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Source PMCID: PMC3458990
Orphanet J Rare Dis. 2012; 7: 41.
Published online 2012 Jun 18. doi: 10.1186/1750-1172-7-41
Cushing’s disease, or pituitary ACTH dependent Cushing’s syndrome, is a rare disease responsible for increased morbidity and mortality. Signs and symptoms of hypercortisolism are usually non specific: obesity, signs of protein wasting, increased blood pressure, variable levels of hirsutism. Diagnosis is frequently difficult, and requires a strict algorithm. First-line treatment is based on transsphenoidal surgery, which cures 80% of ACTH-secreting microadenomas. The rate of remission is lower in macroadenomas. Other therapeutic modalities including anticortisolic drugs, radiation techniques or bilateral adrenalectomy will thus be necessary to avoid long-term risks (metabolic syndrome, osteoporosis, cardiovascular disease) of hypercortisolism. This review summarizes potential pathophysiological mechanisms, diagnostic approaches, and therapies.
Disease name and synonyms
Cushing’s disease, corticotroph adenoma, pituitary dependent Cushing’s syndrome.
Chronic glucocorticoid excess, or Cushing’s syndrome, may be due to ACTH-dependent (80% cases) or –independent (20% cases) causes (Table ?(Table1).1). The latter are mainly due to benign (60%) or malignant (40%) adrenal tumors. ACTH overproduction may be of pituitary origin (85% cases) or result from ectopic tumor secretion (15% cases). The term Cushing’s disease is specifically applied to ACTH-secreting pituitary tumors. Cushing’s disease, first described by Harvey Cushing in 1932, represents the most frequent cause of Cushing’s syndrome .
Classification of most frequent causes of Cushing’s syndrome
Cushing’s disease is defined by Adrenocorticotropin hormone (ACTH) hypersecretion, induced by a corticotroph adenoma, and leading to cortisol hypersecretion (associated with androgens hypersecretion).
The incidence of Cushing’s syndrome is estimated to be equal to 1–3 cases per million inhabitants per year, whereas its prevalence is close to 40 cases per million inhabitants. Of note, prevalence of hypercortisolism is thought to be equal to 2-5% of patients with poorly controlled diabetes and hypertension. Female preponderance is generally assumed to be close to 3:1 . Cushing’s disease is an extremely rare condition in children, with a peak in adults in the 3rd or 4th decade. Cushing’s disease leads to death if untreated; it is responsible for increased morbidity and mortality, due to cardiovascular complications, infections and psychiatric disturbances [3,4].
Clinical and biological characteristics
Hypercortisolic state may include several clinical signs [5,6]
Obesity: obesity with centripetal fat deposition (face, supraclavicular and dorso-cervical fat pads), facial plethora, rounded face, buffalo-hump
Signs of protein wasting: thin skin, abdominal purple to red and wide cutaneous striae (abdomen, flanks, breasts, hips, axillae), easy bruising, slow healing, muscle wasting (lower limbs muscle atrophy)
Bone wasting leading to osteoporosis (possibly leading to fractures)
High blood pressure
Impaired immune defense mechanisms with increased rate of infections
Gonadal dysfunction and hyperandrogenism: hirsutism (more frequently on the face), menstrual irregularity (oligoamenorrhea, amenorrhea)
Mild to severe psychic disturbances(anxiety, depression, irritability…)
The most frequent sign is obesity: abnormal fat distribution is considered as the most sensitive sign . Evidence of protein wasting (osteoporosis, myopathy) is the most specific sign. Conjunction of both should theoretically allow to distinguish between hypercortisolism and simple obesity. However, the severity of hypercortisolism can be highly variable, which frequently makes the diagnosis difficult. Moreover, hypersecretion profiles can be cyclical, leading to very modest phenotypic signs in some patients (subclinical Cushing’s syndrome) . In most cases, diagnosis depends on a high index of suspicion, rather than a florid clinical phenotype. Of note, none of the signs can allow to differentiate Cushing’s disease from any other etiology of hypercortisolism, except in case of tumor related symptoms such as headaches or visual field defect (in macroadenomas).
Non-specific biological signs may include hypokalemia and impaired glucose tolerance or diabetes. Blood count may show increased hemoglobin, increased neutrophils and decreased lymphocytes or eosinophils.
Characteristics of corticotroph adenomas
Cushing’s disease is frequently due to monoclonal benign and slow growing microadenomas (less than 10?mm) [9,10]. Plasma ACTH (and cortisol) classically lose their physiologic circadian periodicity. They are partially resistant to physiologic stimuli (i.e., glucocorticoids), and do not respond to the normal feedback negative loop. In contrast, corticotroph adenomas are inappropriately sensitive to CRH and AVP. Altered CRH secretion as well as POMC qualitative changes in gene expression were also reported to be involved in the pathogenesis of Cushing’s disease. Cushing’s disease can be more atypical: secretion profiles are sometimes cyclic, with hypersecretion preceding a long period of normal secretion [8,11]. Some corticotroph adenomas are called “silent” as they are clinically and biologically comparable to non-secreting pituitary adenomas: diagnosis is made by the pathologist . Finally, rare cases of aggressive pituitary adenomas or carcinomas have been reported . Whether hyperplasia of corticotroph cells is or not a required initial step before the genesis of corticotroph adenoma remains a matter of debate. The origin of the disease, primary pituitary condition or secondary to an abnormality in the hypothalamus (chronic stimulation by CRH ), remains a matter of debate.
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