Pathophysiology and diagnosis of Cushing’s syndrome
Y. Miyachi
First Department of Internal Medicine, Toho University School of Medicine, 6-11-1 Ohmori-nishi, Ota-ku, Tokyo143-0015, Japan
Summary - Prolonged exposure of every tissue in the body to an excess of cortisol produces Cushing’s syndrome.
Endogenous causes of Cushing’s syndrome are ACTH-dependent, including Cushing’s disease, ectopic ACTH-producing tumors, CRH- producing tumors, and ACTH-independent Cushing’s syndrome, including cortisol-producing adrenal benign or malignant tumors, and rare micronodular adrenal hyperplasia.
In Japan the incidence of ACTH-dependent Cushing’s syndrome due to endogenous causes is about 60%, in which autonomous pituitary ACTH secretion is responsible for 95%, and the rest are ectopic ACTH-producing tumors. Cortisol-secreting tumors are responsible for about 40% of endogenous causes, in which benign adenoma is 90% and adrenocortical carcinoma is 10%.
The first step for the diagnosis of Cushing’s syndrome is to demonstrate the presence of hypercortisolism biochemically by determining 24-hour urinary free cortisol excretion and low-dose dexamethasone supression test.
The next step is to identify the precise etiologic causes. To differentiate Cushing’s syndrome, the most important procedures are dynamic endocrine tests to check the integrity of hypothalamic-pituitary-adrenal function by high dose dexamethasone supression test, CRH test and measurement of steroid hormone profile.
Imaging techniques can help to determine the etiology of Cushing’s syndrome. @ 2000 Éditions scientifiques et médicales Elsevier SAS
Cushing’s syndrome / hypercortisolism / radiologic evaluation
Prolonged exposure of every tissue in the body to an excess of cortisol produces Cushing’s syndrome. Clin- ical features of Cushing’s syndrome include centripetal obesity, skin manifestations (thinning of the epidermis, bruising, purple striae, facial lanugo hair and hirsutism, acne), hypertension, proximal myopathy, insulin resis- tance, hyperlipidemia, osteopenia and some psychiatric manifestations. In children this is accompanied by growth retardation [1-4].
Endogenous causes of Cushing’s syndrome are ACTH-dependent, including Cushing’s disease, ectopic ACTH-producing tumors, CRH-producing tumors, and ACTH-independent, including cortisol-producing adrenal benign or malignant tumors, and rare micron- odular adrenal hyperplasia. Exogenous causes are iatrogenic.
In Japan Cushing’s syndrome has a female to male preponderance of 5.2:1; it commonly occurs in 25 to 50-year-old women. The incidence of ACTH-depen- dent Cushing’s syndrome due to endogenous causes is about 60%, in which autonomous pituitary ACTH secretion is responsible for 95%,and the rest are ectopic ACTH-producing tumors [1]. Cortisol-secreting tumors are responsible for about 40% of endogenous causes, in which benign adenoma is 90% and adreno-
cortical carcinoma is 10%. The exogenous Cushing’s syndrome caused by the increasing use of glucocorti- coids has become frequent and exceeds that of the endogenous Cushing’s syndrome. The etiology of Cushing’s syndrome in Japan is different from that in the United States, where ACTH-dependent Cushing’s syndrome is responsible for 85% and benign cortisol- secreting adenomas or adrenocortical carcinamas are responsible for only 15% [1]. The reason for the differ- ence in etiology of Cushing’s syndrome between the United States and Japan remains to be clarified.
PATHOPHYSIOLOGY OF CUSHING’S SYNDROME
ACTH-dependent Cushing’s syndrome
Cushing’s disease
Cushing’s disease is caused mostly by an ACTH- producing pituitary tumor; pituitary hyperplasia due to a CRH-producing tumor is rare. The amplitude and length of ACTH secretion are increased and the increased plasma ACTH induces the bilateral adreno- cortical hyperplasia and hypersecretion of cortisol. Morning plasma ACTH and cortisol levels show
normal to moderate increase, but late evening levels are elevated, which reflects increased urinary excre- tion of cortisol and 17-OHCS excretion. The chronic hypercortisolemia suppress CRH secretion from the hypothalamus and ACTH secretion from the pituitary corticotrophs. The hypothalamic-pituitary ACTH axis in Cushing’s disease is relatively resistant to neg- ative feedback inhibition by glucocorticoids. The set- point for glucocorticoid feedback of the pituitary ade- noma is high compared to that of the normal pituitary corticotrophs. Determination of 24-hour urinary-free cortisol, reflecting daily adrenal cortisol secretion, is the best test for determination of endogenous hypercortisolism.
Ectopic ACTH-producing tumors
Moderately to markedly increased plasma ACTH produced ectopically from pulmonary carcinoma (small cell carcinoma), bronchial and foregut carci- noid, thymoma, pancreatic islet cell tumors, medullary carcinoma of the thyroid and pheochro- mocytoma stimulates bilateral adrenocortical hyper- plasia and cortisol secretion. Urinary excretion of cortisol is high as in Cushing’s disease. High plasma cortisol suppresses the hypothalamic-pituitary- ACTH axis. ACTH secretion from ectopic ACTH- producing tumor is not regulated by glucocorticoids in general. The hypercortisol state starts and pro- gresses rapidly, and is severe. Weight loss, weakness, debility, hypertension, hypokalemia, diabetes melli- tus and hyperpigmentation are common. Cushingoid features are absent in case of the short duration of the disease.
Ectopic CRH syndrome
The secretion of CRH from the nonhypothalamic tumor stimulates hyperplasia of pituitary corticotrophs and hypersecretion of ACTH. Otherwise, ectopic CRH syn- drome is similar to ectopic ACTH syndrome.
ACTH-independent Cushing’s syndrome
Adrenocortical adenoma
With an adrenocortical adenoma increased cortisol secretion suppresses hypothalamic CRH and pituitary ACTH secretion. Pituitary corticotrophs are atrophic as are the uninvolved normal adrenocortical tissues. Serum DHEAS concentration and urinary excretion of 17 KS are low or even normal in relation to the increased excretion of 17-OHCS and free cortisol. The adenoma occasionally may produce large amounts of androgens and rarely estrogens as in adrenocortical carcinomas.
Adrenocortical carcinoma
Adrenocortical carcinoma usually produces an ineffi- cient per unit-weight amount of adrenal steroids, so it produces excessive adrenal steroids sufficient to pro- duce clinical features only when the size of the carci- noma is large.
Iatrogenic Cushing’s syndrome
The iatrogenic form of Cushing’s syndrome is increas- ingly frequent and mostly caused by administration of excessive amounts of potent synthetic glucocorticoids for a long time. The exogenous glucocorticoids inhibit both hypothalamic CRH and pituitary ACTH secretion, and cause bilateral adrenocortical atrophy. Basal plasma levels of cortisol and ACTH are low. Iatrogenic Cushing’s syndrome is likely to be associated with benign intracranial hypertension, cataracts, glaucoma, pancreatitis, or aseptic necrosis of femur head. Cessa- tion of glucocorticoids may be followed by secondary adrenocortical insufficiency, necessitating glucocorti- coid replacement until recovery of the hypothalamic- pituitary axis.
DIAGNOSIS OF CUSHING’S SYNDROME
Once there is a clinical suspicion of Cushing’s syn- drome, the first step for the diagnosis of Cushing’s syndrome is to demonstrate the presence of hypercorti- solism biochemically. Once the diagnosis of endoge- nous Cushing’s syndrome has been made, the next step is then to identify the precise etiologic cause. Imaging techniques can help to determine the etiology of Cush- ing’s syndrome.
Establishment of the diagnosis of Cushing’s syndrome
Having excluded iatrogenic Cushing’s syndrome, the next step is to determine the increased excretion of cor- tisol from the adrenal gland. This can be performed by determining 24-hour urinary free cortisol excretion. If this value is higher than 300 ug/d, then diagnosis of Cushing’s syndrome is most probable [2]. False positive results are obtained in non-Cushing’s hyper- cortisolism such as chronic stress, malnutrition and alcoholism. Twenty-four-hour urinary free cortisol excretion (ug/square meter of body surface area) remains the same throughout life. If a urinary free cor- tisol assay is unavailable, urinary 17OHCS excretion normalized per gram of creatinine is useful although unrelated substances may interfere with this assay. The one-mg dexamethasone overnight supression test is
a screening procedure for the diagnosis of Cushing’s syndrome. Dexamethasone at 1 mg is given orally at 11 p.m., and serum cortisol is measured at 8 a.m. the next morning. Serum cortisol higher than 5 ug/dL is suggestive of Cushing’s syndrome. However, there is a 15% false-positive result in patients with Cushing’s dis- ease and 3% in patients with adrenocortical adenoma [1]. In those cases the standard low-dose dexametha- sone test (0.5 mg every 6 hours for 48 hours) or 24-hour urinary-free cortisol excretion is required to confirm the presence of hypercortisolism. Loss of diurnal vari- ation of plasma ACTH and cortisol is another important point for diagnosing Cushing’s syndrome; however, in 15% of Cushing’s disease and 5% of patients with adrenocortical adenoma the diurnal variation is preserved [1].
Differential diagnosis of Cushing’s syndrome
To differentiate the cause of Cushing’s syndrome, the most important procedures are dynamic endocrine tests to check the integrity of hypothalamic-pituitary-adrenal function and imaging studies for pituitary, adrenal and ectopic tumors.
Plasma ACTH determination
Plasma ACTH levels are undetectable or low in patients with adrenocortical adenoma or carcinoma, whereas levels are normal or elevated in patients with Cushing’s disease, ectopic ACTH or CRH syndrome. Plasma ACTH levels in patients with ectopic ACTH syndrome are frequently very high compared to those in Cushing’s disease. As patients with ectopic ACTH syndrome often have larger ACTH precursor molecules in plasma, a high lipotropin/ACTH ratio indicates a possibility of ectopic ACTH syndrome. In rare patients with CRH syndrome elevated plasma CRH is confirmed.
CRH provocation tests
In most patients with Cushing’s disease CRH adminis- tration stimulates ACTH release, while patients with ectopic ACTH syndrome do not respond to CRH. How- ever some ectopically ACTH-producing tumors show an increase in ACTH release in response to CRH [2]. CRH is administered to patients with radiologically occult pituitary microadenomas and ectopic ACTH- producing tumors during the petrosal sinus sampling with bilateral simultaneous measurement of petrosal sinus and peripheral ACTH. A central-to-peripheral ACTH ratio of more than 2:1 indicates Cushing’s dis- ease [2]. This technique identifies the localization of a pituitary source of ACTH, but is less accurate at iden-
tifying in which side of the pituitary glands the tumor is located. Furthermore, this procedure should be reserved only for patients in whom the noninvasive studies are unable to differentiate the cause.
Dexamethasone suppression test
The administration of a high dose of dexamethasone (2 mg every 6 hours for 48 hours) suppresses ACTH by a pituitary adenoma and decreases cortisol secretion and urinary 17OHCS excretion. Ectopic ACTH syn- drome and Cushing’s syndrome caused by an adreno- cortical tumor are unresponsive to a high dose of dex- amethasone. However, 15% of patients with Cushing’s disease have non-suppressability and about 10% of patients with ectopic ACTH syndrome or Cushing’s syndrome due to an adrenocortical tumor have sup- pressability to high doses of dexamethasone (figure 1) [1]. Measurement of urinary free cortisol is also helpful.
Methyrapone test
The methyrapone test is used to differentiate Cushing’s disease from ectopic ACTH syndrome, but is not as reli- able as the dexamethasone suppression test.
Steroid hormone profile
Analysis of blood steroid hormones is helpful to differentiate the cause of Cushing’s syndrome. Preg- nenolone, 17-OH progesterone, DHEA, androstene- dione, testosterone, estrone and estradiol are signifi- cantly higher in patients with Cushing’s disease compared to patients with cortisol-producing adreno- cortical adenoma (table I) [4].
Radiologic evaluation of Cushing’s syndrome
Once differential diagnosis of Cushing’s syndrome is established, the determination of the location and size of tumors by computed tomography (CT), MRI scan and also by isotope scintiscan is necessary to confirm the causes of Cushing’s syndrome and to decide on the therapeutic strategy.
Pituitary gland
Most ACTH-secreting pituitary tumors are microade- noma (< 10 mm in diameter) and MRI scans at 1.5 T with Ga-DTPA enhancement localize the tumors in about 60% of patients [2]. Pituitary microadenomas usually appear as a small mass with reduced signal- intensity and do not enhance after Gd-DTPA injection. High resolution, contrast-enhanced, 3 mm-section CT scans reveal only one-third of microadenomas.
Dexamethasone supression test
(%)
ACTH
(%)
CRHtest
(%)
low dose (2 mg)
(%)
high dose (8 mg)
100
100
100
100
high
normal
50
50
suppressible
50
50
# non-suppressible
@low
Cushing’s disease
ectopic ACTH syndrome
cortisol producing adrenocortical adenoma
adrenocortical carcinoma
Cushing’s disease
ectopic ACTH syndrome
cortisol producing adrenocortical adenoma
adrenocortical carcinoma
Cushing’s disease
ectopic ACTH syndrome
cortisol producing adrenocortical adenoma
adrenocortical carcinoma
Cushing’s disease
ectopic ACTH syndrome
cortisol producing adrenocortical adenoma
adrenocortical carcinoma
| (A) | F | S | Ald | DOC | E, | E2 | 17-OHP | P | A 4A | T | DHEA | Preg | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| nmol/L | pmol/L | nmol/L | |||||||||||
| Men (N = 10) | |||||||||||||
| Mean | 268 | 2.18 | 0.21 | 0.18 | 124 | 78 | 2.75 | 0.55 | 3.96 | 21.8 | 14.9 | 2.38 | |
| SD | 37.5 | 0.21 | 0.02 | 0.04 | 27.1 | 13.1 | 0.58 | 0.10 | 0.85 | 3.55 | 2.11 | 0.40 | |
| Women (N = 8) | |||||||||||||
| Mean | 245 | 2.04 | 0.21 | 0.15 | 181 | 111 | 2.1 | 1.01 | 3.43 | 0.75 | 10.9 | 2.49 | |
| SD | 23.2 | 0.24 | 0.03 | 0.03 | 15.9 | 3.66 | 0.69 | 0.11 | 1.02 | 0.11 | 1.51 | 0.22 | |
| (B) | F | S | Ald | DOC | E, | E2 | 17-OHP | P | ΔΊΑ | T | DHEA | Preg | |
| Age, y | nmol/L | pmol/L nmol/L | |||||||||||
| Adenoma | |||||||||||||
| 1 | 23 | 690 | 4.91 | 0.19 | 0.12 | 221 | 136 | 1.73 | 0.67 | 0.66 | 1.49 | 3.82 | 1.61 |
| 2 | 33 | 690 | 2.89 | 0.18 | 0.11 | 148 | 106 | 2.06 | 0.22 | 0.98 | 2.43 | 4.51 | 1.83 |
| 3 | 37 | 530 | 2.80 | 0.22 | 0.15 | 207 | 117 | 1.82 | 0.95 | 0.70 | 0.69 | 3.09 | 2.21 |
| 4 | 40 | 483 | 2.86 | 0.22 | 0.17 | 181 | 117 | 1.79 | 1.27 | 0.73 | 0.66 | 3.19 | 2.31 |
| Mean | 598 | 3.37 | 0.20 | 0.14 | 187 | 119 | 1.85 | 0.78 | 0.77 | 1.32 | 3.65 | 1.99 | |
| SD | 93.2 | 0.89 | 0.02 | 0.02 | 25.2 | 10.8 | 0.13 | 0.39 | 0.13 | 0.72 | 0.57 | 0.28 | |
| Hyperplasia | |||||||||||||
| 5 | 29 | 442 | 3.18 | 0.19 | 0.12 | 370 | 440 | 4.85 | 0.20 | 7.33 | 4.16 | 20.1 | 2.62 |
| 6 | 36 | 773 | 4.91 | 0.20 | 0.16 | 407 | 587 | 3.64 | 3.82 | 8.73 | 3.47 | 25.0 | 6.00 |
| 7 40 | 566 | 3.76 | 0.18 | 0.20 | 444 | 569 | 4.85 | 0.99 | 6.28 | 3.82 | 23.9 | 4.11 | |
| 8 18* | 911 | 5.78 | 0.22 | 0.15 | 481 | 551 | 5.15 | 0.16 | 8.73 | 6.94 | 31.9 | 2.91 | |
| Mean ** | 593 | 3.95 | 0.19 | 0.16 | 407 | 532 | 4.44 | 1.67 | 7.44 | 3.81 | 23 | 4.24 | |
| SD | 167 | 0.88 | 0.01 | 0.04 | 37.0 | 80.1 | 0.69 | 1.9 | 1.22 | 0.34 | 2.57 | 1.69 | |
* Male: all other subjects were female; **: not including results for the male subject.
Ectopic tumors
If endocrine laboratory findings suggest ectopic ACTH production, thoracic and abdominal CT scans are inevitable, since ectopically ACTH-producing tumors usually are bronchial carcinoid, pulmonary cancer, islet-cell tumors and pheochromocytoma. The MRI scan is useful in identifyng bronchial carcinoid tumors less than 10 mm in diameter. In 111-labeled octreotide, the scintiscan is helpful in detecting occult carcinoids in some cases.
Adrenal glands
High-resolution, thin-sectioned CT scans are the most useful technique for detecting adrenal pathology such as adrenocortical adenomas, bilateral diffuse hyperpla- sia, unilateral or bilateral nodular hyperplasia and car- cinomas. Tumors with diameter greater than 6 cm, irregular surface, inhomogenous mass containing areas of necrosis and local invasion are suggestive of malig- nancy. MRI scan of adrenal glands is as sensitive as CT.
On T2-weighted MRI scans adrenocortical carcinomas show Gd-DTPA enhanced signal intensity unlike adrenocortical adenomas. Unilateral or bilateral radioisotope uptake in the I131-Iodocholesterol scin- tiscans are useful to distinguish between ACTH-depen- dent and ACTH-independent Cushing’s syndrome. Ultrasonography of adrenal glands is not so useful.
REFERENCES
1 Miyachi Y. Special cases of Cushing’s syndrome. Folia Endocrinol 1994 ; 70 : 1-10.
2 Tsigos C, Chrousos GP. Differential diagnosis and management of Cushing’s syndrome. Ann Rev Med 1996 ; 47 : 443-61.
3 Thoner MO, Vance ML, Laws ER Jr, Horvath E, Kovacs K. The anterior pituitary. In: Wilson JD, Foster DW, et al. Textbook of endocrinology. 9th ed. Philadelphia: W.B. Saunders Co; 1998. p. 249-340.
4 Ueshiba H, Segawa M, Hayashi T, Miyachi Y, Irie M. Serum profiles of steroid hormones in patients with Cushing’s syn- drome by a new HPLC/RIA method. Clin Chem 1991 ; 37 : 1329-33.