What conditions are associated with high cortisol levels and low cortisol clearance?

Conditions Associated with High Cortisol Levels and Low Cortisol Clearance

Subclinical Cushing syndrome (now termed mild autonomous cortisol secretion or MACS) is the most common condition associated with high cortisol levels and low cortisol clearance, particularly in patients with adrenal incidentalomas. 1

Primary Conditions with High Cortisol and Low Clearance

Adrenal Causes

• Adrenal incidentalomas with autonomous cortisol secretion

  • Found in up to 30% of adrenal incidentalomas 1
  • Often presents without overt Cushing's syndrome symptoms
  • Characterized by failed cortisol suppression on dexamethasone testing 1

• Adrenal adenomas

  • Benign adrenal tumors that produce cortisol without ACTH influence 1
  • Approximately 50% of adrenocortical carcinomas secrete cortisol specifically 1
  • Can be used as both a prognostic factor and tumor marker 1

Pituitary Causes

• Cushing's disease (ACTH-secreting pituitary adenoma)
  • Accounts for 75-80% of endogenous Cushing's syndrome cases 2
  • Leads to bilateral adrenal hyperplasia and increased cortisol production
  • Characterized by high ACTH levels (≥5 pg/mL) 2

Ectopic Causes

• Ectopic ACTH syndrome
  • Tumors in lung, thyroid, pancreas, or bowel can produce ACTH 1
  • Leads to bilateral adrenal hyperplasia and increased cortisol production

Medical Conditions Associated with Altered Cortisol Metabolism

Metabolic Disorders

• Obesity

  • Associated with increased cortisol production but also increased clearance
  • Can cause false positive results in cortisol testing 2
  • Contributes to visceral adiposity which may persist despite cortisol normalization 1

• Type 2 diabetes mellitus

  • Present in up to 30% of patients with Cushing's syndrome 1
  • Associated with failed cortisol suppression on dexamethasone testing 1
  • May not fully resolve despite remission of hypercortisolism 1

• Hypertension

  • Common in patients with cortisol excess 1
  • May persist despite treatment of hypercortisolism 1

Liver Disease

• Cirrhosis
  • Impairs cortisol metabolism and clearance
  • Leads to increased circulating cortisol levels

Kidney Disease

• Chronic kidney disease
  • Reduces cortisol clearance
  • Can lead to higher circulating cortisol levels

Clinical Manifestations of High Cortisol with Low Clearance

Cardiovascular Effects

• Increased cardiovascular risk
  • May persist despite long-term remission of hypercortisolemia 1
  • Associated with visceral adiposity, adverse adipokine profile, glucose intolerance, hypertension, dyslipidemia, atherosclerosis, and a procoagulant phenotype 1
  • Myocardial infarction, stroke, and other vascular events are primary causes of increased mortality 1

Skeletal Effects

• Osteoporosis and fractures
  • Vertebral fractures occur in 30-50% of patients 1
  • Fractures may occur even with normal or osteopenic bone mineral density 1
  • Men may be at higher risk compared to women 1

Metabolic Effects

• Dyslipidemia
  • Low HDL, high LDL, and high triglycerides reported in 16-64% of cases 1
  • May not fully resolve despite remission of hypercortisolism 1

Muscular Effects

• Proximal myopathy
  • Characteristic of cortisol excess 1
  • Impaired stair climbing and difficulty straightening up
  • May be partially related to growth hormone deficiency in patients in remission 1

Diagnostic Considerations

Testing for Cortisol Excess

• 1 mg Dexamethasone Suppression Test (DST)

  • Recommended for initial screening, especially for adrenal incidentalomas 2
  • Women on estrogen-containing oral contraceptives may have false positive results 2

• Late-Night Salivary Cortisol (LNSC)

  • 90% sensitivity, 100% specificity 2

  • Useful for initial screening and longitudinal surveillance 2

• 24-hour Urinary Free Cortisol (UFC)

  • Reflects overall cortisol production 2
  • Supports diagnosis of hypercortisolism 2

Treatment Approach

Surgical Management

• Unilateral adrenalectomy
  • Recommended for unilateral cortisol-secreting adrenal masses 1
  • Minimally-invasive surgery should be performed when feasible 1
  • Younger patients with MACS who have progressive metabolic comorbidities may benefit from adrenalectomy 1

Medical Management

• Adrenostatic agents
  • Ketoconazole (400-1200 mg/day) is commonly used due to availability and tolerable toxicity profile 1
  • Mitotane can also be used for hypercortisolism management 1

Monitoring

• Annual clinical screening
  • Patients with MACS not managed surgically should undergo annual screening for new or worsening comorbidities 1
  • Long-term monitoring is essential as normalization of cortisol levels leads to significant improvement in comorbidities but may not result in complete resolution 1

Clinical Pitfalls and Caveats

• Progression from subclinical Cushing's syndrome to overt Cushing's syndrome is rare 1
• Despite remission of hypercortisolism, increased cardiovascular risk and other comorbidities may persist 1
• Mental stress, recent infections, and incorrect sampling times can affect cortisol test results 2
• Early diagnosis and treatment of hypercortisolism, along with aggressive management of comorbidities, is crucial for optimal recovery 1