Serum retinol-binding protein 4 as a predictor of fibrosis regression and response to direct-acting antiviral drugs in chronic hepatitis C virus patients
Egyptian Liver Journal volume 13, Article number: 16 (2023)
Hepatitis C virus is the underlying cause of chronic hepatitis which frequently progresses to cirrhosis and hepatocellular carcinoma. In addition, HCV is thought to cause steatosis, dyslipidemia, insulin resistance, diabetes, obesity, and cardiovascular events. The aim of this study is to evaluate the role of serum RBP-4 in the prediction of fibrosis regression and the response of treatment among chronic HCV patients receiving direct-acting antiviral agents.
This study included 40 chronic HCV Egyptian patients, divided into two groups: Naive cases, 20 chronic HCV patients before starting first line of treatment; Relapser cases, 20 chronic HCV patients who were non-responders before starting second line treatment; and 10 healthy subjects as control. Laboratory investigations including complete blood count, full hepatic profile, fibroscan assessment, and retinol-binding protein-4 level at baseline and re-assessed 12 weeks after the end of treatment [sustained virological response SVR12]. Student T test, analysis of variance, chi-square, Tukey’s test, and Pearson correlation coefficient tests were used for statistical analysis.
Baseline retinol-binding protein-4 level was significantly higher in the naïve case group than in the relapser and control groups with a P value of P value of < 0.001. All the naïve patients had 100% SVR12, only 90% of the relapser group achieved SVR12. A significant reduction in retinol-binding protein-4 and fibrosis staging and measurements by fibroscan among all studied patients were noted after receiving direct acting antivirals (P value < 0.001). Retinol-binding protein-4 levels before and after treatment were significantly lower among F4 patients in comparison to those of F1–F3 patients (P value 0.002, 0.009, respectively). The best cutoff value of retinol-binding protein-4 in the prediction of liver cirrhosis (F4) was ≤ 46 pg/ml with sensitivity of 100% and specificity of 66.67%.
Serum retinol-binding protein-4 was found to be higher in chronic HCV infection with a significant reduction after successful eradication. Its level is much lower in cirrhotic patients [F4]. As a result, retinol-binding protein-4 may have a promising role in assessing direct acting antivirals response, as well as a prognostic value in predicting liver cirrhosis.
Hepatitis C virus (HCV) infection is a serious global health concern; it causes chronic infection in over 80 million people worldwide, with 3–4 million new infections and 350,000 deaths annually . The recent emergence of potent direct acting antivirals (DAAs) has revolutionized HCV treatment, providing a high potential for achieving HCV eradication and consequently preventing disease progression .
Retinol-binding protein 4 (RBP4) is a lipocalin protein,  that is secreted primarily by hepatocytes (80%) and adipose tissue (20%) . RBP4 was discovered to induce hepatic expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase and to impair insulin signaling in mouse muscle . It was therefore suggested to connect obesity-associated comorbidities, especially insulin resistance (IR), and certain components of the metabolic syndrome, such as nonalcoholic fatty liver disease (NAFLD), in either a retinol-dependent or retinol-independent way with RBP4 ; plasma RBP4 levels tended to decrease concomitantly with increased necro-inflammatory activity, NAFLD activity score, and fibrosis score in NAFLD patients [6, 7]. However, clinical data regarding the links among RBP4, IR, and NAFLD are conflicting.
Although the exact mechanisms that allow HCV infection to cause IR are not fully understood, HCV infection may provide a clearer perspective on RBP4’s hidden role in the development of IR. Although, the relationship between HCV infection and RBP4 has been studied. Meanwhile, the role of disease progression and severity on RBP4 expression in HCV infection remains unknown .
The aim of this study is to evaluate the role of serum RBP-4 in the prediction of fibrosis regression and the response to treatment among chronic HCV patients receiving direct-acting antiviral agents.
During the period of January to October 2019, 40 Egyptian chronic HCV-infected patients (22 males and 18 females) > 18 years old eligible for antiviral treatment with DAAs and agreeing to regular follow up were recruited from the National Committee for Control of Viral Hepatitis (NCCVH) Regional Center in Ain Shams University Hospital after approval by the Ain Shams University ethics committee (FWA 000,017,585) and obtaining informed consent from all patients.
They were divided into two groups: Naïve cases included 20 patients: 13 males and 7 females with a mean age of 43.55 ± 11.03 treated with Sofosbuvir 400 mg + Daclatasvir 60 mg ± Ribavirin1000–1200 mg; the relapse case group included 20 patients: 9 males and 11 females with a mean age of 40.2 ± 4.23 treated with Sofosbuvir 400 mg + Qurevo + Ribavirin 1000–1200 mg as second regimen according to the Egyptian NCCVH protocol ; and 10 healthy, age and sex-matched volunteers served as a control group (7 males and 3 females).
Exclusion criteria were co-infection with HBV or HIV, Child C, thrombocytopenia below 50,000/mm3, hepatocellular carcinoma, or other malignancies with exception of 2 years illness free, obesity (BMI > 30), pregnancy, uncontrolled diabetes (HbA1c > 9%), previous or current heavy alcohol intake, patients on statins or fibrates, organ transplant recipients, previous bariatric surgeries, drugs causing steatosis like amiodarone, corticosteroids, tamoxifen, and valproic acid.
All participants underwent a relevant history and clinical examination, as well as biochemical investigations, including complete blood count, liver function tests, kidney function tests, fasting, and 2 h postprandial blood glucose level, HBA1c, lipid profile, HBsAg, HIV Ab using ELISA technique, and α-fetoprotein. HCV quantitative RNA was measured using real-time polymerase chain reaction (PCR) at baseline and 12 weeks after the end of treatment to document SVR (SVR 12).
Serum RBP4 was measured by quantitative sandwich ELISA kits (Quantikine, R&D Systems, Minneapolis) according to the manufacturer’s instructions. RBP4 was assessed for patient groups at baseline and at SVR 12.
Abdominal ultrasonography was performed after overnight fasting (8 h) with emphasis on liver size, splenic bipolar diameter, and portal vein diameter.
Transient elastography was performed using the FibroScan device (FibroScan; Echosens, Paris, France) at baseline and at SVR12, and it was expressed in kPa.
Liver stiffness measurement (LSM) was used to estimate the METAVIR fibrosis stage as follows: F0-F1: 2.5–6.9 kPa; F2: 7.0–9.4 kPa; F3: 9.5–12.4 kPa; and F4: greater than or equal to 12.5 kPa .
The collected data were analyzed using IBM SPSS statistics software version 20. Quantitative data were expressed as mean ± SD.
In quantitative data, independent t test, paired t test, ANOVA, and post hoc test and Tukey’s test were used. While in qualitative data, chi-square test was used. Correlations were done using Pearson correlation coefficient test. A P value less than 0.05 was sufficient to show statistical significance.
Regarding biochemical parameters, the mean values of PCR, platelet count, and prothrombin time before treatment were statistically significantly lower in the relapser group compared to naïve group (Table 1).
Sonographic parameters and fibrosis degree measurements by fibroscan before treatment showed no statistically significant difference between naïve and relapser patient groups (Table 2).
The mean values of baseline RBP4 were significantly higher in naïve case group in comparison to relapse and control groups (Table 3).
All naïve patients had cure (SVR12 was 100%). While in the relapser group, SVR12 was 90%, as two patients failed to achieve SVR12.
For the naïve group, prothrombin time, AST, and ALT showed a significant reduction, while platelet count showed a significant elevation at SVR12 in comparison to their baseline levels (Table 4).
However, in the relapser group, a significant reduction in ALT and AST levels was noted together with a significant elevation in platelet count and serum albumin on achieving SVR12 (Table 4).
Moreover, in comparison to their baseline level, naïve and relapser patients experienced a significant reduction in RBP4 levels at SVR12 (Table 4).
An overall reduction in the fibroscan measurements was noted among the naïve and relapser groups after receiving DAAs in comparison to their baseline levels. Yet, this reduction was insignificant in the relapser group (Table 5). Also, a significant reduction in fibrosis measurements as well as staging among all patients collectively was noted after receiving DAAs (Table 6).
RBP4 level before and after treatment was significantly lower among F4 patients in comparison to its level in F1–F3 patients (Table 7).
In the Naïve group, a significant negative correlation was found between baseline RBP4 and the fibrosis degree measurements by fibroscan, with an insignificant correlation with all other parameters (Table 8).
In the relapser group, a significant positive correlation was found between baseline RBP4 and age, total cholesterol, triglyceride, LDL, and ALT, with an insignificant correlation with all other parameters (Table 9).
Finally, our study demonstrated the best cutoff value of baseline RBP4 in the detection of liver cirrhosis (F4) among all studied patients as ≤ 46 pg/ml with 100% sensitivity, 66.67% specificity, 50% PPV, 100% NPV, and an overall accuracy of 80.5% (Fig. 1).
Chronic HCV is an important health concern globally. It accounts for about 400,000 annual fatalities worldwide, primarily due to end-stage complications and HCC .
Timely introduction of DAAs targeted at eliminating HCV by 2030. DAAs have demonstrated safety and efficiency. Consequently, initial treatment expansion initiatives have been adopted by various countries, including Egypt .
Glucose intolerance is more common among chronic liver disease patients, especially those with HCV, than in the general population. IR seems to be a key characteristic of HCV-induced glucose intolerance. HCV eradication with DAAs has been found to reduce insulin resistance .
Gouthamchandra et al.  studied whether RBP4 is involved in HCV replication and stated that RBP4 may have a suppressive effect. RBP4 is known to modulate the insulin receptor signaling pathway and hence gluconeogenesis and lipogenesis. RBP4 reduction promotes the mTORC1 (mammalian target of rapamycin complex 1) pathway, leading to elevated SREBP-1 (sterol regulatory element-binding protein 1) levels and thus lipogenesis. Because lipid raft formation is essential for HCV replication and assembly, RBP4 suppression could be beneficial to the virus.
Because the liver is still the main source of RBP4 synthesis, any changes in liver function have a significant impact on RBP4 levels .
The aim of this study was to evaluate the role of serum RBP-4 in the prediction of fibrosis regression and the response to treatment among chronic HCV patients receiving direct-acting antiviral agents.
The current study revealed that all the naïve patients had been cured (SVR12 was 100%). While in the relapser group, SVR12 was 90%, as two patients failed to achieve SVR12.
The present study showed that platelet count was significantly lower among the relapser group than naïve group; this was in keeping with results published by Osada et al. , who showed that platelets are significantly decreased in chronic hepatitis due to reduced production, endothelial dysfunction, splenic sequestration, and autoimmune destruction.
Subsequently, there was a significant improvement in platelet count at SVR12 in the naïve and relapser groups (P < 0.001) which was similar to Dahal et al. , who studied the effect of DAAs on platelets in patients with pretreatment thrombocytopenia. as well as van der Meer et al. , who discovered an improvement in platelet count in patients achieving SVR.
The current study showed significant improvement of ALT and AST in all patients at SVR12 with a P value of 0.001. This was in agreement with van der Meer et al. , who found that ALT, AST, and alkaline phosphatase were significantly reduced 12 weeks after successful DAA treatment.
Using transient elastography (fibroscan) to assess fibrosis revealed a significant regression of fibrosis degree after treatment in the naïve group (from 8.930 to 7.09 kPa) with a P value of < 0.001, yet an insignificant reduction in the relapser group (from 10.75 to 9.75 kPa) with a P value of 0.052.
This was consistent with the findings of a study conducted on 549 HCV patients by Bachofner et al. , who found a rapid decline in fibrosis degree by fibroscan during and shortly after DAAs completion; their median measurement prior to DAA was 12.65 kPa and decreased to 8.55 kPa post-treatment.
With a P value of < 0. 001, the baseline RBP4 level was statistically significantly higher in naïve group (59.025 ± 8.012 ng/ml) than in the relapser group (39.45 ± 6.134 ng/ml) than in the healthy control group (32.8 ± 4.66 ng/ml). This was in conformity with ElRazik et al. , who studied RBP4 in 30 HCV patients, including 10 responders, 10 relapsers, and 10 breakthrough patients and found that serum RBP4 levels were 64.9 ± 13 ng/ml for the responder group versus 38 ± 9.8 ng/ml in the relapser group.
This was supported by a study by Seo et al. , who hypothesized that RBP4 levels are elevated in liver diseases other than cirrhosis, such as non-alcoholic steatohepatitis (NASH) and chronic HCV.
Although one study of nondiabetic, nonobese patients with genotype 1 chronic HCV showed that serum RBP4 level was positively linked to viral steatosis and chronic HCV patients had higher RBP4 levels than the controls, other chronic HCV studies either failed to link RBP4 positively with steatosis or demonstrated a lower RBP4 level than the controls. Given the inconclusive relationship between HCV infection and RBP4 levels, how RBP4 affects metabolism, including IR, in chronic HCV patients remains even more unclear .
These results could be explained by several lines of evidence that demonstrate the involvement of HCV in the retinoid pathway: HCV core protein stimulates cell growth by antagonizing all-trans retinoic acid and enhancing retinoid X receptor-α-dependent transcriptional activity via epigenetic downregulation of retinoid acid receptor-β2; HCV NS3/4A protein disrupts retinoic acid-inducible gene I signaling pathways to halt HCV defense. However, the relationship between HCV infection and RBP4 remained elusive .
RBP4 levels were even higher among healthy subjects with a strong family history of diabetes. All of these findings imply that RBP4 could be used as an IR marker. HCV infection itself may provide a better perspective on the involvement of RBP4 in the development of IR .
The current study showed a significant reduction in serum RBP4 level 12 weeks after the end of treatment with DAAs (P value < 0.001) in both naïve (from 59.025 to 49.875 ng/ml) and relapsers (from 39.45 to 34.07 ng/ml), and this reduction may be attributed to successful eradication of HCV in both naïve and relapser groups.
This was in partial agreement with the study conducted by Emam et al. , where RBP4 declined in the responder group from 64.9 ± 13 to 45.5 ± 14.7 ng/ml, while it increased in the relapser group from 38 ± 9.8 to 50.5 ± 28 ng/ml, and this may possibly be due to failure to achieve SVR.
Also, this was in accordance with El Razik et al. , who displayed that RBP4 at the 72nd week was significantly lower in responders than relapsers and described this normalization in the responders as reflecting the recovered metabolic abnormalities; however, the increased level of RBP4 in relapsers reflects again the disturbed metabolic background of this group.
Gastaldi et al.  explained these results by stating that complete suppression of HCV replication in patients without significant fibrosis improves insulin sensitivity and that HCV alters the circulating levels of factors involved in the development of reduced insulin sensitivity.
A significant reduction in RBP4 at the end of treatment may predict SVR; however, failure to achieve this reduction and, more importantly, persistent elevation in RBP4 at the end of treatment were linked to breakthrough and relapse .
On the contrary, Yagmur et al.  and Iwasa et al.  showed that RBP4 levels were lower in chronic hepatitis C (CHC) patients than in controls (34.6 ± 12.3 μg/mL vs. 46.2 ± 10.5 μg/mL; P ≤ 0.001). They also declared that only patients with SVR had significantly elevated RBP4 levels after treatment, reaching levels seen in healthy subjects, and that these levels continued to rise after 6 months to become significantly higher than the baseline, whereas RBP4 levels in relapsers and non-responders remained unchanged during the follow-up period. In addition, they discovered no link between plasma RBP4 levels and hepatic steatosis in CHC patients.
Iwasa et al.  explained their results by stating that there is a discrepancy between the studies as regard the degree of steatosis that was measured in only 5 (12%) out of 41 HCV patients in their study, and in most of their cases, steatosis was associated with more severe fibrosis.
This controversy could be attributed to the differences in patient characterization, especially the histopathologic features of the liver and the viral genotype .
On applying fibrosis stage assessment by fibroscan among the studied patients, the baseline RBP4 level was significantly lower among F4 (39.5 ± 5.74 ng/ml) than in those with F1–F3 (52.48 ± 12.04 ng/ml) with a P value of 0.002. Also, there was a significant negative correlation between RBP4 level and fibroscan stage and measurement (P value 0.010) among naive patients. This was consistent with Tacke et al. , who highlighted that the degree of liver fibrosis and cirrhosis was the main histological factor linked to lower RBP4 levels. Because the liver is the primary source of circulating RBP4, hepatic function must be considered when assessing RBP4 levels .
These results were supported by Alkhouri et al. , who studied RBP4 in patients with NAFLD and found a stepwise decline in RBP4 levels from patients without fibrosis to those with cirrhosis and a significant negative correlation between fibrosis stage and RBP4 levels. They also found that for every stage increase in fibrosis, mean RBP4 levels decreased by 3.06 mg/L, with the lowest RBP4 levels reported in patients with advanced fibrosis and cirrhosis, implying that serum RBP4 is directly linked to liver function.
The current study showed a significant positive correlation between baseline RBP4 and total cholesterol and triglyceride (TG) levels among relapser group of patients, this goes along with Graham et al. , who conducted a study on 311 chronic liver disease patients and discovered that RBP4 was significantly correlated with total cholesterol in cirrhotic patients and was linked to features of the metabolic syndrome as increased BMI, waist to hip ratio, serum triglyceride levels, systolic blood pressure, and low HDL levels.
RBP4 may have a role in hepatic TG production and the development of hepatic insulin resistance, as well as the metabolic implications of obesity. However, a recent study found that RBP4 has a causal role in hepatic lipogenesis: RBP4 enhanced intracellular triglyceride synthesis in cultured human HepG2 cells in a dose-dependent manner, and the effect was verified in vivo using animal models .
The present study showed that the best cutoff level of RBP4 in the prediction of hepatic fibrosis stage F4 was ≤ 46 ng/ml with sensitivity of 100%, specificity of 66.67%, PPV of 50%, NPV of 100%, and test accuracy of 80.5%.
This agreed with ElRazik et al.  who found that patients with advanced necro-inflammation and fibrosis stage (A3F3) exhibited lower RBP4 levels than those who had (A1F1) and (A2F2) in liver biopsy (38.8 ± 12.7, 57 ± 18, and 48 ± 17 ng/ml, respectively).
Serum RBP4 levels were found to be higher in chronic HCV infection, with a significant reduction after successful eradication. Its level is much lower in cirrhotic patients [F4]. As a result, RBP4 may have a promising role in assessing and predicting DAAs response, as well as prognostic value in liver cirrhosis prediction.
Availability of data and materials
The datasets that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
Analysis of variance
Body mass indexs
Chronic hepatitis C
Direct acting antivirals
Glucose transporter 4
Hepatitis c virus
Liver stiffness measurement
National Committee for Control of Viral Hepatitis
Negative predictive value
Positive predictive value
Retinol-binding protein 4
Sustained virologic response after 12 weeks
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The authors express their gratitude to staff members of both Internal Medicine Department [ Hepatology and Gastroenterology Department] and clinical pathology Department, Faculty of medicine, Ain Shams University, Cairo, Egypt.
This research did not receive any specific grant from any funding agencies.
Ethics approval and consent to participate
This study was performed according to the ethical standards for human experimentation and in accordance with the ethical principles of the 1975 Declaration of Helsinki. Patients included in this study signed an informed written consent to participate and all the procedures were in accordance with the standards of the Research Ethics Committee (REC) of the Faculty of Medicine, Ain Shams University (FWA 000017585).
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Rasmy, H.S., Elmalatawy, M.A.E., ElKarmoty, K.Z. et al. Serum retinol-binding protein 4 as a predictor of fibrosis regression and response to direct-acting antiviral drugs in chronic hepatitis C virus patients. Egypt Liver Journal 13, 16 (2023). https://doi.org/10.1186/s43066-023-00251-1