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Polycystic ovarian disease

Pseudo-Cushing (e.g., alcoholism, physical stress, severe major depression)

DIAGNOSTIC TESTS & INTERPRETATION

Initial Tests (lab, imaging)

Recent guidelines (1)[C]

–The 2008 Endocrine Society guidelines recommend against widespread testing for Cushing syndrome except in patients with the following:

Adrenal incidentaloma

Multiple progressive features suggestive of Cushing syndrome

Unusual features for their age such as osteoporosis and HTN

Abnormal growth (children)

Late-night salivary cortisol, 24-hour urinary free cortisol, or low-dose dexamethasone suppression testing

–Elevated late-night salivary cortisol: Obtain at least two measurements. Cortisol secretion is highest in the morning and lowest between 11 PM and midnight. The nadir of serum cortisol is maintained in pseudo-Cushing (e.g., obesity, alcoholism, depression) but not in Cushing syndrome. Sensitivity and specificity are >90–95% (2)[B].

–24-hour urinary free cortisol level: Obtain ≥2 samples to rule out intermittent hypercortisolism if results are normal and suspicion is high. Also measure 24-hour urinary creatinine excretion to verify adequacy of collection. Results may be falsely low if glomerular filtration rate <30 mL/min. Overall sensitivity and specificity varies, 90–97% and 85–99%, respectively (2)[B]. Avoid drinking excessive amounts of water due to risk of false-positive values. False-positive values can be seen in the presence of pseudo-Cushing states.

–Low-dose dexamethasone suppression testing: Dexamethasone 1 mg is given between 11 PM and midnight, and fasting plasma cortisol is measured between 8 and 9 AM the following morning. Aserum cortisol level below 1.89 µg/dL excludes Cushing syndrome, but specificity is limited. The presence of pseudo-Cushing states (depression, obesity, etc.), hepatic or

renal disease, or any drug that induces cytochrome P450 enzymes may cause a false result.

High-dose dexamethasone suppression test may be useful when baseline ACTH levels are indeterminate:

–8 mg overnight dexamethasone suppression test: 8 mg of oral dexamethasone is given at 11 PM, with measurement of an 8-AM cortisol

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level the next day. Abaseline 8-AM cortisol measurement is also obtained the morning prior to ingesting dexamethasone. Suppression of serum cortisol level to <50% of baseline is suggestive of a pituitary source of ACTH rather than ectopic ACTH or primary adrenal disease. Sensitivity and specificity are 95% and 100%, respectively (3)[B].

If the initial results are positive or if clinical suspicion is high, perform additional studies to confirm diagnosis. Other tests to consider include the following:

–Awake midnight plasma cortisol: Obtain samples on three consecutive nights. Alate-evening serum cortisol >7.5 µg/dL has a sensitivity of 99% and specificity of 100% (4)[B]. Persistently elevated serum cortisol implies Cushing syndrome; nadir of serum cortisol is maintained in obese patients but not in Cushing.

–Corticotropin-releasing hormone (CRH) after dexamethasone: used to distinguish Cushing syndrome from pseudo-Cushing syndrome. Dexamethasone 0.5 mg is given q9h for 48 hours starting at noon. CRH (1 µg/kg) is given 2 hours after the last dose of dexamethasone. Plasma cortisol is >1.4 µg/dL 15 minutes after CRH in patients with Cushing

syndrome but not in those with pseudo-Cushing. Pituitary MRI scan if pituitary tumor is suspected Abdominal CT scan if adrenal disease is suspected

Chest CT scan if ectopic ACTH secretion is suspected

Octreotide scintigraphy to look for occult ACTH-secreting tumor

Dual energy x-ray absorptiometry to evaluate for osteoporosis

ALERT

Antiepileptic drugs, progesterone, oral contraceptives (withdraw estrogencontaining drugs 9 weeks before testing), rifampin, and spironolactone may cause a false-positive dexamethasone suppression test.

Pregnancy (1)[C]: Urine free cortisol is recommended instead of dexamethasone testing in the initial evaluation of pregnant women. Only urine free cortisol in the 2nd or 3rd trimester >3 times the upper limit of normal can be taken to indicate Cushing syndrome.

Epilepsy (1)[C]: best to use measured cortisol from saliva and urine instead of serum cortisol after dexamethasone. No data to guide length of time needed after withdrawal of such medication to allow dexamethasone metabolism to return to normal; such medication change may not be clinically possible.

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Follow-Up Tests & Special Considerations

Once the diagnosis of Cushing syndrome is confirmed, localization is the next step:

–ACTH level: elevated in ACTH-dependent Cushing syndrome (e.g., pituitary and ectopic tumor) and low in ACTH-independent Cushing syndrome (e.g., adrenal tumors and exogenous glucocorticoids)

–High-dose dexamethasone suppression testing: used to distinguish between an ACTH-secreting pituitary tumor and ectopic ACTH-secreting tumors. 0.5 mg dexamethasone is given q9h for 8 doses, with serum cortisol measured at 2 and 9 hours after last dose (sensitivity 79%, specificity 74%) (3)[B].

Diagnosis of Cushing syndrome is complicated by the nonspecificity and high prevalence of clinical symptoms in patients without the disorder and involves a variety of tests of variable sensitivity and specificity. Efficient screening and confirmatory procedures are essential before considering therapy.

Diagnostic Procedures/Other

Diagnostic procedure depends on clinical judgment. Inferior petrosal sinus sampling with CRH stimulation can be considered if ACTH-dependent tumor is suspected but not localized.

Test Interpretation

Thyroid function suppressed

HTN

Dyslipidemia

Polycystic ovarian syndrome/hyperandrogenism

Oligomenorrhea/hypogonadism

Myopathy/cutaneous wasting

Neuropsychiatric problems

Ipsilateral adrenal gland hyperplasia and contralateral adrenal gland atrophy

Hypercoagulable state

Osteoporosis

Nephrolithiasis

Growth hormone reduced

TREATMENT

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MEDICATION

Drugs usually not effective for primary long-term treatment; used in preparation for surgery or as adjunctive treatment after surgery, pituitary radiotherapy, or both

Metyrapone, ketoconazole, and mitotane all lower cortisol by directly inhibiting synthesis and secretion in the adrenal gland. Replacement glucocorticoid therapy is often required. As initial treatment, remission rates up to 85% (5)[C].

Etomidate also inhibits the adrenals and is the only medical treatment available for severe hypercortisolism who are not immediate surgical candidates and who cannot take oral medication.

Mifepristone is a potent glucocorticoid receptor antagonist. It is FDAapproved to control hyperglycemia in adults with endogenous Cushing syndrome who have type 2 diabetes or glucose intolerance secondary to hypercortisolism that has not responded to (or who are not candidates for) surgery.

Pasireotide is a somatostatin receptor ligand with affinity for somatostatin receptor 5. It was approved by the FDAin 2012 for the treatment of Cushing disease when surgery is not successful or cannot be performed.

Cabergoline is a dopamine agonist that has shown some promise in small studies but still remains off-label use.

SURGERY/OTHER PROCEDURES

Transsphenoidal surgery

–Primary treatment for Cushing disease due to remission range of 95–90% (6)[C]

–Resection of the ACTH-producing ectopic tumor

Adrenal surgery

–For unilateral adrenal adenomas, laparoscopic surgery is the treatment of choice.

–For nodular hyperplasia, bilateral adrenalectomy is usually recommended.

–For patients with Cushing disease, bilateral laparoscopic adrenalectomy can be considered if the patient has persistent disease even after pituitary surgery and radiotherapy.

Radiotherapy and stereotactic radiosurgery (SRS) can be used to treat persistent hypercortisolism after transsphenoidal surgery in Cushing disease.

Fractionated radiotherapy

– Rates of remission range from 59% to 84%.

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– Its related complications of hypopituitarism have limited its usefulness.

SRS

Rates of remission range from 17% to 83%.

Can be used as primary treatment without resection in patients with cavernous sinus tumors

ONGOING CARE

PATIENT EDUCATION

Teaching regarding diet and monitoring daily weight, early treatment of infections, emotional lability

National Adrenal Disease Foundation. Great Neck, NY 11021; 519-407-4992

PROGNOSIS

Guardedly favorable prognosis with surgery for Cushing disease; generally chronic course with cyclic exacerbations and rare remissions

Better prognosis following surgery for benign adrenal tumors; long-term recurrence rate is 20%.

Poor with small cell carcinoma of the lung producing ectopic hormone; neuroendocrine tumors (bronchial carcinoid) have much better prognosis.

COMPLICATIONS

Osteoporosis

Increased susceptibility to infections

Metastases of malignant tumors

Increased cardiovascular risk even after treatment

Lifelong glucocorticoid dependence following treatment with bilateral adrenalectomy

Nelson syndrome (pituitary tumor) after treatment with bilateral adrenalectomy (can occur in 8–38% of patients)

REFERENCES

1.Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing’s syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2008;93(5):1526–1540.

2.Putignano P, Toja P, Dubini A, et al. Midnight salivary cortisol versus urinary free and midnight serum cortisol as screening tests for Cushing’s syndrome. J

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Clin Endocrinol Metab. 2003;88(9):4153–4157.

3.Aytug S, Laws ER Jr, Vance ML. Assessment of the utility of the high-dose dexamethasone suppression test in confirming the diagnosis of Cushing disease. Endocr Pract. 2012;18(2):152–157.

4.Isidori AM, Kaltsas GA, Pozza C, et al. The ectopic adrenocorticotropin syndrome: clinical features, diagnosis, management, and long-term followup. J Clin Endocrinol Metab. 2006;91(2):371–377.

5.Nieman LK, Ilias I. Evaluation and treatment of Cushing’s syndrome. Am J Med. 2005;118(12):1340–1346.

6.Biller BM, Grossman AB, Stewart PM, et al. Treatment of adrenocorticotropin-dependent Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab. 2008;93(7):2454–2462.

SEE ALSO

Algorithm: Cushing Syndrome

CODES

ICD10

CLINICALPEARLS

Cushing disease is due to excessive ACTH secretion from a pituitary tumor, resulting in corticosteroid excess.

Cushing syndrome is due to excessive corticosteroid exposure from exogenous sources (medications) or endogenous sources (pituitary, adrenal, pulmonary, etc.) or tumor.

Depression, alcoholism, medications, eating disorders, and other conditions can cause mild clinical and laboratory findings similar to those in Cushing syndrome (pseudo-Cushing syndrome).

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CUTANEOUS DRUG REACTIONS

Chris Place, MD

BASICS

DESCRIPTION

An adverse cutaneous reaction in response to administration of a drug. Rashes are the most common adverse drug reactions.

Severity can range from mild eruptions that resolve within 48 hours after the removal of the inciting agent, to severe skin damage with multiorgan involvement.

Morbilliform/simple exanthem (75–95%) and urticarial (5–6%) eruptions are most common, but multiple morphologic types may occur.

System(s) affected: skin/mucosa/exocrine, hematologic/lymphatic/immunologic

EPIDEMIOLOGY

All ages are affected.

Predominant sex: female > male

There is no correlation between development of adverse reaction and patient’s age, diagnosis, or survival.

Special consideration in the geriatric population who are on multiple medications: increased likelihood of severe cutaneous and systemic reactions; also consider in the pediatric group: difficult to distinguish from viral exanthems

Incidence

In the United States, prevalence of 2–3% in hospitalized patients; estimated 1/1,000 hospitalized patients has had a severe cutaneous reaction.

ETIOLOGYAND PATHOPHYSIOLOGY

Predictable adverse reactions are due to overdose, side effect, or drug interaction.

Unpredictable reactions include intolerance, drug idiosyncrasy secondary to abnormality in metabolism, or immune reaction. >700 drugs are known to cause a dermatologic reaction:

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–Immunologically mediated reaction: immunoglobulin (Ig) E–mediated reaction (type I hypersensitivity), cytotoxic/IgG/IgM induced (type II), immune complex reactions (type III), and delayed-type hypersensitivity (type IV) with T cells, eosinophils, neutrophils, and monocytes

–Acneiform: OCPs, corticosteroids, iodinated compounds, hydantoins, lithium

–Erythema multiforme/Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN): >100 drugs reported. Most common include sulfonamides, cephalosporins, NSAIDs, barbiturates, hydantoins, anticonvulsants tetracycline, terbinafine.

–Fixed drug eruptions: NSAIDS, sulfonamides, tetracycline, barbiturates, salicylates, OCPs

–Lichenoid: thiazides, NSAIDs, gold, ACE inhibitors, proton pump inhibitors, antimalarials, sildenafil

–Photosensitivity: doxycycline, thiazides, sulfonylureas, quinolones, sulfonamides, NSAIDs

–Hypersensitivity vasculitis: hydralazine, penicillins, cephalosporins, thiazides, gold, sulfonamides, NSAIDs, propylthiouracil

–Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome: anticonvulsants, sulfonamides, dapsone, minocycline, allopurinol

–Acute generalized exanthematous pustulosis (AGEP): penicillins, cephalosporins, macrolides, calcium channel blockers, antimalarials, carbamazepine, acetaminophen, terbinafine, nystatin, vancomycin

–Sweet syndrome (acute febrile neutrophilic dermatosis): sulfa drugs, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), diazepam, minocycline, nitrofurantoin, captopril, penicillamine

–Serum sickness-like reaction: cephalosporins, penicillins, TMP/SMX, propranolol, bupropion, minocycline

–Morbilliform/urticarial/exfoliative erythroderma: numerous medications, including penicillins, cephalosporins, sulfonamides, tetracyclines, ibuprofen, naproxen, allopurinol, acetylsalicylic acid, radiocontrast media (1)[A]

Genetics

Genetics may play a role, as certain HLAantigens have been associated with increased predisposition to specific drug eruptions:

HLA-B*5801, HLA-B*5701, and HLA-B*1502 have been linked to

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allopurinol-induced and carbamazepine-induced SJS/TEN, respectively.

HLAclass I antigens, such as HLA-A2, HLA-B12, and HLA-B22, have been linked to TEN and fixed drug eruptions, respectively.

RISK FACTORS

Previous drug reaction, multiple medications, concurrent infections, immunocompromised, disorders of metabolism, and certain genetic HLA haplotypes

GENERALPREVENTION

Always ask patients about prior adverse drug events. Be aware of medications with higher incidence of reactions as well as drug cross-reactions.

DIAGNOSIS

HISTORY

New medications within the preceding 6 weeks, most commonly within preceding 2 weeks: all oral, parenteral, and topical agents, including over-the- counter drugs, vitamins, and herbal remedies

Consider other etiologies: unrelated acute or chronic urticaria, bacterial infections, viral exanthems, or underlying skin disease including cutaneous lymphoma.

PHYSICALEXAM

May present as a number of different eruption types, including, but not limited to the following:

Morbilliform eruptions (exanthems)

–Most frequent cutaneous reaction (75–95%); difficult to distinguish from viral exanthem; often secondary to an antibiotic

–Starts on trunk as pruritic red macules and papules, then extends to extremities in confluent fashion, sparing face, palms, soles, and mucous membranes

–Onset 7 to 21 days after drug initiation (2)

Urticaria

–Pruritic erythematous wheals distributed anywhere on the body, including mucous membranes; may progress to angioedema, appears as nonpitting edema without erythema or margins

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– Individual lesions fade within 24 hours, but new lesions may develop (2).

Acneiform eruptions

–Folliculocentric, monomorphous pustules typically involving the face, chest, and back distinguished from acne vulgaris by absence of gross and/or microscopic comedones

–Often may become secondarily infected (2)

Fixed drug eruptions

–Single/multiple, round, sharply demarcated, violaceous plaques with gray center that may leave postinflammatory hyperpigmentation; occur on skin or on mucous membrane

–Appear shortly after drug exposure and recur in identical location after reexposure; some patients have a refractory period during which the drug fails to activate lesions.

–Onset usually is 48 hours after ingestion of drug (2).

AGEP

–Multiple nonfollicular sterile pustules on erythematous background with desquamation after 7 to 10 days

–Involves intertriginous areas but can be generalized and involve the face

–Appears similar to pustular psoriasis, but AGEPoften causes fever and marked leukocytosis with neutrophilia and/or eosinophilia (2)[C].

DRESS syndrome

–Classic triad of fever, exanthem, and internal organ involvement with possible pharyngitis and lymphadenopathy

–Can lead to exfoliative dermatitis, often accompanied by facial edema

–Internal organ involvement: 80% hepatic, 40% renal, 33% pulmonary, and cardiac lab tests show elevated liver transaminases and eosinophilia

–Onset 2 to 8 weeks after drug exposure; may develop 3 months or later into therapy (3)[B]

Erythema multiforme

–Relatively common, acute, often recurrent

–Most commonly associated with herpes simplex virus (HSV) and other viral/bacterial etiologies (i.e., mycoplasma); less likely secondary to drug exposure; 50% with unknown etiology

–Three-zone target lesions and raised atypical two-zone targets with localized erythema

–Lesions predominant on distal extremities including on acral surface with limited mucosal involvement; <10% epidermal detachment (4)[B]

SJS/TEN

– Classification and distinction between SJS and TEN determined by affected

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