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Exophthalmic goiter —An etiological enigma
J. chron. Dis. 1967, Vol. 20, pp. 251-254. Pergamon Press Ltd. Printed in Great Britain
Editorial EXOPHTHALMIC
GOITER-AN
ETIOLOGICAL
ENIGMA
(Received 10 February 1967)
ASTWOODrecently stated “The cause of hyperthyroidism is almost as obscure today as it was a half-century ago.” [l] Since the earliest published reports of exophthalmic goiter by Calleb Parry in 1825 and Robert Graves in 1835, many etiologies have been proposed. Most of them fit within the following categories : 1. Constitutional or genetic basis. 2. Excessive stimulation of the sympathetic nervous system. 3. Psychosomatic basis. 4. Stimulator of pituitary origin. 5. Stimulator of extrapituitary origin. 6. Infectious agent. A satisfactory theory of the cause of Graves’ disease (exophthalmic goiter) should account for the following features : excessive thyroid hormone secretion, exophthalmos, familial occurrence, and the preponderance of female patients. A valid theory must be experimentally verifiable and must show concomitant variation of the etiological factor(s) and the expression of the disease. By these criteria, none of the proposed theories is valid. Some appear more promising at the present time; others may be of historical interest. The difficulty in evaluating the role of constitutional factors is the lack of agreement about the meaning of the term. Does it include morphologic, genetic, physiologic, or psychologic factors? With regard to morphology, no general pattern of body build appears to characterize these patients. The striking occurrence of several cases in a family or in several generations suggests a genetic basis. MARTINfound evidence for a recessive factor. [2] The preponderance of female patients with a sex ratio varying from 2 : 1 to 10 : 1 in different series also suggests a genetic basis. INGBAR,FREINKEL,DOWLING and KUMAGAIshowed that euthyroid relatives of patients with Graves’ disease often had an increased rate of peripheral degradation of thyroxine and an increased thyroid uptake of radioiodine. [3] INGBARand FREINKELalso found that patients with hyperthyroidism had an increased turnover of thyroxine long after they were restored to a euthyroid state. [4] Their findings suggest the hypothesis that a genetic abnormality of the peripheral metabolism of thyroxine may be a causal factor. Cannon postulated that hyperthyroidism might be due toexcessive stimulationofthe sympathetic nervous system, possiblyemotional in origin. He and his colleagues producedtachycardia, weightloss, hairloss, increased heat production, adrenalhypertrophy, andexophthalmos incats’by fusing the right phrenic nerve and superior cervical ganglion. [5] However, further work did not substantiate the initial findings or the theory. POCHIN showed that stimulation of the cervical sympathetic nerves did not cause 251
252
JEROME
M. HER~HMAN
exophthalmos in man as it did in some experimental animals. [6] Recently, drugs which block the action of catecholamines have been used to treat some of the manifestations of hyperthyroidism, implying that thyroid hormones and catecholamines express their effects in a final common pathway. BRAYhas pointed out that the effects of thyroid hormones do not involve a direct interaction with adrenergic receptors, and if they have any effect on the response to catecholamines, it is an indirect one. [7] Proponents of a psychosomatic etiology hypothesize that patients with Graves’ disease have a predisposition basedon their personality pattern and that an emotionally traumatic event such as death of a relative or an equivalent loss may trigger the disease. In the reports of the psychosomaticists these factors occur in a very high proportion of patients. In contrast, a recent study designed to test specific psychologic factors postulated to play a causal role in Graves’ disease failed to show a different frequency of the factors in these patients as compared with a control group. [8] In 1922, SMITHand SMITHshowed that the pituitary contained a thyrotropic factor. [9] LOEB and his colleagues demonstrated that guinea pigs injected with pituitary extracts rich in this factor developed excessive thyroid activity and exophthalmos providing an experimental basis for the theory that the pituitary is responsible for hyperthyroidism. [lo, 1l] This theory implies that the normal pituitary-thyroid feedback mechanism is inoperative. Although some bioassays of sera from patients with Graves’ disease detected high levels of thyrotropin, more specific assays did not confirm this. [12] In a patient who became hypothyroid after radioiodine treatment of Graves’ disease, ADAMSand KENNEDYshowed that the serum thyrotropin increased, indicating preservation of the normal pituitary-thyroid relationship. [13] The reports of Graves’ disease occurring or persisting after surgical hypophysectomy are strong evidence that the pituitary does not produce a hormone responsible for hyperthyroidism. 114,151 In 1956, ADAMSand PURVESfound a thyroid stimulator in the sera of patients with hyperthyroidism. [15] In bioassays, this stimulator had a longer duration of action than pituitary thyrotropin and, consequently, was called long-acting thyroid stimulator or LATS. With special concentration procedures, LATS has been found in a majority of patients with Graves’ disease, but not in patients with autonomous hyperfunctioning thyroid adenomas. [16] Chemically, it is a yG globulin; consequently it can be separated from thyrotropin by several means. It can be inactivated by antibodies to YG globulin but not by antibodies to pituitary thyrotropin. 1151MCKENZIEreported that white cells from hyperthyroid patients produce LATS when incubated in vitro. [17] The relationship of LATS to exophthalmos is still unclear, but it appears likely that this substance is responsible for the hyperthyroidismper se. [ 15,181 KRISS, PLESHAKOV and CHIEN showed that this stimulator is inactivated by thyroid tissue. [19] BEALLand SOLOMON found that thyroid microsomes inactivated it more effectively than did other sub-cellular fractions. [20] Experiments are under way in several laboratories to induce the formation of LATS by immunizing animals with thyroid tissue components. That these can be antigenic has been well demonstrated in the experimental production of immune thyroidids. [21] Two additional observations suggest a relationship between Graves’ disease and immune disorders of the thyroid. Lymphocytic infiltration of the thyroid similar to that found in Hashimoto’s thyroiditis is usually present in exophthalmic goiter. Antibodies to thyroid tissue components occur in low titer in two-thirds of these patients. [22]
Editorial
253
If LATS is the stimulator of the thyroid in Graves’ disease and is also an antibody to thyroid tissue what initiates its production? In this issue of the Journal, GREENWALD presents a scholarly, epidemiologic study of exophthalmic goiter. [23] He believes that the epidemiologic data support the hypothesis that a specific infectious agent of unknown nature may be involved in its cause. Although an infectious agent has not yet been demonstrated to be etiologically implicated, the possibility that such an agent may trigger the production of an antibody which is also a thyroid stimulator now lies within the realm of provocative speculation.
REFERENCES 1. 2. 3. 4. 5.
ASTW~OD, E. B.: Thyroid disorders. A half-century of innovation, Ann. intern. Med. 63, 553, 1965. MARTIN, L. : Hereditary and familial aspects of exophthalmic and nodular goitre, Q. JI. Med. 14, 207,1945. INGBAR, S. H., FREINKEL, N., DOWLING, J. T. and KUMAGAI, L.: Abnormalities of iodine metabolism in euthyroid relatives of patients with Graves’ disease, J. clin. Invest. 35,714, 1956. INGBAR, S. H. and FREINKEL, N. : Studies of thyroid function and the peripheral metabolism of I1sl labeled thyroxine in patients with treated Graves’ disease, J. clitt. Invest. 37,1603,1958. CANNON,W. B., BINGER, C. A. L. and Frrz, R. : Experimental hyperthyroidism, Am. J. Physiol. 36,
363,1914. 6. POCHIN, E. E. : Ocular effects of sympathetic stimulation in man, Clin. Sci. 4,79,1939. 7. BRAY, G. : Studies on the sensitivity to catecholamines after thyroidectomy, Endocrinology79,554, 1966. 8. HERMANN, H. T. and QUARTON, G. C.: Psychological changes and pscyhogenesis in thyroid hormone disorders, J. clin. Endocr. Metab. 25,327,1965. 9. SWTH, P. E. and SMITH, I. P: Repair and activation of the thyroid in the hypophysectomized tadpole by the parenteral administration of fresh anterior lobe of the bovine hypophysis, J. med. Res. 43,267,1922. 10. LOEB, L., BASSET, R. B. and FRIEDMAN, H.: Further investigations concerning the stimulating effect of anterior pituitary gland preparation on the thyroid gland, Proc. Sot. exp. Biol. and Med. 28,209, 1930. 11.
12. 13.
LOEB, L. and FRIEDMAN, H. : Exophthalmos produced by injections of acid extract of anterior pituitary gland ofcattle, Proc. Soc.exp. Biol. Med. 29,648, 19j2. MCKENZIE. J. M. : Bio-assav of thvrotrooin in man. Phvsiol. Rev. 40.398. 1960. ADAMS, D.D. and KENNED;, T. H:: Evidence of a ho&ally functioiing dituitary TSH secretion mechanism in a patient with a high blood level of long acting thyroid stimulator, J. clin. Endocr.
Metab. 25, 571, 1965. 14. BECKER, D. V. and FURTH, E. D.: Total surgical hypophysectomy 15. 16.
in nine patients with Graves’ disease: Evidencefor the extrapituitary maintenance of this disorder, in Current Topics in Thyroid Research. P. 596. (Ed. by CASSANO.C. and ANDREOLI. M.). Academic, New York, 1965. ADAMS, D: D. : Pathogenesis of the hyperthyroidism of Giaves’ disease, Br. med. i. 1,1015,1965. MCKENZIE, J. M.: Hyperthyroidism caused by thyroid adenomata, J. clin. Erzdocr. Metab. 26,
779, 1966. 17. MCKENZIE, J. M. : The gamma globulin of Graves’ disease: Thyroid stimulation by fraction and fragment, Trans. Ass. Am. Phys. 78,174,1965. 18. MCKENZIE, J. M. : Review: Pathogenesis of Graves’ disease: Role of the long-acting thyroid stimulator, J. clin. Endocr. Metab. 25,424, 1965. 19. KRISS, J. P., PLESHKOV,V. and CHIEN, J. R. : Isolation and identification of the long-acting thyroid stimulator and its relation to hyperthyroidism and circumscribed pretibial myxedema, J. c/in. Elrdocr. Metab. 24,1005,1964. 20. BEALL, G. N. and SOLOMON, D. H.: Inhibition of long-acting thyroid stimulator by thyroid particulate fractions, J. clin. Invest. 45, 552, 1966. 21. ROSE, N. R. and WITEBSKY, E.: Studies on organ specificity. V. Changes in the thyroid glands of rabbits following active immunization with rabbit thyroid extracts, J. Zmmun. 76,417, 1956.
254 22. 23.
JEROME M. HERSHMAN ROITT, I. M. and DONIACH, D. : Thyroid auto-immunity, Br. med. Bull. 16,152,1960. GREENWALD, I.: Studies of exophthalmic goiter, J. chron. Dis. 20,255,1967. JEROME M. HERSHMAN,
Clinical Investigator, Veterans Administration Research Hospital, Department of Medicine, Northwestern University Medical School, Chicago, Illinois.
M.D.
Editorial EXOPHTHALMIC
GOITER-AN
ETIOLOGICAL
ENIGMA
(Received 10 February 1967)
ASTWOODrecently stated “The cause of hyperthyroidism is almost as obscure today as it was a half-century ago.” [l] Since the earliest published reports of exophthalmic goiter by Calleb Parry in 1825 and Robert Graves in 1835, many etiologies have been proposed. Most of them fit within the following categories : 1. Constitutional or genetic basis. 2. Excessive stimulation of the sympathetic nervous system. 3. Psychosomatic basis. 4. Stimulator of pituitary origin. 5. Stimulator of extrapituitary origin. 6. Infectious agent. A satisfactory theory of the cause of Graves’ disease (exophthalmic goiter) should account for the following features : excessive thyroid hormone secretion, exophthalmos, familial occurrence, and the preponderance of female patients. A valid theory must be experimentally verifiable and must show concomitant variation of the etiological factor(s) and the expression of the disease. By these criteria, none of the proposed theories is valid. Some appear more promising at the present time; others may be of historical interest. The difficulty in evaluating the role of constitutional factors is the lack of agreement about the meaning of the term. Does it include morphologic, genetic, physiologic, or psychologic factors? With regard to morphology, no general pattern of body build appears to characterize these patients. The striking occurrence of several cases in a family or in several generations suggests a genetic basis. MARTINfound evidence for a recessive factor. [2] The preponderance of female patients with a sex ratio varying from 2 : 1 to 10 : 1 in different series also suggests a genetic basis. INGBAR,FREINKEL,DOWLING and KUMAGAIshowed that euthyroid relatives of patients with Graves’ disease often had an increased rate of peripheral degradation of thyroxine and an increased thyroid uptake of radioiodine. [3] INGBARand FREINKELalso found that patients with hyperthyroidism had an increased turnover of thyroxine long after they were restored to a euthyroid state. [4] Their findings suggest the hypothesis that a genetic abnormality of the peripheral metabolism of thyroxine may be a causal factor. Cannon postulated that hyperthyroidism might be due toexcessive stimulationofthe sympathetic nervous system, possiblyemotional in origin. He and his colleagues producedtachycardia, weightloss, hairloss, increased heat production, adrenalhypertrophy, andexophthalmos incats’by fusing the right phrenic nerve and superior cervical ganglion. [5] However, further work did not substantiate the initial findings or the theory. POCHIN showed that stimulation of the cervical sympathetic nerves did not cause 251
252
JEROME
M. HER~HMAN
exophthalmos in man as it did in some experimental animals. [6] Recently, drugs which block the action of catecholamines have been used to treat some of the manifestations of hyperthyroidism, implying that thyroid hormones and catecholamines express their effects in a final common pathway. BRAYhas pointed out that the effects of thyroid hormones do not involve a direct interaction with adrenergic receptors, and if they have any effect on the response to catecholamines, it is an indirect one. [7] Proponents of a psychosomatic etiology hypothesize that patients with Graves’ disease have a predisposition basedon their personality pattern and that an emotionally traumatic event such as death of a relative or an equivalent loss may trigger the disease. In the reports of the psychosomaticists these factors occur in a very high proportion of patients. In contrast, a recent study designed to test specific psychologic factors postulated to play a causal role in Graves’ disease failed to show a different frequency of the factors in these patients as compared with a control group. [8] In 1922, SMITHand SMITHshowed that the pituitary contained a thyrotropic factor. [9] LOEB and his colleagues demonstrated that guinea pigs injected with pituitary extracts rich in this factor developed excessive thyroid activity and exophthalmos providing an experimental basis for the theory that the pituitary is responsible for hyperthyroidism. [lo, 1l] This theory implies that the normal pituitary-thyroid feedback mechanism is inoperative. Although some bioassays of sera from patients with Graves’ disease detected high levels of thyrotropin, more specific assays did not confirm this. [12] In a patient who became hypothyroid after radioiodine treatment of Graves’ disease, ADAMSand KENNEDYshowed that the serum thyrotropin increased, indicating preservation of the normal pituitary-thyroid relationship. [13] The reports of Graves’ disease occurring or persisting after surgical hypophysectomy are strong evidence that the pituitary does not produce a hormone responsible for hyperthyroidism. 114,151 In 1956, ADAMSand PURVESfound a thyroid stimulator in the sera of patients with hyperthyroidism. [15] In bioassays, this stimulator had a longer duration of action than pituitary thyrotropin and, consequently, was called long-acting thyroid stimulator or LATS. With special concentration procedures, LATS has been found in a majority of patients with Graves’ disease, but not in patients with autonomous hyperfunctioning thyroid adenomas. [16] Chemically, it is a yG globulin; consequently it can be separated from thyrotropin by several means. It can be inactivated by antibodies to YG globulin but not by antibodies to pituitary thyrotropin. 1151MCKENZIEreported that white cells from hyperthyroid patients produce LATS when incubated in vitro. [17] The relationship of LATS to exophthalmos is still unclear, but it appears likely that this substance is responsible for the hyperthyroidismper se. [ 15,181 KRISS, PLESHAKOV and CHIEN showed that this stimulator is inactivated by thyroid tissue. [19] BEALLand SOLOMON found that thyroid microsomes inactivated it more effectively than did other sub-cellular fractions. [20] Experiments are under way in several laboratories to induce the formation of LATS by immunizing animals with thyroid tissue components. That these can be antigenic has been well demonstrated in the experimental production of immune thyroidids. [21] Two additional observations suggest a relationship between Graves’ disease and immune disorders of the thyroid. Lymphocytic infiltration of the thyroid similar to that found in Hashimoto’s thyroiditis is usually present in exophthalmic goiter. Antibodies to thyroid tissue components occur in low titer in two-thirds of these patients. [22]
Editorial
253
If LATS is the stimulator of the thyroid in Graves’ disease and is also an antibody to thyroid tissue what initiates its production? In this issue of the Journal, GREENWALD presents a scholarly, epidemiologic study of exophthalmic goiter. [23] He believes that the epidemiologic data support the hypothesis that a specific infectious agent of unknown nature may be involved in its cause. Although an infectious agent has not yet been demonstrated to be etiologically implicated, the possibility that such an agent may trigger the production of an antibody which is also a thyroid stimulator now lies within the realm of provocative speculation.
REFERENCES 1. 2. 3. 4. 5.
ASTW~OD, E. B.: Thyroid disorders. A half-century of innovation, Ann. intern. Med. 63, 553, 1965. MARTIN, L. : Hereditary and familial aspects of exophthalmic and nodular goitre, Q. JI. Med. 14, 207,1945. INGBAR, S. H., FREINKEL, N., DOWLING, J. T. and KUMAGAI, L.: Abnormalities of iodine metabolism in euthyroid relatives of patients with Graves’ disease, J. clin. Invest. 35,714, 1956. INGBAR, S. H. and FREINKEL, N. : Studies of thyroid function and the peripheral metabolism of I1sl labeled thyroxine in patients with treated Graves’ disease, J. clitt. Invest. 37,1603,1958. CANNON,W. B., BINGER, C. A. L. and Frrz, R. : Experimental hyperthyroidism, Am. J. Physiol. 36,
363,1914. 6. POCHIN, E. E. : Ocular effects of sympathetic stimulation in man, Clin. Sci. 4,79,1939. 7. BRAY, G. : Studies on the sensitivity to catecholamines after thyroidectomy, Endocrinology79,554, 1966. 8. HERMANN, H. T. and QUARTON, G. C.: Psychological changes and pscyhogenesis in thyroid hormone disorders, J. clin. Endocr. Metab. 25,327,1965. 9. SWTH, P. E. and SMITH, I. P: Repair and activation of the thyroid in the hypophysectomized tadpole by the parenteral administration of fresh anterior lobe of the bovine hypophysis, J. med. Res. 43,267,1922. 10. LOEB, L., BASSET, R. B. and FRIEDMAN, H.: Further investigations concerning the stimulating effect of anterior pituitary gland preparation on the thyroid gland, Proc. Sot. exp. Biol. and Med. 28,209, 1930. 11.
12. 13.
LOEB, L. and FRIEDMAN, H. : Exophthalmos produced by injections of acid extract of anterior pituitary gland ofcattle, Proc. Soc.exp. Biol. Med. 29,648, 19j2. MCKENZIE. J. M. : Bio-assav of thvrotrooin in man. Phvsiol. Rev. 40.398. 1960. ADAMS, D.D. and KENNED;, T. H:: Evidence of a ho&ally functioiing dituitary TSH secretion mechanism in a patient with a high blood level of long acting thyroid stimulator, J. clin. Endocr.
Metab. 25, 571, 1965. 14. BECKER, D. V. and FURTH, E. D.: Total surgical hypophysectomy 15. 16.
in nine patients with Graves’ disease: Evidencefor the extrapituitary maintenance of this disorder, in Current Topics in Thyroid Research. P. 596. (Ed. by CASSANO.C. and ANDREOLI. M.). Academic, New York, 1965. ADAMS, D: D. : Pathogenesis of the hyperthyroidism of Giaves’ disease, Br. med. i. 1,1015,1965. MCKENZIE, J. M.: Hyperthyroidism caused by thyroid adenomata, J. clin. Erzdocr. Metab. 26,
779, 1966. 17. MCKENZIE, J. M. : The gamma globulin of Graves’ disease: Thyroid stimulation by fraction and fragment, Trans. Ass. Am. Phys. 78,174,1965. 18. MCKENZIE, J. M. : Review: Pathogenesis of Graves’ disease: Role of the long-acting thyroid stimulator, J. clin. Endocr. Metab. 25,424, 1965. 19. KRISS, J. P., PLESHKOV,V. and CHIEN, J. R. : Isolation and identification of the long-acting thyroid stimulator and its relation to hyperthyroidism and circumscribed pretibial myxedema, J. c/in. Elrdocr. Metab. 24,1005,1964. 20. BEALL, G. N. and SOLOMON, D. H.: Inhibition of long-acting thyroid stimulator by thyroid particulate fractions, J. clin. Invest. 45, 552, 1966. 21. ROSE, N. R. and WITEBSKY, E.: Studies on organ specificity. V. Changes in the thyroid glands of rabbits following active immunization with rabbit thyroid extracts, J. Zmmun. 76,417, 1956.
254 22. 23.
JEROME M. HERSHMAN ROITT, I. M. and DONIACH, D. : Thyroid auto-immunity, Br. med. Bull. 16,152,1960. GREENWALD, I.: Studies of exophthalmic goiter, J. chron. Dis. 20,255,1967. JEROME M. HERSHMAN,
Clinical Investigator, Veterans Administration Research Hospital, Department of Medicine, Northwestern University Medical School, Chicago, Illinois.
M.D.