Full text of DOI:10.1089/105072501750362736

THYROID
Volume 11, Number 7, 2001
Mary Ann Liebert, Inc.
Transient Stimulatory Effects on Pituitary-Thyroid Axis in
Patients Treated with Interleukin-2
1
2
2
3
2
1
Oliver Witzke, Toni Winterhagen, Bernhard Saller, Ulla Roggenbuck, Iris Lehr, Thomas Philipp,
2
2
Klaus Mann, Walter Reinhardt
It has been shown that various cytokine therapies may influence thyroid hormone parameters that may lead
to serious side effects including nonthyroidal illness. Interleukin-2 is effective in increasing CD4-T cell num-
bers in human immunodeficiency virus (HIV)-infected patients and it is used in the treatment of various ma-
lignant tumours. However, the association of interleukin-2 (IL-2) therapy and thyroid function is not clearly
established as serial systematic measurements of thyroid parameters have not been performed with interleukin-
2
as the sole therapeutic agent. Therefore, it was the aim of this study to examine prospectively the impact of
a 5-day interleukin-2 therapy on thyroid parameters in asymptomatic HIV-infected patients. Twenty male eu-
thyroid patients (mean age, 42.6 6 3.2 years; body weight, 73.4 6 3.0 kg) received 9,000,000 IU/d interleukin-
2
. Thyroid function was evaluated by measurements of serum thyrotropin (TSH), triiodothyronine (T ), thy-
3
roxine (T ), free thyroxine (FT ), reverse T (rT ), thyroglobulin (Tg), thyroxine-binding globulin (TBG), and
4
4
3
3
anti-thyroid-peroxidase (TPO)-antibodies from day 1–4 and on days 7, 14, 20, 40, 60, 80, and 100. All results
are given as mean 6 SD. On day 4, we observed a significant increase that was still within normal range of T4
and T (p , 0.05). TSH increased from 1.33 6 0.57 to 4.53 6 1.39 mU/I (p 5 0.0001) and FT from 18.1 6 4.2 to
3
4
4
8.9 6 10.9 pmol/L (p 5 0.0001) on day 4 with a gradual decrease thereafter. Normalization to baseline levels
for TSH (1.45 6 0.75 mU/L) and FT (18.1 6 3.0 pmol/L) was achieved only on day 14. The increase of FT was
4
4
more pronounced (well in the hyperthyroid range) than the increase in total T in the presence of normal TBG
4
and albumin concentrations whereas TBG was not affected. We did not observe changes in anti-TPO-antibody
levels up to day 100. Our data clearly demonstrate that the administration of interleukin-2 has a stimulatory
effect on the pituitary-thyroid axis. The increase of TSH suggests a central stimulation directed by the action
of IL-2 as the major mechanism.
Introduction
pothyroidism and hyperthyroidism have been shown to oc-
cur after cytokine therapy, sometimes necessitating termi-
ECENTLY, SEVERAL STUDIES DEMONSTRATED a beneficial im-
nation of the treatment (10–12). However, most studies
munological effect of interleukin-2 (IL-2) therapy in hu- found features of nonthyroidal illness after the administra-
R
man immunodeficiency virus (HIV) infection with a striking tion of cytokines, such as IL-1 or 6 (10,13,14). In contrast to
increase in the number of T lymphocytes (1–4). Furthermore, IL-2, these cytokines have divergent actions on many cells
it is used in the treatment of malignant tumors, such as met- of the immune system, particularly activating nonspecific in-
astatic renal cell carcinoma and melanoma (5–7). IL-2 is the flammatory responses.
principal cytokine that induces T-cell activation and differ-
The association of IL-2 therapy and thyroid function, how-
entiation whereas most other cytokines have divergent func- ever, has not been clearly established because serial system-
tions on the immune system and are redundant in their ac- atic measurements of thyroid parameters have not been per-
tion. IL-2 is unique in its action on T cells and can only formed using IL-2 as the sole therapeutic agent (15–20).
marginally be substituted by other cytokines (8,9).
Asymptomatic patients with HIV disease display normal thy-
It has been reported that therapy with IL-2 in combination roid hormone parameters with only modest increases in TBG
with other cytokines is associated with several serious side concentrations that are well within the normal range (21).
effects that may lead to the termination of therapy. Hy-
Therefore, it was the good of this study to examine
1Department of Medicine, Division of Nephrology and Hypertension, 2Department of Medicine, Division of Endocrinology, 3Depart-
ment of Medical Informatics, Biometry and Epidemiology, University Clinic Essen, Essen, Germany.
6
65

666
WITZKE ET AL.
TABLE 1.
FT4
TSH
mU/L)
(0.3–4.0)
T3
(nmol/L)
(0.9–3.1)
T4
(nmol/L)
(50–158)
rT3
(ng/mL)
(0.09–0.35)
Tg
(ng/mL)
(10–40)
TBG
(mg/L)
(10–35)
(
(pmol/L)
(10–25)
Day
0
4
7
1.33 6 0.57
2.09 6 0.43
85 6 20
18.1 6 4.2
0.21 6 0.08
36.0 6 26.1
21.6 6 4.1
4.53 6 1.39
p 5 0.0001
3.39 6 1.73
p 5 0.0001
1.45 6 0.75
2.54 6 0.46
p 5 0.0338
2.34 6 0.43
p 5 0.1981
2.09 6 0.34
120 6 23
p 5 0.016
101 6 23
p 5 0.0929
89 6 24
48.9 6 10.9
p 5 0.001
31.0 6 10.2
p 5 0.0001
18.1 6 3.0
0.26 6 0.08
p 5 0.1017
0.25 6 0.07
p 5 0.1927
0.24 6 0.07
49.0 6 30.4
p 5 0.3347
54.7 6 33.1
p 5 0.1399
50.4 6 34.3
21.2 6 3.9
p 5 0.7988
20.9 6 4.1
p 5 0.6595
20.8 6 3.5
1
2
4
0
1.42 6 0.68
p 5 0.727
2.15 6 0.42
p 5 0.7461
86 6 20
p 5 0.8309
19.1 6 5.0
p 5 0.5062
0.22 6 0.08
p 5 0.6228
45.2 6 24.4
p 5 0.3740
21.7 6 3.8
p 5 0.9570
TSH, thyrotropin; T3, triiodothyronine; T4, thyroxine; FT4, free thyroxine; rT3, reverse triiodothyronine; Tg, thyroglobulin; TBG,
prospectively the impact of a 5-day regimen of IL-2 therapy roid as assessed by normal thyrotropin (TSH), triiodothyro-
on thyroid parameters in asymptomatic HIV-infected pa- nine (T3), free thyroxine (FT4), and negative thyroid peroxi-
tients.
dase (TPO) and TSH-receptor antibodies, and none of the pa-
tients received thyroid hormones. Patients received 9 Mio.
IU/day IL-2 (Aldesleukin, Proleukin, Chiron, Ratingen, Ger-
many) either intravenously or subcutaneously. We had pre-
Patients and Methods
Patients who were 18 years and older, with HIV-infection viously shown that both protocols were similar regarding
were treated with IL-2 as previously reported (22). The 20 their immunological consequences as far as numbers of CD4
male patients (mean age, 42.6 6 3.2 years; body weight, and CD8 positive lymphocytes and HIV viral load were con-
7
8
3.4 6 3.0 kg; time from first diagnosis of HIV infection: 35 6 cerned (22). Treatment was performed for up to 5 days or
months) provided written informed consent. Patients had until adverse events or severe constitutional symptoms
to be in a stable clinical situation without any signs of acute (fever higher than 39.5°C, malaise, headache) precluded fur-
or chronic opportunistic infections. All patients were euthy- ther therapy. Treatment with acetaminophen, novaminsul-
FIG. 1. Triiodothyronine (T3) serum levels in the course of the interleukin-2 (IL-2) treatment protocol. There is a signifi-
cant increase of T3 levels after IL-2 treatment with a peak level on day 4. All values are given as mean 6 SD.

THYROID DYSFUNCTION AND INTERLEUKIN-2
667
fone, and antiemetic agents was permitted to treat such con- results for different thyroid hormone parameters during the
stitutional symptoms. A total of 3 patients received meto- course of time. The study was not sponsored by a company
clopramide in an oral dose of 1–2 3 10 mg on day 2 (1 pa- and was approved by the local ethical committee.
tient), on day 3 (3 patients), and on day 4 (1 patient).
Furthermore all patients were treated with a combination
of HIV antiviral drugs (usually two reverse-transcriptase in-
Results
hibitors and one protease-inhibitor). The antiviral treatment
IL-2 therapy was maintained for a mean period of 4.5 6
was started at least 6 weeks prior to the start of the study 0.1 days. Only 7 patients completed the full cycle of 5 days
and was maintained throughout the whole period of the of treatment but all patients received at least 4 days of treat-
study.
ment. Therapy was stopped in these remaining 13 patients
Immunological parameters (hematocrit, differential blood because of side effects such as fever, hypotension, myalgias,
count, number of CD41 and CD8 lymphocytes, HIV-viral exanthema, nausea, fatigue, and malaise.
1
load) were measured in regular intervals. Thyroid function
was evaluated by measurements of serum TSH (normal range, creases in the number of CD41 lymphocytes (baseline: 298 6
.3–4.0 mU/L), T3 (normal ranges, 0.9–3.1 nmol/L), T4 (nor- 62 cells per microliter to a maximum on day 7: 712 6 171
IL-2 administration was associated with significant in-
0
mal range, 50–158nmol/L), FT4 (normal range, 10–25 pmol/L), cells per microliter p , 0.001). This increment in the number
rT3 (normal range, 0.09–0.35 ng/mL), Tg (normal range, 10–40 of CD41 lymphocytes persisted for more than 100 days (day
ng/mL), TBG (10–35 mg/L) and anti-TPO-antibodies from day 100: 410 6 46 cells per microliter) (22). Hematocrit decreased
1
–4 and on days 7, 14, 20, 40, 60, 80, and 100. All samples were more than 3 g/dL in 7 of 20 patients.
taken in the morning between 8–9 A.M. In order to avoid in-
On day 4, we observed a significant increase within the
terassay variability all samples for one patient were measured normal range of T and T (Table 1, Figs. 1 and 2). rT was
4
3
3
in one assay. Total T3, total T4, FT4, and TSH were measured within the normal limits at the beginning of the study with
by immunoluminescence-assay (ACS Ciba Corning), anti-TPO no significant increase during the further observation period.
antibodies by enzyme-immunoassay (Anti-TPO, Fa, Biermann, TSH increased from 1.33 6 0.57 to 4.53 6 1.39 mU/L (p 5
Bad Nauheim, Germany), reverse T3 by radioimmunoassay 0.0001) and FT from 18.1 6 4.2 to 48.9 6 10.9 pmol/L (p 5
4
(
Biochem. Immunosystems Cie, Freiburg, Germany). TBG was 0.0001) on day 4 with a gradual decrease thereafter (Figs. 3
measured by radioimmunoassay (Brahms, Germany, Berlin), and 4). Normalization to baseline levels for TSH (1.45 6 0.75
and Tg by luminescence-assay (Brahms).
mU/L) and FT (18.1 6 3.0 pmol/L) was achieved only on
4
All results are given as mean 6 SD. Statistical analysis was day 14. All patients presented a uniform pattern of their thy-
performed using the SAS program. General linear models roid hormone parameters. Tg levels were in the high-normal
procedure for repeated measures was performed to compare range on day 0. The small increase of Tg from day 0 to day
FIG. 2. Thyroxine (T4) serum levels in the course of the interleukin-2 (IL-2) treatment protocol. There is a significant in-
crease of T4 levels after IL-2 treatment with a peak level on day 4. All values are given as mean 6 SD.

668
WITZKE ET AL.
FIG. 3. Thyrotropin (TSH) serum levels in the course of the interleukin-2 (IL-2) treatment protocol. There is a significant
increase of TSH levels after IL-2 treatment with a peak level on day 4. All values are given as mean 6 SD.
7
was not statistically significant (p 5 0.1399). TBG was not range with a gradual decrease after IL-2 treatment was
affected by IL-2 administration. We did not observe changes stopped.
in TPO-antibody levels up to day 100.
These data are in contrast to findings in other studies eval-
Also no further changes were seen beyond day 20 in any uating thyroid function after cytokine administration.
of the parameters measured (data not shown). Results were
So far studies were carried out to evaluate the long-term
not different in the three patients receiving metoclopramide effects of continuous IL-2 treatment either alone or in com-
(
data not shown).
bination with interferon-a (IFN-a) or tumor necrosis factor-
a (TNF-a). Krouse et al. (16) reported hypothyroidism in 35%
and hyperthyroidism in 7% of patients treated with IL-2 alone
for metastatic renal cell carcinoma or melanoma. However,
the IL-2 preparations available at the time of this study were
Discussion
These data clearly demonstrate that the administration of clearly different from the recombinant IL-2 used for our
IL-2 has a stimulatory effect on the pituitary-thyroid axis study. Thus, the dosage/effect ratio may be different in the
within days. We found a significant increase of TSH to lev- study by Krouse et al. (16). This study did not have a defined
els slightly above the normal range and the peripheral thy- time frame for the testing of the thyroidal hormone levels and
roid hormone parameters T4 and T3 to the upper normal the patient population was more heterogenous (16). Further
FIG. 4. Free thyroxine (FT4) serum levels in the course of the interleukin-2 (IL-2) treatment protocol. There is a significant
increase of FT4 concentrations following IL-2 treatment with a peak on day 4. All values are given as mean 6 SD.

THYROID DYSFUNCTION AND INTERLEUKIN-2
669
support for this comes from the fact that our patients showed tween IL-6 and T3 concentrations was found in this study.
a very uniform response in their thyroidal response whereas Similar findings were observed in a different study using
this was not the case in the study by Krouse et al. (16).
long-term IL-6 therapy (13). In an animal model IL-1, a cy-
Vassilopoulou-Sellin et al. (20) observed hyperthyroidism tokine also known for its pyrogenic properties, exerts sup-
within the first 4 weeks of IL-2 administration in combina- pressive effects on T3, T4, and TSH concentrations (11). Thus,
tion with either IFN-a or TNF-a. The technetium uptake by it is very unlikely that the thyroidal effects observed in our
the thyroid gland was negative during the hyperthyroid pe- study were mediated by the secondary induction of other
riod and during a period of hypothyroidism in the follow- cytokines, such as IL-1 and IL-6.
ing weeks suggesting silent thyroiditis in the absence of de-
In conclusion, we were able to demonstrate that IL-2 has
tectable anti-thyroid antibodies (20). Monig et al. (17) a stimulatory effect on the pituitary-thyroid axis within a few
reported similar results in patients receiving a combined IL- days. Our data suggest a direct stimulatory effect of IL-2 on
2
and IFN-a therapy for metastatic melanoma. Here the au- pituitary TSH release and an additional effect on the bind-
thors observed frank hyperthyroidism in 3 of 17 patients ing-affinity of T4 to its binding-proteins.
with also a reduction in TSH levels in the remaining 14 pa-
tients. Again, thyroid hormone antibodies were unaffected
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2
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