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 elevated

Decreased

Normal

Decreased +

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E31 Endocrinology Toronto Notes 2023

Clinical Features

Table 20. Clinical Features of Hypothyroidism Subclinical Hypothyroidism: A Review

JAMA 2019;322:153-160

Ebckground Up a MS ot the adultpopialion

tiptnencn jubtlinital hypethyro dism,defined

a elevated ISH (»4.4 mUfl|with notmalleeeIsol

fiee 14. The deqiee of abnormality that warrants

management is controversial.

Observations:Sjbtlinical hypotfiyrodism is most

often caused byautoimmune thyroiditis, ttmay

be associated w th increased nskof OIF and CAD

events.Further.

*

substantial portion of patients

with subclinical hypothyroidism progress to overt

hypothyroidism,hrdence from large RCIs to support

levotbyroiine therapy in these patients is lacking.

The rationale for treatment is thereforebased on

levathyronme'spotential to prevent cardiovascular

events and progress-on to overt hypothyroidism.

Recommendations : Most individualswith subclinical

hypothyioidismcan beobsetvedvi thou!treatment.

Candidates for levotbyroiine therapy include

those with serumISH levels >10 mU/Land young

and middle-agedpatientswith symptor.sof mild

hypothyroidism.

General Fatigue,cold intolerance,slowing of mental and physical performance,hoarseness, macroglossia

Pericardial effusion,bradycardia,hypotension.worsening CHF * angina.hypercholesterolemia,hypcihomocystcincmia,

myxedema heart

Respiratory Decreased exercise capacity,hypoventilation secondary to weak muscles,decreasedpulmonary responses lohypoxia, sleep

apnea due to macroglossia

Weightgain despite poor appetite.constipation

Neurology Paresthesia,slow speech, muscle Clamps, delayed deep tendon reflex relaxation|“hung reflexes"),carpal tunnel syndrome,

asymptomatic elevated CK. scuures

Menorrhagia,amenorrhea, impotence,pre-menopausal abnormal vaginal bleeding

CVS

Gl

GU

Dermatology Facial pulfmess. periorbital edema, cool and pale,dry and rough skin,dry and coarse hair,eyebrows thinned (lateral 1/3),

discolouration (carotenemia)

Hematology Anemia:1D\pernicious due to piesencc ol anti parietal cell antibodies with Hashimoto'sthyioidilis

Treatment

• L-thyroxine (dose range: 0.05-0.2 mg PO once daily, up to 1.6 pg/kg/d)

• elderly patients and those with CAD:start at 0.025 mg daily and increase gradually every 6 wk (start

loss’

,go slow)

• after initiating L-thyroxine,TSH needs to be evaluated in 6 wk; adjust dose until TSH returns to

normal reference range

• once maintenance dose achieved,follow up TSH with patient annually

• secondary/tertiary hypothyroidism: monitor via measurement of free T4 (TSH is unreliable in this

setting) Signs and Symptoms of

HYPOthyroidism

CONGENITAL HYPOTHYROIDISM

• see Paediatrics, P34 HIS FIRM CAP

Hypoventilation

Intolerance to cold

Slow HR

Fatigue

Impotence

Renal Impairment

Menorrhagia/amenorrhea

Constipation

Anemia

Paresthesia

Hashimoto’s Thyroiditis

Definition

• most common form of primary hypothyroidism in North America

• chronic autoimmune thyroiditis characterized by both cellular and humoral factors in the destruction

of thyroid tissue

• two major forms: goitrous and atrophic; both formsshare same pathophysiology but differ in the

extent of lymphocytic infiltration, fibrosis, and thyroid follicular cell hyperplasia

• goitrous variant usually presents with a small, rubbery goitre and euthyroidism, then hypothyroidism

becomes evident

• associated with fibrosis

• atrophic variant patients arc hypothyroid from onset

• risk factor for rare primary thyroid lymphoma

Etiology and Pathophysiology

• defect in a T-suppressor clone leads to cell-mediated destruction of thyroid follicles

• B lymphocytes produce antibodies against thyroid components including thyroglobulin, thyroid

peroxidase, TSH receptor, Nat /I- symporter

Risk Factors

• F:M=7:1

• genetic susceptibility: increased frequency in patients with Down's syndrome, Turner's syndrome,

certain HLA alleles, cytotoxic T-lymphocyte-associatcd protein

-1 (CTLA-4)

• family Hx or personal Hx of other autoimmune diseases

• cigarette smoking

• high iodine intake

Investigations

• high TSH, low T4 (not necessary to measure T3as it will be low as well)

• presence of TPOAb and TgAb in serum

Treatment

• if hypothyroid, replace with L-thyroxine (analog of'

1

'

4)

r »

L J

Myxedema Coma

Definition

• medical emergency -severe hypothyroidism complicated by trauma, sepsis, cold exposure.Ml,

inadvertent administration of hypnotics or narcotics, and other stressful events

• rare; high level of mortality (up to 40%, despite therapy)

+

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E32 Endocrinology Toronto Notes 2023

Clinical Features

• decreased mental status and hypothermia are hallmark symptoms

• hyponatremia, hypotension, hypoglycemia, bradycardia, hypoventilation, and generalized non-pitting

edema often present

Investigations

• decreased T4, increased TSH, decreased glucose

• check ACTH and cortisol for evidence of adrenal insufficiency

Treatment

• aggressive and immediate treatment required

• ABCs:1CU admission

• corticosteroids (for risk of concomitant adrenal insufficiency): hydrocortisone 100 mg q8 h

• L-thyroxine 0.2-0.5 mg IV loading dose, then 0.1 mg IV once daily until oral therapy tolerated: also

consider T3 therapy

• supportive measures:mechanical ventilation, vasopressors, passive rewarming, IV' dextrose, fluids if

necessary (risk of overload)

• monitor for arrhythmia

Non-Thyroidal Illness (Sick Euthyroid Syndrome)

Definition

• changes in the regulation of the hypothalamic-pituitarv-thyroid axis, and thyroid hormone

metabolism and transport among patients with severe illness, trauma,surgery, or starvation

• not due to intrinsic thyroid, pituitary, or hypothalamic disease

• initially low free T3 may be followed by low TSH and, if severe illness, low free T4

• with recovery of illness, TSH may become transiently high

Pathophysiology

• abnormalities include alterationsin:

peripheral transport and metabolism of thyroid hormone

regulation of TSH secretion

• may be protective during illness by reducing tissue catabolism

Labs

• initially decreased free T3 followed by decreased TSH and Anally decreased free T4

• with recovery of illness,TSH may become elevated

Treatment

• treat the underlying disease; thyroid hormone replacement has notshown to be benefleial

• thyroid function tests normalize once patient is well (initially with a transient increase in TSH)

Non-Toxic Goitre

Definition

• generalized enlargement of the thyroid gland in a euthyroid individual that does not result from

inflammatory or neoplastic processes

Pathophysiology

• the appearance of a goitre is more likely to present during adolescence, pregnancy, and lactation due

to increased thyroid hormone requirements

• early stages:goitre is usually diffuse

• laterstages:multinodular non-toxic goitre with nodule,cyst formation, and areas of ischemia,

hemorrhage, and ftbrosis

Etiology

• iodine deftciency or excess

• goitrogens: brassica vegetables (e.g. turnip, cassava)

• drugs: iodine, lithium, para-aminosalicylic acid

• any disorder of hormone synthesis with compensatory growth

• peripheral resistance to thyroid hormone

Treatment

• remove goitrogens

• radioiodine therapy (very high doses required given low iodine uptake, used as last resort in very

highly selected cases where the goiter is causing symptoms and surgery is not feasible)

• suppression with L-thyroxine (rarely done)

• surgery may be necessary’ifsevere compressive symptoms develop (rare);patients are often asymptomatic

n

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Complications

• compression of neck structures causing stridor, dysphagia, pain, and hoarseness of voice

• multinodular goitre may become autonomousleading to toxic multinodular goitre and hy'perthyroidism

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E33 Endocrinology Toronto Notes 2023

Thyroid Nodules

Definition

• discrete lesion that can be distinguished sonographically from the rest of the thyroid parenchyma

• 19-67% prevalence based on incidentally found nodules on U/S

Etiology

• benign tumours (e.g. follicular adenoma)

• thyroid malignancy

• hyperplastic area in a multinodular goitre

• cyst: true thyroid cyst, area of cystic degeneration in a multinodular goitre

Investigations

• approach to thyroid biopsy depending on U/S characteristics ofthe nodule

• benign or very small nodules suspicious for thyroid cancer do not require ongoing surveillance

• small nodules suspicious for thyroid cancer require up to five years of surveillance

• larger nodules suspicious for thyroid cancer require biopsy

Thyroid nodule on U/S

Third generation TSH

LowTSH Normal/elevated TSH

U/S-guided biopsy if

indicated based on U/S

characteristics

Thyroid scan

Hot nodule Cold nodule

1

U/S-guided biopsy it

indicated based on U/S

characteristics

No biopsy

Treat hyperthyroidism

Treat hyperthyroidism

Figure 13. Approach to the evaluation of a thyroid nodule

Adapted from Of.J Goguen.University of Toronto.MMMD 2013

Thyroid Malignancies

• see Otolaryngology. OT37

Adrenal Cortex

Adrenocorticotropic Hormone

• a polypeptide (cleaved from prohormone POMC), secreted in a pulsatile fashion from the anterior

pituitary with diurnal variability (peak: 0200-0400 h;trough: 1800-2400 h)

• secretion regulated by CRH and AV'P

• stimulates growth of adrenal cortex and release of glucocorticoids, adrenal androgens and, to a very

limited extent, mineralocorticoids

• ACTH can directly bind to MSH receptors on melanocytes, enhancing melanogenesis

Tblood glucose,trauma,infection,

emotion,circadian rhythm

i

CNS -4

i

Adrenocortical Hormones Hypothalamus

-a -

Q

Aldosterone o ® !©

• a mineralocorticoid which regulates ECPV through Na '(and C1-) retention and R '(and H ’) excretion

(stimulates distal tubule Na 1/K+ATPase)

• regulated by the RA AS and hyperkalemia

• negative feedback to juxtaglomerular apparatus(|GA) by long loop (aldosterone volume expansion)

and short loop (angiotensin 111 peripheral vasoconstriction)

CRH A\ P

Pituitary

-4 - -

i

G ACTH Cult SL

i ri

—Adrenal gland

Figure 14.Regulation of CRH-ACTHadrenal gland axis

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E31Endocrinology Toronto Notes 2023

Cholesterol © 17-hydroxylase

©3-Pdehydrogenase

@21-hydroxylase

(T) 11-hydroxylase

(f) 17-pdehydrogenase

(ff) Aromatase

(

£) 5-areductase

(jP) 18-hydroxylase

(

018-oxidase

’

Most common enzyme defect

© Pregnenolone

*

Layers of the Adrenal Cortex

I© OUTSIDE © 17-OH-pregnenolone Zona Glomerulosa produces

mineralocortlcoids (aldosterone)

Progesterone >

DHEAS

I® I© 1

®

Zona Fasciculate produces

glucocorticoids(cortisol)

11-deoxycorticosterone 17-OH-progesterone Androstenedione

I© I® I©

@ Zona Reticularis produces

androgens IDHEA,

androstenedione)

Corticosterone 11-deoxycortisol Testosterone

|

© |

©

INSIDE 18-hydroxycorticosterone Cortisol Estradiol Dihydrotestosterone

I©

Aldosterone

Mineralocorlicoids

(zona glomerulosa)

Glucocorticoids

(zona fasciculata)

Figure 15. Pathways of major steroid synthesis in the adrenal gland and their enzymes

Sex Steroids

(zona reticularis)

iuolume

iarterial pressure

iNa delivery to macula densa

Prostaglandins

Sympathetic stimulation

tvolume

Tarterial pressure

Dopamine

Renal Na ' retention

I l

Stimulation of JGA Inhibition of JGA

i

Renin (kidney) ACE (lung and kidney)

Angiotensinogen Angiotensin I Angiotensin II

(withnegative feedback to inhibit JGA)

1

*

Aldosterone release Renal Na retention,K excretion

Arteriolar vasoconstriction

Promotion ol ADH release

ACE - angiotensin converting enzyme

JGA - juxtaglomerulai apparatus

Figure 16. Renin-angiotensin-aldosterone axis (see Nephrology, NP4)

Cortisol

• a glucocorticoid regulated by the HPA axis

• involved in metabolism regulation

• supports blood pressure and vasomotor tone

• also involved in behavioural regulation and immunosuppression

Table 21. Physiological Effects of Glucocorticoids

Stimulatory Effects Inhibitory Effects

Stimulate hepatic glucose production (gluconcogencsis)

Increase insulin resistance in peripheral tissues

Increase proteincatabolism

Stimulate leukocytosis and lymphopenia

Increase cardiac output,vascular tone.Na ’

retention

Increase PIN release,mine calcium excretion

Inhibit bone formation;stimulate bone resorption

Inhibit fibroblasts,causing collagen andconnechve tissue loss

Suppress Inflammation;impair cell-mediated immunity

Inhibit growth hormone axis*

Inhibit reproductive axis’

Inhibit vitamin (Hand inhibit calcium uplakc

'Typically only occurs with cortisol excess

Androgens

• sex steroids regulated by ACT H;primarily responsible for adrenarche (growth of axillary and pubic

hair)

• principal adrenal androgens are: DHEA, androstenedione, and l l-hydroxyandroslenedione

• proportion of total androgens (adrenal to gonadal) increases with age

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Adrenocortical Functional Workup

STIMULATION TEST

• purpose: diagnose hormone deficiencies

• method: measure target hormone after stimulation with tropic (pituitary) hormone

Tests of Glucocorticoid Reserve

• Cosyntropin (ACTH analogue) Stimulation Test

administer 250 pg cosyntropin 1V/1M, and measure plasma cortisol levels before and 30 and 60

min after administration

physiologic response:stimulated plasma cortisol of >500 nmol/L (>18 pg/dL) at 30 or 60 min

physiologic response rate threshold may be lower with newer assays and should be confirmed

with local lab

« inappropriate response:inability to stimulate increased plasma cortisol;peak cortisol levels below

500 nmol/L (18 pg/dL) at 30 or 60 min

SUPPRESSION TESTS

• purpose: diagnose of hormone hypersecretion

• method: measure target hormone after suppression of its tropic (pituitary) hormone

1. Tests of Pituitary-Adrenal Suppressibility

• DXM suppression test

• principle: DXM suppresses pituitary ACTH,plasma cortisol should be lowered if HPA axis is normal

• screening test:low-dose overnight DXM suppression test

oral administration of 1 mg DXM between 11 pm and midnight,then measure plasma

cortisol levels the following day between 8 am and 9 am

physiologic response: plasma cortisol <50 nmol (<1.8 pg/dL)

inappropriate response:failure to suppress plasma cortisol

false positive results due to obesity,depression, alcoholism, medications inducing the

metabolism of DXM

• testing of excess cortisol production

elevated 2-1 h urine free cortisol (shows overproduction of cortisol)

midnightsalivary cortisol (if available) showslack of diurnal variation

- inappropriately remains high, >145 ng/dL (4 nmol/L) (normally will be low at midnight)

2. Tests of Mineralocorticoid Suppressibility

• multi

and t

• positive screen for PA is elevated aldosterone:renin ratio in the presence of high aldosterone

• there is variability in the interpretation of aldosteronc:renin ratio depending on the assays used

• confirmation of PA requireslack of aldosterone suppression:with expansion of ECE'V, plasma

aldosterone should be lowered

• ECE'

V Expansion with NS

IV infusion of 500 mL/h of NS for 4 h, then measure plasma aldosterone levels

plasma aldosterone >277 pmol/L is consistent with PA, <140 pmol/L is normal

• inappropriate response:failure to suppress plasma aldosterone

pie medications can interfere with the interpretation ofscreening and confirmatory testsfor PA

nese may need to be held prior to testing

Mineralocorticoid Excess Syndromes

Definition

• PA:excess aldosterone production (intra-adrenal cause) (previously called hyperaldosteronism)

• SA:aldosterone production in response to excess RAAS (extra-adrenal cause)

Etiology

• aldosterone-producing adrenal adenoma (Conn’ssyndrome)

• bilateral or idiopathic adrenal hyperplasia

• glucocorticoid-remediable aldosteronism

• aldosterone-producing adrenocortical carcinoma

• unilateral adrenal hyperplasia

• ectopic aldosterone-producing tumours

• familial hyperaldosteronism (I

'

H) types l

-IV

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Hypertension end Hypokalemia

i r

Plasma renin activity (PRAI

Plasma aldosterone concentration IPAC)

tPRA t PRA iPRA

t PAG t PAC iPAC

PAC:PRA ratio>20 ng/dLng/mUh

and

PAC >15 ng/dlI>416 pmol/U

Investigate for

causes ol secondary

hyperaldosteronism

Investigate for

Primary aldosteronism

Investigate for:

Congenital adrenal hyperplasia

Exogenous mineralcortrcoid

DOC-producing tumour

Cushing's syndrome

11- f

)HSD deficiency

Altered aldosterone metabolism

Liddle'

s syndrome

Glucocorticoid resistance

Renovascular HTN

Diuretic use

Renin-secreting tumour

Malignant HTN

Coarctation of the aorta

Figure 17. Approach to mineralocorticoid excess syndromes

Clinical Features

• HTN

• hypokalemia (± mild hypernatremia), metabolic alkalosis

• normal K ’ hyponatremia in secondary hyperaldosteronism (low effective circulating volume leads to

ADH release)

• increased cardiovascular risk: LV hypertrophy, atrial fibrillation,stroke, and Ml

• elevated risk of metabolic syndrome and T2DM

• fatigue, weakness, paresthesia, headache; severe cases present with tetany, intermittent paralysis (only

if KK <2.5 mEq/L)

Diagnosis

• investigate plasma aldosterone:renin ratio in patients with HTN and hypokalemia,drug resistant

HT N, HTN and a first degree relative with PA, HT N and a family history of stoke in a first degree

relative 240 yr, HT N and adrenal incidentaloma

• confirmatory testing for PA: aldosterone suppression test (demonstrate inappropriate aldosterone

secretion with ECF volume expansion), adrenal vein sampling maybe required to determine whether

there islateralization of aldosterone excess

• imaging: O'

adrenal glands

Table 22. Diagnostic Tests in Hyperaldosteronism

Test Primary Hyperaldosteronism Secondary Hyperaldosteronism

Plasma Aldosterone to Renin Ratio (PAC/PRA) Elevated |t aldosterone. » renin)

Salt Loading Test (confirmatory test)

A) Oral Salt Test

B) II/ Saline lest

Normal ( t aldosterone,

*

renin)

t 24 hour urine aldosterone

Plasma aldosterone concentration >111 pmol/L

(140-277 indeterminant range)

Not performed

Not performed

Treatment

• inhibit action of aldosterone:spironolactone, eplerenone,triamterene, amiloride (act on sodium

channels)

• surgical excision of adrenal adenoma

• secondary hyperaldosteronism: treat underlying cause

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Cushing’s Syndrome

Definition

• metabolic disorder caused by chronic glucocorticoid excess

Etiology

• ACTH-dependent (85%) - bilateral adrenal hyperplasia and cortisol hypersecretion due to:

• ACTH-secreting pituitary'adenoma (Cushing’

s disease;80% of ACTH-dependent)

• ectopic ACTH-secreting tumour (e.g.small cell lung carcinoma, bronchial, pancreatic islet cell,

pheochromocytoma, or medullary thyroid tumour)

• ACTH-independent (15%)

• primary adrenocortical tumours:adenoma and carcinoma (uncommon)

bilateral adrenal nodular hyperplasia

• iatrogenic Cushing’ssyndrome is likely more common than endogenous cortisol excess but is

infrequently reported; it is ACTH-independent

Clinical Features

• symptoms: weakness, insomnia, mood disorders, impaired cognition, easy bruising,oligo-/

amenorrhea, hirsutism, and acne (ACTH dependent)

• signs:central obesity,round face (“moon face”),supraclavicular and dorsal fat pads,facial plethora,

proximal muscle wasting, purple abdominalstriae,skin atrophy, acanthosis nigricans, HTN,

hyperglycemia, osteoporosis, pathologic fractures, hyperpigmentation, hyperandrogenism (if ACTH- Figure 18. Clinical featuresof

Cushing’s syndrome

Red cheeks,

acne,

moon face Dorsalfatpad

$

: \ I

Purple

striae

0

3

0 steoporosis

Thin arms

and legs *

r

Large 3

abdomen|

i

, „ /•/

(Si Poor wound * ? *

l

healing

L

dependent)

Diagnosis

• rule out excessive glucocorticoid exposure leading to iatrogenic Cushing'

s syndrome by conducting a

thorough drug history before conducting biochemical testing

• perform one of:1) 24 h urine free cortisol (>2 tests),2) low dose DXM suppression test, or 3) late night

salivary cortisol (S2 tests)

• consider reasons for a false positive (e.g. pregnancy, depression, alcoholism, morbid obesity, poorly

controlled DM,glucocorticoid resistance,physical stress, malnutrition, anorexia nervosa, intense

chronic exercise, hy'pothalamic amenorrhea)

• confirm with one of the remaining tests

Treatment

• adrenal

• adenoma: unilateral adrenalectomy (curative) with glucocorticoid supplementation

postoperatively, tapering slowly until HPA axis has recovered

carcinoma:adrenalectomy in patients with disease localized to the adrenal, adjunctive mitotane

for individuals with high-risk for current disease Mitotane ± chemotherapy for patients with

metastatic disease

medical treatment: ketoconazole to reduce cortisol, mitotane can be used -typically reserved for

patients with malignant disease

• pituitary'

• transsphenoidal resection, with glucocorticoid supplementation postoperatively

• if surgery delayed, contraindicated, or unsuccessful, consider medical management e.g.

ketoconazole, mitotane, pasireotide,or cabergoline

• ectopic ACTH tumour (paraneoplastic syndrome): usually bronchogenic cancer (poor prognosis) -

surgical resection, if possible; chemotherapy/radiation for primary tumour

• medical treatment with mitotane or ketoconazole to reduce cortisolsynthesis. Often required

when surgery is delayed, contraindicated, or unsuccessful

• treat comorbidities associated with hypercortisolism

Congenital Adrenal Hyperplasia

• see Paediatrics. P35

r “i

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Hyperandrogenism

Definition

• state of having excessive secretion of androgens (DHEA, DHEA-sulfate, testosterone)

Etiology and Pathophysiology

Table 23. Etiology of Hyperandrogenism

Medications Androgen-Mediated

Ovarian

Anabolic steroids.ACIH. androgens, progestational agents

PCOS

Ovarian hyperthecosis

theca cell tumours

Pregnancy:placentalsullatase/aromalase deficiency

Congenital adrenal hyperplasia (CAH, late-onsel CAN)

tumoursladenoma.carcinoma)

Cushing'

s disease - high AC1H

Hyperprolactinemia

Adrenal

Pituitary

Clinical Features

Females

• hirsutism

male pattern growth of androgen-dependent terminal body hair in women:back, chest, upper

abdomen, face, linea alba

Eerriman-Gallwey scoring system is used to quantify severity of hirsutism (score of >8 is

abnormal for white/black women, >9 abnormal for Mediterranean/Hispanic/Middle-Eastern

women,i2 for Asian women)

scores should be interpreted in the context of the specific patient and acknowledge limitations

such asthe use of cosmetic hair removal

scores between 8-15 are mild, 16-25 moderate, and >25 severe hirsutism

• virilization

frontal balding, ditoromegaly, increased muscle mass,deepening of the voice

• amenorrhea, breast size, infertility, anabolic appearance, acne

Conditions that do Not Represent True

Hirsutism

• Androgen-independent hair (e.g.

lanugo hair)

• Drug-induced hypertrichosis (e.g.

phenytoin, diazoxide,cyclosporine,

minoxidil)

• Topical steroid use

Males

• minimal effects on hair, muscle mass, etc.

• inhibition of gonadotropin secretion may cause reduction in testicular size, testicular testosterone

production, and spermatogenesis

Investigations

• testosterone, DHEA-S as a measure of adrenal androgen production

• LH/I

'

SH (commonly in PCOS >2.5)

• 17-OH progesterone, elevated in CAH due to 21-OH deficiency; check on day 3 of menstrual cycle with

a progesterone level

• for virilization:CT/MRI of adrenals and ovaries (identify tumours)

• if PCOS, check blood glucose and lipids

Treatment

• discontinue causative medications (e.g.oral DHEA, valproate, danazol)

• antiandrogens,e.g.spironolactone

• oral contraceptives (increase sex hormone binding globulin, which binds androgens>estrogens;

reduces ovarian production of androgens)

• surgical resection of tumour

• glucocorticoid ± mineralocorticoid ifCAH confirmed

• treatspecific causative disorders, e.g. tumours, Cushing'

s, etc.

• cosmetic therapy (laser, electrolysis)

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Adrenocortical Insufficiency

Definition

• state of inadequate cortisol and/or aldosterone production by the adrenal glands

Etiology

PRIMARY ADRENOCORTICAL INSUFFICIENCY

Table 24.Etiology of Primary Adrenocortical Insufficiency

Autoimmune (70-90%) Isolated adrenal insulliciency (Addison's Disease)

Polyqlandular autoimmune syndromes types I and II

Antibodies often directed against adienal cniymcs and 3 cortical cones

tuberculosis (7 20% ) (most common in developing world)

fungal: histoplasmosis, paracoccidioidomycosis

HIV. CMV

Syphilis

Alncan trypanosomiasis

Metastatic cancer|lung>slomach >csophagus>coion >brcast):lymphoma

Sarcoidosis, amyloidosis,hemochromatosis

Dilateral adienal hemorrhage (risk increased by heparin and warfarin)

Sepsis (meningococcal.Pseudomonas)

Coagulopathy in adults or Walethouse f riderichsen syndrome in children

Ihiombosis.embolism, adrenal infarction

Inhibit cortisol:kcloconarole. etomidatc. megestrol acetate

Increase cortisol metabolism: rifampin, phenylpin. barbiturates

Adrenoteukodystrophy and adrenomyeloneuiopathy

Congenital adrenal hypoplasia (impaired steroidogenesis)

familial glucocorticoid deficiency oi resistance

Defective cholesterol metabolism

Inlections

Infiltrative

Vascular

Drugs

Others

SECONDARY ADRENOCORTICAL INSUFFICIENCY

• inadequate pituitary ACTH secretion

• multiple etiologies (see Hypopituitarism,t23),including withdrawal of exogenous steroids

Clinical Features

Table 25. Clinical Features of Primary and Secondary Adrenal Insufficiency (Al)

Primary Al (Addison's or Acute Al) Secondary Al

Skin and Mucosa

Potassium

Dark ( palmar crease,extensor surface) Pale

High Normal

Normal or Low

Absent

Central hypogonadism or hypothyroidism, growth

hormone deficiency, Dl

Weakness, fatigue, weight loss, hypotension, postural

dizziness, myalgia, arthralgia, headaches, visual

abnormalities

Insulin tolerance test

Cosyntropin Stimulation Test

low or inappropriately normal morning plasma ACTH

Sodium

Metabolic Acidosis

Normal or low

Present

Associated Diseases Primary hypothyroidism.T1DM.vitiligo

Associated Symptoms Weakness,fatigue, weight loss, hypotension,salt

craving, postural dizziness, myalgia,arthralgia

Gl:N/V.abdominal pain,diarrhea

Cosyntropin Stimulation Test

Nigh morning plasma ACTH

High renin

Diagnostic Test

Adapted from:Salvatori R. JAMA 2005494:2481-2488

Treatment

• acute adrenal crisis- can be life-threatening

IV NS 1 L within the first hour followed by continuous IV NS guided by patient requirements; add

D5W if hypoglycemic

• hydrocortisone 100 mg IV stat followed by 50 mg IV q6 h

• identify and correct precipitating factors

• maintenance

• hydrocortisone 15-25 mg PO or cortisone acetate 20-35 mg PI) total daily dose in 2-3 divided

doses, highest dose in the morning

• prednisolone 3-5 mg once daily or 3-5 mg BID can be used as an alternative to hydrocortisone,

especially in patients with reduced compliance

• Plorinef *

(fludrocortisone,synthetic mineralocorticoid) 0.05-0.2 mg PO once daily if

mincralocorticoid deficient

• stress dosing

increase dose of steroids 2-3 fold for a few days during moderate-severe illness (e.g. with

vomiting, fever)

• majorstress(e.g. surgery, trauma ) requires 150-300 mg hydrocortisone IV daily divided into

3 doses

• medical alert bracelet and instructionsfor emergency hydrocortisone/dexamethasone IM/SC

injection

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Adrenal Medulla

Catecholamine Metabolism

ABC of Adrenaline

• catecholamines are synthesized from tyrosine in postganglionic sympathetic nerves (norepinephrine)

and chromaffin cells of adrenal medulla (epinephrine)

• broken down into metanephrines and other metabolites(VMA, HVA) and excreted in urine

Adrenaline activates

g-receptors. increasing

Cyclic AMP

Pheochromocytoma/Paraganglioma

Definition

• paragangliomas are rare neuroendocrine tumoursthat arise from the extra-adrenal autonomic

paraganglia (small organs comprised of neuroendocrine cells that secrete catecholamines)

• pheochromocytomas are catecholamine-secreting tumours derived from chromaffin cells of the

adrenal gland

Epidemiology

. most commonly a single tumour of adrenal medulla

• rare cause of HTN (<0.2% of all hypertensives)

Etiology and Pathophysiology

• pheochromocytomas and paragangliomas have the greatest genetic inheritance among

neuroendocrine tumours

• 30-40% cases are linked to germline mutations, including mutationsin the RET, YHL,SDHx, NET,

and SDHAF2 genes

• pheochromocytomas and paragangliomas are divided into clusters:cluster 1 - Pseudohypoxia subtype

(FH, VHL/EPASl-related), cluster 2 - Kinase signaling group (HRAS), cluster 3- WNT signaling group

(CSDE1, UBTF-MAML3fusion)

• most cases are sporadic;40% of affected patients have an associated familial disorder.In these

patients,the tumours are more likely bilateral adrenal pheochromocytomas/paraganglioma

• hereditary forms present earlier than sporadic cases

• several familial disorders are associated with adrenal pheochromocytoma,all have autosomal

dominant inheritance,e.g.multiple endocrine neoplasia type 2 (MEN2)- 50% frequency,von HippelLindau (VHL)syndrome - 10-20% frequency, and less commonly, neurofibromatosis type 1 (NF1)

- 0.1-5.7% frequency

• some tumours, via an unknown mechanism, are able to synthesize and release excessive

catecholamines

Clinical Features

• 50% suffer from paroxysmal HTN; others have sustained HTN

• classic triad ( not found in most patients):episodic “pounding"

headache, palpitations/tachycardia,

diaphoresis

• other symptoms:tremor, anxiety, chest or abdominal pain, N/V, visual blurring,weight loss, polyuria,

polydipsia

• other signs:orthostatic hypotension, papilledema, hyperglycemia,dilated cardiomyopathy

• symptoms may be triggered by stress, exertion, anesthesia, abdominal pressure,certain foods

(especially tyramine containing foods-such as aged/strong cheese and cured meats)

Investigations

• urine metanephrines

increased catecholamine metabolites (metanephrines) and catecholamines

plasma metanephrines, if available (most sensitive)

• cut-off values will depend on assay used

• CT abdomen

if negative,whole body CT and meta-iodo-benzoguanidine (M1BG) scintigraphy,Octreoscan, or

MRI

Treatment

• surgical excision of tumour (curative) with careful pre- and postoperative ICC monitoring

• adequate preoperative preparation

a-blockade for BP control:doxazosin or phenoxybenzamine (these are the most frequently used

cJ

alpha blockers) (10-21 d preoperative), IV phentolamine (perioperative if required)

• (5-blockade if needed for H R control once a blocked for a few days

• metyrosine (catecholamine synthesis inhibitor) + alpha blocker

volume restoration with vigorous salt-loading and fluids

• rescreen urine 1-3 mo postoperatively

• all patients are currently offered genetic testing - probability of germline disease increases with young

age, multifocal disease,in the setting of paraganglioma

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Disorders of Multiple Endocrine Glands

Multiple Endocrine Neoplasia

• neoplastic syndromes involving multiple endocrine glands

• tumours of neuroectodermal origin

• autosomal dominant inheritance with variable penetrance

MEN1Affects the 3Ps

Pituitary

Parathyroid

Pancreas

Table 26. MEN Classification

Type Tissues Involved Clinical Manifestations

MEN1(chromosome11)

Pituitary (30-40%)

Anterior pituitary adenoma

Headache,visualfield defects,most

commonly secrete PRL(prolactinomas are

the most common pituitary functional tumour

in MEN 1leading to galactorrhea,erectile

dysfunction, decreased libido.amenorrhea).

GH (acromegaly).GH-PRL.ACIH (Cushing's),

non functional less common

3 Ps (Pituitary,parathyroid and pancreas)

Parathyroid (>95%)

Primary hyperparathyroidism from hyperplasia

or adenomas Nephrolithiasis, bone abnormal t es.MSK

complaints, symptoms of hypercalcemia

Entero-pancrealic endocrine (30-80%)

Pancreatic islet cell tumours

Gastrinoma

Insulinomas

Vasoactive intestinalpeptide

(VlP)-omas

Glucagonoma

Carcinoid syndrome

Non-functional pancreatic neuroendocrine

tumours

Epigastric pain (peptic ulcers andesophagitis)

Hypoglycemia

Secretory diarrhea

Rash (necrotytic migratory erythema),

anorexia,anemia,diarrhea,glossitis

Flushing,diarrhea,bronchospasm

Adrenal tumours (~40%)

MEN 2 (chromosome10)

1.MEN 2A (Sipple's Syndrome) Thyroid (>90%)

Medullary thyroid cancer (MIC)

Physical signs arevariable and often subtle

Adrenal medulla (40-50%)

Pheochromocytoma (40-50%)

Neck mass or thyroid nodule:non-tender.

anterior lymphnodes

HIN,palpitations,headache,sweating

Parathyroid (20-30%)

1‘parathyroid hyperplasia Symptomsof hypercalcemia

Skin

Cutaneous lichen amyloidosis

Thyroid

MIC (100%)

Thyroid

MIC (»90%)

Scaly skin rash

MIC without other clinical manifestations of

MEN 2Aor MEN 2B

MfC:most common component,more

aggressive and earlier onset than MEN 2A

2.Familial MIC

(a variant of MEN 2A)

3.MEN 2B (also known as MEN3)

Adrenal medulla HTN. palpitations,headache,sweating

Pheochromocytoma (»50%)

Neurons

Mucosal neuroma,intestinal

ganglioneuromas (100%)

Chronic constipation:megacolon

MSK Marfanoid habitus (no aortic abnormalities)

Marfanoid

Investigations

. MEN 1

laboratory

offer genetic testing to all patients with a clinical diagnosis of MEN 1 and their first-degree

relatives

gastrinoma:significantly elevated serum gastrin level with a low gastric pH:when gastrin is

<10.x ULN a secretin stimulation test may be required

insulinoma:hypoglycemia with insulin and C-peptide levels that are inappropriately high for

the level of glucose

glucagonoma:elevated glucagon levels

pituitary tumours:assess GH, IGF-1, 24 h urine cortisol, and PRL levels (for overproduction), TSH,free T4,8am cortisol, LH, ESH, bioavailable testosterone or estradiol (for

underproduction due to mass effect of tumour)

hyperparathyroidism:serum Ca -'

and albumin, PTH levels; bone density scan (DEXA)

• imaging

MR1 for pituitary tumours,CT or MR1 for gastrinoma,CT, MRi, or endoscopic ultrasound for

insulinoma, parathyroid scan for parathyroid adenomas

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E42 Endocrinology Toronto Notes 2023

•MEN 2

laboratory

genetic screening for RET mutations on chromosome 10 is the clinical standard of care in

all individuals with a family history of MEN2 and haslong-term benefits(early cure and

prevention of MTC)

calcitonin levels (MIC);24 h urine and serum metanephrines (pheochromocytoma);serum

Ca-'

and PTH levels (hyperparathyroidism)

pentagastrin ± calcium stimulation test if calcitonin level is within reference range

FNA for thyroid nodules cytology

• imaging

neck U/S or CT to identify thyroid nodules and lymphadenopathy

CT or MRI of adrenal glandsto localize pheochromocytoma

metastatic disease generally picked up with cross-sectional imaging

Primary Hyperparathyroidism

Increased PIH secretion commonly due

to parathyroid adenoma, lithium therapy;

less often due to parathyroid carcinoma

or parathyroid hyperplasia

Secondary Hyperparathyroidism

Partial resistance to PTH action leads

to parathyroid gland hyperplasia

and increased PTH secretion, often

in patients with renal failure and

osteomalacia (due to low or low-normal

serum calcium levels)

Treatment

•MEN 1

• medical

proton pump inhibitor (PP1) for acid hypersecretion in gastrinoma

cabergoline or other dopamine agonists to suppress PRL secretion and shrink prolactinomas

somatostatin analogue for control of symptoms ofsome of the G1 neuroendocrine tumours

such as glucagonoma

• surgery for hyperparathyroidism when surgical indications met,functional pancreatic tumours

(e.g. insulinoma, glucagonoma, gastrinoma),functioning pituitary tumours (except for

prolactinomas where dopamine agonists are used), and nonfunctioning pituitary tumours if

associated with mass effect

trans-sphenoidal approach is generally preferred for pituitary tumours, pituitary irradiation

ifsurgery is not possible or has failed

Tertiary Hyperparathyroidism

Irreversible monoclonal outgrowth of

parathyroid glands, usually in longstanding inadequately treated chronic

renal failure on dialysis

•MEN 2

prophylactic thyroidectomy recommended in individuals with documented pathogenic RET

mutation and an increased risk of aggressive MTC;if incident case, thyroidectomy after diagnosis

of MTC

rule out presence of pheochromocytoma and hyperparathyroidism prior to thyroidectomy

thyroid hormone supplementation following total thyroidectomy

prostaglandin inhibitorsto alleviate diarrhea associated with thyroid cancer

pheochromocytoma managed with resection

a-blocker for at least 10-21 d for pheochromocytoma preoperatively

• hyperparathyroidism managed with resection of parathyroid adenoma

hydration, IV bisphosphonates, or denosumab for severe hypercalcemia

PH is the most common cause of

hypercalcemia In healthy outpatients.

PH is most commonly related to a

solitary adenoma or. less commonly,

multiple gland hyperplasia.Surgical

eidsion is the definitive treatment and

is recommended for patients who have

symptomatic hypercalcemia,loss in bone

density,kidney stones, or renal failure.

For asymptomatic disease, medical

surveillance may be appropriate with

annual serum calcium, creatinine, and

bone mineral density (8MD)

For asymptomatic patients,surgery is

recommended for those who meet >1of

the following criteria:

• Serum [Ca 2-j >0.25 mmolf L (1.0 mg'dl)

above the upper limit of normal

• Creatinine clearance <60 mL/min

• BMD T-scote<-2.5 at hip.spine, or

distal radius,and’or previousfragility

frachre

• Clinical development of a kidney stone

or by imaging (x-ray, ultrasound, or CT)

• Age <S0yr

Calcium Homeostasis

• normal total serum C a 2 . 2-2 . 6 mmol/L

• ionic/free Ca -+levels:1.15-1.31 mmol/L

• serum Ca 2+is 40% protein bound (mostly albumin), 45% ionized, and 15% complexed with PO-t 3-and

citrate

• regulated mainly by: PTH and vitamin D, whose actions are on three main organs:GI tract, bone, and

kidney

Table 27. Major Regulators in Calcium Homeostasis

Major Regulators Source Regulation Net Effect

Parathyroid glands Stimulated by low serum Ca 2-and high serum POi 3-

Inhibited byhigh serum Cat-,highcalcitriol,FGF23,and

chronic low serum Mg2-

Oietary mtakeof cholecalciferol (03) orergocalciferol Stimulated by:

low serum POi3'

High PTH

t Catt C ::: :

* - -