Journal List > Int J Thyroidol > v.8(2) > 1082731

Int J Thyroidol. 2015 Nov;8(2):230-234. English.
Published online November 30, 2015.  https://doi.org/10.11106/ijt.2015.8.2.230
Copyright © 2015. the Korean Thyroid Association. All rights reserved.
Interferon-Alpha Induced Severe Hypothyroidism Followed by Graves' Disease in a Patient Infected with Hepatitis C Virus
Kyoung Jin Kim, Kang Won Lee, Ju Hee Choi and Jee Hyun An
Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.

Correspondence: Jee Hyun An, MD, PhD, Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, 73 Inchon-ro, Seongbuk-gu, Seoul 02841, Korea. Tel: 82-2-920-6272, Fax: 82-2-953-9355, Email: jeehyunan@gmail.com
Received July 07, 2015; Revised September 19, 2015; Accepted October 02, 2015.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.


Abstract

Interferon-alpha (IFN-α) is an important therapeutic agent for hepatitis C virus (HCV) infection, but has various side effects including thyroiditis. We report a case of interferon-induced non-autoimmune hypothyroidism followed by autoimmune-medicated Graves' disease. A 59-year-old woman was diagnosed with chronic active hepatitis C; she had been treated with IFN-α and ribavirin for 24 weeks. Before starting the IFN-α, her thyroid function was normal and she was negative for autoantibodies. Severe hypothyroidism developed 5 weeks after halting the IFN-α, with the Graves' disease phase arising at 32 weeks. For accurate diagnosis and appropriate treatment of thyroid dysfunction during treatment with IFN-α, we need to understand and consider rare cases of multiphasic disorder involving both non-autoimmune and autoimmune thyroiditis induced by IFN-α.

Keywords: Interferons; Non-autoimmune hypothyroidism; Graves' disease

Introduction

Affecting more than 3.5 million individuals annually worldwide, hepatitis C virus (HCV) infection is among the leading causes of chronic liver disease, cirrhosis, and hepatocellular carcinoma.1) Since 2001, pegylated-interferon-α (PEG-IFN-α) with ribavirin has been recommended as a standard therapy for chronic HCV. A type I interferon, IFN-α has many side effects, ranging from influenza-like symptoms to hematological effects, neuropsychiatric symptoms, and thyroid disease. Thyroid dysfunction has been reported in 2-13% of HCV-infected patients; however, this incidence increases to 15-40% with the use of interferon.2)

Interferon-induced thyroiditis (IIT) was first reported in 1985, when the association between IFN-α and thyroid disease was recognized in patients treated with IFN-α for carcinoid tumors and breast cancer. IIT can be classified into autoimmune and non-autoimmune subtypes according to autoantibody status.3) Autoimmune IIT can manifest as the development of thyroid antibodies without clinical disease, or as clinical disease including both autoimmune hypothyroidism (Hashimoto's thyroiditis) and autoimmune hyperthyroidism (Graves' disease). Non-autoimmune IIT can manifest as destructive thyroiditis or as hypothyroidism without thyroid antibodies.2) Here, we report an unusual case of IFN-α-related thyroid dysfunction in a patient with HCV infection: severe hypothyroidism caused by nonautoimmune thyroiditis and subsequent autoimmunemediated Graves' disease.

Case Report

A 59-year-old Korean woman was diagnosed with chronic active hepatitis C based on a liver biopsy, and treated with pegylated IFN-α 80 µg weekly and ribavirin 800 mg daily for 24 weeks. Before treatment, her thyroid function tests were normal and all thyroid antibodies tested were negative, including anti-microsomal, anti-thyroglobulin, and anti-thyroid stimulating hormone (TSH) receptor antibodies. She had no personal or family history of thyroid dysfunction and the physical examination showed no manifestations suggesting thyroid disease, such as goiter or ophthalmopathy. After 12 weeks of treatment, her serum HCV RNA viral load became negative and remained so during follow-up. Her thyroid function tests were within the normal ranges 12 weeks after treatment and she had no symptoms during treatment. However, 5 weeks after completing treatment, she experienced mild fatigue and myalgia. Laboratory tests showed a decreased free T4 level, to 0.04 ng/dL (reference range, 0.79-1.86 ng/dL), with a TSH level over 100 µIU/mL (reference range, 0.14-4.05 µIU/mL) and negative thyroid antibodies. On thyroid ultrasonography, diffuse parenchymal heterogeneity was noted in the thyroid gland bilaterally, without increased vascularity. A diagnosis of severe hypothyroidism caused by non-autoimmune IIT was made and she was given levothyroxine 75 µg/day. After 7 weeks of treatment for hypothyroidism, the free T4 and total T3 levels increased slightly to 2.09 ng/dL and 229.9 ng/dL (reference range, 78-182 ng/dL), respectively, while the TSH level was suppressed mildly to 0.13 µIU/mL. Tc-99m scintigraphy showed slightly increased Tc uptake (Fig. 1A). The levothyroxine was tapered off over 18 weeks.


Fig. 1
Tc-99m scintigraphy in the thyrotoxic period. (A) After taking levothyroxine for hypothyroidism for 7 weeks. (B) Eight weeks after discontinuing levothyroxine with confirmed TSH receptor antibody positivity.
Click for larger image

After 8 weeks, despite discontinuing the levothyroxine, she complained of lethargy and a 7 kg weight loss. Thyroid function tests showed thyrotoxicosis, elevated free T4 at 2.39 ng/dL, T3 at 224.9 ng/dL, and suppressed TSH 0.02 at µIU/mL. TSH receptor antibody was positive with an elevated titer of 5.4 IU/L (reference range, 0-1.5 IU/L). On Tc-99m scintigraphy, both thyroid lobes showed diffusely increased Tc uptake (Fig. 1B). Anti-microsomal and anti-thyroglobulin antibodies were negative. Ultimately, she was diagnosed with Graves' disease caused by the de novo production of TSH receptor antibody. Methimazole and beta-blockade were started and continued. Fig. 2 shows the biphasic course of the thyroid function tests of this patient.


Fig. 2
The clinical course of thyroid function in the HCV-infected patient on IFN-α therapy: the biphasic pattern of thyroid function after initiation of IFN-α therapy.
Click for larger image

This report describes two different features of IFN-α-induced thyroiditis in one patient with HCV infection: non-autoimmune hypothyroidism and subsequent autoimmune Graves' disease.

Discussion

Thyroiditis is among the most common side-effects of IFN-α therapy; subclinical thyroiditis occurs in 20-40% of patients and clinical thyroiditis in 5-10%.4) IFN-α triggers thyroiditis in genetically predisposed individuals via both immune-modulatory and direct thyroid-toxic mechanisms.4, 5) Autoimmune IIT can manifest as clinical disease, i.e., Graves' disease or Hashimoto's thyroiditis, or as subclinical disease in which thyroid autoantibodies are present in the absence of abnormal thyroid functions. Non-autoimmune IIT, which comprises approximately 50% of IIT cases, can manifest as destructive thyroiditis or non-autoimmune hypothyroidism without detectable antibodies.4, 5, 6)

Several studies have demonstrated that IFN induces thyroid cell death by necrosis in vitro, supporting the hypothesis that IFN can cause thyroiditis via a direct thyroid-toxic mechanism.7, 8) In our case, the patient's initial presentation after IFN therapy was compatible with non-autoimmune hypothyroidism, as the patient was hypothyroid without autoantibodies. Destructive thyroiditis, another manifestation of non-autoimmune IIT, usually starts with an early thyrotoxic phase and progresses to a hypothyroid phase, with complete resolution observed in most cases.2) These are difficult to distinguish when a patient is in a hypothyroid state because both destructive thyroiditis and non-autoimmune hypothyroidism share a hypothyroid phase. Although we did not observe an early thyrotoxic phase in our patient, it is possible that the patient experienced very mild symptoms related to a thyrotoxic state that were overlooked. However, as destructive thyroiditis is usually followed by a mild or subclinical hypothyroid phase, our patient is more compatible with non-autoimmune hypothyroidism as she did not experience thyrotoxic symptoms and showed severe hypothyroidism.

In our case, the severe hypothyroid phase was followed by thyrotoxicosis with positive TSH receptor antibody, i.e., Graves' disease. Our patient began to exhibit mild thyrotoxicosis after 8 weeks of levothyroxine treatment for severe hypothyroidism. Although we confirmed TSH receptor antibody positivity several weeks after discontinuing levothyroxine, the mildly increased uptake on thyroid scintigraphy indicated that Graves' disease had already developed during the levothyroxine treatment. In addition to the typical single phasic pattern, such as hypothyroidism or hyperthyroidism, multi-phasic patterns have been reported, as in our case (summarized in Table 1). Kim et al.9) described a woman with HCV infection who was treated with IFN-α and developed destructive thyroiditis followed by transient Graves' disease. Their patient was treated with IFN-α for 48 weeks and Graves' disease was diagnosed 2 months after completing treatment. As in our case, de novo production of thyroid antibody was observed. Tran et al.3) also reported a case involving a tri-phasic pattern, with destructive thyroiditis followed by Graves' thyrotoxicosis. Bohbot et al.10) reported three cases of IFN-α-induced tri-phasic thyroiditis. These patients initially experienced silent destructive thyroiditis, but eventually developed Graves' disease. Savvas et al.11) reported IFN-α-induced Hashimoto's thyroiditis followed by Graves' disease.


Table 1
Summaries of multi-phasic thyroiditis in five cases
Click for larger image

As an underlying mechanism by which IFN can induce autoimmune thyroiditis, IFN-α activates several signaling pathways, including the Janus kinase/signal transducers and activators of transcription (JAK-STAT), Crk, insulin receptor substrate (IRS) signaling, and mitogen-activated protein (MAP) kinase pathways.12) Through these pathways, the transcription of target proteins leads to immune and anti-tumor effects that might be associated with IFN-induced thyroiditis. IFN- α can induce over-expression of major histocompatibility complex (MHC) class I antigen on thyroid epithelial cells, which switches the immune response to the Th1 pattern thereby stimulating an inflammatory response and tissue damage.13, 14) IFN can cause thyroid autoimmunity de novo or exacerbate pre-existing thyroid autoimmunity.2) The incidence of the de novo development of thyroid antibody is 10-40%,15, 16) and the majority of patients remain positive when the treatment course is completed.17) The most common clinical manifestation of IIT is Hashimoto's thyroiditis. Approximately 45-60% of patients with pre-existing thyroid antibodies are likely to develop Hashimoto's thyroiditis, while only 3-5% of those without circulating antibodies before IFN treatment develop the disease.9) Graves' disease is a less common manifestation of autoimmune IIT. Wong et al.18) reported that 10 of 321 patients with IFN-α developed thyrotoxicosis; only six of these cases were consistent with Graves' disease. Lisker-Melman et al.19) reported that 2 of 327 patients on IFN-α treatment were diagnosed with Graves' disease that required treatment. The majority of IFN-induced Graves' disease cases require prolonged treatment with anti-thyroid medications even after the IFN-α therapy is stopped.16) In cases of mild Graves' disease, it is not necessary to stop IFN-α, and anti-thyroid drugs can be added at low-doses to control thyrotoxicosis. However, IFN-α-induced Graves' disease usually does not enter remission upon completion or cessation of IFN-α therapy and anti-thyroid drugs often aggravate liver dysfunction in patients with hepatitis. In these cases, radioiodine or thyroidectomy should be considered in the treatment of Graves' disease.20)

In summary, IFN-α can induce a broad spectrum of IIT. Here, we report a case that showed a bi-phasic swinging pattern of thyroiditis with severe destructive hypothyroidism followed by Graves' disease. This case will contribute to our understanding of the pathogenesis of IIT, a rare but important adverse effect of interferon treatment.

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