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The Relationship of Hepatitis C Virus Infection with Diabetes in the United States Population: HCV & Diabetes Not Associated, same for Pre-Diabetes - NHANES
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"In conclusion, in the U.S. population, we were unable to demonstrate an association of HCV infection with diabetes or with insulin resistance. Elevated liver enzyme activities were associated with both diabetes and with insulin resistance. We suggest that previous reports of relationships of HCV with diabetes may in large measure have been due to this effect of elevated liver enzymes."
"In this large U.S. national population-based study, HCV infection was not associated with diabetes. No relationship was found in unadjusted analyses or in analyses adjusted for multiple factors associated with HCV or diabetes. Neither ever having had HCV infection nor current HCV infection was related to diabetes in overall analysis......We also studied the relationship of HCV infection with insulin resistance (as estimated by HOMA-IR) among persons with normal glucose and with pre-diabetes and did not find associations. As with diabetes, we did observe a relationship of elevated enzyme activities with insulin resistance......NHANES is a cross-sectional study, which is the most important limitation of our work. Thus we cannot, for example, rule out the possibility that persons with both HCV and diabetes may have been under-represented because increased morbidity and mortality prevented them from participating. Such a potential problem could be addressed in a cohort study that followed persons with HCV from time of infection for a long enough time to determine if the incidence of diabetes was greater than among uninfected but otherwise comparable persons."
"Because elevation of liver enzymes (ALT and GGT) has been found to increase the risk of diabetes without regard to underlying liver disease, we hypothesized that the association of HCV and diabetes found in clinical studies might be attributable to nonspecific elevation of liver enzyme activity rather than to an effect of HCV infection itself. Therefore, we examined the combined effect of HCV markers and activities of ALT or GGT on the odds of diabetes and pre diabetes. The prevalence of elevated enzymes was much higher among participants with HCV markers (Table 3). In multivariate-adjusted analyses, elevated enzymes were associated with increased odds of diabetes irrespective of HCV status (Figure 2a). In contrast, the presence of HCV markers did not increase the odds of diabetes. Similar relationships were seen when separate analyses were performed for diagnosed and undiagnosed diabetes (data not shown). For pre-diabetes, there was also a positive association with elevated enzyme activity (Figure 2b). Beyond the effect of elevated enzymes, a positive association of pre-diabetes with HCV markers was evident for ALT, but not GGT......We further examined the relationship of HCV status to HOMA-IR according to enzyme activity. Elevated ALT and GGT activities were associated with increased HOMA-IR regardless of HCV status among persons with either normal glucose (Figure 3a) or with pre-diabetes (Figure 3b). Neither anti-HCV nor HCV RNA positivity was associated with increased HOMA-IR among persons with normal enzyme activities. Only among persons with elevated enzyme activity could a relationship be seen of markers of HCV with HOMA-IR.......A decreased incidence of diabetes following successful treatment of HCV (sustained virological response) has also been reported.(31) ALT elevation at the beginning of follow-up was not an independent predictor of diabetes development, but the relationship of treatment outcome with liver enzyme levels was not presented.....An association of HCV with diabetes was found only in the presence of increased liver enzyme activities. Increased ALT and GGT activities are markers of fatty liver, which itself is associated with diabetes. "
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The Relationship of Hepatitis C Virus Infection with Diabetes in the United States Population
Hepatology Feb 5 2014
Constance E. Ruhl, M.D., Ph.D. Social & Scientific Systems, Inc.
Andy Menke, Ph.D. Social & Scientific Systems, Inc.
Catherine C. Cowie, Ph.D. National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services
James E. Everhart, M.D., M.P.H. National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record
ABSTRACT
An association of hepatitis C virus (HCV) infection with diabetes has been reported in many studies, but few have been population-based and applied standard criteria for diabetes diagnosis. We examined this relationship using recent population-based data from the U.S. National Health and Nutrition Examination Survey. 15,128 adult participants in the 1999-2010 surveys had data on diabetes status and serum HCV antibody (anti-HCV) or HCV RNA. Using American Diabetes Association criteria, diabetes was defined as a health care provider diagnosis, serum hemoglobin A1C (A1C) ≥6.5%, or fasting plasma glucose (FPG) ≥126 mg/dL; pre-diabetes as A1C 5.7%-<6.5% or FPG 100-<126 mg/dL; and normal glucose as A1C <5.7% and FPG <100 mg/dL. Odds ratios (OR) for diabetes and pre-diabetes, comparing persons with HCV infection to those without, were adjusted for demographics, BMI, C-reactive protein, smoking, drinking, and blood transfusion before 1992. Among participants without diabetes, we compared mean insulin resistance, estimated using homeostasis model assessment (HOMA-IR), by HCV status. The overall prevalence of anti-HCV+ was 1.7%, of HCV RNA+, 1.1%, of diabetes, 10.5%, and of pre-diabetes, 32.8%. The prevalence of diabetes and pre-diabetes did not differ by HCV status. In multivariate-adjusted analysis, diabetes remained unassociated with anti-HCV (OR=1.0, 95% confidence interval (CI), 0.6-1.7) or with HCV RNA (OR=1.1, 95% CI, 0.6-1.9). In contrast, elevated alanine aminotransferase and gamma glutamyltransferase activities were associated with diabetes regardless of HCV status. HOMA-IR was not associated with HCV markers in unadjusted or multivariate-adjusted analyses (p>0.05).
Conclusion. In the U.S. population, HCV was not associated with diabetes, or with insulin resistance among persons with normal glucose. Previously reported relationships of HCV with diabetes were possibly attributable to the effect of elevated liver enzymes.
Both hepatitis C virus (HCV) infection and diabetes are common conditions with an estimated 3.2 million persons chronically infected with HCV in the U.S.(1) and 25.8 million suffering from diabetes.(2) An association of HCV infection with type 2 diabetes has been reported since shortly after the discovery of HCV in 1989. For example, in two meta-analyses of a total of 47 unique studies, HCV was associated with diabetes with an adjusted odds ratio (OR) of 1.7 (95% confidence interval (CI), 1.2-2.2) in cross-sectional studies and an adjusted hazard ratio (HR) of 1.7 (95% CI, 1.3-2.1) in cohort studies in the first report(3) and an overall odds ratio of 1.7 (95% CI, 1.2-2.4) in the second report.(4) However, many of these studies were based on clinical series and may have suffered from ascertainment bias. Among the few population-based studies that have been conducted, results were inconsistent. In the third U.S. National Health and Nutrition Examination Survey (NHANES), 1988-1994, a non-statistically significant association was found overall, while a stronger relationship was reported among persons aged 40+ years.(5)
In a U.S. community-based prospective study, persons with HCV infection had a non statistically significant increased risk of diabetes overall.(6) An elevated HR was found among persons at high risk for diabetes, but was based on a small number of HCV positive cases. The strongest population-based association of HCV infection with diabetes risk was found in a Taiwanese community-based cohort study (HR, 1.7; 95% CI, 1.3-2.1).(7) In contrast, in a recent Italian population-based cohort study, HCV infection was unrelated to incident diabetes in multivariate-adjusted analysis.(8) An association of HCV infection with insulin resistance has also been reported in clinical series,(9) HCV treatment studies,(10-12), in comparison with hepatitis B virus (HBV)-infected controls,(13) and inconsistently in population-based studies.(6, 14, 15) We examined the association of HCV infection with diabetes using recent U.S. national population-based data. Additionally, we examined the relationship of HCV infection with
insulin resistance among persons without diabetes.
RESULTS
When the data on the 15,128 participants were weighted to be representative of the U.S. population, the overall prevalence of anti-HCV+ was 1.7% and of HCV RNA+ was 1.1%. Diagnosed diabetes was found in 7.3%, undiagnosed diabetes in 3.2%, and pre-diabetes in 32.8%. Increasing impairment of glucose metabolism was associated with older age, non-Hispanic black ethnicity, less education, higher BMI and waist circumference, higher triglycerides, lower HDL cholesterol, higher systolic blood pressure, elevated C-reactive protein, having received a blood transfusion before 1992, a past history of smoking, lower alcohol consumption, and higher insulin, HOMA-IR, and ALT and GGT activities (Table 1). For most factors, diagnosed and undiagnosed diabetes did not differ greatly from each other. Therefore, for the remainder of analyses, results are shown with all diabetes cases combined to increase statistical power. Supplementary Online Table 1 provides results for individual analyses of diagnosed and undiagnosed diabetes.
Relationship of HCV infection with diabetes
The unadjusted prevalence of diabetes and pre-diabetes did not differ among participants positive for anti-HCV or for HCV RNA compared to persons without HCV infection (Table 2). After adjusting for age or for multiple factors, diabetes and pre-diabetes remained unassociated with HCV infection (Table 2). Substituting waist circumference for BMI, adding history of illegal injection drug use and first sexual intercourse before age 18 years, or adding lipid and blood pressure measures had little effect on results (data not shown). In some previous reports the relationship of HCV infection and diabetes varied by age or BMI subgroup; therefore, we conducted analyses stratified by these factors. No association of HCV with diabetes was found in any age or BMI subgroup (p>0.05) and interaction terms for HCV and age or BMI were not statistically significant (data not shown).
Because elevation of liver enzymes (ALT and GGT) has been found to increase the risk of diabetes without regard to underlying liver disease, we hypothesized that the association of HCV and diabetes found in clinical studies might be attributable to nonspecific elevation of liver enzyme activity rather than to an effect of HCV infection itself. Therefore, we examined the combined effect of HCV markers and activities of ALT or GGT on the odds of diabetes and pre diabetes. The prevalence of elevated enzymes was much higher among participants with HCV markers (Table 3). In multivariate-adjusted analyses, elevated enzymes were associated with increased odds of diabetes irrespective of HCV status (Figure 2a). In contrast, the presence of HCV markers did not increase the odds of diabetes. Similar relationships were seen when separate analyses were performed for diagnosed and undiagnosed diabetes (data not shown). For pre-diabetes, there was also a positive association with elevated enzyme activity (Figure 2b). Beyond the effect of elevated enzymes, a positive association of pre-diabetes with HCV markers was evident for ALT, but not GGT.
Relationship of HCV infection with insulin resistance
Among participants with normal glucose, mean HOMA-IR did not differ in persons negative compared to positive for anti-HCV or for HCV RNA (p>0.05 for both) (Table 4). HCV markers remained unassociated with age-adjusted and multivariate-adjusted HOMA-IR (p>0.05) (Table 4). Among participants with pre-diabetes, HOMA-IR was higher in persons positive than persons negative for anti-HCV and HCV RNA, but these differences were not statistically significant (except the multivariate-adjusted analysis among persons with pre-diabetes (p<0.05 for both anti-HCV and HCV RNA)) (Table 4). We further examined the relationship of HCV status to HOMA-IR according to enzyme activity. Elevated ALT and GGT activities were associated with increased HOMA-IR regardless of HCV status among persons with either normal glucose (Figure 3a) or with pre-diabetes (Figure 3b). Neither anti-HCV nor HCV RNA positivity was associated with increased HOMA-IR among persons with normal enzyme activities. Only among persons with elevated enzyme activity could a relationship be seen of markers of HCV with HOMA-IR.
DISCUSSION
In this large U.S. national population-based study, HCV infection was not associated with diabetes. No relationship was found in unadjusted analyses or in analyses adjusted for multiple factors associated with HCV or diabetes. Neither ever having had HCV infection nor current HCV infection was related to diabetes in overall analysis.
An association of HCV infection with diabetes has been found in comparison with non-infected controls in mostly clinical studies of patient samples.(3, 4) A similar relationship has been reported in comparison with HBV-infected controls with adjusted ORs of 1.8 (95% CI, 1.2-2.4) in one meta-analysis(3) and 1.9 (95% CI, 1.4-2.6) in a second meta-analysis.(4) While some studies matched HCV- and HBV-infected patients on various factors including disease severity, the association with diabetes may have been influenced by the greater prevalence of liver enzyme elevation with HCV infection compared with HBV infection.(27) Many studies that used HBV-infected controls did not conduct multivariate-adjusted analyses or did not include liver enzymes in adjusted analyses. In one study that did adjust for ALT, HCV infection was no longer statistically significantly associated with diabetes in adjusted analysis, while ALT was an independent predictor.(28) In another study, insulin resistance in non-diabetic individuals was not independently associated with HCV infection after adjustment for ALT and GGT elevation, while ALT and GGT elevation were independent predictors.(29) In a third study, both HCV infection and ALT elevation were independently associated with diabetes.(30) A decreased incidence of diabetes following successful treatment of HCV (sustained virological response) has also been reported.(31) ALT elevation at the beginning of follow-up was not an independent predictor of diabetes development, but the relationship of treatment outcome with liver enzyme levels was not presented.
Among the few previous population-based studies of the relationship of HCV infection and diabetes, findings were inconsistent. A positive association was found in a Taiwanese community-based cohort study in which anti-HCV positive persons had a higher risk of incident diabetes (based on fasting glucose ≥126 mg/dL or casual glucose ≥200 mg/dL).(7) The association was strongest at a younger age and higher BMI. In the U.S. community-based prospective Atherosclerosis Risk in Communities (ARIC) Study, anti-HCV positive persons were at increased risk for incident diabetes (based on self-report or fasting glucose), but the association was not statistically significant (HR, 1.9, 95% CI, 0.6-6.2).(6) An elevated HR was found among persons at high risk for diabetes (defined by older age and higher BMI), but was based on a small number of anti-HCV positive cases.
Several previous U.S. studies have utilized NHANES data to examine the association of HCV and diabetes. In an analysis of the third NHANES, 1988-1994, a non-statistically significant association with diabetes (based on self-report or fasting glucose) was found overall, while a stronger relationship was reported among persons aged 40+ years (OR, 3.8; 95% CI, 1.8-7.9).(5) In a study that used later NHANES cycles, no association was found in NHANES 1999-2004 (OR, 0.9; 95% CI, 0.6-1.6) or NHANES 2005-2008 (OR, 1.3; 95% CI, 0.7-2.3).(14) In a second study by the same group using NHANES 1999-2010, persons with chronic HCV infection were reported to be over twice as likely to have diabetes (OR, 2.3; 95% CI, 1.2-4.5).(32) However, the control group was limited to persons with no evidence of chronic liver disease, for which no liver enzyme elevation was a criterion. We believe those criteria were overly restrictive, resulting in a control group at low risk of diabetes. As we have shown in the current study, diabetes was associated with liver enzyme elevation, rather than with HCV infection per se. Also differing from other studies, we applied recognized standard diabetes criteria to rule out diabetes and pre-diabetes among controls. Previous studies, including those that analyzed NHANES data, have most often employed less precise definitions of diabetes and normal glucose and have not examined the relationship with pre-diabetes at all.
An association of HCV with diabetes was found only in the presence of increased liver enzyme activities. Increased ALT and GGT activities are markers of fatty liver, which itself is associated with diabetes. The causal direction of this association is unclear. Fatty liver may increase the
risk of diabetes, but diabetes might also increase the risk of fatty liver, or there are common factors that might increase the risk of both. In any case, it was not surprising in the current study that elevated ALT and GGT activities were associated with diabetes, a relationship documented (for ALT) by a recent meta-analysis of incident type 2 diabetes.(25) On the other hand, it is not entirely clear why diabetes was found to be relatively underrepresented among participants with HCV infection and normal enzyme activities (Figures 2a and 2b). It may be that persons infected with HCV who have normal enzyme activity are at particularly low risk of fatty liver. However, this is a side issue to the major findings and one that we were not able to pursue further in the current analysis. In a recent Italian population-based prospective study in which there was no overall association of HCV infection with incident diabetes, a higher risk was found among persons with abnormal ALT.(8) With cross-classification by both ALT elevation and HCV status, increased diabetes risk with HCV positivity was seen only with ALT elevation. We are unaware of other studies that have considered specifically the effect of liver enzyme elevations in their reports of associations of HCV and diabetes. Most studies have relied on patients undergoing clinical care for HCV. It would be expected that the large majority of such patients would have elevated liver enzymes. Additionally, patients under clinical observation and treatment for HCV likely have more advanced liver disease than persons in the general population with unrecognized HCV. Because advanced liver disease is associated with diabetes, regardless of cause,(33, 34) clinical series that over-represent patients with advanced HCV would be expected to show a stronger association than that found in the current study.
We also studied the relationship of HCV infection with insulin resistance (as estimated by HOMA-IR) among persons with normal glucose and with pre-diabetes and did not find associations. As with diabetes, we did observe a relationship of elevated enzyme activities with insulin resistance. We are unaware of other studies that adequately considered the influence of enzyme elevation on insulin resistance. For example, treatment studies that have demonstrated improvement in HOMA-IR following a sustained virological response have not shown that the improvement was independent of improvement in liver enzymes. (10-12).
NHANES is a cross-sectional study, which is the most important limitation of our work. Thus we cannot, for example, rule out the possibility that persons with both HCV and diabetes may have been under-represented because increased morbidity and mortality prevented them from participating. Such a potential problem could be addressed in a cohort study that followed persons with HCV from time of infection for a long enough time to determine if the incidence of diabetes was greater than among uninfected but otherwise comparable persons. Although the participation rate was relatively high, sampled persons who did not come to the mobile examination center represent a potential source of bias in studies using NHANES data because they may be less healthy than examined persons. An additional source of bias is the restriction of the NHANES sample to the civilian non-institutionalized population. Some non-sampled groups, particularly incarcerated persons, are known to have a high prevalence of HCV.(35, 36)
However, we are unaware of any literature on the relationship of HCV and diabetes among the incarcerated, and have no reason to believe that the prevalence of diabetes would be particularly high among HCV+ incarcerated persons. There were other less significant limitations. The number of participants with HCV infection was relatively small, despite utilizing 12 years of data. The prevalence of diabetes was lower than if oral glucose tolerance test (OGTT) results had been included in the definition,(37) however OGTT data were not available for all survey years. In addition, we were unable to distinguish type 1 diabetes, which is not thought to be increased with HCV infection,(38) from type 2 diabetes. However, 90-95 percent of diabetes cases in this adult cohort would be expected to have type 2 diabetes.(2) Finally, analyses of the relationship of HCV infection with insulin resistance used HOMA-IR as a surrogate measure of insulin resistance.(39) While this is a limitation, HOMA-IR is a commonly used marker for insulin resistance in epidemiologic studies in which more direct measurement cannot be performed. An important strength of our study was the precise case definitions for diabetes status, as discussed above. Other strengths of this large, national, population-based sample include the avoidance of ascertainment bias that occurs in clinical studies of selected patients and the ability to generalize the results to the U.S. population.
In conclusion, in the U.S. population, we were unable to demonstrate an association of HCV infection with diabetes or with insulin resistance. Elevated liver enzyme activities were associated with both diabetes and with insulin resistance. We suggest that previous reports of relationships of HCV with diabetes may in large measure have been due to this effect of elevated liver enzymes.
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