High Incidence of Type 1 Diabetes Mellitus During or Shortly After Treatment Wit

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High Incidence of Type 1 Diabetes Mellitus During or Shortly After

Treatment With Pegylated Interferon A for Chronic Hepatitis C Virus

Infection

Posted 01/28/2008

Abstract and Introduction

Abstract

Background: Development of diabetes mellitus (DM) during or shortly

after treatment with interferon & #945; (IFN- & #945;) in patients with chronic

hepatitis C virus (HCV) infection has been reported sporadically. We

prospectively screened for DM during and after IFN- & #945; therapy for

chronic HCV infection.

Methods: Blood glucose levels of patients with chronic HCV infection

were routinely assessed at all outpatient visits during and after

treatment with pegylated-IFN- & #945; (Peg-IFN- & #945;) and ribavirin (Riba).

Results: Between December 2002 and October 2005, 189 non-diabetic

patients were treated with Peg-IFN- & #945;/Riba, of whom five developed

type 1 DM (2.6%), three type 2 DM (1.6%) and one an indeterminate

type of DM. Classical symptoms of DM were present in three patients

who developed DM shortly after cessation of Peg-IFN- & #945;/Riba. In the

other patients, symptoms of DM were either indistinguishable from

side effects caused by Peg-IFN- & #945;/Riba or absent.

Conclusion: Our study showed a high incidence of type 1 DM during Peg-

IFN- & #945;/Riba therapy for chronic HCV infection. Symptoms of DM may be

absent or mistaken for Peg-IFN- & #945;/Riba-associated side effects. To

diagnose DM without delay, we propose routine assessment of blood

glucose at all outpatient visits during and after Peg-IFN- & #945;/Riba

treatment in chronic HCV patients.

Introduction

Interferon & #945; (IFN- & #945;) and ribavirin (Riba)-based therapy for chronic

hepatitis C virus (HCV) infection is effective in 40-80% of patients

but causes a wide range of side effects, such as influenza-like

symptoms, depression, insomnia, headache, fatigue, fever and anaemia.

[1] IFN- & #945; treatment for chronic HCV infection is associated with the

development of autoimmune disorders such as autoimmune thyroiditis,

hypothyroidism, hyperthyroidism and Sjögren's syndrome in 2.5-20% of

patients.[1,2] Type 1 diabetes mellitus (DM) can also occur during or

after IFN- & #945; treatment for chronic HCV infection. Several cases have

been published,[3-10] but the exact incidence of DM during or after

treatment with IFN- & #945; is unknown. An Italian retrospective study among

11 241 patients with chronic HCV infection treated with IFN- & #945;

revealed only 10 new diagnoses of DM (0.08%) after at least 16 weeks

of treatment.[11] Development of type 1 DM during treatment with IFN-

& #945; for chronic hepatitis B infection, hairy cell leukaemia, Kaposi's

sarcoma and renal cell carcinoma has also been reported,[3] but the

majority of cases occurred in patients with chronic HCV infection.[3]

The prevalence of type 2 DM was found to be significantly higher in a

cohort of IFN- & #945;-naïve chronic HCV patients (14.5%) compared with

patients suffering from other chronic liver diseases (7.3%) and the

general population (7.8%); the difference was even more pronounced in

patients with advanced histological disease.[12,13] Recent studies

have shown that insulin resistance is common in non-diabetic chronic

HCV patients, and that insulin resistance decreases during treatment

with IFN- & #945;.[14-18]

We screened for DM during and after treatment with pegylated-IFN- & #945;

(Peg-IFN- & #945;) and Riba for chronic HCV infection. This started after we

observed two index cases of DM during Peg-IFN- & #945;/Riba treatment in our

hospital in December 2002. In the first patient, DM-related symptoms,

commencing after 16 weeks of antiviral treatment, had been attributed

to Peg-IFN- & #945;/Riba; DM was diagnosed because symptoms were persistent

after cessation of Peg-IFN- & #945;/Riba treatment. The second patient was

presented at the emergency room after 11 weeks of Peg-IFN- & #945;/Riba

therapy because of severe debilitation, where DM was diagnosed (blood

glucose 54 mmol/L). Because of the atypical clinical picture of DM in

these two patients, we amended our treatment protocols, and blood

glucose levels of patients with HCV were routinely measured in all

patients at all outpatient visits before, during and after treatment

with Peg-IFN- & #945;/Riba as of December 2002

Discussion

In this prospective cohort study, we found the incidence of DM,

especially type 1, during or shortly after treatment with Peg-IFN-

& #945;/Riba for chronic HCV infection to be higher than reported

previously. Most patients who developed DM were identified through

routine assessment of blood glucose levels, as DM-related complaints

were absent or mistaken for Peg-IFN- & #945;/Riba-related side effects.

So far, 31 cases of de novo type 1 DM during or after treatment of

chronic HCV infection with IFN- & #945;, IFN- & #945;/Riba or Peg-IFN- & #945;/Riba

have

been described.[3,5-10] Through screening, we identified five certain

cases and one possible case of de novo type 1 DM during or after

treatment of chronic HCV infection with Peg-IFN- & #945;/Riba.

In our study, only two of the nine patients who developed DM tested

positive for type 1 DM-associated autoantibodies before IFN- & #945; was

started. These findings agree with those of Fabris et al.,[3] who

analysed the presence of ß-cell autoantibodies in a number of

studies: anti-GAD65, ICA or anti-IA2 was present in 3% of patients

with chronic HCV infection (12 of 440) before treatment; two of 440

patients (0.45%) developed type 1 DM during antiviral therapy, and

both tested positive for ICA before treatment (i.e. two of the 12

patients with anti-GAD65, ICA or anti-IA2 before treatment). In

contrast, pretreatment autoantibodies associated with the development

of type 1 DM - assessed in 26 of the 31 reported cases so far - were

positive in 50% of patients who developed type 1 DM.[3,5,9] Taken

together, both the positive and the negative predictive value of ß-

cell autoantibodies seem too low to identify patients at a high risk

or to effectively rule out the possibility of developing IFN- & #945;-

associated type 1 DM.

The destruction of pancreatic ß-cells in type 1 DM may be mediated by

IFN- & #945;.[22,23] Enhanced expression of IFN- & #945; by pancreatic islet cells

in transgenic mice induces inflammation,[22,24] autoreactive T cells

[22,25] and precedes DM.[22,24,26] Enhanced expression of IFN- & #945; by

pancreatic islet cells has also been demonstrated in patients with

type 1 DM.[27,28] Riba and amantadine are not associated with the

development of DM.

Certain HLA haplotypes (DR3, DQ2, DR4 and DQ8) are associated with

increased susceptibility to type 1 DM.[29] In the analysis by Fabris

et al.,[3] HLA haplotype was determined in 13 patients with chronic

HCV infection who developed type 1 DM during IFN- & #945; or IFN- & #945;/Riba

therapy; all 13 patients had an HLA haplotype associated with

increased susceptibility to type 1 DM. In our study, four of the nine

patients had a type 1 DM-associated HLA haplotype, of whom three

patients also tested positive for one or more autoantibodies ( Table

2 ). We classified one patient as indeterminate owing to the absence

of autoantibodies. Taken together, these results suggest that certain

HLA haplotypes may predispose to the development of type 1 DM during

Peg-IFN- & #945;/Riba therapy in chronic HCV patients. In the patients who

seroconverted, the absence of concomitant anti-TPO antibodies argues

against induction of a polyglandular autoimmune syndrome by IFN- & #945;.

In addition, we described three cases of de novo type 2 DM during

treatment of chronic HCV infection with Peg-IFN- & #945;/Riba. The

prevalence of type 2 DM is high among chronic HCV patients,

especially in patients with advanced fibrosis or cirrhosis.[12,30]

The pathogenesis is unclear, but insulin resistance and the

development of DM may be mediated by pro-inflammatory cytokines such

as IL-6 and TNF- & #945;.[31,32]

Four of the nine patients who developed DM were treated with triple

antiviral therapy with high doses of IFN- & #945; during the first 6 weeks (

Table 1 , patients 2, 4, 5, 6); one of these patients had been

treated with IFN- & #945; previously. The incidence of DM was similar in the

standard treatment group (five of 98 patients, 5.1%) compared with

the triple treatment group (four of 91 patients, 4.4%). The

prevalence of DM before treatment with triple therapy was higher in

previous IFN- & #945; non-responders (six of 46 patients) than in treatment-

naïve patients (three of 54) but this was not significant (P = 0.29,

Fisher's exact test). The prevalence of DM before treatment with

standard therapy was similar in previous IFN- & #945; non-responders (two of

17 patients) compared with treatment-naïve patients (seven of 90, P =

0.63, Fisher's exact test). Taken together, these findings suggest

that the development of DM is not associated with higher doses of IFN-

& #945; or multiple courses of treatment.

Whether pegylation of IFN- & #945; has an effect is uncertain. Three of the

31 previously described patients and all five patients in our study

who developed type 1 DM during IFN- & #945; treatment were treated with Peg-

IFN- & #945;.[5,6]

Our study has several limitations: (i) we only assessed type 1 DM-

associated autoantibodies in patients who developed DM and (ii) we

did not use a control group such as chronic hepatitis B patients

undergoing IFN- & #945; treatment, or untreated chronic HCV patients.

However, our study, prompted by two index patients who developed DM

during treatment for chronic HCV infection, was based on a clinical -

ad hoc - adjustment of two treatment protocols to monitor development

of DM. Interestingly, the two index cases in our study (patients 1

and 2), who both required insulin at the time of diagnosis, had

developed type 2 DM. Five of the seven patients who were subsequently

identified had developed type 1 DM. Given the low positive and

negative predictive values of type 1 DM-associated autoantibodies

(~50%),[3] and the similar clinical presentation of both types of DM,

we chose to monitor glucose levels rather than rely on autoantibodies.

No recommendations have been made in HCV treatment guidelines on

glucose assessment during therapy.[33] Considering (i) the high

incidence of types 1 and 2 DM in our study, (ii) the atypical

clinical picture of DM during Peg-IFN- & #945;/Riba therapy, (iii) the

availability of an easy method to identify patients who develop DM

and (iv) the importance of the treatment of diabetes, we suggest that

routine glucose assessment at all outpatient visits for all HCV

patients before, during and shortly after Peg-IFN- & #945;/Riba treatment

should be incorporated into the treatment guidelines, similar to the

existing recommendation to screen for autoimmune thyroid disease.

In conclusion, this is the first prospective study on the development

of DM in chronic HCV patients during treatment with Peg-IFN- & #945;/Riba.

We have shown that the incidence of DM, especially type 1, during

treatment with Peg-IFN- & #945;/Riba for chronic HCV infection is markedly

higher than reported previously. DM-related complaints are frequently

absent or mistaken for Peg-IFN- & #945;/Riba-related side effects. Routine

assessment of random blood glucose is an easy method to identify

patients who develop DM during Peg-IFN- & #945;/Riba treatment. These

results support routine assessment of blood glucose levels at all

outpatient visits before, during and in the first month after Peg-IFN-

& #945;/Riba treatment to detect DM without delay.