HyperthyroidismHyperthyroidism

Department of endocrinology Department of endocrinology and metabolismand metabolism

Renji HospitalRenji Hospital

HyperthyroidismHyperthyroidism

Definition:

A clinical syndrome is brought about by

thyroid hormonethyroid hormone overproduction

of various causes.

T4,T3-TBG------------ FT4,FT3

receptor

TSH

CNS input

TRH

thyroid

hypothalamus

pituitary

Target tissue Target cell

FT4 FT3

TSH

THYROID

pituitary

Classification of hyperthyroidismClassification of hyperthyroidism

Abnormal thyroid stimulator

FT3,FT4

Adenoma

Resistance to T3,T4Greaves’ desease

TSI TSH analog HCG

tumor

THYROID

Classification of hyperthyroidismClassification of hyperthyroidismDiffuse toxic goiter

Hyperfunction adenoma

Toxic multinodular goiter

Toxic adenoma(Plummer’s disease)

Carcinoma

Subacute thyroiditis

Chronic thyroiditis

FT3, FT4

Extrathyroid source of hormone

transient thyrotoxicosis

Disorder of storageThyroid destruction

Iod-Basedow’s disease

Excess iodide

Graves' diseaseGraves' disease

Thyroid hormone overproduction Thyroid hormone overproduction

AutoImmune (AutoImmune (TSI - - TSH-R Ab) mediated) mediated

Graves' diseaseGraves' disease

Featured as:Featured as:• Hyperthyroidism

• Autoimmune mediated

Diffuse goiter

Exophthalmos

Pretibial myexedema

HLA-DR3HLA-DR3

genetic factors

Infection

Environmental risk factor

defect in immunoregulation with failure of “suppressor ” T lymocytphes function.

allowing “helper” T lymocytphes to stimulate B lymphocytes to produce TSH receptor antibodies(TRAb)

Thyroid-stimulating antibody (TSAb)

Thyroid- stimulating blocking antibody (TSBAb)

Etiology And Pathogenesis - autoimmune diseaseEtiology And Pathogenesis - autoimmune disease

mental factors

Graves' diseaseGraves' disease

Thyroid manifestations of Graves' disease Thyroid manifestations of Graves' disease • diffuse toxic goiterdiffuse toxic goiter

Extrathyroidal manifestations of Graves' diseaseExtrathyroidal manifestations of Graves' disease

• Ophthalmopathy Ophthalmopathy • DermopathyDermopathy

Be immunologically mediated activation of Be immunologically mediated activation of fibroblasts in the extraocular muscles and fibroblasts in the extraocular muscles and skin, with accumulation of skin, with accumulation of glycosaminoglycans, leading to the trapping glycosaminoglycans, leading to the trapping of water and edema. Later, fibrosis becomes of water and edema. Later, fibrosis becomes prominentprominent

The fibroblast activation is caused by The fibroblast activation is caused by cytokines derived from locally infiltrating T cytokines derived from locally infiltrating T cells and macrophages.cells and macrophages.

Clinical ManifestationsClinical Manifestations

Hyperthyroidism- common to any cause of thyrotoxicosis

Autoimmune mediated- specific for Graves' disease

Diffuse goiter

Exophthalmos

Pretibial myexedema

Clinical ManifestationsClinical Manifestations

The clinical presentation depends on the severity of thyrotoxicosis, the duration of the disease, individual susceptibility to excess thyroid hormone, and the age of the patient.

Symptoms of hypermetabolism • unexplained weight loss, despite an enhanced unexplained weight loss, despite an enhanced

appetiteappetite

• sweating and heat intolerance, particularly sweating and heat intolerance, particularly during warm weatherduring warm weather, ,

Symptoms of sympathetic hyperactivity • hyperactivity, nervousness, and irritabilityhyperactivity, nervousness, and irritability• Insomnia and impaired concentration Insomnia and impaired concentration • Fine tremor Fine tremor • hyperreflexia, muscle wasting, and proximal hyperreflexia, muscle wasting, and proximal

myopathy without fasciculation. myopathy without fasciculation.

Gastrointestinal : :• Gastrointestinal transit time is decreased, leading to Gastrointestinal transit time is decreased, leading to

increased stool frequency, often with diarrhea and increased stool frequency, often with diarrhea and occasionally mild steatorrhea. occasionally mild steatorrhea.

Sex::• Women frequently experience oligomenorrhea or Women frequently experience oligomenorrhea or

amenorrhea; in men there may be impaired sexual amenorrhea; in men there may be impaired sexual function and, rarely, gynecomastia. function and, rarely, gynecomastia.

bone::• osteopenia in long-standing thyrotoxicosisosteopenia in long-standing thyrotoxicosis

cardiovascular manifestation

palpitations (sinus tachycardia, supraventricular palpitations (sinus tachycardia, supraventricular tachycardia, Atrial fibrillation )tachycardia, Atrial fibrillation )

a bounding pulse, widened pulse pressure, and a bounding pulse, widened pulse pressure, and an aortic systolic murmur (due to high cardiac an aortic systolic murmur (due to high cardiac output ) output )

worsening of angina or heart failure in the elderly worsening of angina or heart failure in the elderly or those with preexisting heart disease. or those with preexisting heart disease.

Diffuse goiter

Thyroid is usually diffusely enlarged to two Thyroid is usually diffusely enlarged to two to three times its normal size. to three times its normal size.

There may be a thrill or bruit due to the There may be a thrill or bruit due to the increased vascularity of the gland and the increased vascularity of the gland and the hyperdynamic circulation.hyperdynamic circulation.

Exophthalmos

a staring appearance -Lid retraction, is the result of a staring appearance -Lid retraction, is the result of sympathetic overactivity. sympathetic overactivity.

a sensation of grittiness, eye discomfort, and excess a sensation of grittiness, eye discomfort, and excess tearing. tearing.

proptosisproptosis some cases of euthyroid ophthalmopathy.some cases of euthyroid ophthalmopathy. the enlarged extraocular muscles typical of the the enlarged extraocular muscles typical of the

diseasedisease compression of the optic nerve at the apex of the compression of the optic nerve at the apex of the

orbit, leading to papilledema, peripheral field defects, orbit, leading to papilledema, peripheral field defects, and, if left untreated, permanent loss of vision.and, if left untreated, permanent loss of vision.

NO SPECS schemeNO SPECS scheme

0 0 NNo signs or symptomso signs or symptoms   1 1 OOnly signs (lid retraction or lag), no nly signs (lid retraction or lag), no

symptomssymptoms   2 2 SSoft tissue involvement (periorbital edema)oft tissue involvement (periorbital edema)   3 3 PProptosis (roptosis (22 mm)22 mm)   4 4 EExtraocular muscle involvement (diplopia)xtraocular muscle involvement (diplopia)   5 5 CCorneal involvementorneal involvement   6 6 SSight lossight loss

Special Clinical ManifestationsSpecial Clinical Manifestations

Thyroid storm

Infiltrating exophthalmos

Hyperthyroid heart disease

Periodic paralysis

Atypical Hyperthyroidism

T3 .T4 type hyperthyroidism

Subclinical hyperthyroidism

Pregnancy hyperthyroidism

Pretibial myexedema

Thyrotoxic crisisThyrotoxic crisis

be precipitated bybe precipitated by• acute illness (e.g., stroke, infection, trauma, acute illness (e.g., stroke, infection, trauma,

diabetic ketoacidosis)diabetic ketoacidosis)• surgery (especially on the thyroid)surgery (especially on the thyroid)• overdoses of thyroid hprmoneoverdoses of thyroid hprmone• radioiodine treatment of a patient with radioiodine treatment of a patient with

partially treated or untreated hyperthyroidism. partially treated or untreated hyperthyroidism.

Thyrotoxic crisisThyrotoxic crisis

Manifestation:Manifestation:• Fever(>39C) Fever(>39C) • Increased heart rate,Af,AF,Increased heart rate,Af,AF,• Weight lossWeight loss• sweatingsweating• vomiting, diarrhea, and jaundicevomiting, diarrhea, and jaundice• delirium, seizures, coma, delirium, seizures, coma,

hypokalemic periodic paralysishypokalemic periodic paralysis

this disorder is particularly common in Asian males with thyrotoxicosis.

Hypokalemia was recovered after patasium supplement or rest

Released after hyperthyroidism well control

Thyroid dermopathyThyroid dermopathy

the anterior and lateral aspects of the the anterior and lateral aspects of the lower leg (lower leg (pretibial myxedemapretibial myxedema))

noninflamed, indurated plaque with a noninflamed, indurated plaque with a deep pink or purple color and an "orange-deep pink or purple color and an "orange-skin" appearance.skin" appearance.

Nodular involvement can occur, and the Nodular involvement can occur, and the condition can rarely extend over the whole condition can rarely extend over the whole lower leg and foot, mimicking lower leg and foot, mimicking elephantiasis. elephantiasis.

Hyperthyroid heart disease

Featured as:Featured as:• heart enlargementheart enlargement• arrhythmiasarrhythmias• Heart failureHeart failure

Other causes excludedOther causes excluded Be recovered after hyperthyroidism Be recovered after hyperthyroidism

well controlwell control

T4,T3-TBG------------ FT4,FT3

receptor

TSH

CNS input

TRH

THYROID

hypothalamus

pituitary

Target tissueTarget cell

spontaneous rhythms

Diurnal rhythmsits highest levels occur at night.

in a pulsatile manner

FT4 FT3

T4rT3 T3

45

nmol

35

nmol

25 nmol

TETRAC

Thyroid

5 nmol<5 nmol

Protein bound T3T4

99.96%TBG

TPBAT4 >T3

Type I/II deiodinase

Measure the level of Measure the level of hormonehormone

total vs. freeBasal level(rhythms)

Stimulation test

Inhibitory test

T4,T3------------ FT4,FT3

receptor

TSH

TRH

THYROID

hypothalamus

pituitary

Target tissueTarget cell

T3 inhibitory test

set-point" in this axis , a sensitive and specific marker

step1: Biochemically confirmed thyrotoxicosis

FT4 FT3

TRH stimulated test

TBG

illness, medicationsgenetic factors

estrogens, androgens, the nephrotic syndrome

①

②

③

④

I-I-TPO

I0

Tg

I-I-

T4T3-Tg

DIT,MIT-Tg

T4

T3

Tg

H2O2

Tyr DI

Na/I symporter Tg

Tg-ITPO

coupling

TSH

I-I-TPO

I0

Tg

I-I-

T4T3-Tg

DIT,MIT-Tg

T4

T3

Tg

H2O2

Tyr DI

Na/I symporter Tg

Tg-ITPO

coupling

TSH

TPOAb,TGAb

I uptake

thyroid scan

Step: Etiological diagnosis

TRAb ① ①

②

③ ④ FNA biopsies

Graves' disease is characterized by an enlarged gland and increased tracer uptake that is distributed homogeneously.

Toxic adenomas appear as focal areas of increased uptake, with suppressed tracer uptake in the remainder of the gland.

In toxic multinodular goiter, the gland is enlargedoften with distorted architectureand there are multiple areas of relatively increased or decreased tracer uptake.

Subacute thyroiditis is associated with very low uptake because of follicular cell damage and TSH suppression.

Thyrotoxicosis factitia, caused by self-administration of thyroid hormone, is also associated with low uptake.

Diagnosis of Graves' diseaseDiagnosis of Graves' disease

function diagnosis:function diagnosis:• manifestations of hyperthyroidism• diffuse goiter on palpationdiffuse goiter on palpation• OphthalmopathyOphthalmopathy• biochemically confirmed thyrotoxicosisbiochemically confirmed thyrotoxicosis

Etiological diagnosis :• positive TRAb, (TGAb, TPOAb,possible) antibodiespositive TRAb, (TGAb, TPOAb,possible) antibodies• often a personal or family history of autoimmune often a personal or family history of autoimmune

disorders. disorders.

Differential Diagnosis

Simple goiter

Neurosis

pheochromocytomapheochromocytoma

TREATMENTTREATMENT

Reducing thyroid hormone synthesis ---- Reducing thyroid hormone synthesis ---- antithyroid drugsantithyroid drugs

Reducing the amount of thyroid tissue---- Reducing the amount of thyroid tissue---- radioiodine (radioiodine (131131I) treatment or subtotal I) treatment or subtotal thyroidectomy.thyroidectomy.

antithyroid drugsantithyroid drugs

propylthiouracil, methimazole. propylthiouracil, methimazole. inhibit the function of inhibit the function of TPO, reducing oxidation , reducing oxidation

and organification of iodide. and organification of iodide. also reduce thyroid antibody levels by also reduce thyroid antibody levels by

mechanisms that remain unclear, and they mechanisms that remain unclear, and they appear to enhance rates of remission. appear to enhance rates of remission.

Propylthiouracil inhibits deiodination of T4 Propylthiouracil inhibits deiodination of T4 T3. T3. However, this effect is of minor benefit, except in However, this effect is of minor benefit, except in the most severe thyrotoxicosis, and is offset by the most severe thyrotoxicosis, and is offset by the much shorter half-life of this drug (90 min) the much shorter half-life of this drug (90 min) compared to methimazole (6 h).compared to methimazole (6 h).

The initial dose : The initial dose : • methimazole 10 to 20 mg q8h or q12 h, but once-daily methimazole 10 to 20 mg q8h or q12 h, but once-daily

dosing is possible after euthyroidism is restored. dosing is possible after euthyroidism is restored. • Propylthiouracil 100 to 200 mg q6h or q8 h, and Propylthiouracil 100 to 200 mg q6h or q8 h, and

divided doses are usually given throughout the divided doses are usually given throughout the course. course.

titration regimen: dose be gradually reduced as titration regimen: dose be gradually reduced as thyrotoxicosis improves. thyrotoxicosis improves. • The usual daily maintenance doses :The usual daily maintenance doses :

methimazole 2.5 to 10 mg methimazole 2.5 to 10 mg propylthiouracil 50 to 100 mgpropylthiouracil 50 to 100 mg

block-replace regimen: high doses combined block-replace regimen: high doses combined with levothyroxine supplementation to avoid with levothyroxine supplementation to avoid drug-induced hypothyroidism.drug-induced hypothyroidism.

Maximum remission rates are achieved by 18 to Maximum remission rates are achieved by 18 to 24 months 24 months

Thyroid function tests and clinical Thyroid function tests and clinical manifestations are reviewed 3 to 4 weeks manifestations are reviewed 3 to 4 weeks after starting treatment, and the dose is after starting treatment, and the dose is titrated based on free T4 levels. titrated based on free T4 levels.

All patients should be followed closely for All patients should be followed closely for relapse during the first year after treatment relapse during the first year after treatment and at least annually thereafter.and at least annually thereafter.

side effectsside effects

common :rash, urticaria, fever, and common :rash, urticaria, fever, and arthralgia (1 to 5% of patients). arthralgia (1 to 5% of patients).

hepatitis, an hepatitis, an SLESLE-like syndrome-like syndrome agranulocytosis (e.g., sore throat, fever, agranulocytosis (e.g., sore throat, fever,

mouth ulcers) (mouth ulcers) (1%). 1%). monitor blood counts, as the onset of monitor blood counts, as the onset of

agranulocytosis is idiosyncratic and agranulocytosis is idiosyncratic and abrupt.abrupt.

Other regimen Other regimen

PropranololPropranolol (20 to 40 mg every 6 h) or (20 to 40 mg every 6 h) or longer acting beta blockers, such as longer acting beta blockers, such as atenolol, may be useful to control atenolol, may be useful to control adrenergic symptoms, especially in the adrenergic symptoms, especially in the early stages before antithyroid drugs take early stages before antithyroid drugs take effect. effect.

complex iodidecomplex iodide

RadioiodineRadioiodine

causes progressive destruction of thyroid cellscauses progressive destruction of thyroid cells be used as initial treatment or for relapses after be used as initial treatment or for relapses after

a trial of antithyroid drugs. a trial of antithyroid drugs. The risk of thyrotoxic crisis can be avoided by The risk of thyrotoxic crisis can be avoided by

pretreatment with antithyroid drugs for at least a pretreatment with antithyroid drugs for at least a month before treatment. month before treatment.

Antithyroid drugs must be stopped 3 to 5 days Antithyroid drugs must be stopped 3 to 5 days before radioiodine administration to achieve before radioiodine administration to achieve optimum iodine uptake.optimum iodine uptake.

dose based on clinical features, such as the dose based on clinical features, such as the severity of thyrotoxicosis, the size of the goiter severity of thyrotoxicosis, the size of the goiter (increases the dose needed), and the level of (increases the dose needed), and the level of radioiodine uptake (decreases the dose radioiodine uptake (decreases the dose needed).needed).

131I dosage generally ranges between 185 131I dosage generally ranges between 185 MBq (5 mCi) to 555 MBq (15 mCi). MBq (5 mCi) to 555 MBq (15 mCi).

Many authorities favor an approach aimed at Many authorities favor an approach aimed at thyroid ablation (as opposed to euthyroidism), thyroid ablation (as opposed to euthyroidism), given that levothyroxine replacement is given that levothyroxine replacement is straightforward.straightforward.

Pregnancy and breast feeding are Pregnancy and breast feeding are absolute contraindications to radioiodine absolute contraindications to radioiodine treatment, but patients can conceive safely treatment, but patients can conceive safely 6 to 12 months after treatment. 6 to 12 months after treatment.

Surgery Surgery

Careful control of thyrotoxicosis with Careful control of thyrotoxicosis with antithyroid drugsantithyroid drugs

followed by potassium iodide (3 drops followed by potassium iodide (3 drops SSKI orally tid) to avoid thyrotoxic crisis SSKI orally tid) to avoid thyrotoxic crisis and to reduce the vascularity of the gland. and to reduce the vascularity of the gland.

Management of Management of Thyrotoxic crisisThyrotoxic crisisPrevention

Treatment principles: intensive monitoring and supportive careintensive monitoring and supportive care identification and treatment of the precipitating causeidentification and treatment of the precipitating cause measures that reduce thyroid hormone synthesis.measures that reduce thyroid hormone synthesis.

• inhibitory action on T4 inhibitory action on T4 T3 conversion: Large doses of T3 conversion: Large doses of propylthiouracil (600-mg loading dose and 200 to 300 mg every propylthiouracil (600-mg loading dose and 200 to 300 mg every 6 h) should be given orally or by nasogastric tube or per rectum6 h) should be given orally or by nasogastric tube or per rectum

• One hour after the first dose of propylthiouracil, stable iodide is One hour after the first dose of propylthiouracil, stable iodide is given to block thyroid hormone synthesis :potassium iodide (5 given to block thyroid hormone synthesis :potassium iodide (5 drops SSKI every 6 h), may be given orally. drops SSKI every 6 h), may be given orally.

• Propranolol should also be given to reduce tachycardia and Propranolol should also be given to reduce tachycardia and other adrenergic manifestations (40 to 60 mg orally every 4 h; or other adrenergic manifestations (40 to 60 mg orally every 4 h; or 2 mg intravenously every 4 h). 2 mg intravenously every 4 h).

• glucocorticoids (e.g., dexamethasone, 2 mg every 6 h), glucocorticoids (e.g., dexamethasone, 2 mg every 6 h), antibiotics if infection is present, cooling, and intravenous fluids.antibiotics if infection is present, cooling, and intravenous fluids.

OphthalmopathyOphthalmopathy

mild or moderate :requires no active treatment mild or moderate :requires no active treatment Discomfort can be relieved with artificial tears Discomfort can be relieved with artificial tears

(e.g., 1% methylcellulose) and the use of dark (e.g., 1% methylcellulose) and the use of dark glasses with side frames.glasses with side frames.

Periorbital edema responds to a more upright Periorbital edema responds to a more upright sleeping position.sleeping position.

Corneal exposure during sleep can be avoided Corneal exposure during sleep can be avoided by taping the eyelids shut. Minor degrees of by taping the eyelids shut. Minor degrees of diplopia improve with prisms fitted to spectacles. diplopia improve with prisms fitted to spectacles.

Severe ophthalmopathySevere ophthalmopathy• high-dose glucocorticoids + cyclosporine high-dose glucocorticoids + cyclosporine

(sometimes)(sometimes)be tapered by 5 mg every 1 to 2 weeks, be tapered by 5 mg every 1 to 2 weeks, • Pulse therapy: intravenous methylprednisolone Pulse therapy: intravenous methylprednisolone

followed by an oral regimen followed by an oral regimen • External beam radiotherapy of the orbitsExternal beam radiotherapy of the orbits• OctreotideOctreotide• LT4:adjust hypothalamus-pituitary-thyroid axisLT4:adjust hypothalamus-pituitary-thyroid axis

Graves' disease inGraves' disease in pregnancy pregnancy absolute contraindications to radioiodine treatmentabsolute contraindications to radioiodine treatment Propylthiouracil is usually used because of relatively low Propylthiouracil is usually used because of relatively low

transplacental transfer and its ability to block T4 transplacental transfer and its ability to block T4 T3 T3 conversion. conversion.

The lowest effective dose of propylthiouracil should be The lowest effective dose of propylthiouracil should be given, as blocking doses of these drugs produce fetal given, as blocking doses of these drugs produce fetal hypothyroidism. hypothyroidism.

Breast feeding is safe with low doses of antithyroid Breast feeding is safe with low doses of antithyroid drugs.drugs.

Subtotal thyroidectomySubtotal thyroidectomy is an option during pregnancy is an option during pregnancy (4th-6th)(4th-6th)

Radioactive iodine therapySimple method for the treatment of thyrotoxicosis, no

increased prevalence of thyroid carcinoma, leukemia or transmissible genetic damage.

1.complication• Hypothyroidism

• Radiation throiditis

• Exacerbation of hyperthyroidism

2.indication

3. Forbidden Cases