Thyroid gland diseases



Thyroid gland diseases. The diagnosis, the differential diagnosis,

preventive maintenance and craw treatment.

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The thyroid is a firm vascular organ lying in the neck, caudal to cricoid cartilage. It is composed of two nearly equal lobes connected by a thin isthmus and weights approximately 20 gr. Rests of thyroid tissue are occasionally presents in sublingual or retrosternal areas.

Thyroid secrets: T3, T4,thyrocalcitonin. The thyroid hormones, thyroxine (T4) and triiodothyronine (T3) are secreted under the stimulatory influence of pituitary thyrotropin (thyroid-stimulating hormone or TSH). TSH secretion is primary regulated by a dual mechanism:

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- thyrotropin-releasing hormone (TRH);

- thyroid hormone.

Thyroid hormones exits in circulation in both free and bound forma. The thyroid gland is the sole source of T4 and only 20% of T3 is secreted in the thyroid. Approximately 80% of T3 in blood is derived from peripheral tissue (mainly hepatic or renal) deiodinatoin of T4 to T3.

Iodide, ingested in food or water, is actively concentrated by the thyroid gland, converted organic iodine by peroxidase, and incorporated (by the thyroid gland) into tyrosine in intrafollicular thyroglobulin. The thyrosines are iodinated at either one (monoiodotyrosine, MIT) or two (diodotyrosine, DIT) sites and then coupled to form the active hormones (diiodotyrosine + diiodotyrosine → tetraiodothyronine (thyroxine, T4); diiodotyrosine + monoiodotyrosine → triiodotyronine (T3).

Thyroglobuline, a glycoprotein, containing T3 and T4 within its matrix, is taken up from the follicle as colloid droplets by the thyroid cells. Lysosomes containing proteases cleave T3 and T4 from thyroglobulin, resulting in release of free T3 and T4. The iodotyrosines (MIT and DIT) are also released from thyroglobulin but do not normally reach the bloodstream. They are deiodinated by intracellular deiodinases, and their iodine is neutralized by the thyroid gland.

Although some of free T3 and T4 is deiodinated in the thyroid gland with the iodine reentering the thyroid iodine pool, most diffuses into the bloodstream where it is bound to certain serum proteins for transport. The major thyroid transport protein is thyroxine binding globulin (TBG), which normally accounts for about 80% of the bound thyroid hormones. Other thyroid binding proteins, including thyroxine-binding prealbumin (TBPA) and albumin, account for the remainder of the bound serum thyroid hormone (20 %). About 0,05 % of the total serum T4 and 0,5 % of the total serum T3 remain free but in equilibrium with the bound hormone.

About 15 - 20 % of the circulating T3 is produced by the thyroid. The remainder is produced by monodeiodination of the auter ring of T4, mainly in the liver. Monodeiodination of the inner ring of T4 also occurs in hepatic and extrahepatic sites, including kidney, to yield 3,3/, 5/-T3 (reverse T3 or rT3). This compound has minimal metabolic activity but is present in normal human serum or globulin.

Observations pertaining to rT3 metabolism in fetal life are of great importance. Total amniotic T4 and T3 are low, in contrast to levels in maternal serum. Fetal rT3 levels in amniotic fluid are much higher than the corresponding values in maternal serum throughout pregnancy (15 to 42 wk). These data imply that rT3 derives primarily from the fetus and that it may be possible to diagnose fetal hypothyroidism as early as 15 wk of pregnancy, utilizing radioimmunoassay for rT3. These levels appear to decrease after 30 wk gestation and may be serve as a useful index of pregnancies of < 30 wk duration.

Physiologic effects of thyroid hormones .

Thyroid hormones have a major physiologic effects:

1) they increase protein synthesis in virtually every body tissue

2) they increase O2 consumption by increasing the activity of Na+ H+ ATPase (Na pump), primarily in tissues responsible for basal O2 consumption (i.e., liver, kidney, heart and skeletal muscle).)

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Hyperthyroidism (thyrotoxicosis) Toxic diffuse goiter. Grave’s disease-

is the condition resulting from the effect of excessive amounts of thyroid hormones on body tissues.

Thyrotoxicosis is a main syndrome. Sometimes the term hyperthyroidism can be used in a narrower sense to denote this state when the thyroid gland is producing too much thyroid hormones in contrast with excessive ingestion of thyroid hormone medication. At one time or another, approximately 0,5 % of the population suffers from hyperthyroidism. Graves disease is the most common cause of hyperthyroidism and is fairly common in the population. It is responsible for over 80 % of hyperthyroid cases. It occurs most often in young women, but it may occur in men and at any age.

Cause:

Autoimmune disorders, which can be provoked by:

- insolation;

- acute infections;

- hormone disbalance (pregnancy and others).

Pathogenesis.

Insufficiency of T suppressors ( excessive level of T helpers ( increasing function of B lymphocyte ( secretion of thyroid – stimulating immunoglobulin (TSI) ( blood ( the thyroid. TSI works as an antibody to the thyrotropin receptor on the thyroid follicular all resulting in stimulation of this receptor ( secretion of T4, T3.

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Clinical manifestations

The clinical presentation may be dramatic or subtle.

Cardiovascular system

Dysfunction of the cardiovascular system is common, and in some instances, the only manifestation of hyperthyroidism. Heart rate and cardiac output are increased, and peripheral resistance is decreased. These changes result in:

- permanent palpitation;

-sinus tachycardia or atrial fibrillation;

-heart failure.

Examination reveals:

- tachycardia;

- widened pulse pressure;

- a prominent apical impulse;

- bounding arterial pulsation;

- accentuated heart sounds;

- systolic ejection murmurs;

- occasionally cardiac enlargement..

Other than arrhythmia, electrocardiographic changes are limited to nonspecific ST and T wave abnormalities.

Psychological symptoms:

- nervousness;

- physical hyperactivity;

- emotional lability;

- anxiety;

- distractibility;

- insomnia.

These changes occur commonly and often result in impairment of work or school performance and disturbances in home and family life.

Neuromuscular symptoms:

- a fine tremor is often evident in the hands and fingers;

- performance of skills requiring fine coordination becomes difficult;

- deep tendon reflexes are hyperactive;

- some evidence of myopathy is common;

- weakness lit usually develops gradually, is progressive, and may be accompanied by muscle wasting.

Skin.

The skin is warm, fine, moist and its texture is smooth or velvety erythema and pruritus may be present. Increased sweating is common complaint . Hair may become thin and fine, and alopecia occurs. Infiltrative dermopathy, also known as pretibial mixedema (a confusing term, since mixedeme suggests hypothyroidism), is characterized by nonpitting infiltration of proteinaceous ground substance, usually in the pretibial area. The lesion is very pruritic and erythematous in its early stages and subsequently becomes browny it may appear years before or after the hyperthyroidism. TSIS are invariably present. The dermopathy usually remits spontaneously after months or years.

Eyes. Eye sings include:

- stare (Schtelvag’s symptom);

- lid lag;

- lid retraction (symptoms of Dalrympl; Greffe; Koher),

which results in “apparent” proptosis, but not eye and is often accompanied by symptoms of:

- conjunctival irritation.

These eye signs are largely due to excessive adrenergic stimulation and zemit promptly after upon successful treatment of thyrotoxicosis

- infiltrative ophthalmopathy is present in 20 to 40% of patients with Graves’ disease. It is characterized by increased retro-orbital tissue, producing exophthalmos and by lymphocyte infiltration of the extraocular muscles, producing a spectrum of ocular muscle weakness frequently leading to blurred and double vision. The pathogenesis of infiltrative ophthalmopatny is poorly understood.

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It may occur before the onset of hyperthyroidism or as 15 to 20 years afterward and frequently worseness or improves independent of the clinical course of hyperthyroidism. Infiltrative ophthalmopathy results from immunoglobulins directed to the extraocular muscles and specific antibodies that cause retro – orbital inflammation and subsequent edema (it is not because of TSH or LATS). The antibodies are distinct from those initiating Graves’ type hyperthyroidism.

The symptoms include:

- pain in the eyes;

- lacrimation;

- photophobia;

- diplopia;

- blurring or loss of vision.

The major signs are:

- proptosis (exophthalmos);

- periorbital and conjunctival congestion and edema (chemosis);

- limitation of ocular mobility.

Thyroid gland

Enlargement of thyroid gland is very common. Both thyroid lobes are usually moderately symmetrically enlarged, but thyroid enlargement may be absent.

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Degrees of thyroid gland enlargement.

0- we can’t see or palpate thyroid gland;

I- we can palpate but can’t see;

II – we can palpate and see thyroid gland in any position of the head.

Respiratory function

Abnormalities of respiration include:

- decreased vital capacity;

- decreased pulmonary compliance.

They result in dyspnea and hyperventilation during exercise and sometimes rest.

Gastrointestinal system

Increased caloric utilization is almost always present. It results in increased appetite and food intake, but compensation is usually inadequate, and modest loss occurs.

Increased gastrointestinal motility may result in increased frequency of bowel movements and even frank diarrhea.

Minor abnormalities in hepatic function are often found.

Hematopoetic system

Some patients have a modest anemia, caused by mild deficiency in one or more hematopoetic nutrients or increased plasma volume. Mild granulocytopenia and thrombocytopenia may be present.

Energy and intermediary metabolism because of increased energy expenditure, energy production must be augmented, this is accompanied by increased oxygen consumption and heat production. In patients with diabetes mellitus, requirement for exogenous insulin catabolism.

Endocrine system

In women, hypomenorrhea or amenorrhea may occur, although no changes are noted.

In men, there may be loss of libido and impotence hypercalcemia is found occasionally; it is caused by increased bone resorption, but clinical osteopenia is rare.

In patients mild adrenal insufficiency may occur. It is present by low diastolic blood pressure and darkness of upper lid (Elyneck(s symptom).

Degrees of severity

I. mild degree: work capacity is normal;

heart beat – is under 100/min;

weight loss is less than 10 %.

II. moderate degree: work capacity is decreased;

heart beat – is 100 to 120/min;

weight loss is 10 to 20 %.

III. severe degree: patients can(t work;

heart beat – is over 120/min and arrhythmia is present;

weight loss is more than 20%.

Diagnosis of toxic diffuse goiter.

I. Clinical manifestations (were discussed).

II. Laboratory findings.

(The diagnosis of hyperthyroidism is usually

straightforward and depends on careful clinical history and physical examination, a high index of suspection, and routine thyroid hormone determination).

1. In most patients serum total T3 and T4 concentrations, are increased (however, these changes, also can be caused by increased thyroxine – binding globulin production, e.g. as a result of estrogen therapy).

2. Elevation of T3 - resin uptake.

(T3 - resin uptake is not a measurement of circulating T3. In normal patients, 25 to 35% of TBG binding sites are occupied by thyroid hormone. When 131I-T3 is added to the patients serum, in vitro, a portion binds to unoccupied TBG sites. After equilibration, a resin is added that binds the remaining unbound 125/-T3).

Thus in hyperthyroidism, characterized by increased levels of circulating thyroid hormone, there are more occupied and less unoccupied TBG binding sites. Less 131I-T3 is bound to TBG, resulting in more uptake of 131I-T3 by the resin.

3. TSN (serum thyroid stimulating hormone) may be decreased, but it is not very sensitive assay in the assessment of thyroid hyperfunction.

4. If the diagnosis of hyperthyroidism remains unclear after these initial tests, more expensive, sophisticated and time – consuming tests may be required, e.g. A TRH test (thyrotropin - releasing hormone).

Serum TSN is determined before and after an i/v injection of 500 mkg of synthetic TRH. Normally, there is a rapid rise in TSH of 5 to25 mkU/ml, reaching a peak in 30 min and returning to normal by 120 min.

In patients with hyperthyroidism TSH release remains suppressed, even in response to injected TRH, because of the inhibitory effects of the elevated free T4 and T3 on the pituitary thyrotroph cells.

The diagnosis of infiltrative ophthalmopathy when hyperthyroidism is or recently was present is not difficult. The diagnosis is less certain if the patient is not or never was hyperthyroid orbital ultrasonography or computed tomography is the best procedure to confirm the diagnosis of ophtalmopathy such as orbital pseudotumor and orbital tumors.

Other forms of hyperthyroidism.

Toxic adenoma and toxic multinodular goiter (Plummer’s disease)

One or more thyroid nodules occasionally hyperfunction autonomously for unknown reasons. The excess T3 and T4 inhibit the hypothalamic – pituitary axis, stopping TSH production and decreasing production of hormone in the rest of the thyroid. RAI uptake in the hyperfunctioning nodule is increased while in the rest of the gland, it is decreased. Multinodular goiter with or without hyperthyroidism is more common in older people. Neither toxic multinodular goiter nor toxic adenoma is associated with LATS, exophthalmos, or the pretibial myxedema found in Grave’s disease. Since nodules often produce selective increases in T3 levels, determination of the serum total T3 should be included in the thyroid function tests selected for evaluation of nodular goiter.

Toxic adenoma and multinodular goiter are treated surgically or with radioiodine.

T3 toxicosis. Both T3 and T4 are regularly increased in patients with hyperthyroidism. Increases in serum T3 are usually somewhat greater proportionally compared to T4, probably because of both increased thyroidal secretion of T3 and increased peripheral conversion of T4 to T3. In some thyrotoxic patients, only T3 is elevated; this condition is called “T3 toxicosis”. It is difficult to diagnose because T3 is not measured by the ordinary thyroid function tests, but requires a specific RIA. The criteria to establish the diagnosis are:

1) symptoms and signs of hyperthyroidism;

2) normalT4 and 131I uptake;

3) nonsuppressible 131I uptake;

4) failure to release TSH in response to TRH;

5) elevated serum T3.

T3 toxicosis may be seen in any of the natural disorders producing hyperthyroidism, including Graves’ disease, multinodular goiter, and the autonomously functioning solitary thyroid nodule. If T3 toxicosis continues untreated, the patient eventually develops the typical laboratory abnormalities of hyperthyroidism; i.e., elevated T4 and 131I uptake. This suggests that T3 toxicosis is an early manifestation of ordinary hyperthyroidism and should be treated as such.

Thyrotoxicosis fastitia.

This syndrome of hyperthyroidism results from self-administration of thyroid hormone; patients (commonly medical or paramedical personnel) may be surreptitiously taking T4 or T3. Laboratory evaluation will vary accoringly. If the disorder is caused by ingestion of preparations containing T4, the serum T4 will be elevated. When ingestion of T3 is the cause, serum T4 will be below normal. In either case, serum T3 levels will be increased, particularly when preparations containing T3 are the causative agnts; there will be no goiter.

Excess TSH produced by a pituitary tumor can cause secondary hyperthyroidism through overproduction of thyroid hormone. Hyperthyroidism secondary to metastatic embryonal carcinoma or choriocarcinoma is due to the TSH-like properties of human chorionic gonadotropin (HCG). Struma ovarii is generally benign ovarian teratoma containing predominantly thyroid tissue. Approximately 5 % of the patients with struma ovarii develop hyperthyroidism. Treatment involves removal of teratoma.

Treatment.

I. 1. Antithyroid drugs.

2. Drugs to ameliorate thiroid hormone effects .

II. 131 I- therapy

III. Surgery.

I. 1. Antithyroid drugs

Propylthiouracil (PTU) and methimazole (MML) are effective inhibitors of thyroid hormone biosynthesis. PTU also inhibits extrathyroidal conversation of T4 to T3.

The usual starting dosage is 100 to 150 mg orally g 8h and for MML 10 to 15 mg when the patient becomes eythyroid the dosage is decreased to the lowest effective amount, usually 100 to 150 mg PPU in 2 or 3 divided doses or 10 to 15 mg MML daily. In general control can be achieved within 6 wk to 3 month. More rapid control can be achieved by increasing the dose of PPU to 400 to 600 mg /day , the risk of increasing the incidence of side effects, maintenance doses can be continued for one year or many years depending on the clinical circumstances.

Carbinazole (merkazolile ) is rapidly converts in vivo to MML. The usual starting dosage is 10 to 15 mg orally q 8h, maintenance dosage is 10 to 15 mg/ daily. The incidence of agranulocytosis appears to be higher for carbimazole than for eighter PPU or MML.

Adverse effects include:

- allergic reactions;

- nausea;

- loss of weight;

- fever;

- arthritis, hepatitis;

- anemia, thrombocytopenia;

- agranulocytosis (in < 1% of patients).

If the patient allergic to one agent, it is acceptable to go to other, but there is a chance of cross sensitivity. In case of agranulocytosis, it is unacceptable to go to another agent, and more definitive therapy should be invoked, such as radioiodine or surgery.

2. Some manifestations of hyperthyroidism are ameliorated by adrenergic antagonists - β – adrenergic blocking drugs.

Propranolol has had the greatest use phenomena that can be improved: tachycardia, tremor, mental symptoms, heat intolerance and sweating (occasional), diarrhea (occasional), proximal myopathy (occasional).

II. Radioactive sodium iodine (131I)

It can be used in patients > 40 yr. of age, because 131I might cause thyroidal or other neoplasm or gonadal damage.

There are only two important untoward effects of 131I therapy: persistent hyperthyroidism and hypothyroidism.

III. Surgery is used: - in patient 30,0 % |

|of palpation | | | | |

|Frequency of goiter (%) increase of|schoolboys |5,0–19,9 % |20,0–29,9 % |> 30,0 % |

|volume of gland from data of USI | | | | |

|Concentration of iodine in urine |schoolboys |50–99 |20–49 |< 20 |

|(median, mkg/l) | | | | |

|Frequency of the TSH level > 5 |babies |3,0–19,9 % |20,0–39,9 % |> 40,0 % |

|mIU/ml at neonatal screenning | | | | |

|Level of thyroglobulinum in a blood|children adult |10,0–19,9 |20,0–39,9 % |> 40,0 |

|(median, ng/ml) | | | | |

Spectrum of iodine-deficiency pathology (WHO, 2001)

|Age periods |Iodine-defcit pathology |

|Inwardly-uterine period |• Abortions |

| |• Stillborn |

| |• Innate anomalies |

| |• Increasing of perynatal death rate |

| |• Increasing of child’s death rate |

| |• Neurological cretinism: |

| |mental backwardness |

| |deaf-and-dumb |

| |squint |

| |• Mixedemic cretinism: |

| |mental backwardness undersized (low height) hypothyroidism |

| |• psycho-motor violations |

|New-born |• hypothyroidism neonatal |

|Children and teenagers |• Violation of mental and physical development |

|Adults |• Goiter and its complication |

| |• Iodine-inducted thyrotoxicosis |

|For any age |• Goiter |

| |• hypothyroidism |

| |• Cognitive function disorders |

| |• Increase of absorption of radio-active iodine at |

| |nuclear catastrophes |

Methods of prophylaxis of iodine-defcit diseases

– a mass iodine prophylaxis is a prophylaxis in the scale of population; it is carried out by addition of iodine in the most widespread food stuff (kitchen salt);

– a group iodine prophylaxis is a prophylaxis in the scale of certain groups of the high risk of the IDD development: children, teenagers, pregnant and breast-feeding women. It is carried out by the regular prolonged reception of medicaments which contain the physiological doses of iodine;

– an individual iodine prophylaxis is the prophylaxis of individuals by the prolonged reception of medicaments which contain the physiological doses of iodine.

Histological classifcation of thyroid gland tumors (WHO, 1988)

1. Epithelial tumors 1.1. Benign tumors

1.1.1 Follicular adenoma:

* normofollicullar

* macrofollicular

* microfollicullar

* trabecullar solid

1.1.2 Others

1.2 Malignant

1.2.1 Follicular carcinoma:

* minimum invasive

* wide invasive

oxyfphilic cellular variant light cellular variant

2. Papillary carcinoma: papillar microcarcinoma encapsulated variant follicular variant diffuse-sclerosis variant oxyphilic cellular variant

3. Medullary carcinoma:

mixed medullar-follicular carcinoma

4. Undifferentiated (anaplastic) carcinoma

5. Other carcinomas

2. Unepithelial tumors:

thyroid sarcoma

malignant hemangiothelioma

3. Malignant lymphoma

4. Mixed tumors

5. Secondary tumors

6. Unclassifed tumors

List of diseases with the single nodules of thyroid gland

which is necessary to differentiate

Primary thyroid gland damage Non thyroidic damage

|Adenoma |Lymphadenopathy |

|Carcinoma |Adenoma or prothyreoid cyst |

|Cyst |Cyst-like hygroma |

|Thyroiditis autoimmune |Carotid aneurism |

|Lymphoma |Metastases |

|Previous hemithyroidectomy | |

|Cyst of thyroid-tongue duct | |

|Thyroid hemiagenesy | |

Clinical classifcation of thyroid gland cancer

TNM – classifcation of differentiated thyroid gland cancer

(actual since 01.01.2003)

T – primary tumor

Тх – conclusion about a primary tumor is impossible;

T0- primary tumor is not found;

Т1 – tumor size is to 2 cm, localized in a gland;

Т2 – tumor size is more than 2 cm and to 4 cm, limited by the gland capsule;

Т3 – tumor size over 4 cm, localized only in a thyroid gland, or tumor of any size with minimum extrathyroid spreading (by an invasion in M. sternohyoіdales or in parathyroid muscles and cellular tissue);

Т4а – tumor spreads outside the thyroid gland capsule with the invasion in one or a few of such anatomic structures: hypodermic cellular tissue, trachea, throat, gullet, recurrence nerve

T4b – tumor infltrate paravertebral fascia, vessels of mediastinum and surrounds a carotid artery

* multifocal tumors not depending on their histological analysis must be marked by the letter of “m”, thus the gradation “Т” is determined by the tumor of most size.

N – regional lymphatic nodules (lymphatic nodules of neck and mediastinum) (LN)

Nх – conclusion about the regional LN damage is impossible;

N0 – metastases in regional LN is not found;

N1 – metastases in regional LN;

N1а – damage of pretracheal, paratracheal, laryngeal LN;

N1b – damage of other neck LN uni- or bilateral, contralateral on both sides or only on opposite and/or superior LN of mediastinum.

** pT, pN, pM categories which specify on morphological confrmation of the Т, N, M factors.

*** pN0 – is proposed after conducting of selective lymphadenectomy and histological investigation usually from 6 LN and more. In case if in investigated LN is not determined metastatic process, but their amount does not arrive at 6, pN0-stage have to be appropriated.

М – distant metastases

Мх – conclusion about distant metastases is impossible;

М0 – distant metastases are not determined;

М1 – there are distant metastases.

Ultrasonic signs of nodular formation in thyroid gland

|True cyst |Clear limited, spherical, echo-negative, non-echogenic formation of regular shape with even and thin walls, with |

| |homogeneous incorporations, has a capsule |

|Nodes with focal There is a node in thyroid lobule with presence of hypoecho-cystic changes genic areas, in which blood fow is absent at |

|coloured echodo-plerography. Has a clear capsule |

|Colloid node |Nodes formation in thyroid gland with expressed hypoecho-genic, has a clear capsule, on periphery hydrophillic halo-rim |

| |can be determined (rim is low echogenic, width 1–2 mm, located around the formation) |

|Adenoma |Nodes formation of round form with clear contours, encapsulated, of decreased echogenic |

|Adenocarcinoma |Thyroid gland formation with unclear contours, dense structure, of decreased echogenic with the presence of |

| |microcal-cinats in formation and (or) absence or unclear capsule. A suspicious node does not change during pressure on |

| |it by an ultrasonic sensor. Enlarged regional lymphatic nodes as hypoechogenic formations of round or oval form are |

| |often determined |

References

Main literature

1. Endocrinology. Textbook/Study Guide for the Practical Classes. Ed. By Petro M. Bodnar: - Vinnytsya: Nova Knyha Publishers, 2008.-496 p.

2. Basіc & Clіnіcal Endocrіnology. Seventh edіtіon. Edіted by Francіs S. Greenspan, Davіd G. Gardner. – Mc Grew – Hіll Companіes, USA, 2004. – 976p.

3. Harrison‘s Endocrinology. Edited J.Larry Jameson. Mc Grew – Hill, USA,2006. – 563p.

4. Endocrinology. 6th edition by Mac Hadley, Jon E. Levine Benjamin Cummings.2006. – 608p.

5. Oxford Handbook of Endocrinology and Diabetes. Edited by Helen E. Turner, John A. H. Wass. Oxford, University press,2006. – 1005p.

Additional literature

6. Endocrinology (A Logical Approach for Clinicians (Second Edition)). William Jubiz.-New York: WC Graw-Hill Book, 1985. - P. 232-236. Pediatric Endocrinology. 5th edition. – 2006. – 536p.

7. Thyroid Disordes (Aclevelend Clinic Guide) by Mario Skugor, Jesse Bryant Wilder Clevelend Press,2006. – 224p.

Lecture prepared assistant, c.m.s. Chernobrova O.I.

It is discussed and confirm on endocrinology department meeting

" 31 " august 2012 y. Protocol № 1.

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