Glucocorticoid excess

The term Cushing’s syndrome is used to describe state of excess free circulating glucocorticoid.
  • Spontaneous forms of the syndrome are very rare – it generally occurs as a result of administered ACTH or glucocorticoid.
  • The incidence of spontaneous Cushing’s syndrome is 5 per 1,000,000 per year.

Clinical features

The clinical features of Cushing’s syndrome are varied, and as spontaneous disease is rare, the diagnostic ability of any one factor is weak.
It is also possible to confuse diagnosis with other condition, such as depression and obesity, because many of the diagnostic factors are non-specific.
The clinical features are those of glucocorticoid excess:
Symptoms:

  • Weight gain
  • Change of appearance
  • Depression
  • Insomnia
  • Amenorrhoea / oligomenorrhoea
  • Poor libido
  • Thin skin / easy bruising
  • Hair growth
  • Acne
  • Slow growth in children
  • Back pain
  • Polyuria
  • Dyspepsia

Signs:

  • Moon face
  • Frontal balding (female)
  • Pigmentation
  • Skin infections
  • Hypertension
  • Osteoporosis
  • Pathological fractures – particularly vertebrae and ribs
  • ‘buffalo hump’ – a dorsal fat pad
  • Kyphosis – hunch back
  • Striae – stretch marks – can be purple or red- occur on the abdomen.
  • Oedema
  • Proximal myopathy
  • Glycosuria
A cushingoid appearance can also result from alcohol excess (pseudo-Cushing’s syndrome) although the pathology of this is poorly understood.

Pathology

There is an important distinction to make with Cushing’s syndromes; those that are ACTH dependent, where levels of ACTH are raised, and will not fall when steroids are administered, and those that are ACTH independent, where ACTH will fall when steroids are administered.
  1. Cushing’s disease – this is where there is an increase in pituitary ACTH production. This accounts for 65% of cases. There is a variation of this (account for a further 10% of cases) whereby there is an ‘ectopic’ tumour that secretes ACTH.
  2. Adrenal tumour – this accounts for 25% of cases. It results in a glucocorticoid excess, but suppresses ACTH secretion. Thus the two types can be distinguished serologically. A variation of this type can occur where there is an abnormality of receptors in adrenal cells.
  • Note that pigmentation can only occur with ACTH dependent causes (due to POMC), and that impaired glucose tolerance (leading to diabetes) and hypokalemia both occur, but only with the ectopic ACTH type of the disease. This is because, unlike an excess pituitary secretion (probably due to a pituitary tumour), the ectopic tissue does not respond to feedback from excess cortisol in the blood, and as a result, ACTH levels are likely to be higher with this type of the condition.
  • Adrenal tumour is an ACTH-independent mechanism. The most common type of this is actually caused by steroids given as a treatment for another condition.

Clinical assessment

  • It is very important to rule out other causes first. Take a very detailed drug history.
  • Confirming diagnosis is difficult. Often obese and depressed patients will have abnormal cortisol values. Taking a random cortisol value is of no benefit whatsoever, due to daily variations, and variations caused by stress and illness. Investigations used to confirm the diagnosis of Cushing’s include:
  • 48-hour low does dexamethasone test – administration of cortisol in normal individuals will result in a reduced secretion of CRH, thus reduced ACTH, and thus reduced cortisol release. Patients with Cushing’s will fail to suppress their cortisol level to less than 50nmol/L. There is a simpler overnight test, but this produced more false positive results
  • 24-hour urinary free cortisol measurements – you have to do this test lots of times. Many normal values are unlikely to be Cushing’s, but it is still possible. It involves taking several samples to complete one test – you have to measure their total cortisol output over a 24 hour period. This should not exceed 280nmol/L. false positives are seen often, particularly in alcoholics and those with depression.
  • Circadian rhythm – patients in hospital have values of blood cortisol take at 0900 and 2400 without warning. Normal patients will show considerable variation, whilst Cushing’s patients are likely to have a high 2400 level, although probably a normal 0900 level.

Clinical differentiation between pituitary and ectopic disease is difficult, and not perhaps even necessary, as the disease is so similar clinically. Often the ectopic tumours are benign.
It does however have implications for treatment.
If ACTH is very low or even undetectable, then this suggest an adrenal tumour – the ACTH has been suppressed so much that it is no longer detectable – this can only occur in ACTH independent disease.
In differentiating ectopic from pituitary disease, you should remember that pituitary disease tends to retain some features of suppression, whilst ectopic disease will not.

Investigations

  • MRI / CT – in the case of adrenal adenomas and carcinomas (ACTH-independent Cushing’s), then the tumours are nearly always large and can be spotted on CT. Carcinomas can be distinguished by their irregular outline and possible metastasis. Often there is also adrenal hyperplasia in ACTH-dependent causes.
  • Pituitary MRI can show a pituitary tumour, but it is often very small, and in many cases may be missed.
  • Potassium levelshypokalaemia is common ectopic disease.
  • High-dose dexamethasone test – lack of any suppression suggests an adrenal tumour or an ectopic source of ACTH.
  • Chest x-ray – should always be performed to check for a carcinoma of the bronchi. However, if ectopic disease is suspected, then full CT of the lungs should be performed.
Ectopic lesions are notoriously hard to find. Further investigations may involve administration of radioactive octreotide, or even many blood tests taken from all over the body to look for the location of an ectopic source.

Treatment

Untreated, Cushing’s has a very bad prognosis. Death will usually result from MI, hypertension, infection or heart failure. There is a 50% 5-year mortality if the disease is left untreated.
The two main options of treatment are surgery and radiotherapy. In both cases, the hypersecretion of cortisol should be controlled before the ‘proper’ treatment begins.
If this preparatory medication is not given, then there is a much higher mortality once treatment begins. The usual drug for treatment is metyrapone which is an 11β-hydrolase blocker. Sometimes ketoconazole is used. When this drug is given, levels of cortisol in the urine should be measured, and amounts of the drug titrated against these values. Levels of cortisol in the urine should be kept between 150-300nmol/L.
Further treatment depends on the cause:
Cushing’s disease – pituitary dependent hyperadrenalism.
  • Trans-sphenoidal removal of the tumour is the treatment of choice. This will result in a cure in 75-80% of cases – however this is highly dependent on the surgeon.
  • External pituitary irradiation – this is slow! It is effective in 50-60% of cases, but requires a lot of follow up. It tends to be used when pituitary surgery has failed. In children, 80% of cases are cured this way.
  • Medical therapy – to reduce ACTH secretion is rarely effective. Examples of drugs include bromocryptine and cyproheptadine.
  • Bilateral adrenalectomy – this is an effective last resort if other treatments have failed.
Adrenal adenoma
  • Should be resected after remission with drug treatment has been achieved. Contralateral adrenal suppression may last for years.
Adrenal carcinoma
  • These are very aggressive and the prognosis is poor. Generally, if there are not widespread metastasis, then you should treat the primary tumour surgically. There is a drug call op’DDD (mitotane) that is adrenolytic, and this can slow progression of the disease considerably. Radiotherapy may be beneficial to some patients.
Ectopic ACTH tumours
  • These should be removed wherever possible, and if not, then chemo and radiotherapy can be beneficial.
  • Drug control of the disease will help manage symptoms, and in patients where the tumours are thought benign, the patient can often benefit from adrenalectomy.
Nelson’s syndrome
This is a syndrome that occurs after bilateral adrenalectomy for Cushing’s disease. In this syndrome, there is hyperpigmentation due to very high levels of ACTH secretion. It occurs in 20% of those who have had bilateral adrenalectomy. The syndrome is now rare, due to fact that adrenalectomy is not a first line treatment for Cushing’s disease. Its incidence can be reduced if you give radiotherapy to the pituitary after the adrenalectomy has occurred.
 

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