- Email: [email protected]
Cushing's syndrome
PITUITARY DISORDERS
Cushing’s syndrome
Key points
Eleni Daniel
C
A diagnosis of Cushing’s syndrome must be established before any attempt is made to consider a differential diagnosis for the cause
C
Cushing’s disease (adrenocorticotrophic hormone-dependent Cushing’s syndrome caused by a pituitary gland corticotroph tumour) is the most common cause
C
Surgical excision of the tumour causing the endogenous Cushing’s syndrome is the mainstay of therapy
C
Underlying molecular mechanisms of adrenal and pituitary causes of Cushing’s syndrome have been delineated
C
The number of medical treatments is increasing
C
International guidelines summarize approaches to diagnosis and treatment
John Newell-Price
Abstract Endogenous Cushing’s syndrome results from prolonged, excessive, inappropriate concentrations of circulating cortisol. Cushing’s syndrome should be considered in patients with unusual features for age, patients with multiple and progressive features, children with decreasing height percentile and increasing weight, and patients with adrenal adenoma found incidentally. Endogenous Cushing’s syndrome is more common in women than men. Adrenocorticotrophic hormone (ACTH)-dependent causes account for about 80% of cases. Of ACTH-dependent cases, 80% result from pituitary adenomas (Cushing’s disease) and the remainder from ectopic ACTH secretion. Non-ACTH-dependent Cushing’s syndrome is caused by benign adrenal adenomas in 60% and carcinomas in 40%. Specialist assessment and treatment warrants referral to major centres. For diagnosis, the most discriminating clinical features are thin skin, easy bruising and proximal myopathy. Biochemical diagnosis is by a combination of low-dose dexamethasone suppression tests, assessment of loss of circadian rhythm and urinary free cortisol. When differentiating pituitary and non-pituitary sources of ACTH, reliance should be placed on biochemical evaluation. Medical therapy is often used preoperatively to lower plasma cortisol, postoperatively to control concentrations in patients not cured, and after radiotherapy. Trans-sphenoidal surgery is the treatment of choice for Cushing’s disease; laparoscopic bilateral adrenalectomy can be used in refractory cases.
Definitions and epidemiology Cushing’s syndrome results from prolonged and inappropriate exposure to excessive circulating free glucocorticoid e cortisol in endogenous Cushing’s syndrome.1 The incidence of Cushing’s syndrome is quoted as 1/250,000, with no specific geographical variation, but is likely to be higher as patients are increasingly found with milder disease.
Keywords Adrenal; adrenocorticotrophic hormone; cortisol; Cush-
Aetiology
ing’s syndrome/disease; dexamethasone; ectopic; MRCP; pituitary
Endogenous Cushing’s syndrome is more common in women than men; adrenocorticotrophic hormone (ACTH)-dependent causes account for about 80% of cases. Of ACTH-dependent cases, 80% are caused by a pituitary adenoma (termed Cushing’s disease) and the remainder by ectopic ACTH secretion, mainly as a consequence of neuroendocrine tumours, particularly bronchial. Cushing’s disease is the cause in 90% of women.1,2 ACTH-independent Cushing’s syndrome is caused by benign adrenal adenoma in 60% of cases and carcinoma in 40%. Very rare adrenal causes are bilateral primary pigmented nodular hyperplasia (isolated or part of Carney complex), macronodular adrenal hyperplasia, ectopic actions of G-protein-coupled receptors (e.g. gastric-inhibitory peptide receptor, b-adrenergic receptor), and McCuneeAlbright syndrome. Somatic mutations in the catalytic subunit of protein kinase A,3 and in the deubiquitinase gene USP8,4 cause adrenal and pituitary Cushing’s in around 40e50% of cases, respectively.
Introduction Cushing’s syndrome is challenging, and it is recommended that early referral be made to an endocrine centre familiar with all the inherent pitfalls of diagnosis and management.
Eleni Daniel MSc MRCP is a research fellow at the University of Sheffield, and Sheffield Teaching Hospitals Trust, UK. Her research interests include adrenal disease and hormone treatment replacement strategies. Competing interests: none declared. John Newell-Price MA PhD FRCP is Professor of Endocrinology and Consultant Endocrinologist at the University of Sheffield, and Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Trust, UK. Research and clinical interests include glucocorticoids and pituitary and neuroendocrine tumours, and he has published widely in these areas. He is co-author of international guidelines on Cushing’s syndrome (2008, 2015) for the Endocrine Society (USA) and adrenal incidentaloma (2016) for the European Society for Endocrinology. Competing interests: JNP has research and consultancy income from Novartis, HRA Pharma and Ipsen.
MEDICINE --:-
Clinical features Patients often have a history of symptoms lasting 1e2 years before confirmation of the diagnosis (Table 1). The signs that most reliably distinguish Cushing’s syndrome are thin skin, easy bruising and proximal myopathy. It is essential to exclude 1
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Daniel E, Newell-Price J, Cushing’s syndrome, Medicine (2017), http://dx.doi.org/10.1016/ j.mpmed.2017.05.007
PITUITARY DISORDERS
sometimes over many years. This can cause considerable diagnostic difficulty, and reinvestigation at intervals and on several occasions may be required. Oral oestrogens increase cortisol-binding globulin and therefore lead to falsely elevated serum cortisol concentration; they should be stopped for 6 weeks before investigation.
Clinical features of Cushing’s syndrome C C C C C C C C C C C C C C C
a
Obesity Moon facies Hypertension ‘Buffalo hump’ Thin skina Hirsutism Oligomenorrhoea/amenorrhoea Purple striae Impaired glucose tolerance/diabetes mellitus Proximal muscle atrophya Psychiatric disturbance Osteoporosis Bruisinga Acne Hypokalaemia
Diagnosis of Cushing’s syndrome Three principal tests are commonly used to establish the diagnosis (Figure 2):1,2 low-dose dexamethasone suppression test late-night salivary or midnight serum cortisol 24-hour urinary free cortisol. At least two different concordantly abnormal tests are needed to establish the diagnosis. Low-dose dexamethasone suppression test: two tests are in common use: 1 mg overnight (dexamethasone, 1 mg, is given at 11:00 hours and serum cortisol measured at 09:00 hours the next day) 48-hour test (dexamethasone, 0.5 mg, is given at 09:00 hours, 15:00 hours, 21:00 hours and 03:00 hours, and serum cortisol measured at 09:00 hours at the start and end of the test) In healthy subjects, serum cortisol is <50 nmol/litre (1.8 micrograms/dl) following either test. Both tests can give falsepositive results if patients are taking drugs that increase hepatic clearance of dexamethasone, including carbamazepine, phenytoin, phenobarbital and rifampicin. Five per cent of patients with Cushing’s disease show serum cortisol suppression to <50 nmol/litre; therefore, if the clinical index of suspicion is high, re-testing and use of other tests is advised.
Most discriminating features.
Table 1
exogenous glucocorticoids as the cause of a ‘Cushingoid appearance’. Who to test? Testing for Cushing’s syndrome is indicated in patients with unusual features for their age (e.g. osteoporosis and livid striae in young men) (Figure 1), patients with multiple and progressive features, children with decreasing height percentile and increasing weight, and patients with adrenal adenoma found incidentally on computed tomography (CT) scans performed for other reasons.2
Diagnosis
Assessment of loss of circadian rhythm of salivary or serum cortisol: the normal circadian rhythm of cortisol secretion is lost in Cushing’s syndrome. Late-night salivary cortisol is a useful screening test and can be performed in the community. Use of liquid chromatography tandem mass spectrometry (LC-MS/MS) is recommended. Sleeping midnight serum cortisol concentration is also used for this purpose but requires hospital admission, is recommended only in endocrine units and is not needed in patients with a florid Cushing’s phenotype and other positive tests as detailed in this section: a value <50 nmol/litre effectively excludes Cushing’s syndrome.
Diagnosis of Cushing’s syndrome is a two-step process (Figure 2). It is essential that the diagnosis be confirmed before attempting to determine the cause (see below). Acute intercurrent illness causes hypercortisolaemia and false-positive results for the diagnosis of Cushing’s syndrome. For unknown reasons, some patients with Cushing’s syndrome exhibit cyclical secretion of cortisol, which can fluctuate and remit spontaneously,
24-Hour urinary free cortisol: at least three collections are required to avoid missing mild disease. The amount excreted is reduced in renal impairment. Determining the cause of Cushing’s syndrome After confirming Cushing’s syndrome (Figure 2), plasma ACTH is measured. To avoid obtaining falsely low results, samples must be cold-centrifuged immediately after sampling, and ‘flashfrozen’ (40 C) before storage for later assay.1,2,5 Plasma ACTH <5 pg/ml (<1.1 pmol/litre) indicates a primary adrenal cause of Cushing’s syndrome, and the adrenal glands should be imaged by CT or magnetic resonance imaging (MRI).
Figure 1 Striae in Cushing’s syndrome.
MEDICINE --:-
2
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Daniel E, Newell-Price J, Cushing’s syndrome, Medicine (2017), http://dx.doi.org/10.1016/ j.mpmed.2017.05.007
PITUITARY DISORDERS
The diagnosis and differential diagnosis of Cushing’s syndrome Differential diagnosis Cushing’s syndrome confirmed Diagnosis of Cushing’s syndrome Clinical suspicion/decision to screen
• Low-dose dexamethasone suppression test (LDDST) or overnight dexamethasone suppression test (ONDST) • Urinary free cortisol (UFC) • Midnight serum cortisol (Midnight F) • Late night salivary cortisol
• • • •
Cushing’s syndrome confirmed if: Serum cortisol >50nmol/litre on LDDST/ONDST UFC elevated Midnight F >50nmol/litre asleep or >207nmol/litre awake Salivary cortisol elevated
>15pg/ml
Measure plasma ACTH
ACTH-dependent Cushing’s syndrome
ACTH-independent Cushing’s syndrome
Pituitary MRI and CRH test: Adenoma >6mm Inconclusive AND Positive CRH response AND Suppression on Dexamethasone
+ve ACTH gradient
Cushing’s disease
Small/no adenoma
Adrenal imaging with CT
BIPSS Adrenal lesion
No adrenal lesion
Adenoma Carcinoma AIMAH
PPNAD Exogenous glucocorticoid
No ACTH gradient
CT/MRI thorax and abdomen ± Somatostatin scintigraphy Ectopic ACTH
If any doubt, tests should be repeated
<5pg/ml on more than two occasions
AIMAH, ACTH-independent macronodular adrenal hyperplasia; PPNAD, primary pigmented nodular adrenal disease. For other abbreviations, see text Figure 2
ACTH concentrations persistently >15 pg/ml can be confidently ascribed to ACTH-dependent pathologies and require investigation as discussed below. ACTH concentrations of 5e15 pg/ml require cautious interpretation because individuals with Cushing’s disease can have plasma ACTH concentrations <10 pg/ml. At least two or three estimations are made, to avoid inappropriate classification.
Plasma potassium: ectopic ACTH secretion is usually associated with higher circulating concentrations of cortisol in Cushing’s disease. These overwhelm the 11b-hydroxysteroid dehydrogenase type II enzyme, allowing cortisol to act as a mineralocorticoid in the kidney. Hypokalaemia is consequently more common in ectopic ACTH secretion, but is also present in 10% of patients with Cushing’s disease.1,2,5 Dynamic tests High-dose dexamethasone suppression test: dexamethasone, 2 mg orally, is administered strictly 6-hourly and serum cortisol measured basally and at 48 hours. In about 80% of patients with Cushing’s disease, cortisol is reduced to <50% of the basal concentration. However, this is lower than the pre-test likelihood of Cushing’s disease in women (90%), so this test is no longer recommended where there is access to bilateral inferior petrosal sinus sampling (BIPSS) (see below).1,5
ACTH-dependent Cushing’s syndrome: ACTH-secreting nonpituitary neuroendocrine tumours (e.g. carcinoid tumours) can mimic many of the clinical features of Cushing’s disease (pituitary). Biochemical evaluation rather than imaging should be relied on to differentiate pituitary from non-pituitary sources of ACTH, and it is strongly recommended that this be performed in a major referral centre. Basal tests Plasma ACTH: circulating concentrations of plasma ACTH in Cushing’s disease and ectopic ACTH secretion overlap considerably and are not useful for discriminating between the two.
MEDICINE --:-
Corticotrophin-releasing hormone (CRH) test: CRH stimulates release of ACTH from the corticotrophs of the anterior pituitary. Patients with Cushing’s disease typically exhibit an excessive
3
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Daniel E, Newell-Price J, Cushing’s syndrome, Medicine (2017), http://dx.doi.org/10.1016/ j.mpmed.2017.05.007
PITUITARY DISORDERS
increase in plasma cortisol, whereas those with ectopic ACTH secretion usually do not.5 BIPSS: this is a highly specialized, invasive investigation, but is the most reliable test for differentiating pituitary and nonpituitary sources of ACTH. A basal central to peripheral ACTH gradient of >2:1, or a CRH-stimulated gradient of >3:1, is indicative of Cushing’s disease.1,5
Optic chiasm
Pituitary tumour
Imaging Pituitary: most corticotroph adenomas are <1 cm in diameter and give a hypo-intense signal on MRI that fails to enhance with gadolinium (Figure 3 shows an MRI scan without labels; Figure 4 shows it fully labelled). Using standard MRI protocols, 40% of corticotroph microadenomas are not visualized,1,5 and ‘incidentalomas’ are found in 10% of the healthy population,5 emphasizing the importance of biochemical assessment.
Normal pituitary
Figure 4 T1-weighted gadolinium-enhanced MRI of the pituitary, labelled accordingly.
Adrenal: CT provides the greatest spatial resolution for assessment of adrenal anatomy.
The prognosis following removal of adrenocortical cortisolsecreting adenomas is good. In contrast, prognosis is usually poor in patients with adrenocortical carcinoma. In ACTH-dependent Cushing’s syndrome of any cause, bilateral adrenalectomy may be required to control cortisol concentration. Nelson’s syndrome (development of a locally aggressive pituitary tumour secreting high concentrations of ACTH, resulting in pigmentation) is a major concern following bilateral adrenalectomy in patients with refractory Cushing’s disease. The tumour can be treated with further surgery and radiotherapy, but these seldom cure the disease.
Imaging in ectopic ACTH secretion: the most common sites of ectopic ACTH secretion are small cell lung cancers and bronchial carcinoid tumours, but tumours can arise in any tissue. Highdefinition, multislice CT is required. Carcinoid tumours can be visualized by radiolabelled octreotide scintigraphy.
Management Surgery for Cushing’s syndrome Trans-sphenoidal surgery: selective microadenomectomy by an experienced surgeon is the treatment of choice in most patients with Cushing’s disease. Long-lasting remission without other pituitary hormonal deficiency is achieved in 50e60% of cases.1,5
Ectopic ACTH: complete excision of an ACTH-secreting tumour usually results in long-lasting remission. Other treatments Medical therapy to lower cortisol can be used in preparation for surgery or after unsuccessful surgery. It is seldom a long-term solution, and is mainly used as an adjunctive treatment with other modalities such as pituitary radiotherapy.1,5 Metyrapone, increasing every 72 hours up to 500e1000 mg three or four times daily, and ketoconazole, increasing at 4e5-day intervals, up to 200e400 mg three times daily, are often used to inhibit cortisol synthesis, aiming for a mean serum cortisol of 150 e300 mmol/litre, or correction of abnormal elevated urinary free cortisol excretion. Stomach acid is needed for absorption of ketoconazole. Metyrapone causes an increase in corticosteroid androgenic precursors, and hirsutism is an adverse effect in women; this does not occur with ketoconazole. In the UK, o,p0 DDD (mitotane) is usually reserved for the treatment of adrenocortical carcinoma. Pasireotide, a multi-receptor somatostatin analogue, reduces ACTH secretion and is effective in approximately 25% of patients with Cushing’s disease,5 but hyperglycaemia is a major adverse effect. Mifepristone (unlicensed in the UK), a glucocorticoid receptor antagonist is also effective for treatment, but is very challenging to use as biochemical monitoring of response is not possible.5
Adrenal surgery: laparoscopic unilateral adrenalectomy is the treatment of choice in patients with an isolated adrenal adenoma.
Pituitary radiotherapy: following trans-sphenoidal surgery, persisting hypercortisolaemia can be treated with pituitary
Figure 3 T1-weighted gadolinium-enhanced MRI of the pituitary.
MEDICINE --:-
Pituitary stalk
4
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Daniel E, Newell-Price J, Cushing’s syndrome, Medicine (2017), http://dx.doi.org/10.1016/ j.mpmed.2017.05.007
PITUITARY DISORDERS
radiotherapy or gamma knife radiosurgery.5 Progressive anterior pituitary failure is the major adverse effect; growth hormone deficiency is present in almost all patients 10 years after treatment and gonadotrophin deficiency in about 15%. About 4 years after treatment, 80% of patients are in remission with respect to circulating serum cortisol concentration. Associated conditions such as hypertension and diabetes mellitus must also be treated.
2 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: 1526e40. G, et al. Constitutive activation of 3 Beuschlein F, Fassnacht M, Assie PKA catalytic subunit in adrenal Cushing’s syndrome. N Engl J Med 2014; 370: 1019e28. 4 Reincke M, Sbiera S, Hayakawa A, et al. Mutations in the deubiquitinase gene USP8 cause Cushing’s disease. Nat Genet 2015; 47: 31e8. 5 Nieman LK, Biller BM, Findling JW, et al. Endocrine Society. Treatment of Cushing’s syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2015; 100: 2807e31.
Prognosis Inadequately treated Cushing’s syndrome has a 5-fold standardized mortality rate; this returns to normal with timely control of hypercortisolaemia, although some cardiovascular risk remains (see Further reading). Depression often persists for years after cure.1,5 A
FURTHER READING Clayton RN, Jones PW, Reulen RC, et al. Mortality in patients with Cushing’s disease more than 10 years after remission: a multicentre, multinational, retrospective cohort study. Lancet Diabetes Endocrinol 2016; 4: 569e76.
KEY REFERENCES 1 Newell-Price J, Bertagna X, Grossman AB, Nieman LK. Cushing’s syndrome. Lancet 2006; 367: 1605e17.
TEST YOURSELF To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the end of the issue or online here.
Question 1
What is the most appropriate further diagnostic test? A CT scan of the adrenal glands B MRI scan of the pituitary C Bilateral inferior petrosal sinus sampling D CT scan of the thorax E Octreotide scintigraphy scan
A 36-year-old woman presented with a 6-month history of central weight gain, bruising and weakness when climbing stairs. On clinical examination, heart rate was 76 beats per minute and blood pressure 154/98 mmHg supine. Bruises were noted on her legs, and purple striae on her abdomen. What is the most appropriate initial diagnostic test? A Urine metanephrine concentrations B Midnight serum cortisol C Overnight 1 mg dexamethasone suppression test D Plasma adrenocorticotrophic hormone E Corticotrophin-releasing hormone test
Question 3 A 44-year-old man is diagnosed with Cushing’s disease. Magnetic resonance imaging of the pituitary showed a 6 mm tumour. He was taking an angiotensin-converting enzyme inhibitor and calcium channel antagonist for hypertension. On clinical examination, there were clear signs of Cushing’s syndrome. Heart rate was 74 beats/minute and blood pressure 138/80 mmHg supine. There was little evidence of myopathy.
Question 2 A 36-year-old woman had endogenous Cushing’s syndrome confirmed biochemically; her 09:00 hours plasma adrenocorticotrophic hormone was <5 pg/ml (normal range 5e47) on two occasions.
MEDICINE --:-
What is the next most appropriate form of management? A Metyrapone therapy B Ketoconazole therapy C Trans-sphenoidal pituitary surgery D Bilateral adrenalectomy E Gamma knife radiosurgery to the pituitary lesion
5
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Daniel E, Newell-Price J, Cushing’s syndrome, Medicine (2017), http://dx.doi.org/10.1016/ j.mpmed.2017.05.007
Cushing’s syndrome
Key points
Eleni Daniel
C
A diagnosis of Cushing’s syndrome must be established before any attempt is made to consider a differential diagnosis for the cause
C
Cushing’s disease (adrenocorticotrophic hormone-dependent Cushing’s syndrome caused by a pituitary gland corticotroph tumour) is the most common cause
C
Surgical excision of the tumour causing the endogenous Cushing’s syndrome is the mainstay of therapy
C
Underlying molecular mechanisms of adrenal and pituitary causes of Cushing’s syndrome have been delineated
C
The number of medical treatments is increasing
C
International guidelines summarize approaches to diagnosis and treatment
John Newell-Price
Abstract Endogenous Cushing’s syndrome results from prolonged, excessive, inappropriate concentrations of circulating cortisol. Cushing’s syndrome should be considered in patients with unusual features for age, patients with multiple and progressive features, children with decreasing height percentile and increasing weight, and patients with adrenal adenoma found incidentally. Endogenous Cushing’s syndrome is more common in women than men. Adrenocorticotrophic hormone (ACTH)-dependent causes account for about 80% of cases. Of ACTH-dependent cases, 80% result from pituitary adenomas (Cushing’s disease) and the remainder from ectopic ACTH secretion. Non-ACTH-dependent Cushing’s syndrome is caused by benign adrenal adenomas in 60% and carcinomas in 40%. Specialist assessment and treatment warrants referral to major centres. For diagnosis, the most discriminating clinical features are thin skin, easy bruising and proximal myopathy. Biochemical diagnosis is by a combination of low-dose dexamethasone suppression tests, assessment of loss of circadian rhythm and urinary free cortisol. When differentiating pituitary and non-pituitary sources of ACTH, reliance should be placed on biochemical evaluation. Medical therapy is often used preoperatively to lower plasma cortisol, postoperatively to control concentrations in patients not cured, and after radiotherapy. Trans-sphenoidal surgery is the treatment of choice for Cushing’s disease; laparoscopic bilateral adrenalectomy can be used in refractory cases.
Definitions and epidemiology Cushing’s syndrome results from prolonged and inappropriate exposure to excessive circulating free glucocorticoid e cortisol in endogenous Cushing’s syndrome.1 The incidence of Cushing’s syndrome is quoted as 1/250,000, with no specific geographical variation, but is likely to be higher as patients are increasingly found with milder disease.
Keywords Adrenal; adrenocorticotrophic hormone; cortisol; Cush-
Aetiology
ing’s syndrome/disease; dexamethasone; ectopic; MRCP; pituitary
Endogenous Cushing’s syndrome is more common in women than men; adrenocorticotrophic hormone (ACTH)-dependent causes account for about 80% of cases. Of ACTH-dependent cases, 80% are caused by a pituitary adenoma (termed Cushing’s disease) and the remainder by ectopic ACTH secretion, mainly as a consequence of neuroendocrine tumours, particularly bronchial. Cushing’s disease is the cause in 90% of women.1,2 ACTH-independent Cushing’s syndrome is caused by benign adrenal adenoma in 60% of cases and carcinoma in 40%. Very rare adrenal causes are bilateral primary pigmented nodular hyperplasia (isolated or part of Carney complex), macronodular adrenal hyperplasia, ectopic actions of G-protein-coupled receptors (e.g. gastric-inhibitory peptide receptor, b-adrenergic receptor), and McCuneeAlbright syndrome. Somatic mutations in the catalytic subunit of protein kinase A,3 and in the deubiquitinase gene USP8,4 cause adrenal and pituitary Cushing’s in around 40e50% of cases, respectively.
Introduction Cushing’s syndrome is challenging, and it is recommended that early referral be made to an endocrine centre familiar with all the inherent pitfalls of diagnosis and management.
Eleni Daniel MSc MRCP is a research fellow at the University of Sheffield, and Sheffield Teaching Hospitals Trust, UK. Her research interests include adrenal disease and hormone treatment replacement strategies. Competing interests: none declared. John Newell-Price MA PhD FRCP is Professor of Endocrinology and Consultant Endocrinologist at the University of Sheffield, and Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Trust, UK. Research and clinical interests include glucocorticoids and pituitary and neuroendocrine tumours, and he has published widely in these areas. He is co-author of international guidelines on Cushing’s syndrome (2008, 2015) for the Endocrine Society (USA) and adrenal incidentaloma (2016) for the European Society for Endocrinology. Competing interests: JNP has research and consultancy income from Novartis, HRA Pharma and Ipsen.
MEDICINE --:-
Clinical features Patients often have a history of symptoms lasting 1e2 years before confirmation of the diagnosis (Table 1). The signs that most reliably distinguish Cushing’s syndrome are thin skin, easy bruising and proximal myopathy. It is essential to exclude 1
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Daniel E, Newell-Price J, Cushing’s syndrome, Medicine (2017), http://dx.doi.org/10.1016/ j.mpmed.2017.05.007
PITUITARY DISORDERS
sometimes over many years. This can cause considerable diagnostic difficulty, and reinvestigation at intervals and on several occasions may be required. Oral oestrogens increase cortisol-binding globulin and therefore lead to falsely elevated serum cortisol concentration; they should be stopped for 6 weeks before investigation.
Clinical features of Cushing’s syndrome C C C C C C C C C C C C C C C
a
Obesity Moon facies Hypertension ‘Buffalo hump’ Thin skina Hirsutism Oligomenorrhoea/amenorrhoea Purple striae Impaired glucose tolerance/diabetes mellitus Proximal muscle atrophya Psychiatric disturbance Osteoporosis Bruisinga Acne Hypokalaemia
Diagnosis of Cushing’s syndrome Three principal tests are commonly used to establish the diagnosis (Figure 2):1,2 low-dose dexamethasone suppression test late-night salivary or midnight serum cortisol 24-hour urinary free cortisol. At least two different concordantly abnormal tests are needed to establish the diagnosis. Low-dose dexamethasone suppression test: two tests are in common use: 1 mg overnight (dexamethasone, 1 mg, is given at 11:00 hours and serum cortisol measured at 09:00 hours the next day) 48-hour test (dexamethasone, 0.5 mg, is given at 09:00 hours, 15:00 hours, 21:00 hours and 03:00 hours, and serum cortisol measured at 09:00 hours at the start and end of the test) In healthy subjects, serum cortisol is <50 nmol/litre (1.8 micrograms/dl) following either test. Both tests can give falsepositive results if patients are taking drugs that increase hepatic clearance of dexamethasone, including carbamazepine, phenytoin, phenobarbital and rifampicin. Five per cent of patients with Cushing’s disease show serum cortisol suppression to <50 nmol/litre; therefore, if the clinical index of suspicion is high, re-testing and use of other tests is advised.
Most discriminating features.
Table 1
exogenous glucocorticoids as the cause of a ‘Cushingoid appearance’. Who to test? Testing for Cushing’s syndrome is indicated in patients with unusual features for their age (e.g. osteoporosis and livid striae in young men) (Figure 1), patients with multiple and progressive features, children with decreasing height percentile and increasing weight, and patients with adrenal adenoma found incidentally on computed tomography (CT) scans performed for other reasons.2
Diagnosis
Assessment of loss of circadian rhythm of salivary or serum cortisol: the normal circadian rhythm of cortisol secretion is lost in Cushing’s syndrome. Late-night salivary cortisol is a useful screening test and can be performed in the community. Use of liquid chromatography tandem mass spectrometry (LC-MS/MS) is recommended. Sleeping midnight serum cortisol concentration is also used for this purpose but requires hospital admission, is recommended only in endocrine units and is not needed in patients with a florid Cushing’s phenotype and other positive tests as detailed in this section: a value <50 nmol/litre effectively excludes Cushing’s syndrome.
Diagnosis of Cushing’s syndrome is a two-step process (Figure 2). It is essential that the diagnosis be confirmed before attempting to determine the cause (see below). Acute intercurrent illness causes hypercortisolaemia and false-positive results for the diagnosis of Cushing’s syndrome. For unknown reasons, some patients with Cushing’s syndrome exhibit cyclical secretion of cortisol, which can fluctuate and remit spontaneously,
24-Hour urinary free cortisol: at least three collections are required to avoid missing mild disease. The amount excreted is reduced in renal impairment. Determining the cause of Cushing’s syndrome After confirming Cushing’s syndrome (Figure 2), plasma ACTH is measured. To avoid obtaining falsely low results, samples must be cold-centrifuged immediately after sampling, and ‘flashfrozen’ (40 C) before storage for later assay.1,2,5 Plasma ACTH <5 pg/ml (<1.1 pmol/litre) indicates a primary adrenal cause of Cushing’s syndrome, and the adrenal glands should be imaged by CT or magnetic resonance imaging (MRI).
Figure 1 Striae in Cushing’s syndrome.
MEDICINE --:-
2
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Daniel E, Newell-Price J, Cushing’s syndrome, Medicine (2017), http://dx.doi.org/10.1016/ j.mpmed.2017.05.007
PITUITARY DISORDERS
The diagnosis and differential diagnosis of Cushing’s syndrome Differential diagnosis Cushing’s syndrome confirmed Diagnosis of Cushing’s syndrome Clinical suspicion/decision to screen
• Low-dose dexamethasone suppression test (LDDST) or overnight dexamethasone suppression test (ONDST) • Urinary free cortisol (UFC) • Midnight serum cortisol (Midnight F) • Late night salivary cortisol
• • • •
Cushing’s syndrome confirmed if: Serum cortisol >50nmol/litre on LDDST/ONDST UFC elevated Midnight F >50nmol/litre asleep or >207nmol/litre awake Salivary cortisol elevated
>15pg/ml
Measure plasma ACTH
ACTH-dependent Cushing’s syndrome
ACTH-independent Cushing’s syndrome
Pituitary MRI and CRH test: Adenoma >6mm Inconclusive AND Positive CRH response AND Suppression on Dexamethasone
+ve ACTH gradient
Cushing’s disease
Small/no adenoma
Adrenal imaging with CT
BIPSS Adrenal lesion
No adrenal lesion
Adenoma Carcinoma AIMAH
PPNAD Exogenous glucocorticoid
No ACTH gradient
CT/MRI thorax and abdomen ± Somatostatin scintigraphy Ectopic ACTH
If any doubt, tests should be repeated
<5pg/ml on more than two occasions
AIMAH, ACTH-independent macronodular adrenal hyperplasia; PPNAD, primary pigmented nodular adrenal disease. For other abbreviations, see text Figure 2
ACTH concentrations persistently >15 pg/ml can be confidently ascribed to ACTH-dependent pathologies and require investigation as discussed below. ACTH concentrations of 5e15 pg/ml require cautious interpretation because individuals with Cushing’s disease can have plasma ACTH concentrations <10 pg/ml. At least two or three estimations are made, to avoid inappropriate classification.
Plasma potassium: ectopic ACTH secretion is usually associated with higher circulating concentrations of cortisol in Cushing’s disease. These overwhelm the 11b-hydroxysteroid dehydrogenase type II enzyme, allowing cortisol to act as a mineralocorticoid in the kidney. Hypokalaemia is consequently more common in ectopic ACTH secretion, but is also present in 10% of patients with Cushing’s disease.1,2,5 Dynamic tests High-dose dexamethasone suppression test: dexamethasone, 2 mg orally, is administered strictly 6-hourly and serum cortisol measured basally and at 48 hours. In about 80% of patients with Cushing’s disease, cortisol is reduced to <50% of the basal concentration. However, this is lower than the pre-test likelihood of Cushing’s disease in women (90%), so this test is no longer recommended where there is access to bilateral inferior petrosal sinus sampling (BIPSS) (see below).1,5
ACTH-dependent Cushing’s syndrome: ACTH-secreting nonpituitary neuroendocrine tumours (e.g. carcinoid tumours) can mimic many of the clinical features of Cushing’s disease (pituitary). Biochemical evaluation rather than imaging should be relied on to differentiate pituitary from non-pituitary sources of ACTH, and it is strongly recommended that this be performed in a major referral centre. Basal tests Plasma ACTH: circulating concentrations of plasma ACTH in Cushing’s disease and ectopic ACTH secretion overlap considerably and are not useful for discriminating between the two.
MEDICINE --:-
Corticotrophin-releasing hormone (CRH) test: CRH stimulates release of ACTH from the corticotrophs of the anterior pituitary. Patients with Cushing’s disease typically exhibit an excessive
3
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Daniel E, Newell-Price J, Cushing’s syndrome, Medicine (2017), http://dx.doi.org/10.1016/ j.mpmed.2017.05.007
PITUITARY DISORDERS
increase in plasma cortisol, whereas those with ectopic ACTH secretion usually do not.5 BIPSS: this is a highly specialized, invasive investigation, but is the most reliable test for differentiating pituitary and nonpituitary sources of ACTH. A basal central to peripheral ACTH gradient of >2:1, or a CRH-stimulated gradient of >3:1, is indicative of Cushing’s disease.1,5
Optic chiasm
Pituitary tumour
Imaging Pituitary: most corticotroph adenomas are <1 cm in diameter and give a hypo-intense signal on MRI that fails to enhance with gadolinium (Figure 3 shows an MRI scan without labels; Figure 4 shows it fully labelled). Using standard MRI protocols, 40% of corticotroph microadenomas are not visualized,1,5 and ‘incidentalomas’ are found in 10% of the healthy population,5 emphasizing the importance of biochemical assessment.
Normal pituitary
Figure 4 T1-weighted gadolinium-enhanced MRI of the pituitary, labelled accordingly.
Adrenal: CT provides the greatest spatial resolution for assessment of adrenal anatomy.
The prognosis following removal of adrenocortical cortisolsecreting adenomas is good. In contrast, prognosis is usually poor in patients with adrenocortical carcinoma. In ACTH-dependent Cushing’s syndrome of any cause, bilateral adrenalectomy may be required to control cortisol concentration. Nelson’s syndrome (development of a locally aggressive pituitary tumour secreting high concentrations of ACTH, resulting in pigmentation) is a major concern following bilateral adrenalectomy in patients with refractory Cushing’s disease. The tumour can be treated with further surgery and radiotherapy, but these seldom cure the disease.
Imaging in ectopic ACTH secretion: the most common sites of ectopic ACTH secretion are small cell lung cancers and bronchial carcinoid tumours, but tumours can arise in any tissue. Highdefinition, multislice CT is required. Carcinoid tumours can be visualized by radiolabelled octreotide scintigraphy.
Management Surgery for Cushing’s syndrome Trans-sphenoidal surgery: selective microadenomectomy by an experienced surgeon is the treatment of choice in most patients with Cushing’s disease. Long-lasting remission without other pituitary hormonal deficiency is achieved in 50e60% of cases.1,5
Ectopic ACTH: complete excision of an ACTH-secreting tumour usually results in long-lasting remission. Other treatments Medical therapy to lower cortisol can be used in preparation for surgery or after unsuccessful surgery. It is seldom a long-term solution, and is mainly used as an adjunctive treatment with other modalities such as pituitary radiotherapy.1,5 Metyrapone, increasing every 72 hours up to 500e1000 mg three or four times daily, and ketoconazole, increasing at 4e5-day intervals, up to 200e400 mg three times daily, are often used to inhibit cortisol synthesis, aiming for a mean serum cortisol of 150 e300 mmol/litre, or correction of abnormal elevated urinary free cortisol excretion. Stomach acid is needed for absorption of ketoconazole. Metyrapone causes an increase in corticosteroid androgenic precursors, and hirsutism is an adverse effect in women; this does not occur with ketoconazole. In the UK, o,p0 DDD (mitotane) is usually reserved for the treatment of adrenocortical carcinoma. Pasireotide, a multi-receptor somatostatin analogue, reduces ACTH secretion and is effective in approximately 25% of patients with Cushing’s disease,5 but hyperglycaemia is a major adverse effect. Mifepristone (unlicensed in the UK), a glucocorticoid receptor antagonist is also effective for treatment, but is very challenging to use as biochemical monitoring of response is not possible.5
Adrenal surgery: laparoscopic unilateral adrenalectomy is the treatment of choice in patients with an isolated adrenal adenoma.
Pituitary radiotherapy: following trans-sphenoidal surgery, persisting hypercortisolaemia can be treated with pituitary
Figure 3 T1-weighted gadolinium-enhanced MRI of the pituitary.
MEDICINE --:-
Pituitary stalk
4
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Daniel E, Newell-Price J, Cushing’s syndrome, Medicine (2017), http://dx.doi.org/10.1016/ j.mpmed.2017.05.007
PITUITARY DISORDERS
radiotherapy or gamma knife radiosurgery.5 Progressive anterior pituitary failure is the major adverse effect; growth hormone deficiency is present in almost all patients 10 years after treatment and gonadotrophin deficiency in about 15%. About 4 years after treatment, 80% of patients are in remission with respect to circulating serum cortisol concentration. Associated conditions such as hypertension and diabetes mellitus must also be treated.
2 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: 1526e40. G, et al. Constitutive activation of 3 Beuschlein F, Fassnacht M, Assie PKA catalytic subunit in adrenal Cushing’s syndrome. N Engl J Med 2014; 370: 1019e28. 4 Reincke M, Sbiera S, Hayakawa A, et al. Mutations in the deubiquitinase gene USP8 cause Cushing’s disease. Nat Genet 2015; 47: 31e8. 5 Nieman LK, Biller BM, Findling JW, et al. Endocrine Society. Treatment of Cushing’s syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2015; 100: 2807e31.
Prognosis Inadequately treated Cushing’s syndrome has a 5-fold standardized mortality rate; this returns to normal with timely control of hypercortisolaemia, although some cardiovascular risk remains (see Further reading). Depression often persists for years after cure.1,5 A
FURTHER READING Clayton RN, Jones PW, Reulen RC, et al. Mortality in patients with Cushing’s disease more than 10 years after remission: a multicentre, multinational, retrospective cohort study. Lancet Diabetes Endocrinol 2016; 4: 569e76.
KEY REFERENCES 1 Newell-Price J, Bertagna X, Grossman AB, Nieman LK. Cushing’s syndrome. Lancet 2006; 367: 1605e17.
TEST YOURSELF To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the end of the issue or online here.
Question 1
What is the most appropriate further diagnostic test? A CT scan of the adrenal glands B MRI scan of the pituitary C Bilateral inferior petrosal sinus sampling D CT scan of the thorax E Octreotide scintigraphy scan
A 36-year-old woman presented with a 6-month history of central weight gain, bruising and weakness when climbing stairs. On clinical examination, heart rate was 76 beats per minute and blood pressure 154/98 mmHg supine. Bruises were noted on her legs, and purple striae on her abdomen. What is the most appropriate initial diagnostic test? A Urine metanephrine concentrations B Midnight serum cortisol C Overnight 1 mg dexamethasone suppression test D Plasma adrenocorticotrophic hormone E Corticotrophin-releasing hormone test
Question 3 A 44-year-old man is diagnosed with Cushing’s disease. Magnetic resonance imaging of the pituitary showed a 6 mm tumour. He was taking an angiotensin-converting enzyme inhibitor and calcium channel antagonist for hypertension. On clinical examination, there were clear signs of Cushing’s syndrome. Heart rate was 74 beats/minute and blood pressure 138/80 mmHg supine. There was little evidence of myopathy.
Question 2 A 36-year-old woman had endogenous Cushing’s syndrome confirmed biochemically; her 09:00 hours plasma adrenocorticotrophic hormone was <5 pg/ml (normal range 5e47) on two occasions.
MEDICINE --:-
What is the next most appropriate form of management? A Metyrapone therapy B Ketoconazole therapy C Trans-sphenoidal pituitary surgery D Bilateral adrenalectomy E Gamma knife radiosurgery to the pituitary lesion
5
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Daniel E, Newell-Price J, Cushing’s syndrome, Medicine (2017), http://dx.doi.org/10.1016/ j.mpmed.2017.05.007