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Curation of patient with thyroid storm

June 26, 2024

Curation of patient with thyroid storm.

Curation of patient with adrenal crise.

Thyroid storm.

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

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.

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

– fever;

– marked weakness and muscle wasting;

– extreme restlessness with wide emotional swings;

– confusion;

– psychosis or even coma;

– hepatomegaly with mild jaundice;

– the patient may present with cardiovascular collapse or shock.

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.

It is very important to:

• Maintain a patent airway and adequate ventilation.

• Monitor continually for cardiac dysrhythmias.

• Monitor vital signs every 30 minutes.

• Provide comfort measures, including a cooling blanket.

• Give medicament treatment (antithyroid drug, propranolol, glucocorticoids, nonsalicylate antipyretics) as ordered.

Even with treatment, thyroid storm has a mortality rate of 25%

Adrenal crisis –

is a medical emergency caused by sudden marked insufficiency of adrenocortical hormones.

Precipitating factors.

1) stress (infection (especially with septicemia, trauma, surgery, prolonged fasting, salt loss due to excessive sweating during hot weather);

2) sudden withdrawal of adrenocortical hormone therapy in patients with chronic insufficiency.

Clinical features.

An adrenal crisis is characterized by:

– profound asthenia,

– severe pains in the abdomen, lower back or legs;

– nausea, vomiting diarrhea;

– peripheral vascular collapse;

– renal shutdown with azotemia.

– Body temperature may be subnormal, through severe hyperthermia due to infection is often seen.

Treatment

The main principles of adrenal crise treatment:

1) substitutional gluco- and mineralocorticoid therapy;

2) liquidation of electrolyte disturbances;

3) treatment of hypoglycemia, dehydration;

4) prevention and treatment of recurrent infection.

Therapy should be instituted immediately once a provisional diagnosis of adrenocortical failure has been made.

1) hydrocortisone 100 – 150 mg as a water – soluble ester (usually the succinate or phosphate) is injected IV over 30 seconds, followed by infusion of 1 L of 5 % glucose – in – saline solution containing 100 mg hydrocortisone ester given over 2 h.

2) Additional saline is given until dehydration and hyponatremia have been corrected. Hydrocortisone therapy is given continuously to a total dosage in 24 h of 400 – 600 – 800 mg. Mineralocorticoids are not required when high – dose hydrocortisone is given. Restoration of BP and general improvement may be expected within 1h or less after the initial dose of hydrocortisone. Vasopressors may be needed until the full effect of hydrocortisone is apparent (a delay in instituting corticosteroid therapy may result in the patient’s death, particularly if hypoglycemia and hypotension are present). A total dose of hydrocortisone 150 mg is usually given over the second 24-h period if the patient is markedly improved, and 75 mg is given on the third day. Maintenance oral doses of hydrocortisone (30 mg) and fludrocortisone acetate (0.1 mg) are given daily there – after. Recovery depends upon treatment of the underlying cause and adequate hydrocortisone therapy.

3) Total infusion of saline and 5 % glucose – 2,5 – 3,5 l during first day

4) Treatment of complications (hyperpyrexia, psychotic reactions).

Prognosis.

With a substitution therapy, the prognosis is excellent and a patient with Addison’s disease should be able to lead a full life.

We recommended you to repeat general information about pathology of thyroid and adrenal glands.

A follicle is structural and functional unit of the thyroid gland. The follicle contains colloid (which consists of thyroglobuline, a glycoprotein, containing T3 and T4 within its matrix)

Follicular cells in the thyroid gland produce the main two thyroid hormones: thyroxin (T₄) and triiodothyronine (T₃). parafollicular cells secrete hormone calcitonin.

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.

Physiologic effects of thyroid hormones

Thyroid hormones have a major physiologic effects:

1) they are required for normal brain and somatic tissue development in the fetus and newborn;

2) they regulates protein, carbohydrate, and fat metabolism in all ages;

3) they increase O₂ consumption by increasing the activity of Na⁺ H⁺ ATPase (Na pump), primarily in tissues responsible for basal O₂consumption (i.e., liver, kidney, heart and skeletal muscle).)

Calcitonin released in response to hypercalcemia and lowers serum Ca levels (see pathology of parathyroid glands).

The thyroid hormones, T₄ and 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.

With regard to thyroid function disorders determination of the plasma TSH level is the single most important measurement.

In an ambulant settings very useful is algorithm for the diagnosis of thyroid function disorders (Table 1).

Table 1. Diagnosis of thyroid function disorders

Hormone

TSH

Level

Low

normal

high

Hormone

Free T₄

Diagnosis

No primary (but can be secondary or tertiary) thyroid dysfunction

Level

low

High

low

high

normal

Diagnosis

Non-thyroid illness. Secondary or tertiary hypo-thyroidism

Hyperthyroidism

(thyrotoxicosis)

Overt

hypothyroidism

Secondary or tertiary hyper-thyroidism. Thyroid hormone resistance

Hormone

T₃

Level

high

normal

Diagnosis

T3-toxicosis

Subclinical hyperthyroidism

Subclinical

hypothyroidism

It is important to recognize that analytical problems can occur, most frequently due to concomitant medication (Table 2).

Table 2. Influence of different indications on thyroid gland function

Concomitant medication	Thyroid hormone’s disorders
Dopamine, glucocorticoids, somatostatin analogues	Inhibition of TSH secretion
Amiodarone, lithium	Inhibition of T₄secretion
Amiodarone, iodide	Stimulation of T₄ secretion
Biliary salts, iron, antacids, calcium carbonate, aluminium hydroxide, sucralfate	Impaired T₄absorption
Oestrogens, opioids	Stimulation of TBG secretion
Androgens, glucocorticoids	Inhibition of TBG secretion
Amiodarone, β-blockers, glucocorticoids	Inhibition of 5’deiodinase
Furosemide, heparin	TBG-T₄ dissociation

Muller, et al. /Thyroid function disorders – Guidelines of the Netherlands Association of Internal Medicine/ The Netherlands Journal of Medicine. – March 2008, Vol.66, No3.-P134 – 142.

Euthyroid sick syndrome (nonthyroid illness syndrome) – it is changing of thyroid hormones levels in patients without thyroid gland disorders.

Different chronic and acute heart diseases and severe somatic disorders (uremia, ketoacidosis, prolonged hunger, surgery, severe infections, liver diseases) can change metabolism of thyroid hormones: decrease total or free T₃. The levels of TSH and T₄ are normal, as a rule. Sometimes they can be increased or decreased. Such disturbances occur as a result of adaptation for calories and protein serve in organism. Treatment with thyroid hormone replacement is not appropriate, when the underlying disorder is treated, thyroid tests normolize.

Hyperthyroidism

(thyrotoxicosis)

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

Thyrotoxicosis is a main syndrome.

Sometimes the term hyperthyroidism can be used in a narrower sense to denote this state when the thyroid gland is producing too much thyroid hormones in contrast with excessive ingestion of thyroid hormone medication.

Epidemiology

At one time or another, approximately 0.5 % of the population suffers from hyperthyroidism. Graves disease is the most common cause of hyperthyroidism and is fairly common in the population. It is responsible for over 80 % of hyperthyroid cases. It occurs most often in young women, but it may occur in men and at any age.

Etiology of hyperthyroidism

1) increased synthesis and secretion of the thyroid hormones from the thyroid (approximately 75% of cases are due to Graves’ disease, 15% to multinodular goiter and 5% to toxic adenoma);

2) excessive release of thyroid hormone from thyroid without increased synthesis (due to destructive changes of various types of thyroiditis)

3) may be iodide-induced (drugs (amiodarone, α-interferon), supplementation);

4) fastitious (resulting fom conscious or accidental overingestion of thyroid hormone);

5) TSH-secreting pituitary tumor;

6) struma ovarii (develops when ovarian teratomas contains enough thyroid tissue);

7) molar poregnancy, choriocarcinoma and hypermensis gravidarum (produce high levels of serum chorionic gonadotropin, a weak thyroid stimulator, transient condition).

Grave’s disease (toxic diffuse goiter)

Definition

It is thyroid disease, which is characterized by hyperthyroidism and diffuse enlargement of the thyroid gland.

Etiology

Autoimmune disorders

Predisposing factors

· insolation;

· acute infections;

· hormone disbalance (pregnancy and others).

Pathogenesis.

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

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.

Psychiatric symptoms

· nervousness;

· physical hyperactivity;

· emotional lability;

· logorrhea;

· 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:

· rare winking (Schtelvag’s symptom);

· stare (Crause’s symptom);

· impairment of convergence of eyeballs (Moebius’s symptom)

· lid retraction (symptoms of Dalrympl (palpebral fissures are widely opened with expression of surprise); Greffe (retraction of upper lid, owing to what during the movement of an eyeball downwards between upper lid and the iris appears a white strip of sclera);

Koher (the same but during the movement of an eyeball upwards),

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 (Graves’ orbitopathy) 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.

Typical ophthalmopathy in the presence of normal thyroid function is called euthyroid Graves’ disease.

Endocrine system

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 (WHO, 1994).

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

I – goiter is palpable but not visible;

II – thyroid gland is palpable and visible

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.

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.

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

There are three degrees of severity of thyrotoxicosis (table 1).

Table 1. Degrees of thyrotoxicosis severity

Diagnostic criteria	Degree of severity
Diagnostic criteria	mild	*moderate*	severe
work capacity	normal	decreased	can¢t work
heart beat	under 100/min	100 to 120/min	over 120/min
weight loss	less than 10 %	10 to 20 %.	more than 20%
Changes from another organs	absent	not prominent	atrial fibrillation, endocrine ophthalmopathy

Diagnosis of toxic diffuse goiter

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.

I. Clinical manifestations (is written above).

II. Laboratory findings.

1. In most patients serum total and free T₄ and/or T₃concentrations, are increased (however, these changes, also can be caused by increased thyroxine – binding globulin production, e.g. as a result of estrogen therapy).

2. TSH is decreased.

3. 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-T₃is bound to TBG, resulting in more uptake of ¹³¹I-T₃by the resin.

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

Serum 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.

III. Instrumenal findings.

1. Ultrasonography of thyroid gland: thyroid gland diffusely enlarged, parenchyma is hypoechogenic, structure is homogeneous, boundary is clear, bloodstream in gland is increased.

2. X-ray of thyroid (to establish retrosternal replacement of gland, to determine an esophagous and a trachea compression)

3. CT (detailed information about arrangement of an organ, its correlation with other organs, suspicion of cancer and its metastasis)

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.

Treatment of Grave’s disease

I. Medicamental:

1. Antithyroid drugs.

2. Drugs to ameliorate thyroid hormone effects .

II. ¹³¹I– 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 of PTU is 100 to 150 mg orally g 8h and for MML 30 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 (titration regimen). 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.

Recent meta-analysis concluded that with respect to reaching euthyroidism a block-and-replace (high-dose antithyroid) regimen is as effective as a titration (low-dose antithyroid) regimen. In this case MML starting dose 30 mg once daily. Free thyroxine have to be checked after 4-6 weeks, if iormal range L-thyroxine full replacement dose have to be added. The dose of L-thyroxine will be depended on the basis of thyroid function test results made every 6 – 8 weeks or each 3 months (stable function). Duration of the Graves’ disease treatment is nearly 12 – 18 months.

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

Adverse effects include:

· allergic reactions;

· nausea;

· loss of weight;

· fever;

· arthritis, hepatitis;

· anemia, thrombocytopenia;

· agranulocytosis (in < 1% of patients).

If the patient allergic to one agent, it is acceptable to go to other, but there is a chance of cross sensitivity.

In a case of sore throat in combination with fever the use of antithyroid drugs should be postponed until agranulocytosis is excluded. In case of agranulocytosis, it is unacceptable to go to another agent, and more definitive therapy should be invoked, such as radioactive iodine or surgery.

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

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

3. 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 0,5 gr 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).

II. Radioactive iodine (¹³¹I)

A relapse of Graves’ disease after previous medical or surgical treatment, severe visceropathic forms of diffuse toxic goiter (when there is a high risk of surgical interventions) – should preferably treated with radioactive iodine.

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

Contraindications for radioactive iodine treatment include retrosternal goiter or nodular forms of goiter, pregnancy, breast-feeding, disease of blood, kidney, gastrointestinal tract organs.

In elderly patients and in those with a cardiovascular history it is advised to pretreat with antithyroid drugs until euthyroidism is achieved before treatment with radioactive iodine. MML should be stopped 3 to 5 days and PTU at least 15 days prior to radioactive iodine treatment.

After treatment with radioactive iodine antithyroid drugs should not be restarte within 4 days after treatment. In order to prevent a worsening of the symptoms – due to destruction of thyroid tissue – antithyroid treatment should be continued until at least three months after radioactive iodine treatment. Beta blockers are also prescribed (they prevent from thyrotoxic crises) during 2 – 3 weeks.

Adverse effects

The risk of permanent hypothyroidism depends on the administered radioiodine dose. In about 10 % of patients the hypothyroidism that ensues after treatment with radioactive iodine is transient; therefore, it is advised that this is stopped six monthes after starting thyroxine supplementation for determination of TSH.

In a case hypothyroidism patient will need replacement therapy.

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) or severe mechanical complaints;

– in some patients with toxic adenoma, multinodular goiter or malignancy is suspected;

– hyperthyroidism during pregnancy;

– recurrent hyperthyroidism after course of antithyroid treatment.

Precautions:

– patient must be euthyroid before operation (usual antithyroid treatment have to be prescribed).

Preoperative treatment

· standard: usual antihyroid terapy until euthyroidism is restored

· in patients allergic to antithyroid drugs:

= β – blockers until heart rate during exercise <80/min: propranolol 80 – 240 mg daily

= Iodide: start 10 – 14 days preoperatively: KI 50 – 250 mg thrice daily (1-5 drops solution iodi spirituosa) or solution iodo aquosa (Lugol’s solution) 0,1-0,3 ml thrice daily (3-5 drops).

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;

· damage to the laryngeal recurrent nerve;

· hypoparathyroidism.

Iodine is used in preparing the patient for surgery KI 50 – 250 mg daily (1 – 5 drops solution iodi spirtuosa). Surgical procedures are more difficult in patients who previously have undergone thyroidectomy or radioiodine therapy.

Treatment endocrine ophthalmopathy include:

· achievement of euthyroidism

· steroid therapy: prednisolone 20 – 40 mg daily (and to prevent of development of endocrine ophthalmopathy after radioactive iodine treatment);

· 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;

· retrobulbar radiotherapy (mild cases).

Hypothyroidism

(myxedema)

Definition

It is the condition resulting from a lack of the effects of thyroid hormones on body tissues. 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.

Epidemiology

Hypothyroidism is a common condition. Congenital hypothyroidism is diagnosed in 1 of every 4000 newborns by screening methods, in adults over 50 the frequency is approximately 2 – 4%, 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. The overall frequency in the population is approximately 0,5 – 1,0 %.

Hypothyroidism occurs in 3 to 6 for the adult population,

Classification

I. 1. Congetial.

2. Acquired:

II. The level of damaging:

1. Primary (thyroid gland disturbances).

Primary hypothyroidism in ioddeficiency area

2. Secondary (due to pituitary disease with deficient secretion of TSH).

3. Tertiary (due to hypothalamic disease with lack of secretion of TRH).

4. Peripheral.

III. 1. Laboratory (subclinical) hypothyroidism.

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

IV. Stages of compensation:

1. Compensation.

2. Subcompensation.

3. Decomposition.

V. 1. Without complications.

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

Etiology

A cause is usually evident from the history and physical examination (table 1).

Table 1. Etiology of hypothyroidism

Type of

hypothyroidism

Etiology

Congenital

· Maldevelopment –hypoplasia or aplasia of thyroid gland or hypopituitarism;

· Inborn deficiencies of biosynthesis or action of thyroid hormone;

· Atypical localization of thyroid gland

Acquired

Primary (thyroidal)

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

· 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);

· during or after therapy with propylthyouracil, methimazole, iodides or beta-blockers;

· 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);

· trauma;

· iodine deficiency (worldwide, iodine deficiency is the most prevalent cause of hypothyroidism).

Secondary and tertiary

· Tumor;

· Infarction;

· Infiltrative process;

· Trauma;

· Drugs (reserpin, parlodel).

Peripheral

· peripheral tissue resistance to thyroid hormones;

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

· production of antibodies to thyroid hormones.

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 edema of the hands, feet and periorbital regions (myxedema). Pitting edema 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.

Cardiovascular system

There may be bradycardia, reduced cardiac output, quiet heart sounds, a flabby myocardium, pericardial effusion, cardiac wall is thick, it is increased by interstitial edema. (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.

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

Reduced excretion of a water load may be associated with hyponatriemia. Renal blood flow and glomerular filtration rate are reduced, but serum creatinine is normal. May be mild proteinuria and infections of urinary tract.

Respiratory system

Dyspnea of effort is common. 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 plural 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 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. It is an asymptomatic state in which serum T₄ and free T₄ are normal, but serum TSH is elevated. 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.

The risk of development of overt hypothyroidism is positively associated with TSH and the presence of TPO antibodies. If TSH <6,0 mU/l the cumulative rask for development of overt hypothyroidism is close to sero, if TSH is between 6 and 12 mU/l this is 42,8% and with TSH >12 mU/l the cumulative incidence of overt hypothyroidism is 76,9%.

Diagnostic of hypothyroidism is based on:

I. History of the disease

II. Clinical features;

III. Laboratory findings:

1. blood analysis: anemia; hypercholesterolemia;

2. levels of thyroid hormone:

· subclinical hypothyroidism: increased TSH level, normal T₄ level, absence of clinical featuers

· clinical primary hypothyroidism: increased TSH level and both serum free T₄ and T₃ are decreased (but in 25% of patients with primary hypothyroidism may be normal circulating levels of T3);

· secondary hypothyroidism: decreased or normal TSH level, free T₄ is decreased

· If the diagnosis of primary or secondary hyperthyroidism remains unclear after these initial tests, TRH test can be recommended.

Serum TSH is determined before and after an i/v injection of 500 mkg of synthetic TRH. In a case of primary hypothyroidism, there is rise in TSH more than 25 mkU/ml, in a case of secondary one TSH will on the same level.

3. The levels of yroid autoantibodies (thyroid peroxidase or microsomal fracion) will increased in a case of autoimmune thyroiditis.

IV. Instrumental investigations:

1. ECG.

2. Examination of tendon reflexes.

3. Ultrasonic examination of thyroid gland.

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. Diet №10.

2. Regimen is not restricted.

3. Pharmacological treatment:

Treatment is substituting the deficient hormone.

1) replacement therapy:

– 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.

– Dose is depend on underlying course and weight. The dosage can be 1.8 µg/kg of ideal weight for autoimmune hypothyroidism and about 2 µg/kg after total thyroidectomy. However, interindividual variance is large.

– In young and healthy person full-dose can be given at once. In the elderly and those with cardiovascular morbidity it is advise to start more slowly (12.5-25 µg with dose adjustment based on TSH every four to six weeks)

– The dosage can be increased in 25-50 µg/day 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.

– The average maintenance dosage is 100 to 150 µg/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 (not fT₄) levels to normal (though this criterion cannot be used in patients with secondary hypothyroidism).

– TSH has to be checked once a year in stable patients.

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

– Several drugs such as iron, antacids, calcium carbonate, aluminium hydroxide, biliary salts, sucralfate interfere with thyroxine uptake. It is advise to take these medications two or four hours apart from thyroxine. Phenytoin, carbamazepine, fenobarbital and rifampicin lead to an increased clereance of thyroxine, thus the need for thyroxine increases.

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 µg/day) results in rapidly increasing serum T₃ levels to between 300 and 1000 µg 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) in the dose of 20 – 40 – 60 mg/day;

– hypolypidemic agents;

– vitamins (A, B, E);

– diuretics and others.

Patients before and after treatment

Subclinical hypothyroidism

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.

Myxedema coma

Definition

It is a life-threatening complication of hypothyroidism, which is extremely rare in warm climates but not uncommon in cold areas.

Predisposing factors

· exposure to cold;

· acute infection;

· trauma;

· myocardial infarction;

· sedatives.

Diagnostic criteria

Myxedema coma characteristics include a background of long-standing hypothyroidism with

сlinical signs of extreme hypothermia (temperatures 24 to 32⁰C), areflexia, seizures, CO₂ retention, and respiratory depression caused by decreased cerebral blood flow. Severe hypothermia may be missed unless special low reading thermometers are used. Rapid diagnosis (based on clinical judgement, history, and physical examination) is imperative because early death is likely.

Laboratory investigations show hyponatraemia, anaemia, hypoglycemia, hypercholesterolemia, elevated LDH and creatinine kinase. If secondary hypothyroidism is suspected, hydrocortisone should also be taken. However, to establish the diagnosis determination of TSH and free T4 are essential; in this respect it is important to be aware that TSH levels can be only slightly elevated as a result of nonthyroidal illness.

Treatment of myxedema coma

Treatment should take place in an intensive care unit. Thyroid hormone substitution should not be delayed until results of thyroid function tests are known.

It is treated with large doses of T₄ (200-250 µg I/v followed by 100 µg after 24 hours and thereafter 50 µg daily (preferably oral otherwise intravenously) or T₃ if available (10 µg I/v bolus 3 times a day until normalization of vital function), because TBG must be saturated before any free hormone is available for response. The maintenance dose for T4 is 50 µg day I/v and for T3 10 20 mkg/day I/v until the hormone can be given orally.

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.

Thyroiditis

The various types of thyroiditis encompass a heterogeneous group of inflammatory disorders of diverse etiologies and clinical features. Thyroid inflammation can be caused by physical stimuli, micro-organisms and autoimmunity. With all forms of thyroiditis, destruction of the normal architecture of the thyroid follicular occurs, yet each disorder has distinctive histological characteristics. For the purposes of understanding the clinical manifestations, thyroiditis are classified according to either the severity or duration of illness using the following scheme:

1. Acute thyroiditis.

2. Subacute thyroiditis:

– subacute granulamatous thyroiditis;

– subacute lymphocytes thyroiditis.

3. Chronic thyroiditis:

– Hashimoto thyroiditis;

– Ridel struma.

4. Specific thyroiditis.

5. Thyroiditis caused by mechanical or physical factors.

Acute thyroiditis

Definition

It is an acute inflammation of thyroid gland caused by bacterial infection.

Etiology

The most common of a bacterial pathogens are staphylococcus aureus, streptococcus hemolytic, streptococcus pneumonia, anaerobic streptococcal organisms. Infection due to other bacterial pathogens, such as salmonella and Escherichia coli have been reported, as well as fungal infections such as coccidiodomycosis. Infection occurs either secondary to hematogenous or lymphatic spread, or as a result of direct introduction of an infective agent by trauma. Persistent thyroglossal duct abnormalities have also been associated with acute thyroiditis.

Clinical features

Fever, chills and other systemic signs or symptoms of abscess formation are present. Anterior neck pain and swelling are usual, with pain occasionally radiating to the ear or mandible.

The physical examination suggests the presence of an abscess, with erythema of the skin, marked tenderness to palpation, and at times fluctuance.

Laboratory tests

Leucocytosis with a left shift, increased ESR are usually present. Thyroid hormone concentrations in blood are normal, although hyperthyroxinemia has been reported.

Treatment

Patient should be treated at surgical department.

· Parental antibiotics should be administered according to the specific pathogen identified.

· Nonsteroid anti-inflammatory drugs can be prescribed for a few days.

· Symptomatic therapy (β-blockers) have to be prescribed in a case of transient thyrotoxicosis.

· If fluctuance is present, incision and drainage might be required. Bacterial thyroiditis must be treated early and aggressively, since abscess formation can occasionally dissect downward into the mediastinum. Recurrences of the disorder are very rare.

Duration of the treatment must be nearly 1,5-2 month.

Folow-up – recovery.

Rare complications

· purulent mediastinitis

· sepsis

· neck thrombophlebitis

Subacute thyroiditis

Subacute granulomatous thyroiditis (Quervain’s thyroiditis, giant cell thyroiditis, SAT).

Definition

It is an acute inflammatory disease of the thyroid probably caused by a virus.

SAT has an incidence that is one-fifth to one-eight of the Graves’ disease and is more common in momen.

Etiology

SAT is most likely caused by virus or post-viral inflammation. The specific agent responsible for the disorders is not known, although coxsackie virus, adenovirus and the mumps, echovirus, influenza and Epstein-Barr viruses have been implicated in the etiology.

A genetic predisposition is likely because of the association of HLA-BW 35 histocompatibility antigens.

Clinical features

Syndrome of local changes

The most common symptom is unilateral anterior neck pain, often associated with unilateral radiation of pain to the ear or mandible. Pain is often proceeded by a few weeks prodrome of myalgias, low-grade fever, malaise and sore throat. Dysphagia is also common, pain can migrate to the contralateral side.

Physical examination discloses an exquisitely tender, very hard, nodular enlargement, which is most often unilateral. Tenderness is often so extreme that palpation is limited. Bilateral tenderness and goiter can occur as well. Tachycardia, a widened pulse pressure, warm skin and diaphoresis are also observed when hyperthyroidism is present.

Syndrome of dysfunction of thyroid gland

SAT duration includes four phases: hyperthyroid (symptoms of hyperthyroidism such as tachycardia, weight loss, nervousness, and diaphoresis occur in up to 50% of patients), euthyroid, hypothyroid, recovery.

Laboratory findings

Syndrome of inflammation

Early in the disease we can find an increase in T₄, a decrease in RAI uptake (often 0), leucocytosis and a high ESR. After a several weeks, the T4, is decreased and the RAI uptake remains low. Full recovery is the rule; rarely, patients may become hypothyroid.

Treatment

An acute phase lasts from 4-8 weeks, during which treatment is symptomatic (aspirin 600 mg q 3-4 h, prednisolone 10-20 mg orally tid; after 1 week prednisolone can be tapered by 5 mg every 2-3 days; thus glucocorticoids are usually not required for longer than several weeks. Symptoms of hyperthyroidism are effectively controlled by the use of beta-blockers).

Following the acute phase euthyroidism is restored, and the thyroid becomes depleted of stored hormone. Patients can either remain euthyroid or progress to hypothyroid phase. It rarely lasts longer than 2-3 months, and during this phase thyroid hormone replacement in the form of levothyroxine 0,10-0,15 mg/day should be given. After several months of treatment T4 can be discontinued.

Following the hypothyroid phase recovery occurs, and the normal histologic features and secretory capacity of the thyroid are restored.

Subacute lymphocytic thyroiditis

(silent thyroiditis)

A subacute disorder occurring most commonly in women , often in the postpartum period, characterized by a variable, but mild degree of thyroid enlargement, absence of thyroid tenderness, and self-limited hyperthyroid phase of several weeks to several months, often followed by transient hypothyroidism but with eventual recovery to the euthyroid state.

Etiology

Recent evidence suggests on:

1) autoimmune component (because of autoantibodies observed);

2) genetic predisposition (this is a significant prevalence of HLA-DRW3 and HLA-DRW5 histocompatibility agents);

3) viral etiology (viral antibody titers are rarely elevated);

Clinical features

Hyperthyroid symptoms are frequent and vary from mild to normal. (Postpartum thyroiditis occur 6 weeks to 3 months after delivery).

Physical examination usually discloses a mildly enlarged, diffuse, firm, nontender goiter it has been reported that up to 50 % of patients do not have goiter.

Laboratory findings

Serum total and free T₄ and T₃ are elevated. Biopsies reveal lymphocytic infiltration as seen in Hashimotos thyroiditis.

Thyroid autoantibodies are positive in greater than 50 % of patients.

Treatment

Hyperthyroid phase lasts from 6 weeks to 3 month. Treatment is conservative, usually requiring only B-adrenergic blockers with propranolol.

Euthyroid interval lasts for 3-6 weeks.

During hypothyroid period (it usually lasts no longer than 2-3 months thyroid hormone supplementation with T4 0,10-0,15 mg/day may be required. Following the hypothyroid phase patients usually remain clinically euthyroid.)

Chronic thyroiditis

Hashimoto thyroiditis (chronic lymphocytic thyroiditis) HT

Etiology

HT is an organ – specific autoimmune disorder, a chronic inflammation of the thyroid with lymphocytic infiltration of the gland generally though to be caused by autoimmune factors.

Epidemiology

It is mire prevalent (8:1) in woman than men and is most frequent between the ages of 30 and 50. A family history of thyroid disorders is common, and incidence is increased in patients with chromosomal disorders, including Turners, Down and Klinefelters syndromes. Histological studies reveal extensive infiltration of lymphocytes in the thyroid.

The basic defect underlying this disease suggests an abnormality in suppressor T lymphocytes that allows helper T lymphocytes to interact with specific antigens directed against the thyroid cell. A genetic predisposition is suggested because of the frequent occurrence of the HLA- DR5 histocompatibility antigen in patients with HT.

Clinical features

HT is characterized by a wide spectrum of clinical features, ranging from no symptoms and the presence of small goiter to frank myxedema.

Occasionally patients complain of a vague sensation of tightness in the area of the anterior neck or mild dysphagia. In general, however, thyroid enlargement is insidious and asymptomatic. Symptoms of hypothyroidism may or may not be present, depending on the presence or absence of biochemical hypothyroidism.

Physical examination usually discloses a symmetrically enlarged, very firm goiter, a smooth or knobby consistency is common. Occasionally patients present with a single thyroid nodule.

A small group of patients have a form of HT termed primary idiopathic hypothyroidism, goiter is usually absent in this group.(atrophic form of HT).

Yet a small subset of patients(probably 2-4%) present with hyperthyroidism and have so-called hashitoxicosis (hypertrophy from of HT).

Laboratory findings

early in the disease a normal T₄ and high titers of antithyroid (antimicrosomal) antibodies can be detected. Late in the disease, the patient develops hypothyroidism with a decreased in T₄ and antibodies in this stage are usually no longer detectable/

Instrumental investigations

1) the thyroid scan typically shows a irregular pattern of iodine uptake;

2) fine-needle biopsy of the nodule or enlarging area should be done to rule out a coexistent neoplasm.

Treatment

1) treatment of HT requires lifelong replacement with thyroid hormone to correct and prevent hypothyroidism. The average oral replacement dose with l-thyroxine is 100 to 150 mkg/day;

2) symptomatic therapy

Ridel thyroiditis

Etiology

This extremely rare inflammatory disorder is of uncertain etiology, and earlier suggestions that it might be a fibroid variant of HT have not been substained.

Clinical features

Clinically, Ridel thyroiditis presents with pressure symptoms, and on examination an extremely hard , immobile thyroid gland is palpated The thyroid can be uniformly enlarged, or only one lobe might be affected. The disorder can be associated with other focal sclerosing symptoms, including retroperitoneal and mediastenal fibrosis and ascending cholecystitis.

Laboratory findings

1. Thyroid function tests show hypothyroidism in approximately 25 % of patients.

2. Thyroid antibodies are usually negative.

3. The thyroid scan shows decreased uptake in involved areas.

Treatment

– is surgical for those patients in whom symptoms of obstruction occur.

– Thyroid hormone is required for treatment of hypothyroidism, but thyroid hormone alone will not result in goiter shrinkage.

ADRENAL GLANDS

Historical perspectives

• 1563: Eustachius first described adrenal glands

• 1855: Thomas Addisooted real importance of adrenal glands

• 1856: Brown Sequard demonstrated that adrenals are very necessary for life (without adrenal glands animals could not survive)

Schematic showing the cellular zonation of the adrenal cortex and blood flow through the cortex to the collecting veins in the medulla

ADRENOCORTICAL INSUFFICIENCY.

It is an insidious and usually progressive disease resulting from adrenocortical hypofunction.

Classification.

A. 1. Acute

2. Chronic

B. 1. Primary adrenocortical insufficiency (Addison’s disease).

2. Secondary adrenocortical insufficiency .

Primary adrenal insufficiency occurs when the adrenal gland itself is dysfunctional. Secondary adrenal insufficiency, also termed central adrenal insufficiency, occurs when lack of corticotropin-releasing hormone (CRH) secretion from the hypothalamus or adrenocorticotropic hormone (ACTH) secretion from the pituitary is responsible for hypofunction of the adrenal cortex. Adrenal insufficiency can be classified further as congenital or acquired.

Etiology of

primary adrenocortical insufficiency:

1. In developed countries, the most common cause is autoimmune destruction (50 – 65 %) of the adrenal cortex. This disorder may exist in isolation or may be part of a polyglandular autoimmune disorder

– Type 1 autoimmune polyglandular disease presents in the first decade of life and is transmitted as an autosomal recessive disorder with all or some of the following:

o Adrenal failure

o Hypoparathyroidism

o Hypothyroidism

o Gonadal failure

o Diabetes mellitus type 1

o Vitiligo

Vitiligo.

o Alopecia

o Pernicious anemia

o Chronic mucocutaneous candidiasis

– Type 2 autoimmune polyglandular disease consists of type 1 diabetes mellitus, autoimmune thyroid disease, and adrenal failure. This condition presents in the second and third decades of life and is transmitted as an autosomal disorder with variable penetrance.

2. Less common causes of adrenal failure include the following:

1) Tuberculosis;

2) neoplasm, metastatic carcinoma;

3) inflammatory necrosis;

4) amyloidosis;

5) bilateral adrenal hemorrhage or infarction, intra – adrenal hemorrhage (Waterhouse – Friedrichsen syndrome following meningococcal septicemia);

6) heamochromatosis (may cause either primary or secondary adrenal insufficiency. Iron deposition in the pituitary and/or adrenal glands in multiply transfused patients with thalassemia patients also may cause adrenal insufficiency);

7) bilateral adrenalectomy;

3. Congenital primary adrenal insufficiency

o Congenital disease may occur from adrenal hypoplasia or hyperplasia.

o Adrenal hypoplasia congenita (AHC), inherited as an X-linked disorder, is caused by deletion of the DAX1 gene on chromosome X and often is part of a contiguous gene deletion that involves glycerol kinase deficiency, Duchenne muscular dystrophy, and hypogonadotropic hypogonadism. An alternate form, also X-linked, has been described characterized by intrauterine growth retardation and skeletal and genital anomalies. A third form of AHC is autosomal recessive.

o CAH results from a deficiency of 1 of several enzymes required for adrenal synthesis of cortisol. Adrenal insufficiency most often develops with combined deficiencies of cortisol and aldosterone. The most prevalent form of CAH is caused by a steroid 21-hydroxylase deficiency.

o Lipoid adrenal hyperplasia is another rare form of adrenal insufficiency caused either by a mutation in the steroid acute regulatory protein or a mutation in the cholesterol side chain cleavage gen. This disease causes a defective synthesis of all adrenocortical hormones and, in its complete form, is lethal.

o Mutations or deletions of P450 oxidoreductase, a flavoprotein that provides electrons to various enzyme systems, results in combined deficiencies of 17 hydroxylase, 21 hydroxylase, and 17-20 lyase activities resulting in adrenal insufficiency often accompanied by primary hypogonadism.

Etiology of

secondary adrenocortical insufficiency:

1) Most cases are iatrogenic, caused by long-term administration of glucocorticoids. A mere 2 weeks’ exposure to pharmacological doses of glucocorticoids can cause CRH-ACTH-adrenal axis suppression. Suppression can be so great that acute withdrawal or stress may prevent the axis from responding with sufficient cortisol production to prevent an acute adrenal crisis. Recently, treatment with megesterol acetate, an orixegenic agent, has resulted in iatrogenic adrenal suppression, presumably through glucocorticoid properties of megesterol acetate.

2) hypothalamic or pituitary disease (primary injury of these organs leads to insufficiency of ACTH secretion that cause the two – side atrophy of adrenal glands).

Pathogenesis.

Cortisol deficiency contributes to the hypotension and produces in carbohydrate, fat, and protein metabolism, and severe insulin sensitivity. In the absence of cortisol, insufficient carbohydrate is formed from protein; hypoglycemia and diminished liver glycogen result. Weakness, due in part to deficient neuromuscular function follows. Resistance to infection, trauma, and other stress is diminished because of reduced adrenal output. Cardiac output is reduced and circulatory failure can occur. Reduced cortisol blood levels result in increased pituitary ACTH production and an increase in beta – lipotropin, which has melanocyte – stimulating activity and produces the hyperpigmentation of skin and mucous membranes characteristic of Addison’s disease.

There is increased excretion of Na and decreased excretion of K chiefly in the urine, but also in the sweat, saliva, and gastrointestinal tract. Low blood concentrations of Na and Cl and high serum K result. These changes in electrolyte balance produce increased water excretion with severe dehydration, increased plasma concentration, decreased circulatory volume, hypotension, and circulatory collapse.

Symptoms and signs.

Presentation may be acute and chronic. Frequently clinical signs of the primary chronic adrenocortical insufficiency are manifested in that time when adrenocortical tissue is destroyed on 70-90 %.

The most common complaints are: weakness, malaise, weight loss, anorexia, depression.

Objective examination:

1. Increased pigmentation (in patients with primary adrenal insufficiency) is characterized by diffuse tanning of both exposed and nonexposed portions of the body, especially on pressure points (bony prominences), skin folds, scars, and extensor surfaces, black freckles over the forehead, face, neck, and shoulders; bluish – black discoloration of the areolas and the mucous membranes of the lips, mouth, rectum and vagina are common. After compensation hyperpigmentation will decrease. Patients in 15 – 20 % of cases may have areas of vitiligo (depigmentation) as the sign of autoimmune process.

Hyperpigmentation

2. Hypotension or postural hypotension (88 – 90 %) with syncopal attacks can occur.

3. Tachycardia.

4. Weight loss (due to dyspeptic syndrome, true muscle tissue catabolism, dehydration).

5. Anorexia, nausea, vomiting, abdominal pain, diarrhea are often. Gastritis, ulcer disease can occur.

6. Decreased cold tolerance, with hypometabolism may be noted.

7. Sexual disorders.

8. Neurologic and psychiatric disorders: decreasing of the memory, mental activity, concentration of attention, depressions, hallucinations can occur due to chronic hypoglycemia which leads to changes of metabolism in brain tissue.

9. Hypoglycemia.

There are three stages of severity: mild, moderate and severe.

Laboratory findings.

Clinical suspicion is important because presentation of the disorder may be insidious and subtle. When adrenal insufficiency is suspected, the following laboratory studies help establish the diagnosis:

Electrolytes
Fasting blood sugar
Serum ACTH
Plasma renin activity
Serum cortisol
Serum aldosterone

1. A low serum Na level and a high serum P level together with a characteristic clinical picture suggest the possibility of Addison’s disease.

2. Adrenal insufficiency can be specifically diagnosed by:

– low levels of plasma glucocorticoids and mineralocorticoids, or urinary 17 – hydroxycorticosteroid (17 – OHCS) or 17 – ketogenic steroid (17 – KGS);

– demonstrating failure to increase plasma cortisol levels, or urinary 17 – OHCS or 17 – KGS excretion, upon administration of ACTH (in patients with primary adrenal insufficiency).

3. To distinguish between primary and secondary adrenal insufficiency, me have to find the level of plasma ACTH: primary shows increased, and secondary shows decreased level: when plasma ACTH determination is not available, 0.25 mg of cosyntropin or depo-senacten(a synthetic ACTH that has fewer side effects than the natural preparations) may be infused IV (after dilution with dextrose or sodium chloride solution) over a period of 8 h daily for 2 days. Patients with primary adrenocortical insufficiency will show a little or no increase in plasma cortisol or 24 – h urinary corticosteroid levels. Those with secondary adrenocortical insufficiency will have a significant increase in plasma cortisol or 24 – h urinary corticosteroid levels.

So, when hyponatremia or hyperkalemia is found, conduct a spot urine or 24-hour urine test for sodium, potassium, and creatinine, along with a simultaneous serum creatinine test to determine whether inappropriate natriuresis is occurring.

o Interpret random serum cortisol concentrations within the context from which they were obtained. (For example, adrenal insufficiency is unlikely in an otherwise healthy individual with an 8:00 am serum cortisol concentration more than 10 mcg/dL. Yet a serum cortisol concentration less than 18 mcg/dL in a sick and stressed patient highly suggests adrenal insufficiency.)

o A diagnosis of adrenal insufficiency is confirmed by a serum cortisol concentration less than 18 mcg/dL in the presence of an elevated serum ACTH concentration and plasma renin activity, or a concentration lower than that level obtained 60 minutes following cosyntropin administration.

o Diagnosis also is confirmed when serum cortisol concentrations fail to increase to more than 18-20 mcg/dL by 60 minutes following cosyntropin administration.

o Note that these guidelines do not apply to premature and low birth weight infants, who have much lower cortisol secretion.

If serum cortisol is low with elevated ACTH, measure antiadrenal antibodies. Antibodies to 1 or more steroidogenic enzymes, particularly 21-hydroxylase, often are found in autoimmune adrenal disease.

Cosyntropin administration is controversial because whether the best dose is the standard 250 mcg, the 1 mcg, or the low 0.5 mcg/m² is unresolved, particularly in the pediatric age group. The standard dose, therefore, is suggested. The common preparation of cosyntropin makes it cumbersome to deliver 1 mcg or less, and both doses seem supraphysiological.

When serum cortisol response to cosyntropin is subnormal, but serum ACTH is not elevated, confirm the possibility of central adrenal insufficiency. In this context, a 6-hour or 3-day treatment with ACTH can produce a normal cortisol response, confirming that initial low cortisol response to cosyntropin was related to chronic ACTH deficiency. The dose of ACTH for the 6-hour test is 25 IU administered IV over the 6 hours. If the 3-day test is chosen, administer 25 mg/m² of ACTH gel IM every 12 hours for the 3 days. Plasma cortisol should increase to more than 40 mcg/dL in response to either of these tests. Alternatively, 24-hour urinary 17-hydroxysteroid concentrations should increase 5-10 fold in response to the 3-day ACTH stimulation test.

If the patient has recent onset (ie, <10 d) of central adrenal insufficiency (as in a recent surgery in the hypothalamus or pituitary regions), resorting to a more cumbersome and risk-bearing insulin tolerance test or metyrapone stimulation test may be preferable. These conditions are the only real indication for performing these tests in a patient with adrenal insufficiency

An insulin tolerance test requires IV administration of insulin (usually 0.05-0.15 units regular insulin/kg) to induce a 50% drop in blood sugar. Measure cortisol and glucose concentrations every 15 minutes for 60 minutes. The test is considered adequate if the blood sugar drops by at least 50%. In response to this hypoglycemic stimulus, serum or plasma cortisol concentrations should rise to more than 20 mcg/dL. This test involves some risk of hypoglycemic seizure; therefore, closely monitor the patient and reverse the hypoglycemia if the patient becomes overly symptomatic.

Standard metyrapone stimulation tests involve administering 300 mg/m² metyrapone in 6 divided doses over 24 hours. Because metyrapone inhibits 11-hydroxylase, the last enzyme step in cortisol synthesis, the cortisol precursor 11-deoxycortisol increases in the plasma. A normal response is a rise in 11-deoxycortisol concentrations to more than 10.5 mcg/dL 4 hours following the last dose of metyrapone or a 2- to 3-fold increase in 24-hour urinary 17-hydroxycorticosteroid concentrations (which include tetrahydro compound S [urinary metabolite of 11-deoxycortisol]), on the day or day following metyrapone administration. This test is cumbersome and carries some risk of inducing an adrenal crisis.

When primary adrenal insufficiency is confirmed, antiadrenal antibodies can confirm an autoimmune cause for the disorder. If the test results for antiadrenal antibodies are negative, search for another etiology such as TB, adrenal hemorrhage, or adrenoleukodystrophy.

The standard ovine or human CRH stimulation test is reliable in the diagnosis and differential diagnosis of adrenal insufficiency.

Patients with glucocorticoid deficiency of any etiology have subnormal cortisol responses.

Patients with primary glucocorticoid deficiency have elevated ACTH concentrations basally and after CRH administration.

Patients with secondary glucocorticoid deficiency have low ACTH levels throughout the test if they suffer from a primary pituitary deficiency, or these patients have exaggerated responses if their problem is tertiary.

Imaging Studies:

1. The ECG may decreased voltage and prolonged P – R and Q – T intervals.

2. The EEG shows alized slowing of the α – rhythm.

3. CT is the imaging study of choice and helps identify adrenal hemorrhage, calcifications, or infiltrative disease. MRI is not as useful as CT.

4. Abdominal radiographs may reveal bilateral adrenal calcifications, which suggest a history of bilateral adrenal hemorrhage, TB, or Wolman disease.

5. Ultrasonography is a poor imaging modality for investigation of the adrenal glands.

6. Iodocholesterol scanning is not particularly useful.

Procedures:

CT-guided fine-needle aspiration sometimes helps diagnose the etiology of infiltrative adrenal diseases.

Histologic Findings:

Findings depend on the underlying cause. In cases of autoimmune adrenal failure, the adrenal gland is destroyed by lymphocytic infiltration. Granulomatous changes within the adrenal glands indicate tuberculous adrenal insufficiency. Neoplastic infiltrations are caused by metastatic tumors. Hemorrhagic adrenal insufficiency shows hemorrhagic destruction of adrenals. Fungal disease produces typical pictures.

Differential diagnosis.

– primary and secondary adrenocortical insufficiency (patients with secondary adrenal insufficiency are not hyperpigmented, they have relatively normal electrolyte values; those with panhypopituitarism have depressed thyroid and gonadal function; tests to differentiate primary and secondary adrenal insufficiency were discussed earlier);

Primary and secondary

adrenal insufficiency

– hyperpigmetation due to bronchogenic carcinoma, ingestion of heavy metals such as iron or silver, chronic skin conditions or hemochromatosis; Peutz – Jeghers syndrome (pigmentation of the buccal and rectal mucosa);

– hyperinsulinism;

– neuropsychiatric weakness;

– anorexia nervosa:

Treatment.

I. Etiologic: appropriate treatment of complicating infections (e.g., tuberculosis).

II. Pathogenic:

1. Diet (enough quantity of proteins, vitamins, salt and water).

2. Glucocorticoids (normally, glucocorticoids are secreted maximally in the early morning hours, little being secreted at night).

Average dosage is:

– cortisol: 20 – 25 mg daily;

– prednisolone 5 – 7.5 mg daily;

– hydrocortisone 30 – 40 mg orally daily.

2/3 of the dose can be given in the morning and 1/3 in the afternoon. Night doses should be avoided, as they may produce insomnia.

3. Mineraloocorticoids.

DOCSA 5 mg orally daily should be used in patients with severe and moderate duration or fludrocortisone 0.1 – 0.2 mg orally once a day is recommended (this mineralocorticoid replaces aldosterone, some times it is necessary to reduce the dose to 0.05 mg every 2^nd day on initial institution of therapy because of ankle edema, but the patient usually adjusts and can then take the larger doses)

4. Intercurrent illnesses (e.g., infections) should be regarded as potentially serious and the patient should double his dosage until he is well.

5. If nausea or vomiting preclude oral therapy, medical attention should be sought immediately and parental therapy started.

Adrenal tumors

Adrenal tumors may be malignant and benign, hormone-active and hormone-inactive. Hormone active adrenal tumors refer to serious endocrine diseases and differ on morphology of their cells and character of hormones secreted by them.

Cushing’s syndrome.

Definition

Cushing’s syndrome is a constellation of signs and symptoms caused by chronic high blood levels of cortisol or related corticosteroids (table 1).

Cushing’s disease is Cushing’s syndrome that results from excess pituitary production of ACTH, usually secondary to pituitary adenoma.

Epidemiology

Age and sex play an important role in the frequency of a given type of Cushing’s syndrome. Although Cushing’s syndrome occurs in both sexes and at all ages, the most typical patient is a female between the ages of 30 and 50. Adrenal carcinoma is the cause in 65 % of patients younger than 15, nonpituitary ACTH secretion predominates in males, and 75 % of patients with pituitary – dependent Cushing’s disease are females.

Table 1. The sources of cortisol excess

The sources of cortisol excess	Type of disease
hyperfunction of agrenal cortex	endogenous Cushing’s syndrome or Cushing’s disease
administration of supraphysiologic doses of a glucocorticoid	exogenous Cushing’s syndrome

Hyperfunction of adrenal cortex can be:

1) ACTH – dependent, caused by:

– increased pituitary ACTH secretion (it has frequently been referred to as Cushing’s disease, implying a particular physiologic abnormality. Patients with Cushing’s disease may have a basophilic adenoma of the pituitary, or a chromophobe adenoma. In some cases, patients have microadenomas, which are difficult to visualize radiographically);

– nonpituitary ACTH secretion by nonendocrine tumors (small cell carcinoma of the lung, prostate, ovaries, pancreas or carcinoid tumor (ectopic ACTH syndrome));

– administration of exogenous ACTH;

2) Non – ACTH – dependent (Cushing’s syndrome):

– caused by cortisol secretion by benign or malignant adrenal adrenal tumors;

– micronodular or macronodular dysplasia of the adrenal (the condition occurs most commonly in children and young adults).

In pituitary-dependent hypercorticism, increased secretion of endogenous ACTH leads to bilateral adrenal hyperplasia and cortisol overproduction. ACTH secretion continues despite high circulating cortisol, indicating an abnormality in the feedback mechanism. A good number of these patients harbor a pituitary microadenoma which secretes ACTH. Despite normal x-rays of the sella, including tomograms, the neurosurgeon often finds and removes the microadenoma through the transsphenoidal route. Pituitary – dependent adrenal hyperplasia accounts for about 60 to 70 percent of endogenous Cushing’s syndrome cases.

A polypeptide that resembles pituitary ACTH in its biologic and immunologic action can be secreted by a great variety of nonendocrine tumors, particularly oat cell carcinoma of the lung, but also by carcinoid bronchial adenomas, and by carcinomas of the prostate, ovaries, and pancreas, as well as others. Nonpituitary ACTH stimulates the adrenals to hypertrophy and to overproduce cortisol. Because the feedback mechanism is intact, pituitary ACTH secretion is suppressed by cortisol.

In patients with adrenal tumors, the excessive production of cortisol suppresses endogenous secretion of ACTH by the pituitary gland. An adrenal tumors is found in 20 percent of the patients.

Exogenous, or iatrogenic, Cushing’s syndrome is caused by administration of supraphysiologic doses of glucocorticoids. Besides cortisol, other synthetic steroids with glucocorticoid activity have the ability to suppress ACTH secretion by the anterior pituitary. Adrenal atrophy and a decrease in cortisol secretion then result. Although the patients exhibits the clinical manifestations of Cushing’s syndrome, adrenal insufficiency may actually occur if the steroid is discontinued abruptly. Because of the widespread use of glucocorticoids, iatrogenic Cushing’s syndrome is the most common type.

Diagnosis

There are two phases of investigation:

– confirmation of the presence or absence of Cushing’s syndrome;

– differential diagnosis of its cause.

Diagnosis is usually suspected based on the history of the disease and characteristic symptoms and signs. Confirmation, and the investigation of the underlying cause, generally requires hormonal and imaging tests.

Clinical manifestations

The signs and symptoms of Cushing’s syndrome or disease represent an exaggeration of cortisol’s physiologic actions.

Obesity is a common manifestation of Cushing’s syndrome. Typically the distribution of fat involves the trunk, particularly the cervicodorsal region (buffalo hump), supraclavicular area, and abdomen. The face is round and plethoric (moonlike face). The extremities are thin in relation to the rest of the body. Moderate obesity is the rule. In patients with massive abdomen obesity, especially when it involves the extremities, the diagnosis of Cushing’s syndrome is extremely unlikely. If the disease was present in those patients, one should expect to find most of the typical physical abnormalities which accompany the states of cortisol overproduction.

The skin of patients with Cushing’s syndrome is thin and fragile, which is another expression of the increase in protein catabolism seen in this disease.

The tendency in situations of minor trauma to develop ecchymoses and hematomas results from a combination of thin skin and capillary fragility.

Skin hyperpigmentation, which is found in about one-third of patients with endogenous Cushing’s syndrome, is an extremely useful sign that suggests the presence of increased circulating ACTH, either pituitary or nonpituitary, and essentially rules out the possibility of an adrenal tumor.

Striae, when present, are usually located on the abdomen, breast, perineum, buttocks, and axillae. Occasionally, they may be found on the back and on the extremities. They are pink or purplish in color and wider than 1 cm.

Acne and hirsutism may be present in females.

Hypertension is found in as many as 90 percent of patients with endogenous Cushing’s syndrome. It is rarely severe and seldom leads to retinopathy or to cardiovascular, renal, or central – nervous – system complications. The exact causes of the hypertension arc unknown, but two explanations are generally accepted: (1) volume expansion, secondary to stimulation of sodium and water retention, and (2) increased sensitivity of the arterioles to circulating catecholamines.

Proximal muscular weakness affecting predominantly the muscles of the pelvic girdle should point in the direction of the correct diagnosis. Patients have difficulty in climbing stairs. A useful maneuver is to ask the patient to perform a deep knee bend. Patients with Cushing’s syndrome are often unable to carry out this task. The myopathy is in great part secondary to loss of muscle mass as a result of increased cortisol-induced protein catabolism. However, the steroid may also have a direct toxic effect on muscle.

Acne, hirsutism, and menstrual irregularities are mostly secondary to the androgen overproduction which sometimes accompanies the state of cortisol excess. Signs of androgenicity are most often seen with adrenal tumors, although they are also prominent in some patients with pituitary-dependent Cushing’s syndrome.

Osteoporosis, usually affecting the spine, is one of the most disabling complications of Cushing’s syndrome. Compression fractures and persistent back pain may be the chief complaint. Cortisol inhibits collagen synthesis, and thus bone-matrix formation, but also stimulates calcium resorption from bone.

Peripheral edema is relatively rare, occurring in only 20 percent of the patients. Its presence suggests the existence of the nonpituitary ACTH secretion syndrome, since this physical finding is seldom observed in patients with Cushing’s syndrome of other etiologies.

A variety of psychiatric manifestations, including anxiety, depression, and even frank psychosis, may be part of the clinical spectrum in patients with Cushing’s syndrome. Not infrequently these patients are first admitted to a psychiatric ward. The pathophysiologic mechanism of these symptoms is poorly understood.

Many of the signs and symptoms described above are present in patients with iatrogenic Cushing’s syndrome, but it is important to emphasize that myopathy, glucose intolerance, and osteoporosis tend to be more prominent in this condition than in endogenous Cushing’s syndrome. Also, cataracts and aseptic necrosis of the femoral head, which are rare in patients with endogenous Cushing’s syndrome, are more common in patients receiving supraphysiologic doses of glucocorticoids. On the other hand, hypertension is much less common in iatrogenic Cushing’s syndrome, and signs of androgenicity or hyperpigmentalion of the skin do not occur. The reason for the absence of hyperpigmcntalion is the fact that glucocorticoids inhibit ACTH secretion, thereby decreasing the concentration of ACTH in blood.

Laboratory examination

Glucose intolerance is present in about one-half of Cushing’s syndrome patients. Despite hyperglycemia, the serum insulin concentration is increased in these patients, indicating the existence of tissue insulin resistance. The abnormalities in glucose tolerance are also, at least in part, secondary to the hypercortisolemia which enhances hepatic gluconeogenesis and inhibits uptake of adipose tissue and muscle glucose. Glucosuria is often seen, but ketoacidosis or the chronic complications of hyperglycemia are very uncommon, probably because the abnormalities in cortisol secretion are corrected before these complications develop.

Perculiaritis of laboratory findings in patients with hypercorticism.

I. Exogenous Cushing’s syndrome should offer no problems in diagnosis since a history of chronic ingestion of supraphysiologic doses of glucocorticoids is usually present. However, occasionally patients deny, either deliberately or because of ignorance, that they have been taking the glucocorticoids. In this case, the diagnosis can easily be made by obtaining a blood sample at 8 AM. for urinary free cortisol (UFC), cortisol and ACTH, all of them are characteristically low. Glucocorticoids suppress ACTH secretion, causing adrenal atrophy and decreased cortisol synthesis. Current radioimmunoassay techniques for measuring cortisol in plasma are very specific and do not detect appreciable quantities of any of the synthetic glucocorticoids (prednisone, prednisolone, dexamethasone, etc.) that the patient may be taking. Cortisol is unlikely to yield a significant plasma level as well since the steroid has a short half-life; it disappears from blood 4 to 8 h after oral administration. If a plasma ACTH assay is not available, a plasma cortisol determination is sufficient.

II. Elevated level UFC is present in all patients with Cushing’s syndrome. Patient with suspected Cushing’s syndrome with grossly elevated UFC (> 4 times the upper limit of normal) almost certainly has Cushing’s syndrome. Two or more normal collections virtually exclude the diagnosis slightly elevated levels generally necessitate further investigation.

III. Tradiotionally, further investigation is accomplished with the dexamethasone suppression test.

1. Single-dose dexamethasone suppression test. This is the preferred procedure for screening patients for Cushing’s syndrome. The patient ingests 1.0 mg of dexamethasone at bedtime (10 to 12 PM.), and a blood sample for plasma cortisol is obtained the following morning at 8 AM. Iormal patients, the steroid suppresses plasma cortisol below 5 mkg/dl. whereas patients with Cushing’s syndrome do not respond and cortisol values of greater than 20 mkg/dl are not unusual. This procedure is simple, convenient, and inexpensive since it does not require hospitalization. It is also very reliable, being accurate in about 95 percent of the patients. A few patients with Cushing’s syndrome will respond to 1.0 mg of dexamethasone by suppression of plasma cortisol. If the clinical suspicion is strong, 0.5 mg of dexamethasone should be given and cortisol determination should again be made. This procedure takes advantage of the fact that while normal subjects suppress equally well with 0.5 and 1.0 mg of dexamethasone, the few patients with Cushing’s syndrome who suppress with 1.0 mg will not suppress with the lower dosage.

(There are a few clinical situations in which failure of dexamethasone suppression occurs in the absence of Cushing’s syndrome. Patients who are under acute stress, particularly those with fever and infections, and depressed individuals may not respond to dexamethasone. Therapy with estrogen, and occasionally phenobarbital or phenothiazines may alter the response to dexamethasone. To some extent, all these drugs induce the hepatic microsomal enzymes that metabolize dexamethasone, and acceleration of the hepatic metabolism of the steroid results in insufficient plasma levels to yield a normal response. In these conditions, and in any others in which an abnormality in the metabolism of dexamethasone is suspected, simultaneous quantitation of the plasma dexamethasone concentration offers extremely useful information. Compared with individuals who exhibit no abnormalities in the metabolism of the steroid, individuals with altered hepatic metabolism have a much lower plasma concentration. Estrogens also increase the synthesis of corticosteroid-binding globulin (CBG) by the liver. Since plasma cortisol assays measure both bound and free cortisol, values are high in people on estrogen medication.)

2. 48 – hour low dose dexamethasone test. The results obtained with the single-dose dexamethasone suppression test are comparable to those of the first suppression test developed by Liddle. In this procedure, eight 0.5-mg doses of dexamethasone at 6-h intervals are given orally; 24-h urine samples for 17-hydroxycorticosteroids (17-OHCS) excretion are collected before and during dexamethasone administration. Iormal subjects, 17-OHCS values are below 3 mg per 24 h on the second dexamethasone day. Patients with Cushing’s syndrome fail to suppress. Not only is this test less convenient and more expensive but it may not be accurate if incomplete urine collections have been obtained.

3. High-dose dexamethasone suppression test. After the oral administration of a single dose of 4.0 mg of dexamethasone between 10 p.m. and midnight, the measured 8 a.m. cortisole the following morning is less than 2 mkg/dl iormal individuals. Patients with pituitary-dependent Cushing’s syndrome demonstrate a plasma cortisol suppression of more than 50 % compared with the baseline values. Those with adrenal tumors or nonpituitary ACTH-secreting tumors do not respond. (This procedure is comparable to the high-dose dexamethasone suppression test developed by Liddle (2.0 mg dexamethasone every 6 h for eight doses with three 24-h urine sample collections for 17-OHCS, one collection before and two during dexamethasone administration). The single-dose 4.0 mg dexamethasone suppression test is simpler, less expensive, and more convenient.

Instrumental investigations

Radiologic diagnosis includes:

· X-ray examination for a pituitary tumor,

· CT or MRI for visualizing the adrenals in patients with Cushing’s syndrome.

Treatment

Management of hypercorticism will depend on the source of cortisol excess

Surgery

If clinical manifestations are severe and definitive correction is immediately required, surgery will be the procedure of choice for most patients with Cushing’s syndrome.

Pituitary surgery is the preferred therapeutic modality for pituitary-dependent Cushing’s syndrome. The transsphenoidal route is most commonly utilized, but transfrontal exploration may be required for large tumors or areas where there is extrasellar extension. There is general agreement that once the diagnosis of pituitary-dependent Cushing’s syndrome has been established the pituitary should be explored with or without radiological evidence of a pituitary tumor. Operative morbidity of pituitary surgery is 2 to 5 %. Transphenoidal hypophysectomia is usually successful when carried out by an experienced neurosurgeon. While the majority of patients may be cured by this operation and normal pituitary function will remain intact, recurrences occur and may appear months or years after the operation.

Because a pituitary adenoma is not found in all cases, complete tumor removal is difficult, and recurrences arise following adenomectomy, partial or even total hypophysectomy has been recommended by some clinicians. With partial hypophysectomy best results are obtained by removing the central mucoid zone which contains most of the ACTH-secreting cells. With total hypophysectomy, the problem of recurrences is resolved but hypopituitarism develops, necessitating permanent hormone-replacement therapy. Therefore, indiscriminate use of total hypophysectomy is not justified.

Adrenalectomy is the treatment of choice in patients with adrenal tumors. Since the lesion is unilateral in most cases, only one adrenal is removed. Therapy with glucocorticoids, is required for as long as a year because of chronic suppression of ACTH secretion and atrophy of the contralaleral adrenal.

Bilateral adrenalectomy is utilized to treat patients with primary adrenocortical nodular dysplasia. although a few patients with this condition have responded to hypophysectomy. Bilateral adrenalectomy is a difficult procedure, with an operative mortality of 4 to 10 percent of patients. There is a recurrence of the disease as the result of hyperplastic remnant in 10 percent of patients, and development of hyperpigmentation with rapid growth of pituitary tumors in 10 to 20 percent.

In patients with nonpituitary tumors that are secreting ACTH, surgery or chemotherapy may be helpful. In patients with severe hypercorticoidism that is not controlled by surgery or drugs, bilateral adrenalectomy may be necessary.

Pituitary irradiation

If clinical manifestations are not severe, pituitary irradiation may be tried initially. Pituitary irradiation is delivered by means of conventional cobalt radiotherapy (4500 rads), by proton-beam irradiation, or by pituitary implantation of radioactive material. Conventional cobalt radiotherapy has a cure rate in 46 to 83 percent of patients. Two-thirds of these patients experience a complete resolution of the signs and symptoms, and the others manifest some degree of improvement. The response is better in younger individuals. Improvement, however, is slow and may take 6 to 18 months. Radiation effects continue for many years, and the incidence of hypopituitarism is 80 percent at 20 years. If there is no response to pituitary irradiation after 6 month, adrenalectomy is indicated.

Drugs

Several drugs have been used to treat patients with Cushing’s syndrome. Improvement of the clinical manifestations is the result of a decrease in ACTH secretion by the pituitary gland or cortisol secretion by the adrenals.

Cyproheptadine (Periactin) and peritol have been helpful in some patients with pituitary-dependent Cushing’s syndrome. Cyproheptadine has peripheral and central antiserotonergic, antihistaminergic, anticholinergic, and antidopaminergic actions, but the inhibition on ACTH secretion is the result off its antiserotonin effect on the hypothalamus. The drug is administered orally at an initial dose of 4 mg three times a day, which is increased to a maximum dose of 4 mg every 4 h over 2 to 4 weeks. Clinical and biochemical responses occur within 2 to 3 months after initiation of therapy, and the return of dexamethasone suppressibility and ACTH and cortisol periodicity are observed by 6 to 12 months. Remission of the disease occurs in 30 to 50 percent of the patients and the longest duration of remission has been 5 years. Although a few cases of permanent remission after discontinuation of the drug have been reported, relapse is the rule. Cyproheptadine can be used in combination with pituitary irradiation. The drug is given for 4 to 6 months to control symptoms before the effects of irradiation are manifested. The two major side effects are hyperphagia (with weight gain) and somnolence.

The dopamine agonist bromocriptine is very useful. The usual dose is 2.5 mg three times a day. But the therapy has to be began from the ¼ of a tablet (2.5 mg) at a bedtime for 3 to 4 days (because of its side effect such as somnolence), then it has to be increased on ¼ of a tablet each 3 days to 7.5 mg.

Several adrenal cortisol inhibitors are available to treat patients with Cushing’s syndrome, particularly those with adrenal carcinomas or nonpituitary ACTH-secreting tumors. Mitotane, Lysodren inhibit adrenal growth and interferes with cortisol synthesis by blocking the conversion of cholesterol into pregnenolone. The dose is 1 to 10 g/day. Side effects include gastrointestinal complaints, sedation, depression, and adrenal insufficiency. Because of its inhibitory effect on adrenal growth, the drug is preferred for the treatment of adrenal cancer. Aminoglutethimide (Cytadren, Elipten) inhibits the conversion of cholesterol into pregnenolone as well, but it does not have any effect on adrenal growth. The usual dose is 250 to 500 mg four times a day. Side effects are gastrointestinal complaints, drowsiness, skin rash, goiter, and adrenal insufficiency. Metyrapone (Metopirone) inhibits the last step in cortisol synthesis – the conversion of 11-deoxycortisol into cortisol. Effective doses range from1 to 4 g/day. Better results are obtained when metyrapone is administered every 2 h rather than every 4 h. Hirsutism is the most frequent problem with prolonged metyrapone usage. Trilostane, at a dosage of 0.25 to 1.0 g/day, can reduce cortisol synthesis effectively. A combination of two drugs, such as aminoglutethimide and metyrapone, usually is more effective than any drug alone. Problems shared by all of these drugs are (1) the fact that their effects cease as the result of both a compensatory increase in ACTH secretion and of stimulation of partially suppressed adrenals and (2) the development of adrenal insufficiency. These problems can be minimized by administering physiologic amounts of a glucocorticoid, such as 0.5 mg/day of dexamethasone. If hypotension and electrolyte problems develop, 0.1 mg/day of the mineralocorticoid 9-alfa-fluorohydrocortisone (Florinef) should be given.

Hypothalamic syndrome of pubertal period

Peculiarities of diagnostic criteria

1. Obesity is not cushingoid (not central).

2. Striae (pink and not very large).

3. Hypertension (constant or permanent).

4. Glucose intolerance.

Treatment

1. Diet 8.

2. Parlodel (2.5 – 5 mg for 3 – 6 month).

3. Peritol (4 mg 2 times a day for 1 month).

4. Dehydration therapy (hypothiazid 50 – 100 mg/day MgSO₄ 25 % solution intramuscular 10 – 15 times).

5. Nonsteroid anti-inflammatory drugs (indometacine).

6. Biogenic stimulators (aloe, plasmol).

7. Increasing of microcirculation of the blood in the brain (cavinton, piracetam).

8. Vitamin therapy.

9. Symptomatic therapy (hypotensive therapy).

10. Physiotherapy.

PHEOCHROMOCYTOMA

Definition

It is a tumor of chromaffin cells that secretes catecholamines.

Epidemiology

Pheochromocytomas appear equally in both sexes, are bilateral in 10 % of cases (20 % in children), and are usually benign (90 – 95 %). Although pheochromocytomas may occur at any age, the maximum incidence is between the third and fifth decades. Pheochromocytoma secretes catecholamine and is responsible for < 0.1 % cases of hypertension. There is a useful “rule of tens”: ~ 10% are malignant, ~ 10% are extra-adrenal, ~ 10% are familial.

Because of excessive catecholamine secretion, pheochromocytomas may precipitate life-threatening hypertension or cardiac arrhythmias. If the diagnosis of a pheochromocytoma is overlooked, the consequences could be disastrous, even fatal; however, if a pheochromocytoma is found, it is potentially curable.

The term pheochromocytoma (phios means dusky, chroma means color, and cytoma means tumor) refers to the color the tumor cells acquire when stained with chromium salts

Etiology is unknown.

In about 80 – 90 % of cases, pheochromocytomas are found in the adrenal medulla, but may also be found in other tissues derived from neural crest cells (e.g., tumors may be found in the paraganglia of the sympathetic chain, retroperitoneally along the course of the aorta, in the carotid body, in the organ of Zuckerkandl (at the aortic bifurcation) in the genitourinary system, in the brain, and in the dermoid cysts.

Pheochromocytoma can be found along or as a part of the syndrome of familial multiple endocrine neoplasia (MEN syndrome) – Type II (Sipple’s syndrome: associated with medullary thyroid carcinoma and parathyroid adenoma), Type III (associated with mucosal (oral and ocular) neuroma and medullary thyroid carcinoma). There is a significant association (10 %) with neurofibromatosis (von Recklinghausen’s disease) and may be found with hemangiomas (von Hippel – Lindau disease).

Classification

1. Paroxysmal form (45 %).

2. Permanent form (50 %):

· with crisis;

· without crises.

3. Latent or silent form (nonsymptomatic).

Clinical features

are due to secretion of one or more of the catecholamine hormones or precursors: norepinephrine (noradrenaline), epinephrine (adrenaline), dopamine.

Cardiovascular disorders

The most prominent feature is hypertension. Additionally, postural hypotension, palpitation, tachycardia, angina, tachypnea, dyspnea, visual disturbances.

Gastrointestinal disturbances

Patients can present nausea, vomiting, epigastric pain, constipation or diarrhea.

Neurological and psychiatric manifestations

Severe headache, diaphoresis, flushing, cold and clammy skin, parasthesias, anxiety with fear to death and a sense of impending doom are common; some or all of these symptoms and signs may occur in any patient.

Symptoms “The 5 P’s”

– Pressure increase (hypertension )

– Palpitation (tachycardia)

– Perspiration

– Pain (abrupt onset of throbbing headache, chest (angina), abdominal pain)

– Pallor (due to vasoconstriction) cold and clammy skin

Paroxysmal attacks may be spontaneous or provoked by palpation of tumor, postural changes, abdominal compression or massage, induction of anesthesia, emotional trauma, β – adrenergic blocking agents, and, rarely, micturition.

Duration of hypertensive crisis is variable, lasting from a seconds or few minutes to a days, but 50 % of the paroxysms last less than 15 min. Permanent form of the disease’s duration looks like malignant hypertension. Nonsymptomatic form of the disease is rare.

Physical examination, except for the common finding of the hypertension, usually is normal, unless performed during a paroxysmal attacks. The severity of the retinopathy and cardiomegaly is often less extensive than might be expected for the degree of hypertension present.

Investigations

1. An increased 3-h (24-h) urinary excretion of epinephrine, norepinephrine and their metabolic products (VMA or metanephrines).

2. Plasma free metanephrine is up to 99% sensitive. Thas test has superior sensitivity to measurement of circulating epinephrine, norepinephrine because plasma metanephrines are elevated continuously, unlike epinephrine and norepinephrine, which are secreted intermittently; however, grossly elevated plasma norepinephrine renders the diagnosis highly probable.

False negative results may be obtained due to intermittent catecholamine secretion.

3. Imaging tests to localize tumor:

– CT scanning and MRI of the chest and abdomen with and without contrast.

– Radiopharmaceuticals with nuclear imaging techniques can help to localize pheochromocytomas when the lesion is large enough to be obvious on CT or MRI.¹²³I-metaiodobenzylguanidine (MIBG) is the most used compound for this investigation. Normal adrenal tissue rarely picks up this isotope, but 90% of pheochromocytomas do.

Differential diagnosis

Essential and symptomatic hypertension.

Treatment

1. Surgical removal of the tumor is the treatment of choice.

The most effective and safest preprooperative α-blocade phenoxybenzamine 0,5 mg/kg IV in 0,9% saline over 2 h on each of three days before the operation. Sodium nitroprusside can be used for hypertensive crises preoperatively and intraoperatively. When bilateral tumors are suspected, sufficient hydrocortisone (100 mg IV bid) given before and during surgery avoids acute glucocorticoid insufficiency from bilateral adrenalectomy.

Most pheochromocytomas can be removed laparascopically

2. During crisis a combination of α– and β-adrenergic blocking agents (phentolamine (tropaphen) 2 – 4 mg every 5 – 10 min till stopping of the crisis, phenoxybenzamine 10 – 20 mg 3 – 4 times daily, propranolol 30 – 60 mg/day) and infusion of sodium nitroprusside.

β-antagonists must not be given before the α-antagonists as this may cause paradoxical rise of blood pressure.

Hyperaldosteronism

Definition

It is a disease caused by an excess production of the normal adrenal hormone, aldosterone.

Hyperaldosteronism causes high blood pressure and low serum potassium.

Epidemiology

Hyperaldosteronism represents under 1% of of hypertensive causes. Peak age is 30-50 years and most patients are women.

Pathogenesis

Aldosterone is responsible for sodium and potassium balance, which then directly controls water balance to maintain appropriate blood pressure and blood volume.

Aldosterone excess leads to increased renal distal tubular sodium reabsorption and as a result increased total body sodium content and increased water retention. But escape phenomenon develop in patients due to compensatory increasing of ANF secretion. So, hypertension may not be solely volume expansion.

Another changes which can be found in patients with hyperaldosteronism are:

I. Increased peripheral vascular resistance:

1. Hypokalemia: Potassium lost in distal renal tubule;

2. Alkalosis: Ammoniagenesis

II. Polyuria: Decreased renal concentrating ability.

III. Plasma renin suppressed:

1. Unresponsive to intravascular volume depletion

Classification of Hyperaldosteronism

1. Primary Hyperaldosteronism (Conn’s Disease)

2. Secondary Hyperaldosteronism

Risk Factors

1. Primary hyperaldosteronism

– No known risk factors

2. Secondary hyperaldosteronism

· Hypertension, particularly when uncontrolled

· States of decreased renal blood flow and/or perfusion pressure

§ Atherosclerosis

§ Renal artery stenosis

§ Fibromuscular hyperplasia

§ Severe arteriolar nephrosclerosis (malignant hypertension)

§ Profound renal vasoconstriction (accelerated phase of hypertension)

· Edematous disorders

§ Congestive heart failure

§ Cirrhosis

§ Nephrotic syndrome

· Pregnancy (normal physiologic response to estrogen-induced increases in circulating levels of renin substrate (angiotensinogen) and plasma renin activity, and to the antialdosterone actions of progesterone).

Etiology

Primary Hyperaldosteronism (Conn’s Disease) – excess aldosterone is produced autonomously by the adrenal gland independent of the renin-angiotensin and serum potassium regulatory systems:

1. Solitary adrenal adenomas (80-90%)

2. Bilateral adrenal hyperplasia (10-20%)

3. Adrenal Carcinoma (rare)

4. Unilateral Adrenal Hyperplasia (very rare)

Secondary Hyperaldosteronism – hypersecretion of aldosterone by the adrenal gland occurs in response to excessive plasma renin activity (PRA) and/or is an adaptive response to perceived hypovolemia and/or low intrarenal perfusion.

1. Hypertensive States

· Primary Reninism (rare renin producing tumor)

· Secondary reninism due to decreased renal perfusion

2. Edematous States

· Cirrhosis

· Nephrotic syndrome

Diagnostic criteria

Clinical features

Hyperaldosteronism is often asymptomatic. Patients can have such complains as frontal headache, muscle weakness to flaccid paralysis (as a result of hypokalemia), polyuria and polydipsia (due to carbohydrate intolerance).

Physical examination reveal:

– hypertension, which may be severe but rarely malignant;

– decreased muscle strength.

Laboratory findings (primary aldosteronism)

1. Serum Electrolytes

1. Serum Potassium decreased (Hypokalemia)

2. Serum Sodium increased (Mild)

3. Metabolic Alkalosis

2. Morning Aldosterone to PRA ratio

1. Ratio over 20-25 (esp if >100) suggests Hyperaldosteronism

2. Aldosterone >15 ng/dl and plasma renin low

3. Saline suppression

1. IVF: 300-500 cc/hour for 4 hours

2. Normal response

Instumental findings

When a tumor is suspected, radiologic proof with a CT scan or MRI will usually help to confirm the diagnosis

Differential Diagnosis

Hypertension with Hypokalemia

· Cushing’s Disease: low aldosterone and low plasma renin

· Secondary aldosteronism in a case of cardiovascular failure, renal cause (Renal Artery Stenosis), nephritic syndrome, liver cirrhosis or other: high aldosterone and high plasma renin.

Management

The treatment depends on the cause.

1. Adrenal Adenoma

If there is a single tumor, surgical removal of that tumor can cure the disease. The remaining adrenal gland is usually normal and individuals with this form of the disease will have enough adrenal hormone production from the remaining gland to live normally. Unfortunately, quite often there is still some residual hypertension even after the surgery, so sometimes antihypertensive medication is still necessary.

2. Adrenal Hyperplasia

If bilateral hyperplasia is the cause of hyperaldosteronism, this is treated with specific medications that block the effect of aldosterone.

1. First-Line Agents: Spironolactone (Aldactone)

2. Alternative agents if Gynecomastia develops on Spironolactone: Eplerenone (Inspra), Amiloride (Midamor). Precautions: Follow serum potassium and serum creatinine every 6 months with these agents.

These medications are very effective, but are sometimes used in combination with other antihypertensive medications for the management of hypertension in individuals with hyperaldosteronism.