Regarding Cushing Syndrome answer the following questions

Regarding Cushing Syndrome answer the following questions

1. What is the difference between Cushing's syndrome and Cushing's disease?
2. What is the most common cause of Cushing's syndrome?
3. What are the clinical features of Cushing's syndrome?
4. What are the biologic effects of glucocorticoids?
5. What are the screening tests used to diagnose Cushing's syndrome?

Answers;

1. What is the difference between Cushing's syndrome and Cushing's disease?
Cushing's syndrome refers to the phenotypic and clinical sequelae due to hypercortisolism resulting from any cause.
Cushing's disease refers specifically to the hypercortisolism due to an ACTH-secreting pituitary corticotroph adenoma or pituitary corticotroph hyperplasia.

2. What is the most common cause of Cushing's syndrome?
The widespread use of potent corticosteroids in the practice of clinical medicine, particularly in the treatment of autoimmune, allergic, and pulmonary disorders, has made iatrogenic hypercortisolism the most common cause of Cushing's syndrome. How ever, once the iatrogenic causes are eliminated, pituitary adenoma (68%) becomes the most common cause.

3. What are the clinical features of Cushing's syndrome?
Cushing's syndrome is associated with many clinical features.

Obesity, found in 94%, is the most common manifestation and weight gain is usually the earliest symptom of Cushing's syndrome. The obesity tends to be central, but fat can also be redistributed to the face (moon facies; 75%), as well as supraclavicular (80%) and dorsocervical areas (“buffalo hump”; 80%). The latter two areas, particularly the supraclavicular fat pad, are more specific findings for Cushing's syndrome.



Skin changes occur in 85% of the patients and arise because cortisol induced atrophy of the epidermis leads to thinning and a transparent appearance of the skin, facial plethora, easy bruisability, and the formation of striae. The latter are purplish red areas that are depressed below the skin surface, but are wider than the pinkish white striae that appear after pregnancy or weight loss. Wounds heal slowly in these patients and may dehisce. Hyperpigmentation occurs in the setting of the ectopic ACTH syndrome, but is rare in patients with Cushing's disease and should not be found in those with primary adrenal Cushing's syndrome.

Acne (40%) is also a symptom and is due to androgen excess; it may be more generalized than what the patient experienced before.

Hirsutism affects 80% of the patients and typically consists of a darkening and coarsening of the hair. Female patients complain of increased growth of hair over the face, upper thighs, abdomen, and breasts. Virilism occurs in approximately 20% of the cases of adrenal carcinoma.

Hypertension is a problem in 75% of the patients. Elevated diastolic BP is a classic feature of spontaneous Cushing's syndrome, and it contributes greatly to the morbidity and mortality associated with the disorder. The increased sodium retention also leads to edema (18%).

Congestive heart failure (22%) can be aggravated because of the increased BP and fluid load.

Gonadal dysfunction occurs in 75% of the patients. Elevated androgen levels can result in amenorrhea and infertility in 75% of affected premenopausal w omen. In men, the elevated cortisol level may cause a decrease in libido.

Muscle weakness arises in 60% of patients, in particular proximal weakness that most often occurs in the low er extremities. This weakness stems from the catabolic effects of glucocorticoids on muscle tissues, steroid-induced myopathy, and possibly electrolyte imbalances. Weakness can be assessed
clinically by asking the patient to stand from the chair without assistance of arms.

Radiographically detectable osteoporosis is present in most patients with Cushing's syndrome (60%), and back pain is the initial complaint in 58% of the cases. Pathologic fractures are found in the ribs and vertebrae in severe cases. It takes some time for the hypercortisolism to decalcify bone; therefore, Cushing's syndrome due to adrenal carcinoma and some ectopic ACTH cases is not present long enough to cause osteoporosis.

Psychological disturbances can arise in 40% of patients. These complaints range from mild symptoms, such as emotional lability, increased irritability, anxiety, insomnia, euphoria, poor concentration, poor memory, and mild depression, to severe symptoms, which include frank psychosis associated with delusions or hallucinations, paranoia, severe depression, and even suicidal behavior.

Renal calculi form in 15% of patients as a result of glucocorticoid-induced hypercalcemia. Renal colic may be the presenting symptom of Cushing's syndrome.

Thirst and polyuria are seen in 10% of patients. The thirst is due to glucocorticoid-induced hyperglycemia [or worsening of existing diabetes mellitus (DM)] that causes an osmotic (glucose) diuresis. Diabetic ketoacidosis (DKA) and diabetic microvascular complications are rare in the
diabetes seen with Cushing's syndrome.

4. What are the biologic effects of glucocorticoids?
From a molecular perspective, glucocorticoid hormones enter the cell by diffusion and activate specific gene transcription by binding to the nuclear glucocorticoid receptor. The glucocorticoid receptor is therefore a conditional transactivator that influences the rate of RNA polymerase II
transcription initiation by binding to specific short DNA sequence elements (glucocorticoid response elements) in the promoter regulatory region of the various target genes. Although this is the best-established pathway of glucocorticoid action, other mechanisms that mediate the rapid effects of
glucocorticoids, such as the fast-feedback inhibition of ACTH secretion and possibly modulation of the γ-aminobutyric acid receptor, must also exist.
In terms of their effects on metabolism, glucocorticoids accelerate hepatic gluconeogenesis by stimulating phosphoenolpyruvate carboxykinase and glucose-6-phosphatase activity, and induce a permissive effect in other gluconeogenic hormones (glucagon and catecholamines). Glucocorticoids
also enhance hepatic glycogen synthesis and storage and inhibit glycogen breakdown. In muscles, glucocorticoids inhibit amino acid uptake and protein synthesis and stimulate protein breakdow n as well as the release of amino acids, lactate, free fatty acids (FFAs), and glycerol. In adipose tissue, glucocorticoids primarily accelerate lipolysis, w ith a resultant release in the formation of glycerol and FFAs. Although glucocorticoids are lipolytic, an increased central fat deposition is a classic feature of Cushing's syndrome. The steroid-induced increase in appetite and hyperinsulinemia may account for this, but the basis for this abnormal fat deposition in the setting of hypercortisolism remains unknown.

5. What are the screening tests used to diagnose Cushing's syndrome?
A key aspect of the initial workup in a patient with suspected Cushing's syndrome is to distinguish true hypercortisolism from obesity, depression, or alcoholism, or a combination of these, because many clinical and laboratory features of these disorders display significant overlap. A key aid in
establishing the clinical diagnosis of hypercortisolism is examining the patient's sequential photographs that span several years.
Once Cushing's syndrome is suspected on clinical grounds, the overnight 1-mg dexamethasone suppression test (DST) and the 24-hour urinary free cortisol (UFC) determination are used as screening tests. If the results of the overnight 1-mg DST are normal (8 a.m. plasma cortisol <2 μg/dL after the administration of 1 mg of dexamethasone at 11 p.m. the night before), the diagnosis is very unlikely. If the results of the UFC test are also normal (i.e., <90 to 100 μg per day), Cushing's syndrome is effectively excluded.
A third, recently available, but not yet widely accepted screening test is the late night salivary cortisol. This test takes advantage of the loss of normal circadian variation in cortisol level in Cushing's disease by measuring cortisol at a time when it is normally virtually absent.
Several situations can cause false-positive results for the screening DST, including acute and chronic illness, obesity, high-estrogen states, certain drugs (phenytoin and phenobarbital), alcoholism, anorexia, renal failure, and depression. How ever, in the setting of obesity, high-estrogen states, and certain drugs, the results of a 24-hour UFC are normal. In the other situations, repeated testing is necessary to exclude the diagnosis. Rarely false-negative results can occur, such as in the event of prolonged dexamethasone clearance or episodic hypercortisolism.