The Netherlands Journal of Medicine

REVIEW

Thyrotoxic periodic paralysis: an unusual

presentation of hyperthyroidism
M. Salih1,2*, C.M.J. van Kinschot1,2, R.P. Peeters2, W.W. de Herder2,
E.J.J. Duschek3, J. van der Linden1, C. van Noord1
1
Department of Internal Medicine, Maasstad Hospital, Rotterdam, the Netherlands, 2Department of
Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands, 3Department of Internal
Medicine, Reinier de Graaf Hospital, Delft, the Netherlands, *corresponding author:
email: [email protected]

ABSTR ACT of 1 in 100,000.2 This is caused by mutations of voltage-

dependent calcium, sodium or potassium channels of
Thyrotoxic periodic paralysis (TPP) is a complication of the skeletal muscle membranes, with symptoms typically
hyperthyroidism among Asians, characterised by sudden beginning in the first or second decade of life. Although
onset of hypokalaemia and muscle paralysis. Several clinical features of sporadic hypokalaemic paralysis are
factors may contribute to a delay in diagnosis, including similar to HPP, de novo mutations were identified in a
the subtlety of hyperthyroidism, the transient nature minority of patients.3
of the events and the rarity of this disease in the West. In Asia, the acquired form is common although, to our
As life-threatening arrhythmias may occur during an knowledge, its exact prevalence has not been reported.
attack, awareness among physicians is necessary for early Due to its association with hyperthyroidism, this form is
recognition and treatment. Advances have been made called thyrotoxic periodic paralysis (TPP), and it usually
in understanding the pathophysiological mechanism occurs after the second decade of life. TPP has an incidence
leading to hypokalaemia, which include recently identified of 1.8% among patients with hyperthyroidism in Asia,
mutations of the inwardly rectifying potassium channel whereas rates are estimated to be around 0.1% in the West
Kir2.6. Treatment includes the supplementation of and usually include patients of Asian background. 4-6 Only
potassium, a nonselective beta-blocker, and ultimately few cases of Caucasians with TPP have been described
treatment of the underlying hyperthyroidism. Here we in the literature.7,8 In contrast to primary autoimmune
report three cases of TPP in the Netherlands, and review hyperthyroidism occurring predominantly in females,
the literature on clinical features, pathophysiological TPP mostly affects males (male-to-female ratio 26:1).9,10
hypothesis and treatment. The average age of onset is around 30 years which,
unsurprisingly, coincides with the average age of onset of
Graves’ disease.9-15
K EY WOR DS Because this condition is rare, it may be frequently
overlooked and misdiagnosed, while recognition and
TPP, hypokalaemia, periodic paralysis therapy could prevent deleterious outcomes. Mortality rates
are unknown, but TPP may explain a portion of sudden
cardiac deaths among young Asians.16 With increasing
INTRODUCTION migration it is likely to be seen more frequently in Western
countries. Here, we briefly report three cases of TPP
Periodic paralysis is an intriguing medical emergency, patients in the Netherlands, and review the literature.
with otherwise healthy young individuals presenting with
acute painless muscle weakness due to potassium shifts.
Two subtypes of hypokalaemic periodic paralysis can be HISTORY
distinguished: a hereditary and an acquired form.1 In
Western countries, autosomal dominant hypokalaemic The combination of muscle weakness and hyperthyroidism
periodic paralysis (HPP) is common, with a prevalence was first described in 1902.17 In 1931, four cases of

© Van Zuiden Communications B.V. All rights reserved.

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hyperthyroidism and attacks of muscle weakness were that encodes for a noncoding RNA and regulates KCNJ2
described in the English literature.18 Treatment of the expression, to be associated with TPP.35 With these recent
hyperthyroidism resulted in resolution of the periodic findings, it seems the inward rectifier potassium channels
paralysis, but this recurred in one case during a relapse of play a pivotal role in the predisposition of TPP.
hyperthyroidism.18 Subsequently, the decrease in serum These findings, however, do not explain why TPP patients
potassium levels was found to be proportional to the have attacks of hypokalaemia during hyperthyroidism.
severity of the paralysis. 4 Further evidence indicates that increased activity of the
Na+/K+-ATPase may be the link ( figure 1). Indeed, Na+/
K+-ATPase abundance and activity is exaggerated in
G E N E T I C S A N D PA T H O P H Y S I O L O G Y TPP as compared with healthy control subjects, but
also as compared with non-TTP patients with primary
Genetic predisposition only combined with hyperthyroidism.36 This is attributed to a direct effect
hyper­­­thyroidism is thought to induce TPP ( figures 1 and 2).19 of hyperthyroidism, but also through an increased
Observations indicating a genetic predisposition include a expression of β2-adrenergic receptors.37 In addition,
higher prevalence among Asians, and the association of insulin, adrenergic stimulation, androgens or exercise
paralysis with recurrence of hyperthyroidism. Because of further increase Na+/K+-ATPase activity.38-40 This explains
the clinical similarity between TPP and HPP, candidate why these factors may predispose to an attack in TTP
genes that cause HPP were initially evaluated. These patients.9,10,12,41 Impaired potassium efflux caused by
included genes that encode for channels needed for mutations of the inward rectifier potassium channels,
membrane potential stability or excitability, including the combined with increased Na+/K+-ATPase activity may lead
voltage-gated skeletal sodium channel Nav1.4 (SCN4A), to paradoxical depolarisation with muscle inexcitability and
calcium channel Cav1.1 (CACNA1S) and less frequently eventually paralysis ( figure 1). 42
the inward rectifier potassium channel Kir2.1 (KCNJ2).20-24
Despite clinical resemblance, no mutations of these
genes have been identified in patients with TPP.25,26 CLINICAL FEATURES
However, single-nucleotide polymorphisms (SNP) in
the CACNA1S region (encoding for Cav1.1) have been Hypokalaemic paralytic attacks only occur during
discovered. Expression of this calcium channel may alter hyperthyroidism ( figure 2). Prodromes include muscle
thyroid hormone action.26 aches, stiffness, weakness or cramps 1 hour to 3 days
Ryan and colleagues identified a mutation of KCNJ18, before paralysis. 4,12 Before presentation, most patients have
which encodes for the potassium channel Kir2.6.27 Kir2.6 experienced less severe muscle weakness that resolved
associates with other Kir2.x subunits, such as Kir2.1, spontaneously. Attacks usually begin with weakness
forming a homotetrameric complex and, thereby, alters of the proximal muscles of the lower extremities, and
inward potassium trafficking.28 Potassium fluxes are may progress to tetraplegia, with the degree of muscle
required for stabilising the resting membrane potential. weakness corresponding to serum potassium levels.15 No
Interestingly, Kir2.6 contains a thyroid responsive correlations with serum T3 or T4 levels have been found.
element that may regulate gene transcription ( figure Bowel and bladder function, facial expression, swallowing
1). Decreased inward currents of potassium predispose and respiration are usually unaffected.12,15 A precipitating
the sarcolemma to paradoxical depolarisation, which factor for an attack could be identified in 34% of patients.9
in turn may lead to muscle paralysis.27,29 Very recently Precipitating factors include high carbohydrate ingestion,
one c-terminus mutation of Kir2.6 (D252N) was shown alcohol, infection (mainly respiratory or urinary tract
to decrease potassium currents by 34%.30 However, the infections have been described), excessive exercise and
KCNJ18 mutation is only present in 25-33% of TPP patients use of β2-adrenergic bronchodilators ( figure 2).9,10,12,41
from France, United States, Brazil and Singapore, and Furthermore, an attack was inducible by glucose loading in
it was absent in Chinese and Thai subjects.27 Therefore, a minority of patients.9 Patients usually experience attacks
the majority of TPP patients have as yet unidentified in the early mornings, and during warm seasons. 4,10
disease-causing mutations. Genome-wide association
studies identified the genetic variant rs312729, which is Laboratory findings
located downstream and may affect Kir2.1 expression, as At presentation, laboratory findings include very low
a new susceptible locus for TPP in Thai patients.31 This levels of serum potassium (on average 2.0 mmol/l),
association, but also other variants such as rs312691, were without acid-base disturbances.9,10,12-15 Renal excretion
further confirmed in Chinese and Korean TPP patients.32-34 of potassium is also low, excluding renal potassium
In Chinese patients, Song and colleagues identified the wasting. Some reports also mention low serum phosphate
genetic variant rs312736, which mapped to CTD-2379E21.1 and magnesium levels, which also tend to resolve

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Figure 1. A single myocyte is depicted with channels is the first presentation of hyperthyroidism in about 80%
relevant to the membrane potential. In thyrotoxic of the cases. 46
periodic paralysis (TTP), increases in thyroxin (T4)
stimulate the sodium-potassium channel directly Electrocardiogram
and indirectly through exaggerated insulin and In TPP, both hyperthyroidism and hypokalaemia may
catecholamine responses. Also, a thyroid-responsive cause cardiac arrhythmias that will be apparent on the
element (TRE) adjacent to the KCNJ18 gene is electrocardiogram (ECG). Sinus tachycardia, and also
thought to alter gene expression of the mutated atrial fibrillation or flutter, are common findings in
Kir2.6 channel. Both increased27 and decreased30 gene hyperthyroidism. 47 During an attack, hypokalaemia
expression have been found in the hyperthyroid state.
slows repolarisation, prolongs the refractory period and
With the decrease in potassium excretion by Kir2.6,
thereby predisposes to arrhythmias. This is exacerbated
membrane potential increases resulting in a state of
as ventricular repolarisation is also lengthened in
cell in-excitability
hyperthyroidism;48 the ECG may show supraventricular
or ventricular ectopic beats, prolonged PR interval,
Hyperthyroidism
and U waves.14 Because the risk of serious ventricular
arrhythmias is high, including life-threatening ventricular
T4
tachycardia or fibrillation,16 cardiac monitoring is necessary
until hypokalaemia is corrected.

+
Na
Insulin TREATMENT
Catecholamines
Androgens
+
K To prevent major complications, such as cardiac
arrhythmias, the initial therapy of TTP should be directed
to the correction of the hypokalaemia. Some report a
TRE shortened recovery time of the paralysis by potassium
supplementation, 49 while others do not.12 Because total
Kir2.6 KCNJ18 body potassium levels are normal, aggressive treatment
+
K may result in rebound hyperkalaemia, which occurs
in approximately 40-60% of TPP.12,14 Therefore,
low-dose potassium supplementation (10-20 mmol/h) is
recommended, unless there are serious cardiovascular
complications. 49,50 Propranolol (a nonselective beta-blocker)
Nav1.4 Cav1.1 has been reported to normalise serum potassium
Na
+
Ca
+ within two hours without rebound hyperkalaemia. The
mechanism of action of this drug is the reversal of the
adrenergic stimulation of the Na+/K+-ATPase and reduction
of the conversion of T4 to T3 in the liver resulting in lower
circulating T3 levels.51,52 Propranolol may be continued until
spontaneously.12-14 A high urinary calcium-to-phosphate a euthyroid state is achieved. However, awaiting correct
ratio has been proposed to distinguish TPP patients from diagnosis, potassium supplementation should also be
those with HPP.13 initiated, with frequent monitoring of serum potassium
Furthermore, suppressed serum thyroid-stimulating levels. Meanwhile, patients should be advised to avoid
hormone (TSH) with high T4 and T3 levels are precipitating factors, such as alcohol, high carbohydrate
pathognomonic for TPP, and distinguish TPP from HPP ingestion and excessive exercise.
patients. Free T4 levels are similar to those in non-TTP Initially, thyrotoxicosis should be treated with antithyroid
patients with primary hyperthyroidism.10,12-14 Graves’ drugs. Block and replace therapy is recommended because
disease is diagnosed in the majority of TPP patients, which of better control of thyroid hormone levels compared
is also unsurprisingly the main cause of hyperthyroidism with a titration strategy.53 Next, definitive treatment of
in general. However, other causes such as toxic adenoma, the hyperthyroidism is required to prevent relapse of
toxic multinodular goitre, thyroiditis, and TSH-producing paralytic attacks, which may occur in 62% of patients in
pituitary tumours have been reported in patients with the first three months after diagnosis.10 Antithyroid drug
TPP.9,12,43-45 Notably, 17-85% of TPP patients have mild signs treatment was associated with relapse of TPP, mostly
of hyperthyroidism at the time of diagnosis,9,10,12 and TPP during withdrawal or tapering of medication. 46 Radioactive

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Figure 2. Predisposition requires a multitude of triggers, of which hyperthyroidism is a necessity, to develop

thyrotoxic periodic paralysis (TTP)

Hyperthyroidism Clinical manifestation

Symptoms
Acute paralysis
Symptoms of hyperthyroidism
Palpitations
Weight loss
Tremor
Predisposition Triggers Heat intolerance

Physical signs
Demographic Night or early morning Paralysis without sensory abnormalities
Male > Female Summer Signs of hyperthyroidism
Age 20-40 years High carbohydrate load
Asian heritage Alcohol ECG findings
Heavy exertion Sinus tachycardia
Genetic mutations Infection Prolongation of PR interval
Unknown Stress Atrial flutter or fibrillation
KCNJ18 β-2 bronchodilators U-waves
Ventricular tachycardia or fibrillation
Genetic variants
rs312729 Laboratory findings
rs312691 Suppressed TSH, high T3 and T4
rs312736 Hypokalaemia
Hypomagnesaemia
Hypophosphataemia
Hypercalciuria and hypophosphaturia
Low urinary potassium excretion

iodine or surgical treatment is the most definitive indicating hyperthyroidism in all three cases. Serum
treatment, thereby avoiding the risk of recurrence of TPP. TSH was only measured after correction of serum
When thyroid hormone replacement is initiated because potassium, as causes of low potassium and paralysis were
of iatrogenic hypothyroidism, utmost care in dosing is evaluated. Therefore, none were treated with propranolol at
essential, as even slight overtreatment can lead to TPP admission, and two patients had rebound hyperkalaemia
relapse. 4 after potassium supplementation. Graves’ disease was
diagnosed in all three cases based on high anti-TSH
receptor antibody levels and diffuse thyroid uptake of
ILLUSTR ATI VE CASE REPORTS radioactive iodine in combination with suppressed serum
TSH and elevated serum free T4 levels. In all three cases
Table 1 shows the characteristics and main clinical findings the paralysis disappeared within hours of treatment,
of three patients with TPP who presented to the medical and patients were subsequently also treated for their
emergency department. All three patients were male, of primary hyperthyroidism. One patient (case 3) required
Asian descent and presented with complaints of muscle thyroidectomy because of a recurrence of the paralysis
weakness. One patient had experienced muscle weakness shortly after initiation of treatment, which was likely
previously but this had resolved spontaneously. Possible triggered by alcohol consumption. Definitive treatment was
triggers were high carbohydrate and alcohol consumption. advised to the other two patients, but case 1 declined and
Physical examination revealed paresis of the extremities case 2 was lost to follow-up.
in all three cases, while sensation was intact. In two cases,
severe tetraparesis was present. Serum potassium levels
were low to extremely low (1.4 to 2.4 mEq/l), without CONCLUSION
metabolic abnormalities. With low urinary potassium
excretion, renal causes of hypokalaemia were excluded. Sudden onset of paralysis with hypokalaemia, especially
All cases had abnormal ECG findings, corresponding with in Asian males, should trigger clinicians to consider
hypokalaemia. Interestingly, there were no prodromes acquired periodic paralysis. In many cases, TPP may

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Table 1. Characteristics of three cases of patients with thyrotoxic periodic paralysis (TTP)

Case 1 Case 2 Case 3

Age, years 26 31 20

Gender Male Male Male

Race, background Asian, Taiwan Asian, Taiwan Asian, Indonesian

History Unremarkable Unspecified arrhythmia Unremarkable

Presenting symptoms Tetraparesis, mostly upper Tetraparesis Paresis of lower

extremities extremities

Previous muscle weakness Yes No No

Possible trigger High carb diet None Alcohol

ECG findings Tachycardia, prolonged PR Prolonged PR time, Intraventricular

time, U-waves, frequent U-waves, right bundle conduction delay, U-waves
premature ventricular branch block pattern
complexes

Potassium, mEq/l (ref 3.5-5.5) 1.5 1.4 2.4

pH and bicarbonate levels Normal Normal Normal

Urine potassium, mmol/l 11 12 13

Clinical signs of hyperthyroidism* No No No

Free T4, pmol/l (ref < 24) 53.8 36.3 80.0

Anti-TSH receptor antibody, IU/l (ref < 1) 13.6 14.6 12.7

Thyroid disease Graves’ disease Graves’ disease Graves’ disease

Treatment Propranolol, thiamazole Propranolol, thiamazole Propranolol, thiamazole

and later thyroidectomy

Relapse hyperkalaemia No Yes Yes

Recurrence No No Yes, once

*Including anxiety, tremor, palpitations, heat intolerance or weight loss.

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