Transarterial chemoembolization (TACE) is usually followed by hepatic dysfunction. We evaluated the effects of L-carnitine on post-TACE impaired liver functions.
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third most common cause of cancer-related deaths [
Intermediate-stage HCC is defined as an extensive multifocal disease without vascular invasion in patients with preserved liver functions and absence of cancer-related symptoms. Transarterial chemoembolization (TACE) is considered the standard treatment for intermediate-stage HCC [
Hepatic failure after TACE is expected even in patients with relatively good hepatic reserve, significantly impairing the outcome of TACE, including patient survival [
L-carnitine (4-
The protective role of L-carnitine against hepatotoxicity has been proposed in many studies [
Branched-chain amino acids (BCAA) are essential amino acids and include L-valine, L-leucine, and L-isoleucine. Several studies demonstrated that BCAA nutritional therapy decreased the risk of hepatic failure and improved general outcome in HCC patients undergoing variable treatment options [
In this study, we examined the protective effects of L-carnitine regarding liver dysfunction after TACE in intermediate-stage HCC patients when administered alone or in combination with BCAA.
The study included 53 HCC patients who underwent TACE between December 2012 and November 2013 at Osaka Medical College Hospital. All patients provided written informed consent to participate in the study. Study protocol conformed to the ethical guidelines of the Declaration of Helsinki (1975) and was approved by the Osaka Medical College ethical review committee. All patients were Japanese and had liver cirrhosis diagnosed by abdominal ultrasound and liver functions tests. HCC diagnosis was based on data obtained by contrast-enhanced computed tomography and hepatic-artery angiography. No patients had vessel invasion at the time of study enrollment, and none had been prescribed L-carnitine supplements before enrollment to the study.
The study was prospective, and the patients were randomly assigned into two groups; the L-carnitine group included twenty-seven consecutive HCC patients who received a 300 mg tablet of L-carnitine twice daily starting from 2 weeks before TACE to week 12 after TACE. The control group included 26 consecutive HCC patients who did not receive L-carnitine supplementation. Thirty-one of the study patients had already been supplemented by late evening snacks of BCAA granules (LIVACT granules containing L-isoleucine 952 mg, L-leucine 1,904 mg, and L-valine 1,144 mg) prior to enrolment in this study and continued throughout study duration (we identified these patients as BCAA+ patients) while 22 patients did not receive BCAA granules (identified as BCAA−).
All patients were followed up in Osaka Medical College Hospital including clinical follow-up and laboratory measurements. The primary end point was improvement in Child-Pugh (CP) score and serum albumin. The secondary end point included improvement in other liver functions.
TACE for HCC was performed in conformity with Japanese guidelines by catheterization via femoral artery with superselective cannulation to the HCC hepatic feeding artery [
Laboratory measurements were performed 2 weeks before and 1, 4, and 12 weeks after TACE. Ascites was diagnosed by computed tomography or ultrasound. Laboratory measurements included serum albumin, total bilirubin, prothrombin time (PT), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGTP), and aspartate aminotransferase (AST) in addition to calculation of CP scores.
Data were analyzed using SPSS version 22. Differences in laboratory data between study groups and differences within groups were analyzed using the Mann-Whitney
A total of 53 patients with HCC were enrolled in the current study. Three patients were withdrawn from the study because of non-liver-related deaths. There were no statistically significant differences between the two groups regarding demographic characteristics, tumor staging, and anticancer drugs used during TACE and baseline laboratory tests (Table
Baseline clinical and laboratory data.
Parameter (mean ± SD) | L-carnitine group ( |
Control group ( |
|
---|---|---|---|
Sex (male/female) | 17/7 | 21/5 | 0.5 |
Age | 71.6 ± 7.6 | 72.3 ± 6.8 | 0.7 |
CP score | 6.04 ± 1.04 | 5.88 ± 0.99 | 0.4 |
Stage (2/3/4) | 7/15/2 | 9/15/2 | 0.9 |
Drug (cisplatin/others) | 18/6 | 21/5 | 0.3 |
BCAA (yes/no) | 16/8 | 12/14 | 0.1 |
S. albumin (g/dL) | 3.22 ± 0.57 | 3.35 ± 0.56 | 0.2 |
PT (%) | 86.7 ± 19.4 | 89.2 ± 17 | 0.5 |
T. bilirubin (mg/dL) | 1.02 ± 0.57 | 0.93 ± 0.46 | 0.4 |
ALT (U/L) | 32.6 ± 17.6 | 41.8 ± 28.8 | 0.3 |
AST (U/L) | 51.5 ± 25.9 | 57 ± 37.8 | 0.7 |
GGTP (U/L) | 70.7 ± 80.9 | 66.3 ± 67.3 | 0.8 |
Ascites (no/moderate/massive) | 21/3/0 | 21/5/0 | 0.2 |
Encephalopathy (yes/no) | 24/0 | 26/0 | 0.6 |
SD: standard deviation; CP: Child-Pugh; BCAA: branched-chain amino acids; S. albumin: serum albumin; PT: prothrombin time; T. bilirubin: total bilirubin; ALT: alanine aminotransferase; AST: aspartate aminotransferase; GGTP: gamma-glutamyl transpeptidase.
In the L-carnitine group in this study, CP scores showed a nonsignificant deterioration at 1 week after TACE. CP scores showed significant improvement at 4 weeks after TACE (
Effects of L-carnitine in overall study patients.
Parameter (mean ± SD) | Pretreatment | After TACE | |||
---|---|---|---|---|---|
1 week | 4 weeks | 12 weeks | |||
Control group ( |
CP score | 5.88 ± 0.99 | 6.24 ± 1.05 |
6.04 ± 1.07 | 6.39 ± 1.55 |
S. albumin (g/dL) | 3.35 ± 0.56 | 2.94 ± 0.57 |
3.29 ± 0.58 |
3.21 ± 0.63 | |
PT (%) | 89.2 ± 17 | 85.9 ± 16.9 |
88.2 ± 17.7 | 87.1 ± 18.2 | |
T. bilirubin (mg/dL) | 0.93 ± 0.46 | 1.13 ± 0.51 |
0.96 ± 0.55 |
1.21 ± 0.7 | |
ALT (IU/L) | 41.8 ± 28.8 | 56.2 ± 31 |
38.7 ± 21.1 |
37.6 ± 18.8 | |
AST (IU/L) | 57 ± 37.8 | 50.8 ± 26.5 | 55.3 ± 31.6 | 60.3 ± 44.3 | |
GGTP (IU/L) | 66.3 ± 67.3 | 84.5 ± 100.3 |
91.8 ± 84.7 |
59.9 ± 74.7 | |
Ascitis (no/moderate/massive) | 21/5/0 | 20/5/1 | 19/5/2 | 17/5/4 | |
Encephalopathy (no/yes) | 26/0 | 26/0 | 26/0 | 26/0 | |
|
|||||
L-carnitine group ( |
CP score | 6.04 ± 1.04 | 6.17 ± 0.86 | 5.75 ± 0.73 |
5.91 ± 0.92 |
S. albumin (g/dL) | 3.22 ± 0.57 | 3.05 ± 0.46 |
3.33 ± 0.5 |
3.26 ± 0.49 | |
PT (%) | 86.7 ± 19.4 | 91.5 ± 18.4 | 93.3 ± 16.8 |
90.7 ± 16.4 | |
T. bilirubin (mg/dL) | 1.02 ± 0.57 | 0.97 ± 0.55 | 0.93 ± 0.46 | 1.05 ± 0.63 | |
ALT (IU/L) | 32.6 ± 17.6 | 41.7 ± 23.1 |
34.7 ± 20.8 | 33.9 ± 11.6 | |
AST (IU/L) | 51.5 ± 25.9 | 50.2 ± 32.1 | 54.5 ± 28 | 49.4 ± 15.6 | |
GGTP (IU/L) | 70.7 ± 80.9 | 91.4 ± 124.4 | 97.1 ± 148.6 | 61.8 ± 43.4 | |
Ascitis (no/moderate/massive) | 21/3/0 | 22/2/0 | 24/0/0 | 23/0/1 | |
Encephalopathy (no/yes) | 24/0 | 24/0 | 24/0 | 24/0 |
SD: standard deviation; CP: Child-Pugh; S. albumin: serum albumin; PT: prothrombin time; T. bilirubin: total bilirubin; ALT: alanine aminotransferase; AST: aspartate aminotransferase; GGTP: gamma-glutamyl transpeptidase.
L-carnitine effects on CP score and serum albumin. (a) L-carnitine effects on mean CP score changes from baseline in study patients overall. (b) L-carnitine effects on mean CP score changes from baseline in BCAA+ patients. (c) L-carnitine effects on mean serum albumin changes from baseline in study patients overall. (d) L-carnitine effects on mean serum albumin changes from baseline in BCAA+ patients. CP: Child-Pugh; TACE: transarterial chemoembolization. Error bars represent standard errors.
To investigate the combined effects of BCAA granules and L-carnitine, we evaluated BCAA+ and BCAA− patients. L-carnitine group in BCAA+ patients achieved significant CP score improvement from week 1 to week 4 after TACE (
Effects of L-carnitine in BCAA+ patients.
Parameter (mean ± SD) | Pretreatment | After TACE | |||
---|---|---|---|---|---|
1 week | 4 weeks | 12 weeks | |||
Control group ( |
CP score | 6 ± 1.04 | 6.5 ± 1.16 | 6.25 ± 1.28 | 6.64 ± 1.69 |
S. albumin (g/dL) | 3.25 ± 0.52 | 2.81 ± 0.55 |
3.25 ± 0.51 |
3.01 ± 0.52 | |
PT (%) | 87.4 ± 17.3 | 83.4 ± 19.1 |
88.4 ± 18.3 | 83.6 ± 19.8 | |
T. bilirubin (mg/dL) | 1.1 ± 0.58 | 1.2 ± 0.55 | 1.05 ± 0.63 | 1.41 ± 0.63 | |
ALT (IU/L) | 43.5 ± 19.3 | 56.5 ± 26.6 | 42.9 ± 19.8 | 38.4 ± 11.4 | |
AST (IU/L) | 52.4 ± 20.4 | 45.8 ± 9 | 50 ± 21 | 52.7 ± 21.1 | |
GGTP (IU/L) | 80.4 ± 93.9 | 104.3 ± 140.5 | 116.3 ± 120 |
43.9 ± 32.3 | |
Ascitis (no/moderate/massive) | 8/4/0 | 8/3/1 | 6/4/2 | 6/4/2 | |
Encephalopathy (no/yes) | 12/0 | 12/0 | 12/0 | 12/0 | |
|
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L-carnitine group ( |
CP score | 6.25 ± 1.6 | 6.38 ± 0.88 | 5.88 ± 0.8 |
5.93 ± 0.99 |
S. albumin (g/dL) | 3.13 ± 0.61 | 2.97 ± 0.42 | 3.25 ± 0.56 |
3.16 ± 0.49 | |
PT (%) | 87.2 ± 20.7 | 92.3 ± 16.1 | 94.1 ± 18.2 | 91.6 ± 14.2 | |
T. Bilirubin (mg/dL) | 1.01 ± 0.62 | 1.02 ± 0.62 | 0.95 ± 0.53 | 1.1 ± 0.78 | |
ALT (IU/L) | 32.2 ± 12.5 | 42.7 ± 22.6 | 30.6 ± 8.3 | 36.1 ± 11 | |
AST (IU/L) | 51.7 ± 25.3 | 51.2 ± 31.9 | 51.3 ± 18.7 | 53.5 ± 16.8 | |
GGTP (IU/L) | 62 ± 53.7 | 72.8 ± 56.6 | 70.6 ± 36.8 | 60.4 ± 38.5 | |
Ascitis (no/moderate/massive) | 14/2/0 | 14/2/0 | 16/0/0 | 15/0/1 | |
Encephalopathy (no/yes) | 16/0 | 16/0 | 16/0 | 16/0 |
SD: standard deviation; CP: Child-Pugh; S. albumin: serum albumin; PT: prothrombin time; T. bilirubin: total bilirubin; ALT: alanine aminotransferase; AST: aspartate aminotransferase; GGTP: gamma-glutamyl transpeptidase; TACE: transarterial chemoembolization.
Effects of L-carnitine in BCAA− patients.
Parameter (mean ± SD) | Pretreatment | After TACE | |||
---|---|---|---|---|---|
1 week | 4 weeks | 12 weeks | |||
Control group ( |
CP score | 5.79 ± 0.97 | 6 ± 0.91 | 5.86 ± 0.86 | 6.17 ± 1.46 |
S. albumin (g/dL) | 3.42 ± 0.6 | 3.06 ± 0.59 |
3.32 ± 0.66 |
3.37 ± 0.6 | |
PT (%) | 90.8 ± 17.3 | 88.3 ± 15.1 | 88 ± 17.9 | 90.4 ± 16.9 | |
T. bilirubin (mg/dL) | 0.78 ± 0.29 | 1.06 ± 0.49 |
0.89 ± 0.48 | 1.05 ± 0.74 | |
ALT (IU/L) | 40.3 ± 35 | 55.9 ± 35 | 35.1 ± 22 | 36.9 ± 24 | |
AST (IU/L) | 60.9 ± 48 | 55.3 ± 35 | 59.7 ± 38 | 67.3 ± 58 | |
GGTP (IU/L) | 54.2 ± 30 | 66.3 ± 35 | 72.6 ± 35 |
74.5 ± 98 | |
Ascitis (no/moderate/massive) | 13/1/0 | 12/2/0 | 13/1/0 | 11/1/2 | |
Encephalopathy (no/yes) | 14/0 | 14/0 | 14/0 | 14/0 | |
|
|||||
L-carnitine group ( |
CP score | 5.63 ± 0.91 | 5.75 ± 0.7 | 5.5 ± 0.53 | 5.88 ± 0.83 |
S. albumin (g/dL) | 3.38 ± 0.47 | 3.22 ± 0.52 | 3.5 ± 0.54 | 3.45 ± 0.48 | |
PT (%) | 85.6 ± 17.7 | 89.7 ± 24.3 | 91.8 ± 14.8 | 89.2 ± 20.6 | |
T. bilirubin (mg/dL) | 1.05 ± 0.48 | 0.87 ± 0.42 | 0.9 ± 0.34 | 0.97 ± 0.24 | |
ALT (IU/L) | 33.5 ± 26.1 | 39.8 ± 25.7 | 43 ± 34.1 | 30 ± 12.3 | |
AST (IU/L) | 51.1 ± 28.7 | 48.1 ± 34.6 | 61.1 ± 41.9 | 42.1 ± 10.4 | |
GGPT (IU/L) | 88.1 ± 121 | 128.6 ± 204 | 150.1 ± 254 | 64.3 ± 53 | |
Ascitis (no/moderate/massive) | 7/1/0 | 8/0/0 | 8/0/0 | 8/0/0 | |
Encephalopathy (no/yes) | 8/0 | 8/0 | 8/0 | 8/0 |
SD: standard deviation; CP: Child-Pugh; S. albumin: serum albumin; PT: prothrombin time; T. bilirubin: total bilirubin; ALT: alanine aminotransferase; AST: aspartate aminotransferase; GGTP: gamma-glutamyl transpeptidase; TACE: transarterial chemoembolization.
In the L-carnitine group, serum albumin had significantly decreased by the first week after TACE (
Nevertheless, in the control group, serum albumin had significantly decreased by the first week after TACE (
At 4 and 12 weeks following TACE, the L-carnitine group in BCAA+ patients had serum albumin levels higher than baseline values. Conversely, in the control group, serum albumin levels had significantly declined at 1 week after TACE (
In the L-carnitine group, PT was elevated at week 1 after TACE and significantly higher than baseline at week 4 after TACE (
L-carnitine effects on PT and total bilirubin. (a) L-carnitine effects on mean PT changes from baseline in study patients overall. (b) L-carnitine effects on mean PT changes from baseline in BCAA+ patients. (c) L-carnitine effects on mean total bilirubin changes from baseline in study patients overall. (d) L-carnitine effects on mean total bilirubin changes from baseline in BCAA− patients. Footnote: PT: prothrombin time; TACE: transarterial chemoembolization. Error bars represent standard errors.
At 1, 4, and 12 weeks after TACE, L-carnitine group of BCAA+ patients reported higher PT values compared with baseline. Conversely, the control group demonstrated a significant PT decline at 1 week after TACE (
The current study demonstrated that L-carnitine prevented total bilirubin elevation at 1 week after TACE; total bilirubin at 12 weeks after TACE showed nonsignificant elevation over baseline values (Table
In BCAA+ patients, we observed no significant differences between L-carnitine and control groups (Table
A week after TACE, the control group demonstrated a significant rise in ALT (
The protective effects of L-carnitine in preventing occurrence and deterioration of ascites were shown at follow-up of study patients. In L-carnitine group, the number of ascites patients was fewer than baseline at 1 week after TACE and no ascites was detected at 4 weeks after TACE. On the contrary, the number of ascites patients in control group elevated at all follow-up periods with increased observation of massive ascites (Table
Similar results were shown in L-carnitine and control groups in both BCAA+ patients and BCAA− patients (Tables
In this study, none of study patients developed hepatic encephalopathy after TACE.
The previously mentioned follow-up results of CP score, serum albumin, and PT demonstrated the additive beneficial effects of combining BCAA and L-carnitine. Patients who received combination of L-carnitine and BCAA achieved better post-TACE liver functions compared to patients who received monotherapy of BCAA or L-carnitine (Tables
Subgroup analysis of data obtained from BCAA+ and BCAA− patients in the current study irrespective of L-carnitine therapy revealed that BCAA+ patients achieved improvement of CP score at 4 weeks after TACE compared to baseline and significant improvement compared to 1 week after TACE (
Subgroup analysis in BCAA+ and BCAA− patients.
Parameter (mean ± SD) | Pretreatment | After TACE | |||
---|---|---|---|---|---|
1 week | 4 weeks | 12 weeks | |||
BCAA+ ( |
CP score | 6.14 ± 1.04 | 6.43 ± 0.99 | 6.04 ± 1.03 |
6.24 ± 1.36 |
S. albumin (g/dL) | 3.18 ± 0.56 | 2.90 ± 0.48 |
3.25 ± 0.53 |
3.10 ± 0.49 | |
PT (%) | 87.32 ± 18.99 | 88.50 ± 17.69 | 91.59 ± 18.19 | 88.13 ± 16.96 | |
T. bilirubin (mg/dL) | 1.05 ± 0.59 | 1.10 ± 0.58 | 1.00 ± 0.56 | 1.22 ± 0.72 | |
ALT (IU/L) | 37.07 ± 16.50 | 48.68 ± 24.95 |
35.89 ± 15.43 |
37.16 ± 11.05 | |
AST (IU/L) | 52.04 ± 22.97 | 48.93 ± 24.65 | 50.79 ± 19.39 | 53.20 ± 18.43 | |
GGTP (IU/L) | 69.89 ± 72.74 | 86.36 ± 100.41 |
89.26 ± 82.77 | 53.16 ± 36.19 | |
|
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BCAA− group ( |
CP score | 5.73 ± 0.93 | 5.90 ± 0.83 | 5.73 ± 0.76 | 6.05 ± 1.23 |
S. albumin (g/dL) | 3.41 ± 0.55 | 3.12 ± 0.56 |
3.38 ± 0.61 |
3.40 ± 0.60 | |
PT (%) | 88.9 ± 17.2 | 88.8 ± 18.2 | 89.5 ± 16.5 | 89.9 ± 18.0 | |
T. bilirubin (mg/dL) | 0.88 ± 0.38 | 0.99 ± 0.46 | 0.89 ± 0.43 | 1.02 ± 0.58 | |
ALT (IU/L) | 37.86 ± 32.04 | 49.81 ± 32.60 | 38.00 ± 26.65 | 34.15 ± 20.24 | |
AST (IU/L) | 57.36 ± 42.03 | 52.62 ± 34.73 | 60.27 ± 38.91 | 57.25 ± 46.66 | |
GGTP (IU/L) | 66.59 ± 76.06 | 90.05 ± 127.71 | 100.82 ± 154.50 | 70.50 ± 82.04 |
SD: standard deviation; CP: Child-Pugh; S. albumin: serum albumin; PT: prothrombin time; T. bilirubin: total bilirubin; ALT: alanine aminotransferase; AST: aspartate aminotransferase; GGTP: gamma-glutamyl transpeptidase; TACE: transarterial chemoembolization.
BCAA+ patients achieved significant improvement of serum albumin at 4 and 12 weeks after TACE (
Moreover, patients who did not receive L-carnitine or BCAA showed highly significant deterioration of serum albumin at 1 week after TACE compared to baseline (
Total bilirubin showed significant elevation at 1 week after TACE compared to baseline in patients who received neither BCAA nor L-carnitine therapy while no significant elevation was reported in patients who received BCAA (Tables
Hepatic failure after TACE is expected and is proportional to pre-TACE synthetic liver functions status [
The present study reported very beneficial effects of L-carnitine on CP score showing a significant improvement at 4 and 12 weeks following TACE. These effects may be attributed to the combination of the favorable L-carnitine effects on serum albumin, PT, total bilirubin, and ascites. As regards ascites, better results were observed in L-carnitine group compared to control group that may be justified by less deteriorated serum albumin profile after TACE with L-carnitine intake.
L-carnitine plays an important role in energy production by transporting long-chain fatty acids across mitochondrial membranes in skeletal muscles [
In a similar fashion, Malaguarnera and his colleagues, in a study evaluating L-carnitine as an adjuvant therapy for interferon plus ribavirin-treated HCV patients, demonstrated that L-carnitine inhibited serum albumin decline at the end of treatment course [
L-carnitine in this study had improved PT at all follow-up intervals. These finding are in concordance with the effects of L-carnitine on PT reported in children with acute lymphoblastic leukemia receiving chemotherapy [
The favorable effects of L-carnitine on PT and total bilirubin may be due to its ability to relieve hepatic oxidative stress [
HCC patients undergoing variable treatment options earned many benefits from BCAA oral therapy [
In our study, L-carnitine combination with BCAA revealed more pronounced effects on CP scores, serum albumin, and PT than observed effects in BCAA− patients. We found no available data of previous studies evaluating BCAA and L-carnitine combination therapy. This study is also the first report of the combination effect of L-carnitine and BCAA on liver functions.
On the other hand, comparison between BCAA+ and BCAA− patients regardless of L-carnitine therapy revealed lesser post-TACE deterioration of CP score, serum albumin, and liver enzymes in BCAA+ patients.
The beneficial effects of BCAA therapy without L-carnitine intake were more cleared up in the present study by analyzing data obtained from patients who received neither BCAA nor L-carnitine compared to patients who received BCAA alone. These data demonstrated favorable effects of BCAA on serum albumin, PT, and total bilirubin.
There were no adverse effects by L-carnitine intake in any of study patients.
This study has the following limitations: (1) The relatively small number of patients may inflate the beneficial effects of L-carnitine on liver functions after TACE. (2) Oral administration may decrease the L-carnitine efficacy as it has low oral bioavailability and poor absorption in cirrhotic patients. Parenteral administration is more effective but decreases patient tolerability.
In conclusion, L-carnitine maintained and improved liver functions following TACE. The hepatoprotective effects of L-carnitine in this study were enhanced by BCAA granules combination. L-carnitine and BCAA combination therapy may be offered as a new liver support tool in patients with HCC.
The authors declare that there is no conflict of interests regarding the publication of this paper.
The corresponding author was supported by a scholarship from the Egyptian government “Joint supervision scholarship.”