endocr4

5.4. Pathophysiology of thyroid gland 325

mental retardation is not a common clinical symp-tom. ACTH deficiency in children with panhypopi-tuitarism results in the tendency to hypoglycemiaand neuroglycopenic attacks. Besides insufficientproduction of glucocorticoids, ACTH deficiency alsoleads to a decreased secretion of sex hormones ofadrenal cortex, which together with GTH deficiencyparticipates in the origin of hypogonadism.

Postpubertal panhypopituitarismThe peripheral manifestations of panhypopituitarismin adults are mostly the consequences of deficiency offive tropic hormones: gonadotropins (LH and FSH),TSH, ACTH, and MSH. Characteristically, evidenceof target gland deficiencies appears in the above men-tioned order, i.e., gonadal, thyroidal, and cortical de-ficiency.

The early symptoms of developing panhypopitu-itarism are usually the symptoms of gonadotropindeficiency. GTH deficiency in female leads to sec-ondary amenorrhea and diminishing libido. Inwomen with Sheehan’s syndrome the failure to lac-tate and resume menses after delivery are the mostcommon initial clinical symptoms. In men loss oflibido and impotence appear.TSH and ACTH deficiencies are manifested by

the same clinical symptoms as at primary hypothy-roidism and at primary hypoglucocorticoidism. Thesymptoms of secondary hypothyroidism are, how-ever, less intensive than at primary hypothyroidism.Loss of the thyroid function causes dry skin, coldintolerance, somnolence, bradycardia, and constipa-tion. However, at secondary hypothyroidism typi-cal myxedema usually does not originate. Secondaryadrenal insufficiency results from the lack of ACTHstimulation of the adrenal cortex, and, therefore, af-fects only adrenal steroids under predominant ACTHregulation, namely cortisol and adrenal androgens.Mineralocorticoid secretion, primarily regulated byrenin and angiotensin, is preserved, although it maynot be optimal. More common symptoms of glu-cocorticoid deficiency are malaise, anorexia, weightloss, hypoglycemia or hypoglycemia-induced seizure,hypovolemia, postural hypotension, and orthostaticdizziness. ACTH deficiency results also in abnormalresponse to stress, and a higher mortality rate. A de-crease of adrenal androgen production causes in bothsexes gradual thinning even loss of axillary and pubichair (in men there is a coexistent GTH deficiency).In men also facial hair may diminish. MSH defi-

ciency (to a certain extent also ACTH deficiency) ismanifested by hypopigmentation or depigmentationof the skin, which is expressive mainly in physiolog-ically hyperpigmentated areas of the body (breastareolae, perigenitally, perianally), and by decreasedtolerance to sunshine.

If panhypopituitarism is caused by intrasellar orextrasellar expanding tumor, in the clinical picturealso local symptoms resulting from compression ofsurrounding structures are present.

In the past, gradually developing panhypopitu-itarism was called Simmond’s cachexia, becausein the clinical picture of this disease extreme lossof body weight and atrophy of organs dominated.Those were the patients with severe total insuffi-ciency of adenohypophysis without longterm substi-tution therapy. Due to present day system of healthcare, the patients do not reach such progressive phaseof the disease, and, therefore, expressive cachexiadoes not occur in them.

5.4 Pathophysiology of thy-roid gland

The thyroid gland is the largest classic endocrineorgan. Its disorders are very frequent. If diabetesmellitus, which regularly ranks among metabolic dis-eases, is not considered, the thyroid gland disor-ders make about 4/5 of the total number of en-docrinopathies. The thyroid gland disorders aremuch more frequent in women than in men (7:1).They can be classified as follows:

1. Simple goiter

2. Hypothyroidism

3. Hyperthyroidism

4. Inflammations of the thyroid gland (Thyroiditis)

5. Thyroid neoplasms

5.4.1 Goiter (struma)

Goiter is a clinical and morphological term signifyingany enlargement of the thyroid gland situated in situor ectopic. The goiter placed in situ can be diagnosed

326 Chapter 5. Pathophysiology of endocrine system ( L.Zlatos )

by palpation or visually. The size of the goiter canbe objectively determined by ultrasonographic volu-metric measurement of the thyroid gland. Ectopicstruma (struma lingualis, struma mediastinalis, orstruma ovarii) is rare and may be diagnosed only byscintigraphy.

From the morphological point of view enlargementof the thyroid gland can be caused by:

a) Hypertrophy and hyperplasia of the epithelialcells of follicles;

b) Increased coloid accumulation in the follicles;

c) Inflammation process (inflammatory infiltrationand augmentation of connective tissue);

d) Neoplastic process.

From the functional view-point the term goiter(struma) does not explain the actual functional stateof the thyroid gland, i.e., what is the production ofthyroid hormones in relation to demands of organismtissues.

Goiter may be characterized from several view-points. Goiter may be associated with normal, de-creased, or increased hormone secretion. Therefore,according to the state of functional activity of its tis-sue, eufunctional goiter, hypofunctional goiter, andhyperfunctional goiter are distinguished. From thepoint of view of functional consequences for metabo-lism of organism, toxic goiter (hyperfunctional) andnontoxic goiter (eufunctional or hypofunctional) maybe distinguished.

According to the histopathological process prevail-ingly leading to the enlargement of the thyroid gland,parenchymatous goiter, colloidal goiter, and fibrousgoiter are known.

The enlargement of the thyroid gland (normally 15to 20 g in adults) may be generalized or focal. Ac-cording to that, diffuse goiter and nodular goiter aredistinguished. In the thyroid gland only one (solitarynodule) can be present (mononodular, uninodulargoiter), or more nodules may occur (multinodulargoiter). Nodular goiter (struma nodosa) is a clin-ical term including various morphological changes,e.g., nodular hypertrophy and hyperplasia of the aci-nar cells, colloido-cystic or fibrous changes, intrathy-roidal hematoma, adenoma, carcinoma, sarcoma, fi-brosarcoma, and metastases.

Another classification of nodular goiter is due tointensity of radioiodine accumulation at scintigra-

phy. Hot nodule (toxic, hyperfunctional) accumu-lates a radioactive isotope of iodine in a higher ex-tent. Scintigraphic cold nodule (afunctional, inac-tive) does not uptake radioiodine and is always sus-pect of malignity. If the nodular goiter is causedby neoplasia, according to the character of neoplas-tic process, which leads to the origin of the nodulargoiter, benign goiter and malignant goiter can bedistinguished.

According to the number of population affected bygoiter in a certain geographic region, sporadic goiteror endemic goiter are known.

Most goiters cause neither functional nor mechan-ical problems. At the beginning it may be only acosmetic defect. If the thyroid enlargement is con-siderable, the symptoms resulting from displacementor compression of surrounding structures may ap-pear, mainly of the esophagus, the trachea, the re-current laryngeal nerve, and the superior vena cava.Compression of the esophagus or the trachea leadsto dysphagia, a choking sensation, and rarely to in-spiratory stridor. Superior mediastinal obstructionmay occur with a large retrosternal goiter. Narrow-ing of the thoracic inlet may compromise the venousreturn from the head, neck, and upper limbs suf-ficiently to produce venous engorgement. This ob-struction is accentuated when the patient’s arms areraised above the head (Pemberton’s sign). Suffusionof the face, giddiness, and even syncope may resultfrom this manoeuvre. Compression of the recurrentlaryngeal nerve leading to hoarseness is rare in sim-ple goiter, and, therefore, its presence suggests ma-lignant neoplasm rather than nontoxic goiter. Sud-den hemorrhage into a nodule or cyst may lead to anacute painful enlargement in the neck and may pro-duce the origin or the enhancement of compressivesymptoms. The set of introduced symptoms, con-ditioned by compression of the neck or mediastinalstructures neighbouring the goiter, is called mechan-ical local syndrome.

Along with the symptoms of mechanical local syn-drome, symptoms resulting from dysfunction of thethyroid gland (hypothyroidism or hyperthyroidism)may also occur.

5.4.1.1 Simple goiter

Simple goiter (nontoxic goiter) may be defined asany thyroid enlargement that is not associated withhyper– or hypothyroidism and that is not the result


of inflammatory or neoplastic process. Hence, it is aneufunctional (euthyroid) goiter, the tissue of whichproduces sufficient amount of thyroid hormones formaintaining of euthyroid status.

Simple goiter is the most frequent endocrinopathy.It occurs much more in women than in men (7:1).The higher occurrence of simple goiter in women isassociated with the increased demands to the thy-roid hormone production at puberty, adolescence,pregnancy, and lactation. With increasing numberof deliveries, especially in the regions with iodinedeficiency in soil and in drinking water, the occur-rence of simple goiter or later also of nodular goiterincreases. Nowadays, in our country 25 % of mid-dle aged women are affected. It is even more oftenpresent at puberty or in adolescent girls (pubertalgoiter, adolescent goiter). In some patients simplegoiter may later diminish (regresses), in others it maybe present lifelong. But in some young women thesimple goiter may henceforth grow, and change mor-phologically, or sometimes change even functionally,due to gravidity and lactation, but also due to theage if influence of etiological factors recurs.

In certain geographic regions simple goiter mayoccur sporadically or endemically. Sporadic simplegoiter arises as a result of factors that do not affectthe population generally. If in particular geographiclocalities incidence of simple goiter is more than 10%of the adult population, or more than 20 % of thechildren population, it is denoted as endemic goi-ter. Endemic goiter implies an etiologic factor (en-vironmental iodine deficiency is regarded the majoretiologic factor), or factors common to a particulargeographic region.

Endemic goiter is still a problem of vast publichealth significance and has been estimated to afflictmore than 200 million people throughout the world.Except perhaps in North America, it is present on allcontinents and occurs mostly in mountainous areassuch as Andes, Himalayas, and Alps, where iodinedeficiency still exists. But endemic goiter also mayoccur in nonmountainous regions remote from thesea, such as Central Africa, where iodized salt is notused.

At the beginning of 50s of this century incidence ofsimple goiter in Slovakia was very high. In some re-gions, namely Kysuce, Slovenske rudohorie and Zitnyostrov, it was present in 50–80% of adult women.

Etiology of simple goiter is multifactorial. It is

often due to a definable cause of impaired thyroidhormone biosynthesis, such as iodine deficiency, andingestion of goitrogens. Sometimes it is due to aninborn defect in a hormone synthesis pathway, butin some instances its cause is not exactly known.

1. Iodine deficiency in food and water. Iodine andtyrosine are the basic substances for the thyroid hor-mone biosynthesis. At present the optimal dailyiodine intake is considered 150–200 microgrammes.However, for eufunctional status of the thyroid glandminimum daily iodine intake of 100 microgrammesis needed. If its daily intake falls under this value,the production of thyroid hormones significantly de-creases. Therefore, the compensatory goiter beginsto develop, however, in some people it is being de-veloped also if daily iodine intake is somewhat morethan 100 microgrammes. The compensatory aug-mentation of thyroid parenchyma is to secure theuptake of such total amount of iodine from circu-lating blood, which in spite of its insufficient supplyto organism, will be sufficient for securing euthyroidstatus. The uptake and the content of iodine perunit of thyroid tissue weight are, however, signifi-cantly lower.

Iodine deficiency may be absolute or relative. Theabsolute iodine deficiency in food and water, and soin the organism as well, in the past was often presentin the geographic regions with incidence of endemicgoiter. In the noted regions endemic goiter had oc-curred in several generations. If the iodine deficiencywas severe, in considerable number of the patientsgoitrous enlargement was also associated with vary-ing degree of hypothyroidism. The incidence of en-demic goiter has been greatly reduced in many coun-tries by the introduction of iodized salt (in Slovakiasince 1951). In our country table salt is enrichedwith potassium iodide containing 25mgKI/1 kg.

The relative iodine deficiency may originatemainly during those periods of ontogenesis, whichare associated with increased demands to the thy-roid hormone production. In girls it is especiallyduring puberty and adolescence, in women duringpregnancy and lactation. The origin of simple goi-ter due to iodine deficiency in boys is rather rare.The increased need of the thyroid hormones is as-sociated with increased demands to iodine intake.However, if the iodine intake remains at the level be-fore the onset of the above mentioned periods of life,it becomes relatively insufficient with respect to the


increased needs of organism. Therefore, it is neces-sary to increase iodine intake by occasional consuma-tion of sea fish, respectively by use of iodine medicaldrugs. This is important especially for women dur-ing gravidity and lactation because of the demandsof the fetus and newborn for iodine.

2. Increased intake of goitrogens. A wide variety ofchemical agents have the capacity to inhibit the syn-thesis of thyroid hormones. When the effect of suchagents is sufficient to reduce the secretion of thyroidhormones to subnormal levels, secretion of TSH is in-directly increased (via the feedback mechanism), andso they induce goiter formation. Hence such agentsare commonly termed goitrogens (strumigens).

From the standpoint of the aspect of iodine me-tabolism that they inhibit, goitrogens (antithyroidagents) can be grouped into two classes: goitrogensthat inhibit iodide transport and thereby reduce sub-strate for hormone formation, and those that inhibitthe initial oxidation (organic binding) of iodide, de-crease the proportion of diiodotyrosine (DIT) rel-ative to monoiodotyrosine (MIT), and block cou-pling of iodotyrosines to form the hormonally activeiodothyronines.

Increased intake of goitrogens participates in theorigin of the goiter especially if it is associated withmild iodine deficiency in food and water. Increasedintake of goitrogens may be applied also in the periodof increased needs of the thyroid hormones (puberty,adolescence, pregnancy, and lactation), respectivellyin the persons with mild hereditary deficiencies ofenzymes participating in biosynthesis and secretionof thyroid hormones (the persons with heterozygousform of enzymopathy).

Goitrogens are natural or synthetic chemicalagents. Natural goitrogens are contained in somekinds of vegetables, such as cabbage, cauliflower,kale, kohlrabi, Brussels sprouts, turnips, mustard,cassava, and others belonging to the Brassica andCrucifera plants. They may be also in some animalforage, e.g., clover, rape, and soya. Natural goitro-gens contained in forage may be successively foundin milk, and probably even in meat of domestic an-imals, which may so become a source of goitrogenswhen they are consumed. Well known natural goitro-gens are: thiocyanate, 1-5-vinyl-2-thiooxazolidone,and allylisotiocyanate. The role of dietary goitro-gens in the induction of disease in humans is uncer-tain. Their effect may depend on the concomitant

iodine intake. Although humans rarely, if ever, eatgoitrogenic foods in quantities to lead to goiter (thecontent of natural goitrogens in the mentioned kindsof vegetables is low), sufficient quantities of goitro-gens to cause goiter may be present in milk.

The other group of natural goitrogens areflavonoids (polyhydroxyphenols). They are presentin groundnut, beans, and soya. However, their mostimportant source is millet, a significant food in manycountries.

Synthetic goitrogens. The most known syntheticgoitrogens are: chlorates, perchlorates, iodates, peri-odates, nitrates, and some medical drugs, e.g., para-aminosalicylic acid, para-aminobenzoic acid, thio-barbiturates, phenylbutazone, resorcine, resorcinol,some antidiabetic drugs (sulfonylureas, tolbutamide,carbutamide), sulfonamids, and lithium drugs. Goi-ter originated as a sequel of long-term taking largerdoses of pharmacological goitrogens is called strumamedicamentosa.

In the last decades the higher attention is paidto the contaminants occurring widely in the envi-ronment (anthropogenic goitrogens). They includemainly:

a) polychlorinated biphenyls used in the plasticmaterial industry. By their decompositiongoitrogenic more effective resorcinols, hydrox-ypirimidins, and phtalates originate. From thesechemical agents goitrogenic dihydroxybenzoicacids originate;

b) polycyclic aromatic hydrocarbons (benzpyreneand methylcholanthrene), which also play an im-portant role in the carcinogenesis;

c) nitrates;

d) insecticides (the most known agent from thisgroup is dichlorophenyl-trichloranthen – DDT,which was used mainly in the past); pesticides(parathione and metathione). From the om-nipresent polyvinyl-chloride (PVC) goitrogenicphtalate esters and dihydroxybenzoic acids arebeing released by moisture, therefore, thosechemical agents are present in plastic packetmilk, in the vegetables grown in plastic foilgreenhouse, and in other foodstuffs.

Simple goiter may be also caused by chronic ex-cessive iodine intake in food (organic form of iodine)or in medical drugs (inorganic form of iodine). The


doses of iodine are supposed to be large (more than10mg daily). Large iodine intake inhibits synthe-sis of thyroid hormones. Chronic administration oflarge doses of iodine is seen most commonly in pa-tients with chronic respiratory diseases, who are of-ten given potassium iodide as an expectorant. How-ever, iodine goiter (iodide goiter) develops in onlya small proportion of patients given iodine. In sea-side areas, where large quantities of food with ex-cessive content of iodine are consumed (seafish andseaweed), iodide goiter occurs endemically (so calledseaside goiter). Increased iodine supply in pregnantwomen, e.g., long-term therapy by expectorants con-taining iodine, causes the origin of goiter in newborninfants. In such cases, the mother is usually freeof goiter. It is not known whether iodide goiter innewborns results from hypersensitivity of the fetalthyroid to iodine or from the fact that the placentaconcentrates iodide several-fold.

3. Hereditary factors. Genetically determined de-fects in thyroid hormone biosynthesis are rare andtheir share in the origin of simple goiter is not clearenough. In most instances, the defect appears tobe transmitted as an autosomal recessive trait. Itis supposed, that in some persons with inborn en-zyme defect only mild decrease of activity of someof the enzymes in the pathways of thyroid hormonesynthesis is present (heterozygous individuals). Un-like severe hereditary enzymopathy (homozygous in-dividuals) resulting in sporadic cretinism, the thy-roid gland of heterozygous individuals is, therefore,eufunctional and normal size. This mild enzymopa-thy may, however, participate in the origin of sim-ple goiter if in the affected person increased needsfor production of thyroid hormones (puberty, ado-lescence, pregnancy, and lactation), mild iodine de-ficiency, or increased intake of goitrogens occur.

4. Increased concentration of estrogens in blood.In the origin of simple goiter in girls at pubertyor adolescence (juvenile goiter) , and in pregnantwomen, besides increased need of the thyroid hor-mones, also estrogen overproduction could partici-pate. Increased plasma estrogen concentration in-duces the increase of plasma level of the thyroxine-binding globulin (TBG), and thereby also increase ofits binding capacity. Increased concentration of TBGmay reduce plasma concentration of free thyroid hor-mones. Because only free thyroid hormones are bi-

ologically active, their reduced blood concentrationvia the feedback mechanism leads to increased secre-tion of TSH. The increased plasma TSH concentra-tion results in the origin of goiter.

5. Immunoglobulins. Recently it has been assumed,that in blood of some patients there may exist a classof thyroid immunoglobulins stimulating only growthof the thyroid gland (thyroid growth immunoglob-ulins – TGIs). TGIs, like TSH, stimulate growthof the thyroid gland by hypertrophy and hyperpla-sia of epithelial cells of follicles. However, unlikeTSH and thyroid immunoglobulins present in pa-tients with Graves-Basedow disease, they do not in-crease biosynthesis of thyroid hormones. This mightexplain why in some persons simple goiter is eufunc-tional already from the very beginning of its origin.Patients in whom such ”autoimmune nontoxic goi-ter” is thought most likely are those in whom otherautoimmune phenomena are present in themselves orin their families.

Pathogenesis of simple goiter. The action of oneor several above mentioned etiologic factors (exceptTGIs) results in reduction of functional efficiency ofthe thyroid gland. As a sequel of this state, the pro-duction of its hormones is not adequate to the needsof the peripheral tissues. The decrease of plasmaconcentration of thyroid hormone reduces feedbackinhibition of TSH secretion. The increased bloodlevel of TSH causes hypertrophy and hyperplasia ofepithelial cells of follicles, and also the increase invascularity of the thyroid gland tissue. The resultof these processes is diffuse parenchymatous goiter.This augmentation of parenchyma is a compensa-tional process securing increased uptake of iodidefrom blood, and thereby normalizing plasma concen-tration of thyroid hormones, and normalizing TSHsecretion as well. The patient becomes again euthy-roid and eumetabolic, though goitrous. Therefore,the eufunctional goiter may usually remain only asymptom of a temporary deficiency of thyroid hor-mones, which appeared sometimes in the past.

If the etiologic factor acts only once and temporar-ily, the hypertrophy and hyperplasia of the epithelialcells may almost disappear. This process of involu-tion leads to a return of the gland to nearly normalsize if the hypertrophy and hyperplasia are of rela-tively short duration, but probably results in a dif-fuse colloid goiter if the hyperplastic phase has beenpresent for years. In long-standing goiter, repeated


cycles of hyperplasia and involution eventually leadto formation of nodules, and a multinodular goiterresults, and it may reach considerable size. Areas ofinvolution are often interspersed with patchy areasof focal hyperplasia. Fibrosis may demarcate hyper-plastic or involuted nodules. Nodules often undergohemorrhagic or cystic degeneration and may becomeirregularly calcified.

According to the clinical criteria the simple goitermay be classified as follows:

1. Diffuse goiter with homogenous hyperplasia

2. Diffuse goiter with nodular hyperplasia

3. Nodular goiter (mononodular or multinodular)

Clinical features of simple goiter. In patients withsimple goiter, the clinical manifestations arise solelyfrom enlargement of the thyroid, since the metabolicstate is normal. A small diffuse goiter does not causeany problems, it is only a cosmetic defect. A middlesize nodular goiter may induce feeling of a tighten-ing of garments worn about the neck and sometimesfeeling of irritation to coughing. A large retrosternalnodular goiter may cause the symptoms of mechan-ical local sydrome. The symptoms of this syndromeusually occur in the middle age, when evidently en-larged goiter descended behind sternum and becamefirm in consistency (augmentation of fibrous tissue).

In the patients with simple goiter also functionaldisorders of the thyroid gland may develop later.In the regions with high incidence of endemic goi-ter, and with insufficient health education and pre-vention, goitrous enlargement also may be associ-ated with varying degrees of hypothyroidism. Onthe other hand, in older patients with long-standingmultinodular goiter, the ingestion of excess iodide(mostly by medical drugs) may result in the devel-opment of thyrotoxicosis (jodbasedow phenomenon).At the scintigraphy hyperfunctional nodules aremanifested as hot nodules. However, in the patientswith simple goiter the prognosis is prevailingly good.

5.4.2 Hypothyroidism

Hypothyroidism is the clinical state resulting fromthyroid hormone deficiency. This clinical state origi-nates if in the consequence of various morphologicalor functional abnormalities the production of thy-roid hormones is lower than the demands of periph-eral tissues for supply of these hormones. Like other

diseases of the thyroid, it occurs more frequently inwomen, mainly in the elderly.

From the etiopathogenetic point of view hypothy-roidism is divided into two groups:

1. Peripheral hypothyroidism;

2. Central hypothyroidism.

1. Peripheral hypothyroidism (primary hypothy-roidism). The cause of the thyroid gland hypofunc-tion is in its parenchyma. Decreased plasma concen-trations of thyroid hormones increase TSH produc-tion by feedback mechanism followed by the increaseof its plasma concentration. According to the size ofthe thyroid gland two types of peripheral hypothy-roidism are known:

A. Peripheral hypothyroidism without goiter (thy-roprivic hypothyroidism, nongoitrous peripheralhypothyroidism). It is due to subtotal surgicalremoval of the thyroid gland, or due to lesionof its parenchyma, e.g., extensive strumectomy,overdose of external therapeutic radiation, ex-cessive dosage radioiodine or antithyroid agents(iatrogenic hypothyroidism). For this type ofhypothyroidism also developmental defects ofthe thyroid gland can be responsible. These de-fects may take the form of hypoplasia or apla-sia of the thyroid, or failure of the thyroid todescend properly during embryological develop-ment (its ectopic location). The loss or atrophyof thyroid tissue leads to inadequate synthesisof thyroid hormones, despite maximum stimula-tion of any thyroid remnant by TSH.

B. Peripheral hypothyroidism with goiter (goi-trous hypothyroidism). It may develop in thepatient with Hashimoto thyroiditis or with thetumor massively infiltrating the thyroid gland.This type of hypothyroidism is always presentin the patients with heritable defects in thy-roid hormone biosynthesis (homozygous individ-uals). Finally, in areas of environmental iodinedeficiency, goitrous hypothyroidism can occuron an endemic basis.

2. Central hypothyroidism (trophoprivic hypothy-roidism). This type of hypothyroidism is charac-terized by insufficient stimulation of an intrinsicallynormal thyroid gland as a result of hypothalamic or


pituitary disease. Production of TSH and its plasmaconcentration are decreased resulting in atrophy ofthe thyroid gland. It may originate either due toprimary disorder in adenohypophysis (central ade-nohypophyseal hypothyroidism, secondary hypothy-roidism, pituitary hypothyroidism), or as a sequelof primary hypothalamic disorder (central hypotha-lamic hypothyroidism, tertiary hypothyroidism, hy-pothalamic hypothyroidism).

Pituitary hypothyroidism is rare. Its unique ori-gin may be due to isolated TSH hyposecretion. It is,however, more often a part of panhypopituitarism.The cause of TSH deficiency may be a tumor ofthe pituitary gland or adjacent region, aneurysm inthis region, or adenohypophyseal necrosis (most com-monly postpartum pituitary necrosis).

Hypothalamic hypothyroidism is less common andresults from inadequate secretion of TRH, which isdue to the damage of the hypothalamic tissue byinflammatory process, trauma, or tumor.

Peripheral hypothyroidism (nongoitrous and goi-trous together) accounts for approximately 95% ofcases of hypothyroidism, only 5 % or less being cen-tral (trophoprivic, suprathyroid) hypothyroidism.

The consequences of thyroid hormone deficiencyand so the clinical features of hypothyroidism de-pend on the age at which undersecretion of thyroidhormones occurs. They also depend on the degreeand duration (early diagnosis) of thyroid hormonedeficiency, as well as on the promptness of adequatereplacement therapy. If the thyroid hormone de-ficiency occurs already during intrauterine life andperinatal period, or at least during the first year ofpostnatal life, i.e., in the period of the most intensiveCNS development, the clinical picture of infantile hy-pothyroidism originates. The origin of the thyroidgland hypofunction after the first year of life, i.e., af-ter the CNS development has almost ceased, but inthe period of intensive development of the skeleton,results in the clinical picture of juvenile hypothy-roidism. The origin of thyroid hormone deficiencyafter epiphyseal closure causes the development ofthe clinical picture of adult hypothyroidism.

The clinical picture of peripheral hypothyroidismis usually characterized by more severe symptoms ofthyroid hormone deficiency than that of central hy-pothyroidism. At central hypothyroidism myxedemadoes not occur. The clinical symptoms of central hy-pothyroidism are milder because in spite of the total

TSH absence the atrophied thyroid gland preservescertain autonomous function, and, therefore, somebasal production of its hormones persists. As a con-sequence of that, the thyroid hormone concentrationat central hypothyroidism is not so low as that atperipheral hypothyroidism. In the clinical picture ofcentral hypothyroidism the symptoms of ACTH defi-ciency (mainly tendency to hypoglycemia), and alsothe symptoms of gonadotropin deficiency (amenor-rhea, atrophy of the breast and ovaries) are oftensimultaneously present.

5.4.2.1 Infantile hypothyroidism

Infantile hypothyroidism is a disease caused by thethyroid hormone deficiency which originates in pre-natal period (congenital hypothyroidism), in peri-natal period (neonatal hypothyroidism), or when-ever during the first year of life. According to thenumber of affected children in a geographic region,endemic infantile hypothyroidism and sporadic in-fantile hypothyroidism are distinguished. Accord-ing to the duration of thyroid hormone deficiency,temporary neonatal hypothyroidism and permanentneonatal hypothyroidism are known. The temporaryneonatal hypothyroidism requires substitutive ther-apy only for certain time, mainly during the crucialphase of CNS development. Later only regular med-ical checks of the child are needed. The permanentneonatal hypothyroidism requires long-life substitu-tive treatment.

The temporary neonatal hypothyroidism may de-velop as a sequel of:

1. Insufficient iodine supply during the lasttrimester of pregnancy. In a newborn the com-pensatory goiter is usually present.

2. Large doses of iodine during pregnancy, e.g., io-dine medical drugs. In some newborns goitermay be extremely large and may cause death byasphyxiation.

3. Transplacental passage of maternal antithyroidantibodies, which probably block TSH receptors(TSH inhibiting immunoglobulins). This type oftemporary neonatal hypothyroidism has a famil-ial occurrence frequently accompanied by irre-versible CNS disorders originating already dur-ing intrauterine development. It seems to be


analogical, but functionally contrary state likeat Graves-Basedow disease in newborns.

4. Transplacental passage of antithyroid drugs orlithium during therapy of pregnant women.

The permanent neonatal hypothyroidism may oc-cur as a sequel of:

1. Anatomical anomaly of the thyroid gland orig-inated due to the disorder of its embryologicaldevelopment (hypoplasia, aplasia, or rudimen-tary ectopic thyroid).

2. Genetically determined defects in thyroid hor-mone biosynthesis (disorder of hormonogenesis).

3. Specific disorder of the thyroid that occurs inregions of severe endemic goiter.

Severe degree of nontreated infantile hypothy-roidism associated with irreversible CNS disorders,as well as with irreversible disorders of bone ossifica-tion, skeletal maturation, and linear body growth istermed cretinism. Irreversible CNS disorders are dueto deficiency of thyroxine (tetraiodo-L-thyronine,T4), which is essential for the development of thecentral nervous system. It is unconditionally neededfor maturation of neurons of cerebral cortex, for thegrowth and myelination of nerve fibres, and for form-ing of dendritic connections (synapses). Its defi-ciency in fetal life or at birth results in retardation ofthe infantile characteristics of the brain, hypoplasiaof cortical neurons with poor development of cellularprocesses, retarded myelination, and reduced vascu-larity. If the deficiency is not corrected in early post-natal life, irreversible damage results. The both thy-roid hormones, i.e., T4 and T3 (triiodo-L-thyronine),are necessarily needed also for maturation of bonetissue, respectively for normal ossification and lon-gitudinal bone growth until the period of epiphysealgrowth plates fusion. Therefore, the most typicalsymptoms of the clinical picture of cretinism are re-tardation of mental development and retardation ofsomatic development. In the past it often occurredas endemic cretinism. Possibility of the origin ofsporadic cretinism still persists. However, thanks tosystematic screening at present the danger of the ori-gin of sporadic cretinism is minimal, and exists onlywhen screening duty is neglected, hence if the diag-nosis and therapy of sporadic congenital hypothy-roidism are very late.

Severe disorder of intellectual development may re-sult also from nontreated T4 deficiency, which mayoccur whenever in the course of the first year oflife. Certain degree of milder, but permanent dis-order of mental abilities of the aflicted child may ap-pear also when T4 deficiency originates from 12th to18th month of postnatal life. If thyroid hormone de-ficiency develops between 18th and 24th months oflife its clinical picture merges more with that of ju-venile hypothyroidism. Nontreated hypothyroidismoriginated after CNS development finished (after thesecond year of life), causes only typical disordersof bone ossification and linear body growth. Men-tal disorders associated with hypothyroidism whichoriginates after the second year of life are reversible.These mental disorders result from actual thyroidhormone deficiency.

The clinical features of infantile hypothyroidismreflect the degree of thyroid hormone deficiency. Atmoderate T4 deficiency only very mild symptoms ofretardation of mental and physical development arepresent. They may be found out only after moredetailed medical examination of a newborn. Moreexpressive T4 deficiency is manifested by various de-grees of cretinous stigmatization. At persisting se-vere degree of T4 deficiency, which in the past oc-curred quite often in regions with endemic goiter,the clinical picture of cretinism fully develops.

Endemic cretinism. It is a severe developmentaldisorder that in the past occurred in regions wheresome inhabitants had the severe endemic goiter dur-ing several generations. Pathogenesis of its origin is,however, still not exactly known. Aflicted childrenwere usually born to mothers with nodular goiter,iodine deficiency, or hypothyroidism. It is generallyaccepted that the risk of the origin of foetal hypothy-roidism in the mother with hypothyroidism is essen-tially higher than in the mother without hypothy-roidism.

It is supposed, that long-term severe iodine de-ficiency in mother plays an important role in theorigin of foetal endemic hypothyroidism. Produc-tion of thyroid hormones in mother is low, therefore,transplacental supply of the foetus by maternal thy-roxine is insufficient. Transplacental T4 supply is,however, unconditionally needed for the supplementof foetal needs also in healthy mother with normal io-dine intake. Therefore, as a sequel of thyroxine defi-ciency during pregnancy irreversible disorder of CNS


development originates already in the foetus. Exces-sive intake of goitrogens in the food of the motherduring pregnancy may to a certain extent partici-pate in the origin of endemic congenital hypothy-roidism. Thanks to the introduction of iodized saltin our country endemic cretinism does not occur.

Sporadic cretinism. It occurs in one in every 4to 5 thousand births. It is due to the morhologi-cal anomaly of the thyroid gland in newborn, whichoriginates during embryogenesis, e.g., its aplasia, hy-poplasia, or rudimentary ectopic thyroid gland. Themost frequent form of the ectopic thyroid is lingualthyroid. It originates if its migration is incomplete,and, therefore, ectopic thyroid tissue lies at the baseof the tongue. The form of the congenital hypothy-roidism which is due to the morphological anomaliesof the thyroid gland is called nongoitrous sporadiccretinism.

Genetically determined defects in hormone biosyn-thesis are a rare cause of sporadic cretinism. It ishereditary enzymopathy transmitted as an autoso-mal recessive trait. Individuals with sporadic cre-tinism are homozygous for the abnormal gene. Sev-eral members of a family are usually affected, and,therefore, it is denoted as familial cretinism. As inpatient usually compensatory goiter is present, it iscalled goitrous sporadic cretinism. These hereditarydefects in hormone biosynthesis are more commonin boys than in girls. The goiter may be present al-ready at birth or shortly thereafter, and since thenit is usually associated with severe hypothyroidism.The absence of goiter in a child does not exclude,however, the presence of hypothyroidism.

Five specific defects in the pathways of hormonesynthesis have been identified: iodide transport de-fect, organification defect (peroxidase deficiency),iodotyrosine-coupling defect, iodotyrosine dehaloge-nase defect (deiodinase defect), and abnormal secre-tion of iodoproteins (defect of thyroglobulin synthe-sis).

At endemic cretinism irreversible CNS disordersusually originate already during intrauterine life.On the contrary, CNS disorders conditioned by T4prenatal deficiency in sporadic congenital hypothy-roidism are mild, and after the prompt diagnosis andadequate substitutional therapy they are reversible.In most newborns with sporadic neonatal hypothy-roidism, however, significant thyroid hormone defi-ciency originates in the postnatal period only.

Clinical features. Presence of the clinical symp-toms of congenital hypothyroidism already at birthis very rare. The age in which its symptoms appeardepends on the degree of prenatal and postnatal T4deficiency. The newborns with this disease clinicallydo not usually significantly differ from healthy new-borns. Only in about 4 % of newborns with con-genital hypothyroidism (a very severe degree of T4deficiency) cosiderable clinical symptoms are presentat birth or in perinatal period. Therefore, it is dif-ficult to detect the presence of congenital hypothy-roidism during the first two weeks of life only on thebasis of clinical symptoms. Suggestive symptoms,which could denote the presence of congenital hy-pothyroidism already in this early period, usuallyinclude: higher birth weight and body length, en-largement of the posterior fontanelle, delay in thepassage of meconium, hypothermia, dry skin, pro-tuberance of abdomen, slightly protruding tongue,decreased motility, somnolence, and persistence ofneonatal jaundice.

More evident and typical symptoms of infantile hy-pothyroidism will develop not earlier as at the endof the first month of life, but more often during thesecond or the third month of life. However, the diag-nosis of congenital hypothyroidism, detected on thebasis of the clinical symptoms appearing in this pe-riod, is very late. Peristence of T4 deficiency duringthe first 2–3 months of life has, therefore, permanentand severe consequeces for intellectual and motor de-velopment of an affected child. Substitutional ther-apy introduced as late as in this period is able to pre-vent the origin of disorder of somatic development,but the symptoms of permanent impairment of psy-chomotor development of an affected child are usu-ally present. By clinical examination it is possible todetect: e.g., decrease of mental capacity, impairmentof psychic concentration, impairment of muscular co-ordination (mainly fine motor activity), impairmentof speech development, and the like. Therefore, onlythe treatment from the first days of life, realized byadministration of thyroxine in doses adequate to theweight and age of a child, may prevent the origin ofpermanent conseqences of neonatal hypothyroidism.

With regard to the need of prompt diagnosis andtherapy of neonatal hypothyroidism screening ofcongenital hypothyroidism in all newborns has beendone in our country since 1985. The aim is to securetheir normal psychomotor and physical development.


Screening examination of newborns is the only pos-sible prevention of permanent consequences of suchsporadic congenital hypothyroidism, in which signifi-cant T4 deficiency followed by CNS impairment doesnot occur prenatally, but as late as in the first days ofpostnatal life. However, it is generally accepted, thateven a short period (lasting only a few days) of sig-nificant T4 deficiency in early postnatal period leadsto permanent disorders of psychomotor development,at least to disorders of perception and coordination.

By neonatal screening, concentrations of total andbound T4 or TSH concentration are measured insamples of capillary blood. The samples are takenafter the heel puncture of a newborn on 3rd–5th dayof life. The first examination found out only serumT4 concentration. If its level is low, by another ex-amination of the taken blood sample serum, TSHconcentration is assessed as well. By screening exam-ination neonatal hypothyroidism may be diagnosedreliably within the first week of life.

In the past the diagnosis was not frequentlymade until full-blown signs emerged several weeks ormonths after birth. Fortunately, this delay has beenlargely eradicated by the measurement of blood thy-roxine level in neonatal screening programs. Suchprograms are highly successful in preventing themental retardation and other neurological sequelaethat result from prolonged hypothyroidism duringearly infancy. In the past, when hormonal substi-tutional therapy did not exist, every severe neonatalhypothyroidism resulted in gradual development ofthe clinical picture of cretinism. At present, the termcretinism is, however, archaic because in our countrythanks to the introduction of iodised salt, endemiccretinism does not exist at all. Alike in instances ofsporadic congenital hypothyroidism, thanks to thescreening of newborns and following adequate sub-stitutional hormonal therapy, the fully developedclinical picture of sporadic cretinism does not oc-cur as well. In spite of this fact, physicians as wellas students of medicine should know the possibleconsequences of not only delayed diagnosis and de-layed therapy of neonatal hypothyroidism, but alsothe consequences of nontreated neonatal hypothy-roidism.

The clinical features of cretinism gradually de-velop from early childhood to adulthood. In a childwith congenital hypothyroidism the typical symp-toms of infantile hypothyroidism begin to develop

from the second or the third month of life. De-creased motility and somnolence of a child becomemore and more evident. Anorexia causes small incre-ment of body weight. The voice of a child becomesdeeper and hoarse, the child cries very little. Largertonque (macroglossia) is gradually protruding fromthe permanently open mouth. Constipation is moreevident, muscular hypotony and decreased intensityof reflexes appear. Umbilical or inquinal hernia oftenoccurs.

The skin becomes evidently cold, dry, and rough.It is of yellowish colour and feels rough and doughy.Hair becomes dry and grow slowly. Nails are brit-tle and their growth is pure. The facial appearanceof the child gradually acquires myxedematous fea-tures. The anterior and posterior fontanelles are notyet closed. Holding up of the head is delayed. Psy-chomotor development and linear growth of the childare also delayed. Nowadays, when the screening ofcongenital hypothyroidism is provided for all new-borns, such stage of infantile hypothyroidism shouldnot, however, occur.

In the next period the clinical picture of non-treated infantile hypothyriodism is characterized bydelayed eruption of the deciduous teeth, by delayedorigin of ossification centres and successive delay inbone age. X-ray examination reveals decreased num-ber of obviously followed ossification centres of skele-tal bones as well as their slow enlargement. Theretardation of ossification and longitudinal growthof bones originates because thyroid hormone defi-ciency is accompanied by both a decrease in secre-tion and lessened effectiveness of STH as well as withinsufficient skeletal maturation. STH efficiency is de-creased probably as a sequel of impaired formationof IGF I production, which influences the cartilage ofepiphyseal growth plate. Decreased proteosynthesisparticipates also in retardation of skeletal develop-ment.

The deciduous teeth persist for a long time andpermanent dentition is rather delayed. The skullshows a poorly developed base. Delayed closure ofthe fontanelles leads to a head that is large in rela-tion to the body. Neck is usually short and wide.Both, shortening of the skull base and disorder ofnasal bones development cause pulling the root ofthe nose back. Retardation of mental and physicaldevelopment is manifested by delay in reaching thenormal milestones of development, such as holding


up the head, sitting, standing, walking, and talk-ing. Though epiphyseal plates remain open quitelong, often even longlife, linear body growth is sig-nificantly retarded and finishes prematurely, what ismanifested by a short stature.

In the adult, the clinical picture of cretinism ischaracterized mainly by various degrees of oligophre-nia (from debility to idiocy), and by thyroiddwarfism. The severe disorder of mental develop-ment is the result of insufficient differentiation andmaturation of cerebral cortex neurons, as well asof their cut in number. The short stature of anadult cretin is characterized by the disproportion-ately short limbs in relation to the trunk. Impairedbone ossification gives also rise to the origin of vari-ous skeletal deformities, which occur especially in themost mechanically loaded spots. Thoracic kyphosisand coxarthrosis originate most frequently. Defor-mity and restriction of motion of hip joint cause thetypical waddling gait (duck gait) of the cretin.

The skin of cretin is dry, coarse, rough, wrinkly,and it often desquamates. It has a yellow tint or evenpeculiar wax-orange colour. It feels doughy and cool.The secretions of the sweat glands and sebaceousglands are reduced, leading to dryness and coarse-ness of the skin. Its peculiar colour is induced by hy-percarotenemia and successive deposition of caroteninto the skin. Hypercarotenemia is due to the dis-order of caroten transformation to vitamin A in theliver. Growth of hair is retarded. The hair is dry,brittle, lacks luster, unmanageable sparse, and tendsto fall out. Special mucinous (jelly-like) materialconsisting of protein complexed with mucopolysac-charides (mainly with hyaluronic acid, or also withchondroitin sulphate), electrolytes, and water is ac-cumulated in the dermis. This material is responsiblefor the peculiar edematous look of the patient skintermed myxedema (mucinous edema). Myxedemais a tough edema which on the contrary to normal(true) edema does not leave a pit on the skin surfacewhen an edematous part is pressed on (nonpittingedema).

Special mucinous material infiltrates also othertissues, e.g., tongue muscle, skeletal muscles, my-ocardium, and mucosa and submucosa of pharynx,larynx, stomach, and intestines. Due to thicken-ing of the mucous membranes of the larynx and vo-cal chords, caused by myxedematous infiltration, thevoice becomes deeper and hoarse.

The facial features of the cretin are considerable(characteristic). The mucinous edema is responsi-ble for the thickened features and puffy apearanceof the patient. Dull expressionless face, poor mimic,and permanently open mouth with protruding en-larged tongue are typical. Macroglossia is partiallyresponsible for snuffled speach of the cretin. Lips arethick. Palpebral fissures are narrowed due to peri-orbital myxedema and ptosis. Lower forehead, widecheek bones, and flat, broad, saddle-shaped, pulledback nose, along with prognatism and wrinkly skincause peculiar facial appearance of the cretin, de-noted as simian (pithecoid) physiognomy. The teethare malformed and readily become carious.

Basal metabolic rate (BMR) of the cretin is signifi-cantly decreased. Therefore, slightly decreased basalbody temperature, cold intolerance, and decreasedappetite are present. Serum T4 and T3 concentra-tions are low. Serum TSH concentration is increased.Concentrations of total cholesterol and low-densitylipoproteins (LDLs) in serum are increased. Anemiais often present.

Heart rate and respiratory rate are slow (brady-cardia and bradypnea). Cardiac output and cardiacindex at rest are decreased. Decreased heart rate andcardiac output reflect the loss of the chronotropic andinotropic effects of thyroid hormones. X-ray pictureshows enlarged heart shadow as a result of dilata-tion of flabby myocardium, as well as due to effusioninto the pericardial sac of fluid rich in protein andmucopolysaccharides. Mucinous effusions may alsooccur into any serous cavity.

Cretins are less efficient, they become easily tired.Stiffness, cramping, and aching of muscles are com-mon complaints. Muscles strenght and tonus areslightly decreased. Weakened ligaments cause hy-perextensibility of joints and the origin of flat-feet(pedes plani). Muscle hypotonia gives rise to an evi-dent protuberant abdomen, and ptosis of upper eye-lid. Peristaltic activity is decreased and, togetherwith the decreased food intake, is responsible forchronic constipation.

The symptoms of hypogonadism are often present.Sexual maturation is retarded, sexual infantilism andinfertility are usually present. Defective hearing andeven deafness are very frequent.

Perceptive deafness may occur in association withcongenital hypothyroidism caused by genetically de-termined defect in thyroid hormone biosynthesis,


mainly by a defect in the organic binding of iodine(Pendred syndrome). Goiter and hypothyroidismare usually milder. This syndrome has autosomalrecessive inheritance.

5.4.2.2 Juvenile hypothyroidism

Juvenile hypothyroidism is a disease caused by thethyroid hormone deficiency which originates when-ever in the childhood from the end of the second yearof life until epiphyseal fusion. Its most typical clini-cal symptoms are retardation of somatic and sexualdevelopment. Hypothyroidism results also in mentalslowness but not in permanent mental retardation.

The most common cause of peripheral (primary)juvenile hypothyroidism is autoimmune thyroiditis(Hashimoto disease). Sometimes, it may be the re-sult of decompensation either of an ectopic (dys-genetic) thyroid gland, or of heterozygous type ofgenetically determined defect in thyroid hormonebiosynthesis. Its rare cause is subacute or acute thy-roiditis. In exceptional cases it may originate due toinfiltration of thyroid gland tissue in patients withhistiocytosis and cystinosis. Central juvenile hy-pothyroidism is very rare. It may usually occur dueto a tumor in the area of pituitary or hypothalamus,most often due to craniopharyngioma.Clinical features. In a child whose mental devel-

opment and physical growth were normal before theonset of hypothyroidism, the clinical symptoms ofthyroid hormone deficiency start gradually appaer.Skeletal maturation is markedly delayed. Growthfailure precedes the appearance of other symptoms.The rate of linear growth is characteristically lessthan that of weight gain, which is due to develop-ment of myxedema. Permanent dentition is delayed,too. Perception of the child gradually decreases, thechild becomes less bright, and a poor performance atschool is evident. Poorer psychic activity and intel-lectual performance of the child result from the ac-tual thyroid hormone deficiency, and, therefore, arereversible.Sexual maturation is retarded and the onset of

puberty is delayed. The result of growth and sex-ual development retardation is a patient who ap-pears much younger than his or her chronologicalage (youthful appearance, infantile appearance). Inspite of the delay of epiphyseal union the stature ofthe patient in the adulthood is short and dispropor-tional. Legs are relatively shorter compared with the

trunk, therefore, the ratio between the upper bodysegment (head, neck, and trunk) and lower body seg-ment (legs) is increased.

In the clinical picture of juvenile hypothyroidismthe other symptoms of thyroid hormone deficiencyare also present. They are similar to those of adulthypothyroidism, however, they are present to a vary-ing, but usually milder degree.

Early diagnosis of juvenile hypothyroidism guaran-tees its very good prognosis, because hormone sub-stitutional therapy prevents the origin of disorders ofgrowth and sexual development, and settles psychicactivity and intellectual performance of the child.Permanent mental disorders do not occur, as CNSdevelopment was taking place already in the periodwhen thyroid hormone deficiency was not present.

5.4.2.3 Adult hypothyroidism

Clinical syndrom of adult hypothyroidism (Gull’sdisease) is developed if the thyroid hormone defi-ciency originates as late as the epiphyseal growthplates are closed. It occurs in about 1% of adultpopulation. It is more common in women than inmen (7:1) and appears most often between the agesof 40 and 60. Its characteristic manifestations aredecrease of BMR, fall of all activities of organism,and myxedema. At present, with regard to the suffi-cient health care and therapeutical possibilities, fullydeveloped clinical picture of adult hypothyroidismpractically does not occur.

In most instances it is a peripheral (primary) hy-pothyroidism, which accounts for 95% of all casesof hypothyroidism, the remaining 5% being central(secondary and tertiary) hypothyroidism.

Peripheral hypothyroidism may be either spon-taneous (about 65 %) or iatrogenic (about 35 %).The most common cause of spontaneous primary hy-pothyroidism is Hashimoto thyroiditis, mainly its fi-nal stage in which goiter is either absent or has goneunnoticed. The presence of circulating thyroid au-toantibodies in up to 80% of the patients may berevealed. Rarely it may occur in later life of the pa-tients with multinodular goiter. Iatrogenic primaryhypothyroidism may be postablative (surgery or ra-dioiodine) or postradiation (e.g., for lymphoma).

Central hypothyroidism is most commonly the re-sult of postpartum pituitary necrosis and less com-monly the result of a tumor of the adenohypophysisor adjacent regions (pituitary hypothyroidism). Less


common is hypothalamic hypothyroidism which re-sults from inadequate secretion of TRH due to im-pairment of hypothalamic cells by various destruc-tive processes.

The first symptom of developing primary hypothy-roidism in adults is an increase of serum TSH con-centration. The state of increased serum TSH con-centration, however, still without presence of classicclinical symptoms of hypothyroidism (serum thyroidhormone concentration is still normal) has been re-cently demonstrated as subclinical hypothyroidism.Other synonyms for this phase of primary adult hy-pothyroidism are: preclinical hypothyroidism, bio-chemical hypothyroidism, or decreased thyroid re-serve. Some specialists acquire also the presence ofcirculating thyroid autoantibodies for diagnosis ofthis functional state. In some patients with sub-clinical hypothyroidism also the presence of the dis-order of lipid metabolism (increased plasma LDL,total cholesterol, apoprotein B, and triacylglycerolsconcentrations) was proved. From the total numberof the patients with diagnosed subclinical hypothy-roidism in about 5 % of cases clinically manifestedhypothyroidism develops yearly.

The clinical picture of primary hypothyroidism inadults usually develops very slowly. Its first symp-toms start develop only after destruction of signifi-cant part of thyroid parenchyma. The onset of hy-pothyroidism is usually so insidious that the clas-sic clinical manifestations may take months or evenyears to appear and frequently go unnoticed by per-sons well acquainted with the patient. Therefore, thesymptoms are often attributed incorrectly by the pa-tients and relatives to increasing age. The gradualdevelopment of the hypothyroid state is due to a slowprogression of both thyroid hypofunction and theclinical manifestations after thyroid failure is com-plete.

The early symptoms of adult hypothyroidism arevariable and nonspecific. Cold intolerance, drowsi-ness and slowing of intellectual and motor activitiesmay be early manifestations. Increasing tiredness,weakness, slowness, and lethargy are common andlead to difficulty in performing a full day’s work. Thepatients complain of poor memory and evident som-nolence. They become apathetic and listless, andlose interest in work and environment. Their trainsof thoughts are slow, they are bradypsychic. De-spite a reduction in appetite, modest weight gain of-

ten occurs. Constipation may develop or, if present,become worse. The patients almost do not sweat.Their skin becomes drier and cooler. Women maycomplain of menstrual disturbances. Poor libido oc-casionally occurs in both sexes. At this stage of thedisease the BMR is moderately decreased.

The fully developed clinical picture of adult hy-pothyroidism is characterized by typical facial ap-pearance. Periorbital puffiness, broader and flatnose, thickened lips, sparce eye-brows, and poormimic are evident (facies myxoedematica).

Skin ot the patient is dry, coarse, rough, andscurfy. It feels cool and dougher. Skin is pallor withorange tint. Hair is sparce, dry, and lacks luster.Nails are thin, fragile, brittle, and grow slowly.

Myxedema is most apparent on the face, the dorsaof the hands and feet, forearms, and in supraclav-icular fossae. Mucinous material infiltrates alsoother tissues. Therefore, tongue is thick and en-larged (macroglossia) causing articulatory (pronun-ciational) problems (dysarthria). Dysarthria to-gether with slow train of thoughts (bradypsychism)results in slow speech (bradylalia). Voice becomesdeeper and husky. Myxedemotous infiltration of mu-cous membranes of Eustachian tube and middle ear,as well as myxedematous changes of cochlear fluidcause defective hearing.

With progression of the diesease the BMR falls toits minimal value, usually between –35 and –45%.The decrease in energy metabolism and heat produc-tion is reflected in the low BMR , decreased appetite,cold intolerance, and slightly lower basal body tem-perature (moderate hypothermia). The rate of ab-sorption of glucose from the gut is decreased, there-fore, the oral glucose tolerance curve is characteris-tically flat. The decrease in lipid degradation resultsin the increase of serum cholesterol, triacylglycerols,and LDL concentrations. Serum concentration ofhigh-density lipoprotein (HDL) is decreased. Thesechanges of serum lipid concentrations usually accel-erate the development of atherosclerosis and its com-plications, however, only in the hypothyroid patientswith the presence of arterial hypertension.

Decreased adrenergic activity, respectivelly de-pressed response of tissues to catecholamines accom-panies thyroid hormone deficiency. The mechanismunderlying the decreased adrenergic responsivenessis uncertain. It is assumed that one of the causescould be the decrease of the number of adrenergic


receptors. The cardiac output and cardiac index atrest are decreased because of the reduction in bothstroke volume and heart rate, reflecting loss of the in-otropic and chronotropic affects of thyroid hormones.Peripheral vascular resistance at rest is increased,and blood volume is reduced. These hemodynamicalterations result in narrowing of pulse pressure, pro-longation of circulation time, and decrease in bloodflow to the tissues. The decrease in cutaneous cir-culation is responsible for the coolness and pallor ofthe skin and the increased sensitivity of the patientto cold.

Myocardial contractility is decreased. Dilatationof myocardium is evident, but signs of myocardialhypertrophy are not present. The heart is enlargedowing to the both dilatation and pericardial effu-sion. Electrocardiographic changes include sinusbradycardia, prolongation of the PR interval, lowamplitude of QRS complex, and flattened or in-verted T waves. Histopathological examination ofthe myocardium reveals presence of interstitial de-posits of mucinous material (interstitial myxedema)and swelling of cardiomyocytes, with loss of striation.The set of introduced signs, concerning myocardium,respectively heart, has been termed hypothyroid car-diomyopathy (myxedema heart).

Skeletal muscles are usually stiff and aching. De-layed muscle contraction and relaxation are respon-sible for the slowness of movement. Tendon jerks arealso delayed, evidently Achilles tendon reflex. Onhistopathological examination, the muscle fibers mayshow swelling, loss of normal striations, and separa-tion by mucinous deposits.

Thyroid hormone deficiency and successive my-xedematous infiltration of mucous membranes ofGIT cause decrease of peristaltic activity, as wellas of intestinal wall tonus. Decreased peristaltic ac-tivity, together with the decreased food intake, isresponsible for the frequent complaint of constipa-tion. These intestinal disorders may be extreme,leading to fecal impaction and great distention ofcolon (myxedema megacolon). Gaseous distention ofthe abdomen may also occur (myxedema ileus, ady-namic ileus). The effects of hypothyroidism on in-testinal absorption are complex. Although the ratesof absorption of many substances are decreased, thetotal amount eventually absorbed may be normal be-cause the decreased motility of the bowel may allowmore time for absorption to take place.

Psychic and motor activities of the hypothyroidpatients are slow. The patients are not able toconcentrate to their work. There is loss of initia-tive. One of the characteristic features is a gen-eral slowing of all intellectual functions, includingspeech. Slow-wittedness, slowness in answering ques-tions, and memory defects are common. Lethargyand somnolence are prominent. Dementia may oc-cur and in the elderly patient may be mistaken forsenile dementia. Psychiatric reactions are not un-common and are usually of the paranoid or depres-sive type. The mentioned changes of CNS functionoriginate due to actual thyroid hormone deficiency,and, therefore, they are reversible after adequate hor-mone therapy.

In the both sexes, sexual activity and reproduc-tive function are significantly decreased. In men, hy-pothyroidism is usually accompanied by diminishedlibido, impotence, and oligospermia. In women, itis commonly associated with diminished libido, dis-orders even failure of ovulation, and irregular men-strual bleeding (rarely menorrhagia, but more fre-quently oligomenorrhea even amenorrhea).

The mild normocytic, normochromic anemia of-ten occurs in the patients with hypothyroidism. It isthe result of hypofunction and hypocellularity of thebone marrow. It is the response to the diminishedoxygen requirements of tissues and to decreased pro-duction of erythropoietin. In about 12% of patientswith primary hypothyroidism pernicious anemia as-sociated with the presence of an atrophic gastric mu-cosa occurs. In these patients also achlorhydria aftermaximal histamine stimulation, and achylia gastricaare usually present. The coexistence of perniciousanemia with primary hypothyroidism occurs in thoseinstances in which autoimmune mechanism plays aprimary role in the pathogenesis of primary hypothy-roidism. In circulating blood of these patients be-sides antithyroid immunoglobulins G (IgG) also au-toantibodies against gastric parietal cells have beenfound. Immediate cause of pernicious anemia is thedeficiency of vitamin B12 induced by its impairedabsorption. Insufficient vitamin B12 absorption iscaused by deficiency of intrinsic factor due to atro-phy of parietal cells. Folate deficiency resulting frommalabsorption may also be responsible for a mega-loblastic anemia. The both, menorrhagia and inef-fective absorption of iron resulting from achlorhydriamay lead to a microcytic, hypochromic anemia.


In the blood of a patient with primary hypothy-roidism low T4 and proteine-bound iodine concen-trations, and a high TSH concentration are present.In patients with central hypothyroidism blood TSHconcentration is low.

At present the late stage of fully developed clinicalpicture of adult hypothyroidism does not occur. Inthe past, when the patients with severe long-standinghypothyroidism were untreated, they usually died ofthe consequences of accelerated atherosclerosis (mostfrequently coronary or cerebral), less frequently dueto myxedema coma.Myxedema coma. It is a rare acute complication

of hypothyroidism, which may be fatal. The factorspredisposing to myxedema coma include cold expo-sure, trauma, infection, and administration of CNSdepressants. It is manifested by significant decreaseof all metabolic processes, by evident hypothermia(decrease of rectal temperature to 35–32oC), extremebradycardia, systemic arterial hypotension, threadypulse, and respiratory insufficiency. Extremely som-nolent patient gradually becomes soporous, and fi-nally develops coma. Mortality of the patients withmyxedema coma is high, usually 50–70 per cent.

5.4.3 Hyperthyroidism

The complex of clinical, biochemical, and functionalfindings that originate when the tissues are exposedto, and respond to, excessive quantities of the thyroidhormones is termed thyrotoxicosis. The term hyper-thyroidism is best reserved for denoting only thosedisorders in which sustained hyperfunction of thethyroid gland (overproduction of thyroid hormones)leads to thyrotoxicosis. Thus thyrotoxic states canbe classified according to whether or not they areassociated with hyperthyroidism:

I. Thyrotoxicosis associated with hyperthyroidism

A. Hyperthyroidism due to immunogenic thyroidautonomy

B. Hyperthyroidism due to nonimmunogenic thy-roid autonomy

a) Toxic multinodular goiter

b) Toxic adenoma

C. Hyperthyroidism due to nonimmunogenic ab-normal thyroid stimulator

D. Hyperthyroidism due to increased TSH produc-tion

E. Iodine-induced hyperthyroidism

II. Thyrotoxicosis without hyperthyroidism

A. Thyrotoxicosis factitia

B. Transient thyrotoxicosis associated with thy-roiditis

C. Thyrotoxicosis due to ectopic production of thy-roid hormones

In the patients with thyrotoxicosis total serum T3and T4 concentrations, as well as free T3 and T4concentrations are increased. In some patients withhyperthyroidism only serum T3 concentration maybe extremely increased. Whether this phenomenonresults solely from the preferential increase in thy-roid secretion of T3 or whether there is in addition adisproportionate increase in peripheral conversion ofT4 to T3 is uncertain, but the former factor is likelyresponsible in the majority. The thyrotoxic state re-sulting from extremely increased serum T3 concen-tration has been designated T3 toxicosis. The serumtotal T4 concentration and free T4 concentration arenormal or decreased in the absence of a deficiency ofTBG. In some patients, T3 toxicosis may be the fore-runner of the usual form of thyrotoxicosis in whichproduction of both T3 and T4 is increased, whereasin other patients it may persist as such. T3 toxicosistends to be more frequent in the elderly population.It may occur in association with Graves-Basedow dis-ease, toxic adenoma, or toxic multinodular goiter.Preliminary experience suggests that patients withT3 toxicosis are more likely to enjoy a long-term re-mission after withdrawal of antithyroid drug therapythan patients with the usual form of thyrotoxicosis,in which production of both T4 and T3 is increased.

Thyrotoxicosis may sometimes be associated witha clear elevation of serum T4 concentration, but witha normal or decreased serum T3 concentration. Thissyndrome is termed T4 toxicosis. It occurs most com-monly in the setting of prior excess iodine exposure(iodine-induced thyrotoxicosis) in patients who areelderly, ill, or both. Increased iodine intake favorsT4 biosynthesis. In the absence of a history of excessiodine, the combination of high serum T4 concentra-tion and normal serum T3 concentration presumably


reflects inhibition of peripheral T3 generation fromT4 .

The clinical syndrom of thyrotoxicosis is charac-terized by manifestation of symptoms resulting fromaffection of several organs or organ systems. The ma-jor of these symptoms are induced by hypermetabolicstate of organism. Hyperthyroidism and thyrotoxi-cosis belong to the most frequent endocrine diseases.They occur in 2–5% of adult population, much moreoften in women than in men (5–7:1).

5.4.3.1 Thyrotoxicosis associated with hy-perthyroidism

Thyrotoxicosis associated with hyperthyroidism en-compasses those diseases that lead to sustained over-production of hormones by the thyroid gland itself.The most frequently, hyperfunction of the thyroid re-sults from the action of an abnormal (immunogenicor nonimmunogenic), homeostatically unregulatedthyroid stimulator of extrapituitary origin, as inGraves-Basedow disease (being the most common),or in hyperthyroidism associated with trophoblastictumor (being rare). Hyperthyroidism may be alsorelatively frequent due to the development of one ormore areas of autonomous hyperfunction within thegland itself. The hyperfunction of the thyroid glandrarely results from excessive TSH secretion.

A. Hyperthyroidism due to immunogenic thy-roid autonomy (Graves-Basedow disease)Graves-Basedow disease is the most frequent formof hyperthyroidism. It is an autoimmune disease inwhich the thyroid gland escapes feedback regulatoryinfluence, and becomes autonomous, i.e., indepen-dent from TSH. It is more common in women thanin men and appears most often between the ages of20 and 40. It is very rare before 10 and after 70 yearsof age. In the English-speaking world this disorderis known as Graves disease and on the continent ofEurope as Basedow disease.Etiology and pathogenesis. There is almost uni-

versal agreement that the cause of this disease is theorigin of immunoglobulins of IgG class. These im-munoglobulins act as antibodies against the thyroidTSH reseptors on the plasma membrane of epithelialcells of follicles. They are elaborated by B lympho-cytes found directly in the thyroid gland. However,in circulating blood of the patient several types of

antithyroid antibodies can be present (it is a hetero-geneous group of polyclonal antibodies). Until latelythey were called thyroid-stimulating immunoglobu-lins (TSIs), however, recently a preferable nomencla-ture is to refer to these immunoglobulins as TSH re-ceptor antibodies (TRAbs). This term is preferablebecause only some of these immunoglobulins afterbinding to TSH receptors have a stimulating effectson epithelial cells (in ways analogous to the normalaction of TSH). Others, however, inhibit the bind-ing of TSH to its receptors in thyroid tissue (TSH-binding inhibitory imunoglobulins – TBIIs). TSHreceptor antibodies are present in more than 90% ofpatients with active Graves-Basedow disease.

The thyroid-stimulating immunoglobulins (TSIs)after binding to TSH receptors activate adenylatecyclase – cyclic adenosine monophosphate systemwhich stimulates the cascade of intracellular reac-tions. These reactions lead to the growth of thethyroid gland (via hypertrophy and hyperplasia ofepithelial cells), to the increased vascularity of itsparenchyma, and to the increased biosynthesis andsecretion of thyroid hormones. TSIs are an immuno-genic abnormal thyroid stimulator. TSIs have essen-tially prolonged duration of action relative to that ofTSH. Their high concentration in circulating bloodeffects the epithelial cells of the thyroid parenchymapermanently, while TSH has circadian rythm and arather short half-life. Effects of TSIs are, for thepresent, the only example for such situation whenautoantibodies do not act destructively.

The basic problem of etiopathogenesis of Graves-Basedow disease is the answer to the question whatis antigenic stimulus for the production of antithy-roid autoantibodies, respectively what causes the ori-gin of clones of thyroid-sensitized T lymphocytes.There is a hypothesis about random mutations hav-ing no proofs for the present. But there is a varietyof evidence which links autoimmune thyroid diseaseto infection with the gram-negative enteric bacte-ria. It has been found out that some bacteria ofthis type contain a TSH binding site that also bindsGraves-Basedow-related IgG. Therefore, the initiat-ing event may be the infection with gram-negativebacteria, mainly by Yersinia enterocolitica and E.coli, that gives rise to antibodies that cross-reactwith components of the human thyroid cell mem-branes. In an individual with the predetermined ab-normality in immune surveillance, these antibodies


would persist and give rise to the clinical thyroiddisease. Immediate impulse of the clinical manifes-tation of this disease may be various external factors,as e.g., infectious disease accompanied by fever, se-vere emotinal stress, some medical drugs, or highiodine intake. This hypothesis on cross-reaction ofantibodies, originally elaborated against antigen ofexogenous pathogenic factor, with self-antigen of or-ganism, does not, meanwhile, gives the answer to thequestion, why antibodies against several antigens ofthyroid gland simultaneously originate.

The hypothesis on the origin of clones of thyroid-sensitized T lymphocytes would require that sensi-tized T lymphocytes infiltrate the thyroid and elab-orate stimulatory lymphokines, but an evidence thatthis occurs is lacking. This hypothesis presumes thatin patients with chronic autoimmune thyroid disease,a sustained, genetically determined disorder of im-mune surveillance permits the persistence of clonesof thyroid-sensitized immunocytes. This is likely theresult of abnormalities in suppressor T lymphocytes(disturbance of their function or decrease of theirnumber). Therefore, sensitized helper T lympho-cytes start to produce lymphokines which stimulatethe specific B lymphocytes. These activated B lym-phocytes begin to produce the specific antithyroidIgG.

At present the pathogenesis of infiltrative ophthal-mopathy (orbitopathy), which is the characteristicpart of the clinical picture of Graves-Basedow dis-ease, is not yet clear. The hypothesis on productionof abnormal immunoglobulin is the best accepted forthe present. This hypothesis assumes that an ab-normal IgG acts in concert with an exophthalmos-producing factor composed in part of the beta sub-unit of TSH. The result of their effect is the inductionof mucopolysaccharide synthesis, edema formation,and successive infiltrative changes in retroorbital tis-sues. There has been no evident progress toward elu-cidation of the pathogenesis of the infiltrative der-mopathy. In its origin an abnormal immunoglobulinmay also probably take part.

In etiopathogenesis of Graves-Basedow disease ge-netic factors play an important role. Populationstudies reveal an increased frequency of haplotypesHLA-B8 and HLA-DRw3 in whites. Of particularimportance is the HLA-DRw3, which significantly in-crease the risk of Graves-Basedow disease and mayaffect its response to treatment. Not surprisingly,

there is a distinct familial predisposition to this dis-ease. The hereditary factor in Graves-Basedow dis-ease also appears to involve its autoimmune aspects.This is suggested by the increased incidence in pa-tients with Graves-Basedow disease or in membersof their families of other autoimmune disorders, suchas Hashimoto disease, primary thyroprive hypothy-roidism or pernicious anemia, and probably otherdiseases with prominent autoimmune features.

Clinical features. Graves-Basedow disease is char-acterized by four major manifestations:

1. Diffuse goiter;

2. Thyrotoxicosis;

3. Infiltrative ophthalmopathy;

4. Infiltrative dermopathy.

In the individual patients these four major mani-festations need not appear together. Infiltrative oph-thalmopathy and infiltrative dermopathy may occurindependently of the presence of goiter and symp-toms of thyrotoxicosis. Ophthalmopathy and der-mopathy are specifically related to Graves-Basedowdisease. Thyrotoxicosis is manifested by hyperme-tabolism and by the symptoms resulting from disor-ders of various organ systems. The first two mani-festations, i.e., diffuse goiter and thyrotoxicosis, aretermed diffuse toxic goiter. This term connotes thepresence of thyrotoxicosis resulting specifically fromGraves-Basedow disease.

1. Goiter

Almost in all the patients with Graves-Basedow dis-ease the thyroid gland is enlarged. But only in about3 % of the patients with this disease the thyroid glandis of normal size, however, the symptoms of thyrotox-icosis are usually present. Hyperfunctioning goiter ismostly small or middle size, in some cases it may berather large. Enlargement of the thyroid is diffuseand usually symmetrical. Goiter is soft and vascu-lar, its surface is usually smooth. Enlargement ofthe thyroid may be noted as a fullness in the neck.The rich vascularization of goiter may be sometimesmanifested by evident pulsation of the thyroid witha possible thrill and bruit (murmour) over it (strumapulsans, vibrans et fremens).

2. Thyrotoxicosis

The symptoms of thyrotoxicosis are common for all


forms of thyrotoxicosis irrespectively of the causeof their origin. However, in the clinical picture ofthyrotoxicosis not always all its symptoms must bepresent. Unlike hypothyroidism the clinical symp-toms of thyrotoxicosis are usually developing dur-ing shorter period, in the course of several days orweeks. Only seldom they may develop during sev-eral months. In the patients, emotional stress maybe a forerunner, e.g., a car accident, the death of amember of the family, and the like.

At the onset of the disease mainly subjectivesymptoms dominate, e.g., nervousness, irritability,emotional tension, emotional lability (inappropriatespells of crying or euphoria), and insomnia. The ini-tial manifestations also include excessive sweatingand heat intolerance. Weight loss is usual despitewell-maintained or increased appetite. The patientgets tired and out of breath at work very soon. Dys-pnea and palpitations may occur. Other symptomsof thyrotoxicosis are developing gradually.

Fully developed clinical picture of thyrotoxicosisdue to Graves-Basedow disease is rather variable be-cause its individual symptoms are not always presentand may occur in various combinations. The mostcommon is polysymptomatic thyrotoxicosis, whichis manifested by the symptoms resulting from dis-orders of various organ systems. It is due to thefact that thyroid hormones affect practically all tis-sues of organism. Oligosymptomatic thyrotoxicosismay also appear. The presence of the disease isonly in some organs. Various combinations result-ing from disorders of individual organ systems maybe present. Monosymptomatic thyrotoxicosis is veryrare. It occurs mainly in older patients. In its clinicalpicture disorders of only one organ system dominate.The symptoms of alteration of cardiovascular system(cardial form of thyrotoxicosis), or of skeletal muscles(myopathic form of thyrotoxicosis) are present mostfrequently. The origin of these monosymptomaticforms of thyrotoxicosis is likely due to the increasedsensitivity of tissue of alterated organ system to thy-roid hormones.

Metabolic symptoms of thyrotoxicosis. Overpro-duction of thyroid hormones stimulates metabolic ac-tivity of tissues and gives rise to the state of hyper-metabolism. Excessive activation of oxidative pro-cesses in cells causes the increased consumption ofoxygen per weight unit of tissue mass, what is man-ifested by the increase of BMR (in some instances

even +100%). The both, synthesis and degradationof protein are increased, the latter to a greater ex-tent than the former, with the result that there is netdegradation of tissue protein. This is evident in nega-tive nitrogen balance, loss of weight, muscle wasting,weakness, and mild hypoalbuminemia. The stimu-lation of energy metabolism and heat production isreflected in the increased appetite and heat intoler-ance and in the slightly elevated basal body tem-perature. Cutaneous vasodilatation and excessivesweating (hyperhidrosis) are the protective mecha-nism against possible origin of hyperthermia. Theincreased lipid degradation is reflected in a decreaseof plasma cholesterol, LDL, and triacylglycerols con-centrations. The oral glucose tolerance curve is usu-ally abnormal, often with high amplitude and steepincline (Gothic type). It is probably due to the stim-ulative effect of thyroid hormones to resorption ofglucose in intestine. Pre-existing diabetes mellitus isaggravated by thyrotoxicosis, perhaps as a result ofincreased degradation of insulin.

Cardiovascular symptoms of thyrotoxicosis. Theyare the most frequent and most prominent manifes-tations of thyrotoxicosis. They are present almost inevery patient with Graves-Basedow disease. Hyper-metabolism and increased heat production give riseto the increased demands of tissues for oxygen supplyand thereby also for circulation. These changes leadto the origin of syndrome of hyperkinetic circulation.Thyroid hormones in excess also have a direct car-diostimulatory action, possibly mediated by changesin the state of contractile proteins (mainly myosin)or in the function of sarcoplasmic reticulum. How-ever, increased cardiac sensitivity to catecholaminesin hyperthyroid subjects is also considered.

The most characteristic cardiovascular symptomof thyrotoxicosis is sinus tachycardia (pulse rategreater than 90beats/min). It is almost alwayspresent, even at rest and during sleep. Respiratoryarrhythmia is not present. During excercise heartrate is increasing disproportionately to the degree ofphysical load. Also dyspnea usually appears.

Cardiac arrhythmias are common with thyrotox-icosis. They are almost invariably supraventricular.In some patients, paroxysmal supraventricular tachy-cardia may also occur. Approximately 10% of thepatients with thyrotoxicosis manifest atrial fibrila-tion. Ventricular arrhythmias are unique. Palpita-tions may be rather common subjective symptom.


At rest, peripheral vascular resistance is decreased,and cardiac output is increased as a result of an in-crease in both stroke volume and heart rate. Sys-tolic blood pressure is slightly increased due to theincreased stroke volume. Diastolic blood pressureis decreased due to peripheral vasodilatation. Thepulse pressure is widened as a result of both an in-crease in systolic pressure and a decrease in diastolicpressure.

As a result of a direct effect of increased concen-trations of thyroid hormones on myocardium is long-term increased oxygen consumption in cardiomy-ocytes. Persistence of increased oxygen consump-tion and increased energy consumption (due to in-creased cardiac work) may lead to the origin of hy-poxic changes in the myocardium. Also increaseddegradation of protein has a negative effect on my-ocardium. Due to the noted hypoxic and metabolicchanges in some patients thyrotoxic cardiomyopathy(cor thyreotoxicum) may occur after a long period ofpersisting of thyroid hormone overproduction. It isclinically manifested by severe forms of arrhythmiaand by a congestive heart failure. The response ofsuch heart to digitalis is decreased.

Ocular symptoms of thyrotoxicosis. These symp-toms are a very frequent manifestation of all formsof thyrotoxicosis, regardless of the underlying cause.Spasm and retraction of the upper eyelids (increasedtonus of musculus levator palpebrae), which lead towidening of the palpebral fissure, are most common.These changes of the eyelids are evident as the pres-ence of a rim of sclere between the upper lids andthe superior margin of the iris (Dalrympl symptom).It is responsible for the bright-eyed, staring appear-ance of the patient with thyrotoxicosis. Accompa-nying lid retraction are the phenomena of lid lag, inwhich the upper lid lags behind the globe, exposingmore of the sclera, when the patient is asked to gazeslowly downward. Therefore, the presence of a rimof sclera is constant (Graefe symptom). When thepatient gazes slowly upward the globe often lags be-hind the upper lid. The movements of the lids arejerky and spasmodic. A fine tremor of the lightlyclosed lids can often be observed (Rosenbach symp-tom). The patients blink rarely, 1–2/min, while thenorm is 3–5/min. This infrequent blinking is termedStellwag symptom. Due to the increased lacrimationin the patients with thyrotoxicosis, expressive shinyeyes can be observed. These ocular manifestations

appear to be the result of increased adrenergic ac-tivity and usually subside when the thyrotoxicosis iscorrected. It is important to distinguish these ocularmanifestations, which occur in all forms of thyrotox-icosis, from those of the infiltrative ophthalmopathy,which are characteristic of Graves-Basedow disease.

Skin symptoms of thyrotoxicosis. Thyrotoxicosisleads to a variety of changes in the skin and its ap-pendages. Most characteristic is the warm moist feelof the skin that results from cutaneous vasodilatationand excessive sweating as part of the hyperdynamiccirculatory state. Skin is, therefore, fine with a vel-vety texture. The hands are usually warm and moist,palmar erythema is common. The complexion is rosyand the patient blushes readily. Increased diffuse pig-mentation is formed occasionally, which may resultfrom hypersecretion of ACTH secondary to acceler-ated turnover of cortisol. Hair is fine and friable,does not retain a wave and some may fall out. Nailsare often soft and friable. A characteristic finding isPlummer nails, especially on the ring finger. Thisterm is applied to separation of the distal margin ofthe nail from the nailbed with irregular recession ofthe junction (onycholysis).

Psychic and nervous symptoms of thyrotoxicosis.These symptoms are an almost invariable accompa-niment of thyrotoxicosis. The patients complain ofnervousness, irritability, psychic and motor restless-ness, anxiety, emotional tension, emotional lability,insomnia, and hyperkinesia. Nervousness may man-ifest as a feeling of apprehension and inability toconcentrate. Emotional lability and irritability maylead to difficulty in interpersonal relationships andto inappropriate spells of crying and laughing, oreuphoria and depression. The patients are scaredwithout apparent reason. Their speech is fast andexciting, trains of thoughts are accelerated. Theyrespond quickly to questions or commands. Theirbehaviour is hyperactive and they are always in ahury. During the interview the patient cannot sitstill, drums on the table, taps a foot, or shifts po-sitions frequently. Movements are quick, jerky, ex-aggerated, and often purposeless. Examination re-veals a fine rhythmic tremor of stretched finger tipsof the arms stretched forward (it is better inspectedby touch than by sight). The fine rhythmic tremorof put out tongue and lightly closed eyelids is alsopresent. Tendon reflexes are rapid, mainly Achilles’jerk. The physiological basis of the findings refer-


able to the nervous system is not well understood.In part, they may reflect increased adrenergic activ-ity.Symptoms of thyrotoxicosis due to alterations of

skeletal muscles. Weakness and fatigability are fre-quent. Often the weakness is most prominent in theproximal muscles of the limbs (mainly extensor ofthe legs) and is manifested by difficulty in climb-ing stairs or in maitaining the leg in an extendedposition. The patient is also unable to climb thechair (Plummer symptom) or to rise from a sitting.Thyrotoxicosis may lead to degeneration of skeletalmuscle fibres. The mentioned disorders of skeletalmuscles are termed thyrotoxic myopathy.Other symptoms of thyrotoxicosis. The common-

est of them are referable to the alimentary tract,mainly those related to bowel function. Diarrhea israre. More often stools are less well formed, and thefrequency of bowel movements is increased. Thyro-toxicosis is generally associated with increased excre-tion of calcium and phosphorus in urine and stool.Excessive loss of mineral is sometimes associatedwith demineralization of bones and occasionally withpathological fractures, especially in elders. Thyro-toxicosis in early life may be associated with delayedsexual maturation, although general physical devel-opment is normal and skeletal growth is often ac-celerated. In adults an increase in libido sometimesoccurs in both sexes. In women menstrual function isusually disturbed. The change in menstrual patternusually takes the form of oligomenorrhea with a vari-able intermenstrual period, occasionally progressingto amenorrhea.

3. Infiltrative ophthalmopathy

Infiltrative ophthalmopathy (infiltrative orbitopathy,exophthalmic syndrome) is characteristic only forGraves-Basedow disease. It occurs in about 50 % ofpatients and is induced by a specific immunoglobu-lin. In some patients it may appear in the course ofthyrotoxicosis, most frequently, however, occurs si-multaneously with thyrotoxicosis. Occasionally, in-filtrative ophthalmopathy occurs in the absence ofdiffuse toxic goiter, an entity that is termed euthy-roid ophthalmic Graves-Basedow disease.

In the patients with infiltrative ophthalmopathy,the volume of orbital contents is increased becauseof both an increase in retrobulbar connective tis-sue and an increase in mass of the extraocular mus-cles. This increase in both retrobulbar tissues is

due to edema resulting from the increased content ofthe glycosaminoglycans and also due to an inflam-matory infiltrate. Glycosaminoglycans are very hy-drophilic substances, and, therefore, the water con-tent in retrobulbar tissues is increased. The inflam-matory infiltrate consists of lymphocytes, mast cells,and plasma cells. Also augmentation of connectiveand fat tissues participates in increased volume ofthe orbital contents. The fibres of extraocular mus-cles show degeneration and loss of striations, withultimate fibrosis.

The symptoms associated with infiltrative oph-thalmopathy are diverse and may appear in vary-ing combinations. The most evident symptom isprotruding of the globe (exophthalmos, proptosis),which is usually bilateral and frequently asymmetri-cal, and may be accompanied by a feeling of pressurebehind the globes. The cause of protruding of theglobes is the increased volume of the orbital contents.When exophthalmos is pronounced, the patient maysleep with the eyes partly open (lagophthalmos).

Edematous and infiltrative changes give rise tomyopathy of the extraocular muscles. Patients fre-quently report that their vision is blurred and thattheir eyes tire easily. Double vision (diplopia) mayoccur. Weakness of the extraocular muscles is mostcommonly evident in an inability to achieve or main-tain convergence (Moebius symptom). Limitationof upward gaze and especially of superolateral gazemay be present. Sometimes the paralysis of someextraocular muscles may occur. It is manifested bypermanent anomalous position of more often bothglobes, but sometimes only one of them. Variousforms of bilateral or unilateral strabismus originate.The ocular muscle weakness that results in impairedupward gaze and convergence and strabismus withvarying degrees of diplopia is termed exophthalmicophthalmoplegia.

Severe and long-standing lagophthalmos promotesdrying and corneal damage with subsequent ulcera-tion of the cornea, keratitis ulcerosa develops. Whenexophthalmos progresses rapidly it is termed pro-gressive exophthalmos. In untreated patients infec-tious inflammation of all orbital structures may occur(panophthalmitis), which may lead to destruction ofone or both eyes and thereby to loss of vision (amau-rosis). Ophthalmopathy connected with such severecomplications is termed malignant exophthalmos.


4. Infiltrative dermopathy

It occurs in about 5–10% of patients with Graves-Basedow disease. It is almost always accompanied byinfiltrative ophthalmopathy, usually of a severe de-gree. Pathological immunoglobulins probably partic-ipate in its origin. Skin is infiltrated by glycosamino-glycans and by the cells characteristic for chronic in-flammatory process. This dermopathy is usually lo-calized over the pretibial area (pretibial myxedema)and over the dorsa of the feet. Rarely it is seen onthe face or dorsa of the hands. The skin of the af-fected areas is thickened, raised, and has a peau d’orange appearance. The indurations are usually dis-crete, assuming a plaquelike or nodular configurationbut in some instances are confluent.

Severe complications of Graves-Basedow disease

Besides the both, congestive heart failure and ma-lignant exophthalmos already mentioned, the thirddangerous complication is thyrotoxic crisis.

Thyrotoxic crisis (crisis thyreotoxica)

Thyrotoxic crisis is an extreme accentuation ofthyrotoxicosis. It is an uncommon but serious com-plication of Graves-Basedow disease. Crisis is al-most always of abrupt onset and occurs in patientsin whom pre-existing thyrotoxicosis has been treatedeither incompletely or not at all. It is almost al-ways evoked by a precipitating factors, such as in-fection, trauma, surgical operations, surgical emer-gencies, radiation thyroiditis, toxemia of pregnancy,and parturition. The mechanism whereby such fac-tors lead to an accentuation of thyrotoxicosis hasnot been ascertained. It does not appear to be anacute increase in the severity of thyroid hyperfunc-tion. Rather, it may represent a shift from protein-bound to free thyroid hormones. It is manifestedby extreme hypermetabolism and by fulminating in-crease in all characteristic symptoms of thyrotoxico-sis.The clinical picture of thyrotoxic crisis is domi-

nated by hyperpyrexia (40–41oC), marked tachycar-dia (over 140/min), even tachyarrhythmia associatedwith atrial fibrilation, extreme irritability and rest-lessness, diarrhea, vomiting, profuse sweating, anddehydration. As the crisis progresses, apathy, pros-tration, stupor, and coma may supervene, but withonly slight elevation of temperature. The blood pres-sure, which initially is well maintained, may fall to

hypotensive levels. Mortality of the patients withthyrotoxic crisis is high, usually up to 50 %.

B. Hyperthyroidism due to nonimmunogenicthyroid autonomyThere are two forms of hyperthyroidism due to non-immunogenic (intrinsic) thyroid autonomy: toxicmultinodular goiter and toxic adenoma. In the pastboth these forms were included in a common termtoxic nodular goiter. With regard to their differ-ent pathogenesis and histopathology they are distin-guished as separate nosologic entities.

a) Toxic multinodular goiter

Toxic multinodular goiter is an occasional conse-quence of a long-standing simple goiter, although theproportion of cases in which this complication arisesis uncertain. The symptoms of hyperthyroidism usu-ally originate after the age of 50 in patients who havehad nontoxic multinodular goiter for many years. Itis many times more common in women than in men.

The cause of gradually originating autonomy ofcertain areas of thyroid parenchyma (their indepen-dence from TSH stimulation), which causes transi-tion from nontoxic to toxic multinodular goiter, isnot precisely known. It is probably the result offunctional heterogenity of epithelial cells of follicles.Sometimes, hyperthyroidism may appear abruptly,but this almost always results from exposure to in-creased quantities of iodine in the patients with anontoxic multinodular goiter (iodine-induced hyper-thyroidism, jodbasedow). Administration of iodidespermits autonomous foci to increase their rate of hor-mone biosynthesis and secretion to truly excessivelevels.

From the histopathological and functional view-point two types of toxic multinodular goiter can bedistinguished:

1. The first type of toxic multinodular goiter ismore common. It is characterized by a diffusesmall focal (patchy foci) distribution of radioiso-tope in scintillation scaning. This distribution isnot usually altered by administration of exoge-nous thyroid hormone. Histopathological exam-ination reveals multiple aggregates of small fol-licles with hyperplastic epithelium (micronod-ules), interspersed with variably sized inactivenodules. It is very likely that some of these inac-tive nodules may preserve the ability of hormone


production. They are inactive because TSH se-cretion is suppressed by the increased concentra-tion of thyroid hormones in circulating blood.Thyroid hormones are produced by numerousautonomous micronodules.

2. The second type of toxic multinodular goiter isless common. The accumulation of radioiodineis localized only in one or more discrete noduleswithin the gland, the remainder appearing to beessentially nonfunctional (suppressed). No fur-ther suppresion is produced by exogenous thy-roid hormone, but administration of TSH stim-ulates accumulation of radioiodine in the areaspreviously inactive. Histopathological examina-tion reveals that the hyperfunctioning areas re-semble adenomas in being reasonably well de-marcated from surrounding tissue. They pro-duce hormones autonomously. They consist oflarge follicles, sometimes with hyperplastic ep-ithelium. The remaining tissue appears inac-tive. Zones of degeneration are usually presentin both hyperfunctioning and nonfunctioning ar-eas.

Clinical features. The extent of overproductionof thyroid hormones in toxic multinodular goiter isusually mild compared with that in Graves-Basedowdisease. Therefore, the serum T4 and T3 concen-trations are only slightly above normal. TSH secre-tion is inhibited. The symptoms of infiltrative oph-thalmopathy and infiltrative dermopathy are neverpresent, because toxic multinodular goiter is not adisease with autoimmune pathogenesis.

The clinical picture of thyrotoxicosis due to toxicmultinodular goiter is usually oligosymptomatic.Cardiovascular manifestations tend to predominate,possibly because of the age of the patients in whichthis form of hyperthyroidism may be often acom-panied by ischemic heart disease. These manifesta-tions may include tachycardia, arrhythmias, atrialfibrilation, or congestive heart failure. Weakness,tiredness and wasting of muscles are common. Thenervous manifestations are usually mild or absent,but emotional lability may be pronounced. As thethyroid tissue due to toxic multinodular goiter is oftougher consistency and the goiter is often retroster-nal, the symptoms of mechanical local syndrome maybe also present.

b) Toxic adenoma

Toxic adenoma (Plummer disease) is less commonas toxic multinodular goiter. It occurs in a youngerage group than does toxic multinodular goiter, oftenbetween the ages of 30 and 40. Thyrotoxicosis is usu-ally caused by a solitary hyperfunctional autonomousnodule (toxic uninodular goiter). Occasionally, twoor three adenomas of similar character are present.

From the point of view of histopathology it is truefollicular adenoma being well encapsulated (demar-cated from surrounding tissue). Its pathogenesis isunknown. In anamnesis the patient often reportsthat the nodule (lump) in the neck has grown slowlyover many years. The nodule becomes capable toproduce thyrotoxicosis if it has achieved a diameterof 2.5 to 3 cm. Initially it is present as a small nodulethe function of which is insufficient to disturb hor-monal equilibrium, though its capacity to accumu-late radioiodine is evident in scintiscans as an area ofincreased density within the still-functioning extran-odular tissue (warm nodule). With time, the nodulegrows larger, its function increasing until it is suffi-cient to suppress TSH secretion. Consequently, theremainder of the gland undergoes relative atrophyand complete loss of function. The scintiscan re-veals radioiodine accumulation only in the adenoma(hot nodule). At this time frank thyrotoxicosis usu-ally sepervenes. Hyperthyroidism is not caused bythe whole parenchyma of the thyroid gland, as it isin the patients with Graves-Basedow disease, but itis induced only by its relatively small encapsulatedarea.

Clinical features. The clinical picture of toxic ade-noma is similar to that of toxic multinodular goi-ter. The peripheral manifestations of thyrotoxicosisdue to toxic adenoma are also generally milder thanthose of diffuse toxic goiter. The symptoms of infil-trative ophthalmopathy and infiltrative dermopathyare never present. Cardiovascular symptoms may beprominent, and their relevance increases with the ageof the patient. Toxic adenoma in some patients se-crete T3 predominantly, therefore, serum T4 concen-tration is normal and serum T3 concentration aloneis increased. Relative to its overall rate of occurrence,toxic adenoma is the most frequent of T3 toxicosis.Secretion of TSH is suppressed, its serum concentra-tion is low. On palpation, the nodule is usually feltas a smooth, well-defined, round or ovoid mass thatis firm and moves freely on swallowing.


C. Hyperthyroidism due to nonimmunogenicabnormal thyroid stimulatorThis form of hyperthyroidism may be also termed hy-perthyroidism due to trophoblastic tumors, becausemalignant tumors arising from trophoblastic tissue(hydatidiform mole, choriocarcinoma, or metastaticembryonal carcinoma of the testis) may be some-times accompanied by the symptoms of thyrotoxi-cosis. The increased production of T4 and T3 isinduced by a circulating thyroid stimulator, whichis not, however, identical with TSH. It is probablyhuman chorionic gonadotrophin (hCG), or a proteinclosely related to it (chorionthyrotrophin). It hasbeen found out that alpha subunits of TSH and go-nadotropins are identical.

Serum T4 and T3 concentrations are increasedonly slightly, serum TSH concentration is decreased.Thyrotoxicosis is mild, goiter is absent.

D. Hyperthyroidism due to increased TSHproductionRarely, hyperthyroidism and thyrotoxicosis are theresult of sustained hypersecretion of TSH (centralhyperthyroidism). The cause of overproduction ofTSH may be TSH-secreting pituitary adenoma, se-lective resistance of pituitary to thyroid hormones, orincreased secretion of hypothalamic TRH. All thesevarietes are associated with a diffuse hyperfunction-ing goiter. Features of autoimmune thyroid diseaseare absent in the patient and in the patient’s family.Serum TSH concentration, as well as serum T4 andT3 concentrations are increased. In the clinical pic-ture of TSH-secreting pituitary adenoma some localsymptoms, secondary to compression of surroundingstructures, may be present.

Hyperthyroidism due to ectopic (paraneoplastic)production of TSH is extraordinarily rare. Its pro-duction in bronchogenic carcinoma is most common.

E. Iodine-induced hyperthyroidismFor some time it has been known that administra-tion of supplemental iodine to subjects with endemiciodine-deficiency goiter can result in overproductionof thyroid hormones. This response has been termedjodbasedow. It usually occurs in the patients withnontoxic multinodular goiter, some areas of whichhave autonomous function. This autonomous ar-eas of its tissue, however, has not appeared be-fore administration of iodine. Since such patients

tend to be elderly with the danger of serious cardio-vascular manifestations thyrotoxicosis should ensue,large doses of iodine should not be given to thosewith the multinodular goiter. The jodbasedow phe-nomenon can seldom occur in younger individualswith the diffuse goiter, and here thyroid-stimulatingimmunoglobulins are often present. Thyrotoxicosisis induced by random administrations of pharma-ceuticals containing iodine, such as expectorants, x-ray contrast media, or any other forms. It seemsthat jodbasedow occurs only in thyroid glands inwhich function is independent of TSH stimulationand refers to the induction of thyrotoxicosis in a pre-viously euthyroid patients as a result of exposure toadministration of larger doses of iodine. Mechanismof inducing hyperthyroidism by iodine is not exactlyknown. In these patients, serum T3 concentrationis quite often normal, but serum total and free T4concentrations are increased (T4 toxicosis).

5.4.3.2 Thyrotoxicosis without hyperthy-roidism

Thyrotoxicosis not associated with hyperthyroidismis rare. It may have a iatrogenic origin, it may be as-sociated with various forms of inflammatory diseaseof the thyroid gland, or the source of excess of thy-roid hormones may be outside of the thyroid glanditself.

A. Thyrotoxicosis factitiaThis term designates temporary thyrotoxicosis thatarises from ingestion, usually chronic, of excessivequantities of exogenic thyroid hormone (exogenous,iatrogenic thyrotoxicosis). It occurs rarely. Thesymptoms are typical of thyrotoxicosis and may besevere. If thyrotoxicosis is induced by an excessive in-take of T4 , its symptoms persist several weeks afterthe intake of this hormone has been finished. How-ever, after finishing of an excessive intake of T3 ,the symptoms of thyrotoxicosis will disappear muchmore faster. Due to long-standing intake of exo-genic thyroid hormone, endogenous thyroid functionis suppressed and thyroid parenchyma may becomeatrophic (serum TSH is decreased, therefore, thestimulation of thyroid parenchyma is suppressed).

B. Transient thyrotoxicosis associated withthyroiditisThe symptoms of thyrotoxicosis may appear in the


early phase of subacute thyroiditis. The episode ofthyrotoxicosis may also occur in the patient witha painless form of thyroiditis in which biopsy ofthe thyroid reveals the histopathological changes ofchronic lymphocytic thyroiditis that, however, dif-fers from that of Hashimoto thyroiditis. Circulat-ing antithyroid antibodies, when present, are in lowtiter. This form of thyroiditis has been variously des-ignated as painless thyroiditis, silent thyroiditis, orchronic thyroiditis with spontaneously resolving thy-rotoxicosis. At present the term chronic thyroiditiswith transient thyrotoxicosis is preferred.

In the both above mentioned forms of thyroiditisthe thyrotoxicosis is usually of a mild degree, onlyin some instances its symptoms may be severer. Theclinical features of thyrotoxicosis reflect the extent ofelevation of serum T4 and T3 concentrations. It issupposed not to be induced by the increase biosyn-thesis and secretiom of thyroid hormones. The causeof its origin is presumably larger destruction of thy-roid parenchyma (disruption of follicles) which ap-pears suddenly in the course of inflammatory pro-cess. Due to the disruption of a large number of fol-licles the extensive nonregulated depletion of thyroidhormone stores into circulating blood occurs. Lowor undetectable serum TSH concentration (suppres-sion of its secretion by the increased concentrationsof thyroid hormones in blood), as well as decreasedaccumulation of radioiodine in the thyroid gland arethe evidence of this assumption. Later, as glandularhormones are depleted, the patient may pass througha hypothyroid phase, in which serum T4 and T3 con-centrations are low and serum TSH concentration isincreased. After this hypothyroid phase, duration ofwhich is several months, the patient usually returnsto an euthyroid state.

C. Thyrotoxicosis due to ectopic productionof thyroid hormonesThe symptoms of thyrotoxicosis may be rarely in-duced by hyperfunctioning distant metastases of thy-roid carcinoma (mostly follicular carcinoma) in lungor bones. Ectopic thyroid tissue may also be presentin teratomas, especially in the ovary. About 3 % ofthe whole number of ovarian teratomas are hyper-functioning. The tissue of such teratomas producesthyroid hormones, and, therefore, it may evoke mildthyrotoxicosis (struma ovarii). A severer degree ofthyrotoxicosis can appear due to the origin of au-

tonomous adenoma of this ectopic thyroid tissue.

5.4.4 Inflammations of the thyroidgland (thyroiditis)

Inflammations of the thyroid gland (thyroiditis) arerather common. From the etiological point of viewseveral forms of thyroiditis are distinguished. Thy-roid biopsy and histopathological examination of ob-tained specimens has an important role in the di-agnosis of their certain types. The most commonare lymphocytic thyroiditis, chronic thyroiditis withtransient thyrotoxicosis, and subacute thyroiditis.They are notable for their different clinical coursesand for the fact that each can be associated, at onetime or another, with an euthyroid, thyrotoxic, orhypothyroid state. Acute thyroiditis, chronic fibros-ing thyroiditis, and the other types of thyroiditis arerare.

5.4.4.1 Acute thyroiditis

Acute thyroiditis (pyogenic thyroiditis) is rare. Itis due to an infection of the thyroid gland by pyo-genic microorganisms, most frequently by staphylo-cocci, streptococci, or pneumococci. Less commonlyit may be due to salmonellae or E. coli. Infectiousagents may come from infectious focus located in theclose area of the thyroid and get into it by lymphaticor vascular vessels. Sometimes it may be the resultof hematogenous dissemination from distant primaryseptic foci, or it may be the complication of infec-tious disease. If pyogenic thyroiditis is nontreatedabscesses may develop in the thyroid.

Clinical features. The clinical picture of acutethyroiditis is characterized by sudden origin of ev-idently painful goiter. Usually only one lobe of thethyroid gland is enlarged. The overlying skin is redand warm. The goiter is tender and painful spon-taneously and on palpation. The pain is aggravatedby swallowing (dysphagia is present), yawning, andby turning the head. On the affected side, the paincharacteristically radiates to the ear, jaw, or occiput.Fever, malaise, leukocytosis, and increased erythro-cyte sedimentation rate are present. Serum thyroidhormone concentration is normal. In scintiscan ab-scess, if present, is usually manifested as a cold nod-ule. In circulating blood antithyroid antibodies arenot present.


5.4.4.2 Subacute thyroiditis

Subacute thyroiditis (de Quervain thyroiditis) is con-sidered viral in origin (viral thyroiditis). The specificvirus which would be the cause of its origin, however,has not been found out. The viral infection of thethyroid gland usually follows a cataral upper respi-ratory infection, or influenza. A tendency to a sea-sonal and geographic aggregation of cases has beennoted. The mumps virus, influenza virus, CoxackieB viruses, echoviruses, and adenoviruses are consid-ered the etiological agents of subacute thyroiditis.Women are more frequently affected than men. Themaximal incidence is in the fourth and fifth decades.In about 70 % of the patients the leukocyte antigenHLA-Bw35 is present, what indicates possibility ofexistence of genetic predisposition to this disease.

Histopathological examination reveals that theparenchyma of affected area is infiltrated with cellspredominantly of the mononuclear type. Many ofthe follicles show disruption of epithelium with par-tial or complete loss of colloid. The colloid is found inthe interstitium and is surrounded by the multinucle-ate giant cells (giant cell thyroiditis). The follicularchanges may progress to form granulomas (granulo-matous thyroiditis).

Pathophysiology. Destruction of follicular epithe-lium and loss of follicular integrity are the primaryevents in the pathophysiology of subacute thyroidi-tis. Preformed hormones are released into circulat-ing blood, often in quantities sufficient to producethyrotoxicosis (the thyrotoxic phase). Later in thedisease, when stores of preformed thyroid hormonesare depleted, the patient may pass through a periodof mild transient hypothyroidism (the hypothyroidphase). Ultimately, as biosynthesis of hormones re-sumes and their stores are repleted, the thyroid func-tion usually becomes normal.

Clinical features. The characteristic feature ofsubacute thyroiditis is the gradual or sudden appear-ance of pain in the region of the thyroid, which isslightly to moderately enlarged. One lobe generallybeing more severely affected than the other. Lesscommonly it may be unilateral. The goiter is painfulspontaneously and on palpation. The pain is aggra-vated by swallowing (dysphagia is present), yawning,and turning the head. The pain characteristically ra-diates to the ear, teeth of the lower jaw, or occiput.A painless form of subacute thyroiditis may occur

only rarely. On palpation, the enlarged thyroid isfirm and often nodular.

The origin of painful goiter is usually accompaniedby fever, but in some cases the body temperaturein the morning is increased only slightly. The moststriking laboratory finding of subacute thyroiditis is ahigh erythrocyte sedimentation rate (usually>100).The leukocyte count is normal or, at most, mod-erately increased. Antithyroid antibodies are notpresent.

In the early phase of subacute thyroiditis in somepatients the clinical symptoms of mild transient thy-rotoxicosis (e.g., tachycardia, palpitation, nervous-ness, lassitude, and weakness) may occur. They areevoked by depletion of larger quantities of preformedthyroid hormones due to the disruption of a largernumber of follicles. The thyrotoxic phase lasts aboutone month and results in spontaneous withdrawalfollowed by return of serum thyroid hormone con-centrations to normal (the phase of transient euthy-roidism). Duration of this phase is about 1–3 weeks.Later in the disease serum thyroid hormone concen-trations sometimes decrease below normal level. Thehypothyroid phase lasts 2–5 months. In this phasethe goiter gradually diminishes.

In the phase of transient thyrotoxicosis serum T4and T3 concentrations are slightly increased, serumTSH concentration is decreased. The scintiscan re-veals that radioiodine accumulation in the affectedarea is low. In the hypothyroid phase serum thyroidhormone concentrations are decreased below normaland serum TSH concentration is appropriately ele-vated. In the hypothyroid phase radioiodine accumu-lation may be temporarily increased. With recoverythe normal values for serum thyroid hormones andTSH concentrations are restored.

Occasionally, the locus of maximal involvementmigrates over the course of a few weeks to otherparts of the thyroid gland. This is usually mani-fested by the change of physical findings and by arelapse in other clinical symptoms and laboratoryfindings as well. The disease usually subsides spon-taneously within a few months, leaving no residualdeficiency of the thyroid function. Usually only verymild, functionally non-significant, residual fibrosishas been left. The goiter usually completely dis-appears. Rarely recidivation of subacute thyroiditismay occur, mainly after some viral diseases. In rarecases, the subacute thyroiditis may smoulder with re-


peated exacerbations over many months, permanenthypothyroidism being the result.

5.4.4.3 Chronic thyroiditis with transientthyrotoxicosis

Chronic thyroiditis with transient thyrotoxicosis(painless thyroiditis, silent thyroiditis) is a diseasein which a self-limited episode of thyrotoxicosis is as-sociated with a histologic picture of chronic lympho-cytic thyroiditis that differs from that of Hashimotothyroiditis. It occurs in patients of any age, womenare more frequently affected than men.Etiology and pathogenesis of this disease are un-

clear. Viral antibody titers show no characteristicpattern. Lymphocytic infiltration and presence ofplasma cells within the thyroid could suggest an au-toimmune basis. However, the absence of high titersof circulating antithyroid antibodies and the perma-nent resolution in most would argue against this.

The thyroid gland is enlarged in only about 50%of the patients. The thyroid enlargement is usuallymild and unaccompanied by nodularity. Thyrotoxi-cosis is rarely severe, and elevation of serum T4 andT3 concentrations is consonant with a degree of thy-rotoxicosis. Conventional essays reveal antithyroidantibodies in only about one half of the patients. Un-like subacute thyroiditis, the erythrocyte sedimenta-tion rate is normal or near normal.

It is presumed that thyrotoxicosis results fromleakage of preformed hormones from the thyroidgland (due to the destruction of follicular epithe-lium and loss of follicular integrity), as in subacutethyroiditis. The thyrotoxic phase lasts usually twomanths. About one half of the patients return toan euthyroid state and remain well. The remain-ing half patients pass through a short transient eu-thyroid phase to hypothyroid phase. This phase ofself-limited hypothyroidism varies in duration from2 to 9 months. The tendency of the disorder topass through a hypothyroid phase is not surpris-ing in view of the extensive depletion of glandularhormone stores that must occur while hormones areleaking from the gland and new hormone synthesisis reduced. This phase gives way to a restorationof euthyroidism, but in about 5% of the patientspermanent hypothyroidism develops years later. Insome patients recurrence (sometimes multiple recur-rences) of thyrotoxicosis may occur months or yearsafter restoration of an euthyroid state.The postpartum thyroiditis syndrome is similar

in presentation, course, and pathophysiology. Tran-sient thyrotoxicosis may occur some time within afew months (usually 2–4) after delivery. The thyro-toxicosis phase is often followed by the phase of hy-pothyroidism which lasts several months. The phaseof self-limited hypothyroidism may be only compo-nent of the disease that is diagnosed because the thy-rotoxic phase may be very brief. After the hypothy-roid phase the patient usually returns to an euthyroidstate. The postpartum thyroiditis syndrome may oc-cur in 4–8 % of pregnant women. Very likely, it hasan autoimmune basis. Most patients have a smallgoiter and positive tests for antithyroid peroxidaseantibodies (formerly called antimicrosomal antibod-ies), although titers are low. There is a strong associ-ation with the HLA-DR3 and HLA-DR5 haplotypes.The postpartum occurrence of this syndrome is prob-ably due to a rebound of immune activity after itssuppression during pregnancy.

5.4.4.4 Lymphocytic thyroiditis (Hashimotodisease)

Lymphocytic thyroiditis (Hashimoto thyroiditis,struma lymphomatosa) is the most common type ofinflammations of the thyroid gland. About 3–5% ofpopulation are affected, women more frequently thanmen. It may occur at any age, most often betweenthe ages of 30 and 50. It often develops also at pu-berty participating in more than one half of goitersoriginated in this period. Hashimoto thyroiditis is anautoimmune disease characterized by chronic course(chronic autoimmune thyroiditis), painless goiter,and by gradual development of hypothyroidism. Theevidence of autoimmunity includes the lymphocyticinfiltration of the thyroid tissue and the presence inthe serum of high titers of antibodies against severalcomponents of epithelial cells of follicles.

Etiology and pathogenesis are not exactly known.It is assumed that autoimmunity in Hashimoto dis-ease reflects genetically determined defect in thefunction or deficiency of suppressor T cells (proba-bly of autosomal dominant inheritance). This defectallows the emergence and persistence of forbiddenclones of helper T cells directed against the thyroidantigens. The thyroid-sensitized helper T lympho-cytes cooperate with B cells in the thyroid to producea constellation of the specific antithyroid autoanti-bodies. In patients with Hashimoto thyroiditis, un-like those with Graves-Basedow disease, the number


of cytotoxic T lymphocytes, damaging epithelial cellsof follicles, is increased.

Lymphocytic thyroiditis, primary idiopathic hy-pothyroidism, and Graves-Basedow disease often oc-cur familially. Therefore, it is generally agreed thatthe noted diseases are various variants of the sameautoimmune disease. Mechanisms responsible for thedevelopment of individual clinical forms of the men-tioned triad of autoimmune thyroid disorders are not,however, known.

Hashimoto thyroiditis coexists in some frequencywith other diseases of an autoimmune nature, in-cluding type 1 diabetes mellitus, Addison disease,primary idiopathic hypoparathyroidism, perniciousanemia, rheumatoid arthritis, systemic lupus erythe-matosus, chronic active hepatitis, myasthenia gravis,Sjogren syndrome, vitiligo, early graying of the hair,and others. These diseases, as well as Hashimotodisease, also occur frequently in family members ofthe patients with Hashimoto diesease. A significantassociation between Hashimoto disease and the hu-man leukocyte antigens HLA-DR3, HLA-DR5, andHLA-B8 also exists.

Histopathologic examination of the thyroid glandreveals destruction of epithelial cells and fibrosiswhich is more evident especially in the older lesions.The most characteristic finding is an abundant dif-fuse lymphocytic infiltration of the interstitial tissue.Interfollicular infiltration by plasma cells may be of-ten present. More of the remaining epithelial cellsmay be larger and show oxyphilic changes in the cy-toplasm. They are called Askanazy cells and are con-sidered pathognomic for this disease. In some casesepithelial hyperplasia may be prominent.

From the histopathologic point of view two vari-ants of Hashimoto thyroiditis may be distinguished.The more common is oxyphilic variant which is char-acterized by more evident exyphilic changes in thecytoplasm of epithelial cells, less fibrosis, and moreprominent infiltration with lymphocytes. The fi-brous variant is characterized mainly by evident infil-tration with plasma cells and display of more fibrosis.

Hashimoto thyroiditis usually begins with discov-ering of a small painless goiter, which enlarges grad-ually over many years, especially if left untreated.It is often found during examination for some othercomplaint. Goiter is the outstanding clinical fea-ture of Hashimoto disease. It is usually diffuse andfirm in consistency and moves freely when the pa-

tient swallows. Its surface is either smooth or scal-lopes, but well-defined nodules are unusual. There-fore, compression of adjacent structures, such as tra-chea, esophagus, and recurrent laryngeal nerves, oc-curs rarely. Both lobes of the thyroid are enlarged,but one is often larger than the other. In occasionalinstances, however, the thyroid enlarges rapidly, andwhen accompanied by pain and tenderness the dis-order may mimic subacute thyroiditis.

The goiter is usually the only feature of Hashimotothyroiditis for a long time. It is manifested as aneufunctional goiter, and, therefore, the patient ismetabolically normal. However, clinical symptoms ofhypothyroidism gradually appear and become moreevident over several years. Slowly appearing symp-toms of hypothyroidism may be from the beginningof the disease understood as growing old. In about20 % of the patients, especially those with the fibrousvariant, the symptoms of hypothyroidism may be ob-served already at the first detection of the Hashimotothyroiditis in the patient.

Occasionaly, patients with Hashimoto diseasepresent with hyperthyroidism in association with thethyroid gland that is unusually firm and with hightiters of circulating antithyroid antibodies, a combi-nation which suggests, probably correctly, the con-curence of Graves-Basedow disease and Hashimotothyroiditis. In these patients, usually in midcourseof Hashimoto thyroiditis, develops hyperthyroidism,sometimes called ”Hashitoxicosis”. In other patientswith Hashimoto disease, hyperthyroidism may super-vene presumably due to the emergence of clones oflymphocytes that produce stimulatory anti-TSH re-ceptor antibodies. However, in some patients withHashimoto thyroiditis only transient thyrotoxicosiswithout evidence of thyroid hyperfunction may de-velop. Symptoms of transient thyrotoxicosis mayappear either during initial stage of the disease oras a consequence of rarely occurring exacerbation ofchronic inflammatory process. In this phase of tran-sient thyrotoxicosis serum thyroid hormone concen-trations increase as a result of more extensive de-struction of the follicles, and not as a result of in-creased synthesis of the thyroid hormones. The evi-dence of this is low radioiodine accumulation in scin-tiscan.

Titers of antithyroid antibodies (antithyroglobulinand antimicrosomal) are high already from the onsetof the Hashimoto disease. Circulating autoantibody


titers tend to be higher in patients with the fibrousvariant than in those with the oxyphilic variant.

The results of the tests of thyroid function dependon the stage of the disease. At initial stage serum T4and T3 concentrations are normal, the patient is eu-metabolic. As the disease progresses, thyroid failure,at first subclinical, may supervene owing to progres-sive replacement of the thyroid parenchyma by lym-phocytes or fibrosis. Although damage of the thyroidgland is the obvious cause of the failing thyroid func-tion, a contributing influence may be the presence ofTSH receptor-blocking antibodies. With the passageof time, thyroid function decreases gradually. Abilityof the thyroid tissue to respond to TSH progressivelydiminishes. Therefore, the serum TSH concentrationprogressively rises and the serum T4 concentrationfalls to subnormal values. The thyroid failure is ev-ident first in the rise in serum TSH concentration.At this stage, the serum T3 concentration remainsnormal for some time. However, with time, serumT3 concentration may slightly increase, reflecting inall likelihood maximal stimulation of the failing thy-roid by the increased serum TSH concentration. Theforegoing sequence of symptoms (concerning serumTSH, T4 and T3 concentrations) in the evolution ofcomplete thyroid failure has been termed diminishedthyroid reserve or subclinical hypothyroidism. Ulti-mately, the serum T3 concentration also declines tosubnormal values, and frank hypothyroidism super-venes. Autoimmune thyroiditis may account for asmany as 90% of cases of hypothyroidism.

5.4.4.5 Chronic fibrosing thyroiditis

Chronic fibrosing thyroiditis (Riedel thyroiditis) israre and is observed chiefly in middle-aged women.The etiology is unknown. From the histopathologicalpoint of view it is characterized by extensive fibrosisof the thyroid gland which gradually becomes unusu-ally hard (a woody gland). Infiltrative growth of fi-brous tissue into adjacent structures, including adja-cent vessels, nerves, and muscles, is typical, too. Suc-cessive compression of the esophagus, trachea, andrecurrent laryngeal nerves gives rise to the symptomsof local mechanical syndrome. The goiter is mildin size, usually asymmetrical, fixed, and stony hard.The patient is usually euthyroid, hypothyroidism oc-curs only occasionally.

5.4.4.6 Other types of thyroiditis

They are very rare. These miscellaneous types ofthyroiditis include post-irradiation thyroiditis andtrauma thyroiditis. They also include chronic non-pyogenic bacterial thyroiditis, which may originatedue to some specific infections (e.g., brucellosis, tu-berculosis, and syphilis). Occasionally thyroiditismay occur also due to sarcoidosis, amyloidosis, andsystemic mycosis.

5.4.5 Thyroid neoplasms

Tumors of the thyroid gland are the most frequentamong the tumors of the endocrine system. Theyare traditionally classified to benign and malignantneoplasms. They may arise from epithelial cells (fol-licular cells or parafollicular cells), also from thecells of connective tissue or from lymphoreticularcells. Therefore, epithelial, nonepithelial, or miscel-laneous primary neoplasms of the thyroid gland maybe distinguished. Secondary neoplasms (metastasesof extrathyroid tumors to the thyroid) of the thyroidgland may also occur.

5.4.5.1 Benign neoplasms

Benign neoplasms of the thyroid gland (benign goi-ter) include predominantly follicular adenomas (themore highly differentiated adenomas) being hormon-ally active (toxic adenomas) or hormonally inactive.True adenomas are well encapsulated nodules of thethyroid gland, which do not invade adjacent tissues,and do not metastase.

The patients often report that the nodule hasgrown slowly over many years. Initially, if it is a hor-monally active adenoma, its function is insufficient todisturb hormonal equilibrium, though its capacity toaccumulate radioiodine is evident in scintiscans as anarea of increased density within the still-functioningextranodular tissue (warm nodule). With time, thenodule grows larger, its function increasing until it issufficient to suppress TSH secretion. Consequently,the remainder of the gland undergoes relative atro-phy and loss of the function, and the scintiscan re-veals intensive radioiodine accumulation only in theregion of the nodule (hot nodule). Frank thyrotox-icosis usually supervenes. Relatively to its overallrate of occurrence, hyperfunctioning adenoma is afrequent cause of T3 toxicosis. The function of toxic


adenoma is autonomous, independent of TSH stim-ulation.

About 95 % of adenomas are afunctional. Scin-tiscans reveal no accumulation of radioiodine (coldnodule). Epithelial cells of afunctional adenoma lostthe iodide-trapping mechanism, and, therefore, theycannot produce hormones.

Up to the present time it is not known whetheradenomas arise de novo or arise from hyperplasticperenchyma of the thyroid which is stimulated byTSH for a long time. Toxic adenomas never undergomalignant transformation. It has not been exactlyknown whether malignant transformation of afunc-tional adenomas is possible.

From the histopathological view point structure ofadenomas is not uniform, but it is variable. There-fore, thyroid adenomas are classified into follow-ing histopathological types: embryonal adenoma, fe-tal adenoma, microfollicular adenoma, macrofollic-ular adenoma (colloid adenoma), papillary cystade-noma, and Hurthle cell adenoma (it is composed oflarge acidophilic cells). In the thyroid gland varioushistopathological types of adenomas may be foundin the same time, even in the same adenoma severalof the above mentioned histopathological structuresmay occur.

5.4.5.2 Malignant neoplasms

Malignant neoplasms of the thyroid gland (malignantgoiter) account for about 1 % of all malignant tumorsof the population. Women are affected aproximatelytwice more frequently than men. From the pointof view of histopathology primary malignant neo-plasms are divided into epithelial, nonepithelial, andmiscellaneous. Rarely, metastases of extrathyroidcancers to the thyroid may occasionally occur (sec-ondary malignant neoplasms). Breast cancer, bron-chogenic carcinoma, renal cell carcinoma, malignantmelanoma, and malignant lymphomas metastase tothe thyroid gland most frequently.Epithelial malignant neoplasms of the thyroid

gland arise from follicular cells or parafollicular cells(C cells). Follicular carcinoma, papillary carcinomaand anaplastic carcinoma originate from the fol-licular cells. The parafollicular cells give rise tomedullary carcinoma.Nonepithelial malignant neoplasms and miscella-

neous malignant neoplasms of the thyroid gland oc-cur very rarely. Fibrosarcoma is the best known

of nonepithelial malignant neoplasm of the thy-roid gland. Miscellaneous malignant tumors includemainly carcinosarcoma. The thyroid gland also maybe the site of lymphoproliferative disease, namelythyroid lymphoma. The relative risk of thyroid lym-phoma is 67-fold higher in patients with Hashimotothyroiditis than in the thyroid glands with colloidnodules.

Primary thyroid carcinomas

Primary thyroid carcinomas are the most commonendocrine malignancies, accounting for more than99 % of all thyroid malignancies. It occurs prevail-ingly as a nodular goiter, most commonly as a soli-tary nodule. In the thyroid scintiscans malignantnodules very often appear as a cold area, warm orhot nodules are less common. About 80 % of thy-roid carcinomas apear in the patients between theages of 25 and 65. In children and young adults be-fore the age of 40 mostly papillary carcinoma occurs,accounting for about two thirds of all thyroid car-cinomas occurring in this period of life. Anaplasticcarcinoma is very rare before the age of 40. In adultsafter the age of 40, follicular carcinoma is more com-mon. At the same time the occurrence of anaplasticcarcinoma is also significantly increased. Medullarycarcinoma occurs mainly in elders.

Etiology and pathogenesis of the thyroid carcino-mas are not exactly known. It is assumed that sev-eral factors participate in their origin and develop-ment. The best known are:

1. Genetic factors. They have not been exploredprecisely. However, the existence of familialtype of medullary carcinoma has been consid-ered proved (autosomal dominant inheritance).

2. Ionizing irradiation. It is the best known andmost significant external factor causing the ori-gin of malignant goiter. Its effect depends ongreatness of radiation dose applied to the areaof the thyroid gland or its vicinity, usually fordiagnostic or therapeutic purposes, as well ason the age in time of radiation. X-ray radiationis considered of a greater importance than ra-diation by radioactive isotopes. Radiation dur-ing infancy or childhood is considered decisive.Carcinomas usually appear 6–8 years after radi-ation of the neck area, but they may originateas late as 20 or even more years after the radia-tion exposure. At present, it is assumed that


in most instances only microcarcinoma devel-ops. As this microcarcinoma stops growing, it isso-called ”sleeping carcinoma”. The microcarci-noma may start growing again and later metas-tase only when further stimulating and promo-tional factors are involved (e.g., long-lasting ex-cessive stimulation of the thyroid gland by TSHand suppression of the immune system are con-sidered). It is assumed that also some goitrogensand iodine deficiency may play a pathogeneticrole in the origin of thyroid carcinoma.

Primary thyroid carcinomas are classified into twovarieties depending on whether the lesion arises inthe thyroid follicular epithelium or from the parafol-licular cells forming calcitonin. Three histopatho-logical types of carcinomas of follicular epitheliumare distinguished: follicular, papillary and anaplas-tic carcinomas. Parafollicular cells give rise tomedullary carcinoma.

A. Follicular carcinoma

Follicular carcinomas tend to be slow growing andaccount for 10–15% of all thyroid cancers. In re-gions with iodine deficiency they occur more oftenthan papillary carcinomas. Follicular carcinoma oc-curs in an older age group than papillary carcinoma,most cases arising after the age of 40. Women are af-fected two to three times more commonly than men.The degree of malignancy varies but generally ex-ceeds that of papillary carcinoma. Follicular carci-noma seldom spreads to the regional lymph nodes,but undergoes early hematogenous spread to distantsites, particularly bone, lung, liver, or CNS.

Follicular carcinoma histopathologically resem-bles normal thyroid epithelium, is encapsulated,and differs from benign follicular adenoma onlyby the presence of capsular and/or vascular inva-sion. Histopathological examination reveals the pres-ence of various size follicles containing subnormalamounts of colloid. The cells exhibit mitoses to avarying degree. Invasion of blood vessels and adja-cent thyroid parenchyma is often observed. The de-gree of invasiveness is greatest in the older age groupof patients. The follicular carcinoma usually con-sists of a single nodule. The regional lymph nodesare seldom enlarged. Pain and invasion of the adja-cent structures manifest later than in papillary car-cinoma.

Unlike other types of the thyroid carcinomas, fol-licular carcinoma may accumulate radioiodine, butonly to a small extent. Its metastases are some-times hyperfunctional and may be sufficient to pro-duce clinical thyrotoxicosis, including T3 toxicosis.However, its response to administration of suppres-sive doses of thyroid hormone (regression of the pri-mary tumor and its metastases due to inhibition ofTSH secretion by administrated thyroid hormone) isweaker than that of papillary carcinoma.

B. Papillary carcinoma

Papillary carcinoma accounts for about 60–75%of all thyroid carcinomas. It may occur at any agebut is seen more frequently in children and youngadults. Women are affected 2–3 times more com-monly than men. Papillary carcinoma is the mostcommon thyroid malignancy originating after X-rayradiation exposure to the neck during childhood. Ingeneral, papillary carcinoma is the slowliest growingone of all thyroid carcinomas. Clinically, it usuallyappears as an asymptomatic nodule, which varies insize and is usually uncapsulated. It tends to spreadvia the intraglandular lymphaties from its primarysite to other parts of the thyroid and to the pericap-sular and regional lymph nodes, where it may remainlocalized for years. Hematogenous spread to distantsites is uncommon. Its clinical course is relativelythe most benign of all thyroid carcinomas. Papillarycarcinoma has a tendency to become more malignantwith advancing age. Invasion of adjacent structuresand distant metastases may appear only as late man-ifestations. Papillary carcinoma may sometimes ded-ifferentiate to the highly malignant anaplastic carci-noma.

Histopathological examination reveals that papil-lary carcinoma is composed of columnar epitheliumthat is thrown into folds, forming papillary projec-tions with connective tissue stalks. There may begross or microscopic foci of carcinoma in other partsof the thyroid gland, resulting from spread via theintraglandular lymphaties.

Papillary carcinoma accumulates iodine less ef-ficiently than does follicular carcinoma. However,its response to administration of suppressive dosesof thyroid hormone is better than that of follicularcarcinoma (regression of the primary tumor and itsmetastases is more evident).


C. Anaplastic carcinoma

Anaplastic carcinoma accounts for about 5–10%of all thyroid carcinomas. It occurs after the age of50, usually in the sixth to seventh decade of life. Itis slightly more common in women. It is a highlymalignant tumor, rapidly invading adjacent struc-tures and metastasizing extensively throughout thebody. Invasion of adjacent structures, such as skin,muscles, nerves, blood vessels, larynx, and esopha-gus causes the origin of symptoms of local mechani-cal syndrome. Tumor mass is often fixed to adjacentstructures, therefore, moves poorly on swallowing.

On histopathological examination, anaplastic car-cinoma is composed of atypical cells that exhibit nu-merous mitoses. Spindle-shaped cells and multinu-cleate giant cells are usually predominant. In somecases, small cells are most prominent. Colloid ab-sence is evident. Areas of necrosis and polymor-phonuclear infiltration are frequently present. Some-times elements of papillary or follicular carcinomacan be detected, suggesting that they may be theprecursors of anaplastic carcinoma, probably origi-nating by their malignant dedifferentiation. Accord-ing to histopathological finding spindle-shaped cell,giant cell, and small cell types of anaplastic carci-noma are distinguished.

In general, anaplastic carcinoma does not accu-mulate radioiodine. Therefore, it is refractory to ra-dioiodine therapy, and it also does not response toadministration of suppressive doses of thyroid hor-mone.

D. Medullary carcinoma

Medullary carcinoma makes up about 2 % of allthyroid carcinomas. It arises from the parafollicu-lar cells producing calcitonin. It usually occurs af-ter the age of 40 and is slightly more common inwomen. Medullary thyroid carcinoma is more ma-lignant than follicular carcinoma, and by its malig-nity it may approach anaplastic carcinoma. Initiallyit invades the intraglandular lymphaties, spreadingto other parts of the gland and to the pericapsularand regional lymph nodes. In this phase it resem-bles papillary carcinoma, but unlike the latter, laterit also spreads via the bloodstream to distant sites,particularly lung, bone, liver, and suprarenal gland.In the time of origin of distant metastases medullarycarcinoma may resemble anaplastic carcinoma, butunlike the latter it usually grows slowlier. Medullary

carcinoma is firm, hard, and usually unencapsulatedand fixed nodule. It is sometimes bilateral, usuallylocalized to the upper two thirds of the gland, whichare the anatomical location of the parafollicular cells.

Histopathological examination reveals that medul-lary carcinoma is composed of the cells that varywidely in morphological features and arrangement.Round, polyhedral, and spindle-shaped cells form avariety of patterns. The cells may appear undifferen-tiated and exhibit mitoses. Unlike the anaplastic car-cinoma, necrosis and polymorphonuclear infiltrationare absent. There is an abundant hyaline connec-tive tissue stroma that gives the staining reactionsfor amyloid (a distinctive amyloid stroma).

Medullary thyroid carcinoma occurs in both spo-radic (80 %) and familial (20%) forms. The famil-ial variety, usually appears at a yonger age, is moreoften bilateral, is less likely to have associated cer-vical metastases when diagnosed, and has a betterprognosis. The familial form may occur as a part ofmultiple endocrine neoplasia (MEN) types 2A or 2B,or in a familial non-MEN setting (medullary thyroidcarcinoma unassociated with other endocrine disor-ders). The peak incidence of the sporadic form is inthe sixth and seventh decades of life, and patientsusually have cervical lymph node metastases at pre-sentation.

Differing from all the previously described thy-roid carcinomas, medullary thyroid carcinomas areneuroendocrine neoplasms of parafollicular cell ori-gin. Neuroendocrine cells are widely dispersed in thebody and are capable of elaborating a large varietyof amine and polypeptide bioactive products. There-fore, in addition to calcitonin, medullary thyroid car-cinoma may elaborate a variety of products. So,a variety of symptoms, other than those related tomass lesions, are present in patients with medullarythyroid carcinoma. The carcinoid syndrome (flush-ing, diarrhea, and bronchospasm) and Cushing syn-drome may occur, owing to secretion of serotoninand ACTH, respectively. Prostaglandins, kinins, andvasoactive intestinal peptide (VIP) may also be se-creted and are variously responsible for the attacksof watery diarrhea and circulation disorders.

Clinical manifestation of familial medullary carci-noma is antecedent by a premalignant hyperplasia ofthe C cells of the thyroid gland. This premalignanthyperplasia is the earliest demonstrable abnormality(after the administration of provocative agents) in


the thyroid gland of individuals with familial formof medullary thyroid carcinoma. Infusions of pen-tagastrin or calcium (and also having drunk alcohol)elicit secretion of calcitonin and successively increasecalcitonin concentration in circulating blood. This isconsidered as an early biochemical signal of startingmedullary thyroid carcinoma.

With time, premalignant hyperplasia of the C cellsis followed by progression to nodular hyperplasia,microscopic medullary carcinoma, and finally frankmedullary thyroid carcinoma. Basal plasma calci-tonin concentration is elevated in about two thirdsof patients with clinically developed medullary car-cinoma. In these patients, however, hypercalcemia isusually not present.

In patients with the familial form of medullary thy-roid carcinoma, there is often clinical or laboratoryevidence of hyperparathyroidism and pheochromocy-toma (MEN 2A, Sipple syndrome). Hyperparathy-roidism is most commonly due to parathyroid hyper-plasia, rather than adenoma. Pheochromocytomasare often bilateral. This variant of the MEN 2A syn-drome is one in which medullary thyroid carcinoma,pheochromocytoma, and possibly parathyroid hyper-plasia are associated with ganglioneuromas. If thereare a marfanoid habitus, thickened corneal nerves,multiple mucosal neuromas, and typical facies simul-taneously present in the patient, this disease is de-noted as the variant of the MEN 2B syndrome. Mu-cosal neuromas may occur on the distal portion ofthe tongue, on the buccal mucosa, on the lips (thickbumpy lips), in subconjuctival areas (thickened andfriable eyelids-margin), and throughout the gastroin-testinal tract (ganglioneuromatosis of the GIT). Inthe patients with the variant of the MEN 2B syn-drome tumors originate at younger age and metas-tase more frequently than in those with the variantof the MEN 2A syndrome.

5.5 Pathophysiology of para-thyroid glands

Primary disorders of hormonal activity of theparathyroid glands are rare. The pathophysiologi-

cal state resulting from undersecretion of parathy-roid hormone (PTH) is denoted as hypoparathy-roidism. The pathophysiological state resultingfrom oversecretion of PTH is called hyperparathy-roidism. There is also a pathophysiological statesimilar to hypoparathyroidism in which secretion ofPTH is normal. The disorder is on the level of tar-get tissues, which are insensitive to PTH. It is infact pseudohypofunctional endocrine disorder (pseu-doendocrinopathy) denoted as pseudohypoparathy-roidism.

5.5.1 Hypoparathyroidism

It is a pathophysiological state when the parathyroidglands are not able to maintain normal calcium con-centration in circulating blood (normocalcemia) andthereby its homeostasis in organism. Hypoparathy-roidism is characterized by low plasma PTH concen-tration, hypocalcemia, hyperphosphatemia, and in-creased neuromuscular excitability.

Etiology of hypoparathyroidism is heterogeneous.Organic and functional causes participate in its ori-gin.

A. Organic causes. The most frequent or-ganic causes are various iatrogenic influences, mainlypostsurgical injuries or inadvertent removal of allparathyroid glands, respectively impairment of theirvascular supply during thyroidectomy or during rad-ical dissection in the neck for some form of malignantdisease. Postoperative hypoparathyroidism origi-nates when during surgical intervention more than50 % of parenchyma of parathyroid glands is dam-aged. It occurs as a complication in about 1 % ofpatients after the mentioned operations. The riskof the origin of permanent hypoparathyroidism ex-ists also in the patients after therapeutic subtotalparathyroidectomy for parathyroid hyperplasia. Ac-quired hypoparathyroidism is an extremely rare com-plication of radioactive iodine therapy (postradia-tion hyperparathyroidism). Its onset is generallybetween 5 and 18 months after radiotherapy. Mostcases are associated with large doses of radioiodinein the patients with Graves-Basedow disease ratherthan in those with thyroid carcinoma. In the latterhypoparathyroidism often originates after the ther-apy by external irradiation.

Spontaneous origin of hypoparathyroidism due toorganic lesion is rare. It is denoted as idiopathic

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