Continuing Education Activity

Hypercortisolism refers to the clinical state resulting from excess tissue exposure to cortisol and/or other glucocorticoids. When such exposure is sustained, it results in the development of Cushing syndrome (CS), which is a distinctive constellation of clinical signs and symptoms resulting from chronic exposure to excess cortisol, either exogenous or endogenous. This activity provides a global summary and review of hypercortisolism, including its epidemiology, causes, clinical presentation, diagnosis, and management options, while highlighting the interprofessional team approach required for the detection, prevention, diagnosis, and management of patients with this clinical condition.

Objectives:

• Identify the etiology of hypercortisolism and Cushing syndrome.
• Describe the clinical presentation of hypercortisolism and Cushing syndrome.
• Review the diagnostic algorithms for hypercortisolism and Cushing syndrome while summarizing the treatment strategies and options.
• Outline the interprofessional team approach integral to the successful management of hypercortisolism and Cushing syndrome, describing the roles of various clinical specialists in the diagnosis and management of Cushing syndrome.

Introduction

Hypercortisolism (HCM) refers to the clinical state resulting from excessive tissue exposure to cortisol and/or other related glucocorticoids. It is often but not always associated with excess serum cortisol (hypercortisolemia) and, when sustained over some time, results in the distinctive syndrome known as Cushing syndrome. Cushing syndrome (CS) is the cluster of clinical signs and symptoms resulting from long-term systemic exposure to excess cortisol and/or other glucocorticoids, from either exogenous or endogenous sources. Exogenous CS is most typically the result of the iatrogenic or surreptitious administration of glucocorticoids. Endogenous CS includes two major sub-types: adrenocorticotropic hormone (ACTH) dependent and ACTH independent.[1] This clinical syndrome continues to be linked with Harvey W. Cushing, MD, whose original description of patients with endogenous HCM due to pituitary adenoma remains a seminal classic. The importance of his contributions to the recognition of this entity shows by the fact that pituitary based ACTH dependent HCM is still referred to worldwide as Cushing disease (CD).

The difficulty inherent in the recognition, diagnosis, and subsequent management of HCM is due to the wide range of clinical presentations that it can have. While classic advanced CS has pathognomonic clinical features which are quite obvious with characteristic laboratory findings, that form of HCM is rather uncommon. Other forms of HCM including subclinical Cushing syndrome (SCS), iatrogenic Cushing syndrome, exogenous Cushing syndrome, factitious, cyclical, intermittent, and pseudo-Cushing syndrome (aka physiologic HCM) as a group are way more common than classic CS and often more challenging to recognize, diagnose and manage.[2]

Etiology

Determining the etiology of hypercortisolism is a three-tiered process. First, the presence of true HCM has to be established and confirmed based on clinical manifestations and laboratory test results while excluding differential diagnostic considerations detailed below. This process includes the distinction between true pathologic HCM and pseudo-Cushing syndrome (PCS), also known as physiologic HCM. The utilization of a screening test can help determine the etiology.

After establishing the definitive diagnosis of true pathologic HCM, the next step in etiologic determination should be whether the HCM is ACTH dependent or independent. This evaluation should also include a careful determination of whether the HCM state could have iatrogenic or factitious etiologies.

After resolving the determination of ACTH dependency or independency, the final step of etiologic determination then involves definitive anatomic and pathologic diagnoses.

Iatrogenic Cushing Syndrome: Conservative estimates indicate that over 10 million persons in the United States receive pharmacologic dose glucocorticoids annually, and while all these do not develop HCM, there also evidence that strongly suggests significant under-reporting of both the prevalence and incidence of iatrogenic Cushing syndrome. While iatrogenic Cushing syndrome is the dominant etiologic factor in exogenous Cushing syndrome, it is also important to consider the possibility of the less common factitious Cushing syndrome in this subgroup of HCM.[3][4][5][6][7]

One large cohort that has evaluated retrospectively identified causes of non-iatrogenic, non-exogenous Cushing syndrome in approximately 630 patients at the Vanderbilt University Medical Center identified the following spread of etiologic entities:

• 68% due to ACTH dependent Cushing disease
• 12% due to ectopic ACTH Cushing syndrome
• 10% due to functional adrenal adenomas
• 8% due to functional adrenal carcinomas
• Less than 1% due to ectopic CRH syndrome
• Less than 1% due to micronodular adrenal hyperplasia
• Less than 1% due to macronodular adrenal hyperplasia and
• Approximately 1.5% due to pseudo-Cushing syndrome states, including major depressive disorder or chronic alcoholism.

Epidemiology

Because of the difficulties in the diagnosis and recognition of HCM, estimates of its exact prevalence and incidence are widely variable. The reported numbers are also dependent on whether the cohorts are population-based, primary care-based, or subspecialty clinic-based, as well as whether the analysis is restricted to adults or include pediatric populations.

It generally accepted that iatrogenic Cushing syndrome (ICS) is by far the most prevalent form of HCM. There is some suggestion with more recent data that SCS may be more commonplace than previously presumed. Estimates from one Danish series suggested that during an 11-yr period, the incidence of Cushing syndrome was 1.2 to 1.7/million person-years (Cushing disease), 0.6/million person-years (adrenal adenoma) and 0.2/million person-years (adrenal carcinoma).[2] More recent estimates from a US-based population suggested a range of 39.5 to 48.6 /million person-years, which is very different from the Danish cohort.[8]

Other cohorts report widely variable incidence rates of Cushing disease (the most prevalent form of endogenous CS) ranging between 1.2 to up to 25 million.[2][8]

There is some suggestion that ectopic Cushing syndrome (EcCS) is more common than reported, but most series suggest a prevalence of approximately 10-15% of all CS patients. Small cell lung cancer is the most common etiologic cause of this form of CS. Only 1% of patients with small-cell lung cancer have EcCS suggesting an incidence of approximately 300 new cases annually in the United States.[9]

Adrenal mass lesions causing ACTH independent CS is assuming greater importance as far as prevalence and incidence. Adrenal incidentalomas have become more prevalent with the more widespread use of powerful imaging modalities like CT and MRI scans for the evaluation of various non-specific abdominal complaints. Depending on whether radiologic or autopsy based data are used, adrenal incidentalomas have a prevalence of approximately 1.3 to 8.7%.

All the other etiologic causes, including macronodular adrenal hyperplasia, micronodular adrenal hyperplasia (including primary pigmented nodular adrenocortical disease; PPNAD), ectopic CRH syndrome are rare, but the clinician needs to be aware of their existence as diagnostic considerations in unusual clinical presentation scenarios.

Overall, CS is more prevalent in women (3 to 8 times more frequent); this applies to both pituitary and adrenal based CS as well as both benign and malignant etiologies. The one subgroup in which men have typically had a greater prevalence is with EcCS, and this appears to be due to the greater incidence of tobacco abuse and consequently increased small cell lung cancer in men compared to women. As smoking among women has risen while declining among men, the prevalence disparity of EcCS among the sexes has also declined compared to findings from a series of over three decades ago.

Cushing disease (CD) most common age bracket of diagnosis is 25 to 45 years while that for EcCS is greater than 50 years. CS is less common in pediatric populations, and CD appears to constitute approximately 30% of CS in pediatric cohorts, which are significantly less than in adult cohorts. Also, small pediatric series suggest that in prepubertal children with CS, boys are more commonly afflicted than girls, while in adolescents, the female preponderance seen in adults is also apparent.

Adrenal neoplastic causes of CS have a bimodal age distribution pattern. There is one peak in the first decade of life and a second more significant peak at approximately age 40 years for adrenal carcinomas and around age 50 years for adrenal adenomas. 

Pathophysiology

Central to the development of HCM is the development of clinical features resulting from excessive tissue exposure to glucocorticoids (particularly cortisol). When these are presumed to be due to exaggeration of physiologic states known to be associated with hypercortisolemia, pseudo-Cushing syndrome, PCS (physiologic HCM) is diagnosed. This distinction from pathologic HCM is important as PCS is generally not sustained, generally resolves with the resolution of the etiologic factor responsible and typically is not associated with the overt cutaneous and/or muscular effects associated with pathologic HCM.[10][11][12]

Among the established etiologies of PCS are pregnancy, morbid obesity, severe psychologic stress, severe major depressive disorder, poorly controlled diabetes mellitus with associated marked hyperglycemia, and chronic alcoholism. Even more confusing is the fact that patients with these clinical states can also have true endogenous pathologic HCM.

Other causes of physiologic hypercortisolism that typically don't present with the clinical phenotype of PCS but can have suggestive biochemical anomalies are significant physical stress including surgical and/or hospitalization related stress, severe malnutrition, anorexia nervosa, wasting-cachexia syndrome, intense chronic exercise (including but not restricted to the hyper exercising female athlete syndrome), hypothalamic amenorrhea, various causes of elevated serum cortisol binding globulin (CBG) and glucocorticoid resistance. 

Derangement of the hypothalamic-pituitary-adrenal (HPA) axis is central to the development of HCM. Such disruption can be due to exogenous or endogenous assaults or in some cases, both.

The HPA axis in the normal physiologic state is primarily for maintenance of baseline continuous cortisol production with provocative secretory responses to various stressful stimuli. CRH is the highest hierarchical control hormone in this axis and is produced from the hypothalamus tonically. It acts on the adenohypophysis (anterior pituitary) upon the basophilic corticotrophs to produce ACTH (aka corticotrophin), and this then gets secreted from the pituitary into the general circulation from which it then acts on the adrenal cortex to produce cortisol as the dominant endogenous glucocorticoid.

Circadian and stress-related inputs modulate CRH production from the parvicellular neurons of the paraventricular hypothalamic nucleus. Of note is the fact that many of the same neurons concomitantly produce arginine vasopressin, which has a similar though the less dominant modulatory effect on ACTH production from the adenohypophysis.[12]

ACTH production occurs via post-translational modification of the precursor molecule pro-opiomelanocortin (POMC). ACTH stimulates the production of cortisol from the adrenal cortex in the free form, most of which is then bound by carrier proteins of which CBG is the dominant (roughly 95% of the total in physiologic settings) one. It is a high specificity low capacity binding protein produced mainly from the liver. There is some cortisol binding also to albumin but significantly fewer degrees. At target tissues and organs, cortisol then dissociates from its carrier protein and has its dominant effects mediated by binding to the glucocorticoid (and to a less degree the mineralocorticoid) receptor which then gets transported to the nuclear ribosomal complex of target cells to alter DNA transcription and protein production to mediate its effects. There is also evidence that cortisol has some non-genomic mediated effects. The details and mechanisms by which these get mediated are still the subjects of ongoing study.

Cortisol in both physiologic and pathologic settings has a negative feedback effect on further cortisol, production by inhibiting both pituitary ACTH production and hypothalamic CRH production in addition to other CNS modulatory effects.

The adrenal cortex from which cortisol is produced consists of three distinct anatomic and functional layers: the zona glomerulosa, which predominantly produces aldosterone, the zona fasciculata, which dominantly produces cortisol and the zona reticularis which dominantly produces adrenal androgens. ACTH mediates its stimulatory effects on cortisol production by activating the melanocortin-2 receptor (MC2R) of the zona reticularis cells. It is a typical G protein-coupled receptor with cAMP being the dominant mediatory secondary intracellular messenger.

This intricately orchestrated system has baseline tonic unstressed production that has a well defined circadian rhythm (typical peaks usually soon after early morning waking typically between 6 and 8 AM) with a nadir close to midnight. Superimposed on this circadian baseline rhythm is a pulsatile ultradian rhythm, as well. Various endogenous and exogenous stimuli can perturb this system resulting in either in excess or deficient cortisol production. It is excess of cortisol production and effects at the tissue and organ level of the patient that results in the clinical syndrome of HCM whether or endogenous or exogenous etiology.

Histopathology

The histologic findings in HCM are variable. Some of the tissue findings are of primary etiologic nature, while many others are the result of the complications and comorbidities associated with HCM as detailed below.

As regards the primary disease histopathologic changes, these depend on the underlying etiology. For CNS primary ACTH dependent HCM, the most common histologic finding is of pituitary microadenomas with basophilic staining properties on routine H&E staining as first famously detailed by Harvey Cushing.[13] These benign tumors often demonstrate ACTH and other neuropeptide production on histochemistry. Pituitary carcinomas presenting with HCM are much less common. Other neuroendocrine tumors (often benign but sometimes malignant) by resulting in ectopic CRH production can also lead to presentation with secondary adenohypophyseal hyperplasia and diffuse pituitary enlargement rather than adenomatous lesions in rare cases of HCM. Among the lesions described that result in this are carcinoids, medullary thyroid carcinoma, some ovarian functional tumors, some cases of pheochromocytomas, and some hypothalamic neuroendocrine tumors. Pituitary hyperplasia with global adenophypophyseal enlargement is also present in patients who are status post bilateral adrenalectomy for the treatment of the most resistant cases of HCM as well as in patients with Nelson's syndrome.[14][15][16]

ACTH dependent Cushing syndrome, whether of pituitary, hypothalamic, or ectopic origin, often results in secondary adrenocortical hyperplasia, which is generally diffuse but can be nodular in gross and histologic appearance though this seldom leads to adrenal resection for surgical pathologic analysis. Most surgical adrenal samples obtained for analysis in patients with HCM are typically in the setting of ACTH independent adrenal HCM. The histopathologic findings can range from diffuse adrenal hyperplasia to micro or macronodular adrenal hyperplasia, lone adrenal incidentaloma lesions (often benign adrenal adenomas) to adrenocortical carcinomas.[17][13] The distinction between micro and macronodular adrenal disease has its basis on the macroscopic size of the nodules; nodules greater than 1 cm are macronodules, and those under 1 cm are micronodules. The coexistence of macro and micronodules within the same specimen is common. Awareness of the distinctive micronodular hyperplasia of primary pigmented nodular adrenocortical hyperplasia (PPNAD) and its association with a paradoxical cortisol response on the 6 to 8 day Liddle's test as well with Carney complex is important. Recognition of the unique form of bilateral macronodular adrenocortical hyperplasia (BMAH) associated with the McCune-Albright syndrome is also important.[18][19][20]

History and Physical

While the clinical presentation of classic CS is quite distinctive, the vast majority of HCM patients do not present this way, making a high index of clinical suspicion central to the detection of HCM.  The possible signs and symptoms of HCM are numerous and individually are not pathognomonic. Many of these findings are non-specific, making HCM both over-diagnosed and underdiagnosed depending on the unique clinical scenarios involved. The history and physical examination findings though very important, are often not sufficient to diagnose HCM and generally have to be coupled with appropriate diagnostic laboratory findings. As the clinical presentation of HCM can be non-specific, a missed diagnosis can have catastrophic consequences. To increase diagnostic sensitivity, the suggestion is to consider screening both with careful problem-focused clinical questioning and examination for distinctive examination findings in certain groups of patients determined to be at higher than the typical risk for possible HCM. Among these are young adults with osteoporosis, early-onset hypertension and/or hyperglycemia/diabetes, facial plethora, proximal myopathy, presence of distinctive pigmented palpable wide (greater than 1 cm) striae, easy cutaneous bruising especially in young patients, and patients with adrenal incidentalomas.[13][21]

Since exogenous CS is the most common cause of H, the history must include careful questioning regarding exogenous glucocorticoid exposure, which may be from prescriptions including topical and inhalational glucocorticoids (iatrogenic CS)as well as the possibilities of recreational and factitious abuse.[22][23] A careful medication reconciliation history is a critical part of the historical evaluation of potential HCM patients, as is the attention to the prior history of psychopathology and occupational history that may identify patients with potential occupational access to glucocorticoids, which may be misusing them.

The most common clinical symptom is progressive weight gain, which is typically but not invariably centrally dominant. The weight gain in patients with HCM can, however also be generalized and akin to nonsyndromic obesity.[24] Symptoms related to blood pressure elevation like headaches, dizziness, and visual blurring can occur as can symptoms due to worsening hyperglycemia like polyuria, polydipsia, and either polyphagia or anorexia. Reproductive system-related derangements often manifest symptomatically with women presenting with various menstrual irregularities, including but not restricted to oligomenorrhea, amenorrhea, and subfertility or infertility. Pregnancy in the setting of HCM is thus uncommon and unusual. Among men, reduced libido and symptoms consequent upon secondary hypogonadism such as lower energy levels, fatigue, non-specific weakness, and erectile dysfunction can occur. An easy propensity to bruising is an important symptom to inquire about as it is more distinctive for the syndrome. Muscle weakness, especially in the proximal extremity muscle groups, is also a more specific symptom for HCM and can manifest as difficulty with climbing stairs, difficulty rising unaided from low set chairs, and inability to do standard squats. Among children and adolescents, the coexistence of reduced or arrested linear growth along with significant excess weight gain is typical and suggestive of HCM. The discordance between progressive weight gain that crosses centile lines on the child's weight growth chart as compared to declining or arrested linear growth on the corresponding height charts should raise the suspicion for HCM and spur appropriate diagnostic testing. Sleep deprivation is common, as are vivid dreams and nightmares. Mood decline and frank depression are also more common in patients with HCM. Some other patients present with progressive episodes of wide mood swings ranging from wild elation to sudden dysthymia akin to manic-depressive states. Some patients can also present with severe psychotic episodes in the absence of prior background history of established psychiatric pathology. Among women, hirsutism and marked acne are relatively common findings. Frank virilization should raise the suspicion for a malignant neoplastic disease like adrenal carcinoma as the underlying etiology.  Clinical presentation on account of osteoporosis associated with HCM is more common in older patients and those with chronic, long-standing illness. Such patients may present with chronic back pain, loss of height due to vertebral collapse, low impact fragility fractures, and/or local bone pain.

Among the typical physical examination, findings are facial rounding ("moon facies"), facial flushing including marked malar telangiectasia, enlarged dorsocervical pad (buffalo hump), and supraclavicular fat pads. The supraclavicular fat pads are more specific for HCM than the dorsocervical fat pads. The finding of blood pressure elevation on examination is common. Cutaneous atrophy is a typical clinical finding, and in women, scalp hair loss can occur.

Diffuse cutaneous hyperpigmentation in the setting of HCM should suggest the possibility of EcCS.

It is also not uncommon for patients with HCM to present with clinical features of the comorbidities and complications associated with HCM. HCM is a poly systemic clinical state and thus can impact virtually every organ system of the body. Clinical presentations could, therefore, be consequent upon reproductive, dermatologic, orthopedic, metabolic, cardiovascular, neuropsychiatric, infectious, and bariatric comorbidities.

Further modulating the clinical presentation of the individual with HCM are the duration and degree of severity of the HCM. HCM is associated, therefore, with considerable morbidity and mortality risk, which is why its early recognition and appropriate management is so important. HCM is associated with high to very high excess cardiovascular risk consequent upon its association with hypertension, which can be severe and resistant at presentation, dysglycemia, or frank diabetes mellitus, which is a well established cardiovascular risk equivalent and increased coagulopathic risk including increased risk for thromboembolic events.[25] 

Furthermore, HCM can also be associated with increased risk for heart failure and/or the development of a dilated cardiomyopathy.

Evaluation

Because the clinical presentation of HCM is often non-specific and failure or delay in diagnosis have had significant consequences in terms of considerable morbidity and possible mortality the diagnostic workup for possible HCM is predicated on an initial screening protocol designed to have as high sensitivity as possible to optimize disease detection even if at the expense of some false positive detection.

The first step of diagnostic evaluation involves wide-ranging screening, followed by diagnostic confirmation and then finally anatomic localization of the underlying etiology of the HCM.

It is generally accepted that the diagnosis of HCM is confirmed when at least two different first-tier screening tests are unequivocally abnormally elevated.[26]

The determination of intensity and degree of screening testing is on a case by case basis based on the degree of clinical suspicion (pretest probability) of the diagnosis of HCM. The first-level screening tests include salivary cortisol tests, which should be obtained as duplicates to evaluate the early morning and late-night levels to evaluate both absolute cortisol levels and the preservation of the normal diurnal rhythm, 24-hour urinary free cortisol estimation, and the 1mg dexamethasone suppression test. The generally accepted threshold for diagnostic fidelity of the overnight 1mg dexamethasone suppression test is serum cortisol the morning after over 1.8 mcg/dl (50 nmol/l) after confirmation that the patient actually took the dexamethasone tablet and adequately absorbed it (this can only be objectively confirmed by concurrently measure serum dexamethasone levels the morning after). Some centers use other tests for screening, such as the extended low dose dexamethasone suppression test (involves administering 2mg of dexamethasone daily for two days).[21] These screening tests may need to be repeated multiple times in patients with a high index of clinical suspicion but initially negative findings. Patients with variable discordant results or patients with suspicion of intermittent or cyclical HCM may also require retesting.

In subjects with abnormal screening tests, confirmatory tests need to be done, and included here is the need to distinguish patients with PCS/physiologic HCM. Most experts in the field agree regarding the existence of SCS, which is often clinically distinct and not as clinically striking as typical classical CS. This form of HCM is most commonly associated with adrenal etiologies rather than pituitary or EcCS though there have been cases of the latter described presenting as SCS. The controversy as regards SCS largely revolves around the exact diagnostic criteria and thresholds for the diagnosis. There are at least five clinical practice guidelines in this area.[27][28][21][29][30] Overall the consensus appears to be that the Endocrine Society and the Italian Association of Medical Endocrinologists guidelines are well accepted. It is also crucial to understand that when there is discordance between screening tests obtained, especially on repeated measures, the possibility of cyclical, intermittent, iatrogenic, and even factitious CS merits consideration and excluded. It is also important to understand and exclude the list of other potential variables that can affect the accuracy of these screening tests, including concomitant medication use, variations, and perturbations of dexamethasone metabolism, night shift work, states of cortisol binding globulin excess or deficiency, coexistence sleep disorders, etc.[31]

The combined dexamethasone CRH test is generally the best dynamic test for the distinction between pathologic HCM and physiologic HCM. Its basis is the premise that patients with the latter tend to have a blunted cortisol response (and less consistently) ACTH response to CRH after dexamethasone suppression (using the standard two-day low dose dexamethasone administration protocol) compared to patients with pathological HCM. This testing is still an area of controversy, and there are lingering concerns regarding the sensitivity and specificity of the test in distinguishing pseudo-CS from true pathologic CS. 

Based on clinical presentation and the results of multiple screening test results, after deciding that the patient has HCM the next diagnostic branch point is whether the HCM is ACTH dependent or independent. As ACTH secretion is pulsatile in fashion and has a well-established diurnal rhythm, this measurement needs to be done on multiple occasions over a period of time to reach a consensus. Persistently low serum ACTH levels less than 5 pg/ml are very strongly predictive of ACTH independent HCM, which should include exogenous HCM in the considered etiologic differential diagnosis. Similarly, serum ACTH level consistently greater than 20 pg/ml is typically highly suggestive of ACTH dependent  HCM, which then brings up the clinical decision branch point of distinguishing between pituitary based HCM (which is typically the cause in 70 to 85% of such cases) versus EcCS. This distinction is, however, not always easy and may involve the use of other diagnostic testing strategies detailed below.

For patients with persistent serum ACTH levels between 5 to 20 pg/ml, further dynamic testing is necessary to provide clarity. These could include the CRH stimulation test, the vasopressin (or desmopressin, DDAVP) stimulation test, and/or the metyrapone stimulation test. All these tests tend to cause post provocative increase in ACTH secretion in patients with pituitary based HCM but not in adrenal HCM nor most EcCS patients. The exact diagnostic thresholds, sensitivity, and specificity of these tests are, however, contentious, thus limiting their utility in making firm diagnostic distinctions.

Measurement of serum DHEA-S has some diagnostic utility on repeated measures as it tends to be reduced in ACTH independent HCM but increased or normal in ACTH dependent HCM.[32]

After firmly establishing that a patient has ACTH dependent HCM, the distinction between pituitary and EcCS is the next step in the diagnosis. It is critical to be clear that imaging tests, whether they be adrenal, pituitary, general abdominal, general brain, or another related imaging testing, should only be obtained after a definitive biochemical diagnosis of HCM is made. Incidentalomas are common enough that prior imaging before making clear biochemical diagnoses can lead to unnecessary testing and possibly incorrect diagnoses with a potentially wrong treatment plan, including unnecessary surgery. Furthermore, the fact that most pituitary based HCM is the result of microadenomas makes the absence of an identified lesion on pituitary MRI a fairly common clinical scenario. Some reports have indicated up to 40 to 50% of patients with documented biochemical pituitary based ACTH dependent HCM having reportedly normal pituitary MRI studies.[33][31]. The distinction between EcCS and pituitary based HCM is generally better made using dynamic testing, which includes the CRH stimulation test, the vasopressin (or desmopressin, DDAVP) stimulation test and/or less commonly the metyrapone stimulation test. All these tests utilize the fact that pituitary based HCM tends to preserve the capacity to respond to such secretagogues with a significant increase in ACTH (and less robustly) cortisol levels. Also, high dose dexamethasone tests are an option to provide a distinction between these entities further; this can either use the classic four days extended 8 mg test first described by Liddle and colleagues or the more commonly used overnight 8 mg single dose suppression test. These tests take advantage of the fact that most pituitary based HCM suppress their associated cortisol production to below 5 mcg/dl (140 nmol/L) in the setting of high dexamethasone exposure unlike most patients with EcCS.

The specificity and sensitivity of all these tests are not robust enough nor universal enough to avoid scenarios in which doubt as to the location of the source of ACTH excess persists, and in such settings, direct measurement of central and peripheral ACTH production may be necessary. The best-validated strategy for this is the inferior petrosal sinus sampling (IPSS). The diagnostic utility of the test is heavily dependent on performing the test in the setting of ambient continuous CRH stimulation and requires the availability of high-end imaging for fluoroscopy as well as the availability of highly skilled neuroradiologists. Attempts to obtain similar data using less invasive bilateral internal jugular venous sampling have generally not yielded robust results. Studies of the even more technically difficult cavernous sinus sampling as a method to correctly lateralize the location of tiny pituitary microadenomas causing HCM have shown that they add little if any utility to the established IPSS and are not currently common practice.[34][35][36]

Once the biochemical diagnosis and the anatomic location are determined based on the biochemical and dynamic testing, imaging tests then take center stage. For pituitary and other brain-related causes of HCM pituitary MRI imaging is the preferred imaging modality for lesion localization. Dynamic contrast-enhanced high-resolution pituitary MRI scans may increase detection, but even the best MRI imaging systems presently available are incapable of detecting all functional pituitary microadenomas causing HCM while their high degree of sensitivity has resulted in detection of non-functional pituitary microadenomas in 10 to 20% of healthy volunteers routinely imaged.[37] In patients with unique limitations, an open MRI or cranial CT with pituitary tomographic imaging may be necessary, but these imaging modalities have significantly lower sensitivity in the detection of tiny pituitary or other brain lesions that may be etiologic in pituitary HCM hence the primacy of establishing a biochemical diagnosis before imaging studies. In patients in whom the imaging tests are negative despite the positive biochemical diagnosis of pituitary based HCM because of the considerable morbidity and potential mortality associated with this condition, neurosurgical intervention with pituitary exploration and in some cases, hemi-hypophysectomy is necessary. It is important to note that pituitary imaging has been reported to wrongly suggest a pituitary lesion in approximately 18% of patients who eventually were shown to have EcCS and so caution in treatment decision making is very important.

For patients whose biochemical and dynamic testing is suggestive of EcCs, the process of anatomical localization of the responsible lesion can be particularly challenging. The optimal strategy for imaging such patients is not clearly defined, and the decision is often on a case by case basis based on a careful review of the individual’s clinical presentation. Targeted imaging using CT scans, MRI, PET imaging, and specialized nuclear medicine imaging, including Octreotide scintigraphy and Gallium-68 DOTATATE imaging, is complementary. As most EcCS lesions are found in the chest, chest based imaging may be the best place to begin in the absence of clinical clues from the history and physical examination. Most malignant etiologic lesions are relatively easy to find by these imaging modalities, but benign carcinoids are notoriously difficult to locate and may require multiple repeated imaging obtained over significant periods of time before finally being discovered.

For patients with ACTH, independent HCM imaging is generally focused on the adrenals though they have been a few rare cases described of other organ-related tumors (mainly ovarian) associated with ACTH independent cortisol overproduction associated with HCM. The best imaging study for visualizing the adrenals remains the adrenal dedicated thin slice/section CT scan with and without contrast. Such studies should include clear documentation of the tissue density (Hounsfield units -HU) or CT attenuation value both pre and post-contrast as well as details of the contrast washout properties of identified adrenal lesions. Subsequent decisions regarding diagnosis and management strategies in these patients would depend on whether bilateral or unilateral nodularity is detected, the size of the nodule(s): micronodules vs. macronodules, and the age of the patient. The absence of any obvious nodules in patients with biochemical evidence of ACTH independent HCM may require bilateral adrenal venous sampling as may the presence of multiple nodules in both adrenals or even the presence of a single nodule in older patients (over 65 years old) where the possibility of such a nodule being a non-functional adenoma rather than the cause of the HCM can be as great as 25%. Adrenal venous sampling like IPSS requires the availability of high-end fluoroscopy imaging equipment, high fidelity intravenous catheters as well as highly skilled interventional radiologists and so is not widely available. It also requires careful sample collection and labeling and continuous cosyntropin (ACTH) infusion during the sampling. HU scores of greater than 20 raise the possibility of cancerous etiology of identified adrenal lesions as does suboptimal contrast washout (less than 50% over the timed period of observation). In such settings, adrenal MRI imaging may provide additional diagnostic information. Functional imaging of adrenocortical lesions using the iodo-cholesterol scan (NP-59 I-131 Iodo-cholesterol) is hardly ever done anymore as the test is difficult to execute and has demonstrated rather limited diagnostic sensitivity or specificity. In clinical scenarios where the possibility of the adrenal lesion seen could potentially be of adreno-medullary origin (a few cases of adrenal pheochromocytomas associated with ACTH independent HCM have been reported), obtaining an I-123 MIBG scinti-scan may offer additional diagnostic information. Abdominal sonography has little utility in the evaluation of adrenal lesions involved in ACTH independent HCM but may have utility in the assessment of the rare clinical scenario of ectopic cortisol producing tumors, which are usually of abdominopelvic origin.

Treatment / Management

The management of HCM includes strategies directed at blocking the metabolic and clinical effects of HCM strategies directed at the specific causes of the HCM state (which include medical and surgical interventions) as well as strategies directed at the management and modulation of the complications and co-morbidities associated with HCM.

In the setting where HCM is due to exogenous glucocorticoid use, the central management strategy is a carefully monitored reduction in glucocorticoid use with the ultimate aim of total withdrawal of their use. Depending on the initial indication/reason for their use, the duration, and dose of the glucocorticoids and evidence of secondary cortical atrophy, this may or may not be possible. Exogenous HCM can present the managing clinician with the conundrum of a patient with evidence of HCM who concomitantly has secondary adrenal insufficiency from cortical atrophy, which can become clinically apparent following the withdrawal of glucocorticoid therapy is entirely withdrawn. Serial monitoring of serum DHEA-S and ACTH levels, as well as serial ACTH (cosyntropin) stimulation tests, may be required in these sorts of patients over time while reducing the glucocorticoid dose to the closet dose to physiologic replacement doses required to prevent symptoms and signs of adrenal insufficiency. For some such patients, the secondary adrenocortical atrophy may be permanent, and such patients may require long term/life term physiologic adrenocortical replacement therapy with hydrocortisone (or other equivalent glucocorticoids) with adjunctive mineralocorticoid repletion (typically with fludrocortisone). For other patients, the medical indication for their glucocorticoid use such as rheumatologic or pulmonary inflammatory states may prevent weaning off these medications, and the strategy in those cases becomes weaning to the lowest required dose of glucocorticoids to maintain therapeutic effect with concurrent management of any consequent associated metabolic and clinical effects of the long term persistent HCM.

The general principles of proper management of HCM are to reverse the clinical and metabolic consequences of HCM by bringing endogenous cortisol production back to normal, removing any neoplastic source of the cortisol excess state, avoiding permanent dependence on medications and avoiding long term secondary hormone deficiency. These goals are not always all attainable in individual patients for various unique patient-specific reasons.[38]

In patients where there are delays in making a definitive diagnosis of the underlying etiology of HCM modulation of the HCM, and its complications (such as management of hyperglycemia, diabetes, hypertension, osteoporosis, hypercoagulopathy, etc.) may have to take center stage until achieving definitive diagnosis to enable more permanent and curative treatment. This approach is central to the prevention and reduction of the comorbidities and complications associated with HCM.[38][39][40][41][42]

Medical therapy strategies: While surgical treatment strategies offer the best potential for permanent metabolic resolution and cure many times, this is either delayed or unsuccessful in achieving cure. Among the interventional strategies to include here are the glucocorticoid (and progesterone) receptor antagonist mifepristone (RU-486) and adrenal synthetic enzymes inhibitors like ketoconazole, metyrapone, and mitotane, which is generally restricted for use in adrenocortical carcinoma because of its significant toxicity profile.[43][44][45] Medical therapy for pituitary adenomas causing HCM or neuroendocrine tumors causing EcCS have been described and include cabergoline, pasireotide (Signifor), and other somatostatin analogs including octreotide though the therapeutic effects can be variable.[45][46][38][47][48]. In patients for whom oral therapies are impossible or contraindicated, parenteral use of imidazole anesthetic agent Etomidate has some utility in managing HCM. It blocks 11 beta hydroxylation of deoxycortisol to cortisol.[49]

Further studies are ongoing for the potential utility of other medications in the management of resistant HCM, including fluconazole, levoketoconazole, osilodrostat, and the novel glucocorticoid receptor modulators; CORT-108297 and CORT-125134.[50][51][52][53][54]

For pituitary adenomas causing HCM (Cushing disease), the vast majority (approximately 60 to 70%) are local microadenomas, but close to 30% may be locally invasive, and 0.2 to 0.2% are due to carcinomas that may be associated with CNS and/or systemic metastases. In such patients, surgical treatment is rarely curative, and the prognosis is often poor with the need for consideration of systemic adjunctive chemotherapy.[55] For Cushing disease, the best potential for cure remains early surgical intervention, usually by trans-sphenoidal surgery. Thus identification of a skilled pituitary neurosurgeon in a clinical facility with appropriate support staff and clinical resources is critical in achieving this goal. Referral to well-established pituitary surgical centers that meet this high standard is a worthwhile consideration. There is also a place for pituitary irradiation therapy in scenarios where, despite well documented and proven biochemical HCM, radiologic imaging, and possibly even neurosurgical exploration reveals no apparent tumor. It can also serve as adjunctive therapy following debulking non-curative pituitary surgery. This therapy is deliverable by standard conventional brachytherapy or more precisely by stereotactic radiotherapy, radiosurgery, or "gamma knife" therapy, which requires high-level technical expertise and nuclear medicine imaging resources.

In some scenarios where all other efforts ate achieving control of the HCM fails, bilateral adrenalectomy with subsequent lifelong glucocorticoid and mineralocorticoid repletion therapy may be the last management option to offer. Subsequent follow up of such patients to avoid the development of Nelson syndrome is important.

The management of patients with EcCS depends on the localization of the etiologic lesion(s). Surgical resection again offers the best option for optimal therapy and potential cure. Concomitant medical therapy, as detailed above to control the HCM, is often required until the etiologic lesion is identified and may be required thereafter if curative surgical resection is not feasible.

For patients with adrenal based HCM due to identified unilateral adrenal adenomas, unilateral adrenalectomy is the best strategy for a cure, and the laparoscopic approach is the preferred management method as long as the adenoma is less than 6 cm in diameter. The role and place of adrenocortical sparing surgery in this setting is still in evolution and is not the standard of care at this time.

While HCM is typically associated with subfertility/infertility, the uncommon scenario of HCM in pregnancy occasionally arises. Medical therapy in such settings is often not feasible because of the potential teratogenic effects of most of the available medical treatment options. Metyrapone is the best medical adjunctive treatment option in this setting, but ideally, surgical intervention generally best timed for the second trimester of pregnancy is the preferred therapeutic intervention strategy.

Differential Diagnosis

Among the differential diagnoses to be considered in patients for whom HCM is the presumed underlying diagnosis are all the entities previously discussed as possible causes of the pseudo-Cushing syndrome (physiologic HCM) including but not restricted to: Pregnancy, morbid obesity, melancholic depression, chronic alcoholism, poorly controlled diabetes, various eating disorders including Bulimia nervosa and the night eating disorder, chronic lymphedema, lipoedema, partial lipodystrophy syndromes (both congenital and acquired), Dercum disease and syndromes of hypothalamic obesity including Prada Willi syndrome, Frolich's syndrome and the Bardet Biedl syndrome. Other rare considerations, especially in children, would include POMC and leptin-deficient associated obesity syndromes as well as cerebral gigantism - Soto syndrome.

Other diagnostic considerations would be entities associated with Anasarca, including generalized protein-energy malnutrition (including Kwashiokor in children), congestive heart failure, cirrhosis of the liver with ascites, and nephrotic syndrome.

Biochemical evidence suggestive of possible HCM without concordant physical findings may occur in settings of exogenous HCM, factitious CS (including abuse of various glucocorticoids, anabolic steroids and peptides like ACTHAR, DDAVP, and corticorelin among patients with severe Munchausen syndrome presentations), severe physical stress, severe malnutrition, anorexia nervosa, hyper-exercise syndrome including the female athlete triad of eating disorders, amenorrhea and osteoporosis, hypothalamic amenorrhea and glucocorticoid resistance states. 

There are also reports of rare disorders that can present similarly to HCM, including ectopic non-adrenal cortisol secretion, normal Cushing syndrome, and biochemical HCM in the absence of cushingoid features.[56][57][58] 

Prognosis

Hypercortisolism, when untreated, correlates with marked morbidity and is often fatal. The most common cause of death is cardiovascular events, including acute coronary syndromes, thromboembolic events, and hypertensive complications, including cerebrovascular disease. Less common but also crucial as causative factors in the mortality of these patients are opportunistic bacterial and fungal infections. Older series have indicated a mortality risk as high as 50% within five years after the development of symptoms in the absence of effective treatment. Most cases of pituitary HCM are curable, and HCM should be manageable even if it requires the most drastic strategies of bilateral adrenalectomy of mitotane therapy to achieve that goal. The underlying etiology of the HCM plays a considerable role in the ultimate prognosis with malignant lesions such as small cell lung carcinoma and adreno-cortical carcinoma having the poorest prognosis while patients with benign adrenal adenomas or benign carcinoids with EcCS have the best prognosis.

The clinical symptoms and signs of HCM take time to resolve even with curative therapy and full hormonal and metabolic correction. Resolution typically takes 2 to 12 months, and certain features like associated weight gain, hypertension, and glucose intolerance may never resolve. The loss of bone mass and/or frank osteoporosis typically begins to improve approximately six months after the HCM gets cured. In such patients, the use of calcium and vitamin supplementation, bisphosphonate therapy, and gonadal steroid repletion therapy can accelerate the recovery process. The health-related quality of life (HRQL) decline associated with HCM typically only partially resolves upon cure.[59] In addition, psychiatric symptoms similarly improve with the cure, but some residual psychopathology typically remains.[60][61]

Children with HCM often have a residual decline in intelligence quotient and cognitive functional indices even after cure, and this occurs and persists in the absence of any psychopathology and even with reversal of prior noted cerebral atrophy.[62] Children tend to demonstrate an improvement in bone density and growth velocity following HCM treatment, but again, some persistent residual deficit is evident.

Complications

Hypercortisolism is a clinical syndrome that afflicts virtually every organ system either directly or indirectly.[40][42][41] The following is a list of the associated comorbidities and complications of HCM:

• Decreased bone mass, osteopenia, osteoporosis, or osteonecrosis are particularly associated with exogenous rather than endogenous HCM, with the hips being the most commonly afflicted bones.
• Cardiovascular disease, including hypertension, accelerated atherosclerotic vascular disease (including coronary artery disease and various acute coronary artery syndromes, cerebrovascular disease, and peripheral vascular disease), dilated cardiomyopathy.
• Dyslipidemia including hypertriglyceridemia and hypercholesterolemia
• Development of the dysmetabolic syndrome
• Impaired glucose tolerance or frank diabetes mellitus with all the attendant complications and comorbidities that can accompany that.
• Obesity which is classically described as truncal dominant with relative extremity atrophy (so-called "apple on sticks" phenotype) but can be associated with generalized adiposity
• Linear growth impairment in children
• Proximal myopathy
• Hypogonadism and subfertility or infertility
• Increased predisposition to cutaneous and systemic infections, usually bacterial and fungal.
• Dyspepsia and gastro-esophageal reflux disease
• Nephrolithiasis
• Myriad cutaneous manifestations including cutaneous atrophy, ecchymoses, striae, recurrent cutaneous infections, hyperpigmentation in patients with pituitary CS, EcCS, and ectopic CRH syndrome states, alopecia, hirsutism, hypertrichosis, poor wound healing, acanthosis nigricans, excessive acne, etc.
• Ophthalmic complications of which cataracts and open-angle glaucoma are the most prevalent. Exophthalmos has also been described, especially with exogenous glucocorticoid exposure.
• Myriad neuropsychiatric syndromes including but not restricted to so-called "steroid psychosis," depression, bipolar state, dysthymia, chronic anxiety, etc.
• Cognitive decline, including progressive memory loss and a dementia-like illness in the most severe cases with associated brain cortical atrophy
• A decline in overall quality of life
• Increased coagulopathic risk, including increased risk for deep venous thrombosis and embolism
• Increased risk for secondary or primary adrenal insufficiency and glucocorticoid withdrawal syndrome following the successful treatment of HCM
• Increased risk for development of Nelson syndrome post bilateral adrenalectomy
• Sleep derangements, including sleep deprivation, chronic insomnia, obstructive sleep apnea, and obesity hypoventilation syndrome.

Economic toll: In this age of increasing attention and concern regarding the cost-effectiveness of medical care, this is not a minor issue with some estimates suggesting that HCM is associated with at least a 4x greater total health management costs than age and gender-matched controls. Other more recent estimates suggest that the total cost of care for Cushing disease in the United States amounts to approximately $35000/year just on its own.[63][64]

In the unique and uncommon scenario of HCM in pregnancy, impaired glucose tolerance or gestational diabetes, hypertensive disorders of pregnancy, preeclampsia, heart failure, psychiatric disorders, and increased fetal loss are the most common consequent complications. While the fetus in such pregnancies tend to be somewhat protected from the maternal HCM because of the effects of placental 11 beta-hydroxysteroid dehydrogenase which converts approximately 85% of the maternal cortisol reaching the placenta to relatively inert cortisone this protective system can be overwhelmed with increased fetal loss, intrauterine growth retardation, premature delivery, and neonatal adrenal insufficiency described.[65][66]

Consultations

Hypercortisolism manifests as a multi-organ problem, often with multiple complications and comorbidities. Therefore, primary care providers caring for this patient population are often best served by seeking assistance from numerous other specialists in the diagnosis, clinical care, and subsequent follow up of these patients. The individual consultations required will vary from patient to patient based on the particular circumstances, but almost invariably the following consultations will be necessary: endocrinology, cardiology (for risk stratification in preparation for surgical interventions), clinical psychology and psychiatry, general surgery and/or neurosurgery as well as general medicine hospitalist service. It may also be necessary to consult with reproductive medicine, OBGYN, dermatology, hematology-oncology, sleep medicine, and infectious disease consultants, among others. In patients with exogenous HCM, close coordination of care between the PCP and the specialist(s) prescribed the etiologic glucocorticoids or other related medications is critical in planned dose tapers in preventing relapse of treated disease states and in the prevention of Addisonian crises from excessive glucocorticoid withdrawal. 

Deterrence and Patient Education

Exogenous HCM remains the most common form of HCM statistically, and patients using glucocorticoids must receive thorough education regarding the pros and cons of using hormonal products. The potential side effects have to communicate to the patient clearly, and the fact that long term glucocorticoid use can be dependence forming and often associated with euphoria, and a sense of well-being increases the potential for abuse and potential factitious overuse for which primary care providers need to be alert. Additionally, the primary care provider or the endocrinologist involved in the care of patients receiving these agents needs to be the central coordinator with all the other specialists that prescribe these hormonal products for therapeutic reasons to explore the possibility of steroid-sparing therapeutic alternatives, to ensure the use of the minimum dose of these hormones for the shortest possible duration of time and that responsible closely monitored efforts take place to wean patients off these products. For patients in whom discontinuing, exogenous glucocorticoids are deemed medically impossible; the same caregivers have to be central in partnership with the patient and the other specialists involved in the care of these patients to continue ongoing surveillance for potential side effects of long-term glucocorticoid use. For patients with endogenous HCM, the clinician needs to share the underlying cause, full treatment options, and prognosis of the condition with the patient. The potential of a full swing from cortisol excess to adrenocortical deficiency following effective treatment full detailing to the patient and precautionary measures are necessary to keep the patient safe.

Pearls and Other Issues

HCM is a complex clinical syndrome of multiple different potential etiologies that has considerable potential for morbidity and mortality.

Early recognition of HCM is important to limit morbidity and complications

Exogenous causes of HCM require careful exclusion before embarking on investigation for endogenous etiologies.

The diagnosis of endogenous HCM involves a three-tiered approach that includes comprehensive screening, diagnosis confirmation, and anatomic localization of the causative lesion(s).

While surgical intervention generally offers the best potential for the cure of HCM, several medical adjunctive treatment options can enable management of the metabolic state of HCM even if surgery is not feasible or curative.

Enhancing Healthcare Team Outcomes

Hypercortisolism is a complex diagnosis, with nuanced treatment, and requires long term follow up. Therefore, given these characteristics, HCM invariably requires an interprofessional approach. Beyond the role of the patient’s PCP and the team of specialists, other members of the health care team including the nursing staff, clinical pharmacists, social workers, mental health specialists, and financial assistance professionals are often required and integral to the long term effective care and well-being of these patients.

The PCP is often the gatekeeper of this canopy of care, and when the likelihood of HCM is first recognized, the endocrinologist is generally the first specialty consultant sought. In the process of establishing the formal diagnosis depending on the unique clinical circumstances of the patient other specialists, including the radiologists, nuclear medicine physicians, general and neurosurgeons, often then join the treatment team. Depending on the comorbidities the patient has or develops in the course of the work up other specialists may be required to consult as well. The care of these patients often requires periodic interprofessional case discussion sessions where the various specialists and caregivers can discuss the various aspects and nuances of the ongoing investigative and treatment plan. This communication is particularly useful if contemplating surgical interventions and/or radiation therapy.

Medical management will require the services of a board-certified pharmacotherapy specialist (BCPS) who can review in detail the agents chosen, optimal dosing, verify that there are no significant drug-drug interactions, and help guide the medication approach to such complex cases in tandem with the clinician team. Nursing staff needs to be included in these consultations since they will be administering these drugs, and must be aware of the signs for which to watch regarding adverse events or potential drug interactions.

Patients requiring hospital admission for surgical or radiation treatment will also require evaluation by the hospital care teams, including anesthesiology, hospital nursing staff, clinical nutrition, social workers, physical rehabilitation, and mental health specialists if those specialties are not already part of the managed care plan.

Following definitive therapy, a structured long term follows up plan is required, and again, the primary care provider in close partnership with the endocrinologist and the primary surgeon are central parts of this interprofessional team process. Such follow-up plans need to include periodic evaluation to exclude the possibility of recurrent or persistent HCM, which then requires the development of a new management plan for that. All these examples exemplify the interprofessional team paradigm necessary for managing such involved cases for optimal results. [Level 5]

Available data used in the development of various professional society practice guidelines show that patients with HCM cared for in a structured interprofessional setting have the best outcomes. If such a system is not available in the setting where the patient initially received their diagnosis, then it would be best for the patient’s gatekeeper PCP to refer the patient to a location/center where these resources are available and in place. The potential morbidity and mortality attendant with sub-optimally managed HCM make this vital.