Diagnosis and Differential Diagnosis of Cushing's Syndrome: An Expert Guide

Cushing’s syndrome, also known as hypercortisolism, is a serious endocrine disorder resulting from prolonged exposure to elevated levels of cortisol in the body. While iatrogenic Cushing’s syndrome due to corticosteroid medication is the most prevalent form, endogenous Cushing’s presents a diagnostic challenge. Accurate diagnosis and, importantly, differential diagnosis are crucial steps toward effective management and improved patient outcomes. This comprehensive guide delves into the diagnosis and differential diagnosis of Cushing’s syndrome, aiming to provide healthcare professionals with an in-depth understanding for optimal patient care.

Etiology of Cushing’s Syndrome

Cushing’s syndrome arises from two primary categories of causes: exogenous and endogenous.

Exogenous Cushing’s Syndrome: This is the most common cause and is iatrogenic, stemming from the prolonged use of glucocorticoid medications. These medications, prescribed for various conditions like autoimmune diseases, respiratory illnesses, and organ transplantation, mimic cortisol’s effects in the body when taken in supraphysiologic doses over extended periods.

Endogenous Cushing’s Syndrome: This category involves the body’s overproduction of cortisol. Endogenous Cushing’s can be further classified based on ACTH (adrenocorticotropic hormone) dependency:

ACTH-dependent Cushing’s Syndrome (Cushing’s Disease and Ectopic ACTH Syndrome):
- Cushing’s Disease: The most frequent cause of endogenous Cushing’s, accounting for approximately 80% of cases. It is caused by an ACTH-secreting pituitary adenoma, a benign tumor in the pituitary gland that leads to excessive ACTH production, subsequently stimulating the adrenal glands to produce excess cortisol.
- Ectopic ACTH Syndrome: Less common, this occurs when non-pituitary tumors, often malignant neoplasms like small cell lung cancer, secrete ACTH or corticotropin-releasing hormone (CRH), leading to adrenal hyperstimulation and cortisol overproduction.
ACTH-independent Cushing’s Syndrome (Adrenal Cushing’s Syndrome): This form results from primary adrenal gland abnormalities that cause cortisol overproduction, independent of ACTH stimulation.
- Adrenal Adenomas: Benign tumors of the adrenal cortex that autonomously secrete cortisol.
- Adrenal Carcinomas: Malignant tumors of the adrenal cortex, often larger and associated with more severe hypercortisolism and virilization.
- Adrenal Hyperplasia: Nodular adrenal hyperplasia is a less common cause.

Epidemiology of Cushing’s Syndrome

Determining the exact incidence and prevalence of Cushing’s syndrome is challenging due to variations in diagnostic practices and the underlying conditions requiring steroid therapy. However, it is recognized that iatrogenic Cushing’s significantly outnumbers endogenous cases. Among endogenous causes, Cushing’s disease, driven by pituitary ACTH production, predominates, accounting for up to 80% of cases. Adrenal tumors, ectopic ACTH secretion, and unidentified sources constitute the remaining endogenous Cushing’s cases. The prevalence varies across populations depending on factors like glucocorticoid use and genetic predispositions.

Pathophysiology of Hypercortisolism

Cortisol, a glucocorticoid hormone, is synthesized in the adrenal cortex’s zona fasciculata and plays vital roles in metabolism, stress response, and immune function. In Cushing’s syndrome, excessive cortisol levels disrupt these physiological processes.

Metabolic Effects: Hypercortisolism promotes gluconeogenesis (glucose production from non-carbohydrate sources) and glycogenolysis (breakdown of glycogen into glucose), contributing to hyperglycemia and insulin resistance. Protein catabolism is accelerated, leading to muscle wasting, thin skin, and impaired wound healing. Fat redistribution occurs, resulting in central obesity, moon facies, and buffalo hump.

Immunosuppressive Effects: Cortisol excess suppresses the immune system by reducing lymphocyte proliferation and function, inhibiting pro-inflammatory cytokines (IL-2, TNF-alpha, IFN-gamma), and altering neutrophil dynamics. This increases susceptibility to infections.

Cardiovascular and Bone Effects: Hypercortisolism can lead to hypertension, electrolyte imbalances, and osteoporosis due to its effects on mineralocorticoid receptors and bone metabolism.

History and Physical Examination in Cushing’s Syndrome

A thorough history and physical exam are crucial initial steps in suspecting and evaluating Cushing’s syndrome.

Patient History: Inquire about:

Weight gain: Often central obesity, with increased abdominal fat.
Fatigue and weakness: Generalized muscle weakness and tiredness.
Delayed wound healing and easy bruising: Due to protein catabolism and capillary fragility.
Back pain and bone pain, loss of height: Suggestive of osteoporosis and vertebral fractures.
Psychological changes: Depression, mood swings, anxiety, cognitive dysfunction, irritability.
Decreased libido and erectile dysfunction (males), menstrual irregularities and infertility (females).
Skin changes: Acne, hirsutism (excessive hair growth in women), hyperhidrosis (excessive sweating), and purplish striae.
History of hypertension, diabetes, and peptic ulcer disease.

Physical Examination Findings:

Characteristic fat distribution: “Buffalo hump” (dorsocervical fat pad), “moon facies” (rounded face), and central obesity with relatively thin limbs.
Skin: Thin skin, easy bruising, purplish striae (especially on the abdomen, thighs, and breasts), acne, hirsutism.
Musculoskeletal: Proximal muscle weakness (difficulty rising from a chair or combing hair), muscle atrophy.
Cardiovascular: Hypertension.
Psychiatric: Assess for signs of depression, anxiety, or cognitive impairment.

Diagnosis of Cushing’s Syndrome: Confirming Hypercortisolism

The diagnostic process for Cushing’s syndrome involves two main stages: first, confirming the presence of hypercortisolism, and second, identifying the underlying cause.

Step 1: Confirming Hypercortisolism

Several highly sensitive tests are used to confirm hypercortisolism. It’s essential to perform at least two different tests to increase diagnostic accuracy and reduce false positives.

Late-Night Salivary Cortisol Measurement: This is a convenient and reliable screening test. Cortisol levels normally decrease in the evening. In Cushing’s syndrome, this diurnal variation is lost, and late-night salivary cortisol levels remain elevated. Two measurements on separate nights are recommended. Factors like smoking, licorice consumption, and chewing tobacco can falsely elevate salivary cortisol and should be avoided before testing.
24-Hour Urinary Free Cortisol (UFC) Test: This test measures the total amount of cortisol excreted in the urine over 24 hours. Elevated UFC levels indicate cortisol overproduction. Accurate collection is crucial; improper timing or incomplete collection can lead to false results. Kidney dysfunction (GFR < 60 ml/min) can falsely lower UFC levels. Borderline elevations may be false positives, while levels more than four times the upper limit of normal are highly suggestive of Cushing’s syndrome. Repeat collections might be necessary for confirmation.
Overnight Dexamethasone Suppression Test (ONDST): This test assesses the body’s ability to suppress cortisol production in response to dexamethasone, a synthetic glucocorticoid. Typically, a low dose of dexamethasone (1 mg) given at night should suppress morning cortisol levels. In Cushing’s syndrome, this suppression is impaired. A morning serum cortisol level greater than 1.8 µg/dL (50 nmol/L) after dexamethasone administration suggests Cushing’s syndrome.
Low-Dose Dexamethasone Suppression Test (LDDST): A more prolonged suppression test using a low dose of dexamethasone (0.5 mg every 6 hours for 48 hours). Serum cortisol is measured after 48 hours. Failure to suppress cortisol to below 1.8 µg/dL (50 nmol/L) is indicative of Cushing’s syndrome. This test helps to differentiate Cushing’s syndrome from pseudo-Cushing’s states.

Step 2: Determining the Cause of Cushing’s Syndrome (Differential Diagnosis)

Once hypercortisolism is confirmed, the next step is to differentiate between ACTH-dependent and ACTH-independent Cushing’s syndrome and pinpoint the specific etiology.

Plasma ACTH Measurement: This is the crucial first step in differentiating the causes.
- Low or Undetectable ACTH levels: Suggest ACTH-independent Cushing’s syndrome, pointing towards an adrenal adenoma or carcinoma.
- Normal or Elevated ACTH levels: Indicate ACTH-dependent Cushing’s syndrome, suggesting either Cushing’s disease (pituitary adenoma) or ectopic ACTH secretion.
High-Dose Dexamethasone Suppression Test (HDDST): Used in ACTH-dependent Cushing’s syndrome to differentiate between pituitary and ectopic ACTH sources. High-dose dexamethasone (8 mg) is administered, and cortisol levels are measured.
- Cortisol Suppression by ≥ 50%: Suggests Cushing’s disease (pituitary adenoma), as pituitary tumors are often partially suppressible by high-dose dexamethasone.
- No Significant Cortisol Suppression: Points towards ectopic ACTH secretion, as ectopic tumors are usually resistant to dexamethasone suppression. However, interpretation should be cautious as some pituitary adenomas may also show resistance, and some ectopic sources may be suppressible.
Corticotropin-Releasing Hormone (CRH) Stimulation Test: CRH stimulates ACTH release from the pituitary. In Cushing’s disease, ACTH and cortisol levels typically rise after CRH administration. Ectopic ACTH-secreting tumors usually do not respond to CRH.
Inferior Petrosal Sinus Sampling (IPSS): The gold standard for differentiating pituitary from ectopic ACTH secretion in ACTH-dependent Cushing’s syndrome when imaging is inconclusive. Catheters are inserted into the inferior petrosal sinuses (draining the pituitary gland) and peripheral veins. ACTH levels are measured simultaneously before and after CRH stimulation. A significantly higher ACTH level in the petrosal sinuses compared to peripheral blood confirms a pituitary source (Cushing’s disease).
Imaging Studies:
- Pituitary MRI: Essential for detecting pituitary adenomas in Cushing’s disease. Small microadenomas may be challenging to visualize, and false positives (incidentalomas) can occur.
- Adrenal CT Scan: Used to evaluate adrenal glands for adenomas, carcinomas, or hyperplasia in ACTH-independent Cushing’s syndrome.
- Chest and Abdominal CT Scan: To search for ectopic ACTH-secreting tumors, particularly in the lungs, pancreas, and mediastinum, in cases of ACTH-dependent Cushing’s where pituitary MRI is negative or IPSS suggests an ectopic source.
- Octreotide Scan or Gallium Scan: May be helpful in localizing some ectopic ACTH-secreting tumors.

Differential Diagnosis of Cushing’s Syndrome

It’s crucial to differentiate Cushing’s syndrome from other conditions that can mimic its features, known as pseudo-Cushing’s states, and other endocrine and non-endocrine disorders.

Pseudo-Cushing’s States: These conditions are associated with mild hypercortisolism without true Cushing’s syndrome and often normalize with resolution of the underlying condition. They can cause false-positive results on some screening tests for Cushing’s syndrome.

Obesity: Especially visceral obesity, is frequently associated with mild cortisol elevations.
Depression and Anxiety Disorders: Psychiatric stress can activate the hypothalamic-pituitary-adrenal (HPA) axis, leading to increased cortisol secretion.
Alcohol Use Disorder: Chronic alcohol abuse can cause pseudo-Cushing’s, which resolves with abstinence.
Poorly Controlled Diabetes Mellitus: Metabolic stress can elevate cortisol levels.
Polycystic Ovary Syndrome (PCOS): Some features of PCOS overlap with Cushing’s syndrome, like hirsutism and menstrual irregularities.
Chronic Stress and Sleep Deprivation: Prolonged stress and insufficient sleep can dysregulate the HPA axis.
Certain Medications: Besides corticosteroids, some medications can interfere with cortisol metabolism or testing.

Other Endocrine and Non-Endocrine Disorders:

Primary Aldosteronism: Can present with hypertension and electrolyte imbalances, similar to Cushing’s.
Pheochromocytoma: Can cause hypertension, anxiety, and sweating, mimicking some Cushing’s symptoms.
Metabolic Syndrome: Shares features like obesity, hypertension, and diabetes.
Hypothyroidism: Can cause fatigue and weight gain, but other features are distinct from Cushing’s.

Differentiating Cushing’s Syndrome from Pseudo-Cushing’s:

Clinical Assessment: Pseudo-Cushing’s typically presents with milder symptoms than true Cushing’s syndrome. Striae are less likely to be wide and purplish. Muscle weakness and skin thinning are less pronounced.
Dexamethasone Suppression Tests: Pseudo-Cushing’s may show some degree of cortisol non-suppression on ONDST and LDDST, but the level of non-suppression is usually less marked than in Cushing’s syndrome. HDDST typically suppresses cortisol in pseudo-Cushing’s states.
CRH Stimulation Test: Cortisol response to CRH is usually blunted in pseudo-Cushing’s.
Clinical Course: Pseudo-Cushing’s resolves with treatment of the underlying condition (e.g., weight loss, treatment of depression, alcohol abstinence).

Treatment and Management of Cushing’s Syndrome

Treatment strategies for Cushing’s syndrome are tailored to the underlying cause.

Iatrogenic Cushing’s Syndrome: Gradual tapering and withdrawal of exogenous corticosteroids is the primary treatment. This must be done cautiously to avoid adrenal insufficiency, as prolonged steroid use suppresses the adrenal glands.
Cushing’s Disease (Pituitary Adenoma):
- Transsphenoidal Surgery: The first-line treatment, aiming to selectively remove the pituitary adenoma.
- Radiotherapy: May be used if surgery fails or is incomplete, or as primary therapy in patients not suitable for surgery.
- Medical Therapy: Medications like pasireotide, cabergoline, and mifepristone can be used to control cortisol secretion, especially when surgery or radiotherapy is not feasible or while waiting for these treatments to become effective. Bilateral adrenalectomy might be considered in rare cases of refractory Cushing’s disease.
Ectopic ACTH Syndrome: Treatment focuses on locating and removing the ectopic ACTH-secreting tumor surgically, if possible. If the tumor is unresectable or metastatic, medical therapy to control cortisol excess and chemotherapy or radiotherapy for the underlying malignancy are employed. Bilateral adrenalectomy may be considered to control hypercortisolism in severe cases.
Adrenal Adenoma or Carcinoma: Surgical resection of the adrenal tumor is the primary treatment. In cases of adrenal carcinoma, adjuvant chemotherapy and radiotherapy may be necessary.

Management also includes addressing comorbidities such as diabetes, hypertension, osteoporosis, and psychiatric disorders.

Prognosis of Cushing’s Syndrome

The prognosis of Cushing’s syndrome has significantly improved with advancements in diagnosis and treatment. If left untreated, Cushing’s syndrome carries a high morbidity and mortality due to cardiovascular complications, infections, and metabolic derangements. Successful treatment and normalization of cortisol levels significantly improve prognosis and reduce mortality risk to that of the age-matched general population. Prognosis is less favorable in cases of unresectable malignant tumors causing ectopic Cushing’s syndrome or adrenal carcinoma.

Complications of Cushing’s Syndrome

Untreated or poorly controlled Cushing’s syndrome can lead to various complications:

Cardiovascular: Hypertension, increased risk of cardiovascular disease and stroke.
Metabolic: Type 2 diabetes, dyslipidemia, metabolic syndrome.
Musculoskeletal: Osteoporosis, fractures, muscle weakness and atrophy.
Infections: Increased susceptibility to bacterial, fungal, and viral infections.
Psychiatric: Depression, anxiety, cognitive impairment.
Skin: Skin thinning, easy bruising, poor wound healing.
Gastrointestinal: Peptic ulcer disease.
Reproductive: Menstrual irregularities, infertility, erectile dysfunction.

Deterrence and Patient Education

Preventing iatrogenic Cushing’s syndrome through judicious use of corticosteroids and careful monitoring is crucial. Patient education about the potential side effects of corticosteroids and the importance of adherence to prescribed regimens and follow-up appointments is essential. For patients with endogenous Cushing’s syndrome, early diagnosis and treatment are key to minimizing complications and improving quality of life.

Enhancing Healthcare Team Outcomes

Optimal management of Cushing’s syndrome requires a collaborative interprofessional team, including endocrinologists, surgeons, radiologists, pharmacists, nurses, and dietitians. Effective communication and coordination among team members are vital for accurate diagnosis, personalized treatment planning, and comprehensive patient care. Pharmacists play a crucial role in medication management and patient education regarding corticosteroids. Nurses are essential for monitoring patients, providing education, and ensuring follow-up. Dietary consultations are beneficial for managing weight gain and associated metabolic issues.

Outcomes of Cushing’s Syndrome

Successful treatment of Cushing’s syndrome and restoration of eucortisolism lead to significant improvements in symptoms, comorbidities, and quality of life. However, even after successful treatment, some long-term sequelae, such as osteoporosis and cardiovascular disease risk, may persist and require ongoing management. Long-term follow-up is essential to monitor for recurrence and manage residual complications. Abrupt cessation of corticosteroids can precipitate adrenal crisis, highlighting the importance of proper tapering and patient education regarding steroid management.

Conclusion

Accurate diagnosis and differential diagnosis are paramount in the management of Cushing’s syndrome. A systematic approach involving clinical evaluation, biochemical testing, and imaging is necessary to confirm hypercortisolism and identify its underlying cause. Differentiating Cushing’s syndrome from pseudo-Cushing’s states and other mimicking conditions is crucial to avoid misdiagnosis and inappropriate treatment. An interprofessional team approach ensures comprehensive and coordinated care, leading to improved outcomes and quality of life for patients with Cushing’s syndrome.

References

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Diagnosis and Differential Diagnosis of Cushing’s Syndrome: An Expert Guide