Differential Diagnosis ( An algorithm  which may be useful is available--Possible Hyperthyroidism-- and readers should see also Chapter 13)

Graves' disease must first be differentiated from other conditions in which thyrotoxicosis is present (Table 11-4). Thyrotoxicosis may be caused by taking T4 or its analogs-- thyrotoxicosis factitia. Most commonly, this is due to administration of excessive replacement hormone by the patient's physician, but hormone may be taken surreptitiously by the patient for weight loss or psychologic reasons. The typical findings are a normal or small thyroid gland, an 131I uptake of zero, a low serum TG, and, of course, a striking lack of response to antithyroid drug therapy. The problem can easily be confused with "painless thyroiditis", but in thyrotoxicosis factitia, the gland is typically small.

Toxic nodular goiter is usually distinguished by careful physical examination and a history of goiter for many years before symptoms of hyperthyroidism developed. The thyrotoxicosis comes on insidiously, and often, in the older people usually afflicted, symptoms may be mild, or suggest another problem such as heart disease. The thyroid scan may be diagnostic, showing areas of increased and decreased isotope uptake.. The results of assays for antithyroid antibodies, including TSAb, are usually negative, but some researchers have found "growth stimulating" antibodies in sera from these patients. As reported in Chapter 13, TMNG is typically produced by activating somatic mutations in TSH-R in one or more nodules, allowing them to be enlarge and become functional even in the absence of TSH stimulation. Interestingly, cats are well known to develop hyperthyroidism,  with thyroid autonomy. Watson et al report that 28 of 50 hyperthyroid cats had somatic or germ-line mis-sense mutations in exon 10 of the TSH-R gene in nodules of their multinodular cat goiters.  Five mutations were similar to those reported in human toxic adenomas, suggesting that feline thyrotoxicosis is  a similar genetic disease(16.1)

A hyperfunctioning solitary adenoma is suggested on physical examination by atrophy of the remainder of the thyroid, and is proved by a scintiscan demonstrating preferential radioisotope accumulation in the nodule. This type of adenoma must be differentiated from congenital absence of one of the lobes of the thyroid. Toxic nodules typically present in adults with gradually developing hyperthyroidism and a nodule > 3 cm in size. As discussed in Chapter 18, these nodules are usually caused by activating somatic mutations in the TSH-R, which endows them with mildly increased function, compared to normal tissue, even in the absence of TSH. Occasionally autonomous nodules produce hyperthyroidism in children.¹⁷   It has been reported that in children many of such lesions can be low grade papillary cancers, in contrast to adults in whom toxic nodules are very rarely malignant. Rarely, functioning thyroid carcinomas produce thyrotoxicosis. The diagnosis is made by the history, absence of the normal thyroid, and usually widespread functioning metastasis in lung or bones. Invasion of the gland by lymphoma has produced thyrotoxicosis ¹⁸.

Thyrotoxicosis associated with subacute thyroiditis is usually mild and transient, and the patient lacks the physical findings of long-standing thyrotoxicosis. If thyrotoxicosis is found in conjunction with a painful goiter and low or absent 131I uptake, this diagnosis may be entertained. Usually the erythrocyte sedimentation rate (ESR) is greatly elevated, and the leukocyte count may also be increased. Occasionally the goiter is non-tender. Antibody titers are low or negative. Many patients have the HLA-B35 antigen, indicating a genetic predisposition to the disease.

The very rare thyrotroph tumor will be missed unless one measures the plasma TSH level, or until the enlargement is sufficient to produce deficiencies in other hormones, pressure symptoms, or expansion of the sella turcica. These patients have thyrotoxicosis with inappropriately elevated TSH levels and may/or may not secrete more TSH after TRH stimulation. The characteristic finding is a normal or elevated TSH, and an elevated TSH alpha subunit level in blood, measured by special RIA. Thyroid stimulatory IgGs are not present. Exophthalmos, family history, and antibodies of Graves' disease are absent. Demonstration of a suppressed TSH level should exclude these rare cases.

The category of patients with thyrotoxicosis and inappropriately elevated TSH levels also includes the very rare persons with excess TRH secretion, or pituitary "T3 resistance".¹⁹ TRH hypersecretion, a possible cause of thyrotoxicosis,²⁰ is marked by an absence of pituitary tumor, elevated TSH levels, and failure to respond to TRH. The syndrome of pituitary thyroid hormone resistance^19,21 is usually marked by mild thyrotoxicosis, elevated TSH levels, absence of pituitary tumor, a generous response to TRH, no excess TSH alpha subunit secretion,¹⁹ and by TSH suppression if large doses of T3 are administered. Final diagnosis depends on laboratory demonstration of a mutation in the TR gene, if possible.

Administration of large amounts of iodide in medicines, for roentgenographic examinations, or in foods can occasionally precipitate thyrotoxicosis in patients with multinodular goiter or functioning adenomas. This history is important to consider since the illness may be self-limiting. 

Induction of thyrotoxicosis has also been observed in apparently normal individuals following prolonged exposure to organic iodide containing compounds such as antiseptic soaps and amiodarone. Amiodarone is of special importance since the clinical problem often is the presentation of thyrotoxicosis in a patient with serious cardiac disease including dysrythmia. This topic is discussed  extensively in Chapter 12. Amodarone can induce thyrotoxicosis in patients without known prior thyroid disease, or with multinodular goiter. The illness appears to come in two forms. In one the RAIU may be low or normal. In the second variety , which appears to be more of thyroiditis-like syndrome, the RAIU is very suppressed, and IL-6 may be elevated. In either case TSH is suppressed, FTI may be normal or elevated, but T3 is elevated if the patient is toxic. Antibodies are usually negative.

An increasingly recognized form of thyrotoxicosis is the syndrome described variously as painless thyroiditis, transient thyrotoxicosis, or "hyperthyroiditis."^22,23 Its hallmarks are self-limited thyrotoxicosis, small painless goiter, and low or zero RAIU. The patients usually have no eye signs, a negative family history, and low antibody titers. This condition is due to autoimmune thyroid disease, and is considered a variant of Hashimoto’s Thyroiditis. It occurs sporadically, usually in young adults. It frequently occurs 3 - 12 weeks after delivery, apparently representing the effects of immunologic rebound from the immunosuppressive effects of pregnancy in patients with Hashimoto's thyroiditis^24,25 or prior Graves’ Disease. The course typically includes development of a painless goiter, mild to moderate thyrotoxicosis, no eye signs, remission of symptoms in 3 -20 weeks, and often a period of hypothyroidism before return to euthyroid function. The cycle may be repeated several times. Histologic examination shows chronic thyroiditis, but it is not typical of Hashimoto's disease or subacute thyroiditis and may revert to normal after the attack.²⁶ In most patients, the thyrotoxic episode occurs in the absence of circulating TSAb. This finding suggests that the pathogenesis is quite distinct from that in Graves' disease.²⁷ The thyrotoxicosis is caused by an inflammation-induced discharge of preformed hormone due to the thyroiditis. The T4/T3 ratio is higher than in typical Graves' disease,²⁸ and thyroid iodine stores are depleted. Since the thyrotoxicosis is due to an inflammatory process, therapy with antithyroid drugs or potassium iodide is usually to no avail, and RAI treatment of course cannot be given. Propranolol is usually helpful for symptoms. Glucocorticoids may be of help if the process -- often transient and mild -- requires some form of therapy. Propylthiouracil and/or ipodate can be used to decrease T4 to T3 conversion and will ameliorate the illness. Repeated episodes may be handled by surgery or by RAI therapy during a remission. Variants of this syndrome have been described. Shigemasa et al.²⁹ described patients with a similar clinical picture but painful chronic thyroid enlargement frequently ending in time with thyroid atrophy and hypothyroidism.  Occasionally painless post-partum thyroiditis is followed by typical Graves' Disease ^29.1

Hyperemisis gravidarum is usually associated with elevated serum T4, FTI, and variably elevated T3, and suppressed TSH ^29.3. As described elsewhere, the final interpretation of this syndrome is uncertain. The abnormalities in thyroid function are caused by high levels of  hCG. This molecule, or a closely related form, share  enough homology with TSH so that it has about 1/1000 the thyroid stimulating activity of TSH, and can produce thyroid stimulation or thyrotoxicosis(29.4). It disappears with termination of pregnancy, or may require treatment temporarily or throughout pregnancy. Patients with minimal signs and symptoms, small or no goiter, and elevation of FTI up to 50 % above normal probably do not require treatment. Those with goiter, moderate or severe clinical evidence of thyrotoxicosis, highly elevated T4 and T3 and suppressed TSH are best treated with antithyroid drugs. If antibodies are positive or eye signs are present, the picture is usually interpreted as a form of Graves’ Disease. Familial severe hyperemesis gravidarum with fetal loss has been reported.   In one family Vassart and co-workers discovered an activating germline mutation in the TSH-R, which made it specifically more sensitive to activation by hCG ^29.2. Hyperthyroidism can be induced by “hyperplacentosis”, which is characterized by increased placental weight and circulating hCG levels higher than those in normal pregnancy.  After hysterotomy, hCG levels declined in the one case reported and hyperthyroidism was corrected (29.3).

Congenital hyperthyroidism caused by a germ-line activating mutation in the TSH-R has recently been recognized . The mutations are usually single aminoacid transitions in the extracellular loops or transmembrane segments of the receptor trans-membrane domain ^29.1. The diagnosis may be difficult to recognize in the absence of a family history. However the patients lack eye signs, and have negative assays for antibodies.

Hydatidiform moles, choriocarcinomas, and rarely seminomas secrete vast amounts of hCG. hCG, with an alpha subunit identical to TSH , and beta subunit related to TSH , binds to and activates the thyroid TSH receptor with about 1/1,000th the efficiency of TSH itself (Fig.11-3).  Current evidence indicates that very elevated levels of native hCG,^30,29.4 or perhaps desialated hCG,^31,32 cause the thyroid stimulation.   Many patients have goiter or elevated thyroid hormone levels or both, but little evidence of thyrotoxicosis, whereas others are clearly thyrotoxic.³³ Diagnosis rests on recognizing the tumor (typically during or after pregnancy) and measurement of hCG. Therapy is directed at the tumor.³³

^{Hyperthyroidism also is seen as one manifestation of autoimmune thyroid disease induced by interferon-alpha treatment of chronic hepatitis c. It can be self limiting, or severe enough to require cessation of IFN, or in some cases continue on after INF is stopped (33.1).}
Hyperthyroidism also occurs during immune reconstitution  seen in effective anti-viral therapy of patients with HIV (33.2) , and has occurred during recovery of low lymphocyte levels induced by therapy with CAMPATH in patients with Multiple sclerosis.

Two common diagnostic problems involve (1) the question of hyperthyroidism in patients with goiter of another cause, and (2) mild neuroses such as anxiety, fatigue states, and neurasthenia. Most patients with goiter receive a battery of examinations to survey their thyroid function at some time. Usually these tests are done more for routine assessment than because there is serious concern over the possibility of thyrotoxicosis. In the absence of significant symptoms or signs of hyperthyroidism and ophthalmologic problems, a normal FTI or sTSH determination is sufficiently reassuring to the physician and the patient. Of course, the most satisfactory conclusion of such a study is the positive identification of an alternate cause for enlargement of the thyroid.

Some patients complain of fatigue and palpitations, weight loss, nervousness, irritability, and insomnia. These patients may demonstrate brisk reflex activity, tachycardia (especially during examinations), perspiration, and tremulousness. In the abscence of thyrotoxicosis, the hands are more often cool and damp rather than warm and erythematous. Serum TSH assay should be diagnostic.

Mild and temporary elevation of the FTI may occur if there is a transient depression of TBG production -- for example, when estrogen administration is omitted. This problem is occasionally seen in hospital practice, usually involving a middle-aged woman receiving estrogen medication that is discontinued when the patient is hospitalized. Estrogen withdrawal leads to decreased TBG levels and a transiently elevated FTI. After two to three weeks, both the T4 level and the FTI return to normal (Table 11-3).

Table 11-4. Causes of Thyrotoxicosis

Subclinical hyperthyroidism It should be remembered that thyrotoxicosis is today not only a clinical but also a laboratory diagnosis. Consistent elevation of the fT4, and the T3 level, and suppressed TSH, or only suppression of TSH, can indicate that thyrotoxicosis is present even in the absence of clear-cut signs. These elevations themselves may be a sufficient indication for therapy, especially in elderly patients with coincident cardiac disease. Antithyroid drug treatment of patients with subclinical hyperthyroidism was found to result in a decrease in heart rate, decrease in number of atrial and ventricular premature beats, a reduction of the left ventricular mass index, and left ventricular posterior wall thickness, as well as a reduction in diastolic peak flow velocity.   These changes are considered an argument for early treatment of subclinical hypothyroidism (33a).  Subclinical hyperthyroidism may disappear, evolve into Graves hyperthyroidism., or, with MNG, persist for long periods unchanged (33b).

In the differential diagnosis of heart disease, the possibility of thyrotoxicosis must always be considered. Some cases of thyrotoxicosis are missed because the symptoms are so conspicuously cardiac that the thyroid background is not perceived. This is especially true in patients with atrial fibrillation.

Many disorders may on occasion show some of the features of hyperthyroidism or Graves' disease. In malignant disease, especially lymphoma, weight loss, low grade fever, and weakness are often present. Parkinsonism in its milder forms may initially suggest thyroid disease. So also do the flushed countenance, bounding pulse, thyroid hypertrophy, and dyspnea of pregnancy. Patients with chronic pulmonary disease may have prominent eyes, tremor, tachycardia, weakness, and even goiter from therapeutic use of iodine. One should remember the weakness, fatigue, and jaundice of hepatitis and the puffy eyes of trichinosis and nephritis. Cirrhotic patients frequently have prominent eyes and lid lag, and the alcoholic patient with tremor, prominent eyes, and flushed face may be initially suspected of having thyrotoxicosis. Distinguishing between Graves' disease with extreme myopathy and myopathies of other origin can be clinically difficult.
   
The term chronic thyrotoxic myopathy is used to designate a condition characterized by weakness, fatigability, muscular atrophy, and weight loss usually associated with severe thyrotoxicosis. Occasionally fasciculations are seen. The electromyogram result may be abnormal. If the condition is truly of hyperthyroid origin, the thyroid function tests are abnormal and the muscular disorder is reversed when the thyrotoxicosis is relieved. Usually a consideration of the total clinical picture and assessment of TSH and FTI are sufficient to distinguish thyrotoxicosis from polymyositis, myasthenia gravis, or progressive muscular atrophy. True myasthenia gravis may coexist with Graves' disease, in which case the myasthenia responds to neostigmine therapy. (The muscle weakness of hyperthyroidism may be slightly improved by neostigmine, but never relieved.) Occasionally electromyograms, muscle biopsy, neostigmine tests, and ACH-receptor antibody assays must be used to settle the problem.

Apathetic hyperthyroidism designates a thyrotoxic condition characterized by fatigue, apathy, listlessness, dull eyes, extreme weakness, often congestive heart failure, and low-grade fever.^34,35 Often such patients have small goiters, modest tachycardia, occasionally cool and even dry skin, and few eye signs. The syndrome may, in some patients, represent an extreme degree of fatigue induced by long-standing thyrotoxicosis. Once the diagnosis is considered, standard laboratory tests should confirm or deny the presence of thyrotoxicosis even in the absence of classical symptoms and signs.