Insulin resistance and insulin secretion in chronic hepatitis C virus infection

BACKGROUND/AIMS: Diabetes mellitus (DM) is frequently observed in patients with chronic hepatitis caused by hepatitis C virus infection (CHC). The present study was designed to determine the pathogenic factors responsible for glucose intolerance in CHC patients. METHODS: A total of 131 patients with CHC were enrolled in this study. Insulin resistance and beta-cell function were determined after 75 g oral glucose tolerance tests. RESULTS: Glucose intolerance was detected in 27.5% (36/131) of CHC patients; 10 had DM and 26 impaired glucose tolerance. HOMA-R [insulin 0xglucose 0/22.5] was greater in patients with both impaired glucose tolerance and DM than in those with normal glucose tolerance (P<0.01). Matsuda index [10(4)/ (square root) (mean insulinxmean glucosexglucose 0xinsulin 0)] was lower in diabetic patients than in those with normal glucose tolerance (P<0.05). The insulinogenic index [Deltainsulin 30-0/Deltaglucose 30-0] and DeltaC-peptide 30 [DeltaC-peptide 30-0/Deltaglucose 30-0] were significantly lower even in patients with impaired glucose tolerance than in patients with normal glucose tolerance (P<0.01). CONCLUSIONS: Both insulin resistance and beta-cell dysfunction contribute to glucose intolerance in CHC patients.     

Interferon-alpha in patients with chronic hepatitis C and normal transaminase levels.

OBJECTIVE: to assess the response to interferon-alpha therapy in patients with chronic hepatitis C and normal alanine transferase levels. METHODS: 16 patients with normal transaminases (group A) and 36 patients with elevated ALT levels (group B) were treated with interferon-alpha-2b at a dose of 3 MU for 6 months. The biochemical, virological (HCV RNA in serum, liver and peripheral blood mononuclear cells) and histological responses were analyzed. RESULTS: no significant differences were observed between the two groups in age, sex, parenteral or sporadic transmission, hepatic lesion, Knodell index or HCV genotype, except for the higher proportion of women in group A. We found no significant differences between the groups in rates of patients with normal ALT in the follow-up period (6 months post-interferon, group A 44%, group B 17%) or in post-therapy negativization of HCV RNA levels (group A 31%, group B 17%). In 7 patients (44%) in group A, ALT remained normal throughout the study, whereas in the rest of the patients we observed some elevation during or after interferon treatment. Post-therapy mean Knodell index was 6 +/- 3 in group A versus 9 +/- 4 in group B (p < 0.05). CONCLUSIONS: the response to interferon was similar in patients with normal or elevated transaminases.     

Impact of steatosis on insulin secretion in chronic hepatitis C patients

OBJECTIVES: Liver steatosis is frequently observed in patients with chronic hepatitis C (CHC) and is an identified risk factor for progression of liver fibrosis. This study aimed to evaluate the relationship between steatosis and host/viral factors, and the correlation between steatosis and insulin secretion in CHC patients with normal glucose tolerance (NGT). METHODS: A total of 212 CHC patients were enrolled in this study. Insulin resistance and insulin secretion were determined in response to oral loading of 75 g glucose. Liver fibrosis and steatosis were quantified by the image analysis. RESULTS: Of the 212 CHC patients, 165 (78%) had steatosis, mostly of a mild degree. Multiple ordinal regression analysis revealed body mass index (BMI) (P= 0.011) as the main factor associated with severe steatosis. Of the 212 CHC patients, 148 (61%) showed NGT, and the serum insulin response to oral glucose loading in these NGT patients with steatosis was significantly different from that in patients with NGT but no steatosis. The peak insulin response occurred at 60 min in cases of mild steatosis, and at 90 min in patients with moderate or severe steatosis. The insulin level at 120 min in patients with severe steatosis was higher than that in those without steatosis. The total area under the response curve of insulin during OGTT in the patients with steatosis is higher than that in those without steatosis. CONCLUSION: Exaggerated insulin secretion was observed even in CHC patients with mild steatosis and NGT, suggesting the presence of insulin resistance. Exaggerated insulin secretion may accelerate the progression of liver fibrosis in CHC patients.     

Interferon-alpha induced and ribavirin induced thyroid dysfunction in patients with chronic hepatitis C

Chronic hepatitis C (CHC) is one of the commonest infectious diseases of the liver and may lead to cirrhosis or hepatocellular carcinoma. Combination therapy with pegylated interferon (PEG-IFN) and Ribavirin is the treatment of choice for CHC. Combination therapy is thought to act by means of antiviral mechanisms and immunomodulation. Thyroid dysfunction is the most common autoimmune adverse effect associated with combination therapy; hypothyroidism is more common than hyperthyroidism. Antithyroid antibodies and female sex have a predictive value in the development of interferon induced thyroid disease (IITD). Patients with CHC should be informed of the possibility of side effects on the thyroid gland. Screening for antithyroid antibodies and thyroid function tests should be performed in patients with CHC before the commencement of antiviral treatment, and during and after it. This article reviews different aspects of IITD, including its pathogenesis, clinical manifestations, association with treatment regimens and treatment response and the outcome of thyroid dysfunction.     

Previous hepatitis E virus infection,cirrhosis and insulin resistance in patients with chronic hepatitis C

Background

Hepatitis E virus (HEV) infection in patients with pre-existing liver disease has shown high morbidity and lethality. The consequences of HEV superinfection in patients with chronic hepatitis C virus (HCV) infection are not fully understood. This study aimed to evaluate the association between the presence of anti-HEV antibodies, liver cirrhosis, and insulin resistance.

Circulating microRNA-155 is associated with insulin resistance in chronic hepatitis C patients

Background and study aim

Hepatitis C represents a potential public health problem worldwide. Insulin resistance (IR) and type 2 diabetes (T2D) are among the serious metabolic complications for chronic hepatitis C virus (HCV) infection. MicroRNAs (miRNAs) are a group of small non-coding RNAs which are implicated in the modulation of almost all biological processes. The objective of this study was to investigate the levels of both miR-155 and miR-34a in sera of chronic HCV patients with or without T2D.

Association of chronic viral hepatitis B with insulin resistance

AIM:To investigate the relationship between chronic viral hepatitis B(CVHB) and insulin resistance(IR) in Korean adults.METHODS:A total of 7880 adults(3851 men,4029 women) who underwent a comprehensive medical examination were enrolled in this study.Subjects diagnosed with either diabetes mellitus,or any other disorder that could influence their insulin sensitivity,were rejected.Anthropometry,metabolic risk factors,hepatitis B surface antigen,hepatitis B surface antibody,hepatitis B core antibody,fasting plasma glucose and insulin were measured for all subjects.Homeostasis model assessment(HOMA),quantitative insulin check index(QUICKI),and Mf fm index were used for determining insulin sensitivity.Each participant was categorized into a negative,recovery,or CVHB group.To compare variables between groups,a t-test and/or one-way analysis of variance were used.Partial correlation coefficients were computed to present the association between insulin resistance and other variables.Multiple logistic regression analysis was used to assess the independent association between CVHB and IR.RESULTS:The mean age of men and women were 48.9 and 48.6 years,respectively.Subjects in the CVHB group had significantly higher waist circumference [(86.0 ± 7.7 cm vs 87.3 ± 7.8 cm,P = 0.004 in men),(78.3 ± 8.6 cm vs 80.5 ± 8.5 cm,P 0.001 in women)],cystatin C [(0.96 ± 0.15 mg/dL vs 1.02 ± 0.22 mg/dL,P 0.001 in men),(0.84 ± 0.15 mg/dL vs 0.90 ± 0.16 mg/dL,P 0.001 in women)],fasting insulin [(5.47 ± 3.38 U/mL vs 6.12 ± 4.62 U/mL,P 0.001 in men),(4.57 ± 2.82 U/mL vs 5.06 ± 3.10 U/mL,P 0.001 in women)] and HOMA index [(1.24 ± 0.86 vs 1.43 ± 1.24,P 0.001 in men),(1.02 ± 0.76 vs 1.13 ± 0.87,P = 0.033 in women)] compared to control group.The HOMA index revealed a positive correlation with body mass index(BMI)(r = 0.378,P 0.001),waist circumference(r =0.356,P 0.001),percent body fat(r = 0.296,P 0.001),systolic blood pressure(r = 0.202,P 0.001),total cholesterol(r = 0.134,P 0.001),triglycerides(r = 0.292,P 0.001),cystatin C(r = 0.069,P 0.001) and uric acid(r = 0.142,P 0.001).The QUICKI index revealed a negative correlation with BMI(r =-0.254,P 0.001),waist circumference(r = 0-0.243,P 0.001),percent body fat(r =-0.217,P 0.001),systolic blood pressure(r =-0.132,P 0.001),total cholesterol(r =-0.106,P 0.001),triglycerides(r =-0.205,P 0.001),cystatin C(r =-0.044,P 0.001) and uric acid(r =-0.096,P 0.001).For subjects identified with IR,the odds ratio of an accompanying diagnosis of chronic hepatitis B was 1.534(95% CI:1.158-2.031,HOMA index criteria) or 1.566(95% CI:1.124-2.182,QUICKI criteria) after adjustment for age,gender,BMI,and amount of alcohol consumption.CONCLUSION:Our study demonstrates that CVHB is associated with IR.CVHB may need to be monitored for occurrence of IR and diabetes mellitus.     

Interferon-alpha suppresses liver cell proliferation in patients with chronic hepatitis C virus infection

SUMMARY: Interferon (IFN) therapy has been shown to reduce the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C, including virological nonresponders (NR). Whether IFN suppresses liver cell proliferation, i.e. the relevant risk factor for HCC, is unknown. The aim of the study was to evaluate the effect of IFN therapy on liver cell proliferation in chronic hepatitis C. The proliferating cell nuclear antigen-labelling index (PCNA-LI) was assessed prior to and at the end of therapy in the liver of 29 patients with chronic hepatitis C who received 3 MU IFN-alpha2b thrice weekly for 24-48 weeks. Overall, the median value of PCNA-LI was significantly reduced from 2.6% to 1.1% at the end of therapy (P < 0.0001). At baseline, PCNA-LI median values were similar in the 15 virological responders compared with the 14 NRs (2.3%vs 3.4%, P = 0.121) and at the end of therapy, median changes of PCNA-LI (-1.4%vs-1.1%, P = 0.089) were also similar although there was a higher decline of the proliferation index in responders with respect to NRs at the end of therapy (0.7%vs 1.6%, P = 0.004). In the two groups, the rate of fibrosis score reduction was also similar (7%vs 20%, P = 0.326). In contrast, the histological activity index was more often reduced in responders than in NRs both at the >or=2 and >or=4 points reduction level (80%vs 36%, P = 0.02 and 53%vs 14%, P = 0.03, respectively). The study showed a significant suppression of liver cell proliferation in IFN-treated patients with chronic hepatitis C. Although the strongest IFN effect was observed in virological responders, a reduction of proliferative activity was also seen in virological NRs.     

Prevalence of diabetes mellitus and insulin resistance in patients with chronic hepatitis C: comparison with hepatitis B virus‐infected and hepatitis C virus‐cleared patients

Background/Aims: Our aim was to evaluate the relationship between hepatitis C virus (HCV) infection and development of diabetes mellitus (DM) or insulin resistance (IR) in comparison with hepatitis B virus (HBV) infection and eradication of HCV infection by interferon treatment. Methods: This study consisted of 952 outpatients, including 544 HCV‐infected (HCV+chronic), 286 HBV‐infected (HBV+chronic) and 122 patients whose HCV was cleared by interferon treatment (HCV+cleared) (diabetes study). Among 849 without overt DM, IR was assessed in 423 patients, including 232 HCV‐infected (HCV+chronic), 135 HBV‐infected (HBV+chronic) and 56 HCV‐eradicated patients (HCV+cleared) (IR substudy). Results: The prevalence of DM in the HBV+chronic, HCV+chronic and HCV+cleared groups was 6.3, 13.6 and 9.0%, respectively (HBV+chronic vs HCV+chronic, P<0.005), in the diabetes study, and the prevalence of IR in the HCV+chronic group (54.3%) was also higher than that in the HBV+chronic (36.3%) (P<0.005) and HCV+cleared groups (35.7%) (P<0.05) in the IR substudy. However, HCV infection was not shown to be independently associated with DM development [odds ratio (OR) 1.669; P=0.0936] and with IR (OR 1.531; P=0.2154) by multivariate analysis in comparison with HBV infection as control. Conclusions: HCV‐infected patients showed a higher prevalence of DM and IR than those with HBV infection. However, in Japan, other confounding factors appeared to be more important risk factors for the development of disturbance in glucose metabolism.     

Interferon-alpha and liver fibrosis in patients with chronic damage due to hepatitis C virus

The present review focuses on the published information published regarding the effects of interferon alpha therapy on liver fibrosis in patients with chronic liver damage secondary to hepatitis C infection. Data reviewed included results of the in vitro effects of interferon on hepatic cell line cultures with regards to indirect markers of fibrosis, activation of hepatic stellate cells and oxidative stress response. In the clinical arena, there is current clear evidence of a favorable histological outcome in patients with sustained viral response to interferon therapy. For this reason, the current review focuses more on the histological outcomes regarding liver fibrosis in patients who have not attained viral response to therapy (non-responders) or who already have biopsy defined cirrhosis. Data in these patients were analyzed according to the results of objective testing of fibrosis through the assessment of liver biopsy and its change during time, specially because the morbidity and mortality of this disease is directly related to the complications of liver cirrhosis and not necessarily to the persistence of the hepatitis C virus. Lastly, it is concluded that the process of liver fibrosis/cirrhosis is a dynamic one and that there is some evidence to support the usefulness of interferon alpha therapy as a means to halt or retard the progression of hepatic fibrosis. The result of current clinical trials in which interferon therapy is being used to modify the progression of fibrosis in non-responders or cirrhotic patients is eagerly awaited.     

Hepatic iron accumulation may be associated with insulin resistance in patients with chronic hepatitis C

Background/Aim: Insulin resistance and hepatic iron overload are frequently demonstrated in hepatitis C virus (HCV)-related liver diseases. We investigated the relationship between insulin resistance and hepatic iron deposition in patients with chronic HCV infection. Methods: Insulin resistance was evaluated using the homeostasis model assessments for insulin resistance (HOMA-IR) in 56 non-diabetic non-obese patients with biopsy proven chronic hepatitis C. The relationship between insulin resistance and serum ferritin levels or the grade of hepatic iron deposition was assessed. Results: The levels of plasma immunoreactive insulin (IRI) and HOMA-IR were significantly correlated with serum ferritin levels and the grade of hepatic iron deposition (P = 0.003).Although IRI and HOMA-IR increased in parallel with the development of hepatic fibrosis, insulin resistance (HOMA-IR > 2) was observed in 11 (26.2%) of 42 patients even without severe fibrosis (F0-2). Among patients without severe fibrosis, IRI and HOMA-IR were significantly higher in patients with iron deposits than in those without iron deposits. Conclusion: Hepatic iron overload may be associated with insulin resistance in patients with chronic hepatitis C, especially in patients with mild to moderate fibrosis.     

TNF-alpha and CXCL-10 correlation with insulin resistance in patients with chronic hepatitis C virus infection

There are increasing reports of association between HCV infection and type-2 diabetes mellitus. Although the mechanism by which this association remains uncertain, development of insulin resistance may explain this association. We investigated the association of TNF-alpha and CXCL-10 with insulin resistance in HCV infected patients. Forty-four non-diabetic chronic hepatitis C patients and twenty healthy individuals were included. Fasting blood was used for glucose and insulin measurements. Diagnosis of insulin resistance (IR) was based on a mathematical means by the homeostasis model assessment score-insulin resistance index (HOMA-IR). Serum insulin, TNF-alpha and CXCL-10 levels were measured by enzyme linked immunosorbent assay (ELISA). Quantitative measurement of hepatitis C virus was performed by a standardized real time PCR assay. The HCV patients demonstrated a significant increase in serum TNF-alpha, CXCL-10, and HOMA-IR values as compared to normal controls. HOMA-IR level positively correlated with hepatitis C viral load, TNF-alpha and CXCL-10. It is concluded that, TNF-alpha, CXCL-10 correlate with IR and may play a role in the development of type-2 diabetes mellitus in chronic hepatitis C infected patients.     

慢性乙型肝炎病毒感染与胰岛素抵抗的相关性

目的 探讨慢性HBV感染与胰岛素抵抗(IR)的关系.方法 纳入68例慢性乙型肝炎轻度(MCHB)患者为病例组,选择同期无肝炎病毒感染且肝功正常者67例为对照组.采用稳态模型评估的胰岛素抵抗指数(HOMA-IR)判定IR,根据HOMA-IR将MCHB组分为伴IR组(HOMAIR＞ 2.7)和未伴IR组(HOMA-IR≤ 2.7).检测患者肝功能生物化学指标、糖代谢与脂代谢指标、人体质量指数(BMI)、HBV标志物、HBV DNA载量、肿瘤坏死因子α等,并在两组间进行比较.两组间计量资料比较采用独立样本t检验或Mann -Whitney秩和检验;对率的比较采用x2检验;采用Spearman秩相关或点双序列相关分析MCHB患者IR的相关因素;采用二元logistic回归法分析MCHB患者IR的危险因素.结果 MCHB组患者存在高血清胰岛素血症、高ALT和高HOMA-IR值,分别为11.10 (2.90 ～ 53.24) μU/ml、46(9～126) U/L和2.44 (0.55 ～ 11.93),分别高于对照组的7.10(1.20 ～ 16.60)μU/ml、13(5～ 36) U/L和1.61 (0.23 ～ 3.43),Z值分别为-5.451、-8.211和-5.631,P值均＜0.01.MCHB患者有30例(44.12％)存在IR,伴IR组的ALT和BMI值分别为(66.40±32.85)U/L和(22.16±1.03) kg/m2,高于未伴IR组的(47.47±32.87) U/L和(21.58±1.24) kg/m2,t值分别为-2.358和-3.566,P值均＜0.05.在MCHB组中,BMI和ALT与IR呈正相关,相关系数r分别为0.374和0.282,P值均＜0.05.HBV DNA载量与IR无相关性(r=0.015,P＞0.05).二元logistic回归分析提示BMI和ALT是MCHB患者IR的独立危险因素,[Exp (B):1.85,P＜0.01; Exp (B):1.022,P＜0.05].结论 在慢性HBV感染诱导的轻度肝脏炎症者中IR发生率高,可能与肝功能损害和BMI相关,但与HBV DNA载量无关.