J R Soc Med 2003;96:481-485
doi:10.1258/jrsm.96.10.481
© 2003 Royal Society of Medicine
Interferon alpha treatment and endocrine disease
Wing Bun Chan MRCP
Chun Chung Chow FRCP
Clive Stewart Cockram MD FRCP
Department of Medicine and Therapeutics, Prince of Wales Hospital, The
Chinese University of Hong Kong, Shatin, NT HKSAR.
Correspondence to: Dr WB Chan E-mail:
wbchan{at}cuhk.edu.hk
 |
INTRODUCTION
|
|---|
The interferons are a group of proteins with antiviral activity,
growth
regulatory properties, and a wide variety of immunomodulatory
activities.
There is evidence that, when interferon
is used
therapeutically in
chronic hepatitis B and C and in certain
malignancies,
1-5
it can precipitate or exacerbate autoimmune
endocrine diseases, especially of
the thyroid gland.
6
In this
review we examine the published information on such unwanted
effects.
|
THYROID GLAND
|
|---|
The thyroid gland is the most extensively studied in relation
to the effect
of interferon
: more than forty reports document
changes in thyroid
function and autoimmune markers during treatment
of hepatitis C. In the
largest series, 11 241 consecutive patients
with hepatitis C were treated with
interferon
, of whom 71
(0.6%) developed symptomatic thyroid
disorders.
7 This
incidence,
however, is likely to be an underestimate: there was no regular
surveillance of thyroid function, so symptoms related to thyroid
disorders
could easily have been missed or misinterpreted.
Series in which thyroid
function was checked regularly have
shown thyroid dysfunction developing in
4-14% of patients during
interferon
therapy.
8-10
If development of circulating thyroid
antibody is included, the percentage is
much
higher.
11-13
Table 1 summarizes results from
the studies with sizeable
numbers. A noteworthy feature is that the more
frequently thyroid
function was checked the higher the reported rate of
thyroid
dysfunction.
In hepatitis C, interpretation of the data is complicated by the fact that
this disease is itself associated with autoimmune
disorders.14 For
example, up to 20% of chronic hepatitis C patients have circulating thyroid
antibody before treatment with interferon
.15-17
The question whether interferon precipitates or worsens thyroid
dysfunction would best be settled by a randomized placebo-controlled trial, in
which the treated and untreated groups would be comparable. No such trial has
yet been reported, so we have to assess evidence from less reliable
comparisons. In one recent study the incidence of thyroid antibody development
in patients treated with interferon was 21% compared with 10% in
patients not so
treated.11 The
difference was not statistically significant and the authors judged the
thyroid autoimmunity more likely to be due to the virus infection than to the
treatment. However, there were only 65 patients in each group and the study
lacked the statistical power for a confident negative conclusion. Another
study, with similar design, showed a larger difference, with 9/58 (16%)
initially seronegative patients developing thyroid autoimmunity when on
interferon compared with 1/28 (3%) of those declining the treatment. Although
the data are inconclusive, we think it likely that interferon can
exacerbate pre-existing thyroid immunity.
The patients most at risk of developing either biochemical or clinical
thyroid autoimmune disease during interferon treatment are women and
people with pre-existing thyroid peroxidase
antibody.18-21
Other possible risk factors are advanced age and oriental
origin.10,18,19
Of individuals with pre-existing thyroid peroxidase antibody, half or more
have been reported to develop thyroid dysfunction during interferon
treatment.20,21
The disorders include hypothyroidism (the most
common13,22),
Graves' disease with hyperthyroidism and thyroiditis with a two-phase
presentation. The pattern of thyroid dysfunction seems to differ between
patients with pre-existing antibody and those without: patients with
pre-existing thyroid peroxidase antibody tend to develop either an
exacerbation of Graves' disease or Hashimoto's thyroiditis during interferon
treatment, while those without pre-existing antibody tend to develop
thyroiditis.18,23,24
This is illustrated by the work of Roti et
al.25 who
found that 4 out of 32 patients treated with interferon developed
thyrotoxicosis during treatment. Interestingly, 3 of the 4 showed a decreased
uptake of radioactive iodine, suggesting a destructive process, and the
thyrotoxicosis subsided with steroid therapy. Furthermore, all 4 were negative
for thyroid peroxidase
antibody.25 We
think it likely that, in certain series, some of the cases reported as Graves'
disease are in fact thyroiditis—caught in the initial thyrotoxic phase
and thus misdiagnosed.
One reason for thinking that interferon is a direct cause of
thyroid dysfunction is that in some instances the dysfunction ceases when
treatment stops. However, this is not universal: some patients continue to
need treatment such as thyroid hormone replacement for a long time after
stopping interferon. Antibody production follows a similar pattern. In some
patients antibodies decline or disappear when interferon is stopped, in others
they
persist.10,15,18
Carella et
al.26 followed
114 patients after a course of interferon for hepatitis C. At the end of
twelve months of treatment, 36 (32%) had thyroid antibody. At a median
follow-up of 6.2 years, about one-third still had antibody, one-third had lost
their antibody while the remaining third showed a relapsing/remitting pattern.
Of the 12 patients in this series who developed subclinical hypothyroidism,
all were in the group with thyroid antibodies. The findings point to the need
for continued surveillance of thyroid function when interferon
treatment is stopped. The same group looked at patients who received ribavirin
in addition to interferon , but the incidence of thyroid dysfunction
was similar.27
Apart from true thyroid dysfunction, interferon has also been reported
to induce antithyroxine antibody, which can give rise to a spuriously high
free T4 measurement unless special assay procedures are followed. This further
complicates the
picture.28
Interferon has also been used in the treatment of hepatitis B and
hepatitis D. In these contexts, thyroid dysfunction seems less frequent than
in hepatitis C, though the matter has been less well studied. In hepatitis B,
the prevalence of antibodies before interferon treatment is lower than in
hepatitis C, and the incidence of thyroid dysfunction is only
2-4%.15,17
Because of the lower incidence, monitoring of thyroid function is probably not
indicated in these patients after interferon treatment, in the absence
of symptoms.
Interferon has also been used in the treatment of malignant disease,
including haematological malignancy, carcinoid tumour, metastatic melanoma and
breast
cancer.1,3,5
In patients with carcinoid tumour or breast cancer the incidence of thyroid
dysfunction during interferon treatment can be very high—usually 20-30%
and sometimes
50%.29-30
Both Hashimoto's thyroiditis and Graves' disease have been reported. However,
most series are rather small and long-term data are lacking. In patients with
haematological malignancy treated with interferon, the incidence of thyroid
dysfunction during interferon treatment is much
lower.31,32
The reason for such differences is obscure.
Possibly different mechanisms are at work in different types of thyroid
dysfunction. In healthy individuals injected with interferon , thyroid
stimulating hormone (TSH) and tri-iodothyronine (T3) decrease while reverse T3
increases. This biochemical picture is similar to euthyroid sick syndrome and
may be mediated through interleukin
6.33 Such acute
effects are unlikely to account for the thyroid dysfunction described in
patients receiving longer-term treatment. Other effects of interferon
are to increase expression of major histocompatibility complex class I antigen
but suppress the expression of histocompatibility complex class II
antigen.34 However,
autoimmune thyroid diseases are characterized by increased rather than
decreased expression of histocompatibility complex class II
antigen.35
Furthermore, work in animals suggests that the increased production of thyroid
antibody and expression of histocompatibility complex class I and II antigen
are
dissociated.36,37
The role of such changes in the development of autoimmune thyroid diseases
during interferon therapy remains speculative. Interferon is
known to alter the balance between Th1 and Th2 cells. Th1 cells predominate in
Hashimoto's thyroiditis while Th2 cells have an important role in Graves'
disease.38,39
We hypothesize that interferon causes autoimmune thyroid disease by
changing the Th1/Th2 balance. It is also noteworthy that another cytokine,
interferon ß, has been incriminated in induction of thyroid
dysfunction.40
|
DIABETES MELLITUS
|
|---|
Endocrine disorders of other kinds have been less thoroughly
studied than
thyroid dysfunction in relation to interferon
therapy. There are several
reported cases of type 1 diabetes
developing in association with interferon
treatment, but most
of the patients had GAD antibodies before the start of
treatment.
41,42
In one series of 70 patients with hepatitis C receiving interferon,
only 1
developed type 1 diabetes (five months after the beginning
of treatment) and
that patient was anti-GAD positive before
treatment. The causal role of
interferon is therefore
doubtful.
43
|
ADRENAL DYSFUNCTION
|
|---|
Anti-21-hydroxylase antibody has been reported to appear in
4.8% of
hepatitis C patients receiving interferon
therapy.
44 However,
to date there has been no report of adrenal failure
associated with this
phenomenon. There are two reports of pre-existing
Addison's disease showing
increased steroid dependence during
interferon
therapy.
45,46
|
PITUITARY DYSFUNCTION
|
|---|
Interferon
can activate the hypothalamic-pituitary axis in
acute
circumstances.
47
There is one reported case of reversible
hypopituitarism in association with
interferon
therapy
48 and
our
group has seen a patient with irreversible hypopituitarism
after one year of
interferon therapy (unpublished).
|
OTHER AUTOIMMUNE DISORDERS
|
|---|
From the published work it is clear that thyroid dysfunction
is the most
common endocrine disorder to develop during interferon
therapy. The
likely reason is that the thyroid is the most
common site of autoimmune
endocrine disease in the general
population and that interferon
treatment promotes autoimmune
reactions especially in those who are
immunologically predisposed
(antibody positive before treatment). Probably the
risk of
other autoimmune disorders is likewise increased but less obvious
because these conditions are rarer or more difficult to detect.
This notion is
supported by the development of other autoimmune
diseases such as systemic
lupus erythematosus and Sjögren's
syndrome during interferon
treatment.
49
|
RECOMMENDATIONS
|
|---|
Since the incidence of thyroid dysfunction is quite high in
patients
receiving interferon
for hepatitis C and certain
malignancies
(including malignant carcinoid and breast cancer),
we recommend that thyroid
function and thyroid antibody be
checked before initiation of treatment for
these conditions
and monitored during treatment. By contrast, in patients
receiving
the agent for hepatitis B or haematological malignancy, monitoring
of thyroid function may not be worthwhile in the absence of
symptoms. If
thyrotoxicosis develops during interferon treatment,
physicians should also be
aware of the possibility of destructive
thyroiditis as distinct from Graves'
disease with hyperthyroidism.
This is particularly true for patients without
pre-existing
thyroid antibody. Thyroid dysfunction may resolve if interferon
is stopped. However, the development of thyroid dysfunction
does not
necessarily contraindicate further interferon
treatment.
Of those
patients who are antibody positive at the end of interferon
treatment, a
proportion will later develop thyroid dysfunction;
therefore continued
monitoring of thyroid function is needed
in this group. Interferon
induced type 1 diabetes, adrenal
insufficiency and hypopituitarism seem rare
although antibodies
directed against the corresponding organ have been
reported.
Regular monitoring for these disorders is not indicated.
|
REFERENCES
|
|---|
- Kloke O, Opalka B, Niederle N. Interferon alfa as primary treatment
of chronic myeloid leukemia: long-term follow-up of 71 patients observed in a
single center. Leukemia 2000; 14:389
-92[Medline]
- Lindsay KL. Introduction to therapy of hepatitis C.
Hepatology 2002; 36(5 Suppl 1): S114
-20[Medline]
- Oberg K. The action of interferon alpha on human carcinoid tumours.
Semin Cancer Biol 1992; 3:35
-41
- Wong DK, Cheung AM, O'Rourke K, Naylor CD, Detsky AS, Heathcote J.
Effect of alpha-interferon treatment in patients with hepatitis B e
antigen-positive chronic hepatitis B. A meta-analysis. Ann Intern
Med 1993;119:312
-23[Abstract/Free Full Text]
- Agarwala SS, Kirkwood JM. Update on adjuvant interferon therapy for
high-risk melanoma. Oncology (Huntingt) 2002; 16:1177
-87; discussion 1190-2, 1197
- Chedin P, Chanson P, Duranteau L, Guillausseau PJ, Lubetzki J.
Dysthyroidism in patients treated with interferon alpha. Presse
Med 1994;23:1659
-63
- Fattovich G, Giustina G, Favarato S, Ruol A. A survey of adverse
events in 11,241 patients with chronic viral hepatitis treated with alfa
interferon. J Hepatol 1996; 24:38
-47[Medline]
- Murakami M, Kakizaki S, Takayama H, Takagi H, Mori M. Autoimmune
thyroid disease induced by interferon therapy. Nippon
Rinsho 1999;57:1779
-83[Medline]
- Okanoue T, Sakamoto S, Itoh Y, et al. Side effects of
high-dose interferon therapy for chronic hepatitis C. J
Hepatol 1996;25:283
-91[Medline]
- Marazuela M, Garcia-Buey L, Gonzalez-Fernandez B, et al.
Thyroid autoimmune disorders in patients with chronic hepatitis C before and
during interferon-alpha therapy. Clin Endocrinol (Oxf) 1996; 44:635
-42[Medline]
- Rocco A, Gargano S, Provenzano A, et al. Incidence of
autoimmune thyroiditis in interferon-alpha treated and untreated patients:
with chronic hepatitis C virus infection. Neuroendocrinol
Lett 2001;22:39
-44[Medline]
- Carella C, Amato G, Biondi B, et al. Longitudinal study of
antibodies against thyroid in patients undergoing interferon-alpha therapy for
HCV chronic hepatitis. Horm Res 1995; 44:110
-14[Medline]
- Kryczka W, Brojer E, Kowalska A, Zarebska-Michaluk D. Thyroid gland
dysfunctions during antiviral therapy of chronic hepatitis C. Med
Sci Monit 2001; 7:221
-5
- Cacoub P, Renou C, Rosenthal E, et al. Extrahepatic
manifestations associated with hepatitis C virus infection. A prospective
multicenter study of 321 patients. The GERMIVIC. Groupe d'Etude et de
Recherche en Médecine Interne et Maladies Infectieuses sur le Virus de
l'Hépatite C. Medicine (Baltimore) 2000; 79:47
-56[Medline]
- Fernandez-Soto L, Gonzalez A, Escobar-Jimenez F, et al.
Increased risk of autoimmune thyroid disease in hepatitis C vs hepatitis B
before, during, and after discontinuing interferon therapy. Arch
Intern Med 1998;158:1445
-8[Abstract/Free Full Text]
- Huang MJ, Tsai SL, Huang BY, Sheen IS, Yeh CT, Liaw YF. Prevalence
and significance of thyroid autoantibodies in patients with chronic hepatitis
C virus infection: a prospective controlled study. Clin Endocrinol
(Oxf) 1999;50:503
-9[Medline]
- Preziati D, La Rosa L, Covini G, et al. Autoimmunity and
thyroid function in patients with chronic active hepatitis treated with
recombinant interferon alpha-2a. Eur J Endocrinol 1995; 132:587
-93[Abstract/Free Full Text]
- Custro N, Montalto G, Scafidi V, et al. Prospective study
on thyroid autoimmunity and dysfunction related to chronic hepatitis C and
interferon therapy. J Endocrinol Invest 1997; 20:374
-80[Medline]
- Hsieh MC, Yu ML, Chuang WL, et al. Virologic factors
related to interferon-alpha-induced thyroid dysfunction in patients with
chronic hepatitis C. Eur J Endocrinol 2000; 142:431
-7[Abstract]
- Watanabe U, Hashimoto E, Hisamitsu T, Obata H, Hayashi N. The risk
factors for development of thyroid disease during interferon-alpha therapy for
chronic hepatitis C. Am J Gastroenterol 1994; 89:399
-403[Medline]
- Murakami T, Masumoto T, Michitaka K, et al. Prediction of
interferon-alpha-induced thyroid dysfunction in patients with chronic
hepatitis C. J Gastroenterol Hepatol 1995; 10:528
-31[Medline]
- Dalgard O, Bjoro K, Hellum K, et al. Thyroid dysfunction
during treatment of chronic hepatitis C with interferon alpha: no association
with either interferon dosage or efficacy of therapy. J Intern
Med 2002;251:400
-6[Medline]
- Amenomori M, Mori T, Fukuda Y, et al. Incidence and
characteristics of thyroid dysfunction following interferon therapy in
patients with chronic hepatitis C. Intern Med 1998; 37:246
-52[Medline]
- Mazziotti G, Sorvillo F, Stornaiuolo G, et al. Temporal
relationship between the appearance of thyroid autoantibodies and development
of destructive thyroiditis in patients undergoing treatment with two different
type-1 interferons for HCV-related chronic hepatitis: a prospective study.
J Endocrinol Invest 2002; 25:624
-30[Medline]
- Roti E, Minelli R, Giuberti T, et al. Multiple changes in
thyroid function in patients with chronic active HCV hepatitis treated with
recombinant interferon-alpha. Am J Med 1996; 101:482
-7[Medline]
- Carella C, Mazziotti G, Morisco F, et al. Long-term
outcome of interferon-alpha-induced thyroid autoimmunity and prognostic
influence of thyroid autoantibody pattern at the end of treatment.
J Clin Endocrinol Metab 2001; 86:1925
-9[Abstract/Free Full Text]
- Carella C, Mazziotti G, Morisco F, et al. The addition of
ribavirin to interferon-alpha therapy in patients with hepatitis C
virus-related chronic hepatitis does not modify the thyroid autoantibody
pattern but increases the risk of developing hypothyroidism. Eur J
Endocrinol 2002;146:743
-9[Abstract]
- Papo T, Oksenhendler E, Izembart M, Leger A, Clauvel JP.
Antithyroid hormone antibodies induced by interferon-alpha. J Clin
Endocrinol Metab 1992; 75:1484
-6[Abstract]
- Fentiman IS, Balkwill FR, Thomas BS, Russell MJ, Todd I, Bottazzo
GF. An autoimmune aetiology for hypothyroidism following interferon therapy
for breast cancer. Eur J Cancer Clin Oncol 1988; 24:1299
-303[Medline]
- Ronnblom LE, Alm GV, Oberg KE. Autoimmunity after alpha-interferon
therapy for malignant carcinoid tumors. Ann Intern Med 1991; 115:178
-83
- Silvestri F, Virgolini L, Mazzolini A, et al. Development
of autoimmune thyroid diseases during long-term treatment of hematological
malignancies with alpha-interferons. Haematologica 1994; 79:367
-70[Abstract/Free Full Text]
- Vallisa D, Cavanna L, Berte R, Merli F, Ghisoni F, Buscarini L.
Autoimmune thyroid dysfunctions in hematologic malignancies treated with
alpha-interferon. Acta Haematol 1995; 93:31
-5[Medline]
- Corssmit EP, Heyligenberg R, Endert E, Sauerwein HP, Romijn JA.
Acute effects of interferon-alpha administration on thyroid hormone metabolism
in healthy men. J Clin Endocrinol Metab 1995; 80:3140
-4[Abstract]
- Guerin V, Todd I, Hammond LJ, Bottazzo GF, Pujol-Borrell R,
Feldmann M. Suppression of HLA class II expression on thyrocytes by
interferon-alpha 1. Clin Exp Immunol 1990; 79:341
-5[Medline]
- Bottazzo GF, Pujol-Borrell R, Hanafusa T, Feldmann M. Role of
aberrant HLA-DR expression and antigen presentation in induction of endocrine
autoimmunity. Lancet 1983; ii:1115
-19
- Yue SJ, Enomoto T, Matsumoto Y, Kawai K, Volpe R. Thyrocyte class I
and class II upregulation is a secondary phenomenon and does not contribute to
the pathogenesis of autoimmune thyroid disease.
Thyroid 1998; 8:755
-63[Medline]
- Kawai K, Enomoto T, Fornasier V, Resetkova E, Volpe R. Differential
effects of human interferon alpha and interferon gamma on xenografted human
thyroid tissue in severe combined immunodeficient mice and nude mice.
Proc Assoc Am Physicians 1997; 109:126
-35[Medline]
- Watson PF, Pickerill AP, Davies R, Weetman AP. Analysis of cytokine
gene expression in Graves' disease and multinodular goiter. J Clin
Endocrinol Metab 1994; 79:355
-60[Abstract]
- Grubeck-Loebenstein B, Buchan G, Chantry D, et al.
Analysis of intrathyroidal cytokine production in thyroid autoimmune disease:
thyroid follicular cells produce interleukin-1 alpha and interleukin-6.
Clin Exp Immunol 1989; 77:324
-30[Medline]
- Durelli L, Ferrero B, Oggero A, et al. Liver and thyroid
function and autoimmunity during interferon-beta 1b treatment for MS.
Neurology 2001; 57:1363
-70[Abstract/Free Full Text]
- Fabris P, Betterle C, Floreani A, et al. Development of
type 1 diabetes mellitus during interferon alpha therapy for chronic HCV
hepatitis. Lancet 1992; 340:548[Medline]
- Fabris P, Betterle C, Greggio NA, et al. Insulin-dependent
diabetes mellitus during alpha-interferon therapy for chronic viral hepatitis.
J Hepatol 1998; 28:514
-17[Medline]
- Betterle C, Fabris P, Zanchetta R, et al. Autoimmunity
against pancreatic islets and other tissues before and after interferon-alpha
therapy in patients with hepatitis C virus chronic infection.
Diabetes Care 2000; 23:1177
-81[Abstract/Free Full Text]
- Wesche B, Jaeckel E, Trautwein C, et al. Induction of
autoantibodies to the adrenal cortex and pancreatic islet cells by interferon
alpha therapy for chronic hepatitis C. Gut 2001; 48:378
-83[Abstract/Free Full Text]
- Oshimoto K, Shimizu H, Sato N, Mori M. A case of Addison's disease
which became worse during interferon therapy: [insulin secretion under
hyposmolarity]. Nippon Naibunpi Gakkai Zasshi 1994; 70:511
-16[Medline]
- Knost JA, Sherwin S, Abrams P, Oldham RK. Increased steroid
dependence after recombinant leucocyte interferon therapy.
Lancet 1981; ii:1287
-8
- Gisslinger H, Svoboda T, Clodi M, et al. Interferon-alpha
stimulates the hypothalamic-pituitary-adrenal axis in vivo and in
vitro. Neuroendocrinology 1993; 57:489
-95[Medline]
- Sakane N, Yoshida T, Yoshioka K, Umekawa T, Kondo M, Shimatsu A.
Reversible hypopituitarism after interferon alfa therapy.
Lancet 1995; 345:1305
- Wilson LE, Widman D, Dikman SH, Gorevic PD. Autoimmune disease
complicating antiviral therapy for hepatitis C virus infection.
Semin Arthritis Rheum 2002; 32:163
-73[Medline]
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
TOP
INTRODUCTION
THYROID GLAND
