CUSHING SYNDROME AND CUSHING DISEASE

PRELIMINARY
About 70 years ago Harvey Cushing described a clinical phenomenon as a result of
a basophilic pituitary adenoma which later became the name of the disease,
Cushing's disease. Until now the management of patients with excess
glucocorticoids is still a challenge in the field of endocrinology because the case is
rare, varied, and to make the diagnosis requires sophisticated and expensive
investigation for the size of developing countries. The discussion on this paper will
focus on endogenous Cushing syndrome, which is the excess of glucocorticoid
hormones that are not due to the use of steroids from outside the body although
empirically often found are exogenous (Cushingoid phenotype).

DEFINITION
Cushing's syndrome and Cushing's disease are the clinical manifestations of
abnormal long-term abnormal glucocorticoid hormones with all the consequences.
This definition also includes the presence of hypothalamopituit-adrenal axillary
insufficiency and impairment of circadian cortisol circadian secretion rhythm. The
term Cushing's syndrome is a general term used for the phenomenon regardless of
cause, whereas if the cause originates from an excess of ACTH
(adrenocorticotrophic hormone) produced by the pituitary gland, then stimulates
excessive cortisol production in the adrenal, the term Cushing's disease is used.

EPIDEMIOLOGY
Although epidemiological data on Cushing's syndrome is very limited, it is estimated
that the annual incidence of this syndrome is around 2.3 million per year worldwide.
Cushing's disease mainly occurs in women with a female to male ratio ranging from
3: 1 to 10: 1. In tertiary endocrine clinics in developed countries, the prevalence of
Cushing syndrome is found to be around 5% among patients with uncontrolled
diabetes mellitus and osteoporosis. These data will certainly have an impact on the
management of diabetic patients, obesity, hypertension, menstrual disorders,
therefore it is important to screen.
ETIOLOGY AND PATHOGENESIS

Excess production of the hormone cortisol in the adrenal cortex can be as a result of
excess ACTH from various sources or indeed the adrenal gland autonomously
produces excessive cortisol without stimulation from ACTH. Cortisol is a hormone
that is essential for maintaining normal metabolism of glucose and protein,
electrolyte balance, immune function, and blood pressure. There are still many
unanswerable questions as to why the pituitary is so active that it exerts excessive
ACTH, or why the adrenal cortex is autonomously hyperactive resulting in excessive
cortisol production.

About 80% of Cushing's syndrome is ACTH-dependent. where ACTH can be

secreted by pituitary adenoma (80% of ACTH-dependent) or may be non-pituitary
(ectopic, about 20% of ACTH-dependent). The remaining 20% of cases (ACTH-
independent), cortisol are autonomously produced by the adrenal glands with the
details: 60% of cases are adenomas, 38% of cases are carcinomas, and less than
2% of the causes are extremely rare adrenal hyperplasia, such as primary
pigmented nodular adrenal disease (PPNAD) or McCuneAlbright syndrome.

Table 1. Cushing Syndrome Causes (n = 123)

Diagnosis Patient %
ACTH-dependent
 Cushing's syndrome in pituitary 65
disorders (Cushing's disease)
 ectopic ACTH syndrome (eg 7
Bronchial, thymus, or pancreatic
carcinoids, medullary thyroid
carcinoma, etc.)
 ectopic CRH syndrom <1
ACTH-independent
 Adrenal adenoma 18
 Adrenal carcinoma 6
 PPNAD (including Carney 1
complex)
3
  AIMAH (aberrant expression of
ectopic and eutopic membrane
receptors: gastric inhibitor
polypeptide, catecholamine, or LH
/ HCG, vasopressin, and
serotonin)

DIAGNOSIS
Clinical manifestations vary greatly depending on the severity of hypercortisolism,
duration, and glucocorticoid receptor sensitivity. Recommended diagnostic steps are:
recognize Cushing's syndrome, confirm biochemical tests to prove excess cortisol,
look for causes, and seek appropriate therapeutic strategies. Surely a detailed
history (especially distinguishing exogenous or endogenous Cushing's syndrome),
careful physical examination, and proper investigation will lead to a clear etiologic
diagnosis. The classic appearance of the metabolic, cardiovascular, skin,
musculoskeletal, and psychiatric aspects of manifestations, is usually easy for
doctors to recognize, but not infrequently, and only a few signs arise because of the
mild cyclical and cyclic hormone increases. In some psychiatric disorders
(depression, anxiety, convulsive obsessive disorders), uncontrolled diabetes, and
alcoholism, may be accompanied by mild hypercortisolism and result in tests such as
Cushing's syndrome. In the latter circumstances would need a more careful effort to
prove the existence of abnormal excess hormone cortisol.

The duties of the clinicians while suspecting Cushing's syndrome certainly seek to
recognize as closely as possible the symptoms and signs associated with
hypercortisolism. Symptoms and signs that may arise can be seen in table 2.
In table 3 it can be seen how the frequency of each symptom and sign, so that
clinicians can predict what conditions are commonly found.

Table 2. Clinical Features of Cushing's Syndrome

sign symptoms
Fat Distribution  appetite changes
 Buffalo hump  decreased concentration of
 Central Pebelitas thinking
  Facet pletorik *  decreased libido
 Moon face  fatigue
 Weight gain  short-term memory impairment
Preview of protein-wasting  insomnia
 Demineralization of bone and  irritability
osteoporosis  menstrual disorders
 Easy bruising  mood disorder
 Impaired defense mechanism  Osteoporosis
 Leg edema in children
 Proximal muscle weakness  abnormal genital virilization
 Purpura  delayed puberty
 The skin is thinning  stalled growth *
 Striae rubrae *  pseudoprekoks puberty
The picture is not specific  Short stature
 Hypertension  slow growth *
 Diabetes mellitus
 Dyslipidemia
 Endocrine changes
 Glucose intolerance
 Hypercoagulation conditions
 Skin manifestation
Neuropsychiatric disorders
 Major depression
 Mania
 psychosis
* signifies typical symptoms for Cushing's syndrome

Table 3. Frequency of symptoms and signs of Cushing syndrome (n = 423)

Sign/symproms frequency (%)
Central obesity 97
Moon face 89
Hypertension 76
Skin atrophy and bruises 75
Diabetes or glucose intolerance 70
Gonadal dysfunction 69
Muscle weakness 68
Hirsutism, acne 56
Mood disorder 55
Osteoporosis 40
Edema 15
Polyphilis / polyuria 10
Fungal infections 8

Truncal obesity is a frequent sign and often leads to other signs. Weight gain is also
often found although in some cases the increase is minimal so that serial
photographs of patients the last few years often help show changes towards the
moon face. Suspicions may develop when central obesity is found with fat deposits
of the face and supraclavicular area, cervical fat pad, thin skin, striae, proximal
muscle weakness, fatigue, hypertension, glucose metabolism and diabetes, acne,
hisutism and menstrual disorders. Other stigmata in adults are muscle atrophy and
bruising easily. Osteoporosis, fractures, and neuropsychiatric disorders such as
depression, labile emotions, sleep disturbances, and cognitive disorders are also
common. Some signs are referred to as specific signs for Cushing's syndrome such
as redness striae, pletora, proximal muscle weakness, and easy bruising, but many
other non-specific signs are often found in other conditions. There is still need for
laboratory evidence that there is a pathological and persistent hypercortisolism.
After we clinically suspect, the next step is to prove that there is an excess of cortisol
hormone secretion and impaired feedback mechanism of the hypothalamic-pituitary
thoracic axis. For early laboratory examinations many guidelines recommend one of
the following tests: two 24-h urine cortisol-free checks (24-h Urinary Free Cortisol),
late-night salivary cortisol, 1-mg overnight dexamethason suppression test (DST), or
longer low-dose DST. In a survey among endocrinologists, these three checks were
the most common type of preliminary examination to evaluate the possibility of
Cushing's syndrome. Often it is difficult or not yet available for the above mentioned
checks in developing countries, so pragmatically it often only checks for morning
cortisol. For plasma cortisol in the morning the results are quite acceptable if the
results are extreme high.

24h-UFC examination showed a high number of 24-hour cortisol secretions

unaffected by corticosteroid-binding globulin (CBG) levels. This examination
measures cortisol that is not bound to CBG and is infiltrated in the kidney without
undergoing any changes. Thus, of course the kidney function will affect the
interpretation of this examination because the more severe the kidney damage will
be the less cortisol secreted into the urine. The important thing that should be
emphasized to the patient is all urine should really collected for 24 hours, drink as
usual and not excessive, and do not use any kind of corticosteroid. If in 3 times the
examination showed normal urinary cortisol secretion then the diagnosis of Cushing
sindrong can be removed, certainly in normal kidney function.

The free form of free cortisol in the blood is proportional to cortisol in saliva, and the
salivary concentration is not affected by the state of saliva production, and its
concentration is stable at room temperature or refrigerator temperature. The change
in cortisol concentration in the blood will soon be followed by changes in salivary
cortisol concentration. In normal people, salivary cortisol at between 23.00 and 24.00
hours is always below 145 ng / dl (4 nmol / L) _ Reports from several countries say
this examination has sensitivity 92 -100% and specificity 93-100%, with the same
accuracy as 24h-UFC examination, Saliva is collected by passively spitting on a
plastic tube or with a cotton tampon placed in the mouth and chewed 1-2 minutes.

A l-mg overnight examination of dexamethasone suppression test (l-mg DST) may

differentiate patients with Cushing's syndrome or not. Delivery of dexamethasone 1
mg between 23:00 and 24:00, followed by fasting cortisol examination between
08.00 until 09.00 the next day. If there is sufficient evidence of Cushing's syndrome
from clinical and laboratory, then the next step is to look for the cause of the excess
hormone cortisol. ACTH examination is the next step, where if ACTH result is <10 pg
/ mL then Cushing's syndrome is ACTH-independent (adrenal Cushing) and if ACTH
is normal or high settling more than 15 pg / mL then including ACTH-dependent
group. In some cases Cushing's disease shows a normal low ACTH and vice versa
some Cushing's adrenals show unclear ACTH. In such circumstances it is advisable
to repeat the ACTH check before proceeding to the next examination. For adrenal
Cushing, ACTH levels between 10-20 pg / mL are recommended for CRH
stimulation testing, whereas the results are less clear of a Cushing adrenal while
there is a mild increase in ACTH it can be classified as pituitary cushing.

Once it is believed that Cushing's syndrome in the patient is ACTH-independent then

the next step is to perform an adrenal imaging to see if there is a lesion, the type of
lesion. as well as unilateral or bilateral. If an adrenal lesion is present it is likely to be
adrenal adenoma or carcinoma or a more rare form of ACHA independent
macronodular adrenal hyperplasia. If no adrenal lesions are present the usual cause
is PPNAD (primary pigmented nodular adrenal disease) in unilateral adrenal tumors,
the tissue surrounding the contralateral adrenal tumor and adrenal will develop
atrophy or remain normal depending on the degree of ACTH. Adrenal adenomas are
usually of small size varied, homogeneous, clear boundaries, density lower than
water on CT scans, but equal density with liver in MRI. If the lesions are bilateral
then adrenal venous sampling (AVS) is needed to distinguish the main source of
cortisol hypersecretion so as to help the surgeon determine the type of
adrenalectomy. In contrast to adrenal carcinoma, usually more than 6 cm in
diameter, irregular edges with unequal borders, high density and uneven due to
bleeding and / or necrosis, but if with MRI the intensity only increases moderately.
In ACTH-dependent the next step is to find the source of ACTH hypersecretion,
whether pituitary or ectopic. If the patient is female then the thought should be from
the pituitary because the ratio of Cushing's disease to ectopics is 9: 1. The first step
is to do the pituitary. In some cases, the pituitary MRI is not conclusive, therefore
BIPSS procedure (bilateral inferior petrosus sinus sampling) is required to distinguish
the ACTH source whether it is from the pituitary or ectopic. Patients with suspicion of
ACT Hproducing tumor (ectopic) then examined PET CT.

MANAGEMENT
Having known the exact cause of the management is adjusted to the basic illness
and location of the organs involved. Treatment options include surgery, radiotherapy,
or medicament. Certain choices may be effective for certain patients but may be very
limited for other patients because of side effects. For Cushing's disease the first
option is a transfenoid surgery, followed by radiotherapy and medicament if
necessary. For adrenal Cushing the choice of therapy is surgery, in accordance with
the lesions found and always preceded by administration of anti-steroidogenesis
(ketoconazole, mifepristone, mitotan, metirapon). For bilateral adrenalectomy, it is
usually necessary to substitute hormonal glucocorticoids and post-operative post-
operative mineralocorticoids. Currently developing adrenalectomy per laparoscopy
with minimally invasive techniques. In an ACTH dependent ectopic state it is often
difficult to locate the focus where the ACTH spot is produced in excess. From
several studies mentioned the distribution of ACTH sources outside of the most
common pituitary (bronchial carcinoid 25%, 16% cancer cell canlet, 11% small-cell
lung carcinoma, medullary thyroid cancer 8%, disseminated neuroendocrine tumor of
unknown primary source 7% thymic carcinoid 5 %, 3% phaeochromocytoma,
disseminated gastrointestinal carcinoid 1%, other tumors 8%).

Once Cushing's syndrome is diagnosed, while awaiting confirmation of the

underlying disease, it should be administered anti-steroidogenesis (ketoconazole,
mifepristone, mitotan, metirapon) first. Another thing that is often overlooked is that
patients with Cushing's syndrome are particularly susceptible to the rise of comonml
penurnocyst find / iii in the lung, so it should be given prophylaxis with cotrimoxazole.

COMPLICATIONS
Cushing's syndrome leads to a variety of systemic complications including central
obesity, hypertension, impaired glucose tolerance and diabetes, dyslipidemia,
thrombosis, psychiatric disorders, kidney disease, osteoporosis, along with
increased cardiovascular risk. Another thing that also often causes death in
Cushing's syndrome is infection and sepsis. Remission and normalization of cortisol
often do not eliminate these cardiovascular risks and the history of Cushing's
syndrome is a permanent risk factor for cardiovascular disease. The most important
thing that affects life expectancy is cortisol level, so the goal of management is to
lower cortisol levels simultaneously by controlling other cardiovascular risks
throughout the ages. Another thing that is often overlooked is that patients with
Cushing's syndrome experience a significant immunocompromise state due to
excess cortisol. As a result the patient may be infected by a germ that in normal
people only as a commensal germ, as occurs in HIV patients, so prophylaxis for
certain germs such as pneumicystic carlnr'r 'is required.

PROGNOSIS
If not treated adequately, Cushing's syndrome significantly increases morbidity and
mortality, and the median survival of patients is only about 4.6 years. From several
studies, mortality rates were found in non-malignant Cushing syndrome about 2-4
times compared with normal population, while Cushing's syndrome with malignant
diseases was very poor, generally dying during initial treatment efforts. It is also
understood that patients who fail with surgical mortality 5 times higher than the
normal population when compared with patients who are remission with surgery.

(1)1. Setiadi S, Alwi I, Sudoyo aru w., Simadibrata M, Setiyohadi B, Syam ari
fahrial, editors. Buku Ajar Ilmu Penyakit Dalam. VI. InternaPublishing; 2017.
2480-2485 p.