THE THYROID GLAND

THE THYROID GLANDHYPERTYROIDISM

THE THYROID GLANDThe thyroid secretes primarilyThyroxine / T4 /T4 is probably not metabolically active until converted to T3(T4 = prohormone)~85% of T3 is produced by monodeiodination of T4

T3 and T4 circulate in plasma are almost entirely (>99,9%) bound to transport proteins (mainly TBG, less TBPA and albumins)Only free hormones exert its metabolic actionIt is better to measure the concentration in plasma FT3 or FT4THE THYROID GLAND

Patterns of thyroid function test results in patients with hyperthyroidismConventional hyperthyroidism (95% of cases):FT4 ; FT3 ; TSH or undetectableT3-hyperthyroidism (5% of cases):FT4 ; FT3 ; TSH or undetectableSubclinical hyperthyroidism:FT4 ; FT3; TSH or undetectable

NEGATIVE FEEDBACK

Not-thyroidal illness (e.g. myocardial infarction or pneumonia):Decreased peripherial conversion of T4 to T3.Alterations in the binding proteins.Alterations in the affinity of binding proteins for thyroid hormones.TSH levels as a results of the illness itself or the use of drugs (e.g. dopamine or corticosteroids).TSH into the hypothyroid range during convalescence.

THYROTOXICOSIS Hypermetabolic state caused by thyroid hormone excess at the tissue levelHYPERTHYROIDISMIncreased thyroid hormones synthesis and secretionAll patients with hyperthyroidism have thyreotoxicosis Not all patients with thyreotoxicosis are hyperthyroid

AETIOLOGYIt is important to identify the cause of hyperthyroidism in order to prescribe appropriate treatmentPREVALENCEFemales:~20/1000Males:~4/1000

Causes of thyrotoxicosiscommon typesWith high RAIUGraves diseases (60-90%)Multinodular goitre (14%)Autonomously functioning solitary thyroid nodule (5%)Iodine-induced thyrotoxicosisWith low RAIUThyroiditissubacute (3%)silent (painless)post-partumIodine-induced thyrotoxicosisdrugs (e.g. amiodarone)radiografic contrast mediaiodine prophylaxis programme

Causes of thyrotoxicosisuncommon typesWith high RAIUCongenital hyperthyroidismTSH-induced hyperthyroidismTSH-secreting adenomaselective pituitary resistance to thyroid hormoneTrophoblastic tumors

With low RAIUThyrotoxicosis facticia (0.2%)Metastatic thyroid carcinoma (0.1%)Struma ovarii

CLINICAL FEATURES OF HYPERTHYROIDISMMost signs and symptoms are common to all types of thyreotoxicosis;Some of them are specific to defined diseasefor example:ophthalmopathypretibial myxoedemathyroid acropathyGravesdiseasethyroid paintenderneessubacutethyroiditis

CLINICAL FEATURES OF HYPERTHYROIDISM(according to frequency)SYMPTOMSNervousnessPalptationsIncreased sweatingHaet intoleranceFatigueWeight lossDyspneaIncreased appetiteEye symptomsFriable hair and nailsIncreased bowel movementsDiarrhoeaMenstrual disturbancesSIGNSTachycardiaGoitreTremorsSkin changesHyperkinesisThyroid bruitLid lag and retractionOphthalmopathyAtrial fibrillationOnycholisisLocalized (pretibial) myxedemaVitiligoAcropathy

GRAVES DISEASEthe most frequent cause of hyperthyroidismGraves disease is an autoimmune thyroid disease, characterized by diffuse thyroid enlargement, ophtalmopathy and less frequently dermopathy (pretibial myxedema) and acropathy.It can occur at any age (unusual before puberty and most commonly affects the 30-50- years-old age group)the female/ male ratio ~7 : 1

Graves disease - pathogenesisThyroid antigen-specific T lymphocytesHumoral and cell-mediated immune reactionsInfiltration of the thyroid gland by immune effector cells

Graves disease - pathogenesisGenetic and environmental factorsProduction of IgG antibodies(thyroid-stimulating immunoglobulins TSIor TSH-receptor antibodies TRAb)Stimulation thyroid hormone production and goitre formation

Graves disease - pathogenesisGenetic factors:The familial predisposition.The frequent finding of circulating autoantibodies in relatives of Graves patients.The high concordance rate in monozygotic twins.The positive association with haplotypes HLA-B8 and DR3 (Caucasians), HLA-B35 (Japonese population), and HLA-Bw46 (Chinese population).Female sex hormones.

Graves disease - pathogenesisEnvironmental factors:IodineImmune-stimulant effect(in areas of iodine defficiency thyroid autoimmune diseases are rare). Cigarettes(assotiation with Graves ophtalmopathy influence on immune-competent cells?).

Graves disease - pathogenesisEnvironmental factors:Escherichia coli and Yersinia enterocolitica(antibodies to these microbial antigenscross-reaction with the TSH-receptorhyperthyroidism.Stress(relationship between the onset of hyperthyroidism and a major life event).

Graves disease - pathogenesisOphtalmopathy and dermopathy:Pathogenesis is less well understood.Immunologically mediated but TRAb is not implicated.

Proliferation of fibroblasts (adipocytes?) within the orbitIncreased interstitial fluid contentChronic inflammatory cel infiltrateSwelling of the extra-ocular muscles Rise in retrobulbar pressure

Graves disease - clinical findingsTHYROID GLAND: Symmetrically enlargedFirmThrills and bruits

Goiter is absent in 3% of causes

Graves disease clinical findingsLOCALIZED MYXEDEMA: Pretibial regionRaised, light colored or yellow-reddish lesion with orange peel apperanceSometimes pruritus

Graves disease clinical findingsTHYROID ACROPATHY: Swelling and soft tissues of hands feetClubbing of fingers and toes

True ophtalmopathy is specific of Graves diseaseSoft tissue involvement:Lacrimation RednessBurning sensation PhotophobiaGritty sensationProptosis (exophtalmos) and lagophthalmoskeratitisExtra-ocular muscle dysfunctiondiplopiaOptic neuropathyblidness

Cardiovascular systemTachycardiaPalpitationsBlood pressure:systolic diastolic

THYROCARDIAC SYNDROMEPremature heart beatsAtrial fibrillationHeart failure and/or angina

Alimentary systemIncreased appetitebut weight lossIncreased frequency of bowel movements and diarrheaRarely liver dysfunction

Nervous systemNervousnessAnxietyEmotional instability

HyperactivityInsomniaFine tremorsMusclesMuscular weaknessIn most severe cases muscular atrophy

Skeletal systemMetabolismIncreased oxygen consumptionDiabetes mellitus may be exacerbatedSerum cholesterol plasma triglycerides

ThyrotoxicosisIncreasedloss of boneosteoporosis

GRAVES DISEASE DIAGNOSTIC PROCEDURESLabolatory investigationimportant particularly in the absence of goitre and eye diseaseImaging studiesImportant particularly in diagnostic of Graves ophtalmophathyComputed tommographyMagnetic resonance

LABORATORY INVESTIGNATIONHyperthyroidism

Serum concentrations of:TSH: undetectable or FT4: FT3:

T3-toxicosis: TSH: undetectable or FT3: FT4: Graves disease:TRAb TPO ATG

Imaging studies24-hour thyroidal radioactive iodine uptake:increasedthyroid scan diffuse, homogenous goitreThyroid ultrasound:enlarged glandhypoechoic patternincreased blood flowComputed tomography and magnetic resonance

GRAVES DISEASE TREATMENTGeneral principles of treatment Treatments available for Graves diseaseMEDICALSURGICALRADIOIODINEMost treatment regiments are directed at the thyroid, but there is a small place for peripherally acting drugs such as propranolol and ipodate.

GRAVES DISEASE TREATMENTPatient preferenceSmall goitreMild diseaseOther diseasesChildrenPregnancyOphtalmopathyPreoperativePre-radioiodineThyrotoxic crisisRelapse after thyroidectomyIndications for medical treatment

ANTITHYROID DRUGSTHIONAMIDES:Methimazole, Carbimazole, Propylthiouracil

Mechanism of actions:Inhibition of thyroid hormone synthesis and secretionPTUinhibition of peripheral conversion of T4 to T3

THIONAMIDESGoal:Permanent remission of hyperthyroidismLimitations:High recurrence rate of hyperthyroidismPossible side effects

Factors that may influance antithyroid drug therapyassociated with remissionClinicalSmall goitreMild diseaseRapid responce to antithyroid drugsSmall maintenance doseFemale sexLow iodine intakeLaboratoryModest elevation of thyroid hormonesLow urinary iodine excretionLow or absent TSH-R9s) antibodies at end of therapyNormal responce to TRH at end of therapyNormal suppression of thyroidal radioiodine uptake at end of therapy

Factors that may influance antithyroid drug therapyassociated with relapseClinicalLarge goitreVascular goitreSevere diseaseSlow responce to antithyroid drugsLarge maintenance doseMale sexHigh iodine intakeLaboratoryMajor elevation of thyroid hormonesHigh urinary iodine excretionRaised TSH-R(s) antibodies at end of therapyAbsent responce to TRH at end of therapyImpaired or absent suppression of thyroidal radioiodine uptake at end of therapy

GRAVES DISEASE TREATMENTExperienced thyroid surgeon avaliablePatient preferenceAdults up to 40 yearsSevere diseaseNodular goitreLarge goitreRelapse after drug treatmentIndications for surgical treatment

SURGICAL TREATMENTPARTIAL THYROIDECTOMYMechanism of actionremoval of tissue responsible for excessive thyroid hormone synthesis

PARTIAL THYROIDECTOMYGoalthyroid ablation, i.e. hypothyroidism

Contraindicationssystemic contraindications to surgery

PARTIAL THYROIDECTOMY- COMPLICATIONS

EARLYRecurrent laryngeal nerve palsySuperior laryngeal nerve palsyHaemorrhageHypoparathyroidismPneumothoraxThyroid crisisDamage to thoracic drugDamage to carotic arteryDamage to jugular veinLATECheloid scarTethered scarHypothyroidismRecurrence of hyperthyroidismRecurrent upper pole nodules

GRAVES DISEASE TREATMENTPatient preferencePoor-compliance with antithyroid drugsPatients over 40 yearsRecurrence after thyroidectomy

Severe uncontrolled diseaseLarge goitreUnco-operative patientsPresence of other disease(s)Indications for radioiodine therapy

RADIOIODINE THERAPYMechanism of actionDestruction of thyrocytes by -radiation

Goalthyroid ablation, i.e. hypothyroidism

Contraindicationspregnancy

RADIOIODINE THERAPYComplcationsPermanent hypothyroidismTransient hypothyroidismThyroiditisSialadenitisThyrotoxic crisisNodule formationPossible exacerbation of ophtalmopathy (preventable by glucocorticoids)

GRAVES DISEASE TREATMENT-adrenergic antagonists (e.g. Propranolol)Inorganic iodidePotassium perchlorateGlucocorticoidsOther drugs

GRAVES DISEASE TREATMENT OF OPHTHALMOPATHY

Mild ophthalmopathyGuanethidine or -adrenergic eye drops (lid retraction)Methylcellulose eye drops (lacrimation, burning sensation)Sunglasses (photophobia)Nighttime tapering of eyes (lagophthalmos)Prisms (mild diplopia)

Severe ophthalmopathyHigh-dose glucocorticoids (active ophthalmopathy)Orbital radiotherapy(active ophthalmopathy)Orbital decompresion(active or inactive ophthalmopathy)Rehabilitative surgery: eye muscles, eyelids (to be performed at least 6 months after rendering ophthalmopathy stable and inactive with other treatments)Immunosuppressive drugs, somatostatin analogues, intravenous immunoglobulins, plasmapheresis.

THYROTOXIC STORMRARE BUT VERY SERIOUS COMPLICATION OF HYPERTHYROIDISM

Severe manifestations of hypermetabolic(fever, profound sweating, dehydration, restlessness, insomnia)In patients with not diagnosed or inadeguately treated hyperthyroidismSURGERYINFECTIONSTRAUMASTHYROTOXIC STORM

THYROTOXIC STORM - TREATMENTHigh doses of thionamideIodide or iodinated contrast agentsGlucocorticoids -adrenergic antagonists The treatmnent of underlying non-thyroidal illnessCorrection of dehydrationNormalisation of body temperaturePlasmapheresis or peritoneal dialysis

TOXIC ADENOMAAn autonomously functioning, benign thyroid nodule causing thyrotoxicosisFREQUECYIodine-deficientareasIodine-sufficient areas10%>10%

TOXIC ADENOMAotherwise normal thyroid glandgoiterSolitary nodule in:Pathogenesis:Somatic mutations in the gene encoding the TSH receptorconstitutive activation of TSH receptor

TOXIC ADENOMASmptoms and signs of thyrotoxicosis Ophthalmopathy, localized myxedema and acropachy are absent

Thyroid scanPrevalent tracer uptake in the nodule(hot nodule)

TreatmentRadioiodine or surgeryAntithyroid drugs only for preparation of definitive treatment

TOXIC MULTINODULAR GOITERMultiple hyperfunctioning thyroid nodules or areas of autonomously functioning thyroid follicles

Commonly found in older patients with long-standing multinodular goiter.

UNUSUAL FORMS OF THYROTOXICOSISThyrotoxicosis factitia

Clinical and biochemical picture is typical of thyrotoxicosisGoiter is absentRAIU is very low/suppressedSerum thyroglobulin very low or undetectableCongenital hyperthyroidismGermline mutations of the TSH-R geneConstitutional activation in all thyroid follicular cells

UNUSUAL FORMS OF THYROTOXICOSISMetastatic thyroid carcinoma

Follicular thyroid arcinomaMetastases to lung and boneThyrotoxicosis (rarely)Struma ovariiFunctioning thyroid tissue within an ovarian teratoma or dermoid

UNUSUAL FORMS OF THYROTOXICOSISTrophoblastic tumors

High serum and urine concentrations of -subunit of chorionic gonadotropinstimulation of TSH receptor