This article follows a recent court case where a hospital in Coimbatore was fined for misdiagnosis and unnecessary surgery in a patient suffering from Cushing’s Disease – Ref. to medico legal section: http://tnmgc.com/discus/viewtopic.php?f=32&t=301

Cushing’s Syndrome:
Cushing’s syndrome was first described by Harvey Cushing in 1932. It is the result of changes that occur when the body is exposed for prolonged periods to inappropriately high levels of the hormone cortisol.

Causes of Cushing syndrome:
1. Exogenous Cushing’s syndrome: Unrelated to any pathology. It occurs when a patient is on a high dose of corticosteroid medication for a prolonged period.
2. Endogenous Cushing Syndrome: Due to a pathological cause when excess cortisol is released by the adrenal glands.

Cushing’s disease: Cushing’s disease refers to a pituitary-dependent cause of Cushing’s syndrome: a tumor in the pituitary gland produces large amounts of ACTH, causing the adrenal glands to produce elevated levels of cortisol. It is the most common cause of Cushing’s syndrome, responsible for 70% of cases. While all Cushing’s disease will lead to Cushing’s syndrome, not all Cushing’s syndrome is caused by Cushing’s disease

Therefore if the ACTH levels are high it is usually due to Cushing’s disease. If the measured ACTH levels are lower then a pituitary tumour is unlikely to be the cause. The decrease in ACTH is due to increased negative feedback of cortisol on the hypothalamus and anterior pituitary. However some tumours that arise outside the pituitary can also produce ACTH. This condition is known as Ectopic ACTH syndrome. Lung tumours cause over 50 percent of these cases. The most common forms of ACTH-producing tumours are oat cell, or small cell lung cancer, which accounts for about 25 percent of all lung cancer cases, and carcinoid tumours. Other less common types of tumours that can produce ACTH are thymomas, pancreatic islet cell tumours, and medullary carcinomas of the thyroid.

Causes for release of excess cortisol:
1. A pituitary tumour releasing excess of ACTH which in turn increases the production of cortisol by the adrenal cortex.
2. A tumor of the adrenal gland which increases the production of cortisol.
3. Ectopic tumours: Some tumours in the thyroid, lung or even pancreas can cause increased levels of cortisol

Pituitary tumour causing adrenocorticotropic hormone (ACTH) hypersecretion, is the most common cause for excess cortisol production by the adrenal cortex. The majority of pituitary tumors causing Cushing’s disease measure <1 cm.

Pseudo-Cushing's syndrome:
Elevated levels of total cortisol can also be due to estrogen found in oral contraceptive pills that contain a mixture of estrogen and progesterone, leading to Pseudo-Cushing's syndrome. Estrogen can cause an increase of cortisol-binding globulin and thereby cause the total cortisol level to be elevated.

Symptoms and Signs:
• Obesity confined to face neck and upper body. Round face (moon face) Collection of fat between the shoulders (buffalo hump)
• Stunted growth in children.
• Skin changes like acne, telangiectasia, striae on the skin of the abdomen, thighs, and breasts. Bruising of skin and dryness.
• Muscle and bone changes include: Muscle weakness, Osteoporosis causing backache, Bone tenderness.
• Persistent hypertension
• Insulin resistance (especially common in ectopic ACTH production), leading to diabetes mellitus.
• Men may suffer from impotence.
• Women may show excess facial hair and may have an irregular menstrual cycle due to increased androgen levels.
• Hyperpigmentation due to Melanocyte-Stimulating Hormone production as a by-product of ACTH synthesis
• Other symptoms: depression, anxiety, headache, increased thirst and urination

Investigations: Blood sugar and white blood cell counts may be high. Potassium level may be low.

Specific Chemical tests for excess cortisol production:
• Serum cortisol levels
• Salivary cortisol levels
• 24-hour urine for cortisol and creatinine
• ACTH level
• ACTH (cosyntropin) stimulation test to measure cortisol levels before and after injection of ACTH
• Dexamethasone suppression test to measure the response of adrenal glands to ACTH

Other Investigations:
• Abdominal MRI
• Pituitary MRI
• ACTH test
• Dexa scan for bone density.

Also check for high cholesterol, HDL and LDL.

Treatment:
• If due to excess intake of steroid – consider reducing the dosage. Otherwise must regularly monitor blood sugar, Triglycerides, and check for osteoporosis.
• If Cushing syndrome is caused by a tumor: Surgical removal of the tumour will be necessary’ Removing the tumor may lead to full recovery, but there is a chance that the condition will return.

At experienced centres, following transphenoidal resection of a pituitary tumour, initial surgical remission rate approaches 80% for tumours less than 1 cm, but may be as low as 30% for larger lesions and long-term recurrence in all groups approaches 25%. Residual disease may be managed with more radical surgery, pituitary-directed radiation, bilateral adrenalectomy, or medical therapy.
Following any surgical procedure to reduce the production of cortisol, patients will probably end up requiring oral steroids for the rest of their lives

Medication:
If the tumor cannot be removed or the site of an ectopic tumour cannot be identified or the patient is not suitable for surgery, medications to help block the release of cortisol should be considered. Steroidogenesis inhibitors, neuromodulatory agents and cortisol receptor antagonists are pharmacological agents useful in lowering high cortisol levels.

Steroidogenesis inhibitor medications such as mitotane, cytadren and ketoconazole decrease the production of cortisol by directly inhibiting one or more enzymatic steps. cytadren directly inhibits the production of cortisol from cholesterol, Mitotane inhibits the activity of the cells of the adrenal gland, thereby inhibiting the production of cortisol.

Neuromodulatory Agents
Cortisol secretion is modulated by the release of ACTH from the pituitary, which in turn is controlled by the hypothalamic release of Corticotropin-releasing hormone, CRH. Drugs such as octreotide, bromocriptine and cyproheptadine modulate the release of ACTH from the pituitary gland, thereby moderating the levels of cortisol in the body

Cortisol Receptor Antagonists
Mifepristone is a cortisol receptor antagonist sometimes used in the treatment of elevated levels of cortisol due to ectopic adrenocorticotrophin (ACTH)-producing tumors. Mifepristone competitively binds glucocorticoid receptors and suppresses the peripheral features of hypercortisolism in Cushing's syndromes.

Survival for people with ectopic tumors depends on the tumor type. Untreated, Cushing syndrome can be life-threatening.

Possible Complications of Cushing’s Disease:
• Diabetes
• Fractures due to osteoporosis
• High blood pressure
• Kidney stones
• Infections