Disorders of the Adrenal Cortex

Transcription

1 Disorders of the Adrenal Cortex Cushing s Syndrome and Primary Aldosteronism 凌雁 Yan Ling Department of Endocrinology and Metabolism Zhongshan Hospital Fudan University

2 Cushing s Syndrome

3 Definition of Cushing s Syndrome Cushing's syndrome comprises the symptoms and signs associated with prolonged exposure to inappropriately elevated levels of free plasma glucocorticoids. The use of the term glucocorticoid in the definition covers both endogenous (cortisol) and exogenous (e.g., prednisolone, dexamethasone) excess.

4 Cortex of the Adrenal Gland Secretes Cortisol Zona Glomerulosa Zona Fasciculata Zona Reticularis Medulla

5 Regulation of Cortisol Secretion: Feedback Loops Hypothalamic Anterior Pituitary Adrenal cortex CRH: corticotropin-releasing hormone ACTH: Adrenocorticotropic hormone

6 Causes of Cushing s Syndrome ACTH-dependent Cushing's disease (ACTH-producing pituitary adenoma) (60-70%) Ectopic ACTH syndrome (15-20%) Ectopic CRH syndrome Macronodular adrenal hyperplasia Iatrogenic (treatment with ACTH 1-24) ACTH-independent Adrenal adenoma (10-20%) and carcinoma (<5%) Primary pigmented nodular adrenal hyperplasia and Carney's syndrome McCune-Albright syndrome Aberrant receptor expression (gastric inhibitory polypeptide, interleukin-1β) (ACTH-independent macronodular hyperplasia ) Iatrogenic (e.g., pharmacologic doses of prednisolone, dexamethasone)

7 Effects of Glucocorticoids glucose lipid protein

8 Clinical Features of Cushing s Syndrome (%Patients) (%Patients) (%Patients)

9 Clinical Features of Cushing s Syndrome Obesity Truncal obesity Moon face Fat deposits in supraclavicular fossa and posterior neck- buffalo hump

10 Truncal Obesity Weight gain and obesity are the most common sign, and this is invariably centripetal in nature.

11 Characteristic deposition of adipose tissue Moon face and plethora Enlarged supraclavicular fat pads buffalo hump

12 Clinical Features of Cushing s Syndrome Skin Thin skin Plethora Easy bruising Broad purplish cutaneous striae Pigmentation

13 Broad purplish cutaneous striae The typical red-purple livid striae greater than 1 cm in diameter are most frequently found on the abdomen but may also be present on the upper thighs, breasts, and arms.

14 Clinical Features of Cushing s Syndrome Reproductive Female: menstrual irregularity (oligomenorrhea/amenorrhea), hirsutism, acne Male: loss of libido

15 Clinical Features of Cushing s Syndrome Psychiatric Irritability Depression Lethargy Paranoia Overt psychosis

16 Clinical Features of Cushing s Syndrome Bone Osteoporosis Vertebral collapse Pathologic fractures Osteonecrosis of the femoral and humeral heads Muscle Proximal myopathy (lower limb and shoulder girdle )

17 Clinical Features of Cushing s Syndrome Cardiovascular Hypertension Cardiovascular events and thromboembolic events

18 Clinical Features of Cushing s Syndrome Infections Tuberculosis Fungal infections of the skin and nails Wound infections and poor wound healing

19 Clinical Features of Cushing s Syndrome Metabolic and Endocrine Glucose intolerance and overt diabetes Elevated cholesterol and triglycerides Hypokalemic alkalosis

20 Clinical Features of Cushing s Syndrome Eye Raised intraocular pressure and exophthalmos Cataracts Chemosis

21 Diagnosis of Cushing s Syndrome Functional diagnosis Does the patient have Cushing's syndrome? Etiological diagnosis What is the cause of the Cushing's syndrome?

22 Diagnosis of Cushing s Syndrome Diagnostic criteria Increased cortisol production Failure to suppress cortisol secretion normally when dexamethasone is administered

23 Functional diagnosis Circadian rhythm of plasma cortisol A sensitive screening test False positive (stress of venepuncture, intercurrent illness, and admission to hospital, CBG levels)

24 Functional diagnosis Circadian rhythm of plasma cortisol in normal subjects Highest in the morning Lowest around midnight (<50 nmol/l [<2 mg/dl] in a nonstressed subject).

25 Functional diagnosis Circadian rhythm of plasma cortisol in patients with Cushing's syndrome Circadian rhythm is lost Midnight cortisol > 200 nmol/l (>7.5 mg/dl): indicates the diagnosis Random morning cortisol: of little value in diagnosis

26 Functional diagnosis Urinary free cortisol excretion A useful screening test An integrated measure of plasma free cortisol 24-hour urinary excretion > 140nmol/d (50ug/d) indicates the diagnosis Urinary free cortisol may be normal in up to 8% to 15% of patients with Cushing's syndrome.

27 Functional diagnosis Low-dose dexamethasone suppression test The diagnostic test of Cushing s syndrome

28 Normal Regulation of Cortisol Secretion CRH: corticotropin-releasing hormone ACTH: Adrenocorticotropic hormone

29 The Rationale of Low-Dose Dexamethasone Suppression Test Feedback mechanism of ACTH-adrenal axis: the ACTH release mechanism is sensitive to the circulating glucocorticoid level. When blood levels of glucocorticoid are increased in normal individuals, less ACTH is released from the anterior pituitary and less steroid is produced by the adrenal gland. Test the integrity of this feedback mechanism by administration low but supraphysiologic doses of synthetic glucocorticoid dexamethasone. In normal subjects, the administration of a supraphysiologic dose of glucocorticoid results in suppression of ACTH and cortisol secretion. In Cushing's syndrome of whatever cause, there is a failure of this suppression when low doses of dexamethasone are given.

30 Functional diagnosis Low-dose dexamethasone suppression test Overnight test: 1 mg at midnight. Normal: plasma cortisol < 140 nmol/l (<5 ug/dl) at hours the following morning 48-hour low-dose dexamethasone test: 0.5 mg Q6 hr 48 hours. Urine cortisol during last 24 hours Plasma cortisol at 48 hours Normal: Urine cortisol < 25 nmol/24 hours ( < 10ug/24 hours) Plasma cortisol < 140 nmol/l (<5 ug/dl)

31 Causes of Cushing s Syndrome ACTH-dependent Cushing's disease (pituitary-dependent) (70%) Ectopic ACTH syndrome (15%) Ectopic CRH syndrome Macronodular adrenal hyperplasia Iatrogenic (treatment with ACTH 1-24) ACTH-independent Adrenal adenoma (10-15%) and carcinoma (<5%) Primary pigmented nodular adrenal hyperplasia and Carney's syndrome McCune-Albright syndrome Aberrant receptor expression (gastric inhibitory polypeptide, interleukin-1β) Iatrogenic (e.g., pharmacologic doses of prednisolone, dexamethasone)

32 Etiological diagnosis ACTH-dependent or ACTH-independent? Plasma ACTH Separating ACTH-dependent from ACTH-independent causes 8:00-9:00 plasma ACTH < 2 pmol/l (10 pg/ml) suggests ACTH-independent causes

33 Etiological diagnosis ACTH-dependent or ACTH-independent? CT/MRI Scanning of Adrenals Adrenal adenoma Adrenal carcinoma

34 Etiological diagnosis Cushing s disease or ectopic ACTH syndrome? Differential diagnosis of ACTH-dependent Cushing s syndrome Cushing s disease Ectopic Cushing s syndrome

35 Etiological diagnosis Cushing s disease or ectopic ACTH syndrome? High-Dose Dexamethasone Suppression Test A diagnostic test to distinguish patients with Cushing s disease from those with other forms of Cushing's syndrome

36 The Rationale of High-Dose Dexamethasone Suppression Test In Cushing's disease, there is a relative resistance of ACTH secretion to normal glucocorticoid feedback inhibition. ACTH-secreting pituitary adenomas function at a higher than normal set-point for glucocorticoid feedback. Thus, cortisol levels do not suppress with low-dose, but do so following high-dose dexamethasone. The ACTH release of pituitary has been inhibited in ectopic ACTH syndrome and adrenal neoplasms and will not be effected by dexamethasone further. Thus, cortisol levels do not suppress with both low-dose and high-dose dexamethasone.

37 Etiological diagnosis Cushing s disease or ectopic ACTH syndrome? High-Dose Dexamethasone Suppression Test 2 mg Q6 hr 48 hours Urine cortisol (basal and last 24 hours) Plasma cortisol (basal and at 48 hours) Suppression rate (90%) Cushing s disease > 50% (90%) ectopic ACTH syndrome < 50 %

38 Etiological diagnosis Cushing s disease or ectopic ACTH syndrome? Corticotropin- Releasing Hormone Test CRH 1mg/Kg or 100mg iv. ACTH and cortisol Q15min 2h

39 Diagnostic Tests to Determine the Cause of Cushing s Syndrome

40 Etiological diagnosis Cushing s disease or ectopic ACTH syndrome? MRI Scanning of Pituitary-pituitary microadenoma

41 Tumors Associated with the Ectopic ACTH Syndrome Tumor Type Approximate Incidence (%) Small cell lung carcinoma 50 Non small cell lung carcinoma 5 Pancreatic tumors (including carcinoids) 10 Thymic tumors (including carcinoids) 5 Lung carcinoids 10 Other carcinoids 2 Medullary carcinoma of thyroid 5 Pheochromocytoma and related tumors 3 Rare carcinomas of prostate, breast, ovary, gallbladder, colon 10

42 Etiological diagnosis Inferior Petrosal Sinus Sampling/Selective Venous Catheterization ACTH Ratio=ACTH (the inferior petrosal sinus) / ACTH (peripheral venous) Cushing s disease >2 (baseline) or >3 (post-crh) Ectopic ACTH syndrome <1.4

43 Differential Diagnosis Exogenous obesity Chronic alcoholism Depression Acute illness Iatrogenic Cushing s syndrome

44 Treatment of Cushing's Syndrome Adrenal adenomas Unilateral adrenalectomy 100% cure rate Replacement therapy with glucocorticoid after operation

45 Treatment of Cushing's Syndrome Adrenal carcinomas Surgery Adrenolytic agent: o,p -DDD (Mitotane) Radiotherapy Very poor prognosis: dead within 2 years

46 Treatment of Cushing's Syndrome Cushing's disease Transsphenoidal surgery Replacement therapy with glucocorticoid after operation

47 Treatment of Cushing's Syndrome Ectopic ACTH syndrome Surgery Treatment dependent on the cause

48 Case 1: A patient with cortisol-produing adrenal adenoma History: Female 53-year old 3-year history of hypertension Three antihypertensive medications administered Blood pressure level: 140/95mmHg Symptoms and signs: Heat intolerance, sweating, weight gain Plethora, BMI 26Kg/m 2, waist circumference: 88cm

49 Case 1: A patient with cortisol-produing adrenal adenoma Circadian rhythm of cortisol disappeared ACTH suppressed 皮质醇昼夜节律消失 Dexamethasone suppression test ACTH 降低 地塞米松抑制试验 Functional diagnosis: Cushing s syndrome Localization: cortisolproducing adenoma of the left adrenal

50 Case 1: A patient with cortisol-produing adrenal adenoma Unilateral adrenalectomy by laparoscopy Pathologic diagnosis: cortisolproducing adenoma

51 ???mmhg? BP Case 1: Follow-up of the patient Surgery and antihypertensive drugs CCB ARB+CCB+ β- discontinued used +ARB 治疗 One 手术后 week 1 + β- blocker after surgery and no drug used Two weeks after surgery and no drug Three weeks after surgery and ARB used Four weeks after surgery and ARB dose was 周 halved ??? SBP??? DBP

52 Case 2: A patient with pituitary ACTH-producing adenoma History: Female 35-year old 9-month history of amenorrhea Symptoms and signs: Weight gain Plethora, round face

53 Case 2: A patient with pituitary ACTH-producing adenoma ACTH and cortisol rhythm 8:00 16:00 0:00 ACTH(pg/ml) Cortisol(nmol/l) Urinary free cortisol: ug/24h ACTH and cortisol level after low-dose and high-dose dexamethasone suppression test Low-dose(8:00) High-dose(8:00) ACTH(pg/ml) Cortisol(nmol/l) Pituitary MRI: pituitary microadenoma

54 Case 2: A patient with pituitary ACTH-producing adenoma Inferior petrosal sinus sampling: Position of sampling ACTH (pg/ml) Postcava 67.8 Precava 84.1 Right internal jugular vein 76.3 Left internal jugular vein 75.0 Right inferior petrosal sinus 82.2 Left inferior petrosal sinus Right sigmoid sinus 78.4 Left sigmoid sinus 71.0

55 Case 2: Follow-up of the patient ( 2 months after surgery) Regular menses ACTH and cortisol rhythm 8:00 16:00 0:00 ACTH(pg/ml) Cortisol(nmol/l) Cortisone 20mg/d

56 Questions for Review What is the definition of Cushing s syndrome? What are the clinical manifestations of Cushing s syndrome? What is the difference between Cushing s syndrome and Cushing s disease? What are the main types of Cushing s syndrome? What is the purpose of performing a low-dose dexamethasone suppression test and what s the rationale of this test?

57 Primary Aldosteronism

58 Definition of Primary Aldosteronism A syndrome associated with hypersecretion of the mineralocorticoid aldosterone by abnormal zona glomerulosa tissue of the adrenal gland. Hypertension, suppressed plasma renin activity (PRA), and increased aldosterone excretion characterize the syndrome of primary aldosteronism.

59 Cortex of the Adrenal Gland Secretes Aldosterone Zona Glomerulosa Zona Fasciculata Zona Reticularis Medulla

60 Causes of Primary aldosteronism Aldosterone-producing adenoma (APA) (35%) Bilateral idiopathic hyperplasia (IHA) (60%) Primary (unilateral) adrenal hyperplasia (PAH) (2%) Aldosterone-producing adrenocortical carcinoma (<1%) Familial Hyperaldosteronism (FH) Glucocorticoid-remediable aldosteronism (FH type I) (<1%) FH type II (APA or IHA) (<2%) Ectopic aldosterone-producing adenoma or carcinoma (<0.1%)

61 Effects of Aldosterone Effects on epithelia (the classic functions) Sodium-retaining effect Water-retaining effect Potassium-losing effect Escape phenomenon Escape by the renal tubules from the sodium-retaining action of aldosterone No escape from the potassium-losing effect of aldosterone

62 Effects of Aldosterone on epithelia of distal tubule

63 Effects of Aldosterone Effect on nonepithelial cells Mineralocorticoid receptor identified in a number of nonepithelial cells (e.g., neurons, myocytes, endothelial cells, vascular smooth-muscle cells) Mediating the expression of several collagen genes; genes controlling tissue growth factors (e.g., TGF-β, and PAI-1); or genes mediating inflammation. Leading to microangiopathy, necrosis (acutely), and fibrosis in various tissues such as the heart, the vasculature, and the kidney

64 Effects of Aldosterone Excess aldosterone secretion Causeing hypertension through two main mechanisms: Mineralocorticoid-induced expansion of plasma and extracellular fluid volume. Increasing in total peripheral vascular resistance. Causing hypokalemia Target organ damage (heart and kidney)

65 Regulation of Aldosterone Secretion Factors regulating aldosterone secretion Renin-angiotensin system Potassium ion ACTH

66 Renin-Angiotensin-Aldosterone System Macula densa

67 Regulation of Aldosterone Secretion The interrelationship of the volume and potassium feedback loops on aldosterone secretion

68 Clinical Features of Primary Aldosteronism Hypertension and excess aldosterone Left ventricular hypertrophy Damage of cerebral circulation Impairment of retinal vasculature Damage of kidney

69 Clinical Features of Primary Aldosteronism Potassium depletion and hypokalemia Weakness and fatigue Polyuria and polydipsia Metabolic alkalosis Palpitations ECG: prominent U waves cardiac arrhythmias

70 Diagnosis of Primary Aldosteronism Diagnostic criteria Hypertension Hyposecretion of renin (low plasma renin activity) that fails to increase appropriately during volume depletion Hypersecretion of aldosterone that does not suppress appropriately in response to volume expansion

71 Diagnosis of Primary Aldosteronism Functional diagnosis Screening tests Confirmatory tests Etiological diagnosis Subtype evaluation tests

72 Functional Diagnosis - Screening tests

73 Functional Diagnosis - Confirmatory tests To determine if aldosterone is secreted autonomously by examining if secretion of aldosterone can be suppressed appropriately in response to volume expansion. if aldosterone secretion is regulated by reninangiotensin

74 Functional Diagnosis - Confirmatory tests Oral sodium loading test Sodium load and volume expansion Intravenous saline infusion test Sodium load and volume expansion Fludrocortisone suppression test A synthetic corticosteroid with potent mineralocorticoid effect Sodium retention and volume expansion Captopril challenge test An angiotensin-converting enzyme inhibitor Blocking the synthesis of angiotensin Ⅱ

75 Regulation of Aldosterone Secretion The interrelationship of the volume and potassium feedback loops on aldosterone secretion

76 Functional Diagnosis - Confirmatory tests Intravenous saline infusion test Patients stay in the recumbent position for at least 1 h before and during the infusion of 2 liters of 0.9% saline iv over 4 h, starting at 08:00-09:30 h. Blood samples for renin, aldosterone, cortisol, and plasma potassium are drawn at time zero and after 4 h, with blood pressure and heart rate monitored throughout the test. Postinfusion plasma aldosterone levels < 5 ng/dl make the diagnosis of PA unlikely, and levels >10 ng/dl are a very probable sign of PA. Values between 5 and 10 ng/dl are indeterminate. This test should not be performed in patients with severe uncontrolled hypertension, renal insufficiency, cardiac insufficiency, cardiac arrhythmia, or severe hypokalemia.

77 Etiological diagnosis - Subtype evaluation tests To determine the hypersecretion of aldosterone is due to Unilateral lesion: a unilateral adenoma (APA) or primary adrenal hyperplasia (PAH) Bilateral lesion: bilateral idiopathic hyperplasia (IHA)

78 Diagnosis of Primary Aldosteronism Subtype evaluation tests Adrenal computed tomography / magnetic resonance imaging Unilateral macroadenoma (>1cm) Unilateral microadenoma ( 1cm) Adrenal thickening/nodularity (unilateral or bilateral) Normal-appearing adrenals

79 Diagnosis of Primary Aldosteronism Subtype evaluation tests Adrenal venous sampling The reference standard test to differentiate unilateral from bilateral disease in patients with primary aldosteronism Dividing the right and left adrenal vein PACs by their respective cortisol concentrations (cortisol-corrected aldosterone) A cutoff of the cortisol-corrected aldosterone ratio from high side to low side more than 4:1 indicating unilateral aldosterone excess (APA or PAH)

80 Diagnosis of Primary Aldosteronism Subtype evaluation tests

81 Differential Diagnosis Primary or Secondary Aldosteronism? Plasma renin activity is useful to distinguish between primary or secondary aldosteronism

82 Treatment of Unilateral Hypersecretion of Aldosterone Unilateral hypersecretion of aldosterone Aldosterone-producing adenoma (APA) Primary adrenal hyperplasia (PAH) Unilateral adrenalectomy Normalization of hypokalemia in all Hypertension is improved in all and is cured in approximately 30% to 60% of them

83 Treatment of Bilateral Idiopathic Hyperplasia Pharmacologic treatment Aldosterone receptor blocker Spironolactone (non-selective aldosterone receptor blocker) Antagonist at the testosterone receptor (painful gynecomastia, erectile dysfunction, and decreased libido in men) Agonist at the progesterone receptor (menstrual irregularity in women ) Eplerenone (selective aldosterone receptor blocker) Other antihypertensive agents Adrenalectomy seldom corrects the hypertension

84 A patient with aldosterone-producing adenoma History: Female 33-year old 8-month history of hypertension Two antihypertensive medications administered Blood pressure level: 140/90mmHg Symptoms: fatigue, increased nocturia Laboratory: potassium 3.5 mmol/l

85 A patient with aldosterone-producing adenoma ARR 236 Captopril challenge test Intravenous saline infusion test Functional diagnosis: primary aldosteronism Localization: aldosteroneproducing adnoma of the right adrenal

86 A patient with aldosterone-producing adenoma Unilateral adrenalectomy by laparoscopy Pathologic diagnosis: aldosterone-producing adenoma

87 BP mmhg Follow-up of the patient CCB +ARB CCB and ARB discontinued. Spironolactone 240mg qd Surgery and Spironolactone discontinued. One week after surgery Two weeks after surgery Potassium mmol/l SBP DBP K

88 Questions for Review What is the definition of Cushing s syndrome? What are the clinical manifestations of Cushing s syndrome? What is the difference between Cushing s syndrome and Cushing s disease? What are the main types of Cushing s syndrome? What is the purpose of performing a low-dose dexamethasone suppression test and what s the rationale of this test?

89 Thank you!