Thyrotoxic periodic paralysis associated with hypokalemia and hypophosphatemia

CASE REPORTS

Thyrotoxic Periodic Paralysis Associated With Hypokalemia and Hypophosphatemia Keith C. Norris, MD, Barton Levine, MD, and Kalpana Ganesan, MD 0 We report the rare case of a &year-old African-American man with thyrotoxic periodic paralysis associated with hypokaiemia and hypophosphatemia. Both serum potassium and serum phosphate levels returned to normal after supplementation with only potassium. We consider the unusual condition of hyperthyroid-related hypokaiemia and hypophosphatemia to have contributed to the acute paralysis in this patient. 8 lSS6 by the National Kidney Foundation, Inc. INDEX WORDS: Thyrotoxic American.

periodic

paralysis;

hypokaiemia;

T

HYROTOXIC periodic paralysis is characterized by the abrupt onset of severe hypokalemia and profound muscle weakness in patients with hyperthyroidism. This syndrome is most frequently reported in patients from Japan and China, where the incidence of hypokalemic periodic paralysis in hyperthyroid patients ranges from 1.9% to 8.8%.‘*’ Thyrotoxic periodic paralysis is uncommon in the United States, where it is reported most frequently in males of Asian descent, less often in whites, and rarely in Hispanics, African-Americans, and Native American Indians3 It occurs most commonly between the second and fourth decades of life.4 In rare instances, hypophosphatemia has been reported in association with thyrotoxic periodic paralysis and hypokalemia.‘-lo Intracellular shifts of potassium and possibly phosphate are thought to be responsible for the neuromuscular symptoms that are the hallmark of this syndrome. We report a case of thyrotoxic paralysis with both hypokalemia and hypophosphatemia in a middle-aged African-American man. CASE

REPORT

A 43-year-old African-American man was brought to the West Los Angeles Veterans Affairs Medical Center emergency department with acute paralysis and inability to ambu-

From the Departments of Medicine, Charles R. Drew University of Medicine and Science, and West Los Angeles Veterans Affairs Medical Center, Los Angeles, CA. Received December 29, 1995; accepted in revised fom March 26, 19%. Address reprint requests to Keith C. Norris, MD, Department of Medicine, King-Drew Medical Center, 12021 S Wilmington Blvd. Los Angeles, CA 90059. 0 1996 by the National Kidney Foundation. Inc. 0272-6386/96L?802-0016$3.00/O 270

American

Journal

hypophosphatemia;

hyperthyroidism;

African-

late. There was a history of mild progressive bilateral lower extremity weakness for 2 days. On the morning of admission the patient awoke, but was unable to get out of bed. In addition, he also reported having difficulty in swallowing. The patient did not have a history of any similar episodes. He denied anorexia, nausea, vomiting, or diarrhea. The patient also denied any weight loss, change in bowel habits, palpitations, increased sweating, or heat intolerance. Past medical history was significant for hypertension of 2 years’ duration. He was taking 25 mg of hydrochlorothiaxide daily, without potassium supplements. He denied taking any other medications, including antacids or over-the-counter herbal products. His appetite was good and he was not on a special diet. The social history, past medical history, and family history were noncontributory. In particular, there was no family history of endocrine disorders. The physical examination revealed a well-developed black man in no acute distress. Pulse was 80 beats/mm, respiratory rate was 16 breaths/mm, blood pressure was 145/55 mm Hg, and temperature was 97.9”F. Head and neck examination was significant for a smooth, nontender, 5 X 6 cm thyroid gland without a bruit. The results of chest, heart, and abdominal examinations were normal. Cranial nerves were intact. Lower extremity strength was l/5 normal, with slightly decreased reflexes. Upper extremities were 2/5 normal, with decreased biceps reflexes. Sensation was normal. No atrophy, cionus, or fasciculations were noted. The remainder of the neuroiogic examination was unremarkable. Laboratory studies on admission revealed the following: serum sodium, 143 mEq/L; potassium, 1.4 mEq/L; chloride, 109 mEq& bicarbonate, 28.1 mEq/L; blood urea nitrogen, 18 mg/L; creatinine, 0.7 mg/L; glucose, 127 mg/L; calcium, 9.6 mg/L; phosphorus, 1.l mg/L; magnesium, 1.5 mg/L; total protein, 6.9 mg/L; albumin, 4.2 mg/L; alkaline phosphate, 361 II& aspartate aminotransferase, 21 Ufi, alanine aminotransferase, 20 Uk total bilirubin, 0.5 mg/L: and hemoglobin, 13.3 g/L. Arterial blood gases revealed pH 7.41; Pco,, 40 mm Hg; PO*. 78 mm Hg; HC03, and 24.8 mPq/L. Single random urine electrolytes were sodium, 73 mEq/L; potassium, 28 mEq/L; and chlorine, 95 mEq/L. Subsequent laboratory studies revealed total thyroxine, 23.0 &lL (normal, 5 to 12 j@lL); triiodothyronine uptake, 1.1 (normal, 0.86 to 1.14); free thyroxine index, 26.4 (normal, 4.3 to 13.7); and thyroid-stimulating hormone, 0.1 pU/L (normal, 0.6 to 4.6 Pun). The patient was admitted to the medical intensive care unit of Kidney

Diseases,

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THYROTOXIC HYPOKALEMIC

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and a central line was placed. He received 75 mEq of potassium chloride intravenously over 8 hours, during which time marked symptomatic improvement occurred. A repeat neurologic examination was normal. Serum potassium following this infusion was 4.6 mEq/L. Serum phosphorus after 18 hours was 3.5 mg/L, despite receiving no supplemental phosphate. The patient was transferred to the medical floor the next day and the diagnosis of Grave’s disease was made. The patient was started on propylthiouracil 300 mg three times a day. His serum potassium and phosphate remained normal and he was discharged home with a follow-up appointment to the endocrinology clinic. DISCUSSION

There have been few reports of both hypokalemia and hypophosphatemia in association with thyrotoxic periodic paralysi?“; to our knowledge, this is the first report of its occurrence in an African-American. The overall rarity of thyrotoxic periodic paralysis in the United States makes definitive comparisons among races difficult. The incidence of thyrotoxic periodic paralysis among hyperthyroid white North Americans is estimated to be one tenth the rate reported in Japanese and Chinese populations.” Ober recently reviewed nearly 100 reported cases of thyrotoxic periodic paralysis in the United States. Race or ethnicity were identified in 83 subjects, of which 32 were white, 30 were Asian, 11 were Hispanic, and only five each were Native American Indian and African-American.3 There is a dramatic gender difference in patients with thyrotoxic periodic paralysis. Although thyrotoxicosis is nearly 10 times more common among women, only approximately 5% of cases of periodic paralysis occur in females.1~2~39’2*13 As in our patient, the paralytic attacks can precede any overt symptoms and/or signs of tbyrotoxicosis. Attacks can range from mild weakness to respiratory paralysis or cardiac arrest leading to death. Several major factors (Table 1) reported to precipitate paralysis in these patients include excessive physical activity and excessive carbohydrate ingestion.2”V9s12*14 Other factors include trauma, emotional stress, and exposure to cold. 3,4,5*12 Medications such as hydrochlorothiazide, which our patient was taking, may also precipitate an acute paralytic attack. In addition, thyrotoxic periodic paralysis has been reported to occur more often during warm summer months, possibly precipitated by increased sweating and potassium loss coupled with quenching of thirst with cold drinks with a high sugar content; the

271 Table 1. Reported Risk Factors for the Precipitation of Hypokalemic Paralysis in Subjects With Hyperthyroidism Clinical

Factors

Excessive physical activity Excessive carbohydrate intake Cold exposure Infection Emotional stress Trauma Menses

Medications

Adrenaline Physostigmine Pilocarpine Desiccated thyroid Diuretics (potassium wasting) Deoxycorticosterone acetate Adrenocorticotropin hormone Insulin Ammonium glycyrrhizinate

glucose load may result in a shift of potassium into the cells.2 The nature of the periodicity of this disease remains obscure. An alteration in either the sodium/potassium adenosine triphosphatase (ATPase) pump activity or voltage-gated calcium channels, described below, would likely be a constant condition. As to when and why some precipitating events may initiate paralysis awaits further investigation. Although the mechanism of the rapid shift of potassium intracellularly in periodic paralysis has not been clearly defined, several investigators have postulated an acute increase in sodium/potassium ATPase activity.3V5V1s-‘7 Nora and Bems suggested that the potassium shift may be the direct effect of thyroid hormone to stimulate the cell membrane sodium/potassium ATPase and increase the number of beta receptors, thereby augmenting catecholamine-mediated cellular potassium uptake.5 A significant increase in platelet sodium/potassium ATPase activity was reported in patients with thyrotoxic periodic paralysis in comparison to thyrotoxic patients without paralysis.16 Chronos et al reported an exaggerated response of the sodium/potassium ATPase pump activity to adrenaline in isolated leukocytes from a patient with thyrotoxic periodic paralysis.17 This phenomena resolved after the patient became euthyroid. Insulin may play a role in precipitating hypokalemia in this group of patients by activating the sodium/potassium ATPase pump. Shizume et al induced hypokalemia in three patients with thyrotoxic periodic paralysis by infusing glucose and insulin. Paralysis began within 30 minutes and the mean preinduction potassium of 3.7 mEq/L decreased to a nadir of

272

2.1 mEq/L after 60 to 180 minutes.1s Mutations in both calcium and sodium voltage-gated ion channels have been reported in familial hypokalemic and hyperkalemic periodic paralysis.” The voltage-gated calcium channel in muscle appears to be the primary target in familial hypokalemic periodic paralysis.20X21Partial defects in these channels may underlie the selected predisposition of certain ethnicities and/or individuals to the development of hypokalemic periodic paralysis in the setting of hyperthyroidism.19 Further studies evaluating mutations in the subunits of the calcium and sodium voltage-gated channels in patients with acquired periodic paralysis may enhance our understanding of this unique phenomena. Our patient was taking a thiazide diuretic without any potassium supplements, which could have contributed to the hypokalemia. In addition, the patient had mild hypomagnesemia, which can also contribute to potassium wasting. The rapid correction of serum potassium with small amounts of potassium supplementation strongly supports an intracellular shift of potassium as the mechanism for the hypokalemia in our patient. It also supports thyrotoxic periodic paralysis as the etiology of hypokalemia in our patient. The initial potassium level was 1.4 mEq/L and the repeat potassium level after receiving only 75 mEq of potassium was 4.6 mEq/L. Severe potassium deficiency from chronic diuretic administration is associated with a significant reduction in total body potassium and would require several hundred milliequivalents of potassium to return the serum potassium levels to norma1.22 In addition, the lack of metabolic alkalosis further suggests that hypokalemia was not a pre-existing condition related to thiazide ingestion. Interestingly, hyperphosphatemia rather than hypophosphatemia is usually associated with hyperthyroidism. The usual elevation in serum phosphorus with hyperthyroidism results from an increase in the renal phosphate threshold clearance for phosphate, the most accurate parameter used to measure tubular phosphate handling.23 Thus, thyroid hormone increases the reabsorption of phosphate by the proximal tubule, an effect that is accompanied by an increase in the sodiumdependent phosphate transport activity in the brush-border membrane of the renal proximal tubule cell.“325 The etiology of hypophosphatemia

NORRIS,

LEVINE,

AND

GANESAN

in periodic paralysis is therefore enigmatic. Kusakabe et al reported hypophosphatemia and normokalemia with paralysis induced by glucose in a patient with thyrotoxic periodic paralysis.26 Catecholamines can also produce an intracellular shift of phosphate, much as occurs with potassium.27328Perhaps the catecholamine effect can predominate over the renal effect of thyroid hormone during acute exacerbations, as observed in this patient. Several factors may have contributed to the hypophosphatemia in our case, including diuretic therapy and hypomagnesemia, which both enhance renal phosphate wasting. Although our patient denied alcohol ingestion, the possibility of alcoholism should always be considered in patients with hypophosphatemia and/or hypokalemia. However, the marked hypophosphatemia observed in our case was corrected without any phosphate supplementation. This finding was noted by Guthrie et al as we11.6 Phosphate replacement was required in the case reported by Nora and Bems.’ The need for phosphate replacement in the latter case may have suggested a true phosphate-deficient state, although other factors cannot be excluded. In contrast, the rapid correction of the serum phosphate level without the administration of phosphate strongly supports the intracellular shift of phosphate in both our case and the case reported by Guthrie et al. Hypokalemia and hypophosphatemia could have caused the muscle weakness independently or synergistically. Thyrotoxic periodic paralysis should be considered in any patient with a classic clinical presentation irrespective of gender or ethnicity. Because many patients with thyrotoxic periodic paralysis present with few symptoms of thyrotoxicosis, it is important to evaluate thyroid function in any patient presenting with unexplained hypokalemia. REFERENCES 1. Okinaka S, Shizume K, Watanabe A, Irie M, Noguchi A, Kuma S, Kuma K, Ito T: The association of periodic paralysis and hyperparatbyroidism in Japan. J Clin Endocrino1 17:1454-1459, 1957 2. McFadzean AJS, Yeung R: Periodic paralysis complicating thyrotoxicosis in Chinese. BMJ 1:451-455, 1967 3. Ober KP: Thyrotoxic periodic paralysis in the United States. Report of 7 cases and review of the literature. Medicine 71:109-120, 1992 4. Feldman D, Goldberg WM: Hyperthyroidism with periodic paralysis. Can Med Assoc J 101:61-65, 1969

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5. Nora N, Bems A: Hypokalemic, hypophosphatemic thyrotoxic periodic paralysis. Am .I Kidney Dis 13:247-249, 1989 6. Guthrie GP Jr, Curtis J, Beilman KM: Hypophosphatemia in thyrotoxic periodic paralysis. Arch Intern Med 138:1284-1285,

1978

7. Tinker TD, Vannatta JB: Thyrotoxic hypokalemic periodic paralysis: Report of four cases and review of the literature. J Okla State Med Assoc 80:11-U, 1987 8. Bienert I-II Jr, Weaver CD: Thyrotoxicosis presenting as hypokalemic periodic paralysis. South Med J 61:189-192, 1968 9. Lemer E, Wachtel TJ: Thyrotoxic periodic paralysis: Case discussion and review. R I Med J 68:219-222, 1985 10. Woolery WA, Gharib H: Thyrotoxic hypokalemic periodic paralysis: In a white man. South Med J 84:1399-1401, 1991 11. Kelly DE, Gharib H, Kennedy FP, Duda RI Jr, McManis PG: Thyrotoxic periodic paralysis. Report of 10 cases and review of electromyographic findings. Arch Intern Med 149:2597-2600, 1989 12. Ferreiro JE, Arguelles DJ, Rams H Jr: Thyrotoxic periodic paralysis. Am J Med 80~146-150, 1996 13. Stedwell RE, Allen KM, Binder LS: Hypokalemic paralyses: A review of the etiologies, pathophysiology, presentation, and therapy. Am J Emerg Med 10:143-148, 1992 14. Copobianco DJ: Hyperthyroidism and periodic paralysis. J Fla Med Assoc 77:884-888, 1990 15. Layzer RB: Periodic paralysis and the Na-K pump. Ann Neurol 11:547-552, 1982 16. 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 303:1096-1099.1991 17. Chronos N, Mendel P, Ozin RL: Thyrotoxicosis presenting as a life threatening hypokalemic paralysis: Investigation of the Nan< pump in isolated leukocytes. Br J Clin Pratt 47:106-108, 1993 18. Shizume K, Shishiba Y, Sakuma M, Yamauchi H, Nakao K, Okinaka S: Studies on electrolyte metabolism in idiopathic and thyrotoxic periodic paralysis I. Arteriovenous differences of electrolytes during paralysis. Metabolism 15:138-144, 1966

273 19. Fontaine B, Lapie P, Plassart E, Tabti N, Nicole S, Reboul J, Rime CS: Periodic paralysis and voltage gated ion channels. Kidney Int 49:9-18, 1986 20. Fontaine B, Vale Santos JM, Jurkat-Rott K, Reboul J, Plassart E, Rime CS, Elbaz A, Heine R, Guimaraes J, Weissenbach J, Baumann N, Fardeau M, Lehmann-Horn F: Mapping of hypokalemic periodic paralysis to chromosome lq31-q32 in three European families. Nature Genet 6:267272, 1994 21. Casley WL, Allon M, Cousin HK, Ting SS, Crackower MA, Hashimoto L, Cornelius F, Beckmann JS, Hudson AJ, Ebers GC: Exclusion of linkage between hypokalemic periodic paralysis and three candidate loci. Genomics 14:493494, 1992 22. Stems RI-I, Cox M, Feig PV, Singer I: Internal potassium balance and the control of plasma potassium concentration. Medicine 60:339-354, 1981 23. Bijovet OLM: Indices for the measurement of the renal handling of phosphate, in Massry SG, Fleisch H (eds): Renal Handling of Phosphate. New York, NY, Plenum, 1981, pp l-37 24. Ritz E, Kreusse W, Bommer J: Effects of hormones other than parathyroid hormones on renal handling of phosphate, in Massry SG, Fleisch H (eds): Renal Handling of Phosphate. New York, NY, Plenum, 1981, pp 137-195 25. Yusufi ANK, Szczepanska-Konkel M, Hoppe A, Dojusa TP: Different mechanisms of adaptive increase in sodium-phosphate cotransport across renal brush-border membrane. Am J Physiol 256:F852-F861, 1989 26. Kusakabe T, Yoshida M, Nishikawa M: Thyrotoxic periodic paralysis: A peculiar case with unusual dystonic behavior and variable relations of paralysis to serum potassium levels. J Clin Endocrinol Metab 43:730-741, 1976 27. Body JJ, Cryer PE, Offord KP, Hunter H: Epinephrine is a hypophosphatemic hormone in man. Physiologic effects of circulating epinephrine on plasma calcium, magnesium, phosphorus, parathyroid hormone and calcitonin. J Clin Invest 71:572-578, 1983 28. Kjeldsen SE, OS I, Westheim A, Frederichsen P, Hjermann I, Eide IK, Gautvik K: Decreased serum phosphate in essential hypertension related to increased sympathetic tone. Am J Hypertens 1:403-409, 1988