Abstract
The study aimed to investigate the independent effects of serum branched-chain and aromatic amino acid levels on hepatocellular carcinoma (HCC) development. This multicenter retrospective study included patients with chronic liver disease (CLD) from two institutions in Japan. Amino acid imbalance was assessed using BCAA and tyrosine levels. Factors associated with the development of HCC and mortality were assessed using Fine–Gray competing risk and Cox proportional hazards regression models, respectively. Among 563 patients, the median age was 67 years, and 51% were male. During a median follow-up period of 3.5 years, 14% (n = 80) of the patients developed HCC and 23% (n = 130) died. Given mortality as a competing risk, multivariable analysis showed that the serum tyrosine level (sub-distribution hazard ratio [HR], 1.01; 95% confidence interval [CI], 1.00–1.02) was an independent risk factor for the development of HCC. Similarly, using the development of HCC as a time-dependent covariate, the serum tyrosine level (HR, 1.01; 95% CI, 1.01–1.02) and development of HCC (HR 2.91; 95% CI 1.75–4.81) were independent risk factors for mortality. The serum tyrosine level is an independent risk factor for the development of HCC and mortality in patients with CLD.
Supplementary Information
The online version contains supplementary material available at 10.1038/s41598-025-21373-z.
Keywords: Amino acid imbalance, Branched-chain amino acids, Liver cirrhosis, Malnutrition, Survival
Subject terms: Hepatology, Liver cancer
Introduction
Hepatocellular carcinoma (HCC) is a serious complication of chronic liver disease. According to the global burden of disease data, liver cancer is the 8th most common cancer, responsible for 48,500 deaths worldwide in 2019, and HCC is the most common liver cancer1. Improved vaccination strategy and antiviral treatment have contributed significantly to reduced incidence and mortality of HCC in some countries2. However, the incidence of HCC remains highest in East Asia, including Japan, and is also increasing in Western countries due to the increasing burden of alcohol-related liver disease and metabolic dysfunction-associated steatotic liver disease2. Surveillance for HCC in patients with chronic liver disease (CLD) should be performed on those at high risk of developing HCC, such as those with hepatitis B, hepatitis C, or cirrhosis3. However, these factors do not fully explain the risk factors for developing HCC, and there is an urgent requirement to establish an effective method of surveillance and prevention in patients with CLD.
Amino acid imbalance, with decreased branched-chain amino acids (BCAAs), such as leucine, isoleucine, and valine and increased aromatic amino acids (AAAs), such as phenylalanine, tryptophan, and tyrosine, is observed in approximately 30–50% of patients with CLD4,5. Amino acid imbalance is known to be an important risk factor leading to complications of CLD, including hepatic encephalopathy, acute kidney injury, and sarcopenia5–7. In addition, since amino acid balance, particularly reduced levels of BCAAs, determine the prognosis of patients with CLD, intervention through BCAA supplementation may prevent complications and improve the prognosis of patients8,9. Amino acid imbalance is assessed mainly by the ratio of BCAAs to AAAs, with Fischer’s ratio and the BCAA to tyrosine ratio (BTR)5,6. Amino acid imbalance is known to be an important driver of insulin resistance, mitosis, and cell growth9–11; therefore, Fischer’s ratio and the BTR have been suggested to be critical indicators for the development and recurrence of HCC12–14. Notably, the effect of amino acid imbalance on complications of CLD is explained not only by a decrease in Fischer’s ratio or the BTR, but also by changes in individual amino acids, such as a decrease in BCAAs and an increase in AAAs5,15. For instance, serum BCAA and tyrosine levels are independent factors for the development of acute kidney injury in patients with cirrhosis, which can be also seen in terms of HCC development5. Although BCAAs and AAAs have distinct biological effects in humans, the specific contributions of decreased BCAAs and increased AAAs to HCC development remain unclear.
The primary aim of this study was to investigate the effects of amino acid imbalances, including decreased BCAAs and increased AAAs, on the development of HCC in patients with CLD. The secondary aim was to elucidate the effect of amino acid imbalances on mortality in these patients.
Methods
Study protocol and outcomes
A retrospective cohort study was conducted by reviewing patients with CLD who were admitted to Gifu University Hospital or Chuno Kosei Hospital. The Institutional Review Board of Gifu University Graduate School of Medicine (approval number: 2024–269) reviewed and approved the study protocol. The study was conducted in accordance with the principles of the 2013 Declaration of Helsinki. Informed consent was obtained using the opt-out method due to the retrospective nature of the study.
The primary outcome was the development of HCC during the observation period. The secondary outcome was mortality of any cause. Patients were followed up until their last visit, death, or August 2, 2024, whichever was first.
Participants and follow-up
Inclusion criteria were patients with CLD of any etiology aged ≥ 18 years, without previous or current HCC, and admitted between June 2004 and July 2023. Exclusion criteria were liver transplantation or other organ transplantation, active malignancy, previous or current overt hepatic encephalopathy (OHE), life-threatening comorbidities such as heart, lung, or renal failure, and refusal to opt-out. After discharge, the patients were followed up and treated in the outpatient clinic at least every three months, according to the Japanese guidelines16,17.
Data collection and assessment of amino acid imbalance
The following baseline data were collected at each institute: age, sex, weight, height, etiology of CLD, comorbidities including diabetes mellitus, ascites, hepatic encephalopathy, and laboratory data. The body mass index, Child–Pugh score, model for end-stage liver disease (MELD) score, and albumin-bilirubin (ALBI) score were calculated. Demographic variables were assessed at the time of admission, and biochemical parameters, including serum concentrations of BCAA, tyrosine, and BTR (SRL, Inc., Tokyo, Japan), were assessed on the day of admission or on the following day under fasting conditions. According to the cut-off values recommended by SRL, BTR ≤ 4.4, BCAA < 344 µmol/L, and tyrosine > 99 µmol/L were defined as low BTR, low BCAA, and high tyrosine, respectively5. In our hospitals, serum concentrations of BCAA, tyrosine, and the BTR were routinely measured in all inpatients, as these tests are covered by the Japanese national health insurance system. Dates of development of HCC, development of OHE, and death were recorded, and time from inclusion to each event was calculated.
Statistical analysis
Continuous variables are presented as medians and interquartile ranges, and categorical variables are expressed as numbers and percentages. Baseline characteristics between the groups were compared using the Mann–Whitney U test or the chi-square test. With mortality as a competing risk, the cumulative incidence curves of HCC were estimated using the cumulative incidence function, and the groups were compared using Gray’s test. Independent factors for HCC development were examined using the Fine–Gray competing risk regression model considering death as a competing risk, and results were presented as subdistribution hazard ratios (SHRs) with 95% confidence intervals (CIs). The development of HCC and OHE were analyzed as time-dependent covariates to examine the association between occurrence of an event and mortality. Survival curves were estimated using the Kaplan–Meier method, and groups were compared using the log-rank test. Independent risk factors for survival were assessed using the Cox proportional hazards regression model and the results are expressed as hazard ratios (HRs) with 95% CIs. The covariates were selected based on the clinical importance and multicollinearity of each variable. Patients with missing data were excluded from the analyses; therefore, data were not imputed in the study. A two-tailed p < 0.05 was used as the threshold for statistical significance. All statistical analyses were performed using the R software, version 4.4.1 (The R Foundation for Statistical Computing, Vienna, Austria).
Results
Baseline characteristics of the patients with CLD
Of the 668 reviewed patients, 563 were included in the analysis (Supplementary Fig. 1). The baseline characteristics of the included patients are presented in Table 1. The median age was 67 years, 285 (51%) were male, and the median body mass index was 23.1 kg/m2. Type 2 diabetes and ascites were present in 154 (27%) and 190 (34%) patients, respectively. The median Child–Pugh, MELD, and ALBI scores were 6, 8, and − 2.13, respectively. The underlying etiologies of CLD included viral hepatitis (40%), alcohol-associated/related liver disease (24%), metabolic dysfunction-associated steatotic liver disease (10%), and other causes (26%).
Table 1.
Baseline characteristics of patients with CLD divided by HCC development.
| Characteristic | All patients | HCC | No HCC | p-value* |
|---|---|---|---|---|
| (n = 563) | (n = 80) | (n = 483) | ||
| Age (years) | 67 (56–74) | 67 (61–76) | 67 (56–74) | 0.114 |
| Male, n (%) | 285 (51) | 54 (68) | 231 (48) | 0.002 |
| Body mass index (kg/m2) | 23.1 (21.2–25.4) | 23.7 (21.6–25.9) | 23.0 (21.2–25.3) | 0.420 |
| Etiology of CLD (Viral/ALD/MASLD/Others), n | 226/133/57/147 | 48/18/7/7 | 178/115/50/140 | < 0.001 |
| Diabetes mellitus, n (%) | 154 (27) | 30 (38) | 124 (26) | 0.039 |
| Ascites, n (%) | 190 (34) | 22 (28) | 168 (35) | 0.251 |
| Varices, n (%) | 394 (70) | 332 (69) | 62 (78) | 0.146 |
| Liver cirrhosis, n (%) | 434 (77) | 367 (76) | 67 (84) | 0.165 |
| Child–Pugh class (A/B/C) | 301/172/90 | 48/29/44 | 259/143/81 | 0.314 |
| Child–Pugh score | 6 (5–8) | 6 (5–8) | 6 (5–9) | 0.863 |
| MELD score | 8 (7–11) | 9 (7–10) | 8 (7–11) | 0.445 |
| ALBI score | −2.13 (−2.60 to −1.47) | −1.95 (−2.37 to −1.50) | −2.20 (−2.61 to −1.45) | 0.084 |
| International normalized ratio | 1.07 (1.00–1.21) | 1.07 (1.02–1.19) | 1.07 (1.00–1.21) | 0.502 |
| Platelet (109/L) | 103.00 (61–156) | 77 (61–106) | 109 (61–162) | 0.003 |
| Creatinine (mg/dL) | 0.71 (0.57–0.88) | 0.69 (0.54–0.92) | 0.71 (0.58, 0.88) | 0.714 |
| Albumin (g/dL) | 3.50 (2.85–3.90) | 3.2 (2.9–3.7) | 3.50 (2.8–4.0) | 0.083 |
| Bilirubin (mg/dL) | 1.00 (0.80–1.50) | 1.10 (0.80–1.63) | 1.00 (0.80–1.50) | 0.379 |
| Sodium (meq/L) | 139 (137–140) | 139 (137–141) | 139 (137–140) | 0.637 |
| Ammonia (mcg/dL) | 57 (40–80) | 61 (44–90) | 56 (39–78) | 0.100 |
| BTR | 4.35 (3.09–5.53) | 3.63 (2.70–4.97) | 4.39 (3.15–5.70) | 0.003 |
| BCAA (µmol/L) | 379 (304–455) | 386 (304–472) | 379 (304–455) | 0.793 |
| Tyrosine (µmol/L) | 90 (71–113) | 101 (84–120) | 89 (69–112) | < 0.001 |
Values are presented as number (percentage) or median (interquartile range).
*Groups were compared using the chi-square test or Mann-Whitney U test.
Abbreviations: ALBI, albumin-bilirubin; ALD, alcohol-associated/related liver disease; BCAA, branched-chain amino acid; BTR, branched-chain amino acid-to-tyrosine ratio; CLD, chronic liver disease; HCC, hepatocellular carcinoma; MASLD, metabolic dysfunction-associated steatotic liver disease; MELD, model for end-stage liver disease.
The comparison of patients with and without HCC is shown in Table 1. Patients with HCC had a significantly higher prevalence of male sex and type 2 diabetes, different etiology of CLD, lower platelet count, lower serum BTR (3.63 vs. 4.39, p = 0.003), and higher serum tyrosine level (101 µmol/L vs. 89 µmol/L, p = 0.003) than those without HCC (Table 1). Baseline characteristics were also compared according to BTR and serum levels of BCAA and tyrosine (Supplementary Tables 1, 2, and 3).
Serum tyrosine level as an independent factor for development of HCC
During a median follow-up period of 3.5 years (interquartile range, 1.1–5.7), 14% (n = 80) developed HCC and 17% (n = 97) developed OHE. The cumulative incidence rates of HCC at one, three, and five years were 4%, 11%, and 15%, respectively. The adjusted SHRs for determinants of the development of HCC are shown in Table 2. After adjustment, serum tyrosine level (SHR, 1.01; 95% CI, 1.00–1.02; p = 0.004) was an independent risk factor for the development of HCC in addition to age, male sex, etiology, MELD score, platelet count, and serum albumin level (Table 2). Similar results were obtained in a model including the ALBI score instead of the MELD score (Supplementary Table 4). Although serum BTR (Fig. 1a) and BCAA levels (Fig. 1b) remained statistically negative, patients with a high tyrosine level had a significantly higher incidence of HCC than those with a normal level (Fig. 1c; one, three and five years: 4%, 16%, and 20% vs. 3%, 8%, and 11%, respectively; p = 0.002).
Table 2.
Adjusted SHRs for development of HCC in patients with CLD.
| Characteristic | SHR (95% CI) | p-value* |
|---|---|---|
| Age | 1.03 (1.01–1.05) | 0.001 |
| Male | 2.12 (1.12–4.03) | 0.022 |
| Body mass index (kg/m2) | 0.99 (0.93–1.04) | 0.590 |
| Etiology of CLD | ||
| Virala | 1.00 | |
| ALD | 2.09 (1.21–3.62) | 0.009 |
| MASLD | 0.74 (0.19–2.90) | 0.660 |
| Others | 3.16 (1.63–6.11) | < 0.001 |
| Varices | 1.37 (0.73–2.56) | 0.330 |
| MELD score | 1.04 (1.00–1.09) | 0.042 |
| Platelet (109/L) | 1.00 (1.00–1.00) | 0.012 |
| Albumin (g/dL) | 0.40 (0.27–0.58) | < 0.001 |
| Sodium (meq/L) | 0.99 (0.93–1.07) | 0.880 |
| Ammonia (mcg/dL) | 1.00 (0.99–1.01) | 0.820 |
| BCAA (µmol/L) | 1.00 (1.00–1.00) | 0.072 |
| Tyrosine (µmol/L) | 1.01 (1.00–1.02) | 0.004 |
* Multivariable analysis was performed using the Fine–Gray competing risk regression model.
aReference group.
Abbreviations: ALD, alcohol-associated/related liver disease; BCAA, branched-chain amino acid; CI, confidence interval; CLD, chronic liver disease; HCC, hepatocellular carcinoma; MASLD, metabolic dysfunction-associated steatotic liver disease; MELD, model for end-stage liver disease; SHR, sub-distribution hazard ratio.
Fig. 1.
Cumulative incidence of HCC in patients with chronic liver disease categorized by (a) serum BTR (b) BCAA and (c) tyrosine levels. Abbreviations: BCAA, branched-chain amino acid; BTR, branched-chain amino acid-to-tyrosine ratio; HCC, hepatocellular carcinoma.
Serum tyrosine level as an independent predictor of mortality
During the follow-up period, 23% (n = 130) of the patients died of liver failure (n = 89; 68%), HCC (n = 19; 15%), or other causes (n = 22; 17%). The overall survival rates at one, three, and five years were 91%, 82%, and 75%, respectively. The adjusted HRs for mortality in patients with CLD are shown in Table 3. After adjustment, serum tyrosine level (HR 1.01; 95% CI 1.01–1.02; p < 0.001) was an independent factor for mortality, as well as HCC development (HR 2.91; 95% CI 1.75–4.81; p < 0.001) and OHE development (HR 33.93; 95% CI 21.86–52.68; p < 0.001). Similar results were obtained in a model including the ALBI score instead of the MELD score (Supplementary Table 5). Patients with an amino acid imbalance in terms of low BTR (Fig. 2a; p < 0.001), low BCAA (Fig. 2b; p < 0.001), and high tyrosine levels (Fig. 2c; p < 0.001) had significantly higher mortality than those without.
Table 3.
Adjusted HRs for mortality in patients with CLD.
| Characteristic | HR (95% CI) | p-value* |
|---|---|---|
| Baseline covariates | ||
| Age (years) | 1.02 (1.01–1.04) | 0.012 |
| Male | 1.82 (1.06–3.13) | 0.030 |
| Body mass index (kg/m2) | 1.00 (0.95–1.05) | 0.929 |
| Etiology of CLD | ||
| Virala | 1.00 | |
| ALD | 2.43 (1.46–4.03) | < 0.001 |
| MASLD | 0.89 (0.25–3.18) | 0.857 |
| Others | 2.31 (1.30–4.10) | 0.004 |
| Varices | 0.77 (0.43–1.37) | 0.371 |
| MELD score | 1.04 (1.00–1.09) | 0.078 |
| Platelet (109/L) | 1.00 (1.00–1.00) | 0.012 |
| Albumin (g/dL) | 0.66 (0.47–0.92) | 0.014 |
| Sodium (meq/L) | 0.91 (0.86–0.96) | 0.001 |
| Ammonia (mcg/dL) | 1.00 (0.99–1.00) | 0.175 |
| BCAA (µmol/L) | 1.00 (1.00–1.00) | 0.978 |
| Tyrosine (µmol/L) | 1.01 (1.01–1.02) | < 0.001 |
| Time dependent covariates | ||
| HCC development | 2.91 (1.75–4.81) | < 0.001 |
| OHE development | 33.93 (21.86–52.68) | < 0.001 |
* Multivariable analysis was performed using the Cox proportional hazards model.
aReference group.
Abbreviations: ALD, alcohol-associated/related liver disease; BTR, branched-chain amino acid-to-tyrosine ratio; CI, confidence interval; CLD; chronic liver disease, HCC, hepatocellular carcinoma; HR, hazard ratio; MASLD, metabolic dysfunction-associated steatotic liver disease; MELD, model for end-stage liver disease; OHE, overt hepatic encephalopathy.
Fig. 2.
Survival of patients with chronic liver disease categorized by (a) serum BTR serum (b) BCAA and (c) tyrosine levels. Abbreviations: BCAA, branched-chain amino acid; BTR, branched-chain amino acid-to-tyrosine ratio; HCC, hepatocellular carcinoma.
Discussion
Amino acid imbalance is a common metabolic abnormality in patients with CLD and has been suggested as a risk factor for hepatocarcinogenesis. However, little is known about the independent roles of decreased BCAA and increased AAA levels in the development of HCC. The results of the present study clearly show that an increased serum tyrosine level is an even stronger independent risk factor for the development of HCC than a decreased BCAA level. Additionally, the serum tyrosine level and development of HCC were independently associated with mortality.
The first important finding of our study was the independent effect of the serum tyrosine level on the development of HCC in patients with CLD. Amino acid imbalance, assessed by Fischer’s ratio or BTR, has been reported to be associated with the development of HCC12,13. As recent studies have focused on the independent effect of increased BCAAs and decreased AAAs on complications of CLD5,15, we evaluated the significance of the serum BCAA and tyrosine levels as independent variables in the development of HCC. Increased AAAs are mainly caused by a reduced capacity of the liver function reserve to catabolize them18. Notably, the serum tyrosine level was a stronger risk factor for hepatocarcinogenesis than the serum BCAA level, in the present study. BCAAs reduce the serum insulin level and improve insulin resistance, an important factor in the development of HCC, resulting in the inhibition of mitosis, cell growth, and hepatocarcinogenesis9–11,19. Importantly, a previous study found that the serum tyrosine level correlated more strongly with insulin resistance than the BCAA level and predicts the development of type 2 diabetes20,21. Furthermore, a recent basic study found that loss of a tyrosine catabolic enzyme, 4-hydroxyphenylpyruvate dioxygenase, regulates mechanistic target of rapamycin complex 1 signaling, resulting in HCC progression22. Therefore, the quotations above support our study results which identified the serum tyrosine level as an independent risk factor for the development of HCC in patients with CLD.
The second important finding was that the serum tyrosine level was an independent risk factor for mortality in patients with CLD. BTR has been reported to be an indicator of a higher mortality rate in patients with HCC4,14. Previous reports have shown that Fischer’s ratio and the serum tyrosine level are associated with mortality in patients with cirrhosis23,24. Although these studies provided important evidence, previous works lack robust multivariable analysis including both aspects of amino acid imbalance, such as increased BCAAs and decreased AAAs. In the present study, univariable analyses showed that BTR, BCAA and tyrosine levels were significant factors for mortality in patients with CLD. Among these variables, multivariable analysis including the serum BCAA and tyrosine levels showed that the serum tyrosine level was the strongest contributor to mortality of the patients. BTR is a well-known method for assessing amino acid imbalance; however, very few clinicians have focused on an elevated serum tyrosine level. BCAA supplementation is known to suppress HCC and improve the survival of patients with cirrhosis8,13. In addition, BCAA supplementation not only increases the serum BCAA level but also decreases serum the AAA level25. Therefore, clinicians should pay close attention to the serum tyrosine level to identify high-risk individuals and provide early intervention, including administration of BCAAs, to improve outcomes.
Another important finding of the present study was the effect of the development of HCC on mortality in patients with CLD. A previous study found that early recurrence of tumor and decompensation were robust factors for a worse outcome in patients with early HCC26. Decompensation has also been reported as a strong contributor to mortality in patients with HCC treated with atezolizumab plus bevacizumab27. A time-dependent covariate is an effective method to assess the occurrence of events and their impact on outcomes, and in this study, the analysis using the development of HCC as a time-dependent covariate clearly showed that it was a robust driver of mortality in patients with CLD. Although development of HCC is an important event affecting the natural course of CLD, limited information is available regarding the effect of the development of HCC on mortality using time-dependent covariates. Therefore, our longitudinal study adds robust evidence to the existing knowledge on the association between the development of HCC and mortality in patients with CLD.
The present study has some limitations. First, this study is based on a Japanese cohort, which may limit the generalizability of the results to other regions. Second, the retrospective nature and inpatient population of this study cannot exclude the possibility of selection bias. However, we believe that this is not a major concern because this multicenter study utilized databases prospectively collected. Third, the clinical rationale for the cutoff values of BTR, BCAA, and tyrosine has been evaluated in several Japanese reports4,5; however, further international validation is needed to determine the optimal cutoff values for other populations. Lastly, although other AAAs and the Fischer’s ratio may also contribute to HCC development and mortality, these data were not available because they are not covered under the Japanese national health insurance system. Therefore, future studies should evaluate the impact of other amino acids on the outcomes of patients with cirrhosis. Despite the limitations, the study provides a robust analysis with sufficient sample size and number of events to provide reliable evidence.
In conclusion, our study demonstrated that an elevated serum tyrosine level is an independent risk factor for the development of HCC and mortality in patients with CLD. As the development of HCC leads to increased mortality, amino acid imbalance, in particular, the serum tyrosine level should be evaluated to identify high-risk populations for the development of HCC and to improve outcomes.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
We would like to thank all the medical professionals involved in patient care. This study was supported by a Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (24K18908).
Author contributions
Takao Miwa contributed to the study conception and design. All authors contributed to data collection. Takao Miwa and Mikita Oi analyzed the data. All authors contributed to data interpretation. Mikita Oi, Takao Miwa and Masahito Shimizu wrote the first draft, and all authors critically revised the manuscript. All authors have read and approved the final manuscript and agree to be accountable for all aspects of the study.
Funding statement
This study was supported by a Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (24K18908).
Data availability
The datasets generated and/or analyzed data during the current study are available from the corresponding author upon reasonable request. However, additional ethical approval is required to provide the datasets due to the ethical considerations in Japan.
Declarations
Competing interests
The authors declare no competing interests.
Ethics approval statement
The study protocol was reviewed and approved by the Institutional Review Board of Gifu University Graduate School of Medicine (approval number: 2024–269).
Patient consent statement
Informed consent to participate and publish was obtained using an opt-out method due to the retrospective nature of this study.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets generated and/or analyzed data during the current study are available from the corresponding author upon reasonable request. However, additional ethical approval is required to provide the datasets due to the ethical considerations in Japan.