hepatocellular carcinoma ( hcc ) is the fifth most common cancer worldwide and the third most common cause of cancer - related deaths . furthermore , hcc is currently the leading cause of death among patients with liver cirrhosis . 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 [ 4 , 5 ] . the maintenance of hepatic functional reserve is a major concern in patients with hcc who , in general , are treated repeatedly with tace . l - carnitine ( 4-n - trimethyl ammonium 3-hydroxybutyric acid ) is a conditionally essential amino acid synthesized from essential amino acids methionine and lysine in human liver , kidneys , and brain but principally obtained from diet . l - carnitine functions by transferring long - chain fatty acids across the mitochondrial membrane , enabling the oxidative release of energy . l - carnitine deficiency is associated with liver cirrhosis because of limited dietary intake , absorption , and endogenous hepatic synthesis . the protective role of l - carnitine against hepatotoxicity has been proposed in many studies [ 1012 ] . oral l - carnitine supplementation improved liver functions and histological patterns in patients with nonalcoholic steatohepatitis ( nash ) . cirrhotic patients with minimal hepatic encephalopathy achieved improved quality of life with l - carnitine supplementation . l - carnitine was an effective adjuvant to interferon and ribavirin in patients with chronic hepatitis c viral infection ( hcv ) . 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 . 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 . tace for hcc was performed in conformity with japanese guidelines by catheterization via femoral artery with superselective cannulation to the hcc hepatic feeding artery . the infused agent was an emulsion of 50  mg of cisplatin ( ia - call , nihon - kayaku ) or 50  mg of farmorubicin ( epirubicin hydrochloride , pfizer ) or other anticancer agents and 5  ml of lipiodol ( iodine addition products of ethyl esters of fatty acids obtained from poppy seed oil ; mitsui , japan ) . laboratory measurements were performed 2 weeks before and 1 , 4 , and 12 weeks after tace . 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 . differences in laboratory data between study groups and differences within groups were analyzed using the mann - whitney u test and the t - test . 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 1 ) . similarly , no such differences were observed between l - carnitine and control groups in bcaa+ patients and bcaa patients . in the l - carnitine group in this study , cp scores showed significant improvement at 4 weeks after tace ( p < 0.01 compared with 1 week after tace scores ) ; cp scores at 4 and 12 weeks after tace were better than baseline scores ( table 2 ) . in contrast , the control group experienced a significant deterioration in cp scores at 1 week after tace ( p < 0.05 compared to baseline ) , reaching cp scores at 4 weeks after tace worse than at baseline ; cp scores at 12 weeks after tace were significantly worse than baseline scores ( p < 0.05 ) ( table 2 ) . there were significant differences between the l - carnitine and control groups in cp score mean changes from baseline to 4 and 12 weeks after tace ( p < 0.05 ) ( figure 1(a ) ) . 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 ( p < 0.05 ) ( table 3 ) . there were significant differences between the l - carnitine and control groups in mean cp score changes from baseline to 4 weeks after tace ( p < 0.05 ) and 12 weeks after tace ( p < 0.05 ) ( figure 1(b ) ) . l - carnitine group of bcaa patients showed no significant changes in cp scores ( table 4 ) . comparison between the l - carnitine and the control groups revealed no significant differences in bcaa patients . in the l - carnitine group , serum albumin had significantly decreased by the first week after tace ( p < 0.05 ) ; serum albumin had significantly improved at 4 weeks after tace ( p < 0.05 compared to baseline and p < 0.01 compared to week 1 after tace ) . moreover , serum albumin at 12 weeks after tace was higher than baseline and significantly higher than albumin level at 1 week after tace ( p < 0.05 ) ( table 2 ) . nevertheless , in the control group , serum albumin had significantly decreased by the first week after tace ( p < 0.01 ) ; serum albumin was kept at levels lower than baseline at 4 weeks and 12 weeks after tace ( table 2 ) . comparison between the l - carnitine and control groups regarding the means of serum albumin changes from baseline to 1 week and 4 weeks after tace displayed significant differences ( p < 0.05 ) ( figure 1(c ) ) . 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 ( p < 0.01 ) ; serum albumin levels at 12 weeks after tace were lower than at baseline ( table 3 ) . there were significant differences between the l - carnitine and control groups in mean serum albumin decline from baseline to 1 week after tace ( p < 0.05 ) ( figure 1(d ) ) . in bcaa patients , serum albumin at 1 week after tace showed a significant decline from baseline in the control group ( p < 0.01 ) ( table 4 ) . however , no significant differences were observed between the l - carnitine and control groups . in the l - carnitine group , pt was elevated at week 1 after tace and significantly higher than baseline at week 4 after tace ( p < 0.05 ) . l - carnitine maintained better pt values at week 12 after tace compared with baseline values ( table 2 ) . conversely , the control group displayed a significant pt decline at week 1 following tace ( p < 0.05 ) ( table 2 ) . there were significant differences between the l - carnitine and control groups in mean pt changes from baseline to 1 week after tace ( p < 0.05 ) and 4 weeks after tace ( p < 0.05 ) ( figure 2(a ) ) . 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 ( p < 0.05 ) ; pt values at 12 weeks after tace were lower than baseline values ( table 3 ) . there were also significant differences between the l - carnitine and control groups in pt mean changes from baseline to 1 week after tace ( p < 0.05 ) ( figure 2(b ) ) . in bcaa patients , l - carnitine maintained pt values higher than at baseline at all follow - up intervals ( table 4 ) , but there were no significant differences between the groups . 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 2 ) . on the contrary , the control group exhibited total bilirubin levels significantly higher than baseline at the first week after tace ( p < 0.01 ) . furthermore , total bilirubin at week 12 after tace was significantly higher than at baseline ( p < 0.05 ) and at 4 weeks after tace ( p < 0.05 ) ( table 2 ) . a comparison between the l - carnitine and control groups revealed significant differences in mean total bilirubin changes from baseline to 1 week after tace ( p < 0.05 ) ( figure 2(c ) ) . in bcaa+ patients , we observed no significant differences between l - carnitine and control groups ( table 3 ) . in bcaa patients , l - carnitine maintained total bilirubin at levels lower than baseline level at 1 , 4 , and 12 weeks after tace ; on the contrary , total bilirubin levels at week 1 after tace were significantly higher than baseline level in the control group ( p < 0.05 ) ( table 4 ) . comparison between the l - carnitine and control groups revealed significant differences in mean total bilirubin changes from baseline to 1 week after tace ( p < 0.01 ) ( figure 2(d ) ) . a week after tace , however , l - carnitine limited alt elevation at 1 week following tace ( table 2 ) . in the control group , ggtp levels were significantly higher than baseline levels at week 1 ( p < 0.05 ) and week 4 after tace ( p < 0.01 ) ( table 2 ) . conversely , in the l - carnitine group , elevated ggtp levels did not differ significantly from baseline levels ( table 2 ) . there were no significant changes in ast patterns in this study ( table 2 ) . in the control group of bcaa+ and bcaa patients , ggtp levels were significantly higher than baseline levels at week 4 after tace ( p < 0.01 ) ; l - carnitine did not affect alt and ast patterns in both bcaa+ and bcaa patients ( tables 3 and 4 ) . 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 2 ) . similar results were shown in l - carnitine and control groups in both bcaa+ patients and bcaa patients ( tables 3 and 4 ) . in this study , 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 3 and 4 ) . 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 ( p < 0.05 ) , while no significant improvement was observed in bcaa patients ( table 5 ) . bcaa+ patients achieved significant improvement of serum albumin at 4 and 12 weeks after tace ( p < 0.001 and p < 0.05 , resp . , compared to 1 week after tace ) . on the other hand , less significant improvement of serum albumin was shown in bcaa patients at 4 and 12 weeks after tace ( p < 0.01and p < 0.05 , resp . , compared to 1 week after tace ) ( table 5 ) . 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 ( p < 0.001 ) and showed pt deterioration at 4 weeks after tace compared to baseline and 1 week after tace ( table 4 ) . conversely , patients who received bcaa alone achieved less significant deterioration of serum albumin at 1 week after tace ( p < 0.01 ) and accomplished pt improvement at 4 weeks after tace compared to baseline and 1 week after tace ( table 3 ) . 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 4 and 3 ) . hepatic failure after tace is expected and is proportional to pre - tace synthetic liver functions status . in this study , l - carnitine exhibited hepatoprotective effects following tace evinced by accomplishing improved cp scores and preventing deterioration of serum albumin , total bilirubin , and pt . to the best of our knowledge , this is the first study evaluating the effects of l - carnitine on liver functions following tace . the current study clarified early and late post - tace improvement in liver functions by l - carnitine therapy . 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 . this l - carnitine deficiency inhibits fatty acid mobilization and hence oxidation for energy in skeletal muscles ; skeletal muscles are presumed to utilize bcaa as a substitute for fatty acids to produce energy . bcaa usage as energy source in skeletal muscles adds an additional burden to cirrhotic patients , rendering them more albumin deficient . l - carnitine supplementations correct l - carnitine deficiency ; thus , it may preserve bcaa for albumin synthesis and improve serum albumin profiles . in the current study , l - carnitine suppressed early deterioration of serum albumin and maintained its levels better than at baseline . 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 . conversely , there was no significant effect of l - carnitine supplementation for 6 months on serum albumin levels in nash patients . mean baseline serum albumin levels in l - carnitine - supplemented nash patients ( 4.7  0.5  g / dl ) were optimal and much better than mean baseline levels in l - carnitine - supplemented cirrhotic patients in our study ( 3.2  0.5  g / dl ) ; that difference may explain why l - carnitine had no effects on serum albumin levels in patients with nash . 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 . in addition , l - carnitine improved total bilirubin profiles , resembling the observed effect of l - carnitine on total bilirubin in hepatic encephalopathy patients . conversely , l - carnitine showed no effects on total bilirubin in interferon plus ribavirin - treated patients with hcv . this controversy may be due to long duration of follow - up for hcv patients as total bilirubin was evaluated at 12 months after treatment initiation , while the adverse effect of ribavirin elevating total bilirubin because of hemolysis was usually observed within 3 months from treatment initiation . the favorable effects of l - carnitine on pt and total bilirubin may be due to its ability to relieve hepatic oxidative stress . l - carnitine significantly improved liver antioxidant capacity in cisplatin - treated rats by increasing the glutathione pool , blockage of the free radical production , and regulation of peroxisome proliferator - activated receptor alpha . bcaa granules therapy for decompensated cirrhotic patients revealed improvement in event - free survival , quality of life , and serum albumin concentrations . reported that bcaa granules significantly suppressed the deterioration in hepatic functional reserve ( serum albumin and cp score ) at 3 and 6 months after tace . 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 . 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 .