hyperthyroidism and hypothyroidism
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HYPERTHYROIDISM AND HYPOTHYROIDISM
- JOSE D. AMARO JR.
Thyroid Pathophysiology
Hypothalamic-Pituitary-Thyroid Axis
• This is a negative feedback system. TRH produced in the paraventricular nuclei of the hypothalamus stimulates release of TSH from the pituitary.
• TSH stimulates thyrocytes to pump in iodine. Then there is “organification” of iodine by thyroid
peroxidase. This forms T3 and T4, which is stored as colloid. T4 secretion >> T3 secretion.
• Most T3 is formed peripherally, by deiodination of T4. T3 is far more active, T4 is a prohormone. Conversion of T4 to T3 is inhibited by starvation, illness, drugs (amiodarone, contrast dyes).
• More than 99% of T3 and T4 in blood is bound to Thyroid Binding Globulin (TBG) and albumin.
• T3 acts at nuclear receptors to stimulate CHO/fat metabolism, glycogenolysis, thermogenesis, protein synthesis, myocardial contractility, oxygen delivery, digestion, and sympathetic activity. It is critical for normal growth and metabolism.
Assessing Thyroid Function
• The most common hormone measurements are free T4 and TSH.
• These have an inverse log-linear relationship, in which TSH varies logarithmically with T4.
• **Therefore, the TSH level is the most sensitive index of thyroid function.
• **Low TSH suggests hyperthyroidism. High TSH suggests primary hypothyroidism.
Hyperthyroidism
• presents as a constellation of symptoms due to elevated levels of circulating thyroid hormones. Because of the many actions of thyroid hormone on various organ systems in the body, the spectrum of clinical signs produced by the condition is broad. The presenting symptoms can be subtle and nonspecific, making hyperthyroidism difficult to diagnose in its early stages without the aid of laboratory data.
• The term hyperthyroidism refers to inappropriately elevated thyroid function. Though often used interchangeably, the term thyrotoxicosis, which is an excessive amount of circulating thyroid hormone, is not synonymous with hyperthyroidism. Increased levels of hormone can occur despite normal thyroid function, such as in instances of inappropriate exogenous thyroid hormone or excessive release of stored hormone from an inflamed thyroid gland.
Graves disease
• (diffuse toxic goiter), the most common form of overt hyperthyroidism, is an autoimmune condition in which autoantibodies are directed against the thyroid-stimulating hormone (TSH) receptor.
• As a result, the thyroid gland is inappropriately stimulated with ensuing gland enlargement and increase of thyroid hormone production.
• Risk factors for Graves disease include family history of hyperthyroidism or various other autoimmune disorders, high iodine intake, stress, use of sex steroids, and smoking.
• The disease is classically characterized by the triad of goiter, exophthalmos, and pretibial myxedema.
Thyroid storm• is a rare and potentially fatal complication of
hyperthyroidism. It typically occurs in patients with untreated or partially treated thyrotoxicosis who experience a precipitating event such as surgery, infection, or trauma.
• Thyroid storm must be recognized and treated on clinical grounds alone, as laboratory confirmation often cannot be obtained in a timely manner.
• Patients typically appear markedly hypermetabolic with high fevers, tachycardia, nausea and vomiting, tremulousness, agitation, and psychosis.
• Late in the progression of disease, patients may become stuporous or comatose with hypotension.
Pathophysiology
• In healthy patients, the hypothalamus produces thyrotropin-releasing hormone (TRH), which stimulates the anterior pituitary gland to secrete thyroid-stimulating hormone (TSH); this in turn triggers the thyroid gland to release thyroid hormone.
• Thyroid hormone concentration is regulated by negative feedback by circulating free hormone primarily on the anterior pituitary gland and to a lesser extent on the hypothalamus. The secretion of TRH is also partially regulated by higher cortical centers.
• The thyroid gland produces the prohormone thyroxine (T4), which is deiodinated primarily by the liver and kidneys to its active form, triiodothyronine (T3). The thyroid gland also produces a small amount of T3 directly. T4 and T3 exist in 2 forms: a free, unbound portion that is biologically active and a portion that is protein bound to thyroid-binding globulin (TBG). Despite consisting of less than 0.5% of total circulating hormone, free or unbound T4 and T3 levels best correlate with the patient's clinical status.
• Mortality/Morbidity– Thyroid storm, if unrecognized and
untreated, is often fatal.– Adult mortality rate from thyroid storm
is approximately 10-20%, but it has been reported to be as high as 75% in hospitalized populations. Underlying precipitating illness may contribute to high mortality.
• Sex– A slight predominance of
hyperthyroidism exists among females.
• Age– Thyroid storm may occur at any age but
is most common in those in their third through sixth decades of life.
– Graves disease predominantly affects those aged 20-40 years.
– The prevalence of toxic multinodular goiter increases with age and becomes the primary cause of hyperthyroidism in elderly persons.
CLINICAL
• History– The clinical presentation of
hyperthyroidism ranges from an array of nonspecific historical features to an acute life-threatening event. Historical features common to hyperthyroidism and thyroid storm are numerous and represent a hypermetabolic state with increased beta-adrenergic activity.
• Weight loss• Patients typically report an average loss of approximately 15% of
their prior weight.• Basal metabolic rate is increased with a stimulation of lipolysis and
lipogenesis.• Palpitations• Chest pain - Often occurs in the absence of cardiovascular disease• Psychosis• Menstrual irregularity• Disorientation• Tremor• Nervousness, anxiety, or emotional lability• Heat intolerance• Increased perspiration• Fatigue• Weakness - Typically affects proximal muscle groups• Edema• Dyspnea• Frequent bowel movements
Physical•Fever •Thyromegaly
•Tachycardia (often out of proportion to the fever)
•Exophthalmos
•Diaphoresis (often profuse) •Atrial fibrillation
•Dehydration secondary to GI losses and diaphoresis
•Myopathy
•Warm, moist skin •Thyroid bruit - Relatively specific for thyrotoxicosis
•Widened pulse pressure •Fine, resting tremor
•Congestive heart failure (may be a high output failure)
•Weight loss
Causes
• Hyperthyroidism results from numerous etiologies, including autoimmune, drug-induced, infectious, idiopathic, iatrogenic, and malignancy.
• Autoimmune– Graves disease– Chronic thyroiditis (Hashimoto thyroiditis) -
Although the primary cause of hypothyroidism, the disease process occasionally presents initially with thyrotoxicosis
– Subacute thyroiditis (de Quervain thyroiditis) - Diffuse, painful inflammation of the thyroid producing a transient state leakage of stored hormone
– Postpartum thyroiditis - Presents similarly to subacute thyroiditis 2-6 months postpartum but typically painless with mild symptoms
• Drug-induced– Iodine-induced - Occurs after
administration of either supplemental iodine to those with prior iodine deficiency or pharmacologic doses of iodine (contrast media, medications) in those with underlying nodular goiter
– Amiodarone - Its high iodine content is primarily responsible for producing a hyperthyroid state, though the medication may itself induce autoimmune thyroid disease.
• Infectious– Suppurative thyroiditis - Often bacterial,
results in a painful gland commonly in those with underlying thyroid disease or in immunocompromised individuals
– Postviral thyroiditis
• Idiopathic– Toxic multinodular goiter - The second
most common cause of hyperthyroidism, characterized by functionally autonomous nodules, typically after age 50 years
• Iatrogenic– Thyrotoxicosis factitia - A psychiatric
condition in which high quantities of exogenous thyroid hormone are consumed
– Surgery - Now uncommon secondary to preventative measures, manipulation of the thyroid gland during thyroidectomy historically caused a flood of hormone release, often resulting in highly toxic blood levels
• Malignancy– Toxic adenoma - A single,
hyperfunctioning nodule within a normally functioning thyroid gland commonly among patients in their 30s and 40s
– Thyrotropin-producing pituitary tumors– Struma ovarii - Ovarian teratoma with
ectopic thyroid tissue
• Thyroid storm can be triggered by many different events, classically in patients with underlying Graves disease or toxic multinodular goiter.– Infection– Surgery– Cardiovascular events– Toxemia of pregnancy– Diabetic ketoacidosis, hyperosmolar coma, and
insulin-induced hypoglycemia– Thyroidectomy– Discontinuation of antithyroid medication– Radioactive iodine– Vigorous palpation of the thyroid gland in
hyperthyroid patients
TREATMENTS
• The large and generally accepted modalities for treatment of hyperthyroidism in humans involve initial temporary use of suppressive thyrostatics medication (antithyroid drugs), and possibly later use of permanent surgical or radioisotope therapy. All approaches may cause under active thyroid function (hypothyroidism) which is easily managed with levothyroxine supplementation.
Temporary medical therapy
• Thyrostatics (Antithyroid drugs)– Thyrostatics are drugs that inhibit the
production of thyroid hormones, such as carbimazole and methimazole, and propylthiouracil. Thyrostatics are believed to work by inhibiting the iodination of thyroglobulin by thyroperoxidase, and thus, the formation of tetra-iodothyronine (T4).
• Propylthiouracil also works outside the thyroid gland, preventing conversion of (mostly inactive) T4 to the active form T3. Because thyroid tissue usually contains a substantial reserve of thyroid hormone, thyrostatics can take weeks to become effective, and the dose often needs to be carefully titrated over a period of months, with regular doctor visits and blood tests to monitor results.
• Beta-blockers–Many of the common symptoms of
hyperthyroidism such as palpitations, trembling, and anxiety are mediated by increases in beta adrenergic receptors on cell surfaces. Beta blockers, typically used to treat high blood pressure, are a class of drug which offset this effect, reducing rapid pulse associated with the sensation of palpitations, and decreasing tremor and anxiety.
• Thus, a patient suffering from hyperthyroidism can often obtain immediate temporary relief until the hyperthyroidism can be characterized with the Radioiodine test noted above and more permanent treatment take place. Note that these drugs do not treat hyperthyroidism or any of its long term effects if left untreated, but, rather, they treat or reduce only symptoms of the condition.
Permanent treatments
• Surgery as an option predates the use of the less invasive radioisotope therapy (radioiodine 131 thyroid ablation), but is still required in cases where the thyroid gland is enlarged and causing compression to the neck structures, or the underlying cause of the hyperthyroidism may be cancerous in origin. Some patients suffering from the related condition of thyroid eye disease leading to diplopia because this condition can be worsened by radiotherapy treatment.
• Surgery– Surgery (to remove the whole thyroid or
a part of it) is not extensively used because most common forms of hyperthyroidism are quite effectively treated by the radioactive iodine method, and because there is a risk of also removing the parathyroid glands, and of cutting the recurrent laryngeal nerve, making swallowing difficult, and even simply generalized staph infection as with any major surgery.
• Some Graves' disease patients, however, who cannot tolerate medicines for one reason or another, patients who are allergic to iodine, or patients who refuse radioiodine may opt for surgical intervention. Also, some surgeons believe that radioiodine treatment is unsafe in patients with unusually large gland, or those whose eyes have begun to bulge from their sockets, fearing that the massive dose of radioiodine 131 needed will only exacerbate the patient's symptoms.
• Radioiodine– In iodine-131 (radioiodine) radioisotope
therapy, radioactive iodine-131 is given orally (either by pill or liquid) on a one-time basis, to severely restrict, or altogether destroy the function of a hyperactive thyroid gland.
– This isotope of radioactive iodine used for ablative treatment is more potent than diagnostic radioiodine (iodine-123) which has a biological half life from 8–13 hours. Iodine-131, which also emits beta particles which are far more damaging to tissues at short range, has a half-life of approximately 8 days.
• Patients who do not respond sufficiently to the first dose are sometimes given an additional radioiodine treatment, at a larger dose.
• Iodine-131 in this treatment is picked up by the active cells in the thyroid and destroys them, rendering the thyroid gland mostly or completely inactive. Since iodine is picked more readily (though not exclusively) by thyroid cells, and (more importantly) is picked up even more readily by over-active thyroid cells, the destruction is local, and there are no widespread side effects with this therapy.
• Radioiodine ablation has been used for over 50 years, and the only major reasons for not using it are pregnancy and breast-feeding (breast tissue also picks up and concentrates iodine). Once the thyroid function is reduced, replacement hormone therapy taken orally each day may easily provide the required amount of thyroid hormone the body needs. There is, however, a contrasting study noting increased cancer incidence after radioiodine treatment for hyperthyroidism.
• The principal advantage of radioiodine treatment for hyperthyroidism is that it tends to have a much higher success rate than medications.
Hypothyroidism
• Hypothyroidism is a common endocrine disorder resulting from deficiency of thyroid hormone. It usually is a primary process in which the thyroid gland produces insufficient amounts of thyroid hormone.
• It can also be secondary—that is, lack of thyroid hormone secretion due to inadequate secretion of either thyrotropin (ie, thyroid-stimulating hormone [TSH]) from the pituitary gland or thyrotropin-releasing hormone (TRH) from the hypothalamus (secondary or tertiary hypothyroidism).
• The patient's presentation may vary from asymptomatic to, rarely, coma with multisystem organ failure (myxedema coma).
• Cretinism refers to congenital hypothyroidism, which affects 1 per 4000 newborns.
• Subclinical hypothyroidism, also referred to as mild hypothyroidism, is defined as normal serum free T4 levels with slightly high serum TSH concentration.
Pathophysiology
• Localized disease of the thyroid gland that results in decreased thyroid hormone production is the most common cause of hypothyroidism.
• Under normal circumstances, the thyroid releases 100-125 nmol of thyroxine (T4) daily and only small amounts of triiodothyronine (T3). The half-life of T4 is approximately 7-10 days.
• T4, a prohormone, is converted to T3, the active form of thyroid hormone, in the peripheral tissues by 5’-deiodination.
• Early in the disease process, compensatory mechanisms maintain T3 levels. Decreased production of T4 causes an increase in the secretion of TSH by the pituitary gland.
• TSH stimulates hypertrophy and hyperplasia of the thyroid gland and thyroid T4-5'-deiodinase activity. This, in turn, causes the thyroid to release more T3.
• Because all metabolically active cells require thyroid hormone, deficiency of the hormone has a wide range of effects. Systemic effects are due to either derangements in metabolic processes or direct effects by myxedematous infiltration (ie, accumulation of glucosaminoglycans in the tissues).
• The myxedematous changes in the heart result in decreased contractility, cardiac enlargement, pericardial effusion, decreased pulse, and decreased cardiac output. In the GI tract, achlorhydria and decreased intestinal transit with gastric stasis can occur. Delayed puberty, anovulation, menstrual irregularities, and infertility are common.
• Decreased thyroid hormone effect can cause increased levels of total cholesterol and low-density lipoprotein (LDL) cholesterol and a possible change in high-density lipoprotein (HDL) cholesterol due to a change in metabolic clearance. In addition, hypothyroidism may result in an increase in insulin resistance.
• Frequency– Iodine deficiency as a cause of
hypothyroidism is more common internationally. The prevalence is reported as 2-5% depending on the study, increasing to 15% by age 75 years.
• Mortality/Morbidity– In developed countries, death caused by
hypothyroidism is uncommon.
• Sex– Community studies use slightly different criteria for
determining hypothyroidism; therefore, female-to-male ratios vary. Generally, thyroid disease is much more common in females than in males, with reports of prevalence 2-8 times higher in females.
• Age– The frequency of hypothyroidism, goiters, and
thyroid nodules increases with age. Hypothyroidism is most prevalent in elderly populations, with 2% to as much as 20% of older age groups having some form of hypothyroidism, the odds of having hypothyroidism were 5 times greater in persons aged 80 years and older than in individuals aged 12-49 years.
CLINICAL
• History– Hypothyroidism commonly manifests as a
slowing in physical and mental activity but may be asymptomatic. Symptoms and signs of this disease are often subtle and neither sensitive nor specific.
– Many of the more common symptoms are nonspecific and difficult to attribute to a specific cause.
– Consequently, the diagnosis of hypothyroidism is based on clinical suspicion and confirmed by laboratory testing.
• Myxedema coma is a severe form of hypothyroidism that results in an altered mental status, hypothermia, bradycardia, hypercarbia, and hyponatremia. Cardiomegaly, pericardial effusion, cardiogenic shock, and ascites may be present.
• Myxedema coma most commonly occurs in individuals with undiagnosed or untreated hypothyroidism who are subjected to an external stress, such as low temperature, infection, or medical intervention (eg, surgery or hypnotic drugs).
SYMPTOMS•Fatigue, loss of energy, lethargy •Emotional lability, mental
impairment
•Weight gain •Forgetfulness, impaired memory, inability to concentrate
•Decreased appetite •Constipation
•Cold intolerance •Menstrual disturbances, impaired fertility
•Dry skin •Decreased perspiration
•Hair loss •Paresthesia and nerve entrapment syndromes
•Sleepiness •Blurred vision
•Muscle pain, joint pain, weakness in the extremities
•Decreased hearing
•Depression •Fullness in the throat, hoarseness
• The following are symptoms more specific to Hashimoto thyroiditis:– Feeling of fullness in the throat– Painless thyroid enlargement– Exhaustion– Neck pain, sore throat, or both– Low-grade fever
• OTHER PHYSICAL SIGNS INCLUDE:Hypothermia Pallor
Slowed speech and movements Jaundice
Loss of scalp hair, axillary hair, pubic hair, or a combination
Coarse, brittle, strawlike hair
Periorbital puffiness Dull facial expression
Macroglossia Decreased systolic blood pressure and increased diastolic blood pressure
• Pericardial effusion• Goiter• Bradycardia• Abdominal distension, ascites (uncommon)• Hyporeflexia with delayed relaxation, ataxia, or
both• Nonpitting edema (myxedema)• Pitting edema of lower extremities• Metabolic abnormalities associated with
hypothyroidism include anemia, dilutional hyponatremia, hyperlipidemia, and reversible increase in creatinine.
Causes• Worldwide, iodine deficiency remains
the foremost cause of hypothyroidism.• Autoimmune: – The most frequent cause of acquired
hypothyroidism is autoimmune thyroiditis (Hashimoto thyroiditis). The body recognizes the thyroid antigens as foreign, and a chronic immune reaction ensues, resulting in lymphocytic infiltration of the gland and progressive destruction of functional thyroid tissue.
• Postpartum thyroiditis: – Up to 10% of postpartum women may
develop lymphocytic thyroiditis in the 2-10 months after delivery.
– The frequency may be as high as 25% in women with type 1 diabetes mellitus.
– The condition is usually transient (2-4 mo) and can require a short course of treatment with levothyroxine (LT4), but postpartum patients with lymphocytic thyroiditis are at increased risk of permanent hypothyroidism
• Subacute granulomatous thyroiditis: – Inflammatory conditions or viral
syndromes may be associated with transient hyperthyroidism followed by transient hypothyroidism (de Quervain or painful thyroiditis, subacute thyroiditis).
– These are often associated with fever, malaise, and a painful and tender gland.
• Drugs: –Medications such as amiodarone,
interferon alpha, thalidomide, lithium, and stavudine have also been associated with primary hypothyroidism.
• Iatrogenic– Use of radioactive iodine for treatment of Graves
disease generally results in permanent hypothyroidism within 1 year after therapy. The frequency is much lower in patients with toxic nodular goiters and those with autonomously functioning thyroid nodules. Patients treated with radioiodine should be monitored for clinical and biochemical evidence of hypothyroidism.
– Thyroidectomy– External neck irradiation (for head and neck
neoplasms, breast cancer, or Hodgkin disease) may result in hypothyroidism; patients who have received these treatments require monitoring of thyroid function.
• Rare: – Rare causes include inborn errors of thyroid hormone
synthesis.
• Iodine deficiency or excess: – Worldwide, iodine deficiency is the most common
cause of hypothyroidism. – Excess iodine, as in radiocontrast dyes, amiodarone,
health tonics, and seaweed, inhibits iodide organification and thyroid hormone synthesis.
– Most healthy individuals have a physiologic escape from this effect; however those with abnormal thyroid glands may not. These include patients with autoimmune thyroiditis, surgically treated Graves hyperthyroidism (subtotal thyroidectomy) and prior radioiodine therapy.
• Central hypothyroidism– Central hypothyroidism (secondary or
tertiary) results when the hypothalamic-pituitary axis is damaged. Various causes should be considered:
– Pituitary adenoma– Tumors impinging on the hypothalamus– History of brain irradiation– Drugs (eg, dopamine, lithium)– Sheehan syndrome– Genetic disorders
TREATMENT• Hypothyroidism is treated with the levorotatory forms of thyroxine (L-
T4) and triiodothyronine (L-T3). Both synthetic and animal-derived thyroid tablets are available and can be prescribed for patients in need of additional thyroid hormone. Thyroid hormone is taken daily, and doctors can monitor blood levels to help assure proper dosing. There are several different treatment protocols in thyroid replacement therapy:
• T4 Only– This treatment involves supplementation of levothyroxine alone, in a synthetic
form. It is currently the standard treatment in mainstream medicine.
• T4 and T3 in Combination– This treatment protocol involves administering both synthetic L-T4 and L-T3
simultaneously in combination.
• Desiccated Thyroid Extract– Desiccated thyroid extract is an animal based thyroid extract, most commonly
from a porcine source. It is also a combination therapy, containing natural forms of L-T4 and L-T3.
•Fatigue, loss of energy, lethargy
•Emotional lability, mental impairment
•Weight gain •Forgetfulness, impaired memory, inability to concentrate
•Decreased appetite •Constipation
•Cold intolerance •Menstrual disturbances, impaired fertility
•Dry skin •Decreased perspiration
•Hair loss •Paresthesia and nerve entrapment syndromes
•Sleepiness •Blurred vision
•Muscle pain, joint pain, weakness in the extremities
•Decreased hearing
•Depression •Fullness in the throat, hoarseness
HYPOTHYROIDISM
HYPERTHYROIDISM•Fever •Thyromegaly
•Tachycardia (often out of proportion to the fever)
•Exophthalmos
•Diaphoresis (often profuse) •Atrial fibrillation
•Dehydration secondary to GI losses and diaphoresis
•Myopathy
•Warm, moist skin •Thyroid bruit - Relatively specific for thyrotoxicosis
•Widened pulse pressure •Fine, resting tremor
•Congestive heart failure (may be a high output failure)
•Weight loss
•Disorientation, Psychosis, Nervousness, anxiety
•Heat intolerance
