Endocrinology: Adrenal Disorders - PowerPoint Presentation

Slide1

Endocrinology:Adrenal Disorders

Sona Sharma MDAssociate Professor of Clinical MedicineDivision of Endocrinology, Diabetes and MetabolismUniversity of Cincinnati College of MedicineFebruary 2018

Southwest Ohio Regional Updates

in

Internal Medicine 2017Slide2

Mineralocorticoids like aldosterone

Renin-Angiotensin

System

Renin

Catecholamines

(Norepinephrine, epinephrine)

Zona

Reticularis

Zona Glomerulosa

Medulla

Zona

Fasciculata

Glucocorticoids

like cortisol

CRH (Hypothalamus)

ACTH (Pituitary)

Hypothalamus

Pituitary

Adrenal Glands: Normal Anatomy and Physiology

Cortex Slide3

Adrenal

Hormones: Pathophysiology

Hormones

Tumors/ Syndromes associated with overproduction

Tumors/ Syndromes associated with under production

Cortex

Mineralocorticoids (Aldosterone)

Primary

Aldosteronism

Primary Adrenal insufficiency

Hypoaldosteronism

Glucocorticoids (Cortisol)

Cushing syndrome

Primary Adrenal insufficiency

Adrenal androgens (DHEAS, DHEA)

Virilizing

or feminizing tumors

Medulla

Catecholamines

(epinephrine, norepinephrine)

PheochromocytomaSlide4

Mineralocorticoids like aldosterone

Renin-Angiotensin

System

Renin

Catecholamines

(Norepinephrine, epinephrine)

Zona

Reticularis

Zona Glomerulosa

Medulla

Zona

Fasciculata

Glucocorticoids

like cortisol

CRH (Hypothalamus)

ACTH (Pituitary)

Hypothalamus

Pituitary

Applying

n

ormal

p

hysiology to work up of adrenal diseases

Cortex Slide5

Tests of overproduction and underproductionApplying concepts from physiology:-

Using diurnal rhythm of Cortisol productionCortisol production peaks in morning and nadir at nightSuspecting Cortisol deficiency –> check level when it is expected to be highest (8 am morning cortisol) Suspecting excess –> check level when it is expected to be lowest (midnight cortisol)

Using feedback regulation of adrenal hormone production

Suspecting

deficiency –>

stimulation tests

Suspecting excess –> suppression

tests Slide6

Cushing Syndrome/disease

Williams’s Textbook of endocrinology

History/Symptoms

Weight gain/centripetal obesity

Menstrual irregularity

Osteoporosis/osteopenia

Hypertension

Prediabetes or diabetes

Easy bruising

Acne/Hirsuitism

Examination findings

Purple

striaeDorsocervical,Supraclavicular fat padsMoon facies

Proximal myopathy

Definition:- large group of signs & symptoms that reflect prolonged and inappropriately high exposure of tissue to

glucocorticoids (exogenous and endogenous)Slide7

Diagnostic work up forCushing syndrome/disease

Step 1: Exclude exogenous steroids intake (most common cause of Cushing syndrome) Slide8

Cortisol (with

diurnal rhythm)ACTH (under CRH from

hypothalamus

)

-

Low

dose

Dexamethasone

Suppression Test (DST)= Failure

to suppress Endogenous Cortisol by 1 mg Dexamethasone 24 hour Urinary Free

Cortisol = Excessive cortisol production=> 24 UFC X2 with Creatinine Midnight salivary cortisol (MSC X2) =

Loss of normal diurnal rhythm

Step 2: Biochemical w/u to confirm endogenous Cushing

Pituitary

AdrenalsSlide9

Step 3: Establish level/cause/source of Cushing syndrome

Pituitary

Adrenals

ACTH

Ectopic

Source

of ACTH

production

Cortisol

ACTH

ACTH:- First step

ACTH

High Dose Dexamethasone suppression tests

MRI

sella

CT/MRI of chest/abdomen

Inferior Petrosal Sinus Sampling Slide10

Adrenal InsufficiencyDeficiency of glucocorticoid hormones (cortisol) with or without deficiency of mineralocorticoids (aldosterone)

Clinical Presentation:- Anorexia, nausea/vomiting, involuntary weight loss, generalized weakness, volume depletion, hypotension, abdominal painShock: Adrenal crisis: a medical emergencyHyponatremia, hypoglycemia

H

yperkalemia

,

hyperpigmentation (primary)Slide11

Causes of Adrenal Insufficiency

Primary (adrenal)

Central (Hypothalamus/Pituitary)

Autoimmune

adrenalitis

(Addison's)

m

ost common cause

Infections (e.g. TB, HIV, fungal)Infiltrations Adrenal hemorrhage (trauma, coagulopathy, sepsis)Drugs (e.g. mitotane

, ketoconazole)MetastasisBilateral adrenalectomyCongenital Adrenal Hyperplasia Adrenoleukodystrophy in males

Supraphysiologic doses of exogenous steroids is most common cause Megace, IpilimumabPituitary disease (e.g. tumor, trauma)

After surgery for Cushing diseaseSlide12

Diagnostic work up of Adrenal Insufficiency

Step 1: Confirm diagnosis Am cortisol < 5 ug/dL suggests adrenal insufficiency Standard 250 mcg Cosyntropin Stimulation test: Peak cortisol levels <18 μg/dL at 30 or 60 minutes confirms adrenal insufficiency

Step 2: Identify level of

defect

=> ACTH is the main test

Level of defect

Cortisol

ACTH

Aldosterone Renin

Primary AdrenalsLow

High

Low High

Central

Secondary (pituitary)

Tertiary (hypothalamus) Low Low or Normal

NormalNormal

Step 3: Work up of underlying causeSlide13

Treatment of Adrenal InsufficiencySevere

adrenal insufficiency/adrenal crisis is medical emergencyStart glucocorticoids (hydrocortisone) urgently without waiting for results of diagnostic tests Start intravenous fluids Chronic treatment:- Primary adrenal insufficiency needs both: Glucocorticoids (hydrocortisone, dexamethasone, prednisone) Mineralocorticoids (fludrocortisone)

Secondary/tertiary adrenal insufficiency need only glucocorticoids

Stress dosing of steroids during illness or

surgery

Medic alert/Intramuscular kit for prn use at home Slide14

Primary Aldosteronism (PA)

Definition of PA:- excessive, inappropriate, autonomous production of aldosterone hormone Too much aldosterone => Plasma Aldosterone Concentration (PAC) Suppressed renin => Plasma renin activity (PRA)

Clinical Presentation:-Most

common cause of

secondary HTN. Suspect

PA if:-

Severe or resistant HTN

+/- hypokalemia (even on diuretic) Early onset of HTNHTN + adrenal tumorFamily h/o early onset HTN, strokes <40 yrs, PA Slide15

Diagnostic work up of Primary Aldosteronism (PA)

Step 1: Biochemical Confirmation of Primary Aldosteronism (PA)Case detection/Screening tests:- PAC (ng/dL) => Aldosterone to renin ratio (ARR)PRA (ng/mL/min) ARR > 30 suggestive of PA (some authors also include PAC >10-15)ARR >30, positive screening tests, need confirmatory tests in most cases

Most antihypertensive meds can usually be continued except MRB, K sparing diuretics

(stop

for >/= 4 weeks prior to test)

Confirmatory

tests:- Measure aldosterone in 24 hour urine after oral salt loading or serum after IV saline infusionSlide16

Diagnostic work up of Primary Aldosteronism (PA)

Step 2: Subtype Classification of Primary Aldosteronism (PA)Imaging:- Abdomen CT scan is initial imaging unless contraindicatedAdrenal Vein Sampling (AVS):- to differentiate between unilateral vs bilateral aldosterone

overproduction (done only in surgical candidates)Slide17

Treatment of Primary Aldosteronism (PA)

Treatment: Medical vs surgicalUnilateral overproduction of aldosterone: Adrenalectomy (only in surgical candidates)Bilateral overproduction of aldosterone or patient not surgical candidate or declines surgerymedical treatment with mineralocorticoid receptor blockers (MRB: Spironolactone or Eplerenone) Slide18

Pheochromocytoma

Definition: Pheochromocytoma: tumor arising from adrenal medulla that commonly produces catecholamines“Extra adrenal pheochromocytomas”: ParagangliomaClinical presentation: HTN (can be labile, resistant, severe with hypertensive crises), sweating, palpitations, headaches, orthostatic hypotensionCan occur in familial conditions (MEN2, NF1, VHL, SDH mutations)

Can

be malignantSlide19

Diagnostic work of Pheochromocytoma

Lab tests: 24 hour urinary fractionated metanephrines with creatinine or Plasma free metanephrines (normetanephrine, metanephrine) Stress, meds (TCA, sympathomimetic, cocaine): false positive testsImaging: CT scan- Initial choice of imaging Usually large, heterogeneous, vascular, high HU, marked contrast enhancement

Other modalities:-

MRI

MIBG

scan (I-

Metaidodobenzylguanidine

) PET ScanSlide20

Pheochromocytoma

Treatment:-Surgery is mainstay but is high risk: Hypertensive crises/tachyarrhythmias Requires careful preoperative management:Control of HTN: Alphablockers, followed by betablockers Volume expansion: High sodium and fluid intake

Careful hemodynamic monitoring

Lifelong

annual biochemical and clinical monitoring requiredSlide21

Adrenal Incidentaloma

Definition:- adrenal mass discovered incidentally on imaging done for reasons other than adrenal diseaseClinical significance:- can be malignant or hormonally overproducing tumors. Most are benign and nonfunctionalRadiological exam is most helpful diagnostic testImaging features suggestive of benignity on CT scanSize:- < 4 cmImaging characteristics:- <10 HU on noncontrast CT scan, homogeneous, smooth bordered

Absence of these features: suspicious or

indeterminate

Other

d

iagnostic modalities:- MRI/PET Scan

Biopsy is only RARELY indicatedSlide22

Adrenal Incidentaloma

Recommend hormonal evaluation on initial presentation in:-All patients for pheochromocytoma (24 hour urinary fractionated metanephrines or plasma free metanephrines)

All patients for Cushing by 1 mg (low dose) DST

Only patients with HTN for

aldosteronism

(PRA, PAC)

Only patients with symptoms of

virilization in women or feminization in men for androgen secreting tumors (DHEAS, estradiol)Slide23

Adrenal Incidentaloma

Indications for surgery:-Most tumors > 4 cm in size (except adrenomyelolipoma)All pheochromocytoma Cushing and aldosteronoma in some people

Tumors that enlarge on follow up imaging

Need clinical, biochemical or imaging monitoringSlide24

Question 1

46 year old lady History:- resistant hypertension X 3 years + hypokalemia X 2 years No palpitations, headaches or sweating Periods are regular. No hirsuitism. No h/o CAD or PVD Meds: Lisinopril 40 mg/day, Metoprolol 25 mg X 2/day, Amlodipine 10 mg/day, HCTZ 25 mg/day, KCL 40 meq X 2/dayExam: BMI 25 kg/m2, BP 160/100 mm Hg, pulse 80/minute. No centripetal obesity or purple striae

Labs:- Na 143

meq

/L, K 3.3

meq

/L. No worsening of Cr after starting LisinoprilSlide25

Question 1

What would be the next step to diagnose her condition?Plasma metanephrines CT scan to look at adrenal glands Duplex ultrasound for renal arteries Plasma renin activity (PRA) and aldosteroneDexamethasone suppression test (DST)Slide26

She probably has primary aldosteronism (high BP+ hypokalemia)A-Plasma

metanephrines: IncorrectNo signs or symptoms of pheochromocytomaB-CT scan to look at adrenal glands: IncorrectBiochemical diagnosis should precede imaging C-Duplex ultrasound for renal arteries: IncorrectDuplex ultrasound is done to r/o renal artery stenosis (RAS) but she has no suggestive features of RAS

D-Plasma renin activity (PRA) and

aldosterone:

Correct

Check

PRA & aldosterone (for primary hyperaldosteronism

)E-Dexamethasone suppression test (DST): IncorrectDST is done to r/o Cushing but she has no signs or symptoms of CushingAnswersSlide27

Question 265 year old man

History:- referred after his colonoscopy got cancelled because BP rose to > 200/110 mm Hg prior to getting procedure Also c/o episodes of sudden rise in BP, sweating, palpitations, headaches in past few months Current meds: Losartan 50 mg, HCTZ 25 mgExam: BP 156/96 mm Hg, pulse 104/min, BMI 27 kg/m2Labs: normal serum K, PRA, PAC, elevated plasma metanephrines and normetanephrinesCAT scan abdo: 4.5 cm right adrenal mass with marked contrast enhancementSlide28

Question 2

What is the best next step in his management?Monitor him since BP is already getting betterRefer to surgeon for urgent adrenalectomy Start alphablocker like phenoxybenzamineStart betablockers like metoprololIncrease hydrochlorothiazide to 50 mg daily Slide29

He has pheochromocytoma: clinical symptoms + elevated plasma metanephrines

+ adrenal mass on CT ScanA- Monitor him since BP is already getting better: Incorrect Pheochromocytoma should be removed since it can be fatal. He is also symptomatic.B- Refer to surgeon for urgent adrenalectomy: IncorrectAdrenalectomy is a high risk surgery and requires preoperative and perioperative medical preparationC- Start

alphablocker

like

phenoxybenzamine

:

CorrectS

tart alphablocker before sending him for surgeryD- Start betablockers like metoprolol: IncorrectStarting betablockers before alpha blockers can precipitate hypertensive crisis because of unopposed alpha adrenergic actionE- Increase hydrochlorothiazide to 50 mg daily: Incorrect: HCTZ not enough to control HTN in him. May cause orthostasis

AnswersSlide30

Question 3

42 year old woman History: Unexplained weight gain of 20 lbs Worsening of DM over past 6 monthsIrregular periods, facial hair Exam: BMI 35 kg/m2, BP 158/86 mm HgCentripetal obesity, dorsocervical fat pads, purple striaeLabs: blood glucose 230 mg/dl, K 3.9 meq/L, am cortisol 16.7 mcg/dL, ACTH 5 pg/mLSlide31

Question 3

What is the next best test to confirm the diagnosis?250 mcg cosyntropin test Low dose dexamethasone test (DST)High dose dexamethasone suppression test (DST)Abdominal CT scan to look at adrenal glandsSellar MRI to look at pituitary glandSlide32

She has clinical signs/symptoms suggestive of Cushing. Needs biochemical confirmation of diagnosisA- 250 mcg

cosyntropin test: IncorrectCosyntropin test is to diagnosis adrenal insufficiencyB- Low dose dexamethasone test (DST): CorrectLow dose DST is an appropriate test to confirm diagnosis of Cushing disease/syndromeC- High dose dexamethasone suppression test (DST): Incorrect

H

igh

dose DST is done

to

differentiate between pituitary vs ectopic source and is done after diagnosis of Cushing has been confirmed

D- Abdominal CT and E Sellar MRI: IncorrectImaging tests are done after biochemical confirmation of Cushing AnswersSlide33

Question 439 year old man seen for the first time

History: T1DM since age 12 years and hypothyroidism C/o increased, unexplained hypoglycemia for past few monthsC/o some n/v, dizziness, weight loss of 6 lbs in last 3 monthsExam: BP 90/56 mm Hg, pulse104 beats/min. Increased pigmentation in his hands Current meds: glargine and aspart insulin, levothyroxineLabs: Na 132

meq

/L, K 5.6

meq

/L,

Tsh 5.5 U/mL (ULN 5.2), 8 am cortisol 2.6 mcg/dL with ACTH 670

pg/mLSlide34

Question 4

In addition to decreasing his insulin dose, what is the next best step in his management?Order an urgent brain MRI to rule out pituitary tumor Increase dose of levothyroxine to normalize tshStart hydrocortisone as soon as possibleCheck for celiac disease Order insulin induced hypoglycemia test to confirm adrenal insufficiencySlide35

A Order an urgent brain MRI to rule out pituitary tumor: wrongEven though ACTH is high, since his corresponding cortisol is low, he has adrenal insufficiency and not an ACTH producing

tumorB Increase dose of levothyroxine to normalize tsh: IncorrectBorderline high tsh can not explain his clinical picture/lab abnormalities. Glucocorticoids should be replaced before replacing/increasing LevothyroxineC Start hydrocortisone as soon as possible: CorrectHigh likelihood of primary adrenal insufficiency based on his symptoms and labs. Glucocorticoids should be started as soon as possibleD Check for celiac disease: Incorrect

C

eliac

disease cannot explain low

cortisol

E

Do insulin induced hypoglycemia test to confirm adrenal insufficiency: IncorrectIn a stable patient, test of choice to confirm adrenal insufficiency is Cosyntropin testAnswersSlide36

Question 5

62 year old man History: presented to ER for abdominal painAbdominal CT scan revealed a round, 2.2 cm adrenal mass, HU 9 No h/o HTN or hypokalemiaNo sweating or palpitationsExam: BMI 32 kg/m2, BP 132/80 mmHg. No purple striae, dorsocervical fat padSlide37

Question 5

What should be included in the diagnosis work up of this adrenal tumor?Biopsy of adrenal tumor No further tests needed since tumor looks benign on CT scanPRA and PAC8 mg (high dose) DSTPlasma or 24 hour urine metanephrinesSlide38

A Biopsy of adrenal tumor: IncorrectBiopsy is rarely indicated and only in specific situations. Always r/o

pheochromocytoma before performing biopsy B No further tests needed since tumor looks benign on CT scan: IncorrectAll patients with adrenal incidentaloma should be tested for Cushing and pheochromocytoma C PRA and PAC: IncorrectIn setting of adrenal tumor only hypertensive patients need to be tested for PA

D 8 mg (high dose)

DST:

Incorrect

1

mg or low dose DST (not high dose DST), is

the test of choice for adrenal incidentaloma to r/o cushingE Plasma or 24 hour urine metanephrines: CorrectDo Plasma or 24 hour urine metanephrines to rule out pheochromocytomaAnswersSlide39

References

The Management of Primary Aldosteronism: Case detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline (2016)Pheochromocytoma and Paraganglioma: An Endocrine Society Clinical Practice Guidelines (2014)Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline (2015)The Diagnosis of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline (2008)American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons Medical Guidelines for the Management of Adrenal Incidentaloma (2009)Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors (2016)