Hospital Medicine

Adrenal hyperplasia

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I. What every physician needs to know.

Adrenal hyperplasia as a cause of Cushing's syndrome can be considered either adrenocorticotropic hormone (ACTH) dependent or independent.

ACTH-dependent (secondary) adrenal hyperplasia is most commonly due to an ACTH-secreting pituitary adenoma (Cushing's disease) and ectopic ACTH from a non-pituitary tumor. Corticotropic releasing hormone (CRH) producing tumors can also cause adrenal hyperplasia.

ACTH-independent (primary) adrenal hyperplasia in bilateral glands ia usually due to two main types of adrenal nodular hyperplasias: ACTH-independent bilateral macronodular adrenal hyperplasia (AIMAH) or primary pigmented adrenocortical disease (PPNAD) and will be discussed here. Adrenocortical adenomas and malignancy are discussed elsewhere.

Bilateral adrenal hyperplasia may be discovered in the work-up of a patient who exhibits features of Cushing's syndrome in the absence of exogenous steroid administration. An important step in the diagnosis and management of these patients is determining whether the adrenal hyperplasia is ACTH-dependent or independent. Bilateral adrenal hyperplasia associated with an ACTH-secreting pituitary adenoma is also called Cushing's disease and will also be discussed in this section.

Congenital adrenal hyperplasia, most commonly due to 21-hydroxylase deficiency, leading to excessive androgen synthesis is not considered here. Adrenal hyperplasia can also cause Conn's syndrome (hyperaldosteronism), which is considered in further detail elsewhere.

II. Diagnostic Confirmation: Are you sure your patient has adrenal hyperplasia?

Because the symptoms of obesity, hypertension, emotional irritability, osteoporosis and metabolic disturbances can be common, it is important to confirm the diagnosis through laboratory testing and careful history-taking.

Easy bruising, facial plethora and proximal myopathy are the most sensitive features of Cushing's syndrome.

Laboratory testing to confirm Cushing's syndrome includes:

  • 24-hour urinary free cortisol, 4-fold greater than the normal level

  • Late-night salivary cortisol, elevated above normal of less than 150ng/dL

  • 1mg overnight dexamethasone suppression test (serum cortisol level of 5μg/dL can be reduced to 50nmol/liter for greater sensitivity)

The diagnosis of adrenal hyperplasia is often made with imaging, either computed tomography (CT) or magnetic resonance imaging (MRI), to identify the character and size of the adrenal glands. Imaging will also help to identify the presence of an adrenal adenoma, as opposed to hyperplasia of the glands.

A. History Part I: Pattern Recognition:

Patients with adrenal hyperplasia present with Cushing's syndrome. Additionally, patients with Cushing's disease can also have hypertension, osteopenia, menstrual irregularities, and neuropsychological disorders. These patients may also have visual field defects due to mass effect of the pituitary lesion.

The most common forms of bilateral adrenal hyperplasia, which are ACTH-independent, are AIMAH and PPNAD. AIMAH is thought to be mediated by abnormal or aberrantly expressed receptors in the adrenal cortex. It has rarely been associated with other syndromes due to genetic defects, including multiple endocrine neoplasia type 1 (MEN 1), familial adenomatous polyposis, renal cell carcinoma, and McCune-Albright syndrome. PPNAD is the main endocrine manifestation of the Carney complex (CNC) which is a familial multiple neoplasia syndrome (autosomal dominant transmission). CNC consists of spotty skin pigmentation, myxomas and other endocrine and non-endocrine tumors.

B. History Part 2: Prevalence:

Cushing's disease is uncommon, with an incidence of 2.4 new cases per million inhabitants per year. It occurs mostly in young adult females (mean age of diagnosis is 36 years) and is generally sporadic except for cases in patients with familial MEN 1.

ACTH-independent bilateral adrenal hyperplasia causing hypercortisolism accounts for approximately 10-15% of all adrenal causes of Cushing's syndrome. AIMAH and PPNAD are both rare, with AIMAH thought to represent less than 1% of endogenous cases of Cushing's syndrome. AIMAH is most often diagnosed in the 6th decade of life.

C. History Part 3: Competing diagnoses that can mimic adrenal hyperplasia.

Conditions that can mimic endogenous Cushing's syndrome can include the following:

  • Iatrogenic Cushing's syndrome (glucocorticoid administration)

  • Metabolic syndrome

  • Chronic alcoholism

  • Depression

Other causes of Cushing's syndrome can include:

Adrenocorticotropic hormone-dependent:

  • Pituitary adenoma (Cushing's disease)

  • Ectopic ACTH-syndrome (bronchial, thymic, carcinoid tumors)

  • Ectopic CRH syndrome

Adrenocorticotropic hormone-independent:

  • Adrenal adenoma

  • Adrenal carcinoma

D. Physical Examination Findings.

Physical exam findings are typical of Cushing's syndrome and include the following:

  • Truncal obesity

  • Moon facies

  • Skin atrophy or easy bruising

  • Muscle weakness

  • Edema

  • Facial plethora

  • Proximal myopathy

As above, easy bruising, facial plethora and proximal myopathy are the most sensitive features of Cushing's syndrome.

E. What diagnostic tests should be performed?

Once Cushing's syndrome has been confirmed, it is important to establish the role of ACTH as a cause of the adrenal hyperplasia. Both laboratory tests and imaging are important for distinguishing ACTH-dependent and independent adrenal hyperplasia.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Plasma adrenocorticotropic hormone levels

  • These must be measured, preferably two separate times

  • ACTH levels less than 10pg/mL indicates suppression and points to ACTH-independent causes

  • Normal or elevated ACTH levels indicate Cushing's disease or ectopic ACTH production

  • A CRH stimulation test is suggested if ACTH levels are between 10-20pg/mL

Corticotropin-releasing hormone stimulation test

  • Blunted ACTH response indicates ACTH-independent hyperplasia

  • Brisk rise in ACTH is seen in Cushing's disease

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Computed tomography or magnetic resonance imaging of adrenal glands

Bilateral enlargement of adrenal glands can indicate either AIMAH or ACTH-dependent hyperplasia, which warrants further imaging to locate a pituitary or other source of ACTH or CRH. Normal or smaller adrenal glands with multiple small cortical nodules can represent PPNAD. Solitary or single large nodules are more typical of adrenal carcinoma or adenomas.

Magnetic resonance imaging of pituitary with gadolinium

This should be done for patients with ACTH-dependent Cushing's. For patients with ACTH-dependent Cushing's but with discordant biochemical, clinical or radiological findings, bilateral inferior petrosal sinus sampling is recommended and is considered the gold standard for diagnosing the origin of ACTH.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

A combination of laboratory and imaging tests are needed to establish the diagnosis and underlying cause of Cushing's syndrome.

The desmopressin test can be useful in this work-up, but may have limited utility if used alone to distinguish the source of ACTH.

III. Default Management.

Management will rely on whether the adrenal hyperplasia is ACTH-dependent or independent and can be surgical or medical.

For ACTH-independent adrenal hyperplasia, adrenalectomy is recommended and is curative. The decision for bilateral versus unilateral is still controversial. Medical therapy can be useful prior to surgery or in patients with subclinical disease. Steroid synthesis inhibitors can be used:

  • Ketoconazole, starting at 200mg by mouth daily, and can be increased until cortisol secretion is normalized.

  • Metyrapone

Pharmacological therapies directed towards aberrant or abnormal hormone receptors in AIMAH are emerging.

For ACTH-dependent adrenal hyperplasia, surgery options include surgical resection of ectopic tumor producing ACTH. Transsphenoidal surgery is first-line therapy for Cushing's disease. Other options include pituitary radiation and adrenalectomy (if pituitary treatment options fail, or if the patient is not a surgical candidate).

Medical therapy includes steroidogenesis inhibitors as above. Pituitary neuromodulatory drugs have failed to demonstrate consistent benefits but options include:

  • Dopamine receptor agonists (bromocriptine, cabergoline)

  • Somatostatin analogues

  • Peroxisome proliferator-activated receptor gamma therapies

A. Immediate management.

Medical therapy can be initiated immediately to decrease circulating cortisol levels prior to surgical therapies. Endocrinologist and endocrine surgical consultations should be requested immediately for definitive management.

B. Physical Examination Tips to Guide Management.

InstructionPhysical exam findings are not as useful in monitoring response to treatment in the acute setting. However, blood pressure control, muscle weakness and edema can improve in the acute setting in response to treatment. Findings consistent with Cushing's syndrome are expected to improve over time with treatment.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Treatment success is monitored biochemically.

  • 24-hour urinary free cortisol at normal levels

  • Cortisol levels are normal

  • Hypoadrenalism (if bilateral adrenalectomy)

D. Long-term management.

Complications of therapies (listed below) need to be managed long-term. Ideally, patients should be referred to an endocrinologist for continued monitoring of hormones and success of surgical or medical therapies.

For patients who have treatment failure, either medical or surgical, repeat surgeries or bilateral adrenalectomies may be indicated.

E. Common Pitfalls and Side-Effects of Management

Surgical treatments

  • Adrenalectomy

    • ◦ Patients will be obligated to lifelong gluco- and mineralocorticoid replacement therapy

    • ◦ 15-25% are at risk for Nelson's syndrome (pituitary tumor growth)

  • Transsphenoidal surgery

    • ◦ Diabetes insipidus

    • ◦ Hypopituitarism OR hypogonadism, hypothyroidism, growth hormone deficiency

    • ◦ Cerebrospinal fluid rhinorrhea

    • ◦ Meningitis

Pituitary radiation

  • Hypopituitarism (as above)

  • Opthalmoplegia, cerebrovascular events, second brain tumors are rare complications

Medical treatments

  • Ketoconazole: hepatic injury, gynecomastia, gastrointestinal disturbance, edema, skin rash

  • Metyrapone: dizziness, anxiety, nausea, skin rash, hypertension

IV. Management with Co-Morbidities

The standard approach to the management of adrenal hyperplasia must include an assessment of the patient's co-morbidities to determine if the patient is a surgical candidate for adrenalectomy or pituitary surgery.

Optimization of co-morbid conditions should be provided as part of perioperative medical care. Medical therapy is recommended for patients who are poor surgical candidates based on preoperative risk stratification.

A. Renal Insufficiency.

No change in standard management if the patient is a surgical candidate.

B. Liver Insufficiency.

No change in standard management if the patient is a surgical candidate.

C. Systolic and Diastolic Heart Failure

No change in standard management if the patient is a surgical candidate. Additionally, because of the increased cardiovascular risk in patients with hypercortisolism, aggressive management of cardiac risk factors is recommended during the acute and long-term treatment of these patients.

D. Coronary Artery Disease or Peripheral Vascular Disease

No change in standard management if the patient is a surgical candidate. Additionally, because of the increased cardiovascular risk in patients with hypercortisolism, aggressive management of cardiac risk factors is recommended during the acute and long-term treatment of these patients.

E. Diabetes or other Endocrine issues

Patients with hypercortisolism are at risk for osteoporosis and fractures. Regular assessment of bone mineral densities and directed therapies for osteoporosis is recommended for long-term treatment plans.

F. Malignancy

No change in standard management if the patient is a surgical candidate. See also chapters covering adrenal carcinoma or ectopic ACTH for further details.

G. Immunosuppression (HIV, chronic steroids, etc).

No change in standard management if the patient is a surgical candidate.

H. Primary Lung Disease (COPD, Asthma, ILD)

No change in standard management if the patient is a surgical candidate.

I. Gastrointestinal or Nutrition Issues

No change in standard management if the patient is a surgical candidate.

J. Hematologic or Coagulation Issues

No change in standard management if the patient is a surgical candidate.

K. Dementia or Psychiatric Illness/Treatment

No change in standard management if the patient is a surgical candidate.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

Patients may be hypertensive or have impaired glucose control prior to therapy. Sign out should include appropriate management and indicate that these symptoms may be due to an excess of cortisol.

For patients who undergo pituitary surgery, it is important to note that the patient may require steroid replacement therapy postoperatively.

B. Anticipated Length of Stay.

Length of stay is usually 3-7 days, depending on complications postoperatively or response to medical therapy.

C. When is the Patient Ready for Discharge.

The following suggest the patient is ready for discharge:

  • Afebrile and hemodynamically stable postoperatively, consider at least 24 hours of postoperative monitoring

  • Decreasing levels of serum cortisol

  • Decreasing levels of urinary free cortisol

D. Arranging for Clinic Follow-up

The patient should have follow-up arranged with his or her primary care physician, endocrinology and the surgeon who performed any surgeries.

1. When should clinic follow up be arranged and with whom.

  • Primary care physician: within 1-2 weeks

  • Endocrinologist: within 1-2 weeks

  • Endocrine or other surgeon: within 2 weeks

2. What tests should be conducted prior to discharge to enable best clinic first visit.

None

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

  • Pituitary hormone levels (including ACTH, thyroid-stimulating hormone (TSH), gonadotropin-releasing hormone (GnRH))

  • Cortisol levels or urinary free cortisol

E. Placement Considerations.

None

F. Prognosis and Patient Counseling.

For ACTH-independent adrenal hyperplasia, most patients respond favorably to adrenalectomy. However, long-term follow-up is recommended for monitoring of complications.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.

None

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

None

VII. What's the evidence?

Boscaro, M, Arnaldi, G. "Approach to the Patient with Possible Cushing's Syndrome". J Clin Endocrinol Metab. vol. 94. 2009. pp. 3121-3131.

Shirodkar, M, Jabbour, S. "Endocrine Incidentalomas". Int J Clin Pract. vol. 62. 2008. pp. 1423-1431.

Bourdeau, I, Lampron, A, Costa, M, Tadjine, M, Lacroix, A. "Adrenocorticotropic hormone-independent Cushing's Syndrome". Curr Opin Endocrinol Diabetes Obes. vol. 14. 2007. pp. 219-225.

Martin, M, Giraldi, F, Cavagnini, F. "Cushing's Disease". Pituitary. vol. 9. 2006. pp. 279-287.

Carroll, T, Findling, J. "Cushing's syndrome of non-pituitary causes". Curr Opin Endocrinol Diabetes Obes. vol. 16. 2009. pp. 308-315.

Lacroix, A, Bourdeau, I. "Bilateral Adrenal Cushing's Syndrome: Macronodular Adrenal Hyperplasia and Primary Pigmented Nodular Adrenocortical Disease". Endocrinol Metab Clin N Am. vol. 34. 2005. pp. 441-458.

Stewart, P, Petersenn, S. "Rational for treatment and therapeutic options in Cushing's disease". Best Practice & Research Clinical Endocrinology & Metabolism. vol. 1. 2009. pp. S15-S22.

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