Cushing's Syndrome: Diagnosis and Pathophysiology
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Which of the following best describes the pathophysiologic derangements of the hypothalamic-pituitary-adrenal (HPA) axis in Cushing's syndrome?

  • Decreased cortisol secretion, loss of diurnal variation, and increased sensitivity to ACTH feedback inhibition.
  • Decreased cortisol secretion, preserved diurnal variation, and increased sensitivity to ACTH feedback inhibition.
  • Excess cortisol secretion, loss of diurnal variation, and autonomy from central ACTH control. (correct)
  • Normal cortisol secretion, preserved diurnal variation, and normal sensitivity to ACTH feedback inhibition.

A patient presents with several signs and symptoms suggestive of Cushing's syndrome. Which of the following is the MOST critical initial step in establishing the diagnosis?

  • Measure ACTH levels to determine if the syndrome is ACTH-dependent or ACTH-independent.
  • Perform a dexamethasone suppression test to determine the source of excess cortisol.
  • Rule out exogenous steroid use through a thorough patient history. (correct)
  • Immediately order an MRI of the pituitary gland to assess for adenomas.

A researcher is investigating the loss of diurnal variation in cortisol secretion in patients with Cushing's syndrome. Which aspect of cortisol regulation is MOST directly affected by this loss?

  • The metabolism of cortisol by the liver and other peripheral tissues.
  • The feedback inhibition of cortisol on corticotropin-releasing hormone (CRH) release.
  • The pulsatile release of adrenocorticotropic hormone (ACTH) from the pituitary gland.
  • The normal circadian rhythm that regulates the hypothalamic-pituitary-adrenal axis. (correct)

Which clinical manifestation, while less common, might suggest the presence of Cushing's syndrome and warrant further investigation, particularly in the absence of more typical signs?

<p>Persistent, unexplained backache. (B)</p> Signup and view all the answers

Considering the classic signs and symptoms of Cushing's syndrome, which laboratory investigation would provide the most direct evidence of excessive cortisol secretion?

<p>A 24-hour urine free cortisol measurement. (B)</p> Signup and view all the answers

Why is a 24-hour urinary free cortisol test considered a more accurate measure of cortisol production than a single cortisol blood test?

<p>It accounts for the variations in cortisol production rates throughout the day, offering an integrated measure over a complete diurnal cycle. (A)</p> Signup and view all the answers

What is the significance of performing serial late-night salivary cortisol measurements instead of a single measurement?

<p>Serial measurements improve the reliability of the test by minimizing the impact of isolated fluctuations and potential collection errors. (A)</p> Signup and view all the answers

In the context of Cushing's investigation, what does the loss of diurnal variation in cortisol secretion, as assessed by late-night salivary cortisol, suggest?

<p>Autonomy from central ACTH control, indicating the adrenal glands are producing cortisol independently of the normal feedback mechanisms. (B)</p> Signup and view all the answers

What is a key limitation of using a 24-hour urine collection for cortisol measurement in the diagnosis of Cushing's syndrome?

<p>It provides an integrated measure of total cortisol excretion but does not reveal the circadian rhythm of cortisol secretion. (C)</p> Signup and view all the answers

Why is it important to consider a patient's sleep-wake cycle when interpreting late-night salivary cortisol results?

<p>Sleep disturbances elevate cortisol levels, mimicking the loss of diurnal variation seen in Cushing's syndrome, leading to false-positive results. (A)</p> Signup and view all the answers

Considering Ms. F's symptoms and initial examination, which of the following is the MOST appropriate initial diagnostic test to screen for Cushing's syndrome?

<p>Overnight dexamethasone suppression test (1 mg) (B)</p> Signup and view all the answers

If Ms. F's initial screening test suggests Cushing's syndrome, and her plasma ACTH level is found to be low, what is the MOST likely underlying cause?

<p>Adrenal adenoma (A)</p> Signup and view all the answers

Which of the following historical details is LEAST likely to be directly related to the development of Cushing's syndrome in Ms. F?

<p>Smoking 10 cigarettes daily for 10 years (A)</p> Signup and view all the answers

Upon further investigation, Ms. F is diagnosed with Cushing's disease (a pituitary adenoma). Which imaging modality is MOST appropriate for visualizing the pituitary gland?

<p>MRI of the brain with pituitary protocol (B)</p> Signup and view all the answers

If Ms. F's Cushing's disease is confirmed, what is the FIRST-LINE treatment option typically recommended?

<p>Transsphenoidal surgery (A)</p> Signup and view all the answers

What is the MOST likely reason for Ms. F's elevated blood pressure, given her diagnosis of Cushing's syndrome?

<p>Increased angiotensinogen production due to elevated cortisol (C)</p> Signup and view all the answers

Following successful treatment of her Cushing's disease, which of the following hormonal changes would be expected in Ms. F during the immediate post-operative period?

<p>Development of temporary secondary adrenal insufficiency (B)</p> Signup and view all the answers

Which of the following physical exam findings, NOT explicitly mentioned, would be MOST consistent with a diagnosis of Cushing's syndrome?

<p>Dorsocervical fat pad (buffalo hump) (C)</p> Signup and view all the answers

A patient presents with central obesity, facial plethora, and purple striae. Which underlying mechanism best explains the development of these findings in Cushing's syndrome?

<p>The catabolic effects of cortisol on collagen and connective tissue contribute to skin thinning and abdominal striae. (B)</p> Signup and view all the answers

A patient with suspected Cushing's syndrome exhibits a dorsocervical fat pad and proximal muscle weakness. Which of the following hormonal mechanisms most directly contributes to these specific manifestations?

<p>Elevated glucocorticoids promote protein catabolism in muscles and stimulate lipogenesis in specific fat depots. (B)</p> Signup and view all the answers

In a patient presenting with hirsutism and acne alongside other signs suggestive of Cushing's syndrome, what is the most probable hormonal cause?

<p>Elevated levels of androgens due to the adrenal glands being stimulated by excess cortisol. (D)</p> Signup and view all the answers

A patient exhibits facial plethora as a sign of Cushing's syndrome. What is the primary physiological mechanism by which excess cortisol induces this presentation?

<p>Elevated cortisol levels increase red blood cell production, raising the hematocrit and causing facial redness. (D)</p> Signup and view all the answers

What is the most critical implication of recognizing physical exam signs such as striae, dorsocervical fat pad, and facial plethora in the diagnosis of Cushing's syndrome?

<p>These signs prompt further investigation to confirm hypercortisolism and initiate appropriate management, regardless of the underlying cause. (C)</p> Signup and view all the answers

A 40-year-old female presents with recent onset acne, hirsutism, and menstrual irregularities. Physical examination reveals central obesity, thin skin, and purple striae on her abdomen. Considering these findings, which of the following laboratory tests would be most specific and appropriate to initially evaluate for Cushing's syndrome?

<p>A 24-hour urinary free cortisol excretion test. (A)</p> Signup and view all the answers

How does the pathophysiology of striae in Cushing's syndrome differ from striae associated with pregnancy or adolescent growth spurts?

<p>Cushing's syndrome striae result from collagen degradation due to excessive cortisol, whereas pregnancy and growth striae are primarily due to skin stretching. (D)</p> Signup and view all the answers

Why might a patient with Cushing's syndrome exhibit an unremarkable thyroid examination despite presenting with other endocrine abnormalities like hirsutism or acne?

<p>Cushing's syndrome primarily affects adrenal hormone production and does not directly influence thyroid function. (C)</p> Signup and view all the answers

In a low-dose dexamethasone suppression test (DST), what distinguishes the action of dexamethasone from that of naturally produced cortisol?

<p>Dexamethasone exhibits a stronger binding affinity to glucocorticoid receptors, leading to more potent suppression of ACTH release compared to cortisol. (A)</p> Signup and view all the answers

A patient exhibits elevated cortisol levels despite undergoing a low-dose dexamethasone suppression test (DST). Which of the following mechanisms is least likely to explain this result?

<p>Primary hypothyroidism leading to increased CRH secretion. (A)</p> Signup and view all the answers

A patient's low-dose dexamethasone suppression test (DST) reveals a cortisol level of 331 nmol/L (12 mcg/dL). Given a reference range of less than 50 nmol/L, what is the most accurate interpretation of this result?

<p>Failure of cortisol suppression, necessitating further investigation into the source of cortisol excess. (D)</p> Signup and view all the answers

In the context of the dexamethasone suppression test (DST), what is the rationale for administering dexamethasone at 11 PM and measuring cortisol at 8 AM?

<p>To allow sufficient time for dexamethasone to suppress ACTH secretion, thereby reducing cortisol levels overnight. (D)</p> Signup and view all the answers

A patient with suspected Cushing's syndrome has a 24-hour urine free cortisol level of 658 µg/24hrs (reference range: 20-90 µg/24hrs). How does this result influence the interpretation of a subsequent positive low-dose dexamethasone suppression test (DST)?

<p>It strengthens the likelihood of Cushing's syndrome, suggesting the need to differentiate between ACTH-dependent and ACTH-independent causes. (A)</p> Signup and view all the answers

What is the most crucial assumption underlying the use of dexamethasone in the low-dose suppression test (DST) for diagnosing Cushing's syndrome?

<p>The negative feedback mechanism of the HPA axis is functional, allowing dexamethasone to suppress ACTH secretion. (B)</p> Signup and view all the answers

In a patient undergoing a low-dose dexamethasone suppression test (DST), the primary mechanism by which dexamethasone is expected to reduce cortisol production involves:

<p>Suppressing the release of ACTH from the pituitary gland. (D)</p> Signup and view all the answers

Following a confirmed diagnosis of Cushing's syndrome based on a positive low-dose dexamethasone suppression test (DST) and elevated 24-hour urine free cortisol, what is the next most appropriate step in determining the etiology?

<p>Measure plasma ACTH levels to differentiate between ACTH-dependent and ACTH-independent causes. (C)</p> Signup and view all the answers

Flashcards

Cushing's Syndrome

A hormonal disorder caused by prolonged exposure to high cortisol levels.

Moon Facies

A round, fuller face seen in Cushing's Syndrome patients.

BMI

Body Mass Index, a measure of body fat based on height and weight.

Vital Signs

Clinical measurements that indicate the state of a patient's essential body functions.

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Hypertension

High blood pressure, often associated with serious health risks.

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Sedentary Lifestyle

A type of lifestyle with little to no physical activity.

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Easy Bruising

A condition where a person forms bruises with minimal or no injury.

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Familial Hypertension

High blood pressure in family members, which can indicate genetic predisposition.

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Late Night Salivary Cortisol

Test measuring cortisol levels late at night, indicating loss of normal diurnal variation.

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Dexamethasone Suppression Test

Test assessing cortisol autonomy by measuring response to dexamethasone, indicating lack of ACTH control.

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24-Hour Urinary Free Cortisol

Test measuring total cortisol output in urine over 24 hours, more accurate than single measures.

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Cushing's Syndrome Diagnosis

Cushing’s likely if urinary cortisol exceeds 3 times upper normal limit, requiring serial tests.

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Circadian Rhythm of Cortisol

Natural fluctuations of cortisol levels throughout the day, lost in Cushing's syndrome.

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HPA Axis

Hypothalamic-Pituitary-Adrenal axis; a major system regulating stress response and cortisol levels.

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Common Signs of Cushing's

Includes obesity, round face, hirsutism, and hypertension.

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Diurnal Variation of Cortisol

Normal cortisol levels fluctuate throughout the day; lost in Cushing's syndrome.

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Initial Investigation for Cushing's

24-hour urine free cortisol test to check for excess cortisol secretion.

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Cortisol autonomy

Condition where cortisol production is not properly regulated by ACTH.

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ACTH

Adrenocorticotropic hormone that stimulates cortisol production from the adrenal glands.

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Normal physiology of HPA axis

Under normal conditions, cortisol suppresses ACTH due to negative feedback.

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Supraphysiologic dose

A dose of medication that exceeds normal physiological levels.

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Positive dexamethasone test

Result indicating failure to suppress cortisol production after dexamethasone administration.

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Corticotropin-releasing hormone (CRH)

Hormone responsible for stimulating ACTH release from the pituitary gland.

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24-hour urine free cortisol test

A test measuring cortisol levels in urine to assess adrenal function over a day.

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Striae

Stretch marks often seen on the abdomen, typically purple or red in color.

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Dorsocervical Fat Pad

Fat accumulation at the back of the neck, also known as a buffalo hump.

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Facial Plethora

Redness and swelling of the face due to increased blood flow or inflammation.

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Hirsutism

Excess hair growth in areas where males typically grow hair, particularly on the face and back.

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Cushing’s Syndrome

A condition caused by excess cortisol secretion, leading to symptoms like obesity and facial changes.

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Proximal Muscle Weakness

Weakness that primarily affects muscles closer to the body's center, like the hips and shoulders.

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Differential Diagnoses for Obesity

Possible conditions related to obesity, including metabolic syndrome, type II diabetes, and Cushing’s Syndrome.

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Study Notes

Case Based Teaching: Cushing's

  • Presented by Professor O'Reilly, Consultant Endocrinologist at RCSI
  • Focuses on the diagnosis and management of Cushing's Syndrome

New Referral to the Endocrine Clinic

  • Ms. F, a 37-year-old female, was referred to the Endocrine Clinic by her General Practitioner (GP)
  • Presenting Symptoms: 10 months history of 12 kg weight gain (self-attributed to inactivity), easy bruising, muscle weakness and fatigue (difficulty climbing stairs), and irregular menstrual cycles.

Further History

  • Past Medical History: Hypertension (3 years), Class 1 Obesity (BMI 31 kg/m²), on medication Amlodipine, Hydrochlorothiazide, and Ramipril
  • Past Surgical History: None
  • Family History: Father with high blood pressure
  • Social History: Works as an engineer, sedentary lifestyle, 10 cigarettes/day for 10 years, 2 glasses of wine on weekend.
  • No significant changes to her diet or exercise regime.

Vital Signs

  • Blood Pressure (BP): 150/90 mmHg
  • Heart Rate (HR): 87 BPM
  • Oxygen Saturation (O2 sat): 99% on Room Air (RA)
  • Temperature: Apyrexial
  • Height: 162 cm
  • Weight: 83.2 kg
  • Body Mass Index (BMI): 31 kg/m²

Comparing Pictures 2 Years Ago & Now

  • Visual comparison of the patient's appearance over two years, highlighting physical changes.
  • Moon Facies.

Physical Exam Signs

  • Pictures illustrating striae, dorsocervical fat pad (buffalo hump), ecchymoses, facial plethora, hirsutism, acne.
  • These images are for educational purposes only, and not intended to be used for any patient identification.

On Physical Examination

  • Facial plethora
  • Hirsutism (on sides of face and lower back)
  • Acne (on chest, back, and face)
  • Thyroid Examination: unremarkable
  • Purple striae on abdomen
  • Central obesity (increased fat accumulation in face and trunk)
  • dorsocervical fat pad
  • proximal muscle weakness

Differential Diagnoses

  • Obesity
  • Metabolic Syndrome
  • Type II Diabetes
  • Cushing's Syndrome

Cushing's Syndrome Definition

  • Results from continued exposure to high levels of glucocorticoid steroids, either endogenous or exogenous.

Pathophysiologic "Derangements" of the HPA Axis

  • Excess cortisol secretion
  • Loss of diurnal variation of cortisol secretion
  • Autonomy from "central" ACTH control - loss of response to feedback inhibition

Investigations You Would Order

  • 24-hour urine free cortisol
  • Late night salivary cortisol
  • 1 mg overnight dexamethasone suppression test

24-Hour Urinary Free Cortisol

  • Measures cortisol production over 24-hour period.
  • More accurate than single cortisol check.
  • High levels suggest Cushing's.

Late Night Salivary Cortisol

  • Measures free cortisol (a surrogate for serum free cortisol) at 11 PM.
  • Stable, easily collected at home, serially (2-3 nights).
  • Reflects diurnal rhythm.

1 mg Overnight Dexamethasone Suppression Test

  • Dexamethasone is given at 11 PM
  • Cortisol is measured at 8 am the next morning.
  • Positive test indicates failure of cortisol suppression.
  • Inappropriately high cortisol secretion.

Results: Confirming Elevated Cortisol

  • 24-hour urine free cortisol: Elevated (658 µg/24hrs for reference range 20-90µg/24h)
  • Low-dose Dexamethasone suppression test: Elevated (331 nmol/L, reference range less than 50 nmol/L)
  • Late Night Salivary cortisol: Elevated.

Cushing's Syndrome Confirmed

  • The findings support the diagnosis of Cushing's syndrome, based on the clinical features and elevated cortisone levels.

Next Step: Determining the Source of Excess Cortisol

  • Rule out exogenous steroid use as a primary cause.
  • Identify the source of excess cortisol (pituitary, adrenal or ectopic) using additional tests.

8mgs High Dose Dexamethasone Suppression Test

  • Higher dose of dexamethasone (more than 10 times daily endogenous cortisol) to confirm the source of elevated ACTH.
  • Suppressibility : Pituitary source.
  • Non-suppressibility : Ectopic or other source. In this case, the 8mg does is able to control the cortisol levels.

What is the best modality to image a Pituitary Gland?

  • MRI scan of the pituitary gland is the best modality.

Radiologic Test Choices

  • The choice of imaging tests depends on the results of hormone tests.

Pituitary MRI

  • Key anatomical structures to be visualized during a pituitary MRI.
  • Images differenciating a healthy pituitary from a pituitary adenoma.

Ms. F's MRI Findings

  • MRI images showing the presence of an adenoma.

Treatment Algorithm for Cushing's Disease

  • A decision tree outlining subsequent steps in the management of Cushing's disease, including treatment options.
  • Surgery (transsphenoidal pituitary surgery) is often the initial treatment.
  • Further action, such as radiation or medical therapies, is considered when surgery is not successful or for recurrent disease.

Ms. F Was Referred to Neurosurgery

  • She underwent transsphenoidal surgery.

Pathology of Pituitary Adenoma

  • Examining the histological features of corticotroph micro-adenomas using various staining techniques (ie, reticulin, ACTH and PAS-OG stain).

Management

  • Referral for evaluation and surgical intervention (transsphenoidal resection).
  • Postoperative follow-up with serial hormone assays.

Post-operative MRI (3 Months)

  • Visual representation of the MRI scan taken three months after the transsphenoidal resection.

Features of Cushing's Post-Op.

  • Comparison photos showing the changes in Ms. F's appearance after 1, 2, 3, and 16 months post-surgery.

Our Patient (Ms. F)

  • Provided successful resection of the adenoma.
  • Resolution of symptoms.
  • Normalization of hormonal assays (follow-up).

Cushing's Investigation Algorithm

  • Flow chart demonstrating the diagnostic process for Cushing's Syndrome, including cortisol and ACTH measurements and imaging techniques.

Take Home Message

  • Cushing's Syndrome is a set of signs and symptoms resulting from exposure to high cortisol levels.
  • Causes include long-term corticosteroid use, pituitary tumours, ectopic tumours or adrenal tumours.
  • Typical symptoms include truncal obesity, moon face, buffalo hump, muscle wasting, stretch marks, easy bruising, skin and bone thinning, hirsutism and menstrual irregularities (females).
  • Diagnosis is made via history, physical exam and lab/imaging investigations.

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Cushing's Case Teaching PDF

Description

Explore the complexities of Cushing's syndrome with questions covering the HPA axis, diagnostic steps, and cortisol regulation. This quiz assesses understanding of clinical manifestations and lab investigations for diagnosing excessive cortisol secretion. It covers topics like diurnal cortisol variation and urinary free cortisol testing.

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