Cushing Syndrome and the Heart

Basics

Description

Cushing syndrome (CS) produces a combination of clinical features and biochemical abnormalities that occur as a result of excessive tissue exposure to cortisol.
Cardiovascular impact is prominent and can impact outcomes, due to increased HTN, hyperlipidemia, and obesity
Cardiac disease/metabolic syndrome:
- Untreated CS patients go on to develop a clinical picture and risk profile similar to metabolic syndrome.
  - Metabolic syndrome shares many of the common clinical features as CS-both lead to decreased insulin sensitivity, increased abdominal girth (waist-to-hip ratio), dyslipidemia, and HTN.
  - Leads to greater risk of cardiac events.
- Cortisol also directly leads to progression of atherosclerosis through vascular remodeling.

Epidemiology

Incidence

Cushing disease estimated incidence ~0.1-1 new case per 100,000.
Pituitary hyperproduction of adrenocorticotropic hormone (ACTH) accounts for ~70% of all cases of CS.

Prevalence

Predominant age: Varies with the cause:
- Pituitary (corticotroph) adenoma: 25-40 yr
- Ectopic ACTH secretion: >40 yr
- Adrenal carcinoma: Bimodal age distribution with peaks in childhood/adolescence and late in life.
- Adrenal adenoma: ~35 yr.
Predominant sex: Varies with the cause:
- Adrenal adenomas, adrenal carcinomas, and corticotropin adenomas are 4-6 times more common in women than in men.
- Ectopic ACTH secretion is more common in men than women (may change as more women develop lung cancer, the most common cause of ectopic ACTH secretion).

Risk Factors

Genetics
Multiple promising genetic targets have been implicated in the pathogenesis of CS �

General Prevention

Exogenous or iatrogenic administration of steroids is included under the umbrella of CS and causes all the manifestations and complications of endogenous disease. �

Pathophysiology

Normal hypothalamic → pituitary → adrenal (HPA) axis: �

Corticotropin-releasing hormone (CRH) synthesized in the hypothalamus is primary positive activator of ACTH production in anterior pituitary.
ACTH, the principle product from a large precursor pro-opiomelanocortin (POMC), induces cortisol production from adrenal fasciculata.
Cortisol, the primary glucocorticoid of the human body, plays a prolific role in metabolism including:
- Protein and fat catabolism
- Hepatic gluconeogenesis
- Immunosuppression and antiinflammatory
- Stress response
Cortisol exerts autonegative feedback on the HPA axis at both the level of the anterior pituitary and the hypothalamus.
CS is caused by any disruption in this axis (endogenous or exogenous) that results in hyperproduction of cortisol:
- Increased production of ACTH (most common cause in adults) by an adrenal tumor (Cushing disease) or by other ectopic paraneoplastic malignancy.
- Increased production of cortisol, most commonly because of adrenal adenomas, carcinomas, or hyperplasia.
- Increased production of CRH (rare because of double-pronged negative feedback loop of cortisol).
- Exogenous glucocorticoid/corticotrophin
The hyperproduction of cortisol leads to the pathologic signs and symptoms notable in CS

Etiology

Exogenous (iatrogenic or factitious):
- CS secondary to use of high-dose glucocorticoids (most common cause of CS)
Endogenous:
- ACTH (corticotropin)-dependent: Adrenal activation (overall ~80%):
  - Pituitary corticotroph adenoma (80%) = Cushing disease (CD)
  - Ectopic ACTH secretion (20%): Most commonly associated with small-cell lung carcinoma; less commonly with carcinoid or islet cell tumors, pheochromocytoma, neuroblastoma, ganglioma, paraganglioma, and medullary carcinoma of the thyroid
  - Ectopic corticotropin-releasing hormone (CRH)/corticotroph hyperplasia, corticotroph carcinomas very rare
  - ACTH-independent: Adrenal activation (overall ~20%)
  - Adrenal adenoma (40-50%)
  - Adrenal carcinoma (40-50%)
  - Macronodular adrenal hyperplasia
  - Micronodular adrenal hyperplasia (including Carney complex)

Associated Conditions

Affective disorders
Opportunistic infections
Perforated viscus
Renal calculi
Metabolic syndrome
Increased atherosclerosis and cardiac risk

Diagnosis

Signs and symptoms: Untreated CS can lead to a picture similar to metabolic syndrome or diabetes. �

History

Weight gain; fatigue
Decreased libido; impotence
Menstrual changes/infertility
Mood changes, depression, psychosis; insomnia; impaired concentration or memory
Easy bruising; poor wound healing
Fractures
Headache, backache, abdominal pain

Physical Exam

Obesity: Increased fat deposition in abdomen (truncal obesity, 96%), face (moon facies, 82%), supraclavicular or temporal fossae, dorsocervical area ("buffalo hump"�)
HTN: Present in 80-90% of patients. Consider the diagnosis in patients with HTN who are <40 yr of age, especially if BP is difficult to control.
Striae: Purple, >1 cm in diameter, usually over the abdomen
Hirsutism; fragile and thin skin; ecchymoses after minimal trauma; acne; female balding
Edema; proximal muscle wasting and weakness with preservation of distal strength
Growth retardation (in children)

Tests

Patients with central obesity or other cutaneous features; metabolic syndrome; hypogonadotrophic hypogonadism; and osteoporosis at age <65. �
Lab

White blood cell count ≥11,000/mm3
Hypokalemic metabolic alkalosis
Glucose intolerance: Hyperglycemia with resultant glucosuria and polydipsia.
Elevated triglycerides, LDL, or HDL levels.
Decreased thyroid-stimulating hormone, luteinizing hormone, follicle-stimulating hormone levels
EKG abnormalities
Osteopenia/osteoporosis on X-ray
Establish the diagnosis of high cortisol:
- 1st-line screening:
  - Salivary cortisol at bedtime (~11:00 p.m.)- sensitivity/specificity approaching 95%
  - 24-hr urine for free cortisol; generally on 2-3 consecutive days; 50% sensitive (improves with successive days of testing) and ~100% specific
  - Low-dose, 2-day or overnight dexamethasone suppression test
- 2nd-line screening:
  - Dexamethasone-CRH test: In pseudo-CS, plasma cortisol levels are low (<1.4 mcg/dL) after administration of dexamethasone and remain low when CRH is given soon after. In patients with CS, levels are higher.
CS vs. pseudo-CS:
- Insulin tolerance test: Plasma cortisol levels increase in response to insulin-induced hypoglycemia in patients with pseudo-CS but not in patients with CS.
- Administration of naloxone releases less CRH (and therefore less ACTH and cortisol) in patients with CS than in those with pseudo-CS.
Distinguish sub-type of CS:
- Determine if CS is ACTH-dependent or ACTH-independent
- Measurement of ACTH by radioimmunoassay
- If ACTH-dependent, determine the source of excess ACTH secretion
- High-dose dexamethasone suppression test:
  - 2-Day or overnight tests: A decrease in plasma cortisol by ≥50% is suggestive of CD.
  - Sensitivity approaching 70% and specificity ~100% for Cushing disease
- Metyrapone stimulation test
- CRH stimulation test:
  - Corticotropin-secreting tumors retain sensitivity to CRH, whereas noncorticotroph tumors do not respond to CRH.

Imaging
Not useful for making the diagnosis of CS and should be used only for localization of tumors: �

Thin-section CT or MRI of the adrenal glands
If the patient has CD, high-resolution CT or MRI of the sella turcica prior to transsphenoidal surgery

Surgery
Bilateral inferior petrosal sinus sampling: �

Most precise and direct way of measuring ACTH
Perform only if the results of ≥2 noninvasive tests are inconsistent

Pathological Findings

1% of patients with small-cell lung cancer have ectopic ACTH syndrome (~660 per million per year)
Adrenal tumors:
- Incidentally discovered at autopsy or by radiographic studies in 1.3-8.7% of adults
Pituitary adenoma creating ACTH-dependent Cushing syndrome is 5-6 times more common than CS due to adrenal tumors.

Differential Diagnosis

Glucocorticoid resistance: Compensatory increases in ACTH and excessive glucocorticoid production
Pseudo-CS: Mild glucocorticoid excess of unclear pathophysiology seen in affective disorders, renal failure, chronic alcoholism, withdrawal from alcohol, hypoglycemia, strenuous exercise, and HIV:
- Up to 80% of patients with major depression have abnormal regulation of cortisol.
- In pseudo-CS evening plasma cortisol concentrations may be preserved and the degree of hypercortisolism is usually mild and transient.

Treatment

Medication

Medications should be considered 2nd-line therapies for patients who cannot safely undergo surgery or for those with occult or metastatic tumors.
Agents that modulate CRH or ACTH release at HPA level (rarely effective alone):
- Serotonin antagonists: Cyproheptadine, ritanserin, metergoline, ketanserin
- Dopamine agonists: Bromocriptine, lisuride
- γ-Aminobutyric acid (GABA) reuptake inhibitors: Valproic acid
- Somatostatin analog: Octreotide
Agents that inhibit steroidogenesis at adrenal level-most effective category of the drugs-generally work via cytochrome P450:
- Mitotane most commonly used
- Trilostane
- Metyrapone
- Aminoglutethimide
- Ketoconazole
- Etomidate
Agents that bind competitively to the glucocorticoid receptor and inhibit the action of the endogenous ligand.
- RU 486 (Mifepristone)

Additional Treatment

General Measures

Cardiac risk factors and disease should be assessed and treated aggressively.
Impaired glucose tolerance should be treated with insulin.
For iatrogenic CS, weaning and eventual discontinuation of glucocorticoid ingestion should be attempted.

Surgery

Directed toward resection of abnormal tissue (ACTH- or cortisol-producing).
In Cushing disease:
- Trans-sphenoidal selective adenomectomy:
  - Most widely accepted treatment modality
  - Total remission rates of ~80-90%
- Other therapy: Pituitary irradiation
In primary adrenal hypersecretion:
- Bilateral adrenalectomy:
  - 100% cure rate, with life-long glucocorticoid and mineralocorticoid replacement
  - Also viable option in Cushing disease patients who fail trans-sphenoidal surgery and radiotherapy.
  - Carcinomas generally continue progression.
  - Risk of developing Nelson syndrome with dark pigmentation, high ACTH levels, and radiographic pituitary adenoma.

In-Patient Considerations

Given their hypercoagulable state, all CS in-patients should be treated with heparin prophylaxis. �

Potential complications of pregnancy are maternal diabetes, HTN, preeclampsia, heart failure and premature delivery.
Use of ketoconazole, aminogluthemide, or mitotane is contraindicated in pregnancy.

Ongoing Care

Follow-Up Recommendations

Patient Monitoring

Underlying suppression of the HPA axis is unmasked after surgical correction of CS.
Once routine postoperative supraphysiologic doses of glucocorticoids have been tapered off, patients should have morning serum cortisol and daily urine free cortisol measured for 3 days.
After pituitary surgery, patients should have serum osmolality, serum sodium, and urine output monitored to detect diabetes insipidus.

Patient Education

Patients should wear an identification bracelet that notes the requirement for glucocorticoids.
Patients should be aware of signs and symptoms of adrenal insufficiency, and the need to increase the oral dose of glucocorticoids for fever, nausea, and diarrhea.

Prognosis

Life expectancy with malignant causes depends on the type of tumor; recurrence is common with adrenal carcinoma, rare with adrenal adenoma, and uncommon with pituitary adenoma.
Up to 99% remain in remission after successful pituitary surgery after 2 yr and ~75% after 10 yr.
~20-50% of patients remain obese, hypertensive, dyslipidemic despite treatment.

Additional Reading

1Arnaldi �G, Angeli �A, Atkinson �B. Diagnosis & complications of Cushing's syndrome: A consensus statement. J Endocrinol Metab. 2005;88:5593-5602.2Lindsay �JR, Nieman �LK. Differential Diagnosis and Imaging in Cushing's Syndrome. Endocrinol Metabol Clin. 2005;34:403-421. �[View Abstract]3Pivonello �R, Faggiano �A, Lombardi �G. The metabolic syndrome and cardiovascular risk in Cushing's syndrome. Endocrinol Metabol Clin. 2005;34:327-339. �[View Abstract]

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