Cushing Syndrome 

 

Clinical features

Fat deposition

Obesity: 

 

Weight gain is the commonest symptom & thus obesity commonest sign

Centripetal; truncal obesity (lemon on stick): fat deposition in mesenteric bed

Generalized obesity – not uncommon

 

Moon face

Due to fat deposition in upper part of face (supramalar region)

 

Buffalo hump

Due to fat deposition in interscapular region

 

Skin and hair changes:

• Plethoric appearance: due to thinning of skin and rarely due to polycythemia
• Purple striae: 

Break down of collagen fibers in the dermis

                           ↓

Vascularised connective tissue is exposed

 

Pregnancy striae	Striae in Cushing syndrome
Site : only abdomen	Abdomen + other sites
whitish	Reddish / pink
? Longitudinal	? Transverse
Painless	Painful

 

WPOS: wide, purple, oblique striae

 

• Easy bruising and ecchymosis: due to loss of perivascular supporting tissue (increased capillary fragility)

          

•  Hyperpigmentation: due to increased ACTH 
• Thinning of hair
• Increased incidence of skin infection (e.g. tinea versicolor)

 

Myopathy:

• loss of protein in muscle leads to proximal myopathy 
• difficulty in combing hairs or getting up from squatting position)      

 

Bony change: 

• osteoporosis is commonly seen in spine, ribs and femurs due to loss of protein matrix in bone.
• Patients complains of backache (vertebral fracture)

 

Hypertension: Due to:

1. Increase plasma volume
2. Increased vascular response to catecholamines
3. Sodium retention

Cortisol can also activate mineralocorticoid receptors, but it does not normally do so because most cells containing mineralocorticoid receptors also express an enzyme called 11 β-hydroxysteroid dehydrogenase type 2 (11 β-HSD2), which inactivates cortisol by converting it to cortisone. Inhibitors of 11 β-HSD2 (such as liquorice) or mutations in the gene that encodes 11 β-HSD2 cause cortisol to act as a mineralocorticoid, resulting in sodium retention and hypertension

 

DM

 

Sexual:

• Female- hirsutism, acne, oligomenorrhoea or amenorrhea, clitromegaly, recession of temporal hair
• Male – loss of libido, impotence

Psychiatric:

• Depression
• Emotional instability
• Irritability

 

Growth:

• Growth retardation in children
• Diminution of height in adult (due to collapse of vertebrae)

 

Miscellaneous:

• Cataract
• PUD
• Poor wound healing with little inflammatory response
• Mild bilateral exophthalmos
• Avascular necrosis of bone 

 

Investigations:

 

The diagnosis of Cushing’s is a two-step process:

1. To establish Cushing’s syndrome 
2. To define its cause 

 

Investigation	Finding
Serum cortisol at 8 A.M	Increased: Cushing’s syndrome  Decreased: iatrogenic non prednisolone steroid intake (prednisolone cross react with immunoassay)
Establishing the presence of Cushing’s syndrome: at least 2 concordet abnormal test →Cushig cofirmed
ONDST (preferred): 1 mg at midnight  (11 Pm) Or LDDST: 0.5 mg 6 hourly for 48 hours Measure cortisol at 8-9 AM	> 50 nmol/L → Cushing’s
Late-night salivary cortisol	Abnormal if above local reference range
24 hr urinary free cortisol	Elevated if above reference range → Cushing’s
Determining the underlying cause
Serum ACTH at 9 A.M.	Adrenal: undetectable (< 1.1 pmol/L) ACTH dependent: > 3.3 pmol/L Pituitary: Normal level or Moderate increased  Ectopic: Moderate to Severe increased
Pituitary MRI with contrast:  if plasma ACTH –  high	adenoma may be found to exclude pituitary lesio
CRH stimulation test 100 mg hCRH IV administration measure serum cortisol & ACTH	When: high ACTH, adenoma > 6 mm  50% rise ACTH, > 20% rise of cortisol Ectopic: no response
HDDST 2 mg 6 hourly for 48 hrs Serum cortisol at baseline and after 48 hours	When: high ACTH, adenoma > 6 mm  > 50% suppression in serum cortisol from baseline  Ectopic: No suppression
BIPSS Catheter placed in both inferior petrosal sinuses Sampling from sinuses and from peripheral blood	When: ACTH high, adenoma < 6 mm, HDDST/CRH test negative  ACTH central to peripheral gradient > 2:1 at baseline or > 3:1 at 5–10 mins after 100 mg CRH IV → Cushing disease
To find out ectopic source of ACTH Chest: X ray/CT/MRI  Abdomen: USG/CT/MRI Skull: CT/MRI Somatostatin scintigraphy	carcinoma of bronchus, bronchial Carcinoid
Others  Plasma electrolytes, ABG, creatinine  glucose, HbA1C, lipid profile BMD X ray spine, pelvis	To see complication  hypokalemia metabolic alkalosis IGT, DM osteopenia, osteoporosis vertebral collapse, fracture neck of femur

 

Management 

Mode of treatment: 

• Surgery
• medical therapy: metyrapone, ketoconazole, osilodrostat → inhibit glucocorticoid biosynthesis 

 

Cushing’s disease: 

• Trans-sphenoidal surgery → need life-long follow-up (chance of recurrence); if unsuccessful →
• Laparoscopic bilateral adrenalectomy: complication: Nelson syndrome: 

1. consist of pituitary macroadenoma (causing local mass effects) and very high ACTH levels (causing pigmentation). 
2. management: pituitary irradiation

• The somatostatin analogue: pasireotide (suppressing ACTH secretion by the tumor.) 

 

Adrenal tumors 

• Laparoscopic adrenal surgery: prognosis is poor with high rates of recurrence.
• Radiotherapy to the tumor bed.
• Systemic therapy: adrenolytic drug mitotane, and chemotherapy, 

 

Ectopic ACTH syndrome:

• Localized tumors, such as bronchial carcinoids: surgical removal  
• Incurable malignancy: 
  • medical therapy (see above) or, 
  • if appropriate, bilateral adrenalectomy.

 

Prognosis: Untreated severe Cushing’s syndrome has a 50% 5-year mortality. 

cause of death:

1. HTN with its complications
2. Heart failure, myocardial infarction
3. Infection 

 

Surgery:

 

The syndrome of inappropriate antidiuretic hormone (SIADH) is a well-known complication of pituitary surgery. Theoretically, this is caused by ischemia of the neurohypophysis that occurs at surgery followed by necrosis and an abrupt release of vasopressin (antidiuretic hormone) 5 to 10 days postoperatively, often after the patient has been discharged. Hospitalization is often required, with fluid restriction. This problem usually resolves spontaneously without any long-term sequelae. 

 

Rarely, patients develop permanent diabetes insipidus.

 

PSEUDO-CUSHING’S SYNDROME

Definition

A pseudo-Cushing’s state can be defined as some or all of the clinical features of Cushing’s syndrome together with some evidence for hypercortisolism. 

Resolution of the underlying cause results in disappearance of the Cushingoid state. 

Causes

Alcohol 

Urinary and plasma cortisol levels were elevated and failed to suppress with dexamethasone. Plasma ACTH has been found to be normal or suppressed. 

Depression 

Although the cause is unknown, it is recognized that patients with depression may exhibit the hormonal abnormalities of patients with Cushing’s syndrome. These abnormalities are reversible on correction of the psychiatric condition. Conversely, patients with Cushing’s syndrome are frequently depressed and a careful clinical and endocrinologic assessment is required.

Obesity 

Patients with obesity have mildly increased cortisol secretion rates, and the data suggest that this is due to activation of the HPA axis. However, circulating cortisol concentrations are invariably normal and urinary free cortisol concentrations are either normal or only slightly elevated. The stimulus to the increased secretion rate appears to be increased peripheral metabolism and hence clearance of cortisol (principally reduced hepatic conversion of cortisone to cortisol by 11β-HSD1 and increased conversion of cortisol to 5α-reduced derivatives).

 

Investigations

 

Pseudo-Cushing’s or True Cushing’s syndrome? 

In patients with depression, urinary free cortisol concentrations may be elevated and overlap with those seen in patients with true Cushing’s syndrome. 

Dexamethasone suppression test 

Compared with patients with Cushing’s disease, depressed patients have greater suppressibility following dexamethasone and reduced response to CRF but neither of these tests is diagnostic. However, by performing a CRF test after the standard 2-day low-dose dexamethasone suppression test, separation of true versus pseudo-Cushing’s syndrome has been reported. 

Insulin tolerance test 

In normal subjects and in patients with endogenous depression, insulin-induced hypoglycemia results in a rise in ACTH and cortisol levels, a response that is usually not seen in Cushing’s syndrome. 

Loperamide test

Loperamide lowers cortisol values in patients with pseudo-Cushing’s but not in true Cushing’s syndrome

 

Steroid withdrawal:

 

                                                         

 

                                                        Short synacthen test

 

                                                         ↓                         ↓                     

 

                                     S cortisol < 550              S cortisol > 550       

    

                                                  ↓                                      ↓

 

                                                  ?                            Withdrawal    

   

Hydrocortisone is short acting, so serum basal cortisol can be measured without error in result; same to alternative day therapy (after one day off serum cortisol is measured.)   

 

STEROID EFFECTS ON BLOOD PICTURE

 

1. Hb ↑
2. Platelets ↑
3. WBC   

• Neutrophilic leucocytosis  [due to decreased  adhesion molecules → ↓demargination of   

                                                    neutrophils ]      

• ↓Basophils, Eosinophils, Lymphocytes (BEL)