Screening For Cushing’s Syndrome in Primary Care: Which Test is The Best?

Cushing’s syndrome (CS) is defined as an outcome of prolonged exposure to glucocorticoids whether from outside or inside sources. It’s a relatively rare condition with an incidence of 0.7-2.4 per million population per year [1]. Clinical presentation in primary care setting can be highly variable, and establishing the diagnosis can often be difficult and is frequently missed due to its rarity and overlapping characteristics with common disorders like metabolic syndrome. Early diagnosis and treatment of CS is associated with a decrease in morbidity and mortality [2]. The objective of this article is to discuss the most appropriate screening test that could be performed in primary care in clinically suspected cases of CS.


Introduction
Cushing's syndrome (CS) is defined as an outcome of prolonged exposure to glucocorticoids whether from outside or inside sources. It's a relatively rare condition with an incidence of 0.7-2.4 per million population per year [1]. Clinical presentation in primary care setting can be highly variable, and establishing the diagnosis can often be difficult and is frequently missed due to its rarity and overlapping characteristics with common disorders like metabolic syndrome. Early diagnosis and treatment of CS is associated with a decrease in morbidity and mortality [2]. The objective of this article is to discuss the most appropriate screening test that could be performed in primary care in clinically suspected cases of CS.

Etiology of Cushing's Syndrome
Exogenous administration of glucocorticoids (Iatrogenic CS) is the most common cause of CS. Table 1 shows the various causes of endogenous CS. ACTH dependent CS accounts for 80-85% of cases, of which around 75-80% are due to pituitary adenoma. Chronic alcoholism, depression and severe obesity may lead to reversible hyperactivity of HPA axis and cause pseudo-CS [1,2].  Table 2 discusses the various clinical features of CS. Certain features of the skin, muscles and bones are specific for CS that helps to differentiate it from simple obesity. Clinical features like cataract, raised intraocular pressure, aseptic necrosis of femoral head and osteoporosis are more common in iatrogenic CS [1].

Specific Features
General Features Body -Abnormal fat deposition leading to Weight gain, obesity, moon face, buffalo hump.

Reproductive system-Decreased
libido, menstrual irregularities in women mainly amenorrhea due to reduced gonadotrophin secretion due to effect of cortisol Bone-Osteopenia, osteoporosis, mainly involving the vertebrae leading to reduced linear growth.

Muscle-Weakness and proximal myopathy
Blood and immune system-Hypercoagulation with risk of DVT or pulmonary embolism and susceptibility to infections.

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• Patients with multiple, progressive, and discriminatory findings suggestive of CS.

•
Cases with unusual features like hypertension or osteoporosis at a young age • Children with a decreasing height percentile and increasing weight • Adrenal incidentalomas • Patients with familial disease that puts them at risk of CS.
• It recommends against widespread testing for CS other than the above patient group.

24hr UFC
24 hr UFC looks at the unbound cortisol secretion that is filtered by the kidneys over a 24hr period and is not affected by conditions and medications that alter Cortisol Binding Globulin (CBG). Normal values: <90 microgram/24hours (250nmol/ day). Values more than 300microgram/day (830nmol/day) are considered diagnostic. Sensitivity of this test in detecting cortisol excess is 95%, specificity is 98%. False positive and false negative results may occur (Table 3). UFC should be confirmed with repeat testing [5].

Late night salivary cortisol
Physiological cortisol secretion follows a circadian rhythm. Serum cortisol concentration reaches its peak in the morning (0600-0800h) and is lowest in the night during the first half of normal sleep. Normal circadian rhythm of cortisol secretion is lost in patients with CS. Salivary cortisol is measured at 23:00 hours and 07:00 hours using a standard cortisol radioimmunoassay (RIA). The upper limit of reference range is 145ng/dl (3.6nmol/L) and sensitivity is >92%. LNSF is a simple and reliable screening test for spontaneous Cushing's Syndrome and useful for screening large, high risk population (patients with diabetes mellitus) [4].

Dexamethasone suppression test (DST)
In standard DST patient is given 1mg dexamethasone orally at 11pm and the plasma cortisol level is measured at 8 am next morning. In the 48-h low dose DST test, dexamethasone is given at the dose of 0.5 mg every 6 h for 2 days at 090h, 1500h, 2100h, and 0300h with measurements of cortisol in serum 6 hours after the last dose of dexamethasone (normal<1.8ug/dl). The sensitivity of this test is 98%; specificity is 80%. Normal findings in both the test make CS unlikely. Obesity, chronic illness, chronic alcoholism and depression can cause false positive results (pseudo-Cushing syndrome) [5].

Discussion
Cushing's syndrome is a relatively rare condition [6], and can present to primary care in many different ways, making the diagnosis a challenging one to reach. It is an important diagnosis to consider, as it has a significant impact upon morbidity and mortality, and early detection and treatment can have a significant impact on improving life expectancy [7]. Unfortunately, however, it is a diagnosis that is frequently 'missed', with a mean time to diagnosis of 6 years in one study [8].
In the primary care setting, the ideal first-line screening test would be very sensitive (ie. all those with Cushing's syndrome would be detected, and none would be missed), practically possible in the community, acceptable to the patient and costeffective [6].

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Around the world all other tests except 24hr UFC, need to be performed in the hospital setting so the most readily available in the primary care setting is the 24hr UF [9]. 24hr UFC looks at the unbound cortisol secretion that is filtered by the kidneys over a 24hr period. This test is usually considered overall to have a high diagnostic sensitivity in adults and children, it is important to correlate test results with creatinine ratios to ensure a complete collection [4]. This test also has multiple external factors that can cause or mask false negative/positive results such as excess fluid intake, certain medications and improper collections. It is vital to obtain a thorough assessment to take place to accurately access results. [3]. In the pediatric population, even with a high sensitivity of 89% it is still recommended to follow up the UFC with a second test mentioned above to confirm a diagnosis [10].
24 hour urinary free cortisol levels appears to be the most practical first-line test to perform in primary care in patients where there is a high probability of Cushing's Syndrome, because it is non-invasive and widely available [8]. However, in patients who have a lower probability of Cushing's syndrome, it may be advantageous to consider late night salivary cortisol or 1-mg overnight dexamethasone, because both of these tests are more sensitive, reducing the likelihood of false negative results [8]. Unfortunately, late night salivary cortisol is not a test that is widely available to primary care physicians in the UK [11]. The 1mg overnight dexamethasone suppression test is possible to organize in primary care, with a well motivated patient, but the practicalities of timing the administration of the drug and the blood test, make it slightly more of a challenge [12].

Conclusion
In summary, when screening for Cushing's syndrome in primary care in the UK, a 24hour urinary free cortisol level is a useful test for the majority of patients, particularly when they have symptoms that make the diagnosis of Cushing's Syndrome likely. In a patient who is less likely to have Cushing's Syndrome, but needs screening to exclude the diagnosis, 1mg overnight dexamethasone testing may be preferable, due to the higher sensitivity of the test.