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Novel etiopathophysiological aspects of thyrotoxic periodic paralysis

Nature Reviews Endocrinology volume 7, pages 657–667 (2011)Cite this article

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Abstract

Thyrotoxicosis can lead to thyrotoxic periodic paralysis (TPP), an endocrine channelopathy, and is the most common cause of acquired periodic paralysis. Typically, paralytic attacks cease when hyperthyroidism is abolished, and recur if hyperthyroidism returns. TPP is often underdiagnosed, as it has diverse periodicity, duration and intensity. The age at which patients develop TPP closely follows the age at which thyrotoxicosis occurs. All ethnicities can be affected, but TPP is most prevalent in people of Asian and, secondly, Latin American descent. TPP is characterized by hypokalemia, suppressed TSH levels and increased levels of thyroid hormones. Nonselective β adrenergic blockers, such as propranolol, are an efficient adjuvant to antithyroid drugs to prevent paralysis; however, an early and definitive treatment should always be pursued. Evidence indicates that TPP results from the combination of genetic susceptibility, thyrotoxicosis and environmental factors (such as a high-carbohydrate diet). We believe that excess T3 modifies the insulin sensitivity of skeletal muscle and pancreatic β cells and thus alters potassium homeostasis, but only leads to a depolarization-induced acute loss of muscle excitability in patients with inherited ion channel mutations. An integrated etiopathophysiological model is proposed based on molecular findings and knowledge gained from long-term follow-up of patients with TPP.

Key Points

  • Thyrotoxic periodic paralysis (TPP) is characterized by attacks of acute muscle weakness, hypokalemia and thyrotoxic symptoms; it results from the combination of genetic susceptibility, thyrotoxicosis and environmental factors

  • People of Asian descent are most often affected, but all ethnicities can present with TPP

  • Hypokalemia is typical during paralysis, but is not always detected; administration of potassium during the attacks should be offered cautiously, preferably orally, to prevent rebound hyperkalemia

  • Most patients are first diagnosed with paralysis and later with thyrotoxicosis; delay in the diagnosis is frequent and, therefore, all cases of acute weakness in young males should raise suspicion

  • Early and definitive treatment of thyrotoxicosis is necessary to prevent new attacks of muscle weakness

  • Mutations in Kir2.6, a potassium ion channel, which occur in up to 33% of patients, reinforces the hypothesis of genetic heterogeneity in patients with TPP

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Figure 1: Etiopathogenic hypothesis.
Figure 2: Representative oral glucose tolerance test of a patient with thyrotoxic periodic paralysis—glucose, insulin and potassium levels.
Figure 3: Thyrotoxic periodic paralysis pathophysiology hypothesis; major events that determine insulin sensitivity and the response of potassium intracellular shift in skeletal muscles are enhanced by excess T3 and increased activity of the 3Na/2K ATPase pump.

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Acknowledgements

The authors thank the team of the Laboratory of Molecular and Translational Endocrinology, especially Reinaldo Furlanetto, Luiza Matsumura, Jairo Hidal, João Roberto Martins, Teresa Kasamatsu, Maria Izabel Chiamolera, Janete Cerutti, Ana Luiza Rolim, Cléber Camacho and Beatriz Freitas and all the collaborators at the Division of Endocrinology, Department of Medicine, Escola Paulista de Medicina, Federal University of Sao Paulo. We also thank the colleagues who referred patients for our genetic study, Drs. Adelaide Albergária-Pereira, Gisah Carvalho, Maria Cristina Costa, Cássia Jurado, Cláudio Kater, Maria Conceição Mamone, Gláucia Mazeto, Gabriela Saraiva, Célia Tengan and Matthias Kugler. The authors' research is supported by São Paulo State Research Foundation (FAPESP), Brazilian Research Council (CNPq) and Fleury Group.

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Authors and Affiliations

  1. Department of Medicine, Laboratory of Molecular and Translational Endocrinology, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua Pedro de Toledo 669, 11° Andar, São Paulo, 04039-032, SP, Brazil

    Rui M. B. Maciel & Susan C. Lindsey

  2. Department of Biochemistry, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua Pedro de Toledo 669, 11° Andar, São Paulo, 04039-032, SP, Brazil

    Magnus R. Dias da Silva

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  1. Rui M. B. Maciel
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All authors contributed equally to all aspects of this review.

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Correspondence to Magnus R. Dias da Silva.

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Maciel, R., Lindsey, S. & Dias da Silva, M. Novel etiopathophysiological aspects of thyrotoxic periodic paralysis. Nat Rev Endocrinol 7, 657–667 (2011). https://doi.org/10.1038/nrendo.2011.58

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