Cushing’s syndrome refers to a series of clinical consequences caused by the overproduction of glucocorticoids (mainly cortisol) in the clinical setting. In addition to being caused by exogenous overconsumption of glucocorticoids, it is mostly due to overproduction of glucocorticoids by tumors or hyperplastic tissues or overproduction of glucocorticoid-stimulating superhormones such as adrenocorticotropic hormone (ACTH) and adrenocorticotropin-releasing hormone (CRH) that directly or indirectly cause glucocorticoid overproduction [1]. Cortisol plays a crucial role in maintaining normal human metabolism, but prolonged hypercortisolism causes a hypercatabolic state in the body, which in turn leads to a series of significant clinical signs and symptoms: decreased libido, weight gain, full moon face, hypertension, impaired glucose tolerance, polycythemia face, purple lines, hirsutism, menstrual disorders, decreased muscle strength, susceptibility to petechiae, thinning of the skin, and some Psychosomatic symptoms, such as depression. Growth retardation is mostly found in pediatric patients [2]. Cushing’s disease refers to the pituitary ACTH-dependent type of Cushing’s syndrome and is the most common clinical type of Cushing’s syndrome. Cushing’s disease predominates in young people and failure to diagnose and control cortisol levels early will lead to serious clinical consequences, increasing the risk of developing other serious diseases such as cardiovascular disease and diabetes mellitus, seriously affecting the quality of life of patients and even affecting their lives. Currently, Cushing’s disease is still one of the most challenging and controversial endocrine diseases in terms of clinical diagnosis and treatment, and there are many issues worthy of attention and consideration in its diagnosis and treatment, especially in the perioperative endocrine treatment and control. Du Shiwei, Department of Neurosurgery, Armed Police General Hospital
I. Diagnosis of Cushing’s disease
In clinical practice, there are few cases with atypical clinical symptoms and endocrine-related examinations. If a patient is considered for the diagnosis of Cushing’s disease, he must undergo a series of endocrine laboratory tests and imaging and other related examinations before deciding to surgically explore the saddle area.
1.The first step To clarify hypercortisolism (diagnosis of Cushing’s syndrome)
Cortisol secretion is regulated by ACTH, a peptide hormone secreted by the anterior pituitary gland and released in a pulsatile manner, thus causing plasma cortisol levels to fluctuate constantly and exhibit a specific circadian rhythm. Normal cortisol secretion levels are generally highest in the morning (around 6-8am) and lowest in the early morning (around 0-2am). Cortisol levels usually drop abruptly between 8am-12pm and then continue a slow downward trend throughout the day. Cortisol levels begin to rise again from their lowest point around 2:00 a.m. Therefore, measuring plasma cortisol concentrations at a particular time point is of limited use in diagnosing hypercortisolism. Hypercortisolism should be characterized not only by an increase in blood cortisol levels but also by a loss of the rhythm of cortisol secretion. The collection and measurement of 24-hour urinary free cortisol (UFC) and low-dose dexamethasone suppression tests are currently the first-line screening methods for the diagnosis of Cushing’s syndrome, but more recently the use of midnight salivary cortisol levels to screen for Cushing’s syndrome has gained increasing attention. The method of screening for Cushing’s syndrome by measuring midnight salivary cortisol levels has received increasing attention.
1.1. 24-hour urinary free cortisol
Urinary free cortisol (UFC) is the result of glomerular filtration of free cortisol in blood, and its level is positively correlated with the change of physiologically active free cortisol concentration in blood. 24-h urinary free cortisol measurement can more reliably reflect the status of high cortisol secretion because it is not affected by circadian changes. Currently, urinary cortisol is mainly measured by exoneration method and high performance liquid chromatography. High performance liquid chromatography has relatively high specificity and can distinguish cortisol from other glucocorticoids. The range of 24-hour urinary free cortisol detected using it in normal subjects is <50ug/d [1]. 24-hour urinary free cortisol has a high sensitivity but relatively low specificity, and in general Cushing's syndrome is diagnosed if the test result is more than four times the upper limit of normal (>250-300ug/d). Three consecutive test results less than 90ug/d can basically exclude the possibility of Cushing’s syndrome. Mild elevations in 24-hour urinary free cortisol (90-300ug/d) can be found in pseudo-Cushing’s state and in pregnant women. Urine creatinine should be measured along with 24-hour urine free cortisol because false-negative results may occur in patients with Cushing’s syndrome with severe renal failure (glomerular filtration rate <30 ml/min).
1.2. Low-dose dexamethasone suppression tests (LDDSTs)
Dexamethasone can inhibit cortisol secretion through a negative feedback loop in the hypothalamo-pituitary-adrenal axis (HPA). The low-dose dexamethasone test is one of the most important diagnostic tests for Cushing’s syndrome and is used to detect the sensitivity of the HPA to negative feedback inhibition of glucocorticoids. The test is divided into an overnight method and a 2-day method of low-dose dexamethasone suppression test. The overnight low-dose dexamethasone suppression test requires oral dexamethasone 1 mg at midnight (11PM-12PM) and monitoring of blood cortisol levels early the next morning (8AM-9AM). A serum cortisol level below 5ug/dl essentially excludes the diagnosis of Cushing’s disease. In a recent international conference on the treatment of Cushing’s syndrome, experts reached a consensus to recommend lowering the cut point of blood cortisol level to 1.8ug/dl, thus greatly improving the sensitivity of the test, especially for the diagnosis of mild Cushing’s syndrome. However, at the same time, its specificity has decreased, which means that the false-positive rate of “patients” screened at this cut point has increased. False-positive results may occur in some patients with high hepatic metabolism of dexamethasone, which is common in patients taking oral drugs such as carbamazepine and phenytoin. Pregnancy and long-term oral administration of some exogenous estrogens can increase blood levels of cortisol-binding protein, which can also lead to false-positive results. In these cases, dexamethasone intake should be adjusted accordingly to ensure that adequate levels can be achieved in plasma, and oral estrogens must be discontinued for at least 6 weeks before a low-dose dexamethasone test can be performed. In some patients with pseudo-Cushing’s status and chronic disease, false-positive results have been observed in the low-dose dexamethasone test.
The 2-day low-dose dexamethasone suppression test involves oral administration of 0.5 mg of dexamethasone every 6 hours for 48 hours, collection of 24-hour urine the next day, and UFC testing, along with serum cortisol levels at 9 and 48 hours after the first dexamethasone intake. The normal suppression response was a 24-hour urine free cortisol value of less than 10ug/dl, and an early morning serum cortisol level of less than 1.8ug/dl after the last dose of dexamethasone. 2-day dexamethasone suppression test has the highest specificity of all screening tests and can also be used as a confirmatory test for Cushing’s syndrome.
1.3, midnight salivary cortisol (late night salivary cortisol)
The latest screening test for Cushing’s syndrome is the midnight salivary cortisol level test. Salivary cortisol can reflect the level of blood cortisol, and the sensitivity of 10PM salivary cortisol for the diagnosis of Cushing’s syndrome can reach 100% and the specificity can reach 84.2%-100% [6]. The time at which the specimen is taken represents the moment of lowest human blood cortisol level under normal physiological conditions. The advantage of this test is that it is easy to retain the specimen and it is easy to store the specimen for up to 1 week at room temperature, which makes it very useful for screening of outpatients. Furthermore, renal failure has little effect on the results of the test because the secretion of salivary cortisol is not dependent on the kidneys. In addition, its secretion is not affected by changes in the levels of cortisol-binding proteins. Other advantages include suitability for pediatric patients, avoidance of hormonal changes due to blood collection or stress, ease of repeat testing, ease of diagnosis in patients with intermittent cortisol elevation, and monitoring of disease recurrence. As with blood cortisol, false-positive results can occur in some cases, such as in women who are pregnant or taking oral contraceptives, and in cases of hypertension, diabetes, and psychiatric abnormalities [7,8] Currently, midnight salivary cortisol results vary widely depending on the test method and reagents, and each laboratory has its own standards. Currently the most commonly used test method is the release method, if the test result is greater than 350ng/dl then it suggests the diagnosis of Cushing’s syndrome, less than 150ng/dl then the diagnosis of Cushing’s syndrome can be basically excluded, if the result is between the two, then it is recommended to resample the test or combine with other tests for analysis and diagnosis.
1.4. Pseudocushing state
Pseudo-Cushing state refers to the effect of alcoholism, anxiety, depression and obesity on the HPA axis, resulting in some clinical manifestations and related biochemical abnormalities similar to mild Cushing’s syndrome, which may be caused by excessive secretion of CRH from the hypothalamus. Unlike true Cushing’s syndrome, cortisol levels in patients with pseudo-Cushing’s state are suppressed by a low-dose dexamethasone test, but CRH does not produce a transient increase in cortisol secretion in patients with pseudo-Cushing’s, and patients retain a normal urinary cortisol rhythm, these characteristics facilitate clinical differentiation.
2. Step 2: Identify ACTH-dependent Cushing’s syndrome
Cushing’s syndrome is divided into ACTH-dependent and non-ACTH-dependent. Most Cushing’s syndrome is ACTH-dependent (80%), and in ACTH-dependent Cushing’s syndrome, about 80% are pituitary ACTH-dependent Cushing’s disease. Most non-ACTH-dependent Cushing’s syndrome is caused by adrenal adenomas, and the occupancy can be clarified by CT or MRI scan. Measurement of plasma ACTH is an important method for determining the site of lesions in Cushing’s syndrome. Typical ACTH-dependent Cushing’s syndrome has elevated or normal plasma ACTH with little or no decrease. Non-ACTH-dependent Cushing’s syndrome has decreased ACTH levels. The diagnosis of non-ACTH-dependent Cushing’s syndrome is considered if plasma ACTH is less than 10 pg/ml, provided that Cushing’s syndrome has been clearly defined, and ACTH-dependent if plasma ACTH is greater than 20 pg/ml. In general, when ACTH levels are very high (>500 pg/ml), the tendency is to support a heterogenous diagnosis. Between 10 and 20 pg/ml further differentiation is required using other tests such as CRH stimulation test. Furthermore, ACTH breaks down very rapidly in blood specimens, so specimens should be stored at -20°C and the time interval between blood collection and testing should be minimized to reduce the possibility of false negative results
3 Step 3 Identify the source of ACTH
3.1. High-dose dexamethasone suppression test (HDDST)
The high-dose dexamethasone suppression test can be used to identify Cushing’s disease from Cushing’s syndrome caused by ectopic tumor secretion of ACTH. In about 80-90% of patients with Cushing’s disease, ACTH secretion can be suppressed by high-dose dexamethasone, whereas ACTH secretion from ectopic tumors such as carcinoid tumors of the bronchus, pancreas, and thymus, and medullary thyroid carcinoma, is mostly not suppressed by dexamethasone. Moreover, the autocrine overproduction of cortisol caused by adrenal tumors is usually not inhibited by high-dose dexamethasone tests. The high-dose dexamethasone test can be performed by the standard 2-day method, which is basically the same as the low-dose dexamethasone suppression test, except that each oral dose of dexamethasone is 2 mg. Because of the cumbersome steps of the 2-day method, the 8 mg overnight dexamethasone test or the intravenous high-dose dexamethasone suppression test (4-7 mg dexamethasone) has been proposed. If the test results show a suppression of urinary free cortisol levels of more than 90%, it strongly suggests a diagnosis of Cushing’s disease [13].
3.2, CRH stimulation test
The CRH stimulation test is based on the theory that pituitary ACTH adenomas still respond to CRH and that CRH injection causes a rise in plasma ACTH and cortisol, whereas adrenal adenomas and ectopic ACTH tumors are largely unresponsive, so this test can be used for the differential diagnosis of ACTH-dependent Cushing’s syndrome. There is considerable overlap between normal subjects and patients with Cushing’s disease to the CRH stimulation test, so it is not sufficient to confirm the diagnosis of Cushing’s disease, but it can be used to identify the cause of Cushing’s syndrome. Before the test, the basal values of ACTH and cortisol should be measured, then 1ug/kg or 100ug of CRH should be injected, and blood should be collected at 15, 30, 60, 90 and 120 min after the test to measure the levels of ACTH and cortisol. A rise of 50% or more in ACTH and 20% or more in blood cortisol from basal values suggests a diagnosis of Cushing’s disease. If ACTH does not rise by more than 50% from basal values or cortisol does not rise by more than 20%, the diagnosis of ectopic or adrenal-derived Cushing’s syndrome is suggested. If ACTH rises more than 100% or blood cortisol rises more than 50%, the diagnosis of ectopic Cushing’s syndrome can be ruled out. the CRH stimulation test combined with bilateral blood sampling from the subxiphoid sinus (BIPSS) can significantly improve the accuracy of the test.
3.3. MRI scan of the saddle area
Saddle MRI scan in patients with ACTH-dependent Cushing’s syndrome can reveal pituitary adenoma in about 60% of patients. If the endocrine findings are consistent with Cushing’s disease changes and the saddle MRI scan results show pituitary adenoma, the diagnosis of Cushing’s disease is basically clear, and postoperative pathological tests can clarify whether the tumor is ACTH-secreting or not. Most Cushing’s disease is a pituitary microadenoma, which appears as a low signal within the pituitary gland on MRI. On plain MRI, the low signal of pituitary adenomas correlates with the relaxation time of the signal within the tumor. On enhanced MRI, the time difference between pituitary tissue enhancement and pituitary adenoma enhancement can be obtained not only by injecting enhancer, but also by obtaining enhanced images of both. Since pituitary tissue is richer in blood flow than pituitary adenoma, the enhancement of pituitary tissue is earlier than that of pituitary adenoma during enhancement. If the sequence of enhancement of the two can be distinguished, the lesion can be shown more clearly, thus improving the diagnosis of pituitary microadenoma. However, because plain-enhanced MRI is scanned after all of the enhancer is injected, the difference between the two is sometimes not captured, whereas dynamic MRI is scanned while the enhancer is continuously injected, thus showing the time difference between the two enhancements in a timely manner. For patients diagnosed with Cushing’s disease by clinical presentation and endocrinological examination, when pituitary adenoma is not detected by plain scan and enhancement MRI, the use of dynamic MRI can improve the detection rate of pituitary adenoma.
3.4. Bilateral blood sampling from subxiphoid sinus (BIPSS)
BIPSS is an invasive test that is a confirmatory test for Cushing’s disease. It is of great clinical diagnostic significance, especially for the diagnosis and differential diagnosis of patients with Cushing’s syndrome who cannot be localized on imaging and who have difficulty in identifying the cause by ordinary endocrine techniques. The veins on the left and right side of the pituitary gland return to the ipsilateral cavernous sinus and then descend posteriorly into the subclavian sinus and then directly into the jugular venous return. Because the infundibular sinus receives blood directly from the pituitary into the cavernous sinus, the blood sample from this area has the highest level of pituitary hormone secretion and is the most ideal sample for monitoring changes in pituitary hormone concentrations. In patients with Cushing’s disease, ACTH levels are significantly higher in blood from the infratentorial sinus than in peripheral blood, whereas there is no significant difference in patients with ectopic secretion. It has been suggested that BIPSS combined with CRH stimulation tests may improve the sensitivity of the test. When the basal central to peripheral ACTH ratio (IPS:P) is ≥2:1, or after CRH stimulation test (IPS:P) ≥3:1, it indicates excessive pituitary-derived ACTH secretion, and if the ratio decreases, it is usually ectopic ACTH secretion. If the ratio of ACTH in the subclavian sinus on one side is ≥1.4 compared to the contralateral side, the tumor is considered to be partially located on one side.
It is important to note that the most reliable results of subxiphoid sinus sampling can only be obtained in a high blood cortisol state. Because there is no inhibition of the HPA axis at normal blood cortisol concentrations, ISP:P is a false positive result. Therefore, patients with Cushing’s syndrome can have false positive results in the following situations: (1) medication to reduce cortisol to normal. (2) Intermittent Cushing’s syndrome in a normal cortisol secretion state. (3) The presence of ectopic CRH secretion. Therefore, for patients with cortisolism whose blood cortisol is currently normal, sublithic sinus sampling should be repeated to determine the results.
II. Perioperative management of Cushing’s disease
Once the diagnosis of Cushing’s disease is clear, transsphenoidal sinus surgery is the treatment of choice. The goal of surgery is to completely remove the tumor and correct the hyper-ACTHemia and hypercortisolism, while preserving pituitary function as much as possible. In a small number of patients with obvious signs and symptoms of cortisolism, where endocrine findings suggest a pituitary origin and imaging of the pterygoid saddle area fails to reveal a tumor, trans-pterygoid pituitary surgery is also the safe, reliable and effective method of choice.
As with other transsphenoidal pituitary surgeries, oral antibiotics and chloramphenicol eye drops are required for three days before surgery, but unlike other pituitary adenoma surgeries, patients with Cushing’s disease do not require preoperative and intraoperative glucocorticoids to facilitate assessment of the surgical outcome. Most adenomas found during surgery are soft in texture and postoperative pathology plays a crucial role in clarifying the diagnosis. For microadenomas, it has been advocated that in addition to the tumor itself, the majority of the perineural pituitary should be resected to reduce the recurrence rate of the tumor. After resection of a large number of ACTH-secreting tumors, the blood cortisol level in most patients rapidly decreases to below the low limit of normal within 48 hours and is not even measurable, so the postoperative blood cortisol level is an accepted indicator to evaluate the surgical effect and predict the possibility of long-term recurrence. It is now generally accepted that a patient’s blood cortisol level below 2ug/dl or even undetectable within 72 hours after surgery can indicate successful surgery and a 10-year recurrence rate of less than 10%. The 24-hour postoperative UFC, low-dose dexamethasone test also provides a good evaluation of the postoperative patient’s endocrine status. However, if postoperative patients continue to experience no or insignificant decrease in blood cortisol levels below the low limit of normal, this is an indication of possible residual tumor or a higher risk of recurrence. For recurrent or residual tumors, reoperative treatment remains the first option when the diagnosis is clear.
In patients with Cushing’s disease, glucocorticoid replacement therapy is not administered in the early 2-3 days after surgery in order to observe and evaluate the surgical outcome. As the patient is in a high cortisol state for a long time before surgery and the blood cortisol drops rapidly after surgery, the patient will develop glucocorticoid withdrawal symptoms (glucocorticoid withdrawal symptoms) with nausea, vomiting, increased heart rate, decreased blood pressure, and mental abnormalities. Moreover, it has been observed that clinical symptoms and hemodynamic indices can remain relatively stable even when blood cortisol drops to 5ug/dl after surgery. When the symptoms are mild, only symptomatic treatment is needed to ensure patients’ water-electrolyte balance, slow down heart rate, and maintain blood pressure without hormone supplementation, but when the withdrawal reaction is serious, patients should be treated with high-dose supplemental glucocorticoids in time when they have severe blood pressure drop or even shock, but high-dose glucocorticoid treatment can inhibit the HPA axis and hinder the relief of postoperative symptoms in Cushing’s disease, therefore, when patients After severe withdrawal reactions, the dose should be gradually reduced to a replacement dose within one month after surgery. Because the HPA axis is suppressed for a long time, postoperative recovery is slow and it generally takes 11-18 months for cortisol to reach normal levels. During this period, patients are plagued by complications associated with low cortisol levels, and appropriate glucocorticoid replacement therapy is necessary if patients develop symptoms of low cortisol or have blood cortisol levels below 2ug/dl. In case of illness, surgery and other stressful situations, the glucocorticoid dose should be increased by 2-4 times to prevent adrenal crisis. Since surgery also affects other endocrine functions of the pituitary gland, thyroid and gonadal function should be evaluated during the perioperative period, and replacement therapy should be administered if necessary. Although surgical treatment of Cushing’s disease has a cure rate of 65-90%, patients should be aware that this “cure” can recur and that the likelihood of recurrence is high, so lifelong endocrine monitoring is essential and necessary.