Management of patients with thyrotoxicosis.

Management of patients with Hyperparathyroidism.

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.

antranik.org

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.

www.endocrinesurgery.net.au

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)

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

Table. Causes of Thyrotoxicosis

 

Diffuse toxic goiter (Grave’s disease)

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.

 

www.bio.davidson.edu

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 diffuse toxic 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.

Diagnosing and Managing Thyroid Disease in the Nursing Home . JAMDA. Volume 9, Issue 1 , Pages 9-17, January 2008

 

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.

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.

 

 

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.

 

 

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 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.

 

doctorsgates.blogspot.com

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, 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).

 

Beta-Adrenergic Receptor Blockade in the Treatmentof Thyrotoxicosisa

 

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 cannot 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 (133). 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 (134,135).

Postoperative routine supplementation with oral cal­cium and calcitriol decreases development of hypocalcemic symptoms and intravenous calcium requirement, allowing for safer early discharge (136). 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 (137,138). 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.

 

Iodine-induced thyrotoxicosis

Iodine excess can lead to thyrotoxicosis. In vulnerable people such as those with a history of Graves’ disease or with nodular goitre, excess iodine can lead to thyrotoxicosis: iodine-induced thyrotoxicosis (IIT). Common sources of excess iodine are: iodine-containing radiographic contrast agents, amiodarone, kelp, iodine-containing multivitamins and large quantities of Japanese food.

 

IIT due to iodine-containing radiographic contrast agents

IIT after administration of radiographic contrast agents occurs in 0 to 1.2% of patients without underlying thyroid disease. In patients with an underlying thyroid disorder the incidence is 5.2%. Risk factors are higher age, nodular goitre and suppressed TSH. The thyrotoxicosis is usually mild and resolves spontaneously. Prevention is possible with methimazole (20 mg once daily) and sodium perchlorate (300 mg thrice daily). Despite treatment thyrotoxicosis is not preventable in all patients and side effects are common. Therefore preventive treatment should be considered only in those patients at high risk for serious cardiac arrhythmia.

 

Prevention of contrast agent induced thyrotoxicosis:

Methimazole once daily 20 mg and sodium perchlorate three times daily 300 mg

 

Amiodarone-induced thyrotoxicosis

Amiodarone administration has several effects on parameters of thyroid function. Amiodarone consists for 39.3% of iodine. A dose of 200 to 400 mg daily therefore leads to a substantial iodine excess. Such an excess leads to inhibition of thyroid iodine organification (Wolff-Chaikoff effect) resulting in an increase in TSH (resulting in a TSH of about 5 to 15 mU/l) which – due to escape of Wolff-Chaikoff effect – normalises after approximately three months. Peripheral effects of amiodarone on thyroid hormone metabolism collectively lead to higher T4 and f T4 levels while TSH remains normal. During amiodarone use the upper limit of normal for T4 and f T4 should be increased by about 25%. The clinical picture shows a wide variety; often the presenting symptom is worsening of cardiac arrhythmia. Development of AIT is not associated with cumulative dose. It occurs unpredictably and in a short period of time.

There are two types of AIT: type I and type II. As treatment differs it is important to carefully evaluate patients with AIT.

Type I is a thyrotoxicosis with hyperthyroidism occurring in patients with nodular goitre or Graves’ disease. Thyroid antibodies are frequently present. As a result of increased thyroid hormone synthesis radioactive iodine uptake can still be increased and the thyroid is hypervascularised.

Type II is a destruction-mediated thyrotoxicosis that results from the cytotoxic effect of amiodarone on thyroid follicular cells.

Treatment can be difficult. Type I AIT is preferably treated with methimazole 30 mg daily in combination with potassium perchlorate 500 mg twice daily.  As excess iodine renders methimazole less effective, methimazole alone does not significantly shorten the period of thyrotoxicosis in most patients. It is advised to stop administration of amiodarone if possible; unfortunately most patients are still thyrotoxic six to nine months after discontinuation of amiodarone. Radioactive iodine uptake is sometimes high enough to make radioactive iodine therapy possible. In case of type II AIT the treatment of choice is prednisone: 30 mg daily for two weeks and thereafter tapering to zero in three months. In type II AIT continuation of amiodarone is usually possible. In extremely therapy resistant cases thyroidectomy can be an option.

Treatment of AIT

·       Type I: methimazole 30 mg daily in combination with potassium perchlorate 500 mg twice daily. If possible stop amiodarone

·        Type II: prednisone: 30 mg daily for two weeks and thereafter tapering to zero in 3 months. Continuation of amiodarone usually possible

 

Subclinical hyperthyroidism

Subclinical hyperthyroidism is a biochemical diagnosis characterised by suppressed TSH and normal free T4 and T3 concentrations. When other causes of suppressed TSH – medication (steroids, dopamine), nonthyroidal illness, (supra) sellar disease – are excluded a suppressed TSH is indicative of a T4 concentration that is above the individually determined setpoint.

 

The prevalence of endogenous subclinical hyperthyroidism is 0.7 to 1.9%, of exogenous hyperthyroidism 1.3 to 2.0%. Causes are nodular goitre, Graves’ disease and thyroiditis. Subclinical hyperthyroidism is statistically associated with atrial fibrillation: in subjects in the Framingham heart study with a TSH <0.1 the cumulative ten-year incidence for atrial fibrillation was 28% compared with 11% in those with normal TSH levels. These findings were recently confirmed by Capolla et al. who found in persons with a TSH <0.4 mU/l during a period of 13 years a twofold increased incidence of atrial fibrillation compared with euthyroid subjects. Besides rhythm disturbances subclinical hyperthyroidism also leads to adverse changes in echocardiographic measurements. In postmenopausal women subclinical hyperthyroidism is associated with osteoporosis. With regard to fractures it can be said that women with a suppressed TSH have a higher fracture incidence than women with a normal TSH. Finally, the risk of dementia seems threefold increased in subclinical hyperthyroidism. However, whether there is an increased mortality in patients with subclinical hyperthyroidism is controversial. Based on the above it is advised to treat patients with subclinical hyperthyroidism if there are toxic symptoms, atrial fibrillation or osteopenia.70 Regardless of signs and symptoms it should be considered to treat persons older than 60 years, postmenopausal women especially if TSH is <0.1 mU/l.

 

Toxic nodular goiter

 

A toxic nodular goiter (TNG) is a thyroid gland that contains autonomously functioning thyroid nodules, with resulting hyperthyroidism. TNG, or Plummer’s disease, was first described by Henry Plummer in 1913. TNG is the second most common cause of hyperthyroidism in the Western world, after Graves disease. In elderly individuals and in areas of endemic iodine deficiency, TNG is the most common cause of hyperthyroidism.

Toxic nodular goiter (TNG) represents a spectrum of disease ranging from a single hyperfunctioning nodule (toxic adenoma) within a multinodular thyroid to a gland with multiple areas of hyperfunction. The natural history of a multinodular goiter involves variable growth of individual nodules; this may progress to hemorrhage and degeneration, followed by healing and fibrosis. Calcification may be found in areas of previous hemorrhage. Some nodules may develop autonomous function. Autonomous hyperactivity is conferred by somatic mutations of the thyrotropin, or thyroid-stimulating hormone (TSH), receptor in 20-80% of toxic adenomas and some nodules of multinodular goiters.Autonomously functioning nodules may become toxic in 10% of patients. Hyperthyroidism predominantly occurs when single nodules are larger than 2.5 cm in diameter. Signs and symptoms of TNG are similar to those of other types of hyperthyroidism.

Toxic nodular goiter occurs more commonly in women than in men. In women and men older than 40 years, the prevalence rate of palpable nodules is 5-7% and 1-2%, respectively.

Most patients with toxic nodular goiter (TNG) are older than 50 years.

 

Clinical features

1.              Thyrotoxic symptoms – Most patients with toxic nodular goiter (TNG) present with symptoms typical of hyperthyroidism, including heat intolerance, palpitations, tremor, weight loss, hunger, and frequent bowel movements.

Elderly patients may have more atypical symptoms, including the following:

§                Weight loss is the most common complaint in elderly patients with hyperthyroidism.

§                Anorexia and constipation may occur, in contrast to frequent bowel movements often reported by younger patients.

§                Dyspnea or palpitations may be a common occurrence.

§                Tremor also occurs but can be confused with essential senile tremor.

§                Cardiovascular complications occur commonly in elderly patients, and a history of atrial fibrillation, congestive heart failure, or angina may be present.

F. Lahey, MD, first described apathetic hyperthyroidism in 1931; this is characterized by blunted affect, lack of hyperkinetic motor activity, and slowed mentation in a patient who is thyrotoxic.

2.              Obstructive symptoms – A significantly enlarged goiter can cause symptoms related to mechanical obstruction.

o               A large substernal goiter may cause dysphagia, dyspnea, or frank stridor. Rarely, this goiter results in a surgical emergency.

o               Involvement of the recurrent or superior laryngeal nerve may result in complaints of hoarseness or voice change.

3.              Asymptomatic – Many patients are asymptomatic or have minimal symptoms and are incidentally found to have hyperthyroidism during routine screening. The most common laboratory finding is a suppressed TSH with normal free thyroxine (T4) levels.

 

Diagnostic

1.            Thyroid function tests – evidence of hyperthyroidism must be present in order to consider a diagnosis of toxic nodular goiter (TNG).

o               Third-generation TSH assays are generally the best initial screening tool for hyperthyroidism. Patients with TNG will have suppressed TSH levels.

o               Free T4 levels or surrogates of free T4 levels (ie, free T4 index) may be elevated or within the reference range. An isolated increase in T4 is observed in iodine-induced hyperthyroidism or in the presence of agents that reduce peripheral conversion of T4 to triiodothyronine (T3) (eg, propranolol, corticosteroids, radiocontrast agents, amiodarone).

o               Some patients may have normal free T4 levels (or free T4 index) with an elevated T3 level (T3 toxicosis); this may occur in 5-46% of patients with toxic nodules. Note that the total T3 and T4 levels may often be within the reference range but may be higher than the normal range for a particular individual; this is especially true in patients with nonthyroidal illness in which T3 levels are decreased.

o               Some patients may have subclinical hyperthyroidism (suppressed TSH levels with normal free T4 and total T3 levels).

2.            Patchy uptake of iodine (123I) in a toxic multinodular goiter.

3.            Nuclear scintigraphy – nuclear scans should be performed on patients with biochemical hyperthyroidism. Nuclear medicine scans can be performed with radioactive iodine-123 (¹²³ I) or with technetium-99m (^99m Tc). These isotopes are chosen for their shorter half-life and because they provide lower radiation exposure to the patient when compared with sodium iodide-131 (Na¹³¹ I).

4.                Ultrasonography – ultrasonography is a highly sensitive procedure for delineating discrete nodules that are not palpable during thyroid examination. Ultrasonography is helpful when correlated with nuclear scans to determine the functionality of nodules. Dominant cold nodules should be considered for fine-needle aspiration biopsy prior to definitive treatment of a TNG.

5.                Fine-needle aspiration is not usually indicated in an autonomously functioning (ie, hot) thyroid nodule. The risk of malignancy is quite low. Interpretation of the cytology specimen is difficult, because it is likely to demonstrate a follicular neoplasm (ie, sheets of follicular cells with little or no colloid), and distinguishing between a benign lesion and a malignant lesion is not possible without histologic sectioning to examine for the presence of vascular or capsular invasion.Perform a fine-needle aspiration biopsy if a dominant cold nodule is present in a multinodular goiter. A clinically significant nodule is larger than 1 cm in maximum diameter, based on either palpation or ultrasonographic images, unless there is an increased risk of malignancy. Nonpalpable nodules may be biopsied with the assistance of ultrasonography.

  

 

Surgical Care

Surgical therapy is usually reserved for young individuals, patients with 1 or more large nodules or with obstructive symptoms, patients with dominant nonfunctioning or suspicious nodules, patients who are pregnant, patients in whom radioiodine therapy has failed, or patients who require a rapid resolution of the thyrotoxic state.

·  Subtotal thyroidectomy results in rapid cure of hyperthyroidism in 90% of patients and allows for rapid relief of compressive symptoms.

·  Restoring euthyroidism prior to surgery is preferable.

·  Complications of surgery include the following:

o                         In patients who are treated surgically, the frequency of hypothyroidism is similar to that found in patients treated with radioiodine (15-25%).

o                         Complications include permanent vocal cord paralysis (2.3%), permanent hypoparathyroidism (0.5%), temporary hypoparathyroidism (2.5%), and significant postoperative bleeding (1.4%).

o                         Other postoperative complications include tracheostomy, wound infection, wound hematoma, myocardial infarction, atrial fibrillation, and stroke.

o                         The mortality rate is almost zero.

Fig. Subtotal thyroidectomy specimen of a patient with a multinodular goitre that weighed over 1000 g

 

Management of thyrotoxicosis due to unusual causes

These are several unusual causes of thyrotoxicosis that should be considered in the differential diagnosis. Since effective treatment depends on accurate diagno­sis, it is important to clearly identify the etiology in every patient presenting with thyrotoxicosis.

 

Unusual Causes of Thyrotoxicosis

 

TSH-secreting pituitary tumors

Functional pituitary tumors secreting TSH are rare. In a multicenter review of 4400 pituitary tumors seen over a 25-year period, 43 (1%) were TSH-secreting adenomas. The majority of patients present with diffuse goiter and clinical signs of thyrotoxicosis. In addition, serum TSH levels may be elevated or, especially in patients who have not had thyroid ablation, they may be inappropriately normal. Cosecretion of either prolactin or growth hormone occurs in up to 25% of cases; 1%–2% secrete both growth hormone and prolactin, and a similar percentage cosecrete gonadotropins. Most TSH-producing adenomas are larger than 1 cm, and approximately 40% of patients have associ­ated visual field deficits.

The diagnosis of TSH-secreting pituitary tumor should be based on an inappropriately normal or ele­vated serum TSH level associated with elevated free T4 estimates and T3 concentrations, usually associated with the presence of a pituitary tumor on MRI and the absence of a family history or genetic testing consis­tent with thyroid hormone resistance in a thyrotoxic patient.

Distinction between a TSH-secreting adenoma and thyroid hormone resistance is important, since thyroid function test results are similar, yet management is quite different for these two disorders. TSH-secreting adeno­mas are more likely to have concurrent alpha-subunit elevation (not useful in postmenopausal women due to concurrent gonadotropin elevation), a blunted TSH response to thyrotropin-releasing hormone (TRH) (when available), elevated sex-hormone-binding globulin and resting energy expenditure, and clinical evidence of thy­rotoxicosis, as well as an anatomic abnormality on MRI of the pituitary.

Surgery is generally the mainstay of therapy for TSH-producing pituitary tumors. The patient should be made euthyroid preoperatively. Long-term ATD therapy should be avoided. Preoperative adjunctive therapy with octreo­tide and dopamine agonist therapy has been examined. Treatment with octreotide results in a >50% reduction in serum TSH values in the majority of patients treated, and a concurrent return to euthyroidism in most. A reduction in tumor size has been observed in 20%–50% of patients treated with octreotide, but less impres­sive results have been obtained with bromocriptine therapy. Sterotactic or conventional radiotherapy has also been used in cases that prove refractory to medical therapy. For patients with TSH-producing adenomas who are con­sidered poor surgical candidates, primary medical therapy with octreotide can be considered.

 

  Struma ovarii

Struma ovarii, defined as ectopic thyroid tissue exist­ing as a substantial component of an ovarian tumor, is quite rare, representing <1% of all ovarian tumors. Approximately 5%–10% of patients with struma ovarii present with thyro­toxicosis due to either autonomous ectopic thyroid function or the coexistence of GD, and up to 25% of struma ovarii tumors contain elements of papillary thyroid cancer. Patients previously treated for GD may have persistent or recurrent hyperthyroidism due to the action of TRAb on the ectopic thyroid tissue. Treatment of struma ova­rii generally involves surgical removal, performed largely due to the risk of malignancy within the struma tissue and of curing the hyperthyroidism. Preoperative treatment with beta-adrenergic-blocking agents and antithyroid drugs is warranted to restore euthyroidism before surgery.

 

 Choriocarcinoma

Patients with choriocarcinoma, including molar preg­nancy and testicular cancer, may present with thyrotoxico­sis due to the effect of tumor-derived hCG upon the TSH receptor. This cross-stimulation only occurs at very high levels of hCG, since hCG is only a weak agonist for the TSH receptor. Treatment of hyperthyroidism due to choriocarcinoma involves both treatment directed against the primary tumor and treatment designed to prevent the thyroid from responding to hCG stimulation, such as with antithyroid drugs.

 

Thyrotoxicosis factitia

Thyrotoxicosis factitia includes all causes of thyrotox­icosis due to the ingestion of thyroid hormone. This may include intentional ingestion of thyroid hormone either surreptitiously or iatrogenically, as well as unintentional ingestion either accidentally, such as in pediatric poison­ing or pharmacy error, or through ingestion of supplements that contain thyroid extracts. Historically, accidental thy­roid hormone ingestion has occurred as a result of eating meat contaminated with animal thyroid tissue (“hamburger thyrotoxicosis”). Whereas iatrogenic causes of thy­rotoxicosis factitia are easily identified, surreptitious use of thyroid hormone may present a diagnostic quandary. Clues to this diagnosis are an absence of goiter, a sup­pressed serum thyroglobulin level, and a decreased uptake of radioactive iodine. A disportionately elevated T3 level suggests that the patient may be ingesting liothyronine or a combination T4/T3 preparation.

 

Functional thyroid cancer metastases

Thyrotoxicosis due to functional metastases in patients with thyroid cancer has been described in a handful of cases. Typically, patients have either a very large primary follicular cancer or widely metastatic follicular thyroid cancer, and may have coexisting TRAb as the proximate cause of the thyrotoxicosis. More recently, thyrotox­icosis has been reported following multiple injections of recombinant human TSH in patients with metastatic thy­roid cancer in preparation for imaging. In general, function­ing metastasis are treated with radioactive iodine with the addition of ATDs as needed for persistent hyperthyroidism. Recombinant human TSH should be avoided in these patients.

 

 

Hyperparathyroidism.

Diagnostic criteria. Treatment.

 

Parathyroid glands.

Usually, 4 parathyroid glands develop, although approximately 10% of people may have 2, 3, or 5 glands. The superior glands are typically located on the posterior aspect of the upper thyroid, whereas the location of the inferior glands is more variable. The inferior glands may be posterior to the inferior aspect of the thyroid or ectopically located in the thyroid gland, along the carotid sheath, or attached to the thymus. Superior glands may also be ectopic and in a retroesophageal, retrotracheal, or retropharyngeal location. Typical parathyroid glands are approximately 5 X 3 X 1 mm.

Parathyroid hormone (PTH) is secreted by the parathyroid glands. PTH and vitamin D are the principle regulators of Ca and phosphorus (P) homeostasis; their metabolic actions are interrelated. PTH promotes renal formation of the active metabolite of vitamin D. Conversely, with a deficiency of the vitamin or any resistance to its action, some of the effects of the hormone are blunted.

The most important actions of PTH are:

1)    increasing the rate of bone resorption with mobilization of Ca and P from bone;

2)    increasing intestinal absorption of Ca (mediated by an action on the metabolism of vitamin D);

3)    stimulation of Ca resorption in the distal tubule of the kidney;

4)    decreasing renal tubular reabsorption of phosphate (PO4).

These actions account for most of the important clinical manifestations of PTH excess or deficiency.

(Calcitonin is synthesized in the C cells of the thyroid gland. The major regulator of calcitonin secretion is the serum Ca concentration. In contrast to their effect on PTH, hypercalcemia stimulates and hypocalcemia suppresses calcitonin secretion. A number of gastrointestinal hormones including gastrin, glucagon, and cholecystokinin are pharmacologic secretegogues for calcitonin, but gastrin is the most potent.

Physiologic actions:

–         inhibiting osteoclastic bone resorption;

–         decreasing renal tubular calcium reabsorption and others.

www.bloodwork.com

 

Normal serum calcium (Ca) levels range between 2, 25 – 2,75 mmol/l (8.8 – 10.4 mg/100 ml. Approximately 40 % of the total blood Ca is bound to serum proteins while the remaining 50 % is ultrafilterable and includes ionized Ca plus Ca comlexed with phosphate and citrate. The ionized Ca fraction (about 50 % of the total blood Ca) is influenced by pH changes. Acidosis is associated with decreased protein – binding and increased ionized Ca and alkalosis with a fall of ionized Ca due to increased protein – binding. These pH – induced changes in ionized Ca occur independently of any change in total blood Ca concentration. In the laboratory determination of serum Ca, only total serum Ca is usually measured.

 

Maintenance of the blood Ca level is partially dependent upon dietary Ca intake (0,5 – 1,0 gm/day), gastro-intestinal absorption of Ca, and renal Ca excretion. The major factor preserving the constancy of blood Ca concentration is the bone Ca reservoir. About 99 % of body Ca is in bone, of which 1 % is freely exchangeable with ECF.

 

HYPERPARATHYROIDISM.

It is a generalized disorder resulting from excessive secretion of parathyroid hormone by one or more parathyroid glands; it is usually characterized by hypercalcemia, hypophosphatemia, and abnormal bone metabolism.

 

Background:

In 1891, von Recklinghausen described the classic bone disease termed osteitis fibrosa cystica. In 1925, the Viennese surgeon Mandl performed the first parathyroid exploration and adenoma resection. Mandl noted improvement of the patient’s severe skeletal abnormalities postoperatively, linking hyperparathyroidism with bone disease. Albright later described the clinical entity of classic primary hyperparathyroidism in the 1930s on the basis of 17 cases from his clinical practice. Historically, the disorder was marked by characteristic skeletal changes, nephrolithiasis, and neuromuscular dysfunction.

Today, primary hyperparathyroidism is a different entity. Since the advent of chemical screening with an autoanalyzer in 1960s, most cases are discovered in asymptomatic patients with hypercalcemia. Patients may also present with nonspecific complaints of back pain, or they may have osteopenia, as depicted on radiographic studies. Primary hyperparathyroidism is the most common cause of hypercalcemia in the outpatient population, second only to malignancy in the inpatient population. The natural progression of disease in asymptomatic patients is unclear.

 

Pathophysiology:

Normal parathyroid glands function to maintain appropriate serum calcium concentrations and to regulate bone metabolism by means of the production of parathyroid hormone (PTH). In the nonpathologic state, PTH secretion increases in response to low serum calcium concentrations and enhances the synthesis of 1,25-dihydroxyvitamin D. PTH and 1,25-dihydroxyvitamin D act together to increase calcium reabsorption in the gut and kidney and to promote osteoclastic resorption and the demineralization of bone.

Primary hyperparathyroidism is caused by an overproduction of PTH, in excess of the amount required by the body. In contrast, secondary hyperparathyroidism involves an increase in PTH levels to meet some bodily requirement. In 75-80% of cases of primary hyperparathyroidism, one or more adenomas account for the overproduction, whereas approximately 20% of cases are secondary to diffuse hyperplasia of all glands. Carcinoma accounts for less than 2% of all cases.

The effects of hyperparathyroidism on bone are numerous. Excess PTH results in an increase in bone breakdown by means of osteoclastic resorption with subsequent fibrous replacement and reactive osteoblastic activity. The bone may have microfractures, with subsequent hemorrhage and growth of fibrous tissue and an influx of macrophages. The resulting mass is called a brown tumor because of the brown color of the vascular elements and blood in the mass. The process of bone resorption and fibrous replacement results in the characteristic radiologic features of generalized bone demineralization, resorption, cysts, brown tumors, erosion of the dental lamina dura, and pathologic fractures.

Other effects of hypercalcemia include nephrolithiasis or nephrocalcinosis, neurologic changes, peptic ulcer disease, and pancreatitis.

Mortality/Morbidity: Evidence supports an increase in the morbidity and mortality rates in patients with hyperparathyroidism that is primarily related to cardiac disease. The topic is controversial, with the results of more recent studies refuting the increased risk. Differences in mortality data may reflect the different clinical profiles of classic primary hyperparathyroidism and the modern asymptomatic cohort of patients.

Sex: Incidence of primary hyperparathyroidism in women is 2-3 times the incidence in men.

Age: The average patient age at diagnosis is 55 years.

·  The incidence peaks in those aged 40-70 years.

·  The disease is rare in children. 

Classification due to etiology.

1.     Primary (due to parathyroid glands):

–         adenoma of a single gland (80 %), multiple adenomata (5 %);

Pict. Low power view of parathyroid adenoma (left side)

compressing normal parenchyma (right side)

–         hyperplasia of parathyroid glands (15 %);

–         carcinoma of a gland (< 5 %);

–         associated with syndromes of familial endocrine neoplasia (MEN-types I and II).

2.     Secondary (due to increased physiological demand of hormone in response to low serum Ca in chronic renal failure, malabsorption, rickets and osteomalacia):

–         renal;

–         intestinal;

–         vitamin D insufficiency.

–        

www.medscape.org

3.     Tertiary (due to development of parathyroid tumor against a background of prolonged secondary hyperparathyroidism).

Clinical forms of hyperparathyroidism.

1.     Bone:

–        osteoporosis;

–        osteodystrofya.

2.     Visceropatic:

–        dyspeptic;

–        gastrointestinal;

–        nephrotic;

–        pancreatic.

3.     Mixed:

–        myopathy;

–        mixed damaging of organs and systems

Clinical presentation.

www.zuniv.net

 

Many patients with mild hypercalcemia are asymptomatic, and the condition is discovered accidentally during routine laboratory screening.

Onset is usually gradual with bone pain or swelling, rarely sudden with fracture or renal colic.

The clinical manifestations of hypercalcemia include constipation, anorexia, nausea, vomiting with abdominal pain and ileus, weight loss.. More severe elevation of serum calcium is associated with emotional lability, confusion, delirium, psychosis, stupor and coma. Myopathy may cause prominent skeletal muscle weakness. Seizures are rare.

Reversible impairment of the renal concentrating mechanism leads to polyuria, nocturia and polydipsia. Hypercalciuria with nephrolithiasis or urolithiasis is common (is noted in 50 % of patients). Less often, prolonged and severe hypercalcemia may produce reversible acute renal failure or irreversible renal damage, due to precipitation of Ca salts within the kidney parenchyma (nephrocalcinosis). Renal damage may result in azotemia and hypertension.

Pict. Sonogram of medullary nephrocalcinosis in a patient with primary hyperparathyroidism

Peptic ulcers and pancreatitis may also be associated with hyperparathyroidism.

Hyperparathyroidism is a disease of increased bone resorption and bone formation. Subsequently, plain radiographic findings may include resorption and sclerosis and numerous sites the skeletal system. Historically, osteitis fibrosa cystica was used to describe the advanced skeletal disease in primary hyperparathyroidism.

Osteitis fibrosa cystica, in which increased osteoclastic activity causes rarefying osteitis with fibrous degeneration, the formation of cysts, and the development of fibrous nodules in the affected bone, may develop in patients severe hyperparathyroidism. Other bony manifestations include bone pain, tenderness, fracture, deformity, swelling of mandible due to cyst formation (rarely), falling of teeth.

Pict. Gross Photograph demonstrates advanced cystic rarefaction of the femur, due to a functioning parathyroid adenoma (primary hyperparathuroidism)

Pict. Microscopic view of osteitis cystica. The picture shows zones of decalcification, increased numbers of osteoclasts, with scalloped resorbtion of bone

Pict. Radiograph of the proximal tibia and fibula. Diffuse demineralization attributed to trabecular resorption is the most common plain radiographic sign of primary hyperparathyroidism.

Pict. Subperiosteal resorption resulting in severe tuftal resorption (white arrows) in a patient with primary hyperparathyroidism. Also note the subperiosteal and intracortical resorption of the middle phalanges (black arrows).

Pict. Distal clavicular resorption in a patient with primary hyperparathyroidism

Pict. Diffuse bone resorption and dimineralization, most apparent at areas of greatest surface area.

Cardiovascular disorders are presented as hypertension, arrhythmia, left ventricle hypertrophy.

Investigations.

1.     Increased level of serum Ca.

2.     A low serum phosphate level.

3.     Elevated serum parathyroid hormone.

4.     Increased alkaline phosphatase.

5.     Hypercalciuria, hyperphosphaturia.

 

6.     X-ray: cortical erosions most marked in phalanges especially radial side of middle phalanx; destructive bone lesions; Ca deposition on kidney.

7.      Ultrasound and CT scan: localizing of the parathyroid tumor.

8.     Technetium-99m imaging has a sensitivity of 70-95% in depicting parathyroid tumors, and it allows 3-dimensional imaging with anterior-to-posterior localization of the tumor. Studies reveal equal sensitivities of technetium-99m sestamibi imaging and MRI in the localization of abnormal glands prior to repeat surgery, with sensitivities of 82-85%. By combining the 2 modalities, the sensitivity increases to 94%.

 

Pict. Hyperparathyroidism, primary. Initial (A) and 3.5-hour delayed (B) technetium-99m sestamibi images demonstrate a 6-cm parathyroid adenoma

 

Pict. Tc99m MIBI scintigraphy. Parathyroid adenomas typically retain activity on late scans after wash-out in the thyroid has occurred. http://radiopaedia.org

 

Differential diagnosis.

Polyarthritis, radiculitis, tumors of the bones, diabetes insipidus and others.

Treatment.

1.     Conservative  treatment include (may be used in patients with hypercacemic crisis, which is medical emergency and characterized by dehydration, hypotension, abdominal pain, vomiting, fever and altered consciousness):

–         rehydration 2 – 6 l of sodium chloride solution and furosemid 40 – 160 mg;

–         calcitonine 1 – 4 units/kg;

–         prednisolone 40 – 60 mg/day.

2.     Surgery.

lomalindahealth.org

It is indicated if the disease is symptomatic or progressive. Chances of cure depend on successful removal of all excess functioning tissue and on reversibility of renal damage; renal insufficiency may progress despite cure of the underlying disease. Abnormally functioning parathyroid glands may be found in unusual locations and experience is required to find them. Preoperative localization of abnormally functioning parathyroid tissue is possible by immunoassay of the thyroid venous drainage. When hyperparathyroidism is mild, no special postoperative precautions are required. In patients with severe osteitis fibrosa cystica, prolonged symptomatic hypocalcemia may occur and require large doses of Ca together with vitamin D, usually for 1 to 3 month.

 

Prevention of secondary hyperparathyroidism due to renal failure

ocw.tufts.edu

Guidelines for surgery (Guidelines for the Management of Asymptomatic Primary Hyperparathyroidism: Summary Statement from the Third International Workshop)

1.     • The threshold value for serum calcium, above which surgery would seem to be appropriate, has been maintained at more than 1 mg/dl (_0.25 mM/liter) above the upper limits of normal.

2.     • Hypercalciuria, in the absence of renal stones or nephrolithiasis, is no longer regarded as an indication for parathyroid surgery. The basis for this change in recommendation is that hypercalciuria per se has not been established specifically as a risk factor for kidney stones in PHPT. It is one of several factors contributing to stone formation. Urinary calcium excretion does vary with age, gender, and race. Although the presence of hypercalciuria is no longer considered to be a guideline for surgery, it is recommended to obtain a 24-h urine for calcium as part of the initial evaluation of the patient. A 24-h urinary calcium, adjusted for the GFR, can be helpful diagnostically if familial hypocalciuric hypercalcemia is part of the differential diagnosis.AGFRless than60ml/min _ 1.73m2 defines a stage 3 level of renal insufficiency according to the K/DOQI guidelines. Although patients may have reached that level of renal function due to age or comorbidity and not due to the presence of PHPT, it is still regarded by many as a threshold of concern. Below this level, elevations in serum PTH occur, and pathophysiological abnormalities associated with declining renal function may influence negatively the hyperparathyroid state. However, there is no evidence that this threshold is actually associated with increasing levels of PTH in PHPT. There is also no evidence from controlled, randomized trials that correction of PHPT by successful surgery leads to an improvement in GFR. This revised guideline, using a numerical cut-point for GFR, acknowledges a return to an absolute standard of renal function, as opposed to ageand sex-specific norms. It is now consistent with the densitometric guidelines that are also based upon an age-invariant standard (the T-score) in postmenopausal women and in men over 50. Clinical judgment guides intervention, particularly in the elderly individual who may have other comorbidity affecting operative risk. • Reductions in bone density continue to be a cause for concern in PHPT, either as patients present or as they are monitored. The previous densitometric criteria are maintained. Surgery is recommended for peri- or postmenopausal women and men age 50 and older who have a T-score of _2.5 or less at the lumbar spine, femoral neck, total hip, or 33% (one third) radius. In premenopausal women and in men younger than 50, the Z-score of _2.5 or less is recommended as the cutpoint below which surgery is advised. The use of Z-scores instead of T-scores is consistent with the International Society of Clinical Densitometry (ISCD) official position in evaluating BMD in this population. This recommendation recognizes, however, that in PHPT, other effects of PTH on bone size and structure could influence fracture proclivity in this disease. It is attractive to consider application or modification of a 10-yr absolute fracture risk model, such as the FRAX tool, in those with low bone density and asymptomatic PHPT. This would allow assessment of fracture risk based on other important predictors of fracture independent of BMD. Because there are no data validating theFRAXtool in PHPT, this remains a goal for future research. In recognition of the fact that the presence of a fragility fracture provides clinical confirmation of the presence of osteoporosis, the presence of a fragility fracture is now included in the guidelines for surgical intervention.

3.      • Age less than 50 continues to be a guideline for surgery, with evidence supporting a greater risk of complications of PHPT in these individuals over time than in those who are older than 50.

 

References

А. Main

1.                 Davidson’s Principles and Practice of Medicine / Edited by Nicki R. Colledge, Brian R. Walker, Stuart H. Ralston, 1st Edition. – – Philadelphia : Churchill Livingstone, 2010. – 1376 p.

2.                 Harrison’s Principles of Internal Medicine (18th edition) / D. Longo, A. Fauci, D. Kasper, S. Hauser, J. Jameson, J.Loscalzo. – New York : McGraw-Hill Education – Europe, 2011.–4012 p.

3.                 Kumar and Clark’s Clinical Medicine (8th Revised edition) (With STUDENTCONSULT Online Access) / Edited by P. Kumar, M.L. Clark . – London : Elsevier Health Sciences, 2012. – 1304 p.

B. Additional

1. Greenspan’s Basic and Clinical Endocrinology ( 9th Revised edition) / David G. Gardner, Dolores M. Shoback. – New York : McGraw-Hill Education – Europe, 2011. – 880 p.

2. Oxford Textbook of Endocrinology and Diabetes (2nd Revised edition) / Edited by John A. H. Wass, P.Stewart, S. A. Amiel, M. J. Davies. – Oxford : Oxford University Press, 2011. – 2160 p.

3. Web-sites:

a)                  http://emedicine.medscape.com/endocrinology

b)                http://aace.com/

ATA/AACE Guidelines Hyperthyroidism and other causes of thyrotoxicosis:guidelines // Endocrine practice. – 2011. – Vol. 17, No. 3 May/June.