Cycling from hypothyroidism to hyperthyroidism during early treatment of differentiated thyroid carcinoma

Differentiated thyroid cancer
Thyroid carcinoma is the most common endocrine malignancy with more than 550
new cases in the Netherlands and an estimated 37.000 new cases in the European
Union each year.(1) Differentiated thyroid cancer (DTC) encompasses papillary
and follicular thyroid cancer. Those are the most frequent types and have a
favorable prognosis: 10-year overall survival rates of 80% to 95%.(2) Patients
with DTC are treated with a total thyroidectomy, followed by iodine-131
(hereafter, radioiodine) ablation therapy to destroy residual thyroid cancer.
To prevent recurrences, subsequent thyroid hormone suppression therapy (THST)
is administered.(3) With THST, high doses of thyroid hormone are prescribed,
with the aim to lower or suppress the thyroid stimulating hormone (TSH) level,
as TSH is considered to be a growth factor for thyroid (cancer) cells.

In patients with DTC, hypothyroidism arises after total thyroidectomy. This is
useful for radioiodine ablation therapy, as the thyroid cells take up the
radioiodine much better in a hypothyroid state. After this therapy patients
need THST, which creates subclinical hyperthyroidism. After half a year of
THST, patients may need a second radioiodine therapy, preceded by thyroid
hormone withdrawal. Patients can therefore cycle several times from hypo- to
hyperthyroidism during the initial treatment phase.

Differentiated thyroid cancer and cardiovascular risk
Various adverse (so-called *off-target*) effects of long-term exposure to THST
have been described in patients with DTC, e.g. atrial fibrillation, impaired
systolic and diastolic cardiac function, and adverse metabolic and
prothrombotic effects.(4-8) Our own data showed that patients with DTC have an
increased risk of cardiovascular (HR 3.35, 95% CI 1.66-6.74) and all-cause
mortality (HR 4.4, 95% CI 3.15-6.14).(9)

Not only THST is associated with cardiovascular mortality; hypothyroidism and
hyperthyroidism themselves are also associated with cardiac changes. Thyroid
hormones affect the heart directly as well as indirectly, by mediating the
autonomic nervous system, the renin-angiotensin-aldosterone system, vascular
compliance, vasoreactivity, and renal function.(10,11)

Hyperthyroidism
Tachycardia is the most common finding in patients with hyperthyroidism. Atrial
arrhythmias, including atrial fibrillation occur, and are most common in older
patients.(12) In patients with hyperthyroidism, cardiac output may be increased
by 50% to 300% over that of normal subjects due to the combined effect of
increased resting heart rate, contractility, ejection fraction, and blood
volume with decreased systemic vascular resistance (SVR).(13) Advanced heart
failure may rarely occur in patients with hyperthyroidism, usually in the
setting of prolonged and severe hyperthyroidism or after the onset of atrial
fibrillation. However, high-output heart failure is more common in
hyperthyroidism. Because cardiac output at rest is increased, the increased
output that normally accompanies exercise is blunted.(12,14)

Hypothyroidism
The cardiovascular manifestations of hypothyroidism are more subtle. Those
include bradycardia, diastolic hypertension, a narrow pulse pressure, and a
relatively quiet precordium. Hemodynamic changes of hypothyroidism are
diametrically opposite to those of hyperthyroidism.(10) Additionally, in
hypothyroidism there is increased risk of atherosclerosis often associated with
hypercholesterolemia and hypertension. (11)

In patients treated for DTC, both hypothyroidism and hyperthyroidism are
inevitable during common treatment of DTC. Identification of markers of early
cardiovascular and metabolic abnormalities may help to identify patients at
highest risk. In a broader perspective, patients treated for DTC may be
regarded as a controlled model of both hypothyroidism and hyperthyroidism.
Understanding the adverse cardiovascular and metabolic effects of these
conditions may help to treat patients without DTC that suffer from
(subclinical) hypo- or hyperthyroidism.

MRI for cardiac imaging
Until recently, echocardiography was considered standard for the evaluation of
cardiac function. Latest ESC guidelines recommend cardiac MRI (CMR) above
echocardiography to measure LV and RV dysfunction. CMR is a non-invasive
technique that provides most of the anatomical and functional information. CMR
is considered the reference standard for measurement of ventricular volumes and
function. (15) CMR has never been used to study the effects of standard DTC
therapy on cardiac function.

Differentiated thyroid cancer and cholesterol balance
In hypothyroidism there is increased risk of atherosclerotic cardiovascular
disease, often associated with hypercholesterolemia and hypertension.(11,16)
Using the set-up of short-term profound hypothyroidism following thyroidectomy
for DTC, we previously observed profound robust increases in total cholesterol,
LDL cholesterol and triglycerides, and decreases in HDL cholesterol(17)
However, the pathophysiological mechanisms that cause these changes remain
unknown. The THETA-study is a unique set-up to compare the effects of thyroid
hormones on the cholesterol balance. Knowledge of the effects of hypothyroidism
on cholesterol balance could contribute to the discussion about the use of
rhTSH in the treatment of DTC, a treatment which prevents hypothyroidism.

Primary Objective: To compare the effects of hypothyroidism and hyperthyroidism
on cardiac left ventricular function, as assessed by CMR, in subjects with
differentiated thyroid cancer during their early treatment.

Secondary Objective(s): To compare the effects of hypothyroidism and
hyperthyroidism on:
• Cardiorespiratory fitness
• Vascular function
• Cardiovascular risk profile
• Cholesterol function and balance
• Mood and cognitive function
• Quality of Life

Design: Single center, prospective cohort study

Duration and setting:
Patients will be recruited at the University Medical Center Groningen (UMCG)
between May 2016 and November 2017. The study consists of ± 20 weeks between
radioiodine ablation therapy and Thyreoglobulin (Tg) testing.

Sub-study Cholesterol function and balance:
To assess cholesterol function and balance in hypothyroidism and
hyperthyroidism, in patients with differentiated thyroid carcinoma during their
early treatment, an expansion of the original study is created. Subjects of the
THETA-study can choose to sign an additional informed consent and participate
in the sub-study THETA Cholesterol. In addition, subjects that do not
participate in the THETA-study can participate in the sub-study THETA
Cholesterol.

Study visits:
The study will have three main visits, the first visit will be combined with
the hospitalisation for regular treatment. The second and third visit will be
combined with a normal follow-up visit to the outpatient clinic if possible.
The screening visit takes place before radioiodine ablation therapy. Subjects
will subsequently be invited at week 0, 10, and 20. Study visits will be
planned as much as possible within those weeks. However, exceptions can be made
to reschedule the study visit to two weeks prior or after the preferred week.

For the subjects participating in the sub-study THETA Cholesterol, an
additional visit to a dietician will be scheduled approximately one week prior
to the first main study visit. Where possible, this visit to the dietician will
be combined with a pre-ablation visit (regular care). During the visit to the
dietician, instructions for food diaries and advises about a diet will be
given. Prior to the other two study visits, a consultation with the dietician
will take place by telephone.

Benefits: patients who participate in this study receive cardiovascular
evaluation. This will lead to early detection of cardiovascular risk factors
and detection of (pre)clinical damage. For example, the presence of atrial
fibrillation or micro albuminuria. Any abnormality will reported to the general
practitioner of the regarding patient. Patients with abnormalities will be
treated according to national guidelines.
Risks: Patient who participate will have prolonged visits at the UMCG, as we
try to combine each study visit with a visit for regular care. Participation is
accompanied with only minor risks. All measurements are non-invasive, except
vena puncture and gadolinium-contrast injection for the cardiac MRI.
Group relatedness: Cardiovascular and all cause mortality risks are increased
in patients with DTC. Cycling from hypothyroidism to hyperthyroidism may
contribute to these risks. Identification of markers of early abnormalities may
help to identify patients at highest risk. Results of the present study may
contribute to personalize optimal treatment for DTC patients, including early
identification and treatment of off-target effects.