98 Journal of The Association of Physicians of India ■ Vol.
65 ■ November 2017
Thyrotoxic Channelopathies
Pankaj Singhai1, Shruti Krishnan2, Vikram Uttam Patil3
Abstract
Thyrotoxic periodic paralysis (TPP), a disorder most commonly seen in Asian men,
is characterized by abrupt onset of hypokalemia and paralysis. The condition
primarily affects the lower extremities and is secondary to thyrotoxicosis. Early
recognition of TPP is vital to initiating appropriate treatment and to avoiding the
risk of rebound hyperkalemia that may occur if high-dose potassium replacement
is given.
Here we present a case of 31 year old male with thyrotoxic periodic paralysis with
diagnostic and therapeutic approach.
Introduction
T hyrotoxic periodic paralysis
(TPP) is most common in Asian
populations, with an incidence of
approximately 2% in patients with
thyrotoxicosis of any cause. TPP is
characterized by acute onset of severe
hypokalemia and profound proximal
muscle weakness in patients with
thyrotoxicosis.2 TPP is commonly
misdiagnosed in western countries
because of its similarities to familial
periodic paralysis. Familial periodic
paralysis is an autosomal dominant
disorder caused by a defect in the gene
coding for L-type calcium channel
1-subunit (CACNA1S) on chromosome
1q31–32. The neuromuscular
presentations of both are identical, and
to enhance diagnosis of TPP, physicians
need to look for subtle features of
hyperthyroidism in the presence of
hypokalemic periodic paralysis. Early
diagnosis not only aids in definitive
management with nonselective
beta-blockers and correction of
hyperthyroidism, but also prevents the
risk of rebound hyperkalemia due to
excessive potassium supplementation.
Case Report
A 31 year old South Indian man
with a history of recurrent muscle
weakness and hypokalemia presented
in our Emergency department with
generalized muscle weakness, more
pronounced in his lower extremities.
The patient’s symptoms started in the
early morning, and he was unable to
walk to the bathroom. He had had
similar episodes before and took
potassium supplements sporadically.
His initial episode of hypokalemia and
paralysis had occurred 6 years earlier.
He denied use of diuretics, laxatives,
alcohol, or recreational drugs. He
reported intermittent palpitations and
diarrhea and had no family history of
periodic paralysis.
On physical examination, he had
a mildly enlarged thyroid with firm
consistency, irregularly irregular
heart rate (Figure 1) and decreased
muscle strength and tendon reflexes
in both lower extremities. He had no
exophthalmos or sensory or cranial
nerve deficits.
In the Emergency department,
his initial potassium level was 2.4
mEq/L with normal acid- base status.
His phosphorous level was 2.6mg/dL
Fig. 1: ECG at the time of presentation in casualty
1
HOD & Consultant Internal Medicine, 2Registrar Internal Medicine, 3Resident Internal Medicine, Manipal Hospitals, Bangalore,
Karnataka
Received: 06.03.2016; Revised: 24.09.2016; Accepted: 30.09.2016
(reference range 2.7-4.5 mg/dL) and
serum magnesium level was 1.9 mg/
dL(reference range-1.7-2.6 mg/dL) on
admission. His CPK enzyme levels were
85 U/L (reference range 51 – 294 U/L)
. Urine potassium per 24 hours was 2.3
mmol/day (reference range 2.5- 125
mmol/day). Electrocardiogram showed
atrial fibrillation with a ventricular rate
of 130 beats per minute. Initial diagnosis
of hypokalemic periodic paralysis was
made. Patient was commenced on
intravenous potassium 10mEq/hr. Oral
potassium supplementation was also
given. His symptoms improved the
next day with the complete recovery of
muscle power in the lower extremities.
On the following day, thyroid
function test showed serum TSH of
0.005 µIU/ml (reference range 0.50-6.8
µIU/ml) and a free T 4 level of 3.34 ng/
dl (reference range 0.89-1.76 ng/dl).
Patient was further evaluated for cause
of thyrotoxicosis and was found to
have high titres of TRab (TSH Receptor
Anti-body). Tc 99m scan of the thyroid
showed homogenous uptake in both
the lobes, suggestive of Graves Disease
(Figures 2 and 3). He was commenced
on Carbimazole 10 mg twice a day
and Propranolol 40mg twice daily.
Patient’s serial serum potassium levels
continued to remain normal without

Fig. 2: Thyroid nuclear scan
oral potassium supplements during his
stay in hospital and he was sent home
with the diagnosis of TPP secondary to
Graves Disease. Patient is on regular
follow up on OPD basis and there is
no further episode of hypokalemia and
or quadripareseis. Last Thyroid profile
report is as follows – TSH of 1.067 µIU/
ml and fT4 – 1.08 ng/dl.
Disscussion
Even though it is commonly seen
in Graves’ disease, TPP is not related
to the etiology, severity, and duration
of thyrotoxicosis. 2 Family history of
periodic paralysis is usually absent.
The pathogenesis of thyrotoxic
periodic paralysis has long been thought
related to increased Na + -K + ATPase
activity stimulated by thyroid hormone
and/or hyperadrenergic activity and
hyperinsulinemia. This mechanism
alone, however, associated paradoxical
depolarization of the resting membrane
potential. Recent findings that loss
of function mutations of the skeletal
muscle-specific inwarding rectifying
K + (Kir ) channel, Kir2.6, associate with
thyrotoxic periodic paralysis provide
new insights into how reduced outward
K + efflux in skeletal muscle, from either
Journal of The Association of Physicians of India ■ Vol. 65 ■ November 2017
Fig. 3: Thyroid nuclear scan
channel mutations or inhibition by
hormones (adrenaline or insulin), can
lead to a vicious cycle of hypokalemia
and paradoxical depolarization. 3
Thyroid hormones can increase Na/
K-ATPase activity in skeletal muscle,
liver, and kidney to induce an influx
of potassium into the intracellular
s p a c e . 4 A m o n g t h e va r i o u s N a / K -
ATPase subunits, the α1-, α2-, β1-,
β2-, and β4-subunits are expressed in
skeletal muscles. 5 Thyroid hormone-
responsive elements (TREs) are present
in the upstream region of these five
genes, and thyroid hormones has
been shown to increase Na/K-ATPase
activity via both transcriptional and
posttranscriptional mechanisms. 6 The
enhanced β-adrenergic response in
thyrotoxicosis further increases Na/K-
ATPase activity and may explain why
nonselective β-adrenergic blockers can
abort or prevent paralytic attacks.
The events that lead to paralysis with
hypokalemia and hypophosphatemia
in patients with TPP are complex.
They include hyperthyroidism, a
genetic and racial predisposition, and
an exaggerated insulin response, a
hyperadrenergic state, and probably
other mechanisms leading to the
99
intracellular shift of K + . Episodes of
paralysis occurred during the night in
more than 80% on patients with TPP. It
has been shown that plasma glucose and
insulin responses to meals are markedly
h i g h er i n th e even i n g t h a n i n t h e
control subjects. Such a phenomenon
suggests the possible mechanism
for the nocturnal preponderance of
TPP; another explanation could be
the circadian rhythmicity of many
hormones reaching their peak levels
during sleep.
In conclusion, the diagnosis of TPP
at the initial encounter is often delayed
and confused with other more familiar
causes of lower extremity paralysis,
partially because of the subtleness of
the thyrotoxicosis and partially because
of unfamiliarity with this disorder by
physicians. When a young male of
Asian descent is initially seen with
severe lower extremity weakness or
paralysis, TPP should be considered as
the most likely diagnosis until proven
otherwise. This is important because
TPP is a curable disorder that resolves
when a euthyroid state is achieved.
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