Mechanism of thyrotoxic periodic paralysis

Abstract

The pathogenesis of thyrotoxic periodic paralysis has long been thought related to increased Na(+)-K(+) ATPase activity stimulated by thyroid hormone and/or hyperadrenergic activity and hyperinsulinemia. This mechanism alone, however, cannot adequately explain how hypokalemia occurs during acute attacks or the associated paradoxical depolarization of the resting membrane potential. Recent findings that loss of function mutations of the skeletal muscle-specific inward rectifying K(+) (Kir) channel, Kir2.6, associate with thyrotoxic periodic paralysis provide new insights into how reduced outward K(+) efflux in skeletal muscle, from either channel mutations or inhibition by hormones (adrenalin or insulin), can lead to a vicious cycle of hypokalemia and paradoxical depolarization, which in turn, inactivates Na(+) channels and causes muscle unexcitability and paralysis.

Figure 1.

Mechanism of TTP. (A) A traditional pathogenesis of TPP. An increased Na⁺–K⁺ ATPase activity directly induced by thyroid hormone and indirectly induced by hyperadrenergic activity, hyperinsulinemia, and androgen is mostly involved. The open circle denotes the skeletal muscle cells and Na⁺/H⁺ exchanger (NHE). (B) Reduced K⁺ channel efflux in TPP. The enhanced Na⁺–K⁺ ATPase activity causes initial hypokalemia, and the reduced outward Kir current caused by hypokalemia, loss of function mutation, or hormone (adrenalin or insulin) -mediated inhibition on Kir channels can potentially inhibits total K⁺ efflux, leading to the trapping of K⁺ in the cell; a vicious cycle of hypokalemia-induced paradoxical depolarization and an inactivation of Na⁺ channel with muscle inexcitability and paralysis can result.