DEVELOPMENT OF THE CLINICAL PICTURE AND THE COURSE OF THE DISEASE

Graves' disease displays an array of possible clinical patterns extending from that of goiter and thyrotoxicosis, but without ophthalmopathy, to that of ophthalmopathy without goiter or thyrotoxicosis.

In classic exophthalmic goiter, or Graves' disease, the most common onset is the simultaneous and gradual development, over a period of weeks or months, of the symptoms of thyrotoxicosis, enlargement of the thyroid, and prominence or related abnormality of the eyes (Figure 10-4). It is quite possible for classic Graves' disease to develop in a patient with preceding (probably unrelated) nontoxic goiter. This is common in a goitrous country. Often the onset of symptoms is so gradual that it is difficult or impossible for the patient or physician to fix its date. The more abrupt onset may sometimes be sufficiently rapid to justify the term fulminating. The picture of classic full- blown exophthalmic goiter has appeared in a person apparently previously well in as short a period as two to five days. Rare patients have first developed hypothyroidism and later thyrotoxicosis, ^36.1 probably because the initial development of TSBAb is followed by some natural immune modulation and development of stimulatory antibodies. Continuous significantly elevated titers of anti-TSH-R antibodies  (measured as TBII) in the months after diagnosis are positively correlated with serious ophthalmopathy (36.11).

Figure 10-4 Classic severe Graves' ophthalmopathy demonstrating a widened palpebral fissure, periorbital edema, proptosis, chemosis, and conjunctival injection.

In many patients, the symptoms of Graves' disease are first noted after some emotional trauma. These associations are certainly of importance in understanding the patient's backgound, but, as noted above, whether or not they bear a causal relationship to the development of Graves' disease remains conjectural.

As noted in Chapter 14, Graves' disease is frequently partially or totally suppressed during pregnancy, and initial or recurrent manifestations can occur in the postpartum period.  (Figure 10-10) Sometimes the "painless thyroiditis" characteristic of this period co-exists and masks the development of Graves' disease.^47.2

Figure 10-10 Clinical course of a patient who had transient exacerbation of Graves' disease on two occasions shortly following delivery.

Weight reduction, as mentioned above, has also constituted an activating episode in Graves' disease.

At present, the natural history of the thyrotoxic process is usually altered by definitive therapy. Before the general availability of good treatment, hyperthyroidism tended to progress through periods of exacerbation and remission. In perhaps a quarter of the patients, especially those with a mild form of the disease, the process was self-limited to one year or more, as the patients returned spontaneously to a euthyroid state.

M.S., 27-Year-Old-Man: Thyrotoxicosis with Spontaneous Remission

This young physician developed tachycardia, hyperkinesis, decreased heat tolerance, slight tremor, and weight loss over three or four months. On examination, blood pressure (BP) was 150/50, pulse rate 86, and the skin was sweaty. There was a fine tremor. The eyes were entirely normal. There was a grade 1 precordial systolic murmur. The thyroid was about twice the normal size, diffusely enlarged, and firm. There were several cervical lymph nodes bilaterally. PBI was 11(nl 4--8ug/dl), and the rT3U level was elevated. RAIU was 57% and BMR-10. All tests were repeated once, and the results all remained as indicated.

The patient was given 100 mg PTU three times daily and was maintained on this program for 18 months. During this time, the T4 level was maintained in the range of 7.3 ug/dl and the FTI in the range of 6; the white cell count remained normal. The TGHA titer was 1/320, and there was a borderline positive TSAb bioassay response. During the course of therapy, the 20-minute technetium uptake test was repeatedly measured while the patient received both antithyroid drugs and suppressive doses of T3; suppressibility of the thyroid gradually fell to the normal range. Eighteen months after the initiation of therapy, the patient developed an acute gastroenteritis and was briefly hospitalized. At this time, because of the possible association of PTU with gastric irritation, the medication was discontinued.

He subsequently remained well for three months, but then developed symptoms of mild hyperthyroidism. The thyroid was again found to be two to three times the normal size, the T4 level to be 10.3 µg/dl, and the FTI to be 11.9. Since the symptoms were mild, it was elected to observe events without therapy for a period. Initially, the symptoms, signs, and laboratory test results remained abnormal, but over several months the mild tachycardia, increased sweating, and increased nervousness gradually dissipated. Six months later, the T4 level was 6.7 µg/dl and the FTI 8. The TSAb bioassay result remained positive. No further treatment was given, and the patient has remained entirely well with a moderate thyroid enlargement, normal thyroid function test results, and no symptoms over the subsequent 20 years.

In one of the few documented reports of untreated thyrotoxicosis, White ¹⁵⁹ found that of 12 patients, 7 died in an average of three and a half years and the remainder lived on without therapy. From a large series, Sattler estimated that in the past mortality was up to 11%.¹⁵⁹ Fortunately, death due to hyperthyroidism is now rare, but we are aware of two patients who died of severe undiagnosed and untreated thyrotoxicosis in Chicago within the past few years. ¹⁴⁵ Deaths most frequently are attributed to cardiovascular complications such as myocardial infarction, arrhythmia, or heart failure, or infections secondary to debility. Some patients become spontaneously hypothyroid, and in fact most individuals apparently cured of Graves' thyrotoxicosis demonstrate evidence of hypothyroidism decades later. Coincident autoimmune thyroiditis presumably plays a role in such thyroid atrophy. Since in some patients  treatment of thyrotoxicosis is associated with the spontaneous reestablishment of thyroid homeostasis after a period of enforced reduction in hormone formation (by drugs, surgery, or 131I treatment), it is obvious that the thyrotoxic phase of the disease can  be self-limiting.

Toxic crisis, or thyroid storm, was also a frequent feature of Graves' disease in the past. This serious and often fatal development was a marked accentuation of the thyrotoxicosis, with hyperthermia, uncontrolled tachycardia, weakness, and delirium. This situation, now rarely encountered, is discussed in Chapter 12.

The ophthalmopathy of Graves' disease may follow a course quite different from that of thyrotoxicosis. This topic is also discussed in Chapter 12.

SYMPTOMS AND SIGNS OF GRAVES’ DISEASE AND THYROTOXICOSIS

In patients with Graves' disease, the ocular changes, lymphoid hyperplasia, localized abnormalities of skin and connective tissue (e.g., acropachy) and the goiter itself represent parts of the autoimmune syndrome. The remainder of the changes appear to be entirely attributable to an excess of thyroid hormone. Certain systems or organs (e.g., the muscles and cardiovascular system) play paramount roles in the disease, but as far as can be determined, these changes are all fundamentally related to and dependent on the excessive serum concentration of thyroid hormones.

Often the presenting symptoms are weight loss, weakness, dyspnea, palpitations, increased thirst or appetite, hyperdefecation, irritability, profuse sweating, sensitivity to heat or increased tolerance to cold, or tremor. Occasionally, prominence of the eyes or diplopia is the apparent symptom, and goiter may long antedate all other manifestations. Often a relative or friend notices eye signs, goiter, or nervous phenomena before the patient is conscious of any departure from his or her usual status. This asymptomatic phase of thyrotoxicosis is more commonly found in men and children. The excess of thyroid hormone produces an intoxication that in some persons takes the form of exhilaration. They may feel not only healthy but healthier than usual at a time when they are displaying unmistakable objective evidence of thyrotoxicosis. In older patients particularly, the symptom or symptoms may point to the heart more than to any other part of the body, "thyrotoxicosis masquerading as heart disease."

The habitus in Graves' disease shows nothing characteristic. In childhood, those afflicted are tall for their age. This association is an effect of the disease, not an etiologically related variable.

The nutritional state varies greatly. Sometimes the patient is severely emaciated, but on average the weight loss is 5 - 20 lbs. Infrequently, perhaps in 1 out of 10 instances, the patient actually gains weight while thyrotoxic.

The face may may instantly provide the diagnosis. An expression of fright or extreme anxiousness is common, largely because of the peculiar eye signs that may be present. Marked flushing is often noted. A drawn or sunken appearance may result from emaciation or dehydration. It is possible, especially in older patients, to find a considerable degree of thyrotoxicosis without any distinguishing evidence in the facies.

A change in reaction to external temperature is a very good symptom. The development of a preference for cold weather, of a desire for less clothing and less bed covering, and of decreased ability to tolerate hot weather is highly suggestive of hyperthyroidism.

The tongue tends to be red and smooth; it may also exhibit a definite tremor. The tonsils, if present, are usually rather large, as is the postpharyngeal lymphoid tissue.

The neck is usually conspicuous due to the goiter. It is possible, although rare, for thyrotoxicosis to exist without a visible or palpable goiter. We note reports in the literature that up to a quarter of patients may not have a goiter,¹⁶¹ but this is not our experience. In the neck, the carotids will often be seen to throb violently; this condition may contribute to the anxiety of the patient.

The eye signs characteristic of Graves' disease often constitute the most striking feature (Fig. 10-4 above, Fig. 10-5, Fig. 10-6 below). Prominence of the eyes is the most important sign. A wild or staring expression is often observed. Lag of the lids behind the globes on downward rotation and lag of the globes behind the lids in upward rotation, infrequent blinking, failure to wrinkle the forehead on looking upward, and decreased ability to converge are also cardinal manifestations. Swelling of the lids is a characteristic and frequent eye sign. The bulbar conjunctiva may be edematous (chemosis). The insertions of the medial and lateral rectus muscles are often enlarged, inflamed, and quite obvious . The lacrimal gland may protrude below the orbital bone margin.

Figure 10-5
(a) This MRI image from a patient with Graves' ophthalmopathy provides a coronal view of the eyes.  In this depiction the muscles appear white, and are enormously enlarged, especially in the left eye.	(b) In this transverse view the enlarged muscles are seen (appearing dark against the light fat signal) and the exophthalmos is apparrent.

Figures 10-6 (a), (b), and (c)
	Histologic appearance of (a) extraocular muscle,
	(b) retrobulbar fat, and
	(c) lacrimal gland removed during a Kronlein procedure on a patient with severe exophthalmos.

For convenience, the ophthalmic phenomena may be grouped as in Table 10-4. A classification of the eye changes and a system of grading of their severity have been adopted by the American Thyroid Association ¹⁶² and is given in Chapter 12.

The eye signs may vary independently of the intensity of the thyrotoxicosis. Although it is true that in most patients with Graves' disease, eye signs, goiter, and symptoms of thyrotoxicosis appear more or less coincidentally, it is also true that in certain cases eye signs may appear long before thyrotoxicosis is evident, or become worse when the thyrotoxicosis is subsiding. Indeed, in some patients, serious exophthalmos may develop at a time when the thyrotoxicosis has been controlled by treatment.

The eye symptoms are extremely distressing. Diplopia is common; decreased visual acuity and other visual disturbances are less common. More frequent are symptoms due to conjunctival or corneal irritation. These symptoms include burning, photophobia, tearing, pain, and a gritty or sandy sensation.

Horner's syndrome on one side is occasionally encountered when the goiter has pressed upon the trunk of the cervical sympathetic chain. This syndrome consists of unilateral enophthalmos, ptosis of the lid, and miosis, as well as decreased sweating on the homolateral face.