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Mechanism of Thyrotoxic Periodic Paralysis

Shih-Hua Lin* and Chou-Long Huang†
*Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center,
Taipei, Taiwan; and †Division of Nephrology, Department of Medicine, UT Southwestern Medical Center, Dallas, Texas

ABSTRACT
The pathogenesis of thyrotoxic periodic paralysis has long been thought related to in- have chronic hypokalemia associated
creased Na+–K+ ATPase activity stimulated by thyroid hormone and/or hyperadrenergic with the use of diuretics, laxative, miner-
activity and hyperinsulinemia. This mechanism alone, however, cannot adequately ex- alocorticoid excess state, or concurrent
plain how hypokalemia occurs during acute attacks or the associated paradoxical depo- renal tubular disorders such as renal tu-
larization of the resting membrane potential. Recent findings that loss of function bular acidosis or Bartter’s or Gitelman’s
mutations of the skeletal muscle-specific inward rectifying K+ (Kir) channel, Kir2.6, asso- syndrome.
ciate with thyrotoxic periodic paralysis provide new insights into how reduced outward K+ An assessment of renal K+ excretion
efflux in skeletal muscle, from either channel mutations or inhibition by hormones (adren- and acid–base status at presentation as
alin or insulin), can lead to a vicious cycle of hypokalemia and paradoxical depolarization, well as the amount of KCl required to
which in turn, inactivates Na+ channels and causes muscle unexcitability and paralysis. correct hypokalemia are very helpful in
diagnosing TPP. Several clinical and labo-
J Am Soc Nephrol 23: 985–988, 2012. doi: 10.1681/ASN.2012010046
ratory findings are characteristic of TPP
(Table 1).3,4 Regarding acute therapy, the
dose of KCl should be minimal to avoid
Muscle weakness progressing to paralysis the incidence in non-Asian ethnic popu- rebound hyperkalemia, and nonselective
caused by hypokalemia is a potential life- lations (0.1%–0.2%), TPP is increasingly b-blockers may be the alternative choice,
threatening but reversible medical emer- reported in Western countries because of especially for those patients who devel-
gency. Hypokalemic muscle paralysis can globalization and immigration.3 oped hypokalemia associated with an ev-
result from renal or gastrointestinal loss idence of hyperadrenergic activity.5 The
of K+ or shift of K+ into cells induced by goal of chronic therapy in TPP is to nor-
acid–base disturbances or stimulated by DIAGNOSIS AND MANAGEMENT malize thyroid function and avoid the pre-
drugs or endogenous hormones.1 OF TPP cipitating factors for acute attack.
Hypokalemic periodic paralysis
(HypoPP) is a heterogeneous group disor- TPP characterized by a triad of muscle
der portraying episodic muscle weakness paralysis, acute hypokalemia without PATHOGENESIS OF
associated with hypokalemia from acute total body K+ deficit, and hyperthyroid- HYPOKALEMIA IN TPP
shift of K+ into cells unrelated to known ism is not only a neurologic and endo-
acid–base disorders or exogenously ad- crinological emergency but also quite The pathogenesis of TPP has remained
ministrated substances. The causes of interesting to nephrologists. It is fraught largely mysterious for decades since
HypoPP may be familial, which is more with diagnostic and therapeutic chal- the discovery of the first case in early
common among non-Hispanic Cauca- lenges. Rapid recognition and termination 20th century. Acute hypokalemia is the
sians, and predominantly caused by of TPP is mandatory to avoid poten-
mutations in the Cav1.1 skeletal muscle tially fatal complications from severe
voltage-gated Ca2+ channel or the Nav1.4 hypokalemia. Patients with TPP often Published online ahead of print. Publication date
available at www.jasn.org.
Na+ channel. Nonfamilial HypoPP in- have subtle symptoms related to hyper-
cludes thyrotoxic periodic paralysis thyroidism. 3 Assessment of thyroid Correspondence: Prof. Shih-Hua Lin, Division of
Nephrology, Department of Medicine, Tri-Service
(TPP) and sporadic periodic paralysis function is also often not immediately
General Hospital, No. 325, Section 2, Cheng-Kung
(SPP), which are more common among available. Furthermore, acute discovery Road, Neihu 114, Taipei, Taiwan, Republic of
Asians and Hispanics.2 Although the in- of thyrotoxicosis and hypokalemia does China. Email: l521116@ndmctsgh.edu.tw
cidence of TPP in Asian countries (2%) not always make the diagnosis of TPP; Copyright © 2012 by the American Society of
is approximately 10–20 times higher than patients with hyperthyroidism may Nephrology

J Am Soc Nephrol 23: 985–988, 2012 ISSN : 1046-6673/2306-985 985

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Table 1. Distinct clues for the
diagnosis of TPP
Clues
A. Sex: adult males
B. History: nonfamilial paralysis
but familial hyperthyroidism
C. Clinical symptoms and sign
associated with hyperthyroidism
D. Electrocardiographic findings
sinus tachycardia or sinus arrhythmia
first-degree atrioventricular block
left ventricular hypertrophy pattern
E. Electromyographic findings
low compound muscle action
potential amplitudes
F. Blood and urine electrolytes
and acid–base
hypokalemia with low urine
K+ excretion rate
relatively normal blood acid–base balance
hypophosphatemia with low urine
phosphate excretion
normal or increased serum calcium
with hypercalciuria
hypocreatininemia (increased GFR)
G. Less K+ dose to achieve recovery
principle laboratory finding, and it cor-
relates with the severity of paralysis.
Normalization of serum K+ levels leads
to recovery of muscle strength. Skeletal
muscle is the largest single pool of total
body K+ stores, and it plays an important
role in extracellular K+ homeostasis. In
the skeletal muscle, Na+–K+ ATPase and
K+ channels, including inward rectifying
K+ (Kir) and delayed rectifying K+ chan-
nels, provide the main access for inward
and outward K + movements, respec-
tively.6 It is estimated that active uptake
of K+ through Na+–K+ ATPase at a rate
of 125 mmol/min can decrease serum K+
concentration by 3 mM within 1 minute,
providing that there is no concomitant
K+ efflux from myocytes.6 The critical
role of myocyte K+ efflux in extracellular
K + homeostasis is supported by the
finding that patients with barium (an
inhibitor of skeletal muscle K+ channels)
poisoning develop acute hypokalemia
and muscle paralysis.6
The important role of Na+–K+ ATPase
pumps in the pathogenesis of TPP is
supported by the finding that their activ-
ity in the skeletal muscle is significantly
986 Journal of the American Society of Nephrology
increased.7 Thyroid hormone can stim-
ulate Na+–K+ ATPase in skeletal muscle
by genomic mechanism, acting on the
thyroid hormone responsive elements
to upregulate the transcription of the
gene encoding Na + –K + ATPase, and
through nongenomic mechanisms by
enhancing the intrinsic activity or pro-
moting membrane insertion of the
pump. Hyperthyroidism may also en-
hance the stimulation of pump activity
by b2-adrenergic agonists by amplifying
the production of intracellular cAMP.
Hyperinsulinemia is also observed in
acute attack of TPP, and the release of
insulin in response to oral glucose chal-
lenge is exaggerated in TPP patients, sup-
porting the idea that insulin participates
in the pathogenesis of hypokalemia in
TPP.8
Insulin induces cellular K+ shifts by
stimulating the intrinsic activity or
membrane insertion of Na+–K+ ATPase.
The effect of insulin may account for the
observation that a high-carbohydrate
diet can be a precipitating factor for
TPP. Sympathetic stimulation of insulin
release in pancreas b-cells provides ad-
ditional rationale for using nonselective
b-blockers to treat acute hypokalemia
and paralytic attack of TPP.5,9 TPP is
also known to occur predominately
among males despite a higher incidence
of thyrotoxicosis in women, suggesting the
potential role of androgen on Na+–K+
ATPase activity. Although more work
needs to be done in this area, androgens
may increase Na+–K+ ATPase activity
through androgen receptor10 and hyper-
adrenergic state. The traditional mecha-
nisms of Na+–K+ ATPase activation in
TPP are shown in Figure 1A.
Activation of Na+–K+ ATPase cannot
be the only mechanism for TPP, because
only a minority (;2%) of patients with
hyperthyroidism develop hypokalemic
paralysis. By itself, the increased Na+–K+
ATPase activity in muscle may be com-
pensated by increased K+ efflux, limiting
its impact on the extracellular K+ homeo-
stasis and the extent of hypokalemia; in-
deed, the total intracellular K+ content
measured in the diaphragm muscle of a
thyrotoxic mouse is unchanged from the
normal.11
Thus, additional factors such as de-
creased K+ efflux must be at play to cause
clinically significant hypokalemia. Stud-
ies have shown that the outward Kir cur-
rent is decreased in intercostals muscle
fibers of both patients with TPP and fa-
milial HypoPP.12 Moreover, insulin and
catecholamine not only activate Na+–K+
ATPase but also inhibit Kir channels.13
Two recent studies report that muta-
tions in the gene encoding Kir2.6, a
skeletal muscle-specific Kir channel, are
associated with TPP and predispose these
patients to acute paralytic attacks. In a
report by Ryan et al.,14 the prevalence
of Kir2.6 mutation was up to 33% in
Caucasians and Brazilians. Thyroid hor-
mone upregulates the transcription
of Kir2.6 through an upstream thyroid
hormone responsive element in the pro-
moter region of channel gene. In the an-
other report, Cheng et al.15 found three
additional loss of function mutations in
Kir2.6 channels in patients with TPP as
well as SPP. The work by Cheng et al.15
also reported that Kir2.6 forms func-
tional homotetramer and heterotetramer
with Kir2.1, another Kir channel in the
skeletal muscle. Kir2.6 mutants exert a
dominant negative effect on both WT
Kir2.1 and Kir2.6 channels.
Overall, these two recent papers pro-
vide compelling support for the role of ge-
netic mutations in Kir2.6 channel in the
pathogenesis of TPP. Loss of function of
Kir2.6 together with increased activity of
Na+–K+ ATPase may trigger a positive
feed-forward cycle of hypokalemia, lead-
ing to paradoxical depolarization with
consequent inactivation of Na+ channel
and muscle inexcitability (Figure 1B).16
MUSCLE PARALYSIS ASSOCIATED
WITH HYPOKALEMIA-INDUCED
PARADOXICAL DEPOLARIZATION
IN TPP
Based on the Nernst equation (E = 258
mV 3 log {[K]in/[K]out}), the resting
membrane potential should hyperpolar-
ize when extracellular K + decreases.
However, muscle fibers from patients
with HypoPP depolarize under low ex-
tracellular K+ conditions (;3 mM). This
J Am Soc Nephrol 23: 985–988, 2012
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mutations in the coding region of Kir2.6

and voltage-gated Na+ and Ca2+ chan-
nels, remain. Although it remains to be
studied, reduced expression of Kir2.6
channel protein from mutations in the
noncoding region of the channel gene or
inhibition of the channel by endogenous
factors, such as insulin or catechol-
amine, or exogenous factors, such as
caffeine alone or combined, may lead to
periodic paralysis in patients without
known mutations in Kir2.6 and voltage-
gated Na+ and Ca2+ channels. New per-
ceptions regarding the pathogenesis of
TPP will be important in understand-
ing overall extracellular K+ homeostasis
and the therapeutic approaches to hypo-
kalemic paralysis.

ACKNOWLEDGMENTS

This study was supported in part by Tri-

Service General Hospital Research Grant
TSGH-C101-114 and the Teh-Tzer Study
Group for Human Medical Research Foun-
dation.

DISCLOSURES
None.
Figure 1. Mechanism of TTP. (A) A traditional pathogenesis of TPP. An increased Na+–K+
ATPase activity directly induced by thyroid hormone and indirectly induced by hyper-
adrenergic activity, hyperinsulinemia, and androgen is mostly involved. The open circle
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988 Journal of the American Society of Nephrology J Am Soc Nephrol 23: 985–988, 2012