol, Total cholesterol, Triglyceride), body indicators (BMI, Weight, Waist circumference), inflammatory factors (hs-CRP), and adverse events. Conference papers are also included when data are available. Potential studies in non-English were translated with the aid of translation software or translators, if necessary.

Study selection was performed in two phases: firstly, paired reviewers independently screened titles and abstracts; secondly, another paired reviewers independently screened the full text review of potentially eligible records. Disagreements were resolved by consensus and, if necessary, through discussion with a third reviewer.

Data extraction

We collected information on first author, publication year, country, setting, study design, population characteristics, duration of follow-up, outcome variables of interest, and sources of funding. In the case of multiple records pertaining to the same trial (i.e., original fulltext publication, abstract, and posthoc analyses), we collected all relevant data and analyzed them as a single study. Conversely, if a single record reported on more than one study, we treated each study as a separate study in the analysis. Data collection was done by paired reviewers independently and checked by the other reviewer. Any disagreements are resolved by consensus and, if necessary, through discussion with a fourth reviewer.

Risk of bias assessment

The risk of bias of included studies was assessed independently by paired reviewers according to a modified Cochrane risk of bias tool[22]. This updated risk of bias tool consists of the 10 domains: random sequence generation; allocation concealment; blinding of participants, healthcare providers, data collectors, outcome assessors, data analysts; incomplete outcome data; selective outcome reporting; and other sources of bias (i.e., early trial discontinuation).

Statistical analysis

All analysis were conducted using RStudio version 1.4.17.17 software by the packages of “meta” and “metafor”. We used the method suggested by the Cochrane handbook to calculate the sample size and event[19]. We calculated the effect size as a standardized mean difference of the final scores and summarized it using a Hartung-Knapp-Sidik-Jonkman (HKSJ) random effects meta-analysis. And we switched to the DerSimonian-Laird random effects model if meta-analysis results from HKSJ were counter-intuitive. For dichotomous outcomes (adverse events), we calculated relative risks (RRs) with 95% confidence intervals (CIs). For zero-event, studies were given 0.5 events for both the intervention and control group to be included [23]. We pooled all continuous outcomes reported by more than one study as the weighted mean difference (WMD) and the associated 95% CIs.

We tested the heterogeneity of meta-analysis results by using the Cochrane Q test and quantified it as I² values and the between study variance τ². Significance for heterogeneity was set at p <0.05, and with an I² >50% considered to be evidence of substantial heterogeneity. We used the subgroup analyses to explore the sources of heterogeneity. When 10 or more trials were available for an outcome, we also used meta-regression to explore the sources of heterogeneity as an extension to subgroup analysis. We used the contour-enhanced funnel plots to assess publication bias, if 10 or more trials were available for an outcome (Harbord’s test for dichotomous outcomes and Egger’s test for continuous outcomes)[24, 25].

Subgroup analysis

In order to identify the subgroup differences and potential sources of the observed heterogeneity. We performed the following prespecified subgroup analysis, if data available. After completion, we assessed the credibility of any apparent subgroup effect using the Credibility of Effect Modification Analyses (ICEMAN) tool[26]. (1) Health status: NAFLD versus NASH; hypothesis: may be no difference between the two populations. (2) Age: younger (< 18 years) versus adult (≥ 18 years); hypothesis: no difference in the efficacy of carnitine between younger and adults. (3) Daily dose: ≥ 1000mg verse < 1000mg; hypothesis: more daily doses have better efficacy and may have more adverse events. (4) Duration: 12 weeks verse 24 weeks; longer the duration of treatment, the better the efficacy.

Certainty of evidence

Paired reviewers with experience in using GRADE assessed the certainly of evidence independently, and resolved discrepancies by discussion. We rated the certainty for each comparison and outcome as “high”, “moderate”, “low”, or “very low”, taking into consideration risk of bias[27], inconsistency[28], imprecision[29], indirectness[30], and publication bias[31]. The definition of high certainly is that we are very confident that the true effect lies close to the estimate of the effect. The definition of moderate certainly is that we are moderately confident in the effect estimate (the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different). The definition of low certainly is that our confidence in the effect estimate is limited (the true effect may be substantially different from the estimate of the effect). The definition of very low certainly is that we have very little confidence in the effect estimate (the true effect is likely to be substantially different from the estimate of effect).

Study identification

We initially indentified 196 records from four databases, and zero studies identified from references of relevant reviews. After removed 93 duplicates, screening 86 titles and abstracts and 9 full texts, included eight eligible RCTs[13, 16-18, 32-35] in the final meta-analysis (Figure 1).

Study characteristics

Table 1 shows a summary of included eight RCTs. The eight RCTs were published between 2010 to 2021, and conducted in three countries, included Iran (n=5)[13, 16, 17, 32, 35], Korea (n=2)[32, 33], and Italy (n=1)[18]. The patient’s health status was NAFLD in five RCTs[13, 18, 32, 33, 35] and NASH in three studies[16, 17, 34], and appendix Table S1 shows the inclusion and exclusion criteria of each RCT. In total, 274 participants were randomly assigned to L-carnitine or C-carnitine and 270 were randomly assigned to placebo. The mean age of all participants (n=544) ranged from 12.6 to 59.5 years, mean BMI (kg/cm²)ranged from 26.5 to 31.3, and proportion of males ranged from 34.33% to 82.5%. Six RCTs had a duration treatment of 12 weeks[13, 16-18, 32, 33], and two RCTs had a duration treatment of 24 weeks[34, 35]. Six RCTs reported liver function tests (AST, ALT, γ-GT)[13, 18, 32-35], four RCTs reported Lipid profile tests(HDL-cholesterol, LDL-cholesterol, Total cholesterol, Triglyceride)[13, 32-34], six RCTs reported Body Indicators(BMI, Weight, Waist circumference)[17, 18, 32-35], two RCTs reported Inflammatory factors(hs-CRP)[16, 33], and two RCTs reported adverse events[32, 33].

Quality assessment

Appendix Table S2 presents risk of bias of included RCTs for each outcomes. One study[35] was at the “definitely low” or “probably low” in all domains. Three studies[32-34] were at the “definitely low” or “probably low” or “probably high” in all domains. All outcomes of the four studies[13, 16-18] were “high” in the domain of “Incomplete outcome data”.

Meta-analysis outcomes

Liver function tests

Figure 2 shows the outcomes of the meta-analysis of liver function texts. Six RCTs[13, 18, 32-35] involving 406 patients provided low certainty evidence (Table 2) that L-carnitine supplementation significantly changes (reduced) in the AST levels (MD: -15.89, 95%CI: -29.87 to -1.91), and low certainty evidence (Table 2) that L-carnitine supplementation significantly changes (reduced) in the ALT levels (MD: -26.38, 95%CI: -45.46 to -7.30). Three RCTs[32-34] involving 204 patients provided low certainty evidence (Table 2) that L-carnitine supplementation may induced or no difference on changes in the γ-GT levels (MD: -8.88, 95%CI: -25.43 to 7.67).[34]

Lipid profile tests

Figure 3 shows the outcomes of the meta-analysis of lipid profile texts. Three RCTs[32-34] involving 204 patients provided moderate certainty evidence (Table 2) that L-carnitine supplementation significantly changes in the HDL-cholesterol levels (MD: 1.14, 95%CI: 0.21 to 2.07), low certainty evidence (Table 2) that L-carnitine supplementation may induced or no difference on changes in the LDL-cholesterol levels (MD: -6.80, 95%CI: -23.27 to 9.68). Three RCTs[13, 33, 34] involving 186 patients provided low certainty evidence (Table 2) that L-carnitine supplementation may induced or no difference on changes in the Total cholesterol levels (MD: -11.80, 95%CI: -27.13 to 3.53). Four RCTs[13, 32-34] involving 264 patients provided moderate certainty evidence (Table 2) that L-carnitine supplementation may induced the Triglyceride levels (MD: -6.92, 95%CI: -13.82 to -0.03).

Body Indicators

Figure 4 shows the outcomes of the meta-analysis of body indicators. Six RCTs[17, 18, 32-35] involving 417 patients provided moderate certainty evidence (Table 2) that L-carnitine supplementation no difference on changes in the BMI (MD: 0.00, 95%CI: -0.23 to 0.24). Three RCTs[17, 18, 32] involving 211 patients provided low certainty evidence (Table 2) that L-carnitine supplementation no difference on changes in the Waist circumference (MD: -0.57, 95%CI: -1.82 to 0.67). Four RCTs[17, 18, 32, 35] involving 291 patients provided moderate certainty evidence (Table 2) that L-carnitine supplementation no difference on changes in the Weight (MD: -0.20, 95%CI: -0.50 to 0.09).

Inflammatory factor

Figure 5 shows the outcomes of the meta-analysis of inflammatory factor. Two RCTs[16, 33] involving 123 patients provided very low certainty evidence (Table 2) that L-carnitine supplementation no difference on changes in the hs-CRP (MD: -1.03, 95%CI: -3.23 to 1.16).

Safety

Figure 6 shows the outcomes of the meta-analysis of adverse events. Three RCTs[18, 32, 33] involving 192 patients provided moderate certainty evidence (Table 2) that L-carnitine supplementation probably has little or no difference on adverse events (RR: 0.72, 95%CI: 0.47 to 1.08).

Subgroup analysis and other analysis

Appendix Table S3 shows the subgroup analysis results. Subgroup analyses identified no suggestion of subgroup effects for the outcome of Changes in the γ-GT, HDL-cholesterol, and Triglyceride level, and Changes in the Weight and Waist circumference. Therefore, the use of ICEMAN to assess subgroup effects of the above outcomes were not applicable. In the outcome of changes in the AST levels, moderate credibility of ICEMAN result show that L-carnitine supplementation no difference on changes in younger (MD: 0.5, 95%CI: -0.70 to 1.70), but have significantly changes (reduced) in the adults (MD: -20.3, 95%CI: -28.62 to -12.28). In the outcome of changes in the ALT levels, moderate credibility of ICEMAN result show that L-carnitine supplementation no difference on changes in younger (MD: 0.4, 95%CI: -1.32 to 2.12), but have significantly changes (reduced) in the adults (MD: -31.7, 95%CI: -47.61 to -15.79).

In the outcome of changes in the LDL-cholesterol levels, low credibility of ICEMAN result show that carnitine supplementation no difference on changes in NAFLD/daily dose ≥ 1000mg/Duration_12 weeks (MD: 1.7, 95%CI: -4.66 to 8.06), but have significantly changes (reduced) in the NASH/daily dose < 1000mg/Duration_24 weeks (MD: -20.9, 95%CI: -27.92 to -13.84). In the outcome of changes in the Total cholesterol levels, low credibility of ICEMAN result show that L-carnitine supplementation no difference on changes in NAFLD/Duration_12 weeks (MD: -2.5, 95%CI: -14.85 to 9.81), but have significantly changes (reduced) in the NASH/ Duration_24 weeks (MD: -20.7, 95%CI: -28.22 to -13.22); low credibility of ICEMAN result show that carnitine supplementation no difference on changes in daily dose < 1000mg (MD: -2.1, 95%CI: -15.00 to 10.80), but have significantly changes (reduced) in the daily dose ≥ 1000mg (MD: -20.3, 95%CI: -27.68 to -12.92).

In the outcome of changes in the BMI, moderate credibility of ICEMAN result show that L-carnitine supplementation no difference on changes in adults (MD: 0.1, 95%CI: -0.07 to 0.31), but have significantly changes (reduced) in the youngers (MD: -0.2, 95%CI: -0.30 to -0.10). In the outcome of changes in the hs_CRP, very low credibility of ICEMAN result show that carnitine supplementation no difference on changes in daily dose < 1000mg (MD: 0.05, 95%CI: -0.07 to 0.17), but have significantly changes (reduced) in the daily dose ≥ 1000mg (MD: -2.19, 95%CI: -2.98 to -1.40).

In addition, sensitivity analyses after excluding zero-event studies showed similar results to the primary analyses. We were not evaluated for publication bias because none of outcomes included more than 10 studies.

We found low certainly evidence that L-carnitine supplementation significantly reduce the AST/ALT levels for patient with NAFLD compared to placebo. Analysis showed that L-carnitine reduced the AST by an mean of 6.85 IU/L when used for the treatment of NAFLD, and reduced the ALT by an mean of 11.15 IU/L. However, moderate credibility subgroup analysis showed that L-carnitine was effective to reduce AST/ALT levels in adults but failed in youngers. Moderate certainty evidence showed that L-carnitine supplementation significantly changes in the HDL-cholesterol and Triglyceride levels for patient with NAFLD compared to placebo. Analysis showed that L-carnitine improved the HDL-cholesterol by an mean of 0.5 mmol/l when used for the treatment of NAFLD, and reduced the Triglyceride by an mean of 6.24mg/ml.

Strengths and weaknesses of this review

This systematic review and meta-analysis was registered and reported with PRISMA[21], and to include the full of original trials whenever possible. The review included more studies than previous reviews and covered more outcomes. The heterogeneity in this study was substantial, and we speculate that most of the heterogeneity may have come from clinical sources. Therefore, the inclusion exclusion criteria for each original study are provided in the appendix to this study. In order to assess study level risk of bias we used the modified Cochrane risk of bias tool[22], and we evaluated the certainty of the evidence using the GRADE[20]. We performed a predetermined subgroup analysis, and used the ICEMAN tool[26] assessing the credibility of subgroup effect. To facilitate the interpretation of results, we presented absolute effects for all outcomes.

There are also some weakness in our study. Compared with previous systematic review, although more trials and sample size were included in our study, but still relatively small. Although we performed comprehensive literature searches and no restrictions on language, however, trials published in other languages may also been missed. There are two RCTs[32, 33] in which the intervention is Carnitine-Orotate Complex, although we only counted the daily dose of L-carnitine, it is possible that other ingredients in Carnitine-Orotate Complex may have an impact on efficacy and safety. After all, biphenyl dimethyl dicarboxylate[36], adenine[37], cyanocobalamin[38], pyridoxine and riboﬂavin may all have effects on NAFLD.

Evidence update

The most comparable to our study is another meta-analysis published by Abolfathi et al. in 2020[15]. Firstly, our study had 204 patients in three more RCTs than the previous meta-analysis. More studies and patients can make the results of the analysis more reliable. Secondly, our study used the GRADE tool assess the quality of evidence, which is of greater relevance to clinical practice. Thirdly, similar to our study, Abolfathi et al. also found that L-carnitine can improved liver function in patients with NAFLD. However, there are indeed different findings in improving lipids in patients with NAFLD. Our study found that L-carnitine improved the HDL-cholesterol levels. Finally, the present study found, by assessing the reliability of subgroup analyses, that almost all subgroup analyses were unreliable, limited by the fact that both the number of included studies and the sample size were small. They should be interpreted with caution in clinical in application.

Meaning of the study

L-carnitine is a water-soluble that can be obtained not only from the diet (around 75%)[39], but also synthesized in the body. It is can synthesize from the two amino-acids, lysine and methionine. The key enzyme for the synthesis of L-carnitine, however, is located in the liver, kidneys and in the brain[11]. If the liver is metabolically compromised, then the synthesis pathway may be inhibited. The main drivers in NAFLD are inflammation and accumulation of lipid[40], and L-carnitine has been shown to have anti-inflammatory effects by upregulating the Peroxisome Proliferator Activator Receptor-γ (PPAR-γ) in the liver[41]. L-carnitine is also closely related to fat metabolism[9]. It can be seen that there is also an interaction between abnormal liver function and the absorption of L-carnitine. The pooled analysis of clinical data in our study suggests that L-carnitine does improve liver function and affects triglyceride metabolism in patients with NAFLD. Although the level of evidence is not very high, it is the best summary of the current evidence. The results of the basic study and the clinical trials corroborate each other, which is an important significance of our study.

Implications for clinical practice

This systematic review of eight RCT provides detailed information for decision makers about the benefits and harms of L-carnitine supplementation on NAFLD. Despite results from a low confidence subgroup analysis, higher doses and longer courses of treatment may yield greater benefits without causing serious side effects. Therefore, for patients with NAFLD, especially those with a restricted diet (e.g., meat)[42], it is safe to supplement with L-carnitine. However, it is important to note in clinical practice that this does not mean that L-carnitine is a substitute for other lipid-regulating and anti-inflammatory drugs.

Unanswered questions and future research

Although the present study provides the best evidence available, the total number of studies and sample size is inadequate. Therefore, a larger RCT is highly warranted, especially in the field of dose and duration. In addition, L-carnitine is being used as a supplementation therapy, and the best and safe combination with which therapy is used is a point to be considered in the future. Because the absorption of L-carnitine is also very critical, which is also related to liver function. The region where the patient’s location is also important because the diet of people in different regions is not consistent. If possible, multicenter clinical trials should be conducted in as many regions as possible.

L-carnitine supplementation may improve liver function and regulates triglyceride metabolism in patients with NAFLD, and with no significant adverse effects. Multicenter and large sample clinical trials should be conducted in as many regions as possible, and to explore which interventions work best when combined with L-carnitine.

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Table 1 Basic characteristics of included studies

Author, year	Country	Health status	Sample sizes(Intervention/Control)	Male(n, %)	Age(Mean year)	BMI(kg/m2)	Intervention	Daily dose	Control	Duration (weeks)	Outcomes
Hossein, 2021	Iran	NAFLD	31/31	41, 66.13%	12.6	26.7	L-carnitine	1000mg	placebo	12	①③⑤
Shirin, 2015(1)	Iran	NASH	36/35	23, 34.33%	43.3	31.3	L-carnitine	2000mg	placebo	12	③
Shirin, 2015(2)	Iran	NASH	36/35	23, 34.33%	43.3	31.3	L-carnitine	2000mg	placebo	12	④
Pezhman, 2016	Iran	NAFLD	30/30	38, 63.33%	59.5	29.1	L-carnitine	2250mg	placebo	12	①②
Bae, 2015	Korea	NAFLD	39/39	54, 69.23%	51.3	27.5	C-carnitine	900mg	placebo	12	①②③⑤
Hong, 2014	Korea	NAFLD	26/26	36, 69.23%	51.8	27.1	C-carnitine	900mg	placebo	12	①②③④⑤
Mariano, 2010	Italy	NASH	36/38	40, 54.05%	47.8	26.5	L-carnitine	2000mg	placebo	24	①②③
Mohamad, 2014	Iran	NAFLD	40/40	66, 82.50%	40.7	29.0	L-carnitine	500mg	placebo	24	①③

NAFLD: Non-alcoholic Fatty Liver Disease; NASH: non-alcoholic steatohepatitis; C-Carnitine: Carnitine-Orotate Complex; ① Liver function tests(AST, ALT, γ-GT); ② Lipid profile tests(HDL-cholesterol, LDL-cholesterol, Total cholesterol, Triglyceride); ③ Body Indicators(BMI, Weight, Waist circumference); ④ Inflammatory factors(hs-CRP); ⑤ Adverse Events

Table 2 Certainty of evidence of each outcomes

Outcome

Study results and measurements

Absolute effect estimates

Certainty of the Evidence

Plain language summary

placebo

L-carnitine

AEs

Relative risk: 0.72

(CI 95% 0.47 - 1.08)

Based on data from 192 participants in 3 studies

Follow up 12 weeks

323

per 1000

233

per 1000

Moderate†

L-carnitine probably has little or no difference on AEs

Difference: 90 fewer per 1000

(CI 95% 171 fewer - 26 more)

Changes in the AST level

Measured by:

Scale: High better

Based on data from 406 participants in 6 studies

Follow up 12/24 weeks

6.85

Mean

Low‡

L-carnitine may increase changes in the AST level

Difference: MD 15.89 lower

(CI 95% 29.87 lower - 1.91 lower)

Changes in the ALT level

Measured by:

Scale: High better

Based on data from 406 participants in 6 studies

Follow up 12/24 weeks

11.15

Mean

Low‡

L-carnitine may increase changes in the ALT level

Difference: MD 26.38 lower

(CI 95% 45.46 lower - 7.30 lower)

Changes in the γ-GT level

Measured by:

Scale: High better

Based on data from 204 participants in 3 studies

Follow up 12/24 weeks

12.9

Mean

Low‡

L-carnitine may have little or no difference on changes in the γ-GT level

Difference: MD 8.88 lower

(CI 95% 25.43 lower - 7.67 lower)

Changes in the HDL-cholesterol level

Measured by:

Scale: High better

Based on data from 204 participants in 3 studies

Follow up 12/24 weeks

0.5

Mean

Moderate†

L-carnitine probably increases changes in the HDL-cholesterol level

Difference: MD 1.14 higher

(CI 95% 0.21 higher - 2.07 higher)

Changes in the LDL-cholesterol level

Measured by:

Scale: High better

Based on data from 204 participants in 3 studies

Follow up 12/24 weeks

5.4

Mean

Low‡

L-carnitine may have little or no difference on changes in the LDL-cholesterol level

Difference: MD 6.8 lower

(CI 95% 23.27 lower - 9.68 higher)

Changes in the Total cholesterol level

Measured by:

Scale: High better

Based on data from 186 participants in 3 studies

Follow up 12/24 weeks

Mean

Low‡

L-carnitine may have little or no difference on changes in the Total cholesterol level

Difference: MD 11.8 lower

(CI 95% 27.13 lower - 3.53 higher)

Changes in the Triglyceride level

Measured by:

Scale: High better

Based on data from 264 participants in 4 studies

Follow up 12/24 weeks

6.24

Mean

Moderate†

L-carnitine probably increases changes in the Triglyceride level

Difference: MD 6.92 lower

(CI 95% 13.82 lower - 0.07 lower)

Changes in the BMI

Measured by:

Scale: High better

Based on data from 417 participants in 6 studies

Follow up 12/24 weeks

0.45

Mean

Moderate†

L-carnitine probably has little or no difference on changes in the BMI

Difference: MD 0 lower

(CI 95% 0.23 lower - 0.24 higher)

Changes in the Waist circumference

Measured by:

Scale: High better

Based on data from 211 participants in 3 studies

Follow up 12 weeks

1.5

Mean

Low‡

L-carnitine may have little or no difference on changes in the Waist circumference

Difference: MD 0.57 lower

(CI 95% 1.82 lower - 0.67 higher)

Changes in the Weight

Measured by:

Scale: High better

Based on data from 291 participants in 4 studies

Follow up 12/24 weeks

0.6

Mean

Moderate†

L-carnitine probably has little or no difference on changes in the Weight

Difference: MD 0.2 lower

(CI 95% 0.5 lower - 0.09 higher)

Changes in the hs-CRP

Measured by:

Scale: High better

Based on data from 123 participants in 2 studies

Follow up 12 weeks

0.27

Mean

Very low§

We are uncertain whether l-carnitine increases or decreases changes in the hs-CRP

Difference: MD 1.03 lower

(CI 95% 3.23 lower - 1.16 higher)

†Rated down 1 level for risk of bias due to incomplete data; ‡Rated down 2 level for risk of bias due to incomplete data, and for serious inconsistency due to statistical heterogeneity; §Rated down 2 level for risk of bias due to incomplete data, and for serious inconsistency due to statistical heterogeneity, and for serious imprecision due to few patients.

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Editorial decision: Major revision
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Reviewers invited by journal
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Efficacy and safety of carnitine supplementation on NAFLD: a systematic review and meta-analysis

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