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General Practitioners must be made aware! "HCV patients were more than 11 times as likely as those without infection to develop diabetes" Insulin resistance is associated with chronic hepatitis C and virus infection fibrosis progression
Gastroenterology
December 2003, Volume 125, Number 6
Jason M. Hui
ABSTRACT/SUMMARY
Background & Aims: Chronic hepatitis C virus infection is associated with
an increased prevalence of type 2 diabetes. We hypothesized that
virus-induced insulin resistance may be a mechanism for fibrogenesis in
chronic hepatitis C virus infection.
Methods: In 260 hepatitis C virus-infected subjects, we examined the
relationship between histological findings and anthropometric and
biochemical data, including insulin resistance determined by the
homeostasis model assessment (HOMA-IR). We also compared fasting serum
insulin, C peptide, and HOMA-IR levels between the subset of 121 hepatitis
C virus patients with stage 0 or 1 hepatic fibrosis and 137 healthy
volunteers matched by sex, body mass index, and waist-hip ratio.
Results: Hepatitis C virus-infected subjects with stage 0 or 1 hepatic
fibrosis had higher levels of insulin, C peptide, and HOMA-IR (all P=0.01)
compared with matched healthy controls. In the 250 hepatitis C virus
patients (fibrosis stage 0 to 4), viral genotype and portal, but not
lobular, inflammation were univariate predictors of HOMA-IR. By multiple
linear regression analysis, independent predictors of HOMA-IR included
body mass index (P < 0.001), previous failed antiviral treatment (P <
0.001), portal inflammatory grade (P < 0.001), and genotype 3 status (P =
0.01). Genotype 3 had significantly lower HOMA-IR than other genotypes
(which were comparable when adjusted for effects of the remaining
independent predictors). HOMA-IR was an independent predictor for the
degree of fibrosis (P < 0.001) and the rate of fibrosis progression (P =
0.03).
Conclusions: Hepatitis C virus may induce insulin resistance irrespective
of the severity of liver disease, and this effect seems to be genotype
specific. Further, our findings support the hypothesis that insulin
resistance may contribute to fibrotic progression in chronic hepatitis C
virus infection.
BACKGROUND
Recent evidence suggests that chronic hepatitis C virus (HCV) infection is
associated with an increased risk for the development of type 2 diabetes.
Thus, type 2 diabetes is more prevalent among patients with chronic HCV
compared with those with other liver diseases and the general population,
irrespective of whether cirrhosis is present. Likewise, HCV seropositivity
among patients with type 2 diabetes mellitus is higher than in the general
population, a finding that has been validated for different ethnic groups.
Finally, even if liver function is restored by transplantation, post-liver
transplantation diabetes mellitus occurs more frequently among patients
who undergo transplantation for HCV than for other conditions.
Insulin resistance (IR) plays a primary role in the development of type 2
diabetes mellitus. This is supported by prospective longitudinal studies
showing that IR is the best predictor for the development of diabetes,
preceding the onset of diabetes by 10 to 20 years, and by cross-sectional
studies showing that IR is a consistent finding in patients with type 2
diabetes. In view of the strong association between HCV infection and the
development of diabetes mellitus, it is important to determine whether HCV
infection can predispose to the development of IR before diabetes occurs.
Such a potential link is particularly cogent in light of recent data that
indicate that diabetes may be associated with increased fibrosis
progression in patients with chronic HCV infection. In this study, we
tested the hypothesis that HCV infection itself may promote IR, by
comparing the degree of IR (determined by fasting glucose, insulin, and C
peptide levels and the homeostasis model [HOMA-IR]) between HCV-infected
individuals and healthy volunteers. We then examined whether histological
markers of HCV activity (portal and lobular inflammation) were associated
with HOMA-IR and whether there were genotype-specific alterations in the
extent of HOMA-IR. Finally, we assessed whether such virus-induced IR may
be a mechanism for fibrogenesis in chronic HCV infection, by determining
the relationship between the magnitude of HOMA-IR and the severity of
hepatic fibrosis and the rate of fibrosis progression.
Case selection
This study comprised 260 consecutive patients with chronic HCV who
underwent liver biopsy at Westmead Hospital between May 1999 and August
2002. Some of these cases (n = 117) have been the subject of a previous
report. All subjects had antibodies against HCV (Monolisa anti-HCV; Sanofi
Diagnostics Pasteur, Marnes-la-Coquette, France) and detectable HCV RNA by
polymerase chain reaction (Amplicor HCV; Roche Diagnostics, Branchburg,
NJ). HCV genotyping was performed with a second-generation reverse
hybridization line probe assay (Inno-Lipa HCV II; Innogenetics,
Zwijndrecht, Belgium). Thirty-three subjects (13%) had previous antiviral
therapy (interferon or pegylated interferon monotherapy [n = 30] or
combination therapy with interferon and ribavirin [n = 3]) and either were
nonresponders (n = 20) or had relapsed after treatment (n = 13). Liver
biopsies were performed at least 6 months after the completion of
antiviral therapy (median, 5 years; range, 0.5–10 years). No patient had
clinical evidence of hepatic decompensation (hepatic encephalopathy,
ascites, variceal bleeding, or serum bilirubin level greater than 2-fold
the upper limit of normal).
Clinical and laboratory assessment
The following data were collected at the time of liver biopsy: age, sex,
ethnicity, average current daily alcohol intake (g/day) in the past 6
months, past alcohol intake (g/day) before the last 6 months, weight,
height, and waist-hip ratio (WHR; waist circumference at umbilicus/hip
circumference at the maximal circumference over the buttocks). Body mass
index (BMI) was calculated as weight in kilograms/height in square meters.
Past exposure to HBV was determined by the presence of HBV core antibody.
The estimated duration of infection was defined as the time elapsed from the presumed date of infection to the date of liver biopsy. The former was estimated as follows: the date of transfusion of blood products (before 1990), the first year of intravenous drug use, or the date of a single specific and convincing parenteral exposure (e.g., needlestick injury). We defined fibrosis progression per year as the ratio of the fibrosis stage by the Scheuer score to the estimated duration of infection in years.
After an overnight fast of 12 hours, venous blood was drawn to determine
the serum levels of albumin, bilirubin, alanine aminotransferase (ALT),
aspartate aminotransferase (AST), ALT/AST ratio, -glutamyltransferase (GGT),
ferritin, cholesterol, insulin and C peptide, plasma glucose
concentration, platelet count, and international normalized ratio. Serum
insulin was determined by radioimmunoassay (Phadaseph Insulin RIA;
Pharmacia and Upjohn Diagnostics AB, Uppsala, Sweden). Serum C peptide was
estimated by a competitive immunoassay (IMMULITE; Diagnostic Products, Los
Angeles, CA). All other biochemical tests were determined by automated
procedures in the clinical pathology laboratories of Westmead Hospital. IR
was determined by the homeostasis model assessment (HOMA) method by using
the following equation: Insulin resistance(HOMA-IR)=Fasting insulin(µU/mL)xFasting
glucose(mmol/L)/22.5 IR calculated by this method has been validated
against insulin sensitivity measured directly with the euglycemic/hyperinsulinemic
clamp technique in both diabetic and nondiabetic subjects. To take into
account the effect of advanced hepatic fibrosis on increasing serum
insulin levels that is partly due to impaired insulin clearance, we
determined insulin secretion by using the serum C peptide-insulin ratio. C
peptide and insulin are secreted in equimolar amounts, and serum C peptide
is not significantly cleared by the liver; hence, the C peptide-insulin
ratio allows hyperinsulinemia due to impaired insulin degradation (low
ratio) to be distinguished from insulin hypersecretion (normal ratio).
The following conditions were excluded, as described previously:
concurrent active hepatitis B virus (HBV; positive for hepatitis B surface
antigen) or human immunodeficiency virus infection, autoimmune hepatitis,
primary biliary cirrhosis (PBC), sclerosing cholangitis, hemochromatosis,
1-antitrypsin deficiency, and Wilson’s disease. Patients with an
established diagnosis of diabetes mellitus were excluded from this study.
The study protocol was approved by the Human Ethics Committee of the
Western Sydney Area Health Service, and written, informed consent was
obtained.
Histopathology
The degree of necroinflammatory activity and fibrosis were scored
semiquantitatively as described by Scheuer by an experienced
hepatopathologist ( J. G. K.) blinded to the clinical data. Portal or
periportal and lobular inflammatory activities were both scored from 0 to
4. Fibrosis was scored as follows: F0, no fibrosis; F1, enlarged fibrotic
portal tracts; F2, periportal or portal-portal septa, but intact
architecture; F3, architectural distortion but no obvious cirrhosis; and
F4, probable or definite cirrhosis. Steatosis was assessed as the
percentage of hepatocytes containing macrovesicular fat droplets. It was
graded as 0 (no steatosis), 1 (<33% of hepatocytes affected), 2 (33%–66%
of hepatocytes affected), or 3 (>66% of hepatocytes affected).
Case controls: healthy volunteers
One hundred thirty-seven apparently healthy volunteers with normal liver
function tests and no known history of diabetes mellitus were enrolled.
They were matched by sex, BMI, and WHR with the 121 HCV-infected subjects
with minimal (stage 1) or no (stage 0) hepatic fibrosis. Markers of IR
(fasting glucose, insulin, HOMA-IR, and C peptide) were compared between
these 2 groups of matched subjects.
Case controls: primary biliary cirrhosis
Twenty-four subjects with PBC and no known history of diabetes mellitus
were identified from the Westmead Hospital database. The liver biopsy
samples of these subjects were reviewed (by J. G. K). To allow comparison
with the HCV cases, the fibrosis stage of these biopsy samples was scored
by Scheuer’s method; all had fibrosis stages 1 to 3, and none had
cirrhosis. The markers of IR (fasting glucose, insulin, HOMA-IR, and C
peptide) were compared among the PBC subjects, the HCV patients with stage
0 fibrosis, and the 137 healthy volunteers.
RESULTS
Patient characteristics and liver biopsy findings
The mean age was 41 ± 9 years (range, 16–72 years); 175 (67%) were male,
and the mean BMI was 26.9 ± 5.2 kg/m2 (range, 17.2–47.3 kg/m2). HCV
genotype was available in 250 patients. Of the remaining 10 patients, 5
were not typeable by the line probe assay, and 5 were not tested. These 10
cases were missing at random and were excluded from subsequent analyses
involving genotype. Because liver biopsy specimens were required to show
at least 4 portal tracts for reliable scoring, complete histological
analysis of necroinflammatory grade and fibrosis staging was available in
only 258 cases; however, steatosis grade could be assessed in all 260
cases. Fibrosis was absent in 39 (15%) patients, was stage 1 in 82 (32%)
patients, was stage 2 in 85 (33%) patients, and was stage 3 in 30 (12%)
patients, whereas cirrhosis (stage 4 fibrosis) was present in 22 (9%)
patients.
Reliable data on the date of infection were available for 117 (45%)
patients. The mean age of infection was 22 ± 7 years; the mean estimated
duration of infection was 19 ± 8 years, and the mean rate of fibrosis
progression was 0.13 ± 0.21 stages per year.
Insulin resistance of hepatis C virus cases compared with matched healthy
volunteers
To assess the influence of HCV infection on IR independent of any effect
of hepatic fibrosis, 121 HCV subjects with minimal (stage 1) or no (stage
0) fibrosis were compared with 137 healthy volunteers matched by sex, BMI,
and WHR. Ideally, a comparison population would also be age matched,
because the frequency of IR increases with age. However, even though the
HCV subjects were younger than the healthy volunteers, they had
significantly higher levels of all markers of IR, including fasting
glucose, insulin, C peptide, and HOMA-IR.
Viral factors associated with the degree of insulin resistance
To determine the possible virus-related factors involved in the
pathogenesis of IR, we assessed whether HOMA-IR was associated with the
viral genotype or the severity of portal or periportal and lobular
inflammation after controlling for other demographic and biochemical
variables. By univariate analysis, the factors associated with HOMA-IR
were portal or periportal inflammatory grade, viral genotype, age, BMI,
WHR, GGT, albumin, bilirubin, C peptide, and previous treatment (either
nonresponders or relapse after treatment—see Methods. Lobular inflammatory
grade was not associated with HOMA-IR (P = 0.6).
The final model for the independent predictors of HOMA-IR by multiple
linear regression analysis included portal or periportal inflammatory
grade, genotype 3 status (yes or no), BMI, and previous treatment. These
variables explained 30% of the variability in the degree of HOMA-IR.
At each stage of fibrosis, the genotype 3 patients had higher (unadjusted)
mean HOMA-IR than the non-genotype 3 patients. After adjusting for the
effect of other independent predictors in the model, the various
non-genotype 3 groups had comparable HOMA-IR levels, and the adjusted
estimated difference in HOMA-IR between the genotype 3 and non-genotype 3
subjects was –0.58 (95% confidence interval [CI], –0.13 to –1.02; P =
0.01). There was no significant interaction between the effects of
genotype 3 status and fibrosis stage, either unadjusted (P = 0.5) or
adjusted (P = 0.4) for the other independent variables.
Because cirrhosis is known to cause IR, the multivariate analysis was
repeated for the subset of 236 noncirrhotic subjects (fibrosis stages 0 to
3). The independent predictors for HOMA-IR were the same as for all
subjects: genotype 3 status (P = 0.005), portal inflammatory grade (P =
0.007), BMI (P < 0.001), and previous treatment (P < 0.001) remained in
the model.
Factors associated with the severity of hepatic fibrosis and the rate of
fibrosis progression
We next assessed whether the extent of IR was associated with the severity
of hepatic fibrosis. By univariate analysis, factors associated with the
stage of fibrosis were age, male sex, past alcohol intake, WHR, ALT, AST,
GGT, albumin, bilirubin, platelet count (negative association),
international normalized ratio, glucose, insulin, C peptide, HOMA-IR,
ferritin, and cholesterol (negative association), portal or periportal
inflammatory grade, lobular inflammatory grade, steatosis, and viral
genotype. By multiple ordinal regression analysis, independent predictors
for the degree of fibrosis were portal or periportal inflammatory grade,
past alcohol intake, HOMA-IR, age, and ALT; platelet count and cholesterol
were significant negative predictors. Together, these factors accounted
for 52% of the variability in hepatic fibrosis stage. Multiple linear
regression analysis with stepwise variable selection confirmed the fitted
model.
The probability of moderate to severe fibrosis (stage 2 to 4) was 45% for
those with a HOMA-IR of 1 compared with 68% for those with a HOMA-IR of 5
(evaluated at the mean value of other independent predictors: portal
inflammatory grade, 2.0; past alcohol intake, 10–40 g/day; age, 41.1
years; ALT, 115 U/L; platelet count, 234; and cholesterol, 4.4 mmol/L).
Although steatosis was associated with fibrosis by univariate analysis, it
was not an independent predictor of fibrotic stage after adjusting for
other factors.
Because genotype 3 subjects had significantly lower HOMA-IR, subgroup
analyses were performed to determine whether HOMA-IR was an independent
predictor for fibrosis in both genotype 3 and non-genotype 3 subjects. By
multiple ordinal regression analysis, HOMA-IR remained independently
associated with the fibrosis stage for both the genotype 3 (OR, 1.4; 95%
CI, 1.0–2.0; P = 0.03) and non-genotype 3 subgroups (OR, 1.2; 95% CI,
1.1–1.4; P = 0.007).
Because cirrhosis is known to cause IR, the multivariate analysis for
predictors of fibrosis stage was repeated on the 236 noncirrhotic subjects
(fibrosis stages 0 to 3). The independent predictors for fibrosis were
unchanged, and HOMA-IR remained in the model (OR, 1.3; 95% CI, 1.1–1.5; P
< 0.001). Furthermore, there was no significant association between the C
peptide-insulin ratio and the fibrosis stage for the noncirrhotic patients
(r = –0.1; P = 0.1).
To determine whether HOMA-IR was a cause or a consequence of hepatic
fibrosis, we analyzed the subgroup of 117 patients with a known duration
of infection. By multiple linear regression analysis, HOMA-IR was
independently associated with an increased rate of fibrosis progression.
Factors associated with the extent of hepatic steatosis
To examine the hypothesis that IR was associated with fibrosis through an
effect on hepatic steatosis, we performed a multiple ordinal regression
analysis to determine independent predictors for steatosis grade.
Independent predictors for hepatic steatosis grade were genotype 3 status
(P < 0.001), BMI (P = 0.002), portal inflammation (P = 0.03), and
cholesterol (negative association; P = 0.004). Genotype 3 status remained
a significant factor in the model (P < 0.001) even when cholesterol was
not entered into the model. Although HOMA-IR was not an independent
predictor for steatosis grade, it should be noted that BMI was associated
with HOMA-IR (r = 0.5; P < 0.001).
Insulin resistance of primary biliary cirrhosis cases compared with hepatitis C virus cases and healthy volunteers
We next considered the possibility that hepatic fibrosis from any
etiology, even in the absence of cirrhosis, may cause IR. We therefore
examined markers of IR in 23 noncirrhotic PBC subjects in whom fibrosis
was staged according to Scheuer (11 with stage 1 fibrosis, 10 with stage 2
fibrosis, and 2 with stage 3 fibrosis) and compared the results with those
of the 39 HCV subjects with no hepatic fibrosis (stage 0) and the 137
healthy volunteers. After controlling for the effects of BMI and sex, HCV
subjects with stage 0 fibrosis were found to have higher levels of serum
insulin (P = 0.01), C peptide (P < 0.01), and HOMA-IR (P = 0.01) than
patients with PBC or healthy controls. However, markers of IR were not
significantly different between the PBC subjects and healthy volunteers.
DISCUSSION by authors
This study, in subjects without a history of diabetes mellitus, shows that
HCV infection increases IR compared with healthy volunteers. There are
genotype-specific effects on IR, and the extent of portal inflammation in
chronic HCV is associated with the degree of IR. Furthermore, increased
HOMA-IR values are associated with a higher rate of fibrosis progression
and more advanced stages of hepatic fibrosis. These data support the
concept that viral-induced IR may facilitate fibrogenesis in chronic HCV
infection.
Use of the homeostasis model assessment model
The HOMA model used in this study has been validated and widely used for
determining the degree of IR in epidemiological studies. HOMA-IR accounts
for approximately 65% of the variability in insulin sensitivity assessed
by the glucose clamp technique. It seems to be as good a predictor of
clamp-determined insulin sensitivity as the short insulin tolerance test
or the intravenous glucose tolerance test analyzed with the minimal model.
HOMA-IR strongly predicts the development of type 2 diabetes, independent
of obesity, body fat distribution, and glucose tolerance status.
Evidence that hepatitis C virus infection is specifically associated with insulin resistance
In this study, HCV-infected subjects in whom there was no or minimal
hepatic fibrosis were closely matched to healthy volunteers by sex and
anthropometric predictors of IR, namely, BMI and WHR. Although the
HCV-infected subjects were younger than the volunteers, fasting serum
insulin, C peptide, and HOMA-IR were greater in those with HCV infection.
Earlier studies, which found increased fasting insulin levels and reduced
insulin sensitivity in HCV-infected subjects, included patients with
moderate to severe hepatic fibrosis. The present data extend these
findings to HCV-infected subjects with minimal or no fibrosis.
In this study, the grade of portal inflammation, a hallmark of chronic HCV
infection that correlates with fibrotic progression, was associated with
HOMA-IR in nondiabetic subjects. This suggests that the virus itself or
the host inflammatory response to HCV infection contributes to the
development of IR and increases the long-term risk for the development of
type 2 diabetes. We also considered the converse possibility, that is, IR
plays a pathogenic role in hepatic necroinflammation, as is the case for
nonalcoholic steatohepatitis (NASH). However, we believe this to be
unlikely because there was no association among the grade of lobular
inflammation, the predominate site of inflammation in NASH, and HOMA-IR.
Further, the findings of 2 small studies that insulin sensitivity and
glucose tolerance improve with antiviral therapy are consistent with our
proposal that IR is mediated by viral infection or the inflammatory
response to HCV, rather than the converse.
It was of interest that patients with previously failed antiviral
treatment had significantly higher IR, independent of BMI, than those who
had not received previous antiviral therapy. It has been suggested that
the impaired response to antiviral therapy in African Americans may relate
to their high rate of central obesity and IR. Prospective studies to
assess whether IR is an independent predictor for a reduced response to
antiviral therapy are required. This is important because implementation
of lifestyle changes can improve insulin sensitivity.
The mechanisms for IR in chronic HCV infection remain unclear. In a recent
report, hyperinsulinemic clamp assessment in 5 HCV-infected subjects
showed reduced glucose disposal consistent with peripheral IR. Activation
of the tumor necrosis factor (TNF) system occurs in chronic HCV infection
and correlates with disease activity, and higher levels of TNF expression
may be predictive of a failed response to interferon therapy. TNF also
plays an important role in the pathogenesis of IR and may provide the
pathogenic link between chronic HCV infection and the IR we observed.
The effect of hepatitis C virus infection on insulin resistance varies between genotypes
An important novel finding of this work is that the effect of HCV
infection on IR depends on viral genotype. Thus, for each stage of hepatic
fibrosis, genotype 3 subjects have lower IR compared with other genotypes,
even after adjusting for the effect of BMI and other confounders. This
would confer a lower risk for developing type 2 diabetes compared with
other HCV genotypes. Indeed, the increased prevalence of diabetes in HCV
has been shown to be predominately among genotype 1– and 2-infected
subjects. It is of interest that, despite lower IR levels, subjects with
HCV genotype 3 have more extensive hepatic steatosis. The implication that
steatosis in genotype 3 is mediated predominately by viral factors and not
IR is consistent with earlier reports.
Insulin resistance is associated with more rapid fibrosis progression in chronic hepatitis C virus infection
IR and diabetes mellitus are independent predictors of the severity of
hepatic fibrosis in nonalcoholic fatty liver disease; diabetes mellitus is
also associated with increased fibrosis in chronic HCV. The most important
finding of this study (which excluded those with type 2 diabetes mellitus)
is that increased HOMA-IR is a predictor of the stage of fibrosis and the
rate of fibrosis progression, independent of other known factors including
age, male sex, past alcohol intake, platelet count, and portal
inflammation. A recent report found that weight loss can improve hepatic
fibrosis in HCV. This is likely to be a result of the improvement in IR
associated with weight loss, which is consistent with the proposal that IR
is a clinically important determinant of the rate of fibrosis progression
in HCV.
An alternative explanation for the observed association between HOMA-IR
and fibrosis stage is that hepatic fibrosis led to impaired insulin
degradation. Several findings help to exclude that possibility. First,
HOMA-IR remained an independent predictor of fibrosis stage even after the
exclusion of subjects with cirrhosis, which is known to cause IR and
impaired insulin clearance. Second, the observations that C peptide was a
univariate predictor of fibrosis stage and that the serum C
peptide-insulin ratio was similar in different fibrosis stages indicate
that insulin hypersecretion, and not impaired degradation, accounts for
the increase in HOMA-IR in HCV infection. Third, markers of IR in PBC,
even in the presence of moderate portal fibrosis, were lower than those in
nonfibrotic HCV and similar to those in healthy volunteers (after
controlling for the effects of BMI). However, we acknowledge the
possibility that the factors responsible for IR may also be responsible
for causing progressive fibrosis and that the association between HOMA-IR
and fibrosis stage does not prove a casual relationship.
In earlier studies, steatosis in chronic HCV infection has been associated
with increased fibrosis stage. IR was not determined in any of these
reports, but is known to be an important pathogenic factor for steatosis
in NASH. Although IR was not an independent predictor of steatosis in our
cohort, this may be due to the confounding effect of BMI, a predictor of
steatosis that is closely associated with IR.
Plausible mechanisms exist to explain the role of IR in hepatic
fibrogenesis. Hyperinsulinemia can directly stimulate hepatic stellate
cells to proliferate and to secrete extracellular matrix. Further, high
glucose levels and hyperinsulinemia cause up-regulation of connective
growth factor, a cytokine involved in the pathogenesis of fibrosing liver
diseases.
In conclusion, this study provides the first direct evidence for a
genotype-specific association between chronic HCV infection and IR. Our
data support the hypothesis that IR may increase the rate of fibrosis
progression. Strategies to improve insulin sensitivity should be explored
because they may complement antiviral therapy in the management of chronic
HCV infection, particularly in mitigating against fibrotic progression in
nonresponders to interferon-based antiviral therapies.
Hepatology. 2003 Jul;38(1):50-6. Departments of Epidemiology and Medicine, Johns Hopkins University, Baltimore, MD; and the Division of Epidemiology, University of Minnesota School of Public Health, Minneapolis, MN. Although hepatitis C virus (HCV) infection is more common among adults with type 2 diabetes, it is uncertain whether HCV precedes the development of diabetes. Thus, we performed a prospective (case-cohort) analysis to examine if persons who acquired type 2 diabetes were more likely to have had antecedent HCV infection when enrolled in a community-based cohort of men and women between the ages of 44 and 65 in the United States (Atherosclerosis Risk in Communities Study [ARIC]). Among 1,084 adults free of diabetes at baseline, 548 developed diabetes over 9 years of follow-up evaluation. Incident cases of diabetes were identified by using fasting glucose and medical history and HCV antibodies were assessed at baseline. A priori, persons were categorized as low-risk or high-risk for diabetes based on their age and body mass index, factors that appeared to modify the type 2 diabetes-HCV infection incidence estimates. The overall prevalence of HCV in this population was 0.8%. Among those at high risk for diabetes, persons with HCV infection were more than 11 times as likely as those without HCV infection to develop diabetes (relative hazard, 11.58; 95% confidence interval, 1.39-96.6). Among those at low risk, no increased incidence of diabetes was detected among HCV-infected persons (relative hazard, 0.48; 95% confidence interval, 0.05-4.40). In conclusion, pre-existing HCV infection may increase the risk for type 2 diabetes in persons with recognized diabetes risk factors. Additional larger prospective evaluations are needed to confirm these preliminary findings. PMID: 12829986 [PubMed - in process]
HCV/HIV
Coinfected Patients at
Patients with an ICD-9
diagnosis of HIV were identified from the VA Autoimmune
Liver Disease
HCV Linked to Type 2 Diabetes DG DISPATCH - ISVHLD: Hepatitis C Infection
Linked to Type 2 Diabetes ATLANTA, GA -- April 14, 2000 -- Type 2 diabetes (diabetes mellitus) may be associated with hepatitis C virus (HCV) infection, according to researchers at the 10th International Symposium on Viral Hepatitis and Liver Disease (ISVHDL). Shruti Mehta, a doctoral student at the School of Hygiene & Public Health, Johns Hopkins University, Baltimore, MD., and colleagues from the Johns Hopkins University, examined data from the third National Health and Nutrition Examination Survey (NHANES III), conducted between 1988-1994 in the US. Of the 9,841 subjects over the age of 20 who were assessed for diabetes and HCV infection, 1,242 (8.4 percent) had diabetes (type 1 and type 2) and 230 (2.1 percent) were anti-HCV positive. After adjusting for factors such as age, race, and socioeconomic status, the researchers found that HCV-infected subjects were four times more likely to have type 2 diabetes than those without HCV infection (adjusted odds ratio 3.77; 95 percent confidence interval, 1.80-7.87). They found no association, however, between HCV infection and type 1 diabetes. Similarly, they found no association between hepatitis B virus (HBV) infection and diabetes type 1 or 2. Suggesting a cause for the association, Mehta told Doctor's Guide that "it might be a combination of factors that produce this association. Hepatitis C virus has been shown to replicate outside the liver and in the pancreas so it could be that HCV may be causing some concomitant beta cell dysfunction." Mehta could not confirm whether the fact that diabetics have to inject themselves could cause HCV transmission or if HCV transmission caused beta cell dysfunction and, consequently, diabetes. "We're not sure what the mechanisms are or which condition causes which," she said. "Providers should consider screening persons with one condition for the other since the adverse outcomes of each can be medically prevented," she added. Hepatitis C Virus: Associated With New Onset Diabetes Mellitus Dr. Terrault and Dr. Khalili from the University of California, San Francisco, also presented very careful data from a study assessing the association of new onset diabetes after liver transplantation in patients with hepatitis C.[6] It has been previously shown by Drs. Mason and Perillo that the incidence of diabetes mellitus is 2 to 16 times higher in patients with hepatitis C compared to those with hepatitis B infection or other types of liver disease. As a corollary, these investigators attempted to determine the rate of diabetes mellitus in patients who were hepatitis C positive after liver transplantation. Their results also indicate that chronic hepatitis C was predictive of persistent diabetes mellitus and that the risk was increased approximately 2- to 3-fold compared to the HCV noninfected population. The authors carefully controlled for immunosuppression -- which may influence glucose intolerance -- and found through multiple analyses that the strongest independent predictor of diabetes post liver transplantation was chronic hepatitis C infection. Again, these findings suggest a possible etiologic relationship between both chronic hepatitis C and diabetes mellitus. References Mika BP, Lam NP, McCarthy ME, Layden TJ, et al: Pretreatment Histology activity index (HAI) is an indicator of early HCV viral clearance with IFN therapy [Abstract L0290]. Digestive Disease Week, Orlando, Fla, 1999. Bonkovsky HL, Israel J, Fontana R, et al: Iron reduction prior to and during interferon therapy of chronic hepatitis C: Initial results of a multicenter, randomized, controlled trial in previously untreated patients [Abstract L0051]. Digestive Disease Week, Orlando, Fla, 1999. Brillanti S, Levantesi F, Foli M, et al: Amantadine and RebetronTM exert a synergistic antiviral effect on HCV replication in Interferon-a non-responders with chronic hepatitis C [Abstract L0057]. Digestive Disease Week, Orlando, Fla, 1999. Bellobuono AA, Tempini SS, Mondazzi LL, et al: Breakthrough incidence may be decreased by alpha Interferon and Ribavirin combination treatment in chronic hepatitis C [Abstract L0044]. Digestive Disease Week, Orlando, Fla, 1999. Yoshida H, Arakawa Y, Yokosuka O, et al: How long will the virological sustained responder to IFN remain at risk of developing hepatocellular carcinoma? [Abstract L0493]. Digestive Disease Week, Orlando, Fla, 1999. Khalili M, Watson J, Bass N, et al: Hepatitis C virus (HCV) is associated with new onset diabetes mellitus (DM) after orthotopic liver transplantation (OLT) [Abstracts L0457]. Digestive Disease Week, Orlando, Fla, 1999. Hepatitis C Infection Increases Diabetes Risk Monday October 16 5:36 PM ET NEW YORK (Reuters Health) - People who are 40 years of age or older and infected with hepatitis C have more than triple the risk of developing type 2 diabetes, the type of diabetes that commonly occurs in adulthood. Nearly 3 million Americans have chronic hepatitis C, a viral infection of the liver. The virus can lead to cirrhosis and liver cancer and is the leading cause of liver transplant in the US. In the new study, Shruti Mehta and associates from Johns Hopkins University in Baltimore, Maryland looked at more than 9,800 adults who took part in a health survey. Just over 8% of the study participants had type 2 diabetes and about 2% had evidence of hepatitis C virus (HCV) infection, according to a report in the October 17th issue of the Annals of Internal Medicine. The rate of type 2 diabetes was notably higher in the HCV-positive group than in the HCV-negative group, the researchers note, except in persons younger than 40 years of age. In the 40 to 49 year age group, those with HCV infection were 3.1 times as likely to have type 2 diabetes as those without HCV infection. Previous studies have linked HCV to diabetes, but only in people with severe liver disease. These results confirm that type 2 diabetes occurs at higher rates even among patients with milder forms of HCV infection, the authors conclude. Further research is needed to determine exactly how HCV contributes to the development of diabetes. However, Mehta and colleagues believe that the findings are ''consistent with the inference that HCV infection causes type 2 diabetes through progressive liver damage.'' SOURCE: Annals of Internal Medicine 2000;133:592-599. Audrey Spolarich Health Policy Analysts, Inc. Washington, DC 202-638-0551. Excess Prevalence Of Hepatitis C Seen In Diabetics Diabetes Care 1996;19:998-1000. WESTPORT Sep 20 (Reuters) The prevalence of hepatitis C virus infection was found to be four times higher among diabetics than controls in a recent study from Spain, leading the researchers to speculate the virus may play a role in the etiology of the disease. SERUM CHOLESTATIC
ENZYMES AND PREVALENCE OF DIABETES AND GALLSTONES IN CHRONIC VIRAL LIVER
DISEASE.
In conclusion diabetes, gallstones and serum increases of ALP and GGT were significantly more frequent in cirrhosis than in chronic hepatitis. In chronic hepatitis diabetes was more frequent in patients with cholestasis, while gallstones were observed more frequently in cholestatic cirrhosis. The physiopathologic relationships of diabetes and gallstones with cholestasis and their effects on antiviral therapy require further evaluation in viral chronic liver disease. |
