From Knee Pain Consultation to Pituitary Surgery: The Challenge of Cushing Disease Diagnosis

Abstract Cushing syndrome (CS) is a rare endocrinological disorder resulting from chronic exposure to excessive cortisol. The term Cushing disease is used specifically when this is caused by excessive secretion of adrenocorticotropic hormone (ACTH) by a pituitary tumor, usually an adenoma. This disease is associated with a poor prognosis, and if left untreated, it has an estimated 5-year survival rate of 50%. We present the case of a 66-year-old female patient who received a referral to endocrinology for an evaluation of obesity due to right knee arthropathy. Taking into consideration her age, she was screened for osteoporosis, with results that showed diminished bone density. Considering this, combined with other clinical features of the patient, suspicion turned toward hypercortisolism. Laboratory findings suggested that the CS was ACTH-dependent and originated in the pituitary gland. After a second look at the magnetic resonance imaging results, a 4-mm lesion was identified on the pituitary gland, prompting a transsphenoidal resection of the pituitary adenoma.


Introduction
Chronic excessive exposure to glucocorticoids leads to the diverse clinical manifestations of Cushing syndrome (CS), which has an annual incidence ranging from 1.8 to 3.2 cases per million individuals [1].The syndrome's signs and symptoms are not pathognomonic, and some of its primary manifestations, such as obesity, hypertension, and glucose metabolism alterations, are prevalent in the general population [2], making diagnosis challenging.Endogenous CS falls into 2 categories: adrenocorticotropic hormone (ACTH)-dependent (80%-85% of cases), mostly due to a pituitary adenoma, or ACTHindependent (15%-20% of cases), typically caused by adrenal adenomas or hyperplasia [3].Cushing disease (CD) represents a specific form of CS, characterized by the presence of an ACTH-secreting pituitary tumor [1].Untreated CD is associated with high morbidity and mortality compared to the general population [1], with a 50% survival rate at 5 years [2].However, surgical removal of a pituitary adenoma can result in complete remission, with mortality rates similar to those of the general population [2].This article aims to highlight the challenges of suspecting and diagnosing CD and to discuss the current management options for this rare condition.

Case Presentation
A 66-year-old woman received a referral to endocrinology for an evaluation of obesity due to right knee arthropathy.During physical examination, she exhibited a body mass index of 34.3 kg/m 2 , blood pressure of 180/100, a history of non-insulin-requiring type 2 diabetes mellitus with glycated hemoglobin (HbA1c) of 6.9% (nondiabetic: < 5.7%; prediabetic: 5.7% to 6.4%; diabetic: ≥ 6.5%) and hypertension.Additionally, the patient complained of proximal weakness in all 4 limbs.
These findings indicated the presence of endogenous ACTH-dependent hypercortisolism of pituitary origin.Consequently, magnetic resonance imaging (MRI) was requested, but the results showed no abnormalities.Considering ectopic ACTH production often occurs in the lung, a highresolution chest computed tomography scan was performed, revealing no lesions.

Treatment
Upon reassessment, the MRI revealed a 4-mm adenoma, prompting the decision to proceed with transsphenoidal resection of the pituitary adenoma.

Discussion
CD is associated with high mortality, primarily attributable to cardiovascular outcomes and comorbidities such as metabolic and skeletal disorders, infections, and psychiatric disorders [1].The low incidence of CD in the context of the high prevalence of chronic noncommunicable diseases makes early diagnosis a challenge [2].This case is relevant for reviewing the diagnostic approach process and highlighting the impact of the availability bias, which tends to prioritize more common diagnoses over rare diseases.Despite the absence of typical symptoms, a timely diagnosis was achieved.
Once exogenous CS is ruled out, laboratory testing must focus on detecting endogenous hypercortisolism to prevent misdiagnosis and inappropriate treatment [5].Screening methods include 24-hour urinary free cortisol (UFC) for total cortisol load, while circadian rhythm and hypothalamicpituitary-adrenal (HPA) axis function may be evaluated using midnight serum cortisol and LNSC [5].An early hallmark of endogenous CS is the disruption of physiological circadian cortisol patterns, characterized by a constant cortisol level throughout the day or no significant decrease [2].Measuring LNSC has proven to be useful in identifying these patients.The LNSC performed on the patient yielded a high result.
To assess HPA axis suppressibility, tests such as the overnight and the standard 2-day LDDST [5] use dexamethasone, a potent synthetic corticosteroid with high glucocorticoid receptor affinity and prolonged action, with minimal interference with cortisol measurement [6].In a normal HPA axis, cortisol exerts negative feedback, inhibiting the secretion of corticotropin-releasing-hormone (CRH) and ACTH.Exogenous corticosteroids suppress CRH and ACTH secretion, resulting in decreased synthesis and secretion of cortisol.In pathological hypercortisolism, the HPA axis becomes partially or entirely resistant to feedback inhibition by exogenous steroids [5,6].The LDDST involves the administration of 0.5 mg of dexamethasone orally every 6 hours for 2 days, with a total dose of 4 mg.A blood sample is drawn 6 hours after the last administered dose [6].Following the LDDST, the patient did not demonstrate suppression of endogenous corticosteroid production.
After diagnosing CS, the next step in the diagnostic pathway involves categorizing it as ACTH-independent vs ACTH-dependent.ACTH-independent cases exhibit low or undetectable ACTH levels, pointing to adrenal origin.The underlying principle is that excess ACTH production in CD can be partially or completely suppressed by high doses of dexamethasone, a response not observed in ectopic tumors [6].In this case, the patient presented with an ACTH of 38.1 pg/mL (8.4 pmol/L), indicative of ACTH-dependent CD.
Traditionally, measuring cortisol levels and conducting pituitary imaging are standard practices for diagnosis.Recent advances propose alternative diagnostic methods such as positron emission tomography (PET) scans and corticotropinreleasing factor (CRF) tests [7].PET scans, utilizing radioactive tracers, offer a view of metabolic activity in the adrenal glands and pituitary region, aiding in the identification of abnormalities associated with CD.Unfortunately, the availability of the aforementioned tests in the country is limited.
Once ACTH-dependent hypercortisolism is confirmed, identifying the source becomes crucial.A HDDST is instrumental in distinguishing between a pituitary and an ectopic source of ACTH overproduction [2,6].The HDDST involves administering 8 mg of dexamethasone either overnight or as a 2-day test.In this case, the patient received 2 mg of dexamethasone orally every 6 hours for 2 days, totaling a dose of 16 mg.Simultaneously, a urine sample for UFC is collected during dexamethasone administration.The HDDST suppressed endogenous cortisol production in the patient, suggesting a pituitary origin.
In ACTH-dependent hypercortisolism, CD is the predominant cause, followed by ectopic ACTH syndrome and, less frequently, an ectopic CRH-secreting tumor [3,5].With the pretest probability for pituitary origin exceeding 80%, the next diagnostic step is typically an MRI of the pituitary region.However, the visualization of microadenomas on MRI ranges from 50% to 70%, requiring further testing if results are negative or inconclusive [5].Initial testing of our patient revealed no pituitary lesions.Following a pituitary location, ACTH-secreting tumors may be found in the lungs.Thus, a high-resolution chest computed tomography scan was performed, which yielded negative findings.Healthcare professionals must keep these detection rates in mind.In instances of high clinical suspicion, repeating or reassessing tests and imaging may be warranted [3], as in our case, ultimately leading to the discovery of a 4-mm pituitary adenoma.
It is fundamental to mention that the Endocrine Society Clinical Practice Guideline on Treatment of CS recommends that, when possible, all patients presenting with ACTHdependent CS and lacking an evident causal neoplasm should be directed to an experienced center capable of conducting inferior petrosal sinus sampling to differentiate between pituitary and nonpituitary or ectopic cause [8].However, in this instance, such a referral was regrettably hindered by logistical constraints.
Regarding patient outcomes and monitoring in CD, there is no consensus on defining remission criteria following tumor resection.Prolonged hypercortisolism results in suppression of corticotropes, resulting in low levels of ACTH and cortisol after surgical intervention.Typically, remission is identified by morning serum cortisol values below 5 µg/dL (138 nmol/L) or UFC levels between 28 and 56 nmol/d (10-20 µg/d) within 7 days after surgical intervention.In our case, the patient's morning serum cortisol was 115.8621 nmol/L (4.2 µg/dL), indicating remission.Remission rates in adults are reported at 73% to 76% in selectively resected microadenomas and at 43% in macroadenomas [8], highlighting the need for regular follow-up visits to detect recurrence.
Following the surgery, the patient experienced diabetes insipidus, a relatively common postoperative occurrence, albeit usually transient [8].It is recommended to monitor serum sodium levels during the first 5 to 14 days postsurgery for early detection and management.Additionally, pituitary deficiencies may manifest following surgery.In this patient, prolactin levels were compromised, potentially impacting sexual response.However, postoperative somatomedin levels were normal, and gonadotropins were not measured due to the patient's age group, as no additional clinical decisions were anticipated based on those results.Secondary hypothyroidism was diagnosed postoperatively.
Moving forward, it is important to emphasize certain clinical signs and symptoms for diagnosing CD.The combination of low bone mineral density (Likelihood Ratio [LR] +21.33), central obesity (LR +3.10), and arterial hypertension (LR + 2.29) [9] has a higher positive LR than some symptoms considered "characteristic," such as reddishpurple striae, plethora, proximal muscle weakness, and unexplained bruising [2,10].It is essential to give relevance to the signs the patient may present, emphasizing signs that have been proven to have an increased odds ratio (OR) such as osteoporosis (OR 3.8), myopathies (OR 6.0), metabolic syndrome (OR 2.7) and adrenal adenoma (OR 2.4) [9][10][11].The simultaneous development and worsening of these conditions should raise suspicion for underlying issues.Understanding the evolving nature of CD signs highlights the importance of vigilance during medical examinations, prioritizing the diagnostic focus, and enabling prompt initiation of treatment.
Recognizing the overlap of certain clinical features in CS is fundamental to achieving a timely diagnosis.

Learning Points
• CS diagnosis is challenging due to the absence of pathognomonic signs and symptoms and the overlap of features present in many pathologies, such as metabolic syndrome.• Early detection of CS is crucial, given its association with high morbidity and mortality resulting from chronic exposure to glucocorticoids.• Recognizing the combination of low bone mineral density, obesity, hypertension, and diabetes as valuable clinical indicators is key in identifying CS.
• Interdisciplinary collaboration is essential to achieve a comprehensive diagnostic approach.