Thymoma-associated hypocalcemic crisis.

Abstract: A previously healthy male was diagnosed with a malignant thymoma. During the workup, he had syncope, which was due to severe unrecognized hypocalcemia. Additional workup was suggestive of parathyroid failure. In particular, there was no evidence of autoimmune parathyroid failure due to antibodies against the calcium-sensing receptor. Literature review reveals one additional thymoma case with these clinical features of chronic hypoparathyroidism of unknown cause.

Key Words: autoimmune system, malignant thymoma, parathyroid

**********

Thymomas frequently are associated with autoimmune, hematologic, neuromuscular, and other forms of paraneoplastic conditions. (1) In addition, endocrine abnormalities such as Graves disease, Cushing syndrome, Addison disease, syndrome of inappropriate secretion of antidiuretic hormone, and panhypopituitarism have been reported. (1-3) In rare instances, calcium abnormalities have involved hyperparathyroidism. (4-6)

Case Report

A formerly healthy 38-year-old black male was brought to the emergency department after a syncopal episode; while walking, he felt lightheaded and lost consciousness for 4 to 5 minutes. On arrival, the patient was alert and conscious of his surroundings, albeit with no memory of the event. There was no observed seizure activity. He recalled feeling lightheaded during exercise for at least the preceding month but reported no overt fatigability. The medical history included bilateral subcapsular cataracts and a recent abnormal chest radiograph showing an enlarged mediastinum (Fig. 1). A computed tomography scan revealed a large mediastinal mass with right pleural effusion and compression of the carina and superior vena cava (Fig. 2). A mediastinoscopy revealed an invasive thymoma, lymphocyte-rich type, with evidence of focal invasion into fibroadipose tissue and skeletal muscle and extension to the pleural surface, leading to the diagnosis of a stage IV thymoma. A positron emission tomography scan showed an intense uptake in the tumor area with increased uptake in the pleural space on the right side (a specific finding in invasive thymoma).

There was no significant family history of endocrine, oncologic, or autoimmune diseases.

Physical examination was notable for a distended neck, the absence of a goiter, decreased air sounds in the base of the right lung, and a negative Chvostek sign. The neurologic examination failed to uncover signs of myasthenia gravis such as ptosis or unusual eye movements, or proximal muscle weakness. The electrocardiogram showed a sinus rhythm with a prolonged QT interval (QTc = 488 ms). Computed tomography scan of the brain showed extensive fine periventricular and basal ganglia calcification bilaterally.

The pertinent laboratory studies showed hemoglobin, 11.2 (13.2 to 17.3 g/dL); hematocrit, 33.7% (38.6 to 50.1%); total calcium, 3.7 (9 to 10.5 mg/dL); magnesium, 1.3 (1.8 to 2.8 mg/dL); phosphorus, 7.2 (3 to 4.5 mg/dL); and albumin, 3.5 (3.5 to 5.5 g/dL). The C-terminal PTH was 53 pg/mL (70 to 270 pg/mL), intact parathyroid hormone (PTH) was 6 pg/mL (10 to 65 pg/mL), PTHrP was less than 0.3 pmol/L (normal, <1.4 pmol/L), and thyroid-stimulating hormone was 0.37 mIU/L (0.40 to 4.70 mIU/L). Immunology studies showed that antigliadin IGA was less than 7 U (normal, <20 U), anti-GAD-65 was less than 1.0 U/mL (normal, <1.0 U/L), anti-nuclear antibody was 1.640 (<1.40), anti-thyroid peroxidase antibody (TPO) was less than 0.5 IU/mL (normal, <2.0 IU/mL), and antiendomysial antibody was 3 U (normal, <20 U). In addition, an electrophoresis gel was performed with quadruple loading of wild-type human calcium-sensing receptor (CaSR) with the proteins electrotransferred onto nitrocellulose membrane, using published protocol. (7) One of the membrane strips was blotted with a locally produced monoclonal mouse anti-human CaSR antibody (raised against a synthetic peptide corresponding to residues 214-235 of human CaSR protein as a positive control), with normal results. Three other identical membrane strips were blotted individually with serum samples (from two negative normocalcemic patient controls and from the hypocalcemic index patient) at a dilution of 1:100 followed by incubation with secondary rabbit antihuman antibody. None of the serum samples exhibited binding to the CaSRr, and only a few faint and nonspecific bands were observed.

The patient was admitted to the hospital and the calcium was corrected with intravenous calcium gluconate and calcitriol. Neoadjuvant chemotherapy was started with pleural disease response but minimal cytoreduction of the mediastinal mass. Subsequent tumor resection and debulking was accomplished revealing a lymphocyte-rich thymoma at pathology. During the course of treatment, the intact PTH levels were persistently low, although both total calcium and phosphorus were normal after oral supplementation of calcium and vitamin D.

Discussion

One previous report described a 62-year-old male with symptomatic chronic hypocalcemia, a stage II thymoma with an intact PTH that was undetectable, and hypocalcemia, which persisted after thymectomy. The patient required long-term replacement therapy with vitamin D and calcium. (8) The current case also revealed chronic hypocalcemia with subcapsular cataracts and intracranial calcifications. The profound hypocalcemia was unlikely to be due to causes such as the mild degree of hypomagnesemia and the lack of PTH response to magnesium repletion (ie, hypomagnesemia can cause acute increase in PTH or impair PTH secretion if prolonged). Another patient had hypocalcemia associated with thymoma, which was reportedly due to tumor lysis syndrome. This, however, was not evident in our case (ie, no renal failure, no increase in uric acid or potassium). (9) Other possible causes for hypoparathyroidism such as infiltrative damage to the parathyroids from disorders such as hemochromatosis, Wilson disease, sarcoidosis, and amyloidosis were not grossly evident (although specific studies for exclusion were not performed).

Thymomas are known to be associated with polyendocrine syndromes, including Graves disease. Because there was no family history or concurrent endocrine disorders such as Addison disease in the current case, the most likely diagnosis was that of idiopathic (autoimmune) hypoparathyroidism. (10) Patients with autoimmune hypoparathyroidism were first demonstrated to have antiparathyroid antibodies in 1966. (11) In a subsequent study, 56% of patients with acquired hypoparathyroidism and autoimmune polyglandular syndrome 1 had autoantibodies directed against the extracellular portion of the parathyroid calcium-sensing receptor (CaSR), the autoantigen now suggested to cause parathyroid failure. (12) Several additional cases of autoantibodies to the CaSR with autoimmune hypoparathyroidism have been described. (13) These autoantibodies may be cytotoxic (14) or occur without cellular destruction. (14)

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

The mechanism of action of these CaSR antibodies may involve decreased secretion of PTH, mimicking cases with an activating mutation of the parathyroid CaSR seen in sporadic hypoparathyroidism with autosomal dominant-type hypocalcemia. (15,16) Indeed, CaSR-blocking antibodies have been reported to result in hypocalciuric hypercalcemia, (17) and in vitro inhibition of PTH secretion to antibodies to the parathyroid cell surface was reported to occur in three cases of idiopathic hypoparathyroidism. (18) Anti-CaSR antibodies were also shown to be biochemically active in two patients with autoimmune hypoparathyroidism. (13)

Although we failed to uncover such an antibody in our patient, similar negative findings have been reported in 73 patients with autoimmune polyglandular syndrome 1 with hypoparathyroidism. (19) Indeed, in studies of subjects without autoimmunity but with classical hypoparathyroid features, 51% had serologic autoimmunity to the CaSR. (20) Positive serology in asymptomatic control subjects has also been noted in several series. (11,20) Thus, the method and the type of detection used may explain the variability in reporting. (13,19) The actual pathophysiological role of the CaSR antibodies is currently unknown. (21) From the perspective of a thymoma, it is of interest that T-cell activation has been noted to occur in adult idiopathic hypoparathyroidism, without B-cell participation. (22)

Conclusion

A malignant thymoma was diagnosed in a previously healthy man. This was associated with severe hypocalcemic crisis in a background of chronic hypocalcemia and hypoparathyroidism. Although thymomas often have immune-associated dysregulation, the CaSR antibody was negative in this case. Although a chance association cannot be excluded, a previously described case of thymoma and hypoparathyroidism has also been reported. (8)

Acknowledgment

Dr. Jianxin Hu, Molecular Pathophysiology Section, NIDCD, NIH, performed the Western blot for the CaSR Ab.

References

1. Cameron RB, DeVita VT, Hellman S, Rosenberg SA. Neoplasms of the mediastinum, in DeVita, Hellman, Rosenberg (eds): Principles and Practice of Oncology. Philadelphia, Lippincott, Williams and Wilkins, 6th ed. 2000, pp 1024.

2. Souadjian JV, Enriquez P, Silverstein MN, et al. The spectrum of diseases associated with thymoma. Arch Intern Med 1974;134:374.

3. Donadio AC, Dragnev KH, Schwartz GK. Thymoma associated with syndrome of inappropriate antidiuretic hormone secretion and myasthenia gravis. South Med J 1998;91:278-279.

4. Suzuki T, Suzuki S, Kitami A, et al. A thymoma associated with hyperparathyroidism. Thorac Cardiovasc Surg 1997;45:211-212.

5. Rizzoli R, Pache JC, Didierjean L, et al. A thymoma as a cause of true ectopic hyperparathyroidism. J Clin Endocrinol Metab 1994;79:912-915.

6. Byrne DJ, Gunn A, Davidson DL, et al. Parathyroid hyperplasia associated with thymoma. Postgrad Med J 1989;65:310-311.

7. Hu J, Hauache O, Spiegel AM. Human Ga2+ receptor cysteine-rich domain. Analysis of function of mutant and chimeric receptors. J Biol Chem

2000;275:16382-16389.

8. Hao LJ, Han TM, Yang CY, et al. Late-onset idiopathic hypoparathy-roidism with thymoma: a case report. Zhonghua Yi Xue Za Zhi 1996; 57:146-151.

9. Trobaugh-Lotrario AD, Liang X, Janik JS, et al. Difficult diagnostic and therapeutic cases: case 2, thymoma and tumor lysis syndrome in an adolescent. J Clin Oncol 2004;22:955-957.

10. Jan de Beur SM, Streeten EA, Levine M. Hypoparathyroidism and other causes of hypocalcemia, in Becker KL (ed): Principles and Practice of Endocrinology and Metabolism. 3rd ed. Philadelphia, Lippincott Williams & Wilkins, 2001, pp 586-591.

11. Blizzard RM, Chee D, Davis W. The incidence of parathyroid and other antibodies in the sera of patients with idiopathic hypoparathyroidism. Exp Immunol 1996;1:119-128.

12. Li Y, Song YH, Rais N, et al. Autoantibodies to the extracellular domain of the calcium sensing receptor in patients with acquired hypoparathyroidism. J Clin Invest 1996;97:910-914.

13. Kifor O, McElduff A, Leboff M, et al. Activating antibodies to the calcium-sensing receptor in two patients with autoimmune hypoparathyroidism. J Clin Endocrinol Metab 2004;89:548-556.

14. Brandi ML, Aurbach GD, Fattorossi A, et al. Antibodies cytotoxic to bovine parathyroid cells in autoimmune hypoparathyroidism. Proc Natl Acad Sci U S A 1986;83:8366.

15. Baron J, Winer KK, Yanovski JA, et al. Mutations in the Ca(2+)-sensing receptor gene cause autosomal dominant and sporadic hyperparathyroidism. Hum Mol Genet 1996;5:601-606.

16. DeLuca F, Ray K, Mancilla EE, et al. Sporadic hypoparathyroidism caused by de novo gain-of-function mutations of the Ca(2+)-sensing receptor. J Clin Endocrinol Metab 1997;82:2710-2715.

17. Pallais JC, Kifor O, Chen Y-B, et al. Acquired hypocalciuric hypercalcemia due to autoantibodies against the calcium-sensing receptor. N Engl J Med 2004;351:362-369.

18. Posillico JT, Wortsman J, Srikanta S, et al. Parathyroid cell surface autoantibodies that inhibit parathyroid hormone secretion from dispersed human parathyroid cell. J Bone Miner Res 1986;1:475-483.

19. Soderberg A, Myhre AG, Ekwall O, et al. Prevalence and clinical associations of 10 defined autoantibodies in autoimmune polyendocrine syndrome 1. J Clin Endocrinol Metab 2004;89:557-562.

20. Goswami R, Brown EM, Kochupillai N, et al. Prevalence of calcium sensing receptor autoantibodies in patients with sporadic idiopathic hypoparathyroidism. Eur J Endocrinol 2004;150:9-18.

21. Eisenbarth GS, Gottlieb P. Hypoparathyroidism and autoimmune polyendocrine syndromes. N Engl J Med 2004;351:1032-1033.

22. Wortsman J, McConnachie P, Baker JR Jr, et al. T-lymphocyte activation in adult onset idiopathic hypoparathyroidism. Am J Med 1992;92:352-356.

Wassim McHayleh, MD, Bruce Kressel, MD, and Eric S. Nylen, MD

From the Department of Medicine and Endocrinology, George Washington University Medical Center, Washington, DC.

Reprint requests to Dr. E. S. Nylen, VAMC, 50 Irving St., Room GE 246, Washington, DC 20422. Email: [e-mail]

Accepted January 24, 2005.

RELATED ARTICLE: Key Points

* Hypocalcemic crisis can present as a syncopal episode.

* Hypocalcemia can be associated with thymoma.

* Autoimmune hypocalcemia can be associated with antibodies against the calcium-sensing receptor.