Genetics[edit] => Genetic mutations in the L-type calcium channel α1-subunit (Cav1.1) have been described in Southern Chinese with TPP. The mutations are located in a different part of the gene from those described in the related condition familial periodic paralysis. In TPP, the mutations described are single-nucleotide polymorphisms located in the hormone response element responsive to thyroid hormone, implying that transcription of the gene and production of ion channels may be altered by increased thyroid hormone levels. Furthermore, mutations have been reported in the genes coding for potassium voltage-gated channel, Shaw-related subfamily, member 4 (Kv3.4) and sodium channel protein type 4 subunit alpha (Na41.4).[1]
Of people with TPP, 33% from various populations were demonstrated to have mutations in KCNJ18, the gene coding for Kir2.6, an inward-rectifier potassium ion channel. This gene, too, harbors a thyroid response element.[3]
Certain forms of human leukocyte antigen (HLA)—especially B46, DR9, DQB1*0303, A2, Bw22, AW19, B17, and DRW8—are more common in TPP. Linkage to particular forms of HLA, which plays a central role in the immune response, might imply an immune system cause, but it is uncertain whether this directly causes TPP or whether it increases the susceptibility to Graves' disease, a known autoimmune disease.[1]
Thyroid disease[edit] => The most common underlying form of thyroid disease associated with TPP is Graves' disease, a syndrome due to an autoimmune reaction that leads to overproduction of thyroid hormone.[6] TPP has also been described in people with other thyroid problems such as thyroiditis, toxic nodular goiter, toxic adenoma, TSH-producing pituitary adenoma, excessive ingestion of thyroxine or iodine,[1] and amiodarone-induced hyperthyroidism.[2]
Hypokalemia (low blood potassium levels) commonly occurs during attacks; levels below 3.0 mmol/l are typically encountered. Magnesium and phosphate levels are often found to be decreased. Creatine kinase levels are elevated in two thirds of cases, usually due to a degree of muscle injury; severe elevations suggestive of rhabdomyolysis (muscle tissue destruction) are rare.[1][2] Electrocardiography (ECG/EKG) may show tachycardia (a fast heart rate) due to the thyroid disease, abnormalities due to cardiac arrhythmia (atrial fibrillation, ventricular tachycardia), and conduction changes associated with hypokalemia (U waves, QRS widening, QT prolongation, and T wave flattening).[2] Electromyography shows changes similar to those encountered in myopathies (muscle diseases), with a reduced amplitude of the compound muscle action potentials (CMAPs);[4] they resolve when treatment has commenced.[1]
TPP is distinguished from other forms of periodic paralysis (especially hypokalemic periodic paralysis) with thyroid function tests on the blood. These are normal in the other forms, and in thyrotoxicosis the levels of thyroxine and triiodothyronine are elevated, with resultant suppression of TSH production by the pituitary gland.[1][6] Various other investigations are usually performed to separate the different causes of hyperthyroidism.[6]
An attack often begins with muscle pain, cramping, and stiffness.[5] This is followed by weakness or paralysis that tends to develop rapidly, usually in late evening or the early hours of the morning. The weakness is usually symmetrical;[5] the limb muscles closer to the trunk (proximal) are predominantly affected, and weakness tends to start in the legs and spread to the arms. Muscles of the mouth and throat, eyes, and breathing are usually not affected, but occasionally weakness of the respiratory muscles can cause life-threatening respiratory failure. Attacks typically resolve within several hours to several days, even in the absence of treatment.[1][2][5] On neurological examination during an attack, flaccid weakness of the limbs is noted; reflexes are usually diminished, but the sensory system is unaffected.[1][5] Mental status is not affected.[5]
Attacks may be brought on by physical exertion, drinking alcohol, or eating food high in carbohydrates or salt. This may explain why attacks are more common in summer, when more people drink sugary drinks and engage in exercise. Exercise-related attacks tend to occur during a period of rest immediately after exercise; exercise may therefore be recommended to abort an attack.[1]
There may be symptoms of thyroid overactivity, such as weight loss, a fast heart rate, tremor, and perspiration;[1][2] but such symptoms occur in only half of all cases.[5] The most common type of hyperthyroidism, Graves' disease, may additionally cause eye problems (Graves' ophthalmopathy) and skin changes of the legs (pretibial myxedema).[6] Thyroid disease may also cause muscle weakness in the form of thyrotoxic myopathy, but this is constant rather than episodic.[5]