And It's About Time There Was Some Support For Cushing's!
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Medstudents' Homepage Cushing' Syndrome Laboratorial Diagnosis
Cushing's Syndrome may be defined as a persistent and continuous state of endogenous cortisol overproduction, not being in accordance with ordinary circadian rhythm patterns (It was first fully clinically described by Harvey Cushing in 1912.). As a consequence, it leads to various symptoms and signs, namely:
* The main Cushing's obesity feature is centripetal, but generalized obesity can occur - often to children.
Apart from that, the finding of violet estriae, associated or not with the above characteristics, raises the suspicious of the syndrome. Also, it must be stressed out that the term "Cushing's Disease" is a specific type of Cushing's Syndrome whose ethiology is Pituitary Adenoma ACTH producer (generally it is due to microadenoma). The other types of Cushing Syndrome are classified according to the following:
a) ACTH dependent
* The most common in order of frequency:
b) ACTH independent
c) Factitious (excess of exogenous glucocorticoid)
Pseudo Cushing's Syndrome main causes:
Such classification is of extreme importance as, logically, either the diagnostic and therapeutic conduct differs for each ethiology. So, when will our investigation be started? The strong clinical suspicion of Cushing's Syndrome must be confirmed biochemically.
First of all, the process should start with a detailed anamnesis and physical exam of the suspect patient as there are various situations that may bring confusion to the analysis: classified as Pseudo Cushing's Syndrome or Cushing ACTH independent (facticia type) Syndrome, for instance. The clinical epidemiology of the Syndrome (prevalence of the clinical findings) and the natural history of incidentally discovered adrenal masses are very important. Once these factors provide a direct evaluation in the majority of cases, the differential diagnosis of Cushing's Syndrome can easily be performed in the ambulatory setting without subsequent unnecessary procedures.
The different screening tests may be carried away randomly. The screening tests' variety is used accordingly to both the clinical of the patient (quantity of specific clinical findings) and the physician's suspicions. For example: Hypertension and obesity in a nonspecific pattern are very common in the general population and it depends on the physician whether or not this screening test should be carried away. The question is: should we initiate a laboratory assessment to find out whether these isolated signs indicate the Cushing's Syndrome?
There is big disagreement amongst the physicians about such point. Because so many of the problems found in Cushing's Syndrome are also seen in the absence of the disorder, we look particulary for features of Cushing's syndrome not often seen in the general population (e.g., severe hypertension in young person, severe metabolic bone disease, violaceous striae). The finding of any of these clinical suspicions of the Syndrome (also including centripetal obesity, plethora), is no doubt the reason for a screening test. But, before submitting the patient to unnecessary expenses and deleterious intervention, we should analyse if these suspicions are due to hypercortisolism. Next, we should investigate if he has the Cushing's Syndrome as well as the cause of the Syndrome.
There are various diagnostic screening tests for hypercortisolism, but they vary with their specificity, sensitivity, dosing laboratorial methods and other variables. Even so, misleading diagnosis may occur on average in 30% of cases. This is why we are going to elucidate how a diagnosis process could be more acurate.
Hypercortisolism/Cushing's Syndrome
Unlike one could imagine, the direct and isolated dosage of plasmatic cortisol per si is not sensitive or specific for this diagnosis due to the pulsatile nature of its secretion during the day. Hence, we will verify hypercortisolism by some indirect methods described below. Such methods are the most used tests for screening. But we should emphasise that a single measure of any of these tests does not confirm hypercortisolism, as explained above:
It is used after 3 years old, only after that the HPA (Hypothalamus-Pituitary-Adrenal) axis is established and so the rhythm becomes cyclic. Two collects of plasmatic cortisol are made, one at 8:00 and the other at 23:00. The hypercortisolism diagnosis is established when the level of evening cortisol is higher than 50% of the morning level. As many of the tests that will be discussed below, we always have to consider the presence of cortisol secreting estimulating factors, such as stress. This test is not done anymore. Because only two single determinations obtained in just one day (AM/PM) are absolutelly uninterpretable. Since the hallmark of the Syndrome is the absence of diurnal rhythm. Normally, cortisol is secreted episodically with a diurnal rhythm paralleling the secretion of ACTH. In Cushing, the pulsatility of pathologic and physiologic ACTH and cortisol secretion. So cortisol levels could be normal or not.
The test consists of oral administration of 1 mg of dexamethasone in
adults at 23:00 and dosing of cortisol at 8:00 the next morning.
Why the dexa (dexamethasone)? It is important to notice that dexamethasone,
characterized for its high potency, is used in the laboratorial tests for
hypercortisolism, because it does not interfere with dosing of endogenous
cortisol unlike other corticoids.
Dexamethasone has to be administered by night because the secretion rythm of
ACTH reaches its peak at this time, so, in patients without hypercortisolism,
morning cortisol levels would be fisiologically suppressed (< 5mg/dL in 98%
of the patients), in contrast to those with hypercortisolism with a dose >
5mg/dL.
This test is vulnerable to various pathologies, causing many false positives
and negatives, decreasing its sensibility and specificity which are discussed
below:
False positive results occur in overnight and other low-dose dexa suppression tests when:
False Negative may happen in:
Nevertheless, this study should be employed only as a screening tool for the consideration of Cushing's Syndrome, the biochemical confirmation must rely on UFC secretion.
This test does not confirm a definitive diagnosis for Cushing; it just gives us the possibility that a patient has the Syndrome or not.
Urine from 24 hours is collected and UFC is dosed. If it is higher than 100mg/day, we will have hypercortisolism.Thus, the daily UFC measurement emerges as a very simple, cost effective and accurate accessment confirming or not the presence of the Syndrome.
For less than 5% of obese patients, the UFC measurements may be within the normal range. However, as many as 10-15% will have elevations in urinary 17OHCS excretion (derived from the metabolism of cortisol). The diagnostic sensitivity and specificity of UFC values were 100% and 98%, compared to only 73% and 94%, respectively for 17OHCS. So, UFC determination, will usually provide clearcut distinction between patients with hypercortisolism and obese non-cushing's patients. As discussed above, in obese patients the CBG increases, giving us a False positive diagnosis. Then, in other screenning tests this distinction couldnot be done.
Because of that, the UFC is considered the "gold-standard" of the screening tests, since it excludes many of false positives and negatives.
Low doses of dexamethasone suppression test, classically described by Dr. Grant Liddle in 1960 (Liddle I), are generally done when the overnight suppression test and UFC will be boderline or abnormal.
Dexamethasone, 0.5 mg, is administered every 6 hours during two consecutive days:urine from 24 hours is gathered on the second day of dexamethasone and plasmatic cortisol is dosed in the morning of the third day. Interpretation is made as following:
- Patients are said to be with Cushing's Syndrome when they present plasmatic cortisol level >5mg/dL, UFC> 20mg or 170HCS > 4mg, yielding 88% specificity and 100% sensitivity (associated). Measurements of just 17OHCS has a sensitivity of 54% and accuracy of 69%.
This test shows that patients who did not present suppression after low dexamethasone dose have their limit of liberation cortisol suppression by ACTH increased, that is why they are designed as carriers of the Syndrome. As for the patients "suppressed" , we discard the Syndrome and they would not follow on our investigation. They may have pathologies that might lead to a hypercortisolism state not due to the Syndrome.
Nowadays, this test is not done as a screening test to confirm the Syndrome. UFC is the standard, because at the light of the expense and cumbersome nature of consecutive urine collections and frequent dexa administration, the continued use at Liddle I for the diagnosis of Cushing's Syndrome cannot be justified.
As discussed above there are various types of screening tests, but the most used screening is: Overnight suppression test associated with UFC. It provide a higher positive value.
The consense is that one single abnormal results of any of these tests must be confirmed with another one. If both of them were abnormal, hypercortisolism is present and the diagnosis of Cushing's Syndrome is established, if the conditions that cause false positive were been excluded. In spite of that, we are facing another problem. We do not know if a depressed patient is found like that because of Cushing's Syndrome or if depression has led to a state of Pseudo Cushing. So, when we have Pseudo Cushing, what do we do?
Let's remember phisiology of the HPA axis- CRH is produced by the nucleous paraventricular hypothalamus and it stimulates pituitary to liberate ACTH which will stimulate adrenal to liberate cortisol so that, facing a stressing situation, we can respond on the best way. [We also know that in this system there is a strong correlation with the serotoninergic, adrenergic and colinergic systems]. Hence, facing stressing situations, axis is activated, being primarily liberated CRH. This is the greater difference between the states of Pseudo and Cushing's Syndrome. The first presents high levels of CRH and the second, as there is production of ACTH or tumoral cortisol, this would lead to a negative feedback on hypothalamus, suppressing secretion of CRH.
If suspicions of Pseudocushing are raised, the best clinical approach is to repeat the screening tests done before followed by at least four week recovery from that stress, if possible. When the alcohol was been entirely withdrawn and the patient has recovered from any withdrawn symptons. After the four weeks of "recovering", the Insuline Tolerance Test should be done. The "True" Cushing patient would not answer to this test, in the opposite of Pseudo one.
It's pointed out that in most of these cases, an excelent psychiatry clinical approach must be done. Because such pathologies requires a cronic treatment, a definite biochemical diagnosis cannot be done frequently.
Once the diagnosis is made, the major task facing the physician is identifying the cause of the excess cortisol secretion.
For the patients that have not suppressed by Liddle I and/or other screenning tests, the next step is: Measurement of plasma ACTH.
a)Patients with ACTH-independent Syndrome, ACTH levels are reduced or suppressed (<5pg/mL). Therefore, we have four diagnostic possibilities:
b)For patients ACTH dependets (ACTH>10pg/mL), we suspect of:
In these ACTH dependent patients, we make the suppression test with high doses of dexamethasone (Liddle II), which consisted of dosing basal cortisol and administrating 2.0 mg dexamethasone every 6 hours during two consecutive days, on the third day we can dose plasmatic cortisol and/or on the second day with urine from 24 hours, we can dose UFC or 17OHCS (70-80% of accuracy). Another way is called isolated suppression with high doses when we administer 8 mg dexamethasone at 23:00 with measurement of plasmatic cortisol on the next morning (90% sensitivity and 92% specificity).
If there is suppression, in other words, cortisol after test is 50% inferior than basal, dignosis is made as Cushing's Disease. If only plasmatic cortisol were dosed, we would have a 69% sensitivity and 100% specificity, but when the three are associated, we have 83% sensitivity and 100% specificity.
If there is not suppression, sugests: Ectopic Tumor
It is important to notice that only had we established once laboratorial diagnosis for the Syndrome, we can go to image exams.
For the ACTH independent patients, we will make TC on adrenals The finding of a bilateral adrenal hiperplasia suggests Macronodular Adrenal Hyperplasia or Primary Pigmented Nodular Adrenal Disease (PPNAD). The later differs from the Macro, because of the seize of the nodules and the absence of an enlargement of the Gland (often seen in the Macro). The appearence of the Gland is usually of the normal size. If there is Unilateral Hyperplasia the diagnostic is Adrenal Tumors.
As discussed above, in the ACTH dependent patients suppressed by Liddle II, it is done a pituitary MRI to comprove adenoma, since the Pulmonar Carcinoid Tumors could have mimetized the Syndrome, even after Liddle II, they could not be suppressed.
If the MRI evidenciate Pituitary Adenoma the diagnostic is Cushing's Disease (it can be detected in just 50% of the cases). Otherwise, through laboratorial tracking (high ACTH and suppressed Liddle II), we can diagnose Cushing's Disease in 99.9% of the cases.
In hospitals where the IPSS with CRH infusion is available, when the finding adenoma on MRI is not made, the next step to be taken is IPSS, because it can still be Cushing's Disease or Ectopic.
IPSS - Inferior Petrosal Sinus Sampling with CRH stimulation This method consists of a central bilateral access (at the side of the sinus) and peripheral. Ideally, both sinuses are catheterized simultaneously, and plasma for ACTH is drawn from a peripheral vein simultaneously. So we can dose ACTH levels and establish a central-peripheral gradient We administer 1mg/kg weight I.V. of CRH. Levels of ACTH are dosed at the times: -15, 0, 15, 30, 60, 90 and 120 minutes. If the relation between ACTH peripheral-central is ³2, this implies a pituitary source (Cushing's Disease).
But, if the gradient were <1,8, then there is an ectopic tumour. So, the next step is a "body screenning", looking for the source of ACTH with a TC exam - Chest and abdominal.
If the TC or MRI is normal, we will do a screenning:
The main function of IPSS is to detect a presence of Pituitary tumor and have been used to preoperative localization of corticotroph adenomas. It is an expensive exam and sometimes is not appropriate. It is already attainable in some centres but it requires a skilled invasive neuroradiologist, but in experienced hands the procedure has yielded high accuracy.
We have 100% specificity and 97% sensitivity for Cushing's Disease. CRH administration helps increasing our discriminatory power between the disease and another hidden source.
It is already indicated when we cannot diagnose a pituitary Adenoma by laboratorial methods (not suppressed by Liddle II). Next we do an MRI, if it is positive (there is an adenoma), the IPSS is indicated. If there is evidence of Ectopic tumor, we start the investigation as described above. If nothing is found by pituitary exam, with no response to any treatment, bilateral adrenalectomia is procclaimed.
It is important to notice that image method may not be used before a previous laboratorial diagnosis as "incidentalomas"in pituitary are frequent. As they do not express a clinical disease, there is no need for surgery. Even with all of this available tests discussed WE STILL DO NOT HAVE A TEST THAT LEAD TO A DEFINITE DIAGNOSIS FOR THE ETHIOLOGY OF THE SYNDROME.
A fluxogram will show in a simplified way all of the steps for diagnosis that was described in the text.
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2) ARON, David C., MD, TYRRELL, J. Blake, MD, FINDLING, James W., MD and DOPPMAN, John L., MD: "Biochemical and Radiologic Diagnosis of Cushing's Syndrome", Cushing's Syndrome in Endocrinology and Metabolism Clinics of North America, Vol 23, No 3, September 1994, W.B. Saunders Company A Division of Harcourt Brace & Company, Philadelphia, London, Toronto, Montreal, Sydney, Tokyo, 1994, pp 512-533
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7) MILLER, Jeff, MD & CRAPO, Laurence, MD, Ph.D.: "The Biochemical Diagnosis of Hypercortisolism". The Endocrinologyst 1994; Vol 4, No 1, pp 7-15
8) BESSER, G. Michael, MD, THORNER, Michael O: "Cushing's Syndrome", "Imaging of the pituitary and Hypothalamus". Clinical Endocrinology, 1994, 2nd ed, Wolfe, pp 8.2; 24.6-7.
Special aknowlegments to Flavia Lucia Conceição M.D., Resident of the 3rd year of Endocrinology at Federal University of Rio de Janeiro for her great helpful and supervision review of this article.
If you have suggestions or comments send an e-mail to Daniele de Menezes Ferreira and Karina Naomi Une
