Everyone knows that there’s too much of a good thing. Even a cool glass of lemonade on a hot summer’s day can turn into a sticky mess if the person pouring it isn’t paying attention. We need the hormone cortisol to help us deal with stressful situations. In Cushing’s syndrome, the body experiences the effects of too much cortisol for too long of a period of time. The result? Cortisol, which usually mediates the effects of stress, instead ends up causing damage to the body. 

Cortisol is made by the adrenal glands, a pair of glands that rest on top of the kidneys. You can think of the steps of the cortisol pathway as a baseball player who runs the bases after hitting a home run. The pathway starts in the hypothalamus, the part of the brain responsible for much of the body’s ‘autopilot’ activity – things like breathing and heart rate. When the hypothalamus receives a stimulus that the body’s under stress, it releases corticotropin-releasing hormone (or CRH). This speeds to the pituitary, where it tells the master gland to release adrenocorticotropic-stimulating hormone (or ACTH). ACTH races to the adrenal glands to release cortisol. Cortisol then goes on to do things like increase blood sugar levels, lower inflammation, and raise blood pressure. 

Before we dig into what causes Cushing’s syndrome, we should clarify the relationship between Cushing’s syndrome and Cushing’s disease. A syndrome is different from a disease, which is a specific disturbance in a part of the body. Cushing’s disease is just one cause of Cushing’s syndrome. In other words, not all cases of Cushing’s syndrome are caused by Cushing’s disease. 

CAUSES

Most medical professionals divide these causes into two large categories.

The first is exogenous, meaning ‘generated from without.’

• Long-term use of corticosteroid medications can cause Cushing’s syndrome.

• Iatrogenic steroids often prescribed for inflammatory diseases like arthritis or given by injection for pain. Cushing’s syndrome may develop if the dosage of medication is or becomes larger than the body can handle. 

The second large category is endogenous, meaning ‘generated from within.’ Endogenous cases of Cushing’s syndrome are usually caused by one of three things: 

• The first is a pituitary adenoma, a benign tumor of the pituitary gland. An adenoma may secrete large amounts of ACTH in a way that the body can’t control. A large amount of ACTH will stimulate the adrenal gland to produce a large amount of cortisol. Here, finally, we have the specific cause of Cushing’s disease. Roughly 70% of endogenous cases of Cushing’s syndrome are caused by pituitary adenomas and therefore are classified as actual cases of Cushing’s disease. 
• The second endogenous cause is called ectopic syndrome. You may recall that ‘ectopic’ means ‘in an abnormal place.’ Sometimes tumors of the lungs, pancreas, or thyroid release ACTH. Again, the body does not have the means to control this unplanned ACTH, and it stimulates the adrenal glands to produce too much cortisol. 
• The third endogenous cause is primary adrenal disease. In these cases, a tumor of the adrenal gland (again, usually benign) goes rogue and secretes large amounts of cortisol.

Clinical Features

Common Findings:

• Weight gain/ lemon on sticks/ central obesity
• Increase in peripheral resistance = Hypertension
• Increase in blood sugar, FBS = more than 126 mg%
• Increase in cortisol levels causes insulin resistance, which increases sugar in the blood causing secondary DM
• Decrease in bone calcium causes osteoporosis, calcium is needed for muscle contraction.
• Cortisol effects on sex steroid receptors causing oligomenorrhoea, infertility, PCOD and hirsutism

More specific findings include:

• Moon facies
• Proximal myopathy
• Easy bruising
• Purple striae and Thin, fragile skin
• Fat deposition in the face
• Hypokalaemia and metabolic alkalosis are prominent, particularly with ectopic production of ACTH

Screening test
– measurement of 24-h urinary free cortisol
– late-night salivary cortisol measurement
– 1-mg overnight dexamethasone test

Investigation of choice
– low dose dexamethasone suppression test
– inadequate suppression of urinary cortisol [<10 μg/d (25 nmol/d)] or plasma cortisol [<5 μg/dL (140 nmol/L)] after 0.5 mg dexamethasone every 6 h for 48 h.

Biochemical testing
– Low levels of plasma ACTH levels suggest an adrenal adenoma or carcinoma
– Normal or high plasma ACTH levels suggest a pituitary or ectopic source

Imaging
– MRI of the pituitary
– Imaging of the chest and abdomen

Treatment

1. Iatrogenic steroids- Taper steroids and Azathioprine
2. Oar=T cell ca lung- cisplatin + Trinotecam
3. Pituitary adenoma Cushing disease – transsphenoidal surgery
4. Adrenal Adenoma – Medical Adrenolectomy