Re: 지방산 운반체 카르니틴 보충제의 간경화 치료(ALT) 효과 RCT 리뷰논문 2022

[문형철]

https://kr.iherb.com/search?kw=carnitine

https://kr.iherb.com/pr/now-foods-l-carnitine-1000-mg-100-tablets/2507

J Pers Med

. 2022 Jun 27;12(7):1053. doi: 10.3390/jpm12071053

Impact of l-Carnitine Supplementation on Liver Enzyme Normalization in Patients with Chronic Liver Disease: A Meta-Analysis of Randomized Trials

Hyunwoo Oh 1, Chan Hyuk Park 2,*,†, Dae Won Jun 3,*,†

Editor: Frank Vinholt Schiødt

• Author information
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PMCID: PMC9322040  PMID: 35887550

Abstract

The effectiveness of l-carnitine in chronic liver disease remains controversial. We conducted this meta-analysis to assess the efficacy of various forms of l-carnitine in the treatment of chronic liver disease.

Methods: We searched the Cochrane Library, EMBASE, KMBASE, and Medline databases for all relevant studies published until April 2022 that examined the ability of l-carnitine or its derivatives to normalize liver enzymes in patients with chronic liver disease. We performed meta-analyses of the proportion of patients with alanine aminotransferase (ALT) normalization and post-treatment serum aspartate aminotransferase (AST) and ALT levels. A random effects model was used for meta-analyses.

Results: Fourteen randomized controlled trials (1217 patients) were included in this meta-analysis. The proportion of patients in whom ALT normalized was higher in the carnitine-orotate treatment group than in the control group (pooled odds ratio (OR), 95% confidence interval (CI) = 4.61 (1.48–14.39)). The proportion of patients in whom ALT normalized was also higher among those who received the carnitine-orotate complex, a combination of carnitine-orotate, biphenyl dimethyl dicarboxylate, and other minor supplementary compounds than in those who did not without significant heterogeneity (pooled OR (95% CI) = 18.88 (7.70–46.27); df = 1; p = 0.51; I2 = 0%). l-carnitine supplementation effectively lowered serum ALT levels compared to controls (pooled mean difference (95% CI) = −11.99 (−22.48 to −1.49)).

Conclusions: l-carnitine supplementation significantly lowered ALT and AST levels and normalized ALT levels in patients with chronic liver disease.

요약

만성 간 질환에 대한

L-카르니틴의 효과는 여전히 논란의 여지가 있습니다.

우리는

만성 간 질환 치료에 다양한 형태의 L-카르니틴의 효능을 평가하기 위해

이 메타분석을 수행했습니다.

방법:

우리는 2022년 4월까지 발표된 모든 관련 연구를 Cochrane Library, EMBASE, KMBASE, 및 Medline 데이터베이스에서 검색하여

만성 간 질환 환자의 간 효소 정상화에 대한

L-카르니틴 또는 그 유도체의 효과를 평가했습니다.

우리는

알라닌 아미노전달효소(ALT) 정상화 환자 비율 및 치료 후

혈청 아스파르테이트 아미노전달효소(AST)와 ALT 수치를 대상으로

메타분석을 수행했습니다. 메타분석에는 무작위 효과 모델을 사용했습니다.

결과:

이 메타분석에는 14건의 무작위 대조 시험(1,217명)이 포함되었습니다.

ALT가 정상화된 환자의 비율은

카르니틴-오로테이트 치료군에서 대조군보다 높았습니다(풀링 오즈비(OR), 95% 신뢰 구간(CI) = 4.61 (1.48–14.39)).

카르니틴-오로테이트 복합제(카르니틴-오로테이트,

비페닐 디메틸 디카르복실레이트, 및 기타 소량 보조 성분을 투여받은 환자에서

대조군보다 유의미한 이질성 없이 높았습니다

(풀링된 OR (95% CI) = 18.88 (7.70–46.27); 자유도 = 1; p = 0.51; I2 = 0%).

l-카르니틴 보충은

대조군에 비해 혈청 ALT 수치를 유의미하게 감소시켰습니다

(풀링 평균 차이 (95% 신뢰 구간) = −11.99 (−22.48 to −1.49)).

결론:

l-카르니틴 보충은

만성 간 질환 환자의 ALT 및 AST 수치를 유의미하게 감소시키고

ALT 수치를 정상화시켰습니다.

Keywords: carnitine, acetylcarnitine, carnitine-orotate, chronic liver disease

1. Introduction

l-carnitine (3-hydroxy-4-N-trimethylammonium butyrate) is an endogenous compound that plays a pivotal role in fatty acid metabolism [1]. l-carnitine supplementation is marketed in the form of acetyl-l-carnitine (analogs of l-carnitine) [2] and carnitine-orotate (l-carnitine and an ion complex salt of orotic acid) [3,4]. Commercially, the carnitine-orotate complex, a combination of carnitine-orotate, biphenyl dimethyl dicarboxylate, and other minor supplementary compounds, is also available [5].

l-carnitine is mainly derived from foods, such as meat and dairy products. It is also synthesized in the human liver and kidneys; in other words, l-carnitine deficiency occurs more frequently in patients with chronic liver disease or liver cirrhosis [2,6]. Carnitine acts as a carrier for fatty acids across the mitochondrial membrane for subsequent β-oxidation and reduces hepatic free fatty acids, causing decreased triglyceride accumulation in the cytoplasm of hepatocytes [7]. Moreover, it plays an important role in reducing oxidative stress and increasing proinflammatory cytokine expression‎ [8]. l-carnitine, acetyl-l-carnitine, and carnitine-orotate supplements have been used as adjuvant therapies in chronic liver disease, including non-alcoholic steatohepatitis, alcoholic fatty liver disease, viral hepatitis, and cirrhosis [9,10,11].

Accordingly, many studies have investigated the effect of l-carnitine on liver enzymes and liver disease, but the results are inconclusive. In a previous meta-analysis, a pooled analysis suggested that l-carnitine supplementation significantly decreased serum liver enzyme levels [12,13]. However, the previous meta-analysis included healthy volunteers as well as patients with chronic liver disease. In addition, previous studies analyzed only l-carnitine, and many randomized controlled trials (RCTs) on various forms of carnitine were omitted. Therefore, this meta-analysis investigated the effects of l-carnitine supplementation, including acetyl-l-carnitine and carnitine-orotate, in patients with chronic liver disease.

1. 서론

l-카르니틴 (3-하이드록시-4-N-트라이메틸아미노부티레이트)은

지방산 대사에서 핵심적인 역할을 하는

내인성 화합물입니다 [1].

l-카르니틴 보충제는

아세틸-l-카르니틴(l-카르니틴의 유사체) [2] 및

카르니틴-오로테이트(l-카르니틴과 오로트산의 이온 복합 염) [3,4] 형태로 시판되고 있습니다.

acetyl-l-carnitine (analogs of l-carnitine) [2] and

carnitine-orotate (l-carnitine and an ion complex salt of orotic acid)

상업적으로는 카르니틴-오로테이트 복합체(카르니틴-오로테이트, 비페닐 디메틸 디카르복실레이트 및 기타 소량의 보조 성분으로 구성된 복합체)도 판매되고 있습니다 [5].

l-카르니틴은

주로 고기 및 유제품과 같은 식품에서 유래됩니다.

또한 인간 간과 신장에서 합성되며,

즉 L-카르니틴 결핍은

만성 간 질환이나 간경변 환자에게 더 자주 발생합니다 [2,6].

카르니틴은

지방산을 미토콘드리아 막을 통해 운반하여 β-산화를 촉진하며,

간 내 자유 지방산을 감소시켜

간세포 세포질 내 트리글리세라이드 축적을 줄입니다 [7].

또한

산화 스트레스 감소와 염증성 사이토킨 발현 증가에

중요한 역할을 합니다 [8].

L-카르니틴, 아세틸-L-카르니틴, 카르니틴-오로테이트 보충제는

비알코올성 지방간염, 알코올성 지방간 질환, 바이러스성 간염, 간경변증 등

만성 간 질환의 보조 치료제로 사용되어 왔습니다 [9,10,11].

이에 따라

L-카르니틴이 간 효소 및 간 질환에 미치는 영향을 조사한 많은 연구가 진행되었지만,

결과는 일관되지 않습니다.

이전 메타분석에서 통합 분석 결과,

L-카르니틴 보충이 혈청 간 효소 수치를 유의미하게 감소시켰다는 결과가 제시되었습니다 [12,13].

그러나 이전 메타분석에는

만성 간 질환 환자뿐만 아니라 건강한 자원자도 포함되었습니다.

또한 이전 연구들은 L-카르니틴만을 분석했으며,

다양한 형태의 카르니틴을 대상으로 한 많은 무작위 대조 시험(RCT)이 제외되었습니다.

따라서

이 메타분석은 만성 간 질환 환자를 대상으로

L-카르니틴 보충제(아세틸-L-카르니틴 및 카르니틴-오로테이트 포함)의 효과를

조사했습니다.

2. Materials and Methods

2.1. Search Strategy

We searched the Cochrane Library, EMBASE, KMBASE and Medline databases for all relevant studies published between January 1990 and April 2022 that examined the ability of carnitine to normalize liver enzymes in patients with chronic liver disease. The following search string was used: ((carnitine) OR (l-carnitine) OR (carnitine-orotate) OR (carnitine-orotate) OR (carnitine complex) OR (godex) OR (hepadif) OR (biphenyl dimethyl dicarboxylate) OR (BDD) OR (DDB)) AND ((liver) OR (hepatic) OR (hepatitis) OR (cirrhosis)). The detailed search strategies used for each database are presented below.

Cochrane library

#1: carnitine or L-carnitine or ‘carnitine-orotate’ or ‘carnitine orotate’ or ‘carnitine complex’ or godex or hepadif or ‘biphenyl dimethyl dicarboxylate’ or BDD or DDB;

#2: liver or hepatic or hepatitis or cirrhosis;

#3: #1 and #2 (with publication year from 1990 to 2022, in Trials).

EMBASE (search interface: Ovid)

1: ((carnitine or L-carnitine or carnitine-orotate or carnitine orotate or carnitine complex or godex or hepadif or biphenyl dimethyl dicarboxylate or BDD or DDB) and (liver or hepatic or hepatitis or cirrhosis)).ab,ti;

2: Limit 1 to (embase and yr=“1990–Current”).

KMBASE

(((((((((([ALL=carnitine] OR [ALL=L-carnitine]) OR [ALL=carnitine-orotate]) OR [ALL=carnitine orotate]) OR [ALL=carnitine complex]) OR [ALL=godex]) OR [ALL=hepadif]) OR [ALL=biphenyl dimethyl dicarboxylate]) OR [ALL=BDD]) OR [ALL=DBB]) AND ((([ALL=liver] OR [ALL=hepatic]) OR [ALL=hepatitis]) OR [ALL=cirrhosis])).

MEDLINE (Search interface: PubMed)

(carnitine[tw] OR L-carnitine[tw] OR (carnitine-orotate[tw]) OR (carnitine orotate[tw]) OR (carnitine complex[tw]) OR godex[tw] OR hepadif[tw] OR (biphenyl dimethyl dicarboxylate[tw]) OR BDD[tw] OR DDB[tw]) AND (liver[tw] OR hepatic[tw] OR hepatitis[tw] OR cirrhosis[tw]) AND (“1990/01/01”[Date—Publication]: “3000”[Date—Publication]).

2.2. Inclusion/Exclusion Criteria

The inclusion criteria were as follows: (a) patients: diagnosis of chronic liver disease; (b) intervention: taking the target drugs, including carnitine-orotate, carnitine-orotate complex, and l-carnitine; (c) comparator: no target drugs; (d) outcome: proportion of patients with alanine aminotransferase (ALT) normalization or difference in post-treatment serum aspartate aminotransferase (AST) and ALT levels between the treatment and control groups; and (e) study design: RCT (Table 1). Non-human studies or abstract-only publications were excluded.

2.2. 포함/배제 기준

포함 기준은 다음과 같습니다:

(a) 환자: 만성 간 질환 진단;

(b) 개입: 대상 약물(카르니틴-오로테이트, 카르니틴-오로테이트 복합체, L-카르니틴) 복용;

(c) 대조군: 대상 약물 미복용;

(d) 결과: 알라닌 아미노전달효소 (ALT) 정상화 환자 비율 또는 치료군과 대조군 간의 치료 후 혈청 아스파르테이트 아미노전달효소 (AST) 및 ALT 수치 차이; 및

(e) 연구 설계: 무작위 대조 시험 (RCT) (표 1).

인간 대상 연구가 아닌 연구 또는 초록만 게재된 논문은 제외되었습니다.

Table 1.

Inclusion criteria of the present meta-analysis. ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Inclusion CriteriaDescription

Population	Patients with chronic liver disease
Intervention	Taking the target drugs, including carnitine-orotate, carnitine-orotate complex, and L-carnitine
Comparison	No target drugs
Outcomes	Proportion of patients with ALT normalization or difference in post-treatment serum AST and ALT levels
Study design	Randomized controlled trial

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2.3. Study Selection

Duplicates from multiple search engines were removed from the literature search results. After the titles and abstracts were reviewed, irrelevant studies were excluded based on the inclusion and exclusion criteria. Thereafter, we reviewed the full text of all the remaining studies. Two investigators (H.O. and C.H.P.) independently assessed the eligibility of each study. Any disagreements were resolved by discussion and consensus. If no agreement was reached, a third investigator (D.W.J.) determined the final eligibility.

2.4. Quality Assessment

Two investigators (H.O. and C.H.P.) independently assessed the methodological quality of the individual studies using the Cochrane Risk of Bias assessment tool for RCTs [14].

2.5. Data Extraction

The data were extracted using a form developed in advance. Two investigators (H.O. and C.H.P.) independently extracted the following information: first author, year of publication, study design, study period, country, baseline characteristics of the study participants, dosage of target drugs, proportion of participants with ALT normalization, post-treatment serum AST and ALT levels, and other major findings of each study. If values for the meta-analysis were not sufficiently reported by the individual studies, we asked the corresponding author for the data.

2.6. Study Endpoints

The primary endpoint of this meta-analysis was the proportion of patients with post-treatment ALT normalization. The secondary endpoint was the mean difference in the post-treatment serum AST and ALT levels between the treatment and control groups.

2.7. Statistical Analysis

As most studies of carnitine-orotate (or the carnitine-orotate complex) investigated the proportion of patients with ALT normalization, pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. A random-effects model was used. For a meta-analysis of studies that reported continuous variable outcomes (e.g., post-treatment serum AST and ALT levels), mean differences (MDs) and 95% CIs between the treatment and control groups were calculated.

We assessed heterogeneity using two methods: Cochran’s Q test, wherein p values < 0.1 were considered statistically significant for heterogeneity, and I2 statistics, wherein values > 50% were suggestive of significant heterogeneity [15]. Based on Cochrane recommendations, publication bias was assessed when ≥10 studies were included [14]. Publication bias was assessed using a funnel plot [16], a radial plot [17], Egger’s test [18], and the AS-Thompson test [19]. We performed sensitivity analyses after excluding studies (1) involving decompensated cirrhosis; and (2) with a high risk of bias. Additionally, we performed a jackknife sensitivity analysis after excluding one different study each time.

All P values were two-tailed, and those <0.05, except on the heterogeneity test, were considered statistically significant. Analyses and reporting were performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines [20]. All statistical analyses were conducted using Review Manager 5.3 (version 5.3.5; Cochrane Collaboration, Copenhagen, Denmark) and R (version 4.4.4; R Foundation for Statistical Computing, Vienna, Austria).

Details of the protocol for this systematic review were registered on PROSPERO and can be accessed at https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022332856 (accessed on 28 May 2022)[21].

3. Results

3.1. Study Selection and Characteristics

Fourteen studies including 1217 patients were included in this meta-analysis (Figure 1). The characteristics of the included studies are summarized in Table 2. The studies were published during 2000–2016 and included enrollment periods during 2000–2014 [22,23,24,25,26,27,28,29,30,31,32,33,34,35]. Among the 14 studies included, four investigated the efficacy of carnitine-orotate or carnitine-orotate complex and reported the proportion of patients with post-treatment ALT normalization [22,23,24,25]. The other 10 studies assessed the impact of l-carnitine on serum AST and ALT levels [26,27,28,29,30,31,32,33,34,35]. Of the 14 included studies, one involved patients with decompensated cirrhosis [31].

3.1. 연구 선정 및 특성

이 메타분석에는 1,217명의 환자를 포함한 14개의 연구가 포함되었습니다(그림 1). 포함된 연구의 특성은 표 2에 요약되어 있습니다. 연구는 2000년부터 2016년 사이에 발표되었으며, 2000년부터 2014년 사이에 환자 모집 기간을 포함했습니다 [22,23,24,25,26,27,28,29,30,31,32,33,34,35].

포함된 14개 연구 중 4개는

카르니틴-오로테이트 또는 카르니틴-오로테이트 복합제의 효능을 조사했으며,

치료 후 ALT 정상화 환자 비율을 보고했습니다[22,23,24,25].

나머지 10건의 연구는

L-카르니틴이 혈청 AST 및 ALT 수치에 미치는 영향을 평가했습니다 [26,27,28,29,30,31,32,33,34,35].

포함된 14건의 연구 중 1건은 비보상성 간경변증 환자를 대상으로 했습니다 [31].

Figure 1.

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Study flow diagram.

Table 2.

Baseline characteristics of the included studies.

Publication YearFirst AuthorStudy DesignStudy PeriodCountryStudy PopulationInclusion of Patients with Decompensated CirrhosisTreatmentControlOther Medication (Both Treatment and Control Groups)Number of ParticipantsAge, Years, Mean ± SDMale Sex, %BMI, kg/m2, Mean ± SDBaseline Laboratory FindingsRisk of BiasAST, IU/mL,Mean ± SDALT, IU/mL,Mean ± SD

2001

Kang JS [22]

Double-blinded RCT

2000

Korea

Chronic hepatitis

No

Treatment A: Carnitine-orotate (900 mg/day) Treatment B: Carnitine-orotate (600 mg/day)

Placebo

BDD 150 mg/day

95

Treatment A: 49.0 ± 9.7; Treatment B: 41.6 ± 11.7; Control: 44.0 ± 11.6

Treatment A: 63.6; Treatment B: 63.3; Control: 71.9

N/A

N/A

N/A

Unclear

2001

Park MS [23]

Double-blinded RCT

N/A

Korea

Chronic hepatitis

No

Treatment A: Carnitine-orotate (900 mg/day) Treatment B: Carnitine-orotate (600 mg/day)

Placebo

BDD 150 mg/day

154

Treatment A: 44.6 ± 11.5; Treatment B: 43.2 ± 13.0; Control: 45.6 ± 13.8

Treatment A: 92.5; Treatment B: 77.6; Control: 82.7

N/A

NA

N/A

Unclear

2013

Jun DW [24]

Open-label RCT

N/A

Korea

Chronic hepatitis B

No

Carnitine-orotate complex (900 mg/day as carnitine-orotate)

No carnitine-orotate complex

Entecavir 0.5 mg/day

130

Treatment: 43.0 ± 9.8; Control: 44.9 ± 10.0

Treatment: 63.5 Control: 66.1

N/A

Treatment: 118.8 ± 70.3; Control: 111.3 ± 70.2

Treatment: 159.4 ± 67.5; Control: 160.3 ± 74.9

Unclear

2015

Bae JC [25]

Double-blinded RCT

2011–2012

Korea

NAFLD with type 2 DM

No

Carnitine-orotate complex (900 mg/day as carnitine-orotate)

Placebo

78

Treatment: 50.6 ± 9.3; Control: 52.0 ± 9.4

Treatment: 64.1; Control: 74.4

Treatment: 28.2 ± 2.6; Control: 26.7 ± 3.7

Treatment: 61.8 ± 25.5; Control: 51.7 ±22.1

Treatment: 94.9 ± 36.4; Control: 79.2 ± 27.2

Low

2000

Uygun A [26]

Open-label RCT

N/A

Turkey

NAFLD

N/A

Treatment A: l-carnitine 1 g/day; Treatment B: 2 g/day; Treatment C: 3 g/day

No l-carnitine

101

Treatment A: 43.4 ± 10.8; Treatment B: 42.5 ± 9.7; Treatment C: 40.0 ± 9.1; Control: 42.6 ± 7.3

Treatment A: 79.2; Treatment B: 61.5; Treatment C: 75.0; Control: 69.6

Treatment A: 4.4 ± 2.3; Treatment B: 26.2 ± 3.1; Treatment C: 25.4 ± 2.7; Control: 25.8 ± 2.5

Treatment A: 57.5 ± 3.9; Treatment B: 47.8 ± 2.1; Treatment C: 51.0 ± 6.3; Control: 46.3 ± 6.0

Treatment A: 72.3 ± 5.4; Treatment B: 71.5 ± 4.6; Treatment C: 75.1 ± 7.0; Control: 70.5 ± 7.3

High

2002

Malaguarnera M [27]

Open-label RCT

N/A

Italy

Chronic hepatitis C

No

L-carnitine 2 g/day

No L-carnitine

IFN-α 3 million IU three times a week

70

Treatment: 56.8 ± 7.2; Control: 57.7 ± 6.1

Treatment: 62.9; Control: 60.0

Treatment: 26 ± 1.9; Control: 26 ± 2.4

Treatment: 110 ± 86; Control: 114 ± 79

Treatment: 186 ± 99; Control: 163 ± 108

Unclear

2008

Malaguarnera M [28]

Double-blinded RCT

2000–2003

Italy

Minimal hepatic encephalopathy

No

Acetyl-L-carnitine 4 g/day

Placebo

115

Treatment: 48 ± 10; Control: 45 ± 11

Treatment: 55.0; Control: 63.6

Treatment: 24.8 ± 3.1; Control: 25.1 ± 3.3

Treatment: 68 ± 31; Control: 67 ± 32

Treatment: 71 ± 40; Control: 68 ± 44

Unclear

2008

Romano M [29]

Open-label RCT

2000–2003

Italy

Chronic hepatitis C

No

L-carnitine 2 g/day

No -carnitine

IFN-α 3 million IU three times a week + ribavirin 1000 mg

70

Treatment: 50.1 ± 6.1; Control: 50.4 ± 5.6

Treatment: 56.7; Control: 53.3

Treatment: 25.8 ± 3.1; Control: 25.7 ± 3.2

Treatment: 125.0 ± 46.2; Control: 116.0 ± 49.3

Treatment: 162.0 ± 49.2; Control: 156.0 ± 47.4

Unclear

2010

Malaguarnera M [30]

Double-blinded RCT

2004–2006

Italy

NASH

N/A

L-carnitine 2 g/day

Placebo

74

Treatment: 47.9 ± 5.4; Control: 47.8 ± 5.8

Treatment: 55.6; Control: 52.6

Treatment: 26.6 ± 3.7; Control: 26.5 ± 3.8

Treatment: 132.8 ± 14.7; Control: 135.4 ± 15.1

Treatment: 125.7 ± 12.9; Control: 120.2 ± 12.8

Unclear

2011

Malaguarnera M(Metab Brain Dis)a [31]

Double-blinded RCT

2002–2006

Italy

Severe hepatic encephalopathy

Yes

Acetyl-L-carnitine 4 g/day

Placebo

60

Treatment: range, 37–64; Control: range, 35–65

Treatment: 46.7; Control: 50.0

N/A

Treatment: 119.2 ± 13.1; Control: 114.2 ± 24.5

Treatment: 106.7 ± 15.7 b; Control: 136.3 ± 31.0

High

2011

Malaguarnera M(Scand J Gastroenterol)a [32]

Double-blinded RCT

2002–2005

Italy

Minimal hepatic encephalopathy

No

Acetyl-L-carnitine 4 g/day

Placebo

67

Treatment: range, 37–65; Control: range, 34–67

Treatment: 60.6; Control: 55.9

N/A

Treatment: 102.1 ± 15.2 b; Control: 80.4 ± 19.8

Treatment: 117.4 ± 16.0 b; Control: 90.2 ± 14.3

Unclear

2011

Malaguarnera M(World J Gastroenterol)a [33]

Open-label RCT

2004–2007

Italy

Chronic hepatitis C

No

L-carnitine 4 g/day

Placebo

Peg-IFN-α 2b 1.5 μg/kg/week + rivavirin 800–1200 mg/day (adjusted to body weight)

69

Treatment: 47.6 ± 4.9; Control: 47.1 ± 5.4

Treatment: 62.9; Control: 58.8

Treatment: 27.1 ± 3.1; Control: 27.4 ± 2.9

Treatment: 145.0 ± 44.2; Control: 136.0 ± 41.4

Treatment: 182.1 ± 46.2; Control: 174.1 ± 42.2

Unclear

2014

Somi MH [34]

Open-label RCT

2012–2014

Iran

NAFLD

No

L-carnitine 1 g/day

No L-carnitine

80

Treatment: 40.3 ± 7.8; Control: 41.1 ± 8.3

Treament: 82.5; Control: 82.5

Treatment: 29.4 ± 3.9; Control: 28.6 ± 3.2

Treatment: 60.5 ± 28.3; Control: 52.6 ± 24.4

Treatment: 81.7 ± 40.1 b; Control: 54.1 ± 17.6

High

2016

Alavinejad P [35]

Double-blinded RCT

N/A

Iran

NAFLD with type 2 DM

No

L-carnitine 2.25 g/day

Placebo

54

Treatment: 60 ± 5; Control: 59 ± 9

Treatment: 75.0; Control: 65.4

Treatment: 28.6 ± 4.6; Control: 29.5 ± 3.6

Treatment: 122.7 ± 13.6; Control: 125.3 ± 14.0

Treatment: 124.0 ± 11.3; Control: 120.0 ± 10.8

Unclear

Open in a new tab

a Parentheses indicate the journal in which the study was published. b There was a significant difference in baseline values between treatment and control groups. ALT, alanine aminotransferase; AST, aspartate aminotransferase; BDD, biphenyl dimethyl dicarboxylate; BMI, body mass index; DM, diabetes mellitus; DNA, deoxyribonucleic acid; IFN, interferon; IU, international unit; N/A, not available; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; RCT, randomized controlled trial; SD, standard deviation.

The risk of bias assessment is shown in Figure S1. Five (36%) patients had an unclear risk of bias in the domain of random sequence generation because random sequence generation methods were not clearly described in those studies. The other nine studies (64%) had a low risk of bias for random sequence generation. The risk of allocation concealment was unclear in 13 (93%) studies. All studies were assessed as having a low risk of performance and detection bias because the current study outcomes were less likely to be affected by participant and investigator blinding. Incomplete outcome data and selective reporting were not identified in any RCT. Four studies (27%) were assessed as having a high risk of other biases because baseline AST or ALT levels differed between the treatment and control groups despite randomization [26,31,32,34].

3.2. Impact of Carnitine-Orotate (or Carnitine-Orotate Complex) on ALT Normalization

The impact of carnitine-orotate (or carnitine-orotate complex) on ALT normalization is shown in Figure 2. In studies on carnitine-orotate, the proportion of patients with ALT normalization was higher in the treatment group versus that in the control group (pooled OR (95% CI) = 4.61 (1.48–14.39)). Heterogeneity was not identified (degrees of freedom (df) = 1, p = 0.16, I2 = 49%). In studies of the carnitine-orotate complex, the proportion of patients with ALT normalization was also higher in the treatment versus control group without significant heterogeneity (pooled OR (95% CI) = 18.88 (7.70–46.27); df = 1, p = 0.51, I2 = 0%).

3.2. 카르니틴-오로테이트(또는 카르니틴-오로테이트 복합체)의 ALT 정상화 영향

카르니틴-오로테이트(또는 카르니틴-오로테이트 복합체)의 ALT 정상화 영향은

그림 2에 표시되어 있습니다.

카르니틴-오로테이트에 대한 연구에서

ALT 정상화 환자의 비율은 치료군에서 대조군보다 높았습니다

(통합 오즈비 (95% 신뢰구간) = 4.61 (1.48–14.39)).

이질성은 확인되지 않았습니다(자유도 (df) = 1, p = 0.16, I2 = 49%).

카르니틴-오로테이트 복합체에 대한 연구에서

ALT 정상화 환자의 비율은 치료군에서 대조군보다 높았으며,

이질성은 유의미하지 않았습니다(풀링된 오즈비(95% 신뢰구간) = 18.88 (7.70–46.27); 자유도(df) = 1, p = 0.51, I2 = 0%).

Figure 2.

Open in a new tab

Forest plot of alanine aminotransferase normalization after carnitine-orotate (or carnitine-orotate complex) versus control treatment. The carnitine–orotate complex includes carnitine-orotate, BDD, and other minor supplementary compounds. The dosage of carnitine-orotate in the included studies in this analysis was 900 mg per day, which is the usual dosage for clinical purposes. * The values in this study were provided by the corresponding author. BDD, biphenyl dimethyl dicarboxylate; M-H, Mantel–Haenszel; CI, confidence interval; df, degrees of freedom.

Since two studies on carnitine-orotate analyzed the efficacy of different drug dosages (carnitine-orotate 900 mg vs. 600 mg), we further performed dosage subgroup analyses (Figure S2). When the usual dosage for clinical purposes (carnitine-orotate 900 mg) was used, it effectively normalized ALT levels, as described in the main results (Figure 2). However, the efficacy of lower-dosage carnitine-orotate (600 mg) was not identified in the subgroup analysis (pooled OR (95% CI) = 1.27 (0.66–2.44); df = 1, p = 0.72, I2 = 0%).

3.3. Impact of l-Carnitine (or Acetyl-l-Carnitine) Supplementation on Serum AST and ALT Levels

Since 10 studies on l-carnitine or acetyl-l-carnitine supplementation assessed and reported the main outcomes as continuous variables (i.e., serum AST and ALT levels), the mean difference in post-treatment AST or ALT levels between the treatment and control groups was analyzed (Figure 3). In a meta-analysis of post-treatment AST levels, l-carnitine or acetyl-l-carnitine supplementation effectively lowered serum AST levels compared to the control (pooled MD (95% CI) = −15.84 (−24.56 to −7.13)). The post-treatment serum ALT level was lower in the treatment group than in the control group (pooled MD (95% CI) = −11.99 (−22.48 to −1.49)). Significant heterogeneity was identified in both meta-analyses (AST level: df = 9, p < 0.01, I2 = 94%; ALT level: df = 9, p < 0.01, I2 = 96%). Egger’s test and the AS-Thompson test for publication bias found no significant asymmetry in the funnel plot and radial plot (p > 0.1) (Figure S3).

3.3. L-카르니틴(또는 아세틸-L-카르니틴) 보충제의 혈청 AST 및 ALT 수치에 미치는 영향

L-카르니틴 또는 아세틸-L-카르니틴 보충제에 대한 10개의 연구에서 주요

결과 변수를 연속 변수(즉, 혈청 AST 및 ALT 수치)로 평가하고 보고했기 때문에,

치료 후 AST 또는 ALT 수치의 평균 차이를 분석했습니다(그림 3).

치료 후 AST 수치에 대한 메타분석 결과,

L-카르니틴 또는 아세틸-L-카르니틴 보충은

대조군에 비해 혈청 AST 수치를 유의미하게 감소시켰습니다(통합 MD (95% CI) = −15.84 (−24.56 to −7.13)).

치료 후 혈청 ALT 수치는

치료군에서 대조군보다 낮았습니다(풀링된 MD (95% CI) = −11.99 (−22.48 to −1.49)).

두 메타분석 모두에서 유의미한 이질성이 확인되었습니다

(AST 수치: 자유도 = 9, p < 0.01, I2 = 94%; ALT 수치: 자유도 = 9, p < 0.01, I2 = 96%).

출판 편향에 대한 Egger의 검정과 AS-Thompson 검정은 깔때기 그림과 방사형 그림에서

유의미한 비대칭성을 발견하지 못했습니다 (p > 0.1) (그림 S3).

Figure 3.

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Forest plot of post-treatment serum AST and ALT levels after l-carnitine (or acetyl-l-carnitine) supplementation versus control treatment. Parentheses following the first author’s name indicate the journal in which the study was published. * Multiple doses were investigated in this study. Data from the maximal dosage group (3 g/day) were used in the analysis. ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; df, degrees of freedom; IV, inverse variance; SD, standard deviation.

3.4. Sensitivity Analysis

Two sensitivity analyses were performed. First, we performed a sensitivity analysis of l-carnitine or acetyl-l-carnitine supplementation on serum AST and ALT levels after excluding a study of patients with decompensated cirrhosis [31] (Figure S4). Post-treatment AST levels were also lower in the l-carnitine or acetyl-l-carnitine supplementation group than in the control group (pooled MD (95% CI) = −17.39 (26.90 to −7.88)). The post-treatment ALT levels tended to be lower in the treatment group than in the control group despite no significant difference (pooled MD (95% CI) = −10.25 (−21.60 to 1.10)). Second, in the sensitivity analysis, after the exclusion of four studies showing different baseline characteristics in AST or ALT levels [26,31,32,34] (Figure S5), post-treatment AST and ALT levels were also lower in the l-carnitine or acetyl-l-carnitine supplementation group than in the control group (pooled MD (95% CI): AST level, −25.77 (−32.92 to −18.62); ALT level, −17.14 (–27.89 to −6.38)). In jackknife sensitivity analyses (Figure S6), a significant study that affected the pooled meta-analysis results was not identified. These sensitivity analyses showed the robustness of our meta-analyses.

4. Discussion

The current meta-analysis found that carnitine-orotate and carnitine-orotate complexes taken at the usual dosage significantly affected ALT normalization in patients with chronic liver disease. We also showed that l-carnitine (or acetyl-l-carnitine) supplementation significantly decreased serum AST and ALT levels. Our findings suggest that l-carnitine and its derivatives have beneficial effects in normalizing liver enzymes in patients with chronic liver disease. The novelty of this study lies in the fact that we extracted and analyzed data from studies of patients with chronic liver disease and elevated liver enzyme levels. Previous meta-analyses suggested the efficacy of l-carnitine supplementation for reducing serum liver enzyme levels, similar to our study findings; however, some individual studies in the previous meta-analyses involved healthy volunteers or patients with liver enzyme elevations caused by reasons other than chronic liver disease [12,13]. In addition, clinically useful information can be provided through the analysis of carnitine-orotate complex containing other minor supplements that have not been previously analyzed.

AST and ALT are enzymes that transport the amino groups of aspartate and alanine to ketoglutaric acid. AST is present in the liver and other organs, including the muscle, while ALT is primarily present in the liver; thus, ALT is a more specific marker of hepatocellular injury than AST [36]. We adopted the odds ratio of the ALT normalization rate as an important analysis target. In real-world practice, clinicians aim to normalize ALT in patients with various chronic liver diseases to ensure a satisfactory prognosis [37,38,39,40,41]. In recent studies, elevated liver enzymes were associated with significantly increased liver-related mortality, and normal-range AST and ALT levels were associated with a lower risk of death [42,43]. Therefore, l-carnitine and its derivatives may help improve the prognosis of patients with chronic liver disease and elevated liver enzyme levels.

There are considerable limitations to the present study. First, there was substantial heterogeneity in the included studies, although the current meta-analysis had a limited study population of patients with chronic liver disease. Interstudy heterogeneity was observed due to various disease etiologies, including chronic viral hepatitis B, chronic viral hepatitis C, and non-alcoholic fatty liver disease, as well as different dosages and durations of l-carnitine supplementation. Therefore, further studies are needed to examine the time- and dose-dependent effects of l-carnitine supplementation. Second, it is also important to note that our study findings should not be generalized to patients worldwide since studies on carnitine-orotate were conducted only in Korea and studies on l-carnitine or acetyl-l-carnitine were conducted only in Italy and other countries. In Italy, the majority of studies were conducted by the same research group. In the future, it will be necessary to assess the efficacy of l-carnitine supplementation in various regions and races worldwide. Third, we should be careful when interpreting the effect size since medications other than l-carnitine (e.g., antiviral agents) were administered to the treatment and control groups in 6 of the 14 enrolled studies. Finally, the patient follow-up period of the studies included in this paper is relatively short, within one year. As mentioned above, the relationship between the improvement of ALT and the prognosis of the disease is emphasized, so long-term follow-up studies are needed in the future.

4. 논의

현재 메타분석 결과,

카르니틴-오로테이트 및 카르니틴-오로테이트 복합체를 일반 용량으로 투여한 경우

만성 간 질환 환자의 ALT 정상화에 유의미한 영향을 미쳤습니다.

또한

l-카르니틴(또는 아세틸-L-카르니틴) 보충이

혈청 AST 및 ALT 수치를 유의미하게 감소시켰습니다.

본 연구 결과는

L-카르니틴 및 그 유도체가 만성 간 질환 환자의

간 효소 정상화에 유익한 효과를 갖는다는 것을 시사합니다.

본 연구의 신규성은 만성 간 질환 및 간 효소 수치 상승 환자를 대상으로 한 연구에서 데이터를 추출 및 분석했다는 점에 있습니다. 이전 메타분석은 우리 연구 결과와 유사하게 L-카르니틴 보충이 혈청 간 효소 수치를 감소시키는 데 효과적임을 제시했습니다. 그러나 이전 메타분석의 일부 개별 연구는 건강한 자원자나 만성 간 질환 이외의 원인으로 간 효소 수치가 상승한 환자를 대상으로 진행되었습니다 [12,13]. 또한, 이전에 분석되지 않은 다른 미량 보충제를 포함한 카르니틴-오로테이트 복합체의 분석을 통해 임상적으로 유용한 정보를 제공할 수 있습니다.

AST와 ALT는

아스파르테이트와 알라닌의 아미노 그룹을

케토글루타르산으로 운반하는 효소입니다.

AST는

간과 근육 등 다른 장기에도 존재하지만,

ALT는 주로 간에 존재하므로

ALT는 AST보다 간세포 손상의 더 특이적인 지표입니다 [36].

우리는 ALT 정상화율의 오즈 비율을 중요한 분석 목표로 채택했습니다.

실제 임상 현장에서는

다양한 만성 간 질환 환자의 ALT를 정상화하여

만족스러운 예후를 확보하는 것을 목표로 합니다 [37,38,39,40,41].

최근 연구에서 간 효소 수치 상승은

간 관련 사망률의 유의미한 증가와 연관되었으며,

정상 범위 내 AST 및 ALT 수치는 사망 위험 감소와 연관되었습니다 [42,43].

따라서 L-카르니틴과 그 유도체는

만성 간 질환 및 간 효소 수치 상승 환자의 예후 개선에 도움을 줄 수 있습니다.

본 연구에는 상당한 한계가 있습니다.

첫째,

포함된 연구 간에 상당한 이질성이 존재했으며,

현재 메타분석은 만성 간 질환 환자의 제한된 연구 대상 인구로 진행되었습니다.

연구 간 이질성은

만성 B형 바이러스성 간염, 만성 C형 바이러스성 간염, 비알코올성 지방간 질환 등

다양한 질환의 원인, L-카르니틴 보충제의 용량 및 투여 기간 차이로 인해 관찰되었습니다.

따라서

L-카르니틴 보충제의 시간 의존적 및 용량 의존적 효과를 평가하기 위한

추가 연구가 필요합니다.

둘째,

본 연구 결과는 전 세계 환자에게 일반화할 수 없습니다.

왜냐하면

카르니틴-오로테이트에 대한 연구는 한국에서만 수행되었고,

L-카르니틴 또는 아세틸-L-카르니틴에 대한 연구는

이탈리아와 다른 국가에서만 수행되었기 때문입니다.

이탈리아에서는 대부분의 연구는 동일한 연구 그룹에 의해 수행되었습니다.

향후 전 세계 다양한 지역과 인종에서

L-카르니틴 보충제의 효능을 평가하는 것이 필요할 것입니다.

셋째,

L-카르니틴 이외의 약물 (예: 항바이러스제)가 투여되었습니다.

마지막으로,

본 논문에 포함된 연구의 환자 추적 관찰 기간은

1년 이내로 상대적으로 짧습니다.

위에서 언급된 대로 ALT 개선과 질병 예후 간의 관계가 강조되므로, 향후 장기 추적 관찰 연구가 필요합니다.

5. Conclusions

In conclusion, the pooled data from RCTs provide evidence of the beneficial effects of l-carnitine supplementation for lowering serum ALT and AST levels. Our findings also showed that carnitine-orotate can be effective in patients with chronic liver diseases with intervention doses of 900 mg/day for ALT normalization.

5. 결론

결론적으로,

무작위 대조 시험(RCT)의 통합 데이터는

L-카르니틴 보충이 혈청 ALT 및 AST 수치를 낮추는 데 유익한 효과를 제공한다는 증거를 제공합니다.

본 연구 결과는 또한

만성 간 질환 환자에게 900 mg/일 투여량으로 ALT 정상화를 위해

카르니틴-오로테이트가 효과적일 수 있음을 보여주었습니다.

Supplementary Materials

The following supporting information can be downloaded from https://www.mdpi.com/article/10.3390/jpm12071053/s1,: Figure S1. Traffic light plot for risk of bias in individual studies; Figure S2. Forest plot for ALT normalization between carnitine-orotate and control groups according to the dosage of carnitine-orotate (900 mg vs. 600 mg); Figure S3. Analysis of publication bias. Using Egger’s test (post-treatment AST level: p-value 0.2498, post-treatment ALT level: p-value 0.5642) and AS-Thompson’s test (post-treatment AST level: p-value 0.3925, post-treatment ALT level: p-value 0.675) for publication bias, no significant asymmetry is seen in the funnel plot and radial plot (p > 0.1) for pooled analysis of mean difference; Figure S4. Sensitivity analysis of l-carnitine (or acetyl-l-carnitine) supplementation for post-treatment ALT level after excluding a study involving patients with decompensated cirrhosis [31]; Figure S5. Sensitivity analysis of l-carnitine (or acetyl-l-carnitine) supplementation for post-treatment ALT level after the exclusion of four studies showing different baseline AST or ALT levels between treatment and control groups [26,31,32,34]; Figure S6. Sensitivity analysis of the effect of l-carnitine (or acetyl-l-carnitine) supplementation on post-treatment AST and ALT levels with jackknife sensitivity analysis showing the robustness of meta-analysis.

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Author Contributions

Conceptualization, D.W.J.; methodology, C.H.P.; formal analysis, C.H.P.; investigation, H.O. and C.H.P.; data curation, H.O. and C.H.P.; writing—original draft preparation, H.O. and C.H.P.; writing—review and editing, H.O., C.H.P. and D.W.J.; visualization, C.H.P.; supervision, D.W.J.; project administration, D.W.J. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Ethical review and approval were waived for this study because it was a meta-analysis based on previously published studies.

Informed Consent Statement

Not applicable.

Data Availability Statement

All relevant data are included in the study and supplementary information.

Conflicts of Interest

The authors declare no conflict of interest.

Funding Statement

This study was supported by a research grant from Celltrion Pharm Inc., Incheon 21975, Korea (Grant number CTP-GOD 4.10).

Footnotes

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References

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