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Subclinical Glucose Abnormalities & Undiagnosed Diabetes Noted in HCV+
 
 
  "The current study demonstrated that the prevalence of glucose abnormalities validated by OGTT among CHC patients was significantly higher than that before the test. Based on OGTT results, we found that 18.6% of CHC patients who readily met with DM criteria were undiagnosed. In addition, there was a 3.5-fold increase in the prevalence of glucose abnormalities in CHC (65.8%) patients in comparison with controls (35.3%). Taken together, our data indicated that glucose abnormalities are common and is easily underestimated among patients with HCV infection. It therefore provided further evidence for the association between HCV infection and early-stage of abnormal glucose metabolism as well as overt DM stage.....The current study presents OGTT as a viable option for the assessment of glucose abnormalities and uncovering of diabetes, with a potential impact on the successful management of both disorders....Our data indicated that abnormal glucose metabolism may be initiated at early stage of HCV infection and HCV infection might contribute to the subtle development of glucose abnormalities at young age. Determination of glucose abnormalities by OGTT may be suggested for CHC patients....
 
...CHC patients carried a high prevalence of glucose abnormalities. Determination of glucose abnormalities by OGTT may be suggested.....The prevalence of normoglycemia, IGT, and T2DM in 683 CHC patients was 27.7%, 34.6%, and 37.8%, respectively. For those CHC patients without fibrosis, the prevalence of glucose abnormalities reached 67.9%.....For those without known DM, there was a 3.5-fold increase in the prevalence of glucose abnormalities in CHC (65.8%) patients in comparison with controls (35.3%) (OR 3.51"
 
EDITORIAL
Uncovering Glucose Abnormalities in People With Hepatitis C Infection: Should Oral Glucose Tolerance Test Become a Standard of Care?
 
The American Journal of Gastroenterology Aug 2008
 
Ayse Aytaman, M.D. 1 and Samy I. McFarlane, M.D., M.P.H. 2 1 Division of Gastroenterology, VA New York Harbor Healthcare System ; and 2 SUNY Health Science Center at Brooklyn, Brooklyn, New York
 
"Among 683 patients with hepatitis C infection, 131 (19.2%) had type 2 DM at the baseline, 146 (21.4%) had IFG, and 406 (59.4%) had normoglycemia. These numbers showed a significant change after OGTTs were performed. In fact, only 189 (34.2%) patients had normoglycemia, while 127 (23%) had DM and 236 (42.8%) had IGT. A higher prevalence of DM was uncovered by OGTT in CHC patients with a normal baseline FBG fasting plasma glucose in comparison to controls. The diabetic patients were older, with a linear trend for advancing fibrosis stage for patients from normoglycemia (26.5%) to DM (48.4%) (P < 0.001). As expected, the family history of DM, male gender, and fibrosis stage were strongly associated with DM. These numbers were significantly lower among non-hepatitis C controls."
 
ABSTRACT
 
Hepatitis C and type 2 diabetes mellitus (DM) are two rising epidemics with significant impact on each other. Hepatitis C-infected patients have a higher incidence of type 2 diabetes, and diabetic patients have a high prevalence of hepatitis C. There is mounting evidence that glucose abnormalities have a negative impact on the disease progression as well as antiviral therapy outcomes. Utilization of oral glucose tolerance testing has the potential to uncover previously undetected DM as well as impaired glucose tolerance or prediabetes in patients with chronic hepatitis C (CHC). Early detection of diabetes and prediabetes with oral glucose tolerance testing in CHC patients can lead to interventions, with significant positive impact on disease progression and antiviral therapy outcomes.
 
Article Text
 
We are at the crossroads of two major epidemics: hepatitis C infection and type 2 diabetes. These rising epidemics represent major challenges both to the clinicians and to the health-care systems, at large, in terms of diagnostic, therapeutic, and economic implications. In 2003, there were over 194 million people diagnosed with diabetes worldwide, with an estimated 333 million persons to be afflicted by 2025 (1). These numbers, however, do not include those with undiagnosed diabetes, a population that is currently estimated to represent over 26% of the U.S. population alone (2). Parallel to the diabetes epidemic, hepatitis C currently affects about 3% of the world population, estimated 170 million people around the world, leading to a substantial rise in the prevalence of chronic liver disease, with its enormous health and economic impacts (3, 4).
 
The association of hepatitis C and type 2 diabetes has been previously described in several epidemiological studies. In the National Health and Nutrition Statistical Survey (NHANES) III, hepatitis-C-positive patients over the age of 40 yr had an adjusted odds ratio of 3.77 for the development of type 2 diabetes. Interestingly, hepatitis B infection was not associated with an increased diabetes risk among this patient population. Lecube et al. reported a high prevalence of glucose abnormalities in their Spanish patient cohort and suggested screening for glucose abnormalities in hepatitis C patients (5). While obesity and increasing age are among the strongest risk factors for type 2 diabetes, the data from our group indicate that diabetes occurs at a significantly lower body mass index (BMI) and about a decade earlier among hepatitis C patients compared to controls (submitted for publication). Furthermore, the risk of hepatitis C appears to increase in people with diabetes. The prevalence of hepatitis C antibodies in type 2 diabetic patients ranges from 1.78 to 12.1% in some studies (7, 8). Although type 1 diabetes mellitus (DM) has been observed in patients treated with alpha-interferon, the majority of hepatitis-C-associated diabetes is of type 2 and is thought to be associated with insulin resistance (IR) (9). Steatosis and IR, together with type 2 DM, are manifestations of a metabolic syndrome and are observed to occur more frequently with hepatitis C virus (HCV) infection than other chronic inflammatory liver diseases (10). Significant amount of research is currently being directed toward understanding the mechanisms underlying the interaction of metabolic syndrome and chronic HCV infection and its implications.
 
HCV is associated with steatosis, which is genotype-specific. Genotype 3-associated steatosis is not associated with IR, but is related to the virus and can be successfully treated and disappears after viral eradication only to recur upon viral relapse. The mechanism of the alteration in lipid metabolism might be related to the decrease in the secretion of triglyceride-rich very low-density lipoproteins (VLDL) from the hepatocyte by direct inhibition of the microsomal triglyceride transfer protein by the HCV core protein, leading to excess fat accumulation in the hepatocytes (11). The HCV core protein also induces oxidative stress via mitochondrial injury, with perturbed lipid peroxidation leading to steatosis (12). In genotype non-3 chronic hepatitis C (CHC) patients, on the other hand, IR with steatosis, together with overproduction of proinflammatory cytokines, plays a substantial role in the development of type 2 DM. Multiple molecular pathways are currently under investigation to explain the diabetogenic role of HCV and its effect on IR. HCV increases the tumor necrosis factor alpha levels, which can lead to IR through interference with insulin signaling pathways (13). HCV is also associated with the upregulation of suppressor of cytokine signaling 3(SOC3), with the resultant dysfunction of insulin signaling (14). There is also data to suggest a decrease in signal transducer and activator of transcription 3 (STAT-3), which is essential for a normal glucose hemostasis and insulin sensitivity (15).
 
The clinical implications of IR and steatosis on the natural history of hepatitis C, on the extent of hepatic fibrosis, as well as on the antiviral therapy outcomes, are substantial. IR has been found to be an independent predictor of hepatic fibrosis (16). IR and DM can lead to an enhanced steatosis and liver fibrosis in patients with chronic HCV (17, 18) and even increase the risk of hepatocellular carcinoma (19). Glucose abnormalities and dysglysemia are independent risk factors for the response to antiviral therapy (20), and a sustained virological response (SVR) correlates with a reduction in the incidence of dysglysemia in patients with CHC infection (21). The SVR rates are decreased in patients with impaired fasting glucose (IFG) as well as type 2 diabetes, and the eradication of CHC infection by antiviral therapy significantly reduces the incidence of glucose abnormalities in this patient population.
 
These data collectively highlight the need for the assessment of dysglycemia in hepatitis C patients more rigorously prior to antiviral therapy. Calculation of IR by the homeostasis model assessment (HOMA) is laborious and expensive, especially if we would like to add the hepatic insulin extraction rates to its measurement as the hepatic insulin clearance rates can be impaired in advanced liver fibrosis.
 
In this issue of the Journal, Huang et al. (22) evaluated the prevalence of glucose abnormalities associated with CHC infection and compared them to community controls (9). The study assessed BMI and blood pressure, baseline fasting glucose, alanine transaminase, cholesterol, triglycerides, and quantitative HCV RNA and genotype. They also performed oral glucose tolerance test (OGTT) in 522 CHC patients and 447 community volunteers without documented type 2 DM. The prevalence of IFG, impaired glucose tolerance (IGT), and type 2 DM was evaluated in both groups according to the American Diabetes Association criteria. Among 683 patients with hepatitis C infection, 131 (19.2%) had type 2 DM at the baseline, 146 (21.4%) had IFG, and 406 (59.4%) had normoglycemia. These numbers showed a significant change after OGTTs were performed. In fact, only 189 (34.2%) patients had normoglycemia, while 127 (23%) had DM and 236 (42.8%) had IGT. A higher prevalence of DM was uncovered by OGTT in CHC patients with a normal baseline FBG fasting plasma glucose in comparison to controls. The diabetic patients were older, with a linear trend for advancing fibrosis stage for patients from normoglycemia (26.5%) to DM (48.4%) (P < 0.001). As expected, the family history of DM, male gender, and fibrosis stage were strongly associated with DM. These numbers were significantly lower among non-hepatitis C controls. Although the control group had a selection bias, as it was composed of healthy, and presumably, more health-conscious volunteers taking part in a preventive medical evaluation, Huang et al. were able to demonstrate that OGTT uncovers a substantial number of diabetic and dys-glycemic patients who were not diagnosed by fasting serum glucose alone.
 
The current study presents OGTT as a viable option for the assessment of glucose abnormalities and uncovering of diabetes, with a potential impact on the successful management of both disorders. The economic implications for such interventions are largely unknown. With the lack of large prospective studies to assess the long-term implications of these interventions on the outcomes of both diseases, physicians should utilize OGTT to uncover diabetes in patients in whom the risk of diabetes is rather high by virtue of classic risk stratification such as increasing age, obesity, dyslipidemia, and family history of the disease, as well as if liver biopsy or visualization studies are suggestive of steatosis or steatohepatitis.
 
Prospective, large-scale trials are needed to evaluate the effect of aggressive therapy of metabolic syndrome, IR and tight control of DM, and obesity on the outcome of hepatitis C infection, as well as antiviral therapy.
 
In the future, a deeper understanding of the pathophysiology of the interactions of metabolic syndrome and hepatitis C will add new antiviral drugs to our armamentarium: modifiers of IR pathways, pre-emptive therapy of IR, and modifiers of anti-inflammatory cytokines.
 
Reappraisal of the Characteristics of Glucose Abnormalities in Patients With Chronic Hepatitis C Infection
 
Jee-Fu Huang, M.D. 1,2,3 , Ming-Lung Yu, M.D., Ph.D. 3,4 , Chia-Yen Dai, M.D. 2,3,4 , Ming-Yen Hsieh, M.D. 3 , Shang-Jyh Hwang, M.D. 4,5 , Pi-Jung Hsiao, M.D. 6 , Li-Po Lee, M.D. 3 , Zu-Yau Lin, M.D. 3,4 , Shinn-Chern Chen, M.D., Ph.D. 3,4 , Ming-Yuh Hsieh, M.D. 3,4 , Liang-Yen Wang, M.D. 3,4 , Shyi-Jang Shin, M.D., Ph.D. 4,6 , Wen-Yu Chang, M.D., Ph.D. 3 , and Wan-Long Chuang, M.D., Ph.D. 3,4 1 Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan ; 2 Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan ; 3 Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan ; 4 Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan ; 5 Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan ; and 6 Endocrine Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
 
ABSTRACT
 
OBJECTIVES: There is growing evidence suggesting the mutual link between type 2 diabetes mellitus (T2DM) and hepatitis C virus (HCV) infection. However, the impact of HCV infection on the suite of glucose abnormalities has rarely been investigated. The study aimed to determine the difference regarding the prevalence and the characteristics of glucose abnormalities between chronic hepatitis C (CHC) patients and community-based controls. It also aimed to investigate the related clinical, virological, and histological features of glucose abnormalities in HCV infection.
 
METHODS: Six hundred eighty-three CHC patients and 515 sex-/age-matched controls were included. Oral glucose tolerance test (OGTT) was performed in 522 CHC patients and 447 controls without known T2DM. Clinical data were assessed upon the different stages of glucose abnormalities based on OGTT results.
 
RESULTS: The prevalence of normoglycemia, IGT, and T2DM in 683 CHC patients was 27.7%, 34.6%, and 37.8%, respectively. There was a significant linear trend from normoglycemia to T2DM in terms of age, family history of T2DM, and advanced liver fibrosis in CHC patients. For those CHC patients without fibrosis, the prevalence of glucose abnormalities reached 67.9% high. All CHC patients carried a significantly higher prevalence than controls regarding those aged <65 yr. For those without known DM, there was a 3.5-fold increase in the prevalence of glucose abnormalities in CHC (65.8%) patients in comparison with controls (35.3%) (OR 3.51, 95% CI 2.70-4.56, P < 0.001).
 
CONCLUSIONS: CHC patients carried a high prevalence of glucose abnormalities. Determination of glucose abnormalities by OGTT may be suggested.
 
INTRODUCTION
 
Hepatitis C virus (HCV) infection is one of the most important causes of cirrhosis and hepatocellular carcinoma and has a strong impact on public health worldwide. In addition to its hepatotropic characteristic, HCV is also a lymphotropic virus in nature (1). Replication of HCV in diseased extrahepatic organs and tissues may have direct cytopathic effects, thus leading to a wide spectrum of extrahepatic manifestations (2-4). Diabetes mellitus (DM), mostly type 2 diabetes mellitus (T2DM), is a less well-recognized extrahepatic manifestation of HCV infection. A higher prevalence of T2DM among patients with HCV infection has been consistently reported during the past decade (5-8). Our previous epidemiological study also demonstrated the mutual link between T2DM and HCV viremia state in a community-based setting (8). Taken together, T2DM represented one more disease to be included in the list of established extrahepatic manifestations of chronic HCV (CHC) infection and there is growing evidence to support the concept that HCV infection is a risk factor for developing T2DM.
 
T2DM is a common endocrine disorder encompassing stepwise, multifactorial, pathogenetic mechanisms. These mechanisms include resistance to the action of insulin, increased hepatic glucose production, and a defect in insulin secretion, all of which contribute to the development of overt hyperglycemia (9). T2DM is often present at least 4-7 yr before diagnosis (10). Therefore, almost all T2DM patients have experienced the prediabetic condition, that is, impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT), before a definite diagnosis of T2DM was made. In addition to future DM development, the prediabetic condition also carries a risk for cardiovascular disease (11, 12). Previous data linking HCV infection and DM mainly focused on patients with overt DM. However, the impact of HCV infection on the entire suite of glucose abnormalities as well as the extent, severity, and characteristics of glucose abnormalities in HCV infection has rarely been investigated.
 
This study aimed to determine the difference regarding the prevalence and the characteristics of glucose abnormalities between CHC patients and community-based controls according to the results of oral glucose tolerance test (OGTT). The related clinical, virological, and histological features regarding glucose abnormalities in patients with HCV infection were also analyzed.
 
DISCUSSION
 
Although previous epidemiological studies have demonstrated the mutual link between T2DM and HCV infection, the extent, severity, and characteristics of T2DM among CHC patients remain unclear. Meanwhile, previous data addressing this mutual link were limited to those with overt DM. The impact of HCV infection on the suite of glucose abnormalities has rarely been investigated. The current study demonstrated that the prevalence of glucose abnormalities validated by OGTT among CHC patients was significantly higher than that before the test. Based on OGTT results, we found that 18.6% of CHC patients who readily met with DM criteria were undiagnosed. In addition, there was a 3.5-fold increase in the prevalence of glucose abnormalities in CHC (65.8%) patients in comparison with controls (35.3%). Taken together, our data indicated that glucose abnormalities are common and is easily underestimated among patients with HCV infection. It therefore provided further evidence for the association between HCV infection and early-stage of abnormal glucose metabolism as well as overt DM stage.
 
T2DM is often present at least 4-7 yr before clinical diagnosis (10). Studies have shown that DM diagnosis improves estimates of cardiovascular risk and provides an opportunity for earlier and more intensive treatments, such as more aggressive hypertension and lipid control, to reduce cardiovascular events in these patients and to prevent related complications (11, 12). In addition to the future development of DM, the prediabetic condition also carries risk for cardiovascular disease. In terms of DM prevention, previous clinical trials indicated that medical interventions could prevent development in high-risk patients (15, 16). Therefore, definitive diagnosis of glucose abnormalities is an important issue because it allows attempts to improve clinical outcomes, such as weight reduction and lifestyle modification (17, 18). FPG level alone is commonly used as a screening test for the diagnosis of DM. However, this practice is based on the relative convenience and lower cost of FPG compared with an OGTT (13, 19). The discrepancy of distribution of glucose abnormalities before and after OGTT in our study was consistent with previous observations that 19.3-59.3% of glucose abnormalities remained undetected using the revised IFG criteria (20, 21). Our data concordantly demonstrated the higher sensitivity of the OGTT compared with the FPG test for detecting abnormal glucose metabolism. Lecube et al. demonstrated that 18% more new DM cases and 30% more new cases of IGT were uncovered by OGTT in anti-HCV (+) patients, which were significantly higher than those values in anti-HCV (-) patients (22). However, limited cases in a hospital-based setting and measuring anti-HCV instead of HCV RNA might have undermined their results. Noteworthy was that the present study included, to our knowledge, the largest number of HCV viremic patients for the elucidation of the actual distribution of glucose abnormalities by OGTT. Our data may implicate that neither two consecutive FPG measurements nor random glucose level > 200 mg/dL were comprehensive and sufficient for the elucidation of glucose abnormalities among CHC patients. To avoid underestimation, an OGTT might be a better tool and therefore provide a more accurate estimate of glucose abnormalities among CHC patients. It might also suggest that different criteria might be necessary for DM diagnosis in patients with HCV infection, such as a lower cutoff for normoglycemia, prediabetes, and DM.
 
The precise mechanisms whereby HCV infection leads to glucose abnormalities are not fully clear. HCV may induce a Th1 lymphocytes immune-mediated response, which leads to activation of tumor necrosis factor (TNF)-_ system and elevation of interleukin-6 levels. Meanwhile, HCV directly causes liver steatosis. All the above events may precipitate to the development of liver fibrosis. TNF-_ system activation, liver steatosis, and fibrosis contribute to the development of insulin resistance, which plays a pivotal role in the pathogenesis of DM associated with HCV infection (23). Because glucose abnormalities are more frequent in patients with advanced liver disease, the extent of liver injury should be considered when evaluating the prevalence of DM in patients with HCV infection (24). By stratifying CHC patients into different stages of glucose abnormalities, we demonstrated that a significant linear trend existed regarding advanced fibrosis as well as age and family history. In addition, by stratifying CHC patients into different fibrotic stages, we also demonstrated there was a linear increase of prevalence of glucose abnormalities regarding the degree of fibrosis staging. Our data were results echoing previous prospective cross-sectional study by Zein et al. (24), which showed that the presence of advanced histological disease in genetically predisposed CHC patients was associated with a higher prevalence of DM and IFG. Nonetheless, among those without fibrosis in our study, the prevalence of prediabetes/DM and DM alone reached high as 67.9% and 26.6%, respectively. Delicate exploration of glucose abnormalities by OGTT in the current study may suggest that the high prevalence of glucose abnormalities was not totally attributed to advanced histological alteration. Our findings thus suggested that HCV in itself may play a direct pathogenetic role in the emergence of DM even in the early stage of the liver histological changes. It differs from the usual pathogenesis of DM in those with non-HCV liver diseases. Further study addressing the difference of insulin resistance at different stages of glucose abnormalities between CHC patients and general population will be helpful to clarify this issue.
 
On the other side, the distribution of age-specific prevalence of glucose abnormalities within and between different age groups in the current study showed that although age was a crucial contributing factor in the pathogenetic process of glucose abnormalities, HCV infection may also play a part in it, especially for the nonaged. Previous HCV core gene transgenic mice study (25) demonstrated that the ability of insulin to lower the plasma glucose level was impaired without gain in body weight at young age. Intriguingly, our study also demonstrated the discrepancy of prevalence between those CHC patients and controls increased inversely with age. It might provide evidence of human study that HCV infection may contribute to the subtle development of glucose abnormalities at young age.
 
Our study included a large number of CHC patients for validation of glucose abnormalities by OGTT. However, there were some potential limitations. The relationship between T2DM and HCV genotypes remains controversial (5, 6, 8, 24). Our results showed that neither HCV genotypes (genotype 1 and 2) nor viral loads predisposed CHC patients to glucose abnormalities. HCV genotypes other than 1 and 2 are quite rare in Taiwan, as observed in previous HCV molecular epidemiological studies (26). The cross-sectional nature of the current study and incomplete coverage of all genotypes did not allow us to make definite conclusion about this issue. A large collaborative study comparing patients with different genotypes is needed to further clarify whether there is any specific HCV genotype that predisposes or protects individuals from insulin resistance and glucose abnormalities. Another limitation of the current study is that the control group from somewhat limited sources might raise possible selection bias and thus undermine the results and/or conclusion. OGTT is a cumbersome and inconvenient medical testing for general population. This study was performed on a voluntary basis for control group, and subjects who participated in it were probably more health-conscious than randomly chosen participants would be. Therefore, the actual prevalence of abnormal glucose metabolism might be underestimated in control group. No significant difference of sex and age between CHC patients and controls and its multipurpose health check-up in intent of controls much lessened the limitations of our study.
 
In conclusion, we demonstrated the prevalence of IGT and DM validated by OGTT among CHC patients was significantly higher than that before the test. CHC patients carried a significantly higher prevalence of IGT as well as DM than community controls. Neither HCV genotypes (1 and 2) nor viral loads predisposed CHC patients to glucose abnormalities. Our data indicated that abnormal glucose metabolism may be initiated at early stage of HCV infection and HCV infection might contribute to the subtle development of glucose abnormalities at young age. Determination of glucose abnormalities by OGTT may be suggested for CHC patients.
 
RESULTS
 
Baseline Characteristics of All CHC Patients

 
There were 683 CHC patients (men = 363, mean age = 52.9 ± 12.0 yr) enrolled, which included 315 patients of genotype 1 and 368 of genotype non-1 (213 of 2a, 37 of 2b, 74 of mixed infection, and 44 of unclassified). The mean viral load was 5.29 ± 0.95 log IU/mL. Their baseline demographic data are shown in Table 1. Among the 683 CHC patients at enrollment, 131 (19.2%) patients had history of T2DM and were defined as cases of CDM. The prevalence of normoglycemia and IFG dependent of FPG level and medical history was 59.4% (N = 406), and 21.4% (N = 146), respectively.
 
Clinical Features of All CHC Patients Stratified by Stages of Glucose Abnormalities
 
By stratification of all CHC patients into different stages of glucose abnormalities based on OGTT results, there were 189 patients with normoglycemia, 236 with IGT, and 258 with DM (both SDM and CDM) (Table 1). There was no significant difference between the various stages of glucose abnormalities with regard to gender, body mass index, ALT levels, triglycerides levels, cholesterol levels, HCV genotypes, or viral loads. The mean age among the 258 DM patients was 56.2 ± 9.5 yr, which was significantly higher than those with normoglycemia (50.3 ± 13.1 yr) or IGT (51.3 ± 12.7 yr, P < 0.001). Family history of DM was depicted in 16.4% (31/189), 21.6% (51/236), and 36.4% (94/258) of patients with normoglycemia, IGT, and DM, respectively, and a statistically significant linear trend was observed (P < 0.001). There was also a significant linear increment of advanced fibrosis stage (F3-4) for patients ranging from normoglycemia (26.5%) to DM (48.4%, P < 0.001). The prevalence of IGT/DM at F0, F1-2, and F3-4 stages were 67.8% (74/109), 70.7% (227/321), and 80.2% (203/253), respectively, while that of DM alone increased from 26.6% (29/109) at F0, 32.4% (104/321) at F1-2, and 49.4% (125/253), respectively. The prevalence of glucose abnormalities (IGT/DM) among those with advanced fibrosis (F3-4) was significantly higher than that of absence (F0) or mild fibrosis (F1-2) (OR 1.89, 95% CI 1.31-2.73, P= 0.001). The prevalence of DM alone among those with advanced fibrosis (F3-4) was also significantly higher than that of F0 or F1-2 (OR 2.16, 95% CI 1.57-2.97, P < 0.001). For those patients without fibrosis (F0), the prevalence of IGT/DM and DM alone was 67.9% (74/109) and 26.6% (29/109), respectively.
 
Distribution of Glucose Abnormalities Assessed by OGTT in All CHC Patients
 
With OGTT assessment, the prevalence of normoglycemia, IGT, and DM was 27.7% (N = 189), 34.6% (N = 236), and 37.8% (N = 258), respectively. After OGTT, patients carried a significantly lower prevalence of normoglycemia (27.7%, N = 189) than that before the test (58.6%, N = 406, P < 0.0001). The prevalence of IGT was 34.6% (N = 236), which consisted 201 normoglycemia and 35 IFG patients before OGTT, was significantly higher than that of IFG before the test (21.4%, N = 146, P < 0.0001). The prevalence of SDM, including 32 normoglycemia and 95 IFG patients before OGTT, reached 18.6% (N = 127) with OGTT load (Table 2).
 
Multiple logistic regression analyses of variables associated with DM development in all 683 CHC patients demonstrated that family history was the leading variable associated with DM (OR 3.06, 95% CI 2.08-4.52, P < 0.001), followed by male gender (OR 2.20, 95% CI 1.52-3.18, P < 0.001), fibrosis stage (OR 1.20, 95% CI 1.05-1.38, P= 0.009), and age (OR 1.05, 95% CI 1.03-1.07, P < 0.001) (Table 3).
 
Comparison Between CHC Patients and Controls Excluding Known Diabetics
 
A total of 552 CHC patients (278 men, mean age = 52.0 ± 12.4 yr) without known DM were enrolled into further analysis. On the other side, a total of 447 sex- and age-matched subjects (mean age = 50.5 ± 13.7 yr, men = 222) without known DM from a community-based setting who received OGTT were served as controls for the comparison of distribution of glucose abnormalities (Table 2). By OGTT, the prevalence of normoglycemia, IGT, and DM among CHC group was 34.2% (189/552), 42.8% (236/552), and 23.0% (127/552), respectively. By contrast, the prevalence of normoglycemia, prediabetes, and DM among control group was 64.7% (289/447), 32.4% (145/447), and 2.9% (13/447), respectively. There was a 3.5-fold increase in the prevalence of glucose abnormalities in CHC (65.8%, 363/552) patients in comparison with controls (35.3%, 158/447) (OR 3.51, 95% CI 2.70-4.56, P < 0.0001).
 
Among those who had normal FPG level at enrolment, CHC patients carried a significant higher prevalence of IGT (49.5%, 201/406) than controls (10.8%, 34/316) (OR 8.13, 95% CI 5.42-12.20, P < 0.0001). A higher prevalence of DM, i.e., SDM was also uncovered by OGTT in CHC patients with normal FPG level (7.9%, 32/406) in comparison with controls (0.9%, 3/316) (OR 8.93, 95% CI 2.71-29.43, P < 0.0001). Taken together, for those with normal FPG levels, CHC patients had a significantly higher prevalence of glucose abnormalities than that of controls (OR 10.16, 95% CI 6.84-15.08, P < 0.0001) (Table 2).
 
The age-specific prevalence of glucose abnormalities in both groups was shown in Figure 1. There existed an age-dependent increase in the prevalence of glucose abnormalities in controls, CHC patients excluding CDM, and all CHC patients. The prevalence of glucose abnormalities in CHC patients excluding CDM was significantly higher than that of controls in those aged <45 yr (OR 7.32, 95% CI 4.18-12.79, P < 0.001), 45-54 yr (OR 3.68, 95% CI 2.26-5.99, P < 0.001), and 55-64 yr (OR 3.13, 95% CI 1.88-5.21, P < 0.001), respectively. All CHC patients also carried a significant higher prevalence than controls regarding those aged <45 yr (OR 8.21, 95% CI 4.71-14.29, P < 0.001), 45-54 yr (OR 5.28, 95% CI 3.28-8.50, P < 0.001), and 55-64 yr (OR 4.36, 95% CI 2.64-7.20, P < 0.001), respectively. However, control group did not demonstrate significant difference of prevalence comparing with either all CHC patients (P= 0.06) or excluding CDM (P= 0.517) among those aged >64 yr.
 
 
 
 
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