2MEDICINE8 Thyroid Gland Disorders UERM2015B.pdf

7/27/2019 2MEDICINE8 Thyroid Gland Disorders UERM2015B.pdf

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Sarah M. | Hezer | Mariz | April | Tsen | Victor UERM 2015B Page 1 of 16

2.8 DISORDERS OF THE THYROIDGLAND

Michael D. Rosario MD, FPSEM August 16, 2013

Legend: Italicized: Recordings

Lecture outline:

-Thyroid anatomy and physiology

-Thyroid work up

-Hypothyroidism

-Hyperthyroidism

-Thyroiditis

-Special situations

-Goiter

-Thyroid cancer

ANATOMY AND PHYSIOLOGY OF THE THYROID

GLAND

Figure 1. Anatomy of the thyroid

ANATOMY

2 lobes + isthmus Between cricoid cartilage and suprasternal notch 12-20 grams, highly vascular and soft 4 parathyroid glands posterior (behind the thyroid

gland)o Removal: Hypocalcemia

Lateral nerves: Recurrent laryngeal nerveso Damage: Vocal cord paralysis

***Thyroidectomy may cause removal of parathyroid gland anddamage to recurrent laryngeal nerves

Medullary C cells

o Neural crest derivativeso Produce Calcitonin

Calcium lowering hormone Minimal role in calcium

homeostasis Clinical significance: Tumor marker

for medullary thyroid cancer

DEVELOPMENT

Orchestrated by coordinated expression of severaldevelopmental factors: TTF1, TTF2 and pairedhomeobox 8 (PAX-8)

o Expressed selectively but not exclusively inthe thyroid gland

o Dictate thyroid cell developmento Induction of thyroid specific genes for the

following proteins Thyroglobulin (Tg) Thyroid peroxidase (TPO) Sodium iodide symporter (NIS) Thyroid stimulating hormone

receptor (TSH-R)o Clinical significance: Mutations in these

transcription factors or their target genesleads to congenital hypothyroidism

CONGENITAL HYPOTHYROIDISM

Figure 2. Congenital hypothyroidism

Occurs in 1/4000 newborns Part of neonatal screening

o Transplacental passage of MATERNALthyroid hormone occurs before the fetalthyroid glands to function (11th week) andprovides partial hormone support to a fetuswith congenital hypothyroidism

o Clinical significance: early detection throughneonatal screening allows early replacementin newborns preventing potentially severedevelopmental abnormalities

*** Thyroid gland of fetus will be fully developed at 11 weeks AOG

before this, supply depends on the transplacental passage of maternalhormone

REGULATION OF THE THYROID AXIS

Figure 3. HPT Axis

Hypothalamus TRH (Thyrotropin releasing hormone) Major positive regulator of TSH synthesis and

secretionPituitary

TSH (Thyroid stimulating hormone)

Stimulates thyroid hormone synthesis secretion 31kDa hormone with alpha and beta sub-units Most useful physiologic marker of thyroid hormone

production

Thyroid stimulating hormone receptor (TSH R)

G protein coupled receptor (GPCR) subunit of stimulatory G protein

o Activates adenylyl cyclase leading toincreased production of cyclic AMP

Recessive loss of function mutation=hypoplasia orhypothyroidism


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Sarah M. | Hezer| Mariz| April| Tsen |Victor UERM 2015B Page 2 of 16

Dominant gain of function mutation = thyroid cell

hyperplasia, goiter, autonomous function Somatic mutations=clonal expansion of affected

thyroid cell=autonomously functioning thyroidnodules

Thyroid Thyroid hormones Low levels

o Increase basal TSH productiono Enhance TRH mediated stimulation of TSH

High levelso Rapidly and directly suppress TSH gene

expression and secretion

o Inhibit TRH stimulation of TSHIODINE TRANSPORT TO THYROID

Ingested iodine is bound to serum proteins (albumin)o Unbound iodine is excreted in urine

Thyroid glands extracts iodine in the circulation in ahighly efficient manner

Iodine uptake the critical first step; mediated by NIS Clinical significance:

o Iodine deficiency leads to goiter andpossibly hypothyroidism and cretinism

o Iodine oversupply through supplements oriodine enriched foods (kelp, shellfish) is

associated with increased incidence of

autoimmune thyroid disease

CRETINISM

Mental and growth retardation Affects children who:

o Live in iodine deficient regiono Not treated with iodine or thyroid hormone

immediately during early life

oBorn to mothers with iodine deficiencywhich worsens the condition

o Concomitant selenium deficiency Iodine supplementation has markedly reduced the

prevalence of cretinism

IODINE DEFICIENCY

Common sources of dietary iodine:

Breads Cheese, Cows milk

Eggs Frozen yogurt

Ice cream Iodine-containing multivitamins

Iodized table salt Saltwater fish

Seaweed (dulce, nori) Soy sauce

Shellfish Soy milk, Yogurt

FIDEL Fortification for Iodine Deficiency Elimination

**Why salt? Does not spoil easily and consumed by a lot of people so

effective vehicle.

Table 1. Recommended Daily Intake

Recommended intake

Children 90-120 ug/day

Non pregnant adults 150-250 ug/day

Pregnant and lactating women 250 ug/day

IODINE UPTAKE - NIS Expressed at the basolateral membrane of the thyroid

follicular cells

Also present in salivary glands (parotid,submandibular), lactating breast and placenta but a

lower levels (so if radioiodine is given, there will also

be uptake in parotid which is NORMAL)

Affected by dietary iodine intakeo Low levels increased NIS expression and

iodine uptake; increased thyroid blood flow

o High levels decreased NIS expression andiodine uptake

Clinical significanceo Radioactive iodine treatment for

differentiated thyroid cancer

o Mutation leads to a congenitalhypothyroidism

*** Iodine uptake in thyroid cells is secondary to sodium iodide

symporter. Iodide absorption (via NIS) transported out in the apex(via pedrin, a protein Iodide oxidation (through hydrogen

peroxide and TPO/thyroid peroxidase enzyme After iodination,

attached to tyrosine residue found in thyroglobulin converted to 3

mono or 35 di-iodo tyrosine coupled to form T3 or T4 catalyze

by thyroid peroxidase. Thyroglobulin is reabsorbed in follicular cells

(where T3 and T4 are cleaved) released of T3 and T4 in

circulation. Excess MIT and DIT, iodine is removed by dehalogenase

iodine goes back to pool.

ORGANIFICATION, COUPLING, STORAGE ANDRELEASE

Iodide is transported to the apical membrane whereto be oxidized in an organification reaction thatinvolves TPO and hydrogen peroxide

The reactive iodine atom is added to selected tyrosylresidues within Tg

The iodotyrosines in Tg are then coupled via an etherlinkage in a reaction that is also catalyzed by TPO

forming either T4 or T3

After coupling, Tg is taken back into the thyroid cell,where it is processed in lysosomes to release T4 and

T3.

Dehalogenase enzymes deiodinate uncoupled monoand diiodotyrosines (MIT, DIT) to recycle iodide

THYROID HORMONE TRANSPORT BINDINGPROTEINS

Purpose of binding proteins:

Increase pool of circulating hormone Delay hormone clearance Modulate hormone delivery

Thyroxine binding globulin (TBG)

Low concentration but high affinity for thyroidhormones = 80%

Albumin

High concentration but low affinity = 10% T4 & 30%T3

Transthyretin (TTR aka TBPA) 10% T4 & little T3

Unbound hormones

Biologically available for tissues T3 less tightly bound than T4 (99.7% T3 vs 99.98% T4) But there is less unbound or Free T3 in the circulation

because it is produced in lesser amounts and is

cleared more rapidly

ABNORMALITIES OF THE THYROID HORMONEBINDING PROTEINS

Disease

condition

Total

T3

&T4

Free T3

and T4

TSH Clinical

X linked TBG

deficiency

Absent TBG

leads to rapid

hormone

clearance

Low Normal Normal Euthyroid


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Pregnancy or

OCP use

Increased

estrogen levels

-elevated TBG

High Normal

Normal

or Low Euthyroid

Euthyroid

Hyperthyroxine

mia

Increased

binding affinityfor T4 or T3

High Normal Normal Euthyroid

DEIODINASES

Figure 4. Deiodinases

*** If hormone is in target cell, will be acted upon by deiodinases

(removal of one iodine from T4). Active hormone: T3

Table 2. Types of deiodinases

Type 1 Type 2 Type 3

Location

Thyroid,

Liver,

Kidneys

Pituitary,

Brain,

Brown

Fat, Thyroid

Placenta

Placenta, CNS,

Hemangiomas,

Adult and

Fetal Liver,

Skeletal

Muscle

T4 affinity Low High

Response to

increased T4Increased Decreased Increased

Susceptibility

to PTUHigh Absent Absent

Physiologic

role

Source of

plasma T3

in

thyrotoxic

patients

Provide

intracellular

T3 in specific

tissues,

source of

plasma T3

Inactivate T3

and T4

Most important

source of

Reverse T3

*** in T4 results to type 1 (produces active hormone and source of

plasma T3 in thyrotoxic patient, but susceptible to PTU). Type 2

produces intracellular T3 in specific tissues. Type 3 produces reverse

T3 and inactivating enzyme. Clinical significance: infant with very

big hemangioma (high level of T3) inactivation of T3 and T4

resulting to congenital hypothyroidism

NUCLEAR THYROID HORMONE RECEPTORS

Figure 5. Thyroid hormone receptors

Enter cells by passive diffusion and via themonocarboxylate 8 (MCT8) transporter

High affinity to nuclear thyroid hormone receptors (TRs) & which are expressed in most tissues, but their

relative expression levels vary among organs

o TR is particularly abundant in brain,kidney, gonads, muscle, and heart

o TR expression is relatively high in thepituitary and liver.

o The TR 2 isoform is selectively expressed inthe hypothalamus and pituitary, where it

plays a role in feedback control of the

thyroid axis.

Receptors are occupied mainly by T3, reflecting T4 toT3 conversion by peripheral tissues, greater T3

bioavailability in the plasma, and receptors greater

affinity for T3.

The aporeceptors bind to corepressor proteins thatinhibit gene transcription.

Thyroid hormone binding dissociates these co-repressors and allows the recruitment of coactivators

that enhance transcription.

ACTION OF THYROID HORMONES (TH)

Child

Brain development Growth and development in latter stages of

childhood

Adult

Primarily metabolismo Carbohydrate, lipid, protein and vitamin

metabolism

o Regulation of oxygen consumption Other actions on mood, cognition, heart, bone and

muscle

NON- GENOMIC ACTION OF TH

Major effects of T3 are mediated by nuclear ThyroidHormone Receptor regulation of target gene

transcription

However, it has some non genomic actiono Vasculature reduced systemic vascular

resistance which rapidly occurso Acts on glucose transporters in certain

tissues allowing increased uptake of glucose

THYROID HORMONES RESISTANCE

Autosomal dominanto Similar hormonal abnormalities found other

family members

Mutation leading to loss of thyroid hormone receptorfunction


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o They also function as antagonists of theremaining normal thyroid hormone

receptors

Elevated unbound thyroid hormone levels Inappropriately normal or elevated TSH The resistance is partial hence signs and symptoms of

hypothyroidism are not full blown

o Goiter, attention deficit, mild IQ reduction,delayed skeletal maturation

THYROID WORK UPTHYROID FUNCTION TESTS

TSH Total T3 and Total T4

o Highly protein bound which can be affectedby numerous factors (refer to abnormalities

of thyroid hormone binding proteins)

o Elevated when TBG is high (increasedestrogen conditions)

o Decreased when TBG is low (Androgens,Nephrotic syndrome)

Free T3 and Free T4 (unbound)

o Represents the biologically availablehormonal pool

o Isolated Free T3 elevation occurs in 2-5% ofpatients (T3 toxicosis)

o Normal FT3 may occur in 25% of patientswith Hypothyroidism

*** TSH and unbound hormones (total hormones are highly protein

bound so affected by various factors)

Table 3. Match the following

Thyroid Function Thyroid Condition

1. High TSH, Low FT4,

Low FT32. Normal TSH, Low FT4,

Low FT3

3. Low TSH, Normal FT4,

Normal

FT3

4. Low TSH, High FT4,

High FT3

5. Normal TSH and FT4,

Low FT3

A. Central Hypothyroidism

B. Subclinical Hyperthyroidism

C. Autoimmune

Hypothyroidism

D. Sick Euthyroid Syndrome

E. Hyperthyroidism

***Answer:

1: C (Autoimmune hypothyroidism) low production, compensatory

action of pituitary2: A (Central hypothyroidism)

3: B (Subclinical hyperthyroidism) - asymptomatic

4: E (Hyperthyroidism)

5: D (Sick euthyroid syndrome)

(See Thyroid Patterns in Appendix)

THYROID PROTEINS AND ANTIBODIES

Thyroglobulin (Tg)o Follow up of thyroid cancero To rule out thyrotoxicosis factitiao Elevated in thyroiditis

Antibodies to thyroid proteinso Anti thyroglobulin (Anti Tg)

Follow up of thyroid cancerpatients

Autoimmune thyroid illness (notroutinely included)

o Anti Thyroid Peroxidase (Anti TPO) Autoimmune thyroid illness

o Anti TSH receptor (TRAB) TSH stimulating

Hyperthyroidism

TSH blocking Hypothyroidism

*** Tg = sign of thyroid cancer recurrence and to rule out

Thyrotoxicosis factitia (Thyrotoxicosis factitia: Tg is normal but px

has symptoms of thyrotoxicosis, either faking it or taking thyroid

medication). Among Ab, the best is TPO (best indicator of

autoimmune thyroid illness).

Table 4. Thyroid Antibodies in subset of population (%)

Patient Group

TSH

receptorAntibody

Thyroglobulin

(TG) Antibody

Thyroid

Peroxidase

(TPO)

antibody

General

Population0% 5-20% 8-27%

Graves

Disease80-95% 50-70% 50-80%

Autoimmune

thyroiditis10-20% 80-90% 90-100%

RADIONUCLIDE IMAGING

The thyroid gland selectively transports radioisotopes of

iodine (123I, 125I, 131I) and 99mTc pertechnetate, allowing

thyroid imaging and quantitation of radioactive tracerfractional uptake.

Iodine uptake measures thyroid function High in Graves Disease Low in thyroiditis (hyperthyroid phase)

Figure 6. Thyroid Scan Imaging

Figure 7. Radionuclide Imaging: Whole Body Scan

***Whole body scan done after thyroid cancer treatment to check for

metastasis. Notice pick-up in salivary gland (normal)


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ULTRASOUND OF THE THYROID

Figure 8. Ultrasound of the Thyroid

***Nodule: hypoechoic compared to thyroid tissues, regular/defined

border, no calcification. Only does Biopsy if there are suspicious

features

Micro calcification Increased vascularity especially in the center Irregular/ill-defined border

HYPOTHYROIDISM

Figure 9. Classifications of Hypothyroidism

*** Most common worldwide: iodine deficiency. In iodine sufficient

areas: autoimmune or iatrogenic(See appendix for algorithmevaluation of hypothyroidism)

***Request for the complete panel (TSH, FT3, FT4) if suspecting

thyroid disease (to avoid delay and multiple blood extraction)

AUTOIMMUNE HYPOTHYROIDISM

HistologyHashimotos or

GoitrousThyroiditis

AtrophicThyroiditis

Lymphocyticinfiltration

Markedlymphocytic

infiltration with

germinal cellformation

Less pronounced

Thyroid folliclesAtrophy of thyroid

follicles withabsent colloid

Almost completelyabsent

Fibrosis Mild to moderate Extensive

***Autoimmune hypothyroidism- 2nd most common, can present as

atrophy or a goiter, subclinical, overt/clinical

Genetic Factorso HLA-DR and CTLA-4 polymorphisms account for

approximately half of the genetic susceptibility to

autoimmune hypothyroidism.

o Both of these genetic associations are shared by otherautoimmune diseases(type 1 diabetes mellitus,

Addisons disease, pernicious anemia, and vitiligo)

Sexo Female preponderance: sex steroid effect on immune

response vs X chromosome-related genetic factor Diet

o A high iodine intake may increase the risk ofautoimmune hypothyroidism by immunologic effects

or direct thyroid toxicity

Infectiono Congenital Rubella syndrome associated with high

frequency of autoimmune hypothyroidism

o Viral thyroiditis does not induce subsequentautoimmune thyroid disease.

PATHOGENESIS

Figure 10. Pathogenesis of Hashimotos thyroiditis and Graves

disease

CD8 + cytotoxic T cellso Primary mediatoro Perforin-induced cell necrosiso Granzyme B induced apoptosis

Local production of Cytokineso TNF, IFN, IL-1o Impair thyroid cell function directlyo Induce thyroid cells to express pro-inflammatory

molecules

o Renders thyroid cells more susceptible to apoptosis B cells

o Secondary role; merely amplifies ongoingautoimmune response

o TPO ab:-Useful marker for autoimmunity

- Complement fixation

- Transplacental passage does not damage fetal

thyroid

o TSH receptor Ab:-Seen in 20% of patients with autoimmunehypothyroidism

-Blocking antibodies which block TSH binding

-Hypothyroidism and atrophy

-Transplacental passage=neonatal hypothyroidism

***Autoimmune hypothyroidism: blocking antibodies leading to

hypothyroidism and atrophy (remember there are 2 types of TSH-

receptor antibodies; in autoimmune hypothyroidism it is the blocking

type). Can be passed on the fetus resulting to neonatal

hypothyroidism


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SIGNS AND SYMPTOMS

Symptoms:o Tiredness, weaknesso Dry skino Feeling coldo Hair loss; thinning of outer third of eyebrows (Queen

Annes sign)

o Difficulty concentrating and poor memoryo Constipationo Weight gain with poor appetiteo Dyspneao Hoarse voiceo Menorrhagiao Paresthesiao Impaired hearing

Signso Dry coarse skino Cool peripheral extremitieso Puffy face, hands and feet(myxedema)o Diffuse alopeciao Bradycardiao Peripheral edemao Delayed tendon reflex relaxationo Carpal tunnel syndromeo Serous cavity effusions***Decreased in metabolism (patient slows down literally)

TREATMENT

Levothyroxine Replacement1. Start levothyroxine replacement 1.6-1.8ucg/kg BW(100-

150ucg/day)

2. Check TSH every 6-8 weeks

3. Adjust dose by 12.5 to 25 ucg until TSH goal of Lower

half of Normal range is achieved

Special situations:

o Pregnancy: higher requirements; need to increase dose by50 % and reduce after delivery

o Elderly, coronary artery disease patients: starting dose12.5-25 ug/day

*** Taken 30 minutes before breakfast (if taken incorrectly can results

to poor absorption and patient may need higher dose). ONLY request

for TSH every 6-8 weeks (FT3 and FT4=unnecessary). If TSH is

within target (lower half of normal range) no need to adjust (if high

or low, adjust in this range: 12.5 to 25 ucg)

Non-levothyroxine Replacemento Dessicated animal thyroid prepations (thyroid extract

USP) are not recommended as the ratio of T3-T4 is

nonphysiologic.

o Benefit of using levothyroxine combined withliothyronine (triiodothyronine, T3) has not been

confirmed in several prospective studies.

o There is no place for liothyronine alone as long-termreplacement, because the short half-life necessitates

three or four daily doses and is associated with

fluctuating T3 levels.

***For replacement, levothyroxine is preferred over liothyronine

(since levothyroxine only required less dosage and can be taken oncea day unlike liothyronine which required multiple dosages).

Liothyronine is usually indicated for 1). preparing the patient for

radioactive iodine uptake and 2). if allergic to levothyroxine (based

on Dr. Rosarios practice)

MYXEDEMA COMA

Clinical manifestations: Reduced level of consciousness,seizures, hypothermia

History of treated hypothyroidism with poor compliance,or the patient may be previously undiagnosed.

Almost always occurs in the elderly Hypothermia also a risk factor Hypoventilation, leading to hypoxia and hypercapnia,

plays a major role in pathogenesis.

o Factors that impair respiration may precipitatemyxedema coma: drug(sedative, anesthetics,

antidepressants), pneumonia, congestive heart failure,

myocardial infarction or cerebrovascular accidents.

***Most severe form of hypothyroidism/ an endocrine emergency

TREATMENT

Levothyroxineo Loading dose: 500 ucgo Maintenance dose: 50-100 ucg g/do Route: Intravenous(preferred) or nasogastric tube

(though aborption may be impaired in myxedema)

Liothyronine(T3)o Dose: 10 to 25 ucg every 8-12 hour intravenously or

via nasogastric tube.

o Advocated because T4-T3 conversion is impaired inmyxedema coma.

o Excess liothyronine has the potential to provokearrhythmias.

o advocated due to T4 to T3 impaired conversion in cases ofMyxedema coma; may be given in combination.

Combined levothyroxine (200ucg) and liothyronine(25ucg)

o Loading: levothyroxine(200ucg) andliothyronine(25ucg)

o Maintenance: levothyroxine(50-100ucg/d) andliothyronine (10ucg every 8 hour)

***Use of liothyronine is advocated since in Myxedema coma,

there is impairment in the conversion of T4 to T3.

HYPERTHYROIDISM Thyrotoxicosis

o State of thyroid hormone excesso Ex. Excessive intake of levothyroxine

Hyperthyroidismo Thyrotoxicosis due to excessive thyroid functiono Ex. Graves Disease

THYROTOXICOSIS

Figure 11. Classification of thyrotoxicosis


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PATHOGENESIS

Thyroid Stimulating Immunoglobulins (TSI)o Synthesized in the thyroid gland, bone marrow and

lymph node

o Aka TRABRISK FACTORS

Polymorphism in HLA-DR, CTLA-4, CD25, PTPN22, TSH-R

Stress via the Neuroendocrine system Smoking

o Minor risk: Graves diseaseo Major risk: TAO

Postpartum Increased iodine uptake After use of HAART tx or alemtuzumab txSIGNS AND SYMPTOMS

Signso Tachycardia; atrial fibrillation in the elderlyo Tremorso Goitero Warm, moist skino Muscle weakness, proximal myopathyo Lid retraction or labo Gynecomastia

Symptomso Hyperactivity, irritability, dysphoriao Heat intolerance and sweatingo Palpitationso Fatigue and weaknesso Weight loss despite increased appetiteo Diarrheao

Polyuriao Oligomenorrhea, loss of libido

THYROID ASSOCIATED OPHTHALMOPATHY (TAO)

Pathogenesis of TAOo TSH-R may be a shared autoantigen expressed in the

orbit

o Infiltration of the EOMs by activated T cells withrelease of cytokines: Orbital fibroblasts become

activated with increased synthesis of

glycosaminoglycans that trap water leading to ocular

muscle swelling.

***risk factor associated with opthalmopathy: Genetics, Stress,

smoking, after delivery, increased iodine intake, after used of anti-

retroviral drugs/therapy (HIV). Patients are very difficult to

interview because of severe anxiousness, agitation, tachycardia.

Euthyroid ophthalmopathy - may occur in the absence ofGraves disease(10%)

Usually occurs 1 year (+/- years) before or after dx ofthyrotoxicosis in 75%

Unilateral only in 10 % of patients Earliest symptoms: gritiness, eye discomfort, excessive

tearing

1/3 have proptosis; may progress to corneal damage ifsevere

5-10 % severe EOM swelling leading diplopia

Most serious manifestation: Optic nerve compression-papilledema-loss of vision.

Course dose not follow thyroid diseaseo Worsens first 3-6mos.o Plateaus next 12-18mos.o Spontaneous improvement in soft tissue changes

Fulminant in 5% of patients Intervention in the acute phase if there is optic nerve

compression or corneal ulceration

General measures

o Achieve euthyroid statuso Smoking cessationo Reassurance

Mild-moderateo Artificial tears, eye ointment and use of dark glasseso Periorbital edema-upright sleeping position or

diuretic

o Eye patches when sleeping to avoid corneal exposure***Elderly may have Apathetic Thyrotoxicosis: weight loss (somedont rather increases appetite), hyperdefecation, palpitation, heat

intolerance, muscle weakness (proximal mostly affected)

Severe ophthalmopathyo First line: high dose oral steroids or pulse steroids

followed by oral steroids

o Orbital decompression: removal of bone from anywall of the orbit

o External beam radiotherapy***Management is mostly supportive ; if severe: use High dose of

Steroids (oral/IV) if not decompress by surgeryremoving bone wallor radiotherapy.

THYROID DERMOPATHY


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Thyroid Gland Sizeo Decrease 1/3-1/2o Unchanged or enlarged remaining half

TSH may remain subnormal for 6 months Maximum remission rates (30-50%) are achieved by

18-24 months

o Relapse likely if severe hyperthyroidism orwith large goiters

***PTUhas additional blocking in the T4-T3 peripheral conversion

Deiodenized enzyme TYPE 1; dosage 450-600mg/day- each tab is50mg3-4x a day; may have poor compliance. Methimazole more

potent; thyroid peroxidase action: starting 40-60mgonce or twice a

day

Figure 14. Monitoring thionamide use

(See Appendix for Comparison of Methimazole vs

Propylthiouracil )

Lithium

Alternative to thionamidesIodine

Saturated solution of Potassium Iodide (SSKI),ipodate, iopanoic acid

Wolff- Chaikoff effect Thyroid storm (give 1 hour after thionamides) Decrease vascularity pre-op

Steroids

Thyroid stormBeta Blockers

Adjunct to treatment To control adrenergic symptoms, especially in theearly stages before anti-thyroid drugs take effect Useful in patients with hypokalemic paralysis

***PTU in selected cases usually given in the first 3 months of

pregnancy (organogenesis)

Methimazolerecommended Latest guidelines in most cases

Doc Rosario: Give the meds up to 1 year assuring that the TSH is

normal, then stop gradually. If no recurrence good, but if does:

proceed to definitive treatmentSurgery, RAI.

Radioactive Iodine- -avoid pregnancy within Six months

HOW TO START:

Starts 1st 3months (check-up every month)

Hypothyroidism monitor TSH Hyperthyroidism monitor FT4, FT3 - why not TSH?

= TSH may resume abnormal for 6months:

o Note: as long as the FT4 and FT3 goingdown and has clinically signs of improving

theres no need to increase the dose.

***Doc Rosario: Starts the meds and followed up patient after 2

weekscheck for possible Side effects (because in 2 weeksmay have

already a clinical improvement; Dec palpitation, tachycardia)

specially with propanolol and inderal.

THYROID STORM

A rare endocrine emergency Life-threatening exacerbation of hyperthyroidism,

accompanied by fever, delirium, seizures, coma,vomiting, diarrhea, and jaundice.

Mortality rate due to cardiac failure, arrhythmia, orhyperthermia is as high as 30%, even with treatment.

Precipitants: acute illness (e.g., stroke, infection,trauma, diabetic ketoacidosis), surgery (especially on

the thyroid), or radioiodine treatment of a patient

with partially treated or untreated hyperthyroidism.

BURCH WARTOFSKY SCORE

The scoring includes the following variables:

Temperature CNS GIT- Hepatic Dysfunction CVS

o Tachycardiao CHFo Atrial Fibrillation

Greater than 45 points is highly suggestive of aThyroid Storm

25 to 44 points is Impending Less than 25 is Unlikely(See appendix for corresponding points and scoring)

TREATMENT

Management requires intensive monitoring andsupportive care, identification and treatment of theprecipitating cause, and measures that reduce thyroid

hormone synthesis.

Large doses of propylthiouracil (600 mg loading doseand 200300 mg every 6 h)per orem, NGT or per

rectum

o Has inhibitory action on T4 to T3 conversion Stable Iodide given one hour after the first dose of

propylthiouracil

o Wolff-Chaikoff effecto The one hour delay allows the antithyroid

drug to prevent the excess iodine from being

incorporated into new hormones.

o A saturated solution of potassium iodide (5drops SSKI every 6 h), or ipodate or iopanoic

acid (0.5 mg every 12 h), may be given

orally.

Propranolol should also be given to reducetachycardia and other adrenergic manifestations (40

60 mg orally every 4 h; or 2 mg intravenously every 4

h)

o High doses of propranolol decrease T4 to T3conversion, and the doses can be easily

adjusted.

Additional therapeutic measures includeglucocorticoids (e.g., dexamethasone, 2mg every 6 h),

antibiotics if infection is present, cooling, oxygen, and

intravenous fluids.

THYROIDITIS

Classification based on duration:

1. Acute Bacterial Fungal Radiation (Iodine 131 treatment)


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Amiodarone2. Subacute

Viral or Granulomatous thyroiditis Silent and Postpartum Throiditis Mycobacterial Infection

3. Chronic Autoimmune

o Hashimotos Thyroiditiso Atrophic Thyroiditis

Riedels Thyroiditis Parasitic Thyroiditis Traumatic (after palpation) Thyroiditis

ACUTE INFECTIOUS THYROIDITIS

Rare suppurative infection with an abruptpresentation

Predisposing factorso Piriform sinus seen in children and young

adults

o Long standing goiter or degeneration in athyroid malignancy in older adults

Signs and Symptomso Thyroid pain referred to throat or ears, fever

and dysphagia

o Small tender goiter, lymphadenopathy Lab Tests

o Elevated ESR and WBC counto Normal Thyroid Function

Treatmento Antibiotic treatmento Surgery for abscess

Uncommon Complicationso Tracheal obstruction, septicemia,

retropharyngeal abscess, mediastinitis,

jugular venous thrombosis

SUBACUTE VIRAL THYROIDITIS

Aka granulomatous, de Quervains thyroiditis Many viruses implicated Common in Females ages 30-50 yrs than males There is patchy inflammatory infiltrate with

disruption of thyroid follicles and presence of

multinucleated giant cells

May progress to granulomas with accompanyingfibrosis

Figure 15. Clinical phases of Subacute viral thyroiditis

a. Thyrotoxic Phase: 6 weeks ;. Increased FT4, decreased TSH

b. Hypothyroid phase: decreased FT3, FT4,

c. Recovery Phase: Increased TSH eventually due to thyroid recovery.

Signs and symptomso May initial present with URTI like

symptoms

o Painful thyroid referred to jaw and ear;exquisitely tender

o Fevero Thyrotoxic symptoms appear abruptly

Lab Testso Elevated ESR and WBC counto Thyroid Function depends on phaseo May present with a low radioiodine

uptake initially

o Thyroid antibodies are low Treatment

o First Line: Large doses of Aspirin &NSAIDS

o Second Line/Alternative: Steroidso Monitor TSH and FT4 every 2 weeks

Thyrotoxic phaseo Propranolol to ameliorate symptomso Antithyroid drugs no role

Hypothyroid phaseo Levothyroxine

For a prolonged phase Low doses to allow TSH

mediated recovery

SILENT THYROIDITIS

Aka Painless Occurs in patients with underlying autoimmune

thyroid disease.

Post-partum thyroiditiso Occurs in 5% of women 3-6 months after

pregnancy

o May recur in subsequent pregnancies Lab tests

o Low ESR and WBC counto Thyroid function depends on phaseo May present with a low radioiodine uptake

initiallyo THYROID ANTIBODIES ARE PRESENT.

Treatmento Anti inflammatory agents (steroids) not

necessary

o Thyrotoxic phase Propranolol to ameliorate

symptoms

Antithyroid drugs no roleo Hypothyroid phase

LevothyroxineCHRONIC THYROIDITIS

Focal Thyroiditiso 20-40% of euthyroid autopsy caseso Associated with autoimmunity; TPO

antibodies are present

Hashimotos thyroiditis Riedels thyroiditis

o Rare; occurs in middle aged womeno Dense extensive fibrosis with no thyroid

dysfunction

o Maybe associated with idiopathic fibrosis atother anatomic sites

o Presents with painless goiter andcompressive symptoms

o Treatment: Surgical relief of compressivesymptoms.

SICK EUTHYROID SYNDROME

Any acute, severe illness can cause abnormalities ofcirculating TSH or thyroid hormone levels in the

absence of underlying thyroid disease.

Unless a thyroid disorder is strongly suspected, theroutine testing of thyroid function should be avoided

in acutely ill patients.


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The major cause of these hormonal changes is therelease of cytokines such as IL-6.

The diagnosis of SES is frequently presumptive, giventhe clinical context and pattern of laboratory values;

only resolution of the test results with clinical

recovery can clearly establish this disorder.

Treatment of SES with thyroid hormone (T4 and/orT3) is controversial

***In sick euthyroid T4 is shunted to T3 (reversed) Decreased

FT3increased reversed T3; bodies way of adapting illness, to lessencatabolic rate: Findings: Low TSH, slightly high FT4, low FT 3

Figure 16. Clinical phases of sick euthyroid syndrome

AMIODARONE EFFECTS ON THYROID FUNCTION

Type III antiarrhythmic agent Structural relation to thyroid hormone; 39% iodine by

weight

Stored in adipose tissues; high iodine levels persist for6 months after discontinuation of the drug

Initial effect

Inhibit thyroid hormone release Decreased T4 Wolff Chaikoff Follow up effect Inhibits Deiodinase activity Metabolites function as weak antagonists of thyroid

hormone action

Increased T4, Decreased T3, Increased rT3 andtransient TSH increase (20mIU/L)

TSH normalize in 1-3 months***Hyperthyroidism (thyrotoxicosis)provide antithyroid drugs and

anti-inflammation

Amiodarone Effects HYPOTHYROIDISM

Correlated to iodine intake Higher incidence in iodine replete countries Pathogenesis: inability to escape from the Wolff

Chaikoff effect in autoimmune thyroiditis

More common in women and those with positiveTPO antibodies

Treatment: May continue amiodarone and just startlevothyroxine replacement

Amiodarone Effects THYROTOXICOSISType 1 AIT

With underlying thyroid problems (subclinicalHyperthyroidism/Nodular goiter)

Jod Basedow phenomenon leads to excessive thyroidhormone synthesis

Doppler shows increased vascularity Tx: Anti-Thyroid drugs

Type 2 AIT

No underlying thyroid problems

Drug induced lysosomal activation leading todestructive thyroiditis

Doppler shows decreased vascularity Tx: oral contrast agents, steroids

THYROID AND PREGNANCY

Five factors alter thyroid function in pregnancy

1. Transient increase in hCG during the first trimester,which stimulates the TSH-R and decreases TSH

2. Estrogen-induced rise in TBG during the firsttrimester, which is sustained during pregnancy

3. Alterations in the immune system, leading to theonset, exacerbation, or amelioration of an underlying

autoimmune thyroid disease

4. Increased thyroid hormone metabolism by theplacenta

5. Increased urinary iodide excretion Maternal hypothyroidism occurs in 23% of women of

child-bearing age and is associated with increased risk of

developmental delay in the offspring.

Women with a precarious iodine intake are most at risk ofdeveloping a goiter during pregnancy, and iodine

supplementation should be considered to prevent

maternal and fetal hypothyroidism and neonatal goiter.

TSH screening for hypothyroidism is indicated in earlypregnancy and should be considered in women who are

planning pregnancy, particularly if they have a goiter or

strong family history of autoimmune thyroid disease.

Thyroid hormone requirements are increased by 2550ucg/d during pregnancy.

GOITERDIFFUSE NONTOXIC GOITER

Simple goitero Most commonly caused by iodine deficiencyo Compensatory effort to trap iodideo Endemic goiter if it affects > 5% of the populationo Women>Meno Greater prevalence of autoimmune thyroid

disease

o Increased iodine demands during pregnancyo TSH levels normal to slight increase onlyo But probably there is increased sensitivity to its

effects

o Patient will present OBSTRUCTIVE SYMPTOMSGoitrogens Cassava root thiocyanate

Cruciferous vegetables brussels sprouts, cabbage,cauliflower

Milk from areas where goitrogens are present in grass S/Sxs

o Obstructive symptomso Tracheal obstruction esp substernal goitero dysphagiao External jugular vein - Pembertons sign

Treatment:

Iodine replacement Levothyroxine replacement Young pxs: 100 mcg/day targeting low to normal TSH Elderly: 50 mcg/day Efficacy greater for younger pxs, soft goiters Significant regression: within 3-6 months Surgery: Near total thyroidectomy Radioiodine: reduced goiter size by about 50% in the

majority of pxs in 6-12 months

NONTOXIC MULTINODULAR GOITER

Most nodules are polyclonal in origin TSH usually not elevated


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Most are asymptomatic and euthyroid; Obstructivesymptoms

Ultrasound: Look for characteristics suggestive ofmalignancy

Levothyroxine replacement rarely effective to reducegoiter size

Radioiodine treatment may decrease goiter size by 40-50%

TOXIC MULTINODULAR GOITER Presence of autonomously functioning nodules Subclinical or mild thyrotoxicosis Elderly patient: tremors, atrial fibrillation or weight

loss

Aggravated by recent exposure to iodine Anti thyroid drugs

o May stimulate growth of goitero Spontaneous remission does not occur lifelong

tx

Radioiodineo Treat areas of autonomy and decrease goiter sizeo Treated areas may be replaced by other new

autonomous nodules

Surgery

Figure 17. Findings on thyroid scan: heterogenous uptake with areas of

increased and decreased uptake

HYPERFUNCTIONING SOLITARY NODULE

Solitary autonomously functioning thyroid nodule Mild thyrotoxicosis Medical treatment is not an optimal long term

treatment

Radioiodine ablation Surgery: Enuceation or lobectomy Ethanol injections or percutaneous radiofrequency

thermal ablation

Figure 18. Findings on thyroid scan: Focal uptake with diminished

uptake in the remainder (normal tissue) as activity in those areas are

suppressed

***Check TSH: if Decreased do thyroid scan if INCREASED

uptake no need for BIOPSY, but if DECREASED uptake- do

Biopsy, If purely cysticno need for biopsy.

THYROID CANCER

Most common malignancy of the endocrine system

Figure 19. Findings on thyroid scan

WELL DIFFERENTIATED

***Classified according to histologic features

Papillary

Most common 70-90% Histology: Psammoma bodies, cleaved nuclei with an

orphan-Annie appearance caused by large nucleoli,

and the formation of papillary structures

Locally invasiveFollicular

More common in iodine-deficient regions. Difficult to diagnose by FNA because the distinction

between benign and malignant follicular neoplasms

rests largely on evidence of invasion into vessels,

nerves, or adjacent structures

Hematogenous spread

Figure 20. Treatment of Well Differentiated

**Treatment: Surgery the RAI to destroy remaining tissues not

removed by surgery, e.g. on Lymph nodes. Provided suppressive

levothyroxine Decreased TSH (note: TSH stimulates growth of

thyroid cells) then monitor by blood test.

POORLY DIFFERENTIATED

Anaplastic

Poor prognosis Poor response to radioiodine treatment Chemotherapy ineffective

Others:

Medullary

Association with Multiple Endocrine Neoplasia 2 Serum calcitonin is a marker of residual or recurrent

disease

Lymphoma

Rapidly expanding thyroid mass Highly sensitive to external radiation (rapidly

expanding!)

SAMPLE CASES

Case 1: Mr. Gollum. What is his

problem (aside from losing thering)?

Appears anxious, keepsmuttering my precious

HR elevated BMI: 17 Neck mass with bruit Irregularly irregular bruit TSH low FT4 and FT3 are high


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Case 2: Patient A at ICU bed 3 presents with palpitations on his

3rd HD (hospital day). TSH was requested which showed asuppressed TSH. Which of the following medications beinggiven to him could explain this findings?

a. Dobutamineb. Hydrocortisone

c. Simvastatind. Levothyroxine

Anwer: both b&d Dopamine, glucocorticoids and somastatin

suppress TSH when these agents are administered in

pharmacological doses.

Case 3: Patient A came in for screening for thyroid disease.

Which of the following times is the best time to perform the

TSH?

a. 8 am after overnight fastb. 12 noonc. 6 pm

d. 12 mn

Answer: any of the following is correct; since TSH has

relatively long half-life and no need to undergo fasting. TSH is

released in a pulsatile manner and exhibits a diurnal rhythm highest level at night. However, TSH excursions are modest

compared to other pituitary hormones because of TSH has a

relatively long plasma half-life. Consequently, single

measurements of TSH are adequate for assessing its circulating

level.

Case 4: Patient I came in for her prenatal check-up. She asks

you, what is the recommended daily intake of iodine for a

pregnant like her?

a. Less than 90 ug/day

b. 90-120 ug/dayc. 150-250 ug dayd. 250 ug/day

Answer: D, refer to table of recommended daily intake

Case: 5. Px F, a 34 yr old female came in with the following

thyroid function results. Low T4 and T3 but normal Free T4

and TSH. What is your explanation for the thyroid function

pattern?a. X linked TBG Deficiency

b. Pregnancy

c. OCP used. Euthyroid Hyperthyroxinemia

Answer: A

Case 6 : SE is a 64/F admitted at the ICU for Heart Failure forthe past 14 days referred for further evaluation of palpitations.She has no prior history of thyroid illness. No other signs orsymptoms of thyroid dysfunction. Thyroid function tests

showed low TSH, slightly high FT4, and low FT 3. Yourimpression is:

A. Secondary hypothyroidismB. HyperthyroidismC. Subacute Thyroiditis

D. Sick Euthyroid Syndrome

Answer: D


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APPENDIX

Figure 21. Evaluation of Hypothyroidism

Figure 22. Evaluation of Thyrotoxicosis


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Table 4. Thyroid Patterns

THYROID

DISORDERTSH FRE T4 TOTAL T4

SIGNS AND

SYMPTOMS

Hyperthyroidism Low High High Present

Subclinical

HyperthyroidismLow Normal Normal Absent

Primary

HypothyroidismHigh Low Low Present

Secondary

Hypothyroidism

Low or

InappropriatelyNormal

Low Low Absent/Present

Subclinical

HypothyroidismHigh Normal Normal Absent

Increased TBG Normal Normal Increased Absent

Decreased TBG Normal Normal Decreased Absent

***Primary hypothyroidism: TSH, pituitary is compensating, in secondary: problem is in pituitary or hypothalamus so TSH (inadequate

elevation in TSH or remain inappropriately normal since normal response is high and normal response means abnormal)

*** or TBG and total T4, but NORMAL, TSH and FT4, patient is asymptomatic

Figure 23. Methimazole vs Propylthiouracil

Table 5. Comparison of drugs used to treat hyperthyroidismINHIBIT

ORGANIFIC

ATION

IMPAIR

CONVERSION OF

T4 TO T3 BY D1

IODIDE

TRANSPORT

INHIBITORS (NIS)

INHIBIT

HORMONE

RELEASE

ADDITIONAL INFO

PTU Yes Yes (600mg)

Methimazole Yes

Thiocyanate Yes

Iodine (SSKI) Yes

3 drops BID with 7-10 day

preop to decrease

vascularity

IpodateIopanoate Yes Yes

Lithium Yes Target Lithium: 1meq/L

DexamethasoneYes (additive to

PTU)

With addition of PTU andSSKI will produce rapid T3

decrease in 48 hours

Propanolol Weakly


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Figure 25. Burch Wartofsky Scoring

Figure 27. Approach to patient with thyroid nodule (ATA 2009 Guidelines for Thyroid Nodules & DTC)


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