THYROITIS
THYROITIS
Definition: inflammatory diseases of the thyroid gland with different etiologic, biologic, histologic and clinical aspects
CLASSIFICATION
• ACUTE: bacterial, viral
• SUBACUTE: de Quervain’s thryoiditis
• CHRONIC:
• chronic autoimmune thyroidits
• Tuberculous
• Mycotic
• Riedel’s thyroidits
ACUTE BACTERIAL THYROIDITIS
Signs and symptoms
• Fever
• Pain profound and severe
• Dysfagy - 90 % din cazuri
• Dyspnea – 50 %
• spasmodic cough
Laboratory data
• increased ESR
• leukocytosis with neutrophilia
• Ultrasound: small or large hypoechoic areas
• FNB: isolation of germs
Treatment : antibiotics or surgery if an abscess is formed
SUBACUTE ”DE QUERVAIN’S” THYROIDITIS
Sex ratio F/M: 3,6/1 – 10,6 /1
1 caz TS for 5 cases of Graves disease and for 20 cases of AIT
• 0,01 % of all hospitalized patients
• 1,89 % of all patiens hospitalized for thyroid diseases
• 9,9 % of subjects presenting with thyrotoxicosis
• 1,52 % of patients investigated by FNB
ETIOLOGY
• probably the disease is a response to a viral infection
GENETICS
• those with HLA-Bw35 have a risk to develop the disease of 8-56.6 %
• HLA-Bw35 allows the development of clinical symptoms
• it has no relationship with the evolution of the disease
PATOGENICITY
• interleukine 6 produced by monocytes si macrophages determine inflammation
• interleukine 2 +TNF ( + interferon ( determine destructive thyroiditis in 10 % of cases
• VEGF, basic FGF, PDGF determine granulomatous reaction
• EGF determines by mitogenic effect the regeneration of the follicles
PATHOLOGY
• Follicular disruption with thyroglobulin liberation is responsible for the initial phase of thyrotoxicosis
• granuloma:
• a center of giant cells surrounded by macrophages
• epithelial cells surrounded by a crown of macrophages involved with antigen presentation
| |Classical |Non classical form |
|Clinical signs and symptoms |form | |
|History of viral infection |1 / 3 | |
|Painful thyroid |90 % |18 % |
|Fever |90 % | |
|Dysfagy | | |
|Painful thyroid enlargement |90 % | |
| |50 % | |
|Pain irradiates to the ears | | |
|Simptoms of thyrotoxicosis |76 % |42 % |
|Malaise | | |
|Laboratory data |Imagery |
|Important increase of ESR |Hipoechogenicity generalized or disseminated points |
|Leukocytosis |Localized hipoechogenicity |
|FT4 si FT3 increased |Absent Tc 99 m uptake |
|Suppressed TSH |Reduced iodine uptake on scintigram |
|Increased thyroglobulin Transitory increased antithyroid |67 Gallium citrat: scintiscan |
|antibodies | |
|HLA-Bw 35+ | |
| | |
|Differential diagnosis |Evolution and complications |
| | |
|Cyst with intracystic hemorrhage |Transient hypothyroidism second phase of evolution Recurrent |
|Tirotoxicosis induced by iodine loading (amiodarone) |disease is unpredictable |
|Thyroid cancer: FNB |Definitive recovery with euthyroidism |
| |Definitive hypothyroidism 6 (U.I./ml
• 60 % of those with TSH > 6 (U.I./ml have anti thyroid antibodies
• 80 % of those with TSH > 10 6 (U.I./ml have anti thyroid antibodies
• 5 % of those with TSH > 6 (U.I./ml develop overt hypothyroidism each year
PATOGENY
• genetic predisposition
• Viral aggression that determine liberation of thyroglobulin and other components of thyroid cells into circulation leading to antibody formation
• excessive iodine supply leading to over iodinated thyroglobulin which becomes antigenic
GENETIC PREDISPOSITION is confirmed by the following facts:
• affected individuals have relatives with autoimmune thyroid diseases
• the disease occurs in individual with type DR3 and DR5 HLA which play the most important role in antigen presentation to immune system by macrophages
• it occurs in patients with genetic abnormalities :Turner, Klinefelter, Down syndrome
• it occurs frequently in association with other autoimmune diseases:
• multiple autoimune endocrine diseases type I and II (type 1 diabetes mellitus, adrenal failure, ovarian failure with precocious menopause), autoimmune hypophysitis Biermer disease , Sjogren’s syndrome, systemic lupus eritematosus, rheumatoid arthritis , miastenia gravis, interstitial lung disease,
• HLA-DR3 si HLA-DR4
|ANTIBODIES |THIROIDITIS and other diseases |
|ANTI-TPO (PEROXIDASE) | Hashimoto’s thyroiditis, Post partum thyroiditis |
|ANTI – Tg Ab | Hashimoto’s thyroiditis |
|TSH -receptor stimulating antibodies | Hashitoxicosis |
|TGI – thyroid growth immunoglobulins | Hashimoto’s thyroiditis with goiter |
|Thyroid stimulating blocking Ab | Atrophic thyroiditis |
| |“Spontaneous” mixoedema in the adult |
|TGBI – thyroid growth blocking immunoglobulins | Atrophic thyroiditis |
| |“Spontaneous” mixoedema in the adult |
|Anti T3 –Ab , anti T4 - Ab | May interfere with hormone assessment |
|Anti pancreatic islet | Diabetes mellitus |
|Anti salivary ducts |Sjogren’s syndrome |
|Anti neuro-muscle plate |Miastenia gravis |
|Anti other endocrine glands: pancreas, adrenals, gonads |Poli immune endocrine disease (PIE): |
| |Type 1: adrenal failure, diabetes mellitus, mucocutaneous |
| |candidiasis |
| |Type 2 : adrenal failure, autoimmune thyroiditis, autoimmune |
| |precocious ovarian failure (or testicular failure) |
Relationship between auto anti thyroid antibodies and
diseases produced by these antibodies
The presence of antithyroid antibodies attracts locally lymphocytic infiltration that progressively leads to limitation of functional thyroid tissue and thyroid hypofunction
Formes of autimmune thyroiditis
HASHIMOTO’S thyroiditis: signs and symptoms
• goiter
• metabolic state
• eutiroidism – 80 %
• hipothyroidism – 15 %
• hiperthyroidism – 5 %
• some may have subclinical hypothyrodism with slightly increased TSH and normal fT4
LABORATORY DATA
• T4, T3 are frequently normal
• TSH normal or slightly elevated
• in autoimmune thyroiditis with thyrotoxicosis TSH is decreased under normal limits
• increased response of TSH to TRH in subclinical or overtly hypothyroid patients
• anti TPO – antibodies – 100 %
• anti TG-antibodies – 90 %
• TSH receptor blocking immunoglobulins – 15-20 %
ULTRASOUND EXAMINATION
THYROID VOLUME: Increased, normal or decreased
Intense hypoechogenicity
Scintiscan : patchy hypoechogenicity
Classical Hashimoto’s thyroiditis has an increased thyroid volume and intense hypoechogenicity in ultrasound examination
FNB: lymphocytes and Hurthle cells
Evolution: in most cases antithyroid antibodies and lymphocytic infiltration determine progressive loss in thyroid function with subclinical hypothyroidism and than overt hypothyroidism. Subclinical hypothyroidism means slightly increased TSH, normal T4 and absence of obvious clinical signs and symptoms of hypothyroidism. Subclinical hypothyroidism is a risk factor for hypercholesterolemia, atherosclerosis and ischemic hearth disease
CLINICAL FORMS
• HASHOTOXICOSIS: autoimmune thyroiditis and thyrotoxicosis
• IN CHILDREN AND ADOLESCENTS: diffuse euthyroid goiter 10-15 % of goiters at in children and adolescents are produced by autoimmune thyroiditis
• ATROPHIC thyroiditis causes “spontaneous” mixedema in adults and elderly patients
• SILENT or PAINLESS thyroiditis occurs mainly between 30-60 years and may produce hypothyroidism in time
• POSTPARTUM THYROIDITIS : TPO-Ab are detectable in predisposed cases in the 6th month of pregnancy: hyperthyroid state + depression it occurs postpartum weeks 11-12 and is followed by transient or definitive hypothyroidism.
• AUTOIMMUNE THYROIDITIS and MALIGN LYMPHOMA: primary lymphoma of the thyroid may develop in a thyroid previously affected by autoimmune thyroiditis
• AUTOIMMUNE THYROIDITIS and THYROID CANCER. Autoimmune thyroidits is not a factor of predisposition for thyroid cancer. Papillary thyroid cancer in the most frequently associated with autoimmune thyroiditis. A thyroid nodule in a patients with known autoimmune thyroiditis must be assessed as all thyroid nodules in order to confirm a thyroid neoplasia.
• IATROGENIC: interpheron, increased iodine intake, external radiotherapy may also produce autoimmune thyroiditis by interfering with immune system.
TREATMENT
THYROID HORMONES if clinical or subclinical hypothyroidism occurs.
Surgery may be done if it a suspicion for an association with thyroid lymphoma or with a thyroid carcinoma as well in cases in which there are compressive symptoms due to large goiter that does not respond to thyroid hormones treatment or even small goiter that does not respond to hormone treatment
THYROID NODULES
The incidence of thyroid nodules depends of the way of assessment of the thyroid gland:
• CLINICAL : 4-7 % (5-20%)
• NECROPSIES:40-50 % (30-60%)
• ULTRASOUND EXAMINATION 16-67 %
CLINICA OF ENDOCRINOLOGY IASI:
- MEN : 27,37 %
- WOMEN: 30,3 %
- CHILDREN: 1-2%
• THE PREVALENCE INCREASES WITH AGE BY : 0,08 % / year
THYROID CANCER: < 10 % OF PALPABLE NODULES, 60 YEARS |24,78 % |
| |Endemic area | |
|Grun 1992 |Germany |27,6 % |
| |Goiter prevalence: 37,7 %, |women 36 %, men: 18,8 % |
|Mettler1992 |Ukrain, Cernobil area |children: 0,5 % |
| | |Adults 14,9 % |
|Mogos 1994 |Iasi, Romania |women: 30,3 % |
| | |meni: 27,7 % |
| | |61,84 < 1 cm, 21 % 1-2 cm.9,2 %> 3 cm |
Incidence of thyroid nodules detected by ultrasound examination
THYROID CANCERS
INCIDENCE
Males /106 Females /106
• USA: 2,4-2,8 5,6-6,2
• Australia: 0,7 2,1
• Japan: 1.1 2
• Hawai: 3,1 4
• Germany: 2,7
• USA: ’85-’95: 13.856 cases = 1 % Cancer Data Base
Necropsies:
Honolulu: 15,16%
Hiroshima: 25,3
USA: 1,09-1,84
There is a trend to increase of papillary thyroid carcinoma in the last decades but its prognosis is very good.
MORBIDITY:
NEW CASES /106/ year
• SOKAL 1954: 12 / 106/ year
• CUTTLER 1975: women: 52 /106/year
men: 21/ 106/year
• INGBAR 1981: 36 / 106/year
• IMPIERI 1984: 10-30 / 106/year
• MAZAFFERRY 1988 : 37 / 106/year
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In all reported date the incidence of thyroid cancer increases with age and is more frequent in women than in men. The incidence increases with age as well as the severity of the disease concerning tumor stage and histological form. Survival rate decreases with age. The cut-off age being that of 45 years.
Classification of thyroid tumors
Benign – derived from follicular epithelium
• Follicular adenoma
• Atipical follicular adenoma
• Trabecular adenoma
• Oxifilic adenoma
• Other adenomas
Benign – non derived from follicular epithelium
• Paraganglioma
• Teratoma
• Mezenchymal tumors
• vascular
• myogenic
• neural
Thyroid cancers
a. Derived from follicular epithelium
Differentiated
• Papillary carcinoma
• Follicular carcinoma
Undifferentiated
• Anaplastic (undifferentiated carcinoma)
b. Derived from calcitonin producing cells
• Medullary thyroid carcinoma - MTC
- Sporadic MTC
- Familial MTC
- MTC as part of Multiple Endocrine Neoplasia (MEN) type 2 A and 2B
Other malignan tumors
• Derived from lymphocytes
• Hodgkin lymphoma
• Nonhodgkin lymphoma
• Plasmocitoma
Sarcomas
Metastasis
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Malignant thyroid tumors
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Thyroid cancers derived from cell normally located into the thyroid gland, their frequency and prognosis
Causes of thyroid tumors derived from follicular epithelium
Differentiated thyroid cancer: papillary and follicular carcinoma
- external irradiation is the only established cause for most of papillary thyroid carcinoma. It was first recognized by Duffy and Fitzgerald 1936, after head and neck irradiation for other diseases. Than it was recognized in individual after the nuclear accident from Tcernobil (Ukrain) which was followed by an impressive increase of papillary thyroid carcinoma, especially in children under 14 years (78.8 %).
- iodine intake favor the development and increased incidence of papillary thyroid carcinoma with a very good prognosis, the decrease in incidence of follicular carcinoma with a less good prognosis and decreased impressively the incidence of undifferentiated (anaplastic) carcinoma.
- papillary carcinoma represents till 70 % of thyroid cancers in areas with high or sufficient iodine intake and less in area with iodine deficiency.
- follicular thyroid cancer is more frequent in areas with iodine deficiency as well as undifferentiated thyroid cancer. Taking into account this situation, iodine profilaxis becomes also a profilaxis for the development of aggressive thyroid cancers.
Normal thyroid cell have a proto-oncogene called RET (10q 11.2)
that encodes a receptor thyrozine kinase receptor for Glyal-derived Nerve Growth Factor(GDNGF) and Neurturin. Binding of its specific ligand leads to receptor dymerization and a cascade of events involving tyrosine-kinase, Braf and RAS gene activation that finally result in cell proliferation and cancer development. This gene is not expressed in normal follicular cells but normally expressed in parafollicular cell (calcitonin secreting cells of neural origin).
In papillary thyroid cancer it is supposed that external irradiation produces a breakdown of DNA and during the process of DNA repair RET protoncogene is placed by a translocation mechanism under the control of genes normally express in follicular cells and become activated. This process is called RET/PTC rearrangement and was described first in papillary cancers that occurred after Tcernobil accident and is now discovered in most papillary thyroid carcinomas.
Most of undifferentiated thyroid cancer, with a very poor prognosis are derived from previously diffentiated papillary of follicular cancer due to mutation or lost of Tumors Suppressor Gene – p53.
In medullary thyroid carcinoma point mutations of different codons of RET protooncogene result in different forms of medullary thyroid carcinomas (sporadic or associated with other cancers of cells derived from neural crest (see below).
Clinical presentation of thyroid carcinomas:
All forms of thyroid cancers are more frequently in women. Sex ratio depends of the histological form.
Important facts:
There are an important differences between differentiated thyroid cancers and other cancers, because differentiated forms preserve the ability to uptake iodine and are sensitive to TSH stimulation. On the bases of these characteristics differentiated thyroid carcinomas may be treated in multimodal way by association between total thyroidectomy and treatment with radioiodine and thyroxine treatment for suppression of TSH and therefore further growth of tumors. For these reasons differentiated thyroid cancer have a good prognosis and a long evolution.
Papillary thyroid cancer. It is the most frequent of thyroid cancers and occurs in 70-80 % on patients residents in areas of sufficient iodine intake. Clinically papillary thyroid carcinoma presents as a solitary thyroid nodule, but multinodular goiter may be also present. Lymph node involvement occurs frequently and some o cases may be announced by previous metastases. In ultrasound examination it presents as a hypoechoic thyroid nodule with irregular margins and microcalcifications.ultrasound guided fine needle biopsy establishes the diagnosis in most cases bringing characteristic cells. The evolution of the disease is slow the tumor remains for a long time confined to the thyroid gland. Most frequent metastases occurs in cervical lymph nodes and than in lung and liver. Bone metastases are rare. Most cases especially those occurring in women under 45 years old have an excellent prognosis.
Follicular thyroid cancer occurs also most frequently in women, later than papillary thyroid cancer. Is more frequently seen in area of iodine insufficiency. Iodine supply in iodine deficient areas decreased the ratio between follicular and papillary thyroid cancer and taking into account that follicular cancer have a less good prognosis than papillary cancers iodine supplementation lead to an overall better prognosis of thyroid cancers. Clinically follicular carcinoma presents as a solitary thyroid nodule that may invade the adiacent structures and give distant metastases by route of blood to liver, bone and brain and spine. Sometimes the diagnosis is made due to distant metastases. The prognosis is less good than in papillary thyroid cancers. Ultrasound examination reveals a solitary thyroid nodule, with irregular margins, without microcalcifications. Scintigraphy shows a cold nodule. Fine needle biopsy is less relevant because the pathologist may say only that is a “follicular neoplasia” but not certainly a follicular cancer. 40 % of nodules with a biopsy of follicular neoplasm may truly have a follicular cancer. As most differentiated thyroid cancer follicular carcinoma may be treated by total thyroidectomy and radioactive iodine if patient is at high risk: large tumor with surrounding structures invasion, distant metastases, particular histologic forms.
Anaplastic thyroid carcinoma
Ussualy occurs in old patients, it is more frequently seen in areas with low iodine supply and the cause is lost of the Tumor Suppressor Gene p53, in some previously differentiated thyroid cancers.
Clinical picture of anaplastic carcinoma is that of a rapidly progressive thyroid tumor, with lymph node involvement, invasion of neck structures with compressive symptoms, and frequently distant metastases at the time of diagnosis.
Medullary thyroid cancer (MTC).
It develops from calcitonin-secreting cells which are of neuroectodermal origin. Calcitonin-secreting cells preserve their ability to produce as other neuroendocrine cells other hormones and mediators: histamine, serotonine, somatostatine, carcino-embrionary antigen, bombesine, ACTH (adreno-corticotropic hormone), CRH (corticotrophin-releasing hormone). The disease is occurs with equal frequency in men and women. More than 70 % of cases occurs as sporadic forms and the others familial forms: isolated familial MTC, MTC as a part of Multiple Endocrine Neoplasia (MEN) type 2A and 2B (see below).
Thyroid tumor may have different dimensions from some millimeters to centimeters, is firm and frequently associated with lymph node involvement. Signs and symptoms of calcitonin and other hormone secretions may produce: flushes (calcitonin ans serotonin), diarrhea (calcitonin), ACTH-dependent Cushing’s syndrome. In familial forms of MEN other signs and symptoms occur: arterial hypertension (pheochromocytoma), hypercalcemia (hyperparathyroidism), ganglioneuromatosis of lips and eyelids (also see below). Increased basal calcitonin and carcinembriogenetic antigen are markers of the disease. In cases in which calcitonin in not obviously elevated calcitonin may be stimulated by pentagastrin or calcium infusion.
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Mutations that occurs in codons that are part of RET gene lead to different forms of medullary thyroid carcinoma, sporadic, familial MTC, or Multiple Endocrine Neoplasia type 2A/B
[pic] MTC and syndromes associated with MTC
A genetic predisposition was also identified in cancers derived from follicular epithelium in carrier for the gene MNG (multinodular goiter)
Evaluation of thyroid nodules and thyroid cancer
- thyroid examination
- history of the disease in individual and relatives
- scintigraphy
- fine needle biopsy
- TSH, T4,
- Antithyroid antibodies
- Calcitonin measurement
Ultrasound examination of thyroid nodules
• Identifies that lesion belongs to the thyroid , if it is solitary or multiple and has or not has lymph node enlargement
• It is the guide for fine needle biopsy
• It allows to detect the anatomic rapports with other structures
• Low risk: pure cyst, hyper or isoechoic, transonic hallo, peripheral large calcification
• High risk: irregular margins, microcalcifications, cyst with solid content inside
• Color Flow Doppler ultrasound: benign: vascular hallo , a few echos inside the nodule, malign: intense vascularity inside, transcapsular vesels.
Scintigraphy of thyroid nodules
Differentiated thyroid cancer
CLASSICAL:
131 I most used ( no uptake in the nodule “cold nodule), also used for follow-up
• 99m Tc : false negative in some cases of thyroid cancers. Nodules positive for 99m Tc but without iodine uptake may be cancers
New scinigraphies
99 Tc MIBI:
o bone metastasis: sensitivity: 73 %, specificity; 90%
o lung metastasis: sensitivity: 21 %, specificity: 94 %
• 99 mTc tetrafosmin
• 201 Tl positive for differentiated thyroid cancers
In some cases computed tomography and MRI imaging allows the surgeon to obtain details about the relationship between nodule and surrounding tissues. Computed tomography is not indicated because it may lead to iodine saturation of thyroid tissue and interfere with further radioactive iodine administration after surgery if the nodule was a differentiated thyroid cancer.
Fine needle biopsy in thyroid nodules
FNB is the most reliable assessment of thyroid nodules and allows:
• a good detection for papillary, medullary and anaplstic carcinoma
• planning for surgery
• selection of tumors in which other therapy may be beneficial (lymphoma)
• non-conventional therapy for thyroid nodules: cyst evacuation, necrotizating of functioning adenomas
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Algorithm for diagnosis in thyroid nodules
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Elements that plead for benignity or malignancy in thyroid nodules
A history of Graves disease of Graves disease in evolution increases the probability of a nodule to be malign.
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TREATMENT OF DIFFERENTIATED THYROID CANCER
SURGERY
• always total or near total thyroidectomy
• loboistmectomy: small papillary carcinoma in low-risk patients, children, young adults
Side effects :
• laringeal palsy : 2-8 %
• hypoparatiroidism: 1-4 %
After surgery patients are classified into:
- Low risk: small papillary or follicular carcinoma in women under 45 years old
- High risk: larger tumors with lymph node involvement, both sexes after 45 years, toll cell tumors, sclerosing papillary tumors
RADIOACTIVE IODINE IN THE TREATMENT OF DIFFRENTIATED THYROID CARCINOMA
Ablation of thyroid remnant after surgery
- In high risk patients is always indicated
- controversial in other patients
- not indicated in low risk patients
- Ablative dose between 30 – 100 mCi depending of the tissue left after surgery and histology
Treatment and follow-up of patients with differentiated thyroid cancer
Suppressive treatment :
• L-Thyroxina >/= 200 (g/day
• 2,1-2,8 (g/b.w./day
• TSH may be maintained < 0.1 (UI/ml
Follow-up:
Tiroglobulin (IRMA) is best indicator for cure or persistent or recurrent disease
• undetectable in 98 % of those in remission
• if detectable when THS values are very high after thyroid hormone withdrawal there is persistent or recurrent disease and a new dose of radioactive iodine is given
Whole body scanning after T4 withdrawal
for 4 week until TSH reaches values of at least 30 mIU/L
rhTSH 0.9 mg may replace thyroid hormone withdrawal
in patients who do not tolerate prolonged hypothyroidism
Tg < 10 ng/ml : treatment with radioactive iodine in dose less than 100 mCi
Tg > 10 ng/ml: treatment with 100 mCi
Immediately patients will receive suppressive doses of l-thyroxine
For those with Tg + si WBS negative: 18 F-FDG-PET
Lung metastases are responsive to large doses of radioiodine and suppressive therapy for TSH with thyroxine. Bone metastases are less responsive and may be surgically removed or irradiated.
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In the case of familial MTC or MEN2A/B there are the flowing recommendations for screening of patients with inherited disease (vide supra).
Anaplastic thyroid cancer could be treated by surgery, followed by external irradiation and chemotherapy, but survival is very poor independently of the treatment .
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