adrenal disorders

ADRENAL DISORDERS

Anand Vaidya, MD MMSc

Director, Center for Adrenal Disorders

Division of Endocrinology, Diabetes, & Hypertension

Brigham and Women’s Hospital

Associate Professor of Medicine, Harvard Medical School

[email protected]

mailto:[email protected]

• Harvard Medical School

• Internal Medicine Residency @BWH

• Clinical Endocrinology Fellowship @BWH

• Cardiovascular Endocrinology Research Post-

Doc @BWH

• Director, Center for Adrenal Disorders @BWH

• Associate Professor of Medicine @HMS

Disclosures

Consulting: Mineralys, Corcept, HRA Pharma

Learning Objectives

1. Review the pathophysiology of adrenal insufficiency and how to

make the diagnosis

2. Review the approach to an adrenal mass and how to conduct a

biochemical evaluation for adrenal hormone excess

3. Review the high and unrecognized prevalence of primary

aldosteronism

• 28yoF presents to ER 6 weeks after having a baby

• Cannot breastfeed well

• Presents with progressive fatigue, dizziness, orthostasis, salt craving,

hyperpigmentation, anorexia, and weight loss

• BP=60/40 mmHg

• IV saline (8L) and BP improves

• Cortisol 0.80 mcg/dL (3-21)

• ACTH>1000pg/mL (15-75)

• (60mins after 250 mcg cosyntropin)= 1.0 mcg/dL

Case 1

Question 1

The most likely diagnosis is:

A) Primary adrenal insufficiency

B) Acute secondary adrenal insufficiency

C) Chronic secondary adrenal insufficiency

D) Ectopic ACTH syndrome

E) Cushing’s disease

Adrenal Cortex: Steroidogenesis

Cholesterol

DHEA

Androstenedione

Testosterone

Estradiol

Pregnenolone

Progesterone

11-Deoxycorticosterone

Corticosterone

Aldosterone

17-Hydroxypregnenolone

17-Hydroxyprogesterone

11-Deoxycortisol

Cortisol

Zona Glomerulosa Zona Fasciculata Zona Reticularis

Target

Organ

Cell

Glucocorticoid

Receptor

Mineralocorticoid

Receptor

CRH

POMC

• ACTH

• (MSH)

H

P

Cortisol

Cortisol

Adrenal

Glucocorticoid

Receptor

11βOH-steroid dehydrogenase 2

Inactivates cortisol to cortisone

Hypothalamic-Pituitary-Adrenal Physiology


1-20mcg/dL

1-20 ng/dL

Schiffer et al. JSBMB 2019

Target

Organ

Cell

Glucocorticoid

Receptor

Mineralocorticoid

Receptor

CRH

ACTH

H

P

Aldosterone

K+

Adrenal

AGT

Ang-I

Ang-II

Renin ACE


1) Cortisol secretion is entirely dependent on ACTH

2) Aldosterone is not dependent on ACTH. It is regulated in part by:

• Angiotensin II (Renin-angiotensin system)

• K+ balance

• ACTH

3) HPA axis responds to:

• Diurnal variation/clock

• “stress”: ACTH & cortisol secretion is augmented “relative” to the degree of stress


25

20

15

10

5

0

2400 0400 0800 1200 1600 2000 2400

TIME

Co

rtis

ol (µ

g/d

L)


Bhake et al. JCEM 2019

Testing the HPA axis

STATIC TEST (entire HPA axis):

•Morning cortisol (and ACTH)

•An “appropriate” AM cortisol should ideally be >14-18 µg/dL, reflecting a

morning peak, but values > 10 µg/dL probably OK when pre-test

probability is low

•An AM cortisol <5 mcg/dL is highly suggestive of adrenal insufficiency

•AM cortisol levels between 5-10 may be difficult to interpret and can be

repeated

Testing the HPA axis

STATIC TEST (entire HPA axis):

•Morning cortisol (and ACTH)

•An “appropriate” AM cortisol should ideally be >14-18 µg/dL, reflecting a

morning peak, but values > 10 µg/dL probably OK when pre-test

probability is low

•An AM cortisol <5 mcg/dL is highly suggestive of adrenal insufficiency

•AM cortisol levels between 5-10 may be difficult to interpret and can be

repeated

PROVOCATIVE TEST (adrenal glands):

•250 µg cosyntropin stimulation test

•Stimulated cortisol <14* mcg/dL highly suggestive of adrenal

insufficiency

*18 mcg/dL is the traditional cutoff. New cortisol immunoassays and LC-MS/MS assays have lower thresholds

Target

Organ

Cell

Glucocorticoid

Receptor

Mineralocorticoid

Receptor

Adrenal

CRH

ACTH

H

P

Cortisol

Aldosterone

Manifestations/Characteristics:

Labs:

• low cortisol

• high ACTH

• low aldosterone

-hyperkalemia, hyponatremia,

hypovolemia

Physical Exam:

• fatigue/lethargy/anorexia

• hypotension/orthostasis/salt craving

• weight loss

• hyperpigmentation

• abdominal pain

• many many more

Primary Adrenal Insufficiency

(Addison’s Disease)

Target

Organ

Cell

Glucocorticoid

Receptor

Mineralocorticoid

Receptor

Adrenal

CRH

ACTH

H

P

Primary Adrenal Insufficiency

(Addison’s Disease)

CosyntropinMorning

60 mins following

250 µg cosyntropin

Cortisol (µg/dL) 1.8 2.1

ACTH (pg/mL) 1100

Response to Cosyntropin:

• sub-optimal

EXAMPLE:

Cortisol

Causes:

• Autoimmune

• Infiltrative infections (TB, fungal)

• Hemorrhage

• Infiltrative malignancy

• Congenital adrenal hyperplasia

• adrenoleukodystrophy

Medications:

• Anti-fungal medications

• Heparin

• Etomidate

Primary Adrenal Insufficiency (Addison’s)

Target

Organ

Cell

Glucocorticoid

Receptor

Mineralocorticoid

Receptor

CRH

ACTH

H

P

ACUTE Secondary Adrenal Insufficiency

Cortisol

Manifestations/Characteristics:

Labs:

• low basal cortisol

• inappropriately low ACTH

• ± hyponatremia

• Normal K and aldosterone regulation

Physical:

• completely normal

• mild, progressive, fatigue at baseline

• severe fatigue, orthostasis,

hypotension, in situations of stress

Adrenal

Target

Organ

Cell

Glucocorticoid

Receptor

Mineralocorticoid

Receptor

CRH

ACTH

H

P

ACUTE Secondary Adrenal Insufficiency

Cortisol

Cosyntropin

Response to Cosyntropin:

• NORMAL

Morning60 mins following

250 µg cosyntropin


ACTH (pg/mL) 10

EXAMPLE:

Adrenal

Target

Organ

Cell

Glucocorticoid

Receptor

Mineralocorticoid

Receptor

CRH

ACTH

H

P

CHRONIC Secondary Adrenal Insufficiency

Cosyntropin

With chronic ACTH deficiency, adrenal cortex

(ZF) will atrophy, and will progressively

respond less to cosyntropin stimulation

Morning60 mins following

250 µg cosyntropin


ACTH (pg/mL) 10

EXAMPLE:

AdrenalCortisol

Causes:

• Pituitary mass: adenoma or metastatic lesion

• Pituitary infection

• Pituitary infiltration (granulomatous disease, iron)

• Pituitary trauma

Medications:

• Glucocorticoids

• Megesterol

• Opioids

Secondary Adrenal Insufficiency

• Diagnosed with primary adrenal insufficiency (Addison’s)

• Treated with IV saline (8L)

• IV hydrocortisone 100mg q8hrs initially

• Transitioned to PO hydrocortisone/fludrocortisone

• Educated regarding recognizing illness or trauma requiring stress

dosing

• Trained to use an IM injection of hydrocortisone for emergencies

Case 1

Case 2

• 46 year old pre-menopausal woman was in a car accident.

• No known medical conditions

• Brought to ER and complained of some abdominal pain. Had a

rapid unenhanced Abdominal CT that revealed no hemorrhage or

other injuries

• Incidental discovery of a 2.2 cm R adrenal mass, with 5 HU

unenhanced densityWhat, if anything, do you tell her about

the incidental adrenal mass??

Incidentally Disovered Adrenal Masses

• Adrenal tumors are incidentally discovered in 1-10% of adults who are scanned.

• A minority represent malignant entities (primary adrenal malignancy or extra-

adrenal metastasis)

• In contrast, ~10-15% of adrenal tumors autonomously secrete adrenal hormones.

These “functional” tumors are associated with an increased risk for

cardiometabolic outcomes, such as CV disease, diabetes, and

osteoporosis/fracture.

• Therefore, all incidentally discovered adrenal tumors should be carefully evaluated

to determine whether they are: 1) malignant and/or 2) functional.

Vaidya et al. Endocrine Practice 2019

Differential Diagnosis of Adrenal Mass

NON-FUNCTIONAL FUNCTIONAL

BENIGN

MALIGNANT

Differential Diagnosis of Adrenal Mass

NON-FUNCTIONAL

(85-95%)

FUNCTIONAL

(5-15%)

BENIGN

(~90-95%)

Adrenocortical Adenoma

Cyst

Ganglioneuroma

Hemangioma

Hemorrhage

Infections and granulomatous

disease (tuberculosis, fungi,

sarcoidosis)

Lymphangioma

Myelolipoma

Pheochromocytoma

Schwannoma

Adrenocortical Adenoma

Aldosterone producing

Cortisol producing

Micro- or Macro-nodular Disease

Aldosterone producing

Cortisol producing

Pheochromocytoma

Myelolipoma*

Ganglioneuroma*

MALIGNANT

(~5%)

Adrenocortical carcinoma

Metastatic cancer from a non-

adrenal primary

Neuroblastoma

Adrenocortical carcinoma

Pheochromocytoma

General Diagnostic Approach

1. Is there evidence for malignancy?

2. Is there adrenal hormone excess?

History and physical exam

for evidence of hormone

excess or malignancy

Laboratory evaluation for

evidence of adrenal

hormone excess

Radiographic evidence

supportive of a benign or

malignant mass

Biochemical

Characteristics

Clinical

CharacteristicsRadiographic

Characteristics

Clinical Characteristics

• Obesity/weight gain

• Lipodystrophy

oCentral adiposity

oSupraclavicular fat pads

oDorsocervical fat pad

oRounded face

• Hyperglycemia/Diabetes

• Hypertension

• Insomnia

• Mood disorder/Psychosis

• Osteoporosis

• Immunesuppression

• Platelet dysfunction

• Hypercoagulable state

• Myopathy

• Atrophic skin

Overt

Cortisol Excess

Overt

Catecholamine Excess

Overt

Aldosterone Excess

• Episodic symptoms

o Hypertension

o Palpitations

o Anxiety/Panic

o Sweats/Tremors

o Headache

o Arrhythmia

• Hypertension

• Hypokalemia

Case 2 – Clinical Phenotype

• No symptoms

• No signs to suggest Cushing syndrome,

pheochromocytoma,

hyperaldosteronism, or hirsutism.

• No evidence of weight loss, abdominal

distention, or androgen excess, to

suggest metastatic cancer or

hyperfunctioning adrenocortical

carcinoma

Unrevealing

Clinical

Phenotype

Case 2 – Radiographic Phenotype

Patient’s non-contrast CTNormal comparison

2.2cm right adrenal mass

5 Hounsfield units

Round, homogenous

Question 2

A 2.2 cm adrenal nodule with an unenhanced density of 5 HU on

CT is most suggestive of:

A)Myelolipoma

B)Adrenocortical adenoma

C)Pheochromocytoma

D)Metastatic lung cancer to the adrenal gland

E)Adrenocortical carcinoma

Case 2 – Radiographic Phenotype

CharacteristicsLikely

BenignPotentiallyMalignant

Irregular Shape No Yes

Heterogeneous content No Yes

Necrosis or Calcifications No Yes

Rate of Growth < 1cm/y ≥1cm/y

Attenuation on unenhanced CT

<10 HU ≥ 10 HU

Contrast washout on CT protocol at 15 minutes

Absolute>60%Relative>40%

Absolute ≤60%Relative ≤40%

MRI chemical shift

suggestive of lipid-rich content

Yes No

FDG avidity on PET No Yes

Size < 4 cm ≥ 4-6 cm

Benign: Suggestive of

adrenocortical adenoma

Case 2 – Biochemical Phenotype

Suggested screening biochemical evaluation for adrenal masses:

Condition Patients Test Abnormal Value

Hypercortisolism ALL

1 mg

Dexamethasone

Suppression Test

None: 1.8 mcg/dL

Possibly/Mild: 1.9-5.0 mcg/dL

Autonomous/Mild CS: 5.0 mcg/dL

Primary

Aldosteronism

HTN and/or

hypokalemia

Serum aldosterone

to plasma renin

activity ratio (ARR)

• Suppressed renin

• Aldosterone > 5-10 ng/dL

• ARR >20

Pheochromocytoma

Lipid poor,

contrast avid,

heterogeneous

adrenal masses

Plasma (or urinary)

fractionated

metanephrines

>> 2-4x ULRR

Adrenal androgen

excess

Hirsutism or

virilization

DHEAS

Total TestosteroneHigher than ULN

~10-15% of individuals who do not have a

catecholamine-producing tumor will have

“positive” biochemistry

(Anxiety/stress/pain, Anti-depressants)

~100% negative predictive value

Case 2 – Biochemical Phenotype

• 1mg DST #1 => cortisol: 8.0 µg/dL

• 1mg DST #2 => 7.8 µg/dL, ACTH<5 pg/mL, dex level normal

• 8mg DST => 8.1 µg/dL, ACTH<5 pg/mL

• 24h Urine Free Cortisol: 45 µg/24h (<45)

•Midnight Salivary Cortisol:

3.7, 3.9, 4.6, 4.3 nmol/L (<4.3)

• Random ACTH: <5 pg/mL

• DHEA-S: low

• Plasma metanephrines: normal

• Aldosterone/PRA: not suggestive

Suggestive of

autonomous and

ACTH-independent

hypercortisolism without

overt Cushing syndrome

• BP = 122/75 mmHg

• Fasting Blood Glucose = 99 mg/dL

• HbA1c = 5.8%

• Bone Mineral Density:

• Spine T= -3.2

• Femoral Neck T= -2.2

• Total Hip T= -2.0

Case 2 – Outcome

• Extensive work-up for secondary causes of osteroporosis: Negative

Case 2 – Clinical Diagnosis

Benign adrenocortical adenoma

Autonomous cortisol secretion

No overt clinical Cushing syndrome, but

unexplained osteoporosis

Should surgery be recommended?

• BP = 122/75 mmHg

• Fasting Blood Glucose = 99 mg/dL

• HbA1c = 5.8%

• Bone Mineral Density:

• Spine T= -3.2

• Femoral Neck T= -2.2

• Total Hip T= -2.0

Case 2 – Outcome

• Extensive work-up for secondary causes of osteroporosis: Negative

• INDIVIDUALIZED DECISION: Laparoscopic R adrenalectomy

• Pathology revealed 2.5 cm adrenal cortical adenoma

• Post-op AM cortisol 4 mcg/dL, ACTH<10 pg/mL (asymptomatic)

• 1 week post-op, morning cortisol = 17 µg/dL

Case 2 – Clinical Diagnosis

↑CVD

↑Mortality

↑Diabetes

↑osteoporosis/fracture

Autonomous Cortisol Secretion:

Lopez et al. Annals Int Med 2016

Elhassan e al Annals Int Med 2019

Kjellbom et al Annals Int Med 2021


Incidentally Discovered Adrenal Mass

Suspicious≥10 HU, contrast avid, heterogeneous, ≥4-6cm

Benign Appearing<10HU, <4cm, non-contrast avid,

homogeneous

No evidence/indication to support

longitudinal radiographic surveillance

If initially “nonfunctional”:

No indication to lab repeat testing unless new or

rapid comorbidities suspicious for hormone

excess

If autonomous cortisol secretion without

clinical syndrome:

• Individualized consideration for surgery based

on comorbidities and other factors.

• Consider longitudinal clinical/biochemical

surveillance

Biochemical Evaluation Radiographic CharacteristicsNonfunctional, or

Mild/autonomous cortisol secretion

without a clinical syndrome

Evaluate for Clinical Signs and Symptoms of Adrenal Hormone Excess

Biochemical Assessments & Evaluation of Radiographic Characteristics

Confirmation of Overt

Hormone Excess with Clinical

Syndrome

Surgery

Overt Hormone Excess

Concern for

metastases or

infection

Biopsy

Bilateral, history of

malignancy, or

immunesuppression?

Repeat Assessments in 3-6

mos•Growth>1 cm/year in any dimension

•Suspicious radiographic features

•New or worsening hormonal excess

Ambiguous results or

indecision regarding

surgery

Uncertainty?

UnilateralConsider confirmation on

alternative imaging such as CT

with washout, MRI, FDG-PET

Unilateral?

Unilateral

Suspicious

Mass

Suggested Diagnostic Algorithm for Incidentally Discovered Adrenal Mass


Case 3

Concerning for primary

aldosteronism!!

Clinical

Phenotype

• 60yo woman with hypertension

• Hypertension for ~30 years

• Currently on lisinopril, amlodipine, HCTZ

• BP 150-160/90-100 mmHg

– Resistant Hypertension

• K+ 2.5-3.5 for >10 years

• HCO3- 28-33 for >10 years

Case 3

• 60yo woman with hypertension

• Hypertension for ~30 years

• Currently on lisinopril, amlodipine, HCTZ

• BP 150-160/90-100 mmHg

– Resistant Hypertension

• K+ 2.5-3.5 for >10 years

• HCO3- 28-33 for >10 years

• PRA < 0.6 ng/mL/h

• PAC 15 ng/dL

Primary aldosteronism!!

Clinical

Phenotype

Treated with spironolactone;

BP controlled on 2 drugs

What is Primary Aldosteronism?

SYNDROME of Inappropriate, Relatively non-suppressible, Renin-independent

aldosterone production that results in excessive activation of the renal-MR, vicious

cycle of volume expansion => can increase BP, increases K+/H+ excretion, increases

risk for CV disease independent of BP (extra-renal MR)

Clinical Manifestations:

Reflect the severity and duration of the renin-independent aldosteronism

BP and potassium are dependent features

Hallmark Biochemical Diagnostics:

Suppression of Renin

Inappropriate/Dysregulated Production of Aldosterone

Vaidya et al. Endocrine Reviews 2018

Why should you care?

Part I: Preventable Cardiovascular Risk

Part II: Under-recognition

Part III: High Prevalence

Risk for Incident Composite Cardiovascular Events

Matched Idiopathic

Hypertension

Overt

Primary Aldosteronism

(No Targeted Therapy)

CAD ~2x -

Heart failure ~2x -

Stroke ~2.5x -

Afib ~3.5x -

LVH ~2.3x -

Monticone et al, The Lancet D&E 2018

↑CVD independent of BP

Risk for Incident Composite Cardiovascular Events

Hundemer et al, The Lancet D&E 2018

Bilateral PA

following Optimized

Medical Therapy

Idiopathic HTN

Years

Unilateral PA

following

Curative Surgery

0

20

40

0 2.5 5 7.5 10Cu

mu

lati

ve I

ncid

en

ce o

f C

om

po

sit

e C

V E

ven

ts (

%)

Primary Aldosteronism increases the risk for

CVD, and we have targeted therapies that

can mitigate this risk

How Common is the

Primary Aldosteronism Syndrome?

Prevalence of Primary Aldosteronism

Burrello et al. Hypertension 2020; Brown et al. Ann Int Med 2020

Resistant HTN ≥ 25%

Stage II HTN ≥ 10-15%

Stage I HTN ≥ 5-10%

HTN + hypokalemia ≥ 25%

HTN + severe hypokalemia ≥ 85%

In Reality…

Screening Rates Among Patients with R-HTN + Hypokalemia

<< 1 - 2%

Ruhle et al. Surgery 2019

Jaffe et al. Hypertension 2020

Liu et al. JAMA Surgery 2021

Cohen et al. Annals Int Med 2021

Primary Aldosteronism in the USA

Brown et al. Annals of Int Med 2020

N=1847

Oral Sodium Suppression Test

“gold standard” diagnostic

0

10

20

30

40

50

60

70

80

90

100

24

h U

rin

ary

Ald

os

tero

ne E

xc

reti

on

(m

cg

)

Number of Participants

Untreated

Normotension

Untreated

Stage I

Hypertension

Untreated

Stage II

Hypertension

12 mcg/24h =

Overt Primary Aldostronism

A severity spectrum of

non-suppressible,

renin-independent,

aldosterone production

(aka primary aldosteronism)


0 50 100 1500 50. 100 150. 200 0 50 0 50 100 150

Treated

Resistant

Hypertension

This is (milder) primary aldosteronism!!

Primary Aldosteronism in the USA

0

5

10

15

20

25

30

9.0%

15.7%

20.7%

24.0%

Cru

de P

revale

nce (

%)

Normotension Stage I HTN Stage II HTN Resistant Hypertension

Prevalence of Overt Primary Aldosteronism

Resistant Hypertension

% with Aldosterone < 10 ng/dL = 24%

Aldosterone production is pulsatile/variable

Aldosterone levels <10 ng/dL can still be inappropriate


Current and Future LandscapeAll Currently

Diagnosed PA

Resistant HTN

Prevalence of PA > 25%

< 1-2% of R-HTN + HypoK

are ever screened

< 1% ever diagnosed

All Currently

Diagnosed PA

Current and Future Landscape

Prevalence of PA

> 5-15%

<<< 1% ever

diagnosed

All HTN(>1 billion ppl)

Resistant HTN

All Currently

Diagnosed PA

True Prevalence of

Overt PA and

clinically-relevant

renin-independent

aldosteronism

amenable to

targeted therapy

Measure Plasma Renin and Aldosterone

Essential Indications

Severe or Resistant Hypertension

Any hypokalemia regardless of BP

HTN + adrenal mass or sleep apnea

Suggestive family history

Future Indications

Stage II hypertension?

New onset hypertension?

Indications to Screen for Primary Aldosteronism

Adapted from: Vaidya et al. JCEM 2020 & Endocrine Reviews 2018

Any time of day

No medication

changes

Do not miss your

chance!

Enhanced

Diagnostic

Pathway

Simplified Exclusionary PathwaySimplified Confirmatory Pathway

Renin Suppressed*

Aldosterone 5-15 ng/dL

POSITIVE SCREEN

Mild PA Likely

Marginal

Suppression

K+ < 3.5 mEq/L ?

Overt PA Likely

ConfirmedRepeat renin and aldosterone

on a future date to confirm

Yes

Consider repeat

evaluation after

cessation of certain

medications& if

applicable

Aldosterone >15 ng/dL

OVERTLY

POSITIVE SCREEN

Aldosterone <5 ng/dL

LIKELY

NEGATIVE SCREEN

PA UnlikelyRepeat renin and aldosterone on a

future date to confirm

MRA Therapy & Dietary

Sodium Restriction

Imaging

AVS to Determine

Potential for Unilateral

Adrenalectomy

Willing/able to undergo

more/advanced testing?

Aldosterone Suppression

Testing

Yes

No Empiric MR antagonist

therapy

Marked

Suppression

Clear Failure

of Suppression

Measure Plasma Renin and Aldosterone

Renin Not

Suppressed*

Adapted from: Vaidya et al. JCEM 2020 & Endocrine Reviews 2018

PRA <0.6 - 1.0 ng/mL/h

PRC <5 - 10 mU/L

MRAs & ENaCi

Rarely Others

Learning Objectives

1. Review the pathophysiology of adrenal insufficiency and how to

make the diagnosis

2. Review the approach to an adrenal mass and how to conduct a

biochemical evaluation for adrenal hormone excess

3. Review the high and unrecognized prevalence of primary

aldosteronism

ADRENAL DISORDERS

Anand Vaidya, MD MMSc

Director, Center for Adrenal Disorders

Division of Endocrinology, Diabetes, & Hypertension

Brigham and Women’s Hospital

Associate Professor of Medicine, Harvard Medical School

[email protected]

mailto:[email protected]

adrenal disorders

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