Dr. Sachin Verma MD, FICM, FCCS, ICFC

Fellowship in Intensive Care Medicine

Infection Control Fellows Course

Consultant Internal Medicine and Critical Care

Web:- http://www.medicinedoctorinchandigarh.com

Mob:- +91-7508677495

Hb 12.4 gm/dl,TLC 4100/mm3Sr creat 0.9 mg/dl,RBS 98mg/dlS Na/K/Ca 140 /2.2/4.26Sr ACTH=10.06 pg/mlLOW DOSE DST= 85 microgm/dlUSG-WHOLE ABDOMEN: ?SOL in tail of pancreas ?SOL in lt adrenal gland,sol in liver,spleen and multiple lymphnodes.

INVESTIGATION

Case presentation

cushing syndrome

Approach to cushing syndrome

In 1972 harvey cushings first described a 23

years old female with obesity, hirsutism and

amenorrhea and 20 years later postulated that

this “polyglandular syndrome” was due to

primary pituitary abnormality causing adrenal

hyperplasia.

Traditionally, cushing syndrome is used to

describe all causes.

Cushing’s disease is reserved for cases of

pituitaty dependent cushing’s syndrome.

Classification and etiology of cushing syndromeACTH Dependent

Cushing disease (pituitary dependent).

Ectopic ACTH syndrome.

Ectopic CRH syndrome

Macronodular hyperplasia

Iatrogenic (Treatment with ACTH).

Classification and etiology of cushing syndromeACTH Independent

Adrenal adenoma and carcinoma

Primary pigmented nodular adrenal hyperplasia and carney’s complex.

McCune albright syndrome

Aberrant receptor expression

Iatrogenic (Pharmacologic doses of prednisolone, dexamethasone)

Pseudo-cushing’s

Alcoholism

Deposiiton

Obesity

Symptoms of Excess Cortisol Truncal obesity Moon face Fat deposits supraclavicular fossa

and posterior neck- buffalo hump HTN Hirsutism Amenorrhea or impotence Depression Thin skin Easy bruising Purplish abdominal striae Proximal muscle weakness Osteoporosis Diabetes Mellitus Avascular necrosis Wound healing impaired Pysch symptoms Hyperpigmentation Hypokalemic alkalosis

Investigation of a patient with cushing syndrome There are two stages in the investigation of a

patient with cushing’s syndrome.

Stage I - Does this patient have cushing syndrome?

Stage II - If yes what is the cause?

Note : Radiological investigations to be deferred

until cushing’s syndorme has been confirmed

biochemically.

Diagnosis

Q1 Does this patient have cushing’s syndorme?

Circadian rhythm of plasma cortisol.

In normal subjetcs plasma cortical levels are

highest in morning lowest at around midnight.

This circadian rhythm is lost in cushing syndrome.

– Midnight cortisol >7.5 µg/dl indicates cushing

syndrome.

– Sensitive test but due to many false positives not

used .

Screening testSalivary cortisol

– >2.0 ng/ml (5.5 nmol/L)

– 100% sensitive

– 96% specific

Urinary free cortisol excretion

– Normal : <220 to 330 nmol/24 hrs (80 to 120

µg/d)

– Useful screening test

Spot - Urinary cortisol - creatinine ratio

– >25 nmol cortisol/mmol creat

Screening test(cont)Low dose/ overnight Dexamethasone

suppression test

Procedure:Oral adm of 1 mg dexamethasone previous

night and next day 8.00 am plasma cortisol < 5µg /d is normal and < 2µg/day excludes cushings syndrome.

0.5mg dexamethasone 6 hourly for 2 consecutive day and plasma cortisol at 48 hrs < 5µg/dl is normal <2µg/dl excludes cushing’s.

Low dose DST differentiates those who have cushing’s from those who donot have.

Screening testLoperamide test : To differentiate true cushing’s from pseudocushing’s

lopermide lowers cortisol values in patients with pseudocushing’s but not in true cushing’s.

Q.2 Haring confirmed cushing’s syndrome clinically and biochemically then go for the causative factor.

Plasma ACTH: A Midnight ACTH > 5 pmol/L. (> 22pg/ml).

In a patient with biochemical hypercortisolism confers that the underlying disease is ACTH dependant.

Note : pts with bilateral MAH and Adrenal carcinoma /adenoma have variable levels.

Screening testPlasma potassium

Hypokalemia alkalosis is present in more than 95% of

patients with ectopic ACTH syndrome but is present in fever

than 10% of patients with cushing’s disease.

High dose dexamethasone suppression test

2 mg dexamethasone 6 hourly for 48 hours and greater than

50% decrease in urinary cortisol at 48 hours defines or

positive response.

Alternating 8 mg give at 11.00 pm plasma cortisol at 8.00 am

next morning can be done.

Note : 50% of patients with ectopic ACTH syndrome exhibit

suppression and conversely patients with putuitary ACTH

macroadenoma show no suppression.

High dose DST distinguish tose pts with cushing’s disease from those having ectopic ACTH syndrome/adrenal tumor

PITUITARY MACROADENOMA

PITUITARY MICRO

ECTOPIC ACTH SYNDROME

ADRENAL TUMOR

ACTH

HIGH DOSE DST

< 10% >95% <10% <10%

CRH>90% >90% <10% <10%

Metyrapone testCholesterol

↓

Pregnenolone

↓

Progesterone 17OH-progesterone

↓ ↓

DOC11deoxy cortisol

↓ 11 beta OH ase ↓

Corticosterone cortisol

↓

Aldosterone Metyrapone

750 mg 4 hrly for 24 hrs.

Exaggerated rise in ACTH and 11

deoxycortisol val > 35µ/dl at 24 hours.

Used to distinguish cushing’s disease

from adrenal cause.

Value of this test is questioned in

modern endocrine practice due to more

false positive result.

CRF TestPROCEDURE

IV CRF 1 µg/kg (or) 100 µg bolous measure

plasma ACTH and cotisol every 15 mins for 1

to 2 hours.

Results

Normal ACTH and cortisol increase by 15

to 20%.in cushing disease ACTH increase

by 50%; Cortisol increase by 20%

In ectopic ACTH syndrome no response.

Inferior petrous sinus sampling Selective venous catheterisation

Most robust test to distinguish cushing

disease from ectopic ACTH syndrome is IPSS.

Normal value

Pituitary ACTH : Peripheral ACTH < 1.4 : 1

Cushing disease >2

Or

Post CRF pituitary/peripheral ACTH >3

(97% sensitive, 100% specific)

Investigation algorithmScreening tests :

– 24 hours urinary free cortisol

(or)

– 1 mg overnight DST

Or

– 11 PM midnight salivary cortisol

Confirmation :

– Low dose DST

or

– Midnight plasma cortisol

Defining the cause

Suppression on high dose DST and ↑ ACTH

ACTH +high dose DST<50% suppression of UFC

(or) plasma cortisol

Fails to suppress on high dose + ↑ ACTH

Fail to suppress on high dose and ACTH

Cushing disease or bronchial carcinoid

Ectopic ACTH syndrome

•Adrenal tumor

•Adrenal macro nodular hyperplasia

•Surreptitous use of glucocorticoids

CT chest/adrenal

MRI/CT of Pituitary

Pituitary tumor present No Pituitary mass

Surgery

CT of the adrenals

Do CRH stimulation test

↑ >50% ACTH

↑ 20% cortisol

Inconclusive

IPSS with CRH ectopic ACTH syndrome

Cushing’s disease Repeat radiological studies

False Positives

Severe depressionSevere stressPhenytoin/phenobarbital/rifampin

(accelerated metabolism of dex)Estrogen (pregnancy or OCP)Morbid obesity

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Imaging Modalities

Plain abdominal filmUltrasound (grey scale and

Doppler) CT scanMRIAdrenal scintigraphy

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Plain Abdominal Film

Plain abdominal film finding are non specific

May be helpful in detecting

Mass in adrenal area

Calcification in adrenal

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Ultrasound

Adult appearance

Entirely hypoechoic

Concave with straight margin

Newborn

Cortex hypoechoic, Medulla hyperechoic

Cortex>>medulla thickness

Convex border

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Ultrasound

Investigation of first choice in infant , children and pregnant women

Indication

adrenal masses ( larger than 2 cm)

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CT Scan

On precontrast scan adrenal have soft tissue density similar to that of liver

Normal adrenal appear inverted V or Y shape within retroperitoneal fat

Consist of body , medial limb and lateral limb

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Ct ScanThickness of each limb is 5 mm

Maximum width of the body is 10-12mm

Indication masses (adenoma & cancer) Cyst abscess metastasis

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CT Scan

Attenuation is measured in Hounsfield unit (HU)

Benign masses have low attenuation values (< 20 HU )

Malignant masses have high attenuation values (> 20 HU )

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CT Scan

Unenhanced CT Scan

Adenomas : < 10 HU

Malignancies : > 20 HU

Delayed enhanced CT Scan

Adenoma : < 30 HU

Malignancies : > 30 HU

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MRI

Equally effective as CT in imaging adrenal disorder

Normal adrenal is intermediate signal intensity to liver and hypo intense to fat on TIW1 image

On T2W2 image adrenal hypo intense to fat, iso intense to liver &hyper intense to crus

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MRI

Carcinoma have hyper-intense signal on T2W2 and hypointense on T1W1 images

On contrast enhancement show rapid enhancement with sluggish washout

Adenoma are hypointense, show mild enhancement & rapid contrast washout

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Adrenal scintigraphy

Usual role of scintigraphy is to clarify inconclusive result of imaging

Indication Functional status of adrenal nodule Assess contralateral adrenal function Detect functional metastasis Detect recurrence after surgery Detect ectopic site of hormone

production

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Adrenal Scintigraphy

Adrenocortical imaging agent

NP-59 ( 6-B-iodomethyl-19-norcholesterol )

Selenium-75 6-B-selenomethylnorcholesterol

Sympathoadrenal imaging agent

MIBG ( metaiodobenzylguanidine )

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Adrenal Scintigraphy

Indication for MIBG Pheochromocytoma Neuroblastoma, carcinoid, adrenal

metastasis

Indication for NP-59 Adrenocortical carcinoma Adenoma Adrenal hyperplasia

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MIBG Scintigraphy

MIBG Scintigraphy: high uptake in LT adrenal ,Pheochromocytoma

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MIBG Scintigraphy

MIBG : Inc tracer accumulation in lt adrenal mass

Treatment

Cushing’s Disease: Transphenoidal resection of pituitary adenoma

Adrenal neoplasms: resectionEctopic ACTH: resection if possibleBilateral adrenal hyperplasia: may

need adrenalectomies (lifelong glucocorticoid and mineralcorticoid replacement)

‘Medical’ Adrenalectomy

Medications that inhibit steroidogenesisKetoconazole (600 to 1200 mg/day)metyrapone (exacerbates female

virilization) (2-3 g/day)Mitotane(2-3 G/day)- slow onsetAminoglutethinide (1g/day)Ocreotide can work in 1/3 of patients.Major side affect is adrenal insufficiency,

therefore start at lowest dose and titrate

Complications of Cushing's if UntreatedDiabetesHTNOsteoporotic fractures and

avascular necrosisInfectionsNephrolithiasisPsychosisDeath from vascular causes within

5yrs

Prognosis

Benign adrenal adenoma- 95% 5 year survival, 90% 10 year

Cushing’s disease (pituitary adenoma) same survival, but 10-20% transphenoidal resection failure rate over 10 years.

Ectopic ACTH survival depends on malignancy

Unknown cause of elevated ACTH- 65% 5 year survival, 55% 10 year survival

Adrenal carcinoma- median survival 7 months upto 2 yrs

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THANK YOU