Non-invasive tests (aspartate aminotransferase-to-platelet ratio index [APRI] and transient elastography [FibroScan]) were recommended in the 2015 WHO guidelines to guide treatment decisions in people with chronic hepatitis B. We updated the systematic review and meta-analysis that informed the 2015 guidelines to inform new cutoffs for non-invasive tests for the diagnosis of significant fibrosis and cirrhosis for the 2024 WHO guidelines for chronic hepatitis B.

We searched PubMed (MEDLINE), Embase, and Science Citation Index Expanded (Web of Science) for studies published in any language between Jan 1, 2014, and Feb 15, 2023. We included all studies that reported cross-sectional data on the staging of fibrosis or cirrhosis with APRI, Fibrosis-4 (FIB-4), and FibroScan compared with liver biopsy as the reference standard in people with chronic hepatitis B. We excluded studies in which the maximum interval between liver biopsy and non-invasive fibrosis test was more than 6 months; that reported on fewer than ten patients with advanced fibrosis or cirrhosis; that were done exclusively in children; and did not report diagnostic accuracy across our prespecified ranges of test cutoffs. The results of this updated search were collated with the meta-analysis that informed the 2015 guidelines. Outcomes of interest were the sensitivity and specificity of non-invasive tests using defined index test cutoffs for detecting significant fibrosis (≥F2), advanced fibrosis (≥F3), and cirrhosis (F4) based on the METAVIR staging system. We performed meta-analyses using a bivariate random-effects model.

Of 19 933 records identified by our search strategy, 195 were eligible for our systematic review and combined with the 69 studies from the previous meta-analysis to total 264. Two studies were at low risk of bias, 31 studies had unclear risk of bias, and 231 studies had a high risk of bias. Of these 264, 211 studies with 61 665 patients were used in the meta-analysis. For the diagnosis of significant fibrosis (≥F2), sensitivity and specificity were 72·9% (95% CI 70·2-75·5) and 64·7% (95% CI 61·0-68·2) for the APRI low cutoff (>0·3 to 0·7), 30·5% (23·7-38·3) and 92·3% (89·3-94·6) for the APRI high cutoff (>1·3 to 1·7), and 75·1% (72·2-77·7) and 79·3% (76·2-82·2) for FibroScan (>6·0 to 8·0 kPa), respectively. For the diagnosis of cirrhosis (F4), sensitivity and specificity were 59·4% (53·2-65·2) and 73·9% (70·1-77·4) for the APRI low cutoff (>0·8 to 1·2), 30·2% (24·2-36·9) and 88·2% (85·4-90·6) for the APRI high cutoff (>1·8 to 2·2), and 82·6% (77·8-86·5) and 89·0% (86·3-91·2) for FibroScan (>11·0 to 14·0 kPa), respectively. Using a hypothetical population of 1000 unselected patients with chronic hepatitis B with a 25% prevalence of significant fibrosis (≥F2), the APRI low cutoff for significant fibrosis (≥F2) would result in 262 (26·2%) false positives but only 68 (6·8%) false negatives. The FibroScan cutoff would result in 158 (15·8%) false positives and 63 (6·3%) false negatives. In a population with a 5% prevalence of cirrhosis (F4), the APRI low cutoff for cirrhosis (F4) would result in 247 (24·7%) false positives and 21 (2·1%) false negatives and the FibroScan cutoff would result in 105 (10·5%) false positives and nine (0·9%) false negatives.

These findings have informed new thresholds of APRI and FibroScan for diagnosis of significant fibrosis and cirrhosis in the 2024 WHO guidelines on chronic hepatitis B, with an APRI score greater than 0·5 or a FibroScan value greater than 7·0 kPa considered to identify most adults with significant fibrosis (≥F2) and an APRI score greater than 1·0 or a FibroScan value greater than 12·5 kPa to identify most adults with cirrhosis (F4). These patients are a priority for antiviral treatment.

WHO.

The question of whether to treat patients with chronic hepatitis B (CHB) during the immune tolerance (IT) period is a matter of ongoing debate, as it is difficult to discern different levels of liver disease severity. We created and assessed a novel diagnostic model for identifying significant liver tissue damage in individuals with CHB in IT phase.

From November 2018 to December 2022, a cross-sectional study of 311 patients with chronic hepatitis B virus infection (HBV DNA > 30 IU/mL) at Ningbo No. 2 Hospital, Ningbo, China, who underwent liver biopsy, including 44 patients in IT phase. Utilizing univariate regression analyses and logistics analysis, and model was developed and validated to predict the severity of hepatic inflammatory and fibrosis in CHB patients and in IT phase.

Chitinase 3-like Protein (CHI3L1), albumin (ALB), alanine transaminase (ALT) / aspartate aminotransferase (AST) were identified as independent predictors of liver lesion severity in CHB patients with IT. The three were combined to build the model (named as CAA index), which demonstrated good performance. The CAA index achieved an area under the receiver operating characteristic curve (AUC) of 0.916 (95 % CI, 0.820-1.000) and AUC of validation group was 0.875 (95 % CI, 0.683-1.000).

CHI3L1 serves as an independent measure of liver fibrosis and inflammation in CHB. This diagnostic model has some value in assessing the severity of the patient's liver lesion severity and may be a reliable non-invasive diagnostic model helping determine whether treatment is necessary among CHB patients in IT phase.

While liver fibrosis remains a serious, progressive, chronic liver disease, and factors causing damage persist, liver fibrosis may develop into cirrhosis and liver cancer. However, short-term liver fibrosis is reversible. Therefore, an early diagnosis of liver fibrosis in the reversible transition phase is important for effective treatment of liver diseases. Chitinase-3-like protein 1 (CHI3L1), an inflammatory response factor that participates in various biological processes and is abundant in liver tissue, holds promise as a potential biomarker for liver diseases. Here, we aimed to review research developments regarding serum CHI3L1 in relation to the pathophysiology and diagnosis of liver fibrosis of various etiologies, providing a reference for the diagnosis, treatment, and prognosis of liver diseases.

Defective neutrophil regulation in inflammatory bowel disease (IBD) is thought to play an important role in the onset or manifestation of IBD, as it could lead to damage of the intestinal mucosal barrier by the infiltration of neutrophils in the inflamed mucosa and the accumulation of pathogens. Like neutrophils in the context of innate immune responses, immunoglobulin A (IgA) as an acquired immune response partakes in the defense of the intestinal epithelium. Under normal conditions, IgA contributes to the elimination of microbes, but in connection with the loss of tolerance to chitinase 3-like 1 (CHI3L1) in IBD, IgA could participate in CHI3L1-mediated improved adhesion and invasion of potentially pathogenic microorganisms. The tolerance brake to CHI3L1 and the occurrence of IgA autoantibodies to this particular target, the exact role and underlying mechanisms of CHI3L1 in the pathogenesis of IBD are still unclear.

To determine the predictive potential of Ig subtypes of a novel serological marker, anti-CHI3L1 autoantibodies (aCHI3L1) in determining the disease phenotype, therapeutic strategy and long-term disease course in a prospective referral cohort of adult IBD patients.

Sera of 257 Crohn's disease (CD) and 180 ulcerative colitis (UC) patients from a tertiary IBD referral center of Hungary (Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen) were assayed for IgG, IgA, and secretory IgA (sIgA) type aCHI3L1 by enzyme-linked immunosorbent assay using recombinant CHI3L1, along with 86 healthy controls (HCONT).

The IgA type was more prevalent in CD than in UC (29.2% vs 11.1%) or HCONT (2.83%; P < 0.0001 for both). However, sIgA subtype aCHI3L1 positivity was higher in both CD and UC patients than in HCONT (39.3% and 32.8% vs 4.65%, respectively; P < 0.0001). The presence of both IgA and sIgA aCHI3L1 antibodies was associated with colonic involvement (P < 0.0001 and P = 0.038, respectively) in patients with CD. Complicated disease behavior at sample procurement was associated with aCHI3L1 sIgA positivity (57.1% vs 36.0%, P = 0.009). IgA type aCH3L1 was more prevalent in patients with frequent relapse during the disease course in the CD group (46.9% vs 25.7%, P = 0.005). In a group of patients with concomitant presence of pure inflammatory luminal disease and colon involvement at the time of diagnosis, positivity for IgA or sIgA type aCH3L1 predicted faster progression towards a complicated disease course in time-dependent models. This association disappeared after merging subgroups of different disease locations.

CHI3L1 is a novel neutrophil autoantigenic target in IBD. The consideration of antibody classes along with location-based prediction may transform the future of serology in IBD.

Chitinase-3-like 1 protein (CHI3L1) is a secreted glycoprotein, strongly correlated with fibrosis severity in chronic liver diseases including non-alcoholic steatohepatitis (NASH). However, the mechanisms by which CHI3L1 contributes to fibrogenesis remain undefined. Here, we showed that infiltrating monocyte-derived liver macrophages represent the main source of CHI3L1 in murine NASH. We developed a floxed CHI3L1 knock-out (KO) mouse to further study the cell-specific role of CHI3L1 ablation. Wildtype (WT) and myeloid cell-specific CHI3L1 KO mice (CreLyz) were challenged with a highly inflammatory and fibrotic dietary model of NASH by administering choline-deficient high-fat diet for 10 weeks. Macrophage accumulation and inflammatory cell recruitment were significantly ameliorated in the CreLyz group compared to WT (F4/80 IHC p < 0.0001, CD11b IHC p < 0.0001). Additionally, hepatic stellate cell (HSC) activation and fibrosis were strongly decreased in this group (α-SMA IHC p < 0.0001, picrosirius red staining p < 0.0001). In vitro studies were performed stimulating bone marrow derived macrophages, THP-1 (human monocytes) and LX2 (human HSCs) cells with recombinant CHI3L1 to dissect its relationship with fibrosis development. Results showed an important role of CHI3L1 regulating fibrosis-promoting factors by macrophages (TGFB1 p < 0.05, CTGF p < 0.01) while directly activating HSCs (ACTA2 p < 0.01, COL1A1 p < 0.01), involving IL13Rα2 as the potential mediator. Our findings uncovered a novel role of CHI3L1 derived from liver macrophages in NASH progression and identifies this protein as a potential anti-fibrotic therapeutic target. KEY MESSAGES: We showed that CHI3L1 expression is increased in murine CDAA-HFAT diet NASH model, and that infiltrating macrophages are a key source of CHI3L1 production. Myeloid cell-specific CreLyz CHI3L1 knock-out in mice fed with CDAA-HFAT diet improved the NASH phenotype, with significantly reduced accumulation of pro-inflammatory macrophages and neutrophils compared with WT group. DEG and qPCR analysis of genes in CreLyz CHI3L1 knock-out mouse liver showed the mechanistic role of CHI3L1 in cellular chemotaxis. HSC is directly activated by CHI3L1 via receptor IL13Rα2, leading to upregulation of collagen deposition and pro-fibrotic gene, TIMP-1 and TIMP-2 release in whole liver. Direct stimulation of macrophages with CHI3L1 leads to upregulated expression of HSC-activation factors, suggesting its role in modulating macrophage-HSC crosstalk.

To explore the value of chitinase-3-like protein 1 (CHI3L1) for the diagnosis of patients with chronic liver diseases such as chronic viral hepatitis B, liver cirrhosis and hepatocellular carcinoma (HCC), and analyze the correlation between serum CHI3L1 level and Child-Pugh grading of chronic liver diseases.

The serum CHI3L1 levels of 154 cases of chronic viral hepatitis B, 132 cases of liver cirrhosis and 88 cases of HCC were detected by ELISA, and 92 healthy subjects were taken as the control.

The -serum CHI3L1 levels in HCC group, liver cirrhosis group and chronic viral hepatitis B group were higher than in healthy control group (P < 0.001). Serum CHI3L1 level showed a trend of increase in patients with chronic hepatitis to liver cirrhosis and to HCC. The diagnostic efficacy of serum CHI3L1 level on liver cirrhosis showed the sensitivity of 64.4% and the specificity of 96.7%. The diagnostic efficacy of serum CHI3L1 level on HCC showed the sensitivity of 86.8% and the specificity of 97.8%. Serum CHI3L1 level was higher in Child-Pugh grade B and C patients than in Child-Pugh grade A patients, and was positively correlated with Child-Pugh grading of liver function (rs = 0.301, P < 0.001).

Serum CHI3L1 level increased in chronic liver diseases and showed an increase trend with the progression of liver diseases. Serum CHI3L1 could be a biomarker for the auxiliary diagnosis of chronic liver diseases.