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diabetes and combo treatment

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  • kantarci2001
    Hello, 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
    Message 1 of 3 , Apr 11 9:36 AM
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      Hello,

      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.

      We are a little bit confused. What are the experiences of group
      members?

      Thanks
    • Tatezi
      Fortunately, diabetes is not an issue I ve had to deal with yet and I m on my second round of treatment. This is probably a question for Claudine or Doc...if
      Message 2 of 3 , Apr 11 2:56 PM
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        Fortunately, diabetes is not an issue I've had to deal with yet and I'm on my second round of treatment.

        This is probably a question for Claudine or Doc...if you put their names in the subject line, one of them will get back to you.

        Tatezi
        ----- Original Message -----
        From: kantarci2001
        To: GIWorld-Hepatitis@yahoogroups.com
        Sent: Sunday, April 11, 2004 11:36 AM
        Subject: [GIWorld-Hepatitis] diabetes and combo treatment


        Hello,

        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.

        We are a little bit confused. What are the experiences of group
        members?

        Thanks





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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 3 of 3 , Apr 11 9:48 PM
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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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