Evolution in the indications for anti-viral therapy in chronic hepatitis B / 临床肝胆病杂志

In order to reduce the disease burden of chronic hepatitis B (CHB) and improve the treatment rate of CHB, the indications for anti-viral therapy have been gradually expanded and simplified in guidelines for the prevention and treatment of CHB released by Chinese Medical Association from 2005 to 2022. This article elaborates on the evolution in the indications for anti-viral therapy in CHB from the five aspects of converging indications of HBeAg-positive and HBeAg-negative CHB, reduction in the treatment threshold of HBV DNA, reduction in the treatment threshold of serum alanine aminotransferase, emphasis on the risk factors for disease progression, and gradual loosening of the requirements for virological indicators in patients with liver cirrhosis.

Clinical features and long-term prognosis of primary biliary cholangitis in patients with past hepatitis B virus infection / 中华肝脏病杂志

Objective: To investigate the clinical features and long-term prognosis of primary biliary cholangitis (PBC) in patients with past hepatitis B virus (HBV) infection. Methods: 353 cases with PBC who visited the Liver Disease Center of Beijing Friendship Hospital Affiliated to Capital Medical University between January 2000 and January 2018 were retrospectively analyzed and were divided into the past HBV infection group (156 cases) and the no HBV infection group (197 cases). The two groups' baseline clinical features were compared. Ursodeoxycholic acid response rate after one year, GLOBE score, UK-PBC score, and long-term liver transplantation-free survival rate were compared through outpatient and telephone follow-up. Results: PBC with past HBV infection had a significantly reduced female proportion compared to the no HBV infection group (91.9% vs. 79.5%, P = 0.001). However, there were no statistically significant differences in age, biochemical indices, immunological indicators, platelet count, cirrhosis proportion, and others. Ursodeoxycholic acid biochemical response rate was reduced in patients with past HBV infection at the end of one year of treatment, but the difference was not statistically significant (65.8% vs. 78.2%, P = 0.068). In addition, there were no statistically significant differences between the GLOBE score (0.57 vs. 0.59, P = 0.26) and UK-PBC 5-year (2.87% vs. 2.87%, P = 0.38), 10-year (9.29% vs. 8.2%, P = 0.39) and 15-year liver transplantation rates (16.6% vs. 14.73%, P = 0.39). Lastly, the overall 5-year liver transplantation-free survival rate had no statistically significant difference between the two groups of patients (86.4% vs. 87.5%, P = 0.796). Conclusion: Primary biliary cholangitis had no discernible effect in terms of age at onset, biochemical indices, immunological indicators, cirrhosis proportion, ursodeoxycholic acid response rate after one year, GLOBE score, UK-PBC score, or overall liver transplantation-free survival rate in patients with past hepatitis B virus infections.

Ten-year changes in clinical characteristics and antiviral treatment patterns of chronic hepatitis B in China: a CR-HepB-based real-world study / 中华肝脏病杂志

Objective: To understand ten-year changes in clinical characteristics and antiviral treatment patterns of chronic hepatitis B in China. Methods: Patients with chronic HBV infection:demographic, virologic, hematologic, blood biochemistry, and antiviral treatment data were extracted from the China Registry of Hepatitis B (CR-HepB) database between 2012 and 2022 for descriptive statistics and change trend analysis. Multiple group comparisons were conducted using the Kruskal Wallis H test, while counting data was compared between groups using χ (2) test. Results: A total of 180 012 patients with chronic HBV infection were included, with a median age of 40 years old, and a male proportion accounting for 60.2%. The HBeAg positive rate was 43.3%. Over time, the median age of new patients each year increased from 39 to 47 years, while the HBeAg positive rate decreased from 51.3% to 32.8%. The initial diagnosis of patients was mainly CHB (71.4%), followed by hepatitis B cirrhosis (11.8%), inactive HBsAg carrier status (10.6%), and chronic HBV carrier status (6.2%). Among the newly registered patients every year from 2012 to 2022, the proportion of hepatitis B cirrhosis remained stable, but after 2019, the proportion of CHB increased and the proportion of other diagnoses decreased. The proportion of patients with cirrhosis increased with age in different age groups, with 3.5%, 19.3%, and 30.4% in the < 40, 40-69, and≥70 age groups, respectively. The proportion of women in patients with cirrhosis also increased with age, from 16.1% in those < 30 years old to 44.3% in those≥80 years old. From 2012 to 2022, the proportion of patients receiving first-line nucleos(t)ide analog antiviral treatment increased year by year, from 51.0% in 2012-2013 to 99.8% in 2022. Conclusion: The CR-HepB registration data reflect the changes in clinical characteristics and antiviral treatment patterns in patients with chronic HBV infection in China over the past ten years and can thus provide a reference to promote hepatitis B diagnosis and treatment practice, as well as scientific research.

Histopathological evaluation of cirrhosis reversal / 中华肝脏病杂志

A normal liver can develop cirrhosis through long-term and repeated stimulation from various etiologies. Histological manifestations like the collapse of hepatic lobular structure (including microvascular structure) and the formation of pseudolobules can lead to portal hypertension and even decompensated cirrhosis. More and more evidence suggests that effective etiological treatment can not only delay but also reverse the progression of cirrhosis. The mechanism of cirrhosis reversal mainly includes the degradation of extracellular matrix, hepatocyte regeneration, and hepatic lobular remodeling. The "gold standard" for the evaluation of cirrhosis reversal at present is still a liver biopsy. Therefore, the histopathological evaluation of cirrhosis reversal is very important for determining the disease's prognosis, efficacy, and mechanism of exploration.

Interpretation of the essential updates in guidelines for the prevention and treatment of chronic hepatitis B (Version 2022) / 中华肝脏病杂志

Chinese Society of Hepatology and Chinese Society of Infectious Diseases, Chinese Medical Association update the guidelines for the prevention and treatment of chronic hepatitis B (version 2022) in 2022. The latest guidelines recommend more extensive screening and more active antiviral treating for hepatitis B virus infection. This article interprets the essential updates in the guidelines to help deepen understanding and better guide the clinical practice.

Expanding initial anti-HBV therapy for chronic hepatitis B: Reducing the treatment threshold of alanine aminotransferase / 临床肝胆病杂志

In order to achieve the global goal of eliminating viral hepatitis as a public health threat by 2030 proposed by the World Health Organization, it is of great importance to expand the treatment of chronic hepatitis B patients. Recent studies have shown that alanine aminotransferase (ALT) is associated with liver inflammation, fibrosis, hepatocellular carcinoma, and outcome events of liver disease. Besides, as a strategy for expanding antiviral therapy, reducing the treatment threshold of ALT can reduce the occurrence of liver cirrhosis, hepatocellular carcinoma, and liver-related death. In the Expert opinion on expanding antiviral therapy for chronic hepatitis B published in China in 2022, the treatment indication for chronic hepatitis B patients was updated to positive serum HBV DNA and ALT above the treatment threshold (30 U/L for male and 19 U/L for female), with the exclusion of other causes.

Hepatocellular carcinoma prediction model performance decreases with long-term antiviral therapy in chronic hepatitis B patients

Background/Aims@#Existing hepatocellular carcinoma (HCC) prediction models are derived mainly from pretreatment or early on-treatment parameters. We reassessed the dynamic changes in the performance of 17 HCC models in patients with chronic hepatitis B (CHB) during long-term antiviral therapy (AVT). @*Methods@#Among 987 CHB patients administered long-term entecavir therapy, 660 patients had 8 years of follow-up data. Model scores were calculated using on-treatment values at 2.5, 3, 3.5, 4, 4.5, and 5 years of AVT to predict threeyear HCC occurrence. Model performance was assessed with the area under the receiver operating curve (AUROC). The original model cutoffs to distinguish different levels of HCC risk were evaluated by the log-rank test. @*Results@#The AUROCs of the 17 HCC models varied from 0.51 to 0.78 when using on-treatment scores from years 2.5 to 5. Models with a cirrhosis variable showed numerically higher AUROCs (pooled at 0.65–0.73 for treated, untreated, or mixed treatment models) than models without (treated or mixed models: 0.61–0.68; untreated models: 0.51–0.59). Stratification into low, intermediate, and high-risk levels using the original cutoff values could no longer reflect the true HCC incidence using scores after 3.5 years of AVT for models without cirrhosis and after 4 years of AVT for models with cirrhosis. @*Conclusions@#The performance of existing HCC prediction models, especially models without the cirrhosis variable, decreased in CHB patients on long-term AVT. The optimization of existing models or the development of novel models for better HCC prediction during long-term AVT is warranted.

Characteristic and prognosis of patients with non-EBV infection-associated hemophagocytic lymphohistiocytosis / 中华血液学杂志

Objective: To explore the clinical characteristics and outcomes of patients with non-Epstein-Barr virus (EBV) infection-associated hemophagocytic lymphohistiocytosis (IAHLH) . Methods: Clinical data of 48 patients diagnosed with non-EBV IAHLH in Beijing Friendship Hospital from January 2015 to March 2021 were collected, and the clinical characteristics, treatment, curative effect and prognosis of the patients were analyzed retrospectively. Results: This study included 48 patients, 28 males and 20 females, with a median (range) age of 34.5 (2-74) years. Pathogens that cause IAHLH were as follows: virus (16 cases, 33.3%) , bacteria (17 cases, 35.4%) , parasitic agents (13 cases, 27.1%) , and fungi (2 cases, 4.2%) . The median time from onset to diagnosis of hemophagocytic syndrome (HLH) was 40 (10-160) days. The median (range) time duration from prodrome to the definite diagnosis of IAHLH was 67 (23-270) days. The clinical characteristics were fever (48 cases, 100%) , splenomegaly (34 cases, 70.8%) , cytopenia (38 cases, 79.1%) , elevated ferritin (45 cases, 93.8%) , elevated fasting triglyceride levels (7 cases, 14.6%) , hypofibrinogenemia (17 cases, 35.4%) , decrease natural killer cell activity (26 in 44 cases, 59.1%) , and elevated sCD25 (35 cases, 74.5%) . Twenty-five patients (52.1%) had adenopathy. Once a certain pathogen was identified as the causative factor of hemophagocytic lymphohistiocytosis (HLH) , cytotoxic agents and glucocorticoids were withdrawn, and specific pathogen-directed treatment was initiated. After treatment, 36 cases (75.0%) achieved complete response, and 14 of 15 patients (93.3%) with parasitic and fungal HLH got a response; however, the response rate of patient with bacterial and viral HLH was only 66.7% (22 of 33 patients) . The estimated 5-year overall survival rate was 72.3% (95%CI 50.3%-69.8%) . The adverse prognostic factors were total bilirubin over the upper limit of normal (OR=20.0, 95%CI 1.1-378.3, P=0.046) and pathogenic infection not fully controlled (OR=19.9, 95%CI 2.9-134.5, P=0.002) . Conclusion: Non-EBV IAHLH has a good prognosis. When diagnosed, cytotoxic agents and glucocorticoids should be tapered off, and pathogen-targeted therapy should be critically administered to clear the triggering infection.

Neoadjuvant chemotherapy for patients with locally advanced penile cancer: an updated evidence / 亚洲男科学杂志(英文版)

Neoadjuvant chemotherapy (NAC) has shown promising results in patients with locally advanced penile cancer. However, no consensus exists on its applications for locally advanced penile cancer. Thus, it is unclear which kind of chemotherapy regimen is the best choice. Consequently, a systematic search of PubMed, Web of Science, and EMBASE was performed in March 2021 to assess the efficacy and safety of NAC for the treatment of patients with locally advanced penile cancer. The Newcastle-Ottawa Scale was used to assess the risk of bias in each study. This study synthesized 14 published studies. The study revealed that patients who achieved an objective response to NAC obtained a better survival outcome compared with those who did not achieve an objective response. In addition, the objective response rates (ORRs) and pathological complete response (pCR) rates were 0.57 and 0.11, respectively. The incidence of grade ≥3 toxicity was 0.36. Subgroup analysis found that the ORR and pCR of the taxane-platinum (TP) regimen group performed better than those of the nontaxane-platinum (NTP) regimen group (0.57 vs 0.54 and 0.14 vs 0.07, respectively). Moreover, the TP regimen group had more frequent toxicity than the NTP regimen group (0.41 vs 0.26). However, further studies were warranted to confirm the findings.

Paying attention to other systemic diseases of hepatic manifestations: a return to common sense in clinical practice / 中华肝脏病杂志

Liver have complex functions with a high workload. Various liver diseases are the result of the interaction of diverse genetic and environmental factors. Moreover, other systemic diseases may also affect liver, producing corresponding manifestations, such as abnormal liver function tests, portal vein or hepatic vein thrombosis, portal hypertension, hepatosplenomegaly and liver space-occupying lesions. Therefore, it is extremely important for hepatologists to have an in-depth understanding of other systemic diseases of hepatic manifestations, especially hematologic, connective tissue, endocrine, and circulatory, in order to improve the level of clinical diagnosis and treatment.

Study on the relationship between nonalcoholic fatty liver disease and hepatocellular carcinoma in patients with prior hepatitis B virus infection / 中华肝脏病杂志

Objective: To explore the role of nonalcoholic fatty liver disease (NAFLD) in the development of hepatocellular carcinoma (HCC) in patients with prior hepatitis B virus infection (HBsAg-negative and anti-HBC-positive). Methods: 1605 hospitalized patients who were first diagnosed with HCC at Nanfang Hospital between 2015 to 2017 were retrospectively studied. Patients who developed HCC on the basis of active HBV infection (HBsAg-positive, anti-HBc positive) were used as control. Multivariate logistic regression model was used to analyze the relationship between NAFLD and HCC in patients with prior hepatitis B virus infection. Results: Among HCC patients with both HBsAg and anti-HCV negative, the proportion of prior HBV infection accounted for 86.7%. NAFLD prevalence was higher in patients with HCC based on prior HBV infection than active HBV infection (19.7% vs. 8.5%, P < 0.001). After adjusting for gender, age, hypertension, alanine aminotransferase, and liver cirrhosis, patients with HCC based on prior HBV infection were more likely to develop NAFLD (OR: 2.29, 95% CI: 1.40-3.74), and this phenomenon was observed only in patients with non-cirrhosis (OR: 5.26, 95% CI: 2.53-10.96) and aged≥50 years (OR: 2.36, 95% CI: 1.33-4.20). Conclusion: NAFLD may be a risk factor for HCC in a previously infected patients with HBV, especially in non-cirrhotic and population aged≥50 years.

Liver cirrhosis: Decompensation and "recompensation" / 临床肝胆病杂志

The evolution concept of decompensated cirrhosis rebuilds the clinical staging system for decompensated cirrhosis, which changes the focus from the pattern of disease progression to refining the status of acute decompensation onset and proposing "recompensation" of decompensated cirrhosis. During the process, factors such as portal hypertension and systemic inflammatory changes can affect the clinical outcome of decompensated cirrhotic patients. Significantly, more evidence is warranted to elucidate the clinical characteristics and potential mechanisms of achieving "recompensation" after etiology control, such as in viral hepatitis patients.

Effect of the change in antiviral therapy indication in increasing the treatment rate of chronic hepatitis B / 临床肝胆病杂志

Objective To investigate the impact of the change in anti-hepatitis B virus (HBV) therapy indication on treatment rate and the features of the population requiring treatment. Methods The treatment-naïve patients with chronic hepatitis B (CHB) in the China Registry of Hepatitis B (CR-HepB) database were selected as subjects, and related demographic, virological, hematological, and biochemical data were collected. The Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups, and the Kruskal-Wallis H test was used for comparison between multiple groups; the chi-square test or the Fisher's exact test was used for comparison of categorical data between groups. Results A total of 3640 treatment-naïve CHB patients were included in this study, among whom 64.4% were male, 68.7% had an age of 30-59 years, and 46.8% had an indeterminate clinical stage. According to the 2015 and 2019 editions of Guidelines for the prevention and treatment of chronic hepatitis B and the 2022 edition of expert consensus, the number of patients who had the indication for antiviral therapy was 625(17.2%), 1333(36.6%), and 2890(79.4%), respectively. The number of patients requiring treatment was increased by 1557 according to the 2022 edition of expert consensus, among whom 1424(91.5%) met the treatment threshold of alanine aminotransferase (ALT) > 30 U/L for male patients or ALT > 19 U/L for female patients. The additional patients requiring treatment according to the 2022 edition of expert consensus had significantly higher levels of ALT and HBV DNA and significantly lower scores of APRI and FIB-4 than the additional patients requiring treatment according to the 2019 edition of Guidelines (all P < 0.05). Conclusion The expansion of antiviral therapy indications for CHB may significantly increase the proportion of CHB patients receiving antiviral treatment and help mild CHB patients at the risk of disease progression to receive timely treatment and achieve the improvement in long-term prognosis.

Etiological and non-etiological therapies for cirrhotic portal hypertension / 临床肝胆病杂志

Portal hypertension is a serious complication of liver cirrhosis resulting from the increases in portal vascular resistance and portal blood inflow. Both etiological and non-etiological therapies can effectively reduce portal venous pressure to a certain degree, but with an unsatisfactory effect in improving prognosis. New therapeutic drugs targeting the reduction in intrahepatic vascular resistance may help to achieve the reversal of portal hypertension. Based on the pathogenesis of cirrhotic portal hypertension, this article summarizes the current pharmacotherapies from the aspects of etiological and non-etiological therapies, so as to provide a comprehensive theoretical and evidence-based basis for clinical treatment options.

Clinical trial protocols of new drugs for nonalcoholic steatohepatitis: A systematic review / 临床肝胆病杂志

Objective To describe the characteristics and registration status of clinical trials of new drugs for nonalcoholic steatohepatitis (NASH), and to provide a reference for the design and implementation of clinical trials of new drugs for NASH. Methods The U.S. Clinical Trials Database, China Clinical Trial Registry, and Center for Drug Evaluation, National Medical Products Administration, were searched for clinical trials of new drug registration and interventional studies with NASH as the indication published up to August 6, 2021, using NASH in English and Chinese characters as the keywords, and liver cirrhosis was excluded. Two researchers independently searched and screened the articles to extract relevant information. Results A total of 196 clinical trials of new drug registration or interventional studies for NASH were included, among which there were 174 trials registered abroad and 22 trials registered in China, and the number of registrations tended to increase year by year. The numbers of phase Ⅰ, phase Ⅰ/Ⅱ(including Ⅰb/Ⅱa), phase Ⅱ, phase Ⅱ/Ⅲ, and phase Ⅲ clinical trials were 45(23.0%), 8(4.1%), 112(57.1%), 4(2.0%), and 19(9.7%), respectively. The main drug types included farnesoid X receptors, fibroblast growth factors, peroxisome proliferator-activated receptor agonists, and glucagon-like peptide-1, with numbers of 16(8.16%), 14(7.14%), 11(5.61%), and 13(6.63%), respectively. The clinical trials of innovative drugs for NASH initiated by the sponsors in European and American regions accounted for the highest proportion, and there was a gradual increase in the number of clinical trials of innovative drugs in China in recent years, with a similar distribution of single-center and multicenter clinical trials. As for the trials with NASH patients as subjects, the numbers of trials with pathology, imaging, and clinical diagnosis as the main inclusion criteria were 125, 66, and 42, respectively. Phase Ⅰ clinical trials used safety, tolerability, and pharmacokinetic parameters as the main assessment indices, while phase Ⅱ and phase Ⅲ clinical trials often used safety and efficacy as the main assessment indices. The number of clinical trials for the registration of innovative drugs for NASH was relatively low but kept increasing in China, and there were fewer clinical trials of innovative traditional Chinese medicine drugs compared with innovative chemical drugs. Conclusion There is a significant increase in the registration of international clinical trials of innovative drugs for NASH, and most of these trials are in the early phases, with large differences in inclusion criteria and assessment indices, a lack of unified evaluation indices, and relatively few trials with new designs. There are fewer clinical trials of innovative drugs for NASH in China than in European and American countries, and the number of such trials is gradually increasing in China.

Diagnosis and management of primary biliary cholangitis with osteoporosis / 临床肝胆病杂志

Primary biliary cholangitis (PBC) is a chronic progressive cholestatic liver disease often observed in the middle-aged and elderly women and it can eventually lead to liver cirrhosis or liver failure. Osteoporosis is one of the common complications in PBC patients and is characterized by decreased bone mass and increased susceptibility to fractures. Osteoporosis and fractures caused by osteoporosis seriously affect the quality of life of PBC patients, and with the improvement of PBC treatment strategies and the increase in life expectancy, early diagnosis, prevention, and treatment of PBC with osteoporosis is of particular importance. This article briefly summarizes the epidemiology, pathogenesis, and diagnosis and treatment of patients with PBC and osteoporosis and proposes current challenges and future research directions.

Diagnosis and management of primary biliary cholangitis with osteoporosis / 临床肝胆病杂志

Primary biliary cholangitis (PBC) is a chronic progressive cholestatic liver disease often observed in the middle-aged and elderly women and it can eventually lead to liver cirrhosis or liver failure. Osteoporosis is one of the common complications in PBC patients and is characterized by decreased bone mass and increased susceptibility to fractures. Osteoporosis and fractures caused by osteoporosis seriously affect the quality of life of PBC patients, and with the improvement of PBC treatment strategies and the increase in life expectancy, early diagnosis, prevention, and treatment of PBC with osteoporosis is of particular importance. This article briefly summarizes the epidemiology, pathogenesis, and diagnosis and treatment of patients with PBC and osteoporosis and proposes current challenges and future research directions.

Association of Protein Z with Prediabetes and Type 2 Diabetes

Background@#Type 2 diabetes mellitus (T2DM) is a progressive metabolic disease. Early detection of prediabetes is important to reduce the risk of T2DM. Some cytokines are known to be associated with T2DM. Therefore, we aimed to identify cytokines as novel biomarkers of glucose dysmetabolism. @*Methods@#The first stage of the study included 43 subjects (13 subjects with newly diagnosed T2DM, 13 with prediabetes, and 16 with normoglycemia) for cytokine microarray analysis. Blood samples of the subjects were assessed for 310 cytokines to identify potential indicators of prediabetes. The second stage included 142 subjects (36 subjects with T2DM, 35 with prediabetes, and 71 with normoglycemia) to validate the potential cytokines associated with prediabetes. @*Results@#We identified 41 cytokines that differed by 1.5-fold or more in at least one out of the three comparisons (normoglycemia vs. prediabetes, normoglycemia vs. T2DM, and prediabetes vs. T2DM) among 310 cytokines. Finally, we selected protein Z (PROZ) and validated this finding to determine its association with prediabetes. Plasma PROZ levels were found to be decreased in patients with prediabetes (1,490.32±367.19 pg/mL) and T2DM (1,583.34±465.43 pg/mL) compared to those in subjects with normoglycemia (1,864.07±450.83 pg/mL) (P<0.001). There were significantly negative correlations between PROZ and fasting plasma glucose (P=0.001) and hemoglobin A1c (P=0.010). @*Conclusion@#PROZ levels were associated with prediabetes and T2DM. We suggest that PROZ may be a promising biomarker for the early detection of prediabetes. Further large-scale studies are needed to evaluate the relationship and mechanism between PROZ and prediabetes and T2DM.

Effect of ginkgo biloba extract on behaviors in rat with adolescent sedentariness / 解剖学报

Objective To investigate the effect of Ginkgo biloba extract on behaviors in rat with adolescent sedentariness and its possible mechanism. Methods Twenty-four male SD rats (4-week-old) were randomly divided into normal control (NC), adolescent sedentarines (AS), and Ginkgo biloba extract (GBE) groups. After 4 weeks intervention with GBE, open-field test and elevated plus-maze test were performed to detect the behavioral changes. The content of malondialdehyde (MDA) and activity of superoxide dismutase (SOD) in brain were determined by colorimetric method. Protein levels of glycogen synthase kinase 3β(GSK-3β) and β-catenin in cerebral white matter were determined by Western blotting. Results In open-field test, it was shown that the autonomic activity of rats in AS group increased, while the central regional travel time was reduced. Duration and number of residence in the open arm of elevated plus-maze test decreased in AS group. These anxiety-like behaviors were ameliorated by GBE intervention. Compared with the NC group, GSK-3β/ β-catenin ratio and the content of MDA was upregulated in AS group while downregulated in GBE group. And activity of SOD were downregulated in AS group while significantly upregulated in GBE group (P<0. 05). Conclusion Ginkgo biloba extract ameliorate anxiety-like behavior in rat with adolescent sedentariness. Wnt/ β-catenin pathway and antioxidant regulation may play a cerebral protective role.

Association of Protein Z with Prediabetes and Type 2 Diabetes

Background@#Type 2 diabetes mellitus (T2DM) is a progressive metabolic disease. Early detection of prediabetes is important to reduce the risk of T2DM. Some cytokines are known to be associated with T2DM. Therefore, we aimed to identify cytokines as novel biomarkers of glucose dysmetabolism. @*Methods@#The first stage of the study included 43 subjects (13 subjects with newly diagnosed T2DM, 13 with prediabetes, and 16 with normoglycemia) for cytokine microarray analysis. Blood samples of the subjects were assessed for 310 cytokines to identify potential indicators of prediabetes. The second stage included 142 subjects (36 subjects with T2DM, 35 with prediabetes, and 71 with normoglycemia) to validate the potential cytokines associated with prediabetes. @*Results@#We identified 41 cytokines that differed by 1.5-fold or more in at least one out of the three comparisons (normoglycemia vs. prediabetes, normoglycemia vs. T2DM, and prediabetes vs. T2DM) among 310 cytokines. Finally, we selected protein Z (PROZ) and validated this finding to determine its association with prediabetes. Plasma PROZ levels were found to be decreased in patients with prediabetes (1,490.32±367.19 pg/mL) and T2DM (1,583.34±465.43 pg/mL) compared to those in subjects with normoglycemia (1,864.07±450.83 pg/mL) (P<0.001). There were significantly negative correlations between PROZ and fasting plasma glucose (P=0.001) and hemoglobin A1c (P=0.010). @*Conclusion@#PROZ levels were associated with prediabetes and T2DM. We suggest that PROZ may be a promising biomarker for the early detection of prediabetes. Further large-scale studies are needed to evaluate the relationship and mechanism between PROZ and prediabetes and T2DM.