Laboratory Tests in Liver Diseases

  • Yoshio SumidaEmail author
  • Yoshihiro Kamada
  • Masaki Iwai
  • Paul Y. Kwo
  • Masashi Yoneda


Laboratory tests for evaluating liver diseases are essential. This chapter reviews routine biochemical tests and disease-specific laboratory tests. Algorithms for assessing acute and chronic hepatobiliary enzyme elevation are suggested. The degree of hepatic fibrosis has been established to be the most significant determinant of mortality/morbidity in chronic liver diseases. Liver biopsy is the gold standard for the diagnosis of hepatic fibrosis, but it has several drawbacks such as invasiveness, cost, and risk. We here review noninvasive fibrosis parameters, including hepatic fibrosis markers, and several scoring systems. Nonalcoholic fatty liver disease (NAFLD) is becoming the most common liver disease all over the world. Diagnostic algorithm for NAFLD is also established to detect severe fibrosis (stage 3/4). Severity of cirrhosis was usually assessed by Child-Pugh score, MELD score, and ALBI grade. We also discuss the significance of tumor markers such as α-fetoprotein (AFP), fucosylated AFP, and des-gamma-carboxyprothrombin in order to detect liver cancer and evaluate its treatment efficacy.


Hepatic fibrosis NAFLD FIB4 index Type 4 collagen 7S Pro-C3 Child-Pugh score MELD score ALBI grade AFP DCP 



Aromatic amino acid


American Association for the Study of Liver Diseases


Anti-centromere antibodies


American College of Gastroenterology




Fucosylated AFP


Autoimmune hepatitis




Alcoholic liver disease


Alkaline phosphatase


Alanine aminotransferase


Antinuclear antibodies


Antibodies to liver/kidney microsome


Asian Pacific Association for the Study of the Liver


AST to platelet ratio index


Acoustic radiation force impulse


Anti-smooth muscle antibodies


Aspartate aminotransferase


AST to ALT ratio


Branched-chain amino acid


BCAA/tyrosine ratio


Chronic hepatitis B


Chronic hepatitis C


Creatine kinase


Chronic liver disease




Disseminated intravascular coagulation


Drug-induced liver injury


European Association for the Study of the Liver


Extracellular matrix

ELF score

Enhanced liver fibrosis score

FIB4 index

Fibrosis-4 index


γ-glutamyl transferase






Hepatitis B virus


Hepatocellular carcinoma


Hepatitis C virus


Human immunodeficiency virus


High-performance liquid chromatography


Hepatic stellate cell


Heparan sulfate proteoglycan


Indocyanine green


Intrahepatic cholestasis of pregnancy




Immunoglobulin A


Immunoglobulin E


Immunoglobulin G


Immunoglobulin M


International normalized ratio




Japanese Society of Hepatology


Lens culinaris agglutinin A


Lactate dehydrogenase


Liver sinusoidal endothelial cell


Mac-2 binding protein


Mac-2-binding protein glycosylation isomer


Model for end-stage liver disease


Magnetic resonance elastography


Magnetic resonance imaging


Nonalcoholic fatty liver disease


Procollagen type III N-terminal peptide


Primary biliary cholangitis


Pulse dye densitometer


N-terminal propeptide of type III collagen


Primary sclerosing cholangitis


Prothrombin time


Scavenger receptor cysteine-rich domain


Sustained virological response


Type 4 collagen 7S


Tissue inhibitor of matrix metalloprotease-1


Transjugular intrahepatic portosystemic shunt


Tumor necrosis factor-α


Uridine diphosphate


Wisteria floribunda agglutinin


  1. 1.
    Prati D, Taioli E, Zanella A, et al. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med. 2002;137:1–10.PubMedGoogle Scholar
  2. 2.
    Kwo PY, Cohen SM, Lim JK. ACG Clinical Guideline: evaluation of abnormal liver chemistries. Am J Gastroenterol. 2017;112:18–35.PubMedGoogle Scholar
  3. 3.
    Litin SC, O’Brien JF, Pruett S, et al. Macroenzyme as a cause of unexplained elevation of aspartate aminotransferase. Mayo Clin Proc. 1987;62:681–7.PubMedGoogle Scholar
  4. 4.
    Poupon R. Liver alkaline phosphatase: a missing link between choleresis and biliary inflammation. Hepatology. 2015;61(6):2080–90.PubMedGoogle Scholar
  5. 5.
    Matsushita M, Komoda T. Relationship between the effects of a high-fat meal and blood group in determination of alkaline phosphatase activity. Rinsho Byori. 2011;59:923–9.PubMedGoogle Scholar
  6. 6.
    Vilstrup H, Amodio P, Bajaj J, et al. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology. 2014;60:715–35.PubMedGoogle Scholar
  7. 7.
    Kamath PS, Wiesner RH, Malinchoc M, et al. A model to predict survival in patients with end-stage liver disease. Hepatology. 2001;33:464–70.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Wiesner R, Edwards E, Freeman R, et al. Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology. 2003;124:91–6.PubMedGoogle Scholar
  9. 9.
    Johnson PJ, Berhane S, Kagebayashi C, et al. Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach-the ALBI grade. J Clin Oncol. 2015;33:550–8.PubMedGoogle Scholar
  10. 10.
    Chalasani NP, Hayashi PH, Bonkovsky HL, et al. ACG Clinical Guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol. 2014;109:950–66.PubMedGoogle Scholar
  11. 11.
    Hiraoka A, Kumada T, Michitaka K, et al. Usefulness of albumin-bilirubin grade for evaluation of prognosis of 2584 Japanese patients with hepatocellular carcinoma. J Gastroenterol Hepatol. 2016;31:1031–6.PubMedGoogle Scholar
  12. 12.
    Maleki I, Aminafshari MR, Taghvaei T, et al. Serum immunoglobulin A concentration is a reliable biomarker for liver fibrosis in non-alcoholic fatty liver disease. World J Gastroenterol. 2014;20:12566–73.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Oertelt S, Rieger R, Selmi C, et al. A sensitive bead assay for antimitochondrial antibodies: chipping away at AMA-negative primary biliary cirrhosis. Hepatology. 2007;45:659–65.PubMedGoogle Scholar
  14. 14.
    Bataller R, Brenner DA. Liver fibrosis. J Clin Invest. 2005;115:209–18.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Svegliati-Baroni G, De Minicis S, Marzioni M. Hepatic fibrogenesis in response to chronic liver injury: novel insights on the role of cell-to-cell interaction and transition. Liver Int. 2008;28:1052–64.PubMedGoogle Scholar
  16. 16.
    Moller S, Henriksen JH. Cardiovascular complications of cirrhosis. Postgrad Med J. 2009;85:44–54.PubMedGoogle Scholar
  17. 17.
    Mas VR, Fisher RA, Archer KJ, et al. Proteomics and liver fibrosis: identifying markers of fibrogenesis. Expert Rev Proteomics. 2009;6:421–31.PubMedGoogle Scholar
  18. 18.
    Piccinino F, Sagnelli E, Pasquale G, et al. Complications following percutaneous liver biopsy. A multicentre retrospective study on 68,276 biopsies. J Hepatol. 1986;2:165–73.PubMedGoogle Scholar
  19. 19.
    Ratziu V, Charlotte F, Heurtier A, et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology. 2005;128:1898–906.PubMedGoogle Scholar
  20. 20.
    Yoneda M, Yoneda M, Fujita K, et al. Transient elastography in patients with non-alcoholic fatty liver disease (NAFLD). Gut. 2007;56:1330–1.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Yoneda M, Suzuki K, Kato S, et al. Nonalcoholic fatty liver disease: US-based acoustic radiation force impulse elastography. Radiology. 2010;256:640–7.PubMedGoogle Scholar
  22. 22.
    Castera L, Forns X, Alberti A. Non-invasive evaluation of liver fibrosis using transient elastography. J Hepatol. 2008;48:835–47.PubMedGoogle Scholar
  23. 23.
    Harrison SA, Oliver D, Arnold HL, et al. Development and validation of a simple NAFLD clinical scoring system for identifying patients without advanced disease. Gut. 2008;57:1441–7.PubMedGoogle Scholar
  24. 24.
    Angulo P, Hui JM, Marchesini G, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45:846–54.PubMedGoogle Scholar
  25. 25.
    Sumida Y, Yoneda M, Hyogo H, et al. A simple clinical scoring system using ferritin, fasting insulin, and type IV collagen 7S for predicting steatohepatitis in nonalcoholic fatty liver disease. J Gastroenterol. 2011;46:257–68.PubMedGoogle Scholar
  26. 26.
    Imajo K, Kessoku T, Honda Y, et al. Magnetic resonance imaging more accurately classifies steatosis and fibrosis in patients with onalcoholic fatty liver disease than transient elastography. Gastroenterology. 2016;150:626–37.PubMedGoogle Scholar
  27. 27.
    Friedman SL. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J Biol Chem. 2000;275:2247–50.PubMedGoogle Scholar
  28. 28.
    Wake K. Perisinusoidal stellate cells (fat-storing cells, interstitial cells, lipocytes), their related structure in and around the liver sinusoids, and vitamin A-storing cells in extrahepatic organs. Int Rev Cytol. 1980;66:303–53.PubMedGoogle Scholar
  29. 29.
    Kuno A, Ikehara Y, Tanaka Y, et al. A serum “sweet-doughnut” protein facilitates fibrosis evaluation and therapy assessment in patients with viral hepatitis. Sci Rep. 2013;3:1065.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Neuman MG, Cohen LB, Nanau RM. Hyaluronic acid as a non-invasive biomarker of liver fibrosis. Clin Biochem. 2016;49:302–15.PubMedGoogle Scholar
  31. 31.
    Guéchot J, Laudat A, Loria A, et al. Diagnostic accuracy of hyaluronan and type III procollagen amino-terminal peptide serum assays as markers of liver fibrosis in chronic viral hepatitis C evaluated by ROC curve analysis. Clin Chem. 1996;42:558–63.PubMedGoogle Scholar
  32. 32.
    Schanté CE, Zuber G, Herlin C, et al. Chemical modifications of hyaluronic acid for the synthesis of derivatives for a broad range of biomedical applications. Carbohydr Polym. 2011;85:469–89.Google Scholar
  33. 33.
    Stickel F, Poeschl G, Schuppan D, et al. Serum hyaluronate correlates with histological progression in alcoholic liver disease. Eur J Gastroenterol Hepatol. 2003;15:945–50.PubMedGoogle Scholar
  34. 34.
    Rosenberg WMC, Voelker M, Thiel R, et al. Serum markers detect the presence of liver fibrosis: a cohort study. Gastroenterology. 2014;127:1704–13.Google Scholar
  35. 35.
    Toda K, Kumagai N, Kaneko F, et al. Pentoxifylline prevents pig serum-induced rat liver fibrosis by inhibiting interleukin-6 production. J Gastroenterol Hepatol. 2009;24:860–5.PubMedGoogle Scholar
  36. 36.
    Fontana RJ, Dienstag JL, Bonkovsky HL, et al. Serum fibrosis markers are associated with liver disease progression in non-responder patients with chronic hepatitis C. Gut. 2010;59:1401–9.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Arima Y, Kawabe N, Hashimoto S, et al. Reduction of liver stiffness by interferon treatment in the patients with chronic hepatitis C. Hepatol Res. 2010;40:383–92.PubMedGoogle Scholar
  38. 38.
    Andersen ES, Moessner BK, Christensen PB, et al. Lower liver stiffness in patients with sustained virological response 4 years after treatment for chronic hepatitis C. Eur J Gastroenterol Hepatol. 2011;23:41–4.PubMedGoogle Scholar
  39. 39.
    Park SH, Kim CH, Kim DJ, et al. Usefulness of multiple biomarkers for the prediction of significant fibrosis in chronic hepatitis B. J Clin Gastroenterol. 2011;45:361–5.PubMedGoogle Scholar
  40. 40.
    Chen J, Liu C, Chen H, et al. Study on noninvasive laboratory tests for fibrosis in chronic HBV infection and their evaluation. J Clin Lab Anal. 2013;27:5–11.PubMedGoogle Scholar
  41. 41.
    Koo JH, Lee MH, Kim SS, et al. Changes in serum histologic surrogate markers and procollagen III N-terminal peptide as independent predictors of HBeAg loss in patients with chronic hepatitis B during entecavir therapy. Clin Biochem. 2012;45:31–6.PubMedGoogle Scholar
  42. 42.
    Corpechot C, Carrat F, Poujol-Robert A, et al. Noninvasive elastography-based assessment of liver fibrosis progression and prognosis in primary biliary cirrhosis. Hepatology. 2012;56:198–208.PubMedGoogle Scholar
  43. 43.
    Corpechot C, Gaouar F, El Naggar A, et al. Baseline values and changes in liver stiffness measured by transient elastography are associated with severity of fibrosis and outcomes of patients with primary sclerosing cholangitis. Gastroenterology. 2014;146:970–9.PubMedGoogle Scholar
  44. 44.
    Alkhouri N, Carter–Kent C, Lopez R, et al. A combination of the pediatric NAFLD fibrosis index and enhanced liver fibrosis test identifies children with fibrosis. Clin Gastroenterol Hepatol. 2011;9:150–5.PubMedGoogle Scholar
  45. 45.
    Tomita K, Teratani T, Yokoyama H, et al. Serum immunoglobulin a concentration is an independent predictor of liver fibrosis in nonalcoholic steatohepatitis before the cirrhotic stage. Dig Dis Sci. 2011;56:3648–54.PubMedGoogle Scholar
  46. 46.
    Martinez-Hernandez A, Amenta PS. The hepatic extracellular matrix. I. Components and distribution in normal liver. Virchows Arch A Pathol Anat Histopathol. 1993;423:1–11.PubMedGoogle Scholar
  47. 47.
    Kefalides NA, Borel JP. Structural macromolecules: laminins, entactin/nidogen, and proteoglycans (Perlecan, Agrin). Curr Top Membr. 2005;56:147–97.Google Scholar
  48. 48.
    Birk DE, Brückner P. Collagens, suprastructures, and collagen fibril assembly. In: The extracellular matrix: an overview. Berlin: Springer; 2011. p. 77–115.Google Scholar
  49. 49.
    Kalluri R. Angiogenesis: basement membranes: structure, assembly and role in tumour angiogenesis. Nat Rev Cancer. 2003;3:422.PubMedGoogle Scholar
  50. 50.
    Wells RG. Cellular sources of extracellular matrix in hepatic fibrosis. Clin Liver Dis. 2008;12:759–68.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Mak KM, Mei R. Basement membrane type IV collagen and laminin: an overview of their biology and value as fibrosis biomarkers of liver disease. Anat Rec (Hoboken). 2017;300:1371–90.Google Scholar
  52. 52.
    Rojkind M, Ponce-Noyola P. The extracellular matrix of the liver. Coll Relat Res. 1982;2:151–75.PubMedGoogle Scholar
  53. 53.
    Murawaki Y, Ikuta Y, Koda M, et al. Comparison of serum 7S fragment of type IV collagen and serum central triple-helix of type IV collagen for assessment of liver fibrosis in patients with chronic viral liver disease. J Hepatol. 1996;24:148–54.PubMedGoogle Scholar
  54. 54.
    Murawaki Y, Ikuta Y, Nishimura Y, et al. Serum markers for connective tissue turnover in patients with chronic hepatitis B and chronic hepatitis C: a comparative analysis. J Hepatol. 1995;23:145–52.PubMedGoogle Scholar
  55. 55.
    Shimamura T, Nakajima Y, Une Y, et al. Serum levels of the type IV collagen 7s domain in patients with chronic viral liver diseases. Int J Oncol. 1996;8:153–7.PubMedGoogle Scholar
  56. 56.
    Niemela O, Risteli J, Blake JE, et al. Markers of fibrogenesis and basement membrane formation in alcoholic liver disease. Relation to severity, presence of hepatitis, and alcohol intake. Gastroenterology. 1990;98:1612–9.PubMedGoogle Scholar
  57. 57.
    Hirayama C, Suzuki H, Takada A, et al. Serum type IV collagen in various liver diseases in comparison with serum 7S collagen, laminin, and type III procollagen peptide. J Gastroenterol. 1996;31:242–8.PubMedGoogle Scholar
  58. 58.
    Yoneda M, Mawatari H, Fujita K, et al. Type IV collagen 7s domain is an independent clinical marker of the severity of fibrosis in patients with nonalcoholic steatohepatitis before the cirrhotic stage. J Gastroenterol. 2007;42:375–81.PubMedGoogle Scholar
  59. 59.
    Kojima H, Hongo Y, Harada H, et al. Long-term histological prognosis and serum fibrosis markers in chronic hepatitis C patients treated with interferon. J Gastroenterol Hepatol. 2001;16:1015–21.PubMedGoogle Scholar
  60. 60.
    Rosenberg WM, Voelker M, Thiel R, et al. Serum markers detect the presence of liver fibrosis: a cohort study. Gastroenterology. 2004;127:1704–13.PubMedGoogle Scholar
  61. 61.
    Montalto G, Soresi M, Aragona F, et al. Procollagen III and laminin in chronic viral hepatopathies. Presse medicale (Paris, France: 1983). 1996;25:59–62.Google Scholar
  62. 62.
    Hayasaka A, Schuppan D, Ohnishi K, et al. Serum concentrations of the carboxy terminal cross-linking domain of procollagen type IV (NC1) and the aminoterminal propetide of procollagen type III (PIIIP) in chronic liver disease. J Hepatol. 1990;10:17–22.PubMedGoogle Scholar
  63. 63.
    Tanwar S, Trembling PM, Guha IN, et al. Validation of terminal peptide of procollagen III for the detection and assessment of nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease. Hepatology. 2013;57:103–11.PubMedGoogle Scholar
  64. 64.
    Gluba A, Bielecka-Dabrowa A, Mikhailidis DP, et al. An update on biomarkers of heart failure in hypertensive patients. J Hypertens. 2012;30:1681–9.PubMedGoogle Scholar
  65. 65.
    Nielsen MJ, Nedergaard AF, Sun S, et al. The neo-epitope specific PRO-C3 ELISA measures true formation of type III collagen associated with liver and muscle parameters. Am J Transl Res. 2013;5:303.PubMedPubMedCentralGoogle Scholar
  66. 66.
    Nielsen MJ, Veidal SS, Karsdal MA, et al. Plasma Pro-C3 (N-terminal type III collagen propeptide) predicts fibrosis progression in patients with chronic hepatitis C. Liver Int. 2015;35:429–37.PubMedGoogle Scholar
  67. 67.
    Daniels S, Nielsen M, Krag A, et al. Serum Pro-C3 combined with clinical parameters is superior to established serological fibrosis tests at identifying patients with advanced fibrosis among patients with non-alcoholic fatty liver disease. J Hepatol. 2017;66:S671.Google Scholar
  68. 68.
    Karsdal MA, Henriksen K, Nielsen MJ, et al. Fibrogenesis assessed by serological type III collagen formation identifies patients with progressive liver fibrosis and responders to a potential antifibrotic therapy. Am J Physiol Gastrointest Liver Physiol. 2016;311:G1009–17.PubMedGoogle Scholar
  69. 69.
    Iacobelli S, Arno E, D’Orazio A, et al. Detection of antigens recognized by a novel monoclonal antibody in tissue and serum from patients with breast cancer. Cancer Res. 1986;46:3005–10.PubMedGoogle Scholar
  70. 70.
    Koths K, Taylor E, Halenbeck R, et al. Cloning and characterization of a human Mac-2-binding protein, a new member of the superfamily defined by the macrophage scavenger receptor cysteine-rich domain. J Biol Chem. 1993;268:14245–9.PubMedGoogle Scholar
  71. 71.
    Tinari N, Kuwabara I, Huflejt ME, et al. Glycoprotein 90K/MAC-2BP interacts with galectin-1 and mediates galectin-1-induced cell aggregation. Int J Cancer. 2001;91:167–72.PubMedGoogle Scholar
  72. 72.
    Resnick D, Pearson A, Krieger M. The SRCR superfamily: a family reminiscent of the Ig superfamily. Trends Biochem Sci. 1994;19:5–8.PubMedGoogle Scholar
  73. 73.
    Trahey M, Weissman IL. Cyclophilin C-associated protein: a normal secreted glycoprotein that down-modulates endotoxin and proinflammatory responses in vivo. Proc Natl Acad Sci U S A. 1999;96:3006–11.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Ochieng J, Leite-Browning ML, Warfield P. Regulation of cellular adhesion to extracellular matrix proteins by galectin-3. Biochem Biophys Res Commun. 1998;246:788–91.PubMedGoogle Scholar
  75. 75.
    Kamada Y, Ono M, Hyogo H, et al. A novel noninvasive diagnostic method for nonalcoholic steatohepatitis using two glycobiomarkers. Hepatology. 2015;62:1433–43.PubMedGoogle Scholar
  76. 76.
    Haji-Ghassemi O, Gilbert M, Spence J, et al. Molecular basis for recognition of the cancer glycobiomarker, LacdiNAc (GalNAc[beta1-->4]GlcNAc), by Wisteria floribunda Agglutinin. J Biol Chem. 2016;291:24085–95.PubMedPubMedCentralGoogle Scholar
  77. 77.
    Kuno A, Sato T, Shimazaki H, et al. Reconstruction of a robust glycodiagnostic agent supported by multiple lectin-assisted glycan profiling. Proteomics Clin Appl. 2013;7:642–7.PubMedGoogle Scholar
  78. 78.
    Yamasaki K, Tateyama M, Abiru S, et al. Elevated serum levels of Wisteria floribunda agglutinin-positive human Mac-2 binding protein predict the development of hepatocellular carcinoma in hepatitis C patients. Hepatology. 2014;60:1563–70.PubMedPubMedCentralGoogle Scholar
  79. 79.
    Abe M, Miyake T, Kuno A, et al. Association between Wisteria floribunda agglutinin-positive Mac-2 binding protein and the fibrosis stage of non-alcoholic fatty liver disease. J Gastroenterol. 2015;50:776–84.PubMedGoogle Scholar
  80. 80.
    Zou X, Zhu MY, Yu DM, et al. Serum WFA+ -M2BP levels for evaluation of early stages of liver fibrosis in patients with chronic hepatitis B virus infection. Liver Int. 2017;37:35–44.PubMedGoogle Scholar
  81. 81.
    Nishikawa H, Enomoto H, Iwata Y, et al. Impact of serum Wisteria floribunda agglutinin positive Mac-2-binding protein and serum interferon-gamma-inducible protein-10 in primary biliary cirrhosis. Hepatol Res. 2016;46:575–83.PubMedGoogle Scholar
  82. 82.
    Nishikawa H, Enomoto H, Iwata Y, et al. Clinical significance of serum Wisteria floribunda agglutinin positive Mac-2-binding protein level and high-sensitivity C-reactive protein concentration in autoimmune hepatitis. Hepatol Res. 2016;46:613–21.PubMedGoogle Scholar
  83. 83.
    Sterling RK, Lissen E, Clumeck N, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006;43:1317–25.PubMedPubMedCentralGoogle Scholar
  84. 84.
    Imperiale TF, Said AT, Cummings OW, et al. Need for validation of clinical decision aids: use of the AST/ALT ratio in predicting cirrhosis in chronic hepatitis C. Am J Gastroenterol. 2000;95:2328–32.PubMedGoogle Scholar
  85. 85.
    Wai CT, Greenson JK, Fontana RJ, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology. 2003;38:518–26.PubMedPubMedCentralGoogle Scholar
  86. 86.
    Bedossa P, Carrat F. Liver biopsy: the best, not the gold standard. J Hepatology. 2009;50:1–3.Google Scholar
  87. 87.
    Castera L, Pinzani M. Biopsy and non-invasive methods for the diagnosis of liver fibrosis: does it take two to tango? Gut. 2010;59(7):861–6. BMJ Publishing Group.PubMedGoogle Scholar
  88. 88.
    Kennedy OJ, Parkes J, Tanwar S, et al. The enhanced liver fibrosis (ELF) panel: analyte stability under common sample storage conditions used in clinical practice. J Appl Lab Med. 2017;1:720–8.Google Scholar
  89. 89.
    Nobili V, Parkes J, Bottazzo G, et al. Performance of ELF serum markers in predicting fibrosis stage in pediatric non-alcoholic fatty liver disease. Gastroenterology. 2009;136:160–7.PubMedGoogle Scholar
  90. 90.
    Parkes J, Roderick P, Harris S, et al. Enhanced liver fibrosis test can predict clinical outcomes in patients with chronic liver disease. Gut. 2010;59:1245–51.PubMedGoogle Scholar
  91. 91.
    Sands CJ, Guha IN, Kyriakides M, et al. Metabolic phenotyping for enhanced mechanistic stratification of chronic hepatitis C-induced liver fibrosis. Am J Gastroenterol. 2015;110:159–69.PubMedGoogle Scholar
  92. 92.
    Gumusay O, Ozenirler S, Atak A, et al. Diagnostic potential of serum direct markers and non-invasive fibrosis models in patients with chronic hepatitis B. Hepatol Res. 2013;43:228–37.PubMedGoogle Scholar
  93. 93.
    Karlas T, Dietrich A, Peter V, et al. Evaluation of transient elastography, acoustic radiation force impulse imaging (ARFI), and enhanced liver function (ELF) score for detection of fibrosis in morbidly obese patients. PLoS One. 2015;10:e0141649.PubMedPubMedCentralGoogle Scholar
  94. 94.
    Fagan KJ, Pretorius CJ, Horsfall LU, et al. ELF score >/=9.8 indicates advanced hepatic fibrosis and is influenced by age, steatosis and histological activity. Liver Int. 2015;35:1673–81.PubMedGoogle Scholar
  95. 95.
    Lichtinghagen R, Pietsch D, Bantel H, et al. The enhanced liver fibrosis (ELF) score: normal values, influence factors and proposed cut-off values. J Hepatol. 2013;59:236–42.PubMedGoogle Scholar
  96. 96.
    Williams AL, Hoofnagle JH. Ratio of serum aspartate to alanine aminotransferase in chronic hepatitis relationship to cirrhosis. Gastroenterology. 1988;95:734–9.PubMedGoogle Scholar
  97. 97.
    Lurie Y, Webb M, Cytter-Kuint R, et al. Non-invasive diagnosis of liver fibrosis and cirrhosis. World J Gastroenterol. 2015;21:11567.PubMedPubMedCentralGoogle Scholar
  98. 98.
    Zhu X, Wang L-C, Chen E-Q, et al. Prospective evaluation of FibroScan for the diagnosis of hepatic fibrosis compared with liver biopsy/AST platelet ratio index and FIB-4 in patients with chronic HBV infection. Dig Dis Sci. 2001;56:2742–9.Google Scholar
  99. 99.
    Shin W, Park S, Jang M, et al. Aspartate aminotransferase to platelet ratio index (APRI) can predict liver fibrosis in chronic hepatitis B. Dig Liver Dis. 2008;40:267–74.PubMedGoogle Scholar
  100. 100.
    Naveau S, Gaudé G, Asnacios A, et al. Diagnostic and prognostic values of noninvasive biomarkers of fibrosis in patients with alcoholic liver disease. Hepatology. 2009;49:97–105.PubMedGoogle Scholar
  101. 101.
    Sumida Y, Yoneda M, Hyogo H, et al. Validation of the FIB4 index in a Japanese nonalcoholic fatty liver disease population. BMC Gastroenterol. 2012;12:2.PubMedPubMedCentralGoogle Scholar
  102. 102.
    Biggins SW, Rodriguez HJ, Bacchetti P, et al. Serum sodium predicts mortality in patients listed for liver transplantation. Hepatology. 2005;41:32–9.PubMedGoogle Scholar
  103. 103.
    Kim WR, Biggins SW, Kremers WK, et al. Hyponatremia and mortality among patients on the liver-transplant waiting list. N Engl J Med. 2008;359:1018–26.PubMedPubMedCentralGoogle Scholar
  104. 104.
    Tateishi R, Yoshida H, Matsuyama Y, et al. Diagnostic accuracy of tumor markers for hepatocellular carcinoma: a systematic review. Hepatol Int. 2018;2:17–30.Google Scholar
  105. 105.
    Kudo M, Izumi N, Kokudo N, et al. Management of hepatocellular carcinoma in Japan: Consensus-Based Clinical Practice Guidelines proposed by the Japan Society of Hepatology (JSH) 2010 updated version. Dig Dis. 2011;29:339–64.PubMedGoogle Scholar
  106. 106.
    Omata M, Cheng AL, Kokudo N, et al. Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update. Hepatol Int. 2017;11:317–70.PubMedPubMedCentralGoogle Scholar
  107. 107.
    de Lope CR, Tremosini S, Forner A, et al. Management of HCC. J Hepatol. 2012;56(Suppl 1):S75–87.PubMedGoogle Scholar
  108. 108.
    Heimbach JK, Kulik LM, Finn RS, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 2018;67:358–80.PubMedGoogle Scholar
  109. 109.
    Kanwal F, Hoang T, Kramer JR, et al. Increasing prevalence of HCC and cirrhosis in patients with chronic hepatitis C virus infection. Gastroenterology. 2011;140:1182–1188.e1.PubMedGoogle Scholar
  110. 110.
    Mittal S, Sada YH, El-Serag HB, et al. Temporal trends of nonalcoholic fatty liver disease-related hepatocellular carcinoma in the veteran affairs population. Clin Gastroenterol Hepatol. 2015;13:594–601.e1.PubMedGoogle Scholar
  111. 111.
    Ertle J, Dechene A, Sowa JP, et al. Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis. Int J Cancer. 2011;128:2436–43.PubMedGoogle Scholar
  112. 112.
    Tokushige K, Hyogo H, Nakajima T, et al. Hepatocellular carcinoma in Japanese patients with nonalcoholic fatty liver disease and alcoholic liver disease: multicenter survey. J Gastroenterol. 2016;51:586–96.PubMedGoogle Scholar
  113. 113.
    Yasui K, Hashimoto E, Komorizono Y, et al. Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2011;9:428–33.PubMedGoogle Scholar
  114. 114.
    IuS T. Detection of embryo-specific alpha-globulin in the blood serum of a patient with primary liver cancer. Vopr Med Khim. 1964;10:90–1.Google Scholar
  115. 115.
    Kew M. Alpha-fetoprotein. In: Modern trends in gastroenterology, vol. 5; 1975. p. 91.Google Scholar
  116. 116.
    Koteish A, Thuluvath PJ. Screening for hepatocellular carcinoma. J Vasc Interv Radiol. 2002;13:S185–90.PubMedGoogle Scholar
  117. 117.
    McLeod JF, Cooke NE. The vitamin D-binding protein, alpha-fetoprotein, albumin multigene family: detection of transcripts in multiple tissues. J Biol Chem. 1989;264:21760–9.PubMedGoogle Scholar
  118. 118.
    Ruoslahti E, Seppala M. Studies of carcino-fetal proteins. 3. Development of a radioimmunoassay for -fetoprotein. Demonstration of -fetoprotein in serum of healthy human adults. Int J Cancer. 1971;8:374–833.PubMedGoogle Scholar
  119. 119.
    Ohtsubo K, Marth JD. Glycosylation in cellular mechanisms of health and disease. Cell. 2006;126:855–67.PubMedGoogle Scholar
  120. 120.
    Callewaert N, Van Vlierberghe H, Van Hecke A, et al. Noninvasive diagnosis of liver cirrhosis using DNA sequencer-based total serum protein glycomics. Nat Med. 2004;10:429–34.PubMedGoogle Scholar
  121. 121.
    Ito K, Kuno A, Ikehara Y, et al. LecT-hepa, a glyco-marker derived from multiple lectins, as a predictor of liver fibrosis in chronic hepatitis C patients. Hepatology. 2012;56:1448–56.PubMedGoogle Scholar
  122. 122.
    Miyoshi E, Moriwaki K, Nakagawa T. Biological function of fucosylation in cancer biology. J Biochem. 2008;143:725–9.PubMedGoogle Scholar
  123. 123.
    Hashimoto S, Asao T, Takahashi J, et al. alpha1-acid glycoprotein fucosylation as a marker of carcinoma progression and prognosis. Cancer. 2004;101:2825–36.PubMedGoogle Scholar
  124. 124.
    Wang M, Long RE, Comunale MA, et al. Novel fucosylated biomarkers for the early detection of hepatocellular carcinoma. Cancer Epidemiol Biomark Prev. 2009;18:1914–21.Google Scholar
  125. 125.
    Okuyama N, Ide Y, Nakano M, et al. Fucosylated haptoglobin is a novel marker for pancreatic cancer: a detailed analysis of the oligosaccharide structure and a possible mechanism for fucosylation. Int J Cancer. 2006;118:2803–8.PubMedGoogle Scholar
  126. 126.
    Noda K, Miyoshi E, Gu J, et al. Relationship between elevated FX expression and increased production of GDP-L-fucose, a common donor substrate for fucosylation in human hepatocellular carcinoma and hepatoma cell lines. Cancer Res. 2003;63:6282–9.PubMedGoogle Scholar
  127. 127.
    Breborowicz J, Mackiewicz A, Breborowicz D. Microheterogeneity of alpha-fetoprotein in patient serum as demonstrated by lectin affino-electrophoresis. Scand J Immunol. 1981;14:15–20.PubMedGoogle Scholar
  128. 128.
    Taketa K, Izumi M, Ichikawa E. Distinct molecular species of human alpha-fetoprotein due to differential affinities to lectins. Ann N Y Acad Sci. 1983;417:61–8.PubMedGoogle Scholar
  129. 129.
    Aoyagi Y. Carbohydrate-based measurements on alpha-fetoprotein in the early diagnosis of hepatocellular carcinoma. Glycoconj J. 1995;12:194–9.PubMedGoogle Scholar
  130. 130.
    Sato Y, Nakata K, Kato Y, et al. Early recognition of hepatocellular carcinoma based on altered profiles of alpha-fetoprotein. N Engl J Med. 1993;328:1802–6.PubMedGoogle Scholar
  131. 131.
    Taketa K, Endo Y, Sekiya C, et al. A collaborative study for the evaluation of lectin-reactive alpha-fetoproteins in early detection of hepatocellular carcinoma. Cancer Res. 1993;53:5419–23.PubMedGoogle Scholar
  132. 132.
    Yamashita F, Tanaka M, Satomura S, et al. Prognostic significance of Lens culinaris agglutinin A-reactive alpha-fetoprotein in small hepatocellular carcinomas. Gastroenterology. 1996;111:996–1001.PubMedGoogle Scholar
  133. 133.
    Kagebayashi C, Yamaguchi I, Akinaga A, et al. Automated immunoassay system for AFP-L3% using on-chip electrokinetic reaction and separation by affinity electrophoresis. Anal Biochem. 2009;388:306–11.PubMedGoogle Scholar
  134. 134.
    Suzuki M, Shiraha H, Fujikawa T, et al. Des-gamma-carboxy prothrombin is a potential autologous growth factor for hepatocellular carcinoma. J Biol Chem. 2005;280:6409–15.PubMedGoogle Scholar
  135. 135.
    Liebman HA, Furie BC, Tong MJ, et al. Des-γ-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma. N Engl J Med. 1984;310:1427–31.PubMedGoogle Scholar
  136. 136.
    Koike Y, Shiratori Y, Sato S, et al. Des-γ-carboxy prothrombin as a useful predisposing factor for the development of portal venous invasion in patients with hepatocellular carcinoma. Cancer. 2001;91:561–9.PubMedGoogle Scholar
  137. 137.
    Hagiwara S, Kudo M, Kawasaki T, et al. Prognostic factors for portal venous invasion in patients with hepatocellular carcinoma. J Gastroenterol. 2006;41:1214–9.PubMedGoogle Scholar
  138. 138.
    Suehiro T, Sugimachi K, Matsumata T, et al. Protein induced by vitamin K absence or antagonist II as a prognostic marker in hepatocellular carcinoma. Comparison with alpha-fetoprotein. Cancer. 1994;73:2464–71.PubMedGoogle Scholar
  139. 139.
    Imamura H, Matsuyama Y, Miyagawa Y, et al. Prognostic significance of anatomical resection and des-γ-carboxy prothrombin in patients with hepatocellular carcinoma. Br J Surg. 1999;86:1032–8.PubMedGoogle Scholar
  140. 140.
    Toyoda H, Kumada T, Kiriyama S, et al. Prognostic significance of simultaneous measurement of three tumor markers in patients with hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2006;4:111–7.PubMedGoogle Scholar
  141. 141.
    Fujikawa T, Shiraha H, Ueda N, et al. Des-gamma-carboxyl prothrombin-promoted vascular endothelial cell proliferation and migration. J Biol Chem. 2007;282:8741–8.PubMedGoogle Scholar
  142. 142.
    Filmus J, Selleck SB. Glypicans: proteoglycans with a surprise. J Clin Invest. 2001;108:497–501.PubMedPubMedCentralGoogle Scholar
  143. 143.
    Filmus J, Church JG, Buick RN. Isolation of a cDNA corresponding to a developmentally regulated transcript in rat intestine. Mol Cell Biol. 1988;8:4243–9.PubMedPubMedCentralGoogle Scholar
  144. 144.
    Li M, Choo B, Wong ZM, et al. Expression of OCI-5/glypican 3 during intestinal morphogenesis: regulation by cell shape in intestinal epithelial cells. Exp Cell Res. 1997;235:3–12.PubMedGoogle Scholar
  145. 145.
    Farooq M, Hwang SY, Park MK, et al. Blocking endogenous glypican-3 expression releases Hep 3B cells from G1 arrest. Mol Cells. 2003;15:356–60.PubMedGoogle Scholar
  146. 146.
    Capurro M, Wanless IR, Sherman M, et al. Glypican-3: a novel serum and histochemical marker for hepatocellular carcinoma. Gastroenterology. 2003;125:89–97.PubMedGoogle Scholar
  147. 147.
    Zhu Z, Friess H, Wang L, et al. Enhanced glypican-3 expression differentiates the majority of hepatocellular carcinomas from benign hepatic disorders. Gut. 2001;48:558–64.PubMedPubMedCentralGoogle Scholar
  148. 148.
    Jia X, Liu J, Gao Y, et al. Diagnosis accuracy of serum glypican-3 in patients with hepatocellular carcinoma: a systematic review with meta-analysis. Arch Med Res. 2014;45:580–8.PubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Yoshio Sumida
    • 1
    Email author
  • Yoshihiro Kamada
    • 2
  • Masaki Iwai
    • 3
  • Paul Y. Kwo
    • 4
  • Masashi Yoneda
    • 1
  1. 1.AichiJapan
  2. 2.OsakaJapan
  3. 3.KyotoJapan
  4. 4.CaliforniaUSA

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