Interferon-alpha and Autoimmune Thyroid Disease

[Guest guest]

I did 48 weeks of this medication in combination with ribavirin and

amantadine....this article explains some possibilites for me. any

suggestions would of course be appriciated by me.

thanks

steph

Interferon-alpha and Autoimmune Thyroid Disease

from Thyroid

IFN or the Underlying Disease (HCV) as the Cause for AITD

It has been argued that HCV infection itself is associated with

autoimmune thyroid disorders. Fernandez-Soto et al.[12] reported that

27 of 134 (20%) of HCV-infected patients had antibodies against

thyroid peroxidase (TPO), as opposed to only two of 41 (5%) of

hepatitis B virus (HBV)-infected controls. However, the results of

this study can be criticized because the HCV-infected patients had a

higher likelihood to be TPO antibody-positive: They were 10 years

older and more often female (43% vs. 34%) compared with the HBV-

infected controls. Indeed, in a larger study Marazuela et al.[13]

found that the prevalence of TPO antibodies in 95 HCV-infected (but

not IFN -treated) patients was 14.7% and thus very similar to the

rate found in the general population. When these authors summarized

the available studies on this subject, 96 of 626 HCV-infected

patients had TPO antibodies, resulting in a similar prevalence rate

of 15.3%.

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Interferon-alpha and Autoimmune Thyroid Disease

from Thyroid

Risk Factors for IFN -Associated AITD

The factors that increase the risk for thyroid autoimmune disease

during IFN therapy appear to be the same as in the general

population. Thus, females carry a higher risk to develop thyroid

dysfunction during IFN treatment than males. In a compilation of

data from different studies, females have a 4.4 times higher risk

than males (Table 2). Another risk factor is the pretreatment

presence of TPO autoantibodies, which increases the risk for thyroid

dysfunction 3.9-fold (Table 3). Twenty-one percent of TPO antibody-

positive patients developed thyroid dysfunction, as opposed to only

5% of the antibody-negative patients. This figure is almost certainly

an underestimate of the true risk, because antibody positivity is

often seen as a relative contraindication to the use of IFN .

On the other hand, in three studies including 421 patients without

TPO antibodies prior to treatment, TPO antibodies occurred de novo in

40 of 421 (9.5%) patients of whom 23 (58%) developed clinically overt

thyroid dysfunction.[13,15,17]

Interferon-alpha and Autoimmune Thyroid Disease

from Thyroid

Type of Thyroid Dysfunction Induced by IFN Therapy

There are three different types of thyroid dysfunction associated

with IFN treatment: (1) autoimmune (often subclinical)

hypothyroidism; (2) destructive thyroiditis; and (3) Graves'

hyperthyroidism.

These abnormalities can occur at any time during IFN therapy, from

as early as 4 weeks until as late as 23 months after initiation,[6,9]

and there is no clear difference between the three types, with a

median date of onset of 17 weeks after start of IFN treatment.[10]

Pooling of several studies shows that hypothyroidism seems to be more

frequent than thyrotoxicosis (Table 4).

Hypothyroidism

The majority of patients with hypothyroidism also have TPO antibodies

(87%; Table 4), indicating the autoimmune nature of this event.

According to most studies hypothyroidism can be transient, subsiding

after discontinuation of IFN . In a large Italian survey,

hypothyroidism was, however, permanent in 59% of the patients.[6] A

similar result was found in the review of the literature done by Koh

et al.,[8] which showed that 56% of the patients had permanent

hypothyroidism. In a recent long-term follow-up study, Carella et al.

[18] found that 10 of 36 (28%) TPO antibody-positive patients lost

their antibodies at 6 years after discontinuation. On the other hand,

26 patients remained antibody-positive at that time, and subclinical

hypothyroidism was detected in seven of them. An unusual form of

hypothyroidism was seen in five patients with pre-existing thyroid

disease, in whom a reversible form was observed in the presence of

thyrotropin (TSH) receptor autoantibodies.[19]

Thyrotoxicosis

Only a few studies give details regarding the etiology of reported

hyperthyroidism. Fattovich et al.[6] found 34 hyperthyroid patients,

of whom 13 had transient thyrotoxicosis, presumably suffering from

destructive thyroiditis. Twenty-one needed antithyroid drug

treatment, making it likely that these suffered from Graves' disease.

In the study by Kakizaki et al.,[9] all nine hyperthyroid patients

had detectable TSH receptor-stimulating antibodies. In the review by

Koh et al.,[8] 30% of hyperthyroid patients had a transient form of

thyrotoxicosis, in agreement with a study of Hsieh et al.,[14] which

reported that four of 22 hyperthyroid patients had destructive

thyroiditis. In a recent study by Wong et al.[11] 10 thyrotoxic

patients were identified among 321 HCV- or HBV-infected patients

treated with IFN . In six of these Graves' disease was diagnosed

(without eye manifestations). In three patients a typical pattern of

silent thyroiditis occurred: thyrotoxicosis with reduced uptake on

technetium scintigraphy followed by overt hypothyroidism. In the

remaining patient, insufficient information was available to make a

diagnosis.

From these data it appears that Graves' disease is the most common

cause of IFN -associated hyperthyroidism. However, because

destructive thyroiditis is present in about one-third of the

hyperthyroid patients, adequate diagnostic procedures are indicated

when this side effect occurs.

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Section 5 of 7

Thyroid 13(6):547-551, 2003. © 2003 Ann Liebert, Inc.

Interferon-alpha and Autoimmune Thyroid Disease

from Thyroid

Virus-Induced Endogenous IFN : A Putative Factor in the Development

of Clinical AITD

IFN is used therapeutically for its immunostimulatory and antiviral

properties. The pattern of thyroid disease observed during therapy

bears resemblance to the pattern observed during the " endogenous "

immunostimulation occurring during the postpartum period: Circulating

levels of thyroid autoantibodies tend to increase, and subjects with

circulating TPO autoantibodies are at substantially increased risk of

developing thyroid dysfunction. Thyroid function may normalize in

some patients after withdrawal of therapy, and the subtypes of

disease induced are destructive thyroiditis, Graves' disease, and

autoimmune hypothyroidism. Hence IFN -induced thyroid dysfunction may

to some degree be a model of postpartum thyroid dysfunction.

In addition it is interesting to speculate if high endogenous IFN

may be involved in triggering AITD in genetically susceptible

individuals. The most prominent reason for high levels of IFN are

certain viral infections.[20-22] The importance of this was recently

stressed by a study in 56 patients with type 1 diabetes mellitus,[23]

another autoimmune disease that can be triggered by the use of IFN .

[24,25] Chehadah et al.[23] found that IFN could be detected in 70%

of patients with diabetes of recent onset, as compared with none of

37 controls. In 50% of these patients, sackie B virus, a virus

implicated as a cause of type 1 diabetes mellitus, could be detected.

These findings suggest that viral infections capable of inducing an

IFN response in the host may be one of the environmental factors

implicated in the development of AITD in genetically predisposed

individuals. In vitro studies have shown that IFN up-regulates major

histocompatibility complex class I and II expression on xenografted

thyroid tissues from Graves' patients, in parallel with an increase

in anti-TPO antibodies.[26] This, however, only happens if local

infiltrating lymphocytes remain present in the graft, suggesting that

Interferon- may be capable of aggravating an immune response only in

predisposed subjects with some degree of pre-existing thyroiditis.

Viral infections have been suspected to be such a triggering factor,

but clinical studies linking certain viruses to the development of

AITD are lacking.[27] We suspect that this is due to the large number

of different viruses that may affect humans. The data presented above

suggest that it is worthwhile to focus on viruses known to induce an

IFN response. A list of those is presented in Table 5.[28]

In conclusion, IFN therapy of chronic HCV infection is associated

with a risk of inducing or worsening AITD, with some resemblance to

the induction or worsening of AITD often observed during the

postpartum period. The risk of AITD should be evaluated before

initiating IFN therapy. In high-risk patients with a strong family

history of AITD, previous AITD, or subclinical AITD with circulating

thyroid antibodies, thyroid function should be tested at short

regular intervals, and the risks of thyroid disease balanced against

the benefits of IFN therapy.

It may be hypothesized that environmental factors, such as certain

viral infections, by inducing an increase in IFN generation may be

involved in triggering seemingly spontaneous AITD in genetically

susceptible individuals.

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Section 6 of 7

Interferon-alpha and Autoimmune Thyroid Disease

from Thyroid

Clinical Implications

From the evidence presented above, the incidence of clinically

relevant AITD is high enough to advise regular (e.g., every 2-3

months) monitoring of TSH values in females and in patients with TPO

antibodies who will be treated with IFN . When hypothyroidism occurs,

thyroxine therapy should be started, and there is no good reason to

withdraw IFN treatment. If thyrotoxicosis is diagnosed, it is

advisable to perform a thyroid scintigram. In the case of a

homogeneous uptake, Graves' disease is diagnosed and should be

treated accordingly, and IFN may be continued. On the other hand, if

the uptake is low a diagnosis of destructive thyroiditis is made.

Although this disease is usually transient, there is no effective

treatment, and only in these patients discontinuation of IFN therapy

may be considered.

Reprint Address

Address reprint requests to: Mark F. Prummel, M.D. Department of

Endocrinology & Metabolism, F5-171 Academic Medical Center

Meibergdreef 9 1105 AZ Amsterdam The Netherlands. E-mail:

m.f.prummel@...

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