Hyperthyroidism is a condition of thyroid hyperfunction and overproduction of thyroid hormones. Autoimmune Graves' disease is the most common cause in young people, especially women, and toxic goitre or toxic adenoma are more common in older individuals.
In 1786 Caleb Perry made the first description of the association between goitre and exophthalmos. In 1835 Graves and in 1840 von Basedow independently described the condition associated with their names. Toxic multinodular goitre(Plummer's disease) was first described in 1913.
The crucifixion of Saint Andrew (Caravaggio-1607).
Graves' disease accounts for nearly 60% of cases of hyperthyroidism, and occurs at a median age which is 20 years younger than patients with adenoma (about 10% of cases), and 10 years younger than multinodular goitre (30% of cases). Adenoma and multinodular goitre have a higher prevalence in iodine-deficient areas than in iodine-sufficient ones. These different groups of patients have different relationship to diabetes:
Diabetes is more likely to occur in hyperthyroid patients , and glucose intolerance is often present in untreated hyperthyroidism.
Autoimmune thyroid disease also frequently occurs within type 1 diabetes (anti-TPO antibodies are present in up to 50% of insulin dependent diabetes mellitus patients) or vice versa, in the Autoimmune Polyendocrine Syndromes, due to overlapping HLA associations. Thyroid dysfunction does not cause type 1 diabetes, but patients with Graves' disease are more likely to develop type 1 diabetes, and vice versa.
A Japanese study showed that patients on treatment for hyperthyroid Graves’ disease are almost twice as likely to develop type 2 diabetes than members of the general population, are less likely to have been overweight, and are less likely to have a family history of diabetes .
The classic symptoms of hyperthyroidism are weight loss, heat intolerance and sweating, palpitation, anxiety and tremor. Other classical symptoms are fatigue and weakness, insomnia, irritability, impaired concentration, diarrhoea, pruritus, oligomenorrhoea or amenorrhoea in women and erectile dysfunction in men. Less usual symptoms include weight gain, gynaecomastia and urticaria. 
Findings on clinical examination include goitre: diffusely enlarged in Grave's disease or with nodular enlargement in multinodular goitre. Bilateral exophthalmos is often seen in Graves' disease.
A prevalence study in southern Italy confirms the frequent association between Graves' disease and type 1 diabetes and shows that the diagnosis of Graves' disease often preceded diagnosis of type 1 diabetes.
Compressive symptoms can develop in large multinodular goitres. This may sometimes result in difficulty in swallowing or respiratory distress due to tracheal compression. Cardiovascular effects include tachycardia, widened pulse pressure and atrial fibrillation.
Hyperthyroid patients have an higher risk to develop diabetes mellitus.
In the youngest patients with an autoimmune thyroid disease (as Grave's disease) is common to develop type 1 diabetes due to the alteration of the immune system that leads to a pathological reaction against self-antigens in different organs (in fact other autoimmune diseases can also occur).
In older patients hyperthyroidism can be associated with type 2 diabetes. In this case the pathogenetic mechanism is more complex and includes different aspects that acts together in the development of insulin resistance and metabolic derangement (two characteristics of T2DM):
LIVER: Thyroid Hormones in excess cause insulin resistance with direct and indirect effects. The direct effect is to increase basal hepatic glucose output by promoting gluconeogenesis. The indirect effect is due to stimulation of sympathetic activity in the liver mediated by the hypothalamus.
Impact of Hyperthyroidism on Diabetes:
There is little evidence whether thyrotoxicosis is directly responsible for causing diabetes. Hyperthyroidism may unmask latent diabetes by several mechanisms. High levels of thyroid hormones increase hepatocyte membrane GLUT2 that contributes to increased hepatic glucose output.4 There is rapid glucose absorption from the intestine. Thirdly, there is increase in non-oxidative glucose disposal leading to increased production of lactate that enters the Cori cycle promoting neoglucogenesis. Increased levels of GH and catecholamines that accompany hyperthyroidism may further contribute to insulin resistance. As with other endocrinopathies, overt diabetes does not develop in a hyperthyroid patient as long as the function of the pancreatic beta cells remains normal to counter the insulin resistance.
In some young women with Type 1 diabetes, glucose control may fluctuate following childbirth due to post-partum thyroiditis, when a state of hyperthyroidism is followed by hypothyroidism. Routine screening of TSH is recommended in such patients 6 - 8 weeks following delivery.
Impact of Diabetes on Hyperthyroidism
Diagnosis of thyroid dysfunction may pose further difficulty in a state of poorly controlled diabetes. Serum T3 level may be subnormal due to low T4 to T3 conversion. Serum T4 level may be low because of low protein binding and a low serum TSH concentration. Glycaemic control needs to be achieved before a screening with highly-sensitive TSH should be done.
Epidemiological data shows a strong genetic predisposition on the shared susceptibility to autoimmune thyroid disease and type 1 diabetes. The major joint susceptibility genes are HLA-DR3, HLA-DR4 and a specific variant of CTLA4. This studies shows that both the antigen-presenting(HLA-DR3/DR4) as well as the costimulatory molecules for the T lymphocyte regulation pathway(CTLA4) control susceptibility, but it seems that they are independent from each other.
-TSH TEST: This is the best first-line test to evaluate thyroid function.The normal range run from 0.25 to 5.25 μIU/mL, so levels below 0.2 μIU/mL suggest a possible hyperthyroidism.
-FT4-FT3 by RIA (RADIOIMMUNOASSAY): FreeT4 and FreeT3 reflect the amount of thyroxine in the blood. FT4-FT3 are generally elevated in hyperthyroid patients. However in T3-toxicosis, FT3 raises but FT4 is normal. If the TSH is suppressed but FT4-FT3 are normal, the hyperthyroidism is subclinical.
-TRH TEST: The increase in serum TSH levels recorded twenty and sixty minutes after the intravenous administration of 200 μg of synthetic thyrotrophin-releasing hormone (TRH) can be used as a test of thyroid function. Normal people show a rise of TSH after an injection of TRH while it doesn’t increase in hyperthyroid patients. This test can be made in cases of suspected hyperthyroidism without diagnostic serological surveys .
THYROID AUTOANTIBODIES: The biochemical research of autoantibodies is useful to diagnose an autoimmune thyroid disease and to separate it from other forms of thyroiditis.
RADIOACTIVE IODINE UPTAKE (RAIU) WITH THYROID SCAN: This is a functional investigation which uses a radioactive tracer (I-123 or I-131) to measure how much tracer the thyroid absorbs from the blood after two, six or 24 hours (and sometimes after all three times period). A high uptake of radioiodine indicates that the thyroid is overactive. A RAIU test should be done together with a thyroid scan. A thyroid scan shows the size, shape, and location of the thyroid gland. It can find areas of the thyroid gland that are overactive (“hot nodules”) or underactive (“cold nodules”).
ULTRASOUND SCAN: This imaging study allows to assess the size of the gland, the presence of nodules and the vascularization with the Doppler sonographic quantification of thyroid blood flow.
GRAVES' DISEASE: The presence of Thyroid Receptor Antibodies (TRAb) / Thyroid-Stimulating Immunoglobulins (TSI) is diagnostic for this disease. These antibodies are positive from 75 to 95% of patients with Graves’ disease ( less commonly TPO antibodies could be positive in Graves’ patients). In addition the RAIU TEST shows a typical high uptake of tracer evenly spread in the thyroid gland.
MULTINODULAR GOITRE/TOXIC ADENOMA: The evaluation of antibodies is typically negative. The RAIU TEST frequently shows a high uptake of tracer with an irregular distribution in the thyroid gland.
Many studies demonstrated that reaching euthyroid state can improve glucose intolerance, as well as treating diabetes makes easier to control hyperthyroidism, since severe hyperglycemia can falsely lower blood levels of T3 and T4.
- HYPERTHYROIDISM: Appropriate doses of antithyroid drugs (methimazole or propylthiouracil) are required to achieve euthyroidism, and beta-blockers (propanolol) are usually prescribed in order to improve the symptoms of sympathetic activation. The use of this latter class of drugs should be as short as possible, since sympathetic blockade may impair warning symptoms of hypoglycaemia. Thyroidectomy and radioiodine are less used, mostly to treat voluminous goitre.
Graves' orbitopathy is usually treated with steroids, but surgery may be preferred in diabetic patients since steroids increase serum glucose levels. The progression of Graves' orbitopathy is usually well controlled with selenium administration, but long-term selenium therapy has been shown to increase the incidence of type 2 diabetes.
DIABETES: As far as it concerns the control of serum glucose levels, hyperthyroid patients need more insulin administration. In T2DM patients the use of thiazolidinedione(drug increasing insulin sensitivity) should be avoided since it seems to worsen thyroid ophthalmopathy.
THYROTOXICOSIS AND DIABETIC KETOACIDOSIS: when they occur simultaneously, the main priority is electrolytic correction in order to avoid cardiac arrest, aspecially with potassium repletion and intravenous insulin.
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^ This page was created by Ilaria Attili, Michela Ansuinelli, Giuseppa Alaimo and Laura Cesini, medical students at La Sapienza Hospital, Rome