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Etiology of Hypokalemic Paralysis in Korea: Data from a Single Center

Recognizing the underlying causes of hypokalemic paralysis seems to be essential for the appropriate management of affected patients and their prevention of recurrent attacks. There is, however, a paucity of documented reports on the etiology of hypokalemic paralysis in Korea. We retrospectively analyzed 34 patients with acute flaccid weakness due to hypokalaemia who were admitted during the 5-year study period in order to determine the spectrum of hypokalemic paralysis in Korea and to identify the differences in clinical parameters all across the causes of hypokalemic paralysis. We divided those 34 patients into 3 groups; the 1st group, idiopathic hypokalemic periodic paralysis (HPP), the 2nd, thyrotoxic periodic paralysis (TPP), and the 3rd group, secondary hypokalemic paralysis (HP) without TPP. Seven of the patients (20.6%) were diagnosed as idiopathic HPP considered the sporadic form, and 27 patients (79.4%) as secondary HP. Among the patients diagnosed as secondary HP, 16 patients (47.1%) had TPP. Patients of secondary hypokalemic paralysis without TPP required a longer recovery time compared with those who had either idiopathic HPP or TPP. This is due to the fact that patients of secondary HP had a significantly negative total body potassium balance, whereas idiopathic HPP and TPP were only associated with intracellular shift of potassium. Most of the TPP patients included in our study had overt thyrotoxicosis while 3 patients had subclinical thyrotoxicosis. This study shows that TPP is the most common cause of hypokalemic paralysis in Korea. And we suggest that doctors should consider the presence of TPP in patients of hypokalemic paralysis even if they clinically appear to be euthyroid state.


Introduction
Hypokalemic paralysis is an important cause of acute flaccid paralysis that ranges from mild muscle weakness to severe paralysis with life-threatening cardiac arrhythmia and respiratory paralysis 1,2) . A number of underlying etiologies have been described, such as thyrotoxicosis, renal tubular acidosis (RTA), Gitelman-syndrome, barium poisoning, diuretics and diarrhea; however, in some cases, it is difficult to identify the exact etiology of hypokalemic paralysis. Misdiagnosis may lead to mismanagement, interference in appropriate treatments, and to failure for the prevention of recurrent attacks.
Hypokalemic periodic paralysis (HPP) is the most common cause of hypokalaemic paralysis in Caucasians 3) . HPP includes familial and sporadic form. Familial HPP is an autosomal dominant hereditary disorder while the cause of sporadic HPP remains unknown. Most cases of HPP in Western countries are the familial forms while most cases of HPP identified in Asians are sporadic 4) . Most Asian patients of sporadic HPP have been diagnosed as idiopathic HPP, also called primary HPP. In Asian population, however, the most common cause of hypokalemic paralysis is the thyrotoxic periodic paralysis (TPP) 5)

Patients and methods
We retrospectively identified 34 patients with acute flaccid weakness due to hypokalaemia who were admitted to the Kyung-Hee Medical Center from Jan. 1,2006 to the end of Dec. 2011. A definitive diagnosis of hypokalemic paralysis was confirmed based on the following criteria: (1) a transient and severe paralytic attack of the limb observed at the hospital by a physician, (2)

Statistical analysis
Continuous variables were expressed as mean ± standard deviation (SD) and were compared to using Student's T-test or Kruskal-Wallis test. Categorical variables were compared to using the Chi-squared test or two-by-K test.
All statistical analyses were conducted by using the SPSS 17.0 statistical software (Chicago, IL, USA). Differences were considered significant if the p-value less than 0.05.

Results
Those 34 patients with hypokalemic paralysis had a        , which is consistent with previous studies demonstrating TPP as the most common cause in Chinese and Japanese patients. Contrastingly, in Caucasian and Indian, familial HPP is the most common cause of hypokalemic paralysis, whereas in the Asian population, TPP is the most common cause [5][6]14) . There had been a paucity of reports documented on the etiology of hypokalemic paralysis in Korea, and therefore this might be the first to report that TPP is the most common cause of hypokalemic paralysis in Korea.
Earlier work has shown that mutations in the CACNA1S gene, which encodes the alpha 1 sub-unit of the skeletal muscle L-type voltage-dependent calcium channel, are responsible for the majority (70%) of the cases of familial HPP 8,9) . Missense mutations in the SCN4A gene, which encodes the skeletal muscle voltage-gated sodium channel alpha sub-unit, account for approximately 10% of the cases. Each mutation has different penetrance of phenotype, which also depends on gender [10][11] . Several Korean cases of familial HPP have been reported, but cases of previously identified gene mutations are rare. Even without genetic analysis associated with calcium channel or sodium channel in this study, the idiopathic HPP in our study could be regarded as a sporadic form in view of the absence of the familial history or previous symptoms. This is consistent with previous reports that most of the HPP patients in Western countries were of familial forms, whereas those reported from Asia were predominantly sporadic 4) . This raises the possibility that HPP in different ethnic settings may be linked to different types of mutations or to different environmental factors 12) . We were not able to investigate for the presence of mutation in patients with idiopathic HPP, and it seems clear that more genetic studies should be necessary.
We divided the patients with secondary hypokalemic paralysis into two groups, because TPP was clearly the most common cause of hypokalemic paralysis in Korea and it had a distinct clinical character from the other causes of secondary HP. The recurrence of paralytic attacks, presence of respiratory paralysis as a clinical feature, and most serum electrolyte (sodium, creatinine, inorganic phosphate or magnesium) levels were similar in all groups.
There were significant differences in the serum potassium and serum calcium levels, and in the required potassium for the improvement among the three groups. In accordance with earlier reports, patients of secondary hypokalemic paralysis required a larger amount of potassium for the clinical improvement and had a longer recovery time compared with those who have idiopathic HPP or TPP 13) .
Patients of secondary hypokalemic paralysis had a significantly negative total body potassium balance, whereas idiopathic HPP and TPP were associated with only intracellular shift of potassium, thus requiring a less amount of supplemental potassium 14) .
The precipitating causes of paralytic attacks were similar across all groups, including exercise, URI and alcohol intake. The patient's ages at first attack were also similar.
Premoni-tory symptoms such as mild weakness and paralysis of both lower limbs, were more common in the TPP group than the idiopathic HPP group, which may represent one of the most important clinical differences between two groups.
The incidence of TPP among Asians, the most frequently affected population, is approximately 2%. While previously TPP was largely unknown in the West, the number of reported cases in Western countries has increased recently 15) . All reported TPP patients were sporadic cases without a family history of TPP, with the exception of one patient. This feature is important for differentiating TPP from familial hypokalemic periodic paralysis, which is more common among Caucasians 16) .  [17][18] . In hyperthyroid males, significantly increased plasma testosterone levels have been reported 19) .
In Graves'disease, the plasma concentration of 17-β-estradiol is increased in males but remains unchanged in females 20) . The potassium channels in smooth muscle cells are activated by testosterone and estrogen in animal studies 21,22) . Furthermore, the age distribution of TPP patients coincides with the commonly observed age distribution of not only hyperthyroidism but the rapid increase in testosterone production. However, currently, we do not have any concrete evidence to prove the effects of sex hormones and potassium channels on TPP; this might be an important direction for future research.
The leading predictor of TPP in large case series was Graves' disease [23][24] .
We should take note of that Graves' disease was also the most common cause of TPP in our study. Subacutethyroiditis was also an etiological factor in our study. A thyrotoxic state is generally considered necessary for the induction of TPP, however, some studies have reported that acute paralysis had occurred in even in a euthyroid state after a treatment of the thyrotoxicosis [25][26] . Most of the patients included in our study had overt thyrotoxicosis while 3 patients had only subclinical thyrotoxicosis.
We suggest that doctors should consider TPP even if a patient is under taking medicine for thyrotoxicosis or is having the possibility of subclinical hyperthyroidism, i.e., an apparent euthyroid state. Accordingly, those with hyperthyroidism and TPP should not be presumed to have Graves' disease, for some of them may experience hypothyroidism after subacute thyroiditis.
The patients with secondary HPP without TPP in our study required a longer recovery time compared with those who have idiopathic HPP or TPP. Those patients with secondary HP had a significant negative total body potassium balance, and required larger amounts of potassium compared with idiopathic HPP and TPP groups.
Because of the limitations on the retrospective data, the relatively small number of patients and restriction to a single center in this study, further prospective largescale studies are required for delineating the spectrum of etiologies, clinical findings, treatment outcomes, and predictors of hypokalemic periodic paralysis.
In conclusion, our study revealed that, in Korea, idiopathic (primary) hypokalemic periodic paralysis occurred in 20.6% of the patients. The most common cause of hypokalemic paralysis in Korea was thyrotoxicosis (47.1%).