8.5 Additional Reading:Cushing Syndrome
Introduction
Cushing syndrome is caused by prolonged exposure to high circulating levels of cortisol.The most common cause of cushingoid features is iatrogenic corticosteroid use，while some herbal preparations can also increase circulating corticosteroid levels，leading to Cushing syndrome.Cushing syndrome can be interchangeably called hypercortisolism.ACTH-dependent cortisol excess due to a pituitary adenoma is called Cushing disease，and it is responsible for 80%of endogenous Cushing syndrome.
Etiology
There are two main etiologies of Cushing syndrome：endogenous hypercortisolism and exogenous hypercortisolism.Exogenous hypercortisolism，the most common cause of Cushing syndrome，is mostly iatrogenic and results from the prolonged use of glucocorticoids.Endogenous cushing syndrome results from excessive production of cortisol by adrenal glands and can be ACTH-dependent and ACTH-independent.ACTHsecreting pituitary adenomas（Cushing disease）and ectopic ACTH secretion by neoplasms are responsible for ACTH-dependent Cushing Syndrome.Adrenal hyperplasia，adenoma and carcinoma are the major causes of ACTH-independent Cushing syndrome.
Epidemiology
The actual incidence and prevalence of Cushing syndrome remain unknown.The prevalence of the disease is highly variable across different ethnic and cultural groups depending upon the frequency and a spectrum of the medical conditions requiring steroid-based therapy.However，of the known cases，iatrogenic hypercortisolism outweighs the endogenous causes，of the endogenous causes pituitary-mediated ACTH production accounts for up to 80%of cases of hypercortisolism，followed by adrenals，unknown source and ectopic ACTH production secondary to malignancies.
Pathophysiology
Cortisol is a steroid hormone produced by the zona fasciculata of the adrenal cortex.After production the cortisol is carried to different parts of the body by cortisol binding protein，and almost 90%of cortisol binds to these（CBG）proteins and has a bioavailability of 60%to 100%.Synthetic corticosteroids have varying bioavailability and potency，but all affect similar pathways.It is a catabolic hormone that is released under stressful conditions.The excess of cortisol results in an increased rate of gluconeogenesis，glycogenolysis and increased insulin resistance.Cortisol is a steroid hormone，and it directly affects the transcription and translation of enzyme proteins involved in the metabolism of fats，glycogen，protein synthesis，and Kreb’s cycle.It promotes the production of free glucose in the body，elevating glucose levels，while simultaneously increasing insulin resistance.The destruction of protein yields amino acids which are used in gluconeogenesis.The prolonged catabolism of proteins causes purplish striae of the torso，osteoporosis and poor wound healing.All these processes involve collagen，which is a three-amino-based protein.High cortisol levels also cause immune disruptions；this hormone leads to a decrease in lymphocyte level but an increase in the neutrophils.It causes detachment of marginating pool of neutrophils in the bloodstream and increases the circulating neutrophil level，although there is no increased production of the neutrophils.This mechanism explains the typical picture of raised TLC where there is decreased lymphocyte number and increased neutrophils.The corticosteroids mediate the downregulation of NF-kappaB and the regulation of AMPkinase，glycogen phosphorylase，superoxide dismutase，and many other enzymes.Cortisol inhibits the production of IL-2，TNF alpha，IFN alpha，and gamma.Decreased IL-2 level prevents the proliferation of T-lymphocytes.
History and physical
The patient with Cushing syndrome may have a history of weight gain，fatigue，weakness，delayed wound healing，easy bruising，back pain，bone pain，loss of height，depression，mood swings，emotional reactivity，loss of libido，erectile dysfunction in males，irregular menstrual cycles in females，infertility，hyperhidrosis，hirsutism，biparietal visual loss if there is a large pituitary adenoma，recurrent fungal and bacterial infections due to impaired immunity，and difficulty in combing hair or rising from a sitting position.Psychological problems such as cognitive dysfunction and depression are not uncommon.Some patients might develop severe osteopenia and bone fractures.Patients may also have a history of hypertension，peptic ulcer disease，and diabetes.(https://www.daowen.com)
Physical examination of the patient will reveal increased fat deposits in the upper half of the body leading to“Buffalo torso”，characteristic moon face（earlobes are not visible when viewed from the front），thin arms and legs，acne，hirsutism，proximal muscle weakness of shoulder and hip girdle muscles，paper-thin skin，abdominal pain due to gut perforation in rare cases，and wide vertical purplish abdominal striae.
Evaluation
The evaluation of suspected Cushing’s syndrome can include the demonstration of endogenous hypercortisolism with the late-night salivary cortisol or a 24-hour urine free cortisol.Inability to appropriately suppress endogenous cortisol production is detected with the one-milligram overnight dexamethasone suppression test and the 2-day lowdose dexamethasone suppression test.
Treatment/Management
The best therapy for iatrogenic Cushing’s syndrome is to taper exogenous steroids.Chronic exposure to steroids can suppress the adrenal functioning and it can take several months for normal adrenal functioning to recover.Therefore，steroids should be slowly tapered allowing adrenal functioning to recover.Hypercortisolism due to Cushing disease or adrenal tumor or ectopic tumor is best treated with surgical resection.The individualized approach should be followed to evaluate recurrence after surgical resection.Pituitary MRI should be done 1-3 months after surgical resection to evaluate success in Cushing disease.Late night salivary cortisol or serum cortisol or 24-hour urine free cortisol measurement is recommended to ensure eucortisolism after surgical treatment.Radiotherapy is recommended in Cushing disease after failed transsphenoidal surgery or in Cushing disease with mass effect or invasion of surrounding structures.Other oral medications include pasireotide，cabergoline，and mifepristone.In the management of Cushing syndrome，it is crucial to treat comorbidities such as diabetes mellitus，hypertension，osteoporosis，psychiatric issues，and electrolyte disorders.Cushing syndrome due to an ACTH tumor that cannot be resected entirely may require bilateral adrenalectomy followed by lifelong adrenal glucocorticoid replacement and mineralocorticoid.
Prognosis
Although the earliest studies of Cushing syndrome reported a median survival of 4.6 years and five-year survival of only 50%，with recent advances in treatment，the standard mortality ratio is similar to that of the age-matched population.The morbidity and mortality of Cushing syndrome are primarily due to the effects of related conditions such as diabetes，hypertension，heart disease，obesity，and osteoporosis with fractures.The prognosis is worsened in the setting of an unresectable hormone-secreting tumor.
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Task 9 Identify the word elements and define the meaning of each medical term.
