IntroductionCushing syndrome is a condition characterized by long-term exposure to high cortisol levels.
Exogenous hypercortisolism (M/C cause overall):Mostly iatrogenic and results from the prolonged use of glucocorticoids.
Endogenous hypercortisolism:Results from excessive production of cortisol by adrenal glands and can be ACTH-dependent and ACTH-independent.
- ACTH-dependent Cushing syndrome:
- ACTH-secreting pituitary adenomas (Cushing disease)
- Ectopic ACTH secretion by neoplasms
- ACTH-independent Cushing syndrome:
- Adrenal hyperplasia/adenoma/carcinoma
Growth retardation + progressive weight gain:Hallmark of Cushing’s syndrome in children
- Growth retardation: Glucocorticoids act directly on long bones in children to arrest the development of the epiphyseal cartilage. Furthermore, suppression of growth hormone secretion and action leads to blunted somatic growth.
- Weight gain: Cortisol induces hyperphagia
- Signs that distinguish Cushing’s from obesity:
- Proximal muscle weakness
- Easy bruising
- Violaceous striae (> 1 cm in width)
- Moon face
- Signs that distinguish Cushing’s from obesity:
Muscular features:Excess glucocorticoids have a catabolic effect on skeletal muscle with increased activity of myofibrillar proteinases and reduced uptake and conversion of amino acids into proteins.
- Increased protein wasting
- Type II muscle fiber atrophy
- Significant muscle weakness with predominant involvement of the muscles of the pelvic girdle
Mucocutaneous manifestation:Catabolic effects also occur in the epidermis and underlying connective tissue
- Thinning of the skin leads to the development of violaceous striae
- Easy bruisability
- Plethoric appearance of the face
Decreased bone mineral density:Pathogenesis of bone loss is multifactorial: GRs are present on both osteoblasts and osteoclasts. Excess glucocorticoids impair osteoblastic differentiation and increase apoptosis of both osteoblasts and osteoclasts. Increased production of the receptor activator of NF-kappa beta ligand (RANKL), which increases osteoclastogenesis, and decreases osteoprotegrin, a decoy receptor for RANKL that acts to decrease osteoclast differentiation, together lead to increased osteoclastic bone resorption. Hypercortisolism suppresses gonadotropin and growth hormone concentration, further contributing to decreased bone mass. Decreased intestinal and tubular reabsorption of calcium and related normocalcemic hypercalciuria has been as well.
- Osteoporosis and related fragility fractures (60-80% cases)
Neuropsychiatric disturbances (85% cases):Glucocorticoids mediate their effects on brain via both GR and MR. GRs are distributed widely in the central nervous system while MRs are expressed highly in the limbic brain areas such as the hippocampus. MRs in the brain have greater affinity for glucocorticoids than GRs and are almost completely occupied at basal corticosteroid levels. On the other hand, GRs are activated when cortisol levels are higher, as at the peak of the circadian rhythm, during stress and in Cushing’s syndrome
- Depression & irritability (M/C manifestations, 51–86% cases)
- Other features: Emotional lability, mania, paranoia, acute psychosis, anxiety, and panic attacks
- Hypercortisolemia: Associated with a decrease in apparent brain volume, particularly the hippocampus, and related impairment in learning, cognition and short-term memory
Metabolic derangements:Increased hepatic gluconeogenesis, peripheral insulin resistance, and direct suppression of insulin release together area contributing fators
- Impaired glucose tolerance (30-60% cases)
- Overt diabetes (20-50% cases)
- Dyslipidemia: Related to the direct and indirect effect of cortisol to increase lipolysis, VLDL synthesis, fatty accumulation in the liver, and peripheral insulin resistance
Additional cardiovascular risk:May not return to baseline even after remission of hypercortisolemia
- Hypertension (upregulation of the renin-angiotensin system and the mineralocorticoid effects of cortisol)
- Hypercoagulable state (related to increased synthesis of clotting factors like fibrinogen as well as plasminogen activator inhibitor type-1, an inhibitor of the fibrinolytic system)
- Buffalo hump/torso: Increased fat deposits in the upper half of the body
- Characteristic moon facies: Earlobes not visible when viewed from front
- Thin arms and legs
- Acne, hirsutism
- Proximal muscle weakness of shoulder and hip girdle muscles, paper-thin skin
- Wide vertical purplish abdominal striae
Late-night salivary cortisol (LNSC): Screening test
Diagnostic algorithm:Upon suspicion of the syndrome, laboratory and imaging confirmations are necessary. These should be done in a certain order that is important to follow, in order to avoid over-testing, inappropriate imaging and confusing interpretations
- Demonstration of endogenous hypercortisolism:
- 24-hour urinary free cortisol (UFC) collection
- Low-dose dexamethasone suppression test (DST)
- Confirmation of Cushing syndrome:
- Combined dexamethasone-CRH test (differente from pseudo-Cushing syndrome)
- Differential diagnosis between various causes of Cushing syndrome:
- Plasma ACTH levels
24-hour urinary free cortisol (UFC) collection:Cortisol is excreted in the urine in the free form and conjugated to, for example, glucuronides. The physiological theory of the measurement of urine free cortisol (UFC) in a 24 h urinary collection is that it will represent an integration of the activity of the HPA axis over that time.
Low-dose dexamethasone suppression test (DST):One of the hallmarks of the normal HPA axis is cortisol negative feedback inhibition of CRH and ACTH secretion. Dexamethasone (potent GR agonist with a long half-life), has been used for 50 years to test negative feedback sensitivity. In regards to Cushing’s disease (pituitary ACTH-secreting adenomas), corticotroph cells in an adenoma have decreased feedback sensitivity, because they can maintain ACTH hypersecretion in the face of increased endogenous cortisol. Thus, if just the right concentration of plasma dexamethasone were achieved, normal corticotrophs will fully suppress ACTH, and therefore, cortisol secretion, whereas patients with corticotroph adenomas will not. Since ectopic ACTH-secreting neuroendocrine tumors were never normal corticotrophs, they should not be inhibited by dexamethasone. Finally, as adrenal adenomas are not dependent on ACTH, a GR agonist would not suppress their cortisol secretion. DST is often abnormal in patients with adrenal incidentalomas (adrenal masses incidentally discovered during abdominal imaging for other reasons) who have minimal signs and symptoms of Cushing’s syndrome
- 2 forms:
- 1 mg overnight test (oDST): Dexamethasone given at 23:00 h and a serum/plasma cortisol is measured at 08:00 h the next morning
- 2 day 2-mg low-dose DST (LDDST): Divided doses given over several days, and serum or plasma cortisol is measured 6 hours after the last dose.
Plasma ACTH measurements:Measurement of plasma ACTH is critical in the differentiation of ACTH-independent and ACTH-dependent Cushing’s syndrome.
Inferior petrosal sinus sampling (IPSS):Differentiation of ACTH-secreting pituitary tumors (usually small adenomas) and occult ectopic ACTH-secreting tumors: If the pituitary is the primary source of ACTH excess, the concentration of ACTH in the pituitary venous effluent should be higher than in the peripheral circulation (P) (such as the inferior vena cava). Because of the ambient cortisol excess, the normal corticotrophs will be suppressed.
Furthermore, oCRH is injected to stimulate the corticotroph tumor to secrete even more ACTH to maximize the gradient between the petrosal sinuses and a peripheral (e.g., inferior vena cava) sample. If the primary source of ACTH is ectopic, the ambient hypercortisolism will suppress pituitary corticotroph function so that, even under the rare circumstance in which the ectopic tumor is stimulated by oCRH, there will not be a significant gradient between the petrosal sinuses and the vena cava (Fig. 6).
Iatrogenic Cushing’s syndrome:Chronic exposure to steroids can suppress the adrenals functioning and it can take several months for normal adrenal functioning to recover. Therefore, steroids should be slowly tapered allowing adrenal functioning to recover.
- Taper exogenous steroids
Surgical management:Surgical resection of the source of glucocorticoid excess (pituitary adenoma, nonpituitary tumor-secreting ACTH or adrenal tumor[s]) remains the first-line treatment of all forms of Cushing’s syndrome which cures 80% of ACTH-secreting microadenomas.
Pituitary radiotherapyPersistent hypercortisolemia after transsphenoidal surgery due to residual tumor can be treated with radiotherapy. Adjunctive medical control of hypercortisolemia may be needed while awaiting the effects of radiotherapy.
Medical management:Medical control of hypercortisolemia may be needed in occult cases, while awaiting surgery, when surgery is contraindicated or unsuccessful, and while awaiting the effect of radiation treatment.
- Inhibit steroidogenesis: Ketoconazole, metyrapone, mitotane & etomidate
- Modulate ACTH release: Somatostatin and dopamine agonists
- Block glucocorticoid action at the receptor level: Mifepristone