Recurrent hypokalemic paralysis: An atypical presentation of hypothyroidism

Abstract

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INTRODUCTION

Hypokalemic periodic paralysis is the most common periodic paralysis, a rare channelopathy

manifested by episodic flaccid weakness secondary to abnormal sarcolemmal excitability.

Hypokalemic paralysis may be caused by a short-term shift of potassium into cells, seen in

hypokalemic periodic paralysis (caused by familial periodic paralysis or thyrotoxic periodic

paralysis), or a larger deficit of potassium as a result of severe renal or gastrointestinal potassium

loss.

Thyrotoxicosis is the most common cause of secondary hypokalemic periodic paralysis.

Recurrent hypokalemic paralysis is an extremely unusual presentation of hypothyroidism. To the

best of our knowledge, this is the fourth reported case of hypothyroidism associated with

recurrent hypokalemic paralysis.[13]

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CASE REPORT

A 30-year-old female presented with recurrent attacks of acute flaccid paralysis of all four limbs

since last 1 year. Each episode lasted for 2 to 5 days followed by spontaneous complete recovery

without potassium supplement in any form. Frequency of attack gradually increased up to three

episodes per month. It usually started with early morning weakness without any diurnal

variation. There was no history suggestive of altered sensorium, convulsion, visual, respiratory,

or bulbar weakness. She had no symptom suggestive of hypothyroidism.

The patient had quadriparesis with hypotonia, diminished deep tendon reflexes except delayed

relaxation of ankle jerks, flexor plantar response, and prominent neck muscle weakness. She had

normal higher mental function without any cranial nerve, sensory, or sphincter involvement. She

was thin built without pallor or edema. Her thyroid gland was not palpable. Other system

examination including chest and abdomen was within normal limit.

Laboratory investigations showed normal hemoglobin with high ESR, low potassium, and

normal sodium and serum creatine phosphokinase (CPK) level was very high (1067 mg/dl). Her

electromyography and nerve conduction study were normal. Thyroid function test revealed very

low level of thyroxine (both T3 and T4) with very high thyroid-stimulating hormone (TSH >

100). Serum anti-TPO antibody titer was also very high (386.4 IU/ml). Hypokalemia persisted

during attack ranging from 1.6 to 3.2 meq/L. Hypokalemic paralysis was diagnosed based on

clinical and biochemical parameters. No cause of secondary hypokalemia could be detected. Her

24-h urinary potassium excretion was 11.14 meq/L which was much below normal (normal

range 25-120 meq/L). Normal serum magnesium and urinary calcium excretion ruled out the

possibility of Gitelman's syndrome. Urine pH was within normal limit. The computed

tomography (CT) scan of the abdomen demonstrated normal adrenal gland. Her plasma rennin

activity (PRA) was measured normal (2.6 ng/ml/h).

During the acute period in hospital, the patient was treated with intravenous potassium (IV

potassium chloride, 40 meq/L of normal saline through peripheral vein at a rate of 20 meq/h) for

a week that lead to clinical recovery and also biochemical improvement to some extent. After

starting oral levothyroxine replacement, the patient continued with oral potassium replacement

(oral potassium chloride solution 40 meq twice daily) for another 2 weeks after which she could

be safely maintained with levothyroxine only. Hypokalemic state persisted up to 4 weeks of

levothyroxine replacement though the patient was clinically well. Subsequently, serum TSH

became normal with normal serum potassium level. With adequate control of hypothyroidism,

the patient did not have the need to take potassium supplement and no further attack of acute

flaccid weakness has been reported so far (for a period of 1 year during follow up).

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DISCUSSION

Periodic paralysis may be primary or secondary type. The paralytic attack can last from an hour

to several days and the weakness may be generalized or localized.[4] Disturbances of potassium

equilibrium can produce a wide range of disorders including myopathy, marked muscle wasting,

diminution of muscle tone, power, and reflexes.[5] The primary hypokalemic periodic paralysis

is autosomal dominant and is exacerbated by strenuous exercise, high carbohydrate diet, cold and

excitement, which was not found in this case.[4] In the primary type, episodes of weakness recur

frequently.

Many cases of secondary periodic hypokalemic paralysis have been reported in association with

gastroenteritis, diuretic abuse, renal tubular acidosis, Bartter syndrome, villous adenoma of

colon, and hyperthyroidism.[6] There was no history of diarrhea, vomiting, or diuretic abuse in

the present case. The absence of polyuria, polydipsia, nausea, vomiting, constipation,

hypochloremia, and hyponatremia ruled out Bartter syndrome. Normal serum magnesium and

urinary calcium excretion ruled out the possibility of Gitelman's syndrome. Similarly, none of

clinical features of renal tubular acidosis like polyuria, polydipsia, acidotic breathing, rickets,

and pathological fractures were present in this case.[7] Laboratory finding such as normal

urinary pH and lack of hyperchloremia during episode of paralysis also excluded the possibilities

of renal tubular acidosis. Characteristic features of hyperaldosteronism like hypertension and

polyuria were absent with normal adrenal gland in the CT scan of the abdomen.

The levels of thyroid hormones and TSH values in this patient indicate severe deficiency of

thyroxine. The presence of autoimmune thyroiditis is indicated by the high titer positivity of anti-

TPO antibodies in serum. The persistent hypokalemia during early periods of thyroxine

replacement can be due to the fact that thyroxine in pharmacological doses can cause increased

potassium excretion and water diuresis in patients with myxedema during initial part of therapy.

This may result in hypokalemia, especially in a patient with malnutrition and low stores of total

body potassium.

Hypokalemic periodic paralysis though common among Indian population varies greatly in

disease spectrum and magnitude in our country due to the heterogeneous pattern of etiology

behind it. Two case series that studied hypokalemic periodic paralysis in tertiary care centers of

India have observed that around 45% of all those patients had a secondary cause for their

condition and this secondary group had more severe hypokalemia that needed longer time to

recover.[8,9] Thyrotoxicosis, renal tubular acidosis, Gitelman's syndrome, and primary

hyperaldosteronism were among the prime conditions leading to hypokalemic periodic paralysis

but no case of hypothyroidism was found to be the etiology behind it.

The association of periodic hypokalemic paralysis with hypothyroidism has not been established

till now though probably only three similar cases have so far been reported stating the incidence

of recurrent hypokalemic paralysis in the presence of hypothyroidism in different clinical

scenarios.

Thyrotoxic Hypokalemic Periodic Paralysis Last updated Sunday, July 17th, 2011

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Clinical Synopsis

Thyrotoxic periodic paralysis (THKPP) is an uncommon disorder characterized by simultaneous

thyrotoxicosis, hypokalemia, and paralysis that occurs primarily in males of Asian descent,

including patients of Japanese, Chinese, Vietnamese, Korean and Filipino ancestry.

Kilpatrick et al. (1994) found six reports of thyrotoxic hypokalemic periodic paralysis in African-

Americans and described four additional cases, all in males. They concluded that the disorder

may be more frequent in blacks than previously suspected and should be considered when

patients present with unexplained hypokalemia, muscular weakness, and rhabdomyolysis.

Patients with THKPP in the United States reflect the ethnic makeup of the local population: the

predisposition of patients of Asian origin is very evident, but whites are more frequently affected

than most previous reports have recognized. Hispanics and American Indians also appear to be

at increased risk, and blacks have also been affected.

Except for the fact that hyperthyroidism is an absolute requirement for expression of the

disease, THKPP is identical to Hypokalemic periodic paralysis in its clinical presentation but

THKPP is rarely associated with a positive family history. Graves disease is the most common

cause of hyperthyroidism in affected patients, but any cause of thyrotoxicosis (including

administration of excessive amounts of exogenous thyroid hormone) can trigger attacks of

THKPP in susceptible subjects.

Clinical features of thyroid disease may be very subtle or virtually nonexistent; As a result,

thyroid function tests should be routinely monitored in patients with features of HypoKPP. The

thyrotoxicosis may be mild. Attacks can be precipitated by high carbohydrate intake, sleep

(onset of paralysis usually occurs during sleep), unusual exertion, infection, diarrhea, thyroid

hormone or alcohol abuse.

A number of researchers have reported that the serum insulin level is sharply elevated prior to

the attack of paralysis in THKPP. Increased sodium-potassium ATPase pump activity and

enhanced insulin response in patients with THKPP is postulated to contribute to the

hypokalemia. Spontaneous or induced attacks do not occur in persons whose hyperthyroidism

has been corrected.

Patients typically present with an acute episode of paralysis involving the muscles of the

extremities and limb girdles. The lower limbs are more frequently and severely involved than

the upper. Weakness may be asymmetrical. Proximal strength is more severely impaired than

distal strength.

A specific genetic basis is suggested by the fact that although occasional cases occur in

Caucasians the disorder is seen predominantly in Asians. It is primarily found in males,

although the occasional female patient presents. THKPP may be due to a genetic peculiarity of

muscle membranes. Multiple cases in families have been observed but the mode of inheritance

is not clear. (note: one genetic mutation has now been identified. This may not account for all

cases of THKPP, but it does strongly suggest a genetic cause for all cases.)

Genetics and Inheritance

Potassium Channel; In 2010, Ryan et al. identified mutations in KCNJ 18 (Kir 2.6);

Chromosome 17p11.2 as the cause of about 1/3 of cases of susceptibility to Thyrotoxic

HypoKPP. Specific mutations include: Arg399X, Gln407X, T354M; Lys366Arg; Arg205His;

I144fs (c.428 delC)

Laboratory Studies

In one study of 19 men with THKPP initial serum K levels upon admittance to hospital ranged

from 1.1 to 3.4 mmol/L (mean, 1.90.5 mmol/L). Serum Mg level was measured in 18 episodes

during paralysis and in 13 episodes after paralysis. During paralysis episodes, all patients had

low or low-normal Mg levels (0.60-0.80 mmol/L 1.5-1.9 mg/dL). Only two patients received

supplemental magnesium sulphate, but Mg levels increased by 0.1 mmol/L or more (0.24

mg/dL) in all patients who had it checked. Serum creatine phosphokinase levels were obtained

in 18 episodes during paralysis. Twelve patients had elevated creatine phosphokinase values, 5

of which were of 1000 U/L or more. Serum alkaline phosphatase levels were mildly elevated in

12 of 16 patients, ranging from 118 to 268 U/L (normal, 39-117 U/L).

Thyroid Studies

Elevated total thyroxine, triiodothyronine resin uptake, and total triiodothyronine levels.

Radioiodine scan for Graves disease and adenomas

Cardiac Signs

Consistent with Hypokalemia or Thyrotoxicosis; During paralysis, sinus tachycardia, diffuse ST-

T changes, flattening of T waves, prolonged QT intervals, and U waves. Sinus arrest and second-

degree atrioventricular block also have been described in patients with THKPP, ventricular

fibrillation and ventricular tachycardia.

Treatment

The mainstay of emergency treatment has always been potassium replacement, however not all

patients respond to potassium alone and recent evidence suggests that combining potassium

and propranolol is a more effective therapy. It has been recommended that 27 mEq of KCl be

given every 2 hours orally for 6 hours and then every 4 hours with careful monitoring. Because

THKPP patients may develop rebound hyperkalemia, (Manoukian et al 1999) recommends that

K+ replacement therapy should be cautious and should not exceed 90 mEq of KCl per 24 hours

unless there is a reason for K+ loss, such as diarrhea, vomiting or diuretic use.

In the Manoukian study (19 patients) all patients remained attack free as long as they took

methimazole and propranolol hydrochloride or after radioiodine 131 treatment. Eighteen

patients were eventually treated with radioiodine 131 therapy. None of the patients had paralytic

episodes after a euthyroid state was achieved. Nonselective beta-blockers such as propranolol

may be useful to prevent attacks of paralysis once patients begin taking antithyroid medications

but are not yet euthyroid. For information on management of the Hypokalemic aspect of THKPP

see Hypokalemic Periodic Paralysis. http://hkpp.org/physicians/thyrotoxic

Thyrotoxic Hypokalemic Periodic Paralysis FAQ Last updated Saturday, June 25th, 2011

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What is Thyrotoxic Hypokalemic Periodic Paralysis?

Thyrotoxic Hyperkalemic Periodic Paralysis (TPP) is an uncommon disorder with three

characteristics which occur at the same time:

1. too much thyroid hormone

2. low levels of potassium in the blood (hypokalemia)

3. muscle weakness or paralysis

TPP occurs most often in males of Asian descent, including Japanese, Chinese, Vietnamese,

Korean and Filipinos. It also occurs more frequently in those of Native American and Latin

American descent, but only occasionally in those of European descent.

The thyroid gland is part of the endocrine system. It is located in the neck and produces several

hormones that help control growth, digestion, and metabolism. A complex set of mechanisms

control the rate of thyroid gland activity. Too much thyroid hormone (called Hyperthyroidism or

thyrotoxicosis) is due to an overactive thyroid gland. Hyperthyroidism is not a specific disease,

but a symptom of an underlying condition or disease. The causes of hyperthyroidism include

Graves' disease; tumors of the thyroid or other endocrine glands; inflammation or infection of

the thyroid; taking too much thyroid hormone; and taking too much iodine. Graves' disease

accounts for 85% of all cases of hyperthyroidism.

What tests are used to diagnose TPP?

The doctor will do blood tests to check the levels of various thyroid hormones including; TSH

levels, T3, T3 resin uptake and T4. During an attack of weakness the doctor will do a blood test

to check the level of potassium. In TPP, the level of potassium is low during attacks but normal

between attacks.

No one in my family has this disease. How did I get it?

It's been clear for many years that most types of periodic paralysis are inherited, but until

recently the relationship between inheritance and TPP was unclear. It seemed obvious that there

was some genetic factor at work, or TPP wouldn't occur more often in men of Asian ancestry, but

no genetic mutation could be identified. In 2010 a team of researchers discovered a group of

mutations which increase a persons chance of developing TPP. While this does not explain all

cases this is a real breakthrough and helps to establish a genetic basis for the disorder. But even

when a TPP mutation is inherited a person will not develop symptoms unless their thyroid

becomes overactive. This means generations might pass in a family between two affected

individuals.

What triggers attacks of TPP?

The same factors which trigger attacks of Hypokalemic Periodic Paralysis will trigger attacks of

TPP. Meals high in starchy and sweet foods may trigger an attack. Taking thyroid hormones may

trigger an attack. Sleep or resting after exercise may trigger an attack. For a more complete

discussion on triggers see the section on Hypokalemic Periodic Paralysis.

How do I avoid having attacks?

Your physician will treat the underlying thyroid disorder, which will eventually cure your TPP.

In the meantime you should determine what triggers your attacks and avoid those triggers.

Medication is usually necessary until the thyroid problem is brought under control.

What medications are prescribed for TPP?

Beta-blockers like propranolol are used to treat TPP, along with a potassium supplement. But

the overactive thyroid must be treated. Once the underlying thyroid problem is corrected with

medication, radiation or surgery the symptoms of TPP usually disappear.

Low Potassium & Thyroid Relationship

Thyroid hormones help regulate physical development, facilitate energy conversion in cells and affect the

way your organs function. Your body uses potassium to facilitate the proper function of nerve and muscle

cells. Low potassium is associated with high levels of thyroid hormones. Treating low potassium caused

by excess thyroid hormones involves lowering thyroid hormone level.

Hypokalemia Hypokalemia is defined as low levels of potassium in your blood. Normal blood potassium levels should be between

3.6 mEq/L and 4.8 mEq/L, MayoClinic.com says. Hypokalemia means your blood potassium levels have dropped to

less than 2.5 mEq/L. This causes symptoms such as weakness, fatigue, muscle cramps and arrhythmia to occur.

Hypokalemia is fatal if left untreated.

Potassium and Thyroid Gland Thyrotoxic periodic paralysis is a condition that induces moments of muscle weakness and paralysis in people with

elevated levels of thyroid hormones. This form of hyperthyroidism causes your potassium levels to drop. Muscle

weakness or paralysis caused by low potassium commonly occurs in the shoulders and hips and typically lasts

between three hours and a whole day. Hyperthyroidism also causes nervousness, irritability, increased perspiration

and insomnia, KidsHealth notes. Diagnosing potassium and thyroid problems involves testing the blood to

determine blood potassium and thyroid levels. Treating hyperthyroidism sometimes requires surgical intervention to

remove most of the thyroid gland. Thyroid replacement hormones are usually given after surgery to prevent thyroid

hormones from dropping below

Treating Low Potassium and Possible Complications Treating low potassium involves the use of potassium supplements. Eating foods that have potassium

helps prevent hypokalemia. Foods like bananas, bran, kiwi, peaches and tomatoes contain potassium. If

your potassium levels remain low for a prolonged period, complications such as kidney damage are likely

to occur. Consult a doctor before taking potassium supplements in order to determine your treatment

options.