Chemistry

Cushings disease is a condition in which the body produces high amounts of the cortisol hormone (hypercortisolism) for long periods of time due to a rise in the levels of the pituitary ACTH hormone (Mayo, 2008).  The condition tends to occur more often in women compared to men, and in individuals between the ages of 20 to 60 years (Simard, 2004).  The ACTH Hormone controls the levels of cortisol and a rise in the ACTH by the pituitary would result in the adrenal glands secreting high levels of cortisol.  Cushings syndrome on the other hand can be due to consumption of oral cortisol medications or the hormone produced by several carcinomas or adenomas (Rakel, 2007).  There are certain peculiar characteristics of Cushing s disease including a moon-like face, a fatty hump behind the shoulders, pinkish stretch and obesity (Holt, 2009).    About 70  of all cases of Cushings syndrome are from Cushings diseases.  The condition usually develops over several months or years (Rakel, 2007).  In Cushings disease a range of clinical and biochemical features may be seen which arise mainly from the hypercortisolism (Simard, 2004). 
    There has been a lot of debate regarding the cause of Cushings disease.  There is intense debate whether the condition develops due to a pituitary abnormality or from a hypothalamic abnormality (Simard, 2004).  The hypothalamus may be involved in a way that chronic stimulation by the CRH hormone can result in high levels of the ACTH hormones by the pituitary resulting in a rise in the Cortisol levels (Katznelson, 1998).  There are several other studies which effectively demonstrate the problem lies in the pituitary gland and not the hypothalamus.  When the hypothalamus has been implicated, often ectopic CRH-secreting tumours have been suggested, but careful analysis through histopathology has demonstrated that the lesions are basically adenomas.  However, if careful analysis of the pituitary has been suggested, then it may be found that the CRH levels may in fact be normal when the cortisol levels are raised.  Other studies have demonstrated that the hypothalamus may have a role only during initiation of the condition.  However, further development and progression depends on the levels of secretion of the ACTH hormone.  In 85 to 90  of the time, Cushings disease is caused by a pituitary adenoma and in 9  of the cases by hyperplasia.  About 90  of all pituitary tumours from which Cushings disease is present are microadenoma (that is the tumour is less than 1 centimetre in size) and in 10  are macroadenoma (tumour over 1 centimetre in size).  When the tumour is larger in size, there are chances that it would be more aggressive in nature.  Tumours from other parts of the body including the adrenal gland or ectopic tissues can also result in the production of cortisol (Katznelson, 1998). 

Background Information
    The common symptoms of Cushings disease include obesity, skin infections, buffalo hump, hair growth, mental defects, purplish discoloration of the skin, weight gain, bone pain, tiredness, blood pressure rise, etc.   If the condition is not treated promptly, several complications may arise including diabetes, fractures, kidney stones, muscle dysfunctions and infectious (Holt, 2009).  Often the diagnosis of Cushings disease may be difficult for the clinician would rely on several laboratory tests.  The diagnosis of Cushings disease is made based on the history, symptoms, signs, physical examination, blood sugar levels (which may be high), white blood cell count (which may be increased), potassium levels (which may fall down), cortisol levels (which is increased), dexamethasone suppression test, ACTH test, pituitary MRI, abdominal CT scan, and urine tests (Mayo 2008).  When exogenous dexamethasone is given there is a diminished suppressibility of ACHTH and cortisol.  The symptoms of Cushings disease may fluctuate with the cortisol levels, and often it may be difficult to determine the hypercortisolism.  Early detection plays a vital role in treating Cushings disease.  When there is a pituitary adenoma of corticotroph the suppressibility of ACTH by corticosteroids is changed such that larger amounts of cortisol are required to lower the ACTH levels.  In most cases of pituitary adenomas, larger oral doses of dexamethasone in the range of 2mg every 6 hours for 2 days are required.  Smaller doses of dexamethasone will not suffice to lower the ACTH levels and bring the cortisol secretion by the adrenal glands within normal (Simard, 2004). 
Biochemistry
    As understood earlier, Cushings disease can be caused by a pituitary microadenoma and macroadenoma (these tumour release high amounts of ACTH stimulating the adrenal glands to produce and release cortisol hormone).  In macroadenoma, the tumour size is greater than 10 mm and in microadenoma less than 10 mm.  Both pituitary microadenomas and macroadenomas tend to occur at a similar age, but the urine free cortisol levels emitted in microadenoma was less than that emitted in pituitary macroadenoma.  In macroadenoma, the amount excreted was 1341 nmol per day whereas in microadenoma it was 877 nmol per day.  Higher amounts of 17-hydroxysteroid were emitted in macroadenoma compared to microadenoma.  Dexamethasone suppression tests were more effective for microadenoma compared to macroadenoma as the levels of 17-hydroxysteroid and urine free cortisol levels were brought down to a greater range in microadenoma compared to macroadenoma.  In 83  of the macroadenoma cases, the ACTH levels were above normal, compared to 45  in the macroadenoma cases.  Usually in case of Cushings disease, urine free cortisol levels should be measured two to three times to obtain precise results.  The body surface area should be corrected in children whilst performing the test, and in pregnant women the free cortisol levels emitted in urine would be higher.  The cortisol levels usually reach the highest level in the morning and the lowest levels before midnight.  In Cushings disease, the lowest levels may not be reached in the diurnal fashion (Katznelson, 1998).  This can be measured by doing a plasma test or a more sensitive way would be to do a salivary cortisol test.  A cortisol value of above 2 ng per ml of saliva helps to establish Cushings disease.  It is a very sensitive and specific test for Cushings syndrome.  Another test done for evaluation of Cushings syndrome is corticotrophin releasing factor test or CRF Test.  CRF is released by the hypothalamus and helps stimulate the secretion of ACTH.  An intravenous injection of 1 ml per kg body weight of CRF is given and the ACTH response of the patient is monitored.  Blood samples are collected every 15 minutes for about 2 hours.  Usually there is a normal response of 15 to 20  in the ACTH and the cortisol levels, but in Cushings disease, the ACTH levels rise to 50  and the cortisol levels to 20 .  In about 10  of the Cushings disease patient, no response to CRF may be obtained (Kronenberg, 2008).   Conclusion
    Cushings disease is treated based on the cause.  If the Disease is caused by a tumour of the pituitary glands, surgery to remove the pituitary, followed by radiation therapy and subsequent replacement of hormones for the entire patients life should be initiated.  If the condition is caused by an adrenal tumour, adrenal surgery and subsequent replacement of the adrenal hormones should be initiated.  However, relapses following the removal of the tumour should be anticipated and hence constant monitoring may be required (Holt, 2009).  Cushings syndrome if not treated can result in fatal outcomes.