As mentioned postpartum thyroiditis is considered to be very similar if not identical to silent (painless) thyroiditis(35). This condition is discussed in Chapter 14.
Occasionally Hashimoto's thyroiditis is accompanied by mild symptoms of thyrotoxicosis especially in the early phases of the disease. This condition is discussed in Chapter 8.
Although factitious thyrotoxicosis involves all situations in which usage of (excessive doses) thyroid hormone leads to symptoms of thyrotoxicosis, the term "factitious" is usually associated with surreptitious ingestion of thyroid hormone in supraphysiological doses. Patients usually deny taking thyroid hormones in excess. This primarily psychiatric disorder may lead to wrong diagnosis and treatment if physicians are not aware of the phenomenon. Patients are clinically thyrotoxic, however they do not show eyesigns as seen in Graves' disease, except for those related to sympathetic overactivity (lid retraction). Deliberate intake of high doses of thyroid hormone leads to TSH suppression and shrinkage of the thyroid, so that no thyroid tissue is palpated. Serum TSH and the uptake of 123-I or TcO4- are all suppressed. Color flow Doppler sonography shows absent thyroidal vascularity and low-normal peak systolic velocity, while with this technique these signs are increased in Graves' disease. (49a) Thus, factitious thyrotoxicosis is not difficult to differentiate from thyrotoxic Graves' disease, toxic adenoma or toxic multinodular goiter. In subacute (De Quervain's) thyroiditis symptoms are typical in that, apart from thyrotoxicosis, patients may have fever in the initial phase of the disease and the thyroid is very tender. Silent thyroiditis however, is not so easily distinguished from thyrotoxicosis factitia. In both situations the uptake of radioactive iodine is suppressed and patients lack eyesigns. However, in patients with silent thyroiditis a palpable firm painless thyroid gland is present. Furthermore patients with silent thyroiditis show high levels of thyroglobulin. In thyrotoxicosis factitia excessive intake of thyroid hormone leads to suppression of TSH and therefore also to suppression of thyroglobulin leakage from the thyroid gland. Mariotti et al. (50) performed thyroglobulin measurements in 6 women with thyrotoxicosis factitia. They used a very sensitive thyroglobulin assay and excluded the presence of thyroglobulin antibodies that can interfere with the assay. In all 6 women thyroglobulin was undetectable in the serum (lower detection limit 1.25 ng/ml) (Table 13-5).
Table 5. Results of Thyroid-Function Tests in Patients with Thyrotoxicosis Factitia *
|
Patient Number |
T4 |
T3 |
T3 Resin Uptake |
TSH |
Thyro-globulin |
24-Hour Radio-iodine Uptake |
Thyroid Micro-somal Antibody Passive Hemagglu-tination |
Anti-TG Passive Hema-gglu-tination |
Anti-TG Radio-assay |
|---|---|---|---|---|---|---|---|---|---|
|
m g/dl |
ng/dl |
% |
m U/ml |
ng/ml |
% |
||||
|
ND = not done (From Mariotti,50 with permission) |
|||||||||
|
1 |
> 18.0 |
> 450 |
69.1 |
> 0.6 |
> 1.25 |
2.0 |
Negative |
Negative |
Negative |
|
2 |
> 18.0 |
410 |
60.9 |
> 0.6 |
> 1.25 |
2.0 |
Negative |
Negative |
Negative |
|
3 |
11.5 |
262 |
53.6 |
> 0.6 |
> 1.25 |
3.0 |
Negative |
Negative |
Negative |
|
4 |
> 18.0 |
> 450 |
74.0 |
> 0.6 |
> 1.25 |
2.0 |
Negative |
Negative |
Negative |
|
5 |
> 18.0 |
> 450 |
72.3 |
> 0.6 |
> 1.25 |
1.0 |
Negative |
Negative |
Negative |
|
6 |
14.7 |
ND |
63.8 |
> 0.6 |
> 1.25 |
0.8 |
Negative |
Negative |
Negative |
|
Normal |
4.6-12.2 |
100-220 |
37-59 |
>0.6-6.0 |
>1.25-30 |
28-44 |
1:100 |
1:100 |
Negative |
The possibility of this syndrome should be considered especially when thyrotoxicosis appears to be resistant to treatment or where laboratory data are contradictory. Patients may be very persistent in denying the deliberate intake of thyroid hormone and persist in this attitude even after factitious thyrotoxicosis has been unequivocally confirmed. Consultation with a psychiatrist is urgently needed in such patients.
Suppressed radioactive uptake of the thyroid gland in combination with thyrotoxicosis may also exist in patients with hyperfunctioning metastases of follicular thyroid carcinoma. However, in these extremely rare patients, thyroglobulin levels are almost invariably elevated and radioactive iodine uptake will be detected in metastases by using whole body scanning.
It should be noted that the profile of serum thyroid hormones in thyrotoxicosis factitia is determined by the composition of the preparation ingested. Both T4 and T3 are elevated in overdose of L-thyroxine and desiccated thyroid, whereas only T3 is elevated and T4 is low or non-detectable when preparations containing only T3 are being taken. Treatment of thyrotoxicosis factitia is not difficult with regard to thyrotoxic symptoms, as discontinuation of thyroid hormone ingestion is usually sufficient. In more severe cases treatment with propranolol may be helpful. However, treatment of the psychiatric disorder is more challenging and may fail in the long run.
Thyrotoxicosis induced by excessive thyroid hormone intake, not based on deliberate choice of the patient, has been observed in the "hamburger thyrotoxicosis" patients. Two epidemics of thyrotoxicosis in the United States were caused by inclusion of bovine thyroid in hamburger (51,52). Inclusion of the thyroid in neck muscle trimmings is now prohibited by US Department of Agriculture regulations.
Prescription of supranormal amounts of thyroid hormone to suppress serum TSH for medical reasons can be designated as iatrogenic (usually subclinical) thyrotoxicosis. TSH suppression is usually given in patients after thyroidectomy for thyroid carcinoma and also to suppress benign thyroid growth in goiter patients. It is discussed further in the relevant chapters. Long-term use of suppressive amounts of thyroid hormone has been reported to enhance osteoporosis and also cause cardiac abnormalities including arrhythmias and function disturbances (53,54), but other studies have not confirmed these findings (55-56)
Due to the intrinsic TSH-like activity of human chorionic gonadotrophin (hCG), many healthy euthyroid pregnant women have reduced serum TSH values. Gestational transient thyrotoxicosis (i.e. increased serum free T4 and subnormal TSH) is seen in 1.4 % of pregnant women, mostly when hCG levels are above 70-80,000 IU/l (57). In one recently reported case, thyrotoxicosis was related to a TSH-R mutation increasing its responsiveness to hCG (57a). Thyrotoxicosis and other thyroid diseases during or after pregnancy are discussed in Chapter 14.
Thyrotoxicosis may be induced by hCG stimulation during molar pregnancy and also by trophoblastic tumors in males and in females. hCG is composed of an alpha -subunit, identical to the alpha -subunit in pituitary glycoprotein hormones such as LH, FSH and TSH, and a ß- subunit which is specific for hCG. There is structural homology with the ß-subunit of TSH. However, the ß-hCG unit is larger in that it is composed of 147 aminoacids while that of TSH consists of 110 aminoacids, and has additional carbohydrate residues on the COOH terminus.
Weak thyrotropic activity of hCG was found in hCG prepared from pregnancy urine, using a mouse thyrotropin bioassay (58). In another study (59) hCG was purified from molar tissue and had intrinsic TSH bioactivity in the mouse bioassay, although 4000 times less than that of human TSH on a molar basis. Despite this weak activity in hydatidiform mole disease, hCG is produced in sufficient amounts to induce hyperthyroidism. In a study of 20 patients (60) with gestational trophoblastic neoplasia 2 patients were judged to be overtly thyrotoxic, and this was confirmed by elevated serum T4 levels. These 2 patients had extremely high serum (3,220,000 IU/l and 6,720,000 IU/l) and urine hCG levels which correlated closely with TSH-like activity exerted by the serum of these patients in a mouse thyroid bioassay. Patients with moderately (110,000 - 310,000 IU/l) increased serum hCG levels due to trophoblastic neoplasia were euthyroid. In studies using thyroids from different species to test for hCG intrinsic TSH activity, it was found that the mouse thyroid was much more sensitive to stimulation by hCG, whereas the human thyroid was relatively insensitive (61). In another study on the activity of hCG on the human thyroid gland (62), 1.0 IU hCG was found roughly equivalent to 0.27 m IU hTSH. hLH also has intrinsic thyroid stimulating activity, but lower than hCG. 1.0 IU hLH was found equivalent to 44 m IU hTSH. This lower potency of hCG is caused by the C-terminal extension of the ß-subunit that interferes with its binding to the receptor. This extension is lacking in the ß-subunit of hLH, its structure being otherwise almost identical to that of hCG. (63) Carboxy peptidase digestion of hCG, cleaving aminoacid residues 142-145 from the ß-subunit, leads to a dramatic increase in its capacity to stimulate adenylate cyclase in human thyroid membranes (64). A variant of hCG, lacking the C-terminus of the ß-subunit due to enzymatic cleavage has been identified in pregnancy serum and molar tissue (65). Human hCG not only stimulated the mouse thyroid but also displaced human TSH from the plasma membrane receptor of follicular cells (61,62,66). In studies using human thyroid membranes 67 or a cell line transfected with the human TSH receptor (68), desialylated forms of human hCG exhibited stronger inhibition of TSH mediated cAMP responses than native hCG. Both TSH binding, and TSH induced adenylate cyclase stimulation were found more effectively inhibited by desialylated variants of hCG than unmodified hCG (69) From these and other studies it seems that the biological effect of hCG is predominantly confined to hCG containing little or no sialic acid. hCG has also been found to increase iodide uptake in cultured FRTL-5 cells and also causes a dose related increment of adenylate cyclase activity and thymidine uptake (70,71).
In 1955 Tisné and co-workers described a patient with molar pregnancy that had increased thyroidal uptake of radioactive iodine and clinical signs of hyperthyroidism (cited by Hershman and Higgins(72). Earlier reports (73-76) also described molar pregnancy in combination with hyperthyroidism and in all cases a rapid return to normal thyroid function occurred after removal of the mole. The effect of removal of molar tissue on serum T4, serum T3, bioassayable TSH, and hCG (by immunoassay) is shown in Figure 13-8 (below) (77). The patient was pre-treated with iodide. After removal of the tumor there was a rapid normalization of serum T4, T3, serum TSH, and hCG. From the parallelism of thyroid stimulating and hCG activity it was concluded that the same molecule, i.e. hCG, possessed both gonadotrophic and thyrotropic activity. In a later study (72), 2 patients with hydatidiform mole were described with severe hyperthyroidism and rapid disappearance of hyperthyroidism after removal of the mole. The youngest patient described so far was 17years of age (72a) A thyroid stimulator was extracted from the serum of one patient that differed biologically and immunologically from TSH, from hCG found in normal placentas and from thyroid stimulating immunoglobulins. The conclusion that the molar thyrotropin differed from normal placenta hCG was based on differences in antigenic properties and molecular size. hCG extracted from hydatidiform moles contained less sialic acid and was biologically more active than normal pregnancy hCG(78). In Figure 13-9 (below) the relationship is shown between bioassayable TSH and serum T3 values in patients with molar pregnancy. In this study with the exception of one patient, there is a very high correlation between the two parameters, suggesting a causal relationship between serum thyrotropin activity and thyroid function. A similar correlation between serum hCG levels and thyroid stimulating activity in both serum and urine was found in two women who had widely metastatic choriocarcinoma and marked hyperthyroidism (60). In another patient with gestational choriocarcinoma serum thyroid stimulating activity correlated precisely with serum T4, with the ß- subunit of human hCG, and with the quantitation of the host tumor burden (79). Sera from five patients with hydatidiform mole before treatment showed increased stimulating activity in CHO-hTSHR cells that decreased promptly after evacuation of the tumor (79a).
Figure 8. The effect of 1 g of sodium iodide (NAI) and surgical removal of the molar tissue (O.R.) on the circulating levels of serum T4, T3, hCG (immunoassay) and TSH (bioassay) in a patient with hydatidiform mole induced thyrotoxicosis (taken from ref. 77, with permission).
Figure 9. Relationship between T3 serum levels and bioassayable serum TSH activity in 9 patients with hydatidiform mole induced thyrotoxocosis. The correlation coefficient for 8 patients (except x) is 0.94 (taken from ref. 77, with permission).
The clinical syndrome of hyperthyroidism associated with choriocarcinoma in the male is extremely rare, but several reports have appeared in the literature. Orgiazzi et al. (80) cite four cases from the literature and reported a patient who had choriocarcinoma of the colon associated with gynecomastia and hyperthyroidism. Thyroid stimulating activity, measured by mouse bioassay, was detected in the serum. Serum thyroid stimulating activity was partly inactivated by antibovine-TSH antiserum, but was completely neutralized by anti-hCG antiserum. The clinical picture of patients with trophoblastic hyperthyroidism is that of thyrotoxicosis, lacking the characteristic features belonging to Graves' disease (ophthalmic disease, pretibial myxedema and acropachy). hCG-levels are mostly above 300,000 U/l. The thyrotoxicosis is usually not severe because of its shorter duration. (For review see also 80a)
Obviously, removal of the tumor, if feasible, should be carried out as soon as possible. Treatment with antithyroid drugs does not produce euthyroidism rapidly, and patients are therefore also treated preoperatively with oral sodium ipodate 1 g/day, or saturated potassium iodide 3 x 10 drops daily or sodium iodide 0.5 g i.v. every 8 hours. Propranolol may be added to the regimen and additional supportive therapy, replacing fluids and electrolytes, may be necessary. In patients who are not suitable for surgery because of metastatic disease, antithyroid drug treatment using propylthyiouracil or methimazole in combination with chemotherapy is the best treatment available. 131-I therapy is also possible. If hyperthyroidism is so severe that development of thyroid crisis after surgery is possible, anti-thyroid drug treatment should be combined with iodide and propranolol pre-treatment.
Normal or even elevated serum TSH, in combination with clinical hyperthyroidism, and increased serum thyroid hormone levels, may be seen in the presence of a TSH secreting pituitary tumor or selective partial pituitary resistance to thyroid hormone.
This syndrome is described in Chapter 16 and is probably part of the continuous spectrum of the syndromes of thyroid hormone resistance in which the resistance is predominant at the pituitary level. Since the pituitary is selectively resistant to thyroid hormone, the set-point of the pituitary, i.e. the specific TSH: thyroid hormone ratio needed to ensure normal thyroid gland activation, is set at a higher level of serum thyroid hormone concentration. The other body tissues appear more sensitive to thyroid hormones, and the clinical picture of thyrotoxicosis develops. Eye symptoms and other characteristics specific for Graves' disease are absent. This syndrome may be inherited in an autosomal dominant mode. Since there is no pituitary tumor, the ratio of TSH alpha-subunits to total TSH is less than 1, whereas in a TSH producing pituitary tumor (see below) this ratio is usually above 1.
Hyperthyroidism due to a TSH secreting pituitary tumor is rare. In 1978 Tolis et al. (103) reviewed the literature and found that between 10 - 20 patients had been reported. In 1983 another review found 17 women and 16 men with hyperthyroidism due to a TSH producing pituitary tumor (104)
The criteria that are required to confirm this entity are the following. The patient is clinically thyrotoxic while serum levels of free T4 and/or free T3 are elevated and serum TSH concentration is normal or increased. Visualization of the pituitary by magnetic resonance imaging shows a pituitary tumor. The concentration of TSH alpha -subunits in blood is above normal, as is the ratio of TSHalpha /TSH (104a). Pituitary TSH adenoma produce normal forms of TSH but secrete them in variable amount and differing biological activity, explaining the variable degree of hyperthyroidism in these patients (104b) In a study of 9 patients it was found that the mean delay to a correct diagnosis was 6.2 years1(06) Seven of these patients were wrongly treated for presumed primary hyperthyroidism with either thionamides, radioactive iodine or even by thyroidectomy, prior to the final diagnosis. Although in principle this thyrotoxicosis is not accompanied by eyesigns, unilateral exophthalmos may ensue from a thyrotropin secreting pituitary tumor due to invasion of one orbit (107).
When the diagnosis is established, patients should have treatment of the pituitary tumor. This usually consists of surgery plus external radiation. This approach however is not always successful (107). A relapse was seen in 4 of 5 operated and postoperatively irradiated patients during follow-up of 3.5 - 6 years. Another report (108) described a relapse in all 4 similarly treated patients. When the tumor is a macroadenoma, its behavior tends to be aggressive. The prognosis is better in patients with microadenomas(106). Better results with macroadenomas were reported by Smallridge and Smith (104). All patients had large adenomas. Eight out of 9 were cured by surgery plus external radiation, whereas 8 of 16 were cured by surgery alone and 1 out of 4 by radiation alone. Normalization of the elevated biologic to immunologic ratio of serum TSH after operation points to successful treatment of the adenoma (106). From these results a combination therapy consisting of surgery and irradiation seems imperative, at least in TSH-producing macroadenomas. As these tumors may become invasive early treatment is advised.
Administration of dopamine agonists or of somatostatin analogues are useful to shrink the tumor and in surgical failures (104a,109-113). The slow release formulation of the somatostatin analog lanreotide has recently been used in treating a series of 18 patients with pituitary thyrotropin secreting adenomas which had induced hyperthyroidism. In all cases with two or three monthly injections, there was control of hyperthyroidism with mild side effects such as abdominal cramps and diarrhea. There was no significant change in adenoma size. The lanreotide in this formulation appears to be an effective medical therapy for TSH-secreting adenomas. (113a) Long term treatment with lanreotide and cabergoline has also been successful (113b).
Autosomal dominantly inherited non-autoimmune hyperthyroidism was originally described by Duprez et al (114). In 2 kindred's activating germline mutations, Val 509 Ala and Cys 672 Tyr respectively, involving the third and seventh transmembrane segment of the thyrotropin receptor, were found. A third mutation (Phe 631 Leu) was described in a similar patient with congenital hyperthyroidism (114a). Since this was not found in parental DNA, it represented a neo mutation. 114b When mutant receptor gene constructs were transfected into COS cells, constitutive cAMP accumulation was observed (114,114a). Several other gain of function mutations have been recognized, all localized in exon 10 which encodes for the entire trans-membrane region of the TSH receptor. Recently a germline mutations in the extra-cellular portion of the TSH receptor were found to cause congenital hyperthyroidism (114b,114c). It is noteworthy that similar, but somatic, mutations are found in toxic adenoma tissue (see section "toxic adenoma" this chapter). The syndrome is fully discussed in Chapter 16a.
This rare syndrome consists of hyperthyroidism induced by pregnancy. It is caused by a mutation in the TSH receptor rendering it also specific for human CG(114d). See chapter16a.
In rare situations metastatic follicular carcinoma may cause thyrotoxicosis. According to Ehrenheim et al (115), Leiter et al. was the first to describe, in 1946, thyrotoxicosis due to functioning metastases in a patient with adenocarcinoma of the thyroid. Ehrenheim et al. reported 20 similar cases, and recently 54 cases reported in the literature were analyzed (115a). The age and sex distribution in such patients is no different from that of other patients with follicular carcinoma, but without thyrotoxicosis. About 85% of patients are older than 40 years and the female: male ratio is 3: 1. The clinical picture of thyrotoxicosis is similar to the general symptoms of other causes of thyrotoxicosis.
There is generally poor efficiency of iodine uptake and thyroid hormone synthesis and excessive hormone production is due to the large mass of metastatic tissue (116). The inefficient thyroid hormone synthesis is at least partly due to relative iodine deficiency in tumor tissue and the presence of abnormal thyroglobulin (117). Other abnormalities may however be present in the complicated process of thyroid hormone synthesis in carcinomatous tissue. For instance, there is evidence that expression of the TSH receptor in carcinomatous thyroid tissue may be absent or low (118) In many cases clinical symptoms are caused by T3 toxicosis with suppressed serum TSH, and normal or low serum T4 (116,117,119). Uptake of radioactive iodine in metastatic tissue may be low in the absence of normal thyroid tissue and is often absent when the thyroid gland is still present. The metastatic pattern of this type of adenocarcinoma is as is usually found in thyroid adenocarcinoma patients, that is predominantly in bone, lung and mediastinum.
Treatment of metastatic functioning thyroid carcinoma consists of administration of radioactive iodine. The usual dose ranges between 3700 - 7400 MBq (100-200 mCi). Exacerbation of thyrotoxicosis, even precipitating thyroid storm, has been reported(120) For this reason radioactive iodine for therapy of a functioning metastatic thyroid carcinoma should be administered with caution and only after adequate preparation of the elderly patient with cardiovascular disease. If normal thyroid tissue is still present, it is often advantageous to irradicate this tissue either by surgery or by radioactive iodine, to ensure more efficient uptake of therapeutic doses of radioactive iodine in the metastatic tissue. Graves' disease and follicular carcinoma occasionally co-occur, and this may not be a coincidence (121-123). There may be an association between Graves' disease and thyroid carcinoma, possibly because of longstanding thyroid stimulation by immunoglobulins (124). Although it has been postulated that thyroid carcinoma in patients with Graves' disease behaves more aggressively (125), this is uncertain (126).
Struma ovarii is a rare tumor occurring in a teratoma or dermoid in the ovary. It is often admixed with a carcinoid tumor, (127) and has been reported to occur in association with multiple endocrine neoplasia type IIA (128). Ovarian strumal carcinoid tumors have been found to synthesize different peptide hormones including calcitonin, ACTH, SRIF, neuron-specific enolase, chromogranin, synaptophysin, serotonin and other peptides (127-129). Struma ovarii is unilaterally localized in about 90% of patients and about 80% are benign (130). Pardo-Mindan and Vazquez (131) reviewed the world literature on malignant struma ovarii until 1983, finding only 18 cases. As differentiation between carcinoid and struma tissue is sometimes difficult, electron microscopic studies in combination with specific immunochemistry may be necessary.
Struma ovarii seldom causes hyperthyroidism. In thyrotoxicosis due to struma ovarii, uptake of radioactive iodine of the thyroid gland is low in the presence of elevated serum thyroid hormones and suppressed TSH. Uptake of radioactive iodine over the ovarian tumor confirms the diagnosis (131a,b). Although one would suspect that in thyrotoxic cases due to struma ovarii the thyroid gland would be reduced in size, the thyroid in several reports was enlarged (130,132). Possibly this could represent the effect of thyroid stimulating antibodies on both tissues. Treatment of struma ovarii, either with euthyroidism or thyrotoxicosis, should be effected by removal of the ovarian tumor. In the case of co-existent thyrotoxicosis, preparation for surgery should be done by administration of antithyroid drugs, sometimes in combination with beta-blocking agents. Because of the co-existing teratoma, it is sometimes difficult to determine if the thyroid tissue in the tumor is benign or malignant. It is not advised to treat patients with thyrotoxic struma ovarii with radioiodide because of the possibility that the tumor is malignant, which cannot be determined on clinical grounds, and secondly because of the unknown radiation effects on the other elements of the teratoma. Doppler flow may aid in the preoperative diagnosis of struma ovarii. Blood flow signals, detected from the center of the echoic lesion, and low resistance to flow may be more common in struma ovarii (132a). Recently a rare case of thyrotoxicosis was described in a 73 year old women caused by a toxic adenoma of the thyroid and an hyperthyroid struma ovarii (132b)
Thyrotoxicosis arises from several etiologies other than Graves' disease. Toxic adenomas are characterized by a single hyperactive nodule in the thyroid leading to clinical and biochemical thyrotoxicosis. Autonomous or toxic adenomas are considered to originate from somatic mutations in the gene of Gsalpha protein or the gene of the thyrotropin receptor. In toxic adenoma only a hot nodule is visible on the thyroid scan. The frequency of toxic nodules varies in different countries. The frequency of toxic adenoma in patients with hyperthyroidism ranges between 1.5 and 44.5% as reported from different surveys. The possibility of developing thyrotoxicosis in a patient with a hot nodule with a diameter of 3 cm or larger is 20% in 6 years. This risk is substantially less in smaller nodules. Also, older patients with a hot nodule are more likely to become toxic as compared to younger patients. Definitive treatment consists of surgical removal of the nodule, administration of 131I or percutaneous administration of ethanol into the nodule. The likelihood of malignancy in a toxic nodule is very low.
Thyrotoxicosis due to painless thyroiditis was uncommon until 1973, but the reported incidence has increased since then. This is an autoimmune thyroiditis due to lymphocytic infiltration of the thyroid and is identical to postpartum thyroiditis. About half of the patients pass through four classical phases consisting of thyrotoxicosis, euthyroidism, hypothyroidism and back to euthyroidism. The other half of the patients do not become hypothyroid or, in a small minority, remain hypothyroid. Biochemically characteristic is the fact that uptake of radioactive iodine is absent in the thyrotoxic phase and the serum thyroglobulin levels are high. Clinical thyrotoxicosis is mild and treatment with beta blocking agents is often sufficient. Sometimes addition of prednisone is necessary. Relapses may be seen. Although complete recovery is the rule, these patients are at high risk of developing hypothyroidism in later years. Permanent follow-up is therefore necessary.
Thyrotoxicosis factitia (thyrotoxicosis due to surreptitious ingestion of thyroid hormone) is primarily a psychiatric disorder. The diagnosis is straightforward if it is suspected. Patients usually deny thyroid hormone tablets ingestion. Characteristically thyroid uptake of radioactive iodine is low or absent and thyroglobulin is not detectable in the serum. Furthermore, the thyroid is usually small or absent on palpation. Treatment of the psychiatric disorder is difficult. Another form of excessive thyroid hormone intake is the "hamburger thyrotoxicosis". Subjects became thyrotoxic and showed characteristic serum abnormalities due to inclusion of thyroid in ground beef.
Thyrotoxicosis may be seen in association with elevated serum hCG activity in 1 - 2 % of normal pregnant women. hCG has low intrinsic thyroid stimulating activity, and hCG acts on the human thyroid cell through the TSH receptor. Desialylation of hCG renders it more biologically active. In hydatidiform mole disease however, high levels are found in patients' serum. When values are above 300,000 U/l, thyrotoxicosis is likely. Surgical removal of the mole renders the patient euthyroid.
Administration of moderate or high doses of iodine may induce thyrotoxicosis in patients with or without apparent pre-existing thyroid disease. Iodine may be derived from iodine solutions, radiographic contrast agents and medications. A notorious iodine containing agent is the anti-arrhythmic drug amiodarone. Due to its structure it may block pathways of thyroid hormone metabolism and action, leading to hypothyroidism, but it can also cause hyperthyroidism due to its iodine content. Amiodarone may also cause disruption of thyroid follicles resulting in thyrotoxicosis due to release of stored iodothyronines.
Inappropriate TSH secretion by a TSH secreting pituitary tumor may cause hyperthyroidism. Treatment of the pituitary tumor will lead to euthyroidism. The prognosis is better in patients with microadenoma. Treatment consists of surgery with postoperative external irradiation. Administration of dopamine antagonists or somatostatin analogues has been shown to be successful as well.
Rarely metastases of follicular carcinoma may result in thyrotoxicosis with suppressed activity of the thyroid gland. Treatment of the metastases with radioactive iodine will ameliorate thyrotoxicosis.
Struma ovarii, in itself a rare tumor occurring in a teratoma or dermoid in the ovarium, rarely causes hyperthyroidism. Most patients with struma ovarii are clinically and biochemically euthyroid. Treatment consists of removal of the tumor by surgery.
Other causes of thyrotoxicosis, such as multinodular goiter, (sub)acute thyroiditis of De Quervain, postpartum thyroiditis and Hashimoto's thyroiditis, partial selective pituitary resistance to thyroid hormone, inherited toxic hyperplasia and gestational hyperthyroidism are considered elsewhere in this volume.