Treatment

• hormone replacement therapy consisting of androgen (for males) and estrogen and progesterone (for

females) administration

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E22 Endocrinology Toronto Notes 2023

Antidiuretic Hormone

Diabetes Insipidus (see Nephrology. NP12)

Definition

• disorder of ineffective ADH (decreased production or peripheral resistance) resulting in passage of

large volumes of dilute urine

Etiology and Pathophysiology

• central Dl:insufficient ADH due to pituitary surgery, tumours, idiopathic/autoimmune, infiltration or

lesion of the stalk, hydrocephalus, Langerhans cell histiocytosis, trauma, familial central Dl

• nephrogenic Dl:collecting tubules in kidneys resistant to ADH due to drugs (e.g.lithium),

hypercalcemia, hypokalemia,CKD, hereditary nephrogenic Dl

• psychogenic polydipsia and osmotic diuresis must be ruled out

Clinical Features

• passage of large volumes of dilute urine, polydipsia, and dehydration; hypernatremia can develop with

inadequate water consumption or secondary to an impaired thirst mechanism

• central Dl: visual field defect, headache, other neurological features,or evidence of other pituitary

hormone deficiencies may be present

Diagnosing Subtypes of Diabetes

Insipidus with Desmopressin Response

Concentrated urine - Central

No effect * Nephrogenic

Diagnostic Criteria

• fluid deprivation will differentiate true Dl (high urine output persists, urine osmolality < plasma

osmolality) from psychogenic polydipsia

• response to exogenous ADH (DDAVP) will distinguish central Dl from nephrogenic Dl $

Syndrome of inappropriate ADH

secretion (SIADH) vs.Cerebral Salt

Wasting (CSW)

CSW can occur in cases of subarachnoid

hemorrhage. Na» is excreted by

malfunctioning renal tubules, mimicking

findings of SIADH: hallmark is

hypovolemia

Treatment

• central Dl:first line = desmopressin;second line = chlorpropamide, thiazides, NSAlDs,and

carbamazepine

• nephrogenic Dl:solute restriction, thiazide diuretics

Syndrome of Inappropriate ADH Secretion

Diagnostic Criteria

• 1) hyponatremia (serum Nat <135 mEq/L) with 2) plasma hypo-osmolality (<275 mOsm/kg), 3) urine

Na t concentration >40 mEq/L, 4) urine osmolality >100 mOsm/kg), 5) euvolemia (no edema), and 6)

absence of adrenal, renal, or thyroid insufficiency

Etiology and Pathophysiology

• stress (post-surgical)

• malignancy (ectopic ADH production by tumoursincluding small cell carcinoma of the lung,

extrapulmonary small cell carcinomas,squamous cell carcinoma of the head and neck)

• CNS disease (inflammatory, hemorrhage, tumour,Guillain-Barre syndrome)

• respiratory disease (tuberculosis, pneumonia, empyema)

• drugs (SSRls, vincristine, chlorpropamide, cyclophosphamide, carbamazepine, nicotine, morphine,

DDAVP, oxytocin)

Clinical Features

• symptoms of hyponatremia: headaches, nausea, vomiting, muscle cramps, tremors, cerebral edema if

severe (confusion, mood swings, hallucinations,seizures, coma)

Treatment

• goal is to increase serum sodium

• treat underlying cause, fluid restriction (800-1000 mL/d), vasopressin receptor antagonists (tolvaptan,

conivaptan), demeclocycline (antibiotic with anti-ADH properties;rarely used), and furosemide

Pituitary Pathology

Pituitary Adenoma (see Neurosurgery. NS17)

Clinical Features

• local mass effects

• visual held defects (bitemporal hemianopsia due to compression of the optic chiasm), diplopia (due to

oculomotor nerve palsies; rare), headaches; increased ICR is rare

• hypofunction

• hypopituitarism

• hyperfunction

• PRL (galactorrhea, hypogonadism), GH (acromegaly in adults,gigantism in children), ACT'

H

(Cushing’

s disease = Cushing’

ssyndrome caused by a pituitary tumour)

• tumourssecreting TSH are rare

r

Important Deficienciesto Recognite

are:

• Adrenal Insufficiency

• Hypothyroidism

• Concurrent adrenal insufficiency and

hypothyroidism should be treated

with glucocorticoidsfirst and then

with thyroid hormone to avoid

adrenal crisis

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E23 Endocrinology Toronto Notes 2023

Investigations

• radiological evaluation (MKI sella is imaging procedure of choice)

• formal visual field testing for tumours compressing the optic chiasm

• laboratory tests of hypothalamic- pituitary hormonal function

Hypopituitarism

(§)

The Pituitary Hormones

Compression of the pituitary by a mass

leadsto loss of pituitary hormones in the

following usual order:

T5o Look For The Adenoma Please"

GH. LH. FSH, TSH, ACTH.PRL +

posterior pituitary hormones: ADH and

oxytocin

Etiology (The Eight I’s)

• Invasive

pituitary tumours, craniopharyngioma, cysts (Kathke'

s deft, arachnoid, or dermoid), metastascs

• Infarction/hemorrhage

Sheehan’

ssyndrome (pituitary infarction due to excessive postpartum blood loss and

hypovolemic shock)

pituitary apoplexy (acute hemorrhage/infarction of a pituitary tumour; presents with sudden

loss of pituitary hormones, severe headache, and altered LOC;can be fatal if not recognized and

treated early)

• Infiltrative/ inflammatory

sarcoidosis, hemochromatosis, histiocytosis

• Infectious

syphilis, tuberculosis,fungal (histoplasmosis), parasitic (toxoplasmosis)

• Injury

severe head trauma

• Immunologic

autoimmune destruction (hypophysitis)

• Iatrogenic

following surgery or radiation

• Idiopathic

familial forms, congenital midline defects

Clinical Features

• symptoms depend on which hormone is deficient:

» ACTH:fatigue, weight loss,hypoglycemia,anemia, hyponatremia,failure to thrive, and delayed

puberty in children

CiH:short stature in children;adults exhibit increased fat and decreased lean body mass,

decreased BMD, fatigue

TSH: tiredness, cold intolerance, constipation, weight gain

LH and 1-SH: oligo- or amenorrhea, infertility, decreased facial/body hair and muscle mass in

men,erectile dysfunction, delayed puberty

Prolactin:usually asymptomatic, inability to breastfeed

ADH:symptoms of D1 (extreme thirst, polydipsia, hypernatremia)

Oxytocin: usually asymptomatic - only needed during labour and breastfeeding

Investigations

• 8 am cortisol, PRL,TSH, Free T4, LH, FSH, Estradiol or Testosterone, GH,IGF-I, Na +, Osmolality

• insulin tolerance test:insulin (usual dose 0.1 unit/kg of human regular insulin) -> hypoglycemia -»

increased GH and cortisol (normal response)

• initial test:cosyntropin stimulation test (if results equivocal, proceed to insulin tolerance test)

• triple bolus test (rarely done)

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l Endocrinology Toronto Notes 2023

Thyroid

Thyroid Hormones Extra -Thyroidal (actorsImpacting Thyroid

Hormone Homeostasis:A Review

JRM 2015:4|l):40-49

• Most peripheral thyroid metabolism occursin the

liver and kdnejs.thussevere twer disease and CKO

can ugnifrcantiy alter the 13:T4 ratio.

• Alcohol dependence results m hypothalamic'

pituitaryrytod axis dysiunction demonstrated hy

decreased TSH.14, and T3 levels.

• Smoking isassociated with lower TSH levelsin

a dose-dependent manner, with heavy smokers

18-12 ciqarettes

'

d) beaig associated with more TSH

suppression than lightsmokers[«4 cigarettes/d).

• Heavy metal exposure including lead,mecenry.and

cadmmm has been shown to altar thyroid hormone

function and peripheral melabohsm.

C- Lr

Cap tan

Thyroid follicle

Section of the Thyroid Gland

Follicular cell

Follicular cell

Coupling & t

- v:

Patterns of Hormone Levels

TSH Il.Tr

r Hyper

r Hyper

1° Hypo

y »ypo

* t

t t

t

* *

JUT-diodotyrosina; L = lysosome;MU - monoiodotyrosine;Tg -thyroglobulin; NIC ^ sodium iodide cotransporter.TP-thyroid paroxidase enzyme j

Figure12.Thyroid hormone synthesis

Synthetic Function of the Thyroid Gland

• the synthesis of thyroid hormones'

14 and '

13 by the thyroid gland involves trapping and oxidation of

iodide, iodination of thyroglobulin, proteolysis of thyroglobulin, and release of '

14 and T3

more than 90% of thyroid hormone secreted by the thyroid is T4

• free T4 (0.02%) and free T

'

3 (0.3%) represent the hormonally active fraction of thyroid hormones

the remaining fraction is bound toTBG,albumin, and transthyretin, and is biologically inactive

• T3 is more biologically active (approximately 4x as potent as 14),but T3 is present in the blood in

smaller quantities and has a shorter half-life compared to T4

• 85% of '

14 is converted to T

'

3 or reverse T'

3 in the periphery by dciodinase enzymes

• reverse T'

3 is metabolically inactive but produced in times ofstress to decrease metabolic activity

• most of the plasma T

'

3 pool is derived from the peripheral conversion of T4

• calcitonin, a peptide hormone, is also produced in the thyroid by the parafollicular cells (C cells)

calcitonin functions by inhibiting osteoclast activity and increasing renal calcium excretion

Role of Thyroid Hormones

• thyroid hormones act primarily through modifying gene transcription hy binding to nuclear receptors

• diffuse actions, affecting nearly every organ system

• tissue-specific effects determined by the expression of the types of thyroid receptor isoform and the

local production ofT3

• increase basal metabolic rate through increased Na +/K+ATPase activity,increased 02 consumption,

increased respiration, heat generation, and increased cardiovascular activity

• when present at higher than normal levels, potentiate the actions of GH, catecholamines(epinephrine,

norepinephrine),glucagon, and cortisol, resulting in increased gluconeogenesis, ketogenesis, and

proteolysis, mimicking what happens in starvation

• increase sensitivity to catecholamines by up-regulating their receptors, but do not alter their blood

concentrations

• required for normal growth in the fetus and child, including the CNS, via stimulation of GH release, in

synergism with cortisol

r T

\.LJJ

Regulation of Thyroid Function

• extrathyroid

stimulation of thyroid by 'TSH, epinephrine, prostaglandins (cAMP stimulators);T3 negatively

feeds back on anterior pituitary to inhibit TSH and on hypothalamusto inhibit T'

RH

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E25 Endocrinology Toronto Notes 2023

• T3 intrathyroid (autoregulation)

synthesis (Wolff-Chaikoff effect,|od-Basedow effect)

varying thyroid sensitivity to TSH in response to iodide availability

increased ratio ofT3 to T4 in iodide deficiency

increased activity of peripheral 5’

-deiodinase in hypothyroidism increases T3 production despite

low T4levels

Tests of Thyroid Function and Structure

•

TSH

third generation TSH is the best test for assessing thyroid function

e

• hyperthyroidism

primary'

:TSH islow because of negative feedback from increased levels of circulating T4 and 1

'

3

secondary: increased TSH results in increased 14 and T3

• hypothyroidism

» primary: increased T SH (most sensitive test) because of less negative feedback from T4 and T

'

3

secondary: T SH is low or inappropriately normal with variable response to TRH depending on the

site of the lesion (pituitary or hypothalamic)

Thyroid Assessment

. TSH

• Serum free thyroid hormones (T», T3)

. Antibodies (TRAb. TgAb. and TPOAb)

• Thyroglobulin (to monitor thyroid

cancer)

• Thyroid U/S when there is a palpable

thyroid abnormality or suspected

thyroid mass

• Nuclear uptake and scan (for

hyperthyroidism)

• Biopsy (FNA) of thyroid nodules

warranting a cytological evaluation

Free T4 and Free T3

• standard assessment of thyroid function measures TSH and, if necessary, free T4. Tree T3should only

be measured in the small subset of patients with hyperthyroidism and suspected T3 toxicosis. In this

case, T SH would be suppressed, free 14 normal, and free 1 3 elevated

Thyroid Autoantibodies

• TgAb, TPOAb, and TRAb of the blocking variety are increased in Hashimoto’s disease; normal variant

in 10-20% of individuals

• TKAb of the stimulating variety are also referred to as TSI and can cause Graves'

disease. TRAb

receptor blocking and stimulating antibodies are seen in patients with Graves'

disease

Plasma Thyroglobulin

• used to monitor for residual thyroid tissue post-thyroidectomy,e.g. tumour markerfor thyroid cancer

recurrence

• detectable or elevated levels may suggest persistent, recurrent, or metastatic disease

• assay can be impacted by presence of TgAb.Therefore, both must be tested to ensure accurate

thyroglobulin results

Serum Calcitonin

• not routinely done to investigate thyroid nodules

• ordered if suspicion of MTC (e.g. in patients with a thyroid nodule and suspected or confirmed MEN

2A or 2B syndromes or those who have a pathogenic mutation in RETgene)

• used to monitor for residual or recurrent MTC

Doesthis Patient have a Goitre?

from The RationalClinical Examination

JAUA 2009:https://jamaevidence.mhmediial.com/

ccnte-t aspi?l)O0 «ld-8454secto-i d-6m?S08

Study:Systematic review of articles assessing the

accuracy and precision ot the clinical eum I n the

diagnosis of a goitre.

Results:Clinical diagnosiswas based on degree

of lateral prominence,visibility,and palpability of

the thyroid gland. Nn evidence eiiststosupport the

superiority of any one method,

the combined results of 4staindetail the predictive

•hbty of assessing grades of thyroid gland weight:

Weight Reference US* 95% Cl

0-20g Normal

20-40 g 1-2x

>40g >2»

0.15 (0.10-0.21)

1.9 (11-3.0)

25.0 (2.6-175)

Mtemathrtly. defining a goitre asa mass larger than

the distal phalanrof the thumb has been shown to

have an LR*of 3.0 (95% Cl 25-3.5) and 1R- of 0.30

(95% a:0.24-0.37) in children,and an LR-of 4.7

(95% 03.6-0) and LR- of 0.08(95% Cl 0.02-0.27)

for the presence of a govtre.

Conclusions: Use 0!we ightof thyroid tissue Isan

appropriate method of dagnosmga goitre, while

comparing the six of the thyroid nasslo the distal

pbaianof the thumb may be a useful alternative.

Thyroid Imaging/Scans

• normal gland size 15-20 g (estimated by palpation)

. thyroid U/S

to measure size of gland, characterize thyroid nodules, facilitate ENA biopsy (ENAB)

• U/S is the first line tool for identification of thyroid nodules that require ENAB; exception is

hyperthyroid patients with thyroid nodules where use of a radioisotope thyroid scan and RA1U

(see below) permits identification of hyperfunctioning nodules, which generally do not need to be

biopsied

• radioisotope thyroid scan (Technetium-99) only if 1) one or more thyroid nodule(s) and 2) patient

is hyperthyroid to determine whether nodules are hot (functioning -> excess thyroid hormone

production) or cold (non-functioning)

• hot nodule > very low chance of malignancy; treat hyperthyroidism

• cold nodule -» further workup required ( U/S,then ENAB if concerning sonographic features)

. RA1U

test of function:orderif patient isthyrotoxic

RAIU measures the turnover of iodine by thyroid gland in vivo

if t uptake (e.g. incorporated), gland is overproducing thyroid hormone (hyperthyroid)

if

*

uptake (e.g. not incorporated), gland is leaking thyroid hormone (e.g. thyroiditis), exogenous

thyroid hormone use, or excess iodine intake (e.g. amiodarone or contrast dye, which has high

iodine content)

• see figure 12 for further information regarding the utility of these scans

Thyroid Biopsy

• ENA for cytology

differentiates between benign and malignant disease

best done under U/S guidance

« accuracy decreased if nodule is greater than 50% cystic,or if nodule is located posteriorly in the

gland

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E26 Endocrinology Toronto Notes 2023

Table 15. Summary of Diagnostic Testing in Hyperthyroidism and Hypothyroidism

Hyperthyroidism Hypothyroidism

Drugs Affecting Thyroid Function

Thyroid 2010:20(71:763-770

• Lithium playsininhibitory roleinthyroid hormone

release,resulting nchnical hypothyroidism end

goitre.

. AimadaroceTndyred Hypothyroidism glH|:

Ant oderone.a classIII anbarrhythmic drug,

contains 2 atoms ol iodine per molecule and is

structurahy similar to thyroid hormones, and may

exert antagonist

*

effects on liftreceptors.It a

also shorn to inhibit type Ideiodnoses resulting

in high T4 acd lnwT3 levels.AIH occurs in 5-15%

nf patients on amiodarone.UHcan also occur in

people without pre-exisbng thyso d dysfunction.

• Arniodarone Induced ihyrotoxicovs|JU1):occurs In

2-12\ of patents on amiodarone. Iha may be due

to either art increased iodine load in patients with

TSH Decreased in1°hyperthyroidism

Increased in 2° hyperthyroidism

Increasedin 1" hyperthyroidism

Increased in 2" hyperthyroidism

Graves':TRAb

Increased in1° hypothyroidism

Decreased in 2‘hypothyroidism

Decreased in1‘hypothyroidism

Decreased in 2‘hypothyroidism

Hashimoto's:TPOAb,TgAb

Decreaseduptake

Subacute thyroiditis

Recent iodine load

Exogenous thyroid hormone

Freeti

Antibodies

Increased uptake

Graves'

Toxic multinodular goitre

Toxic adenoma

Graves'

:homogenous diffuse uptake

Multinodular goitre:heterogeneous uptake

loxic adenoma: single intense area of uptake with suppression elsewhere

RAIU

Radioisotope

Thyroid Scan

Thyrotoxicosis a prer.ousty autonomous thyroid such as in Graves'

disease and toxic multinodular goitre(AIT type

l|or amiodarone-induceddestructive thyroid tis

Definition

• clinical, physiological, and biochemical findings in response to elevated thyroid hormone

Epidemiology

• 1% of general population have hyperthyroidism

• I:M=5: 1

1

*

11 type It)

Signs and Symptoms of

HYPERthyroidism

Etiology and Pathophysiology

THYROIDISM

Tremor

Heart rate up

Yawning(fatigue due toinsomnia)

Restlessness

Oligomenorrhea/amenorrhea

Intolerance to heat

Diarrhea

Irritability

Sweating

Muscle wasting/weight loss

Table 16. Differential Diagnosis of Thyrotoxicosis

Disorder TSH Free T./Ti Thyroid

Antibodies

RAIU Other

HYPERTHYROIDISM

Graves'Disease Decreased Increased TRAb Increased Homogenous uptake

on scan

Heterogeneous

uptake on scan

Intense uptake in hot

nodule on scan with

suppressed uptake in

the rest of the gland

Toxic Nodular Goitre Decreased Increased None Increased

Toxic Nodule Decreased Increased None Increased

THYROIDITIS

Subacute,Silent.

Postpartum

Up to 50% of cases

(TPOAb. TgAb)

Decreased Increased Decreased (increases In classical subacute

once entering

hypothyroid phase,

when TSH rises)

painful thyroiditis.

ESR increased Common Etiologies

Thyrotoxicosis Hypothyroidism

EXTRATHYROIDAL SOURCES OF THYROID HORMONE

Endogenous

(struma ovarii,

ovarian teratoma,

metastatic follicular

carcinoma)

Exogenous (drugs) Decreased

Graves'Disease Hashimoto's

Toxic Nodular Goitre Congenital

Iatrogenic

(thionamides.

radioactive iodine.o<

surgery)

Decreased Decreased Low thyroglobulin

since endogenous

thyroid hoimone

production

suppressed

Increased None

Toxic Nodule

Increased (Ti would None

be decreased if

taking Tj)

Decreased Hyperthyroid phase of Hypothyroid phase ol

thyroiditis thyroiditis

EXCESSIVE THYROID STIMULATION

Pituitary

Thyrotropinoma

Increased Increased Pituitary mass;

possible PRL or GH

excess

Abnormal THRB gene

analysis

Increased or

inappropriately

normal

Pituitary Thyroid Increased or normal Increased

Hormone Receptor

Resistance

Increased hCG (e.g. Decreased

pregnancy)

None

None Increased

Test is contraindicated

in pregnancy

Increased None

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Clinical Features

Table 17. Clinical Features of Thyrotoxicosis

General Fatigue,heat intolerance, irritability,fine tremor

CVS Tachycardia.alrial fibrillation,palpitations

Elderly patients may have only cardiovascular symptoms,commonly new onset atrial fibrillation

Weight loss withincreased appetite, thirst,increased frequency of bowel movements|hyperdefecalion)

Proximal muscle weakness, hypokalemic periodic paralysis (more common in Asian individuals)

Oligomenorrhea, amenorrhea, decreased feitilily

Fine hair,moist and warm skin, vitiligo, soli nails with onycholysis (Plummer’s nails), palmar erythema, pruritus

Graves' disease:clubbing (acropadiy),prelibial myxedema (rare)

Decreased bone mass, proximal muscle weakness

Graves' disease:leukopenia,lymphocytosis, splenomegaly,lymphadenopathy (occasionally)

Graves’disease:lid lag.retraction, proptosis,diplopia,decreased acuity,puffiness,conjunctival injection

NOTE:Lid lag is a reflection of a hyperadrenergic state and can be present in any form of thyrotoxicosis

Gl

Neurology

GU

Dermatology

MSK

Hematology

Eye

Treatment

• p-blockers for control of adrenergic symptoms

• antithyroidals (thionamidcs): propylthiouracil (R U) or methimazole (MMl); MMI recommended

• to prepare patients with endogenous hyperthyroidism for surgery, for patients with Graves'

disease, and for patients with toxic nodules who do not wish to have definitive treatment with

radioactive iodine or surgery

• radioactive iodine thyroid ablation for Graves'

disease and toxic nodules/adenoma

• surgery in the form of hemi,subtotal, or complete thyroidectomy for toxic nodules

• surgery in the form of total thyroidectomy for Graves’disease

Graves’ Disease

Definition

• an autoimmune disorder characterized by autoantibodies that stimulate the TSH receptor leading to

hyperthyroidism

Graves' Ophthalmopathy

NO SPECS (In the usual order of changes)

No signs

Only signs:lid lag, lid retraction

Soft tissue:periorbital puffiness,

conjuctival injection,diemosis

Proptosis/exophthalmos

Extraocular (diplopia)

Corneal abrasions (unable to close

Epidemiology

• most common cause of hyperthyroidism

• occurs at any age with peak in 3rd and 4th decade

• F:M=7:1, 1.5-2% of women in the United States

• familial predisposition:15% of patients have a close family member with Graves’disease and 50%

have family members with positive circulating antibodies

• association with HLA-B8 and DR3

• may be associated with other autoimmune disorders (e.g. pernicious anemia, Hashimoto’

s disease)

eyes)

Sight loss

Etiology and Pathophysiology

• autoimmune disorder due to breakdown in thyroid tolerance likely due to a combination of factors

including autoreactive B lymphocytes and an imbalance favouring a TH2 vs. TH1 immune response

• B lymphocytes produce '

1 SI that binds and stimulates the I SH receptor, and thus, the thyroid gland

• immune response can be triggered by postpartum state, iodine excess, viral or bacterial infections,

and glucocorticoid withdrawal

• ophthalmopathy (thyroid associated orbitopathy) is a result of increased connective and extraocular

muscle tissue volume due to inflammation and accumulation of glycosaminoglycans,stimulated by

TS1, that increase osmotic pressure within the orbit; thisleads to fluid accumulation and forward

displacement of the eyeball

• dermopathy (pretibial or localized myxedema) may be related to cutaneous glvcosaminoglycan

deposition

Clinical Features

• signs and symptoms of thyrotoxicosis

• diffuse goitre ± thyroid bruit secondary to increased blood flow through the gland

• ophthalmopathy: proptosis,diplopia, conjunctival injection, corneal abrasions, periorbital puffiness,

lid lag, decreased visual acuity (plussigns of hyperthyroidism:lid retraction, characteristic stare)

• dermopathy (rare): pretibial myxedema (thickening of dermis that manifests as non-pitting edema)

• acropachy: clubbing and thickening of distal phalanges

Other Medications Used in the

Treatment of Graves'

Glucocorticoids have been useful

in the treatment of severe Graves’

hyperthyroidism and thyroid storm,by

inhibiting the conversion of peripheral

T« to T3

Lithium can also be used to treat

Graves' hyperthyroidism. It acts by

blocking thyroid hormone release,but its

toxicity has limited its use in practice

Caution

m

with Thionamides

These drugs are highly effective

inhibitors of thyroid hormone synthesis,

inducing permanent remission in

20-30% of patients with Graves'

disease.They are most often employed

to achieve a euthyroid state before

definitive treatment. Adverse effects

include teratogenicity, agranulocytosis,

hepatotoxicity. and ANCApositive

vasculitis

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Investigations

• low TSH

• increased free T4 (and/or increased T3)

• positive for TR Ab (the currently available third-generation T'

RAb tests have sensitivity and specificity

over 98%, allowing their use for determining the etiology of hyperthyroidism)

• increased RA1U

• homogeneous uptake on thyroid scan

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Treatment

• thionamides (antithyroid medications):PTU or methimazole MMI.In 2020, PTU became unavailable

in Canada and it is unclear whether it will be available in the future

PT U and MMI inhibit thyroid hormone synthesis by inhibiting peroxidase-catalyzed reactions,

thereby inhibiting organification of iodide, blocking the coupling of iodotyrosines

PTU also inhibits peripheral deiodination of T4 to T3

treat for approximately 12-18 mo aiming for a normal TSH and TKAb prior to consideration of

treatment discontinuation

small goitre, mild hyperthyroidism, and low TRAb titres are good predictors for long-term

remission with medical therapy

remission (normal thyroid indices one vr after discontinuation of PTU or MMI) rates range

between 20-30% following 12-18 mo of antithyroid medication

major side effects: hepatotoxicity (cholestasis, hepatitis), agranulocytosis,vasculitis

minorside effects:minor rash, pruritus

MMI is preferred to PTU due to longer duration of action (once daily dosing for most), more rapid

resolution of hyperthyroidism, and lower incidence of side effects

in pregnancy: use PTU during first 16 wk of pregnancy and MMI after. MMI is contraindicated in

the first trimester due to risk of aplasia cutis;MMI is preferred in the second and third trimester

due to the potential risk of hepatotoxicity with PTU in the second and third trimesters

• symptomatic treatment with p-blockers

• thyroid ablation with radioactive 1-131 if PT U or MMI trial does not produce disease remission or

patient prefers definitive treatment with RA1

high incidence of hypothyroidism after 1-131 requiring lifelong thyroid hormone replacement

contraindicated in pregnancy

may worsen ophthalmopathy; concurrent treatment with prednisone if high risk for or if

ophthalmopathy present

• total or near total thyroidectomy (indicated for large goitres,suspicious nodule for cancer, if

patient is intolerant to thionamides and dedines/is not a candidate for RAI ablation, women who

wish to conceive in the near future warranting rapid control of hyperthyroidism, uncontrolled

hyperthyroidism not responding to anti-thyroid drugs in pregnancy (surgery safest in second

trimester), patient preference)

• risks: permanent hypothyroidism, hypoparathyroidism, and vocal cord palsy due to potential

laryngeal nerve damage

• ophthalmopathy/orbitopathy

smoking cessation is important

prevent drying of eyes and ulceration of cornea by using artificial tears during the day and

lubricants at night

high dose prednisone or IV methylprednisolone in severe cases

• high dose glucocorticoids preferably IV as well as potential orbital decompression surgery for

sight threatening orbitopathy

orbital radiation,surgical decompression

Prognosis

• course involves remission and exacerbation unless gland is destroyed by radioactive iodine orsurgery

• total and subtotal thyroidectomy are rapid cures with low-risk of recurrence (2% and 10%,

respectively)

• radioactive iodine isless invasive than surgery, but also resultsin permanent hypothyroidism and

requires precautions in contactsseveral days after treatment

• medical therapy with thionamides is not invasive, but has high recurrence rate at

-50%

• lifetime follow-up needed

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Subacute Thyroiditis (Thyrotoxic Phase)

• there are two main types: painful (de Quervain’

s) and painless (silent)

Table 18. Painful vs. Painless Subacute Thyroiditis

Painful Thyroiditis (de Ouervain’s, granulomatous) Painless Thyroiditis (silent, autoimmune)

Pathophysiology Presumed lo be caused by viral infection or postviral inflammatory Considered variant ol Hashimoto'

s thyroiditis

process Associated with HLA 0R 3

Strongly associated with HLA- D35

Thyroid inflammation damages thyroid follicles, resulting in release Also caused by inflammatory damage leading lo

unregulated release ol Ii and 1i into circulation

Postpartum subtype occursfollowing pregnancy

ol large amounts ol T 4 and 13 untilstores are exhausted

Slate ol hypothyroidism often persists until thyroid can generate

suflicient thyroid hormones

Clinical Features Painful swelling of the thyroid (may radiate to jaw and ears).

transient vocal cord paresis, malaise,fatigue, myalgia,fever

Often preceded by IIRTI

Painful condition lasts for a week to lew months

Thyroid enlargement without discomlorl

in association with the typical thyroid function

test abnormalities consisting of hyperthyroidism,

hypothyroidism, and recovery

Signs of hyperthyroidism during hyperthyroid phase (palpitations. Signs of hyperthyroidism during hyperthyroid phase

tachycardia,stare) (palpitations, tachycardia,stare)

Allects women more than men

Initial elevated Tiandh

Near absentRAIU

(SR and CRP often elevated

Laboratory

Investigations

Initial elevated Ti and I:

Near absent RAIU

P-adrenergic blockage is usually eflective in reversing

fl-adrenergic blockage is usually effective in reversing most of the most ol the hypermetabolic and cardiac symptoms

hypcrmctabollc and cardiac symptoms

If symptomatically hypothyroid,may treat short-term with thyroxine with thyroxine

Complete spontaneous recovery to normal thyroid lunction in 90% 10% ol patients may become permanently hypothyroid

ol patients

10% of patients may become hypothyroid and require permanent

replacement

treatment NSAID/prednisone for pain

II symptomatically llypolhyroid, may treat short- term

Prognosis

Al risk ol recunen!episodes of thyroiditis

Toxic Adenoma/Toxic Multinodular Goitre

Etiology and Pathophysiology

• autonomous thyroid hormone production from a functioning adenoma that is hypcrsecreting T4 and

T3

• may be singular (toxic adenoma) or multiple (toxic multinodular goitre (Plummer’

s disease))

• more common in elderly people as opposed to Graves' disease which is more common in younger

individuals

Clinical Features

• multinodular goitre

• tachycardia, heart failure, arrhythmia, weight loss, nervousness, weakness, tremor, and sweats

• local neck compression symptoms such as dysphagia, dysphonia, or dyspnea may be present with

large goitres

Investigations

• low TSH, high free T4 and free T3

• thyroid scan with increased RAIU in nodule(s) and suppression of the remainder of the gland

Treatment

• use high dose radioactive iodine (1-131) to ablate hyperfunctioning nodules

• p-blockers often necessary for symptomatic treatment prior to definitive therapy

• surgical excision may also he used as first-line treatment

• initiate therapy with PTU or MM1 to attain euthyroid state in individuals who do not wish to have

definitive treatment of their disease, in preparation for thyroidectomy, or prior to RA1 in patients at

risk for complications due to exacerbation of hyperthyroidism following RA 1 such as the elderly with

cardiovascular disease

Thyrotoxic Crisis/Thyroid Storm

Definition

• medical emergency - acute exacerbation of all of the symptoms of thyrotoxicosis presenting in a lifethreatening state secondary to uncontrolled hyperthyroidism

• rare, but serious with mortality rate between 10-30%

Etiology and Pathophysiology

• often precipitated by infection, trauma, or surgery in a hvperthyroid patient

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E30 Endocrinology Toronto Notes 2023

Differential Diagnosis

• sepsis, pheochromocytoma, malignant hyperthermia, drug overdose, neuroleptic malignant

syndrome

Clinical Features

• hyperthyroidism

• extreme hyperthermia (S40°C),tachycardia, vomiting, diarrhea, hepatic failure with jaundice, atrial

fibrillation, CHE

• CNS manifestations including agitation, delirium, psychosis, lethargy,seizures, coma

Laboratory Investigations

• increased free T4 and T3, undetectable TSH

• ± anemia, leukocytosis, hyperglycemia, hypercalcemia, elevated LET*

General Measures

• fluids, electrolytes, and vasopressor agents should be used as indicated

• a cooling blanket and acetaminophen can be used to treat the pyrexia

• propranolol or other (1-blockers can additionally be used, but should be used with caution in patients

with decompensated heart failure as they may worsen condition

propranolol is frequently used because it decreases peripheral conversion of T4 to T3

Specific Measures

• PTU isthe anti-thyroid drug of choice and is used in high doses (200 mg q4 h)

• give iodide, which acutely inhibitsthe release of thyroid hormone, 1 h after the first dose of PTU is

given

sodium iodide I g IV drip over 12 h q12 h

OR

Lugol’ssolution 10 drops q8 h

OR

potassium iodide (SSKI) 5 drops q6 h

• hydrocortisone 100 mg IV q8 h or clexamethasone 2- 4 mg IV q6 h for the first 24-48 h;inhibits

peripheral conversion of T4 to T3

Hypothyroidism

Definition

• clinical syndrome caused by insufficient thyroid hormone production

Epidemiology

• 2-3% of general population

. F:M=10:1

• 10-20% of women >50 have subclinical hypothyroidism (normal '

14, TSH mildly elevated)

• iodine deficiency is the most common cause worldwide, but not in North America

f adore Affecting Gastrointestinal Absorption of

levothyrorine:A Review

Cl*

Titer 201);39|2):3« 403

•

(I disorders such as cebac disease,atrophic

gastritis,lactose intolerance.H. pylori infection

nay impede levotbyroiine absorption.

. tv : c:

. i

- q ;::- t i t , -

.net-fr -

;

‘

:.v

to significantly reduce exogenous Ibyroid hormone

absorption from the Gi tract These wictude protonpump inhibitors. H2 receptor antagonists,calcium

carbonate,sucralfate,and aluminum bydronde.

. I c r a t e s s

'

o o - ::

- t e- i t i n a l :::i

oflerothyrorine.

• food, especially soybeans andcoffee. hare been

shown to leduce absorption of levoUiyroxine

significantly.

. Roughly 80% of lerotfiyroiine is absorbed within 3

h after administration of the drug. Thus, patients

Should be educated to take levothyroniae on empty

stomach at least 1 b prior to eating breakfast.

Etiology and Pathophysiology

• primary hypothyroidism (90%)

• inadequate thyroid hormone production due to an intrinsic thyroid defect

u iatrogenic:post-ablative (1-131 or surgical thyroidectomy)

autoimmune: Hashimoto'

s thyroiditis

hypothyroid phase ofsubacute thyroiditis

drugs: goitrogens (iodine), PTU, MM I,lithium

• infiltrative disease (progressive systemic sclerosis, amyloid)

• iodine deficiency

» congenital (1/4000 births)

neoplasia

• secondary hypothyroidism: pituitary hypothyroidism

• insufficiency of pituitary TSH

• tertiary hypothyroidism:hypothalamic hypothyroidism

• decreased TRH from hypothalamus (rare)

• peripheral tissue resistance to thyroid hormone (Refetoif syndrome)

Table 19. Interpretation of Serum TSH and Free T« in Hypothyroidism r n

LJ

Serum TSH FreeTi

Overt Primary Hypothyroidism

SubclinicalPrimary Hypothyroidism

Secondary Hypothyroidism

Increased

Increased

Decreased or not appropriately elevat