Hypokalaemic Thyrotoxic Periodic Paralysis

SN Chugh*, Surekha Dabla**, Kiran Chugh***, HK Aggarwal****

A 22-year-old male person was admitted with symptoms
and signs suggestive of thyrotoxicosis (Fig. 1). He
described sudden weakness of all the four limbs 5 days
before admission. He also complained of shooting pain in
the legs while walking and painful cramps in his arms and
neck associated with difficulty in breathing. There was no
history of any gastrointestinal or any cardio-vascular
problems though he complained of palpitations and
sweating off and on.
Past history
1 years ago the patient had similar episodes of pain,
* Professor of Medicine and Head Unit-V and Endocrinology and Metabolism, ** Lecturer, Department of Medicine,
*** Lecturer, Department of Biochemistry, **** Associate Professor, Department of Medicine,
Pandit BD Sharma Post-Graduate Institute of Medical Sciences, Rohtak, Haryana.
discomfort, and weakness in all the four limbs. He had
been experiencing repeated episodes of weakness during
this period, following either a heavy meal or rest after
exercise.
Personal history
The patient was a non-smoker and a teetotaler.
Family history
There was no history of similar illness in the family.
Examination
The patient was afebrile and had obvious exophthalmos.
The pulse rate was 92/minute, regular, and of good volume.
The blood pressure was 150/60 mm Hg on right arm in
supine posture; the respiratory rate was 24/minute.
Examination of neck revealed diffuse goitre with systolic
bruit over it. Neurological examination revealed fine tremors
of both hands, proximal muscle weakness in both arms and
legs associated with hyporeflexia in all the four limbs.
Cardiovascular system was within normal limits. The patients
look was anxious, whereas the higher mental functions and
the cranial nerves were normal. There was no sensory
abnormality. Systemic examination was normal.
The results of the laboratory investigations done during
hospitalisation of the patient are shown in (Table I).
Table I: The results of the laboratory investigations
done during hospitalisation of the patient.
Investigations Values/results
Haemoglobin (Hb) 9.5 gm%
Total leucocyte count (TLC) 7,900/cu mm
Differential leucocyte count (DLC) Polymorphs - 85; Lymphocytes - 15;
Monocytes - 0; Eosinophils - 0;
Basophils - 0
P O S T G R A D U AT E C L I N I C
JIACM 2006; 7(4): 302-7
Fig. 1:
Blood urea 25 mg%
Blood sugar 88 mg%
Serum sodium 126 mEq/l
Serum potassium 2.1 mEq/l
Serum calcium 10.8 mg%
Serum phosphate 3.4 mg%
Serum magnesium 2.9 mmol/l
T-3; T-4; TSH 454.05 ng/dl; 17.9 ng/dl; < 0.01 IU/ml
Arterial blood gas analysis pH - 7.32; pCO2 - 44.7%; Oxygen
saturation - 75.6%; Bicarbonates (HCO3)
- 20.4
Electrocardiogram (ECG) showed S. tachycardia with QT prolongation and
TUP segment with occasional ventricular
ectopic beats (Fig. 2)
Skiagram of chest showed Mild cardiomegaly
Ultrasonography of thyroid Both lobes of thyroid showed altered
echotexture with increased blood flow.
Each lobe measured 4.3 cms in length
and 2.0 cms in antero-posterior plane.
Urine examination No abnormality was detected
Q. 1. What is the probable clinical diagnosis
in this patient?
Ans: In view of unequivocal evidence of thyrotoxicosis
with frequent periodic paralysis and documented
hypokalaemia (2.1 mEq/l) during the episodes of
paralysis, the diagnosis of hypokalaemic thyrotoxic
periodic paralysis (HTPP) was kept in this case.
Q. 2. What is the clinical presentation of
hypokalaemic thyrotoxic periodic
paralysis (HTPP)?
Ans: Hypokalaemic thyrotoxic periodic paralysis
(HTPP) is a rare disorder affecting mainly men of
Asian descent. It begins at 20 - 40 years of age.
The sex ratio (M:F) is 20:1. It is characterised by
sudden recurrent episodes of painless weakness
or paralysis without alteration in consciousness,
usually occurring after a high-carbohydrate meal
or heavy exertion followed by a prolonged rest
in patients with thyrotoxicosis
1, 2
. Patients usually
present with clinical features of thyrotoxicosis
followed by episodic muscular weakness.
Weakness commonly affects the muscles of arms
and legs lasting from a few hours to a few days.
Occasionally, there may be involvement of
muscles of the eyes, respiration, and swallowing
3
.
The mental functions remain normal, and the
sensory modal i ti es are preserved wi th
diminished tendon reflexes. These patients may
have sinus tachycardia, diffuse ST-T changes,
flattening of T waves, prolonged QT intervals
and U waves and cardiac arrhythmias on ECG
because of a drop in potassium levels (< 3.0 mEq/
l). Sometimes dangerous arrhythmias such as
torsade de pointes and ventricular fibrillation may
develop
4
.
Q. 3. What is the aetiopathogenesis of this
condition?
Ans: The pathogenesis of hypokalaemic thyrotoxic
periodic paralysis (HTPP) has not been clearly
elucidated. However, it is known to occur most
commonly in patients with Graves disease or in
nodular toxic goitre
5
. Attacks of periodic paralysis
can also, though not always, be experimentally
induced by a provocation test with glucose (3 g/
kg) and insulin (0.1 IU/kg IV)
6
indicating that
paralysis is due to hypokalaemia and not because
of thyrotoxicosis itself. Patients with this type of
paralysis have an inherent defect in Na
+
-K
+
-
ATPase activity which is sensitive to thyroid
hormone
7
. The thyroid hormone alters the cell
membrane permeability to potassium through
Na
+
-K
+
- ATPase pump leading to intracellular shift
of potassium resulting in hypokalaemic periodic
paralysis without depleting the total body K
+
(potassium) stores.
Q. 4. What are the causative/aggravating
factors for repeated episodes of
weakness? How can they be
prevented?
Ans: Hypokalaemia is the underlying biochemical
disturbance which provokes periodic paralysis in
these patients
2
.
Factors leading to hypokalemia are:
Gastrointestinal loss of potassium
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Renal loss of potassium
Diet lacking in potassium
High-carbohydrate or high-salt meals
After intake of alcohol
Rest after heavy and unaccustomed exercise
Certain drugs such as diuretics, laxatives, insulin
therapy, Amphotericin B, -adrenergic
antagoni sts, -2 agoni sts, steroi ds
(glucocorticoids as well as mineralocorticoids),
penicillin and its derivatives, etc.
The episodes, hence, can be prevented by taking
low carbohydrate, low salt, and potassium rich diet
including fruit juices. The diuretics, if the patient is
taking for some other disorder, must be stopped
and replaced with other potassium-sparing
diuretics, if needed. Abstinence of alcohol should
always be recommended.
Q. 5. Do the paralytic attacks have any
relation to season or time?
Ans: Yes, the attacks appear to have seasonal variation,
usually occurring during the warmer months (May
through September in our country) and less often
during the colder months (December through
March). The paralysis also follows a diurnal pattern,
often occurring at night when the person is resting
in bed
8
. It does not occur when the person is
performing any physical activity.
Q. 6. What are the common conditions
simulating periodic paralysis?
Ans: The following are the common conditions which
simulate periodic paralysis. Their clinical
differentiation is tabulated (Table II).
Table II: Common conditions simulating periodic
paralysis.
1. Guillain-Barr The weakness in Guillain-Barr
syndrome syndrome follows some infection
(post-infectious) in 60% of the
cases and it lasts for several weeks;
whereas hypokalaemic thyrotoxic
periodic paralysis is a transient
condition lasting from hours to
days. The cerebrospinal fluid (CSF)
is characteristic in Guillain-Barr
syndrome, showing increased
protein content with few or no
cells (albumino-cytological
dissociation) while it is normal in
hypokalaemic thyrotoxic periodic
paralysis.
2. Polymyositis Pol ymyosi ti s i s frequentl y
associated with malignancies and
is characterised by elevated
creatinine kinase (CK) levels and
abnormal electromyography
(EMG). Polymyositis is usually a
diagnosis by exclusion.
3. Myasthenia gravis An acquired autoimmune disorder
in which autoantibodies (IgG) are
produced against acetylcholine
receptors at neuromuscular
j uncti ons; Ocul ar muscl es
weakness is characteristic. The
di agnosi s i s confi rmed by
electromyography (EMG) and
serological tests for the presence
of acetyl chol i ne receptor
antibodies.
4. Spinal cord These cases present with definite
compression focal neurological deficit involving
motor, sensory, and bladder
functions which is progressive.
There is a definite level reflecting
the si te of compressi on.
Radi ol ogi cal i magi ng (CT
myel ogram) confi rms the
diagnosis.
5. Andersen An autosomal disorder with
syndrome mutation in potassium channel
and it is characterised by periodic
paralysis and distinct facial
features with short stature, low-
set ears, hypertelorism, and long
QT interval predisposing to
ventricular tachyarrhythmia.
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6. Brodie disease An autosomal recessive exercise-
induced myopathy that causes
muscular stiffness due to impaired
muscle relaxation.
7. Thomsen An autosomal dominant disorder
disease with the defect lying in the
channel gene. It usually occurs in
infancy and childhood. Myotonia
is worsened by exposure to cold
and decreased by activity. Muscle
strength is normal.
8. Becker muscular An autosomal recessive disorder
dystrophy characterised by severe muscle
weakness associated with muscle
hypertrophy. EMG is diagnostic.
9. Schwartz- An autosomal recessive disorder
Jampel characterised by myopathy,
Syndrome muscle stiffness, short stature,
chondrodystrophy, bone and joint
deformities, hypertrichosis, and
blepharophimosis.
10. Idiopathic familial The clinical and biochemical
periodic paralysis features of hypokal aemi c
thyrotoxic periodic paralysis are
similar to those of idiopathic
familial periodic paralysis except
that in the latter, thyroid functions
are normal and there is positive
family history. Idiopathic familial
periodic paralysis is transmitted by
an autosomal dominant manner
caused by a defect in the gene
CACLNAIA3.
Q. 7. What are the various causes of
hypokalaemic periodic paralysis and
what are their differentiating features?
Ans: The various conditions associated with
hypokalaemia and periodic paralysis are:-
1. Primary idiopathic familial periodic
paralysis: It is caused by mutations in
CACLNAIA3 gene. It is an autosomal dominant
disease in which defect lies in the Ca
++
channels. The patients present with complete
paralysis with sparing of bulbar musculature
usually in childhood or adolescence. Diagnosis
is confirmed by positive family history, absence
of other secondary causes of hypokalaemia,
EMG, and muscle biopsy. Avoidance of high
carbohydrate diet, physical exercise, and
acetazolamide are helpful in treating this
condition.
2. Thyrotoxic periodic paralysis: It is common
in males of Asian descent. Mutations in
potassium channel are identified. Features of
thyrotoxicosis may or may not be observed.
Presentation is usually at adult life with
abnormal thyroid functions. The treatment
consists of restoration of serum potassium
levels and antithyroid drugs.
3. Primary hyperaldosteronism (Conn
syndrome): This condition is characterised by
hypertension (specially diastolic), polyuria,
polydipsia, and muscular weakness. There is
hypersecretion of aldosterone by adrenal glands.
Hypokalaemia, hypernatraemia, and alkalosis are
the underlying metabolic disturbances. The
diagnosis is made by elevated plasma and urine
aldosterone levels and low plasma renin level.
Treatment is of the positive basic cause.
4. Barium poisoning: Barium is used in various
alloys, in paints, soap, paper, and rubber, and in
the manufacture of ceramics and glass; and the
workers in these industries are predisposed to
it. It lowers the serum potassium levels by
blocking calcium-activated potassium channels
that control cellular potassium efflux. Thus,
barium intoxication results in a rise of
intracellular potassium and a corresponding
drop of extracellular potassium leading to
hypokalaemia
9
.
5. Liquorice ingestion: Liquorice is a medicinal
plant having therapeutic uses as expectorant,
demulcent, anti-inflammatory and laxative; and
is also used to normalise immune functions. It
contains glycyrrhizin which inhibits the activity
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of 11-HSDH (hydroxy steroid dehydrogenase)
which ultimately leads to mineralocorticoid
excess and hypokalaemia. Liquorice root toxicity
following prolonged ingestion leads to periodic
paralysis.
6. Thyroid hormone abusers: Thyroid hormone
drives potassium into cells via sodium-
potassium ATPase pump and leads to
hypokalaemia. Iatrogenic use by obese patients
with intention to lower their weight may
predispose them to it.
Q. 8. How will you confirm the diagnosis?
Ans: The diagnosis of hypokalaemic thyrotoxic
periodic paralysis is confirmed by clinical and
biochemical evidence of thyrotoxicosis and
hypokalaemia with or without an abnormal
electrocardiogram (ECG) during the attacks.
Electromyography (EMG) is confirmatory and
shows electrical silence during attacks
10
. Muscle
biopsy occasionally may show abnormality.
Molecular genetic testing identifies the mutation
in the disease causing gene (KCNE 3)
11
.
Q. 9. How will you treat such a patient?
Ans: The aims of treatment are:-
1. To treat the acute episode and to prevent its
further episodes;
2. To normalise the serum potassium levels.
The treatment of hypokalaemia is determined by
severity of symptoms, serum potassium levels, and
the ECG changes, if any. Accordingly, the cases can
be managed as:
Mild hypokalaemia (3 - 3.5 mmol/l): Oral
potassium supplements in the form of potassium
chloride 30 to 100 mmol/day are adequate and
given with juice and at meals.
Moderate hypokalaemia (2.5 - 3.0 mmol/l):
Initially these cases are managed with oral
potassium supplements, and if the patient still
remains symptomatic then 10 mmol of potassium/
hour is started intravenously in 5% mannitol (avoid
glucose and saline as diluent) with cardiac
monitoring and serum potassium levels
monitoring.
Moderately severe hypokalaemia (2 - 2.5
mmol/l): Oral potassium supplements if tolerated
by the patient are given, and if there is no
improvement in 1 to 2 hours then 15 mmol of
potassium per hour is given intravenously in 5%
mannitol with continuous monitoring of cardiac
system and serum potassium concentrations.
Severe hypokalaemia (< 2 mmol/l): Oral
potassium replacement if tolerated by the patient.
In addition, administer upto 20 mmol of potassium
per hour intravenously in 5% mannitol with
continuous cardiac and serum potassium
concentration monitoring.
In the present case, the patient having serum
potassium concentration 2.1 mEq/l was treated as
a case of moderately severe hypokalaemia with
intravenous potassium infusion.
Q. 10. How will you prevent such attacks?
Ans: Prevention of attacks: Preventive treatment is
aimed at decreasing the frequency of symptoms
and paralytic attacks; therefore, the patient is
advised to take oral potassium supplements 20 -
40 mEq/day in 2 to 4 divided doses which are
available as potassium acetate, potassium chloride,
potassium bicarbonate, potassium citrate, and
potassium gluconate, etc. In patients with
hypokalaemia and metabolic alkalosis, the
supplement is given in the form of potassium
chloride, whereas in patients with hypokalaemia
and metabolic acidosis as in d-RTA/type-I RTA (renal
tubular acidosis), potassium gluconate, potassium
citrate, and potassium bicarbonate are the
preferred choice. In addition, the underlying
aetiological or precipitating factor must be
identified and treated/avoided. Acetazolamide is
highly effective in individuals with familial/primary
periodic paralysis; whereas in individuals with
thyrotoxic periodic paralysis; it is not found to be
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beneficial. Beta-blockers may reduce the number
and severity of attacks by controlling hyperthyroid
status and restoration of euthyroid status. The
achievement of euthyroid status is definitive
treatment.
Q. 11. What are the complications of
hypokalaemic thyrotoxic periodic
paralysis?
Ans: The complications of hypokalaemic thyrotoxic
periodic paralysis are:-
Cardiac arrhythmias during attacks
Respiratory muscles paralysis or bulbar paralysis
Malignant hyperthermia
Delayed recovery during anaesthesia
Q. 12. What is the relevance of genetic
counselling in hypokalaemic thyrotoxic
periodic paralysis?
Ans: Genetic counselling and prenatal testing are
indicated in hypokalaemic periodic paralysis
because it is inherited in autosomal dominant
manner. In hypokalaemic thyrotoxic periodic
paralysis, the mode of inheritance is not known
and there is no positive family history and de novo
genetic mutation is also not known
12
; hence
genetic counselling is usually not necessary.
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