Smjernice hrvatskog društva za štitnjaču za racionalnu dijagnostiku poremećaja funkcije štitnjače croatian thyroid society guidelines for rational detection of thyroid dysfunction

Tablica 2. Skupine bolesnika u kojih se primjenjuje algoritam za racionalnu dijagnostiku hipotireoze / Table 2. Groups of patients assigned to the algorithm for rational diagnosis of hypothyroidism

Klinički simpomi i znakovi hipotireoze / Clinical symptoms and signs of hypothyroidism

Rizične skupine - ispitanici i stanja / Risk groups – patients and conditions pozitivna protutijela na TPO / positive TPO antibodies prethodno liječenje Gravesove hipertireoze (operativno, jodom-131, tireostaticima) / prior treatment of Graves' hyperthyroidism (surgery, iodine-131, antithyroid drugs) prethodno vanjsko zračenje vrata / prior external beam radiotherapy of the neck liječenje amiodaronom/ treatment with amiodarone suspektan hipopituitarizam / suspected hypopituitarism guša / goiter obiteljska anamneza autoimune bolesti štitnjače / positive family history of autoimmune thyroid disease osobna/obiteljska anamneza pridruženih autoimunih bolesti / personal/family history of associated autoimmune disorders stariji bolesnici / elderly patients hiperkolesterolemija / hypercholesterolaemia

Slika 1. Algoritam racionalne dijagnostike hipotireoze

Prvi korak u obradi bolesnika sa sumnjom na hipotireozu je određivanje TSH u serumu. Uredan nalaz TSH isključuje hipotireozu, osim u slučaju centralne hipotireoze koja se javlja izuzetno rijetko. U slučaju nalaza TSH 5-10 mU/L, neophodno je ponoviti test za 2-3 mjeseca uz određivanje FT4 (T4) kako bi se izbjegla moguća laboratorijska pogreška ili prolazno povišena vrijednost TSH. Ako je vrijednost TSH veća od 10 mU/L neophodno je odrediti FT4 (T4). Ako je FT4 (T4) snižen, tada je bolesnik u primarnoj hipotireozi. Ako je FT4 (T4) uredan uz blago povišen TSH tada se radi o supkliničkoj hipotireozi. U slučaju primarne, a osobito supkliničke hipotireoze korisno je odrediti protutijela na tireoidnu peroksidazu u serumu (TPO). Pozitivna TPO upućuju na kronični autoimuni (Hashimotov) tireoiditis. Ako su TPO negativna tada se vjerojatno radi o TPO negativnom kroničnom tireoiditisu, a izuzetno rijetko infiltraciji štitnjače. Potrebu za punkcijom u TPO negativnih bolesnika treba procijeniti na temelju kliničke slike. Ako postoji klinička sumnja na centralnu hipotireozu potrebno je uz TSH odrediti FT4 (T4). Centralna hipotireoza je obilježena sniženom razinom T4 (FT4) u serumu uz urednu ili sniženu vrijednost TSH. Daljnja obrada je potrebna radi utvrđivanja uzroka poremećaja (bolest hipofize ili hipotalamusa).

Ako se tijekom obrade utvrdi snižen TSH tada je potrebno odrediti FT4 (T4). Ako je vrijednost FT4 (T4) uredna ili povišena, tada je potrebno slijediti algoritam tireotoksikoze.

Figure 1. Algorithm for rational diagnosis of hypothyroidism

The first step in the management of a patient suspected of hypothyroidism is serum TSH measurement. Normal serum TSH excludes hypothyroidism, except in the rare case of central hypothyroidism. If TSH value is 5-10 mU/L, repeated TSH testing after 2-3 months together with FT4 (T4) measurement is recommended to exclude laboratory error or transient elevation of TSH. If serum TSH level is greater than 10 mU/L, FT4 (T4) should be measured. If serum FT4 (T4) is low, the patient has primary hipothyroidism. Subclinical hypothyroidism is diagnosed if the patient has normal serum FT4 (T4) together with mildly elevated TSH. In the case of primary and especially subclinical hypothyroidism, the measurement of TPO antibodies (TPO) is useful to confirm chronic autoimmune (Hashimoto's) thyroiditis. If TPO are negative, TPO-negative chronic thyroiditis can be present, or rarely, infiltration of the thyroid tissue. Fine needle aspiration biopsy (FNAB) can be performed in these patients according to clinical findings. In the case of suspected central hypothyroidism, both TSH and FT4 (T4) should be measured. Central hypothyroidism is diagnosed when serum FT4 is low and TSH is low or normal. Further evaluation is necessary to confirm the cause of the disorder (pituitary or hypotalamic disease).

If the finding is low serum TSH, the next step in the diagnostic evaluation is the measurement of FT4 (T4). If serum FT4 (T4) is normal or elevated, further evaluation shold be performed according to the diagnostic algorithym of thyrotoxicosis.

Tablica 3 - Smjernice za praćenje bolesnika s hipotireozom / Table 3. Guidelines for follow-up of patients with hypothyroidism

Kod primarne hipotireoze kontrola FT4 (T4) i TSH 6-8 tjedana nakon uvođenja nadomjesnog liječenja L-T4 ili nakon promjene doze L-T4 / In primary hypothyroidism serum FT4 (T4) and TSH should be measured 6-8 weeks after the introduction of supstitution with L-T4 or a change of L-T4 dose

Nakon postizanja eutireoze kontrola TSH jednom godišnje ili češće, ovisno o kliničkim indikacijama / After reaching euthyroid state, serum TSH should be measured yearly or more often if there is clinical indication

U bolesnika u kojih se ne postigne adekvatan učinak supstitucijskim liječenjem L-T4 potrebno je odrediti FT4 (T4) i TSH / In patients without adequate L-T4 supstitution serum FT4 (T4) and TSH should be measured

Praćenje supkliničke hipotireoze bez liječenja L-T4 / Follow-up of subclinical hypothyroidism without L-T4 treatment - u slučaju pozitivnih TPO protutijela kontrola FT4 (T4) i TSH svakih 6 mjeseci / in case of positive TPO antibodies: serum FT4 (T4) and TSH should be measured every 6 months - u slučaju negativnih TPO protutijela kontrola FT4 (T4) i TSH jednom godišnje / in case of negative TPO antibodies: serum FT4 (T4) and TSH should be measured yearly

Tablica 4. Skupine bolesnika u kojih se primjenjuju smjernice i algoritmi za racionalnu dijagnostiku tireotoksikoze / Table 4. Groups of patients assigned to the guidelines and algorithms for rational diagnosis of thyrotoxicosis

Klinički simptomi i znakovi tireotoksikoze / Clinical symptoms and signs of thyrotoxicosis

Rizične skupine / Risk groups - bolesnici s oftalmopatijom / patients with ophtalmopathy - anamneza autoimune bolesti štitnjače u obitelji / positive family history of autoimmune thyroid disease - lijekovi koji utječu na funkciju štitnjače (amiodaron, jod) / drugs that alter thyroid function (amiodarone, iodine) - kardiopati (bolesnici s aritmijama, srčanom dekompenzacijom, osobito stariji bolesnici / patients with cardiovascular diseases (arrithmias, heart failure, especially elderly patients)

Slika 2. Algoritam racionalne dijagnostike tireotoksikoze:

Prvi korak u obradi bolesnika sa sumnjom na tireotoksikozu (hipertireozu) je određivanje tireotropina (TSH) u serumu jer je to najbolji test za isključivanje poremećaja funkcije štitnjače, osobito u ambulantnim uvjetima. Razvoj osjetljivih analitičkih metoda određivanja TSH (III generacija) pojednostavnio je dijagnostički pristup tireotoksikozi i omogućio otkrivanje i supkliničkih oblika bolesti. Tireotoksikoza bilo kojeg uzroka dovodi do supresije TSH (osim izrazito rijetkih stanja poput tireotropinoma i rezistencije na hormone štitnjače). Uredan nalaz TSH isključuje tireotoksikozu. Preporučljiva funkcionalna osjetljivost metode određivanja TSH treba biti ≤ 0,02 mU/L. U slučaju nalaza snižene vrijednosti TSH neophodno je odrediti slobodni tiroksin (FT4) ili tiroksin (T4). Prednost određivanja FT4 u odnosu na ukupni hormon je u izbjegavanju mogućih grešaka zbog povišene koncentracije tiroksin vezujućeg globulina. Nalaz povišene vrijednosti FT4 (T4) potvrđuje dijagnozu tireotoksikoze. Ako je nalaz FT4 (T4) u granicama normale tada je neophodno odrediti FT3 (T3) zbog isključivanja T3 tireotoksikoze. Povišena vrijednost FT3 (T3) uz normalnu vrijednost FT4 (T4) i sniženu vrijednost TSH potvrđuje T3 tireotoksikozu koja je česta na području Europe. Ako su vrijednosti FT4 (T4) i FT3 (T3) uredne, a TSH suprimiran, tada se radi o supkliničkoj tireotoksikozi.

U slučaju kliničke sumnje na tireotropinom ili rezistencije na hormone štitnjače uz TSH se mora odrediti FT4 (T4) jer uredan TSH u tim rijetkim stanjima ne isključuje poremećaj. Serumski FT4 je kod tireotropinoma i rezistencije na hormone štitnjače povišen uz uredan ili blago povišen TSH. Lažno povišen FT4 može se naći u bolesnika s obiteljskom disalbuminemičnom hipertiroksinemijom ili onih koji uzimaju neke lijekove (npr. amiodaron). U tih bolesnika vrijednost TSH je u granicama normale. U slučaju nalaza povišene vrijednosti TSH potrebno je slijediti algoritam hipotireoze.

Figure 2. Algorithm for the rational diagnosis of hyperthyroidism

The first step in the management of patients suspected of thyrotoxicosis (hyperthyroidism) is serum TSH measurement. Serum TSH measurement is the single most reliable test to exclude thyroid dysfunction, particularly in the ambulatory settings. The development of ultrasensitive TSH assays (III generation) simplified clinical approach to the diagnosis of thyrotoxicosis and enabled the detection of subclinical forms of the disease. All types of thyrotoxicosis are accompanied by supressed serum TSH concentration (except rare clinical conditions such as TSH-secreting pituitary adenoma and selective resistance to thyroid hormones). Normal serum TSH level excludes thyrotoxicosis. TSH assay sensitivity must be ≤ 0,02 mU/L. In case od low serum TSH, serum FT4 (T4) should be measured. Free FT4 estimate instead of total T4 is recommended to avoid possible false elevation of T4 due to elevated thyroxine-binding globulin concentration. Elevated serum FT4 concentration confirms the diagnosis of thyrotoxicosis. If serum FT4 concentration is normal, serum FT3 (T3) should be measured to exclude T3 thyrotoxicosis. Elevated serum FT3 (T3) together with normal FT4 (T4) and low serum TSH concentration confirms the diagnosis of T3 thyrotoxicosis that is a common condition in Europe. If both serum FT4 (T4) and FT3 (T3) are normal, and serum TSH is suppressed, the diagnosis is subclinical thyrotoxicosis.

In case of clinical suspicion for TSH-producing pituitary adenoma or resistance to thyroid hormones, serum FT4 (T4) should also be measured because normal serum TSH does not exclude these rare conditions. In TSH-producing pituitary adenoma and resistance to thyroid hormones serum FT4 (T4) concentration is elevated while serum TSH concentration is normal or mildly elevated. Falsely elevated serum FT4 can be found in patients with familial dysalbuminemic hyperthyroxinemia or in patients taking certain drugs (like amiodarone). Serum TSH is normal in these patients. If serum TSH is elevated, further evaluaton should be performed according to the diagnostic algorithm of hypothyroidism.


Slika 3. Algoritam za utvrđivanje uzroka tireotoksikoze
Kada se laboratorijskom obradom utvrdi tireotoksikoza, potrebna je daljnja obrada radi utvrđivanja uzroka poremećaja. Daljnje usmjeravanje obrade ovisi o nalazu palpacije i ultrazvuka (UZV) štitnjače. Ako se palpacijom i ultrazvukom štitnjače ne nađu čvorovi, tada je klinička dijagnoza vjerojatno Gravesova hipertireoza. Nalaz oftalmopatije (egzoftalmus), dodatno govori u prilog Gravesove bolesti. Kod Gravesove hipertireoze ultrazvučno nalazimo difuzne promjene parenhima štitnjače, pojačanu prokrvljenost parenhima štitnjače na obojenom doppleru (kratica CD, od anglosaksonski Color Doppler) i pojačane brzine protoka kroz tireoidne arterije.

U diferencijalnoj dijagnozi tireotoksikoze potrebno je razmotriti mogućnost tireoiditisa. Subakutni tireoiditis ima karakterističnu kliničku sliku. Uzimanje antiaritmika amiodarona također može uzrokovati tireoiditis (amiodaronom potaknuta tireotoksikoza tip II). U slučaju kliničke sumnje na tiroiditis, scintigrafija štitnjače s ^99mTc pertehnetatom ili mjerenje nakupljanja radioaktivnog joda (¹³¹I) u štitnjači će isključiti ili potvrditi dijagnozu. Scintigrafsko obilježje svih tiroiditisa je izrazito oslabljen prikaz funkcionalnog parenhima štitnjače i izrazito snižen test nakupljanja radioaktivnog joda u štitnjači.

Ultrazvuk štitnjače s obojenim dopplerom (CD) je korisna dijagnostička metoda za razlikovanje amiodaronom potaknute tireotoksikoze tipa I i II. Kod amiodaronom potaknute tireotoksikoze tipa I (AIT tip I), čije je obilježje pojačana funkcija štitnjače, nalazimo pojačanu prokrvljenost parenhima štitnjače na CD-u i povećane brzine protoka kroz tireoidne arterije. Kod amiodaronom potaknutog tireoiditisa (AIT tip II) nema pojačane prokrvljernosti parenhima štitnjače na CD-u, a brzine protoka kroz tireoidne arterije nisu povišene.

U slučaju palpatornog i/ili ultrazvučnog nalaza većeg čvora/čvorova u štitnjači, scintigrafija štitnjače je neophodna radi postavljanja dijagnoze uzroka tireotoksikoze. U slučaju nalaza funkcionalnog čvora na scintigramu, obično bez prikaza ostatka parenhima štitnjače, dijagnoza je toksični adenom. U slučaju nalaza više funkcionalnih čvorova na scintigramu, dijagnoza je multinodularna toksična guša. Kod Gravesove hipertireoze štitnjača je na scintigramu difuzno, intenzivno prikazana, a test nakupljanja radioaktivnog joda u štitnjači je povišen. U slučaju nalaza nefunkcionalnog čvora/čvorova neophodno je slijediti algoritam dijagnostike čvor(ova) u štitnjači.

Uz navedene dijagnostičke postupke važno je napomenuti da razina povišenih vrijednosti FT3 (T3) i FT4 (T4), ali i njihov relativni odnos također imaju značaj u dijagnostici uzroka tireotoksikoze. Izrazito visoke vrijednosti hormona štitnjače su obično obilježje Gravesove hipertireoze, rjeđe toksičnog adenoma i multinodularne toksične guše. T3 tireotoksikozu češće nalazimo kod Gravesove hipertireoze, ali je možemo naći i kod toksičnog adenoma i multonodularne toksične guše. Blaga tireotoksikoza uz predominantni porast FT4 (T4) je obično obilježje tiroiditisa.

Figure 3. Algorithm for the determination of the etiology of thyrotoxicosis

If laboratory testing confirms thyrotoxicosis, further diagnostic evaluation is mandatory to determine the etiology of the disorder. The next step in the diagnostic evaluation depends on the finding of thyroid palpation and ultrasound (US). If there are no nodules according to findings of thyroid palpation and US, clinical diagnosis is probably Graves' hyperthyroidism. In addition, clinical finding of ophtalmopathy leads to the diagnosis of Graves' disease. Ultrasound of the thyroid gland in Graves' hyperthyroidism demonstrates diffuse pattern of the thyroid parenchyma. Color Doppler in Graves hyperthyroidism demonstrates increased vascularity of the thyroid parenchyma and increased vascular flow through thyroid arteries.

In a differential diagnosis of thyrotoxicosis thyroiditis should also be suspected. Subacute thyroiditis is characterized by specific clinical symptoms and signs. Furthermore, amiodarone can induce thyroiditis (amiodarone induced thyrotoxicosis type II, AIT type II). If thyroiditis is suspected according to the clinical findings, thyroid scan or radioactive iodine uptake test can exclude or confirm the diagnosis. Thyroiditis is characterized with poor thyroid gland imaging and very low radioioactive iodine uptake test.

Thyroid ultrasound with Color Doppler (CD) is useful diagnostic tool in the differential diagnosis between amiodarone induced thyrotoxicosis type I and II. Amiodarone induced thyrotoxicosis type I (AIT type I) is characterized by increased thyroid function. Color Doppler in AIT type I demonstrates increased vascularity of the thyroid parenchyma and increased vascular flow through thyroid arteries. However, amiodarone induced thyroiditis (AIT type II) is characterized by the absence of increased vascularity of the thyroid parenchyma on CD and vascular flow through thyroid arteries is not increased.

A thyroid scan is mandatory to determine the etiology of thyrotoxicosis if there is large nodule(s) according to finding of thyroid palpation and/or US. Toxic thyroid adenoma is diagnosed if the thyroid scan reveals a functioning nodule, usually with the supression of extranodular thyroid tissue. Multinodular toxic goiter is diagnosed if the thyroid scan reveals more than one functioning nodule. Graves' hyperthyroidism is characterized by intense, diffuse thyroid uptake and an elevated radioiodine uptake test. If the thyroid scan reveals nonfunctioning nodule, further diagnostic evaluation should be according to the algorithm for rational diagnostics of thyroid nodule(s).

Furthermore, the level of elevated serum concentrations of FT3 (T3) and FT4 (T4), and the relative ratio of FT3 (T3) to FT4 (T4) are also important in the evaluation of the etiology of thyrotoxicosis. Very high serum concentrations of FT3 (T3) and FT4 (T4) are usually seen in Graves' hyperthyroidism, rarely in toxic thyroid adenoma and multinodular toxic goiter. T3 thyrotoxicosis is usually seen in Graves' hyperthyroidism, but can also be seen in toxic thyroid adenoma and multinodular toxic goiter. Mild thyrotoxicosis with predominant elevation of FT4 (T4) is usually seen in thyroiditis.

Tablica 5. Smjernice za praćenje bolesnika s hipertireozom / Table 5. Guidelines for follow-up of patients with hyperthyroidism

Tijekom prva 2 do 3 mjeseca po uvođenju tireostatika određivanje FT3 (T3) i FT4 (T4) svakih 4 - 6 tjedana / FT3 (T3) and FT4 (T4) should be measured every 4-6 weeks during the first 2-3 months following the introduction of antithyroid drugs

Nakon 2 – 3 mjeseca liječenja tireostaticima određuje se FT4 (T4) i TSH / After 2-3 months of treatment with antithyroid drugs FT4 (T4) and TSH should be measured

Nakon završetka liječenja Gravesove hipertireoze tireostaticima (nakon 12 – 18 mjeseci liječenja) mogu se odrediti TSH-receptor protutijela / After stopping antithyroid drugs (after 12 -18 months of treatment) TSH-receptor antibodies can be measured

Nakon liječenja Gravesove hipertireoze jodom-131 prva kontrola FT4 (T4) i TSH nakon 2 mjeseca. Potrebno je doživotno praćenje funkcije štitnjače / The first measurement of FT4 (T4) and TSH should be after 2 months following radioiodine therapy of Graves' hyperthyroidism. Life-long monitoring of thyroid function is mandatory.

Nakon liječenja toksičnog adenoma ili multonodularne toksične guše jodom-131 prva kontrola FT4 (T4) i TSH i scintigrafija štitnjače s 99mTc nakon 3-4 mjeseca. Potrebno je doživotno praćenje funkcije štitnjače / The first measurement of FT4 (T4) and TSH together with thyroid scan should be afer 3-4 months following radioiodine therapy for toxic thyroid adenoma or toxic multinodular goiter. Life-long monitoring of thyroid function is mandatory

Nakon nekompletne tireoidektomije prva kontrola FT4 (T4) i TSH nakon 6 tjedana. Ultrazvuk štitnjače se preporuča učiniti nakon 3 mjeseca po operativnom zahvatu. Potrebno je doživotno praćenje funkcije štitnjače / After a subtotal thyroidectomy FT4 (T4) and TSH should be measured after 6 weeks. Thyroid ultrasound is recommended after 3 months following surgery. Life-long monitoring of thyroid function is mandatory.

Supklinička hipertireoza: Praćenje određivanjem FT3 (T3), FT4 (T4) i TSH svakih 6-12 mjeseci / Subclinical hyperthyroidism: Follow up with serum FT3 (T3), FT4 (T4) and TSH measurement every 6-12 months.

Tablica 6. Preporuke za probir poremećaja funkcije štitnjače Hrvatskog društva za štitnjaču / Table 6. Screening for thyroid dysfunction – recommendations of the Croatian Thyroid Society

Određivanje TSH trudnicama na početku trudnoće / Serum TSH measuremet in pregnant women at the beginning of pregnancy

Određivanje TSH ženama starijim od 50 godina, ukoliko traže liječničku pomoć / Serum TSH measurement in women older than 50 years if they seek medical help