Abrupt onset of type 1 diabetes mellitus during recombinant interferon-alpha 2b therapy in a patient with chronic hepatitis B

Abstract

We describe a case of a 33-year-old female patient with chronic hepatitis B who developed type 1 diabetes mellitus (DM) after a 13-mo period of treatment with recombinant human interferon-alpha (IFN-α) 2b. The patient presented with polydipsia, polyuria, hyperglycemia, diabetic ketoacidosis, combined with C-peptide secretion deficiency and positive islet cell autoantibody (ICAb). IFN-α 2b treatment was terminated and instead insulin treatment was initiated. Five months after cessation of the recombinant human IFN-α 2b therapy, the patient remained insulin-dependent. Her serum HBV DNA became negative and serum transaminase returned to the normal level after a 10-mo period of IFN therapy. Type 1 DM induced by IFN-α is relatively rare in patients with chronic hepatitis B. We should pay more attention to patients on IFN-α therapy to avoid destruction of pancreatic beta cells. This is the first case report from China.

Key Words: Interferon-alpha; Islet cell autoantibody; Type 1 diabetes mellitus; Autoimmune disease; Chronic hepatitis B

INTRODUCTION

Interferon-alpha (IFN-α) is now widely used in the treatment of chronic hepatitis B and C. Systemic side effects of IFN-α therapy can affect numerous organ systems. These adverse reactions include flu-like syndrome, hematological abnormalities, cardiovascular and central nervous symptoms, gastrointestinal symptoms, pulmonary dysfunction, depression and retinopathy. Besides, IFN-α has been shown to be related to the development of a variety of autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and autoimmune thyroid diseases (AITDs). However, the development of type 1 diabetes mellitus (DM) is relatively rare and few patients with positive islet cell autoantibody (ICAb) or glutamic acid decarboxylase autoantibody (GADAb) have been reported[1–3]. Here, we report the first case of a patient suffering from chronic hepatitis B who had an unexpected onset of type 1 DM during IFN-α 2b therapy in China.

CASE REPORT

A 33-year-old woman with a body mass index (BMI) of 22.49 kg/m² was treated with recombinant human IFN-α 2b at a dosage of 3 million units (MU) once every other day from April 2006 because of hepatitis B. Ten months after IFN-α 2b treatment, both hepatitis B e antigen (HBeAg) and HBV DNA became negative, and serum aminotransferases returned to normal. However, 13 mo after initiation of IFN-α 2b treatment (reaching 585 MU of total dose in May 2007), the patient complained of weakness, polydipsia, polyuria and a rapid weight loss (5 kg within 10 d). She was then admitted to our hospital. Her clinical data on admission are shown in Table 1. Urinalysis showed glucosuria and ketonuria. Fasting plasma glucose and glycosylated hemoglobin (HbA1c) were 31.7 mmol/L (570.6 mg/dL) and 10.0%, respectively. Arterial blood gas analysis showed metabolic acidosis. Serum asparate aminotransferase (AST) and alanine aminotransferase (ALT) were within normal range. Hepatitis B surface antigen (HBsAg) and anti-HB core antibody (HBcAb) in serum were positive. The fasting plasma C-peptide level was low. The curve of C-peptide response to 75 g glucose load was flat (Table 2). The serum ICAb was positive (Figure 1). The patient had no family history of type 1 DM or other autoimmune disorders. She had no symptoms of other autoimmune diseases. Other autoantibodies including thyroid peroxidase antibody (TPOAb), thyroglobulin antibody (TgAb), antinuclear antibody (ANA), anti-dsDNA antibody, anti-RNP, anti-SSA, anti-SSB, and rheumatoid factor (RF) were all negative. Taken together, clinical and laboratory data confirmed the diagnosis of type 1 DM with ketoacidosis. Administration of IFN was immediately terminated. Her clinical condition improved with diet therapy, intravenous fluids and insulin therapy (isophane protamine biosynthetic human insulin, Novolin^® R, Novo Nordisk, Denmark). Ketonuria disappeared after 12 h insulin therapy for. Following normalization of the acute metabolic disturbances, intensive insulin therapy was recommended with four daily doses of subcutaneous insulin: each before every meal and last at bedtime. Four days later, fasting plasma glucose decreased to 5.6 mmol/L (100 mg/dL). Five months after cessation of IFN-α 2b therapy, the patient remained insulin dependent with a daily requirement of 20 units Novolin^® 30R. The plasma C-peptide level was still low. Serum HbA1c level was 6.5%. Serum aminotransferase was normal, and serum HBV DNA remained undetectable.

Table 1 Laboratory findings in the patient on admission.

	Laboratory findings
Urinalysis
Glucose	(+++)
Ketobody	(++++)
Protein	(-)
CBC
RBC	3.94 × 1012/L
Hb	124 g/L
WBC	5.1 × 109/L
Plt	62 × 109/L
Blood chemistry
Fasting plasma glucose	31.7 mmol/L (570.6 mg/dL)
Arterial blood gas analysis
pH	7.314
PCO2	35.1 mmHg
PO2	70.6 mmHg
HCO3-	11.5 mmol/L
BE	-3.6 mmol/L
TP	87.1 g/L
ALB	48 g/L
AST	36 IU/L
ALT	40 IU/L
ALP	98 IU/L
GGT	21 IU/L
Serology
HbA1c	10.0%
HBs Ag	(+)
HBs Ab	(-)
HBe Ag	(-)
HBe Ab	(-)
HBcAb	(+)
HBV DNA (PCR)	< 1000 copies/mL
IgG	18.37 g/L
IgA	2.79 g/L
IgM	1.87 g/L
TSH	0.636 mIU/mL
FT3	4.03 pmol/L
FT4	16.3 pmol/L
TPOAb	(-)
TgAb	(-)
ANA	(-)
Anti-DNA Ab	(-)
RF	(-)

Figure 1 Positive islet cell autoantibody in pancreas from a mouse at 1:40 serum dilution tested by immunofluorescence assay (× 200).

Table 2 Results of oral glucose tolerance test (75 g).

Time (min)	Blood glucose (mmol/L)	C-peptide (pmol/mL)
0	7.5	0.29
30	10.8	0.40
60	15.0	0.61
120	18.3	0.77
180	14.1	0.78

DISCUSSION

IFN-α has different biologic effects (antiviral, antiproliferative, immunomodulatory), and has been used in treatment of chronic viral hepatitis for nearly 20 years[4]. IFN-α acts on many target cells and organs. The thyroid represents the main target for autoimmunity associated with IFN-α therapy. Although several reports indicate a beneficial effect on glucose metabolism[5–7], IFN-α has been considered to have a variety of effects on pancreatic beta cells[1–389]. In 1992, Fabris et al[10] reported the first case of type 1 DM in a chronic hepatitis C patient treated with IFN-α and concluded that IFN could trigger autoimmune destruction of pancreatic beta cells.

IFN-α therapy-induced autoimmunity of pancreatic beta cells has been evaluated in some studies[11–14]. The prevalence of ICAb, GADAb, insulin autoantibody (IAA), and/or tyrosine-like phosphatase autoantibody (IA2Ab) is not generally increased in patients with chronic viral infection prior to IFN-α therapy compared with normal control subjects. In 50% of the previously reported patients, markers of pancreatic autoimmunity predated treatment, the majority of cases having a genetic predisposition (HLA-DR3/-DR4 was positive)[15]. However, after IFN-α treatment, the prevalence of pancreatic autoantibodies may increase from 3% to 7% with type 1 DM developed in a few cases. Therefore, IFN-α therapy may induce type 1 DM in genetically and immunologically predisposed individuals.

The exact mechanism underlying the development of type 1 DM in chronic viral hepatitis patients treated with IFN-α is unclear. A variety of mechanisms may account for the effect of IFN-α on pancreatic beta cell dysfunction[14]. First, IFN-α activates the oligoadenylate synthase-RnaseL pathway and the protein kinase R pathway, thus inducing apoptosis of pancreatic beta cells. Second, IFN-α may stimulate a counter regulatory hormone secretion (growth hormone, glucagon, etc.), thus resulting in impaired glucose tolerance. Third, regarding type 1 DM, IFN-α may favor the development of Th1 immune reaction and thereby contribute to the development of autoimmune disease by activating CD4 lymphocytes secreting IL-2, IFN-γ, and tumor necrosis factor. IFN-α is also associated with over-expression of MHC classIantigens in human islets of pancreas. In addition to IFN-α, HCV infection can increase the frequency of pancreatic autoimmunity. That is why IFN-α-induced type 1 DM is relatively rare in chronic hepatitis B patients.

Transient insulin dependency was observed in some cases and permanent insulin administration was required in the other reported cases. These data demonstrate that in some cases the autoimmune attack is at least partially reversible with interruption of interferon therapy[15].

In conclusion, development of type 1 DM should be considered as one of the risk consequences after IFN-α therapy. In order to avoid it, administration of IFN-α in special patients should be evaluated, weighing the risk of diabetes and the benefit of the treatment. We conclude that patients having positive islet autoantibodies, HLA-DR3/-DR4, impaired glucose regulation, or positive family history of diabetes mellitus, should be considered to have a higher risk of developing type 1 DM following IFN-α treatment[13]. Physicians should be cautious of the use of IFN therapy.