Thyrotoxic periodic paralysis (TPP) is an uncommon but dangerous complication seen in thyrotoxic patients. It is characterized by hypokalemia associated with acute proximal symmetrical lower limb weakness and can progress to involve all four limbs and the respiratory musculature. The mechanisms of hypokalemia are incompletely understood. The prevailing theories include increased Na-K ATPase pump activity and mutations in genes encoding Kir channels in skeletal muscle. It is often confused with familial periodic paralysis (FPP) due to the similarity in presentation but can be differentiated based on the presence of thyrotoxic features and biochemical testing. Commonly recorded and described in East Asian males, the incidence of TPP has been rising in the West and other parts of the world. Knowledge regarding identification, early treatment, and prevention of future episodes of TPP is essential in mitigating this potentially lethal complication.
Any cause of hyperthyroidism can lead to thyrotoxic periodic paralysis. They include Grave disease (most common), toxic nodular goiter, solitary toxic nodule, iodine-induced thyrotoxicosis, excess exogenous thyroxine use, thyroiditis, thyrotropin-secreting pituitary adenoma, and amiodarone-induced thyrotoxicosis.[1][2]
Common factors triggering attacks of periodic paralysis include the consumption of carbohydrate-rich foods, strenuous physical activity, high salt/sodium intake, stresses (surgical, infectious, psychological), trauma, and drugs (diuretics, estrogens, acetazolamide, epinephrine, laxatives, corticosteroids, non-steroidal anti-inflammatory drugs, licorice, fluoroquinolones, aminoglycosides, and ecstasy).[1][3][4][5][6][7][8]
TPP has been well-documented in the Asian population. Reported incidences vary from 1.9% in Japanese thyrotoxic patients to 1.8% in Chinese thyrotoxic patients.[9][6] Data on the incidence rate in the West is mostly unknown, with one study reporting a rate between 0.1% to 0.2% in thyrotoxic patients in North America.[4] Recently, however, the incidence of TPP in Western countries has increased, whereas the incidence in Japan has reduced.[10][11]
Cases of TPP have also been reported in children, Europeans, Hispanics, Indians, Malaysians, Vietnamese, Saudis, Polynesians, and the Turkish populations.[12][13][8][14] Several studies have shown thyrotoxic males have a much higher incidence of TPP compared to females, albeit the higher incidence of thyrotoxicosis in females.[15][5][16][17][18] The incidence among Japanese thyrotoxic patients was recorded as 4.3% in males and 0.04% in females.[19] In the Chinese, thyrotoxic males demonstrated an incidence of 13% compared to 0.13% in thyrotoxic females.[6] It usually manifests around the age of 30-50.[6][20][21][22]
The mechanism of TPP involves two major factors: the occurrence of hypokalemia and associated muscle paralysis. Skeletal muscles house the largest share of total body potassium in the body (2600mmol) and play a vital role in maintaining extracellular potassium homeostasis. This balance is maintained by the sarcolemmal Na-K ATPase pumps and K channels. The former regulates the intracellular movement of potassium, whereas the latter, including the inward rectifying (Kir) and delayed rectifying potassium channels, regulates the extracellular movement of potassium.[23]
Thyrotoxicity can contribute to hypokalemia by a direct increase in the genetic transcription of genes coding for the Na-K ATPase pump as well as an increase in the pump's intrinsic activity.[24][25] Thyroid hormones also cause Beta-2 adrenergic stimulation and a rise in sensitivity to circulating catecholamines, resulting in an increase in Na-K pump activity.[26]
Hyperinsulinemia seen in attacks of TPP may also contribute to a depletion in extracellular potassium.[27][28] Increased Androgen levels, characteristically seen in males, have been associated with increased Na-K pump activity as well.[29] Loss-of-function mutations in the genes encoding muscle-specific Kir channels (Kir2.6), can prevent the flow of potassium out of skeletal muscle cells, disrupting potassium homeostasis.[30] These mutations have been identified in up to a third of TPP patients.[31] Furthermore, insulin and catecholamines have also been shown to inhibit Kir channels.[32] Following the reduction in extracellular potassium, the sarcolemmal membrane depolarizes, rather than hyperpolarizing. This paradoxical effect leads to the inactivation of sarcolemmal sodium channels, causing the pathognomonic paralysis of skeletal muscles.[33][34] Thyroid hormones have been shown to upregulate transcription oKir channels.
Patients usually present with sudden onset of episodic muscle weakness, more in the proximal muscle compared to distal, along with myalgias. Weakness is also more common in lower extremities compared to upper extremities. Paralytic symptoms usually appear after symptoms of hyperthyroidism appear. They might also present with palpitations, tachycardia, dyspnea, dysphagia, and speech and visual changes. Some patients might present with rhabdomyolysis.[35] Patients might also present with other hyperthyroid symptoms, including heat intolerance, hyper defecation, goiter, and exophthalmos.[36] On examination, they might have ectopic heartbeats, tachycardia, decreased or lack of reflexes. Usually, patients regain strength in between attacks, but weakness can persist with recurrent attacks. Attacks are more common in early mornings and usually precipitated after a heavy carbohydrate meal or after strenuous exercise.[37]
Hypokalemia is present in most of the patients. Hypomagnesemia and Hypophosphatemia are also present in some patients which might be one of the distinguishing features from other forms of familial periodic paralysis.[38] Abnormal thyroid hormones like elevated T4, or elevated T3 and low thyrotropin (TSH) might be present. The thyroid uptake scan might show increased uptake.
Abnormal electrocardiograms with arrhythmias might be present. The most common Electrocardiogram (EKG) changes include ST depression, sinus tachycardia, U waves, and AV blocks.[39] Very rarely, they can present with prolonged QT interval or ventricular tachyarrhythmias. Electromyograms might show a myopathic pattern with decreased duration of muscle action potentials, reduced amplitude, and an increase in polyphasic potentials. These changes might completely disappear during remission.[40]
Here are important treatment goals:
Other muscular disorders like myasthenia gravis, Guillain Barre syndrome, transverse myelitis, botulism, tick paralysis, and other familial periodic paralysis syndromes should be ruled out when patients present with acute muscle weakness.[35]
Patient education is one of the very important steps in treating and preventing the disease.
Patients should be educated about symptoms, including muscle weakness, arrhythmias, and symptoms related to hyperthyroidism, including heat intolerance, goiter, hyper defecation, and exophthalmos. They should avoid heavy meals, intense exercise, high sodium intake, etc.
Patients are instructed to go to the nearest emergency room if they experience any of the symptoms of thyrotoxic periodic paralysis.
Thyrotoxic periodic paralysis is a sporadic form of hypokalemic periodic paralysis, which most commonly presents as sudden onset weakness in the proximal muscles. It is a reversible condition that can be treated with quick replacement of potassium and normalization of thyroid hormones. Interprofessional communication by the total team is essential to timely treat these patients and minimize complications.
Pharmacists should be very vigilant when dispensing intravenous potassium, and they should clearly label the instructions about how to infuse the drug, as it can cause complications, including local skin reactions to severe complications like fatal arrhythmias if given too fast. Nursing staff should double-check the instructions on electrolyte infusion bags to prevent complications. The patients need to be carefully monitored for any rebound symptoms from hyperkalemia and hyperphosphatemia. The discharge staff should provide educational materials for patients and family members upon discharge, as this can be a recurrent condition.
[1] | Lin SH, Thyrotoxic periodic paralysis. Mayo Clinic proceedings. 2005 Jan; [PubMed PMID: 15667036] |
[2] | Chou HK,Tsao YT,Lin SH, An unusual cause of thyrotoxic periodic paralysis: triiodothyronine-containing weight reducing agents. The American journal of the medical sciences. 2009 Jan; [PubMed PMID: 19002009] |
[3] | Lin SH,Lin YF,Chen DT,Chu P,Hsu CW,Halperin ML, Laboratory tests to determine the cause of hypokalemia and paralysis. Archives of internal medicine. 2004 Jul 26; [PubMed PMID: 15277290] |
[4] | Ober KP, Thyrotoxic periodic paralysis in the United States. Report of 7 cases and review of the literature. Medicine. 1992 May; [PubMed PMID: 1635436] |
[5] | Liu Z,Braverman LE,Malabanan A, Thyrotoxic periodic paralysis in a Hispanic man after the administration of prednisone. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2006 Jul-Aug; [PubMed PMID: 16901800] |
[6] | McFadzean AJ,Yeung R, Periodic paralysis complicating thyrotoxicosis in Chinese. British medical journal. 1967 Feb 25; [PubMed PMID: 6017520] |
[7] | Hsieh MJ,Lyu RK,Chang WN,Chang KH,Chen CM,Chang HS,Wu YR,Chen ST,Ro LS, Hypokalemic thyrotoxic periodic paralysis: clinical characteristics and predictors of recurrent paralytic attacks. European journal of neurology. 2008 Jun; [PubMed PMID: 18410374] |
[8] | Forrest L,Platts J, Ecstasy-induced thyrotoxic periodic paralysis. BMJ case reports. 2009; [PubMed PMID: 22190983] |
[9] | OKINAKA S,SHIZUME K,IINO S,WATANABE A,IRIE M,NOGUCHI A,KUMA S,KUMA K,ITO T, The association of periodic paralysis and hyperthyroidism in Japan. The Journal of clinical endocrinology and metabolism. 1957 Dec; [PubMed PMID: 13481091] |
[10] | Kung AW, Clinical review: Thyrotoxic periodic paralysis: a diagnostic challenge. The Journal of clinical endocrinology and metabolism. 2006 Jul; [PubMed PMID: 16608889] |
[11] | Shizume K,Shishiba Y,Kuma K,Noguchi S,Tajiri J,Ito K,Noh JY, Comparison of the incidence of association of periodic paralysis and hyperthyroidism in Japan in 1957 and 1991. Endocrinologia japonica. 1992 Jun; [PubMed PMID: 1425456] |
[12] | Cesur M,Bayram F,Temel MA,Ozkaya M,Kocer A,Ertorer ME,Koc F,Kaya A,Gullu S, Thyrotoxic hypokalaemic periodic paralysis in a Turkish population: three new case reports and analysis of the case series. Clinical endocrinology. 2008 Jan; [PubMed PMID: 17897330] |
[13] | Bazzani M,Benati L,Bosi M,Iorini M,Panizza M, Hypokalemic thyrotoxic paralysis: a rare cause of tetraparesis with acute onset in Europeans. Italian journal of neurological sciences. 1998 Oct; [PubMed PMID: 10933451] |
[14] | Satam N,More V,Shanbag P,Kalgutkar A, Fatal thyrotoxic periodic paralysis with normokalemia. Indian journal of pediatrics. 2007 Nov; [PubMed PMID: 18057690] |
[15] | El-Hennawy AS,Nesa M,Mahmood AK, Thyrotoxic hypokalemic periodic paralysis triggered by high carbohydrate diet. American journal of therapeutics. 2007 Sep-Oct; [PubMed PMID: 17890941] |
[16] | Rivas AM,Thavaraputta S,Orellana-Barrios MA,Payne JD,Sotello D,Vinan-Vega M,Lado-Abeal J, THYROTOXIC PERIODIC PARALYSIS AND COMPLICATED THYROTOXICOSIS, TWO PRESENTATIONS OF HYPERTHYROIDISM WITH NOTABLE DIFFERENCES IN THEIR CLINICAL MANIFESTATIONS. AN EXPERIENCE FROM A TERTIARY CARE HOSPITAL IN THE UNITED STATES. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2020 Mar 11; [PubMed PMID: 32160042] |
[17] | Mohapatra BN,Lenka SK,Acharya M,Majhi C,Oram G,Tudu KM, Clinical and Aetiological Spectrum of Hypokalemic Flaccid Paralysis in Western Odisha. The Journal of the Association of Physicians of India. 2016 May; [PubMed PMID: 27735149] |
[18] | Verma V,Kumar Y,Kotwal N,Upreti V,Hari Kumar KVS,Singh Y,Menon AS, Thyrotoxic periodic paralysis: A retrospective, observational study from India. The Indian journal of medical research. 2020 Jan; [PubMed PMID: 32134013] |
[19] | Sthaneshwar P,Prathibha R,Yap SF, Thyrotoxic periodic paralysis: a report of 3 Malaysian cases and a review of its pathology. The Malaysian journal of pathology. 2005 Jun; [PubMed PMID: 16676690] |
[20] | Aldasouqi S,Bokhari SA,Khan PM,Al-Zahrani AS, Thyrotoxic periodic paralysis in a Saudi patient complicated by life-threatening arrhythmia. Saudi medical journal. 2009 Apr; [PubMed PMID: 19370290] |
[21] | Patel H,Wilches LV,Guerrero J, Thyrotoxic periodic paralysis: diversity in America. The Journal of emergency medicine. 2014 Jun; [PubMed PMID: 24315723] |
[22] | Elston MS,Orr-Walker BJ,Dissanayake AM,Conaglen JV, Thyrotoxic, hypokalaemic periodic paralysis: Polynesians, an ethnic group at risk. Internal medicine journal. 2007 May; [PubMed PMID: 17504277] |
[23] | Clausen T, Hormonal and pharmacological modification of plasma potassium homeostasis. Fundamental [PubMed PMID: 20618871] |
[24] | Chan A,Shinde R,Chow CC,Cockram CS,Swaminathan R, In vivo and in vitro sodium pump activity in subjects with thyrotoxic periodic paralysis. BMJ (Clinical research ed.). 1991 Nov 2; [PubMed PMID: 1660744] |
[25] | Chaudhury S,Ismail-Beigi F,Gick GG,Levenson R,Edelman IS, Effect of thyroid hormone on the abundance of Na,K-adenosine triphosphatase alpha-subunit messenger ribonucleic acid. Molecular endocrinology (Baltimore, Md.). 1987 Jan; [PubMed PMID: 2842662] |
[26] | Ginsberg AM,Clutter WE,Shah SD,Cryer PE, Triiodothyronine-induced thyrotoxicosis increases mononuclear leukocyte beta-adrenergic receptor density in man. The Journal of clinical investigation. 1981 Jun; [PubMed PMID: 6263953] |
[27] | Lee KO,Taylor EA,Oh VM,Cheah JS,Aw SE, Hyperinsulinaemia in thyrotoxic hypokalaemic periodic paralysis. Lancet (London, England). 1991 May 4; [PubMed PMID: 1673496] |
[28] | Soonthornpun S,Setasuban W,Thamprasit A, Insulin resistance in subjects with a history of thyrotoxic periodic paralysis (TPP). Clinical endocrinology. 2009 May; [PubMed PMID: 18759868] |
[29] | Guerra M,Rodriguez del Castillo A,Battaner E,Mas M, Androgens stimulate preoptic area Na ,K -ATPase activity in male rats. Neuroscience letters. 1987 Jul 9; [PubMed PMID: 3039424] |
[30] | Cheng CJ,Lin SH,Lo YF,Yang SS,Hsu YJ,Cannon SC,Huang CL, Identification and functional characterization of Kir2.6 mutations associated with non-familial hypokalemic periodic paralysis. The Journal of biological chemistry. 2011 Aug 5; [PubMed PMID: 21665951] |
[31] | Ryan DP,da Silva MR,Soong TW,Fontaine B,Donaldson MR,Kung AW,Jongjaroenprasert W,Liang MC,Khoo DH,Cheah JS,Ho SC,Bernstein HS,Maciel RM,Brown RH Jr,Ptácek LJ, Mutations in potassium channel Kir2.6 cause susceptibility to thyrotoxic hypokalemic periodic paralysis. Cell. 2010 Jan 8; [PubMed PMID: 20074522] |
[32] | Ruff RL, Insulin acts in hypokalemic periodic paralysis by reducing inward rectifier K current. Neurology. 1999 Oct 22; [PubMed PMID: 10534267] |
[33] | Matthews E,Labrum R,Sweeney MG,Sud R,Haworth A,Chinnery PF,Meola G,Schorge S,Kullmann DM,Davis MB,Hanna MG, Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis. Neurology. 2009 May 5; [PubMed PMID: 19118277] |
[34] | Puwanant A,Ruff RL, INa and IKir are reduced in Type 1 hypokalemic and thyrotoxic periodic paralysis. Muscle [PubMed PMID: 20589886] |
[35] | Manoukian MA,Foote JA,Crapo LM, Clinical and metabolic features of thyrotoxic periodic paralysis in 24 episodes. Archives of internal medicine. 1999 Mar 22; [PubMed PMID: 10090117] |
[36] | Pompeo A,Nepa A,Maddestra M,Feliziani V,Genovesi N, Thyrotoxic hypokalemic periodic paralysis: An overlooked pathology in western countries. European journal of internal medicine. 2007 Sep; [PubMed PMID: 17693226] |
[37] | Vijayakumar A,Ashwath G,Thimmappa D, Thyrotoxic periodic paralysis: clinical challenges. Journal of thyroid research. 2014; [PubMed PMID: 24695373] |
[38] | Venance SL,Cannon SC,Fialho D,Fontaine B,Hanna MG,Ptacek LJ,Tristani-Firouzi M,Tawil R,Griggs RC, The primary periodic paralyses: diagnosis, pathogenesis and treatment. Brain : a journal of neurology. 2006 Jan; [PubMed PMID: 16195244] |
[39] | Lopez S,Henderson SO, Electrocardiogram changes in Thyrotoxic Periodic Paralysis. The western journal of emergency medicine. 2012 Dec [PubMed PMID: 23359336] |
[40] | Puvanendran K,Cheah JS,Wong PK, Electromyographic (EMG) study in thyrotoxic periodic paralysis. Australian and New Zealand journal of medicine. 1977 Oct; [PubMed PMID: 272170] |
[41] | Lin SH,Lin YF, Propranolol rapidly reverses paralysis, hypokalemia, and hypophosphatemia in thyrotoxic periodic paralysis. American journal of kidney diseases : the official journal of the National Kidney Foundation. 2001 Mar; [PubMed PMID: 11228188] |
[42] | Yu TS,Tseng CF,Chuang YY,Yeung LK,Lu KC, Potassium chloride supplementation alone may not improve hypokalemia in thyrotoxic hypokalemic periodic paralysis. The Journal of emergency medicine. 2007 Apr [PubMed PMID: 17394988] |
[43] | Tessier JJ,Neu SK,Horning KK, Thyrotoxic periodic paralysis (TPP) in a 28-year-old sudanese man started on prednisone. Journal of the American Board of Family Medicine : JABFM. 2010 Jul-Aug; [PubMed PMID: 20616298] |