Hypercortisolism

Hypercortisolism refers to a range of conditions characterised by an excess of circulating corticosteroids. Endogenous hypercortisolism is known as Cushing's syndrome, and may arise from the adrenal cortex, e.g. because of an adrenal tumour, or may be secondary to overproduction of pituitary adrenocorticotrophic hormone (ACTH). The most common cause of hypercortisolism is, however, steroid therapy.

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Background

Historical aspec ts

Cushing's syndrome was first described in 1912 when the neurosurgeon Harvey Cushing described a patient known as Minnie G. She showed all the characteristic signs and symptoms of the syndrome, including hyperglycaemia. Since cortisone and adrenocorticotrophic hormone (ACTH) were unknown at the time, Cushing suggested a polyglandular disorder.

The term Cushing's syndrome was coined by Fuller Albright in 1943 to designate the consequences of overproduction of a hormone affecting carbohydrate metabolism by the adrenal cortex.[1]

In 1948 Lewis Sarett synthesised cortisone, which was then widely used without understanding of its potential adverse consequences. Two years later Van Seters demonstrated that Cushing's syndrome could also be induced by chronic treatment with glucocorticoids.[2][3]

Prevalence

Chronic treatment with glucocorticoids is the most common cause of hypercortisolism, whereas endogenous hypercortisolism (Cushing's syndrome) is a rare disease with an incidence of 10–15 per million people per year.[4] Cushing' syndrome is usually due to a pituitary adenoma and is three to five times more common in women than in men.

Hypercortisolism is associated with diabetes, obesity and hypertension, and should be considered in patients with these conditions, and in all those on steroid therapy. Some 20% of patients with Cushing's syndrome have a diagnosis of diabetes, but insulin resistance and glucose intolerance develop in up to 80% of cases. The prevalence of steroid-induced diabetes in the diabetic population may be around 3%.[5]

Subclinical hypercortisolism may also contribute to the risk of diabetes, a risk estimated at about 8/10,000 in those with a diagnosis of type 2 diabetes.[6] The prevalence of iatrogenic hypercortisolism is unknown but a study of patients on steroid therapy for rheumatoid arthritis found that 9% developed diabetes within 2 years of starting treatment.[7]

Another study found that 42% of patients with primary renal disease treated with prednisolone 0.75/kg per day developed 2-hour plasma glucose concentrations after lunch >11.2 mmol/l (200 mg/dl) despite normal fasting glucose levels.[8]

Clinical features

The natural regulation of cortisol is governed by a negative feedback response system. Output is initiated when pituitary gland secretions of ACTH stimulate the adrenal glands, which is the producer of glucocorticoids hormones in the zona fasciculata. Cortisol secretion is affected by stress which, if prolonged, can result in chronic hypercortisolaemia.

Cortisol target tissues include liver, bone, blood, vessels, kidney, muscle, brain, and immune system.

Long-term exposure to cortisol may eventually result in changes such as: osteoporosis, muscle weakening and wasting; high blood pressure, increased fat deposition in the abdomen, shoulders and face; immune dysfunction, leading to delayed healing and steroid-induced diabetes.

Classic clinical signs include a 'moon face', thinning of the skin accompanied by purple or pink stretch marks on the abdomen, easy bruising, acne, increased facial and body hair and decreased scalp hair in women.

Mechanism

The pathophysiology of diabetes mellitus in patients with hypercortisolism involves insulin resistance, enhanced gluconeogenesis and impaired insulin secretion.

Glucocorticoid excess induces an excessive glucose production acting directly on the liver and indirectly on skeletal muscles and adipose tissue.

  • Liver Glucocorticoid excess increases glucose production either directly, by activating a series of genes involved in glucose metabolism, or indirectly, by antagonising the metabolic action of insulin, the major hormone responsible for suppression of endogenous glucose production.

The increase in hepatic glucose production occurs in the basal state and is probably due to a combination of increased gluconeogenesis and stimulation of lipolysis and proteolysis, with consequent increased availability of substrates for gluconeogenesis and potentiation of other hormones involved in glucose metabolism, mainly glucagon.

  • Skeletal muscle Glucocorticoid excess reduces insulin sensitivity, directly via an impairment of insulin receptor signalling, and indirectly through its effects on lipid and protein metabolism. Glucocorticoid excess leads to decreased protein synthesis and increased protein degradation, resulting in a elevation of amino acids, especially alanine. Alanine is a potent stimulator of alpha cells, resulting an increased secretion of glucagon. Glucocorticoid excess also results in increased lipolysis and increased availability of free fatty acids resulting in impaired glucose uptake by muscle.

  • Adipose tissue Glucocorticoids are able to stimulate the differentiation of pre-adipocytes into adipocytes,responsible for increased body fat mass, as in the central obesity associated with the Cushing’s syndrome. In addiction, glucocorticoids significantly affect adipose tissue metabolism, influencing the synthesis and release of different hormones, mainly adipokines, which contribute to the development of insulin resistance. The development of insulin resistance in adipose tissue, with the predominance of visceral adipose tissue, participate in the pathogenesis of the metabolic syndrome, which is associated with the development of diabetes mellitus

  • Effect on insulin secretion Glucocorticoid excess has been found to influence insulin secretion by the pancreatic beta cells. This becomes evident after long-term treatment with glucocorticoids, which seems to induce a pancreatic beta cell dysfunction, probably as a consequence of both the inhibition of insulin synthesis and secretion, as well as apoptosis of the pancreatic beta cells and the development of diabetes mellitus.[9][10]

Investigation

High levels of glucocorticoid in urine or blood could lead to a diagnosis of Cushing's syndrome, but no biochemical test is accurate enough to distinguish Cushing's syndrome from pseudo-Cushing syndrome.

  1. 24-hour urine free cortisol (UFC). This is the best screening test for Cushing's syndrome. Two or three 24-hour collections of urine can be used to increase the accuracy of the test. In adults normal values are less than 80–120 μg (radioimmunoassay (RIA)) or 50 μg (high-performance liquid chromatography (HPLC)). In children values are less then 70 μg/m2; in women who are pregnant higher values are found.

  2. Midnight plasma and salivary cortisol levels. This test considers the normal circadian rhythm of cortisol secretion (peak in the early morning, lowest level in the late evening to a few hours after midnight). In the patients with Cushing's syndrome cortisol secretion does not decrease during this period (cut-off 7.2 μg/dl). The plasma level of cortisol is measured by means of a venous catheter. Measurement of late night salivary cortisol is as sensitive as the plasma cortisol test and is more convenient. Cut-off is 0.27 μg/dl.

  3. 1 mg overnight dexamethasone (DST). In patients with Cushing's syndrome the set point for ACTH secretion is higher than normal, so that low doses of DST cannot suppress ACTH secretion. This test consists of administering 1 mg of DST at 23.00 hours and measuring the serum cortisol level at 08.00 hours the next morning. Normal cortisol level after administration of DST would be less than 2 μg/dl. Concentrations higher than 3 μg/dl indicate Cushing's syndrome.

  4. Low-dose DST. This test consists of oral administration of 0.5 mg of DST every 6 hours for 48 hours. Cortisol level is measured at baseline and at the end of the test (cut-off <2 μg/dl).

Differential diagnosis if Cushing's syndrome

  • DST suppression-CRH stimulation test (cut-off value for cortisol 1.4 μg/dl)
  • Plasma ACTH (values >10 pg/ml are suggestive of ACTH-dependent disease; values <5 pg/ml are suggestive of ACTH-independent disease);
  • High dose DST (>50% suppression of UFC is suggestive of Cushing's syndrome)[11][12]

Treatment

The treatment of Cushing's syndrome depends upon the underlying cause. When Cushing's syndrome is caused by an ACTH-producing tumour ,the treatment can include:

• Surgery. Transsphenoidal surgery allows access to the base of the brain (where the pituitary is located), through the gums above the upper front teeth or the nose. If the tumour cannot be identified, the surgeon can remove half of the pituitary (hemihypophysectomy) or 85–90% of the gland (subtotal hypophysectomy). These treatments cause a loss of function of the pituitary so that the patient needs lifelong hormone replacement.

  • Radiation-chemotherapy. This can be used when the surgery cannot completely remove the tumour. The effects of radiation take 3–12 months to become apparent, so that medical treatment is required in the interim. These medications include ketoconazole, metyrapone and aminoglutethimide, which reduce the adrenal cortisol production.

  • Adrenalectomy. This consists in surgical removal of the adrenal glands, but is recommended only if other treatments are not successful. The patient must begin lifelong daily glucocorticoid and mineralocorticoid replacement therapy. When Cushing's syndrome is caused by an ectopic ACTH-producing tumour, the treatment consists of the surgical removal of the tumour. This kind of tumour is often in the lung. If the surgery is not successful, medications that reduce adrenal cortisol production (ketoconazole, metyrapone and aminoglutethimide) can be used.[13][14]

References

  1. ^ XXX Arq Bras Endocrinol Metabol 2007;51(8):1199–206.

  2. ^ Medvey VC, The history of Cushing syndrome: a controversial tale. J Royal Soc Med 1991;84:000–000

  3. ^ Kater CE et al. J Harvey Cushing and Philip H: when pituitary basophilism meets cortisone excess. Arq Bras Endocrinol Metabol 2007;51(8):1182–4

  4. ^ Guaraldi et al. Cushing maybe not so uncommon of an endocrine disease. J Am Board Fam Med 2012;25(2):199–208

  5. ^ Reimondo. Test di screening della sindrome di Cushing. Editoriale Ame Flash Marzo 2009

  6. ^ Chiodini I et al. Association of subclinical hypercortisolism with type 2 diabetes a case–control study in hospitalized patients. Eur J Endocrinol 2005;153(6):837–44

  7. ^ Keller DL,et al. Glucocorticoid-induced diabetes and adrenal suppression. Cleve Clin J Med. 2012 Apr;79(4):236-7.

  8. ^ Keller DL et al. Glucocorticoid-induced diabetes and adrenal suppression. Cleve Clin J Med 2012;79(4):236–7

  9. ^ Pivonello R. et al.Neuro Endocrinology 2010.Pathophysiology of Diabetes Mellitus in Cushing's Syndrome.92(suppl 1)77-81

  10. ^ Cantalamessa et all.Malattie del corticosurrene.Medicina interna sistematica di Rugarli 2010.from page 1178 to 1197

  11. ^ Marie Simard et Al -The Biochemical Investigation of Cushing Syndrome (Neurosurg Focus 16(4), 2004)

  12. ^ Kola B. et Al- Dynamic testing in Cushing's syndrome (Pituitary 2008)

  13. ^ Atkinson AB et al. Long-term remission rates after pituitary surgery for Cushing's the need for long-term surveillance. Clin Endocrinol (Oxf) 2005;00:549–000.

  14. ^ JEFFREY W. MILLER et al- The Medical Treatment of Cushing's Syndrome (Eur J Endocrinol 2010)

Footnotes

  1. ^ The original version of this page was created as part of a student project by Giulia Biscione, Antonella Caroli, Marzia De Bernardinis and Andrea Carrozzini of La Sapienza Hospital, Rome

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