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Re: [GIWorld-Hepatitis] diabetes and combo treatment

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  • claudine intexas
    Interferon can trigger any autoimmune disorder, although it seems to mainly occur in people who have a familial trait for autoimmune disorders. Type I diabetes
    Message 1 of 3 , Apr 11, 2004
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      Interferon can trigger any autoimmune disorder, although it seems to
      mainly occur in people who have a familial trait for autoimmune
      disorders. Type I diabetes is autoimmune (usually), and therefore
      yes, treatment could cause this type of diabetes. However, it is
      pretty unusual. (Actually, I've never known anyone who developed type
      I diabetes due to treatment.) Far more common is HCV itself causing
      type II Diabetes. The association between treatment (interferon) and
      diabetes is not very strong, but the association between HCV and
      diabetes is definitely strong, and the longer the association is
      studied, the stronger the association has been found. Insulin
      resistance seems to be very high in people with HCV. Also, people on
      treatment often do not eat very well. They may be experiencing a
      great deal of nausea and loss of appetite and getting any food or
      drink down, especially in the early weeks, is often difficult so the
      tendency is to eat and drink what sounds the most appealing, and what
      is convenient. I've noticed that many people on treatment seem to
      crave sweets and foods high in carbs which quickly convert to sugar.
      I don't think there is a simple answer to your question. You can do a
      search on the NATAP web site (http://www.natap.org), which has lots
      of information on this type of thing, but your best bet would be to
      send your patient to an endocrinologist who is familiar with HCV for
      an accurate diagnosis on which type of diabetes he has (if he even
      has it), and treatment if needed. A change of diet at this point may
      be all that is needed, but with diabetes being as serious of a
      disease as it is, and since ultimately it really doesn't matter what
      the cause is, I sure wouldn't want to second guess things. As far as
      your question " Does the glucose level fall after the treatment? ",
      if it is type I (autoimmune) diabetes then probably not. Sometimes
      people who develop thyroid problems while on treatment will
      eventually (1 - 2 years) have their thyroid function return to
      normal, but for most it is permanent. And if it is type II, then
      again, probably not, although diet may be enough to control it now,
      if it has been caught early. On the other hand, sometimes people who
      have extrahepatic disorders which are directly caused by HCV will
      have those problems improve or resolve IF they are SVR's, but I've
      never seen anything at all on diabetes resolving. Like I said, no
      simple answers!

      Here are just a few abstracts from a couple of years ago, and one
      more recent study (Dec. 2003) on insulin resistance, a precursor of
      type II diabetes:

      NATAP - www.natap.org

      DIABETES IN HCV

      CORRELATION OF CHRONIC HEPATITIS B AND C WITH DIABETES MELLITUS

      Ch. Drakoulis, M. Minadaki, L. Karasavidou, M. Panidou, Ch. Liarou,
      Ch. Samaras, K. Stagia, D. Katsadoros Hepatology Department, 2nd
      Pathology Clinic, General Hospital of Nikea, Piraeus, Greece

      Aim: To examine the frequency of Type II diabetes in patients with
      chronic hepatitis B (CHB) or C (CHC).

      Materials & Methods: 850 patients attending our clinic were examined.

      98 were found with CHB (positive for HbsAg, anti-HBe, anti-HBc by
      ELISA and HBV-DNA by PCR) and 117 with CHC (positive for anti-HCV by
      3rd generation ELISA). Patients were classified by gender, age and
      blood glucose levels.

      Results: For the CHB patients, 31 males (57.4%) and 27 females
      (61.3%) had blood glucose < 110 mg/dl, 11 males (20.4%) and 7 females
      (15.9%) had blood glucose 110-126 mg/dl, and 12 males (22.2%) and 10
      females (22.8%) had blood glucose > 126 mg/dl. For the CHC patients,
      48 males (68.6%) and 34 females (72.4%) had blood glucose < 110
      mg/dl, 9 males (12.8%) and 4 females (8.5%) had blood glucose 110-126
      mg/dl, and 13 males (18.6%) and 9 females (12.9%) had blood glucose >
      126 mg/dl.

      Conclusions: In CHB patients, abnormal fasting glucose levels were
      observed in both males and females with similar frequency (mean 18%),
      mostly at ages 41-60 years. In CHC patients, abnormal fasting glucose
      levels were observed more frequently in males (12.8%) than females
      (8.5%), again mostly at ages 41-60 years. The overall frequency of
      Type II diabetes in both CHB and CHC patients is greater than that of
      the general population. Our results show a slightly higher incidence
      of diabetes mellitus in CHB patients, although it is not
      statistically significant.


      GLUCOSE INTOLERANCE IN CHRONIC HEPATITIS C AND B: RISK FACTORS AND
      PREVALENCE IN GENERAL POPULATION

      Emanuel Manesis 1 , Anastasia Mavrogiannaki 1 , Elias Siakavellas 1 ,
      Basil Karamanos 1, Stephanos Hadziyannis 2 1 Academic Department of
      Medicine, Hippokration General Hospital, Athens; 2 Henry Dynan
      Hospital, Athens, Greece

      Diabetes is frequent among patients with chronic hepatitis C (CHC),
      but its pathogenesis is lacking.

      Methods: We prospectively evaluated 100 consecutive patients with
      chronic viral hepatitis (57 CHC, 43 HBeAg-negative chronic hepatitis
      B [CHBeoooo ]) admitted for liver biopsy and compared them to 100
      healthy controls, matched for age, sex and body mass index. Controls
      were randomly selected from a large database of a recent field study
      of diabetes prevalence performed by us.

      Results: Known diabetes was not significantly different among CHC,
      CHBeoooo or controls (12.5%, 4.7% and 10% respectively; P = 0.424),
      but abnormal glucose tolerance (glucose intolerance or diabetes
      discovered by OGTT) was significantly higher in CHC than in controls
      (40.4% vs 14%, respectively; P < 0.001; OR 4.2, 95% CI 1.9-9.0) and
      not different between CHBeoooo and controls (14% vs 14%). By logistic
      regression analysis, significant predictors of abnormal OGTT in
      patients with chronic viral hepatitis were, HCV infection (RH 5.1,
      95% CI 1.4-19.3; P = 0.016), serum ALT (RH 2.3, 95% CI 1.3-5.1; P =
      0.007) and IgG levels (RH 12.4, 95% CI 1.8-84.9; P = 0.010).

      Conclusions: Prevalence of glucose intolerance and new diabetes
      discovered by OGTT is 4.2 times higher in CHC but not different in
      CHBe patients compared to general population. Continuous hepatic
      necroinflammation and chronic immunological stimulation underlie and
      possibly are pathogenetically related to increased prevalence of
      diabetes in CHC.


      HEPATITIS C AND DIABETES MELLITUS: WHAT IS THE CONNECTION?

      Antonio Garrido 1 ,F.J.Guerrero 2 ,J.A.Lepe 3 ,S.Palomo 2 , A. Grilo
      4
      1 Department of Gastrointestinal Medicine, H. Riotinto (Huelva); 2
      Department of Internal Medicine, H. Riotinto (Huelva); 3 Microbiology
      Unit, H. Riotinto (Huelva); 4 Department of Internal Medicine, H.
      Valme, Sevilla, Spain

      Objectives: To carry out a prospective study of baseline insulinemia
      in non-diabetic cirrhotic patients infected with HCV, comparing their
      values with those of a group of non-HCV non-diabetic cirrhotic
      patients. To research the factors involved in both groups in the
      increase of peripheral resistance to insulin.

      Material: A trial including 32 HCV cirrhotic diabetic patients (Group

      I) and 41 non-diabetic cirrhotic patients of other aetiologies (Group
      II) was carried out. Baseline insulinemia as well as insulin
      resistance factors like age, anthropometric indices, stage of
      cirrhosis and iron plasma levels were compared.

      Results: The average baseline insulinemia values in group I was 21.5
      mU/ml (18.6-24.4), vs 14 mU/ml (10-18) in group II (p < 0.001), and
      the percentage of hyperinsulinemia was 87.5% (72.5- 95.9) vs 56%
      (40.8-70.6), respectively (p < 0.01). No differences were observed in
      either group when comparing age, weight, height, body mass index and
      Child-Pugh staging score. Whereas serum ferritin levels in Group I
      patients were higher than those in Group II [123.3 (12.4-289.3) vs
      65.5 (2.4-306) ng/ml, p < 0.05]. Multivariate logistic regression
      study demonstrated that insulinemia values (OR = 1.21; CI 95%
      1.09-1.34, p < 0.001) and ferritin levels (OR = 1.21; CI 95%
      1.02-1.052.69, p < 0.04) were independent factors associated to HCV.

      Conclusions: HCV-positive non-diabetic cirrhotic patients have higher
      baseline insulinemia levels, as well as a greater prevalence of
      hyperinsulinemia than cirrhotics due to other aetiologies. This could
      be explained by an increase of peripheral insulin resistance,
      mediated by the increase of iron deposits in these patients, and may
      be responsible for the increased risk of developing diabetes
      mellitus.

      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(�U/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.

      --- kantarci2001 <kantarci@...> wrote:

      > I have a question. I read articles about combo treatment and
      > diabetes. Some say interferon may trigger type 1 diabetes. Some
      > other says it may trigger type 2 diabetes. Which one is true?
      >
      > Our patient's glucose level is 140. Is this a normal side effect of
      > the treatment? Before the treatment it was 90.
      >
      > Does the glucose level fall after the treatment?
      >
      > Some article says HCV may cause diabetes. We dont think that the
      > increase in the glucose level of our patient is not due to HCV. It
      > must be due to the treatment.




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