The swinging thyroid in hepatitis C infection and interferon therapy

Abstract

Described is a case of triphasic thyroid response in a 53-year-old man while undergoing combination interferon α-2b and ribavirin treatment for chronic hepatitis C infection. He developed the classical biphasic thyroiditis during treatment and was treated expectantly. However, 8 weeks after the completion of therapy, he developed T3-Graves-like thyrotoxicosis, which was confirmed with a diffuse-uptake thyroid scan and positive thyroid stimulating immunoglobulin. He was treated as having Graves’ disease arising de novo with thiourea, and he achieved rapid remission. This is thought to be only the second case described, and it offers a unique opportunity to understand the possible pathogenesis of this fascinating condition. This is a relative novel entity and highlights the need for continuing thyroid monitor after treatment. Management also needs to be specific for each particular phase of the condition.

BACKGROUND

Thyroid diseases are the commonest endocrine manifestations in chronic hepatitis C virus (HCV) infection. These are further exacerbated with the use of interferon (IFN) α-2b related therapy. In addition to non-specific non-thyroidal illness, the spectrum of thyroid diseases ranges from frank hypothyroidism to overt thyroiditis. The latter is a specific condition in which there is a particular pattern of an initial thyrotoxicosis, followed by hypothyroidism with subsequent normalisation, commonly known as biphasic thyroiditis. Presented is a case of triphasic thyroid response in which the IFN-induced biphasic thyroiditis was followed closely with Graves’-like thyrotoxicosis post therapy. This case offers a unique opportunity to understand the immunopathogenesis by analysis of the thyroid autoantibody pattern response. This is a recently described entity and the management needs to be specific for each particular phase of the condition.

CASE PRESENTATION

A 53-year-old Caucasian man presented with acute thyroiditis while undergoing combination ribavirin and INFα-2b therapy for his HCV infection. Because of his HCV genotype 1, treatment duration was to be 48 weeks. He had no medical history of note, smoked 5–10 cigarettes daily and had been tolerating the treatment regimen well. At the 28th week of therapy, he complained of palpitations, unintentional weight loss of 4 kg over 4 weeks, and intermittent diarrhoea. There was no family or prior history of thyroid disease. He did not take any other prescribed or over-the-counter medications. Clinical examination showed a thin man, weight 56 kg, height 1.62 m, (body mass index ∼22 kg/m²). He was in sinus tachycardia at 101 beats/min, blood pressure of 120/80, with no postural hypotension. There were peripheral stigmata of thyrotoxicosis but no signs of Graves’ ophthalmopathy or dermopathy. No goitre was present. His monthly thyroid stimulating hormone (TSH) levels, which had been normal, were now undetectable (reference range (RR) 0.4–4.0 mU/l); free tetra-iodothyronine (fT4) was 28.7 (RR 10.1–24.5 pmol/l), free tri-iodothyronine (fT3) was 6.9 (RR 3.3–5.8 pmol/l). His antithyroglobulin antibody and thyrotropin-stimulating immunoglobulin (TSI) titres were normal at 1:64 (RR <1:400) and <10 (RR <10 U/ml) respectively. His antithyroperoxidase tire was elevated at 1: 640 (RR 1:400). His thyroid ultrasound revealed normal size without any nodular disease and a pertechnetate thyroid uptake was undetectable at <1% (RR 3–8%). A diagnosis of thyroiditis was made and propanolol was initiated. No specific medications were required, specifically no corticosteroid. The patient remained generally well and was keen to complete therapy. IFN therapy was thus continued with monthly thyroid function tests. At 36 week, he became hypothyroid with a TSH level of 27.2 mU/l, fT4 of 4.3 pmol/l and fT3 of 3.9 pmol/l. As there were no hypothyroid symptoms, no thyroxine replacement therapy was given. The patient completed his IFN-based treatment uneventfully at 48 weeks at which time his TSH, fT4 and fT3 levels had returned to normal. At 8 weeks post treatment, he complained of non-specific lethargy and a 2.5 kg weight loss. Repeat thyroid function tests showed T3 thyrotoxicosis with, again, suppressed TSH, fT4 of 21.1 pmol/l and fT3 8.0 pmol/l. His antithyroglobulin antibody titre was 1:64, antithyroperoxidase 1:128 and TSI was elevated at 19 U/ml. A repeat pertechnetate uptake scan showed diffuse and increased uptake at 12%, consistent with Graves’ disease (GD). At 12 weeks post IFN therapy, his T3 toxicosis persisted, with fT3 level of 8.7 pmol/l. A diagnosis of GD was made and propylthiouracil (PTU) treatment was initiated. He was rendered euthyroid 6 weeks later at which time his fT4 and fT3 levels had normalised. PTU was continued for another 18 months. His HCV RNA viral load was absent at 24 weeks post IFN therapy confirming a sustained virological response. He remained euthyroid 3 months after cessation of PTU. Fig 1 shows the swinging pattern of thyroid function tests and pertechnetate-uptake scans.

Figure 1.

The swinging pattern of thyroid function in the patient with hepatitis C infection during and after interferon(IFN)-based therapy. Insets: thyroid uptake scan appearance at the two respective thyrotoxic incidents. fT3, free tri-iodothyronine; fT4, free tetra-iodothyronine; RR, reference range; TSH, thyroid stimulating hormone.

DISCUSSION

HCV infection was first identified in 1989,¹ and since then millions of people around the world have been diagnosed with this condition. It is estimated that ∼3% of the world population (180 million people) is infected with the virus.² In Australia there are estimates of ∼13 000–20 000 cases per year although the number is decreasing annually with improved control.³ In the USA, the prevalence is 1.3% resulting in a substantial 3.2 million cases.⁴ As the number of treated cases is expected to escalate, it is important that side effects of treatment are recognised and managed appropriately. HCV infection, together with IFN-based treatment, is associated with a number of extrahepatic endocrinopathies, the commonest of which is thyroid disease. This is not well appreciated because it is an uncommon adverse reaction and thus is not often reported in clinical trails, limiting its understanding.⁵ As treatment is increasing, the number of thyroid-related complications can only be expected to increase.

The spectrum of thyroid disease in this setting is broad and ranges from overt hypothyroidism to frank hyperthyroidism. Commonly, most patients develop a non-thyroidal illness like pattern with low/undetectable TSH and normal/low free thyroid hormone levels biochemically, and with subsequent recovery.⁶ Approximately ∼3–5% of patients develop (biphasic) thyroiditis, 5–8% hypothyroidism and ∼1% Graves’-like thyrotoxicosis.⁷ Each entity often follows its own course with characteristic natural history and therapeutic response.

This report, thought to be the second worldwide, illustrates a recently described specific thyroid disease in patients with HCV undergoing IFN-based medication.⁸ The patient developed triphasic thyroid dysfunction with two peaks of thyrotoxicosis, bisected by hypothyroidism. This is opposed to the classical biphasic condition that is common in thyroiditis. This swinging pattern of thyroid disease from one extreme to the other is a relatively novel finding. This clinical observation offers an opportunity to add to what little is known about this entity.

The overall pathogenesis of thyroiditis remains unknown. Drug naive HCV infection is known to modulate the immune system, particularly the cytotoxic immune response in CD4 T cells, producing high concentrations of IFNγ and interleukin 2. In the presence of therapeutic IFN, first, the cytotoxic CD4 T cell response is further exaggerated, particularly the T_H1 immunity which induces apoptosis by aberrant and enhancement of major histocompatability complex class I antigen surface expression on thyrocytes. This subsequently evolves into the destruction of thyroid cells and associated follicles.⁹ This is further accentuated by the increased IFNγ level. Furthermore, there is a reduction in T cell apoptosis, which further fuels the immunomodulation induced by the HCV infection. Second, there is the T_H2 response that guides the autoantibody response, particularly of antithyroperoxidase and antithyroglobulin.^10,11 Together with the T_H1 immune response, these result in the hyperthyroid phase of thyroiditis in which there is rupture of the thyroid follicles leading to the release of stored thyroid hormones into the circulation. This first phase is further characterised by the absent/negligible pertechnetate uptake scan and thyroid autoantibody positivity. Following this destructive phase, the thyroid is then depleted of all its hormone reserve, resulting in the second hypothyroid phase. With time, the thyroid recovers back to normality. In de novo thyroiditis, ∼5% remain permanently hypothyroid; however, in IFN-related cases the ultimate outcome is uncertain, but most resolve and remain quiescent. With the development of the high-uptake thyrotoxic third phase, there must be further modulation of the immune system. This phase behaves similarly to GD in the presence of an elevated TSI titre. It is probable that the initial exposure to IFN swings the immune system in favour of the T_H2 system, activating the B cells to generate TSI, resulting in the clinical Graves’-like thyrotoxicosis. This occurs after the cessation of IFN therapy, suggesting that the entire pathogenic process must have been triggered off while undergoing treatment but has taken sometime to develop.¹² In addition, there must be an underlying genetic predisposition so that in the suitable biological milieu, the condition is allowed to proceed inexorably to clinical thyroid disease.¹³ Fig 2 summarises the proposed pathogenesis of this relatively novel entity.

Figure 2.

The proposed pathogenesis of “triphasic” thyroiditis under the influence of interferon (IFN) α-2b in the presence of chronic hepatitis C infection. IL, interleukin; TSI, thyrotropin-stimulating immunoglobulin.

The persistence of T3 toxicosis is another peculiarity in this case. Although T3 toxicosis does occur in de novo GD,¹⁴ this, and its persistence without therapy, has not been previously described in IFN-related toxicosis. The diagnosis is further confirmed by the increased uptake scan and positive TSI. This plausibly indicates that TSI in HCV infection preferentially stimulates iodothyronine deiodinase type 1 (D1) activity, the bulk of which resides primarily in the thyroid and liver, resulting in T3 toxicosis alone. As D1 enzyme is potently inhibited by PTU rather than carbimazole,¹⁵ the former was selected and subsequently proven to be very effective.

The management strategies for each segment of this interesting condition are quite different and thus it is important that the diagnosis is correctly made. In the initial thyrotoxic phase of thyroiditis, thionamides should not be used as they contradict the underlying pathogenesis. If the thyrotoxic phase is too severe, symptomatic control should be managed with β blockade. In severe and symptomatic hypothyroidism, short-term thyroxine supplement should be considered as this phase too is short lived. Corticosteroid should not be used primarily due to its ineffectiveness,¹⁶ but also because of the theoretical risk of precipitating hepatic necrosis.¹⁷ The final thyrotoxic phase should be treated as GD de novo. This entails prolonged use of thionamides, ranging between 12 and 18 months (table 1).

Table 1.

Contrasting features of thyroiditis and Graves’ disease in patients with hepatitis C virus infection treated with interferon-based therapy

Feature	Thyroiditis	Graves’ disease
Characteristics	Biphasic response	Persistent thyroxicosis
Pathogenesis	Rupture/destructive of thyroid gland	Immunostimulation with TSI
Thyroid pertechnetate uptake scan	Absent/negligible	Increased uptake
Natural history	Hyperthyroid phase followed by hypothyroidism with subsequent normalisation	Persistent hyperthyroidism requiring treatment
Treatment	Observation and β blocker if required	Long-term thionamide therapy
	Corticosteroid is relatively contra-indicated

The surveillance for thyroid disease during and after IFN therapy remains inconsistent. The recommendations are either varying or absent according to various governing bodies. The British Society of Gastroenterology recommends thyroid function test at each treatment visit, rather than monthly.¹⁸ The American Gastroenterological Association does not offer any recommendation.¹⁹ The National Institutes of Health consensus statement on hepatitis C management and the National Academy of Clinical Biochemistry surprisingly make no mention of the thyroid issue in relation to IFN therapy.^20,21 With this report in mind, it is plausible and physiological that thyroid screening, using TSH, is performed monthly for the duration and 6 months after the completion of therapy. Beyond this time frame, individual cases should be assessed according to symptomatology.

This case highlights the newly described condition of triphasic thyroid disease,⁸ in response to IFN-based therapy, offering some crucial understanding of the condition. Each phase of this multiphasic thyroid disease needs to be managed appropriately with the background appreciation of the pathogenesis of the condition.

LEARNING POINTS

• Thyroid disease is the commonest endocrinopathy associated with chronic hepatitis C virus infection and interferon-related therapy.

• Thyroid diseases in this setting include Graves’-like thyrotoxicosis, overt primary hypothyroidism, biphasic thyroiditis and, as illustrated in this case, triphasic thyroiditis.

• In this novel triphasic thyroiditis, the first thyrotoxic phase needs symptomatic treatment only; the second thyrotoxic phase behaves more like Graves’ disease and requires long-term treatment with thionamides, preferably propylthiouracil.