History

Fact Explanation
Sudden weight gain Cortisol excess can cause centripetal fat deposition. [4]
Excessive thirst and appetite, increased urination, unusual weight loss or gain, fatigue, nausea/ vomiting,blurred vision, dry mouth, slow-healing sores or cuts, itching skin (especially in the groin or vaginal area) Glucose intolerance or diabetes mellitus [1] The development of diabetes mellitus in Cushing’s syndrome is both a result of a direct and indirect consequence of glucocorticoid excess. GC excess leads to the stimulation of gluconeogenesis and development of insulin resistance mainly in the liver and in the skeletal muscle, which reduces glycogen synthesis and glucose uptake, resulting in an increased blood glucose level. [7]
Severe headache, fatigue or confusion, vision problems, chest pain, difficulty breathing, palpitations Symptoms of increased blood pressure. Hypertension is most likely to develop in patients over 40 years of age [1] and it results from an interplay of several pathophysiological mechanisms regulating plasma volume, peripheral vascular resistance, and cardiac output, all of which are increased in Cushing's syndrome. Insulin resistance and sleep apnea are found to also contribute to the hypertension of CS. More commonly seen in ectopic Cushing's (95%). [5] [6]
Anxiety, depression, insomnia, psychosis, excitability, euphoria, short-term memory/cognitive deficits These psychological disturbances commonly occurs in patients with Cushing's disease. [1] [2] [4] Cushing’s disease has been found to be associated with brain atrophy and cognitive deficits. Atrophy of the prefrontal cortex has been linked with depression, whereas anxiety and excitability have been correlated in the size and activity of the amygdala. [8]
Excessive facial/body hair, Oligomenorrhea, amenorrhea, decreased libido or impotence Menstrual irregularities due to gonadal dysfunction and hyperandrogenism. [4]
Recurrent opportunistic or bacterial infections Excessive corticosteroid excess causes immunosuppression, a cellular immune deficiency, that increases the risk of opportunistic infections. Glucocorticoids have been found to have effect on the humoral immune system causing interference in the immune response to bacterial infections. All these result in an increased rate of infections due to impaired immune defence mechanisms. [4] Frequent vaginal infections in women and yeast infections in both men and women is also indicative of glucose intolerance/ diabetes mellitus. [1]
Pain in neck, shoulders and back. Extreme fatigue and muscle weakness. Pain resulting due to bone wasting caused by osteopenia/ osteoporosis which could possibly lead to fractures. Proximal myopathy can cause muscle weakness. [1]
Past history Medical conditions associated with Cushing’s Disease include diabetes mellitus, hypertension, osteoporosis, and arthralgia. [2]
Drug history A complete thorough drug history must be taken to rule out exogenous glucocorticoid use (oral, rectal, inhaled, topical, or injected) before conducting biochemical testing because exogenous glucocorticoids can produce similar clinical features to those of Cushing’s syndrome, confounding test results and as a result delay appropriate patient care. [2]
References
  1. KIRK LF JR, HASH RB, KATNER HP, JONES T. Cushing's disease: clinical manifestations and diagnostic evaluation. Am Fam Physician [online] 2000 Sep 1, 62(5):1119-27, 1133-4 [viewed 10 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/10997535
  2. ZADA GABRIEL. Diagnosis and Multimodality Management of Cushing’s Disease: A Practical Review. International Journal of Endocrinology [online] 2013 December, 2013:1-7 [viewed 10 August 2014] Available from: doi:10.1155/2013/893781
  3. NEWELL-PRICE J. Diagnosis/differential diagnosis of Cushing's syndrome: a review of best practice. Best Pract Res Clin Endocrinol Metab [online] 2009 Dec:S5-14 [viewed 10 August 2014] Available from: doi:10.1016/S1521-690X(09)70003-X
  4. CASTINETTI FREDERIC, MORANGE ISABELLE, CONTE-DEVOLX BERNARD, BRUE THIERRY. Cushing’s disease. Array [online] 2012 December [viewed 10 August 2014] Available from: doi:10.1186/1750-1172-7-41
  5. SINGH Y, KOTWAL N, MENON AS. Endocrine hypertension - Cushing's syndrome Indian J Endocrinol Metab [online] 2011 Oct, 15(Suppl4):S313-S316 [viewed 11 August 2014] Available from: doi:10.4103/2230-8210.86973
  6. CICALA MARIA VERENA, MANTERO FRANCO. Hypertension in Cushing’s Syndrome: From Pathogenesis to Treatment. Neuroendocrinology [online] 2010 December, 92(1):44-49 [viewed 11 August 2014] Available from: doi:10.1159/000314315
  7. PIVONELLO R, DE LEO M, VITALE P, COZZOLINO A, SIMEOLI C, DE MARTINO MC, LOMBARDI G, COLAO A. Pathophysiology of diabetes mellitus in Cushing's syndrome. Neuroendocrinology [online] 2010:77-81 [viewed 11 August 2014] Available from: doi:10.1159/000314319
  8. PATIL CHIRAG G., LAD SHIVANAND P., KATZNELSON LAURENCE, LAWS EDWARD R.. Brain atrophy and cognitive deficits in Cushing's disease. Neurosurgical FOCUS [online] 2007 September, 23(3):1-4 [viewed 11 August 2014] Available from: doi:10.3171/FOC-07/09/E11

Examination

Fact Explanation
Central obesity Central obesity is the most frequent sign. [2] Fat deposition is mostly in a centripetal distribution i.e. in the face, supraclavicular and dorsocervical fat pads. Patients may also have facial plethora, a rounded face and a buffalo-hump. [1]
Thin skin, striae, easy bruising, slow healing, lower limbs muscle atrophy Signs of protein wasting. Purple to red and wide cutaneous striae can be seen mostly in the abdomen, flanks, breasts, hips and axillae. [1]
Plethora, hirsutism, striae, acne, bruising Skin manifestations usually observed that are commonly associated with excess cortisol causing gonadal dysfunction and hyperandrogenism. [3] Hirsutism is mostly seen on the face. [1]
Fractures Bone wasting leading to osteopenia/ osteoporosis which possibly leads to fractures. [1]
References
  1. CASTINETTI FREDERIC, MORANGE ISABELLE, CONTE-DEVOLX BERNARD, BRUE THIERRY. Cushing’s disease. Array [online] 2012 December [viewed 10 August 2014] Available from: doi:10.1186/1750-1172-7-41
  2. KIRK LF JR, HASH RB, KATNER HP, JONES T. Cushing's disease: clinical manifestations and diagnostic evaluation. Am Fam Physician [online] 2000 Sep 1, 62(5):1119-27, 1133-4 [viewed 10 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/10997535
  3. Hershel Raff, PhD, and James W. Findling, MD. A Physiologic Approach to Diagnosis of the Cushing Syndrome. [online] Ann Intern Med. 2003;138:980-991 [viewed 11 August 2014] Available from: http://www.the-aps.org/mm/publications/journals/pim/raff-pdf.pdf

Differential Diagnoses

Fact Explanation
ACTH-dependent Cushing's syndrome Cushing’s syndrome is mostly caused by an ACTH dependent source (80%), and in most instances it is from a pituitary tumor (Cushing’s disease). Other ACTH dependent sources are from ectopic sources ;and most frequent ectopic sources of ACTH are small-cell lung carcinomas (SCLC) and bronchial carcinoid tumours. A rapid presentation with weight loss, weakness, and pigmentation,rather than the classic Cushingoid phenotype is more likely to occur due to SCLC as the source of ACTH. However, when the phenotype and biochemistry exactly mimics that of Cushing’s disease, the most likely source of ACTH is a carcinoid tumor. The initial step in the differential diagnosis of ACTH-dependent Cushing’s syndrome is pituitary imaging combined with CRH testing. On finding of an adenoma of >6 mm on pituitary imaging, a positive CRH response and dexamethasone suppression concludes that the patient has a pituitary source of ACTH excess (i.e. Cushing’s disease). Upto 40% patients with Cushing's syndrome seem to have normal pituitary MRI imaging. In such instances, BIPSS has been found the most reliable biochemical assay for distinguishing between pituitary and ectopic sources of ACTH hypersecretion. A positive central-to-peripheral gradient of ACTH on BIPSS is a strong indicator of Cushing’s disease. On absence of a ACTH gradient, further evaluation of the thorax and abdomen by CT or MRI, and possibly somatostatin scintigraphy should be done to test for an ectopic source. [2]
ACTH-independent Cushing’s syndrome This is ruled out in the presence of an inappropriately normal or increased ACTH level. Generally ACTH-independent cushing's syndrome arises from an adrenal adenoma, which consequently suppresses pituitary ACTH. Adrenal imaging with CT is used to establish the existence of an adrenal lesion. If an adrenal lesion is identified, the patient is likely to have an adrenal adenoma (60% cases), a carcinoma (40% cases), or much less commonly, ACTH-independent macronodular adrenal hyperplasia (AIMAH) as the aetiology of Cushing’s syndrome. On failure to detect an adrenal lesion after CT imaging, the patient could be suspected to have primary pigmented nodular adrenal disease (PPNAD), a rare form of adrenal Cushing’s syndrome that may not be visible on CT. Alternatively, it may be necessary to reconsider the possibility that the patient is taking exogenous hydrocortisone. [2]
Pseudo-Cushing's syndrome Conditions such as depression, alcoholism, eating disorders and also the intake of medications can cause mild clinical and laboratory findings giving a similar picture to that of Cushing's syndrome and this is termed “pseudo-Cushing's syndrome.” On successfully treating the primary process ,the laboratory and clinical findings of hypercortisolism disappear. [3]
Functional hypercortisolism Seen during pregnancy. [3]
References
  1. DANIEL M. PREVEDELLO, SUE M. CHALLINOR, NESTOR D. TOMYCZ, PAUL GARDNER, RICARDO L. CARRAU, CARL H. SNYDERMAN, AND AMIN B. KASSAM. Diagnosing, Managing Cushing’s Disease: A Multidisciplinary Overview. Review of Endocrinology. [online] January 2009. Available from: http://www.upmc.com/services/neurosurgery/brain/conditions/brain-tumors/documents/review-of-endocrin-cushings.pdf
  2. NEWELL-PRICE J. Diagnosis/differential diagnosis of Cushing's syndrome: a review of best practice. Best Pract Res Clin Endocrinol Metab [online] 2009 Dec:S5-14 [viewed 10 August 2014] Available from: doi:10.1016/S1521-690X(09)70003-X
  3. KIRK LF JR, HASH RB, KATNER HP, JONES T. Cushing's disease: clinical manifestations and diagnostic evaluation. Am Fam Physician [online] 2000 Sep 1, 62(5):1119-27, 1133-4 [viewed 10 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/10997535

Investigations - for Diagnosis

Fact Explanation
Basic blood tests Blood count may show increased hemoglobin, increased neutrophils and decreased lymphocytes or eosinophils. Hypokalemia, impaired glucose tolerance or diabetes and increased triglycerides may be found. [2]
24-hour Urinary free cortisol e UFC (≥ 2 measurements), late-night salivary cortisol (≥2 measurements), Dexamethasone suppression test (DST) These are the first-line screening tests done to confirm suspected Cushing’s syndrome. Perform any one of these and elevated cortisol secretion should be confirmed with ideally, 2 or more additional measurements. UFC: Values < 90 μg per 24 hours (250 nmol per day) are considered normal while values more than 300 μg per day (830 nmol per day) are considered diagnostic for Cushing's syndrome. If the unsuppressed 24-hour urinary free cortisol test is unequivocally positive, a confirmatory DST is usually unnecessary. UFC is the test of choice for the initial evaluation in pregnant women and UFC is not recommended in patients with impaired renal function. [4] It is also the recommended choice of testing in patients suspecting of having cyclic Cushing's syndrome. Late-night salivary cortisol: A healthy individual usually has levels <4.0 nmol/L. Values >4.3 nmol/L suggests Cushing’s syndrome. Not a good choice of test for patients who are stressed or who work over night because changes in their circadian rhythm can produce false-positive results. Recommended test for patients with renal failure. [4] Though a reliable and sensitive test, it has a low specificity in patients with increased age ,and with comorbidities such as hypertension and diabetes in whom a higher incidence of false-positive results were found. DST: This test is designed to demonstrate impaired feedback regulation of the HPA axis (i.e. no suppressive response). DST tests are available at the 1 mg or 2 mg dexamethasone dose. In the 1mg overnight DST ,the patient takes l mg of dexamethasone orally at 11 p.m., and the plasma cortisol level is measured at 8 a.m. the following day. A cortisol value < 50 nmol/l (< 2 μg/dl) excludes Cushing’s syndrome. DST is not a recommended test for pregnant patients and for patients on antiepileptic drugs. UFC or the late-night salivary cortisol test are tests of choice to be done on patients with cyclic disease and DST is not chosen because results could appear normal when the patient’s hypercortisolism is at a low level. False-positive results (pseudo-Cushing's syndrome) on DST and mildly elevated free cortisol values can be caused by conditions such as obesity, chronic illness, chronic alcoholism and depression. [1]
Serum ACTH level Once excess cortisol levels are confirmed a serum ACTH level should be measurement to diagnose whether it is ACTH-dependent or ACTH-independent hypercortisolism. Measurement is done in the late-afternoon (after 4 p.m.) because ACTH levels are normally low at that time. If the plasma ACTH level is >15 pg/mL (2 pmol/L), the process is ACTH-dependent. If the ACTH level is <5 pg/mL (1 pmol/L) on more than 2 occasions then the process is ACTH-independent. Intermediate ACTH levels indicate the need for further study with, for example, a CRH stimulation test. [1]
CRH stimulation test CRH stimulation test can help localize the site of ACTH overproduction. This test is considered to have a diagnostic accuracy similar to that of DST, but it is more cost-effective because it can be performed in one morning in the outpatient setting. 1 μg/kg of CRH is administered intravenously. ACTH and cortisol levels are measured before the CRH injection and then 15, 30, 45, 60, 90 and 120 minutes after the injection. A rise in the cortisol value of 20% or more above basal level or a rise in the ACTH value of at least 50% above basal level is considered evidence for an ACTH-dependent lesion. A 35% increase in the ACTH level at 15 and 30 minutes after corticotropin administration, it is reported to be 93% sensitive and 100% specific for Cushing's disease. [3]
Pituitary MRI and dexamethasone-CRH suppression test When the above test results indicate that a patient has an ACTH dependent lesion, the initial step in the differential diagnosis of ACTH-dependent Cushing’s syndrome is pituitary imaging combined with CRH testing. On finding of an adenoma of >6 mm on pituitary imaging, a positive CRH response and dexamethasone suppression, it can be concluded that the patient has a pituitary source of ACTH excess (i.e. Cushing’s disease). In some cases of small microadenomas or if standard pituitary MR imaging is negative, dynamic contrast MRI has been reported to help in the diagnosis. [1]
Adrenal imagine with CT scan If initial investigations indicate an ACTH-independent lesion, an abdominal CT or MRI scan must be done to localize the site of the lesion. It could be an adrenal lesion such as an adenoma, carcinoma or ACTH-independent macronodular adrenal hyperplasia (AIMAH); or it could be a non-adrenal lesion such as primary pigmented nodular adrenal disease (PPNAD) or reconsider exogenous glucocorticoid. [1]
Bilateral Inferior Petrosal Sinus Sampling (BIPSS) This procedure is considered the gold standard for definitive diagnosis of ACTH-dependent lesions. BIPSS is invasive and expensive but morbidity rates have been found to be low in centers experienced in performing the procedure. If MR imaging is negative, yet if a strong suspicion for Cushing’s Disease exists, or if work-up up to this point are equivocal or if the work-up suggests ectopic ACTH production then BIPSS is indicated because BIPSS has been found to be the most reliable biochemical assay for distinguishing between pituitary and ectopic sources of ACTH hypersecretion. A positive central-to-peripheral gradient of ACTH on BIPSS (90%) is a strong indicator of Cushing’s disease. A petrosal sinus–to–peripheral ACTH ratio of 2:1 is considered diagnostic for a pituitary source. [1]
Thorax and abdominal CT/MRI scan +/-somatostatin scintigraphy On absence of a ACTH gradient on BIPSS, a CT or MRI of the thorax and abdomen, and possibly somatostatin scintigraphy should be done to further evaluate for an ectopic source of ACTH (10%). [1]
References
  1. NEWELL-PRICE J. Diagnosis/differential diagnosis of Cushing's syndrome: a review of best practice. Best Pract Res Clin Endocrinol Metab [online] 2009 Dec:S5-14 [viewed 10 August 2014] Available from: doi:10.1016/S1521-690X(09)70003-X
  2. CASTINETTI FREDERIC, MORANGE ISABELLE, CONTE-DEVOLX BERNARD, BRUE THIERRY. Cushing’s disease. Array [online] 2012 December [viewed 10 August 2014] Available from: doi:10.1186/1750-1172-7-41
  3. KIRK LF JR, HASH RB, KATNER HP, JONES T. Cushing's disease: clinical manifestations and diagnostic evaluation. Am Fam Physician [online] 2000 Sep 1, 62(5):1119-27, 1133-4 [viewed 10 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/10997535
  4. NIEMAN LK, BILLER BM, FINDLING JW, NEWELL-PRICE J, SAVAGE MO, STEWART PM, MONTORI VM. The Diagnosis of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline J Clin Endocrinol Metab [online] 2008 May, 93(5):1526-1540 [viewed 11 August 2014] Available from: doi:10.1210/jc.2008-0125

Investigations - Followup

Fact Explanation
Long-term follow up Low-term follow up and monitoring for signs and symptoms of tumor recurrence is required for patients who have been surgically treated for Cushing's disease. 6-12 months after surgery, patients' pituitary adrenal axis must be evaluated to determine the potential need for lifetime exogenous steroid replacement therapy. Patients who develop panhypopituitarism subsequent to surgery will require lifetime monitoring and titration of hormone therapy. [1]
References
  1. KIRK LF JR, HASH RB, KATNER HP, JONES T. Cushing's disease: clinical manifestations and diagnostic evaluation. Am Fam Physician [online] 2000 Sep 1, 62(5):1119-27, 1133-4 [viewed 10 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/10997535

Management - General Measures

Fact Explanation
Medic alert bracelet Patients who have had pituitary surgery will be given glucocorticoid replacement therapy until recovery of the pituitary and adrenal glands is either well underway or complete. Patients may suffer from illnesses, and the body may not respond normally to the stress ( by increasing cortisol production) and hence can suffer from vomiting or severe diarrhea that results in the poor absorption of glucocorticoids taken by mouth. In such occasions, it may be necessary to receive injections of dexamethasone or another glucocorticoid, and seek emergency medical care. Thus they should wear a MedicAlert bracelet until glucocorticoid replacement therapy is stopped. [1]
References
  1. KIRK LF JR, HASH RB, KATNER HP, JONES T. Cushing's disease: clinical manifestations and diagnostic evaluation. Am Fam Physician [online] 2000 Sep 1, 62(5):1119-27, 1133-4 [viewed 10 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/10997535

Management - Specific Treatments

Fact Explanation
Transsphenoidal surgical resection First line treatment of Cushing’s disease. It is considered curative if the patient develops hypocortisolism in a few days after the surgery. Patients who are rendered hypoadrenal for months to years after the procedure require glucocorticoid replacement therapy. [1]
Glucocorticoid receptor antagonists ,steroidogenesis inhibitors, ACTH-lowering agents. Indications for medical treatment are presence of contraindications or refusal of surgery, lack of adenoma image on pituitary MRI, waiting for radiation techniques to be effective , or as a multimodality approach in the rare cases of pituitary carcinomas. Glucocorticoid receptor antagonists: Mifepristone. It is found to be highly effective in controlling clinical signs of hypercortisolism. Steroidogenesis inhibitors: Op’DDD (mitotane, Lysodren®), Ketoconazole ,Metyrapone (Métopirone®), Etomidate (Hypnomidate®) ACTH-lowering agents: Cabergoline, Pasireotide [2]
Radiation techniques Fractionated radiotherapy and stereotactic radiosurgery are the widely used techniques in the treatment of Cushing's disease. Radiotherapy has been found to induce remission in most of the patients, but also panhypopituitarism in more than 80% of patients. Patients who are not cured may require total bilateral adrenalectomy to control their symptoms. [2]
Bilateral adrenalectomy Indicated in case of failure of pituitary surgery, or when hypercortisolism is severe, requiring a rapidly active treatment. Bilateral adrenalectomy resolves cortisol hypersecretion in majority of patients, with a low risk of perioperative complications. The major and expected side effect is adrenal insufficiency, and another possible adverse effect is Nelson’s syndrome (pituitary tumor progression observed after adrenalectomy). These patients will require glucocorticoid (cortisone) and a mineralocorticoid (fludrocortisone) for the rest of their lives. [2]
References
  1. KIRK LF JR, HASH RB, KATNER HP, JONES T. Cushing's disease: clinical manifestations and diagnostic evaluation. Am Fam Physician [online] 2000 Sep 1, 62(5):1119-27, 1133-4 [viewed 10 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/10997535
  2. CASTINETTI FREDERIC, MORANGE ISABELLE, CONTE-DEVOLX BERNARD, BRUE THIERRY. Cushing’s disease. Array [online] 2012 December [viewed 10 August 2014] Available from: doi:10.1186/1750-1172-7-41