Clinical Review - Cushing's syndrome

Review the causes, investigations and management of Cushing's syndrome.

Stretch marks caused by Cushing's syndrome (Photograph: SPL)
Stretch marks caused by Cushing's syndrome (Photograph: SPL)

Section 1: Epidemiology and aetiology

Cushing's syndrome (CS) is characterised by long-standing exposure to supraphysiological concentrations of circulating glucocorticoids.

The most common cause of CS is the exogenous administration of glucocorticoids, and a detailed drug history is very important.1

The more recent epidemiological studies focusing on endogenous CS have reported an overall incidence of 2.3 per million per year.

More specifically, the incidence was 1.2-1.7 per million per year for Cushing's disease (CD), 0.6 per million per year for adrenal adenomas and 0.2 per million per year for adrenal carcinomas. All the other types of CS were very rare.2

Untreated CS is associated with a high morbidity resulting in increased mortality rates because of metabolic abnormalities and infection susceptibility.

Exogenous causes
The exogenous causes of CS include the administration of glucocorticoids as medical therapy or factitious auto-administration.

A less common cause for exogenous CS is iatrogenic ACTH administration. The administration of topical, inhaled and injected corticosteroids is increasingly recognised as a cause of CS.

Endogenous causes
Endogenous CS is more common in women. The most common types are ACTH-dependent CS (80-85%), CD (80%) (for example, the ACTH-secreting pituitary adenomas) and both ectopic ACTH (20%) and corticotropin-releasing hormone (CRH) (ectopic CS) (<1%) syndromes.1

Tumours more often associated with ectopic CS are those arising from the lung, including small-cell lung carcinoma (3.3-50%) and bronchial carcinoids (5-40%), but can include islet cell tumours/pancreatic carcinoids (7.5-25%), thymic carcinoids (5-42%), phaeochromocytomas (5%) and medullary thyroid carcinoma (2-8%).3

ACTH-independent CS (20%) is caused by unilateral adrenocortical tumours or by bilateral adrenal hyperplasia or dysplasia. The most common pathology in ACTH-independent CS is a cortisol-secreting adrenal adenoma (60%) or carcinoma (40%).

Adrenal adenoma occurs most often around the age of 35 years, with an incidence of 0.6 per million per year.

The incidence of adrenal carcinoma is approximately 0.2 per million per year, is slightly more common in women, and has a bimodal age distribution, with peaks in childhood and adolescence and then later in life.

Other causes
Other causes of ACTH-independent CS are rare and include :

  • ACTH-independent bilateral macronodular adrenal hyperplasia sporadic or secondary to abnormal hormone receptor expression/function (<1%).
  • Primary pigmented nodular adrenal disease or micronodular adrenal disease (<1%), which may be sporadic or associated with Carney complex, the bilateral nodular adrenal disease in McCune-Albright syndrome (<1%).
  • Constitutive activation ACTH receptor by missense mutation (<1%).1

Section 2: Making the diagnosis

Diagnostic assessment is usually prompted by clinical suspicion in florid CS cases. However, a step-by-step diagnostic work-up based on the pathophysiological changes of the hypothalamo-pituitary-adrenal (HPA) axis is needed to confirm the diagnosis in all cases.

Signs that most reliably distinguish CS from obesity and other pseudo-cushingoid syndromes (namely depression, alcoholism, anorexia nervosa, generalised resistance to glucocorticoids, late pregnancy) are those of protein wasting, such as the presence of thin skin in the young, easy bruising and proximal weakness.1,4 The presence of several comorbidities may also raise the suspicion of CS (see box).

COMMON COMORBIDITIES IN PATIENTS WITH CS
  • Hypertension.
  • Left ventricular hypertrophy.
  • Ischaemic heart disease.
  • Prodiabetes.
  • Diabetes.
  • Obesity.
  • Hepatic steatosis.
  • Infections (urinary, lung).
  • Gonadal dysfunction.
  • Osteoporosis.
  • Psychiatric manifestations.
  • Cognitive impairment.
  • Renal calculi.
  • Thyroid disorders.
  • Growth retardation (children).
  • Polycystic ovary syndrome.

Investigations
Hypercortisolaemia must be established before any attempt at differential diagnosis. This is best performed by a combination of the following tests: 24-hour urinary free cortisol, low-dose dexamethasone suppression test (LDDST) or overnight dexamethasone suppression testing, and assessment of midnight serum or late-night salivary cortisol. Using most current assays, estimation of urinary free cortisol is not very sensitive.5-7

The second step is to establish the cause of CS by measuring plasma ACTH, which is either very low indicating an adrenal cause or readily detectable. In ACTH-dependent CS, elevated ACTH secretion results in excess adrenal gland cortisol secretion, but in ACTH-independent CS ACTH is suppressed.

Ectopic CS can have a rapid onset. A paraneoplastic wasting syndrome can mask hypercortisolism but hypokalaemia may reveal its presence. Often it is difficult to differentiate ectopic CS from CD, as both are ACTH-dependent. A rise in cortisol and ACTH to human-sequence CRH test usually suggests CD. However, neuroendocrine tumours may have many similarities to CD.

The high-dose dexamethasone suppression test is no longer in widespread use. Direct sampling of the effluent of the pituitary by bilateral inferior petrosal sinus sampling (BIPSS) most accurately identifies a pituitary source. These tumours, usually microadenomas, may not be visible on MRI.

BIPSS is recommended unless there is a clear pituitary abnormality and an ectopic source has been considered unlikely. Measurement of circulating tumour markers also has a role when ectopic CS is suspected.3

Patient with massive adrenal hyperplasia. Inconclusive diagnostic work-up for the source of ACTH-dependent Cushing’s syndrome (Photograph: Author image)

Imaging
Imaging of the adrenal glands is the main method of diagnosing adrenal causes. High-resolution CT scanning gives the best resolution of adrenal anatomy and is accurate for masses >1cm. A mass >5cm in diameter should be considered to be malignant until proven otherwise.1,3

Axial imaging with thin-cut multislice-CT of the chest and abdomen or with chest MRI has the highest detection rate for ectopic CS. Ectopic CS may be caused by small neuroendocrine tumours expressing somatostatin receptors, so somatostatin receptor scintigraphy may be used.

PET with 18-fluorodeoxyglucose is of little benefit because these tumours are usually of low metabolic activity.

Use of C-5-hydroxytryptophan PET has been proposed as a universal imaging technique for neuroendocrine tumours, but further experience is needed.3

Less commonly, genetic testing for mutations of PRKAR1A may be needed to confirm Carney's complex, selective abdominal angiography and endoscopic ultrasonography for pancreatic neuroendocrine tumours and thyroid ultrasound along with fine needle agoaspiration for medullary thyroid carcinoma.

Section 3: Managing the condition

Treatment aims to normalise cortisol levels with a reversal of clinical symptoms, in order to avoid the long-term consequences of hypercortisolism. Surgical removal of the tumour causing CS is the current first-line approach.

Medical antiglucocorticoid treatment may be required before surgery to reverse the metabolic consequences and poor healing, or in patients who cannot be submitted to surgical procedures, or as an alternative treatment if surgery fails.1,4,8

Neuromodulatory drugs have been used to suppress ACTH secretion in patients with CD.8

Surgical therapy
Selective adenomectomy (trans-sphenoidal surgery, TSS) remains the optimal treatment for ACTH-secreting pituitary adenomas. Remission rates range between 60 and 80% with a recurrence rate of 10-25% after prolonged follow-up; those rates are lower and higher respectively in patients harbouring macroadenomas.

Persistent disease might mandate immediate reoperation. Postoperative hypocortisolaemia needs glucocorticoid replacement treatment until recovery of the HPA axis.

After surgical failure, conventional fractionated external beam radiotherapy achieves control of hypercortisolaemia in 50-60% of patients within three to five years but with the risk of long-term hypopituitarism. Stereotactic radiosurgery may also be used if there is a clear target.9

Resection of the causative tumour is the optimum treatment for ectopic CS. In the case of metastatic or occult disease a multidisciplinary, individualised approach is followed.

Somatostatin analogues, systemic chemotherapy, interferon, newer biological agents, chemoembolisation, radiofrequency ablation and external radiation therapy may be used alone or in combination.3

When surgical therapy fails or in a case of occult ectopic CS and severe symptoms of CS, adrenal-directed therapy (medical or surgical) is commonly followed. Bilateral adrenalectomy induces a rapid resolution of the clinical features but patients will need lifelong treatment with glucocorticoids and mineralocorticoids.

A major concern is the development of Nelson's syndrome - a locally aggressive pituitary tumour in patients with CD. The tumour itself might be treated with further surgery or radiotherapy. Pituitary radiotherapy at the time of adrenalectomy has been considered to reduce the risk of the syndrome, but this is unproven.3,9,10

Laparoscopic adrenal removal is the treatment of choice for unilateral adrenal adenomas. Prognosis after removal of an adenoma is good. Surgical removal of an adrenal carcinoma can be attempted with limited lesions, but when metastatic these tumours are not very radioor chemosensitive. Mitotane is thought to be effective adjuvant therapy.1

Receptor blocking
Finally, in ACTH-independent bilateral macronodular adrenal hyperplasia the cortisol secretion is controlled by blocking the corresponding aberrantly expressed receptor (propranolol for beta-adrenergic receptor, somatostatin analogues for gastric inhibitory peptide receptor, leuprolide for luteinising hormone).

ANTIGLUCOCORTICOID MEDICAL TREATMENT IN CS
  • Metyrapone/ketoconazole Pros: Rapid onset of action; inhibitor of steroidogenesis.
  • Metyrapone Cons: Hypertension, hypokalaemia, oedema; hirsutism (women); escape phenomenon.
  • Ketoconazole Cons: Mild liver enzyme elevation; liver failure (rare); gynaecomastia/hypogonadism (males).
  • Fluconazole Validated only in adrenal causes.
  • Mitotane Pros: Inhibitor of steroidogenesis and adrenolytic drug. Cons: Slow onset of action; digestive symptoms; neurotoxicity; hypercholesterolaemia.
  • Etomidate Pros: Short-acting anaesthetic agent; intravascular administration.
  • Mifepristone Competitive binding glucocorticoid/androgen/progestin receptors. Pros: No follow-up marker to confirm its action.

Section 4: Prognosis

Untreated hypercortisolaemia is associated with a fivefold excess mortality and increased morbidity, and therefore rapid control is vital. The aim of the follow-up is to restore a 24-hour production rate of cortisol within the normal range, even when circadian rhythmicity has not been restored.4

Glucocorticoid withdrawal symptoms (skin flaking, fatigue, nausea, joint aches) should be anticipated in all patients. Supraphysiological doses of glucocorticoids may be initiated in some patients.

Hypocortisolism is managed with glucocorticoid replacement therapy until the HPA axis recovers. Careful advice and written instructions must be given to all patients.

In cases of a successful TSS, replacement therapy can be stopped when the morning cortisol levels or the cortisol response to an ACTH stimulation test is normal.

The possibility of Nelson's syndrome development is 8-29%. In patients with CD undergoing bilateral adrenalectomy, monitoring with regular MRI scans and plasma ACTH levels should be undertaken three to six months after bilateral adrenalectomy and then at regular intervals thereafter.

A high plasma ACTH level (>1,000ng/L) in the year after surgery may be a predictive factor for tumour progression.1,10

In the context of ectopic CS, despite detailed investigation the cause of excess and unregulated ACTH production remains occult in 5-15% of patients, and these patients need meticulous follow-up for identification of the primary tumour.3

Follow-up should be tailored to each patient with CS in relation to the cause and the success of the first-line treatment.

Section 5: Case study

A 38-year-old woman was referred for investigation of CS. Her symptoms started six years earlier when she noticed easy bruising. She had experienced hot flushes and sweating for the past two years. She was referred for premature ovarian failure.

By this time excess hair growth, weight gain, hypertension and striae over her abdomen were noted. A pituitary MRI showed a 0.5cm mass in the left side of the pituitary gland. Chest CT was negative. She did not suppress serum cortisol on the LDDST. She was admitted for further investigation.

Medical history
Her past medical and family histories were unremarkable. She was a smoker (10 pack-years) and social drinker.

On clinical examination she was plethoric with a moon face. She had xanthelasma over her right eye, purplish striae over the abdomen and bruises. The adrenal CT showed mild nodular adrenal hyperplasia. The pituitary MRI confirmed a left-sided lesion. BIPSS confirmed CD with more ACTH secreted from the left side. She had TSS; the histology showed a chromophobe adenoma, immunostaining positive for ACTH; Crooke's changes were also present.

Her postoperative morning cortisol was detectable and she had a second TSS with total hypophysectomy within 12 days. She developed transient diabetes insipidus. She had flaking skin but detectable morning cortisol and hydrocortisone replacement treatment was reduced.

Fifteen months later she was readmitted because of either partial recovery of her HPA axis or mild residual CD. Androgens, morning and midnight cortisol were high. Pituitary MRI indicated residual change on the left side, as a post-surgical change or residual tumour. Recurrence of CD was diagnosed and the plan for her further management included radiosurgery or further re-exploration.

Section 6: Evidence base

Clinical trials

  • Valassi E, Santos A, Yaneva M et al; ERCUSYN Study Group. The European Registry on Cushing's syndrome: 2-year experience. Baseline demographic and clinical characteristics. Eur J Endocrinol 2011; 165(3): 383-92.
  • Clayton RN, Raskauskiene D, Reulen RC et al. Mortality and morbidity in Cushing's disease over 50 years in Stoke-on-Trent, UK: audit and meta-analysis of literature. J Clin Endocrinol Metab 2011; 96(3): 632-42.
    Page 163: ABLE 4. Summary of all studies reporting mortality in CD.
  • Guignat L, Bertherat J. The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline: commentary from a European perspective. Eur J Endocrinol 2010; 163(1): 9-13.
    Page 163: Table 1. Diagnosis of Cushing's syndrome: who should be investigated?
    Page 164: Table 2. How to investigate for Cushing's syndrome.

Guidelines

  • Nieman LK, Biller BM, Findling JW et al. The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2008; 93(5): 1526-40.
    Page 1,528: Table 1. Overlapping conditions and clinical features of Cushing's syndrome.
    Page 1,531: Figure 1. Algorithm for testing patients suspected of having Cushing's syndrome.
  • Biller BM, Grossman AB, Stewart PM et al. Treatment of adrenocorticotropin-dependent Cushing's syndrome: a consensus statement. J Clin Endocrinol Metab 2008; 93(7): 2454-62.
    Page 2,455: Criteria for Cure and Remission of ACTH-Dependent Cushing's Syndrome.

Click here to take a test on this article and claim a certificate on MIMS Learning

CPD IMPACT: EARN MORE CREDITS

These further action points may allow you to earn more credits by increasing the time spent and the impact achieved.

  • Consider how you can optimise the follow-up care of any patients with CS that you see – does your follow-up plan factor in the cause of CS and the treatments used?
  • Review The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline (see Evidence Base, above).
  • Reflect on how well you are able to explain the range of possible treatments to patients. Consider if you need to revise or update your knowledge of these.
  • By Dr Krystallenia Alexandraki, consultant endocrinologist, Barts and The London NHS Trust, and Professor Ashley Grossman, professor of endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism.

References

1. Newell-Price J, Bertagna X, Grossman AB et al. Lancet 2006; 367: 1605-17.

2. Steffensen C, Bak AM, Rubeck KZ et al. Neuroendocrinology 2010; 92 Suppl 1: 1-5.

3. Alexandraki KI, Grossman AB. Rev Endocr Metab Disord 2010; 11: 117-26.

4. Newell-Price J, Trainer P, Besser M et al. Endocr Rev 1998; 19: 647-72.

5. Nieman LK, Biller BM, Findling JW et al. J Clin Endocrinol Metab 2008; 93: 1,526-40.

6. Alexandraki KI, Grossman AB. Curr Opin Endocrinol Diabetes Obes 2011; 18: 259-63.

7. Alexandraki KI, Grossman AB. Neuroendocrinology 2010; 92 Suppl 1: 35-43.

8. Alexandraki KI, Grossman AB. Front Horm Res 2010; 38: 165-73.

9. Biller BM, Grossman AB, Stewart PM et al. J Clin Endocrinol Metab 2008; 93: 2,454-62.

10. Arnaldi G, Angeli A, Atkinson AB et al. J Clin Endocrinol Metab 2003; 88: 5,593-602.

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