Endocrinology
Question 127 of 180
A 27 year old woman presents to the Emergency Department with a severe headache and is found to be hypertensive. She has no past medical history but tells you she is awaiting investigation for suspected Cushing's syndrome. Assuming she has Cushing's syndrome, what is the most likely endogenous cause?
Answer:
Cushing's syndrome may occur due to:- Excess secretion of ACTH
- ACTH secreting pituitary adenoma (most common endogenous cause - Cushing's disease)
- Ectopic ACTH secreting tumours e.g. bronchogenic or neuroendocrine tumours
- Excess adrenal secretion of cortisol
- Adrenal adenoma
- Bilateral adrenal hyperplasia
- Adrenal carcinoma
- Exogenous corticosteroid use (most common cause overall)
Cushing's Syndrome
Endocrinology
Last Updated: 8th September 2021
Cushing's syndrome is the name given to the clinical symptoms and signs induced by pathological hypercortisolism from any cause.
Cushing's disease refers to the specific condition of excess cortisol as a result of an adrenocorticotrophic hormone (ACTH)-secreting pituitary adenoma.
Causes
This may occur due to:
- Excess secretion of ACTH
- ACTH secreting pituitary adenoma (most common endogenous cause)
- Ectopic ACTH secreting tumours e.g. bronchogenic or neuroendocrine tumours
- Excess adrenal secretion of cortisol
- Adrenal adenoma
- Bilateral adrenal hyperplasia
- Adrenal carcinoma
- Exogenous corticosteroid use (most common cause overall)
Clinical features
- Plethoric moon face
- Weight gain and central obesity
- Impaired glucose tolerance or diabetes
- Hypertension
- Menstrual irregularity
- Decreased libido
- Osteoporosis and fragility fractures
- Purple striae and tendency to bruise easily
- Proximal myopathy
- Hirsutism and frontal alopecia
- Ankle oedema
- Interscapular fat pad
- Acne
- Musculoskeletal aches and pains
- Unexplained psychiatric symptoms (including depression)
- Poor wound healing
- Polycythaemia
![By Mikael Häggström (Own work) [CC0], via Wikimedia Commons](https://mrcemsuccess.com/wp-content/uploads/2017/10/Cushings_syndrome_vector_image.svg_.png)
Clinical Features of Cushing's Syndrome. (Image by Mikael Häggström (Own work) [CC0], via Wikimedia Commons)
Diagnosis
- One of four high-sensitivity tests should be used as a first-line diagnostic test in patients with suspected Cushing syndrome. To increase the diagnostic performance, repeat performance of the initial diagnostic test should be undertaken:
- Late-night salivary cortisol
- Overnight 1 mg dexamethasone suppression testing
- 24-hour urinary free cortisol
- 48-hour 2 mg dexamethasone suppression testing.
- Once hypercortisolism has been established, the aetiology should be sought. Morning plasma adrenocorticotrophic hormone (ACTH) is the test of choice in differentiating ACTH-dependent from ACTH-independent Cushing syndrome.
- Suppressed ACTH levels indicate ACTH-independent Cushing syndrome. Further investigation should include imaging of the adrenal glands to identify adrenal pathology causing hypercortisolism, such as adenoma.
- Unsuppressed ACTH levels indicate ACTH-dependent Cushing syndrome. Further investigation in such patients should begin with pituitary/sellar magnetic resonance imaging (MRI) to identify an ACTH-secreting pituitary adenoma. Those without definitive lesions on MRI should undergo inferior petrosal sinus sampling (IPSS). Patients with an IPSS central/peripheral gradient >2:1 or 3:1 after corticotrophin-releasing hormone (CRH) stimulation have Cushing's disease. Those without a gradient should have investigation for ectopic ACTH secretion. This evaluation generally includes computed tomography (CT) scanning of the chest, abdomen, and pelvis to look for a tumour secreting ACTH.
Management
- Treatment should not be undertaken until the diagnosis is firmly established and the source of hypercortisolism is recognised. All patients with moderate to severe hypercortisolism should undergo therapy directed at its underlying cause.
- Cushing's disease (pituitary adenoma)
- First-line therapy is transsphenoidal (TSS) resection of the causative pituitary adenoma.
- A somatostatin analogue (pasireotide), steroidogenesis inhibitors (osilodrostat, ketoconazole, metyrapone, mitotane, etomidate), or glucocorticoid receptor antagonist (mifepristone) is occasionally used for mild hypercortisolism, or short term for severe hypercortisolism, before other therapies are undertaken.
- Adrenal adenoma
- First-line therapy is almost always unilateral adrenalectomy of the affected adrenal gland.
- Adrenal carcinoma
- First-line therapy in many patients is surgical resection; however, at the time of diagnosis the disease has often progressed beyond the point where surgical therapy is effective. The effectiveness of chemotherapy and adjunctive therapies in both early- and late-stage disease has shown mixed results.
- Bilateral adrenal disease
- In these cases first-line therapy generally requires bilateral adrenalectomy. Steroidogenesis inhibitor therapy or glucocorticoid receptor antagonists can be used for patients who wish to avoid bilateral adrenalectomy.
- Ectopic ACTH
- The optimal first-line therapy involves locating and surgically resecting the ACTH-producing tumour. Not infrequently, complete resection of these tumours is not possible. Where surgical resection is not possible, second-line therapies include a glucocorticoid receptor antagonist, steroidogenesis inhibitor therapy, or bilateral adrenalectomy.
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- Biochemistry
- Blood Gases
- Haematology
| Biochemistry | Normal Value |
|---|---|
| Sodium | 135 – 145 mmol/l |
| Potassium | 3.0 – 4.5 mmol/l |
| Urea | 2.5 – 7.5 mmol/l |
| Glucose | 3.5 – 5.0 mmol/l |
| Creatinine | 35 – 135 μmol/l |
| Alanine Aminotransferase (ALT) | 5 – 35 U/l |
| Gamma-glutamyl Transferase (GGT) | < 65 U/l |
| Alkaline Phosphatase (ALP) | 30 – 135 U/l |
| Aspartate Aminotransferase (AST) | < 40 U/l |
| Total Protein | 60 – 80 g/l |
| Albumin | 35 – 50 g/l |
| Globulin | 2.4 – 3.5 g/dl |
| Amylase | < 70 U/l |
| Total Bilirubin | 3 – 17 μmol/l |
| Calcium | 2.1 – 2.5 mmol/l |
| Chloride | 95 – 105 mmol/l |
| Phosphate | 0.8 – 1.4 mmol/l |
| Haematology | Normal Value |
|---|---|
| Haemoglobin | 11.5 – 16.6 g/dl |
| White Blood Cells | 4.0 – 11.0 x 109/l |
| Platelets | 150 – 450 x 109/l |
| MCV | 80 – 96 fl |
| MCHC | 32 – 36 g/dl |
| Neutrophils | 2.0 – 7.5 x 109/l |
| Lymphocytes | 1.5 – 4.0 x 109/l |
| Monocytes | 0.3 – 1.0 x 109/l |
| Eosinophils | 0.1 – 0.5 x 109/l |
| Basophils | < 0.2 x 109/l |
| Reticulocytes | < 2% |
| Haematocrit | 0.35 – 0.49 |
| Red Cell Distribution Width | 11 – 15% |
| Blood Gases | Normal Value |
|---|---|
| pH | 7.35 – 7.45 |
| pO2 | 11 – 14 kPa |
| pCO2 | 4.5 – 6.0 kPa |
| Base Excess | -2 – +2 mmol/l |
| Bicarbonate | 24 – 30 mmol/l |
| Lactate | < 2 mmol/l |
