Thyroid hormone

 

Diseases of thyroid gland.

Hyperthireosis. Ethiology, pathogenesis, clinical pattern. Principles of diagnostics and treatment.

Hypothyreosis. Ethiology, pathogenesis, clinical pattern. Principles of diagnostics and 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 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 iormal 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).)

 

Diffuse Toxic Goitre

         Diffuse toxic goitre (thyrotoxicosis, Basedow’s disease) is caused by thyroid hyperfunction. The disease most commonly occurs in women between the ages of 30 and 50; the incidence in men is 5-10 times lower.

         Aetiology and pathogenesis. Psychic trauma, infection (tonsillitis, rheumatism, etc.), dysfunction of other endocrine glands (pituitary) are important for the development of the disease. Familial factors are also important: toxic goitre can often be found in close relatives.

         Secretion of hormones by the thyroid gland is intensified in stimulation of hypothalamic centres which stimulate secretion of the thyrotropic hor-mon&Tjy the anterior pituitary lobe. The hypothalamic centres can be stimulated by various factors, by psychic traumas in the first instance. Investigations of V, Baranov and other authors demonstrate the essential role of the central nervous system in the pathogenesis of diffuse toxic goitre. The authors have proved that in many patients the development of toxic goitre was preceded by neurocirculatory dystonia which interferes with ¹³¹I capture by the thyroid gland. This form of neurosis is now given great significance in the pathogenesis of diffuse toxic goitre and is regarded as a precursor of this disease.

         Hyperthyroidism causes changes in various tissues and organs and disturbs various types of metabolism: protein-carbohydrate, fat, mineral, water metabolism, etc. Upset function of the sympathico-adrenal system is also a very important factor which accounts for many symptoms of the disease. The role of the pituitary gland in the pathogenesis of thyrotox­icosis cannot be ruled out completely because patients with thyrotoxic goitre suffer from exophthalmos, while the exophthalmic factor is secreted by the pituitary gland.

 

         Pathological anatomy. The thyroid gland enlarges uniformly or by focal hyperplasia; hence diffuse or nodular goitre. Microscopy shows intense blood filling in the thyroid gland and reconstruction of follicular epithelium into columnar or polymorphous epithelium. Sometimes lite affected thyroid gland differs only insignificantly from the normal one by the character of itsepithelium and follicles; the follicles may only have cyst-like dilatations and contain litlle colloidal substance. Lymphocytes are accumulated and lymphoid follicles are formed.

        

Clinical picture.

 

Clinical symptoms in hyperthyroidism

         The onset of the disease may be acute or gradual, with slow development of the symptoms. The main signs of the disease ate enlargement of the thyroid gland, ocular signs, and heart palpitation. The patients complain of increased psychic excitability, non-motivated anxiety, deranged sleep, hyperhidrosis, tremor of the fingers or in the entire body, frequent defaecation, wasting, and muscular weakness.

Inspection of the patient immediately reveals the special features in his behaviour: fussiness, hasty speech; sometimes the patient drops the subject quite unexpectedly and starts discussing another subject. Ophthalmopathy and some other ocular symptoms suggest hyperthyroidism. Despite preserved or even increased appetite, the patient may lose much of his weight (to cachexia). The patient’s skin is smooth, warm and mofst to the touch. Some patients develop diffuse pigmentation of the skin which however does not colour the mucosa. The pigment is sometimes deposited selectively in the skin of the eyelids. The hair of the head becomes thin and soft.

 

Large goiter

 

         During inspection special attention should be paid to the size of the thyroid gland and symmetry of its enlargement. If the thyroid gland is enlarged significantly, the patient’s breathing becomes stridorous. Inspec­tion of the patient should be followed by palpation of thyroid gland.

         Five degrees of thyroid enlargement are distinguished: I—enlarged thyroid gland is difficult to palpate; II—enlarged thyroid gland is clearly seen dur­ing swallowing; III—clearly visible thickening of the neck due to goitre; IV—marked goitre; V—large goitre. Enlargement of the second and third degree occurs most frequently.

 

Palpation of thyroid gland

 

 

A large goiter

 

Exophthalms and large goiter in hyperthyreosis

 

         Ocular symptoms. A common symptom of diffuse toxic goitre is bilateral dilation of the eye slits which gives an expression of astonishment to the patient’s face. Another frequent manifestation is Graefe’s sign, a white strip of sclera between the edge of the eyelid and the upper margin of  the cornea which appears as the eyeball moves downward.

 

 

 

Ocular symptoms

Ocular symptoms

 

         Among other symptoms are Stellwag’s sign (infrequent blinking), Kocher’s sign (exposure of the sclera between the lower edge of the upper eyelid and the upper edge of the iris when the eyes are fixed on an upwardly moving object), and the exophthalmic symptom (protruded eyeballs). The protru­sion is usually more or less uniform but asymmetry is also possible. One eye can only be involved in some cases. In grave exophthalmic goitre, keratitis, ulcers of the cornea can also develop and the patient’s power of vision can thus be endangered. The eyelids can swell, and weakness of con­vergence can be observed; the eyeball can move aside when attention is fixed on a slowly approaching object (Moebius’ sign). This symptom is associated with upset function of the oculomotor muscles.

         Cardiovascular system. Tachycardia is one of the most frequent symptoms of the disease. Pulse rate varies within the range of 90 to 120 and in grave cases to 150 beats per minute. Systolic and minute volumes, the mass of the circulating blood and the rate of the blood flow increase, systolic pressure grows, diastolic pressure falls, and the pulse pressure increases. Auscultation of the heart reveals a snapping first sound and systolic mur mur at the apex and over the pulmonary artery which are due to increased blood flow rate and low tone of the papillary muscles. A most frequent and serious complication is atrial fibrillation (lachysystolic form) due tc tlve toxic effect of the thyroid hormones on the myocardium. Circulatory in­sufficiency can also develop. Electrocardiograhic studies reveal a slighlly increased amplitude of all waves (especially of the T wave), sinus tachycar­dia, extrasystole, and atrial fibrillation. X-rays examination reveals a slightly enlarged left ventricle of the heart.

         Gastro-intestinal tract.  The appetite increases. The increased motor function of the intestine accounts for diarrhoea. Hepatic dysfunction can have various effects: from slight disorders (that can only be revealed by functional lests) to cirrhosis.

         Nervous system. The clinical symptoms of disorders in the higher nervous activity ate excitability, increased reactivity, general motor restlessness, fidgetiness, and fine tremor of the fingers of the stretched arms (Marie’s syndrome).

         Endocrine system. A pronounced clinical picture of the disease is attended by a marked hypofunction of the sex glands (amenorrhoea) and of the adrenal cortex (hypoadrenocorticism); diabetes mellitus can join the process.

 

 

Pretibial myxoedema

 

Pretibial myxoedema

 

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 .

2.     Elevation of  T₃ – resin uptake.

(T₃  – resin uptake is not a measurement of circulating T_3. Iormal 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) decreased.

4.     Assays for thyrotropin-receptor antibodies (particularly TSIs) almost always are positive. Detection of TSIs is diagnostic for Graves disease. The presence of TSIs is particularly useful in reaching the diagnosis in pregnant women, in whom the use of radioisotopes is contraindicated.

5.     Other markers of thyroid autoimmunity, such as antithyroglobulin antibodies or antithyroidal peroxidase antibodies, are usually present.  Other autoantibodies that may be present include thyrotropin receptor–blocking antibodies and anti–sodium-iodide symporter antibody. The presence of these antibodies supports the diagnosis of an autoimmune thyroid disease.

6.     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 TSH 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 certainif 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.

IV.            A radioactive iodine uptake should be performed when the clinical presentation of thyrotoxicosis is not diagnostic of GD; a thyroid scan should be added in the presence of thyroid nodularity.

Ultrasound examination of thyroid gland

 

Ultrasound examination of thyroid gland: normal thyroid gland

 

 

Ultrasound examination of thyroid gland: enlarged thyroid gland

Scanogram of normal thyroid gland

Scanogram of enlarged thyroid gland

 

Scanogram of thyroid gland: diffuse toxic goiter

 

         Serum TSH measurement has the highest sensitivity and specificity of any single blood test used in the evalua­tion of suspected hyperthyroidism and should be used as an initial screening test. However, when hyperthyroidism is strongly suspected, diagnostic accuracy improves when both a serum TSH and free T4 are assessed at the time of the initial evaluation. The relationship between free T4 and TSH (when the pituitary-thyroid axis is intact) is an inverse log-linear relationship; therefore, small changes in free T4 result in large changes in serum TSH concentra­tions. Serum TSH levels are considerably more sensitive than direct thyroid hormone measurements for assessing thyroid hormone excess. In overt hyperthyroidism, usually both serum free T4 and T3 estimates are elevated, and serum TSH is undetectable; however, in milder hyper­thyroidism, serum T4 and free T4 estimates can be normal, only serum T3 may be elevated, and serum TSH will be <0.01 mU/L (or undectable). These laboratory findings have been called “T3-toxicosis” and may represent the ear­liest stages of disease or that caused by an autonomously functioning thyroid nodule. As is the case with T4, total T3 measurements are impacted by protein binding. Assays for estimating free T3 are less widely validated than those for free T4, and therefore measurement of total T3 is frequently preferred in clinical practice. Subclincial hyperthyroidism is defined as a normal serum-free T4 estimate and normal total T3 or free T3 estimate, with subnormal serum TSH concentration. Laboratory protocols that automatically add free T4 estimate and T3 measurements when screen­ing serum TSH concentrations are low avoid the need for subsequent blood draws.

         In the absence of a TSH-producing pituitary adenoma or thyroid hormone resistance, if the serum TSH is normal, the patient is almost never hyperthyroid. The term “euthy­roid hyperthyroxinemia” has been used to describe a num­ber of entities, mostly thyroid hormone-binding protein disorders, that cause elevated total serum T4 concentrations (and frequently elevated total serum T3 concentrations) in the absence of hyperthyroidism. These conditions include elevations in T4 binding globulin (TBG) or trans­thyretin (TTR), the presence of an abnormal albumin which binds T4 with high capacity (familial hyperthyroxin­emic dysalbuminia), a similarly abnormal TTR, and, rarely, immunoglobulins which directly bind T4 or T3. TBG excess may occur as a hereditary X-linked trait, or be acquired as a result of pregnancy or estrogen administration, hepati­tis, acute intermittent porphyuria, or during treatment with 5-flourouracil, perphenazine, or some narcotics. Other causes of euthyroid hyperthyroxinemia include those drugs that inhibit T4 to T3 conversion, such as amiodarone  or high-dose propranolol, acute psychosis, extreme high altitude, and amphetamine abuse. Estimates of free thyroid hormone concentrations frequently also give erroneous results in these disorders. Spurious free T4 elevations may occur in the setting of heparin therapy. When free thyroid hormone concentrations are elevated and TSH is normal or elevated, further evaluation is necessary.

         After excluding euthyroid hyperthyroxinemia, TSH-mediated hyperthyroidism should be considered.A pituitary lesion on MRI and a disproportionately high serum level of the alpha-subunit of the pituitary glycopro­tein hormones support the diagnosis of a TSH-producing pituitary adenoma. A family history and positive result of genetic testing for mutations in the T3-receptor support a diagnosis of thyroid hormone resistance. Rare prob­lems with TSH assays caused by heterophilic antibodies can cause spuriously high TSH values.

         Course. The course of the disease depends on the gravity of thyrotoxicosis and is divided into three degrees: 1 degree thyrotoxicosis is characterized by the absense of complications; not marked, tachycardia is moderate (to 100 beats per mm), basal metabolism increases not more than by 30 per cent; the symptoms are pronounced in II degree of thyrotoxicosis (wasting is considerable, symptoms of nervous disorders are marked, tachycardia from 100 to 120 beats per niin, basal metabolism increases by 30-60 per cent); III degree thyrotoxicosis: grave forms of the disease with pronounced symptoms (rapidly developing cachexia, marked psychic excitability and other nervous symptoms, pronounced tachycardia, over 120 beats per mint, basal metabolism increased by more than 60 per cent). Forms of the disease complicated by atrial fibrillation, heart failure, affections of the liver, and psychoses are also referred to III degree thyrotoxicosis.

         The main complications in thyrotoxicosis are affections of the internal organs, e.g. the heart or the liver, and also psychoses, hypoadrenocorticism, and thyrotoxic crisis.

         Treatment.

The patient should be given calm and rest; sleep should be normalized. The diet must be adequate, rich in proteins and vitamins. An­tithyroid preparations should be given: iodine, Ihiouracyl, and imidazole derivatives. Transition from the second to the third degree is a positive in­dication for surgical intervention, irrespective of the length or gravity of the disease.

 

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 euthyroid 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.

Carbimazole 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.

         There is a need for periodic clinical and biochemical evaluation of thyroid status in patients taking ATDs, and it is essential that the patient understand its importance. An assessment of serum free T4 should be obtained about 4 weeks after initiation of therapy, and the dose of medi­cation adjusted accordingly. Serum T3 also may be moni­tored, since the estimated serum free T4 levels may nor­malize with persistent elevation of serum T3. Appropriate monitoring intervals are every 4–8 weeks until euthyroid levels are achieved with the minimal dose of medica­tion. Once the patient is euthyroid, biochemical testing and clinical evaluation can be undertaken at intervals of 2–3 months. An assessment of serum free T4 and TSH are required before treatment and at intervals after starting the treatment. Serum TSH may remain suppressed for several months after starting therapy and is therefore not a good parameter to monitor therapy early in the course.

         A differential white blood cell count should be obtained during febrile illness and at the onset of phar­yngitis in all patients taking antithyroid medication. Routine monitoring of white blood counts is not rec­ommended.

         If methimazole is chosen as the primary therapy for GD, the medication should be continued for approxi­mately 12–18 months, then tapered or discontinued if the TSH is normal at that time.

         Measurement of TRAb levels prior to stopping anti­thyroid drug therapy is suggested, as it aids in predict­ing which patients can be weaned from the medica­tion, with normal levels indicating greater chance for remission.

         If a patient with GD becomes hyperthyroid after com­pleting a course of methimazole, consideration should be given to treatment with radioactive iodine or thy­roidectomy. Low-dose methimazole treatment for lon­ger than 12–18 months may be considered in patients not in remission who prefer this approach.

         When MMI is discontinued, thyroid function testing should continue to be monitored at 1–3-month intervals for 6–12 months to diagnose relapse early. The patient should be counseled to contact the treating physician if symptoms of hyperthyroidism are recognized.

         A patient is considered to be in remission if they have had a normal serum TSH, FT4, and T3 for 1 year after dis­continuation of ATD therapy. The remission rate varies considerably between geographical areas. In the United States, about 20%–30% of patients will have a lasting remission after 12–18 months of medication.   The remission rate appears to be higher in Europe and Japan; a long-term European study indicated a 50%–60% remis­sion rate after 5–6 years of treatment. A meta-anal­ysis shows the remission rate in adults is not improved by a course of ATDs longer than 18 months (84). A lower remission rate has been described in men, smokers (espe­cially men), and those with large goiters (≥80 g). Persistently high levels of TRAb and high thyroid blood flow identified by color Doppler ultrasound are also associated with higher relapse rates (112,114–116), and these patients should be assessed more frequently and at shorter intervals after antithyroid drugs are discontinued. Conversely, patients with mild disease, small goiters, and negative TRAb have a remission rate over 50%, making the use of antithyroid medications potentially more favor­able in this group of patients.

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 caot 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.

         If surgery is chosen as the primary therapy for GD, near-total or total thyroidectomy is the procedure of choice. Thyroidectomy has a high cure rate for the hyperthy­roidism of GD. Total thyroidectomy has a nearly 0% risk of recurrence, whereas subtotal thyroidectomy may have an 8% chance of persistence or recurrence of hyperthyroidism at 5 years.

         The most common complications following near-total or total thyroidectomy are hypocalcemia (which can be transient or permanent), recurrent or superior laryngeal nerve injury (which can be temporary or permanent), post­operative bleeding, and complications related to general anesthesia.

         Successful prediction of calcium status after total thyroidectomy can be achieved using the slope of 6- and 12-hour postoperative calcium levels or the postopera­tive intact parathyroid hormone (iPTH) level (127–132). Patients can be discharged if they are asymptomatic and their serum calcium levels are 7.8 mg/dL (1.95 mmol/L) or above and are not falling.The use of ionized calcium measurements (or serum calcium corrected for albumin level) are preferred by some, and are essential if the patient has abnormal levels of serum proteins. Low iPTH levels (<10–15 pg/mL) in the immediate postoperative setting appear to predict symptomatic hypocalcemia and need for calcium and calcitriol (1,25 vitamin D) supplementation.

         Postoperative routine supplementation with oral cal­cium and calcitriol decreases development of hypocalcemic symptoms and intravenous calcium requirement, allowing for safer early discharge. Intravenous calcium gluco­nate should be readily available and may be administered if patients have worsening hypocalcemic symptoms despite oral supplementation and/or their concomitant serum cal­cium levels are falling despite oral repletion. Persistent hypocalcemia in the postoperative period should prompt measurement of serum magnesium and possible magne­sium repletion. Following discharge, serum iPTH levels should be measured in the setting of persistent hypocalcemia to determine if permanent hypoparathyroid­ism is truly present or whether “bone hunger” is ongoing. If the level of circulating iPTH is appropriate for the level of serum calcium, calcium and calcitriol therapy can be tapered.

         Factors that favor a particular modality as treatment for Graves’ hyperthyroidism:

a. 131I: Females planning a pregnancy in the future (in more than 4–6 months following radioiodine therapy, provided thyroid hormone levels are normal), individuals with comorbidities increas­ing surgical risk, and patients with previously operated or externally irradiated necks, or lack of access to a high-volume thyroid surgeon or con­traindications to ATD use.

b. ATDs: Patients with high likelihood of remission (patients, especially females, with mild disease, small goiters, and negative or low-titer TRAb); the elderly or others with comorbidities increasing surgical risk or with limited life expectancy; indi­viduals iursing homes or other care facilities who may have limited longevity and are unable to follow radiation safety regulations; patients with previously operated or irradiated necks; patients with lack of access to a high-volume thyroid sur­geon; and patients with moderate to severe active GO.

c. Surgery: Symptomatic compression or large goi­ters (≥80 g); relatively low uptake of radioactive iodine; when thyroid malignancy is documented or suspected (e.g., suspicious or indeterminate cytology); large nonfunctioning, photopenic, or hypofunctioning nodule; coexisting hyperpara­thyroidism requiring surgery; females planning a pregnancy in <4–6 months (i.e., before thy­roid hormone levels would be normal if radioac­tive iodine were chosen as therapy), especially if TRAb levels are particularly high; and patients with moderate to severe active GO.

         Contraindications to a particular modality as treatment for Graves’ hyperthyroidism:

a. 131I therapy: Definite contraindications include pregnancy, lactation, coexisting thyroid cancer, or suspicion of thyroid cancer, individuals unable to comply with radiation safety guidelines and females planning a pregnancy within 4–6 months.

b. ATDs: Definite contraindications to long-term ATD therapy include previous known major adverse reactions to ATDs.

c. Surgery: Factors that may mitigate against the choice of surgery include substantial comorbid­ity such as cardiopulmonary disease, end-stage cancer, or other debilitating disorders. Pregnancy is a relative contraindication and should only be used in this circumstance, when rapid control of hyperthyroidism is required and antithyroid med­ications cannot be used. Thyroidectomy is best avoided in the first and third trimesters of preg­nancy because of teratogenic effects associated with anesthetic agents and increased risk of fetal loss in the first trimester and increased risk of pre­term labor in the third. Optimally, thyroidectomy is performed in the latter portion of the second trimester. Although it is the safest time, it is not without risk (4.5%–5.5% risk of preterm labor).

         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.

         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 Grave’s 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.

 

 

Hypothyroidism  (myxedema).

 

         It is the characteristic reaction to thyroid hormone deficiency. The spectrum of hormone ranges from a few non – specific symptoms to overt hormone, to myxedema coma. Hypothyroidism occurs in 3 to 6 for the adult population, but is symptomatic only in a minor of them. It occurs 8 to 10 times more often in woman than in men and usually develops after the age of 30.

         Classification

1.Congetial.

2. Acquired:         1. Primary (thyroid gland disturbances).

2. Secondary (due to pituitary disease).

3.Tertiary (due to hypothalamic disease).

4.Peripheral.

         Etiology

         A cause  is usually evident from the history and physical examination.

 

Primari and secondary hypothyroidism

 

1.Primary (thyroidal) hypothyroidism.

1)    environmental iodine deficiency is the most common cause of hypothyroidism on a worldwide basis.

2)    autoimmune processes (hypothyroidism usually occurring as a sequel to Hashimoto’s thyroiditis and results in shrunken fibroid thyroid gland with a little or no function and infiltrative diseases (tuberculosis, actynomycosis). Chronic autoimmune thyroiditis (Hashimoto’s thyroiditis) is the most common cause of hypothyroidism in areas of iodine sufficiency. Autoimmune thyroid diseases (AITDs) have been estimated to be 5-10 times more common in women than in men.

Distinct genetic syndromes with multiple autoimmune endocrinopathies have been described, with some overlapping clinical features. The presence of two of the three major characteristics is required to diagnose the syndrome of multiple autoimmune endocrinopathies (MAEs). The defining major characteristics for type 1 MAE and type 2 MAE are as follows:

         Type 1 MAE: Hypoparathyroidism, Addison’s disease, and mucocutaneous candidiasis caused by mutations in the autoimmune regulator gene (AIRE), resulting in defective AIRE protein (51). Autoimmune thyroiditis is present in about 10%-15%.

         Type 2 MAE: Addison’s disease, autoimmune thyroiditis, and type 1 diabetes known as Schmidt’s syndrome;

3)    surgical removal, total thyroidectomy of thyroid carcinoma, subtotal thyroidectomy (hypothyroidism occurs from 25 to 75 of patients in different series);

4)    irradiation (hypothyroidism results from external neck irradiation therapy in doses 2000 rads or more such as are used in the treatment of malignant lymphoma and laryngeal carcinoma); I131 therapy for hyperthyroidism (it results in hyperthyroidism in 20 % to 60 % of patients within the first year after therapy and in 1 % to2 % each year there after);

5)    during or after therapy with propylthyouracil, methimazole, iodides;

6)    Medications such as amiodarone, interferon alpha, thalidomide, lithium, and stavudine have also been associated with primary hypothyroidism.

7)    Trauma.

2.Secondary and tertiary hypothyroidism

It occurs due to either deficient secretion of TSH from the pituitary or lack of secretion of TRH from the hypothalamus. Secondary hypothyroidism accounts for less than 5% or 10% of hypothyroidism cases. Tertiary hypothyroidism accounts for less than 5% of hypothyroidism cases.

1.                hypothalamic tumors (including craniopharyngiomas)

2.                inflammatory (lymphocytic or granulomatous hypophysitis)

3.                infiltrative diseases

4.                hemorrhagic necrosis (Sheehan’s syndrome)

5.                surgical and radiation treatment for pituitary or hypothalamic disease

6.                drugs (reserpin, parlodel).

3. Peripheral hypothyroidism:

–                     peripheral tissue resistance to thyroid hormones;

–                     decreasing of T4 peripheral transformation into T3 (in liver or in kidneys) ;

–                     production of antibodies to thyroid hormones.

Congenital:

–                     Maldevelopment –hypoplasia or aplasia;

–                     Inborn deficiencies of biosynthesis or action of thyroid hormone;

–                     Atypical localization of thyroid gland;

Classification.(cont.)

B.       1. Laboratory (subclinical) hypothyroidism.

2. Clinical hypothyroidism, which can be divided on stages of severity: mild, moderate, severe.

C.       1. Compensation.

2. Subcompensation.

3. Decompensation.

D.       1. Without complications.

2. With complications (myopathy, polyneuroparhy, encephalopathy, coma).

 

Clinical features

The major symptoms and signs of hypothyroidism reflect showing of physiologic function. Virtually every organ system can be affected. The onset of symptoms may be rapid or gradual, severity varies considerably and correlates poorly with biochemical changes. Because many manifestations of hypothyroidism are non-specific, the diagnosis is particularly likely to be overlooked in patients with other chronic illnesses and elderly.

Nervous system

               Most of hypothyroid patients complain of fatigue, loss of energy, lethargy, forgetfulness, reduced memory. Their level of physical activity decreases, and they may speak and move slowly. Mental activity declines and there is inattentiveness, decreased intellectual function, and sometimes may be depression.

Neurological symptoms include also hearing loss, parasthesias, objective neuropathy, particularly the carpal tunnel syndrome, ataxia.

Tendon reflex shows slowed or hung-up relaxation.

Skin and hair.

               Hypothyroidism results in dry, thick and silk skin, which is often cool and pale. Glycosoamynoglicanes, mainly hyaluronic acid accumulate in skin and subcutaneous tissues retaining sodium and water. So, there is nonpitting oedema of the hands, feet and periorbital regions (myxedema). Pitting oedema also may be present. The faces are puffy and features are coarse. Skin may be orange due to accumulation of carotene. Hair may become course and brittle, hair growth slows and hair loss may occur. Lateral eyebrows thin out and body hair is scanty.

 

 

 

 

Facies basedovica

 

                              Hypothyroidism. Before and after treatment.

 

 

Facies basedovica

Alopecia in hypothyroidism

 

        

         Cardiovascular system.

               There may be bradycardia, reduced cardiac output, quiet heart sounds, a flabby myocardium, pericardial effusion (see pict.), cardiac wall is thick, it is increased by interstitial oedema. (These findings, along with peripheral edema, may simulate congestive heart failure). Increased peripheral resistance may result in hypertension. The ECG may show low voltage and/or non-specific ST segment and T wave changes. Hypercholesterolaemia is common. Whether or not these is an increased prevalence of ischemic heart disease is controversial. Angina symptoms, when present, characteristically occur less often after the onset of hypothyroidism, probably because of decreased activity.

Affection of a heart in hypothyroidism (ultrasound)

        

         Gastrointestinal system.

Hypothyroidism does not cause obesity, but modest weight gain from fluid retention and fat deposition often occurs. Gastrointestinal motility is decreased loading to constipation and abdominal distension. Abdominal distension may be caused by ascities as well. Ascitic fluid, like other serous effusions in myxedema, has high protein content. Achlorhydria occurs, often associated with pernicious anemia.

         Renal system.

         Respiratory system.

         Dyspnea of effort is common.                                                                                       on. This complaint may be caused by enlargement of the tongue and larynx, causing upper airway obstruction, or by respiratory muscle weakness, interstitial edema of the lungs, and for Pleural effusions which have high protein content. Hoarseness from vocal curt enlargement often occurs.

         Musculoskeletal system.

         Muscle and joint aches, pains and stiffness are common. Objective myopathy and joint swelling or effusions are less often present. The relaxation phase of the tendon reflexes is prolonged. Serum creatine phosphokinase and alanine aminotransferase activities are often increased, probably as much to slowed enzyme degradation as to increased release from muscle.

         Hemopoetic system.

         Anemia, usually normocytic, caused by decreased red blood cell production, may occur. It is probably from decreased need of peripheral oxygen delivery rather than hematopoetic defect. Megaloblastic anemia suggests coexistent pernicious anemia. Most patients have no evidence iron, folic acid or cyancobalamin deficiency.

         Endocrine system.

         There may be menorrhagia (from anovulatory cycles), secondary amenorrhea, infertility and rarely galactorrhea. Hyperprolactinemia occurs because of the absence of the inhibitory effect of thyroid hormone on prolactine secretion (and causes galactorrhea and amenorrhea or Van – Vik – Cheness – Ross’s syndrome).

Pituitary-adrenal function is usually normal. Pituitary enlargement from hyperplasia of the thyrotropes occurs rarely in patients with primary hypothyroidism –such enlargement also may be caused by a primary pituitary tumor, which resulting TSH deficiency.

Enlargement of thyroid gland in young children with hypothyroidism suggests a biosynthetic defect. Hypothyroidism in adults is caused by Hashimoto thyroiditis.

Secretion of growth hormone is deficient because thyroid hormone is necessary for synthesis of growth hormone. Growth and development of children are retarded. Epiphyses remain open.

         Metabolic system.

Hypothermia is common. Hyperlipidemia with increase of serum cholesterol and trigliceride occurs because of reduced lipoprotein lipase activity.                                                                                                                                   

         Subclinical (laboratory) hypothyroidism.

         It is an asymptomatic state in which serum T4 and free T4 are normal, but serum TSH is elevated. ). This designation is only applicable when thyroid function has been stable for weeks or more, the hypothalamic-pituitary-thyroid axis is normal, and there is no recent or ongoing severe illness. It is a state in which we can’t find clinical features of hypothyroidism and euthyroidism is reached by compensatory increasing of TSH secretion and that’s why synthesis and secretion of such level of thyroid hormone that will be enough for organism.

         An elevated TSH, usually above 10 mIU/L, in combination with a subnormal free T4 characterizes overt hypothyroidism. The presence of elevated TPOAb titers in patients with subclinical hypothyroidism helps to predict progression to overt hypothyroidism—4.3% per year with TPOAb vs. 2.6% per year without elevated TPOAb titers. The higher risk of developing overt hypothyroidism in TPOAb-positive patients is the reason that several professional societies and many clinical endocrinologists endorse measurement of TPOAbs in those with subclinical hypothyroidism.The therapy may provide the patient with more energy, a feeling of well being, desirable weight reduction, improved bowel function or other signs of better health even though the patient is not aware of these symptoms before therapy.

Peculiarities of congenital hypothyroidism

•                     Children are born with increased weight

•                     Subcutaneous edema

•                     Hypotermia

•                     Prolonged jaundice

•                     Physical (dwarfism) and mental retardation (cretinism)

Congenital hypothyroidism

 

Cretinism

 

Diagnostic of hypothyroidism is based on:

1)    history;

2)    clinical features;

3)    blood analysis: anemia; hypercholesterolemia;

4)    levels of thyroid hormone: both serum T4 and T3 are decreased (but in 25% of patients with primary hypothyroidism may be normal circulating levels of T3);

5)    ECG;

6)    examination of tendon reflexes;

7)    ultrasonic examination;

         Measurement of serum TSH is the primary screening test for thyroid dysfunction, for evaluation of thyroid hor­mone replacement in patients with primary hypothyroidism, and for assessment of suppressive therapy in patients with follicular cell-derived thyroid cancer. TSH levels vary diurnally by up to approximately 50% of mean values. TSH secretion is exquisitely sensitive to both minor increases and decreases in serum free T4, and abnormal TSH levels occur during developing hypothyroidism and hyperthyroidism before free T4 abnormalities are detectable. According to NHANES III, a disease-free population, which excludes those who self-reported thy­roid disease or goiter or who were taking thyroid medications, the upper normal of serum TSH levels is 4.5 mIU/L.

 

Recommendations of Six Organizations Regarding Screening of

Asymptomatic Adults for Thyroid Dysfunction

 

Differential diagnosis of primary and secondary hypothyroidism:

1)    clinical features:

           Secondary hypothyroidism is not common, but it often involves other endocrine organs affected by the hypothalamic – pituitary axis. The clue to secondary hypothyroidism is a history of amenorrhea rather than menorrhagia in a woman with known hypothyroidism.

           In secondary hypothyroidism, the skin and hair are dry but not as coarse; skin depigmentation is ofteoted; macroglossia is not prominent; breasts are atrophic; the heart is small without accumulation of the serous effusions in the pericardial sac; blood pressure is low, and hypoglycemia is often found because of concomitant adrenal insufficiency or growth hormone deficiency.

2)    laboratory evaluation:

shows a low level of circulating TSH in secondary hypothyroidism, whereas in primary hypothyroidism there is no feedback inhibition of the intact pituitary and serum levels of TSH are very high.

The serum TSH is the most simple and sensitive test for the diagnosis of pituitary hypothyroidism.

Serum cholesterol is generally low in secondary hypothyroidism, but high in pituitary hypothyroidism.

Other pituitary hormones and their corresponding target tissue hormones may be low in secondary hypothyroidism.

           The TSH test is useful in distinguishing between secondary and tertiary hypothyroidism in the former; TSH is not released in response to TRH; whereas in the later, TSH is released.

         Treatment of hypothyroidism.

1.  No specific diets are required for hypothyroidism.

2.  Regimen is not restricted.

3. 1) replacement therapy:

–                     desiccated animal thyroid (this is an extract of pig and cattle thyroid glands, which standardized based on its iodine content but they are too variable in potency to be reliable and should be avoided);

–                     synthetic preparations of :

T4 (l-thyroxine)

–                     T4 is preparation of choice, because it produces stable serum levels of both T4 and T3.

–                     Absorption is fairly constant 90 to 95% of the dose. T3 is generated from T4 by the liver.

–                     The initial dosage can be 1.6 mkg/kg of ideal weight or 12.5-25 mkg in older patients and 25-50 mkg in young adult. Patients who are athyreotic (after total thyroidectomy and/or radioiodine therapy) and those with central hypothyroidism may require higher doses, while patients with subclinical hypothyroidism or after treatment for Graves’ disease may require less. However, patients with subclinical hypothyroidism do not require full replacement doses. Doses of 25-75 μg daily are usually sufficient for achieving euthyroid levels, with larger doses usually required for those presenting with higher TSH values. Moreover, although elderly patients absorb L-thyroxine less efficiently they often require 20-25% less per kilogram daily than younger patients, due to decreased lean body mass

–                     Young healthy adults may be started on full replacement dosage, which is also preferred after planned (in preparation for thyroid cancer imaging and therapy) or short-term inadvertent lapses in therapy. Starting with full replacement versus low dosages leads to more rapid normalization of serum TSH but similar time to symptom resolution.

–                     The dosage can be increased in 25-50 mkg increments at 4 to 6 week intervals until clinical and biochemical euthyroidism is achieved. In older patients more gradual increments are indicated. Cautious replacement is particularly warranted in patients with ischemic heart disease, because angina pectoris or cardiac arrhythmia may be precipitated by T4 therapy.

Patients older than 50-60 years, without evidence of coronary heart dis­ease (CHD) may be started on doses of 50 μg daily. Among those with known CHD, the usual starting dose is reduced to 12.5-25 μg/day. Clinical monitoring for the onset of anginal symptoms is essential. Anginal symptoms may limit the attainment of euthyroidism. However, opti­mal medical management of arteriosclerotic cardiovascu­lar disease (ASCVD) should generally allow for sufficient treatment with L-thyroxine to both reduce the serum TSH and maintain the patient angina-free.

–                     The average maintenance dosage is 100 to 150 mkg/day orally, only rarely is a larger dosage required. In general, the maintenance dose may decrease in the elderly and may increase in pregnancy.

–                     The dosage should be minimum that restores TSH levels to normal (though this criterion cannot be used in patients with secondary hypothyroidism). The most reliable therapeutic endpoint for the treatment of primary hypothyroidism is the serum TSH value. Confirmatory total T4, free T4, and T3 levels do not have sufficient specificity to serve as therapeutic endpoints by themselves, nor do clinical criteria. Moreover, when serum TSH is within the normal range, free T4 will also be in the normal range. On the other hand, T3 levels may be in the lower reference range and occasionally mildly subnormal.

–                     Patients being treated for established primary hypothyroidism should have serum TSH measurements done at 4-8 weeks after initiating treatment or after a change in dose. Once an adequate replacement dose has been determined, periodic TSH measurements should be done after 6 months and then at 12-month intervals, or more frequently if the clinical situation dictates otherwise.

–                     In patients with central hypothyroidism, assessment of free T4 or free T4 index, not TSH, should be done to diagnose and guide treatment of hypothyroidism.

–                     Patient takes the whole dose of T4 once a day (in the morning), in the summer the dose may be decreased and in the winter should be increased.

–                     When a woman with hypothyroidism becomes pregnant, the dosage of L-thyroxine should be increased as soon as possible to ensure that serum TSH is <2.5 mIU/L and that serum total T4 is in the normal reference range for pregnancy. Moreover, when a patient with a positive TPOAb test becomes pregnant, serum TSH should be measured as soon as possible and if >2.5 mIU/L, T4 treatment should be initiated. Serum TSH and total T4 measurements should be monitored every 4 weeks during the first half of pregnancy and at least once between 26 and 32 weeks gestation to ensure that the requirement for L-thyroxine has not changed.

T3 (liothyronine sodium) should not be used alone for long-term replacement because its rapid turnover requires that it be taken. T3 is occasionally used mainly in starting therapy because the rapid excretion is useful in the initial titration of a patient with longstanding hypothyroidism in whom cardiac arrhythmia may occur early in replacement therapy. The risk of jatrogenic hyperthyroidism is therefore greater in patients receiving these preparations.

         In addition, administering standard replacement amounts of T3 (25 to 50 mkg/day) results in rapidly increasing serum T3 levels to between 300 and 1000 mkg within 2 to 4 h, these levels return to normal by 24 h. Therefore, when assessing serum T3 levels in patients on this particular regimen, it is important for the physician to be aware of the time of prior administration of the hormone. Additionally, patients receiving T3 are chemically hyperthyroid for at least several hours a day and thus are exposed to greater cardiac risks. Similar patterns of serum T3  concentrations are seen when mixtures of T3 and  T4 are taken orally, although the peak levels of T3  are somewhat lower. Replacement regimes with synthetic preparations of T4  reflect a different pattern of serum T3  response increases in serum T3 occur gradually over weeks, finally reaching a normal value about 8 wk. after starting therapy.

         Synthetic T3 and T4 combinations (liotrix, thyreocomb). These preparations were developed before it was appreciated that T4 is converted to T3 outside of the thyroid. These preparations should not be used.

2) Symptomatic therapy:

–                     beta-blockers (should be used in patients with tachycardia and hypertension);

–                     hypolypidemic agents;

–                     vitamins (A, B, E);

–                     diuretics and others.

         Subclinical hypothyroidism

         However, there are virtually no clinical outcome data to support treating patients with subclinical hypothyroidism with TSH levels between 2.5 and 4.5 mIU/L. The possible exception to this statement is pregnancy because the rate of pregnancy loss, including spontaneous miscarriage before 20 weeks gestation and stillbirth after 20 weeks, have been reported to be increased in anti-thyroid antibody-negative women with TSH values between 2.5 and 5.0

         Many endocrinologists would treat such patients with T4, especially if hypercholesterolemia were present. Even in the absence of hyperlipidemia, a trial of therapy might be varianted to determine if the patient experiences improvement presumably the normal serum T4 concentrations before therapy did not reflect adequate tissue effects of thyroid hormones in such patients. Unfortunately, it is also reasonable to follow these patients without T4 therapy by surveying thyroid function at 4-to 6 months intervals to determine whether thyroid failure has occurred, as indicated by the serum T4 falling to subnormal levels along with a greater increase in serum TSH and the appearance of clear symptoms.

         Reviews by the US Preventive Services Task Force and an independent expert panelfound inconclusive evidence to recommend aggressive treatment of patients with TSH levels of 4.5-10 mIU/L. The Endocrine Society recommends thyroxine replacement in pregnant women with subclinical hypothyroidism; the American College of Obstetricians and Gynecologists does not recommend it as a routine measure. The American Association of Clinical Endocrinologists (AACE) guidelines state that treatment is indicated in patients with TSH levels above 10 mIU/mL or in patients with TSH levels between 5 and 10 mIU/mL in conjunction with goiter and/or positive antithyroid peroxidase antibodies, as these patients have the highest rates of progression to overt hypothyroidism. An initial dose of 25-50 mcg/d of LT4 can be used and can be titrated every 6-8 weeks, to achieve a target TSH of between 0.3 and 3 mIU/mL.

         Myxedema coma.

         Myxedema coma is an uncommon presentation of severe hypothyroidism that is potentially fatal. Published mortality rates exceed 60%, and even with early detection and appropriate treatment, death occurs in up to 30% of individuals. The term myxedema coma is a misnomer, as myxedema and coma are neither diagnostic criteria nor common presenting findings. A more proper description would be critical hypothyroidism. Because of its lethal nature and nonspecific features, the actual prevalence of myxedema coma is unknown. However, this syndrome is extensively cited in the literature and is not uncommon in clinical practice.

         Myxedema coma, or critical hypothyroidism, occurs most often in patients with long-standing, preexisting hypothyroidism. Hypothyroidism is 4 times more common in women than in men, and 80% of cases of myxedema coma occur in females. It occurs almost exclusively in persons 60 years or older. There are approximately 300 cases of myxedema coma reported in the literature. Most cases occur during the winter, when thermoregulatory stressors are high. It can develop from all causes of hypothyroidism, including autoimmune thyroiditis, secondary hypothyroidism, and drug-induced hypothyroidism (eg, caused by lithium or amiodarone).

         Clinical Manifestation and Diagnosis

Precipitating factors include:

–                     exposure to cold;

–                     infection;

–                     trauma;

–                     drugs that suppress the CNS.

         Cardiac events (myocardial infarction, congestive heart failure), cerebral infarction, trauma, hemorrhage, hypothermia, hypoglycemia, and respiratory depression secondary to anesthetics or sedatives have also been implicated.

         Clinical findings in myxedema coma are similar to those encountered with hypothyroidism, but they are typically seen in greater magnitude. In short, it is a state of profound decreased metabolic activity. Cardinal features include impaired thermoregulation (hypothermia), hypotension, bradycardia, and mental status depression. Mental status depression is a common clinical feature and may progress to stupor, obtundation, or frank coma. The hypometabolic state and mental status depression may result in centrally mediated hypoventilation and hypercapnic respiratory failure. Concomitant endocrinopathies are commonly encountered, most notably adrenal insufficiency, which may contribute to the electrolyte, thermoregulatory, and cardiovascular derangements commonly seen. Hyponatremia resulting from an increased release of antidiuretic hormone and hypoglycemia caused by decreased gluconeogenesis, infection, or adrenal insufficiency are common features. Myxedema is characterized by generalized skin and soft tissue swelling, periorbital edema, ptosis, macroglossia, and the presence of cool, dry skin. Despite the name of the condition, clinically significant myxedema is infrequently identified and is not a diagnostic criteria.

         Unlike thyroid storm, most patients with myxedema coma have a prior diagnosis of hypothyroidism. Although it is necessary to confirm the diagnosis, thyroid function testing can be confusing. The diagnosis is suspected clinically and confirmed with TFT. Treatment should not be delayed for laboratory confirmation.       Hypothyroidism is diagnosed in individuals with elevated TSH levels and low levels of free T4 and T3. In myxedema coma, T3 and T4 levels may be profoundly diminished or even undetectable. The degree of TFT abnormalities does not distinguish hypothyroidism from myxedema coma. Rather, the distinction is based on clinical findings. Abnormal TFT can be seen in other acute illnesses and does not necessarily reflect myxedema coma or even hypothyroidism. It is important for the clinician to be able to differentiate hypothyroidism from euthyroid sick syndrome, in which patients have a reduction in both TSH and thyroid hormone levels. Given the common association with adrenal insufficiency, a cosyntropin stimulation test should be considered, especially in those with hemodynamic instability.

         Treatment of myxedema coma.

         The treatment of myxedema coma involves rapid replacement of thyroid hormone, treatment of the precipitating cause, and general supportive measures.

It is treated with large doses of T4 (250-500 mkg I/v bolus 3 – 4 times a day) or T3 if available (40 – 100 mkg I/v bolus 3 times a day), because TBG must be saturated before any free hormone is available for response. The maintenance dose for T4 is 50 mkg/day I/v and for T3 10-20 mkg/day I/v until the hormone can be given orally.

Ventilatory support, passive external rewarming, and correction of underlying electrolyte abnormalities are commonly required. The patient should not be rewarmed rapidly because of the threat of cardiac arrhythmia. Hypoxemia is common, so PaO2 should be measured at the outset of treatment. If alveolar ventilation is compromised, immediate mechanical ventilatory assistance is required.

Glucose and steroid replacement should also be considered until recovery. Given the strong association with infectious causes, antimicrobial therapy should be considered.

Thyroiditis

Thyroiditis is an inflammation of the thyroid gland. It may be painful and tender when caused by an infection or trauma, or painless when caused by an autoimmune condition or medications.

There are several types of thyroiditis. The most common forms are Hashimoto’s disease, subacute granulomatous thyroiditis, postpartum thyroiditis, subacute lymphocytic thyroiditis and drug induced thyroiditis. Most forms of thyroiditis result in three phases: overactive thyroid (hyperthyroidism), underactive thyroid (hypothyroidism), and return to normal. When the thyroid is inflamed, it often releases an excess of thyroid hormone, resulting in hyperthyroidism. Alternatively, when the supply of thyroid hormone is depleted, the body has too little, and hypothyroidism results. Young to middle aged women are at greatest risk, however, some forms of thyroiditis occur in both men and women of all ages. With some forms, hypothyroidism may develop years later, even if the thyroiditis has resolved.

Signs and Symptoms:

Depending on the type of thyroiditis, the thyroid gland can have one of the following characteristics:

–         Firm and enlarged, but not tender

–         Enlarged and painful, with pain extending to the jaw or ears

–         Enlarged, but not painful

–         Enlarged on only one side, hard like a stone, and sticking to other neck structures.

Patient may also have one or more of the following symptoms:

–         Cool, dry skin, slow pulse rate (fewer than 60 beats per minute), swelling around the eyes, hoarseness, or slow reflexes

–         No desire to eat, feeling tired and unenergetic, and a slight fever

–         Constipation

–         A rapid heartbeat, slight nervousness, anxiety, weight loss of 5 – 10 pounds, and increased sweating.

Causes

Immune disorders, viruses, and fever disorders can cause thyroiditis. Sometimes thyroiditis develops if you have Graves’ disease (an autoimmune disorder that causes hyperthyroidism). Certain drugs, such as amiodarone, interferon-alpha, inter leukin-2, or lithium can also cause thyroiditis. Pregnant women who test positive for the thyroid antibody during their first trimester have a 30 – 50% chance of developing thyroiditis during the postpartum period. Excessive iodine intake may also contribute to thyroid disorders. In some cases or thyroiditis, there is no identifiable cause.

Investigations

Take a different view of laboratory analysis of thyroid function. Many doctors pay particular attention to levels of T3 hormone, the active form of thyroid hormone that is converted in the body from T4, an inactive thyroid hormone. Conventional lab tests usually monitor T4 and thyroid stimulating hormone (TSH) without examining levels of T3. People with hypothyroidism may be treated with T4 to bring their levels of T4 to normal limits.

Treatment Options

Thyroiditis generally involves three phases: overactive phase, underactive phase, and return to normal. Treatment is individualized to type and phase.

Drug Therapies

Depending on the particular type of thyroiditis, a physician may prescribe one or more of the following treatments:

–         Levothyroxine, if hypothyroidism or large goiter present

–         Aspirin, to relieve pain and inflammation

–         Corticosteroid medications (such as prednisone or dexamethasone), to reduce inflammation in severe cases

–         Propanolol, for hyperthyroidism

–         Thyroxine, to replace thyroid hormone (in cases of hypothyroidism)

–         Short term beta blockers, for hyperthyroid symptoms

–         Antibiotics

Surgical and Other Procedures

In rare cases, partial thyroid removal may relieve pressure.

Complementary and Alternative Therapies

Alternative therapies can help when used along with the medications your health care provider prescribes, but do not replace conventional medications. Make sure your doctor knows about any alternative therapies you are using or considering using. Some supplements can interfere with conventional medications.

Nutrition and Supplements

–                     Foods that depress thyroid activity are broccoli, cabbage, Brussels sprouts, cauliflower, kale, spinach, turnips, soy, beans, and mustard greens. You should include these foods in a diet for hyperthyroid conditions — and avoid them if you have a hypothyroid condition. Use caution because people with thyroiditis can switch from hyperthyroidism to hypothyroidism very quickly.

–                     Avoid refined foods, sugar, dairy products, wheat, caffeine, alcohol.

–                     Essential fatty acids (1,000 – 1,500 mg three times per day), found in flaxseed oil, fish oil, and borage oil, are anti-inflammatory and necessary for hormone production. Essential fatty acids can increase the blood thinning effects of certain medications, including Coumadin, Plavix, or aspirin.

–                     Bromelain (250 – 500 mg 3 times per day between meals), an enzyme from the pineapple plant, may reduce inflammation. Bromelain can increase blood thinning effects of certain medications. Check with your physician.

–                     Vitamin C (1,000 mg per day), vitamin A (10,000 – 25,000 IU per day), B complex [(50 -100 mg per day), augmented with vitamins B2 (riboflavin, 10 mg), B3 (niacin, 10 – 25 mg), and B6 (pyridoxine, 5 – 15 mg)], selenium (200 mcg per day), vitamin E (400 IU per day), and zinc (30 mg per day) are necessary for normal thyroid hormone production.

–                     Calcium (1,000 mg per day) and magnesium (200 – 600 mg per day) may help metabolic processes function correctly.

–                     If you take thyroid hormone medication, talk to your doctor before consuming soy products. Some evidence suggests that soy may interfere with absorption of thyroid hormone.

–                     Iron may also interfere with the absorption of thyroid hormone medication.

          Herbs are generally a safe way to strengthen and tone the body’s systems. As with any therapy, you should work with your health care provider to diagnose your problem before starting treatment. You may use herbs as dried extracts (capsules, powders, teas), glycerites (glycerine extracts), or tinctures (alcohol extracts). Unless otherwise indicated, make teas with 1 tsp. herb per cup of hot water. Steep covered 5 – 10 minutes for leaf or flowers, and 10 – 20 minutes for roots. Drink 2 – 4 cups per day. You may use tinctures alone or in combination as noted.

Talk to your health care provider before taking herbs for thyroiditis, particularly if you are also taking prescription medication.

For hyperthyroid conditions:

–                     Bugleweed (Lycopus virginica) and lemon balm (Melissa officinalis) help normalize the overactive thyroid. Steep the following amount in one cup of boiling water. Strain and cool. For bugleweed, 1 – 2 g; for lemon balm, 2 tablespoons. These herbs may be combined. Bugleweed may interact with some diabetes medications.

–                     Motherwort (Leonurus cardiaca) can help regulate rapid heartbeat. Steep 2 g in one cup of boiling water. Strain and cool. Drink 3 times per day. Do not take motherwort along with sedating medications.

–                     Turmeric (Curcuma longa) makes the effect of bromelain stronger and should be taken between meals, 500 mg 3 times per day. Turmeric can increase the blood thinning effects of certain medications, such as Coumadin. Speak with your physician.

–                     Avoid ashwagandha (Withania somnifera) and bladderwrack (Fucus vesiculosus), as they can stimulate hyperthyroidism.

For hypothyroid conditions:

–                     Coleus forskohlii (50 – 100 mg 2 – 3 times per day) may stimulate thyroid function to increase thyroid hormone. Do not take coleus if you are taking blood thinning medications or Nitrates. Coleus may increase the blood thinning effects of cetain medications, such as Coumadin.

–                     Herbs such as guggul (Commiphora mikul) (25 mg of guggulsterones 3 times per day) and hawthorne (Crataegus monogyna) (500 mg twice a day) are taken to counteract high cholesterol, which often accompanies hypothyroidism. Guggul can interact with many medications, particularly hormone medications, such as oral contraceptives, and other medications, such as Diltiazem (Cardizem, Dilacor, Tiazac). Guggul may also increase bleeding. Speak with your physician. Hawthorne can interact with various blood pressure medications and can increase the blood pressure lowering effects of drugs used to treat male sexual dysfunction, such as Viagra. Hawthorne may also interfere with Nitrate medications.

Physical Medicine

Exercise helps improve thyroid function for both hypothyroidism and hyperthyroidism.

Acupuncture may help correct hormonal imbalances and address underlying deficiencies and excesses involved in thyroiditis.

Therapeutic massage may relieve stress and increase the sense of well being.