THYROID HORMONES – pathology demonstrates very …



THYROID HORMONES – pathology demonstrates very obvious S&S and is the only endocrine gland you can palpate. Generally, regulates metabolism and other hormones. T7 (FTI, Free thryoxine index) is a calculated or derived concentration for the unbound (free) T4.

T3 (3,5,3-triiodothyronine)

➢ Represents about 10% of the thyroid hormone by the thyroid.

➢ Is about 4x as active or potent as T4.

➢ Is found in the blood in much lower amounts then T3. T3 is the active form of thyroid hormone.

➢ Has a much shorter half-life than T4.

➢ About 80% of serum concentration results from conversion of T4 to T3.

T4 (3,5,3,5-tetraiodoithyronine)

➢ Represents about 90% of the thyroid hormone secreted by the thyroid

➢ Is less active or potent than T3.

➢ Has a much longer half-life than T4.

➢ Is found in the blood in much higher amounts then T3.

REFERENCE VALUES (only the free form is biologically active - determined by the number of free forms, half-life thereof, and form or state of the hormone [up- or down-regulation of receptors, and the total:free equilibrium constant ratio ( these two are the fine control mechanisms]. Another consideration is target cell unresponsiveness.):

| |Total |Free |

|T3 |140 ng/mL |0.4 ng/mL |

|T4 |800 ng/mL |1.6 ng/mL |

THYROID BINDING GLOBULINS:

➢ These proteins bind the thyroid hormones and permit them to become soluble plasma constituents and help determine the plasma concentration of T3 and T4.

➢ There are 3 major proteins that act at thyroid binding proteins:

- Thyroxin binding globulin (TBG) – is the major carrier of T4 and T3 (75%). A 10-15 fold greater affinity for T4 than T3. Increased during pregnancy and estrogen therapy (“pill”). Decreased in protein malnutrition, nephrotic syndrome.

- Albumin

- Prealbumin.

ACTIONS OF THE THYROID HORMONES

➢ The thyroid hormones affect many physiological processes and are necessary for the optimal activity of numerous other hormones. Thus, abnormalities of thyroid function can lead to gross alteration of normal physiology.

➢ The thyroid hormones have been shown to:

- Block feedback inhibition of pituitary TSH secretion.

- Enhance the lipolytic response of adipose tissue.

- Increase the number of mitochondria within target cells.

- Increase the rate of intestinal glucose absorption.

HYPOTHALAMIC PITUITARY THYROID AXIS

➢ TRH, secreted by the hypothalamus, stimulates the release of TSH from the pituitary.

➢ TSH stimulates all steps in the synthesis and release of T4, T3.

➢ T3, T4 in the serum suppresses the release of TSH and TRH.

PICTURE

THYROID FUNCTION TESTING:

• Direct tests of thyroid function.

• Test of thyroid regulation.

• Metabolic indices of thyroid status.

• Anatomic evaluation of the thyroid gland.

Currently the best single test is the serum free T4.

DIRECT TEST OF THYROID FUNCTION:

• Serum total T4, T3

• Serum free T4, T3 (FTI or “T7”)

• Thyroxine binding globulin (TBG)

TEST OF THYROID REGULATION:

• TSH levels

• T3 suppression test – in vitro testing of the binding of T3 to a resin.

• TRH infusion test – becoming more common because there are more agonists.

METABOLIC INDICES OF THYROID STATUS

• BMR

• DTR and relaxation rate

ANATOMIC EVALUATION OF THE THYROID GLAND

• Thyroid scan (I-131).

• Thyroid US

• Biopsy

• Palpation

HYPERTHYROIDISM

➢ The clinical syndrome of hyperthyroidism is one of the most dramatic in clinical practice.

➢ The major symptoms associated with this syndrome are predominately a reflection of the hypermetabolism resulting from excess quantities of circulating thyroid hormone.

➢ Hyperthyroidism denotes increased formation and release of thyroid hormones from the thyroid gland.

➢ Thyrotoxicosis describes the clinical syndrome that occurs when tissues are exposed to excess amounts of thyroid hormone.

➢ Excess intake of exogenous thyroid hormone would lead to thyrotoxicosis but not hyperthyroidism however, the terms hyperthyroidism and thyrotoxicosis are often used interchangeably.

CAUSES OF THYROTOXICOSIS

➢ Increased occupancy of TSH receptors by TSI (thyroid stimulating immunoglobulins), TSH, or HCG.

➢ Autonomous overproduction of thyroid hormone by thyroid nodules.

➢ Increased release of thyroid hormone during specific phases of thyroiditis (three causes: Infection, autoimmune, toxic/idiopathic).

➢ Excessive thyroid hormone intake.

➢ Ectopic thyroid hormone formation (two intestinal classes: MEN I and MEN II).

HYPERTHYROIDISM - There are many disorders associated with hyperthyroidism, but the most common is Grave’s disease, as it accounts for about 60-90% of cases.

GRAVE’S DISEASE

➢ As originally described by Graves in 1835, Graves’ diseases is a clinical syndrome of: hypermetabolism, diffuse enlargement of the thyroid, exophthalmos.

➢ Grave’s disease was long considered to be idiopathic. However it is recognized today as an autoimmune disorder in which B lymphocytes produce immunoglobulins, some of which bind to and activate the TSH receptor, stimulating excess thyroid growth and hormone secretion. LATS (long acting thyroid stimulator) in lab mice was a 7s (Svedburg unit in centrifugation) protein - the initiation to understanding the disease process.

➢ For these antibodies, the TSH receptor appears to represent the antigenic site, and they act like TSH and are termed thyroid stimulating immunoglobulins (TSI).

➢ Other antibodies occur in Graves’ and other autoimmune diseases such as Hashimoto’s disease. These antibodies bind to the TSH receptor but stimulate only thyroid growth without increasing thyroid hormone secretion.

➢ Some antibodies bond to the TSH receptor but block TSH action and lead to thyroid atrophy.

➢ Therefore, some antibodies are agonists and some are antagonists.

➢ A diversity of TSH antibodies occurs in autoimmune thyroid diseases, generating a spectrum of illnesses with Grave’s disease and hyperthyroidism at one end and Hashimoto’s disease and thyroid atrophy leading to hypothyroidism at the other.

INCIDENCE OF GRAVE’S DISEASE

➢ Graves disease is relatively common in that it occurs in about 1.7-1.9% of females and about 0.2-0.3% of males.

➢ The peak incidence of onset is in the 30-40 age range and there is a strong familial component.

S & S OF THYROTOXICOSIS OF THYROTOXICOSIS

➢ CNS – nervousness and emotional lability, fine tremor of hands.

➢ Cardiovascular – palpitations, tachycardia, atrial fibrillation, increased difference between systolic and diastolic BP (increased pulse pressure). HTN classically is not a finding.

➢ GI – hyperdefecation, hypermotility, diarrhea.

➢ Muscle – proximal muscle weakness, atrophy, hyperreflexia.

➢ Skin – warm moist smooth, fine hair, hair loss, excessive perspiration.

➢ Metabolic – heat intolerance, weight loss usually with increased appetite.

➢ Thyroid – enlargement or nodule(s).

➢ In older patients, the manifestations of thyrotoxicosis can be considerably modified. Affected patients frequently appear apathetic rather than nervous for unclear reasons. Cardiovascular signs, general muscle weakness, and marked weight loss are more prominent in older adults.

➢ A hallmark finding of Grave’s disease is infiltrative ophthalmopathy. Clinically detectable eye disease occurs in 20-40% of patients with Grave’s disease. This is a result of other simultaneous antibodies affecting the muscles of the eyes. The patient will discuss photophobia, grittiness in the eye, dry eyes all before clinical signs show.

LAB FINDINGS OF GRAVES:

➢ (T3, (T4, (TSH

➢ Also (ALK PHOS, (Ca, (bilirubin, and mild anemia.

TREATMENT:

There are two or three forms of treatment geared toward the antibodies. Often there is an enteric yersinia infection in these patients that leads to an antibody reaction that is similar to body proteins. Immunosuppression is one treatment, but it is global in nature and can suppress the whole body. The other approach is to use metabolic analogues that can block the synthesis of thyroid hormone. Most effective is irradiation of the thyroid gland with lifetime thyroid replacement

HYPOTHYROIDISM

➢ The clinical syndrome that results from decreased secretion of thyroid hormone from the thyroid gland.

➢ It most frequently reflects a disease of the gland itself (primary hypothyroidism) but can also be caused by pituitary disease (secondary hypothyroidism) or hypothalamic disease (tertiary hypothyroidism).

➢ Leads to a slowing of metabolic processes and in its most severe form to the accumulation of mucopolysaccharides in the skin, causing a nonpitting edema termed myxedema.

➢ The term myxedema is reserved by some for a severe form of hypothyroidism, whereas others use the terms interchangeably.

MYXEDEMA - A histological description of the basophilic mucopolysaccharide infiltration of subcutaneous tissue.

HYPOTHYROIDISM

➢ Primary hypothyroidism

• Insufficient amount of thyroid tissue.

- Destruction of tissue by autoimmune process.

- Hashimoto’s thyroiditis (strophic and goitrous forms).

- Graves’ disease – end stage.

• Destruction of tissue by iatrogenic procedures.

- I-131 therapy.

- Surgical thyroidectomy.

- External radiation.

• Destruction of tissue by infiltrative processes.

- Amyloidosis, lymphoma, scleroderma.

• Defects of thyroid hormone biosynthesis.

- Congenital enzyme defects.

- Congenital mutations in TSH receptor.

- Iodine deficiency or excess.

- Drug induced: thionamides, lithium, sulfonamides, interleukins, tumor necrosis factor, and others.

➢ Secondary hypothyroidism

• Pituitary.

- Panhypopitiutarism, e.g., neoplasm, radiation, surgery, Sheehan’s syndrome.

- Isolated TSH deficiency.

• Hypothalamic.

- Congenital.

- Infection.

- Infiltration (sarcoidosis, franulomas).

• Transient hypothyroidism.

- Silent and subacute thyroiditis.

- Thyroxine withdrewel

• Generalized resistance to thyroid hormone.

HYPOTHYROIDISM

➢ Primary accounts for about 90-95% of all cases, the remainder being of pituitary or hypothalamic origin.

➢ The most frequent cause of hypothyroidism in adults is autoimmune disease, with goitrous or thyroprivic Hashimoto’s disease being the prime example.

➢ In autoimmune-based hypothyroidism antibodies are directed against thyoroperoxidase, thyroglobulin, and the TSH receptor.

➢ Antithyroglobulin and antiperoxidase antibodies probably serve only as markers of autoimmunity, but anti-TSH antibodies cause disease.

➢ TSH receptor antibodies can block TSH action and thus contribute to decreased thyroid hormone formation.

CLINICAL MANIFESTATIONS

➢ The slow and progressive onset in most tps can make clinical diagnosis difficult.

➢ This is especially true in elderly patients exhibiting changes like dry skin, reduced body and scalp hair, and memory difficulties, all of which could be due to the aging process in the absence of hypothyroidism.

➢ Typical complaints:

- Increased tiredness and sleep requirement with a depressed mood, feel cold, gaining weight on the same diet, and constipation.

- Increased forgetfulness and increased time needed to fulfill a task. Decreased exercise tolerance associated with muscle cramps on strenuous exercises.

➢ Affected patients relate these complaints in a low-pitched, hoarse voice with a slow speech pattern. Frequently the changes are only fully appreciated by the patient after thyroid hormone replacement.

S&S

➢ CNS – forgetfulness, stoic appearance, myxedematous dementi, cerebellar ataxia.

➢ Cardiovascular – bradycardia, pericardial effusion, hypertension.

➢ Respiratory – depressed ventilatory drive, pleural effusion, sleep apnea.

➢ GI – constipation, hypomotility.

➢ Muscle – delayed tendon reflexes, muscle stiffness, cramps, increased muscle volume, weakness.

➢ Skin – dry, rough, hyperkeratosis, nonpitting puffiness due to mucopolysaccharide deposits.

➢ Metabolic – basal metabolic rate decreased, cold intolerance, weight gain.

➢ Symptoms occur because of loss of hormone and accumulation of metabolites.

DIAGNOSIS

Clinical suspicion of hypothyroidism ( determine free T4 & TSH (normal free T4 & TSH = euthyroid

Clinical suspicion of hypothyroidism ( determine free T4 & TSH (low free T4 & high TSH = primary hypothyroidism.

Clinical suspicion of hypothyroidism ( determine free T4 & TSH (low free T4 & low/normal TSH = secondary hypothyroidism.

Clinical suspicion of hypothyroidism ( determine free T4 & TSH (high free T4 & high TSH = thyroid hormone resistance.

BE SURE TO READ THE TEXT. We think hypothyroidism is increasing because quality of life is diminishing.

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