Table 1.
Significantly altered metabolites in hepatocellular carcinoma patients vs cirrhosis controls
| Ref. | Platform | Tissue (organism) | HCC etiology | Significantly altered metabolites in HCC patients vs cirrhosis controls | Main pathways distinguishing HCC from cirrhosis |
| Patterson et al[29] | UPLC/QTOF-MS; UPLC/ESI-TQMS; GC/MS | Plasma (human) | HCC n = 20: | LPC (14:0) ↓ | LPC metabolism |
| EtOH n = 6 | LPC (18:1) ↓ | ||||
| HBV n = 3 | LPC (20:4) ↓ | ||||
| HCV n = 5 | LPC (20:3) ↓ | ||||
| NASH n = 3 | LPC (22:6) ↓ | ||||
| NASH/alcoholic steatohepatitis n = 1 | FFA (24:0) - lignoceric acid ↓ | Very long chain fatty acid metabolism | |||
| HH n = 2 | FFA (24:1) - nervonic acid ↓ | Hemoglobin metabolism | |||
| Bilirubin ↑ | |||||
| Biliverdin ↑ | |||||
| Xiao et al[37] | UPLC/QTOF-MS | Serum (human) | HCV | 3β, 6β-dihydroxy-5β-cholan-24-oic acid ↓ | Bile acid biosynthesis |
| 3α, 7β-dihydroxy-5β-cholest-24-en-26-oic acid ↓ | |||||
| GCA ↓ | |||||
| GDCA ↓ | |||||
| GCDCA ↓ | |||||
| TCDCA ↓ | |||||
| Linoelaidyl carnitine ↓ | CPT shuttle system | ||||
| Oleoylcarnitine ↓ | |||||
| Palmitoyl carnitine ↓ | |||||
| O-octanoyl-R-carnitine ↓ | |||||
| LPC (20:1) ↓ | LPC metabolism | ||||
| LPC (20:4) ↓ | |||||
| PE (20:4/18:1) ↓ | |||||
| 4E;15Z-Bilirubin IXa ↓ | Hemoglobin metabolism | ||||
| 15,16-dihydrobiliverdin ↓ | |||||
| 3-ganidinopropionicacid ↓ | |||||
| Tetracosahexaenoic acid ↓ | Eicosanoid metabolism | ||||
| 3-hydroxy-eicosanoic acid ↓ | |||||
| Oleamide ↓ | |||||
| Phe-Phe ↑ | |||||
| Wang et al[38] | UPLC/MS-MS; LC/QTOF-MS | Serum (human) | HCC n = 82: | LPC-16:0 ↑ | LPC metabolism |
| HBV-cirrhosis n = 41 | LPC-18:0 ↑ | ||||
| HBV-only n = 41 | 16:0/18:1-PC ↑ | ||||
| 16:0/18:2-PC ↑ | |||||
| 16:0/20:4-PC ↑ | |||||
| 16:0/22:6-PC ↑ | |||||
| 18:0/18:2-PC ↑ | |||||
| Phenylalanine ↓ | Gut flora metabolism | ||||
| GCDCA ↓ | Bile acid metabolism | ||||
| Canavaninosuccinate ↑↑ | Organic acid metabolism | ||||
| Zhou et al[39] | UPLC/QTOF-MS | Serum (human) | HCC n = 69: | LPC (14:0) HCC-C ↓ | LPC metabolism |
| HBV-HCC (HCC-B) n = 38 | LPC (16:1) HCC-C ↓ | ||||
| HCV-HCC (HCC-C) n = 31 | LPC (18:3) HCC-B ↓ | ||||
| HCC-C ↓ | |||||
| LPC (18:2) HCC-B ↓ | |||||
| HCC-C ↓ | |||||
| LPC (18:1) HCC-B ↓ | |||||
| HCC-C ↓ | |||||
| LPC (18:0) HCC-C ↓ | |||||
| LPC (20:5) HCC-C ↓ | |||||
| LPC (20:4) HCC-B ↓ | |||||
| HCC-C ↓ | |||||
| LPC (20:3) HCC-B ↓ | |||||
| HCC-C ↓ | |||||
| LPC (20:2) HCC-C ↓ | |||||
| LPC (20:0) HCC-B ↓ | |||||
| HCC-C ↓ | |||||
| LPC (22:6) HCC-C ↓ | |||||
| LPC (22:5) HCC-B ↓ | |||||
| HCC-C ↓ | |||||
| LPC (22:4) HCC-B ↓ | |||||
| HCC-C ↓ | |||||
| Wu et al[31] | SELDI-TOF-MS; HPLC/MS | Serum (human) | HBV | GRO-α ↑ | Cytokine |
| Thrombin light chain ↑ | Protease cleavage | ||||
| Ressom et al[36] | UPLC/QTOF-MS | Serum (human) | HCC n = 78: | GDCA ↓ | Bile acid metabolism |
| → HCV 67% | TCA ↓ | ||||
| → HBV 15% | TCDCA ↓ | ||||
| → Alcoholism 29% | Sphingosine 1-phosphate ↑ | Sphingolipid metabolism | |||
| → NASH 13% | LPC (16:0) ↑ | LPC metabolism | |||
| → Cryptogenic (8%) | LPC (17:0) ↑ | ||||
| → Autoimmune (3%) | LPC (18:0) ↑ | ||||
| LPC (15:0) ↑ | |||||
| LPC (22:6) ↑ | |||||
| LPE (22:6) ↑ | |||||
| LPE (20:4) ↑ | |||||
| LPE (20:3) ↑ | |||||
| PS ↑ | |||||
| Yang et al[28] | HRMAS 1H NMR | Biopsy (human) | HCC n = 17: | Glucose ↓ | Glycolysis |
| → Cirrhosis n = 9 | Creatine ↓ | ||||
| → No cirrhosis n = 8 | PE ↑ | LPC metabolism | |||
| Glutamine ↑ | Amino acid metabolism | ||||
| Glutamate ↑ | |||||
| PC + GPC ↑ | Bile acid metabolism | ||||
| Nahon et al[40] | NMR | Serum (human) | EtOH cirrhosis | High density lipoproteins | HDL biosynthesis |
| Acetate ↑ | Ketone body metabolism | ||||
| N-acetyl-glycoproteins ↑ | N-acetylglycoprotein | ||||
| Glutamate ↑ | Amino acid metabolism | ||||
| Glutamine ↓ | |||||
| Budhu et al[43] | GC/MS, UPLC/MS-MS | Biopsy samples (human) | HCC n = 356 | Study reported on markers involved in cancer aggressivity through comparison of stem-like HCC to less benign mature hepatocyte HCC | N/A |
| Training cohort n = 30 | |||||
| Testing cohort n = 217 | |||||
| Validation cohort n = 139 | |||||
| Beyoğlu et al[44] | GC/MS | Biopsy samples (human) | Six HCC subtypes, liver fibrosis status unknown | Glucose ↓ | Glycolysis |
| Glycerol 3-phosphate ↓ | |||||
| Glycerol 2-phosphate ↓ | |||||
| Malate ↓ | |||||
| Alanine ↓ | |||||
| Myo-inositol ↓ | PI3K pathway | ||||
| Linoleic acid ↓ | Prostaglandin biosynthesis | ||||
| Fitian et al[45] | UPLC/MS-MS and GC/MS | Serum (human) | HCV cirrhosis-associated HCC n = 30 | Sphingosine ↑ | Sphingolipid |
| HCV-cirrhosis n = 27 | Xanthine ↑ | Oxidative stress metabolism | |||
| Healthy volunteers n = 30 | 2-Pyrrolidinone ↑ | GABA metabolism | |||
| 2-Hydroxybutyrate ↑ | Oxidative stress metabolism | ||||
| Serine ↑ | Amino acid | ||||
| Glycine ↑ | |||||
| Aspartate ↑ | |||||
| 12-HETE ↑ | Inflammation pathway | ||||
| 15-HETE ↑ | |||||
| Isovalerate ↑ | Gut microflora metabolism | ||||
| Dihomo-linolenate ↑ | Inflammation pathway | ||||
| Gao et al[46] | GC-TOF/MS | Serum (human) | HBV cirrhosis-associated HCC n = 39 | Stearic acid | Fatty acid biosynthesis |
| HBV-cirrhosis (n = 52) | Heptadecanoic acid | ||||
| Palmitic acid | |||||
| 5-Aminovaleric acid | Gut microflora metabolism | ||||
| Cholesterol ↑ | Cholesterol metabolism | ||||
| 3-hydroxybutyric acid ↑ | Ketogenesis | ||||
| Malic acid ↑ | TCA metabolism | ||||
| Glutamine ↑ | Amino acid | ||||
| Asparagine ↓ | |||||
| Alanine ↑ | |||||
| Threonine ↓ | |||||
| Leucine ↓ | |||||
| Glutamic acid ↑ | |||||
| β-glutamate ↑ | |||||
| 5-oxoproline ↓ | Glutathione metabolism | ||||
| 1,2,4-cyclopropranodicarboxylic acid ↓ | Dicarboxylic acid metabolism |
Pathways of importance in the comparison of (1A) HCC vs cirrhosis and (2) cirrhosis vs healthy controls are shown. Arrows indicate the metabolite’s expression in cases vs appropriate controls. P < 0.05 was used as the significance level and metabolites reported in table are those which were most significantly upregulated or downregulated in each study. EtOH: Alcohol; TOCSY: Total correlation spectroscopy; HH: Hereditary hemochromatosis; TCA: Tricarboxylic acid; UPLC: Ultrahigh-performance liquid chromatography; QTOF: Quadrupole time of flight; SELDI: Surface-enhanced laser desorption/ionization; HRMAS: High-resolution magic angle spinning; LPE: Lysophosphatidyethanolamine; LPC: Lysophosphatidylcholine; HCC: Hepatocellular carcinoma; MS: Mass spectrometry; TOF: Time-of-flight; GC: Gas chromatography; LC: Liquid chromatography; NMR: Nuclear magnetic resonance; HBV: Hepatitis B virus; HCV: Hepatitis C virus; NASH: Non-alcoholic steatohepatitis; FFA: Free fatty acids; PE: Phosphorylethanolamine; GABA: γ-aminobutyric acid.