Department of Emergency Medicine, Jessa Hospital Hasselt, Hasselt, Belgium; Faculty of Medicine, University of Leuven, Leuven, BelgiumBelgium
Department of Emergency Medicine, Jessa Hospital Hasselt, Hasselt, BelgiumBelgium
Department of Endocrinology, Jessa Hospital Hasselt, Hasselt, BelgiumBelgium
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Thyrotoxic periodic paralysis (TPP) is a rare but potentially life-threatening muscle disease in a thyrotoxic patient. Due to the lack of knowledge, the diagnosis is easily missed. Diagnosis of TPP is made by documentation of hypokalemia and hyperthyroidism in acute generalized muscle weakness. Hypokalemia is caused by an intracellular shift of potassium because of an increased Na-K-ATPase pump activity and the inhibition of the inward rectifying potassium (Kir) channels. The initial treatment aims to treat potentially life-threatening cardiac arrhythmias caused by severe hypokalemia. This can be done with potassium substitution and nonselective beta-blockers, being aware of the potential of rebound hyperkaliemia. Definitive treatment consists of avoiding triggers and correcting the hyperthyroid state with antithyroid drugs, radioactive iodine, or thyroidectomy. Once patients are, permanently euthyroid complete remission of the paralytic attacks usually occurs. We present a case of a 37-year-old male with diffuse muscle weakness after surgery. A new diagnosis of thyrotoxic periodic paralysis was made in the emergency department. This review summarizes the epidemiology, clinical manifestations, pathogenesis, diagnostics, and treatment of TPP.
Keywords: Thyrotoxic periodic paralysis; Hypokalaemia; Potassium
hyrotoxic periodic paralysis (TPP) is a rare but potentially
life-threatening muscle disease in a thyrotoxic patient. TPP T is characterized by hypokalaemia due to an intracellular shift of
potassium and episodes of acute generalized muscle weakness in
a setting of thyrotoxicosis. Prompt identification, restoration of
normal potassium levels, and correction of the underlying thyro-
toxic state are primordial in avoiding cardiopulmonary complica-
tions and recurrences of paralysis.
We present a case with a new diagnosis of TPP after
minor elective surgery and a review of the literature focusing on
pathogenesis, diagnostics, and treatment.
A 37-year-old male in previously good health presented to the
emergency department (ED) with diffuse muscle weakness and
myalgia for a few hours. The day before, he had surgery under
general anesthesia by orthopedists on synostosis of the base of the
right fifth metatarsal. The procedure went without complications,
and the patient could leave the hospital the same day. Progressively he lost the strength in his left leg and had difficulty mobilizing.
Thinking of a post-operative complication, he was admitted to the
ED the next day. On admission, the patient had a full range of mo-
tion in the four limbs but with diffuse reduced strength. No differ-
ences were noted between proximal and distal muscles. Sensation
remained intact.
Serum biochemical parameters showed hypokalaemia
(2.08 mmol/L), hypophosphatemia (0.60 mmol/L), and slightly
elevated creatine kinase (215 U/L). Electrocardiogram showed a
sinus rhythm of 64/min and a prominent U-wave (Figure 1).
Thyroid function tests were measured and showed an
immeasurably low thyroid stimulating hormone (TSH) (<0.0050
mU/L) and increased T4 (39.6 pmol/L) supporting a new diag-
nosis of hyperthyroidism complicated by thyrotoxic periodic pa-
ralysis. Under continuous monitoring of the vital parameters, the
patient received an intravenous infusion with 40 mEq potassium
chloride and 1 g of magnesium sulfate over one-hour, resulting in
the normalization of the potassium levels (3.4 mmol/L), an im-
provement in strength and disappearing of U-waves on the elec-
trocardiogram (Figure 2).
Figure 1. Electrocardiogram before Potassium Substitution
Treatment with antithyroid drugs, beta-blocking medication, and
oral potassium supplementation was started. Further in-depth
anamnesis revealed that the patient showed fatigue, tremor, and
irritability for the past two-months. After three-days of observa-
tion, treatment with antithyroid drugs, beta-blocking medication,
and oral potassium supplementation, the patient had no symptoms
with no occurrence of rebound hyperkalemia. Follow-up was pro-
vided at discharge.
TPP is a sporadic form of hypokalaemic periodic paralysis associ-
ated with hyperthyroidism. Any cause of hyperthyroidism can lead
to TPP. The severe disease is the most common, but it can also be
related to toxic nodular goiter, solitary toxic nodus, iodine-induced
thyrotoxicosis, excess use of exogenous thyroxine, thyroiditis,
thyrotropin-secreting pituitary adenoma and amiodarone-induced thyrotoxicosis.1 Unlike familial hypokalaemic periodic paralysis,
2,3 there is no autosomal inheritance.2,3
Despite the high prevalence of thyrotoxicosis in women,
TPP mainly affects Asian or Polynesian men. The male-to-female
4-7 ratio is 20:1.4-7 In the Chinese and Japanese thyrotoxic populations,
5,6 there is an incidence of respectively 1.8 and 1.9%.5,6 In men, this
5,6 is 8.7-13%.5,6 Due to migration, the incidence in other populations
1,8,9 is increasing to 0.1-0.2%. Eighty percent (80%) of the patients
1,5,8,10 have an onset of the disease at 20-39-years-old. Other forms
of periodic paralysis have a younger onset.
Triggers of the disease include stress (surgery, infec-
tion, trauma, psychological), rest after physical activity, menses,
carbohydrate-rich foods, cold exposure, alcohol, and illegal intake,
drugs (corticosteroid therapy, beta-2-adrenergic bronchodilators,
epinephrine, insulin, thyroid supplements, diuretics, Non-steroidal
anti-inflammatory drugs (NSAIDs), fluoroquinolones, aminogly-
7,11 coside).7,11 Attacks mostly occur during the night or in the early
11,12 morning. In subtropical regions, a seasonal variation can be ob-
served with increased episodes during the summer months.
The pathophysiology of TPP is still not fully known. Skeletal mus-
cles are the largest stores of total body potassium, and potassium
efflux by myocytes plays a vital role in maintaining extracellular
potassium homeostasis. This balance is maintained by the Na-
K-ATPase pump, which provides the intracellular movement of
potassium, and the potassium channels, including inward rectify-
ing potassium (Kir) channels that contribute to the extracellular
movement of potassium.13 Hypokalaemia is not the consequence
of a total body potassium shortage but of an increased intracel-
lular shifting into the muscles (Figure 3).1,13
More significant amounts of thyroid hormone and greater
sensitivity of the pump to thyroid hormone due to genetic predis-
position lead to an increased Na-K-ATPase pump activity in the
sarcolemma and an increased potassium influx into the cell. In
addition, there is also an indirect effect through increased b2 adren-
ergic activity with an increased impact on catecholamines, hyperin-
sulinemia, and the stimulating effect of androgens on the Na-K-
17-21 ATPase pump activity.
Ion channel defects, only interested in hyperthyroid states,
form a second mechanism in the pathophysiology. Several sensitiv-
ity loci allow for KCNJ-2 expression. This gene encodes the Kir2.6
channels in skeletal muscles regulated by the thyroid hormone. In
rd 1/3 of the patients, a loss-of-function mutation occurs in the genes
that correlate for this Kir2.6. As a result, the potassium efflux is dis-
22,23 turbed.
The decreased extracellular potassium leads to depolariza-
tion of the sarcolemma instead of hyperpolarizing. The hypokalae-
mia-induced paradoxical effect causes the inactivation of the sarco-
lemma’s Na channels, leading to paralysis of the skeletal muscles.
Several external causes stimulate the Na-K-ATPase pump
Figure 3. Pathophysiology of TPP and inhibit the Kir channels. Stressful impulses, including surgery, infection, and trauma, cause increased beta-adrenergic activity. Exer- 6,7,11 cise leads to potassium efflux, while rest causes an influx. As a result, 8,25
paralysis occurs more often at night when people are inactive.8,25 In
addition, a carbohydrate-rich diet increases insulin release. Insulin
and catecholamines activate the Na-K-ATPase pump and inhibit the
Kir channels. Finally, the higher incidence of TPP in men can be
explained through the high androgen levels stimulating the pump.
Estrogen and progesterone, on the other hand, have an inhibitory
26,27 effect.
Thyrotoxic periodic paralysis is characterized by sudden episodes
of generalized muscle weakness ranging from mild weakness to
1,13 complete paralysis without loss of consciousness. Proximal muscle
groups and lower extremities are more severely affected than dis-
tal muscles and upper extremities. The muscles affected may be
asymmetrical. Tendon reflexes can be decreased, but sensation re-
mains intact. Less than 50% of the patients experience prodromal
14-16 6 symptoms like mild myalgias and stiffness. In severe cases, bul-
bar weakness, respiratory depression with hypercapnic respiratory
28,29 failure, and fatal ventricular arrhythmias have been reported.
Symptoms of hyperthyroidism do not always precede TPP. Forty-
three to sixty percent (43-60%) of the patients have symptoms at
2,5,6,8,9,26 the moment of the TPP, but often they are very subtle. Oth-
er possible symptoms include palpitations, tachycardia, dyspnoea,
11,12 dysphagia, speech and visual changes, and rhabdomyolysis.
Frequency can vary between once a week to every few months.
Most attacks resolve within 36-hours but can last from minutes to
7,30 days.
Essential is the documentation of hypokalaemia and hyperthyroid-
ism. The severity of hypokalaemia corresponds to the intensity
of muscle weakness. The average value is 3 mmol/l but can go
24,25 1 as low as 1.1 mmol/L. A low serum phosphate and magnesium
are associated with the potassium influx.12 The urine calcium to
phosphate ratio greater than 1.7 mg/mg has a good discrimina-
tory power between TPP and non-TPP hypokalaemic paralysis.31
Hyperthyroidism is characterized by decreased thyroid-stimulating
hormone (TSH) and increased T4 and/or T3. Creatine kinase can
be normal to slightly elevated in 2/3rd of the patients.12
A triad of sinus tachycardia represents electrocardio-
graphic changes due to a hyperadrenergic state, hypokalaemia char-
acteristic (U-waves, ST-depression, QT-prolongation and T-wave
flattening) and paradoxically prolonged PR interval caused by thy-
rotoxicosis. Other findings are tachyarrhythmias, atrioventricular
32,33 blocks and cardiac arrest.
When performed, an electromyogram shows a myopathy
with reduced duration of muscle action potentials, decreased am-
plitudes, and increased polyphasic possibilities. These characteris-
tics can resolve in the euthyroid state.1,34
Acute paralysis can occur due to a problem with the central, pe-
ripheral nerve system, the neuromuscular junction of the skeletal
muscle. TPP, being a muscle disorder, needs to be differentiated
from other muscular disorders like myasthenia gravis, Guillain-
Barré syndrome, transverse myelitis, acute thyrotoxic myopathies,
tick paralysis, and botulism. Other forms of periodic paralysis
1,12,35,36 should also be ruled out.
Treatment of TPP proceeds in steps. Acute therapy includes pre-
venting major cardiopulmonary complications and reversing pa-
ralysis.37 Finally, treatment is needed to restore the euthyroid state
and prevent future attacks.
In the event of electrocardiographic changes, hypokalae-
mia needs to be treated. A proposed scheme consists of 30 mEq
oral potassium every two-hours with a maximum of 90 mEq ev-
ery 24-hours until improvement of the muscle weakness.38 Others
propose a more careful approach with less than 10 mEq each hour
because the pathophysiology of TPP does not involve potassium
depletion but an intracellular shift.39 Therefore, rebound hyperka-
lemia and hyperphosphatemia at improvement is a risk. In the
case of severe hypokalaemia, a faster correction with intravenous
substitution of potassium is more appropriate. Most patients need
10-200 mEq of potassium.39 Because of their risk for cardiac ar-
rhythmias, patients with TPP must permanently be hospitalized
and monitored.
When there is no initial response, oral or intravenous
non-selective beta-blockers, such as propranolol, can be used as
an alternative treatment. The non-selective beta-blockers reverse
the Na-K-ATPase pump’s adrenergic stimulus, causing a decreased
catecholamine-mediated potassium uptake. The proposed dosage
is 1 mg of propranolol intravenous every 10-minutes with a maxi-
mum of 3 mg. Oral intake is dosed at 3 mg/kg. Propranolol can
shorten the recovery time without the risk of rebound hyperkale- 41,42 mia.
The second stage, when hospitalized, includes restoration
of the euthyroid state to eliminate attacks of TPP in the future,
as paralytic episodes can re-emerge if thyrotoxicosis recurs. The
rd 12 management of hyperthyroidism differs according to the underly-
ing etiology. Definitive treatment of TPP requires correction of
the thyrotoxic state with antithyroid drugs, but radioactive iodine
43,44 or thyroidectomy appeared more effective.
Propranolol can be used temporarily until the euthyroid
state is achieved. However, daily potassium supplementation is
1,8,35 not beneficial for prophylaxis against further paralytic attacks.
Precipitating factors, such as heavy exercise and high-carbohydrate
diets, must be avoided while awaiting the normalization of the thy-
1,35 rotoxic state.1,35
1,34 Once patients are, permanently euthyroid complete re-
mission of the paralytic attacks usually occurs.35
Thyrotoxic periodic paralysis is an endocrine emergency because
of the risk of cardiac arrhythmias. Due to the lack of knowledge
of this rare disease, the diagnosis is easily missed. Early diagnosis
allows treatment and prevents recurrent episodes in the future.
Patients with acute muscle weakness or paralysis should be
evaluated for TPP by checking electrolytes and thyroid function
testing. This is usually seen in young Asians, but the incidence
in other populations is increasing caused by migration. The
pathophysiology remains uncertain but seems to be based on
increased Na-K-ATPase pump activity and the inhibition of the
Kir channels, both resulting in increased intracellular potassium.
Acute treatment consists of potassium supplementation and non-
selective beta blockers. Avoiding known triggers and restoring
the euthyroid state by antithyroid drugs, radioactive iodine, or
thyroidectomy prevents morbidity and mortality.
As described in the presented case, surgery is a known
trigger for an acute episode of TPP. When the patient is already
known with TPP, a thyroid function test needs to be checked, and
elective surgery needs to be postponed until the treatment of the
39 45 hyperthyroid state.45 When patients are permanently euthyroid,
12,40 a complete remission of the paralytic attacks is observed, and
surgery can be performed safely.
Yes.
The authors have received written informed consent from the
patient.
The authors declare that they have no conflicts of interest.