By Tapendra Koirala2nd Batch

Senior Clerkship 10th June 3016

Cushing Syndrome

Content

IntroductionEtiologyClassificationClinical FeaturesManagementReferences

Cushing syndrome

Cushing's Syndrome

• Excess cortisol due to any cause

Cushing's Disease• Excess cortisol

due to pituitary micro-adenoma

An array of symptoms as a result of abnormally high levels of cortisol or other glucocorticoids in the blood

Etiology

Exogenous/ iatrogenic

Prolonged administration of

Glucocorticoids

ACTH

Endogenous

ACTH dependent causes

Hypothalamic lesions:Increased

CRH production

Pituitary lesions:

MicroadenomaMacroedema

Ectopic lesions:Oat cell caBronchial carcinoid

Pancreatic caNeuroblastomaWilm’s tumor

ACTH independent causes

Adrenal adenoma/carcinoma/hyperplasia McCune Albright

syndrome

Clinical Features

Body fatCentral (truncal)

obesityMoon facies,

Supraclavicularfat pads, and Buffalo hump

SkinThinning of the

skin, with facial plethora, easy bruising, and violaceous

striae

MuscleProximal muscle weakness, and

atrophyWasting of the

extremities

BoneOsteoporosis and fractures

CVSHypertension, Congestive heart failure,Hyperlipidemia, Diabetes

Reproductive

Gonadal dysfunction

and menstrual

irregularities

ImmunityIncreased

rate of infections

Poor wound healing

Psychologic disturbances

(e.g., depression, emotional

lability, irritability,

sleep disturbances)

Ectopic ACTH productionRapidly progressive hypokalemia, metabolic alkalosis, hyperpigmentation, hypertension, edema, and weakness

Cont’d...

Findings are more obvious in infantsChildren with adrenal tumors

Signs of abnormal masculinizationGrowth impairment

Short stature

In Pediatric Patients

Cont’d...A. Note central

obesity and broad, purple stretch

marks (B. close-up)

C. Note thin and brittle skin in an

elderly patient with Cushing's

D. Hyperpigmentation of the knuckles in a patient with ectopic

ACTH excess.

EvaluationMost important step in suspected CS

is to establish the correct diagnosisExclude exogenous glucocorticoid useScreening tests to confirm hypercortisolism

Overnight/single dose dexamethasone suppression test (DST)24 hr urinary free cortisolLate night salivary cortisol level

Cont’d...

A single-dose DSTA dose of 25-30 ug/kg (maximum of 2 mg) given at 11 PM Plasma cortisol level measured at 8 AM the next morning Value <50 nmol/L Adequate suppressionRules out Cushing syndrome

↓

2nd line screening test: Low dose DSTEight doses of dexamethasone (5ug/kg per dose every six hours for 2 days, 1.25 mg/m2/day four dose for two daysMeasure serum cortisol at 8 AM Suppression (<50 nmol/L) of cortisol rules out Cushing syndrome

Cont’d...

If Dx of Cushing syndrome has been established then,

The next step is to find out the cause↓Serum ACTH level

If low or undetectable– ACTH independent cause [Adrenal cause likely]If high– Cushing’s disease or Ectopic ACTH syndromeTwo differentiate between these two: High dose DST is to be

done

Cont’d...

High dose DST2 mg 6 hrly for 2 daysCortisol level measured at 8 AM on Day 0 and Day 2

Partial suppression of cortisol (>50%) confirms Pituitary cause (Cushing disease)

Failure to suppress suggest Ectopic ACTH syndrome

CRH test100 µg bovine CRH IV is givenSerum ACTH and cortisol measured for 2 hoursIncresed ACTH and cortisol– Pituitary CushingNo response– Ectopic ACTH syndrome

Common causes: Summary of findings

Disorder UFC HDDST ACTH CRH test

Adrenal lesion High Not suppressed

Low -ve

Pituitary Microadenoma Macroadenoma

HighHigh

SuppressedNot suppressed

HighHigh

+ve+ve

Ectopic High Not suppressed

High -ve

Exogenous Low Not suppressed

Low -ve

Other InvestigationsAdrenal cause

USG abdomenCT/MRI abdomen

Cushing diseaseCT/MRI head

↓ No mass seen Bilateral inferior petrosal blood sampling for ACTH level

Ectopic ACTH syndromeCXRCT chest, abdomen

Other tests (to see the effect):x Electrolytes (hypokalemia).x Blood sugarx Bone mass density to see osteoporosis

Looking for Adrenal adenoma or carcinoma

Looking for Pituitary micro/

macroadenoma

Looking for Oat cell ca, Bronchial

carcinoid, Ca panc or Wilms tumour

Fig: Approach to Cushing syndrome

Differential Diagnosis

1. Simple obesity

2. Generalized glucocorticoid resistance

3. Pseudo-Cushing syndrome

Chronic alcoholismSevere depression

Treatment

IATROGENIC • Discontinue or reduce the dose of steroids if possible

PITUITARY

• First-line trans-sphenoidal surgery (90% cure rate) ± pituitary irradiation

• Consider bilateral adrenalectomy and medical therapy for recurrent Cushing’s disease

ADRENAL • Unilateral adrenalectomy

ECTOPIC

• Resection of ectopic source if appropriate

• Otherwise, bilateral adrenalectomy and medical therapy

Cause

Treatment

Trans-sphenoidal pituitary microsurgery

Tx of choice in pituitary Cushing disease in children

The overall success rate with follow-up of less than 10 yr is 60-80%

Low postoperative serum or urinary cortisol concentrations predict–

long-term remission in the majority of cases. Relapses are treated with reoperation or pituitaryirradiation

Adrenalectomy Irresponsive to treatment or if ACTH is

secreted by an ectopic metastatic tumorMay lead to Nelson Syndrome, when there is

Increased ACTH secretion by an unresected pituitary adenoma Evidenced mainly by marked hyperpigmentation

Requires adequate preoperative and postoperative replacement therapy

Postoperative complications may include Sepsis, pancreatitis, thrombosis, poor wound healing, and sudden collapse

Medical therapyInhibitors of adrenal steroidogenesis

[Metyrapone, ketoconazole, aminoglutethimide, etomidate]Used preoperatively to normalize circulating cortisol levels

Centrally acting serotonin antagonist [Cyproheptadine]Blocks ACTH release

References

Part 26, Section 4, Chapter 577, Nelsons Text Book of Pediatrics, 20th edition

Part 16, Section 1, Chapter 406, Harrison’s Principle of Internal Medicine, 19th edition

Thank You

Thank you