HYPERTHYROIDISM

Introduction

Thyrotoxicosis is the clinical syndrome that results from elevated levels of circulating thyroid hormones
Hyperthyroidism (thyroid overactivity, thyrotoxicosis) is common, affecting perhaps 2–5% of all females at some time and with a sex ratio of 5:1, most often between the ages of 20 and 40 years

Pathogenesis

Thyroid hormone increases oxygen consumption by tissues, raising heat production and energy metabolism. It interacts with the sympathetic nervous system in a way that seems to increase tissue sensitivity to catecholamines and adrenergic stimuli (Tachycardia and extremity tremor are the examples of catecholamines hypersensitivity)

Clinical presentation

Clinical examination

Family history of thyroid disease

Patients develop

·   Mild fever

·   Flushing skin

·   Sweating and heat intolerance

·   Significant tachycardia

·   Palpitation, Atrial fibrillation, and cardiac failure

Excess thyroid hormone reduces systemic vascular resistance, enhances cardiac contractility (Positive inotrope) and increases the heart rate (Positive chronotrope)

Significant agitation, nervousness, restlessness, delirium, and coma frequently occur

Gastrointestinal abnormality include nausea, vomiting, and diarrhea

The condition termed apathetic hyperthyroidism is exhibited as flat affect, emotional lability, weight loss, muscle weakness, CHF, and atrial fibrillation resistant to standard therapy

Thyroid storm is a sudden exacerbation of the signs and symptoms of hyperthyroidism.

Precipitating events: concurrent illness (e.g., uncontrolled diabetes mellitus, myocardial infarction, acute infection), trauma, surgery, childbirth, or radioactive iodine therapy

Features: marked fever, tachycardia, and agitation are present and may progress to stupor and coma, with vascular collapse

The mortality rate is 20%–40%

Investigation

Elevated serum thyroxine (T4) and triiodothyronine (T3) and suppressed serum TSH levels are diagnostic for primary hyperthyroidism. By contrast, central (secondary) hyperthyroidism caused by TSH-secreting pituitary tumors is characterized by normal to increased TSH levels despite elevated thyroid hormone concentrations. Radioactive iodine is used to test for increased uptake in primary hyperthyroidism

Hyperthyroidism condition

Grave’s disease

Graves’ disease (diffuse toxic goiter) is the most common cause of hyperthyroidism (50% to 80% of cases of hyperthyroidism)

It is a form of autoimmune thyroid disease in which an abnormal immunoglobulin G (IgG) (thyroid-stimulating immunoglobulin) binds to TSH receptors on the thyroid follicular cells

• Causing diffuse enlargement of the gland (goiter) and stimulation of thyroid hormone production (thyrotoxicosis)
• Eye disease (ophthalmopathy) ranging from tearing to proptosis, extraocular muscle paralysis, and loss of sight as a result of optic nerve involvement
• Thyroid dermopathy, a significant skin thickening without pitting in a pretibial distribution (pretibial myxedema), occurs in 2% to 3% of patients with Graves’ disease
• Onycholysis (separation of the fingernails from their beds), often occurs in patients with Graves’ disease
• The condition termed apathetic hyperthyroidism is exhibited as flat affect, emotional lability, weight loss, muscle weakness, congestive heart failure, and atrial fibrillation resistant to standard therapy

Graves’ disease is most common in women between the ages of 20 and 50 years (1% of the population in the United States)

Pathogenesis

• Graves’ disease results from a form of type II hypersensitivity in which there is stimulation of the thyroid by autoantibodies directed against the TSH receptor
• These autoantibodies, called thyroid-stimulating immunoglobulins (TSIs), override the normal regulatory mechanisms
• TSI also contributes to the two major distinguishing clinical manifestations of Graves’ disease (ophthalmopathy and, perhaps, dermopathy ‘pretibial myxedema’)

 Immune mechanisms: Patients with Graves’ disease have IgG antibodies that bind to the TSH receptor on the plasma membrane of thyrocytes. These antibodies act as agonists; that is, they stimulate the TSH receptor, thereby activating adenylyl cyclase and increasing thyroid hormone secretion

• Under this continued stimulation, the thyroid becomes diffusely hyperplastic and excessively vascular
• Others antibodies seem to be cytotoxic, these include antibodies against thyroglobulin, thyroid peroxidase and the sodium–iodide symporter, all of which may also be involved in the pathogenesis of chronic lymphocytic thyroiditis (Hashimoto disease)
• Patients with Graves’ disease and their relatives have a considerably higher incidence of other autoimmune diseases, including pernicious anemia and Hashimoto thyroiditis

Ophthalmopathy Although exophthalmos (protrusion of eyeballs) is a common complication of Graves’ disease, its occurrence and severity correlate poorly with levels of thyroid hormone. Both T and B lymphocytes are sensitized to antigens shared by thyroid follicular cells and orbital fibroblasts. These cells stimulate orbital fibroblasts to proliferate and produce collagen and glycosaminoglycans, either by cytokine synthesis or by antibody-mediated receptor activation

• Periorbital edema, and extraocular muscle weakness, leading to diplopia (double vision)
• The increased orbital contents displace the eye forward (proptosis)
• The result lead to periorbital edema, conjunctival congestion and swelling, proptosis, extraocular muscle weakness, or optic nerve damage

A small number of individuals with Graves’ disease and very high levels of TSI experience pretibial myxedema (Graves dermopathy), characterized by subcutaneous swelling on the anterior portions of the legs and by indurated and erythematous skin

Graves’s dermopathy is associated with thyrotropin receptor antigens on fibroblasts and recruited T lymphocytes. These manifestations occasionally appear on the hands, giving the appearance of clubbing of the fingers (thyroid acropachy)

Understanding Pathophysiology, (Huether, Understanding Pathophysiology)

In microscopic view, the gland is diffusely hyperplastic and highly vascular. The epithelial cells are tall and columnar and are often arranged as papillae that project into the lumen of the follicles. The colloid tends to be depleted and appears scalloped or “moth-eaten” where it abuts the epithelial cells

Scattered B and T lymphocytes and plasma cells infiltrate the interstitial tissue and may even aggregate to form germinal follicles

Physical examination reveals a symmetrically enlarged thyroid, often with an audible bruit

Proptosis and retraction of the eyelids expose the sclera above the superior margin of the limbus. The skin is warm and moist, and some patients exhibit Graves dermopathy, a peculiar pretibial edema caused by fluid accumulation and glycosaminoglycans

Investigation

Elevated total or free T4 or T3 (or both) and a suppressed TSH confirm the clinical diagnosis of thyrotoxicosis

Thyroid-stimulating immunoglobulin is usually elevated¹

Increased uptake of 123 I differentiates Graves’ disease from early subacute or Hashimoto’s thyroiditis, in which uptake is low in the presence of hyperthyroidism

MRI or ultrasonography of the orbit usually shows orbital muscle enlargement

Treatment of the disorder includes the use of antithyroid medication such as thioisocyanate, destruction of thyroid tissue with radioactive iodine and adjunctive therapy with corticosteroids and adrenergic antagonists. Surgical ablation is not often performed. Unfortunately, despite successful relief of hyperthyroidism, exophthalmos often persists and may even worsen

Understanding Pathophysiology, (Huether, Understanding Pathophysiology)

Toxic Multinodular Goiter

Toxic multinodular goiter occurs in older patients with long standing nontoxic multinodular goiter, especially in patients from iodine-deficient regions when they are exposed to increased dietary iodine or receive iodine-containing radiocontrast dyes

The presenting clinical features are frequently tachycardia, heart failure, and arrhythmias. Physical examination shows a multinodular goiter

In microscopic view, the thyroid shows groups of small hyperplastic follicles mixed with other nodules of varying size that appear to be inactive

The diagnosis is confirmed by laboratory features of suppressed TSH, elevated T₃ and T₄, and a thyroid scan showing multiple functioning nodules

The treatment of choice is often ¹³¹I ablation. It is especially effective in patients with small glands and a high degree of radioactive uptake. Larger glands may require surgery

Toxic nodular goiter (Plummer’s disease) and toxic thyroid adenoma

Toxic adenoma is a benign, solitary, hyperfunctioning, follicular tumor

Usually affect older individuals

Discrete areas of the thyroid function autonomously, secreting excessive amounts of thyroid hormone. The cause is unknown, but activating mutations in the TSH receptor gene or in the stimulatory G protein that couple the TSH receptor to cyclic adenosine monophosphate (cAMP) formation have been found in many cases

Toxic adenoma (1) display autonomous function, (2) are independent of TSH and (3) are not suppressed if thyroid hormone is given

Physical examination shows a distinct solitary nodule

Laboratory investigation shows suppressed TSH and significantly elevated T₃ levels, often with only moderately elevated T₄

Imagery

Thyroid scan shows a hot nodule in the affected lobe with partial or complete suppression of the unaffected lobe

Radionuclide scanning shows that the normal tissue is hypofunctioning; this occurs because TSH is suppressed by the excessive levels of thyroid hormone produced by the abnormal tissue (↑T₃, moderate T₄)

¹³¹I scintiscan shows a solitary focus of iodine uptake (“hot nodule”) in a background of minimal uptake

Subclinical Hyperthyroidism

In subclinical hyperthyroidism, total or free T 4 and T 3 levels are normal and TSH is suppressed

The causes of this condition include early presentation of any form of hyperthyroidism (e.g., Graves’ disease, toxic adenoma, toxic multinodular goiter). Because these patients, especially those who are older, are at an increased risk for cardiac dysrhythmias, many patients with a persistently suppressed TSH should be treated with thiocarbamide drugs or radioactive iodine. A decreased bone mineral density is another indication for treatment

Andreoli and Carpenter's Cecil Essentials of Medicine, (Cecil Medicine)

Thyroiditis

I. Acute thyroiditis

1. Bacterial infection e.g. Staphylococcus, Streptococcus.
2. Fungal infection e.g. Aspergillus, Histoplasma, Pneumocystis.
3. Radiation injury

II. Subacute thyroiditis

1. Subacute granulomatous thyroiditis (de Quervain’s thyroiditis, giant cell thyroiditis, viral thyroiditis)
2. Subacute lymphocytic (postpartum, silent) thyroiditis
3. Tuberculous thyroiditis

III. Chronic thyroiditis

1. Autoimmune thyroiditis (Hashimoto’s thyroiditis or chronic lymphocytic thyroiditis)
2. Riedel’s thyroiditis (or invasive fibrous thyroiditis)

Although thyroiditis may eventually result in clinical hypothyroidism, the initial presentation is often that of hyperthyroidism as a result of acute release of T4 and T3

Hyperthyroidism caused by thyroiditis can be readily differentiated from other causes of hyperthyroidism by suppressed uptake of radioactive iodine in the thyroid gland, reflecting decreased hormone production by damaged cells

A rare disorder, acute suppurative thyroiditis, is caused by infection, usually bacterial

Patients exhibits high fever, redness of the overlying skin, and thyroid gland tenderness; the condition may be confused with subacute thyroiditis
If blood cultures are negative, FNA should identify the organism

Intensive antibiotic treatment and, occasionally, incision and drainage are required

Subacute thyroiditis (also known as de Quervain’s thyroiditis or granulomatous thyroiditis) is an acute inflammatory disorder of the thyroid gland that probably caused by a viral infection and resolves completely in 90% of cases
Patients with subacute thyroiditis complain of fever and anterior neck pain. The patient may have symptoms and signs of hyperthyroidism
The classic feature on physical examination is an exquisitely tender thyroid gland
Initially, the patient may be symptomatically thyrotoxic with elevated serum T4, depressed serum TSH, and low radioactive iodine uptake on the thyroid scan. Subsequently, the thyroid status fluctuates through euthyroid and hypothyroid phases and may return to euthyroidism. An increase in radioactive iodine uptake on the scan reflects recovery of the gland
Treatment usually includes high-dose aspirin or other nonsteroidal anti-inflammatory drugs, but a short course of prednisone may be required if pain and fever are severe
During the hypothyroid phase, replacement therapy with levothyroxine may be indicated

Chronic thyroiditis (Hashimoto’s or lymphocytic thyroiditis), caused by destruction of the normal thyroidal architecture by lymphocytic infiltration, results in hypothyroidism and goiter

Riedel’s struma is probably a variant of Hashimoto’s thyroiditis; it is characterized by extensive thyroid fibrosis resulting in a rock-hard thyroid mass. Hashimoto’s thyroiditis is more common in women and is the most common cause of goiter and hypothyroidism
Chronic thyroiditis can be differentiated from subacute thyroiditis in that, the gland is nontender to palpation and antithyroid antibodies are present in high titer. TPO Ab is usually present early and typically remains present for years
Presence of Tg Ab does not reflect Hashimoto’s thyroiditis and does not provide additional information beyond the TPO Ab finding
Serum T3 and T4 levels are either normal or low; when they are low, the TSH is elevated
FNA of the thyroid shows lymphocytes and Hürthle cells (enlarged basophilic follicular cells)
Hypothyroidism and significant glandular enlargement (goiter) are indications for levothyroxine therapy. Adequate doses of levothyroxine are administered to normalize TSH levels and shrink the goiter

Rare causes of hyperthyroidism include excess TSH production by pituitary tumors, and overproduction of hormone by the thyroid gland following iodine ingestion, which is called the Jod-Basedow phenomenon

Factitious hyperthyroidism may be caused by surreptitious ingestion of thyroid hormone or inadvertent administration of excessive doses of replacement hormone in the treatment of hypothyroidism

Thyrotoxicosis Factitia
Patients with thyrotoxicosis factitia ingest excessive amounts of thyroxine, often in an attempt to lose weight, and exhibit typical features of thyrotoxicosis. Serum T 3 and T 4 levels are elevated and TSH is suppressed, as is the serum thyroglobulin concentration. Radioactive iodine uptake is absent. Patients may require psychotherapy

Rare Causes of Thyrotoxicosis
Struma ovarii occurs when an ovarian teratoma contains thyroid tissue that secretes thyroid hormone. A body scan confirms the diagnosis by demonstrating uptake of radioactive iodine in the pelvis

Hydatidiform mole is caused by proliferation and swelling of the trophoblast during pregnancy, with excess production of chorionic gonadotropin, which has intrinsic TSH-like activity. The hyperthyroidism remits with surgical and medical treatment of the molar pregnancy

(1): Its measurement may be useful in patients with eye signs who do not have other characteristic clinical features

#Source:

NMS Medicine (National Medical Series for Independent Study) by Susan Wolfsthal (Author)
Andreoli and Carpenter's Cecil Essentials of Medicine, (Cecil Medicine) by Ivor Benjamin MD FACC FAHA (Author), Robert C. Griggs MD FACP FAAN (Author), Edward J Wing MD FACP FIDSA (Author), J. Gregory Fitz MD (Author)
Essentials of Rubin's Pathology by Emanuel Rubin MD (Author), Howard Reisner PhD (Author)

Understanding Pathophysiology, (Huether, Understanding Pathophysiology) by Sue E. Huether RN PhD (Author), Kathryn L. McCance RN PhD (Author)