Abstract
Thyrotoxic periodic paralysis is a potentially fatal complication of hyperthyroidism, more common in Asian races, which is defined by a massive intracellular flux of potassium. This leads to profound hypokalaemia and muscle paralysis. Although the paralysis is temporary, it may be lethal if not diagnosed and treated rapidly, as profound hypokalaemia may induce respiratory muscle paralysis or cardiac arrest. The condition is often misdiagnosed in the west due to its comparative rarity in Caucasians; however it is now increasingly described in Caucasians and is also being seen with increasing frequency in western hospitals due to increasing immigration and population mobility. Here we describe the case of a patient with panhypopituitarism due to a craniopharyngioma, who developed thyrotoxic periodic paralysis due to excessive L-thyroxine replacement. This disorder has been described in Asian subjects but, to our knowledge, thyrotoxic periodic paralysis secondary to excessive L-thyroxine replacement has never been described in Caucasians.
Case report
Our patient was a 27-year-old man who was diagnosed at the age of 10 with a craniopharyngioma, which was treated with surgery and cranial radiotherapy. He developed panhypopituitarism and was on replacement therapy with hydrocortisone, growth hormone, testosterone, desmopressin and 200 μg of L-thyroxine. The patient was looked after in a different institution until he presented to our hospital in August 2008 with profound weakness in all four limbs. The patient reported that he had eaten a high carbohydrate meal (pizza) at 21.00 the previous night and woke up at 07.00 unable to get out of bed, with profound weakness in all four limbs. He had no sensory symptoms or visual disturbance. The patient reported similar (but milder) episodes occurring intermittently for the previous few years and was previously investigated for these episodes elsewhere with a 24-hour ECG and brain imaging, but no diagnosis was made.
Examination in the Emergency Department at 11.00 revealed flaccid quadraparesis affecting proximal more than distal muscle groups but no other neurological deficit. Reflexes were normal and all sensory modalities were intact. The patient was otherwise well and the rest of the examination was normal. He was clinically euthyroid. A CT scan that was done on the same day showed a small calcified suprasellar mass consistent with a previously treated craniopharyngioma but not causing any pressure effect.
Investigations revealed a serum potassium level of 1.8 mmol/L (normal = 3.5–5 mmol/L). Serum sodium, chloride, urea and creatinine were normal. Spot urinary potassium was low at 3.1 mmol/L (normal = 5–10 mmol/L). The electrocardiogram was normal. Arterial pH was normal at 7.4, with a normal serum bicarbonate level of 26 mmol/L. The patient's standard steroid replacement of hydrocortisone 10 mg b.i.d. had not been increased to supraphysiological doses at any time prior to admission. His potassium was replaced intravenously as part of sodium chloride infusion at a rate of 10 mmol potassium per hour. Within eight hours, serum potassium was within the normal range (3.6 mmol/L), and all symptoms and signs had resolved.
Endocrine testing following his presentation revealed excessive L-thyroxine replacement with a free T4 of 36.5 pmol/L (normal = 7–16 pmol/L) with undetectable thyroid-stimulating hormone (TSH) (undetectable TSH would be expected in cases of central hypothyroidism, especially following thyroxine treatment) and a total T3 of 4.64 nmol/L (normal = 1–2.8 nmol/L). Our laboratory uses the Beckman DXL assay for all thyroid function assays. Serum insulin-like growth factor-1 was normal (on growth hormone replacement). When his laboratory results from his previous service were obtained, he was found to have had a high free T4 on a few occasions dating back to 2003 (range 31–37 pmol/L); on one occasion only his serum potassium was 2.6 mmol/L with a free T4 of 37 pmol/L, although the patient was clinically euthyroid and asymptomatic then. All other serum potassium measurements that were done routinely before this acute event were normal.
His L-thyroxine dose has been reduced from 200 mcg o.d. to 125 mcg o.d., and he remains well on this dose for one year now without any symptoms with a free T4 of 10.6 pmol/L and an undetectable TSH.
Our working diagnosis was of thyrotoxic periodic paralysis (TPP) due to excessive L-thyroxine replacement. Once his free T4 was corrected, he remained well, with no muscular symptoms and with normal serum potassium. As our patient was biochemically hyperthyroid and hypokalaemic at presentation, his episodic symptoms had a temporal relationship to his thyrotoxic state dating back to 2003, and he had no family history of hypokalaemic periodic paralysis, we feel that thyrotoxic periodic paralysis is the likely diagnosis in this case.
Discussion
To our knowledge, TPP in a Caucasian due to excessive L-thyroxine replacement has not been previously reported. Our patient was over-replaced with thyroxine for a significant period of time, possibly five years, before he presented to us with classic signs and symptoms of TTP on a background of previous similar but milder episodes. He had a very low serum potassium level with low urinary potassium levels during the episode but normal values before and after the event, which is characteristic of this condition. There was no other apparent cause of GI potassium loss such as vomiting, diarrhoea or an eating disorder. He remained asymptomatic once his thyrotoxicosis was corrected.
Hypokalaemic periodic paralysis may be primary or secondary to an underlying, often autoimmune, condition. Primary familial hypokalaemic periodic paralysis is an autosomal dominant condition that mainly affects Caucasians, characterized by recurrent attacks of hypokalaemia and paralysis in patients who are clinically and biochemically euthyroid. TPP is the most common form of secondary hypokalaemic periodic paralysis. In contrast with primary periodic paralyses, it is sporadic in nature and most commonly affects Asian males, especially those of Japanese, Chinese, Vietnamese and Korean origin. The incidence in Japanese patients with thyrotoxicosis is estimated to be 1.9%. 1 It is very rare in Caucasians.
Patients are usually males between 20 and 40 years of age. The attack is characterized by recurrent, transient episodes of muscle weakness. These can be variable in terms of severity, but proximal muscles are affected more severely than the distal muscles. Sensory, bladder and bowel functions are rarely compromised, although it has been reported. 2 Paralysis of respiratory, bulbar and ocular muscles has been reported in a severe attack. 3 Attacks may be recurrent, and are commonly precipitated by ingestion of carbohydrate-rich meals. 4
Hyperthyroidism is often mild or clinically undetectable. 4 Most cases of hyperthyroidism in these patients are due to Graves' disease, but many rarer causes have been reported. There have been only three previous reports of TPP secondary to thyroxine intake. The first was in 1966 when paralytic episodes were experimentally induced in a euthyroid Asian population using therapeutic doses of thyroxine. 5 The two most recent cases both originated in Taiwan, but also involved patients of Asian descent. 6,7
Hypokalaemia during paralytic episodes is usually less than 3.0 mmol/L, with low urinary potassium, but the degree of hypokalaemia does not correlate with the clinical or biochemical severity of thyrotoxicosis. 4
It is thought that increased sodium/potassium-adenosine triphosphatase (Na/K-ATPase) pump activity results in rapid potassium influx into cells, with resulting hypokalaemia and paralysis. It appears that patients with TPP have an underlying predisposition for increased potassium shifts due to increased Na/K-ATPase activity, which is mediated either directly by thyroid hormone or indirectly via the hyperadrenergic state induced by thyroid hormone. The patient then presents with episodic hypokalaemia caused by the combination of an acute stimulus such as exercise with this underlying pathology. 8,9
The only proven preventive therapy is to achieve and maintain a euthyroid state. Acute attacks should be treated with an infusion of potassium chloride in isotonic saline. 4 Non-selective beta-blockers are a useful adjunctive therapy in the acute setting, but their role as monotherapy is unproven in large studies. However, a number of case reports have shown that both intravenous and oral beta-blockers effectively reverse acute attacks and prevent recurrences. 10–12
It is unclear whether patients with TPP have a genetic predisposition to activation of Na/K-ATPase. Certain single-nucleotide polymorphisms of Cav1.1 have been associated with TPP in southern Chinese patients. In contrast to familial hypokalaemic periodic paralysis, which is an autosomal dominant disorder with a well-understood genetic cause, the same does not apply to TPP, and there is little overlap between familial hypokalaemic periodic paralysis and TPP in terms of genetic predisposition. Also, it is difficult to ascertain human leukocyte antigen (HLA) susceptibility as the HLA subtypes associated with TPP in Asians are also associated with Graves' disease. 4
In summary, this represents the first case of TPP in a Caucasian due to excessive therapy with L-thyroxine. Due to increased immigration, it is likely that clinicians in the western world will see more of this condition in the Asian population, and hence clinicians should be aware of its existence and potential severity as it is easily treated and prevented.
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