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Page 2 of 6 Lin et al. Hepatoma Res 2018;4:48 I http://dx.doi.org/10.20517/2394-5079.2018.19

INTRODUCTION
Liver fibrosis is a wound-healing response of liver cells to chronic injuries caused by viral infections, toxins,
alcohol abuse and other causes. Liver fibrosis is accompanied by a constant process of destruction and
repair of the hepatic parenchyma that is caused by inflammation and often results in serious complications,
including portal hypertension and liver failure. Liver fibrosis can also give rise to hepatocellular carcinoma.
Liver fibrosis can lead to cirrhosis, which is defined as the end stage of liver fibrosis . In China, hepatitis B is
[1]
[2,3]
the major cause of inflammation leading to liver fibrosis and cirrhosis . Cirrhosis is an important factor in
the development of hepatocellular carcinoma (HCC) because the cumulative 5-year risk of developing HCC
in patients with cirrhosis ranges from 5% to 30%, depending on several factors, including the presence and
stage of underlying liver disease, ethnicity, age, sex and the duration of exposure to primary hepatotropic
viruses. To reduce the burden of the end stage liver diseases (cirrhosis and HCC), it is critical to identify
liver fibrosis at its early stage, predict the direction and speed of the progression, and finally to monitor and
predict the treatments responses (antiviral or anti-fibrotic treatments).

Although many biomarkers (e.g., APRI, FIB4, fibrometer, fibrotest, etc.) and imaging methods (e.g., Fibroscan,
ARFI, MRE) have been widely proposed for staging liver fibrosis, their abilities in predicting liver fibrosis
progression are very limited. Given that fibrosis is a very slow process, it often takes years to progress or
recede from one pathological stage to the next. Therefore, a biomarker that can fulfill this role is most
desirable. A search for such a biomarker would require an understanding of the mechanism of liver fibrosis
and the key molecules involved in the process.

CHI3L1 (also known as YKL-40) belongs to the chitinase family but lacks chitinolytic activity, which is
[4]
highly enriched in the liver . CHI3L1 acts as a growth factor for fibroblasts and is involved in matrix
remodeling . Serum CHI3L1 levels are associated with the severity of liver fibrosis caused by non-alcoholic
[5]
[6]
[7,8]
fatty liver disease , schistosomiasis , hepatitis C virus (HCV) [9,10] and hepatitis B virus (HBV) .
[11]
CHI3L1 PREDICTS HISTOLOGICAL PROGRESSION OF LIVER FIBROSIS IN CHRONIC HCV
PATIENTS
Fontana et al. analyzed the association of serum fibrosis marker levels with the risk of clinical and
[12]
histological disease progression in a large cohort of patients with chronic hepatitis C consisting of 462
prior non-responders to peg-interferon and ribavirin enrolled in the randomized phase of the Hepatitis C
Antiviral Long-term Treatment against Cirrhosis (HALT-C) trial. They performed pretreatment liver biopsy
and follow-up biopsies at years 2 and 4 and defined histological progression as a ≥ 2-point increase in the Ishak
fibrosis score in patients without cirrhosis. Clinical outcomes included development of decompensation,
hepatocellular cancer, death or an increase in the Child-Turcotte-Pugh score to ≥ 7. They collected and
compared serial YKL-40 levels in patients who progressed clinically to the levels in patients who did not
progress using random effects modeling. YKL-40 levels increased in both groups of patients over time
(P = 0.0026) and were significantly increased in the progressors (P < 0.0001).

CHI3L1 PREDICTS RESPONSE TO INTERFERON THERAPY IN CHRONIC HCV PATIENTS
Saitou et al. analyzed noninvasive markers as predictors of interferon responses with HCV-associated
[10]
diseases. A total of 109 patients with HCV-associated liver disease were enrolled, and 88 patients underwent
liver biopsy. In total, 67 of 109 patients received interferon therapy. YKL-40 was superior to other fibrosis markers
for predicting severe fibrosis (F2-F4) from mild fibrosis (F0-F1) (YKL-40, AUC = 0.809; HA, AUC = 0.805). They
also evaluated the changes of the levels of fibrosis markers before and after interferon (IFN) therapy. After
IFN therapy, only the concentration of serum YKL-40 significantly decreased in the responder group and the
non-responder group (P = 0.03). No changes were noted among type IV collagen, amino-terminal peptide