Review in Internal Medicine 2021

Pituitary

Hypothalamus

TSH

TRH

_

_

Thyroid

T4

T3

1o hyperthyroidism 1o hypothyroidism

TSH Low High

T4 High Low

TSH is the most efficient test for 1o thyroid disease.

Clinical Endocrinology 2011;74, 673-678.

A 2-fold change in FT4 will produce a 100-fold change in TSH.

Usual TFT Interpretation

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! ⬆ $5678&)&7'8#-./*2-.1*&3&+4⬆ ⬆9: ;)'//1*/1&'20#!$"#+07102&*)⬇ ⬇9: <0)21'8#-./*2-.1*&3&+4 *1

:*)#2-.1*&3'8#&88)0++

Pituitary

Hypothalamus

TSH

TRH

_

_

Thyroxine binding globulin (TBG)

Receptor

Thyroid

T4

T3 Screening thyroid disorder: TSHSuspected thyrotoxicosis: TSH, FT4, TT3 (or FT3)Suspected hypothyroidism: TSH, FT4

DDx “Inappropriate TSH secretion”

1. TSHoma

2. Resistance to thyroid hormone

3. Euthyroid hyperthyroxinemia

• Excess/abnormal binding protein

• Antibody to thyroid hormone

!"# !$" %&'()*+&+⬆ ⬆9: ;)'//1*/1&'20#!$"#+07102&*)

Free T4

Total T4

Apdapted from DeGroot LJ, Stanbury JB: The Thyroid and its diseases 4th ed, Wiley, 1975

T4 T3Serum concentration of total hormoneFraction of the free : total formFree (unbound) hormone

8 ug/dl0.02%

21x10-12 M

0.14 ug/dl0.3%

6x10-12 M

1. Thyroxine-binding globulin (TBG)

2. Transthyretin or prealbumin

3. Albumin

Free T4

ProteinBound ThyroidHormone

InitialSteadyState

Increased Binding Protein

New Steady State

Total Thyroid Hormone

DeGroot LJ, Stanbury JB: The Thyroid and its diseases 4th ed, Wiley, 1975

Factors effect Thyroxine-binding globulin

é• "#$%&'()*+,-.(%(#$%&'()/0 #$1$(+(2'2+&%13+0&)$%10(.$/4(*+$15&6/7()*+.%(')1)0-

• 8%9'#:+;./1$(*+<=>*+03&7/?%1$(*+.(%.,()1@/)(

• A()($/0+B/#&%B(%#

ê• C)B%&'()• D$(%&/B+,/',+B&#(• EF1#.1%1'/)1#(*+#3&GF%(3(1#(+)/0&$/)/0+10/B• H13)9$%/$/&)• !(.,%&$/0 #-)B%&5(• A()($/0+B/#&%B(%#

T3/T4 ratio

Graves’ disease

Thyroiditis/Normal

>20 Graves’ diseaseToxic nodular goiter

<15 ThyroiditisIodine induced thyrotoxicosisExogenous T4 ingestion

Seru

m T

3/T4

Rat

io

Normal GravesDisease

Subacutethyroiditis

Quiz #135-yr-old femalePalpitation, tremor, heat intolerance for 6 months, wt loss 10 kg

HR 120/min, thyroid: diffuse goiter 20 g with bruitNo ophthalmopathyTFT: FT4 = 1.3 (0.7-1.48); TSH < 0.0038 (0.35-4.94)Which of the following is the appropriate management?A. ObserveB. NSAIDsC. Free T3 measurement

D. TSH receptor antibody measurementE. Thyroid scan and uptake

• TFT: FT4 1.3 (0.7-1.48)

FT3 5.3 (1.71-3.71)

TSH < 0.0038 (0.35-4.94)

• Diagnosis: 1o hyperthyroidism, T3-toxicosis

• Prevalence: 5.6% (general clinic1) – 16% (thyroid clinic2)

• Cause of T3-toxicosis: early Graves’ disease,

autonomous nodule, high risk of relapsed Graves’ disease

1. Sriphrapradang C, Bhasipol A. Ann Med Surg2016. 2. Snabbon T et al. J Med Assoc Thai 2004;87 Suppl2:S19-21

Answer #1: free T3

32-year-old-female without any symptomsHashimoto’s thyroiditisOn LT4 replacement (LT4 100 ug/day)TFT: FT4 = 1.6 (0.7-1.48); TSH 6 (0.35-4.94)Which of the following is the appropriate management?A. Beta-blockerB. Check lab interferenceC. Anterior pituitary hormones measurementD. Genetic test for thyroid hormone receptor betaE. None

Quiz #2

• FT4 = 1.6 (0.7-1.48); TSH 6 (0.35-4.94)

• Poor compliance

• Owing to their differing half-lives,

intermittent hormone ingestion can result in

normal or even elevated FT4 levels,

but fails to normalize TSH

Answer #2: none

Thyroid Scan (Scintigraphy)Normal

Toxic MNG

Graves’disease

Toxic adenomaThyroiditis

Factitious abuse

Uptake measures function “%”

Scan assess anatomy “picture”

Quiz RAIU (radioactive iodine uptake) Graves’ disease IncreasedToxic MNG IncreasedSolitary functioning nodule IncreasedHydatidiform mole, trophoblastic tumors, choriocarcinoma

Increased

Subacute thyroiditis DecreasedIodine-induced thyrotoxicosis DecreasedFactitious thyrotoxicosis DecreasedStruma ovarii Decreased over the

thyroid, increased in ovarian tumor

TSH receptor Ab• DDx of etiology of thyrotoxicosis in patients with

ambiguous clinical findings

• Diagnosis of euthyroid Graves’

e.g., Exophthalmos in euthyroid pts

• Determining the risk of fetal and neonatal Graves’

• Assessing the risk of Graves’ disease relapse after ATD Rx

TPO Ab & Tg Ab• Diagnosis of autoimmune thyroid diseases• Diagnosis of postpartum thyroiditis• As a risk factor for

– AITD in pts with autoimmune disease e.g., T1DM– Thyroid dysfunction or hypothyroidism before and during

amiodarone, lithium, IFN-alpha– Hypothyroidism in Down syndrome– Thyroid dysfunction during pregnancy – Spontaneous miscarriage

• TgAb: follow-up to assess disease recurrence in thyroid cancer (combination with thyroglobulin level)

Adapted from Autoantibodies Textbook 2013

Sriphrapradang C et al. Poster Presentation in Endocrine Society Meeting 2010 San Diego, CA

TRAb

TPO AbTg Ab

Quiz #339-yr-old prisoner malePalpitation, tremor, heat intolerance for 6 months, wt loss 10 kg

HR 120/min, thyroid: no goiter, no ophthalmopathyFT3 > 7 (1.71-3.71); FT4 = 3 (0.7-1.48), TSH < 0.0038 Thyroglobulin (Tg) < 0.1 ng/mL (3.5-77), TPO Ab & Tg Ab negWhat is the most likely cause of thyrotoxicosis?A. Graves’ diseaseB. Subacute thyroiditis

C. Functioning thyroid metastasisD. TSHomaE. Thyrotoxicosis factitia

• Suppressed thyroglobulin (TgAb neg)

= No thyroid tissue

(history of total thyroidectomy + radioactive iodine)

= Exogenous thyroid hormone ingestion

• “Hamburger thyrotoxicosis”

– Meat in the neck region of slaughtered animals is ground into hamburger

– Outbreak of thyrotoxicosis

Answer #3: factitious thyrotoxicosis

Assess risk of malignancyUltrasound thyroid

Serum TSH

LowNormal or

High

Hot nodule Cold nodule

FNA FNARx toxic adenoma

ThyroidScan

Quiz #460-yr-old female, no underlying diseaseSlow-growing right thyroid nodule for 2 yrs

Exam: BP 130/80, HR 72/min regular rhythm4-cm rubbery and movable thyroid nodule @ Rt lobeFT3 = 2 (1.71-3.71); FT4 = 1.1 (0.7-1.48), TSH < 0.0038 What is the most appropriate next step?A. Thyroid scanB. TSH receptor antibodyC. Doppler USG thyroid

D. Whole body scanE. ESR

Answer #4: thyroid scan but B and C can be helpful too

ATA Guideline ThyrotoxicosisDetermination of etiology • TRAb (help in case of Graves’ disease)• Thyroid uptake(need thyroid scan in case of thyroid nodule)• Thyroidal blood flow on USG (need expertise !)

Toxic adenoma

> 3 cm

Thyroid scan

What is the most appropriate management?A. Percutaneous ethanol injectionB. Radioactive iodineC. LT4 suppression therapyD. Thyroid lobectomy

60-yr-old female, no underlying diseaseSlow-growing right thyroid nodule for 2 yrsExam: BP 130/80, HR 72/min regular rhythm4-cm rubbery and movable thyroid nodule @ Rt lobeFT3 = 2 (1.71-3.71); FT4 = 1.1 (0.7-1.48),TSH < 0.0038

Quiz #4 (continued)

Answer: B

Sensitivity SpecificityMicrocalcification 44% 89%

Tall > wide shape 48% 92%

Irregular margins 55% 79%

Nodular vascularity 62% 77%

Absence of halo 66% 54%

Hypoechoic 81% 53%

Solid 86% 18%

Etiology of Thyroid Nodule• Benign 95%

– Observe, cyst aspiration, surgery,

or LT4 suppressive Tx (selected case)

• Malignancy 5%

– Papillary CA: most common, spreads via lymphatics

– Follicular CA: hematogenous spread (bone, lung, CNS)

– Anaplastic CA: poor prognosis, upper airway obs

– Medullary CA: MEN2

– Rare: lymphoma, metastasis

Quiz #525-yr-old maleRight thyroid nodule ~ 2 cm

Normal TSHFNA: medullary thyroid carcinomaWhich of the following is the most appropriate next step?A. MIBG scanB. Whole body scan

C. Hemoglobin A1cD. Prolactin levelE. 24-hr urine fractionated metanephrine

Medullary thyroid carcinoma (MTC)• Tumor marker: calcitonin, CEA (cheaper)• Genetic screening for RET gene: MEN2A,

MEN2B, familial MTC• Testing for coexisting tumor

– Pheochromocytoma

– Primary hyperparathyroidism

• Rx: surgery• No role of radioactive iodine

Answer #5: 24-hr urine fractionated metanephrine

Mucosal neuromasin MEN2B

Thyrotoxicosis vs Hyperthyroidism

Non-hyper-

thyroidism

Some Clues of Specific Causes of Thyrotoxicosis

Graves’ disease

Toxic adenoma

Toxic MNG

Subacutethyroiditis

Thyroid bruit

> 3 cm

PAINTENDERNESS

Short Duration

Family history, other autoimmune disorders

T3/T4 ratio <20

Slowly progression

S HyperàOvert Hyper

Treatment Advantages Disadvantages

Antithyroiddrugs

• Conservative Rx• Hospitalization • Low risk of subsequent

hypothyroidism• Radiation exposure• No effect on GO• Safe to use during pregnancy

and breastfeeding

• High relapse rate• Frequent clinic visits • Poor adherence• Adverse events (rarely major)

131I • Definitive Rx• Low cost• Hospitalization• No need for surgery or

anaesthetic

• Lifelong hypothyroidism• Radiation exposure• Slow control of hyperthyroidism• Possible progression or de novo

occurrence of GO

Thyroidec-tomy

• Definitive Rx• Radiation exposure• Prompt control of

hyperthyroidism

• Lifelong hypothyroidism• Adverse events related to

surgical procedure and anaesthetic

• Hospitalization• High cost• Permanent scar

Antithyroid Drugs• Methimazole should be used in EVERY

patient who chooses antithyroid drug therapy, EXCEPT

1. 1st trimester of pregnancy2. Treatment of thyroid storm3. Minor reactions to methimazole

Propylthiouracil can cause severe hepatotoxic effects, which might be lethal or require liver transplantation.

PTU vs MMICharacteristics PTU MMIHalf-life Shorter

(bid or tid)Longer(OD)

Inhibit peripheral conversion of T4 to T3

+(at dose

> 600 mg/day)

No

Effectiveness (at dose equivalent)

++ +++(PTU:MMI ~30:1)

Placental and lactation passage

Lower Higher(However, guidelines

recommend MMI during lactation)

Side Effects of Antithyroid Drugs• Minor

– Common (1-5%): urticaria, arthralgia, fever, transient granulocytopenia

– Uncommon (<1%): GI upset, abnormal sense of taste and smell, arthritis

• Major– Rare (0.2-0.5%): agranulocytosis

(PTU, idiosyncracy; MMI, dose-related)– Very rare (<0.1%): aplastic anemia, thrombocytopenia, toxic

hepatitis (PTU), cholestatic hepatitis (MMI), p-ANCA+ vasculitis, hypoglycemia due to anti-insulin antibodies (MMI), embryopathy (MMI), pancreatitis (MMI)

Prompt discontinuation of ATDATD is no longer an option

“DO NOT SWITCH”

Quiz #630-yr-old female

Thyrotoxic state, BP 128/70, HR 120/min regular rhythm

diffuse goiter, mild exophthalmos; TFT: FT4é, TSHê

Rx with MMI 3x1, beta-blocker

F/U 3 months: no thyrotoxic symptom, HR 80/min

FT4 = 1.2 (0.7-1.48), FT3 = 2.8 (1.17-3.71), TSH < 0.0038

What is the most appropriate next step?

A. Increase MMI to 4x1

B. Decrease MMI to 1x1

C. Continue same dose of MMI

Thyroid 2003; 13:1-126.

Quiz #6 Answer: B decrease MMI

• Starting dose depends on initial TFT• Always give beta-blocker (propranolol, atenolol, metoprolol)

F/U T3, T4 not TSH at 4-6 weeks• After 1-3 months, most patients have achieved

normal thyroid hormone levels

Decrease dose when normalized thyroid hormonesMaintain methimazole 1-2 tab/day

• Iatrogenic hypothyroidism or goiter can develop if the dose is not decreased appropriately.

F/U q 2-3 months and then q 4-6 months

• TSH remain suppressed for weeks or even months

• T3 toxicosis indicating the need to increase ATD dose

Duration of treatment: 12-18 (24) monthsin the usual practice

Methimazole (5) 3 tab OD

✗ PTU is used for 1o treatment

✓ PTU is indicated for patients who are intolerant of MMI, pregnant women

1st trimester and patients in thyroid storm

✗ Administered only ATD

✓ β-blocker is important to alleviate thyrotoxic symptoms

[cautions: asthma, CHF, bradyarrhythmia, Raynaud phenomenon)

✗ During 1-2 Mo, adjustment of ATD depends on serum TSH levels

✓Monitoring of FT3 and FT4 because of serum TSH can remain suppressed

ATD = antithyroid drug

Factors associated with a high rate of relapse after antithyroid drug treatment

• Severe hyperthyroidism• Large goiter• T3 predominance• Prior relapse• High levels of TSH receptor antibody • Young age• Male sex• Cigarette smoking• Postpartum period

Adapted from Nat Rev Endocrinol. 2013 Dec;9(12):724-34.

1. Iodine-induced effects– Jöd-Basedow effect

– Wolff-Chaikoff effect

2. Intrinsic drug effects– Blockade of TH entry into cells*

– Inhibition of type 1 and 2 5’deiodinase

– Decreased T3 binding to its receptor*

– Thyroid cytotoxicity

TH = thyroid hormone *Transient effects (< 3 months)

D1 D3D2

D3 D1D2

T4

rT3T3

T2

• 1 tab (200 mg)

= Iodine 75 mg à free iodine 6 mg

(RDA 150-200 ug/d)

• Highly lipophilic

Long T1/2 100 days

• Amiodarone-induced thyrotoxicosis (AIT)

• Type 1: iodine-induced hyperthyroidism

• Type 2: drug-induced destructive thyroiditis

• Amiodarone-induced hypothyroidism (AIH)

AIT type 1 AIT type 2

Pathogenesis Iodine-induced thyrotoxicosis

Destructive thyroiditis

Underlying fn autonomy Present Absent

Physical exam Nodular or diffuse goiter No goiter

T4/T3 ratio < 4 > 4

Thyroid Ab Present Mostly absent

Color flow Doppler US Increased or normal Decreased

RAIU Low or normal Low to absent

Spontaneous remission No Possible

Preferred treatment Thionamide and perchlorate

Glucocorticoids

Subsequent hypothyroidism No Possible

Subclinical Hyperthyroidism Always repeat testsDetermine the cause

SHyperà progression to overt hyper, cv effects/AF/ mortality, osteoporosis, thyrotoxic symptoms/ cognitive function

Hypothyroidism• Etiology: Hashimoto’s thyroiditis, Post Sx/I-131

Graves’ disease, drug (amiodarone, lithium)

• Always evaluate Hypo in bilat CTS, dementia

• éLDL, anemia, hypoNa, éPRL

• Suspected central hypothyroidism à check

cortisol before initiate LT4

Treatment of Hypothyroidism• L-thyroxine (LT4) replacement

– Dose 1.6 ug/kg/day, once daily; before meal

– Absorption site: duodenum, jejunum

• Interference: calcium, iron, PPI, sucralfate, cholestyramine, soybean formula, IBD

– T1/2 7 days: F/U TSH at 4-6 weeks after start LT4

then q 3-6 months

– Old age, CAD risk: start low and slowly titrate up

– Pregnancy: 25-30% édose prepregnancy doseIBD = inflammatory bowel disease

Quiz #760-yr-old maleFatigue, constipation, cold intoleranceSquamous cell CA of tonsil Rx with radiation 3 yrs agoExam: dry skin, mild periorbital edema, no goiter, hyporeflexiaLab: Hb 11 g/dL, Na 129, TSH 1.4 mU/L (0.3-4)

What is the most appropriate next step?A. FT4 measurementB. Repeat TSH measurement in 4 wksC. TPO Ab measurementD. Thyroid scintigraphyE. Thyroid ultrasound

Beck-Peccoz P, et al. Nat Rev Endocrinol. 2017;13(10):588-598.

Central hypothyroidism

FT4

TSH

Quiz #7 Answer: A. FT4 measurement

Quiz #890-yr-old maleModerate fatigue

No signs/symptoms of hyper- & hypothyroidismVital signs & other exams: all normalCBC, metabolic profile: normalTSH 6.4 mIU/L (0.4-4), FT4 = 1.3 (0.7-1.5)What is the most appropriate next step?A. LT4 therapyB. Measurement of total T3

C. Measurement of total T4D. Repeat TSH and free T4 in 6 to 12 weeks

Subclinical Hypothyroidism Always repeat testsAvoid overTx esp >70 yr

SHypoà progression to overt hypo, cv effects/ mortality, hypo symptoms/ cognitive function, infertility & concerns in pregnant women

Quiz #8 Answer: D. repeat

Changes in Thyroid Physiology in Gestation• Increased renal iodide clearance

– Effect on goiter (depending on dietary iodine)

• Binding protein changes (éTBG, êalbumin)– Increase total T4 and total T3

– FT4 assay issue

• First trimester increase in beta-hCG– Decrease in TSH concentration

• Increased degradation of T4 and T3 by placental type 3 deiodinase

TBG, thyroxine-binding globulin

Nat Clin Pract Endocrinol Metab. 2007 Jun;3(6):470-8.

Total T4: 1.5 x nonpregnant range

Free T4: Decreases through gestationAssays are variable

Total T4 FT4 (Elecsys) FT4 (Tosoh)

NP = nonpregnant

0-7 weeks 7-16 weeks 17 - 40 weeks

FT4 FT4TT4 (GA-specific range)

TT4 (GA-specific range)

TT4 pregnant range = 1.5 X nonpregnant rangeTT4 é

5 % per w

k

5%X10 weeks = 50 %

50%

J Clin Endocrinol Metab. 1990 Aug;71(2):276-87.; J Endocrinol Invest. 1993 Dec;16(11):881-8.

éBeta-hCG

êTSH

• Structural homology

of beta-hCG and TSH

• “Receptor spillover”

Peak level at 7-11 wks

FT4 α hCG

Nat Clin Pract Endocrinol Metab. 2007 Jun;3(6):470-8.

TSHTS

H (m

IU/L

)

Nonpregnant

1st 2nd 3rd trimester

Positive TPO antibody

TSH > reference range LT4 recommended

> 2.5 mIU/L but < reference range LT4 may be considered

< 2.5 mIU/L No

Negative TPO antibody

TSH > 10 mIU/L LT4 recommended

> reference range but < 10 mIU/L LT4 may be considered

within reference range No

2017 ATA Guidelines for the Diagnosis and Management of Thyroid Disease during Pregnancy and the Postpartum

CortexMedulla

Cortex

Medulla

Zona glomerulosa

Zona fasciculata

Zona reticularis

Adrenal gland

Mineralocorticoid

Glucocorticoid

Androgen

Catecholamine

Anatomy of normal adrenal gland

Right

Left

2-4 cm1 cm

0.5 cm

Adrenal gland disorders that internists should know

• Adrenal cortex– Cushing’s syndrome– Primary hyperaldosteronism– Adrenal incidentaloma– Adrenal insufficiency– Congenital adrenal hyperplasia (CAH)

• Adrenal Medulla– Pheochromocytoma

Ross EJ, Linch DC. Cushing's syndrome-killing disease: discriminatory value of signs and symptoms aiding early diagnosis. Lancet. 1982;2:646-649.

Symptoms % of patients Discriminant indexWeight gain 91Menstrual irregularity 84 1.6Hirsutism 81 2.8Muscle weakness 29 8.0Signs % of patients Discriminant indexObesity 97• Truncal 46 1.6• Generalized 55 0.8Plethora 94 3.0Moon facies 88Hypertension 74 4.4Bruising 62 10.3Red-purple striae 56 2.5

Compared With Prevalence of Features in Patients With Simple Obesity

Etiologies of Cushing’s Syndrome

ACTH-dependent• Pituitary CS

• Ectopic ACTH

• Ectopic CRH

• Exogenous ACTH

ACTH-independent• Adrenal adenoma• Adrenal CA

• Micronodular hyperplasia– PPNAD

• Macronodular hyperplasia– BMAH

Pituitary Cushing = Cushing’s disease

PPNAD Primary pigmented nodular adrenal disease

BMAH bilateral macronodular adrenal hyperplasia

Steps of work up CS• Recognize and

confirm Dx Cushing's syndrome• Identify the cause of CS

– ACTH-dependent or independent

ü Clinical suspicionü Laboratory confirmationü Localization

Diagnosis of Cushing’s syndrome

24 hr UFC (≥ 2 measurements)

or Late-night salivary cortisol (≥ 2 measurements)

or Overnight low dose DST (1 mg oral 11PM)

• 8AM cortisol > 1.8 ug/dL

or Standard low dose DST (0.5 mg oral q 6 hrs, 2 days)

• Measure serum cortisol > 1.8 ug/dl

UFC = urine free cortisolDST = dexamethasone suppression test

Morning cortisol for exclude exogenous Cushing

Special Populations/Considerations

• Pregnancy: UFC

• Epilepsy: late-night salivary cortisol

• Renal failure: 1-mg overnight DST

• Cyclic CS: UFC or late-night salivary cortisol

• Adrenal incidentaloma: 1-mg overnight DST

The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. 2008

ACTH dependent vs independent

ACTH

ACTH dependent

ACTH > 20 pg/ml

Pituitary adenoma

Ectopic ACTH or

CRH producing tumors

Adrenal adenoma

Adrenal carcinoma

ACTH independent

ACTH < 10 pg/ml

CT adrenal

Why we need to DDx cause of Endogenous Cushing

Pituitary Ectopic ACTH Adrenal

ACTH level Normal/high High Low

HDDST Suppression No suppression No suppression

Adrenal CT Normal/enlarged Normal/enlarged Tumor

Pituitary MRI Tumor Normal Normal

BIPSS Central gradient Peripheral gradient -

BIPSS = bilateral inferior petrosal sinus samplingHDDST = high-dose dexamethasone suppression test

Determining the source of the ACTH in ACTH-dependent CS

• Standard high dose DST– Suppress UFC > 90 %

• Overnight high dose DST– Suppression S.cortisol > 64 %

Inferior petrosal venous sinus sampling

Inconclusive

DefinitePituitary MRI

MRI6 mm

Clinical Discrimination Cushing’s disease and Ectopic CS

ACTH-Secreting Pituitary Tumor

Ectopic ACTH Secretion

Etiology Pituitary corticotrope adenoma

Bronchial, abdominal carcinoidSC lung cancer Thymoma

Gender F > M M > F

Clinical features Slow onset Rapid onsetHyperpigmentation Severe myopathy

Serum K < 3.3 mmol/L

<10% 75%

ACTH levels Inappropriately normal or high

Very high

รถ Pan คนัเลก็

หมอ med ให้ free

Treatment• Surgery• Pituitary irradiation• Medical therapy

– KetoconazoleSE: Elevated hepatic transaminases, gynecomastia, impotence, GI upset, edema

– Metyrapone

– Mitotane– Aminoglutethimide– Etomidate; IV form

Adrenal Carcinoma

• Rare• Poor prognosis• Rapid clinical

progression– Cushing’s syndrome

– Virilization

• Large irregular heterogenous mass

High concentration of DHEA-S is another clue suggesting

adrenal carcinoma.DHEA-S = dehydroepiandrosterone sulfate

Hirsutism

Virilization

J Clin Endocrinol Metab. 2012 Aug;97(8):2584-8

• Severe balding

• Deepening of voice

• Hirsutism

• Acne

• Musculinization

• Menstrual disturbance

• Clitoromegaly

Insights Imaging. 2013 Feb;4(1):119-33.

A 28-year-old woman presents with features of Cushing’s syndrome. Hormonal workup was compatible with ACTH-independent Cushing. CT adrenal showed bilateral adrenal hyperplasia.

What condition could be found in this patient ?

A. Atrial myxomaB. Periungual fibromaC. Calcinosis cutisD. Lisch noduleE. Polydactyly

Pigmented adrenal gland

Insights Imaging. 2013 Feb;4(1):119-33.

Answer: A. Atrial MyxomaSpotty skin pigmentation

Epithelioid blue-nevi

Atrial myxoma Primary pigmented nodular adrenocortical

disease (PPNAD)

Carney complex: a rare multiple familial neoplasia syndrome that is characterized by multiple types of skin tumors and pigmented lesions, endocrine neoplasms, myxomas and schwannomas

Acromegaly Mammary myxoma

Schwannoma Testicular tumor

Cutaneous myxoma

Complications of Cushing’s Syndrome

Lancet Diabetes Endocrinol. 2016 Jul;4(7):611-29.

Quiz #930-yr-old maleCushingoid appearance, new-onset DM

BP 160/90, BMI 30Overnight low dose DEX suppression: cortisol 9 ug/dL24-hr urine free cortisol > 5xULNUndetectable ACTH level Which of the following is the most appropriate next step?A. MRI pituitaryB. CT adrenal

C. Late-night salivary cortisolD. Inferior petrosal sinus sampling

Quiz #9 Answer: B. CT adrenal

Quiz #1020-yr-old male

fatigue, decreased appetite, wt loss, N/V

BP 100/68 mmHg, pulse 90/min, BMI 19

Hyperpigmentation @ knuckles of hands, elbows

Lab: 8AM cortisol 2 ug/dL, Na 133, K 5.8

Which of the following is the most appropriate next step?

A. MRI pituitary

B. ACTH stimulation test

C. ACTH measurement

D. Prednisolone + fludrocortisone

Quiz #10 Answer: D. Prednisolone + fludrocortisone

Addison’ Disease

www.merckmanuals.com

Clinical Clues of 2o HT• Younger patients (< 40 yrs) with gr. 2 HT or onset of any

grade of HT in childhood

• Acute worsening HT in patients with previously documented chronically stable normotension

• Resistant HT

• Severe gr.3 HT or HT emergency

• Presence of extensive HT mediated organ damage

• Suspected endocrine HT or CKD (clinical or biochem)

• Suspected OSA (clinical)

• Suspected pheochromocytoma (symptoms or family history)

ESC/ESH Guideline Arterial Hypertension 2018

Clinical evaluation of 2o HT• Drugs

• Family history

• Pulse, BP 4 extremities

• Orthostatic hypotension

• Abdominal bruit

• Bimanual palpation

• Hx hypoK/proximal m weakness

• Paroxysm

• OSA symptoms

• Signs of Cushing, hyper-, hypothyroidism

• Hx hyperCa (hyperPTH)

NSAIDsOral contraceptivesSympathomimeticCyclosporineTacrolimusErythropoietinVEGF inhibitorTKIAlcoholCocaineAmphetamineAntidepressantsGlucocorticoidMineralocorticoidLiquorice

!"#$%&'$(")*+• C+<IF-(1%F&3B+G&51)+,1#+1+,/#$&%-+&7+,-.(%$()#/&)+7&%+<+-%#

• J9%%()$+5(B/01$/&)

– =48*3&/&)0#>,?@#,#2'6#A%

– B'8+'12')#>,C?@#,#2'6#A%

– =20)*8*8#>D?@#,#2'6#A%

• K(%+LM+/#+N<OPNOO+55+K'+

Na 142 K 3.2

Cl 99 HCO3 32

BUN/Cr 20/0.9

UA: protein –trace,

no wbc, no rbc

HypokalemiaR/O

Pseudohypokalemia

and K shift Urine K (mEq/d)

< 15Extrarenal loss

HT↓ PRA, ↑PAC

↑ PRA, ↑PAC

↓ PRA, ↓PAC

Acidosis

RTA

LowVomiting

HighDiuretic

Mg deficiency

Bartter’s, Gitelman’s

> 15

Alkalosis

Urine Cl

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• Intravenous saline infusion test• 2 L of 0.9% NSS IV with infusion pump in 4 h

• Interpretation: PA likely: PAC > 10 ng/dL; unlikely: PAC < 5 ng/dL

• Oral sodium loading test: • Na intake > 200 mmol (6 g)/d for 3 d

• Interpretation: PA likely: 24-h urine aldosterone > 12-14 ug/d

• Fludrocortisone suppression test

• Captopril challenge test

Confirmatory testing

Endocrine Society Guideline 2016

Subtypes of Primary Aldosteronism

• Adrenal adenoma

• Bilateral adrenal hyperplasia

• Glucocorticoid-remediable hyperaldosteronism: very rare

TreatmentAdenomaà Surgery

• Unilateral adrenalectomy

Hyperplasiaà

Medication- Spironolactone

- 12.5-25 mg initially and increase to 400 mg/day to normokalemia- Spironolactone Û T1/2 digoxin- Antagonism at testosterone receptor : painful gynecomastia, ED, Ü libido in men

- Agonist activity at progesterone receptor: menstrual irregularity

Aldosterone-specific CV morbidity and mortality : Stroke, MI, AF

Adrenal Venous Sampling

Results of Bilateral Adrenal Venous Sampling

Left adrenalectomy

Nat Clin Pract nephrol 2006

This picture shows the mechanism of glucocorticoid remediable hyperaldosteronism or GRA.

Which drug should be given for therapy?

A. SpironolactoneB. Prednisolone

C. ACEID. ACTH

Answer: B.Prednisolone

• Glucocorticoid-remediable aldosteronism: hereditary form of 1oaldosteronism • A chimeric gene duplication leads to ectopic aldosterone synthase activity in

the cortisol-producing zona fasciculata of the adrenal cortex, under the regulation of ACTH.

• Treatment: Glucocorticoid suppression of ACTH • alternative treatments include mineralocorticoid receptor antagonists

Diagnostic criteria for NF-1• ≥ 6 café au lait macules

– > 5 mm in greatest diameter in prepubertal individuals – > 15 mm in greatest diameter in postpubertal individuals

• ≥ 2 neurofibromas of any type or 1 plexiform neurofibroma

• Freckling in axillary or inguinal regions• Optic glioma• ≥ 2 Lisch nodules (iris hamartomas)• Distinctive osseous lesion

– Sphenoid dysplasia or thinning of long bone cortexwith or without pseudoarthrosis

• 1st -degree relative with NF-1(The diagnostic criteria are met if 2 or more of the features listed are present )

1

2

3

2

4

5

6Optic glioma

7) 1st degree relative NF1

Harrison’s Principles of Internal Medicine

Indication for screening of pheochromocytoma

• HT with episodic features• Refractory HT

• Prominent lability of blood pressure• Severe HT during anesthesia, surgery, or angiography• Unexplained hypotension

• Incidentally discovered adrenal masses• Idiopathic dilated cardiomyopathy• Family history of pheochromocytoma or a familial

disorder such as MEN-2,VHL disease, neurofibromatosis, or glomus tumors

Familial Pheochromocytoma• MEN 2A

– 50% Pheo (usually bilateral), MTC, HPT

– RET

• MEN 2B– 50% Pheo (usually bilateral),

MTC, mucosal neuroma, marfanoid habitus

– RET

• Von Hippel-Landau– 50% Pheo (usually bilateral),

retinoblastoma, cerebellar hemangioma, nephroma, renal/pancreas cysts

– VHL

• NF1 (Von Recklinghausen's)– 2% Pheo

(50% if NF-1 and HT)– Café-au-lait spots,

neurofibroma, optic glioma– NF1

• Familial paraganglioma– SDH

MEN 2MEN2A• Medullary CA thyroid

(>90%)• Pheochromocytoma

(40-50%)• Parathyroid hyperplasia

(10-20%)• Cutaneous lichen

amyloidosis• Hirschprung’s disease

MEN2B• Medullary CA thyroid

• Pheochromocytoma

• Other

– Mucosal neuromas

– Intestinal

ganglioneuromas

– Marfanoid habitus

VHL• Major complications:

– Retinal angioma (58%) – visual loss– Cerebellar hemangioblastoma (56%)– Spinal cord hemangioblastoma (14%)– Renal cell carcinoma (25%)– Pheochromocytoma (17%)

• Other associated complications:– Pancreatic neuroendocrine tumours and cysts– Epididymal (male) or broad ligament (female)

cystadenomas– 2o polycythemia (hemangioblastoma and RCC)

VHL; 3p

Anatomical localization: Imaging• Characteristics:

– Pheochromocytomas are typically large tumors (2 - 5 cm in diameter) and may contain areas of hemorrhage or necrosis.

– 90% of tumors are intraabdominal lesions•CT abdomen

-Adrenal pheo sensitivity 93-100%-Extra-adrenal pheo sensitivity 90%

•MRI-More sensitivity than CT for extra-adrenal pheo-Absolute indication for pregnancy, children, contrast allergy

Brightness T2W-MRI

Case vignette• 62-yr-old woman

• underwent CT coronary for check up in the private hospital

• found a 1.8-cm left adrenal mass

• underlying of DM type 2 and hypertension

How should she be evaluated ?

Adrenal incidentaloma

Questions need to be answered

True adrenal mass ?

Malignant ?

Hormonally active ?

How should she be evaluated ?

• Take additional history

and physical exam– History of cancer

– Cancer-specific signs

• Review adrenal imaging with radiologist– Size à 1.8 cm

– Unenhanced CT 25 HU

– CT washout APW 70%

– Homogenous, well-circumscribed, no invasion to adjacent structure

N Engl J Med 2021; 384:1542-1551

How should she be evaluated ?

Take additional history and physical examination• Paroxysm,

BP supine/upright

• Signs of Cushing; purplish striae, easy bruising, proximal muscle weakness

• Serum K+

• Signs of hyperandrogenism

Order for

• 24hr urine metanephrie/ normetanephrine (all)

• Overnight 1 mg dexamethasone suppression test (all)

• Plasma renin, aldosterone (HT or hypoK)

Follow-up

Eur J Endocrinol. 2016;175(2):G1-G34.

European Society of Endocrinology CPG

Quiz #1165-yr-old femaleIncidentally discovered left adrenal mass 2 cm, 5 HU

T2DM diet control, osteoporosis Dx 4 yr on alendronateNa 139, K 4.1In addition to screening test for pheo,which of the following is the most appropriate Dx test?A. Low-dose dexamethasone suppression testB. Plasma renin and aldosteroneC. DHEA-s

D. MRI adrenal glandE. No further testing

Quiz #11 Answer: A. LDDST

A 70-yr-old male

Problem: suspected adrenal insufficiency

Underlying CA rectum Dx 6 Mo S/P surgery

• Not tolerated to chemotherapy

• 3 Mo PTA, received abccdaebabcfghijhbklmnoaNimotuzumab, Opdivo, Chinese herb

• Admitted to many hospitals due to fatigue, hemiballismdue to metabolic cause

• Chronic hyponatremia (Na ~120)

– Currently euvolemic status

– 8AM cortisol < 1 ug/dL, normal TFT

Quiz #12

• Chronic hyponatremia (Na ~120)

– Currently euvolemic status

– 8AM cortisol < 1 ug/dL, normal TFT

• No Cushingoid appearance

• No hyperpigmentation

• Na 123, K 3.86, Cl 89, CO2 25, on NaCl tab 4x3

• ACTH < 5 pg/mL

• Review MRI brain: sellar region looked normal

What is the cause of adrenal insufficiency?

Quiz #12

Hypothalamic-pituitary disease• Tumors

– 1o tumor: germ cell tumor, chordomas, primary CNS Lymphoma, craniopharyngioma

– Metastasis: CA lung, breast, kidney

• Treatment: chronic glucocorticoid treatment, cranial radiation• Hypophysitis: immune checkpoint blockade

Adrenal disease• Metastasis to both adrenal glands: CA lung, breast,

melanoma, GI malignancy (stomach/colon), lymphoma (primary or metastasis)

• Adrenalitis from immune checkpoint blockade

Clues: multiple hormones

deficiency, central DI

Clues: hyperpigmentation, hyperkalemia

Clinical spectrum of Immune-related adverse events

Michot JM et al. Eur J Cancer. 2016;54:139-148.

Hypophysitis

Dry mouth

Hypothyroidism

Hepatitis

Rash, pruritus, vitiligo

Pancreatitis and autoimmune DM Arthralgia

Colitis

Adrenal insufficiency

Pneumonitis

Uveitis and orbital inflammation

*Common irAEs

irAEs

Congenital Adrenal Hyperplasia

1 หน้าHT, 1 หลงั virilization

Steroid synthesis

21-OH deficiencyClassic salt-wasting

Classic simple virilizing

Nonclassic

11-OH deficiency

17-OH deficiency

The Hard WorkPuts YouWhere

the Good LuckCan Find You