v
Search
Advanced Search

Publications > Journals > Journal of Clinical and Translational Hepatology > Article Full Text

  • Review Article
  • OPEN ACCESS

Progress in Biomarkers Related to Biliary Atresia

  • Fanyang Kong,
  • Rui Dong,
  • Gong Chen,
  • Song Sun,
  • Yifan Yang,
  • Jingying Jiang,
  • Lingdu Meng,
  • Huifen Chen,
  • Jiajie Zhu and
  • Shan Zheng* 
 Author information  Cite
Journal of Clinical and Translational Hepatology   2024;12(3):305-315

doi: 10.14218/JCTH.2023.00260

Abstract

Biliary atresia (BA) is a congenital cholestatic disease that can seriously damage children’s liver function. It is one of the main reasons for liver transplantation in children. Early diagnosis of BA is crucial to the prognosis of patients, but there is still a lack of reliable non-invasive diagnostic methods. Additionally, as some children are in urgent need of liver transplantation, evaluating the stage of liver fibrosis and postoperative native liver survival in children with BA using a straightforward, efficient, and less traumatic method is a major focus of doctors. In recent years, an increasing number of BA-related biomarkers have been identified and have shown great potential in the following three aspects of clinical practice: diagnosis, evaluation of the stage of liver fibrosis, and prediction of native liver survival. This review focuses on the pathophysiological function and clinical application of three novel BA-related biomarkers, namely MMP-7, FGF-19, and M2BPGi. Furthermore, progress in well-known biomarkers of BA such as gamma-glutamyltransferase, circulating cytokines, and other potential biomarkers is discussed, aiming to provide a reference for clinical practice.

Graphical Abstract

Keywords

Biliary atresia, Biomarkers, Diagnosis, Liver fibrosis, Native liver survival

Introduction

Biliary atresia (BA) is an idiopathic neonatal liver disease characterized by inflammatory and fibrotic obliteration of intrahepatic and external biliary ducts. It is often manifested as neonatal jaundice, cirrhosis, and portal hypertension.1 The etiology of BA is currently unknown. It may be associated with viral infection,2 environmental toxins like biliatresone,3,4 immune responses,5 and genetic susceptibility.6 BA is currently the main reason for liver transplantation in children,7 with a high incidence in East Asian countries. According to a survey in Taiwan, there is approximately one patient with BA in every 5,000 live births.8 The diagnosis of BA mainly depends on intraoperative cholangiography.1,9,10 Kasai portoenterostomy (KPE) is the first-line treatment for BA, with the primary goal of re-establishing bile drainage.11

An early diagnosis of BA is very important for patients. Children diagnosed with BA who receive KPE within 90 days after birth are likely to have better jaundice clearance and native liver survival rates.12 However, there is currently a lack of reliable non-invasive diagnostic methods, and distinguishing BA from other neonatal cholestatic diseases remains difficult. In addition, some patients will still develop cirrhosis after KPE and need liver transplantation.13 The early identification of high-risk children in need of liver transplantation can help doctors change the treatment strategy and reasonably allocate the liver source to improve the prognosis of patients. Simply and efficiently identifying high-risk patients who need liver transplantation has been the focus of pediatric surgeons.

In recent years, serum biomarkers in patients with BA have shown great potential in clinical diagnosis and prognosis assessments. Many biomarkers with high specificity and sensitivity are gradually being discovered. They are less invasive compared to intraoperative cholangiography. These biomarkers can be used for an early diagnosis of BA, assessment of liver fibrosis in patients, and prediction of native liver survival after KPE.

In this review, recent research progress on serum biomarkers in BA is summarized. We focus on the novel biomarkers of BA and those with high clinical values, including MMP-7, FGF-19, and M2BPGi. We emphasize their role in the pathophysiology of BA and their clinical application according to recent studies. The latest research progress on well-known biomarkers like gamma-glutamyltransferase (GGT) and circulating cytokines, as well as other newly discovered biomarkers, are also discussed.

MMP-7

Matrix metalloproteinases (MMPs) are key enzymes involved in the degradation and deposition of all proteins in the extracellular matrix and play an important role in the process of tissue remodeling and fibrosis.14 Huang et al.15 suggested that matrix metalloproteinase-7 (MMP-7) was overexpressed in liver biopsy samples and there was a significant difference when comparing the control group (children with no liver diseases) and the liver transplantation group among children with BA. Lertudomphonwanit et al.16 found that MMP-7 is also highly expressed in the sera of patients with BA, through large-scale, quantitative serum proteomics. Consequently, the significance of MMP-7 in BA has been receiving increasing attention.

There is a lack of research on the role of MMP-7 in the pathophysiology of BA, which may be presumed from lessons learned from other diseases.17 The first step is likely to be the damage to cholangiocytes from various causes, leading to the release of MMP-7.17,18 As previously mentioned, viral infections, environmental toxins, immune responses, and genetic susceptibility are possible triggers for BA. Specifically, the main viruses investigated in BA include cytomegalovirus (CMV), human herpesvirus-5, human papillomavirus, Epstein-Barr virus, and rotavirus rhesus.5 CMV infection is thought to be the most closely related to BA. This infection may cause disequilibrium of cytokine expression and reduction of regulatory T cells, resulting in an inflammatory response and subsequent bile duct injury.5 Biliatresone, a natural toxin found in plants, can damage extrahepatic cholangiocytes through decreased glutathione and SOX17 levels.19 Immune responses led by Th1, Th17, and Treg cells can also participate in the injury of the bile duct.5 Genome-wide association studies were carried out and identified several genes as susceptibility factors of BA. A previous review has summarized common genetic variants in BA.20 Many of these genetic variants, like ADD3 and GPC1,21,22 can directly or indirectly cause biliary developmental defects and biliary tract damage. It is important to note that these triggers have been mostly studied in experimental models. Whether they can cause damage to the biliary tract in humans still warrants further investigation. An overview of how MMP-7 may be involved in the pathophysiology of BA is shown in Figure 1. Firstly, MMP-7 can degrade collagen type IV; fibronectin; gelatin type I, III, IV, and V; laminin; entactin; and elastin, leading to tissue remodeling.23,24 Secondly, MMP-7 can promote inflammation through macrophages and neutrophils. MMP-7 can cleave latent tumor necrosis factor-alpha to its soluble form and subsequently induce infiltration of macrophages.25 Besides, it can shed the ectodomain of syndecan-1, thereby establishing a local chemokine gradient that controls the influx and activation of neutrophils.26,27 Finally, MMP-7 may play a crucial role in cell apoptosis. A study has shown that MMP-7 could shed and activate FAS ligands, thereby mediating epithelial cell apoptosis through FAS receptor.28 Another study found that MMP-7 can also shed E-cadherin, which is a cell-cell adhesion molecule, leading to reduced cell-to-cell contact and subsequent cell apoptosis.29,30 It can be seen from the above studies that MMP-7 may be involved in various aspects of the development of BA. However, further studies are required to confirm these findings.

Overview of how MMP-7 may be involved in the pathophysiology of biliary atresia.
Fig. 1  Overview of how MMP-7 may be involved in the pathophysiology of biliary atresia.

Viral infection, environmental toxin, immune responses, and genetic susceptibility, which are thought to be the causes of BA, may damage cholangiocytes, leading to the release of MMP-7. (A) MMP-7 can cleave latent tumor necrosis factor-alpha secreted by macrophages, leading to the activation of tumor necrosis factor-alpha and pro-inflammatory effects. (B) MMP-7 can shed the ectodomain of syndecan-1 and establish a local chemokine gradient, resulting in the influx and activation of neutrophils. (C) MMP-7 activates the FAS ligand, which can induce apoptosis of cholangiocytes by binding to the FAS receptor. (D) MMP-7 can shed E-cadherin and reduce cell-to-cell contact. Reduced E-cadherin can finally lead to apoptosis of cholangiocytes. (E) MMP-7 can degrade collagen type IV and other extracellular matrix, leading to tissue remodeling and participating in liver fibrosis. (Figure created on biorender.com). CMV, cytomegalovirus; GSH, glutathione; TNF-α, tumor necrosis factor-alpha; ECM, extracellular matrix.

The role of MMP-7 in the diagnosis of BA seems to be clear. The results of some important clinical studies on MMP-7 from 2018 to 2023 are shown in Table 1.31–40 According to the systematic review by He et al.,31 the sensitivity, specificity, and area under the curve of MMP-7 in the diagnosis of BA were 96%, 91%, and 0.9847, respectively. It is worth noting that the studies by Jiang et al.32 and Yang et al.33 were comparable, because they used the same enzyme-linked immunosorbent assay (ELISA) kit to detect serum MMP-7 concentration, both were conducted in China, and the median ages of the patients in the BA group were similar in the two studies. We found that the cut-off values produced by the two studies considerably differed. Although the sample size in the study by Jiang et al.32 was larger compared to that of Yang et al.,33 the former was a single-center study with fewer subjects from different regions. The subjects in the study by Jiang et al.32 seemed to have more severe liver damage because they had higher ALT and AST levels. This suggests that patients’ liver function may have an impact on the cut-off value of MMP-7. Grouping patients according to liver function and exploring their cut-off value of MMP-7 may be the direction of future research. Rohani et al.,34 Chi et al.,35 Sakaguchi et al.36 and Wu et al.37 used another kind of ELISA kit, but their cut-off values were also very different. The sample sizes of Rohani et al.,34 Wu et al.37 and Sakaguchi et al.36 were relatively small and their cut-off values may not be accurate. Besides, the time point of blood sample collection, methods of sample storage, and the regions of the patients in these studies were different, along with the disease distribution in the control group. Interestingly, both Yang et al.33 and Sakaguchi et al.36 found that MMP-7 levels in patients were positively correlated with age, while Rohani et al.34 suggested that there was no significant relationship between serum MMP-7 levels and age after adjusting for possible confounders (including GGT). Recently, Wu et al.41 suggested that the age-adjusted MMP-7 ratio could distinguish between BA and cholestasis, but there was no significant improvement in its sensitivity and specificity. This may indicate that the degree of liver injury, rather than age, is a crucial factor affecting serum MMP-7 levels. Current studies in this field have been mainly conducted in Asia, and studies in other regions and cross-regional studies are lacking. A recent study in the UK has shown that MMP-7 may also hold significance in the diagnosis of BA among Western patients.38 However, we found the sensitivity of MMP-7 in the diagnosis of BA was much lower in Western studies than in Asian studies, and the cut-off value was much higher. In addition to the use of different ELISA kits, this may also reflect ethnic differences in BA. Although most researchers have recognized the role of MMP-7 in the diagnosis of BA, some have questioned it. A study in Iran found the capability of the MMP-7 to distinguish BA from the non-BA cholestasis group fell significantly short of expectations.39 We note that this study used a different ELISA kit compared to other studies. Besides, in this study, serum samples were stored at −20°C instead of −70°C or −80°C as in other studies, which may have led to protein degradation. The composition of disease in the control group may also be an important factor influencing the results. According to the study, non-BA cholestasis diseases such as inspissated bile syndrome, tyrosinemia, galactosemia, and hemophagocytic lymphohistiocytosis were included in the control group in this study, while the control group of the other studies did not involve these diseases. Therefore, studying the expression level of MMP-7 in other cholestatic diseases may help to improve the diagnostic accuracy of MMP-7 in BA.

Table 1

Clinical studies on MMP-7 from 2018 to 2023

RegionCut-off value, ng/mLSensitivity, %Specificity, %Sample size of BA groupSample size of non-BA cholestasis groupReference
China52.8598.6795.00756033
China10.3795.1993.0718710132
China26.7396.7095.6021422635
China1.4397.3083.20366437
Japan18.60100.0090.00272936
India4.9996.0090.40252140
Iran7.8095.5094.5223234
Iran1.9084.6045.10133139
UK69.0068.0093.00322738
Meta-analysis/96.0091.00–31

BA, biliary atresia; MMP-7, matrix metalloproteinase-7; UK, United Kingdom.

Although the diagnostic significance of serum MMP-7 is steadily increasing, the ability of MMP-7 to assess the stage of liver fibrosis in children remains controversial. A study by Lertudomphonwanit et al.16 determined that there was no significant correlation between serum MMP-7 s and the stage of liver fibrosis in patients, while Jiang et al.32 and Chi et al.35 reported contrasting findings. It is worth noting that Lertudomphonwanit et al.16 and Jiang et al.32 used different systems to evaluate histological fibrosis. Besides, Leung et al.42 used shear wave velocity to measure liver stiffness, an indirect measure of fibrosis. They found that MMP-7 significantly correlates with increased liver stiffness in patients with BA (n = 187), supporting the findings of Jiang et al.32 and Chi et al.35

In addition, many researchers have tried to screen out high-risk children who may need liver transplantation after KPE based on their serum MMP-7 concentrations. Chi et al.35 tracked dynamic changes in MMP-7 concentrations and patient prognosis in children with BA from diagnosis to liver transplantation. They summarized four patterns of MMP-7 changes in these patients after KPE and found that changes in serum MMP-7 concentrations were a significant predictor of survival with the native liver in 2 years at 6 weeks post-KPE and the most accurate predictor at 3 months post-KPE. However, Sakaguchi et al.36 suggested that serum MMP-7 concentrations in patients before KPE as well as 1 and 4 weeks after KPE could not predict whether patients would need liver transplantation 1 year after KPE. According to Wu et al.,37 serum levels of MMP-7 6 months after KPE may predict the need for liver transplantation in patients with BA during the first 3-4 years after KPE. These three studies tracked changes in MMP-7 concentrations after KPE at different times. Long-term detection of MMP-7 levels after KPE may be necessary for doctors to predict the prognosis of patients.

FGF-19

Cholestasis is one of the main characteristics of BA. Studies in vivo and in vitro have confirmed that the accumulation of bile acids in cholestasis can trigger a hepatocyte-specific inflammatory response, leading to damage of the hepatic tissue and fibrosis.43 Fibroblast growth factor-19 (FGF-19) is an endocrine factor mainly secreted by the small intestine and plays an important role in the negative feedback regulation of bile acid synthesis.44,45 It is mainly expressed in the small intestine and is not expressed in the liver under physiological conditions.45–47Figure 2 shows the function of FGF-19 in physiological conditions and BA. In healthy conditions, bile acids are synthesized in the liver and stored in the gallbladder. After a meal, they are released into the duodenum, and 95% of them are reabsorbed in the ileum.45 Bile acids are transported into enterocytes via the apical sodium-dependent bile acid transporter.48 Subsequently, bile acids signal the farnesoid X receptor (FXR), which facilitates the transcription of FGF-19.49 FGF-19 reaches the liver via the portal vein and interacts with fibroblast growth factor receptor-4 and coreceptor b-Klotho on the membrane of the hepatocytes.48 Through subsequent activation of both extracellular signal-regulated kinase and Jun N-terminal kinase pathways, the transcription of the rate-limiting cytochrome P450 enzyme, cholesterol 7 alpha-hydroxylase, is downregulated, resulting in a downregulation of bile acid synthesis.45,48 In BA, the enterohepatic circulation of bile acids is blocked. However, recent studies have shown that hepatocytes can also express FGF-19 during cholestasis.50,51 Another study found that elevated circulating FGF-19 in patients with BA is of hepatic origin.52 Since FXR is also expressed in hepatocytes,48 we can infer that hepatocytes can express and secrete FGF-19 on their own in BA, resulting in reduced bile acid synthesis. Thus, FGF-19 may reflect the degree of cholestasis in BA. Furthermore, enterocytes can sense highly elevated levels of bile acids in the systemic circulation to induce FGF-19,53 indicating that bile acids may also have the ability to activate intestinal FXR-FGF-19 from the basolateral side of enterocytes.

Function of FGF-19 in physiological conditions and biliary atresia.
Fig. 2  Function of FGF-19 in physiological conditions and biliary atresia.

Bile acids are synthesized in the liver and released into the duodenum after meals. When bile acids reach the distal ileal, they are transported into the enterocytes via the apical sodium-dependent bile acid transporter. After they get into enterocytes, FXR on the nucleus is signaled, leading to the transcription of FGF-19. FGF-19 reaches the liver via the portal circulation and binds to the fibroblast growth factor receptor-4–b-Klotho complex on hepatocytes. Subsequently, cholesterol 7 alpha-hydroxylase is inhibited due to the activation of the intracellular Jun N-terminal kinase pathway. As a result, the synthesis of bile acid is downregulated. However, bile acids cannot reach the distal ileal in BA. It seems that excess bile acids can activate FXR in hepatocytes and induce the expression of FGF-19, which may activate the fibroblast growth factor receptor-4–b-Klotho complex on the membrane of hepatocytes and downregulate bile acid synthesis. Besides, bile acids in systemic circulation may also induce enterocytes to secret FGF-19, leading to the upregulation of FGF-19 in serum. Dashed lines represent potential pathways in BA. (Figure created on biorender.com). FGF-19, fibroblast growth factor-19; JNK, Jun N-terminal kinase; FGFR4, fibroblast growth factor receptor 4; KLB, b-Klotho; CYP7A1, cholesterol 7 alpha-hydroxylase; FXR, farnesoid X receptor; ASBT, apical sodium-dependent bile acid transporter.

Recently, FGF-19 has been used to predict native liver survival in BA. Johansson et al.52 found that serum FGF-19 was significantly reduced after KPE, particularly in the group of patients that went on to survive with their native liver at the age of 2 years.52 They focused on the origin and changes of FGF-19 in the sera of patients with BA. However, their study only included 14 children. To further explore the value of FGF-19 as a biomarker for KPE outcomes, Nyholm et al.54 analyzed the sera of 74 children with BA and found that patients with continued elevations of serum bilirubin after KPE had significantly higher serum levels of FGF-19 at KPE. When serum FGF-19 concentration at KPE exceeded 109 pg/mL, the native liver survival was significantly decreased, suggesting that the increased level of FGF-19 at KPE may indicate a poor prognosis. Importantly, this study revealed a positive correlation between serum primary bile acids and FGF-19 at the time of KPE. However, Johansson et al.52 did not find this correlation. The discrepancy in the results of the two studies may be attributed to the administration of ursodeoxycholic acid, an antagonist to FXR. It also indicated that ursodeoxycholic acid may influence the synthesis of FGF-19. In addition, Nyholm et al.54 suggested that serum FGF-19 was associated with ductular reaction in patients with BA. As FGF-19 has a direct ability to enhance proliferation, dedifferentiation, and transformation of cultured cholangiocytes,55 the specific mechanism of FGF-19 in BA-related ductular reaction is worth exploring. Although the study by Nyholm et al.54 had a relatively large sample size, their serum and biopsy samples were stored for more than 14 years. The degradation of protein and mRNA may have affected the accuracy of the results. Besides, the study by Nyholm et al.54 did not track changes in FGF-19 in children with BA after KPE. If the serum level of FGF-19 and the degree of ductular reaction can be tracked after KPE, the relationship between FGF-19 and ductular reaction can be clearly demonstrated. Furthermore, according to Johansson et al.,52 the change of FGF-19 after KPE may also be an important factor in predicting the prognosis of children with BA. Follow-up studies tracking the changes of FGF-19 in patients after KPE are required.

As increased serum FGF-19 levels may reflect liver injury and predict mortality in both primary biliary cholangitis and alcoholic hepatitis,51,56 they could serve as potential prognostic biomarkers for BA. However, only two studies are insufficient to support the current conclusions. More studies with larger sample sizes from different regions are needed to verify the role of FGF-19 in BA. The role of FGF19 in ductular reaction also needs to be investigated, as FGF19 may also be a biomarker of bile duct injury in patients with BA.

M2BPGi

Liver biopsy is still considered the gold standard for stratifying hepatic fibrosis.57 However, this technique is invasive, and histologic interpretations may vary.58 Mac-2 binding protein glycan isomer (M2BPGi), also called WFA-M2BP, is a novel marker of liver fibrosis, which has been confirmed in BA,59 primary biliary cirrhosis,60 autoimmune hepatitis,61 and non-alcoholic fatty liver disease.62,63 Although M2BPGi may be a common marker for evaluating liver fibrosis, M2BPGi COI values seem to differ among the causes of liver fibrosis.64 Therefore, it is worth studying in BA.

M2BPGi is mainly secreted by hepatic stellate cells (HSCs) in liver fibrosis and is involved in the interaction between HSCs and Kupffer cells (KCs).65 The role of M2BPGi in the progression of liver fibrosis is shown in Figure 3. Studies have found that HSCs are the source of M2BPGi.65,66 Exogenous M2BPGi can enhance Mac-2 expression by KCs.65 Furthermore, HSCs can be activated by KCs in the co-culture of HSCs and KCs. Activated HSCs differentiate into myofibroblast-like cells, characterized by the upregulation of alpha-smooth muscle actin (α-SMA).67 These activated HSCs can produce extracellular matrix proteins and play an important role in liver fibrosis.68 Inhibition of Mac-2 expression has been found to significantly impair the ability of KCs to enhance α-SMA expression by HSCs.65 Therefore, M2BPGi may be a juxtacrine-acting messenger sent by HSCs to KCs during liver fibrosis.

Role of M2BPGi in the progression of liver fibrosis.
Fig. 3  Role of M2BPGi in the progression of liver fibrosis.

Firstly, M2BPGi is secreted by HSCs. Next, M2BPGi enhances Mac-2 expression by KCs. Finally, Mac-2+ KCs markedly increased α-SMA expression by HSCs, leading to the activation of HSCs and the production of extracellular matrix. (Figure created on biorender.com). M2BPGi, mac-2 binding protein glycan isomer; HSC, hepatic stellate cell; KC, kupffer cell; α-SMA, alpha-smooth muscle actin; ECM, extracellular matrix.

Several studies from Japan have shown that M2BPGi shows great potential in the evaluation of liver fibrosis in BA. A study by Yamada et al.59 may have been the first to examine the value of M2BPGi in patients with BA. The study included 64 children with BA who underwent living donor liver transplantation; their blood samples were collected the day before transplantation. It was found that M2BPGi showed the strongest ability to predict grade F4 fibrosis (METAVIR fibrosis scores) in children with BA. The area under the curve value of M2BPGi was 0.917. There was high sensitivity (94.1%) and specificity (92.3%) when the cut-off value was 3.53 (C.O.I). However, 79.7 % of patients in the study developed grade F4 fibrosis. There were very few children with mild liver fibrosis, which may have led to a biased conclusion. Ueno et al.69 used the same method to test serum M2BPGi of 37 children with BA and also found that the median M2BPGi in patients with F4 liver fibrosis was significantly higher compared to patients with F0–F3 liver fibrosis. Despite the small sample size, the liver fibrosis stage in their patients was more evenly distributed. Furthermore, Ueno et al.70 tracked serum M2BPGi of 11 children with BA and suggested that the increase of serum M2BPGi in patients may be associated with the progression of liver fibrosis and the decline of liver function.

The research objects of the above three studies covered patients with BA who underwent liver transplantation, those with cirrhosis, and those with normal liver function. All results suggested that M2BPGi could help predict the stage of liver fibrosis in children with BA, especially in children with F4 liver fibrosis. To better understand the value of M2BPGi, studies from different regions with larger sample sizes and long-term follow-ups are warranted.

GGT

GGT is an enzyme that mainly exists in the cell membranes of the liver, kidney, pancreas, and other organs and plays an important role in the transport of amino acids.71 It is generally considered a sensitive but not highly specific indicator of liver function and is widely used in clinical practice.71 As the levels of GGT in the sera of BA patients are usually high,16,72,73 GGT has been widely used for the diagnosis of BA in recent decades. A previous study has shown that serum levels of GGT>300 U/L or a daily increase of 6 U/L could distinguish BA from neonatal hepatitis, with an accuracy of 85% and 88%, respectively.72 However, only 29 patients with BA were included in this study. In recent years, the diagnostic value of GGT in BA has been extensively studied, and some of the results are shown in Table 2.31–34,37,39,74–76 A study by Rendon-Macias et al.73 suggested that combining patient age with GGT levels could improve the reliability of diagnosis. However, the small sample size of their study affected the statistical power of the study. Chen et al.77 enrolled 1,338 children with BA and 131 children with obstructive jaundice and divided them into different age groups, aiming to investigate the cut-off value of GGT in different age groups. Although a large number of patients were included in this study, information on patients younger than 30 days of age is lacking. Recently, Weng et al.74 conducted a multicenter study that divided patients into different age groups. The cut-off value of GGT in patients younger than 30 days was reported in this study. Interestingly, Chen et al.77 and Weng et al.74 both found that the cut-off value of GGT peaks between 61 and 90 days after birth. This interesting finding may indicate that the diagnostic cut-off value of GGT is not simply positively correlated with age but fluctuates with age. Although GGT may not be as accurate as MMP-7 for the diagnosis of BA, it can be used as an alternative when MMP-7 testing is unavailable. Besides, the abovementioned studies were conducted mainly in China. Studies should be conducted in different regions to generalize the conclusion.

Table 2

Studies on the diagnostic value of gamma-glutamyl transferase in biliary atresia

RegionCut-off value, IU/LSensitivity, %Specificity, %Sample size of BA groupSample size of non-BA cholestasis groupReference
China31464.0071.67756033
China18586.0273.2718710132
China5.8*78.6079.601,51221675
China350.059.3085.4015057574
China21683.3384.37366437
Egypt28676.7080.00303076
Iran434.577.3077.80223234
Iran23084.6090.30133139
Meta-analysis/80.0079.00–31

*The value here is In (GGT). BA, biliary atresia; GGT, gamma-glutamyltransferase.

Circulating cytokines

The inflammatory response is one of the important reasons for biliary tract injury in patients with BA.5 As circulating cytokines play an important role in immune inflammatory responses in the systemic and local environment, changes in these inflammatory molecules in serum are generally considered potential biomarkers of tissue damage, and damage to the hepatobiliary system is no exception.78 Previous studies have confirmed the presence of an inflammatory response in the liver of patients with BA, which is mainly characterized by the excessive production of cytokines, including cytokines of T cells, macrophages, and other pro-inflammatory cells.79 Recently, many researchers have attempted to use circulating cytokines as non-invasive biomarkers to diagnose BA and predict the post-KPE progression of patients.

Interleukin-8 (IL-8), a chemokine involved in neutrophil recruitment, is closely associated with bile duct response and liver fibrosis.80–83 Studies have shown that IL-8 is highly expressed in the sera of patients with BA and is involved in disease progression.84–86 Udomsinprasert et al.87 studied the plasma of 82 children with BA and 25 healthy controls. They screened out 17 cytokines with high expression levels in the plasma of children with BA at the time of KPE. When the cut-off value of IL-8 was 2.29 pg/mL, the sensitivity and specificity of IL-8 for the diagnosis of BA were 90.2% and 92.0%, respectively. Furthermore, they found that patients with high plasma IL-8 levels had a significantly reduced survival rate. The primary disadvantage of this study is that the control group did not include patients with non-BA cholestasis. In a study by Godbole et al.,83 which included 115 patients with BA, IL-8 was markedly overexpressed in the sera of these patients at the time of KPE compared with normal controls but was not correlated with the native liver survival rates of children after KPE. Madadi-Sanjani et al.88 also found that IL-8 was not an effective predictor of the stage of cirrhosis and the need for liver transplantation in patients after KPE. Thus, although IL-8 may be a potential auxiliary diagnostic indicator, its value in predicting native liver survival after KPE remains controversial. Further prospective cohort studies are required to validate the existing findings.

Interleukin-33 (IL-33) is a nuclear cytokine that is released after cell death as a consequence of severe tissue injury.89 Previous reviews have explored the pathophysiological function of IL-33 in liver inflammation.90,91 An early study by Dong et al.92 included 18 infants with BA, 12 infants with non-icteric choledochal cysts (CCs), and 10 healthy controls (HCs) and suggested that the level of IL-33 expression in serum was significantly elevated in patients with BA, as compared with the CC and HC groups. Recently, Behairy et al.93 found that serum IL-33 in patients with BA was significantly higher compared to patients with non-BA cholestasis and normal controls. When the cut-off value of IL-33 was 20.8 pg/mL, the specificity and sensitivity for the diagnosis of BA were 95% and 96.7%, respectively. At a cut-off value of ≥45.3 pg/ml, IL-33 can detect liver fibrosis of significant fibrosis (F3) with a specificity of 72.2% and a sensitivity of 66.7%. Although the study included only 30 patients with BA and 30 patients with non-BA cholestasis, it showed that IL-33 may assist in the diagnosis of BA and the evaluation of the grade of liver fibrosis. It is worth noting that Chen et al.94 also explored the value of IL-33 in the diagnosis of BA in a sample size similar to that in the study by Behairy et al.93 Interestingly, their cut-off values varied widely (20.8 pg/mL vs. 314.1 pg/mL), and the study by Chen et al.94 reported much lower specificity and sensitivity. This disparity may be attributed to the different detection methods used in the two studies. Further investigation into this aspect is warranted.

In addition, other circulating cytokines may also have clinical value in the diagnosis and evaluation of BA. Chen et al.94 screened Th17-related cytokines in the sera of patients with BA and found that the serum levels of macrophage inflammatory protein-3alpha (MIP3a) may also aid the diagnosis of BA, with a specificity of 80.00% and a sensitivity of 90.48%. Vejchapipat et al.95 suggested that serum IL-18 levels significantly increased with the degree of jaundice in medium-term survivors of BA, while Urushihara et al.96 also found that the change in serum IL-18 levels may related to the native liver survival of patients with BA. Wu et al.97 found that a preoperative serum IL-12p40 level of >33 pg/mL can significantly predict 3-year survival with native liver. Adawy et al.98 suggested that IL-13 receptor alpha 2 (IL-13Rα2) may reflect liver fibrosis in patients with BA. However, their studies only included a small number of cases in a single region and there is a lack of further research to validate their conclusions.

Other potential biomarkers

In addition to the above widely studied biomarkers, an increasing number of BA-related biomarkers are gradually being discovered, which may also hold potential diagnostic or prognostic value.

Biomarkers that can be used to diagnose BA have always been the focus of attention. Li et al.99 found that human poliovirus receptor (PVR) expression was upregulated in the bile ducts of patients with BA and RRV-induced BA mice. Furthermore, PVR may be involved in the pathogenesis of BA by regulating the NK cell-mediated bile duct injury.99 Besides, the concentration of PVR in the sera of children with BA was significantly higher than that in the sera of healthy controls. This suggests that PVR may be a potential biomarker of BA. However, more studies that compare the serum levels of PVR in patients with BA and non-BA cholestasis are warranted. Madadi-Sanjani et al.100 found that serum caspase-3 activity in children with BA was significantly higher than that in other patients with non-BA cholestasis, suggesting that caspase-3 is also a potential biomarker of BA. Kong et al.101 found increased expression of leukocyte cell-derived chemotaxin 2 (LECT2) mRNA in the liver tissues of children with BA. Another study found that LECT2 was also highly expressed in the sera of children with BA.102 Dong et al.103 used miRNA microarray analysis to screen differentially expressed microRNAs (miRNAs) in the sera of patients with BA and those with non-BA neonatal cholestasis. They found that the expression levels of miR-4429 were significantly downregulated whereas those of miR-4689 were significantly upregulated in the sera of patients with BA, suggesting that miR-4429 and miR-4689 could serve as potential diagnostic biomarkers of BA. Peng et al.104 found that patients with BA had lower plasma levels of miR-140-3p compared to cholestatic disease controls. At the optimal threshold, their sensitivity and specificity in diagnosing BA were 66.7% and 79.1%, respectively. Similarly, a study by Zahm et al.105 found that the miR-200b/429 cluster was significantly increased in the sera of patients with BA relative to infants with non-BA cholestatic disorders. These miRNAs appear to have a significant value in the diagnosis of BA, although studies with larger sample sizes are lacking.

Biomarkers that reflect liver fibrosis in BA are also being explored. Udomsinprasert et al.106 showed that the serum cartilage oligomeric matrix protein (COMP) levels in children with BA were much higher compared to the healthy control group, and higher levels were positively correlated with liver stiffness and liver fibrosis. Xiao et al.107 revealed that serum exosomal long non-coding RNA-H19 (lncRNA-H19) in children with BA is positively correlated with the severity of fibrosis liver injury. Yoneyama et al.108 found that serum miR-214 levels were significantly increased in patients with BA having liver fibrosis stage F3–4, suggesting that serum miR-214 levels may be also used as a non-invasive predictor of liver fibrosis in BA.

In contrast, there are fewer novel serum biomarkers for predicting the native liver survival of patients with BA. In the study by Udomsinprasert et al.,106 a significant reduction in survival rate was observed in patients with BA and high circulating COMP levels (cut-off value: 128.47 ng/mL). However, traditional biomarkers may be useful in predicting the prognosis of patients with BA. Huang et al.109 conducted a retrospective chart review of 90 patients with BA and concluded that serum total bilirubin ≤ 4.85 mg/dL at 1 week after HPE can predict a higher chance of native liver survival. Recently, Harpavat et al.110 measured total serum bile acid levels of 137 patients 6 months after KPE and found that patients with levels of ≤ 40 μmol/L had better liver function, fewer complications, and lower cumulative incidence of liver transplant/death.

The biomarkers mentioned in this chapter also have great potential in clinical practice, but most of them lack follow-up studies to confirm their clinical values. Besides, their role in the pathophysiology of BA needs to be explored.

Comparison and summary

An increasing number of serum biomarkers with diagnostic and prognostic value in BA have been discovered and promoted in recent years. Most of them are listed in Table 3,16,31–37,40,42,52,54,59,69,70,72,75–77,83,87,92–100,102-108,110–113 including all the biomarkers mentioned in this review. Among them, MMP-7 is currently the most reliable biomarker for the diagnosis of BA, which may help clinicians assess the stage of liver fibrosis and predict post-KPE outcomes to a certain extent. Some studies have evaluated the diagnostic value of GGT while studying MMP-7.32–34,37 They also concluded that compared to GGT, MMP-7 showed better sensitivity and specificity for diagnosing BA. However, efforts to improve the diagnostic reliability of GGT are still necessary, because measurement of MMP-7 is not available in most cases. Besides, other biomarkers like circulating cytokines and miRNAs also have potential in the diagnosis of BA. Further studies to confirm their role are warranted.

Table 3

Emerging serum biomarkers of biliary atresia

FunctionBiomarkerReference
DiagnosisMMP-716,31–37,40
GGT31–34,37,72,75–77
IL-3392–94
MIP3a94
PVR99
Caspase-3100
LECT2102
miR-4429 and miR-4689103
miR-140-3p104
miR-200b/429105
Assessing liver fibrosisMMP-732,35,42
M2BPGi59,69,70
APRi59,111–113
IL-13Rα298
COMP106
lncRNA-H19107
miR-214108
Predicting native liver survival after KPEMMP-735,36
FGF-1952,54
Total bile acid110
IL-883,87
IL-1895,96
IL-12p4097
COMP106

There was a duplication of references between biomarkers because some studies involved multiple biomarkers at the same time. MMP-7, matrix metalloproteinase-7; FGF-19, fibroblast growth factor-19; M2BPGi, mac-2 binding protein glycan isomer; GGT, gamma-glutamyltransferase; IL, Interleukin; lncRNA, long non-coding RNA; miRNA, microRNA; MIP3a, macrophage inflammatory protein-3alpha; PVR, human poliovirus receptor; LECT2, leukocyte cell-derived chemotaxin 2; COMP, cartilage oligomeric matrix protein; APRi, aspartate aminotransferase to platelet ratio index.

FGF-19 is a new predictor of outcomes in BA. Although there is little research on FGF-19, it still shows strong potential as a prognostic biomarker. Previously, clinicians often followed serum levels of bilirubin to predict disease progression after KPE.114–116 A recent study by Harpavat et al.110 found that total serum bile acid levels 6 months after KPE were related to a lower cumulative incidence of liver transplant/death, indicating that serum bilirubin levels after KPE can reliably predict poor outcomes, including complications from progressive liver disease and the invariable need for a liver transplant. According to a study by Nyholm et al.,54 serum FGF-19 levels at the time of KPE can be used to predict native liver survival of children with BA. Compared with total serum bile acid, FGF-19 may be able to reflect the prognosis of patients with BA at an earlier stage and may also reflect the degree of ductular reaction. However, the cut-off value of FGF-19 in predicting native liver survival and the ability to predict complications after KPE still remain to be explored.

The role of M2BPGi in the evaluation of liver fibrosis in BA is often compared with aspartate aminotransferase to platelet ratio index (APRi). APRi was first proposed by Wai et al.117 to assess liver fibrosis in chronic hepatitis C and was widely used for the assessment of BA in the past few years.111–113,118,119 A study by Yamada et al.59 reported that M2BPGi had a better diagnostic ability to detect fibrosis of the native liver with grade F4 fibrosis compared to APRi when using the METAVIR fibrosis score. Although the ages of the patients in this study and another study by Ueno et al.69 varied considerably, the latter study also reported similar findings. This indicates that M2BPGi shows a higher accuracy in predicting F4 liver fibrosis in BA. It is also important to note that these studies did not include children with BA diagnosed less than 3 months ago. Early assessment of the stage of liver fibrosis in children with BA would facilitate the selection of children directly for liver transplantation, avoiding KPE wherever appropriate.

We are excited to see more and more biomarkers associated with BA being discovered. As clinical studies advance, there is an urgent need to understand the role of these biomarkers in the development and progress of the disease. For example, our understanding of MMP-7 is mostly based on studies on other diseases,17 and there is still a lack of research in BA. This knowledge gap also exists with regard to biomarkers like FGF-19, M2BPGi, and several others. Therefore, elucidating the pathophysiological role of biomarkers in BA will be an important area of future research.

In conclusion, MMP-7 is currently the most reliable biomarker for the diagnosis of BA. FGF-19 and M2BPGi are novel biomarkers for evaluating native liver survival and liver fibrosis in patients with BA, respectively. GGT and other circulating cytokines could serve as potential diagnostic biomarkers of BA. However, more high-quality, large-size, multicenter clinical trials are warranted to confirm the value of these biomarkers and to elucidate their pathophysiological role in BA.

Abbreviations

APRi: 

aspartate aminotransferase to platelet ratio index

BA: 

biliary atresia

CMV: 

cytomegalovirus

COMP: 

cartilage oligomeric matrix protein

ELISA: 

enzyme-linked immunosorbent assay

FGF-19: 

fibroblast growth factor-19

FXR: 

farnesoid X receptor

GGT: 

gamma-glutamyltransferase

HSCs: 

hepatic stellate cells

IL: 

Interleukin

KCs: 

kupffer cells

KPE: 

Kasai portoenterostomy

M2BPGi: 

mac-2 binding protein glycan isomer

MIP3a: 

macrophage inflammatory protein-3alpha

MMP-7: 

matrix metalloproteinase-7

PVR: 

human poliovirus receptor

Declarations

Funding

This study received financial support from Shanghai Municipal Key Clinical Specialty (No. shslczdzk05703), National Natural Science Foundation of China (No. 82270541, and No. 82201915), and Children’s National Medical Center (No. 2022LCKXJ06).

Conflict of interest

The authors have no conflict of interests related to this publication.

Authors’ contributions

Conceptualization, writing of original draft, reviewing, and editing (FK); and conceptualization, reviewing, and editing (RD, GC, SS, YY, JJ, LM, HC, JZ, and SZ). All authors approved the final version of the manuscript.

References

  1. Hartley JL, Davenport M, Kelly DA. Biliary atresia. Lancet 2009;374(9702):1704-1713 View Article PubMed/NCBI
  2. Zani A, Quaglia A, Hadzić N, Zuckerman M, Davenport M. Cytomegalovirus-associated biliary atresia: An aetiological and prognostic subgroup. J Pediatr Surg 2015;50(10):1739-1745 View Article PubMed/NCBI
  3. Lorent K, Gong W, Koo KA, Waisbourd-Zinman O, Karjoo S, Zhao X, et al. Identification of a plant isoflavonoid that causes biliary atresia. Sci Transl Med 2015;7(286):286ra267 View Article PubMed/NCBI
  4. Zhu JJ, Yang YF, Dong R, Zheng S. Biliatresone: progress in biliary atresia study. World J Pediatr 2023;19(5):417-424 View Article PubMed/NCBI
  5. Quelhas P, Cerski C, Dos Santos JL. Update on Etiology and Pathogenesis of Biliary Atresia. Curr Pediatr Rev 2022;19(1):48-67 View Article PubMed/NCBI
  6. Tsai EA, Grochowski CM, Loomes KM, Bessho K, Hakonarson H, Bezerra JA, et al. Replication of a GWAS signal in a Caucasian population implicates ADD3 in susceptibility to biliary atresia. Hum Genet 2014;133(2):235-243 View Article PubMed/NCBI
  7. de Ville de Goyet J, Baumann U, Karam V, Adam R, Nadalin S, Heaton N, et al. European Liver Transplant Registry: Donor and transplant surgery aspects of 16,641 liver transplantations in children. Hepatology 2022;75(3):634-645 View Article PubMed/NCBI
  8. Hsiao CH, Chang MH, Chen HL, Lee HC, Wu TC, Lin CC, et al. Universal screening for biliary atresia using an infant stool color card in Taiwan. Hepatology 2008;47(4):1233-1240 View Article PubMed/NCBI
  9. Ando H, Inomata Y, Iwanaka T, Kuroda T, Nio M, Matsui A, et al. Clinical practice guidelines for biliary atresia in Japan: A secondary publication of the abbreviated version translated into English. J Hepatobiliary Pancreat Sci 2021;28(1):55-61 View Article PubMed/NCBI
  10. Fawaz R, Baumann U, Ekong U, Fischler B, Hadzic N, Mack CL, et al. Guideline for the Evaluation of Cholestatic Jaundice in Infants: Joint Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr 2017;64(1):154-168 View Article PubMed/NCBI
  11. Kassai M. [Surgical treatment of biliary atresia]. Nihon Geka Gakkai Zasshi 1983;84(9):741-743 PubMed/NCBI
  12. Yang C, Ke M, Zhou Y, Xu H, Diao M, Li L. Impact of early Kasai portoenterostomy on short-term outcomes of biliary atresia: A systematic review and meta-analysis. Front Surg 2022;9:924506 View Article PubMed/NCBI
  13. Lakshminarayanan B, Davenport M. Biliary atresia: A comprehensive review. J Autoimmun 2016;73:1-9 View Article PubMed/NCBI
  14. Yao L, Hu X, Yuan M, Zhang Q, Liu P, Yang L, et al. IGF2-NR4A2 Signaling Regulates Macrophage Subtypes to Attenuate Liver Cirrhosis. J Clin Transl Hepatol 2023;11(4):787-799 View Article PubMed/NCBI
  15. Huang CC, Chuang JH, Chou MH, Wu CL, Chen CM, Wang CC, et al. Matrilysin (MMP-7) is a major matrix metalloproteinase upregulated in biliary atresia-associated liver fibrosis. Mod Pathol 2005;18(7):941-950 View Article PubMed/NCBI
  16. Lertudomphonwanit C, Mourya R, Fei L, Zhang Y, Gutta S, Yang L, et al. Large-scale proteomics identifies MMP-7 as a sentinel of epithelial injury and of biliary atresia. Sci Transl Med 2017;9(417):eaan8462 View Article PubMed/NCBI
  17. Nomden M, Beljaars L, Verkade HJ, Hulscher JBF, Olinga P. Current Concepts of Biliary Atresia and Matrix Metalloproteinase-7: A Review of Literature. Front Med (Lausanne) 2020;7:617261 View Article PubMed/NCBI
  18. Parks WC, Wilson CL, López-Boado YS. Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat Rev Immunol 2004;4(8):617-629 View Article PubMed/NCBI
  19. Waisbourd-Zinman O, Koh H, Tsai S, Lavrut PM, Dang C, Zhao X, et al. The toxin biliatresone causes mouse extrahepatic cholangiocyte damage and fibrosis through decreased glutathione and SOX17. Hepatology 2016;64(3):880-893 View Article PubMed/NCBI
  20. Girard M, Panasyuk G. Genetics in biliary atresia. Curr Opin Gastroenterol 2019;35(2):73-81 View Article PubMed/NCBI
  21. Tang V, Cofer ZC, Cui S, Sapp V, Loomes KM, Matthews RP. Loss of a Candidate Biliary Atresia Susceptibility Gene, add3a, Causes Biliary Developmental Defects in Zebrafish. J Pediatr Gastroenterol Nutr 2016;63(5):524-530 View Article PubMed/NCBI
  22. Cui S, Leyva-Vega M, Tsai EA, EauClaire SF, Glessner JT, Hakonarson H, et al. Evidence from human and zebrafish that GPC1 is a biliary atresia susceptibility gene. Gastroenterology 2013;144(5):1107-1115.e1103 View Article PubMed/NCBI
  23. Theocharis AD, Skandalis SS, Gialeli C, Karamanos NK. Extracellular matrix structure. Adv Drug Deliv Rev 2016;97:4-27 View Article PubMed/NCBI
  24. Wilson CL, Matrisian LM. Matrilysin: an epithelial matrix metalloproteinase with potentially novel functions. Int J Biochem Cell Biol 1996;28(2):123-136 View Article PubMed/NCBI
  25. Haro H, Crawford HC, Fingleton B, Shinomiya K, Spengler DM, Matrisian LM. Matrix metalloproteinase-7-dependent release of tumor necrosis factor-alpha in a model of herniated disc resorption. J Clin Invest 2000;105(2):143-150 View Article PubMed/NCBI
  26. Gill SE, Nadler ST, Li Q, Frevert CW, Park PW, Chen P, et al. Shedding of Syndecan-1/CXCL1 Complexes by Matrix Metalloproteinase 7 Functions as an Epithelial Checkpoint of Neutrophil Activation. Am J Respir Cell Mol Biol 2016;55(2):243-251 View Article PubMed/NCBI
  27. Li Q, Park PW, Wilson CL, Parks WC. Matrilysin shedding of syndecan-1 regulates chemokine mobilization and transepithelial efflux of neutrophils in acute lung injury. Cell 2002;111(5):635-646 View Article PubMed/NCBI
  28. Powell WC, Fingleton B, Wilson CL, Boothby M, Matrisian LM. The metalloproteinase matrilysin proteolytically generates active soluble Fas ligand and potentiates epithelial cell apoptosis. Curr Biol 1999;9(24):1441-1447 View Article PubMed/NCBI
  29. Rims CR, McGuire JK. Matrilysin (MMP-7) catalytic activity regulates β-catenin localization and signaling activation in lung epithelial cells. Exp Lung Res 2014;40(3):126-136 View Article PubMed/NCBI
  30. Sasaki H, Nio M, Iwami D, Funaki N, Sano N, Ohi R, et al. E-cadherin, alpha-catenin and beta-catenin in biliary atresia: correlation with apoptosis and cell cycle. Pathol Int 2001;51(12):923-932 View Article PubMed/NCBI
  31. He L, Ip DKM, Tam G, Lui VCH, Tam PKH, Chung PHY. Biomarkers for the diagnosis and post-Kasai portoenterostomy prognosis of biliary atresia: a systematic review and meta-analysis. Sci Rep 2021;11(1):11692 View Article PubMed/NCBI
  32. Jiang J, Wang J, Shen Z, Lu X, Chen G, Huang Y, et al. Serum MMP-7 in the Diagnosis of Biliary Atresia. Pediatrics 2019;144(5):e20190902 View Article PubMed/NCBI
  33. Yang L, Zhou Y, Xu PP, Mourya R, Lei HY, Cao GQ, et al. Diagnostic Accuracy of Serum Matrix Metalloproteinase-7 for Biliary Atresia. Hepatology 2018;68(6):2069-2077 View Article PubMed/NCBI
  34. Rohani P, Mirrahimi SB, Bashirirad H, Rahmani P, Kamran N, Alimadadi H, et al. Serum matrix metalloproteinase-7 levels in infants with cholestasis and biliary atresia. BMC Pediatr 2022;22(1):351 View Article PubMed/NCBI
  35. Chi S, Xu P, Yu P, Cao G, Wang H, Ye Y, et al. Dynamic analysis of serum MMP-7 and its relationship with disease progression in biliary atresia: a multicenter prospective study. Hepatol Int 2022;16(4):954-963 View Article PubMed/NCBI
  36. Sakaguchi H, Konishi KI, Yasuda R, Sasaki H, Yoshimaru K, Tainaka T, et al. Serum matrix metalloproteinase-7 in biliary atresia: A Japanese multicenter study. Hepatol Res 2022;52(5):479-487 View Article PubMed/NCBI
  37. Wu JF, Jeng YM, Chen HL, Ni YH, Hsu HY, Chang MH. Quantification of Serum Matrix Metallopeptide 7 Levels May Assist in the Diagnosis and Predict the Outcome for Patients with Biliary Atresia. J Pediatr 2019;208:30-37.e31 View Article PubMed/NCBI
  38. Aldeiri B, Si T, Huang Z, Torner N, Ma Y, Davenport M, et al. Matrix Metalloproteinase-7 and Osteopontin Serum Levels as Biomarkers for Biliary Atresia. J Pediatr Gastroenterol Nutr 2023;77(1):97-102 View Article PubMed/NCBI
  39. Karbasian F, Mashhadiagha A, Anbardar MH, Ataollahi M, Dehghani SM, Honar N, et al. Questioning Diagnostic Value of Serum Matrix Metalloproteinase 7 for Biliary Atresia. J Clin Exp Hepatol 2023;13(2):265-272 View Article PubMed/NCBI
  40. Singh TR, Goel P, Bajpai M, Kandasamy D, Malik R, Yadav R, et al. Serum Matrix Metalloproteinase 7 as a Diagnostic and Prognostic Biomarker for Extrahepatic Biliary Atresia. J Indian Assoc Pediatr Surg 2022;27(2):227-235 View Article PubMed/NCBI
  41. Wu JF, Peng SS, Tai CS, Lin WH, Jeng YM, Hsu WM, et al. The magnetic resonance imaging and age-adjusted matrix metalloproteinase-7 assist the diagnosis of biliary atresia. J Gastroenterol 2024;59:138-144 View Article PubMed/NCBI
  42. Leung DH, Devaraj S, Goodrich NP, Chen X, Rajapakshe D, Ye W, et al. Serum biomarkers correlated with liver stiffness assessed in a multicenter study of pediatric cholestatic liver disease. Hepatology 2023;77(2):530-545 View Article PubMed/NCBI
  43. Cai SY, Ouyang X, Chen Y, Soroka CJ, Wang J, Mennone A, et al. Bile acids initiate cholestatic liver injury by triggering a hepatocyte-specific inflammatory response. JCI Insight 2017;2(5):e90780 View Article PubMed/NCBI
  44. Zweers SJ, Booij KA, Komuta M, Roskams T, Gouma DJ, Jansen PL, et al. The human gallbladder secretes fibroblast growth factor 19 into bile: towards defining the role of fibroblast growth factor 19 in the enterobiliary tract. Hepatology 2012;55(2):575-583 View Article PubMed/NCBI
  45. Gadaleta RM, Moschetta A. Metabolic Messengers: fibroblast growth factor 15/19. Nat Metab 2019;1(6):588-594 View Article PubMed/NCBI
  46. Nishimura T, Utsunomiya Y, Hoshikawa M, Ohuchi H, Itoh N. Structure and expression of a novel human FGF, FGF-19, expressed in the fetal brain. Biochim Biophys Acta 1999;1444(1):148-151 View Article PubMed/NCBI
  47. Fon Tacer K, Bookout AL, Ding X, Kurosu H, John GB, Wang L, et al. Research resource: Comprehensive expression atlas of the fibroblast growth factor system in adult mouse. Mol Endocrinol 2010;24(10):2050-2064 View Article PubMed/NCBI
  48. Wang LX, Frey MR, Kohli R. The Role of FGF19 and MALRD1 in Enterohepatic Bile Acid Signaling. Front Endocrinol (Lausanne) 2021;12:799648 View Article PubMed/NCBI
  49. Katafuchi T, Makishima M. Molecular Basis of Bile Acid-FXR-FGF15/19 Signaling Axis. Int J Mol Sci 2022;23(11):6046 View Article PubMed/NCBI
  50. Schaap FG, van der Gaag NA, Gouma DJ, Jansen PL. High expression of the bile salt-homeostatic hormone fibroblast growth factor 19 in the liver of patients with extrahepatic cholestasis. Hepatology 2009;49(4):1228-1235 View Article PubMed/NCBI
  51. Wunsch E, Milkiewicz M, Wasik U, Trottier J, Kempińska-Podhorodecka A, Elias E, et al. Expression of hepatic Fibroblast Growth Factor 19 is enhanced in Primary Biliary Cirrhosis and correlates with severity of the disease. Sci Rep 2015;5:13462 View Article PubMed/NCBI
  52. Johansson H, Svensson JF, Almström M, Van Hul N, Rudling M, Angelin B, et al. Regulation of bile acid metabolism in biliary atresia: reduction of FGF19 by Kasai portoenterostomy and possible relation to early outcome. J Intern Med 2020;287(5):534-545 View Article PubMed/NCBI
  53. Slijepcevic D, Roscam Abbing RLP, Katafuchi T, Blank A, Donkers JM, van Hoppe S, et al. Hepatic uptake of conjugated bile acids is mediated by both sodium taurocholate cotransporting polypeptide and organic anion transporting polypeptides and modulated by intestinal sensing of plasma bile acid levels in mice. Hepatology 2017;66(5):1631-1643 View Article PubMed/NCBI
  54. Nyholm I, Hukkinen M, Pihlajoki M, Davidson JR, Tyraskis A, Lohi J, et al. Serum FGF19 predicts outcomes of Kasai portoenterostomy in biliary atresia. Hepatology 2023;77(4):1263-1273 View Article PubMed/NCBI
  55. Yang J, Sontag D, Kung S, Minuk GY. Fibroblast Growth Factor 19 Induced Changes in Non-malignant Cholangiocytes. J Clin Transl Hepatol 2021;9(6):909-916 View Article PubMed/NCBI
  56. Brandl K, Hartmann P, Jih LJ, Pizzo DP, Argemi J, Ventura-Cots M, et al. Dysregulation of serum bile acids and FGF19 in alcoholic hepatitis. J Hepatol 2018;69(2):396-405 View Article PubMed/NCBI
  57. Rockey DC, Caldwell SH, Goodman ZD, Nelson RC, Smith AD. Liver biopsy. Hepatology 2009;49(3):1017-1044 View Article PubMed/NCBI
  58. Cholongitas E, Senzolo M, Standish R, Marelli L, Quaglia A, Patch D, et al. A systematic review of the quality of liver biopsy specimens. Am J Clin Pathol 2006;125(5):710-721 View Article PubMed/NCBI
  59. Yamada N, Sanada Y, Tashiro M, Hirata Y, Okada N, Ihara Y, et al. Serum Mac-2 binding protein glycosylation isomer predicts grade F4 liver fibrosis in patients with biliary atresia. J Gastroenterol 2017;52(2):245-252 View Article PubMed/NCBI
  60. Umemura T, Joshita S, Sekiguchi T, Usami Y, Shibata S, Kimura T, et al. Serum Wisteria floribunda Agglutinin-Positive Mac-2-Binding Protein Level Predicts Liver Fibrosis and Prognosis in Primary Biliary Cirrhosis. Am J Gastroenterol 2015;110(6):857-864 View Article PubMed/NCBI
  61. Nishikawa H, Enomoto H, Iwata Y, Hasegawa K, Nakano C, Takata R, 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(7):613-621 View Article PubMed/NCBI
  62. Nishikawa H, Enomoto H, Iwata Y, Kishino K, Shimono Y, Hasegawa K, et al. Clinical significance of serum Wisteria floribunda agglutinin positive Mac-2-binding protein level in non-alcoholic steatohepatitis. Hepatol Res 2016;46(12):1194-1202 View Article PubMed/NCBI
  63. Abe M, Miyake T, Kuno A, Imai Y, Sawai Y, Hino K, 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(7):776-784 View Article PubMed/NCBI
  64. Shirabe K, Bekki Y, Gantumur D, Araki K, Ishii N, Kuno A, et al. Mac-2 binding protein glycan isomer (M2BPGi) is a new serum biomarker for assessing liver fibrosis: more than a biomarker of liver fibrosis. J Gastroenterol 2018;53(7):819-826 View Article PubMed/NCBI
  65. Bekki Y, Yoshizumi T, Shimoda S, Itoh S, Harimoto N, Ikegami T, et al. Hepatic stellate cells secreting WFA(+) -M2BP: Its role in biological interactions with Kupffer cells. J Gastroenterol Hepatol 2017;32(7):1387-1393 View Article PubMed/NCBI
  66. Gantumur D, Harimoto N, Muranushi R, Hoshino K, Batbayar C, Hagiwara K, et al. Hepatic stellate cell as a Mac-2-binding protein-producing cell in patients with liver fibrosis. Hepatol Res 2021;51(10):1058-1063 View Article PubMed/NCBI
  67. Yamaoka K, Nouchi T, Marumo F, Sato C. Alpha-smooth-muscle actin expression in normal and fibrotic human livers. Dig Dis Sci 1993;38(8):1473-1479 View Article PubMed/NCBI
  68. Puche JE, Saiman Y, Friedman SL. Hepatic stellate cells and liver fibrosis. Compr Physiol 2013;3(4):1473-1492 View Article PubMed/NCBI
  69. Ueno T, Kodama T, Noguchi Y, Saka R, Takama Y, Tazuke Y, et al. Clinical implications of serum Mac-2-binding protein (M2BPGi) during regular follow-up of patients with biliary atresia. Pediatr Surg Int 2018;34(10):1065-1071 View Article PubMed/NCBI
  70. Ueno T, Kodama T, Noguchi Y, Nomura M, Saka R, Takama Y, et al. Serum Mac-2-binding protein (M2BPGi) as a marker of chronological liver fibrosis in biliary atresia patients with cirrhosis. Pediatr Surg Int 2019;35(10):1065-1070 View Article PubMed/NCBI
  71. Whitfield JB. Gamma glutamyl transferase. Crit Rev Clin Lab Sci 2001;38(4):263-355 View Article PubMed/NCBI
  72. Liu CS, Chin TW, Wei CF. Value of gamma-glutamyl transpeptidase for early diagnosis of biliary atresia. Zhonghua Yi Xue Za Zhi (Taipei) 1998;61(12):716-720 PubMed/NCBI
  73. Rendón-Macías ME, Villasís-Keever MA, Castañeda-Muciño G, Sandoval-Mex AM. Improvement in accuracy of gamma-glutamyl transferase for differential diagnosis of biliary atresia by correlation with age. Turk J Pediatr 2008;50(3):253-259 PubMed/NCBI
  74. Weng Z, Zhou W, Wu Q, Ma H, Fang Y, Dang T, et al. Gamma-Glutamyl Transferase Combined With Conventional Ultrasound Features in Diagnosing Biliary Atresia: A Two-Center Retrospective Analysis. J Ultrasound Med 2022;41(11):2805-2817 View Article PubMed/NCBI
  75. Dong R, Jiang J, Zhang S, Shen Z, Chen G, Huang Y, et al. Development and Validation of Novel Diagnostic Models for Biliary Atresia in a Large Cohort of Chinese Patients. EBioMedicine 2018;34:223-230 View Article PubMed/NCBI
  76. El-Guindi MA, Sira MM, Sira AM, Salem TA, El-Abd OL, Konsowa HA, et al. Design and validation of a diagnostic score for biliary atresia. J Hepatol 2014;61(1):116-123 View Article PubMed/NCBI
  77. Chen X, Dong R, Shen Z, Yan W, Zheng S. Value of Gamma-Glutamyl Transpeptidase for Diagnosis of Biliary Atresia by Correlation With Age. J Pediatr Gastroenterol Nutr 2016;63(3):370-373 View Article PubMed/NCBI
  78. Bonkovsky HL, Barnhart HX, Foureau DM, Steuerwald N, Lee WM, Gu J, et al. Correction: Cytokine profiles in acute liver injury-Results from the US Drug-Induced Liver Injury Network (DILIN) and the Acute Liver Failure Study Group. PLoS One 2019;14(2):e0212394 View Article PubMed/NCBI
  79. Narayanaswamy B, Gonde C, Tredger JM, Hussain M, Vergani D, Davenport M. Serial circulating markers of inflammation in biliary atresia—evolution of the post-operative inflammatory process. Hepatology 2007;46(1):180-187 View Article PubMed/NCBI
  80. Ghasemi H, Ghazanfari T, Yaraee R, Faghihzadeh S, Hassan ZM. Roles of IL-8 in ocular inflammations: a review. Ocul Immunol Inflamm 2011;19(6):401-412 View Article PubMed/NCBI
  81. Langhans B, Krämer B, Louis M, Nischalke HD, Hüneburg R, Staratschek-Jox A, et al. Intrahepatic IL-8 producing Foxp3+CD4+ regulatory T cells and fibrogenesis in chronic hepatitis C. J Hepatol 2013;59(2):229-235 View Article PubMed/NCBI
  82. Mack CL, Feldman AG, Sokol RJ. Clues to the etiology of bile duct injury in biliary atresia. Semin Liver Dis 2012;32(4):307-316 View Article PubMed/NCBI
  83. Godbole N, Nyholm I, Hukkinen M, Davidson JR, Tyraskis A, Eloranta K, et al. Prognostic and Pathophysiologic Significance of IL-8 (CXCL8) in Biliary Atresia. J Clin Med 2021;10(12):2705 View Article PubMed/NCBI
  84. Dong R, Zheng S. Interleukin-8: A critical chemokine in biliary atresia. J Gastroenterol Hepatol 2015;30(6):970-976 View Article PubMed/NCBI
  85. Bessho K, Mourya R, Shivakumar P, Walters S, Magee JC, Rao M, et al. Gene expression signature for biliary atresia and a role for interleukin-8 in pathogenesis of experimental disease. Hepatology 2014;60(1):211-223 View Article PubMed/NCBI
  86. El-Faramawy AA, El-Shazly LB, Abbass AA, Ismail HA. Serum IL-6 and IL-8 in infants with biliary atresia in comparison to intrahepatic cholestasis. Trop Gastroenterol 2011;32(1):50-55 PubMed/NCBI
  87. Udomsinprasert W, Ungsudechachai T, Vejchapipat P, Poovorawan Y, Honsawek S. Systemic cytokine profiles in biliary atresia. PLoS One 2022;17(4):e0267363 View Article PubMed/NCBI
  88. Madadi-Sanjani O, Kuebler JF, Dippel S, Gigina A, Falk CS, Vieten G, et al. Long-term outcome and necessity of liver transplantation in infants with biliary atresia are independent of cytokine milieu in native liver and serum. Cytokine 2018;111:382-388 View Article PubMed/NCBI
  89. Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 2005;23(5):479-490 View Article PubMed/NCBI
  90. Neumann K, Schiller B, Tiegs G. NLRP3 Inflammasome and IL-33: Novel Players in Sterile Liver Inflammation. Int J Mol Sci 2018;19(9):2732 View Article PubMed/NCBI
  91. Heymann F, Tacke F. Immunology in the liver—from homeostasis to disease. Nat Rev Gastroenterol Hepatol 2016;13(2):88-110 View Article PubMed/NCBI
  92. Dong R, Dong K, Wang X, Chen G, Shen C, Zheng S. Interleukin-33 overexpression is associated with gamma-glutamyl transferase in biliary atresia. Cytokine 2013;61(2):433-437 View Article PubMed/NCBI
  93. Behairy OG, Elsadek AE, Behiry EG, Elhenawy IA, Shalan NH, Sayied KR. Clinical Value of Serum Interleukin-33 Biomarker in Infants With Neonatal Cholestasis. J Pediatr Gastroenterol Nutr 2020;70(3):344-349 View Article PubMed/NCBI
  94. Chen P, Zhong Z, Jiang H, Chen H, Lyu J, Zhou L. Th17-associated cytokines multiplex testing indicates the potential of macrophage inflammatory protein-3 alpha in the diagnosis of biliary atresia. Cytokine 2019;116:21-26 View Article PubMed/NCBI
  95. Vejchapipat P, Poomsawat S, Chongsrisawat V, Honsawek S, Poovorawan Y. Elevated serum IL-18 and interferon-gamma in medium-term survivors of biliary atresia. Eur J Pediatr Surg 2012;22(1):29-33 View Article PubMed/NCBI
  96. Urushihara N, Iwagaki H, Yagi T, Kohka H, Kobashi K, Morimoto Y, et al. Elevation of serum interleukin-18 levels and activation of Kupffer cells in biliary atresia. J Pediatr Surg 2000;35(3):446-449 View Article PubMed/NCBI
  97. Wu JF, Kao PC, Chen HL, Lai HS, Hsu HY, Chang MH, et al. A high serum interleukin-12p40 level prior to Kasai surgery predict a favourable outcome in children with biliary atresia. Liver Int 2012;32(10):1557-1563 View Article PubMed/NCBI
  98. Adawy N, El-Araby H, Allam A, Elshenawy S, Khedr M, Ibrahim Y, et al. Serum level of interleukin-13 receptor alpha 2 in infants with biliary atresia - is it of value?. Clin Exp Hepatol 2018;4(2):91-96 View Article PubMed/NCBI
  99. Li Y, Li TY, Qi Q, Zhang MT, Tong MX, Su PJ, et al. Human poliovirus receptor contributes to biliary atresia pathogenesis by exacerbating natural-killer-cell-mediated bile duct injury. Liver Int 2022;42(12):2724-2742 View Article PubMed/NCBI
  100. Madadi-Sanjani O, Bohlen G, Wehrmann F, Andruszkow J, Khelif K, von Wasielewski R, et al. Increased Serum Levels of Activated Caspases in Murine and Human Biliary Atresia. J Clin Med 2021;10(12):2718 View Article PubMed/NCBI
  101. Kong M, Xiang B. Identifying Biomarkers to Predict the Prognosis of Biliary Atresia by Weighted Gene Co-Expression Network Analysis. Front Genet 2021;12:760182 View Article PubMed/NCBI
  102. Zhao J, Xu X, Gou Q, Zheng Q, Ge L, Chen L, et al. TGF-β1-Mediated Leukocyte Cell-Derived Chemotaxin 2 Is Associated With Liver Fibrosis in Biliary Atresia. Front Pediatr 2022;10:901888 View Article PubMed/NCBI
  103. Dong R, Shen Z, Zheng C, Chen G, Zheng S. Serum microRNA microarray analysis identifies miR-4429 and miR-4689 are potential diagnostic biomarkers for biliary atresia. Sci Rep 2016;6:21084 View Article PubMed/NCBI
  104. Peng X, Yang L, Liu H, Pang S, Chen Y, Fu J, et al. Identification of Circulating MicroRNAs in Biliary Atresia by Next-Generation Sequencing. J Pediatr Gastroenterol Nutr 2016;63(5):518-523 View Article PubMed/NCBI
  105. Zahm AM, Hand NJ, Boateng LA, Friedman JR. Circulating microRNA is a biomarker of biliary atresia. J Pediatr Gastroenterol Nutr 2012;55(4):366-369 View Article PubMed/NCBI
  106. Udomsinprasert W, Angkathunyakul N, Jittikoon J, Chaikledkaew U, Vejchapipat P, Poovorawan Y, et al. Cartilage oligomeric matrix protein as a marker of progressive liver fibrosis in biliary atresia. Sci Rep 2021;11(1):16695 View Article PubMed/NCBI
  107. Xiao Y, Liu R, Li X, Gurley EC, Hylemon PB, Lu Y, et al. Long Noncoding RNA H19 Contributes to Cholangiocyte Proliferation and Cholestatic Liver Fibrosis in Biliary Atresia. Hepatology 2019;70(5):1658-1673 View Article PubMed/NCBI
  108. Yoneyama T, Ueno T, Masahata K, Toyama C, Maeda A, Tazuke Y, et al. Elevation of microRNA-214 is associated with progression of liver fibrosis in patients with biliary atresia. Pediatr Surg Int 2022;38(1):115-122 View Article PubMed/NCBI
  109. Huang CY, Chang MH, Chen HL, Ni YH, Hsu HY, Wu JF. Bilirubin level 1 week after hepatoportoenterostomy predicts native liver survival in biliary atresia. Pediatr Res 2020;87(4):730-734 View Article PubMed/NCBI
  110. Harpavat S, Hawthorne K, Setchell KDR, Rivas MN, Henn L, Beil CA, et al. Serum bile acids as a prognostic biomarker in biliary atresia following Kasai portoenterostomy. Hepatology 2023;77(3):862-873 View Article PubMed/NCBI
  111. Yang LY, Fu J, Peng XF, Pang SY, Gao KK, Chen ZR, et al. Validation of aspartate aminotransferase to platelet ratio for diagnosis of liver fibrosis and prediction of postoperative prognosis in infants with biliary atresia. World J Gastroenterol 2015;21(19):5893-5900 View Article PubMed/NCBI
  112. Nagi SAM, Zakaria HM, Elkhadry SW, Hamed WE, Gaballa NK, Elkholy SS. APRI and FIB-4 indices as diagnostic noninvasive scores for prediction of severe fibrosis in patients with biliary atresia. Clin Exp Hepatol 2023;9(3):251-264 View Article PubMed/NCBI
  113. Grieve A, Makin E, Davenport M. Aspartate Aminotransferase-to-Platelet ratio index (APRi) in infants with biliary atresia: prognostic value at presentation. J Pediatr Surg 2013;48(4):789-795 View Article PubMed/NCBI
  114. Goda T, Kawahara H, Kubota A, Hirano K, Umeda S, Tani G, et al. The most reliable early predictors of outcome in patients with biliary atresia after Kasai’s operation. J Pediatr Surg 2013;48(12):2373-2377 View Article PubMed/NCBI
  115. Davenport M, Caponcelli E, Livesey E, Hadzic N, Howard E. Surgical outcome in biliary atresia: etiology affects the influence of age at surgery. Ann Surg 2008;247(4):694-698 View Article PubMed/NCBI
  116. Hung PY, Chen CC, Chen WJ, Lai HS, Hsu WM, Lee PH, et al. Long-term prognosis of patients with biliary atresia: a 25 year summary. J Pediatr Gastroenterol Nutr 2006;42(2):190-195 View Article PubMed/NCBI
  117. Wai CT, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA, Conjeevaram HS, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology 2003;38(2):518-526 View Article PubMed/NCBI
  118. Mo YH, Chen HL, Hsu WM, Chang CH, Peng SS. A noninvasive index to predict liver cirrhosis in biliary atresia. Pediatr Radiol 2021;51(2):257-264 View Article PubMed/NCBI
  119. Chen S, Liao B, Zhong Z, Zheng Y, Liu B, Shan Q, et al. Supersonic shearwave elastography in the assessment of liver fibrosis for postoperative patients with biliary atresia. Sci Rep 2016;6:31057 View Article PubMed/NCBI
Copyright © 2024 Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 4.0 License (CC BY-NC 4.0), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
  • Journal of Clinical and Translational Hepatology
  • pISSN 2225-0719
  • eISSN 2310-8819

Article Options

Metrics

Cite this Article

  • © 2024 Xia & He Publishing Inc.
  • Total visits : 2645359
  • Visits today : 1308
Back to Top

Progress in Biomarkers Related to Biliary Atresia

Fanyang Kong, Rui Dong, Gong Chen, Song Sun, Yifan Yang, Jingying Jiang, Lingdu Meng, Huifen Chen, Jiajie Zhu, Shan Zheng
  • Reset Zoom
  • Download TIFF