Keywords

FormalPara Learning Objectives

  • Graves’ orbitopathy is a common autoimmune disease that affects women 5–6 times more than men.

  • The natural course of Graves’ orbitopathy is characterized by a phase of increasing severity, a plateau phase and a phase of decreasing severity.

  • Graves’ orbitopathy starts with an increase of extraocular muscle volume, which is usually accompanied by signs of inflammation.

  • Smoking, old age, high antibody levels and male gender are the most important risk factors to develop severe Graves’ orbitopathy. Thus, women more often have GO than men, but when men have GO, they mostly have a more severe form.

Incidence, Nomenclature, History

With an estimated incidence of 45 (36.8 females, 8.3 males) per 100,000 persons per year, Graves’ disease (GD) is the most common autoimmune disease [1]. GD (or: Basedow’s disease) serves as an umbrella term for Graves’ thyroid disease, Graves’ eye/orbit disease, pretibial myxedema, and acropachy. These subentities can occur together or separately.

Graves’ thyroid disease (GTD) is the most frequent of them. Although the cause is still unknown, the body produces TSH-receptor-binding immunoglobulins (TBII) which either stimulate, suppress or do not influence thyroid function. As a result, circa 85% of patients with GTD are hyperthyroid, 5–10% are hypothyroid, and the remainder are euthyroid.

Depending upon the criteria used, approximately 50% of GD patients have Graves’ eye/orbit disease, called Graves’ Orbitopathy or Ophthalmopathy in most European countries (GO), Thyroid Associated Orbitopathy (TAO) in the UK, and GO or Thyroid Eye Disease (TED) in the United States of America.

Pretibial myxedema, that is reddish, thickened areas on the lower legs, often associated with pruritis, and acropachy, i.e., soft-tissue swelling of the hands and clubbing of the fingers due to periostitis of the metacarpal bones, is rare. When present together with GO, the symptoms are usually more severe [2].

The oldest descriptions of what we now call GD, among which a combination of goiter, tachycardia and exophthalmos, the so-called Merseburger trias, are from the Welshman Caleb Hillier Parry (Fig. 14.1, 1786, published in 1825), the Dubliner Robert James Graves (Fig. 14.2, 1835) and the German Carl Adolph von Basedow (Fig. 14.3, 1840).

Fig. 14.1
A photograph of Caleb Parry.

Caleb Parry (taken from Wikipedia—public domain)

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Fig. 14.2
A photograph of Robert Graves.

Robert Graves (taken from Wikipedia—public domain)

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Fig. 14.3
A photograph of Carl von Basedow.

Carl von Basedow (taken from Wikipedia—public domain)

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Temporal Relationship Go with GTD, Risk Factors

The majority of patients develop GTD and GO within a time span of 12 months; in a minority of patients, the onset of the eye complaints precedes the thyroid disease, whereas in some more patients, the eye disease starts after the onset of GTD. Approximately, 15% develop GO more than 5 years after the onset of their GTD [3]. Patients may develop GO in the absence of hyperthyroidism. This is called euthyroid GO.

GO is 5–6 times more frequent in females. Although GO may start at any age (from 0 to 100), it is most frequent in women between 30 and 60 years of age. Men often develop GO at older age and suffer from more severe forms. GO at childhood is extremely rare; soft tissue involvement and proptosis are the more frequent signs in children with GO [4].

Risk factors to develop GO are as follows

  1. 1.

    Smoking [5]

  2. 2.

    Female gender

  3. 3.

    Radioactive iodine treatment [6]

  4. 4.

    Iatrogenic hypothyroidism [6]

Risk factors to develop severe GO are as follows

  1. 1.

    Smoking

  2. 2.

    Male gender

  3. 3.

    Old age

  4. 4.

    Concomitant diabetes mellitus [7]

  5. 5.

    Concomitant pretibial dermopathy and/or acropachy [2]

  6. 6.

    High antibody titers [8, 9]

Natural Course

As Rundle described in 1957 [10], untreated GO has a biphasic course. It starts with a period of increasing severity, then reaches a plateau phase and subsequently a phase of spontaneous improvement (Fig. 14.4), although a complete disappearance of symptoms and signs is mostly not to be expected.

Fig. 14.4
A line graph depicts the severity of thyroid eye disease over time. The line plots a concave downward curve that peaks during the active phase and decreases in the severity of disease during the inactive phase.

Natural course of GO: severity versus time

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The initial phase is called the active phase and is usually accompanied by signs of inflammation, such as red, swollen eyelids, pain and worsening (Chap. 15). During the inactive phase, signs of inflammation disappear; exophthalmos, eyelid retraction and motility impairment (might) remain. The duration of the several phases varies considerably. A total length of 3–5 years is no exception.

Exophthalmos in GO is the result of two pathological processes in the orbit: an increase of orbital contents by neo-adipogenesis and an increase of muscle volume (Fig. 14.5). Recently, we have studied the course of mild GO in terms of volume changes. We, therefore, had adopted and validated a CT-based method (Mimics, Materialise) for the calculation of orbital soft tissue volumes [11]. We found that an increase in muscle volume is an early phenomenon and coincides with inflammatory changes. After about 1 year, muscle volume deceases slightly (with 1 cm3), but fat volume starts to increase over the next 4 years (with almost 2 cm3) and then stabilizes. Interestingly, this fat volume increase does not seem to be related to inflammatory changes [12].

Fig. 14.5
Two radiographs of the exophthalmos exhibit two dark rounded patches at the top with increased fat and muscle volume in a light shade.

Exophthalmos in GO due to fat (left) and muscle (right) volume

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Differences in the duration and severity of these two processes might explain the different presentations of GO. Of interest is also that smoking is associated with both muscle volume increase and inflammatory changes [13].

A strong relationship has been found between smoking and the severity of GO (Fig. 14.6) [5].

Fig. 14.6
A bar chart depicts the severity of Graves' orbitopathy versus the odds ratio for different smoking habits. It plots for no smoking and 3 levels of cigarette consumption. More than 30 cigarettes per day exhibit the maximum severity cases, while no smoking is associated with the least severity.

Smoking (X-axis) versus disease severity (Y-axis) after Prummel et al. (1993) [5]

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In 95 newly diagnosed patients with GO, we found that in 25% of them, the muscle and fat volumes were within the limits of normalcy; 61% of the patients only had an increase of muscle volume, 5% only an increase in fat volume and 9% demonstrated an increase in both muscle and fat volume [14].

Auto-antibodies, such as TBII, correlate with the severity and activity of GO [15, 16] and have prognostic significance for the course of GO [16]. Iatrogenic hypothyroidism and treatment with radio-active iodine may worsen the orbitopathy [17, 18].

Once GO has burnt out, it is unlikely to flare up again. However, we have seen recurrences as late as 7 years after the first episode [19].

During pregnancy, TBII serum levels decrease and the orbitopathy declines. However, post-partum antibody titers often increase to levels that exceed pre-pregnancy values and can cause a recurrence of GO and a clinical relapse of disease activity [20].