Hypokalaemic Thyrotoxic Periodic ParalysisSN Chugh*, Surekha Dabla**, Kiran Chugh***, HK Aggarwal****

A 22-year-old male person was admitted with symptomsand signs suggestive of thyrotoxicosis (Fig. 1). Hedescribed sudden weakness of all the four limbs 5 daysbefore admission. He also complained of shooting pain inthe legs while walking and painful cramps in his arms andneck associated with difficulty in breathing. There was nohistory of any gastrointestinal or any cardio-vascularproblems though he complained of palpitations andsweating off and on.

Past history1½ 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 hadbeen experiencing repeated episodes of weakness duringthis period, following either a heavy meal or rest afterexercise.

Personal historyThe patient was a non-smoker and a teetotaler.

Family historyThere was no history of similar illness in the family.

ExaminationThe 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 insupine posture; the respiratory rate was 24/minute.Examination of neck revealed diffuse goitre with systolicbruit over it. Neurological examination revealed fine tremorsof both hands, proximal muscle weakness in both arms andlegs associated with hyporeflexia in all the four limbs.Cardiovascular system was within normal limits. The patient’slook was anxious, whereas the higher mental functions andthe cranial nerves were normal. There was no sensoryabnormality. Systemic examination was normal.

The results of the laboratory investigations done duringhospitalisation of the patient are shown in (Table I).

Table I: The results of the laboratory investigationsdone 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

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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 µ IU/ml

Arterial blood gas analysis pH - 7.32; pCO2 - 44.7%; Oxygensaturation - 75.6%; Bicarbonates (HCO3)- 20.4

Electrocardiogram (ECG) showed S. tachycardia with QT prolongation andTUP segment with occasional ventricularectopic beats (Fig. 2)

Skiagram of chest showed Mild cardiomegaly

Ultrasonography of thyroid Both lobes of thyroid showed alteredechotexture with increased blood flow.Each lobe measured 4.3 cms in lengthand 2.0 cms in antero-posterior plane.

Urine examination No abnormality was detected

Q. 1. What is the probable clinical diagnosisin this patient?

Ans: In view of unequivocal evidence of thyrotoxicosiswith frequent periodic paralysis and documentedhypokalaemia (2.1 mEq/l) during the episodes ofparalysis, the diagnosis of hypokalaemic thyrotoxicperiodic paralysis (HTPP) was kept in this case.

Q. 2. What is the clinical presentation ofhypokalaemic thyrotoxic periodicparalysis (HTPP)?

Ans: Hypokalaemic thyrotoxic periodic paralysis(HTPP) is a rare disorder affecting mainly men ofAsian descent. It begins at 20 - 40 years of age.The sex ratio (M:F) is 20:1. It is characterised bysudden recurrent episodes of painless weaknessor paralysis without alteration in consciousness,usually occurring after a high-carbohydrate mealor heavy exertion followed by a prolonged restin patients with thyrotoxicosis1, 2. Patients usuallypresent with clinical features of thyrotoxicosisfollowed 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 ofmuscles of the eyes, respiration, and swallowing3.The mental functions remain normal, and thesensory modalities are preserved withdiminished tendon reflexes. These patients mayhave sinus tachycardia, diffuse ST-T changes,flattening of ‘T’ waves, prolonged QT intervalsand ‘U’ waves and cardiac arrhythmias on ECGbecause of a drop in potassium levels (< 3.0 mEq/l). Sometimes dangerous arrhythmias such astorsade de pointes and ventricular fibrillation maydevelop4.

Q. 3. What is the aetiopathogenesis of thiscondition?

Ans: The pathogenesis of hypokalaemic thyrotoxicperiodic paralysis (HTPP) has not been clearlyelucidated. However, it is known to occur mostcommonly in patients with Graves’ disease or innodular toxic goitre5. Attacks of periodic paralysiscan also, though not always, be experimentallyinduced by a provocation test with glucose (3 g/kg) and insulin (0.1 IU/kg IV)6 indicating thatparalysis is due to hypokalaemia and not becauseof thyrotoxicosis itself. Patients with this type ofparalysis have an inherent defect in Na+-K+-ATPase activity which is sensitive to thyroidhormone7. The thyroid hormone alters the cellmembrane permeability to potassium throughNa+-K+- ATPase pump leading to intracellular shiftof potassium resulting in hypokalaemic periodicparalysis without depleting the total body K+

(potassium) stores.

Q. 4. What are the causative/aggravatingfactors for repeated episodes ofweakness? How can they beprevented?

Ans: Hypokalaemia is the underlying biochemicaldisturbance which provokes periodic paralysis inthese patients2.

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, insulintherapy, Amphotericin B, α-adrenergicantagonists, β-2 agonists, steroids(glucocorticoids as well as mineralocorticoids),penicillin and its derivatives, etc.

The episodes, hence, can be prevented by takinglow carbohydrate, low salt, and potassium rich dietincluding fruit juices. The diuretics, if the patient istaking for some other disorder, must be stoppedand replaced with other potassium-sparingdiuretics, if needed. Abstinence of alcohol shouldalways be recommended.

Q. 5. Do the paralytic attacks have anyrelation to season or time?

Ans: Yes, the attacks appear to have seasonal variation,usually occurring during the warmer months (Maythrough September in our country) and less oftenduring the colder months (December throughMarch). The paralysis also follows a diurnal pattern,often occurring at night when the person is restingin bed 8. It does not occur when the person isperforming any physical activity.

Q. 6. What are the common conditionssimulating periodic paralysis?

Ans: The following are the common conditions whichsimulate periodic paralysis. Their clinicaldifferentiation is tabulated (Table II).

Table II: Common conditions simulating periodicparalysis.

1. Guillain-Barré The weakness in Guillain-Barrésyndrome syndrome follows some infection

(post-infectious) in 60% of thecases and it lasts for several weeks;whereas hypokalaemic thyrotoxicperiodic paralysis is a transient

condition lasting from hours todays. The cerebrospinal fluid (CSF)is characteristic in Guillain-Barrésyndrome, showing increasedprotein content with few or nocells (albumino-cytologicaldissociation) while it is normal inhypokalaemic thyrotoxic periodicparalysis.

2. Polymyositis Polymyositis is frequentlyassociated with malignancies andis characterised by elevatedcreatinine kinase (CK) levels andabnormal electromyography(EMG). Polymyositis is usually adiagnosis by exclusion.

3. Myasthenia gravis An acquired autoimmune disorderin which autoantibodies (IgG) areproduced against acetylcholinereceptors at neuromuscularjunctions; Ocular musclesweakness is characteristic. Thediagnosis is confirmed byelectromyography (EMG) andserological tests for the presenceof acetylcholine receptorantibodies.

4. Spinal cord These cases present with definitecompression focal neurological deficit involving

motor, sensory, and bladderfunctions which is progressive.There is a definite level reflectingthe site of compression.Radiological imaging (CTmyelogram) confirms thediagnosis.

5. Andersen An autosomal disorder withsyndrome mutation in potassium channel

and it is characterised by periodicparalysis and distinct facialfeatures with short stature, low-set ears, hypertelorism, and longQT interval predisposing toventricular tachyarrhythmia.

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6. Brodie disease An autosomal recessive exercise-induced myopathy that causesmuscular stiffness due to impairedmuscle relaxation.

7. Thomsen An autosomal dominant disorderdisease with the defect lying in the

channel gene. It usually occurs ininfancy and childhood. Myotoniais worsened by exposure to coldand decreased by activity. Musclestrength is normal.

8. Becker muscular An autosomal recessive disorderdystrophy characterised by severe muscle

weakness associated with musclehypertrophy. EMG is diagnostic.

9. Schwartz- An autosomal recessive disorderJampel characterised by myopathy,Syndrome muscle stiffness, short stature,

chondrodystrophy, bone and jointdeformities, hypertrichosis, andblepharophimosis.

10. Idiopathic familial The clinical and biochemicalperiodic paralysis features of hypokalaemic

thyrotoxic periodic paralysis aresimilar to those of idiopathicfamilial periodic paralysis exceptthat in the latter, thyroid functionsare normal and there is positivefamily history. Idiopathic familialperiodic paralysis is transmitted byan autosomal dominant mannercaused by a defect in the geneCACLNAIA3.

Q. 7. What are the various causes ofhypokalaemic periodic paralysis andwhat are their differentiating features?

Ans: The various conditions associated withhypokalaemia and periodic paralysis are:-

1. Primary idiopathic familial periodicparalysis: It is caused by mutations inCACLNAIA3 gene. It is an autosomal dominantdisease in which defect lies in the Ca++

channels. The patients present with completeparalysis with sparing of bulbar musculatureusually in childhood or adolescence. Diagnosisis confirmed by positive family history, absenceof other secondary causes of hypokalaemia,EMG, and muscle biopsy. Avoidance of highcarbohydrate diet, physical exercise, andacetazolamide are helpful in treating thiscondition.

2. Thyrotoxic periodic paralysis: It is commonin males of Asian descent. Mutations inpotassium channel are identified. Features ofthyrotoxicosis may or may not be observed.Presentation is usually at adult life withabnormal thyroid functions. The treatmentconsists of restoration of serum potassiumlevels and antithyroid drugs.

3. Primary hyperaldosteronism (Connsyndrome): This condition is characterised byhypertension (specially diastolic), polyuria,polydipsia, and muscular weakness. There ishypersecretion of aldosterone by adrenal glands.Hypokalaemia, hypernatraemia, and alkalosis arethe underlying metabolic disturbances. Thediagnosis is made by elevated plasma and urinealdosterone levels and low plasma renin level.Treatment is of the positive basic cause.

4. Barium poisoning: Barium is used in variousalloys, in paints, soap, paper, and rubber, and inthe manufacture of ceramics and glass; and theworkers in these industries are predisposed toit. It lowers the serum potassium levels byblocking calcium-activated potassium channelsthat control cellular potassium efflux. Thus,barium intoxication results in a rise ofintracellular potassium and a correspondingdrop of extracellular potassium leading tohypokalaemia9.

5. Liquorice ingestion: Liquorice is a medicinalplant having therapeutic uses as expectorant,demulcent, anti-inflammatory and laxative; andis also used to normalise immune functions. Itcontains glycyrrhizin which inhibits the activity

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of 11β-HSDH (hydroxy steroid dehydrogenase)which ultimately leads to mineralocorticoidexcess and hypokalaemia. Liquorice root toxicityfollowing prolonged ingestion leads to periodicparalysis.

6. Thyroid hormone abusers: Thyroid hormonedrives potassium into cells via sodium-potassium ATPase pump and leads tohypokalaemia. Iatrogenic use by obese patientswith intention to lower their weight maypredispose them to it.

Q. 8. How will you confirm the diagnosis?Ans: The diagnosis of hypokalaemic thyrotoxic

periodic paralysis is confirmed by clinical andbiochemical evidence of thyrotoxicosis andhypokalaemia with or without an abnormalelectrocardiogram (ECG) during the attacks.Electromyography (EMG) is confirmatory andshows electrical silence during attacks10. Musclebiopsy occasionally may show abnormality.Molecular genetic testing identifies the mutationin 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 itsfurther episodes;

2. To normalise the serum potassium levels.

The treatment of hypokalaemia is determined byseverity of symptoms, serum potassium levels, andthe ECG changes, if any. Accordingly, the cases canbe managed as:

Mild hypokalaemia (3 - 3.5 mmol/l): Oralpotassium supplements in the form of potassiumchloride 30 to 100 mmol/day are adequate andgiven with juice and at meals.

Moderate hypokalaemia (2.5 - 3.0 mmol/l):Initially these cases are managed with oralpotassium supplements, and if the patient stillremains symptomatic then 10 mmol of potassium/

hour is started intravenously in 5% mannitol (avoidglucose and saline as diluent) with cardiacmonitoring and serum potassium levelsmonitoring.

Moderately severe hypokalaemia (2 - 2.5mmol/l): Oral potassium supplements if toleratedby the patient are given, and if there is noimprovement in 1 to 2 hours then 15 mmol ofpotassium per hour is given intravenously in 5%mannitol with continuous monitoring of cardiacsystem and serum potassium concentrations.

Severe hypokalaemia (< 2 mmol/l): Oralpotassium replacement if tolerated by the patient.In addition, administer upto 20 mmol of potassiumper hour intravenously in 5% mannitol withcontinuous cardiac and serum potassiumconcentration monitoring.

In the present case, the patient having serumpotassium concentration 2.1 mEq/l was treated asa case of moderately severe hypokalaemia withintravenous potassium infusion.

Q. 10. How will you prevent such attacks?Ans: Prevention of attacks: Preventive treatment is

aimed at decreasing the frequency of symptomsand paralytic attacks; therefore, the patient isadvised to take oral potassium supplements 20 -40 mEq/day in 2 to 4 divided doses which areavailable as potassium acetate, potassium chloride,potassium bicarbonate, potassium citrate, andpotassium gluconate, etc. In patients withhypokalaemia and metabolic alkalosis, thesupplement is given in the form of potassiumchloride, whereas in patients with hypokalaemiaand metabolic acidosis as in d-RTA/type-I RTA (renaltubular acidosis), potassium gluconate, potassiumcitrate, and potassium bicarbonate are thepreferred choice. In addition, the underlyingaetiological or precipitating factor must beidentified and treated/avoided. Acetazolamide ishighly effective in individuals with familial/primaryperiodic paralysis; whereas in individuals withthyrotoxic periodic paralysis; it is not found to be

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beneficial. Beta-blockers may reduce the numberand severity of attacks by controlling hyperthyroidstatus and restoration of euthyroid status. Theachievement of euthyroid status is definitivetreatment.

Q. 11. What are the complications ofhypokalaemic thyrotoxic periodicparalysis?

Ans: The complications of hypokalaemic thyrotoxicperiodic 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 geneticcounselling in hypokalaemic thyrotoxicperiodic paralysis?

Ans: Genetic counselling and prenatal testing areindicated in hypokalaemic periodic paralysisbecause it is inherited in autosomal dominantmanner. In hypokalaemic thyrotoxic periodicparalysis, the mode of inheritance is not knownand there is no positive family history and de novogenetic mutation is also not known12; hencegenetic counselling is usually not necessary.

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thyrotoxicosis in Chinese. Br Med J 1967; 1: 451-5.2. Salifu MO, Otah K, Carroll HJ et al. Thyrotoxic hypokalemic

paralysis in Black man. Quart J Med 2001; 94: 659-60.3. Miller D, del Castillo J, Tsang TK. Severe hypokalaemia in

thyrotoxic periodic paralysis. Am J Emerg Med 1989; 7 (6):584-7.

4. Fisher J. Thyrotoxic periodic paralysis with ventricularfibrillation. Arch Intern Med 1982; 142 (9): 1362-4.

5. Ober KP. Thyrotoxic periodic paralysis: report of 7 cases, areview of literature. Medicine 1992; 71: 109-20.

6. Schulze-Bonhage A, Fiedler M, Ferbert A. Periodic paralysisas the first manifestation of hyperthyroidism. Dtsch MedWochenschr 1996; 121: 1498-1500.

7. Chan A, Shinde R, Chow CC et al. In vivo and in vitro sodium-pump activity in subjects with thyrotoxic periodic paralysis.BMJ 1991; 303 (6810): 1096-9.

8. Charness ME, Johns RJ. Hypokalemic periodic paralysis.Johns Hopkins Med J 1978; 143: 148-53.

9. Goyer R. Toxic effects of metals. In: Klaassen CD, AmdurMO, Doull J (Eds.). Casarett and Doull’s Toxicology- theBasic Science of Poisons. 3rd Ed. New York: MacmillanPublishing Co. 1986; 623-4.

10. Kelley DE, Gharib H, Kennedy FP et al. Thyrotoxic periodicparalysis: Report of 10 cases and review ofelectromyographic data. Arch Intern Med 1989; 149: 2597-2600.

11. Dias Da Silva MR, Cerutti JM, Arnaldi LA, Maciel RM. AMutation in the KCNE3 Potassium Channel Gene isassociated with susceptibi l i ty to ThyrotoxicHypokalemic Periodic Paralysis. J Clin Endocrinol Metab2002; 87 (11): 4881-4.

12. Lin SH. Thyrotoxic Periodic Paralysis. Mayo Clin Pro 2005; 80:99-105.