Special Diets

INTRODUCTION
Background
Graves disease, named after Robert J. Graves, MD,[1] circa 1830s, is an autoimmune disease characterized by
hyperthyroidism due to circulating autoantibodies. Thyroid-stimulating immunoglobulins (TSIs) bind to and
activate thyrotropin receptors, causing the thyroid gland to grow and the thyroid follicles to increase synthesis of
thyroid hormone. Graves disease, along with Hashimoto thyroiditis, is classified as an autoimmune thyroid
disorder.
In some patients, Graves disease represents a part of more extensive autoimmune processes leading to
dysfunction of multiple organs (eg, polyglandular autoimmune syndromes). Graves disease is associated with
pernicious anemia, vitiligo, diabetes mellitus type 1, autoimmune adrenal insufficiency, systemic sclerosis,
myasthenia gravis, Sjgren syndrome, rheumatoid arthritis, and systemic lupus erythematosus. [2]
Graves ophthalmopathy is shown below.

Figure 2.

Enlarge
Graves disease. Varying degrees of manifestations of Graves ophthalmopathy.

Recent studies
Boelaert et al investigated the prevalences of and relative risks for coexisting autoimmune diseases in patients
with Graves disease (2791 patients) or Hashimoto thyroiditis (495 patients). The authors found coexisting
disorders in 9.7% of patients with Graves disease and in 14.3% of those with Hashimoto thyroiditis, with
rheumatoid arthritis being the most common of these (prevalence = 3.15% and 4.24% in Graves disease and
Hashimoto thyroiditis, respectively). Relative risks of greater than 10 were found for pernicious anemia, systemic
lupus erythematosus, Addison disease, celiac disease, and vitiligo. The authors also reported a tendency for
parents of patients with Graves disease or Hashimoto thyroiditis to have a history of hyperthyroidism or
hypothyroidism, respectively.[3]

Pathophysiology
In Graves disease, B and T lymphocyte-mediated autoimmunity are known to be directed at 4 well-known thyroid
antigens: thyroglobulin, thyroid peroxidase, sodium-iodide symporter, and the thyrotropin receptor. However, the
thyrotropin receptor itself is the primary autoantigen of Graves disease and is responsible for the manifestation of
hyperthyroidism. In this disease, the antibody and cell-mediated thyroid antigen-specific immune responses are
well defined. Direct proof of an autoimmune disorder that is mediated by autoantibodies is the development of
hyperthyroidism in healthy subjects by transferring thyrotropin receptor antibodies in serum from patients with
Graves disease and the passive transfer of thyrotropin receptor antibodies to the fetus in pregnant women.

The thyroid gland is under continuous stimulation by circulating autoantibodies against the thyrotropin receptor,
and pituitary thyrotropin secretion is suppressed because of the increased production of thyroid hormones. The
stimulating activity of thyrotropin receptor antibodies is found mostly in the immunoglobulin G1 subclass. These
thyroid-stimulating antibodies cause release of thyroid hormone and thyroglobulin that is mediated by 3,'5'-cyclic
adenosine monophosphate (cyclic AMP), and they also stimulate iodine uptake, protein synthesis, and thyroid
gland growth.
The anti-sodium-iodide symporter, antithyroglobulin, and antithyroid peroxidase antibodies appear to have little
role in the etiology of hyperthyroidism in Graves disease. However, they are markers of autoimmune disease
against the thyroid. Intrathyroidal lymphocytic infiltration is the initial histologic abnormality in persons with
autoimmune thyroid disease and can be correlated with the titer of thyroid antibodies. Besides being the source
of autoantigens, the thyroid cells express molecules that mediate T cell adhesion and complement regulation
(Fas and cytokines) that participate and interact with the immune system. In these patients, the proportion of CD4
lymphocytes is lower in the thyroid than in the peripheral blood. The increased Fas expression in intrathyroidal
CD4 T lymphocytes may be the cause of CD4 lymphocyte reduction in these individuals.
Several autoimmune thyroid disease susceptibility genes have been identified: CD40, CTLA-4, thyroglobulin,
TSH receptor, and PTPN22.[4] Some of these susceptibility genes are specific to either Graves disease or
Hashimoto thyroiditis, while others confer susceptibility to both conditions. The genetic predisposition to thyroid
autoimmunity may interact with environmental factors or events to precipitate the onset of Graves disease.
Pathophysiologic mechanisms are shown in the image below.

Figure 1.

Enlarge
Pathophysiologic mechanisms of Graves disease relating thyroid-stimulating immunoglobulins to hyperthyroidism and
ophthalmopathy. T4 is levothyroxine. T3 is triiodothyronine.

Epidemiology
Frequency
United States

Graves disease is the most common cause of hyperthyroidism in the United States. A study conducted in
Olmstead County, Minnesota estimated the incidence to be approximately 30 cases per 100,000 persons per
year.[5] The prevalence of maternal thyrotoxicosis is approximately 1 case per 500 persons, with maternal Graves
disease being the most common etiology. Commonly, patients have a family history involving a wide spectrum of
autoimmune thyroid diseases, such as Graves disease, Hashimoto thyroiditis, or postpartum thyroiditis, among
others.
International

Among the causes of spontaneous thyrotoxicosis, Graves disease is the most common. Graves disease
represents 60-90% of all causes of thyrotoxicosis in different regions of the world. In the Wickham Study in the

United Kingdom, the incidence was reported to be 100-200 cases per 100,000 population per year.[6] The
incidence in women in the UK has been reported to be 80 cases 100,000 per year. [7]

Mortality/Morbidity
If left untreated, Graves disease can cause severe thyrotoxicosis. A life-threatening thyrotoxic crisis (ie, thyroid
storm) can occur. Long-standing severe thyrotoxicosis leads to severe weight loss with catabolism of bone and
muscle. Cardiac complications and psychocognitive complications can cause significant morbidity. Graves
disease is also associated with ophthalmopathy, dermopathy, and acropachy.

Thyroid storm is an exaggerated state of manifestation of thyrotoxicosis. [8] It occurs in patients who have
unrecognized or inadequately treated thyrotoxicosis and a superimposed precipitating event such as thyroid
surgery, nonthyroidal surgery, infection, or trauma. When thyroid storm was first described, the acute
mortality rate was nearly 100%. In current practice, with aggressive therapy and early recognition of the
syndrome, the mortality rate is approximately 20%.[9]

Long-term excess of thyroid hormone can lead to osteoporosis in men and women. The effect can be
particularly devastating in women, in whom the disease may compound the bone loss secondary to chronic
anovulation or menopause. Bone loss is accelerated in patients with hyperthyroidism. The increase in bone
loss can be demonstrated by increased urinary pyridinoline cross-link excretion. Serum calcium and
phosphate, plasma FGF-23 were significantly higher in the patients with Graves disease than in healthy
control subjects,[10]suggesting that FGF-23 is physiologically related to serum phosphate homeostasis in
untreated Graves disease.

Hyperthyroidism increases muscular energy expenditure and muscle protein breakdown. These
abnormalities may explain the sarcopenia and myopathy observed in patients with hyperthyroid Graves
disease.

Cardiac hypertrophy has been reported in thyrotoxicosis of different etiologies. Rhythm disturbances such
as extrasystolic arrhythmia, atrial fibrillation, and flutter are common. Cardiomyopathy and congestive heart
failure can occur.[11]

Psychiatric manifestations such as mood and anxiety disorders are common. [12] Subjective cognitive
dysfunction are often reported by Graves disease patients and may be due to affective and somatic
manifestations of thyrotoxicosis, which remit after treatment of Graves thyrotoxicosis. [13]

Nonpitting edema is the most prevalent form of dermopathy (about 40%) and are primarily in the pretibial
area. The nearly all (>95%) patients with dermopathy had ophthalmopathy. [14] Advanced forms of
dermopathy are elephantiasis or thyroid acropachy. Severe acropachy can be disabling and can lead to
total loss of hand function.

Progression of ophthalmopathy can lead to compromised vision and blindness. Visual loss due to corneal
lesions or optic nerve compression can be seen in severe Graves ophthalmopathy.

Maternal Graves disease can lead to neonatal hyperthyroidism by transplacental transfer of thyroidstimulating antibodies. Approximately 1-5% of children of mothers with Graves disease (usually with high
TSI titer) are affected. Usually, the TSI titer falls during pregnancy.

Elderly individuals may develop apathetic hyperthyroidism, and the only presenting features may be
unexplained weight loss or cardiac symptoms such as atrial fibrillation and congestive heart failure.

Race

In whites, autoimmune thyroid diseases are, based on linkage analysis, linked with the following loci:
AITD1, CTLA4, GD1, GD2, GD3, HT1, and HT2. Different loci have been reported to be linked with
autoimmune thyroid diseases in persons of other races.

Susceptibility is influenced by genes in the human leukocyte antigen (HLA) region on chromosome 6 and
inCTLA4 on band 2q33. Association with specific HLA haplotypes has been observed and is found to vary
with ethnicity.

Sex

As with most autoimmune diseases, susceptibility is increased in females. Hyperthyroidism due to Graves
disease has a female-to-male ratio of 7-8:1.

The female-to-male ratio for pretibial myxedema is 3.5:1. Only 7% of patients with localized myxedema
have thyroid acropachy.

Unlike the other manifestations of Graves disease, the female-to-male ratio for thyroid acropachy is 1:1.

Age

Typically, Graves disease is a disease of young women, but it may occur in persons of any age.

The typical age range is 20-40 years.

Most affected women are aged 30-60 years.