Biomarkers for the diagnosis and post-Kasai portoenterostomy prognosis of biliary atresia: a systematic review and meta-analysis

Abstract

To evaluate the accuracy of biomarkers for the early diagnosis of biliary atresia (BA) and prognostic stratification after Kasai portoenterostomy (KPE). We conducted a systematic review of PubMed, Web of Science, Embase, Scopus and OVID for English literature reporting BA biomarkers published before August 2020. Screening, data extraction, and quality assessment were performed in duplicate. A total of 51 eligible studies were included in the systematic review, and data from 12 (4182 subjects) were extracted for meta-analysis regarding the following 2 domains: (1) serum matrix metallopeptidase-7 (MMP-7), interleukin33 (IL-33) and γ-glutamyl transferase (GGT) to differentiate BA from non-BA; (2) the aspartate aminotransferase to platelet ratio index (APRi) to predict post-KPE liver fibrosis/cirrhosis. The summary sensitivity, specificity and area under the curve (AUC) of MMP-7 for diagnosing BA were 96%, 91% and 0.9847, respectively, and those of GGT were 80%, 79% and 0.9645, respectively. The summary sensitivity and specificity of IL-33 for diagnosing BA were 77% and 85%, respectively. The summary sensitivity and specificity of APRi for predicting post-KPE liver fibrosis were 61% and 80%, respectively, and the summary sensitivity, specificity and AUC of APRi for predicting post-KPE cirrhosis were 78%, 83% and 0.8729, respectively. Moreover, good evidence was shown in investigations of serum IL-18 and IL-33 in distinguishing BA from healthy controls, serum IL-18 for prognosis of post-KPE persistent jaundice, and serum hyaluronic acid and MMP-7 for prognosis of post-KPE significant liver fibrosis. MMP-7, IL-33 and GGT are useful biomarkers to assist in the diagnosis of BA. APRi might be used to predict post-KPE significant liver fibrosis and cirrhosis. These noninvasive biomarkers can be integrated into the management protocol of BA.

Biliary Atresia – emerging diagnostic and therapy opportunities

“…MMP7 was recently identified as a biomarker with promising potential, in particular as MMP7 levels can be established from a blood test [95] . A recently published meta-analysis has reported high sensitivity and specificity for the use of MMP7 in differentiating BA from other cholestatic diseases in newborns [99] . Genetic mutations can also be identified from DNA acquired through blood tests, but while genes with specific mutations (PKD1L1) [5] or carrying common variants in BA patients, such as ADD3, CRIPTO, NODAL, LEFTY, GPC, EFEMP1, ARF6, PCNT, KIF3B and TTC17 [ [6] , [7] , [8] , 11 ], continue to be identified, genetic screening will likely only capture a small percentage of BA patients, as most cases are nonsyndromic.…”

The Liver Biopsy in Neonatal Cholestasis: Just a Cherry on Top?

“…With universal newborn screening and increased availability of genetic testing, the majority of metabolic and genetic etiologies of neonatal cholestasis can be diagnosed in early infancy without a liver biopsy. For biliary atresia, a recent systematic review of biomarkers of disease showed a correlative value of high GGT with biliary atresia, surpassed only by a high serum MMP‐7 5 . However, the discriminatory value of serum MMP‐7 has not yet been validated in US cohorts.…”

Liver secretin receptor predicts portoenterostomy outcomes and liver injury in biliary atresia

“…With emerging novel medical therapies for pediatric cholestatic disorders including BA 11 , 12 , understanding the pathophysiology of BA liver injury and how it relates to PE outcomes has become increasingly important 4 . As PE outcomes in individual patients remain highly variable, identification of accurate prognostic biomarkers reflecting the underlying key mechanisms driving liver injury would expedite targeted medical therapy, timing of LT and patient counseling 13 , 14 . In this respect, ductular reaction (DR), the histopathological hallmark of cholestatic disorders including BA, has been increasingly viewed as a potential therapeutic target for preventing progressive liver fibrosis 15 .…”