Dr. Sachin Verma MD, FICM, FCCS, ICFC Fellowship in Intensive Care Medicine Infection Control Fellows CourseConsultant Internal Medicine and Critical Care Web:- http://www.medicinedoctorinchandigarh.com Mob:- +91-7508677495
INVESTIGATION Hb 12.4 gm/dl,TLC 4100/mm3 Sr creat 0.9 mg/dl, RBS 98mg/dl S Na/K/Ca 140 /2.2/4.26 Sr ACTH=10.06 pg/ml LOW DOSE DST= 85 microgm/dl USG-WHOLE ABDOMEN: ?SOL in tail of pancreas ?SOL in lt adrenal gland,sol in liver,spleen and multiple lymphnodes.
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.
Investigation of a patient withcushing 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 test Salivary 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 testProcedure: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
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)
Defining the cause ACTH +high dose DST <50% suppression of UFC (or) plasma cortisol Suppression on high Fails to suppress on Fail to suppress on highdose DST and ↑ ACTH high dose + ↑ ACTH dose and ACTHCushing disease or Ectopic ACTH •Adrenal tumorbronchial carcinoid syndrome •Adrenal macro nodular hyperplasia CT chest/adrenal •Surreptitous use of MRI/CT of Pituitary glucocorticoids Pituitary tumor present No Pituitary mass CT of the adrenals Surgery Do CRH stimulation test IPSS with CRH ectopic ACTH syndrome ↑ >50% ACTH Inconclusive ↑ 20% cortisol Cushing’s disease Repeat radiological studies
False PositivesSevere depressionSevere stressPhenytoin/phenobarbital/rifampin (accelerated metabolism of dex)Estrogen (pregnancy or OCP)Morbid obesity
Imaging Modalities Plain abdominal film Ultrasound (grey scale and Doppler) CT scan MRI Adrenal scintigraphy 25
Plain Abdominal FilmPlain abdominal film finding are non specificMay be helpful in detecting Mass in adrenal area Calcification in adrenal 26
UltrasoundInvestigation of first choice in infant , children and pregnant womenIndication adrenal masses ( larger than 2 cm) 28
CT ScanOn precontrast scan adrenal have soft tissue density similar to that of liverNormal adrenal appear inverted V or Y shape within retroperitoneal fatConsist of body , medial limb and lateral limb 29
Ct ScanThickness of each limb is 5 mmMaximum width of the body is 10- 12mmIndication masses (adenoma & cancer) Cyst abscess metastasis 30
CT ScanAttenuation is measured in Hounsfield unit (HU)Benign masses have low attenuation values (< 20 HU )Malignant masses have high attenuation values (> 20 HU ) 31
CT ScanUnenhanced CT Scan Adenomas : < 10 HU Malignancies : > 20 HUDelayed enhanced CT Scan Adenoma : < 30 HU Malignancies : > 30 HU 32
MRIEqually effective as CT in imaging adrenal disorderNormal adrenal is intermediate signal intensity to liver and hypo intense to fat on TIW1 imageOn T2W2 image adrenal hypo intense to fat, iso intense to liver &hyper 33 intense to crus
MRICarcinoma have hyper-intense signal on T2W2 and hypointense on T1W1 imagesOn contrast enhancement show rapid enhancement with sluggish washoutAdenoma are hypointense, show mild enhancement & rapid 34 contrast washout
Adrenal scintigraphyUsual role of scintigraphy is to clarify inconclusive result of imagingIndication Functional status of adrenal nodule Assess contralateral adrenal function Detect functional metastasis Detect recurrence after surgery 35
TreatmentCushing’s Disease: Transphenoidal resection of pituitary adenomaAdrenal neoplasms: resectionEctopic ACTH: resection if possibleBilateral adrenal hyperplasia: may need adrenalectomies (lifelong glucocorticoid and mineralcorticoid replacement)
‘Medical’ AdrenalectomyMedications 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 Cushings ifUntreatedDiabetesHTNOsteoporotic fractures and avascular necrosisInfectionsNephrolithiasisPsychosisDeath from vascular causes within 5yrs
PrognosisBenign adrenal adenoma- 95% 5 year survival, 90% 10 yearCushing’s disease (pituitary adenoma) same survival, but 10-20% transphenoidal resection failure rate over 10 years.Ectopic ACTH survival depends on malignancyUnknown cause of elevated ACTH- 65% 5 year survival, 55% 10 year survivalAdrenal carcinoma- median survival 7 months upto 2 yrs