| Cushing's disease | |
|---|---|
| Other names | Cushing disease, tertiary or secondary hypercortisolism, tertiary or secondary hypercorticism, Itsenko-Cushing disease |
| Specialty | Endocrinology |
Cushing's disease is one cause of Cushing's syndrome characterised by increased secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary (secondary hypercortisolism). This is most often as a result of a pituitary adenoma (specifically pituitary basophilism) or due to excess production of hypothalamus CRH (corticotropin releasing hormone) (tertiary hypercortisolism/hypercorticism) that stimulates the synthesis of cortisol by the adrenal glands. Pituitary adenomas are responsible for 80% of endogenous Cushing's syndrome, when excluding Cushing's syndrome from exogenously administered corticosteroids.
This should not be confused with ectopic Cushing syndrome or exogenous steroid use.
Signs and symptoms
The symptoms of Cushing's disease are similar to those seen in other causes of Cushing's syndrome.
Patients with Cushing's disease usually present with one or more signs and symptoms secondary to the presence of excess cortisol or ACTH.
Although uncommon, some patients with Cushing's disease have large
pituitary tumors (macroadenomas). In addition to the severe hormonal
effects related to increased blood cortisol levels, the large tumor can
compress adjacent structures. These tumors can compress the nerves that carry information from the eyes, causing a decrease in peripheral vision.
Glaucoma and cataracts also may occur in Cushing's syndrome. In
children, the two main symptoms are obesity and decreased linear growth.
The clinical diagnosis must be based on the presence of one or
more of the symptoms listed below, because the syndrome itself has no
true pathognomonic signs or symptoms. The most common symptoms seen in male patients are purple striae, muscle atrophy, osteoporosis, and kidney stones.
Common
Common signs and symptoms of Cushing's disease include the following:
- weight gain
- high blood pressure
- poor short-term memory
- irritability
- excess hair growth (women)
- Impaired immunological function
- red, ruddy face
- extra fat around neck, "Buffalo Hump"
- moon face
- fatigue
- red stretch marks
- poor concentration
- irregular menstruation
Less common
The less-common signs and symptoms of Cushing's disease include the following:
- insomnia
- recurrent infection
- thin skin and stretch marks
- easy bruising
- weak bones
- acne
- balding (women)
- depression
- hip and shoulder weakness
- swelling of feet/legs
- diabetes mellitus
- erectile dysfunction
Diagnosis
Diagnosis
is made first by diagnosing Cushing's syndrome, which can be difficult
to do clinically since the most characteristic symptoms only occur in a
minority of patients. Some of the biochemical diagnostic tests used include salivary and blood serum cortisol testing, 24-hour urinary free cortisol (UFC) testing, the dexamethasone suppression test
(DST), and bilateral inferior petrosal sinus sampling (IPSS or BIPSS
for bilateral IPSS). No single test is perfect and multiple tests should
always be used to achieve a proper diagnosis.
Diagnosing Cushing's disease is a multidisciplinary process involving
doctors, endocrinologists, radiologists, surgeons, and chemical
pathologists.
ACTH blood test
Once Cushing's syndrome has been diagnosed, the first step towards finding the cause is measuring plasma adrenocorticotropic hormone
(ACTH) concentration. A concentration consistently below 1.1 pmol/L is
classified as corticotropin-independent and does not lead to a diagnosis
of Cushing's disease. In such cases, the next step is adrenal imaging
with CT.
If plasma corticotropin concentrations are consistently above 3.3
pmol/L, then corticotropin-dependent Cushing's syndrome is most likely.
Any intermediate values need to be cautiously interpreted and a
corticotropin-releasing hormone (CRH) test is advised in order to
confirm corticotropin dependency. If corticotropin-dependent Cushing's
syndrome is determined then the next step is to distinguish between
Cushing's disease and ectopic corticotropin syndrome. This is done via a
combination of techniques including CRH, high-dose DST, BIPSS, and
pituitary MRI.
Dexamethasone suppression test
Two dexamethasone suppression tests (DSTs) are generally used, the overnight test and the 48 hour test. For both tests, a plasma cortisol level above 50 nmol/L is indicative of Cushing's disease. However, 3–8% of patients with Cushing's disease will test negative due to a retention of dexamethasone suppression abilities. For non-Cushing or healthy patients, the false-positive rate is 30%. The 48-h DST is advantageous since it is more specific and can be done by outpatients upon proper instruction. In the high-dose 48-h DST, 2 mg of dexamethasone is given every 6 hours for 48 hours or a single dose of 8 mg is given. This test is not needed if the 48-h low-dose DST has shown suppression of cortisol by over 30%. These tests are based on the glucocorticoid sensitivity of pituitary adenomas compared to non-pituitary tumors.
ACTH stimulation test
An ACTH stimulation test involving administration of corticotropin-releasing hormone
(CRH) or another agent can differentiate this condition from ectopic
ACTH secretion. In a patient with Cushing's disease, the tumor cells
will be stimulated to release corticotropin and elevated plasma
corticotropin levels will be detected. This rarely occurs with ectopic corticotropin syndrome and thus is quite useful for distinguishing between the two conditions. If ectopic, the plasma ACTH and cortisol
levels should remain unchanged; if this is pituitary related, levels of
both would rise. The CRH test uses recombinant human or bovine-sequence
CRH, which is administered via a 100μg intravenous bolus
dose. The sensitivity of the CRH test for detecting Cushing's disease
is 93% when plasma levels are measured after fifteen and thirty minutes. However, this test is used only as a last resort due to its high cost and complexity.
Imaging
A CT or
MRI of the pituitary may also show the ACTH secreting tumor if present.
However, in 40% of Cushing's disease patients MRI is unable to detect a
tumor.
In one study of 261 patients with confirmed pituitary Cushing's
disease, only 48% of pituitary lesions were identified using MRI prior
to surgery. The average size of tumor, both those that were identified
on MRI and those that were only discovered during surgery, was 6 mm.
Inferior petrosal sinus sampling
IPSS
(inferior petrosal sinus sampling) or BIPSS (bilateral IPSS) is a more
accurate but invasive test used to differentiate pituitary from ectopic
or adrenal Cushing's syndrome.
A corticotropin gradient sample via BIPSS is required to confirm
diagnosis when pituitary MRI imaging and biochemical diagnostic tests
have been inconclusive. A basal central:peripheral ratio of over 3:1 when CRH is administered is indicative of Cushing’s disease. This test has been the gold standard for distinguishing between Cushing's disease and ectopic corticotropin syndrome.
The BIPSS has a sensitivity and specificity of 94% for Cushing's
disease but it is usually used as a last resort due to its invasiveness,
rare but serious complications, and the expertise required to perform
it.
Urinary free cortisol test
Another
diagnostic test used is the urinary free cortisol (UFC) test, which
measures the excess cortisol excreted by the kidneys into the urine.
Results of 4x higher cortisol levels than normal are likely to be
Cushing's disease. This test should be repeated three times in order to exclude any normally occurring periods of hypercortisolism. The UFC test has a specificity of 81% and thus has a high rate of false-positives that are due to pseudo-Cushing states, sleep apnea, polycystic ovary syndrome, familial glucocorticoid resistance, and hyperthyroidism.
Late night (midnight) salivary cortisol test
The late night or midnight salivary cortisol test
has been gaining support due to its ease of collection and stability at
room temperature, therefore it can be assigned to outpatients. The test measures free circulating cortisol and has both a sensitivity and specificity of 95–98%. This test is especially useful for diagnosing children.
Treatment
The first-line treatment of Cushing's disease is surgical resection of ACTH-secreting pituitary adenoma; this surgery involves removal of the tumor via transsphenoidal surgery (TSS).
There are two possible options for access to sphenoidal sinus
including of endonosal approach (through the nostril) or sublabial
approach (through an incision under the upper lip); many factors such as
the size of nostril, the size of the lesion, and the preferences of the
surgeon cause the selection of one access route over the other.
Some tumors do not contain a discrete border between tumor and pituitary
gland; therefore, careful sectioning through pituitary gland may be
required to identify the location of tumor.
The probability of successful resection is higher in patients where the
tumor was identified at initial surgery in comparison to patients where
no tumor was found initially; the overall remission rates in patients
with microadenomas undergoing TSS are in range of 65%–90%, and the
remission rate in patients with macroadenomas are lower than 65%.
patients with persistent disease after initial surgery are treated with
repeated pituitary surgery as soon as the active persistent disease is
evident; however, reoperation has lower success rate and increases the
risk of pituitary insufficiency.
Pituitary radiation therapy is another option for treatment of postoperative persisting hypercortisolemia following unsuccessful transsphenoidal surgery. External-beam pituitary RT is more effective treatment for pediatric CD in children with cure rates of 80%-88%. Hypopituitarism specifically growth hormone deficiency
has been reported as the only most common late morbidity of this
treatment; GHD has been reported in 36% and 68% of the patients
undergoing post pituitary RT for Cushing's disease.
Bilateral adrenalectomy is another treatment which provides
immediate reduction of cortisol level and control of hypercortisolism.
However, it requires education of patients, because lifelong glucocorticoid and mineralocorticoid
replacement therapy is needed for these patients. One of the major
complications of this treatment is progression of Nelson's syndrome
which is caused by enhance level of tumor growth and ACTH secretion post
adrenalectomy in 8%–29% of patients with CD.
During post surgical recovery, patients collect 24-hour urine
sample and blood sample for detecting the level of cortisol with the
purpose of cure test; level of cortisol near the detection limit assay,
corresponds to cure. Hormonal replacement such as steroid
is given to patients because of steroid withdrawal. After the
completion of collecting urine and blood samples, patients are asked to
switch to glucocorticoid such as prednisone to decrease symptoms associated with adrenal withdrawal. Miitotaine is also used.
A study of 3,525 cases of TSS for Cushing's disease in the
nationally representative
sample of US hospitals between 1993 and 2002 was conducted and revealed
the following results: the in-hospital mortality rate was 0.7%; the
complication rate was 42.1%. Diabetes insipidus (15%), fluid and electrolyte
abnormalities (12.5%), and neurological deficits (5.6%) were the most
common complications reported. The analyses of the study show that
complications were more likely in patients with pre-operative comorbidities.
Patients older than 64 years were more likely to have an adverse
outcome and prolonged hospital stay. Women were 0.3 times less likely to
have adverse outcomes in comparison to men.
Epidemiology
Cases
of Cushing's disease are rare, and little epidemiological data is
available on the disease. An 18-year study conducted on the population
of Vizcaya, Spain reported a 0.004% prevalence of Cushing's disease. The average incidence
of newly diagnosed cases was 2.4 cases per million inhabitants per
year. The disease is often diagnosed 3–6 years after the onset of
illness.
Several studies have shown that Cushing's disease is more prevalent in women than men at a ratio of 3–6:1, respectively. Moreover, most women affected were between the ages of 50 and 60 years.
The prevalence of hypertension, and abnormalities in glucose metabolism are major predictors of mortality and morbidity in untreated cases of the disease. The mortality rate of Cushing's disease was reported to be 10–11%, with the majority of deaths due to vascular disease. Women aged 45–70 years have a significantly higher mortality rate than men.
Moreover, the disease shows a progressive increase with time. Reasons
for the trend are unknown, but better diagnostic tools, and a higher
incidence rate are two possible explanations.
History
The disease associated with this increased secretion of cortisol was described by the American neurosurgeon Harvey Cushing in 1912, after he was presented with a unique case of the disease in 1910 a 23-year-old woman called Minnie G. whose symptoms included painful obesity, amenorrhea, hypertrichosis (abnormal hair growth), underdevelopment of secondary sexual characteristics, hydrocephalus and cerebral tension. This combination of symptoms was not yet described by any medical disorder at the time.
However, Cushing was confident that Minnie's symptoms were due to
dysfunction of the pituitary gland, and resembled those associated with
an adrenal tumor. Given this conviction, and his knowledge of the three anterior pituitary cell types, Cushing hypothesized that if acidophil hyperpituitarism (excess secretion from the acidophil cells) caused acromegaly, then an excess of basophil cells must be involved in another pituitary disorder that involves sexual dysfunction (amenorrhea in females and erectile dysfunction in males) and could explain Minnie's symptoms.
Experimental evidence and case reports by Cushing led to his
publication in 1932 on pituitary basophilism as the cause of Cushing's
disease. In this publication, the clinical symptoms of the disease,
named after Cushing, were described. Out of the 12 cases with hypercortisolism
described in Cushing's monograph on the pituitary body, 67% died within
a few years after symptom presentation, whereas Minnie G. survived for
more than 40 years after symptom presentation, despite the fact that she
did not receive any treatments for a pituitary tumor. The prolonged survival made Minnie's case unique at the time. The reason behind this survival remains a mystery, since an autopsy of Minnie was refused after her death. However, the most likely explanation, proposed by J. Aidan Carney and based on statistical evidence, was that the basophil adenoma Minnie might have harbored underwent partial infarction, leading to symptom regression. The other hypothesis was that Minnie might have suffered from Primary Pigmented Nodular Adrenocortical Disease (PPNAD), which when associated with Cushing's syndrome (Carney complex) can infrequently cause spontaneous symptom regression of the latter.
In 1924, the Soviet neurologist Nikolai Itsenko reported two patients with pituitary adenoma. The resulting excessive adrenocorticotropic hormone secretion led to the production of large amounts of cortisol by the adrenal glands.
Considering this impact, the name of Itsenko was added to the title in
some East European and Asian countries, and the disease is called
Itsenko-Kushing disease.
