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Current and Emerging Molecular Markers of Liver Diseases: A Pathogenic Perspective

  • Yuanxin Liang1,
  • Grace L Guo2,3 and
  • Lanjing Zhang4,5,6,7,* 
Gene Expression   2022;21(1):9-19

doi: 10.14218/GEJLR.2022.00010

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Citation: Liang Y, Guo GL, Zhang L. Current and Emerging Molecular Markers of Liver Diseases: A Pathogenic Perspective. Gene Expr. 2022;21(1):9-19. doi: 10.14218/GEJLR.2022.00010.

Abstract

In the past decade, with the rapid development of molecular medicine and the application of more sophisticated methods for disease diagnosis and treatment, a number of molecular markers have become available for liver diseases. Pathogenesis-related markers are likely to be effectively discovered and rigorously validated, due to the unique biological links to diseases. The present study reviews the predominant clinical and research articles in the previous decade to provide a pathogenic perspective of current and emerging biomarkers for liver diseases, including hepatocellular neoplasms (e.g. hepatocellular carcinoma), non-neoplastic hepatocellular diseases, intrahepatic biliary diseases, and other liver diseases. Although it remains challenging to cover all markers for the diagnosis and prognosis of liver diseases, current and emerging molecular markers in clinical practice and under investigation are reviewed in a wide spectrum of liver diseases, in order to help clinicians and researchers identify liver disease markers for reference.

Keywords

Molecular, Marker, Liver, Pathogenic

Introduction

Chronic liver disease and cirrhosis account for 44,000 deaths in the United States and two million deaths worldwide each year, and primary liver cancer was diagnosed in more than 40,000 adults in 2022 in the United States, as estimated by the American Society of Clinical Oncology.1 This leads to the high burden of disability, and increases healthcare utilization. A number of traditional liver markers, including serologic and immunohistochemical markers, do not directly reflect the liver disease mechanism. Therefore, there is a need to identify better molecular markers for its diagnosis and prognosis. In the past decade, with the rapid progress of molecular medicine and the application of more sophisticated methods for disease diagnosis and treatment, a number of molecular markers have become available for liver diseases.2–6 The present review provides a summary of current and emerging molecular markers for common liver diseases. Emerging proteomic and artificial intelligence tools can greatly help identify more sensitive, yet specific, markers.7,8 However, a common challenge in developing molecular markers for liver diseases, as in other fields, is to determine how to effectively identify and rigorously validate these.4 Pathogenesis-related markers may be the best leads for unique biological links to disease development, and these would likely provide a high-yield. Hence, the present review provides a pathogenic perspective on current and emerging biomarkers for liver diseases. It is noteworthy that molecular markers may be associated with and important for predicting the progression of some liver diseases. However, due to the limited space and scope of the present review, this topic was not discussed at length, despite its importance.

Molecular markers for hepatocellular diseases

Malignant hepatocellular tumors

Hepatocellular carcinoma (HCC)

More than 90% of HCCs are correlated to a known etiology,9 and hepatocarcinogenic mechanisms can be classified as etiologically specific and nonspecific mechanisms.10 Specific mechanisms include hepatitis B via viral integration, with the constant cis- and trans-activation of oncogenic factors,11 hepatitis C via the oncogenic effects of the core antigen and NS5A protein,12,13 and aflatoxin via direct genotoxic effects, leading to TP53 codon 249 mutations.14 Nonspecific mechanisms accumulate the abnormalities imposed by chronic liver diseases.15 HCC usually develops from chronic liver disease to a dysplastic nodule, prior to progression into HCC. The molecular markers for high-grade dysplasia include telomere shortening, telomerase reverse transcriptase (TERT) activation, and cell-cycle checkpoint inactivation.16 Early HCC accumulates mutations in CTNNB1, which encodes β-catenin, and progressed HCC further presents with TP53 mutations, DNA amplification, alterations in methylations, and other genetic abnormalities.17 Multiple immunohistochemical markers are used to assist in the HCC diagnosis: polyclonal CEA, CD10, HepPar, arginase-1, and albumin in situ hybridization (ISH) are used as hepatocellular markers, while glypican-3, glutamine synthetase (GS), HSP70, CD34, alpha-fetoprotein (AFP) and clusterin are used to identify hepatocellular malignancy.2 HSP70, glypican-3 and GS have been recommended in international guidelines.18 Molecular testing is used for DNAJB1-PRKACA translocation, in order to diagnose fibrolamellar variant HCCs.3

Serologically, due to the low sensitivity (20%) in early HCC and fluctuating levels in cirrhosis, AFP was removed from the present screening assessment guidelines of the Canadian Association for the Study of the Liver (CASL), and the European Association for the Study of the Liver (EASL).19,20 However, AFP is still presently used with other serological biomarkers, such as Lens culinaris-agglutinin-reactive fraction of AFP, and protein-induced by vitamin K absence or antagonist-II (PIVKA-II), for high risk populations.21 Furthermore, studies have determined the des-gamma-carboxy prothrombin in patients with negative AFP. The results revealed that AFP was positive in 67% of HCCs, while AFP was negative in 66% of small HCCs and 20% of all HCCs.22,23 However, none of the serologic markers were accepted by clinical practice guidelines for HCC screening due to cost-effectiveness, challenges in availability, and study result variations.19

Numerous markers are under investigation. Autophagy-related genes and their regulatory proteins are associated with HCC, including Beclin-1, ATG5 and ATG7, and these control a large number of molecular pathways in HCC oncogenesis, such as phosphatidylinositol-4,5-bisphosphate 3-kinase PI3K/AKT/mTOR, ERK/mitogen-activated protein kinase (MAPK), and apoptosis p53 pathways.24,25 For example, the ATG-4B mRNA expression controlled by autophagy-related genes may contribute to HCC development via the noncoding of miRNA-661, and this has been proven to be clinically useful, with 100% sensitivity, in a clinical validation, especially in early-stage HCC.26 Furthermore, HBV-related HCC is associated with mutated TP53, which involves the genetic integration with host genomes.27 HCV-related HCC overexpress the Kinesin family member 20A, Cyclin B1, Hyaluronan-mediated motility receptor, and other genes. In addition, these markers are linked to lower survival in patients with HCV-associated HCC.28 A study on IL-28 genetic polymorphisms revealed the association of the T allele with higher risk of HCC development.29 Another study revealed that two genotypes of certain single nucleotide polymorphisms (SNPs) of IL-28 were associated with lower risk of HCC development.30 Thus, the role of IL28 in diagnosing and prognosticating HCC appears unclear, if not contradictory.

Molecular factors are also used for the prognosis. Cytokeratin 19 (CK19) positivity is associated with increased recurrence rates, nodal metastasis, and more resistance to trans-arterial chemoembolization and percutaneous radiofrequency ablation.31–33 The expression of miR-1180-3p increases in HCC, and is linked to tumor proliferation and poor survival.34 A study conducted on KEGG pathways revealed that this epigenetic marker is associated with the regulation of the MAPK pathway, cell proliferation, apoptosis, and cell differentiation.34

Immune checkpoint proteins drive signaling pathways that suppress T-cell function,35 including PD-1, PD-L1 and CTLA-4. Nivolumab was the first US Food and Drug Administration (FDA)-approved anti-PD-1 antibody for treating HCC. In addition, in 2020, the FDA granted the accelerated approval to nivolumab, in combination with ipilimumab, which targets CTLA-4 for the treatment of patients with HCC, who were previously treated with sorafenib.36 Furthermore, a study has recommended the anti-PD-1 antibody agent for PD-L1 positive HCC patients.37 Tumor mutation burden and microsatellite instability (MSI)/mismatch repair (MMR) are used to guide the immunotherapy for several cancers. These may play an important role in HCC immunotherapy in the future.2

Hepatoblastoma (HB)

Approximately 80% of HBs exhibit genetic alternations in the Wnt/β-Catenin signaling pathway. These alterations include the deletion of CTNNB1 exon 3, AXIN genes, and the APC gene.38–40 Overexpressed targets for Wnt signaling were also observed, such as cyclin D1, survivin and MYC. In addition, MYC further activates the Wnt signaling as a positive feedback mechanism.41 The genomic profiling of HB can be classified into two subtypes, based on genetic instability (gains of chromosomes 8q and 2p): the overexpression of hepatic progenitor cell markers (AFP, CK19 and EpCAM), and the upregulation of MYC. Tumors with genetic instability are more aggressive, with a higher grade, and are more likely to metastasize.42 Histopathologically, HBs can be classified as epithelial or mixed epithelial, and mesenchymal.43 Epithelial HB may consist of fetal, embryonal, small cell undifferentiated, cholangioblastic and macrotrabecular components. β-catenin and glutamine GS are expressed in mesenchymal and fetal components.44 Furthermore, AFP highlights less-differentiated epithelial components, and HepPar1 can be observed in more differentiated epithelial components. Moreover, glypican-3 is expressed in epithelial fetal and embryonal components.15 In addition, CK7 and CK19 are positive in cholangioblastic components. SMARCB (INI1) highlights all HB components, except for small cell undifferentiated components.15

Benign hepatocellular tumors

Focal nodular hyperplasia (FNH)

The pathogenesis of FNH has not been fully explored. The presence of large vessels and vascular anomalies suggest the etiology of focally elevated blood flow.45 Studies have revealed the altered expression of angiopoietin genes, ANGPT1 and ANGPT2, with an elevated ANGPT1:ANGPT2 ratio in FNH.46 The activation of the β-catenin pathway would result in a “map-like” GS expression, without mutations in CTNNB1 or AXIN1.47,48 The immunohistochemistry for FNH revealed that LFABP retained its normal expression, β-catenin was negative for nuclear expression, and serum amyloid A and C-reactive protein (CRP) were usually negative.6 Furthermore, patchy serum amyloid A or peri-septal CRP staining may be observed in some FNH cases.49

Hepatocellular adenoma (HCA)

HCAs are clonal benign neoplasms of four common subtypes: hepatocyte-nuclear-factor-1α mutated (H-HCA), β-catenin-mutated type with the upregulation of GS (b-HCA), inflammatory type (IHCA) with the serum-amyloid-A overexpression, and unclassified type.50 H-HCA demonstrates biallelic HNF1A and CYP1B1 inactivation mutations. Liver fatty-acid binding protein is the characteristic for this group. IHCA activates IL-6/JAK/STAT due to mutations of the IL6ST gene, which codes gp130, FRK, STAT3, GNAS and/or JAK1. C-reactive protein/serum amyloid A is usually diffuse positive, with a well-defined demarcation. The b-HCA- and β-catenin-activated IHCA (b-IHCA, having features of both IHCA and b-HCA) presents with CTNNB1-activated genomic abnormalities, leading to β-catenin pathway activation. Immunohistochemical marker GS is a good surrogate for genetic abnormality. GS diffuse homogeneous overexpression indicates the exon 3 mutation, GS heterogeneous staining with a starry-sky pattern indicates the exon 3 S45 mutation, and a GS faint expression indicates the exon 7/8 mutation. The exon 3 mutation is usually associated with high risk of HCC.15

The term, “borderline lesion” or “atypical hepatocellular neoplasm,” has been used for b-HCA with cytologic atypia, but this remains insufficient for the diagnosis of HCC. This type has a high likelihood of HCC development. The TERT promoter mutation, as a typical genetic change in HCC, is usually identified in b-HCA/b-IHCA, with malignant transformations.51,52 Since surgical resection is recommended for b-HCA/b-IHCA and borderline lesion, it is crucial for β-catenin activation to be detected for CTNNB1 mutations. Molecular testing for CTNNB1 genomic abnormalities, TERT promoter mutations, and chromosomal gains (1, 7 and 8) may be warranted when GS immunostaining is equivocal.15

In addition to the common HCA subtypes, sonic hedgehog HCA (shHCA) has been reported to present with somatic deletions of INHBE, leading to the fusion of INHBE and GLI1, and this special group may be identified by PTGDS immunostaining.53 Argininosuccinate synthase 1 (ASS1) overexpression has been reported in another subtype of HCA (ASS1-positive HCA), and both subtypes are associated with high risk of hemorrhage.

Non-neoplastic hepatocellular diseases

Autoimmune hepatitis (AIH)

Autoimmune hepatitis (AIH) is an inflammatory liver disease in patients of all ages, and has female dominance. The key diagnostic criterion for all AIH scoring systems is the detection of autoantibodies.54 AIH type 1 can affect both adults and children, with characteristic positive anti-nuclear and/or anti-smooth muscle antibodies. On the other hand, AIH type 2 mostly affects children with characteristic positive anti-liver-kidney microsomal-1 and/or anti-liver cytosol-1 antibody. The autoantigens for type 2 AIH include cytochrome P4502D6 (CYP2D6)55 and formiminotransferase cyclodeaminase (FTCD),56 while those for type 1 AIH remain unclear. The genomic predisposition has been studied in AIH. Type 1 AIH presents with MHC class II HLA DRB1*03, which can be observed in all age groups, and DRB1*04, which is a late onset disease. Type 2 AIH presents with changes in DRB1*07 and DRB1*03.57 It has been reported that the serologic parameters of lymphocyte-to-platelet ratio (LPR) and immunoglobulin-to-platelet ratio (IGPR) are independently linked to the liver fibrosis stage in AIH patients without prior treatment.5

Metabolic-associated fatty liver disease (MAFLD)

MAFLD, which was previously termed as, non-alcoholic fatty liver disease, is defined by the presence of >5% steatosis and metabolic risk factors, especially type-2 diabetes, obesity and metabolic syndrome, with the exclusion of excessive alcohol use.58 The reasons for the interindividual variability may be attributable to the different genetic backgrounds, epigenetic modifications and epitranscriptomics, and these are the recently described biological determinants.59 Genetic variants involved in liver lipid-metabolism are the major genetic risk factors for MAFLD, which include PNPLA3, TM6SF2, GCKR, MBOAT7, and HSD17B13.60,61 Furthermore, epitranscriptomics is an emerging field, which helps understand how chemical RNAs and their modifications control RNA structures and functions, without changing the sequences. A large number (>100) of chemical RNA modifications have been described. Among these, N6-methyladenosine (m6 A) plays an important role in glucose and lipid homeostasis, and is involved in the progression of MAFLD.62 In light of the gut-liver crosstalk, gut-specific PPARα may be applied as a novel target and predictive biomarker of NAFLD treatment.63

Hemochromatosis (HC)

HC is genetically heterogeneous, exhibits the uncontrolled iron absorption in the small intestine, and may present with progressive iron overload.64 Its complications include arthritis, diabetes, heart failure, hepatic cirrhosis, and HCC.65 Recent reviews and guidelines have classified HC into four types, based on its genotype-phenotype correlation, and type 2 and type 4 were further subdivided into subtypes A and B. The involved genes are, as follows: type 1, HFE; type 2a, HJV (hemojuvelin); type 2b, HAMP (hepcidin); type 3, TFR2 (transferrin receptor 2); type 4a and 4b, both SLC40a1 (ferroportin).66,67 Although type 4a and 4b are associated with the same gene, the transferrin saturation (TSAT) in type 4a is usually low-to-normal, unlike the elevated TSAT in type 4b and other types. Liver biopsy is usually used to predict the disease progression and outcomes of patients with repeatedly high serum ferritin levels (>1,000 µg/L), and helps prevent and identify advanced fibrosis or subclinical cirrhosis before cirrhosis is developed. Indeed, the close surveillance for HCC is warranted, even for patients treated with iron depletion, when advanced fibrosis or subclinical cirrhosis is identified.67

Molecular markers of intrahepatic biliary diseases

Intrahepatic cholangiocarcinoma (iCCA)

iCCA is a malignant intrahepatic epithelial neoplasm with biliary differentiation, and expresses biliary markers, such as epithelial membrane antigen (EMA), CK7 and CK19. There are two subtypes of iCCA: large duct and small duct. Large duct iCCA may develop from biliary intraepithelial neoplasia or intraductal papillary neoplasm of the bile ducts,68,69 while the carcinogenesis of small duct iCCA has not been fully explored. This may develop from liver progenitor cells,70 or from transformed and transdifferentiated hepatic progenitor cells, or mature hepatocytes.71,72 Due to the different cell origins of large duct and small duct iCCA, the expression of a number of markers differs between these two subtypes. Small duct iCCA is positive for CD56, C-reactive protein, N-cadherin and IDH1/2 mutations, while large duct iCCA is positive for MUC5AC, MUC6, S100, TTF1, AGR2, MMP7 and KRAS mutations.73–75 Based on the integrative analysis of expression and mutation profiles, iCCA can be classified into proliferation and inflammation subclasses. The inflammation subclass presents with the activation of inflammatory pathways, the overexpression of cytokine IL10/IL6, and STAT activation. The proliferation subclass presents with the activation of oncogene signaling pathways, with the positivity of RAS, MAPK, c-MET, BRAF and KRAS. The proliferation subclass genomically resembles poor-prognostic HCC.15 The C-reactive protein expression in iCCA is associated with a better prognosis, while the EMA expression implies a worse prognosis.71,76 Small duct iCCA has better overall survival and longer time to recurrence, when compared to large duct iCCA.77

Benign biliary tumors

Bile duct adenoma (BDA)

The pathogenesis of BDA remains controversial. It has been considered that BDA is a reactive process, due to post-inflammatory or traumatic injury.78 Subsequent studies have revealed that the majority of BDAs bear the BRAF V600E mutation, and some are associated with cholangiocarcinoma, which suggests the neoplastic process of BDA.79,80 Similar to normal bile ducts, cytokeratin CK7 and CK19 are expressed in BDA, since these also express other foregut antigens, MUC6, MUC5AC and TTF2.81 In order to distinguish BDA from iCCA, the immunohistochemistry for low Ki67 and wild-type p53 may be helpful. Some authors have reported to use EZH2 negativity and p16 positivity to assist in the BDA diagnosis.82,83

Biliary adenofibroma (BAF)

BAF is considered as a primary epithelial neoplasm with secondary stomal changes.84 Although the morphology of BAF resembles the von Meyenburg complex, the immunohistochemical profile remains different. In addition to the expression of EMA, CK7, CK19 and CA19-9, BAF also presents with the amplifications of CCND1 and ERBB2, suggesting its neoplastic nature. Furthermore, the CDKN2A mutation was reported in a case with malignant transformation.85

Non-neoplastic bile duct diseases

Primary biliary cholangitis (PBC)

The pathogenesis of PBC may be attributable to the genetic predisposition, environmental triggers, and complex interactions between the two.86 One of the hallmarks of PBCs is serologically positive anti-mitochondrial autoantibodies (AMAs). However, AMA is not the only autoantibody detected in PBC. For example, disease-specific antinuclear antibodies (ANA) are present in approximately 33% of PBC patients, and present with the characteristic multiple nuclear dots (MND) or a rim-like/membranous (RLM) pattern in indirect immunofluorescence in vitro.87 These patterns are diagnostic hallmarks of PBC, which can establish a diagnosis for PBC in patients without positive AMA (e.g. AMA-negative PBC patients with cholestasis).88 The primary target antigens in RLM-pattern-associated antibodies are nuclear envelope proteins p62 and gp210. The presence of these antibodies is associated with a higher mortality rate, even in the patients without bilirubinemia at the time of diagnosis.89,90

Unlike various autoimmune liver diseases, potential autoreactive liver resident NK cells are enriched in the livers of PBC patients, and exhibit an increase in cytotoxic activities against autologous biliary epithelial cells.91 Biliary epithelial cells express various antigens that allow interactions with the immune system, such as CD1d activates NK T cells.92 Activated biliary epithelial cells are important for maintaining the characteristic inflammation of PBC via chemokine CCL19, cytokines, and vascular cell adhesion molecule-1.93 However, to our knowledge, none of these markers have been proven for use as immunohistochemical markers for PBC diagnosis or prognosis.

Primary sclerosing cholangitis (PSC)

PSC is strongly associated with aberrant HLA alleles.94 The strong link between PSC and inflammatory bowel disease leads to the “microbiota hypothesis.” In the microbiota hypothesis, microbial molecules driven by intestinal dysbiosis reach the liver via portal circulation, and initiate a host of aberrant cholangiocytic behaviors (e.g. senescence).95–97 The histopathologic hallmark of PSC is obliterative-concentric periductal loose fibrosis (“onion skinning”), while its radiological hallmark is the “beaded” biliary trees. During PSC development, cholangiocytic activation leads to the recruitment and infiltration of CD68+ macrophages. These macrophages produce proinflammatory cytokines that activate other immune system cells, and secrete profibrotic mediators, such as TGF-β and platelet-derived growth factor (PDGF), which lead to the activation of hepatic stellate cells.98 Thus, cholangiocytes present with degenerative and atrophic changes, which in turn, causes biliary strictures, biliary occlusions (“bile duct scars”), and a “beaded” appearance on radiological imaging.99 Periodic acid-Schiff staining with diastase can reveal the significantly thickened bile duct basement membrane, with a specificity of 95%, for PSC diagnosis.100

Molecular markers of other liver diseases

Liver fibrosis

Most chronic liver diseases can progress to liver fibrosis, and form fibrous scars. Hepatic stellate cells, which are activated by chronic liver injury, are the major source of fibrous scars in liver fibrosis.101 Myofibroblasts, which are usually not present in normal livers, can be activated in the liver by chronic injury.102 Hepatic fibrosis is the formation of fibrous scars, and is the result of excessive extracellular matrix proteins. The primary source of extracellular matrix proteins are myofibroblasts,103 which are derived mainly from liver resident activated hepatic stellate cells and activated portal fibroblasts. Numerous molecular markers have been reported to be able to label myofibroblasts activated from hepatic stellate cells, including Desmin, CD146, CD105, GFAP, LRAT, Synemin, Synaptophysin, p75 (NGFR), PDGFRβ1, PPARγ, Adipor1, ADFP1, CD36, Cytoglobin, SPP1, LOX, LOXL2, NR1D2 and IL-17RA.104,105 Myofibroblasts may also derive from activated portal fibroblasts.106 The molecular markers that highlight myofibroblasts from this source are, as follows: THY1, Elastin, CD105, Cofilin, Fibulin2, Gremlin, NTPD2, Smoothelin, Calcitonin α, Mesothelin, uroplakin 1β, basonuclin 1, Asporin, Vitrin, IL-18R1 and COL15A1.107–110 The modulation of TGF-β signaling via the TLR4-MyD88–NF-κB axis provides a link between proinflammatory and profibrogenic signals.104 However, none of these molecular markers has been applied for diagnostic or therapeutic use.

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) and undifferentiated liver carcinoma (ULC)

The pathogenesis of cHCC-CCA and ULC remains unclear. cHCC-CCA is molecularly more similar to iCCA, when compared to HCC, and characteristic mutations have been identified in both HCC (CTNNB1) and iCCA (KRAS and IDH1).111–113 cHCC-CCA with progenitor cell morphology is often positive for fetal-type growth factor SALL4.75 Intermediate cell carcinoma of the liver is the term reserved for primary liver carcinoma with monotonous morphological features. These are intermediated between hepatocellular and cholagniocytic cytologic features, and monotonous tumor cells express some HCC and iCCA markers.114 Undifferentiated carcinoma lacks the definitive morphological and immunohistochemical features of any differentiation beyond the epithelial marker expression, and there is no evidence of specific carcinoma differentiation.15

Epithelioid hemangioendothelioma

Epithelioid hemangioendothelioma (EHE) is a malignant endothelial neoplasm that comprises epithelioid endothelial cells in myxohyaline or fibrous stroma. These tumor cells are positive for endothelial markers CD31, CD34, D2-40 and ERG.115 Cytokeratin CK8 and CK18 may be patchy positive in tumor cells.116 The characteristic feature of EHE is t(1;3)(p36;q25) translocation, leading to WWTR1-CAMTA1 gene fusion, and this has been identified in 90% of EHEs.117–119 Immunostaining marker CAMTA1 has been used in studies, presenting a positive result in 85–90% of cases.120,121

Cautionary notes

The present review focused on the current and emerging molecular markers of liver diseases through the lens of pathogenesis. Various diseases, such as various types of cancers, share common signal pathways during their development (e.g. p53, c-Myc and APC). Thus, a number of markers may be found to be useful for diagnosing diseases of other organs. However, these alternations should be interpreted with caution, and combined with other clinicopathological data.

These current and emerging molecular markers remain largely untested in a large population, and warrant additional studies, particularly clinical trials, in order to determine the clinical values. Furthermore, as a limitation of the present study, a number of these markers were qualitative, and not quantitative, which may be subjected to interpretation bias.

Conclusions

The present review discussed the current and emerging molecular markers of common liver diseases. Specific focus was given on molecular, immunohistochemical and serological markers for diagnostic assistance and prognostic prediction, from a pathogenic perspective. Due to the rapid development of this field, it remains challenging to cover all markers for the diagnosis and prognosis of liver diseases. Nevertheless, markers in clinical practice and under investigation were reviewed in a wide spectrum of liver diseases (Table 1).3,15–23,31–34,37–40,42,44,48,49,51,53,54,57,61,65,75,76,80,85,87,88,92,98,111,119,120 Machine learning tools and high-throughput proteomics would help reveal more-sensitive and more specific markers of liver diseases in the future.7,8

Table 1

Molecular markers of common liver diseases

DiseaseMarkerTest methodsPurposeStatus*Reference
Hepatocellular carcinomaCTNNB1 mutationSequencingDiagnosis of early HCCIn practice17
TP53 mutationSequencing; ImmunohistochemistryDiagnosisIn practice17
HSP70ImmunohistochemistryDiagnosisIn practice18
Glypican-3ImmunohistochemistryDiagnosisIn practice18
Glutamine synthetaseImmunohistochemistryDiagnosisIn practice18
Telomere lengthSouthern blottingDiagnosis of dysplasiaUnder Investigation16
DNAJB1-PRKACA translocationFISHDiagnosis of fibrolamellar variantUnder Investigation3
AFPSerologyScreeningIn practice (controversial)19,20
Lens culinaris-agglutinin-reactive fraction of AFPSerologyScreening (with AFP)Under investigation21
PIVKA-IISerologyScreening (with AFP)Under investigation21
des-gamma-carboxy prothrombinSerologyDiagnosis of HCCUnder investigation23
Dickkopf-1SerologyDiagnosis of HCCUnder investigation22
CK19immunohistochemistryPrognosis of HCCIn practice31–33
miR-1180-3pRT-PCRPrognosis of HCCUnder investigation34
PD-L1ImmunohistochemistryTherapy guidanceIn practice37
HepatoblastomaCTNNB1 exon 3 deletionSequencingDiagnosis of HBUnder investigation38
AXIN1/2PCR; SequencingDiagnosis of HBUnder investigation39
APCNot specifiedDiagnosis of HBUnder investigation40
MycWestern blot; PCRDiagnosis of HBUnder investigation42
β-CateninImmunohistochemistryDiagnosis of HBIn practice44
Glutamine synthetaseImmunohistochemistryDiagnosis of HBIn practice44
CK7/19ImmunohistochemistryDiagnosis of HBIn practice44
Focal nodular hyperplasiaAngioporitinRT-PCRDiagnosis of FNHUnder investigation48
serum amyloid AImmunohistochemistryDiagnosis of FNHUnder investigation49
Hepatocellular adenomaLiver fatty-acid binding proteinImmunohistochemistryDiagnosis of HNF1A-inactivated HCAIn practice15
C-reactive protein/ serum amyloid AImmunohistochemistryDiagnosis of inflammatory HCAIn practice15
Glutamine synthetaseImmunohistochemistryDiagnosis of β-catenin activated HCAIn practice15
TERT promoter mutationSequencingmalignant transformation of HCAUnder investigation51
PTGDSImmunohistochemistrysonic hedgehog HCAUnder Investigation53
Argininosuccinate synthase 1ImmunohistochemistryASS1-positive HCAUnder Investigation15
Autoimmune hepatitisAnti-smooth muscle antibodiesSerologyType 1 AIHIn practice54
anti-liver-kidney microsomal-1/anti-liver cytosol-1 antibodySerologyType 2 AIHIn practice54
MHC class II HLA DRB1*03/04ELISARisk assessment of type 1 AIHUnder Investigation57
DRB1*07/03ELISARisk assessment of type 2 AIHUnder Investigation57
Metabolic-associated fatty liver disease (MAFLD)PNPLA3Western blottingRisk assessmentUnder Investigation61
HemochromatosisHFESequencingType 1In practice65
HJVSequencingType 2aIn practice65
HAMP (hepcidin)SequencingType 2bIn practice65
TFR2SequencingType 3In practice65
SLC40a1 (ferroportin)SequencingType 4a and 4bIn practice65
Intrahepatic cholangiocarcinomaCK7/19ImmunohistochemistryDiagnosisIn practice15
CD56ImmunohistochemistrySmall duct typeIn practice15
C-reactive proteinImmunohistochemistrySmall duct type; Better prognosisIn practice15,76
MUC5AC/6ImmunohistochemistryLarge duct typeIn practice15
Bile duct adenomaBRAF V600E mutationPCRDiagnosisUnder Investigation80
Biliary adenomfibromaCDKN2aSequencingMalignant transformationUnder Investigation85
Primary biliary cholangitisAnti-mitochondrial autoantibodiesSerologyDiagnosisIn Practice87
anti-MND/RLM antibodiesSerologyDiagnosisUnder Investigation88
CD1dWestern blotDiagnosis (label cholangiocytes)Under Investigation92
Primary Sclerosing cholangitisCD68ImmunohistochemistryDiagnosis (label macrophages)Under Investigation98
Liver fibrosisTGFβRT-PCRDiagnosisUnder Investigation23
Combined hepatocellular-cholangiocarcinomaCTNNB1PCRDiagnosis (for HCC component)In practice111
KRAS/IDH1PCRDiagnosis (for iCCA component)In practice111
SALL4ImmunohistochemistryDiagnosisUnder Investigation75
Epithelioid hemangioendotheliomaWWTR1-CAMTA1 gene fusionRT-PCRDiagnosisIn Practice119
CAMTA1ImmunohistochemistryDiagnosisIn Practice120

*Since there were no guidelines to distinguish whether the marker is used in practice or under investigation, the status of the marker was based on the experience of the authors. AFP, alpha-fetoprotein; AIH, autoimmune hepatitis; APC, adenomatous polyposis coli; ASS1, Argininosuccinate synthase 1; BRAF, v-raf murine sarcoma viral oncogene homolog B1; CAMTA1, calmodulin-binding transcription activator 1; CD, cluster of differentiation; CDKN2a, cyclin-dependent kinase inhibitor 2A; CK, cytokeratin; CTNNB1, catenin beta 1; DNAJB1, DnaJ heat shock protein family (Hsp40) member B1; FNH, focal nodular hyperplasia; HB, hepatoblastoma; HCA, hepatocellular adenoma; HCC, hepatocellular carcinoma; HFE, homeostatic iron regulator protein; HJV, hemojuvelin; HSP70, heat shock protein 70; iCCA, intrahepatic cholangiocarcinoma; IDH1, Isocitrate Dehydrogenase 1; KRAS, Kirsten rat sarcoma viral oncogene homolog; MHC, major histocompatibility complex; Myc, MYC Proto-Oncogene; PD-L1, programmed death-ligand 1; PIVKA-II, protein induced by vitamin K absence-II; PNPLA3, patatin-like phospholipase domain-containing protein 3; PRKACA , protein kinase CAMP-activated catalytic subunit alpha; PTGDS, prostaglandin D2 synthase; SALL4, spalt like transcription factor 4; TERT, telomerase reverse transcriptase; TFR2, transferrin receptor 2; TGFβ, transforming growth factor beta; TP53, tumor protein p53; WWTR, WW domain containing transcription regulator 1.

Abbreviations

AFP: 

alpha-fetoprotein

AIH: 

autoimmune hepatitis

AMAs: 

anti-mitochondrial autoantibodies

APC: 

adenomatous polyposis coli

ASS1: 

Argininosuccinate synthase 1

BAF: 

biliary adenofibroma

BDA: 

bile duct adenoma

b-HCA: 

β

-catenin-mutated type with the upregulation of GS: 

BRAF: 

v-raf murine sarcoma viral oncogene homolog B1

CAMTA1: 

calmodulin-binding transcription activator 1

CD: 

cluster of differentiation

CDKN2a: 

cyclin-dependent kinase inhibitor 2A

cHCC-CCA: 

combined hepatocellular-cholangiocarcinoma

CK: 

cytokeratin

CRP: 

C-reactive protein

CTNNB1: 

catenin beta 1

DNAJB1: 

DnaJ heat shock protein family (Hsp40) member B1

EHE: 

epithelioid hemangioendothelioma

EMA: 

epithelial membrane antigen

FNH: 

focal nodular hyperplasia

GS: 

glutamine synthetase

HB: 

hepatoblastoma

HC: 

Hemochromatosis

HCA: 

hepatocellular adenoma

HCC: 

hepatocellular carcinoma

HFE: 

homeostatic iron regulator protein

H-HCA: 

hepatocyte-nuclear-factor-1α

mutated: 

HJV: 

hemojuvelin

HSP70: 

heat shock protein 70

iCCA: 

intrahepatic cholangiocarcinoma

IDH1: 

Isocitrate Dehydrogenase 1

IHCA: 

inflammatory type hepatocellular adenoma

ISH: 

in situ hybridization

KRAS: 

Kirsten rat sarcoma viral oncogene homolog

MAFLD: 

metabolic-associated fatty liver disease

MHC: 

major histocompatibility complex

Myc: 

MYC Proto-Oncogene

PBC: 

primary biliary cholangitis

PD-L1: 

programmed death-ligand 1

PIVKA-II: 

protein induced by vitamin K absence-II

PNPLA3: 

patatin-like phospholipase domain-containing protein 3

PRKACA: 

protein kinase CAMP-activated catalytic subunit alpha

PSC: 

primary sclerosing cholangitis

PTGDS: 

prostaglandin D2 synthase

SALL4: 

spalt like transcription factor 4

TERT: 

telomerase reverse transcriptase

TFR2: 

transferrin receptor 2

TGFβ: 

: 

transforming growth factor beta

TP53: 

tumor protein p53

ULC: 

undifferentiated liver carcinoma

WWTR: 

WW domain containing transcription regulator 1

Declarations

Acknowledgement

None.

Funding

This work was supported by the National Science Foundation (IIS-2128307 to L.Z.), the Veterans Administration (I01 BX002741 to G.L.G.), and the National Institutes of Health (1R37CA277812 to L.Z. and 1R01GM135258 to G.L.G.). The funders had no role in the writing of this work, or the decision to submit the same for publication.

Conflict of interest

The authors have no conflicts of interest related to this publication.

Authors’ contributions

YXL, GLG and LJZ contributed to the writing of the manuscript.

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