Hyperthyroidism- etiology, pathogenesis, diagnostic criteria, treatment

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 (pict.) of pituitary thyrotropin (thyroid-stimulating hormone or TSH). TSH secretion is primary regulated by a dual mechanism:

-         thyrotropin-releasing hormone (TRH);

-         thyroid hormone.

Thyroid hormone 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 eihter 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).)

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

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

Cause:

Autoimmune disorders, which can be provoked by:

-         insolation;

-         acute infections;

-         hormone disbalance (pregnancy and others).

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.

Pathology.

The thyroid gland id diffused enlarged, hypercellular, soft and vascular. There is a parenchymatous hypertrophy and hyperplasia. Usually there is little or no colloid present with lymphocytic infiltration

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:

-  constant 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.

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.

Degrees of thyroid gland enlargement.

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

I- we can palpate but can’t see;

II –thyroid gland can see and palpate thyroid gland.

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 T_3. 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/-T_3).

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.     TSH (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.

III.             Instrumental findings: Ultrasound examination of the thyroid gland , MRI, scanography, etc.

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 <21 yr. who should not receive radioiodine;

-         in persons who can not tolerate  other agents because of hypersensitivity or other problems;

-         in patient with very large goiters (100 to 400 gm) (normal thyroid weights 20gm);

-         in some patients with toxic adenoma and multinodular goiter;

-         hyperthyroidism during pregnancy;

-         recurrent hyperthyroidism after course of antithyroid treatment.

Precautions:

- patient must be euthyroid before operation.

Results of the surgery:

-         normalization of thyroid gland function;

-         postoperative recurrences (2-9 %);

-         hypothyroidism (in about 3 % of patient the first years and in about 2 % with each succeeding year);

-         vocal cord paralysis;

-         hypoparathyroidism.

Iodine is used in preparing the patient for surgery. Surgical procedures are more difficult in patients who previously have undergone thyroidectomy or  radioiodine therapy.

Treatment endocrine ophthalmopathy include:

-         steroid therapy: prednisolone 20 – 40 mg daily;

-         electrophoresis with glucocorticoids or KI;

-         aloe, FIBS;

-         dehydration therapy;

-         cavinton, piracetam;

-         lateral tarsorrhaphy: when there is corneal ulcer due to inability to close the lids;

-         extra – ocular muscle surgery: to correct persistent diplopia.

Thyroid storm is a life- threatening emergency requiring prompt and specific treatment.

         In is characterized by abrupt onset of more severe symptoms of thyrotoxicosis, with some exacerbated symptoms and signs atypical of uncomplicated Graves disease:

-         fever;

-         marked weakness and muscle wasting;

-         extreme restlessness with wide emotional swings;

-         confusion;

-         psychosis or even coma;

-         hepatomegaly with mild jaundice;

-         the patient may present with cardiovascular collapse or shock.

Thyroid storm results from:- untreated or inadequately treated thyrotoxicosis

It may be precipitated by:

-         infection;

-         trauma

-         surgery;

-         embolism;

-         diabetic acidosis;

-         fright;

-         toxemia of pregnancy;

-         labor;

-         discontinuance of antithyroid medication;

-         radiation thyroiditis.

Treatment of thyroid storm;

Iodine-30 drops Lugol’s solution/day orally in 30g 4 divided doses; or 1 to 2 gr. sodium iodide slowly by i/v drip.

Iodine in pharmacological doses inhibits the release of T3 to T4 within hours and inhibits the organification of iodine, a transitory effect lasting  from a few days to a week (”escape phenomenon”.)

         Indications it is used for

-         the emergency management of thyroid storm;

-         thyrotoxic patients undergoing emergency surgery;

-         preoperative preparation of thyrotoxic patients selected for subtotal thyroidectomy /since it also decreases the vascularity of the thyroid gland.

 It is not used for routine treatment of hyperthyroidism. The usual dosage is 2 to 3 drops of satured potassium iodide solution orally tid or dig 1300 to 600 mg/day; or 0,5gr sodium iodide in 0,9% sodium chloride solution given i/v slowly g 12h.

         Complication of iodine therapy include:

-         inflammation of the salivary glands;

-         conjunctivitis;

-         skin rashes;

-         a transient hyperthyroidism (iod-BASEDOW phenomenon) (it can be observed in patients with nontoxic goiters after administration of iodine-contrast agents).

Antithyroid drugs

 Propylthiouracil (merkazolil) - 900 to 1200 mg/day orally or by gastric tube.

Doses of PPU of 450-600 mg/day or greater 800 to 1200mg/day are generally reserved for the patient with thyroid storm, because such doses block the peripheral conversation of T₄ to T₃.

β-adrenergic blocking drugs

 Propranolol - 160mg/day orally in 4 divided doses; or 1mg slowly i/v g 4h under careful monitoring; a rate of administration should not exceed 1mg/min; a repeat 1mg dose may be given after 2 min i/v glucose solutions.

Propranolol rapidly decreases heart rate, usually within 2 to 3 h when given orally and within minutes when given i/v.

.Correction of dehydration and electrolyte imbalance cooling blanket for hypertermia.

Digitalis if necessary.

Treatment of underlying disease such as infection.

Corticosteroids-100 to 300mg hydrocortisone/day i/v.